WO1992007829A1 - Indole-3-methanamines useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents - Google Patents

Abstract

The present invention provides novel compounds which are useful in the treatment of NIDDM, obesity, hypertension or atherosclerosis. This invention encompasses a compound of formula (I), wherein R1-R6 represent a variety of substituents, and a method of treatment of the above conditions.

Description

INDOLE-3-METHANAMINES USEFUL AS ANTI-DIABETIC, ANTI-OBESITY

AND ANTI-ATHEROSCLEROTIC AGENTS

FIELD OF THE INVENTION

The present invention provides novel compounds . More particularly, the present invention provides novel indole-3-methaanamines which are useful in treating or preventing certain metabolic disorders of human and animal metabolism, e.g. hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylinemia, excess adiposity or hyperlipidemia. BACKGROUND OF THE INVENTION

There are several metabolic disorders of human and animal metabolism, e.g., hyperglycemia, impaired glucose tolerance, hyperinsulinemia and insulin insensitivity, hyperamylinemia, excess adiposity, and hyperlipidemia. Some or all of the above disorders may occur in the following disease states: non-insulin dependent diabetes mellitus (NIDDM), obesity, hypertension and atherosclerosis.

Hyperglycemia is a condition where the blood glucose level is above the normal level in the fasting state, following the ingestion of a meal, or during a provocative diagnostic procedure, e.g. a glucose tolerance test. It can occur in NIDDM as well as obesity. Hyperglycemia can occur without a diagnosis of NIDDM. This condition is called impaired glucose tolerance or pre-diabetes. Impaired glucose tolerance occurs when the rate of metabolic clearance of glucose from the blood is less than that commonly occurring in the general population after a standard dose of glucose has been orally or parenterally administered. It can occur in NIDDM as well as in obesity, pre-diabetes and gestational diabetes.

Hyperinsulinemia is defined as having a blood insulin level that is above normal level in the fasting state, following ingestion of a meal or during a provocative diagnostic procedure. It can be seen in NIDDM or obesity and can be associated with or causal in hypertension or atherosclerosis. Hyperinsulinemia can occur without a diagnosis of diabetes. It may occur prior to the onset of NIDDM. Insulin insensitivity, also called insulin resistance, occurs when the insulin-dependent glucose clearance rate is less than that commonly occurring in the general population during diagnostic procedures such as a hyperinsulinemic clamp (See.e.g., DeFronzo, R.A. et al Am. J. Physiol. 232 : E214-E233 (1979)) or a minimal model test (See, e.g.Bergman, R.N. et al J. Clin. Invest. 68 : 1456-1467 (1981)). Insulin insensitivity is considered also to occur when the blood glucose concentration is higher than that commonly occurring in the general population after intravenous administration of insulin (insulin tolerance test) or when the ratio of serum insulin-to-glucose concentration is higher than that commonly occurring in the general population after a 10-16 hour fast. Insulin insensitivity may be found in NIDDM or obesity and can also be associated with or causal to hypertension or atherosclerosis.

Hyperamylinemia is defined as having an abnormally high blood amylin level. Amylin is also known as diabetes associated peptide (DAP) and insulinoma associated peptide (IAP). Hyperamylinemia can be seen in NIDDM or obesity.

Excess adiposity can be seen in NIDDM associated with obesity and in obesity without NIDDM. It is defined as a higher fat body mass-to-lean body mass ratio than that commonly occurring in the general population as measured by whole body specific gravity or other generally accepted means.

Hyperlipidemia is defined as having an abnormal level of lipids in the blood. Hyperlipidemia exists when the serum concentration of total cholesterol or total triglycerides or the serum concentration of LDL-cholesterol/HDL-cholesterol is higher than that commonly occurring in the general population. It can be seen in NIDDM or atherosclerosis.

The above disease states could be treated by either ameliorating or preventing the metabolic and biochemical disorders. In addition, humans and animals, which have not been diagnosed as having one of the above disease states but evidencing some or all of the disorders described above, could be benefitted by preventing the development of a currently recognized disease state. Therefore, a compound that is useful in the treatment of hyperglycemia, impaired glucose tolerance, hyperinsulinemia and insulin insensitivity could also be used to treat or prevent NIDDM, obesity, hypertension, or atherosclerosis.

Certain aminomethyl indoles have been used as oral hypoglycemic agents. However, the magnitude and mechanism of blood glucose lowering are not described. See e.g., U.S. Patent 3,542,927 and U.S. Patent 3,459,767. It has also been disclosed that certain imidazolylalkyl indoles ameliorate the vascular complications of diabetes, are insulin lowering agents, and are antiobesity agents and therefore, are useful in the treatment of diabetes. See e.g., U.S. Patents 4,273,782, 4,451,472, 4,500,540 and 4,591,594.

INFORMATION DISCLOSURE

The use of certain 3-aminomethyl indoles as oral hypoglycemic agents has been reported in the normal fasted rat, the mildly alloxanized rat, and in the normal fasted dog. See, e.g. US Patent 3,542,927 and US Patent 3,459,767.

3-Imidazolyl-alkyl indoles, functioning as inhibitors of thromboxane synthetase have been disclosed as a treatment of diabetes via amelioration of the vascular complications of diabetes. See U.S. patents 4,273,782 and 4,451,472. It has also been disclosed that these compounds are useful in treating diabetes via their activity as insulin lowering agents and anti-obesity agents. See U.S. patents 4,500,540 and 4,591,594.

Certain substituted 5-hydroxyindole compounds are known, e.g., 1-benzyl-2-methyl-3- aminomethyl-5-methoxy-indole. See, Danschke, G. and Furst, H. (1960), Chem. Ber. 93:2097- 2106 and Chemical Abstracts 60:2899b of German Application 1,156,813.

Walker, G. and Moore, M., J. Org. Chem. 26:432-439 describes certain N-substituted-3- aminomethyl indoles. Indole derivatives, e.g., 1-benzyl-2-methyl-5-hydroxy-tryptamin, are disclosed in Ehrhart, G. and Henning, I. (1961), Arch. Pharn. 294:550-555.

Derivatives of 2-alkylmethoxygramine are disclosed in Grinev, A. et al. (1961), J. Gen. Chem. USSR 31:447-451. Zakharevskii, A. (1962), Chem. Abstracts 59:3243(a) discloses the effects of serotonin and certain indole derivatives.

Grinev, A. et al (1961), J. Gen. Chem. USSR 31:2146-2148 disclose hydrochloride of 1,2- dimethyl-3-anilinomethyl-5-methoxy indole. Amino-methyl indole derivatives are disclosed in Alemany, A. et al. (1975), Bull. Soc. Chim. Fr. 5-6:1223-1227.

U.S. patent 3,674,809 and U.S. Patent 3,591,603 disclose 3-indole-gloxamides and (3- indole)-lower alkylamines which are useful as central nervous system depressants.

Alemany, E. et al. (1975), An. Quim. 71:512-518 discloses 3-(N-alquilaminometil)indoles. French patent application 2242091, published 28 March 1975 discloses 1-phenyl-2-methyl-3- aminomethyl-5-methoxyindole derivatives having analgesic, antidepressive and anti-arrhythmic properties.

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel indole-3-methanamines of the Formula I

wherein R is

(a) C2-C10 alkyl,

(b) C3-C10 alkenyl,

(c) C3-C10 alkynyl,

(d)

(^e)

^(f)

(m) -(CH₂)_m O(CH₂)_m CH₃ ,

(p) - cycloalkyl (3-8 membered rings), or

(q)

wherein R₁ is

(a) H,

(b) C2-C10 alkyl,

(c) C3-C10 alkenyl,

(d) C3-C10 alkynyl,

wherein R₃ is

(a) H, or

wherein R₄ is H or CH₂OH;

wherein R₅ is H, C2-C10 alkyl or (CH₂)_a OH; wherein R₆ is separate or together is

(a) H,

(b) halogen,

(c) OH,

(d) OR₈,

(e) SR₈,

(f) NO₂,

(g) NH₂

(n) -SR₈ , (o) -C≡N, (p)

-COR₅; or

(q) C1-C10 alkyl;

wherein R₇ is H or C1-C10 alkyl;

wherein R₈ is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,

cycloalkyl (3-8 membered rings); or

CH₂-cycloalkyl (3-8 membered rings);

wherein R₉ is H, M, Rg, or

.

wherein M is Na⁺, K⁺, Ca^{+ +}, Zn^{+ +}, Al^{+ + +}, H₄N⁺ or (R₁₀)₄N⁺;

wherein R₁₀ is C1-C-10 alkyl;

wherein a is 1-4, b is 1-5, m is 1 or 2, and p is 4 or 5 and pharmacologically salts thereof; with the proviso that when R and R₂ are methylphenyl, then R₁, R₃, R₄, R₅ or R₆ is something other than H;

with the proviso that when R₂ is trifluromethylphenylmethyl, then R₆ is something other than just F;

with the proviso that when a is 2, R₆ is something other than methoxy and isopropyl. The present invention also relates to methods of treating or preventing a metabolic disorder consisting of hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylineamina, excess adiposity or hyperlipidemia in a patient susceptible to or experiencing said disorder comprising the systemic administration of the compounds of Formula I. The compounds of the instant invention are useful in the treatment of disorders associated with NIDDM, obesity, hypertension and atherosclerosis.

By "C1-C10 alkyl" we mean straight or branched hydrocarbon chain of one to ten carbon and isomeric forms thereof, including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

By "C3-C10 alkenyl" we mean a straight or branched hydrocarbon chain of three to ten carbons with a double bond and isomeric forms thereof including propylenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl. By "C3-C10 alkynyl" we mean a straight or branched hydrocarbon chain of three to ten carbons with a triple bond and isomeric forms thereof including propynl, butynl, pentynl, hexynl, heptynl, octynl, nonynl and decynl.

The compounds may be supplied in capsules, tablets, suppositories, powders, or as fluid solutions and/or suspensions in aqueous or non-aqueous vehicles or can be added to food. The compounds can be administered orally, intravenously, intramuscularly, intraarterially, intraperitoneally, subcutaneously, sublingually, or buccally to man or to other animals. The dosage is about 0.1-100mg/kg. The dosage will vary with the route of administration and the physical state of the recipient. Also, for example, the dosage by the oral route will depend on the frequency of administration and the weight of the recipient.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples described how to prepare various compounds of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

The compounds of this invention may contain at least one chiral center. In this instance, the invention is meant to include each pure enantiomer and combinations of the enantiomers, such as the racemate.

Of the compounds of the invention, represented by generic Formula I, the following are especially preferred and their preferred utility is in the treatment of non-insulin dependent diabetes mellitus (NIDDM). The preferred compounds are those of Formula I wherein R is methylphenyl; R1 is H; R2 is propylphenyl, methylphenyl, trifluoromethylphenylmethyl methoxy phenylmethyl or hydroxethyl phenyl; R3 is H; R4 is H; R5 is H and R6 separate or together is H, methoxy, methyl, fluorine, or chlorine. More particularly, the preferred compounds are 1-phenylmethyl-N- (S)-(1-phenyl)ethyl-3-indolemethanamine; 1-phenylmethyl-5-methoxy-N-((S)-1-phenyl)ethyl-3- indole-methanamine; 1-phenylmethyl-5-methoxy-N-phenylmethyl-3-indolememanamine; 1- phenylmethyl-5-methoxy-N-((+/-)-1-phenyl)ethyl-3-indolemethanamine; 1-phenyl- methyl-5-methoxy-N-(3-trifluoromethylphenyl)methyl-3-indolemethanamine; 1-phenylmethyl-5- methoxy-N-(4-methoxyphenyl)methyl-3-indolemethanamine;1-phenylmethyl-5-methoxy-N-[(R)-1- phenyl-2-hydroxyethyl]-3-indolemethanamine; 5-methoxy-6-methyl-1-phenylmethyl-N-(3- trifluoromethylphenyl)methyl-3-indolemethanamine; 5,6-dimethoxy-1-phenylmethyl-N-((3- trifluoromethyl)phenyl-methyl)-3-indolemethanamine; 6-fluoro-5-methoxy-1-phenylmethyl-N-((3- trifluoromethyl)phenylmethyl)-3-indolemethanamine; 6-chloro-5-methoxy-1-phenyl-methyl-N-((3- trifluoromethyl)phenylmethyl)-3-indole-methanamine; and 6-fluoro-5-methoxy-1-phenylmethyl-N- ((4-methoxy)phenyl)methyl-3-indolemethanamine. The especially preferred compounds improve hyperglycemia by improving glucose tolerance, reducing insulin resistance, improving insulin sensitivity, improving lipid profile, and reducing the state of hyperinsulinemia. As a result of these effects, the compounds of the invention should also be useful in the treatment of disorders associated with obesity, also of utility in the treatment of hypertension, and atherosclerosis.

Generally, many of the compounds can be prepared as follows. To a solution of 1 equivalent of an appropriate indole-3-carboxaldehyde and 2.5 equivalents of the selected benzylamine, in methanol-THF containing HOAc, ca. 1.2 equivalents of sodium cyanoborohydride is added. The solution is allowed to stir overnight then the mixture is poured into CH₂Cl₂ and 1N aqueous NaOH. The organic phase is separated, washed with brine and dried. Concentration in vacuo affords the crude amine which might be purified by chromatography on a column of silica gel to obtain the desired product.

Alternatively, the selected benzyl amine can be treated with the desired indole- carboxaldehyde, under conditions conducive to the removal of water, to yield the related Schiff base which can be reduced, for example, with NaBH₃ CN or H₂/catalyst. The compounds of the invention might also be prepared by reduction (BH₃ · THF, BH₃ · SHe₂ or LiAlH₄ for example) of an amide prepared from an indole-3-carboxylic acid and a selected benzylamine or derived from an indole-3-methanamine and an aromatic carboxylic acid.

Examples of pharmacologically acceptable salts include but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, benzensulfonates, toluenesulfonates, fumarates, adipates, alginates, aspartates, benzoates, and bisulfates.

The following examples describe the preparation of a number of the compounds of the invention.

Example 1

The starting materials utilized to prepare the compounds of this invention are either available commercially or can be prepare by the following methods.

1-PhenylmethyI-indole-3-carboxaldehyde

To a solution of indole-3-carboxaldehyde (36.29g, 0.25 mol) in N,N-dimethyl formamide (DMF) (74 mL) was added potassium carbonate (K₂CO₃₎ (35.0 g, 0.253 mol) and benzyl chloride (31.2 mL, 0.272 mol). The mixture is warmed to 110°C (internal) and maintained at 110ºC for 2.5 h. After 2.5 h, an additional portion of benzyl chloride (15.6 mL, 0.126 mol) is added and the mixture is heated at 110ºC overnight. After cooling to room temperature, the reaction mixture is cast into water (1.2 L) and the resulting solid is isolated by filtration. Recrystallization from ethanol produces pale yellow-green needles.

MP 197-198°C TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.49. 1H-NMR: δ = 9.98(s, 1), 8.33(m, 1), 7.69(s, 1), 7.15-7.38(8), 5.34(s, 2).

5-Methoxy-indole-3-carboxaldehyde

To dry DMF (47 mL), cooled in an ice-water bath, POCl₃ is added (22.9 g, 0.149 mol, 13.9 mL) over 30 min. After the addition is complete, 5-methoxy-indole (20.0 g, 0.136 mol) in DMF (34 mL) is added over a period of 0.75 h. The yellow suspension is heated in a 50°C oil bath for 1 h and is then cast into ice (100 g) and water (0.1 L). The mixture is treated with a solution of NaOH (19 g) in water (100 mL) over 30 min. The mixture is warmed to reflux and maintained for 2 min before being allowed to cool slowly to room temperature, during which time the pH is adjusted to ca. 8 by the addition of 20% aqueous NaOH. The mixture is cooled in a refrigerator (ca 4°C) overnight to provide fine tan needles which are isolated by filtration, washed with water (2 X 0.5 L) and dried in vacuo (60°C).

MP: 178-180°C

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.21.

1H-NMR: δ = 10.02(s, 1), 7.79(brs, 2), 7.33(d, J = 8.9Hz, 1), 6.96(dd, J = 8.9, 2.5Hz,

1), 3.89(s, 3).

5-Methoxy-1-phenylmethyl-indole-3-carboxaldehyde

As described for the preparation of 1-phenylmethyl-indoIe-3-carboxaldehyde, 5-methoxy-indole-3-carboxaldehyde (23.1 g, 0.132 mol) is added to benzyl chloride (18.4 g, 0.145 mol) and K₂CO₃ (18.40 g, 0.133 mol) in DMF (135 mL) at 90°C (18 h), the mixture is cooled to room temperature and cast into water (1.5 L) to give desired 5-methoxy-1-phenylmethyl-indole-3-carboxaldehyde as a purple solid. The crude product is recrystallized from EtOH to give tan plates.

MP: 103-105ºC.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.39.

¹H-NMR: δ = 9.95(s, 1), 7.80(d, J = 2.5Hz, 1), 7.66(s, 1), 7.32-7.38(3), 7.15-7.21(3), 6.92(dd, J = 8.9, 2.5Hz, 1), 5.31(s, 2), 3.89(s, 3).

¹³C-NMR: δ = 184.3, 156.3, 138.0, 136.1, 133.1, 128.8, 128.1, 126.9, 126.6, 114.4, 111.0, 103.1, 55.5, 50.9.

5-Phenylmethoxy-indole-3-carboxaldehyde

To dry DMF (35 mL), cooled in an ice-water bath, POCl₃ (16.5 g, 0.107 mol, 10 mL) is added over 30 min. After the addition is complete, 5-phenylmethoxy-indole (22.32 g, 0.100 mol) in DMF (25 mL) is added over a period of 1 h. The yellow suspension is heated in a 50°C oil bath for 1 h, and is then cast into ice (100 g) and water (0.1 L). The mixture is treated with a solution of NaOH (19 g) in water (100 mL) over 30 min. The mixture is warmed to reflux and maintained for 3 min before being allowed to cool slowly to room temperature, during which time the pH is adjusted to ca. 8 by the addition of 20% aqueous NaOH. The mixture is cooled in a refrigerator (ca 4°C) overnight to provide a tan powder which is isolated by filtration, washed with water (2 X 0.5 L) and dried in vacuo (80°C) to produce the desired 5-phenylmethoxy-indole-3-carboxaldehyde as buff colored powder.

MP: 230-235 °C

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.23. 5-Phenylmethoxy-1-phenylmethyl-indole-3-carboxaldehyde

As described for the preparation of 1-phenylmethyl-indole-3-carboxaldehyde, 5-phenylmethoxy-indole-3-carboxaldehyde (8.0 g, 31.8 mmol) is treated with benzyl chloride (4.43 g, 35 mmol) and K₂CO₃ (4.43g, 32 mmol) in DMF (50 mL) at 90°C (2 h). An additional portion of benzyl chloride (2.22 g, 17.5 mmol) is added and heating is continued for an additional 3 h. The mixture is cooled to room temperature and cast into water (1.0 L) to give the desired 5- phenylmethoxy-1-phenylmethyl-indole-3-carbox- aldehyde as a brown solid. The crude product is recrystallized from EtOH to produce the compound as tan powder.

MP: 136-136°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.39.

¹H-NMR: δ = 9.92(s, 1), 7.91(d, J = 2.5Hz, 1), 7.61(s, 1), 7.12-7.64(11), 5.26(s, 2), 5.11(s, 2).

¹³C-NMR: δ = 184.5, 155.9, 138.7, 137.1, 135.3, 133.3, 129.1, 128.5, 128.4, 127.9, 127.7, 127.1, 126.2, 118.2, 115.1, 111.3, 104.7, 70.5, 51.1.

(+/-)-1-(3-Trifluoromethylphenyl)-ethyl amine

A solution of 3-trifluoromethyl acetophenone (18.82 g, 0.1mol), in i -PrOH (0.5L), is treated successively with anhydrous ammonium acetate (77.08 g, 1.0 mol), dried, powdered 4Å molecular sieves and NaBH₃CN (6.29g, 0.1mol). The mixture is stirred for 72 h at room temperature under nitrogen, then is filtered through a pad of celite. The filter cake is rinsed with MeOH (1.0L) and the combined filtrates are concentrated in vacuo to furnish the crude product as a clear colorless liquid. The crude amine is dissolved in Et₂O (0.25L) and extracted with 2N aq. HCl (0.25L). The aqueous phase is washed with Et₂O (0.25L); the pH of the solution is adjusted to ca. 14 with 20% aq. NaOH to give a cloudy solution. The solution is cast into CH₂Cl₂ (0.5L), the organic phase is separated, washed with brine (0.4L), and dried (Na₂SO₄). Concentration in vacuo produces the target amine as a clear colorless liquid.

TLC (Merck; CHCl₃-MeOH, 90:10; UV(+); I₂): R_f = 0.32.

1H-NMR: δ = 7.35-7.65(4), 4.19(q, J = 6.60Hz, 1), 1.53(brs, 2), 1.39(d, J = 6.60Hz, 3).

¹³C-NMR: δ = 148.2, 130.1, 129.1, 128.7, 123.5, 122.4, 50.9, 25.6.

IR (CHCl₃): 3375, 3292, 2969, 2873, 1614, 1598, 1451, 13773, 1329; 1163, 1125, 1073, 825, 803, and 704cm^-1. EI/MS (70eV): 188(M⁺, 22.2), 174(base), 127(49.1).

Anal: Calcd. for C₉H₁₀ F₃ N: 189.0765. Found: 189.0762.

N,N-(Dimethyl)-1-phenylmethyl-1H-indole-3-methanamine

37% formalin (0.58 g, 19.32 mmol, 1.45 mL), and dimethylamine (0.87 g, 19.32 mmol, 2.42 mL, 30% aqueous) are added to 1-phenylmethyl-1H-indole (4.0 g, 19.32 mmol) in 95% EtOH. The mixture is heated under reflux for 24 hours, then is cooled to room temperature, and concentrated in vacuo to give the crude amine as a brown oil. The crude product is purified by chromatography on a column of silica gel (230-400 mesh, 200 g, 70 mm OD, packed CH₂Cl₂, eluted CH₂Cl₂-MeOH 93:7, 400 mL fractions) using the flash technique, which produces N,N- (dimethyl)-1-phenylmethyl-1H-indole-3-methanamine as a clear, pale yellow oil.

TLC (Merck; CHCl₃-MeOH- aq. NH₃ 90:5:5; UV(+); ammonium molybdate): R_f = 0.27.

¹H-NMR: δ = 7.70(d, J = 7.2Hz, 1), 7.21-7.34(9), 5.29(s, 2), 3.68(s, 2), 2.31(s, 6). 1-Methyl-5-methoxy indole-3-carboxaldehyde

Sodium hydride (0.60 g of a 50% oil dispersion, 12.6 mmol) is washed with hexanes (3 x 10 mL) and then suspended in DMF (20 mL). A solution of 5-memoxy indole-3-carboxaldehyde (2.00 g, 11.4 mmol) in DMF (20 mL) is added over 20 min. After the mixture stirs for 1 h, a solution of methyl iodide (0.71 mL, 11.4 mmol) in DMF (5 mL) is added over 10 min. The mixture stirs for 3 h before being quenched by the careful addition of H₂O (5 mL). The mixture is cast into H₂O (400 mL) and stirred for 10 min. The resulting mustard-colored solid is collected by suction filtration, washed with H₂O, and air dried. Recrystallization from MeOH-hexanes gives the 1-methyl-5-methoxy indole-3-carboxaldehyde as a yellow solid.

MP 134°C.

TLC (Merck; MeOH-CH₂Cl₂, 2:98; UV(+); ammonium molybdate) R_f = 0.21.

1H-NMR: δ = 9.90(s, 1), 7.77(d, J=2.5, 1), 7.58(s, 1), 7.22(d, J=8.9, 1), 6.96(dd,

J=8.9, 2.5, 1), 3.89(s, 3), 3.81(s, 3).

¹³C-NMR: δ = 184.3, 156.7, 139.5, 132.8, 126.0, 117.7, 114.5, 110.7, 103.3, 55.8, 33.8.

IR (neat): 3108, 1655, 1647, 1634, 1615, 1537, 1482, 1266, 1224, 1197, 1135, 1078, 1035, 847, 813, 789cm^-1.

EI/MS (70eV): 189(M⁺, 55.0), 174(48.1), 146(base).

Anal: Calcd. for C₁₁H ₁₁NO₂: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.99, H, 6.00; N, 7.41.

2,5-Dimethyl-4-nitrophenol

To a solution of 2,5-dimethylρhenol (61.08 g 33.3 mmol) in glacial HOAc (0.5L), cooled to 10°C internal with an ice-salt bath, is added a solution of nitric acid (70%, 39.38 g, 0.625 mol) in glacial acetic acid (0.5L) over a period of 1.5 hours. The resulting red solution is then slowly added to ice-water (5L) over 2 hours. This mixture is extracted with CH₂Cl₂ (5.0L), the organic phase is separated, washed with 1N aqueous HCl (4L), and dried (Na₂SO₄). Concentration in vacuo affords the crude nitro phenol as a red-brown semi-solid which is purified by chromatography on a column of silica gel (in 2 portions) (230-400 mesh, 500 g, 70 mm OD, packed with hexanes, eluted with a gradient - hexanes to hexanes-Et₂O 85:15, 400 mL fractions) using the flash technique which produces the 2,5-dimethyl-4-nitrophenol as a yellow solid.

TLC (Merck; EtOAc-hexanes, 25:75; UV(+); I₂(+)): R_f = 0.23.

1H-NMR: δ = 7.95(s 1), 6.99(s, 1), 5.62(brs, 1), 2.57(s, 3), 2.27(s, 3).

2,5-Dimethy-4-nitroanisole

A mixture of 2,5-dimethyl-4-nitrophenol (4.14 g, 24.8 mmol), K₂CO₃ (3.77 g, 27.2 mmol), and Me₂SO₄ (3.44 g, 27.2 mmol), in absolute EtOH (100 mL) is heated under reflux for 4 hours. The mixture is cooled to room temperature and diluted with water (0.5L). The resulting precipitate is isolated by filtration to give the target anisole as an amber solid.

MP: 90-91°C.

TLC (Merck; Et₂O-hexanes, 10:90; UV(+); I₂(+)): R_f = 0.27.

1H-NMR: δ = 7.92(s, 1), 6.66(s, 1), 3.90(s, 3), 2.63(s, 3), 2.21(s, 3).

¹³C-NMR: δ = 161.7, 134.4, 127.4, 125.5, 112.8, 55.7, 21.5, 15.5.

IR (nujol): 2954, 2925, 1620, 1575, 1519, 1500, 1339, 1327, 1261, and 1067cm^-1. EI/MS (70eV): 181(M⁺, base).

Anal: Calcd. for C₉H₁₁NO₃: C, 59.66; H, 6.12 N, 7.74. Found: C, 59.79; H, 6.24; N, 7.74.

5-Methoxy-6-methyl-1H-indole

A solution of 2,5-dimethyl-4-nitroanisole (18.12 g, 0.1 mol), N, N,-dimethylforamamide dimethyl acetal (35.75 g, 0.3 mol), and pyrrolidine (7.11 g, 0.1 mol) in dry DMF (250 mL) is heated in a 120°C oil bath for 5 hours. The resulting red-black reaction mixture is cooled to room temperature, and then is cast into water (2.5L) and EtOAc (2.5L). The organic phase is dried

(Na₂SO₄) and concentrated in vacuo to furnish the crude nitroaryl enamine as a deep red-black oil which is immediately dissolved in toluene (0.5L). The enamine solution is hydrogenated (40 psi) in a Parr shaker (2.0L) over Raney nickel (10 g, 50% slurry, washed 3X10 mL with absolute

EtOH) until hydrogen uptake ceases (5 hours). The catalyst is removed by filtration through a pad of celite, the filter cake was rinsed with EtOAc (1.0L) and the combined filtrates (clear, pale yellow solution) are dried (Na₂SO₄). Concentration in vacuo affords the crude indole as a yellow-green solid which is purified by chromatography on a column of silica gel (230-400 mesh, 650 g, EtOAc-hexanes 10:90, 400 mL fractions).

MP: 115-116°C. TLC (Merck; EtOAc-hexanes, 20:80 UV(+); ammonium molybdate): R_f = 0.47. 1H-NMR: δ = 7.74(brs, 1), 6.95(m, 3), 6.35(m, 3), 6.35(m, 1), 3.76(s, 3), 2.24(s, 3). 1³C-NMR: δ = 152.8, 130.5, 126.1, 123.6, 122.6, 112.3, 102.0, 100.6, 55.7, 17.1. IR (nujol): 3391, 2955, 2924, 1717, 1704, 1692, 1629, 1471, 1463, 1437, 1310, 1303, 1217, 1193, 1126, 1017, 840, 758, and 725cm^-1.

EI/MS (70eV): 161(M⁺, 80.5), 146(base).

Anal: Calcd. for C₁₀H₁₁NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.48; H, 7.10; N, 8.60.

5-Methoxy-6-methyl-1H-indole-3-carboxaldehyde

To dry DMF (10 mL), cooled in an ice-water bath, is added POCl₃ (4.19 g, 27.3 mmol,

1.6 mL) over 30 minutes. To this stirring mixture is added a solution of 5-methoxy-6-methyl-1H-indole (4.00 g, 24.8 mmol) in dry DMF (8 mL) over 30 minutes After the addition is complete, the tan suspension is warmed in a 50°C oil bath for 1 hour and is then poured into ice-water (100 mL). The pH of the mixture is adjusted to ca. pH= 12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and then is chilled in a refrigerator (4°C) overnight. A tan solid is isolated by filtration, then is rinsed with water (25 mL) and dried in vacuo to provide the crude indole which is recrystallized from absolute EtOH to give the 5-methoxy-6-methyl-1 H-indole-3- carboxaldehyde as fine tan needles.

MP: 202°C

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.24.

1H-NMR: δ = 10.00(s,1), 7.73(m, 2), 7.20(s, 1), 3.92(s, 3), 2.33(s, 3).

IR (nujol): 3185, 2957, 2927, 2856, 1627, 1497, 1471, 1442, 1422, 1282, 1211, 1076, and 712cm^-1.

EI/MS (70eV): 189(M⁺, 97.5), 174(base).

Anal: Calcd. for C₁₁H₁₁NO₂: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.94; H, 5.98; N, 7.43.

5-Methoxy-6-methyl-1-phenylmethyl-1H-indole-3-carboxaldehyde

To a suspension of NaH (0.44 g, 18.3 mmol, washed with hexanes (3X) in dry DMF (25 mL), is added a solution of 5-methoxy-6-methyl-1H-indole-3-carboxaldehyde (3.15 g, 16.6 mmol) in dry DMF (20 mL) over 10 minutes. The mixture is stirred for 30 minutes after the addition is complete, then a solution of benzyl chloride ( 2.23 g, 18.3 mmol) in dry DMF (20 mL) is added in one portion. The mixture is allowed to stir for 24 hours at room temperature, then is diluted with water (0.5L) and the resulting tan precipitate is isolated by filtration. The solid is purified by recrystallization from absolute ethanol to give the target indole as a white powdery solid. The mother liquor is concentrated in vacuo to give a viscous yellow oil which is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, EtOAc-hexanes 1:2, 400 mL fractions).

MP: 118°C.

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.28.

1H-NMR: δ = 9.93(s, 1), 7.73(s, 1), 7.66(s, 1), 7.58(s, 1), 7.35(m, 3), 7.16(m, 2),

7.07(s, 1), 5.30(s, 2), 3.92(s, 3), 2.30(s, 3).

IR (nujol): 3103, 2953, 2925, 2855, 1656, 1628, 1529, 1476, 1452, 1443, 1388, 1259, 1206, 1169, 1044, 857, 837, and 734cm^-1.

EI/MS (70eV): 279(M⁺, 96.9), 91(base).

Anal: Calcd. for C₁₈H₁₇NO₂: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.52; H, 6.40;

N, 5.15.

6-Nitro-3,4-methylenedioxy-toluene

To a solution of 3, 4-methylenedioxy-toluene (56.8 g, 0.417 mol) in glacial HOAc (0.4L), cooled to 10°C internal with an ice-salt bath, is added a solution of nitric acid (70%, 32.8 g, 0.52 mol) in glacial acetic acid (0.4L) over a period of 1.5 hours. The resulting red solution is then slowly added to ice-water (4L) over 2 hours. The resulting pale yellow precipitate is allowed to warm to room temperature and stir overnight. The pale yellow solid is isolated by filtration, washed with water (1.0L), then is dissolved in CH₂Cl₂ (0.5L). The yellow solution is filtered through a plug of silica gel (230-400 mesh, 200 g), the plug is rinsed with CH₂Cl₂ (0.5L) and the combined filtrates are concentrated in vacuo to give 6-nitro-3,4-methylenedioxy-toluene as a yellow solid.

MP: 86-88°C.

TLC (Merck; EtOAc-hexanes, 25:75; UV(+); I₂(+)): R_f = 0.42.

¹H-NMR: δ = 7.54(s, 1), 6.72(s, 1), 6.09(s, 2), 2.57(s, 3).

1³C-NMR: δ = 150.3, 145.1, 141.5, 130.2, 111.1, 105.4, 102.6, 21.4.

5,6-Methylenedioxy-1H-indole

A of solution 3,4-methylenedioxy-6-nitro-toluene (27.17 g, 0.15 mol), N, N,-dimethylforamamide dimethyl acetal (53.62 g, 0.45 mol), and pyrrolidine (10.67 g, 0.15 mol) in dry DMF (210 mL) is heated in a 120°C oil bath for 5 hours. The resulting red-black reaction mixture is cooled to room temperature, and then is cast into water (2.5L) and EtOAc (2.5L). The organic phase is dried (Na₂SO₄) and concentrated in vacuo to furnish the crude nitroaryl enamine as a deep red-black oil which is immediately dissolved in toluene (0.5L). The enamine solution is hydrogenated (30 psi) in a Parr shaker (2.0L) over Raney nickel (5 g, 50% slurry, washed 3X10mL with absolute EtOH) until hydrogen uptake ceases (5 hours). The catalyst is removed by filtration through a pad of celite, the filter cake is rinsed with EtOAc (1.0L) and the combined filtrates (clear, pale yellow solution) are dried (Na₂SO₄). Concentration in vacuo affords the crude indole as a yellow-green solid which is purified by chromatography in 2 portions on a column of silica gel (230-400 mesh, 500 g, packed hexanes, eluted EtOAc-hexanes 5:95, 400 mL fractions). Fractions are combined to produce a white fluffy solid.

MP: 118°C.

TLC (Merck; EtOAc-hexanes, 25:75, UV(+); ammonium molybdate): R_f = 0.31.

¹H-NMR: δ = 7.97(brs, 1), 7.03(m, 2), 6.82(s, 1), 6.42(t, J = 2.41Hz, 1), 5.91(s, 2). 1³C-NMR: δ = 144.6, 142.7, 130.2, 122.7, 121.5, 102.7, 100.5, 99.0, 91.8.

IR (nujol): 3442, 3402, 2955, 2925, 2871, 2856, 1510, 1472, 1212, 1158, 1112, 1042, 947, 837, 827, 758, 751, and 725cm^-1.

EI/MS (70eV): 161(M⁺, base).

Anal: Calcd. for C₉H₇NO₂: C, 67.08; H, 4.38; N, 8.69. Found: C, 67.06; H, 74.55; N, 8.70.

5,6-Methylenedioxy-1H-indole-3-carboxaldehyde

To dry DMF (40 mL), cooled in an ice-water bath, is added POCl₃ (11.15 g, 72.7 mmol) over 30 minutes. To this stirring mixture is added a solution of 5-methoxy-6-methyl-1H-indole

(10.65 g, 66.1 mmol) in dry DMF (10 mL) over 30 minutes. After the addition is complete, the tan suspension is warmed in a 50 °C oil bath for 1 hour and is then poured into ice-water (0.5L).

The pH of the mixture is adjusted to ca. pH= 12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and men is chilled in a refrigerator (4°C) overnight. A tan solid is isolated by filtration, then is rinsed with water (250 mL) and dried in vacuo to provide the crude indole which is recrystallized from MeOH to give fine tan needles.

MP: 221-223°C

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.28.

1H-NMRODMSO-d₆): δ = 12.00(brs, 1), 9.8(s, 1), 8.08(s, 1), 7.48(s, 1), 7.21(s, 1),

6.00(s, 2).

¹³C-NMR (DMSO-d₆): δ = 184.9, 145.5, 144.4, 136.6, 131.9, 118.5, 118.1, 100.9, 99.4, 93.3.

IR (nujol): 3123, 3109, 3047, 3026, 2954, 2925, 2855, 1631, 1614, 1508, 1470, 1445, 1376, 1299, 1290, 1181, 1117, 1041, 1025, 943, 834, and 693cm^-1.

EI/MS (70eV): 189(M⁺, base).

Anal: Calcd. for C₁₀H₇NO₃: C, 63.49; H, 3.73; N, 7.40. Found: C, 63.32; H, 3.95; N, 7.44.

5,6-Methylenedioxy-1-phenylmethyl-1H-indole-3-carboxaldehyde

To a suspension of NaH (1.40 g, 58.1 mmol, washed with hexanes 3X) in dry DMF (50 mL), is added a solution of 5,6-methylenedioxy-1H-indole-3-carboxaldehyde (10.0 g, 52.9 mmol) in dry DMF (50 mL) over 10 minutes. The mixture is stirred for 30 minutes. After the addition is complete, a solution of benzyl chloride ( 7.36 g, 58.1 mmol) in dry DMF (15 mL) is added in one portion. The mixture is allowed to stir for 24 hours at room temperature, then is diluted with water (1.0L) and the resulting tan precipitate is isolated by filtration. The solid is purified by recrystallization from absolute ethanol-THF to give a white powdery solid.

MP: 141-142°C.

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.38.

¹H-NMR: δ = 9.72(s, 1), 7.72(s, 1), 7.57(s, 1), 7.35(m, 3), 7.15(m, 2), 6.71(s, 1), 5.95(s, 2), 5.24(s, 2).

1³C-NMR: δ = 184.4, 146.2, 145.3, 136.8, 134.6, 132.3, 129.0, 128.3, 126.9, 119.5,

118.6, 101.1, 100.9, 91.3, 51.2.

IR (nujol): 2954, 2925, 2855, 1661, 1532, 1494, 1469, 1388, 1264, 1252, 1185, 1167, 1099, 1038, 934, 861, 827, and 738cm^-1.

EI/MS (70eV): 279(M⁺, 65.3), 91(base).

Anal: Calcd. for C₁₇H₁₃NO₃: C, 73.11; H, 4.69 N, 5.02. Found: C, 73.06 H, 4.80 N,

4.77.

5,6-Dimethoxy-1H-indole-3-carboxaldehyde

To dry DMF (8 mL), cooled in an ice-water bath, is added POCl₃ (4.22 g, 27.5 mmol) over 30 minutes. To this stirring mixture is added a solution of 6-fluoro-5-methoxy-1H-indole (2.6 g, 16 mmol) in dry DMF (8 mL) over 30 minutes. After the addition is complete, the yellow solution is cast into ice-water (100 mL). The pH of the mixture is adjusted to ca. pH= 12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and then is chilled in a refrigerator (4°C) overnight. A pale yellow semi-solid is observed but cannot be efficiently isolated by filtration. The mixture is extracted with CH₂Cl₂ (2X 0.13 L ), the combined organic phases are dried (Na₂SO₄) and concentrated in vacuo to give the crude indole-carboxaldehyde as a brown solid. The crude product is purified by recrystallization from hexanes-CH₂Cl₂ to give 5,6-dimethoxy-1H-indole-3- carboxaldehyde as tan needles.

MP: 166.5-167.5°C.

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.38.

¹H-NMR: δ = 9.98(s, 1), 9.42(brs, 1), 7.81(s, 1), 7.74(d, J = 3.04Hz, 1), 6.92(s, 1), 3.93(s, 3), 3.86(s, 3).

¹³C-NMR: δ = 185.3, 147.8, 146.5, 134.4, 131.2, 119.0, 117.2, 102.9, 94.6, 56.1, 55.9.

IR (nujol): 3192, 3115, 1627, 1523, 1480, 1433, 1164, 1071, and 714cm^-1.

EI/MS (70eV): 205(M⁺, base), 190(86.2).

Anal: Calcd. for C₁₁H₁NO₃: C, 64.38; H, 5.40; N, 6.82. Found: C, 64.16; H, 5.63; N, 6.86.

5,6-Dimethoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde

K₂CO₃ (2.06 g, 14.9 mmol) and benzyl chloride (2.04 g, 16.1 mmol), in one portion, are added to 5,6-dimethoxy-1H-indole-3-carboxaldehyde (3.00 g, 14.6 mmol),in dry DMF (20 mL). The mixture is heated in a 100°C oil bath for 18 hours, then is cooled to room temperature and cast into water (0.5 L) and CH₂Cl₂ (0.5 L). The organic phase is separated, washed with brine (0.5 L), and dried (Na₂SO ₄). Concentration in vacuo gives the crude indole as a brown oil which solidifies upon cooling. The crude product is purified by chromatography on a column of silica gel (230-4 00 mesh, 500 g, 70 mm OD, EtOAc-hexanes, 400 mL fractions) using the flash technique, producing a tan solid.

MP: 139-140°C.

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.25.

1H-NMR: δ = 9.90(s, 1), 7.79(s, 1), 7.55(7.40-s, 1), 7.35(m, 3), 7.17(m, 3), 6.73(s, 1), 5.29(s, 2), 3.96(s, 3), 3.84(s, 3).

1³C-NMR: δ = 184.5, 148.0, 147.3, 137.0, 135.2, 131.6, 129.0, 128.2, 127.0, 118.4,

118.2, 103.2, 93.4, 56.2, 56.0, 50.9.

IR (nujol): 2926, 2855, 1653, 1530, 1499, 1483, 1444, 1288, 1252, 1237, 1213, 1178, 1039, 862, 853, 811, 776, and 710,cm^-1.

EI/MS (70eV): 295(M⁺, 61.6), 280(13.8), 176(5.5), 91(base).

Anal: Calcd. for C₁₈H₁₇NO₃: C, 73.20 H, 5.80; N, 4.74. Found: C, 73.06; H, 5.96;

N, 4.74.

2-Chloro-4-nitro-5-methylphenol

To a solution of 2-chloro-5-methylphenol (100 g, 0.7 mol) in acetic acid (225 mL) is added cone. H₂SO₄ (30 mL). The mixture is chilled in an ice-salt bath and a solution of NaNO₂ (50.7 g, 0.735 mol) in water (140 mL) is added over 1 hour. During the addition a deep brown color developed and as the reaction progresses, a precipitate is observed. The mixture is stirred for an additional 30 minutes, then is diluted with water (3L). The solid is isolated by filtration and is added to a heated (55°C) solution of nitric acid (70%, 56 mL) in water (250 mL) over 5 minutes. The solid dissolved in the reaction medium and a precipitate is noted ca. 5 minutes after the addition is complete. The reaction is quenched with water (3L) and the mixture is cooled in a refrigerator (4°C) for 1 hour. The precipitate is isolated by filtration and is purified by recrystallization from ethanol-water to give 2-chloro-5-methyl-4-nitrophenol as a tan solid (102.17 g, 78%).

MP: 147-148°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.52.

¹H-NMR: δ = 7.64(s 1), 6.60(s, 1), 5.50(brs, 1), 2.46(s, 3). IR (nujol): 3375, 2924, 1569, 1513, 1310, 1290, 1106, 894, and 710cm^-1.

EI/MS (70eV): 187(M⁺, 42.9), 170(86.2), 142(25.6), 77(base).

Anal: Calcd. for C₇H₆ClNO₃: C, 44.82; H, 3.22; N, 7.46. Found: C, 44.92; H, 3.18; N, 7.53.

1-Chloro-2-methoxy-4-methyl-5-nitrobenzene

A mixture of 2-chloro-4-nitro-5-methylphenol (18.75 g, 0.1 mol), K₂CO₃ (15.20 g, 0,11 mol), and Me₂SO₄ (14.13 g, 0.11 mol), in absolute EtOH (0.375 L) is heated under reflux for 4 hours. The mixture is cooled to room temperature and diluted with water (0.5L). The resulting precipitate is isolated by filtration to give the target anisole as an amber solid.

MP: 121.1-121.6°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.37.

¹H-NMR: δ = 8.16(s, 1), 6.79(s, 1), 3.99(s, 3), 2.65(s, 3).

¹³C-NMR: δ = 158.5, 135.4, 127.1, 120.4, 114.5, 56.5, 21.4.

6-Chloro-5-methoxy-1H-indole

A solution 2-chloro-5-methyl-4-nitroanisole (10.08 g, 50 mmol), M,

N,-dimethylforamamide dimethyl acetal (17.87 g, 0.15 mol), and pyrrolidine (3.55 g, 50 mmol) in dry DMF (70 mL) is heated in a 120°C oil bath for 5 hours. The resulting red-black reaction mixture is cooled to room temperature, and then is cast into water (1.0L) and EtOAc (1.0L). The organic phase is separated, washed with water (1.0L), brine (1.0L), and dried (Na₂SO₄). Concentration in vacuo furnishes the crude nitroaryl enamine as a deep red-black oil which is immediately dissolved in toluene (0.25 L). The enamine solution is hydrogenated (20 psi) in a Parr shaker (2 L) over Raney nickel (3 g, 50% slurry, washed 3X30 mL with absolute EtOH) until hydrogen uptake ceases (5 hours). The catalyst is removed by filtration through a pad of celite, the filter cake is rinsed with EtOAc (0.2L) and the combined filtrates (clear, pale yellow solution) are dried (MgSO₄). Concentration in vacuo affords the crude indole as a red-black oil which is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, CH₂Cl₂-hexanes 1:1, 500 mL fractions) using the flash technique. Fractions furnish 6-chloro-5-methoxyindole as a pale purple solid. Recrystallization from hexanes-CH₂Cl₂ gives the target indole as white needles.

MP: 131.8-132°C.

TLC (Merck; CH₂Cl₂-hexanes, 1:1, UV(+); ammonium molybdate): R_f = 0.22.

¹H-NMR: δ = 8.05(brs, 1), 7.42(s, 1), 7.18(t, J = 2.74Hz, 1), 7.15(s, 1), 6.48(brs, 1).

¹³C-NMR: δ = 149.5, 131.8, 127.6, 125.0, 112.2, 102.7, 102.4, 56.5.

6-Chloro-5-methoxy-1H-indole-3-carboxaldehyde

To dry DMF (8 mL), cooled in an ice-water bath, is added POCl₃ (3.37 g, 22 mmol, 2.05 mL) over 30 minutes. To this stirring mixture is added a solution of 6-chloro-5-methoxy-1H-indole

(3.63 g, 20 mmol) in dry DMF (7.5 mL) over 30 minutes After the addition is complete, the yellow suspension is wanned in a 50°C oil bath for 1 hour and is then poured into ice-water (50 mL). The pH of the mixture is adjusted to ca. pH=12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and then is chilled in a refrigerator (4°C) overnight. An ivory solid is isolated by filtration, then is rinsed with water (25 mL) and dried in vacuo to provide 6-chloro-5-methoxy-1H-indole-3- carboxaldehyde as fine ivory needles.

MP: 265-265.5°C(decomp)

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.19.

1H-NMR(DMF-d₆): δ = 12.21(brs, 1), 10.03(s, 1), 8.43(s, 1), 7.84(s, 1), 7.69(s, 1), 3.96(s, 3).

¹³C-NMR(DMF-d₆): δ = 185.6, 152.3, 139.8, 125.0, 119.9, 119.4, 114.4, 103.8, 56.6. IR (nujol): 3104, 3010, 1631, 1622, 1473, 1443, 1285, 1153, 1084, 1053, and 815cm^-1. EI/MS (70eV): 209(M⁺, base), 194(64.0), 166(41.1).

Anal: Calcd. for C₁₀H₈ClNO₂: C, 57.29; H, 3.84; N, 6.68. Found: C, 57.16; H, 4.08; N, 6.63.

6-Chloro-5-methoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde

To a suspension of NaH (0.494 g, 16.5 mmol, washed with hexanes 3X) in dry DMF (30 mL), is added a solution of 6-chloro-5-methoxy-1H-indole-3-carboxaldehyde (3.14 g, 15 mmol) in dry DMF (30 mL) over 10 minutes. The mixture is stirred for 30 minutes. After the addition is complete, then benzyl chloride ( 2.09 g, 16.5 mmol) is added in one portion. The mixture is allowed to stir for 24 hours at room temperature, then is diluted with water (2.5 L) and the resulting ivory solid is isolated by filtration, washed with water (2X 0.4L) and is dried in vacuo to give 6-chloro-5-methoxy-1-phenyl- methyl-1H-indole-3-carboxaldehyde as a powderyivory solid.

MP: 120.5-122°C.

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.41.

¹H-NMR: δ = 9.93(s, 1), 7.86(s, 1), 7.66(s, 1), 7.35(m, 4), 7.17(m, 2), 5.29(s, 2), 3.96(s, 3).

¹³C-NMR: δ = 184.4, 151.9, 138.7, 134.9, 131.8, 129.1, 128.5, 127.0, 124.5, 120.5, 118.3, 111.8, 103.9, 56.5, 51.1.

IR (nujol): 1655, 1527, 1478, 1431, 1406, 1252, 1161, 1043, 824, and 732cm^-1.

EI/MS (70eV): 299(M⁺, 38.2), 91(base).

Anal: Calcd. for C₁₇H₁₄ClNO₂: C, 68.12; H, 4.71; N, 4.67. Found: C, 67.99 H, 4.80 N, 4.40.

2-Acetamido-5-methylphenol

A solution of 6-amino-m-cresol (147.8 g, 1.2 mol) in CH₂Cl₂-THF (3.0L, 2:1) is treated with acetic anhydride (134.8 g, 1.32 mol) over 30 minutes. The white precipitate, which gradually forms during the addition, is stirred at room temperature for 2 h. This mixture is then carefully treated with saturated aqueous sodium carbonate (CO₂ evolution) until the pH of the mixture is 8-9. The THF-CH₂Cl₂ solvent mixture is removed in vacuo and the residue is extracted with warm EtOAc (2X3.0L). The combined organic layers are washed with water (4.0L), brine (4.0L), and dried (MgSO₄). Concentration in vacuo affords the crude product as a deep red solid which is dissolved in a minimum volume of hot EtOAc-MeOH (4:1). The resulting solution is allowed to cool to room temperature and then is chilled (4°C) overnight. The ivory solid precipitate is isolated by filtration and dried in a vacuum oven. The mother liquor is concentrated in vacuo and the solid is treated with sodium carbonate (22 g) in 10% aqueous MeOH (0.44L) .and allowed to stir overnight at room temperature ( to hydrolyze remaining acetate). The pH is adjusted to 8-9, and the MeOH is then removed in vacuo and the aqueous layer is extracted with warm EtOAc (2X0.5L). The combined organic layers are washed with water (0.5L), brine (0.5L), and dried (MgSO₄). Concentration in vacuo furnishes an ivory solid which is recrystallized as outlined above. The combined recrystallizations affords 2-acetamido-5-memylphenol as an ivory solid.

MP: 168-169°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.47.

¹H-NMR: δ = 6.64-7.19(m,3), 3.08(brs, 2), 2.27(s, 3), 2.20(s, 3).

IR (nujol): 3270, 1640, 1607, 1593, and 1552cm^-1.

EI/MS (70eV): 165(M⁺, 26.9), 123(base), 106(10.5), 94(12.1).

Anal: Calcd. for C₉H₁₁NO₂: C, 65.44; H, 6.71 N, 8.48. Found: C, 65.17; H, 6.85; N,

8.43.

2-Phenylmethoxy-4-methyl-phenyl acetamide

A mixture of 6-acetamido-m-cresol (99.0 g, 0.6 mol) in acetone (2.2L) is warmed in a 50°C water bath until the starting acetamide dissolves. The water bath is removed and the solution is cooled to 35-40°C (internal), at which time K₂CO₃ (99.5 g, 0.72 mol) is added, followed by the addition of a solution of benzyl bromide (133.41, 0.78 mol) in acetone (0.1L) over a period of 40 minutes. The mixture is maintained at ca. 40°C and vigorous stirring is continued during the addition. The mixture is cooled to room temperature and is allowed to stir for 24 hours, then is diluted with EtOAc (1.0L). The suspended solids are removed by filtration through a pad of celite. The filter cake is rinsed with EtOAc (0.5L) and the combined filtrates are concentrated in vacuo to yield the crude benzyl ether as a tan solid. The solid is dissolved in hot EtOAc (0.5L) and the solution is diluted with hexanes (1.0L). The mixture is cooled to room temperature overnight and deposited the target ether as a white solid (133.3 g). The mother liquor is concentrated in vacuo to give a tan solid which is recrystallized from hexanes-EtOAc (2:1).

MP: 116-117°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.45. ¹H-NMR: δ = 6.72-8.28(m,3), 7.41(s, 5), 5.10(s, 2), 2.30(s, 3), 2.13(s, 3).

IR (nujol): 3357, 1682, 1667, 1614, 1600, and 1533cm^-1.

EI/MS (70eV): 255(M⁺, 22.3), 213(10.5), 164(4.3), 122(56.7), 91(base).

Anal: Calcd. for C₁₆H₁₇NO₂: C, 75.27; H, 6.71 N, 5.49. Found: C, 75.17; H, 6.89; N, 5.43.

2-Phenylmethoxy-4-methylanilinium hydrochloride

A solution of 2-phenylmethoxy-4-methyl-phenyl acetamide (178.7 g, 0.7 mol) in MeOH

(1.4L) is treated with cone. HCl (0.175L) and the resulting solution is heated under reflux for 24 hours. The mixture is cooled to room temperature and any solid materials are removed by filtration. The filtrate is concentrated in vacuo to ca. 1/2 of the original volume and is then diluted with EtOAc (0.5L). The solution is allowed to stand at room temperature and the resulting solid is isolated by filtration, and rinsed with EtOAc (0.2L). The mother liquor is concentrated in vacuo and the resulting solid is recrystallized from EtOAc-MeOH (4:1) affording an additional quantity of product. The combined crystalline products are dried in vacuo to yield the target anilinium hydrochloride as a white powder.

MP: 213-214°C.

¹H-NMR: δ = 6.80-7.49(8), 5.18(s, 2), 3.69(brs, 3), 2.36(s, 3).

IR (nujol): 3198 1628, 1614, 1586, and 1533cm^-1.

EI/MS (70eV): 213(M⁺, 46.7), 122(base), 91(42.7), 77(12.2), 65(15.3).

Anal: Calcd. for C₁₄H₁₆ClNO₂: C, 67.33; H, 6.46, N, 5.61. Found: C, 67.10; H, 6.40;

N, 5.62.

2-Fluoro-5-methylphenol

To 2-phenylmethoxy-4-methyl-anilinium chloride (25.0 g,0.1 mol) in water (0.2L), chilled in an ice-salt barn to 0°C (internal) is added cone. HCl (19.2 mL, 0.23 mol) followed by the addition of a solution of NaNO₂ (8.3 g, 0.12 mol) in water (20 mL) over a period of 30 minutes. Stir 30 minutes at 0°C (internal) after the addition is complete. Then a solution of hexafluorophosphoric acid (60%, 25 mL, 0.14 mol) is added in one portion. A white precipitate is formed immediately, and stirring (0°C) is continued for one hour. The white solid is isolated by filtration, washed with water (0.2L), MeOH-Et₂O (0.4L, 1:4). The white filter cake is broken with a spatula into a free flowing white powder which is dried in vacuo overnight to give the intermediate diazonium hexafluorophosphate.

Mineral oil (0.1L) is added to a 3-neck, 500 mL, round bottom flask equipped with a

Gooch rubber connector and a vacuum distillation apparatus. The flask is placed under vacuum

(30 mm Hg) and heated to 170°C; the powdered diazonium hexafluorophosphate is then added over a period of 2 hours. A distillate is collected in the cooled (ice-salt) receiving flask during the course of the addition. The reaction vessel is cooled to room temperature and is carefully treated with 10% aqueous sodium carbonate until the pH of the mixture is 8-9. The mixture is then acidified (6N aq. HCl) until the pH has been adjusted to 5-6. The mixture is next steam distilled, until ca. 0.3L of distillate has been collected. This distillate is combined with the oil collected during the pyrolysis, saturated with NaCl and extracted with CH₂Cl₂ (2X0.5L). The combined organic phases are washed with brine (1.0L), dried (MgSO₄), and concentrated in vacuo on a rotary evaporator with the bath temperature maintained at ≤30°C. The light yellow 2-fluoro-5-methyl phenol (8.2 g, 65%) is deemed to be of sufficient purity to be utilized witiiout further purification.

%-NMR: δ = 6.62-6.96(3), 5.06(brs, 1), 2.28(s, 3).

2-Fluoro-4-nitro-5-methylphenol

To a solution of 2-fluoro-5-methylphenol (8.2 g, 65 mmol) in acetic acid (19.5 mL) is added cone. H₂SO₄ (2.6 mL). The mixture is chilled in an ice-salt bath and a solution of NaNO₂

(4.7 g, 68.3 mmol) in water (13 mL) is added over 1 hour. During the addition, a deep brown color develops and as the reaction progresses, a precipitate is observed. The mixture is stirred for an additional 30 minutes, then is diluted with water (0.2L). The solid is isolated by filtration and is added to a heated (55°C) solution of nitric acid (70%, 5.3 mL) in water (21.2 mL) over 5 minutes. The solid dissolves in the reaction medium and a precipitate is noted ca. 5 minutes after the addition is complete. The reaction is quenched with water (0.25L) and the mixture is cooled in a refrigerator (4°C) for 1 hour. The precipitate is isolated by filtration and is purified by recrystallization from ethanol-water to give a tan solid (5.63 g). The momer liquor is extracted with EtOAc (0.1L) and the organic layer is washed with water (0.1L), brine (0.1L), and dried

(MgSO₄). Concentration in vacuo gives a light brown oil which is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, EtOAc-hexanes, 50:50, 40 mL fractions).

Fractions homogeneous by TLC are combined to give a yellow solid, which is combined with the recrystallized material to comprise the desired mono-nitro phenol.

MP: 112-113°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.34.

¹H-NMR: δ = 7.94(d, J = 7.2Hz, 1), 6.95(d, J = 7.2Hz, 1), 5.70(brs, 1), 2.61(s, 3).

IR (nujol): 3270, 1623, and 1588cm^"1.

EI/MS (70eV): 171(M⁺, 31.1), 154(59.2), 126(21.5), 98(25.4), 77(76.1), 51(base).

Anal: Calcd. for C₇H₆FNO₃: C, 49.13; H, 3.53, N, 8.16. Found: C, 49.21; H, 3.59; N, 8.07.

1-Fluoro-2-memoxy-4-methyl-5-nitrobenzene

A mixture of 2-fluoro-4-nitro-5-metiιylphenol (5.7 g, 33.3 mmol), K₂CO₃ (9.2 g, 66.6 mmol), and Me₂SO₄ (8.4 g, 66.6 mmol), in absolute EtOH (95.2 mL) is heated under reflux for

4 hours. The mixture is cooled to room temperature and diluted with water (0.5L). The resulting precipitate is isolated by filtration to give the target anisole as an amber solid.

MP: 95-95°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.34. 1H-NMR: δ = 7.90(d, J = 7.2Hz, 1), 6.83(d, J = 7.2Hz, 1), 3.98(s, 3), 2.65(s, 3). IR (nujol): 1618 and 1588cm^-1.

EI/MS (70eV): 185(M⁺, 51.7), 168(90.0), 96(base).

Anal: Calcd. for C₈H₈FNO₃: C, 51.90; H, 4.36, N, 7.57. Found: C, 52.00; H, 4.55; N, 7.45.

6-Fluoro-5-methoxy- 1H-indole

A solution 2-fluoro-5-methyl-4-nitroanisole (4.63 g, 25 mmol), N, N,-dimethylforamamide dimethyl acetal (2.98 g, 25 mmol), and pyrrolidine (1.78 g, 25 mmol) in dry DMF is heated in a 120 °C oil bath for 5 hours. The resulting red-black reaction mixture is cooled to room temperature, and then is cast into water (1.0L) and EtOAc (1.0L). The organic phase is separated, washed with water (1.0L), brine (1.0L), and dried (MgSO₄). Concentration in vacuo furnishes the crude nitroaryl enamine as a deep red-black oil which is immediately dissolved in toluene (30 mL). The enamine solution is hydrogenated (40 psi) in a Parr shaker (500 mL) over Raney nickel (1 mL, 50% slurry, washed 3X10 mL with absolute EtOH) until hydrogen uptake ceased (5 hours). The catalyst is removed by filtration through a pad of celite, the filter cake is rinsed with EtOAc (0.2 L) and the combined filtrates (clear, pale yellow solution) are dried (MgSO₄). Concentration in vacuo affords the crude indole as a yellow-green solid which is purified by chromatography on a column of silica gel (230-400 mesh, 400g, EtOAc-hexanes 1:4, 40 mL fractions). Fractions which are homogeneous by TLC are combined to give the target indole as a yellow solid.

MP: 64-65°C.

TLC (Merck; EtOAc-hexanes, 20:80 UV(+); ammonium molybdate): R_f = 0.47.

1H-NMR: δ = 6.48-7.26(4), 3.93(s, 3).

IR (nujol): 3416, 3338, and 1590cm^-1.

EI/MS (70eV): 165(M⁺, base), 151(27.0), 95(27.0).

Anal: Calcd. for C₉H₈FNO: C, 65.45; H, 4.88; F, 11.50; N, 8.48. Found: C, 65.66; H, 5.21; F, 11.28; N, 8.09.

6-Fluoro-5-memoxy-1H-indole-3-carboxaldehyde

To dry DMF (4.8 mL), cooled in an ice-water bath, is added POCl₃ (2.72 g, 17.6 mmol, 1.6 mL) over 30 minutes. To this stirring mixture is added a solution of 6-fluoro-5-methoxy-1H-indole (2.6 g, 16 mmol) in dry DMF (4.8 mL) over 30 minutes After the addition is complete, the yellow suspension is warmed in a 50°C oil bath for 1 hour and is then poured into ice-water (50 mL). The pH of me mixture is adjusted to ca. pH= 12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and then is chilled in a refrigerator (4ºC) overnight. A pale yellow solid is isolated by filtration, then is rinsed with water (25 mL) and dried in vacuo to provide 6- fluoro-5-methoxy-1H-indole-3-carboxaldehyde as fine yellow needles.

MP: 268-270°C(decomp)

TLC (Merck; acetone-hexanes, 2:1 UV(+); ammonium molybdate): R_f = 0.25.

¹H-NMR: δ = 9.60(s, 1), 7.53(t, J = 1.3Hz, 1), 7.47(d, J = 8.47Hz, 1), 6.86(d, J = 11.12Hz, 1), 3.60(s, 3).

IR (nujol): 3201, 3182, 3109, 1638, 1627, 1600, and 1567cm^-1.

EI/MS (70eV): 193(M⁺, base), 178(67.5), 150(45.5).

Anal: Calcd. for C₁₀H₈FNO₂: C, 62.18; H, 4.81; F, 9.84; N, 7.25. Found: C, 62.22;

H, 4.29; F, 9.94; N, 4.29.

6-Fluoro-5-methoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde

To a suspension of NaH (0.72 g, 18 mmol, washed with hexanes 3X) in dry DMF (9 mL), is added a solution of 6-fluoro-5-methoxy-1H-indole-3-carboxaldehyde (2.9 g, 15 mmol) in dry DMF (45 mL) over 10 minutes. The mixture is stirred for 30 minutes. After the addition is complete, then a solution of benzyl chloride ( 2.28 g, 18 mmol) in dry DMF (5 mL) is added in one portion. The mixture is allowed to stir for 24 hours at room temperature, then is diluted with water (0.5L) and the resulting oily solid is isolated by filtration. The yellow solid is purified by recrystallization from EtOAc-hexanes to give the target indole as a pale yellow solid. The mother liquor is concentrated in vacuo to give a viscous yellow oil which is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, EtOAc-hexanes 1:2, 40 mL fractions). Fractions which are homogeneous by TLC are combined to give an additional amount of 6-fluoro-5-methoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde as a pale yellow solid.

MP: 118-119°C.

TLC (Merck; acetone-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.47.

¹H-NMR: δ = 9.95(s, 1), 7.89(d, J = 8.4Hz, 1), 7.66(s, 1), 7.16-7.38(6), 7.03(d, J = 11.2Hz, 1), 5.29(s, 2), 3.97(s, 3).

IR (nujol): 2720, 1655, and 1587cm^-1.

EI/MS (70eV): 283(M⁺, 45.0), 91(base).

Anal: Calcd. for C₁₇H₁₄FNO₂: C, 72.07; H, 4.98; N, 4.95. Found: C, 72.10; H, 5.09;

N, 4.94.

5-Methoxy-1-phenylmethyl-1H-indole

To a suspension of NaH (3.43 g, 0.143 mol, washed with hexanes 3X) in dry DMF (0.23

L) is added 5-methoxy-1H-indole (1.64 g, 8.67 mmol) over 10 minutes. The mixture is stirred for 30 minutes. After the addition is complete, benzyl chloride (18.85 g, 0.15 mol) is added in one portion. The mixture is allowed to stir for 24 hours at room temperature, then is diluted with water (0.6 L) and extracted with EtOAc-Et₂O (1:1, 4X0.5L). The combined organic layers are washed with water (2L), brine (2L) and dried (Na₂SO₄). Recrystallization from hexanes-Et₂O gives 5-methoxy-1-phenylmethyl-1H-indole as fine, white needles.

MP: 78.5-80.5°C.

TLC (Merck; EtOAc-hexanes, 1:9 UV(+); ammonium molybdate): R_f = 0.43.

¹H-NMR: δ = 7.00-7.35(8) 6.82(dd, J = 8.84, 2.50Hz, 1), 6.46(d, J = 3.01Hz, 1), 5.28(s, 2), 3.84(s, 3).

5-Hydroxy-1-phenylmethyl-1H-indole

To a suspension of NaH (2.02 g, 84.39 mmol, washed with hexanes 3X) in dry DMF (0.12 L), chilled in an ice-water bath, is added EtSH (5.66 g, 88.62 mmol) over 5 minutes. The mixture is stirred for 5 minutes. After the addition is complete, the ice-water bath is removed and stirring continues for 1 hour. To this mixture is added 5-memoxy-1-phenylmemyl-1H-indole(1.64 g, 8.67 mmol) in one portion. The mixture is placed in a 140°C oil bath and the temperature of the bath is immediately increased to 155 °C and maintained at 155 °C overnight. The dark mixture is cooled to room temperature, then is cast into ice cold water (0.4L) and extracted with EtOAc-Et₂O (1:1, 3X 0.2L). The combined organic layers are washed with water (0.2L), brine (0.2L) and dried (Na₂SO₄). Concentration in vacuo gives the crude indole as a dark red oil which is purified by chromatography on a column of silica gel (230-400 mesh, 220 g, 50 mm OD, packed EtOAc-hexanes 20-80, eluted EtOAc-hexanes 20:80, 1L, 30-70, 1L, 40:60, 1L, 100 mL fractions) using the flash technique. Fractions homogeneous by TLC are combined to afford 5-hydroxy-1-phenylmethyl-1H-indole as a brown solid.

TLC (Merck; EtOAc-hexanes, 1:2; UV(+); ammonium molybdate): R_f = 0.45. 1H-NMR: δ = 7.20-7.45(3), 6.95-7.15(5), 6.72(dd, J = 8.75, 2.48Hz, 1), 6.41(dd, J = 3.01, 0.60Hz, 1), 5.25(s, 2), 4.63(s, 1), 4.63(s, 2).

5-Ethoxy-1-phenylmethyl-1H-indole

To a suspension of NaH (0.412 g, 17.19 mmol, washed with hexanes 3X) in dry DMF (70 mL), chilled in an ice-water bath, is added 5-hydroxy-1-phenylmethyl-1H-indole (3.65 g, 16.37 mmol) in one portion. The mixture is stirred for 5 minutes. After me addition is complete, the ice-water bath is removed and the flask is warmed in a 45°C oil bath for 1 hour. The mixture is cooled in an ice-water bath and ethyl bromide (1.89 g, 17.35 mmol) in one portion. The mixture is cooled to room temperature, then is cast into ice-water (0.25 L) and Et₂O (0.25L). The organic phase is separated, the aqueous layer is extracted with Et₂O (0.25 L) and the combined organic phases are washed with water (0.1 L), brine (0.1 L), and dried (Na₂SO₄). Concentration in vacuo gives the indole as a pale yellow, sticky solid which is purified by recrystallization from hexanes-Et₂O to give the target indole as an ivory solid.

TLC (Merck; EtOAc-hexanes, 1:9 UV(+); ammonium molybdate): R_f = 0.46. ¹H-NMR: δ = 7.15-7.35(3), 7.00-7.20(5), 6.82(dd, J = 8.70, 2.50Hz, 1), 6.45(dd, J = 3.00, 0.61Hz,1), 5.28(s, 2), 4.06(q, J = 7.00Hz, 2), 1.42(t, J = 7.00Hz, 3).

5-Ethoxy-1-phenylmethyl-1H-indole-3-carboxaldeayde

To dry DMF (6.9 mL), cooled in an ice-water bath, is added POCl₃ (1.94 g, 12.67 mmol, 1.18 mL) over 30 minutes. To this stirring mixture is added a solution of

5-ethoxy-1-phenylmethyl-1H-indole (2.89 g, 11.51 mmol) in dry DMF (6.9 mL) over 30 minutes.

After the addition is complete, the yellow suspension is warmed in a 50°C oil bath for 1 hour and is then poured into ice-water (120 mL). The pH of the mixture is adjusted to ca. pH= 12 with

20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and then is chilled in a refrigerator (4°C) overnight. The mixture is treated with Et₂O-EtOAc (1:1, 0.125 L) and the organic phase is washed with water

(2X0.125L), and dried (Na₂SO₄₎. Concentration in vacuo gives the crude aldehyde as a pale yellow solid, which is purified by chromatography on a column of silica gel (230-400 mesh, 250 g, 70 mm OD, EtOAc-hexanes, 1:4, 100 mL fractions) using the flash technique. Fractions homogeneous by TLC are combined to yield 5-ethoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde as a white solid.

TLC (Merck; EtOAc-hexanes, 1:2; UV(+); ammonium molybdate): R_f = 0.21.

¹H-NMR: δ = 9.93(s, 1), 7.79(d, J = 2.45Hz, 1), 7.63(s, 1), 7.25-7.40(3),

7.10-7.21(3), 5.29(s, 2), 4.10(q, J = 7.00Hz, 2), 1.43(t, J = 7.00Hz, 3).

5-Ethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H-indolemethanamine

According to the general procedure described in the preparation of Example 2, 3-trifluoromethylbenzyl amine (1.51 g, 8.60 mmol), 5-ethoxy-1-phenylmethyl-1H-indole- 3-carboxaldehyde (2.40 g, 8.60 mmol) and NaBH₃CN (0.54 g, 8.60 mmol) provides crude 5- ethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H-indole-methanamine as a pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 150 g, hexanes-EtOAc, 20:80, 40 mL fractions). Fractions homogeneous by TLC are combined to give 5-ethoxy- 1 -phenylmethyl-N-((3 -trifluoromethyl)- phenylmethyl)-3-1H-indolememanamine as a clear colorless oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.24. 1H-NMR: δ = 7.65(brs, 1), 7.00-7.60(11), 6.84(dd, J = 8.86, 2.38Hz, 1),

5.24(s, 2), 4.06(q, J = 7.00Hz, 2), 3.96(s, 2), 3.92(s, 2), 1.57(s, 1), 1.43(q, J

= 7.00Hz, 3).

IR (nujol): 2979, 2922, 2871, 1620, 1579, 1475, 1452, 1356, 1329, 1224, 1202, 1164, 1123, 1072, 1051, 796, and 703cm^-1.

EI/MS (70eV): 438(M⁺, 49.5), 265(52.5), 264(62.3), 91(base).

Anal: Calcd. for C₂₆H₂₅F₄N₂O: 438.1919. Found: 438.1916. Methylthiocopper(I)

To saturated aqueous ammonia (75 mL) in 95% EtOH (75 mL), cooled in an ice-water bath, is added CuCl (10.0 g, 10 mmol) over 30 minutes. The resulting blue solution becomes blue-green ca. 10 minutes after the addition is completed, men CH₃SH is added as a gas via a gas dispersion tube. The color of the suspension changed from blue-green to blue, aqua, and finally to yellow. At this point the CH₃SH addition is continued for an additional 10 minutes, then the mixture is diluted with an additional 75 mL of 95% EtOH and me stirring is stopped and the mixture is allowed to warm to room temperature overnight. The yellow solid is isolated from the blue supernatant solution by filtration, the solid is washed with water:conc. ammonia (1:1, 0.2L), abs. EtOH (2X 50 mL), Et₂O (0.1L), and dried in vacuo to furnish methylthiocopper(I) as a greenish yellow solid.

5-Methylthio-1H-indole

Quinoline (50 mL), pyridine (7.5 mL), methylthiocopper (I) (4.21 g, 38.26 mmol), and 5-bromo-indole (5.0 g, 25.51 mmol) are combined and heated in a 205°C oil bath for 6 hours. The resulting black reaction mixture is cooled to room temperature and cast into 3N aq. HCl (0.4 L) and EtOAc (0.5L). The two phase mixture is filtered through celite, the organic phase is separated, and the aqueous layer is extracted with EtOAc (0.5 L). The combined organic layers are 2N aq. HCl (0.2 L), brine (0.2 L), and dried (Na₂SO₄). Concentration in vacuo provides a black oily solid. The crude product is dissolved in EtOAc-MeOH (50 mL, 1: 1) and 20 g of silica gel is added. The solvent is removed in vacuo and the free flowing silica supported powder is applied to a column of silica gel (230-400 mesh, 250 g, 70 mm OD, EtOAc-CH₂Cl₂-hexanes 4: 15:81, 100 mL fractions) and is purified by the flash technique. Fractions homogeneous by TLC are combined to yield 5-methylthioindole as yellow oil.

TLC (Merck; EtOAc-hexanes, 1:9 UV(+); ammonium molybdate): R_f = 0.19.

1H-NMR: δ = 7.64(brs, 1), 7.10-7.35(3), 6.49(m, 1), 2.51(s, 3).

EI/MS (70eV): 163(M⁺, base), 148(86.7), 104(26.8).

5-Methylthio-1-phenylmethyl-1H-indole

To a suspension of NaH (0.332 g, 13.85 mmol, washed with hexanes 3X) in dry DMF (50 mL), chilled in an ice-water bath, is added 5-methylthioindole (2.15 g, 13.19 mmol) in DMF (25 mL), in one portion. The mixture is stirred for 45 minutes. After the addition is complete, benzyl chloride (1.83 g, 14.51 mmol) is added in one portion. The mixture is allowed to stir overnight, then is cast into ice-water (0.25 L) and Et₂O (0.25L). The organic phase is separated, dried (Na₂SO₄), and concentrated in vacuo to give the indole as a pale yellow, oil which is purified by chromatography on a column of silica gel (230-400 mesh, 250 g, 50 mm OD, EtOAc-hexanes, 1:99, 40 mL fractions) using the flash technique. Fractions homogeneous by TLC are combined to provide 5- methylthio-1-phenylmethyl-indole as a colorless liquid. TLC (Merck; EtOAc-hexanes, 5:95 UV(+); ammonium molybdate): R_f = 0.34.

¹H-NMR: δ = 7.64(t, J = 1.14Hz, 1), 7.05-7.35(8), 6.48(d, J = 3.14Hz, 1), 5.29(s, 2), 2.50(s, 3).

EI/MS (70eV): 253(M⁺, 85.8), 91(base).

Anal: Calcd. for C₁₆H₁₅NS: 253.0926. Found: 253.0923.

5-Methylthio-1-phenylmethyl-1H-indole-3-carboxaldehyde

To dry DMF (6.6 mL), cooled in an ice-water bath, is added POCl₃ (1.88 g, 12.30 mmol,

1.14 mL) over 30 minutes. To this stirring mixture is added a solution of

5-methylthio-1-phenylmethyl-1H-indole (2.83 g, 11.19 mmol) in dry DMF (6.6 mL) over 30 minutes. After the addition is complete, the yellow suspension is warmed in a 50°C oil bath for

1 hour and is then poured into ice-water (120 mL). The pH of the mixture is adjusted to ca. pH=12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes.

The solution is cooled to room temperature and then is chilled in a refrigerator (4ºC) overnight.

The mixture is treated with Et₂O-EtOAc (1: 1, 0.125 L) and the organic phase is washed with water (2X 0.125L), and dried (Na₂SO₄). Concentration in vacuo gives the crude aldehyde as a pale yellow solid, which is purified by chromatography on a column of silica gel (230-400 mesh, 150 g, 50 mm OD, EtOAc-hexanes, 1:4, 100 mL fractions) using the flash technique. Fractions homogeneous by TLC are combined to yield 5-methylthio-1-phenylmethyl-1H-indole-3- carboxaldehyde as a colorless oil.

TLC (Merck; EtOAc-hexanes, 1:2; UV(+); ammonium molybdate): R_f = 0.31.

¹H-NMR: δ = 9.95(s, 1), 8.24(brs, 1), 7.68(s, 1), 7.20-7.40(7), 5.32(s, 2), 2.55(s, 3).

EI/MS (70eV): 281(M⁺, 90.5), 91(base).

5-Methylthio-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)3-1H-indolemethanamine

According to the general procedure described in the preparation of Example 2, 3-trifluoromethylbenzyl amine (1.88 g, 10.75 mmol), 5-methylthio-1-phenylmethyl-1H-indole-3- carboxaldehyde (3.02 g, 10.75 mmol) and NaBH₃CN (0.677 g, 10.75 mmol) provides crude 5- methylthio-1-phenylmethyl-N-((3-tri- fluoromethyl)phenylmethyl)-3-1H-indolemethanamine as a pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 175 g, hexanes-EtOAc, 10:90, 40 mL fractions). Fractions homogeneous by TLC are combined to give 5-memylthio-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H- indole- memanamine as a clear colorless oil.

TLC (Merck; EtOAc-hexanes, 1:2; UV(+); ammonium molybdate): R_f = 0.15.

¹H-NMR: δ = 7.05-7.70(13), 5.25(s, 2), 3.97(s, 2), 3.91(s, 2), 2.51(s, 3)

2,5-Dimethyl-4-nitrophenol

To a solution of 2,5-dimethylphenol (12.22 g, 0.10 mol) in glacial HOAc (0.1L), cooled to 10°C internal with an ice-salt bath, is added a solution of nitric acid (70%, 7.88 g, 0.125 mol) in glacial acetic acid (0.1L) over a period of 2 hours. The resulting red solution is then slowly added to ice-water (2L) over 2 hours. The resulting mixture is extracted with CH₂Cl₂ (2x0.5L), and the combined organic layers are washed with brine (1L) and dried (Na₂SO₄). Concentration in vacuo affords the crude nitro-phenol as a dark red oil which is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, packed - hexanes, eluted Et₂O-hexanes 10:904L, 20:806L, 400 mL fractions) using the flash technique. Fractions homogenous by TLC furnish 2,5-dimethyl- 4-nitrophenol as an orange solid.

MP: 97-100°C.

TLC (Merck; EtOAc-hexanes, 25:75; UV(+); I₂(+)): R_f = 0.26.

1H-NMR: δ = 6.55(s, 2), 4.80(brs, 1), 2.29(s, 6).

¹³C-NMR: δ = 156.6; 132.7, 115.2, 18.1.

IR (nujol): 3307, 2926, 2855, 1592, 1509, 1467, 1312, 1285, 1098, 852 and 838cm^-1. EI/MS (70eV): 167(M⁺, 91.1), 150(base).

Anal: Calcd. for C₈H₉NO₃: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.79; H, 5.70; N, 8.20.

3,5-Dimethyl-4-nitroanisole

A mixture of 3,5-dimethyl-4-nitrophenol (7.40 g, 48.3 mmol), K₂CO₃ (13.49 g, 97.6 mmol), and Me₂SO₄ (9.26 g, 73.4 mmol), in absolute EtOH (0.25 L) is heated under reflux for 4 hours. The mixture is cooled to room temperature and diluted with water (0.5L). The resulting precipitate is isolated by filtration to give the crude anisole as a sticky orange solid. The crude product is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, EtOAc-hexanes 15:85, 400 mL fractions) using the flash technique. Fractions homogenous by TLC furnish 5,5-dimemyl-4-nitro- anisole as a pale yellow solid.

MP: 50-52°C.

TLC (Merck; EtOAc-hexanes, 25:75; UV(+); I₂(+)): R_f = 0.36.

¹H-NMR: δ = 6.60(s, 2), 3.81(s, 3), 2.32(s, 6).

1³C-NMR: δ = 159.9, 132.3, 113.7, 55.4, 18.2.

IR (nujol): 2952, 2925, 1598, 1510, 1481, 1467, 1357, 1329, 1297, 1192, 1170, 1111, 855, 851 and 838cm^-1.

EI/MS (70eV): 181(M⁺, 95.3), 164(base).

Anal: Calcd. for C₉H₁₁NO₃: C, 59.66; H, 6.12 N, 7.74. Found: C, 59.95; H, 6.48; N, 7.81.

5-Methoxy-7-methyl- 1H-indole

A solution of 3,5-dimethyl-4-nitroanisole (6.70 g, 37.0 mol), N, N,-dimethylforamamide dimethyl acetal (13.1 g, 111 mmol), and pyrrolidine (2.63 g, 37.0 mmol) in dry DMF (100 mL) is heated in a 120°C oil bath for 5 hours. The resulting red-black reaction mixture is cooled to room temperature, and men is cast into water (1.5L) and EtOAc (1.5L). The organic phase is dried (Na₂SO₄) and concentrated in vacuo to furnish the crude nitroaryl enamine as a deep red-black oil which is immediately dissolved in toluene (0.5L). The enamine solution is hydrogenated (30 psi) in a Parr shaker (2.0L) over Raney nickel (3.0 g, 50% slurry, washed 3X10mL with absolute EtOH) until hydrogen uptake ceases (5 hours). The catalyst is removed by filtration through a pad of celite, the filter cake is rinsed with EtOAc (1.0L) and the combined filtrates (clear, pale yellow solution) are dried (Na₂SO₄). Concentration in vacuo affords the crude indole as a brown oil which is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, EtOAc-hexanes 5:95, 2L, 10:90, 2L, 15:85, 4L, 400 mL fractions). Fractions homogenous by TLC give the target indole as a white fluffy solid.

MP: 68-69°C.

TLC (Merck; EtOAc-hexanes, 25:75 UV(+); ammonium molybdate): R_f = 0.38.

¹H-NMR: δ = 7.94(brs, 1), 7.11(t, J = 2.8Hz, 1), 6.95(d, J = 2.2Hz, 1), 6.68(d, J = 1.5Hz, 1), 6.47(dd, J = 3.1, 2.1Hz, 1), 3.82(s, 3), 2.41(s, 3).

1³C-NMR: δ = 154.2, 130.6, 127.5, 124.4, 121.2, 112.9, 102.7, 99.7, 55.7, 16.6.

IR (nujol): 3391, 2956, 2926, 2855, 1601, 1484, 1461, 1454, 1308, 1193, 1147, 1046, 873, 819, and 732cm^-1.

EI/MS (70eV): 161(M⁺, base).

Anal: Calcd. for C₁₀H₁₁NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.44; H, 7.26; N, 8.77.

5-Methoxy-7-methyl-1H-indole-3-carboxaldehyde

To dry DMF (5 mL), cooled in an ice-water bath, is added POCl₃ (1.69 g, 11.0 mmol) over 30 minutes. To mis stirring mixture is added a solution of 5-methoxy-7- methyl-1H-indole (1.61 g, 10 mmol) in dry DMF (4 mL) over 30 minutes. After the addition is complete, the tan suspension is warmed in a 50°C oil bath for 1 hour and is then poured into ice-water (100 mL). The pH of the mixture is adjusted to ca. pH= 12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and then is chilled in a refrigerator (4°C) overnight. A tan solid is isolated by filtration, then is rinsed with water (25 mL) to give 5-methoxy-7-methyl-1H-indole-3-carboxaldehyde as fine tan powder.

MP: 137-138°C

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.24.

¹H-NMR: δ = 9.99(s, 1), 9.64(brs, 1), 7.81(d, J = 3.3Hz, 1), 7.62(d, J = 2.4Hz, 1), 6.77(t, J = 1.5Hz, 1), 3.82(s, 3), 2.48(s, 3).

¹³C-NMR: δ = 185.5, 156.6, 135.9, 131.3, 124.6, 122.2, 119.5, 115.3, 100.5, 55.6, 16.5.

IR (nujol): 3235, 2954, 2925, 2855, 1655, 1636, 1617, 1528, 1496, 1462, 1452, 1283, 1220, 1137, and 1127cm^-1.

EI/MS (70eV): 189(M⁺, base).

Anal: Calcd. for C₁₁H₁₁NO₂: C, 69.83; H, 5.86; N, 7.40. Found: C, 70.08; H, 6.18 N, 7.48.

5-Methoxy-7-methyl-1-phenylmethyl-1H-indole-3-carboxaldehyde

To a suspension of NaH (0.23 g, 9.53 mmol, washed with hexanes 3X) in dry DMF (10 mL), is added a solution of 5-methoxy-7-methyl-1H-indole-3-carboxaldehyde (1.64 g, 8.67 mmol) in dry DMF (5 mL) over 10 minutes. The mixture is stirred for 30 minutes. After the addition is complete, a solution of benzyl chloride ( 1.21 g, 9.53 mmol) in dry DMF (5 mL) is added in one portion. The mixture is allowed to stir for 24 hours at room temperature, then is diluted with water (0.2 L) and the resulting orange solid is isolated by filtration. The solid is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, packed EtOAc-hexanes 10:90, eluted EtOAc-hexanes 25:75 2.0 L, 30:70 6 L, 400 mL fractions). Fractions homogenous by TLC give 5-methoxy-7-methyl-1-phenylmethyl-1H-indole-3- carboxaldehyde as a white fluffy solid.

MP: 136-137°C.

TLC (Merck; EtOAc-hexanes, 1:1 UV(+); ammonium molybdate): R_f = 0.43.

1H-NMR: δ = 9.94( s, 1), 7.72(d, J = 2.5Hz, 1), 7.57(s, 1), 7.30-7.35(3), 6.96(m, 2), 6.65(d, J = 1.9Hz, 1), 5.55(s, 2), 3.87(s, 3), 2.50(s, 3).

1³C-NMR: δ = 184.5, 156.4, 140.5, 137.1, 131.1, 129.0, 127.9, 127.3, 125.6, 122.8,

117.9, 117.3, 100.8, 55.5, 53.1, 19.1.

IR (nujol): 2956, 2925, 2854, 1646, 1602, 1535, 1494, 1469, 1453, 1418, 1262, 1230, 1172, 1055, and 779cm^-1.

EI/MS (70eV): 279(M⁺, 71.2), 91(base).

Anal: Calcd. for C₁₈H₁₇NO₂: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.23; H, 6.29;

N, 5.09.

EI/MS (70eV): 440(M⁺, 16.8), 267(17.0), 266(24.0), 91(base).

5-Phenylmethoxy-1-phenylmethyl-1H-indole

To a suspension of NaH (0.339 g, 14.13 mmol, washed with hexanes 3X) in dry DMF (50 mL), chilled in an ice-water bath, is added 5-phenylmemoxyindole (3.00 g, 13.45 mmol) in DMF (25 mL), in one portion. The mixture is stirred for 45 minutes. After the addition is complete, then benzyl chloride (1.81 g, 14.39 mmol) is added in one portion. The mixture is allowed to stir overnight, then is cast into ice-water (0.25 L) and Et₂O (0.25L). The organic phase is separated, dried (N a₂SO₄), and concentrated in vacuo to give the indole as a pale yellow solid which is purified by recrystallizationfrom Et₂O-hexanes to give 5-phenylmethoxy-1-phenylmethyl-1H-indole as white crystals. The mother liquor is concentrated in vacuo to give an oily yellow solid which is recrystallized to afford an additional amount of the target compound as a white crystalline solid.

MP: 107-108.5°C.

TLC (Merck; EtOAc-hexanes, 10:90, UV(+); .ammonium molybdate): R_f = 0.50.

¹H-NMR: δ = 7.05-7.55(13), 6.90(dd, J = 8.87, 2.46Hz, 1), 6.46(d, J = 2.99Hz, 1), 5.29(s, 2), 5.10(s, 2).

5-Phenylmethyl-1-phenylmethyl-1H-indole-3-carboxaldehyde

To dry DMF (4.3 mL), cooled in an ice-water bath, is added POCl₃ (1.22 g, 7.95 mmol, 0.74 mL) over 30 minutes. To this stirring mixture is added a solution of 5-phenylmethoxy-1-phenylmethyl-1H-indole (2.26 g, 7.23 mmol) in dry DMF (4.3 mL) over 30 minutes. After the addition is complete, the yellow suspension is warmed in a 50°C oil bath for 1 hour and is then poured into ice-water (80 mL). The pH of the mixture is adjusted to ca. pH=12 with 20% aqueous NaOH and the suspension is heated on a steam bath for 15 minutes. The solution is cooled to room temperature and then is chilled in a refrigerator (4°C) overnight. The mixture is treated with Et₂O-EtOAc (1:1, 2X 0.10 L) and the organic phase is washed with water (2X 0.10 L), brine (0.1 L), and dried (Na₂SO₄). Concentration in vacuo gives the crude aldehyde as a pale yellow solid, which is purified by recrystallization from EtOAc-hexanes-Et₂O to yield 5-phenyl-meghoxy-1-phenylmethyl-1H-indole-3-carboxaIdehyde as a white solid.

MP: 137-138°C.

TLC (Merck; EtOAc-hexanes, 1:2; UV(+); ammonium molybdate): R_f = 0.18.

1H-NMR: δ = 9.95(s, 1), 7.92(d, J = 2.46Hz, 1), 7.66(s, 1), 7.15-7.50(11), 7.00(dd, J

= 8.93, 2.55Hz, 1), 5.32(s, 2), 5.14(s, 2).

5-Phenylmethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H-indolemethanamine

According to the general procedure described in Example 2, 3-trifluoro- methylbenzyl amine (1.03 g, 5.86 mmol), 5-phenylmethoxy-1-phenylmeth yl-1H-indole-3-carboxaldehyde (2.00 g, 5.86 mmol) and NaBH₃CN (0.37 g, 5.86 mmol) provides crude 5-phenylmethoxy-1- phenyImethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H- indolemethanamine as a pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 125 g, 50 mm OD, hexanes-EtOAc, 60:40, 40 mL fractions). Fractions homogeneous by TLC are combined to give 5-phenylmethoxy-1-phenylmeth yl-N-((3-trifluoromethyl)phenylmethyl)-3-1H- indolemethanamine as a clear colorless oil.

TLC (Merck; EtOAc-hexanes, 1:1; UV(+); ammonium molybdate): R_f = 0.32.

¹H-NMR: δ = 7.05-7.70(13), 6.85(dd, J = 8.90, 2.57Hz, 1), 5.23(s, 2), 5.10(s, 2), 3.97(s, 2), 3.89(s, 2).

Example 2 1-Phenylmethyl-N-(S)-(1-phenyl)ethyl-3-indolemethanamine

To a solution of (S)-a-memylbenzyl amine (15.15 g, 0.125 mol) in memanol (0.125 L) is added glacial acetic acid (8.75 mL) followed immediately by 1-phenylmethιyl-1H-indole-3- carboxaldehyde (5.9 g, 25 mmol) in THF (0.125 L) in one portion. The mixture is allowed to stir for 10 min at room temperature, then NaBH₃CN (2.00 g, 31.8 mmol) is added in one portion. The resulting pale yellow solution is allowed to stir at room temperature for 48 h; then is concentrated in vacuo, and the white semi-solid residue is treated with 20% aqueous NaOH (0.2 L). The mixture is cast into CH₂Cl₂ (1.0 L) and 1N aqueous NaOH (1.0 L). The organic phase is separated, washed with brine (1.0 L), and dried (Na₂SO₄). Concentration in vacuo affords the crude amine as a pale yellow liquid which is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, ethyl acetate-hexanes 40:60, 500 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.23.

¹H-NMR: δ = 7.59(d, J = 7.22 Hz, 1), 7.0-7.5(14), 5.24(s, 2), 4.11(q, J = 7.13Hz, 1), 3.85(d, J = 13.2Hz, 1), 3.78(d, J = 13.2Hz, 1), 1.65(br s,1), 1.37(d, J = 7.13Hz, 3).

¹³C-NMR: δ = 145.8, 137.6, 136.8, 128.7, 128.4, 127.7, 127.6, 126.9, 126.8, 126.5, 121.8, 119.2, 119.1, 114.4, 109.7, 57.8, 49.9, 42.7, 24.5.

IR (CHCl₃): 3060, 3028, 2963, 2924, 1614, 1604, 1555, 1595, 1481, 1467, 1453, 1369, 1355, 1332, 1172, 1132, 761, 741, and 701cm^-1.

Anal: Calcd. for C₂₄H₂₄N₂: 340.1939. Found: 340.1961.

[a]_D -24° (c = 0.523, CH₂Cl₂).

Example 3 1-Phenylmethyl-N-(3-trifluoromethyl-phenyl)methyl-3-indolemethanamine

To a solution of 3-CF₃-benzyl amine (3.50 g, 20 mmol) in toluene (0.05 L) is added

1-phenylmethyl-1H-indole-3-carboxaldehyde (2.35 g, 10 mmol). The mixture is heated under reflux with azeotropic removal of water for 12 h. The resulting pale yellow solution is cooled to room temperature; men is concentrated in vacuo to yield a clear, yellow, viscous oil. The crude imine is dissolved in MeOH-THF (80 mL, 1:1 (v/v)) and glacial HOAc (1.7 mL) is added, followed immediately by NaBH₃CN (0.80 g, 12.7 mmol) in one portion. The solution is allowed to stir for 48 h at room temperature; then is concentrated in vacuo, and the white semi-solid residue is treated with 20% aqueous NaOH (0.1 L). The mixture is cast into CH₂Cl₂ (0.5 L) and

1N aqueous NaOH (0.5 L). The organic phase is separated, washed with brine (0.5 L), and dried

(Na₂SO₄). Concentration in vacuo affords the crude amine as a pale yellow liquid which is purified by chromatography on a column of silica gel (230-400 mesh, 300 g, 70 mm OD, ethyl acetate-hexanes 25:75, 200 mL fractions) using the flash technique. Fractions homogenous by

TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.23.

1H-NMR: δ = 7.05-7.7(14), 5.26(s, 2), 3.99(s, 2), 3.90(s, 2), 1.65(br s,1).

1³C-NMR: δ = 141.6, 137.5, 136.9, 131.5, 128.7, 127.7, 127.6, 126.8, 126.6, 124.9,

124.8, 123.7, 123.6, 121.9, 119.3, 119.1, 113.9, 109.8, 52.8, 49.9, 44.2. IR (CHCl₃): 3058, 3051, 2920, 2850, 2822, 1605, 1597, 1481, 1466, 1453, 1355, 1329, 1192, 1165, 1122, 1072, 740, and 702cm^-1.

EI/MS (70eV): 394(M⁺, 19.4), 220(44.0), 208(7.6), 187(11.1), 159(11.7), 129(9.1), 91 (base).

Anal: Calcd. for C₂₄H₂₁F₃N₂: C, 73.08; H, 5.36; N, 7.10. Found: C, 72.94; H, 5.31,

N, 7.01.

Example 4 1-Phenylmethyl-N-((R)-1-phenyl)ethyl-3-indolemethanamine

According to the general procedure described in Example 2, (R)-a-methylbenzyl amine (6.06 g, 50 mmol), 1-phenylmemyl-1H-indole-3-carboxaldehyde (2.35 g, 10 mmol) and NaBH₃CN (0.79 g, 12.6 mmol) provide crude 1-phenylmemyl-N-(R)-1-phenyl)ethyl-3-indolemethanamine as a yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 300 g, 70 mm OD, packed EtOAc-hexanes 5:95, eluted ethyl acetate-hexanes 40:60, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.43.

¹H-NMR: δ = 7.01-7.61(15), 5.48(s, 2), 3.88(q, J = 6.6Hz, 1), 3.82(d, J = 6.8Hz, 2), 1.59(br s,1), 1.37(d, J = 6.6Hz, 3).

¹³C-NMR: δ = 149.8, 141.6, 140.8, 132.7, 132.5, 131.8, 131.6, 130.9, 130.5, 125.9, 123.2, 123.2, 118.5, 113.7, 109.7, 57.8, 49.9, 42.7, 24.5.

IR (CHCl₃): 3060, 3028, 2963, 2925, 1496, 1467, 1453, 1356, 1333, 1173, 1028, 1014,

741, and 701cm^-1.

EI/MS (70eV): 340(M⁺), 235, 220, 132, 105, 91, 44(base).

Anal: Calcd. for C₂₄H₂₄N₂: 340.1939. Found: 340.1929.

[a]_D +24° (c = 0.899, CH₂Cl₂) .

Example 5 1-Methyl-N-((S)-1-phenyl)ethyl-3-indolemethanamine

According to the general procedure described in Example 2, (S)-a-methylbenzyl amine (6.06 g, 50 mmol), 1 methyl-1H-indole-3-carboxaldehyde (1.59 g, 10 mmol) and NaBH₃CN (0.79 g, 13 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, ethyl acetate-hexanes 40:60, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, viscous, yellow oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.18.

1H-NMR: δ = 6.94-7.58(10), 3.89(q, J = 6.6Hz, 1), 3.81(d, J = 5.3Hz, 2), 3.72(s, 3), 1.63(brs, 1), 1.37(d, J = 6.6Hz, 3).

1³C-NMR: δ = 145.8, 137.7, 128.4, 127.5, 127.1, 126.8, 126.7, 121.5, 118.9, 118.8,

113.7, 109.1, 57.7, 42.5, 32.5, 24.5. IR (CHCl₃): 3057, 3025, 2962, 2926, 2878, 2824, 1615, 1556, 1492, 1484, 1475, 1450, 1371, 1327, 1253, 1130, 1114, 1066, 1012, 762, 741, and 701cm^-1

EI/MS (70eV): 264(M⁺, 15.5), 159(13.5), 145(34.1), 144(base).

Anal: Calcd. for C₂₅H₂₆N₂ O: C, 81.78; H, 7.63; N, 10.60. Found: C, 81.66; H, 7.78, N, 11.04.

[a]_D -30° (c = 0.607, CH₂Cl₂) .

Example 6 1-Methyl-N-[(4S,5S)-2,2-dimethyl-4 -phenyl-1,3-dioxolan-5-yl]-3-indole- methanamine

According to the general procedure described in Example 3, treatment of the crude imine derived from [4S, 5S]-2,2-dimethyl-4-phenyl-5-amino-1,3-dioxane (2.07 g, 10 mmol) and 1 -methyl- 1H-indole-3-carboxaldehyde (1.31 g, 8.2 mmol) with NaBH₃CN (0.67 g, 10.7 mmol) provide a crude viscous yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, ethyl acetate-hexanes 50:50, 450 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.14.

1H-NMR: δ = 6.95-7.37(9), 6.58(s, 1), 5.14(d, J = 2.3 Hz, 1), 4.08-4 .19(2), 3.91(dd, J = 13.7 Hz, 1), 3.76(d, J = 13.7 Hz, 1), 3.64(s, 3), 2.79(d, J = 2.2 Hz, 1), 2.72(brs, 1), 1.55(s, 6).

1³C-NMR: δ = 139.6, 137.1, 128.3, 127.9, 127.5, 127.4, 126.2, 121.5, 119.3, 118.9,

109.1, 99.4, 73.6, 62.8, 54.0, 42.4, 32.7, 29.8, 28.9.

IR (CHCl₃): 3055, 3029, 2991, 2939, 2872, 1475, 1450, 1380, 1327, 1267, 1237, 1197, 1091, 1073, 846, 740, and 699cm^-1

EI/MS (70eV): 350(M⁺, 11.5), 202(3.3), 186(9.0), 157(2.8), 144(base).

Anal: Calcd. for C₂₂H₂₆N₂O₂: 350.1994. Found: 350.2003.

[a]_D +62° (c = 0.731, CHCl₃).

Example 7 1-Phenylmethyl-N-(2-phenylethyl)-3-indolemethanamine

According to the general procedure described in Example 3, reduction of the crude imine prepared from 2-phenylethyl amine (1.45 g, 12 mmol) and 1-phenylmethyl-1H-indole-3- carboxaldehyde (2.35 g, 10 mmol) with NaBH₃CN (0.79 g, 12.6 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, packed-ethyl acetate-hexanes 40:60, eluted EtOAc-hexanes 55:45, 450 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.13.

¹H-NMR: δ = 7.58(d, J = 7.5 Hz, 1), 7.01-7.30(14), 5.24(s, 2), 3.99(s, 2), 2.98(t, J = 6.8 Hz, 2), 2.89(t, J = 6.8 Hz, 2), 1.52(brs, 1).

¹³C-NMR: δ = 139.9, 137.5, 136.3, 128.7, 128.4, 127.7, 127.6, 126.8, 126.5, 126.1, 121.8, 119.2, 119.0, 115.0, 109.7, 50.8, 49.9, 44.7, 36.4.

IR (CHCl₃): 3060, 3027, 2924, 2854, 2817, 1613, 1604, 1496, 1467, 1453, 1357, 1332, 1254, 1172, 1029, 1014, 741, and 699cm^-1.

EI/MS (70eV): 340(M⁺, 9.4), 220(base).

Anal: Calcd. for C₂₄H₂₄N₂: C, 84.67; H, 7.11; N, 8.23. Found: C, 84.34; H, 6.77; N, 8.25.

Example 8 1-Methyl-N-[(2S)-1-phenyl-2-methoxyethyl]-3-indolemethanamine

According to the general procedure described in Example 3, treatment of the crude imine derived from (R)-(-)-phenylglycinol methyl ether (1.51 g, 10 mmol) and 1-methyl-1H-indole-3- carboxaldehyde (1.31 g, 8.2 mmol) with NaBH₃CN (0.67 g, 10.7 mmol) provide a crude viscous yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, ethyl acetate-hexanes 25:75, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.34.

¹H-NMR: δ = 6.10-7.58(10), 5.24(brs, 2), 4.04(m, 1), 3.88(d, J = 13.2Hz, 1), 3.76(d, J = 13.2Hz, 1), 3.73(s, 3), 3.45(m, 2), 3.30(s, 3), 2.51(brs, 1).

¹³C-NMR: δ = 140.5, 137.1, 128.5, 127.8, 127.5, 127.4, 121.6, 119.0, 118.9, 113.3, 109.2, 77.7, 62.3, 58.7, 42.3, 32.6.

IR (CHCl₃): 3058, 3027, 2898, 2885, 2823, 1615, 1556, 1484, 1474, 1453, 1374, 1327, 1252, 1195, 1130, 1098, 759, 741, and 702cm^-1

EI/MS (70eV): 294(M⁺, 2.2), 249(15.1), 170(3.4), 144(base).

Anal: Calcd. for C₁₉H₂₂N₂O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.53; H, 7.62, N, 9.46.

[a]_D -51° (c = 0.817, CH₂Cl₂).

Example 9 1-Methyl-N-[(2R)-1-phenyl-2-methoxyethyl]-3-indolemethanamine

According to the general procedure described in Example 3, treatment of the crude imine derived from (S)-(+)-phenylalaninol methyl ether (1.65 g, 10 mmol) and 1-metiιyl-1H-indole-3- carboxaldehyde (1.36 g, 8.2 mmol) with NaBH₃CN (0.67 g, 10.7 mmol) provide a crude viscous yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, ethyl acetate-hexanes 40:60, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.20.

1H-NMR: δ = 7.46(d, J = 7.9 Hz, 1), 7.03-7.29(8), 6.90(s, 1), 4.01(s, 2), 3.71(s, 3),

3.36(m, 2), 3.32(s, 3), 3.11(dd, J = 6.8, 5.4 Hz, 1), 2.83(m, 2), 2.20(brs, 1). ¹³C-NMR: δ = 139.0, 136.9, 129.3, 128.4, 127.4, 127.3, 126.2, 121.6, 118.9, 118.8, 113.9, 109.2, 74.2, 58.9, 58.5, 42.6, 38.1, 32.6.

IR (CHCl₃): 3058, 3026, 2924, 2885, 2824, 1615, 1557, 1475, 1454, 1327, 1253, 1242, 1195, 1128, 1122, 1102, 741, and 701cm^-1

EI/MS (70eV): 308(M⁺, 1.3), 263(2.5), 217(10.6), 170(2.8), 144(base).

Anal: Calcd. for C₂₀H₂₄N₂O: C, 77.89; H, 7.84; N, 9.08. Found: C, 77.60; H, 8.00, N, 9.01.

[a]_D +4° (c = 0.400, CH₂Cl₂).

Example 10 1-Phenylmethyl-N-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxolan-5-yl]-3-indoleme thanamine

According to the general procedure described in Example 3, treatment of the crude imine derived from [4S, 5S]-2,2-dimethyl-4-phenyl-5-amino-1,3-dioxane (2.07 g, 10 mmol) and 1-phenylmethyl-1H-indole-3-carboxaldehyde (1.93 g, 8.2 mmol) with NaBH₃CN (0.21 g, 3.33 mmol) provide a crude viscous yellow-brown oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, ethyl acetate-hexanes 25:75, 500 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.31.

1H-NMR: δ = 6.95-7.40(13), 6.50(s, 1), 5.15(s, 2), 5.12(d, J = 2.2Hz, 1), 4.08(brs, 2), 3.88(dd, J = 13.8, 1.8Hz,1), 3.70(dd, J = 13.8, 0.7Hz, 1), 2.70(dd, J = 1.8, 0.7Hz, 1), 2.04(brs, 1), 1.54(s, 6).

¹³C-NMR: δ = 140.0, 137.7, 136.7, 128.6, 127.9, 127.8, 127.5, 127.0, 126.7, 126.5, 126.1, 121.5, 119.5, 118.9, 114.2, 109.4, 99.1, 63.0, 54.0, 49.8, 42.3, 29.7, 18.8.

EI/MS (70eV): 426(M⁺, 15.2), 411(12.7), 278(21.5), 262(36.4), 235(24.6), 220(base). Anal: Calcd. for C₂₈H₃₀N₂O₂: 426.2307. Found: 426.2289.

[a]_D +43° (c = 0.920, CHCl₃).

Example 11 1 -Phenylmethyl-5-methoxy-N-((S)- 1 -phenyl)ethyl-3-indolemethanamine

According to the general procedure described in Example 2, (S)-a-methylbenzyl amine (4.57 g, 37.7 mmol), 1-phenylmethyl-5-methoxy-indole-3-carboxaldehyde (2.00 g, 7.54 mmol) and NaBH₃CN (0.62 g, 9.80 mmol) provide a crude viscous, pale, yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, ethyl acetate-hexanes 40:60, 500 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.23.

1H-NMR: δ = 6.79-7.41(14), 5.21(s, 2), 3.88(q, J = 6.6Hz, 1), 3.83(s, 3), 3.78(d, J =

2.9Hz, 2), 1.65(brs, 1), 1.38(d, J = 6.6Hz, 3). ¹³C-NMR: δ = 153.8, 145.8, 137.6, 132.0, 128.6, 128.4, 128.1, 127.5, 127.1, 126.8, 126.7, 126.7, 113.9, 112.0, 110.5, 100.8, 57.8, 55.7, 50.0, 42.6, 24.5.

IR (CHCl₃): 3062, 2959, 2926, 2831, 1621, 1581, 1487, 1452, 1437, 1261, 1228, 1130, 1112, 1029, 794, 764, and 702cm^-1

EI/MS (70eV): 370(M⁺, 21.5), 265(14.3), 251(78.6), 220(14.5), 159(14.7), 132(21.6),

105(14.4), 91(base).

Anal: Calcd. for C₂₅H₂₆N₂O: C, 81.05; H, 7.07; N, 7.56. Found: C, 81.25; H, 7.20, N, 7.65.

[a]_D -23° (c = 1.079, OH₂Cl₂).

Example 12 N-[(5a, 17b)-androstan-17-yl]-1-(phenylmethyl)-1H-indole-3-methanamine

According to me general procedure described in Example 2, 17-aminoandrostane (1.55 g,

5 mmol), 1-benzyl-indole-3-carboxaldehyde (2.35 g, 10 mmol) and NaBH₃CN (0.75 g, 12 mmol) provide a crude pale yellow solid. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, CH₂Cl₂-acetone 75:25, 100 mL fractions) using the flash technique. Fractions homogenous by TLC provide fine white needles.

MP: 102-104°C

TLC (Merck; CH₂Cl₂-acetone, 75:25; UV(+); ammonium molybdate) R_f = 0.37.

¹H-NMR: δ = 7.67(d, J = 7.18Hz, 1), 7.03-7.35(9), 5.28(s, 2), 4.00(brs, 2), 2.66(t, J = 8.56Hz, 1), 2.05(m, 2), 1.85(brd, J = 12.05Hz, 1), 0.78(s, 3), 0.75(s,3), 0.60-1.70(24).

IR (nujol): 3020, 2980, 1620, 1460, and 1440cm^-1

EI/MS (70eV): 494(M⁺, 6.9), 287(5.5), 274(13.6), 220(base).

Anal: Calcd. for C₃₅H₄₆N₂: C, 84.96; H, 9.37; N, 5.66. Found: C, 84.59; H, 9.49, N, 5.65.

Example 13 5-Methoxy-N-((R)-1-phenyl)ethyl-3-indolememanamine

According to the general procedure described in Example 2, (R)-a-methylbenzyl amine

(3.64 g, 30 mmol), 5-methoxy-indole-3-carboxaldehyde (1.75 g, 10 mmol) and NaBH₃CN (0.82 g, 13 mmol) provide a crude pale yellow solid. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide fine white needles.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.21.

¹H-NMR: δ = 8.25(brs, 1), 6.81-7.42(9), 3.89(q, J = 6.6Hz, 1), 3.82(s, 3), 3.79(d, J = 1.6 Hz, 2), 1.65(brs, 1), 1.38(d, J = 6.6Hz, 3).

¹³C-NMR: δ = 153.7, 145.5, 131.2, 128.2, 127.2, 126.7, 126.5, 123.0, 114.5, 112.0, 111.7, 100.4, 57.5, 55.6, 42.4, 24.2.

IR (nujol): 3133, 3064, 3037, 2958, 2936, 1626, 1590, 1493, 1480, 1569, 1451, 1370, 1350, 1263, 1217, 1174, 1115, 1059, 935, 826, 815, 786, 764, and 710cm^-1 EI/MS (70eV): 280(M⁺, 11.6), 175(12.2), 161(48.8), 160(base).

Anal: Calcd. for C₂₅H₂₆N₂O: C, 77.11; H, 7.19; N, 9.99. Found: C, 76.83; H, 7.32; N, 9.92.

[a]_D +29° (c = 0.881, CHCl₃).

Example 14 1-Phenylmethyl-5-methoxy-N-((R)-1-phenyl)ethyl-3-indolememanamine

According to the general procedure described in Example 2, (R)-a-methylbenzyl amine (3.64 g, 30 mmol), 1-phenylmethyl-5-methoxy-indole-3-carboxaldehyde (2.00 g, 7.5 mmol) and NaBH₃CN (0.61 g, 9.8 mmol) provide a crude viscous, yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate) R_f = 0.39.

1H-NMR: δ = 6.79-7.41(14), 5.20(s, 2), 5.07(s, 2), 3.88(q, J = 6.6Hz, 1), 3.82(s, 3), 3.77(d, J = 2.8Hz, 2), 1.61(brs, 1),1.37(d, J = 6.6Hz, 3).

1³C-NMR: δ = 153.7, 145.7, 137.5, 131.9, 128.5, 128.3, 127.9, 127.54, 127.0, 126.7,

126.6, 113.7, 111.9, 110.4, 100.7, 57.7, 55.7, 49.9, 42.5, 24.4.

IR (CHCl₃): 3062, 3028, 2960, 2925, 2831, 1621, 1580, 1488, 1452, 1437, 1355, 1304, 1261, 1227, 1178, 1112, 1042, 1029, 898, 794, 764, and 702cm^-1

EI/MS (70eV): 370(M⁺, 21.5), 265(14.2), 251(72.2), 220(11.8), 159(12.5), 132(22.0), 105(13.4), 91(base).

Anal: Calcd. for C₂₅H₂₆N₂O: C, 81.05; H, 7.07; N, 7.56. Found: C, 80.68; H, 7.12, N, 7.66.

[a]_D +25° (c = 1.039, CH₂Cl₂).

Example 15 5-Methoxy-N-((S)-1-phenyl)ethyl-3-indolemethanamine

According to the general procedure described in Example 2, (S)-a-methylbenzyl amine

(3.64 g, 30 mmol), 5-methoxy-indole-3-carboxaldehyde (1.75 g, 10 mmol) and NaBH₃CN (0.82 g, 13 mmol) provide a crude a pale yellow solid. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide an off-white solid which is recrystallized from EtOAc/hexanes to furnish fine white needles.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); .ammonium molybdate) R_f = 0.27.

MP: 113-115°C.

¹H-NMR: δ = 8.21(brs, 1), 6.81-7.43(9), 3.89(q, J = 6.6Hz, 1), 3.82(s, 3), 3.78(d, J = 1.0Hz, 2), 1.70(brs, 1), 1.38(d, J = 6.6Hz, 3).

1³C-NMR: δ = 154.0, 145.8, 131.5, 128.5, 127.5, 126.9, 126.8, 125.2, 123.3, 114.8,

112.3, 111.9, 100.6, 57.8, 55.9, 42.6, 24.4. IR (nujol): 3133, 3064, 3037, 2958, 2936, 1626, 1590, 1493, 1480, 1569, 1451, 1370, 1350, 1263, 1217, 1174, 1115, 1059, 935, 826, 815, 786, 764, and 710cm^-1

EI/MS (70eV): 280(M⁺, 9.3), 175(13.6), 161(48.7), 160(base).

Anal: Calcd. for C₂₅H₂₆N₂O: 280.1564. Found: 280.1576.

[a]_D -29° (c = 0.691, CH₂Cl₂).

Example 16 1-Phenylmethyl-5-methoxy-N-1-(3-trifluoromethylphenyl)ethyl-3-indole- methanamine

According to the genera procedure described in Example 2, (+/-)-(m-trifluoro- methyl)-α-methyl-benzyl amine (2.83 g, 15 mmol), 5-methoxy-N-benzyl indole-3-carbox- aldehyde (1.99 g, 7.5 mmol) and NaBH₃CN (0.20 g, 3.05 mmol) provide a crude oily yellow solid. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 350 g, 70 mm OD, ethyl acetate-hexanes 30:70, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.33. 1H-NMR: δ = 7.05-7.70(10), 7.03(d, J = 2.4Hz, 1), 6.99(s,1), 6.83(dd, J = 8.87,

2.4Hz, 1), 5.23(s, 2), 3.95(q, J = 6.58Hz, 1), 3.84(s, 3), 3.80(d, J = 13.1Hz, 1), 3.75(d, J = 13.1Hz, 1), 1.38(d, J = 6.58Hz, 3).

¹³C-NMR: δ = 154.0, 137.6, 132.1, 130.0, 128.9, 128.7, 127.9, 127.6, 127.2, 126.8,

123.7, 123.4, 112.2, 110.6, 100.8, 57.6, 55.8, 50.1, 42.8, 24.6.

IR (neat): 2962, 2931, 2907, 2852, 1660, 1621, 1581, 1488, 1453, 1438, 1328, 1261, 1229, 1206, 1165, 1123, 1071, 803, and 705cm^-1.

EI/MS (70eV): 438(M⁺, 22.7), 265(10.2), 251(59.7), 250(57.6), 238(7.7), 220(12.5), 200(21.7), 159(7.5), 91(base).

Anal: Calcd. for C₂₆H₂₅F₃ N₂O: 438.1919. Found: 438.1900.

Example 17 1-Phenylmethyl-5-methoxy-N-phenylmethyl-3-indolemethanamine

According to the general procedure for Example 2, benzylamine (3.21 g, 30 mmol), 5-memoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde (2.65 g, 10 mmol), and NaBH₃CN (0.82 g, 30 mmol) provide the crude amine as a pale yellow liquid which is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, packed ethyl acetate-hexanes 40:60, eluted ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.13. 1H-NMR: δ = 7.37-7.02(13), 6.84-6.80(1), 5.19(s, 2), 4.05(s, 2) 3.88(s, 2), 3.82(s, 3), 1.76(brs, 1).

1³C-NMR: δ = 153.9, 140.5, 137.6, 132.0, 128.7, 128.3, 128.2, 128.1, 127.5, 127.2,

126.8, 126.7, 113.6, 112.0, 110.5, 100.9, 55.8, 53.3, 50.0, 44.0. IR (neat): 3028, 2935, 2918, 2830, 1621, 1605, 1580, 1487, 1452, 1437, 1356, 1262, 1229, 1177, 1109, 1042, 1029, 833, 794, 778, 736, 700cm^-1.

EI/MS (70eV): 356(M⁺, 23.5), 251(49.6), 220(11.4), 160(6.8), 119(15.8), 91(base). Anal: Calcd. for C₂₄H₂₄N₂O: C, 80.87; H, 6.79; N, 7.86. Found: C, 80.79; H, 6.89; N, 8.25.

Example 18 1-Phenylmethyl-5-methoxy-N-((+/-)-1-phenyl)ethyl-3-indolememanamine

According to the general procedure described in Example 2, (+/-)-α-methylbenzyl amine (2.74 g, 22.6 mmol), 1-benzyl-5-methoxy-indole-3-carboxaldehyde (2.00 g, 7.54 mmol) and NaBH₃CN (0.62 g, 9.80 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, packed EtOAc-hexanes 40:60, eluted ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique. Fractions homologous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.30. 1H-NMR: δ = 7.42-6.79(14), 5.19(s, 2), 3.88(q, J=6.6, 1), 3.82(s, 3), 3.77(d, J=2.9, 2), 1.63(brs, 1), 1.37(d, J=6.6, 1).

¹³C-NMR: δ = 153.8, 145.8, 137.6, 132.0, 128.6, 128.4, 128.0, 127.5, 127.1, 126.8, 126.7(2), 113.8, 112.0, 110.5, 100.8, 57.8, 55.8, 50.0, 42.6, 24.5.

IR (neat): 3028, 2959, 1605, 1580, 1488, 1452, 1437, 1355, 1261, 1228, 1178, 1129, 1112, 1042, 1029, 898, 764, 735, 702cm^-1.

EI/MS (70eV): 370(M⁺, 14.3), 265(12.7), 250(52.8), 159(13.4), 132(18.8), 105(14.8), 91(base).

Anal: Calcd. for C₂₅H₂₆N₂O: C, 81.05; H, 7.07; N, 7.56. Found: C, 80.80; H, 7.34,

N, 7.62.

Example 19 1-Phenylmethyl-5-methoxy-N-(3-trifluoromethyl-phenyl)methyl-3-indole- meth anamine

According to the general procedure described in Example 2, 3-trifluoromethyl- benzyl amine (5.25 g, 30 mmol), 5-methoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde (2.65 g, 10 mmol) and NaBH₃CN (0.82 g, 13 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, packed EtOAc-hexanes 30:70, eluted ethyl acetate-hexanes 40:60 (2 L), 50:50, 400 mL fractions) using the flash technique. Fractions homologous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.24.

1H-NMR: δ = 7.66-6.81(13), 5.19(s, 2), 3.95(s, 2) 3.89(s, 2), 3.83 (s, 3), 1.64(brs, 1). 1³C-NMR: δ = 154.0, 141.6, 137.5, 132.1, 131.5, 128.7, 128.0, 127.5, 127.3, 126.7, 124.8, 123.6(2), 113.3, 112.1, 110.6, 100.9, 55.7, 52.7, 50.0, 44.2.

IR (neat): 3065, 3032, 1621, 1597, 1488, 1452, 1438, 1329, 1315, 1262, 1230, 1203, 1193, 1165, 1123, 1072, 1043, 796, 735, 703cm^-1.

EI/MS (70eV): 424(M⁺, 5.7), 250(23.2), 238(4.6), 220(5.5), 186(4.5), 159(17.0), 91(base).

Anal: Calcd. for C₂₅H₂₃F₃N₂O: C, 70.74; H, 5.46; N, 6.60. Found: C, 70.79; H, 5.23; N, 6.92.

Example 20 1-Phenylmethyl-5-methoxy-N-(3-trifluoromethyl-phenyl)methyl-3-indole- methanammonium chloride

A solution of the compound of Example 19 (1.00 g, 2.36 mmol) in Et₂O (50 mL), cooled in a dry ice-CCl₄ bath under N₂, is treated with HCl gas for 15 minutes, forming a pale purple precipitate. The solid material is isolated by filtration, washed with Et₂O (50 mL), and recrystallized from Et₂O-MeOH to provide a fine white powdery solid.

MP: 201-204°C (dec.)

¹H-NMR (DMSO-d₆): δ = 7.63-7.99(5), 7.20-7.38(6), 6.79(dd, J = 8.84, 2.40, 1), 5.41(s, 2), 4.33(s, 2), 4.29(s, 2), 3.79(s,3).

Anal: Calcd. for C₂₅H₂₄ClF₃N₂O: C, 65.15; H, 5.25; N, 6.08. Found: C, 65.37; H,

5.34; N, 6.23.

Example 21 1-Phenylmethyl-5-methoxy-N-2-furylmethyl-3-indolemethanamine

According to the general procedure described in Example 2, furfurylamine (2.91 g, 30 mmol), 5-methoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde (2.65 g, 10 mmol) and NaBH₃CN (0.82 g, 13 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, packed and eluted ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.18. 1H-NMR: δ = 7.37-7.05(9), 6.84-6.80(1), 6.33-6.31(1), 6.20(d, J=3.2, 1), 5.22(s, 2),

3.94(s, 2), 3.85(s, 2), 3.84(s, 3), 1.72(brs, 1).

¹³C-NMR: δ = 154.0, 153.9, 141.6, 137.5, 132.0, 128.6, 127.5, 127.3, 126.7, 113.0, 112.0, 110.5, 110.0, 106.8, 100.8, 55.8, 50.0, 45.4, 43.6.

IR (neat): 3031, 2936, 2831, 1621, 1580, 1488, 1452, 1438, 1355, 1261, 1226, 1177, 1147, 1109, 1042, 1029, 1009, 795, 780, 736, 704cm^-1.

EI/MS (70eV): 346(M⁺, 10.5), 250(24.4), 220(6.4), 159(6.9), 109(41.3), 91(base). Anal: Calcd. for C₂₂H₂₂N₂O₂: 346.1681. Found: 346.1683.

Example 22 1-Phenylmethyl-5-methoxy-N-(3-methyl-phenyl)methyl-3-indole-methanamine

According to the general procedure described in Example 2, 3-memyl benzyl amine (0.91 g, 7.54 mmol), 5-methoxy-1-phenylmethyl-1H-indoIe-3-carboxaldehyde (2.00 g, 7.54 mmol), and

NaBH₃CN (0.62 g, 9.80 mmol) afford the crude amine as a pale yellow liquid which is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed with ethyl acetate-hexanes 25:75, eluted with an ethyl acetate-hexanes gradient of 30:70 to 60:40, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.12.

¹H-NMR: δ = 7.29-6.80(13), 5.20(s, 2), 3.95(s, 2), 3.83(s, 2), 3.82(s, 3), 2.33(s, 3), 1.64(brs, 1).

¹³C-NMR: δ = 153.9, 140.5, 137.9, 137.6, 132.1, 129.0, 128.7, 128.2, 128.1, 127.6, 127.5, 127.2, 126.7, 125.2, 113.7, 112.0, 110.5, 100.9, 55.8, 53.4, 50.1, 44.1, 21.4.

IR (neat): 3030, 2932, 2917, 1620, 1607, 1580, 1487, 1452, 1437, 1262, 1229, 1177, 1042, 793, 778, 736, 701cm^-1.

EI/MS (70eV): 370(M⁺, 34.0), 251(72.8), 220(16.8), 160(8.9), 133(18.9), 105(18.4), 91(base).

Anal: Calcd. for C₂₅H₂₆ N₂O: C, 81.05; H, 7.07; N, 7.56. Found: C, 80.69; H, 7.41; N, 7.71.

Example 23 1-Phenylmethyl-5-methoxy-N-(4-methoxyphenyl)methyl-3-indole-methanamine

According to the general procedure described in Example 2, p -methoxybenzyl amine (2.74 g, 22.6 mmol), 1-benzyl-5-methoxy-indole-3-carboxaldehyde (2.00 g, 7.54 mmol) and NaBH₃CN (0.62 g, 9.80 mmol) provided a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 450 g, 70 mm OD, packed EtOAc-hexanes 40:60, eluted ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.30.

1H-NMR: δ = 7.42-6.79(14), 5.19(s, 2), 3.88(q, J=6.6, 1), 3.82(s, 3), 3.77(d, J=2.9, 2), 1.63(brs, 1), 1.37(d, J=6.6, 1).

¹³C-NMR: δ = 153.8, 145.8, 137.6, 132.0, 128.6, 128.4, 128.0, 127.5, 127.1, 126.8, 126.7(2), 113.8, 112.0, 110.5, 100.8, 57.8, 55.8, 50.0, 42.6, 24.5.

IR (neat): 3028, 2959, 1605, 1580, 1488, 1452, 1437, 1355, 1261, 1228, 1178, 1129, 1112, 1042, 1029, 898, 764, 735, 702cm^-1.

EI/MS (70eV): 370(M⁺, 14.3), 265(12.7), 250(52.8), 159(13.4), 132(18.8), 105(14.8),

91(base).

Anal: Calcd. for C₂₅H₂₃ N₂O: C, 81.05; H, 7.07; N, 7.56. Found: C, 80.80; H, 7.34, N, 7.62.

Example 24 1 -Phenylmethyl-5-methoxy-N-(4-trifluoromethylphenyl)methyl-3- indolemethanamine

According to the general procedure described in Example 3, p-trifluoromethyl benzyl amine (1.32 g, 7.54 mmol), 1-benzyl-5-methoxy-indole-3-carboxaldehyde (2.00 g, 7.54 mmol) and NaBH₃CN (0.62 g, 9.80 mmol) provided a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed EtOAc-hexanes 30:70, eluted ethyl acetate-hexanes 30:70 (2 L), 40:60 (2 L), then 50:50, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 65:35; UV(+); ammonium molybdate): R_f = 0.27.

¹H-NMR: δ = 7.58-6.82(13), 5.22(s, 2), 3.95(s, 2), 3.91(s, 2), 3.83(s, 3), 1.67(brs, 1).

¹³C-NMR: δ = 154.0, 144.8, 137.6, 132.1, 128.7, 128.4, 128.1, 127.6, 127.3, 126.8, 125.3, 125.2, 113.4, 112.1, 110.6, 101.0, 55.9, 52.7, 50.1, 44.2.

IR (neat): 2936, 2832, 1619, 1581, 1488, 1453, 1438, 1327, 1230, 1164, 1121, 1067, 1043, 1018, 795, 733, 703cm^-1.

EI/MS (70eV): 424(M⁺, 14.1), 250(37.8), 238(10.8), 220(10.0), 187(5.7), 159(13.1), 91(base).

Anal: Calcd. for C₂₅H₂₃F₃N₂O: C, 70.74; H, 5.46; N, 6.60. Found: C, 70.72; H, 5.71;

N, 6.57.

Example 25 5-Methoxy-N-(3-trifluoromethyl-phenyl)methyl-3-indolemethanamine

According to the general procedure described in Example 3, 3-trifluoromethyl- benzyl amine (5.00 g, 28.5 mmol), 5-methoxy-indole-3-carboxaldehyde (5.00 g, 28.5 mmol) and NaBH₃CN (2.33 g, 937.1 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed EtOAc-hexanes 40:60, eluted ethyl acetate-hexanes 40:60 (2L), ethyl acetate-hexanes 50:50 (4L), ethyl acetate-hexanes 60:40 (8L), 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a tan solid which is recrystallized from Et₂O-hexanes to furnish tan needles.

MP: 74-76°C.

TLC (Merck; EtOAc-hexanes, 65:35; UV(+); ammonium molybdate): R_f = 0.23.

¹H-NMR: δ = 8.08(brs, 1), 7.66(s, 1), 7.52(m, 1), 7.42(t, J = 7.51Hz, 1), 7.23(d, J = 8.78Hz, 1), 7.09(dd, J = 5.92, 2.43Hz, 1), 6.86(dd, J = 8.78, 2.43Hz, 1), 3.97(s, 2), 3.92(s, 2), 3.85(s, 3)1.63(brs, 1).

¹³C-NMR: δ = 154.0, 141.8, 131.5, 130.9, 128.7, 127.5, 124.9, 123.7, 123.4, 114.5, 112.5, 111.9, 100.7, 55.8, 52.8, 44.3.

IR (nujol): 3287, 3153, 3048, 1586, 1451, 1327, 1246, 1217, 1209, 1194, 1174, 1122, 905, 843, 803, and 701cm^-1.

EI/MS (70eV): 334(M⁺, 24.4), 203(4.4), 186(7.7), 174(17.0), 160(base).

Anal: Calcd. for C₁₈H₁₇F₃N₂O: C, 64.66; H, 5.13; N, 8.38. Found: C, 64.42; H, 5.28, N, 8.34.

Example 26 N,N-(Dimethyl)-1-phenylmethyl-1H-indole-3-methanammonium chloride

To N,N-(dimethyl)-1-phenylmemyl-1H-indole-3-methanamine (1.60 g, 6.06 mmol) in Et₂O

(0.15 L) is added dry MeOH (6 mL) followed by the addition of a solution of HCl in Et₂O (3.1M, 2.54 mL, 7.88 mmol). The resulting white precipitate and clear supernatant solution are chilled in and ice-water bath, then the white solid is isolated by filtration. The crude salt is purified by recrystallization from EtOAc-MeOH to give a fine white powder.

MP: 219-221 °C (dec.).

EI/MS (70eV): 264(M⁺-HCl, 13.2), 220(59.5), 91(base).

Anal: Calcd. for C₁₈H₂₀C;N₂: C, 72.00; H, 7.00; N, 9.33. Found: C, 71.92; H, 7.28;

N, 9.39.

Example 27 1-Phenylmethyl-5-methoxy-N-[(R)-1-phenyl-2-hydroxyethyl]-3-indole-methanamine According to the general procedure described in Example 2, (R)-phenylglycinol (6.17 g, 45 mmol), 5-methoxy-N-benzyl indole-3-carboxaldehyde (5.30 g, 20 mmol) and NaBH₃CN (0.63 g, 10 mmol) provide a crude clear, tan solid. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, packed CH₂Cl₂, eluted CH₂Cl₂-MeOH 95:5, 500 mL fractions) using the flash technique. Fractions homogenous by TLC provide the target amine as a clear, pale yellow glassy solid which is recrystallized from hexanes-CH₂Cl₂ to furnish light tan needles.

MP: 95.1-95.5°C.

TLC (Merck; CH₂Cl₂-MeOH 90:10; UV(+); ammonium molybdate): R_f = 0.44.

1H-NMR: δ = 6.90-7.45(13), 6.81(dd, J = 6.67, 2.13Hz, 1), 5.22(d, J = 21.2Hz, 1), 5.15(d, J = 21.2Hz, 1), 3.45-3.95(5), 3.80(s, 3), 2.39(brs, 2).

¹³C-NMR: δ = 153.9, 140.7, 137.5, 131.9, 128.6, 128.5, 127.9, 127.5, 127.2, 126.7, 113.3, 112.1, 110.5, 100.7, 66.6, 55.7, 50.0, 42.2.

IR (nujol): 3478, 3287, 3149, 3103, 3056, 1620, 1539, 1492, 1464, 1453, 1436, 1377, 1312, 1231, 1117, 1053, 1039, 1028, 998, 898, 837, 796, and 705cm^-1.

EI/MS (70eV): 386(M⁺, 4.4), 355(4.4), 250(base), 91(41.6).

Anal: Calcd. for C₂₅H₂₆ N₂O₂: 386.1994. Found: 4386.1987.

[a]_D -51° (c = 0.522, CH₂Cl₂).

Example 28 1-(2-Propenyl)-5-methoxy-indole-N-(3-trifluoromethylphenyl)methyl-3- indolemethanamine

According to the general procedure described in Example 2, amine (5.13 g, 29.3 mmol),

5-methoxy-N-allyl indole-3-carboxaldehyde (2.10 g, 9.76 mmol) and NaBH₃CN (0.80 g, 12.7 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed and eluted ethyl acetate-hexanes 40:60, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.21.

¹H-NMR: δ =7.66-6.85(8), 5.94(m, 1), 5.18-5.03(2), 4.62(m, 2), 3.94(s, 2), 3.90(s, 2), 3.84(s, 3).

¹³C-NMR: δ = 153.9, 141.7, 133.5, 131.8, 131.5, 128.6, 127.9, 126.8, 124.8, 124.7, 123.6(2), 117.1, 113.1, 112.0, 110.4, 100.8, 55.7, 52.7, 48.8, 44.2.

IR (neat): 2917, 2833, 1620, 1580, 1488, 1453, 1439, 1329, 1315, 1263, 1231, 1212, 1192, 1164, 1123, 1094, 1072, 1041, 796, 703cm^-1.

EI/MS (70eV): 374(M⁺, 30.1), 214(5.6), 200(base).

Anal: Calcd. for C₂₁H₂₁F₃N₂O : 374.1606. Found: 374.1602.

Example 29 1-Phenylmethyl-5-memoxy-N-[(S)-1-phenyl-2-hydroxyethyl]-3-indolemethanamine

According to the general procedure described in Example 2, (S)-phenylglycinol

(1.71 g, 12.5 mmol), 5-methoxy-N-benzyl indole-3-carboxaldehyde (1.33 g, 5 mmol) and NaBH₃CN (0.16 g, 2.5 mmol) provide a crude brown solid. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 200 g, 70 mm OD, packed CH₂Cl₂, eluted CH₂Cl₂-MeOH 95:5, 100 mL fractions) using the flash technique. Fractions homogenous by TLC provide the target amine as a clear, pale tan glassy solid which is recrystallized from hexanes-CH₂Cl₂ to furnish a light tan solid.

MP: 91.5-92.0°C.

TLC (Merck; EtOAc-hexanes 50:50; UV(+); ammonium molybdate): R_f = 0.11.

¹H-NMR: δ = 6.90-7.45(13), 6.80(dd, J = 6.67, 2.13Hz, 1), 5.23(d, J = 21.2Hz, 1), 5.17(d, J = 21.2Hz,1), 3.45-3.95(5), 3.79(s, 3), 2.40(brs, 2).

¹³C-NMR: δ = 153.8, 140.7, 137.5, 132.0 128.6, 128.4, 128.0 127.5, 127.3, 126.7, 113.3, 112.1, 110.5, 100.8, 66.6, 55.7, 50.1, 42.2.

IR (nujol): 3478, 3287, 3103, 3056, 3029, 3006, 1620, 1538, 1492, 1453, 1436, 1366, 1236, 1117, 1040, 837, 795, and 705cm^-1.

EI/MS (70eV): 386(M⁺, 4.4), 355(4.4), 250(base), 91(41.6).

Anal: Calcd. for C₂₅H₂₆ N₂O₂: 386.1994. Found: 4386.1995.

[a]_D +47° ( c = 0.304, CH₂Cl₂).

Example 30 1-Phenylmethyl-5-methoxy-N-2-pyrimidinyI-3-indolemethanamine

According to the general procedure described in Example 2, 2-aminopyrimidine (2.15 g,

22.6 mmol), 1-benzyl-5-methoxy-indole-3-carboxaldehyde (2.00 g, 7.54 mmol) and NaBH₃CN

(0.62 g, 9.80 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed CH₂Cl₂, eluted CH₃OH/CH₂Cl₂5:95, 400 mL fractions) using the flash technique which produces a clear, pale yellow, viscous oil which crystallized upon standing. An analytical sample is obtained by recrystallization from EtOAc/hexanes to provide a white solid.

MP: 136-138°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.22. 1H-NMR: δ = 8.27(brs, 2), 7.29-7.25(3), 7.13-7.10 (5), 6.83(dd, J=8.9, 2.4, 1), 6.51(t,

J=4.8, 1), 5.51(brs, 1), 5.24(s, 2), 4.73(d, J=5.1, 2), 3.80(s, 3).

¹³C-NMR: δ = 162.3, 157.9, 153.6, 137.4, 131.8, 128.7, 127.6, 127.5, 127.3, 126.7, 112.4, 112.2, 110.6, 110.4, 100.8, 55.7, 50.1, 37.1.

IR (nujol): 3259, 1602, 1580, 1540, 1487, 1442, 1435, 1415, 1365, 1337, 1262, 1240, 1226, 1042, 795, 708, 701cm^-1.

EI/MS (70eV): 344(M⁺, 55.0), 253(16.9), 250(50.9), 148(8.3), 91(base).

Anal: Calcd. for C₂₁H₂₀ N₄O: C, 73.23; H, 5.85; N, 16.27. Found: C, 72.92; H, 6.03; N, 16.54.

Example 31 5-Methoxy-6-methyl-1-phenylmethyl-N-(3-trifluoromethyl-phenyl)methyl-3-indole- methanamine

According to the general procedure described in Example 2, 3-trifluoromethyl-benzyl 3-trifluoromethylbenzyl amine (3.76 g, 21.5 mmol), 1-benzyl-5-methoxy-6-methyl-indole-3- carboxaldehyde (2.00 g, 7.16 mmol) and NaBH₃CN (0.58 g, 9.31 mmol) provides crude a pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed EtOAc-hexanes 30:70, eluted EtOAc-hexanes 40:60, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.26.

1H-NMR: δ = 7.66(s, 1), 7.37-7.54(s), 7.25(m, 3), 7.02-7.09(5), 6.94(s, 1), 5.20(s, 2), 3.95(s, 2), 3.90(s, 2), 3.86(s, 3), 2.29(s, 3), 1.60(brs, 1).

¹³C-NMR: δ = 152.7, 141.7, 137.8, 131.7, 131.4, 131.0, 130.7, 128.6, 126.6, 126.4, 125.9, 124.7, 123.6, 122.7, 113.3, 111.1, 99.1, 55.6, 52.7, 49.8, 44.3, 17.2.

IR (neat): 2938, 2917, 2832, 1628, 1605, 1597, 1552, 1497, 1479, 1464, 1453, 1435, 1356, 1329, 1252, 1239, 1204, 1164, 1123, 1091, 1072, 1045, 848, 840, 800, and 702cm^-1.

EI/MS (70eV): 438(M⁺, 30.1), 264(58.6), 252(15.9), 234(10.2), 187(9.5), 174(6.7),

159(9.4), 91 (base).

Anal: Calcd. for C₂₆H₂₅F₃N₂O: 438.1919. Found: 438.1916.

Example 32 5,6-Methylenedioxy-1-phenylmethyl-N-(3-trifluoromethylphenyl)methyl-3-indole methanamine

According to the general procedure described in Example 2, 3-trifluorometiιyl- benzyl amine (3.94 g, 22.5 mmol), 5,6-methylenedioxy-1-phenylmethyl-1H-indole-3- carboxaldehyde (2.09 g, 7.50 mmol) and NaBH₃CN (0.61 g, 9.75 mmol) provides a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed EtOAc-hexanes 25:75, eluted EtOAc-hexanes 25:75, 2.0L, 30:70, 2.0L, 40:60, 4.0L, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.22. 1H-NMR: δ = 7.21-7.62(7), 6.93-7.09(4), 6.68(s, 1), 5.88(s, 2), 5.16(s, 2), 3.90(d, J = 2.6Hz, 3), 1.57(brs, 1).

¹³C-NMR: δ = 144.9, 142.7, 141.5, 137.3, 131.8, 131.4, 128.7, 127.5, 126.6, 125.3, 124.8, 123.6, 121.6, 113.9, 100.5, 97.8, 90.9, 52.8, 50.2, 44.3.

IR (neat): 2874, 1606, 1503, 1497, 1469, 1454, 1356, 1329, 1243, 1192, 1164, 1123, 1085, 1073, 1038, 942, 833, and 702cm^-1.

EI/MS (70eV): 438(M⁺, 27.2), 265(98.0), 91(base).

Anal: Calcd. for C₂₅H₂₁F₃N₂O ₂: C , 68.49; H, 4.83; N, 6.39. Found: C, 68.21; H, 5.16; N, 6.44.

Example 33 5,6-Dimethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-indole- methanamine

According to the general procedure described in Example 2, 3-trifluoromethyl- benzyl amine (1.05 g, 12.5 mmol), 5,6-dimethoxy-1-phenylmethyl-1H-indole-3-carboxaldehyde (1.48 g, 5 mmol) and NaBH₃CN (0.16 g, 2.5 mmol) provided a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 100 g, hexanes-CH₂Cl₂-EtOAc, 25:25:50, 100 mL fractions). Fractions homogenous by TLC provide a pale yellow oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.11. 1H-NMR: δ = 7.66(brs, 1), 7.10-7.60(8), 6.93(s, 1), 6.71(s, 1), 5.22(s, 2), 3.95(s, 2),

3.92(s, 3), 3.84(s, 3).

¹³C-NMR: δ = 147.0, 144.8, 141.6, 137.4, 131.4, 131.1, 128.7, 128.6, 127.5, 126.6, 125.0, 124.7, 123.5, 120.3, 113.5, 100.9, 93.4, 56.2, 56.1, 52.7, 49.9, 44.3.

IR (CHCl₃): 2910, 1555, 1489, 1453, 1329, 1256, 1072, and 703cm^-1.

EI/MS (70eV): 454(M⁺, 43.8), 281(93.0), 91(base).

Anal: Calcd. for C₂₆H₂₅F₃N₂O ₂: C, 68.71; H, 5.54; N, 6.16. Found: C, 68.48; H, 5.76; N, 6.13.

Example 34 6-Chloro-5-methoxy-1-phenylmethyl-N-((4-carbomethoxy)phenylmethyl)-3-indole- methanamine

According to the general procedure described in Example 2, 4-carbomethoxy- benzyl amine

(1.65 g, 10 mmol), 6-chloro-5-methoxy-1-phenylmethyl-indole-4-carbox-aldehyde (1.00 g, 3.33 mmol) and NaBH₃CN (0.11 g, 1.75 mmol) provide a crude oily yellow solid. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 350 g, 70 mm OD, CH₂Cl₂-CH₃OH, 95:5, 300 mL fractions). Fractions homogenous by TLC provide a viscous, clear yellow oil which slowly solidifies. The solid is recrystallized from hexanes-CH₂Cl₂ to give pale yellow prisms.

MP: 88-90°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.08.

¹H-NMR: δ = 8.00(d, J = 8.27Hz, 2), 7.43(d, J = 8.27Hz, 2), 7.30(m, 4), 7.08(m, 2), 7.03(s, 1), 5.20(s, 2), 3.94(s, 2), 3.93(s, 2), 3.91(s, 3), 1,65(brs, 1).

1³C-NMR: δ = 166.9, 149.2, 145.8, 137.0, 131.6, 129.6, 128.7, 127.9, 127.6, 127.4,

126.6, 118.5, 113.6, 111.2, 101.5, 56.6, 52.8, 51.9, 50.1, 44.0.

IR (nujol): 1706, 1481, 1444, 1285, 1254, 1238, 1115, and 706cm^-1.

EI/MS (70eV): 448(M⁺, 24.5), 285(60.6), 254(9.3), 177(18.5), 149(8.2), 118(7.1 (base).

Anal: Calcd. for C₂₆H₂₅ClN₂O₃: C, 69 56; H, 5.61; N, 6.24. Found: C, 69.21; H, 5.67; ; N, 6.27.

Example 35 6-Fluoro-5-methoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3- indolemethanamine

According to the general procedure described in Example 2, 3-trifluoromethyl- benzyl amine (2.63 g, 15 mmol), 6-fluoro-5-methoxy-1-phenylmethyl-indole-3-carboxaldehyde (0.85 g, 3 mmol) and NaBH₃CN (0.38 g, 6 mmol) provided a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, hexanes-EtOAc, 50:50, 40 mL fractions). Fractions homogenous by TLC provide a pale yellow solid.

MP: 72-73°C.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.29.

1H-NMR: δ = 6.95-7.66(12), 5.19(s, 2), 3.95(s, 2), 3.92(s, 5).

IR (nujol): 3340, 1587, and 1556cm^-1.

EI/MS (70eV): 442(M⁺, 14.3), 269(36.2), 268(31.5), 91(base).

Anal: Calcd. for C₂₅H₂₂F₄N₂O : C, 67.87; H, 5.01; F, 17.18; N, 6.33. Found: C, 67.80; H, 5.22; F, 16.81; N, 6.26.

Example 36 6-Chloro-5-memoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-indo- lemethanamine

According to the general procedure described in Example 3, 3-trifluoromethyl- benzyl amine (7.00 g, 40 mmol), 6-chloro-5-methoxy-1-phenylmethyl-indole-3-carboxaldehyde (2.99 g, 10 mmol) and NaBH₃CN (0.314 g, 5.0 mmol) provided a crude a yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, EtOAc-hexanes, 45:55, 400 mL fractions). Fractions homogenous by TLC provide a viscous, clear yellow oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.22. 1H-NMR: δ = 7.66(s, 1), 7.51(t, J = 7.60Hz, 2), 7.41(t, J = 7.60Hz, 1), 7.27(m, 4), 7.17(s, 1), 7.06(m, 2), 7.01(s, 1), 5.16(s, 2), 3.93(s, 2), 3.91(s, 3), 3.89(s, 2), 1.62(brs, 1).

1³C-NMR: δ = 149.3, 141.5, 137.0, 131.6, 131.4, 130.8, 128.7, 127.7, 127.4, 126.9,

126.0, 124.7, 123.7, 123.6, 118.5, 113.6, 111.2, 101.6, 56.5, 52.7, 50.0, 44.2.

IR (neat): 3336, 2939, 2925, 1480, 1452, 1328, 1242, 1164, 1123, 1072, and 702cm^-1. EI/MS (70eV): 458(M⁺, 16.5), 285(26.7), 254(5.0), 187(9.3), 159(12.2), 91(base). Anal: Calcd. for C₂₅H₂₂FCI₃N₂O : C, 65.43; H, 4.83; N, 6.10. Found: C, 65.41; H, 5.06; N, 6.10.

Example 37 6-Fluoro-5-memoxy-1-phenylmethyl-N-((4-methoxy)phenyl)methyl-3-indolemeth- anamine

According to the general procedure described in Example 3, 4-methoxybenzyl amine (0.99 g, 7.2 mmol), 6-fluoro-5-methoxy-1-phenylmethyl-indole-3-carbox- aldehyde (0.85 g, 3 mmol) and NaBH₃CN (0.38 g, 6 mmol) provided a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, hexanes-acetone, 80:20, 40 mL fractions). Fractions homogenous by TLC provide a pale yellow oil.

TLC (Merck; EtOAc-hexanes, 25:75; UV(+); ammonium molybdate): R_f = 0.21. 1H-NMR: δ = 6.84-7.30(12), 5.17(s, 2), 3.99(s, 2), 3.92(s, 3), 3.83(s, 2), 3.75(s, 3). IR (nujol): 1668, 1614, and 1586cm^-1.

EI/MS (70eV): 404(M⁺, 4.1), 269(57.1, 91(base).

Anal: Calcd. for C₂₅H₂₂F₄N₂O: 404.1900. Found: 404.1890.

Example 38 5-Ethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmemyl)-3-1H- indolemethanammonium chloride

To 5-methylthio-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H- indolemethanamine (1.54 g, 3.52 mmol) in Et₂O (0.13 L) is added a solution of HCl in Et₂O (3.1M, 1.47 mL, 4.57 mmol). The resulting white precipitate and clear supernatant solution are chilled in and ice-water bath, men the white solid is isolated by filtration. The crude salt is purified by recrystallbation from EtOAc-MeOH to give a fine white powder.

MP: 171-172ºC (dec.).

EI/MS (70eV): 438(M⁺-HCl, 27.6), 265(36.0), 264(46.6), 91(base).

Anal: Calcd. for C₂₆H₂₆F₃ClN₂O: C, 65.82; H, 5.49; N, 5.91. Found: C, 65.55; H, 5.81; N, 5.94.

Example 39 5-Methylthio-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H- indolemethanammonium chloride

To 5-methylthio-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H- indolemethanamine (0.971 g, 2.21 mmol) in Et₂O (70 mL) is added a solution of HCl in Et₂O (3.1M, 0.90 mL, 2.80 mmol). The resulting white precipitate and clear supernatant solution are chilled in and ice-water bath, then the white solid is isolated by filtration. The salt is washed with Et₂O, and dried in vacuo to give a fine white powder.

MP: 176°C (dec.).

EI/MS (70eV): 440(M⁺-HCl, 70.2), 267(45.1), 266(69.0), 91(base).

Anal: Calcd. for C₂₅H₂₄ ClN₂OS: C, 63.03; H, 5.04; N, 5.88; S, 6.72. Found: C, 62.98; H, 5.18; N, 6.00; S, 6.77.

Example 40 5-Methoxy-7-methyl-1-phenylmethyl-N-(3-trifluoromethyl-phenyI)methyl-3-indol- emethanamine

According to the general procedure described in Example 2, 3-trifluoromethyl-benzyl amine (1.88 g, 10.7 mmol), 1-benzyl-5-methoxy-7-methyl-indole-3-carbox- aldehyde (1.00 g, 3.58 mmol) and NaBH₃CN (0.29 g, 4.65 mmol) provide a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, packed hexanes, eluted EtOAc-hexanes 10:90, 4 L, 20:804L, 30:70 8L, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; EtOAc-hexanes, 50:50; UV(+); ammonium molybdate): R_f = 0.26.

1H-NMR: δ = 7.66(s, 1), 7.40-7.56(3), 7.19-7.29(3), 6.88-6.98(4), 6.57(d, J = 1.8Hz, 1), 5.48(s, 2), 3.96(s, 2), 3.92(s, 2), 3.83(s, 3), 2.45(s, 3), 1.69(s, 1).

1³C-NMR: δ = 153.7, 141.5, 139.5, 131.4, 130.7, 130.3, 129.1, 129.0, 128.7, 128.6,

127.2, 126.0, 125.3, 124.8, 124.7, 123.6, 122.4, 114.9, 113.3, 98.1, 55.5, 52.7, 52.0, 44.1, . 19.3.

IR (neat): 3031, 2939, 1611, 1592, 1489, 1467, 1451, 1414, 1329, 1165, 1124, 1072, 1057, 800, and 703cm^-1.

EI/MS (70eV): 438(M⁺, 40.1), 265(43.5), 252(13.2), 234(11.8), 187(9.5),

174(20.8),159(13.7), 91(base).

Anal: Calcd. for C₂₆H₂₅F₃N₂O : C, 71.22; H, 5.75; N, 6.39. Found: C, 71.01; H, 6.02; N, 6.48.

Example 41 5-Phenylmethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3- 1H-in- dolemethanammonium chloride

To 5-phenylmethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-1H- indolememanamine (0.886 g, 1.73 mmol) in Et₂O (60 mL) is added a solution of HCl in Et₂O

(3.1M, 0.73 mL, 2.25 mmol). The resulting white precipitate and clear supernatant solution are chilled in and ice-water bath, then the white solid is isolated by filtration. The salt is washed with Et₂O, and recrystallized from EtOAc-Et₂O to give a fine white powder.

MP: 154°C (dec.). EI/MS (70eV): 500(M⁺-HCl, 28.5), 236(69.0), 91(base).

Anal: Calcd. for C₃₁H₂₈F₃ClN₂O: C, 69.40; H, 5.22; N, 5.22. Found: C, 69.00; H, 5.46; N, 5.22.

Example 42 5-Methoxy-6-methyl-1-phenylmethyl-N-(4-methoxyphenyl)methyl-3- indolemethanamine

According to the general procedure described in Example 2, 4-methoxybenzyl amine (1.96 g, 14.3 mmol), 1-benzyl-5-methoxy-6-methyl-indole-3-carboxaldehyde (2.00 g, 7.16 mmol) and NaBH₃CN (0.58 g, 9.31 mmol) provides a crude pale yellow oil. The crude material is purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm OD, packed CH₂Cl₂, eluted CH₃OH-CH₂Cl₂ 2.5:97.5, 400 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.

TLC (Merck; CH₃OH-CH₂Cl₂, 10:90; UV(+); ammonium molybdate): R_f = 0.36.

¹H-NMR: δ = 6.82-7.28(12), 5.16(s, 2), 3.93(s, 2), 3.84(s, 3), 3.79(s, 2), 3.75(s, 3), 2.29(s, 3), 1.61(brs, 1).

1³C-NMR: δ = 158.5, 152.6, 137.9, 132.8, 131.6, 129.4, 128.7, 127.4, 126.6, 126.0,

125.9, 122.5, 113.7, 113.6, 111.1, 99.1, 55.7, 55.2, 52.7, 49.8, 44.0, 17.3.

IR (neat): 3029, 2934, 1610, 1585, 1512, 1479, 1463, 1453, 1445, 1301, 1246, 1208, 1174., 108, 839, and 704cm^-1.

EI/MS (70eV): 400(M⁺, 25.4), 265(base).

Anal: Calcd. for C₂₆H₂₈N₂O₂: 400.2151. Found: 400.2152.

Claims

1. A compound of the Formula

wherein R is

(a) C2-C10 alkyl,

(b) C3-C10 alkenyl,

(c) C3-C10 alkynyl,

(m) -(CH₂)_mO(CH₂)_m CH₃ ,

(p) cycloalkyl (3-8 membered rings), or

(q)

-CH₂-C-O-R₉

wherein R₁ is

(a) H,

(b) C2-C10 alkyl,

(c) C3-C10 alkenyl,

(d) C3-C10 alkynyl,

(e)

(f)

wherein R₂ is

wherein R₃ is

(a) H, or

wherein R₄ is H or CH₂OH;

wherein R₅ is H, C2-C10 alkyl or (CH₂)_aOH; wherein R₆ is separate or together is

(a) H,

(b) halogen,

(c) OH,

(d) OR₈,

(e) SR₈,

(f) NO₂,

(g) NH₂

(o) -C≡N,

(P)

-COR₅; or

(q) C1-C10 alkyl;

wherein R₇ is H or C1-C10 alkyl;

wherein R₈ is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, U

cycloalkyl (3-8 membered rings); or

CH₂-cycloalkyl (3-8 membered rings);

wherein R₉ is H, M, R₈, or

»

wherein M is Na⁺, K⁺, Ca^{+ +}, Zn^{+ +}, Al ^{+ + +}, H₄N⁺ or (R₁₀)₄N⁺;

wherein R₁₀ is C1-C-10 alkyl;

wherein a is 1-4, b is 1-5, m is 1 or 2, and p is 4 or 5 and pharmacologically salts thereof; with the proviso that when R and R₂ are methylphenyl, then R₁, R₃, R₄, R₅ or R₆ is something other than H;

with the proviso that when R₂ is trifluromethylphenylmethyl, men R₆ is something other than just F;

with the proviso that when a is 2, R₆ is something other than methoxy and isopropyl.

2. A compound according to Claim 1 wherein R is methylphenyl, wherein R₁ is H;

wherein R₂ is propylphenyl, methylphenyl, trifluoromethylphenylmethyl, methoxy- phenylmethyl or hydroxethylphenyl;

wherein R₃ is H;

wherein R₄ is H;

wherein R₅ is H; and

wherein R₆, separate or together is H, methoxy, methyl, fluorine or chlorine.

3. A compound according to Claim 1 selected from the group consisting of:

1-phenylmethyl-N-(S)-(1-phenyl)ethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-((S)-1-phenyl)ethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-phenylmethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-((+/-)-1-phenyl)ethyl-3-indole-methanamine;

1-phenylmethyI-5-methoxy-N-(3-trifluoromethylphenyl)methyl-3-indole-methanamine; 1-phenylmethyl-5-methoxy-N-(4-methoxyphenyl)methyl-3-indole-memanamine;

1-phenylmethyl-5-methoxy-N-[(R)-1-phenyl-2-hydroxyethyl]-3-indole-methanamine; 5-methoxy-6-methyl-1-phenylmethyl-N-(3-trifluoromethylphenyl)methyl-3-ind- olemethanamine;

5,6-dimethoxy-1-phenylmethyl-N-((3-trifluoromethyI)phenyl-memyl)-3-indolemethanamine; 6-fluoro-5-methoxy-1-phenylmethyl-N-((3-trifluoromethyl)-phenylmethyl)-3- indolememanamine;

6-chloro-5-methoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3- indolemethanamine; and

6-fluoro-5-methoxy-1-phenyl-methyl-N-((4-methoxy)phenyl)methyl-3-indole-methanamine.

4. A method of treating or preventing a metabolic disorder consisting of hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylineamia, excess adiposity or hyperlipidemia in a patient susceptible to or experiencing said disorder comprising the systemic administration of the compound of Formula I

wherein R is

(a) C1-C10 alkyl,

(b) C3-C10 alkenyl,

(c) C3-C10 alkenyl,

(d)

(m) -(CH₂)_mO(CH₂)_mCH_{3 ,}

(p) cycloalkyl (3-8 membered rings), or (q)

-CH₂-C-O-R₉ wherein R₁ is

(a) H,

(b) C2-C10 alkyl,

(c) C3-C10 alkenyl,

(d) C3-C10 alkynyl,

or

wherein R₃ is

(a) H, or

(b) (R₆)_b

wherein R₄ is H or CH₂OH;

wherein R₅ is H, C2-C10 alkyl or (CH₂)_aOH;

wherein R₆ is separate or together is

(a) H,

(b) halogen,

(c) OH,

(d) OR₈,

(e) SR₈,

(f) NO₂,

(g) NH₂

(h)

(i)

(j)

(k)

.

(l) CF₃ , ,

(n) -SR₈ ,

(o) -C≡N,

(P)

-COR₅; or

(q) C1-C10 alkyl;

wherein R₇ is H or C1-C10 alkyl;

wherein R₈ is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,

cycloalkyl (3-8 membered rings); or

CH₂-cycloaIkyl (3-8 membered rings);

wherein R₉ is H, M, R₈, or

wherein M is Na⁺, K⁺, Ca^{+ +}, Zn^{+ +}, Al ^{+ + +}, H₄N⁺ or (R₁₀)₄N⁺;

wherein R₁₀ is C1-C-10 alkyl;

wherein a is 1-4, b is 1-5, m is 1 or 2, and p is 4 or 5 and pharmacologically salts thereof; with the proviso that when R and R₂ are methylphenyl, men R₁, R₃, R₄, R₅ or R₆ is something other than H;

with the proviso that when R₂ is trifluromethylphenylmethyl, then R₆ is something other than just F;

with the proviso that when a is 2, R₆ is something other than methoxy and isopropyl.

5. A method of Claim 4 wherein R is methylphenyl,; wherein R₁ is H; R₂ is propylphenyl, methylphenyl, trifluoromethylphenylmethyl, methoxyphenyl methyl or hydroxethylphenyl;

wherein R₃ is H;

wherein R₄ is H;

wherein R₅ is H; and

wherein R₆, separate or together is H, methoxy, methyl, fluorine or chlorine.

6. A method of Claim 4 wherein the compound is selected from the group consisting of: phenylmethyl-N-(S)-(1-phenyl)ethyl-3-indolemethanamine;

1-phenylmethyl-5-medthoy-N-((S)-1-phenyl)ethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-phenylmethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-((+/-)-1-phenyl)ethyl-3-indole-methanamine;

1-phenylmethyl-5-methoxy-N-(3-trifluoromethylphenyl)methyl-3-indole-methanamine;

1-phenylmethyl-5-methoxy-N-(4-methoxyphenyl)methyl-3-indole-methanamine;

1-phenylmethyl-5-methoxy-N-[(R)-1-phenyl-2-hydroxyethyl]-3-indole-methanamine;

5-methoxy-6-methyl-1-phenylmethyl-N-(3-trifluoromethylphenyl)-methyl-3- indolemethanamine;

5,6-dimethoxy-1-phenylmethyl-N-((3-trifluoro-methylphenyl-methyl)-3-indolemethanamine;

6-fluoro-5-methoxy-1-phenylmethyl-N-((3-trifluoromethyl)-phenylmethyl)-3- indolemethanamine;

6-chloro-5-methoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3- indolemethanamine; and

6-fluoro-5-methoxy-1-phenyl-methyl-N-((4-methoxy)phenyl)methyl-3-indole-methanamine.

7. A method according to Claim 4 wherein said disorder is hyperglycemia.

8. A method according to Claim 4 wherein said disorder is impaired glucose tolerance.

9. A method according to Claim 4 wherein said disorder is hyperinsulinemia.

10. A method according to Claim 4 wherein said disorder is insulin insensitivity.

11. A method according to Claim 4 wherein said disorder is excess adiposity.

12. A method according to Claim 4 wherein said disorder is hyperamylinemia.

13. A method according to Claim 4 wherein said disorder is hyperlipidemia.

14. A method according to Claim 7 wherein said disorder is seen in NIDDM or obesity.

15. A method according to Claim 8 wherein said disorder is seen in NIDDM or obesity.

16. A method according to Claim 9 wherein said disorder is seen in fatty NIDDM or obesity or is associated with or casual in hypertension or atherosclerosis.

17. A method according to Claim 10 wherein said disorder is seen in NIDDM or obesity or is associated with or casual in hypertension or atherosclerosis.

18. A method according to Claim 11 wherein said disorder is seen in NIDDM or obesity.

19. A method according to Claim 12 wherein said disorder is seen in NIDDM.

20. A composition for preventing or treating a metabolic disorder consisting of hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylineamia, excess adiposity or hyperlipidemia in a patient susceptible to or experiencing said disorder comprising the systemic administration of a compound of Formula

wherein R is

(a) C2-C10 alkyl,

(b) C3-C10 alkenyl,

(c) C3-C10 alkenyl,

(p) cycloalkyl(3-8 membered rings), or (q)

-CH₂-C-O-R₉ wherein R₁ is

(a) H;

(b) C2-C10 alkyl,

(c) C3-C10 alkenyl,

(d) C3-C10 alkynyl,

wherein R₃ is

(a) H, or

(b)

wherein R₄ is H or CH₂OH;

wherein R₅ is H, C2-C10 alkyl or (CH₂)_a OH; wherein R₆ is separate or together is

(a) H,

(b) halogen,

(c) OH,

(d) OR₈,

(e) SR₈,

(f) NO₂,

(g) NH₂

(n) -SR₈ ,

(o) -C≡N,

(p)

-COR₅; or

(q) C1-C10 alkyl; wherein R₇ is H or C1-C10 alkyl;

wherein R₈ is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,

cycloalkyl (3-8 membered rings); or

CH₂-cycloalkyl (3-8 membered rings);

wherein R₉ is H, M, R₈, or

wherein M is Na⁺, K⁺, Ca^{+ +}, Zn^{+ +}, Al ^{+ + +}, H₄N⁺ or (R₁₀)₄N⁺;

wherein R₁₀ is C1-C-10 alkyl;

wherein a is 1-4, b is 1-5, m is 1 or 2, and p is 4 or 5 and pharmacologically salts thereof; with the proviso that when R and R₂ are methylphenyl, then R₁, R₃, R₄, R₅ or R₆ is something other than H;

with the proviso that when R₂ is trifluromethylphenylmethyl, then R₆ is something other than just F;

with the proviso that when a is 2, R₆ is something other than methoxy and isopropyl.

21. A composition of Claim 7 wherein R₁ is methylphenyl; wherein R₁ is H; wherein R₂ is propylphenyl, methylphenyl, trifluoromethylphenylmethyl, methoxy phenylmethyl or hydroxethylphenyl;

wherein R₃ is H;

wherein R₄ is H;

wherein R₅ is H; and

wherein R₆ separate or together is H, methoxy, methyl, fluorine or chlorine.

22. A composition of Claim 4 wherein the compound is selected from the group consisting of: phenyImethyl-N-(S)-(1-phenyl)ethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-((S)-1-phenyl)ethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-phenylmethyl-3-indolemethanamine;

1-phenylmethyl-5-methoxy-N-((+/-)-1-phenyl)ethyl-3-indole-methanamine;

1-phenylmethyl-5-methoxy-N-(3-trifluoromethylphenyl)methyl-3-indole-memanamine;

1-phenylmethyl-5-methoxy-N-(4-methoxyphenyl)methyl-3-indole-methanamine;

1-phenylmethyl-5-methoxy-N-[(R)-1-phenyl-2-hydroxyethyl]-3-indole-methanamine;

5-methoxy-6-methyl-1-phenylmethyl-N-(3-trifluoromethylphenyl)methyl-3- indolemethanamine;

5,dimethoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3-indole-memanamine;

6-fluoro-5-methoxy-1-phenylmethyl-N-((3-trifluoromethyl)-phenylmethyl)-3- indolemethanamine;

6-chloro-5-methoxy-1-phenylmethyl-N-((3-trifluoromethyl)phenylmethyl)-3- indolemethanamine; and

6-fluoro-5-methoxy-1-phenyl-methyl-N-((4-methoxy)phenyl)methyl-3-indole-methanamine.