CA1177086A - Nucleophilic substitution process - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Nitroaralkyl cyanides are prepared by reacting a nitroaromatic compound with an alpha,alpha-disubstituted acetonitrile in a substantially anhydrous aprotic solvent and in the presence of a base so that the nitrile undergoes a nucleophilic substitution on an unsubstituted ring carbon of the halonitroaromatic compound during which an alpha-substituent functions as a leaving group. The nitroaralkyl cyanides formed by the process can be readily converted into derivatives, such as pharmaceuticals.

Description

7~86 Case 4920-Plus NUCLEOPHILIC SUBSTITUTION PROCESSES AND PRODUCTS

This invention relates to processes for pre-paring nitroaralkyl cyanides~and derivatives thereof.
There are known techniques of preparing profen-5. type pharmaceuticals.and other materials having arelatively complex aryl group attached to the alpha--carbon of a substituted.or unsubstituted acetic acid.
For example, U, S. patents 3,755,427 (Adams et al.), : 3,959,364 ~Armitage et al.), and 4,278,516 (Zaiko et 10 al.) disclose processes for converting various starting makerials into flurbiprofen, i.e., 2-(2-fluoro-4-biphenylyl)propionic acid, and similar compounds having anti-inflammatory, analgesic, and anti-pyretic properties; Carney et al., "A Potent Non-Steroidal 15 Anti-Inflammatory Agent: 2-[3-Chloro-4-(3-pyrrolinyl)-phenyl]propionic Acid," ~E~ Vol. 29, page 938 (1973) teach, inter alia, the preparation of their anti-inflammatory agent - also known as pirprofen - via an ethyl 2-(3-chloro-4-nitrophenyl)propionate inter 20 mediate; U. S. Patent 4,239,901 ~Rainer) shows that pyrazol-l-ylphenyl and pyrazolin-l-ylphenylacetic acids having anti-inflammatory properties can be synthesized ~' ~ ~7t~

from various intermediates, including po'lychloronitro--phenylacetic acid esters; and it is known that indoprofen, i.e., 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-

2-yl)phenyl]propionic acid, and indobufen, i.e., - ' - 5 '2-~4-(1',3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]butyric acid, can be prepared from the appropriate 2-(4-nitrophenyl)-alpha-alkylacetic acids.
: - . ; . .
Nitroarylacetic acids and their esters and nitriles, as well as the amino derivatives thereof, 10 have been found to be particularly useful intermediates for the synthesis of thes-e pharmaceuticals. Eowever, in the past, a disadvantage of employing them as pharmaceutical intermediates has been the difficulty of preparing them by conventional techniques. Even the 15 preferred procedures for preparing them have proven to be difficult, tedious, and time-consuming, as evidenced by Example 23 of U. S. Patent 3,868,391 (Carney et al.
II) and Example 16 of 'Rainer, both of which show the use of days of reEluxing to acco~plish only a portion 20 of their syntheses.
It would obviously be a welcome contribution to the art to provide a method of synthesizing nitrophenyl-alkyl cyanides and analogs and derivatives thereof in a simple and straightforward manner.
An object of this invention is to provide processes for preparing nitroaralkyl cyanides in moderate-to-~ood yield with high selectivity in a simple and straightforward manner.
Another object is to provide novel, improved processes for preparing derivatives of the cyanides.
A further object is to provide novel cyanides useful as intermediates Eor the preparation of pharmaceuticals.
. . ~
These and other objects are attained by (A) reacting a nitroaromatic comp~und with an alpha, 10 alpha-disubstituted acetonitrile in a substantially anhydrous aprotic solvent and in the presence of a base so that the nitrile undergoes a nucleophilic substitution on an unsubstituted ring carbon of the nitroaromatic compound during which an alpha-15 substituent functions as a leaving group, therebyforming a nitroarylacetonitrile and (B~ when appropriate, converting the nitroarylacetonitrile to a desired derivative thereof.
Nitroaromatic compounds utilizable in the 20 practice of the invention include a variety oE ~uch compounds - the chieE requirements Eor their utility being that (1) they bear at least one nitro substituent on an aromatic ring, (2) they contain at least one replaceable hydrogen on an aromatic ring to which a 25 nitro group is attached, and (3) they be devoid of substituents which would interfere with the desired ~ ~'7'~

nucleophilic substitution reaction, e.g., substituents -bearing an acidic proton, such as -NH2, -OH, -Sl~, -NHR, etc.
Thus, the utilizable nitroaromatic compounds - 5- include compounds having one or more simple or fused aromatic rings containing five or six members and either bearing no substituents other than nitro . ~ : . ,, -. -. .
substituents or also bearing any of a variety of inert substituents, i.e., substituents that do not inter~ere 10 with the desired nucleophilic substitution reaction, such as halo, alkyl, alkbxy,.alkylmercapto, trifluoro~
methyl, dialkylamino, dialkanoylamino, cyano, dialkyl~
carbamoyl, alkylsulfonyl, dialkylsulfamoyl, alkoxyalkyl, haloalkyl, cycloalkyl, halocycloalkyl, 15 etc. - any alkyl chains in the substituents generally being lower alkyl chains. When the nitroaromatic compound contains more than one ring, any such inert substituent may be on the same ring as the ring bearing a nitro substituent and/or on a ring which is directly 20 or indirectly attached to the ring bearing a nitro substituent.
When the aromatic ring bearing the required nitro substituent is a six-membered ring, there will be at least one replaceable hydrogen in a position para or 25 ortho to the carbon bearing the nitro substituent; and it is preferred that there be a replaceable hydrogen in ~.~7"7~?~3~

the para position. Nitroaromatic compounds having a five-membered ring should have a replaceable hydrogen on a carbon adjacent to, or separated by two ring atoms Erom,.the carbon bearing the nitro substituent.
: 5 In accordance with one embodiment of the invention, the nitroaromatic compound is a compound which is devo.id of halogen on the aromatic ring bearing .
the required nitro group. Illustrative of such compounds are heterocyclic co~pounds which.preferably 10 contain five or six-membered rings having aromatic character, such as nitropyridine-N-oxide, 5-nitroisoquinoline, 5- and 6-nitroquinolines, 2-nitrothiophene9 etc.; fused-ring aromatic compounds, such as the 1- and 2-~itronapthalenes, etc.; aro~atic 15 compounds containing a plurality of simple rings, such as the 2-, 3-, and 4-nitrobiphenyls, the 2-, 3-, and 4-benzylnitrobenzenes, 2-nitrodiphenyl ether, etc.; and aromatic compounds containing a single simple ring, such as nitrobenzene, 2-methylnitrobenzene, the 2,3-, 20 2,5-, and 3,5-dimetllylnitrobenzenes, the 2,4- and 2,6-diethylnitrobenzenes, 3,4-dibutylnitrobenzene, the 1,2- and 1,3-dini~robenzenes, 2,6-dinitrotoluene, the 1,2,3- and 1,2,4-trinitrobenzenes, 2-nitro-N,N-diethyl-aniline, 4-nitro-N-e~hylacetanilide9 2-nitrobenzyl-25 cyanide, 2-nitrophenyl acetate, etc.

.~l'7'7~3~

In accordance with another embodiment of the -invention, the nitroaromatic compound is a compound which bears at least one halo substituent on the aromatic ring bearing the required nitro group.
5iExemplary of such compounds are the 2-, 3-, and 4-chloronitrobenzenes; the 2,3-, 2,4-, 2,5-, 2,6-,

3,4-, and 3,5-dichlor~nitrobenzenes; the various - . ; . . . . .
trichioronitrobenzenes; the corresponding fluoro, bromo, and iodo compounds; the various dimethyl-, 10 diethyl-, and dibutylnitrobenzenes, nitrobiphenyls, benzylnitrobenzenes, nitronaphthalenes, di- and trinitrobenzenes, nitro-N,N-diethylanilines, nitrodiphenyl esters, nitro-N-ethylacetanilides, nitrobenzylcyanides, nitrophenyl acetates, nitro-15 pyridine-N-oxides, nitroquinolines, nitroisoquinolines, nitrothiophenes, and the like bearing one or more ar-chloro, fluoro, bromo, or iodo substituents and containing at least one replaceable hydrogen in an appropriate position.
In some cases, polynitroaromatic reactants may undergo substitution reactions whereby one of the nitro groups is replaced by the nitrile reactant. Therefore, the possibility of this competitive reaction should be kept in mind when selecting a polynitroaromatic 25 reactant for use in the process.

In each of the aforementioned embodiments of the invention, the preferred nitroaromatic compounds are nitrobenzenes having a replaceable hydrogen in the position para to thc nitro group, since the - 5 nucleophilic substitution reaction of the invention tends to be highly selèctive on the para position, and the use of such compounds therefore leads to the .
production o~ nitrophenylacetonitrlles which are ideally suited for the synthe~is of anti-inflammatory 10 agents of the type described in the aforementioned references. Even more preferred in the case of the halonitrobenzenes are such nitrobenzenes having a halo substituent in a position ortho to the nitro group.
Halonitrobenzenes which are especially pre~erred are 15 2-chloronitrobenzene and 2-fluoronitrobenzene which are readily converted wi~h high selectivity into such products as 2-[3-chloro-4-(3-pyrrolinyl)phenyl~propionic acid, 2-(2-fluoro-4-biphenylyl)propionic acid, and related anti-inÉlammatory agents. A non-halogenated 20 nitroaromatic compound that is particularly preferred is nitrobenzene, which is readily converted with high selectivity into pharmaceutically-active agents such as 2-~4-(1,3-dihydro-l-oxo-2~-isoindol-2-yl)phenyl]-propionic acid, 2-[4-(1,3-dihydro-1-oxo-2~1-isoindol-25 2-yl)phenyl]butyric acid, and analogs thereof.

~ 76~ ~

The alpha, alpha-disubstituted acetonitriles that can be used in the practice of the invention also in~
clude a variety of such compounds, which - in general -may be represented by the formula:
- 5 -~ -~ L
/ CHCN
R

wherein L is a leaving group and R is halo (preferably chloro) or, mQre preferably, a hydrocarbyl (e.g., 10 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, etc.) or hydrocarbyloxyhydrocarbyl (e.g., alkoxyalkyl, aryloxyalkyl, alkoxyaryl, alkoxy-cycloalkyl, etc.) group which most preferably contains up to about 10 carbons.
Exemplary leaving groups, L, include halo, aryloxy, haloaryloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, haloalkylthio, halocyclo-alkylthio, haloarylthio, haloaralkylthio, or, less preferably, alkoxy, cycloalkoxy~ aralkoxy, haloalkoxy, 20 halocycloalkoxy, haloaralkoxy, and the like, as well as other suitable leaving groups which have been described in the literature, e.g., in Golinski et al., "'Vicarious' Nucleophilic Substitution oE Hydrogen in Aromatic Nitro Compounds,"Tetrahedron_Letters," Vol.37, 25 pp. 3495-8 (1978) and in Makosza et al., "Vicarious Substitution of Hydrogen in Aromatic Nitro Compounds with Acetonitrile Derivatives," Jou~
~hemistry, Vol. 45, pp. 1534-5 (1980).
When the leaving group is an organic group, it 5 is generally preferred that it contain not more than about 10 carbons, although organic leaving groups having an even higher carbon content are satisfactory .,, . . ~ .
in the pr~ctice of the invention. Preferably the leaving group is halo, i.e., chloro, bromo, fluoro, or 10 iodo; and it is more preferably chloro or bromo, most preferably chloro.
It is notable that acetonitriles ha~ing a single alpha-substituent do not appear to be equivalent to the aforementioned alpha, alpha-disubstituted acetonitriles 15 in the preparation of nitroaralkyl cyanides by a nucleophilic substitution reaction. For example, attempts to prepare substitution products by reacting alpha-chloroacetonitrile with nitrobenzene have not been successful thus far, and Makosza et al. teach that 20 they were also unsuccessful in reacting alpha-chloro-acetonitrile with 4-nitrobiphenyl, although that nitrile did react with l-nitronaphthalene and 4-chloro-nitrobenzene to form the corresponding alpha-nitroaryl-acetonitriles.
A few examples of alpha, alpha-disubstituted acetonitriles that can be used in the practice of the ~ '7~

invention are 2-chloropropionitrile, 2-chlorobutyro-nitrile, 2-chlorovaleronitrile, 2-chlorocapronitrile, 2-chloro-4-pentenenitrile, 2-chloro-3,3-dimethylbu~yro-nitrile, 2-chloro-2-phenylacetonitrile, 2-chloro-2-5 cyclohexylacetonitrile, 2-chloro-3-(3-chloro-o-tolyl)-propionitrile, 2-chloro-3-phenylpropionitrile, the corresponding bromo and iodo compounds, and the like.
The alpha-halo-alpha-hydrocarbylacetonitriles, i.e., alpha-haloalkyl cyanides containing at least three 10 carbons - particularly 2-chloropropionitrile and 2-bromopropionitrile - are e~specially preferred, although similar cyanides in which the alpha-halo substituent is replaced by one of the other leaving groups mentioned above are also highly desirable.
`In another highly desirable embodiment of the invention, the alpha, alpha-disubstituted acetonitrile is an alpha, alpha~dihaloacetonitrile, most preferably an alpha, alpha-dichloroacetonitrile, which leads to the formation of a product having a reactive halo 20 substituent in the alpha-position, e.g., a product corresponding to the formula:

Xn N~2 H~C-CN

~ 3~

wherein X is halo, preferably chloro, and n is an integer of 1 to 3. Such products enable facile synthesis of a variety of end products. Most preferably the nitro group is in the position para to - 5 the ni~rile subs~ituent, although it may be located in an ortho position.
Illustrative aprotlc solvents which may be employed in the process of the invention include ethers such as diethyl ether, dibutyl ether, l-ethoxyhexane, 10 tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, diglyme, 1,2-diethoxyethane, anisole, etc.; tertiary amines such as pyridine, N-ethylpiperidine, triethyl amine, tributyl amine, N,N-diphenyl-N-methyl amine, N,N-dimethylaniline, etc.j and other solvents. However, 15 the preferred aprotic solvents are dipolar aprotic solvents such as dimethyl sulfoxide, N,N-dimethyl-formamide, N,N-dimethylacetamide, dimethyl sulfone, tetramethylene sulfone, N-methylpyrrolidone, and the like.
Bases useful in the practice of the invention include all bases strong enough to activate the nitrile reactant, e.g., alkaline earth metal compounds such as calcium oxide, calcium hydride, calcium hydroxide, barium oxide, barium hydroxide, magnesium hydroxide, 25 zinc hydroxide, etc. However, the base is preferably an alkali metal compound, e.g., an organoalkali metal '7~3~ ~

. compound, alkali metal hydride, alkali metal hydroxide, -alkali metal oxide, alkali metal amide, or alkali metal alcoholate, such as butyllithium, phenyllithium, ethylsodium, amylsodium, butylpotassium, 5 benzylpotassium, sodium dimsylate (i.e., the sodium salt of diethylsulEoxide), sodium hydride, potassium hydride, sodium hydrox-ide, potassium hydroxide, sodium oxide, potassium oxide, sodium amide, potassium amide, lithium diisopropylamide, sodium methoxide, potassium 10 t-butoxide, the sodium salt of the monomethylether of ethylene glycol, sodium phenoxide, and the likeO
Ordinarily the use of sodium hydride or potassium hydride will be found most convenient and economical.
Use of an alkali metal compound as the base 15 permits the alternatives of using the alkali metal compound alone or in conjunction with a phase transfer catalyst, such as a quaternary ammonium salt, ethylene glycol, or a suitable crown ether. When a phase transfer catalyst is employed (1) the alkali metal 20 compound may be any of the alkali metal compounds generically or specifically indicated above, although the type of alkali metal compound being used determines the type of crown ether that is preferably utilized -lithium bases generally calling for the use of a 25 12-crown-4 ether, sodium bases usually calling for the use of a 15-crown-5-ether, and potassium bases generally calling for the use ~f an 18-crown-6-ether, and (2) the reaction medium may be any of the aprotic solvents mentioned above, or it may be an inert liquid hydrocarbon such as benzene, toluene, xylene, hexane, 5 heptane, isooctane, or the lIke.
When an alkali metal hydride, especially a highly pure alkali metal hydride, is employed as the base, it is desirable to include a small amount of a transfer agent such as water, alcohol, or the like in the system.
10 It is believed that the transfer agent activates the hydride by reacting therewith to form a small amount of the alkali metal hydroxide or alcoholate.
The nitroaralkyl cyanide synthesis of the invention is conducted in a substantially anhydrous 15 reaction system, and accordingly, except when a small amount of water (which is itself consumed by reaction with the alkali metal hydride) is employed as a transfer agent, the components of the reaction sy~tem should be brought together and maintained under a dry 20 inert atmosphere. Thus, while it is possible to conduct the process in the presence of air, it is desirable to maintain the reaction system under an atmosphere of dry nitrogen or the like. Since the reaction itself is normally an exothermic reaction, 25 with its initiation readily ascertainable by noting the exotherm produced, the reactants are ordinarily brought together at ambient temperatures, although the temperature may be raised or lowered to suit the needs of the occasion i~ desired.
The nitroaromatic compound and alpha,alpha-5 disubstituted acetonitrile may be used in amounts suchas to provide a stoichiometric excess of either of the reactants or the stoichiometric amount of each. How-ever, when a stoichiometric excess of the nitroaromatic compound is employed, the quantity of product 10 obtainable will be limited by the quantity of nitrile used, so it is desirable to utilize a stoichiometric excess of the nitrile; The amount of base employed is preferably such as to provide at least two molar equivalents of base per mol of nitroaromatic compound, lS since the use of smaller amounts - although permitting the reaction to occur - makes ths base the limiting reagent.
The mode of addition of the ingredients oE the reaction system is not particularly critical. Accord-2~ ingly, it is convenient to add the nitroaromaticcompound to a mixture of the other materials, add the base to a mixture of the other materials, add the reactants to a mixture of the base and aprotic solvent, introduce all four ingredients simultaneously into the 25 reaction zone, or the like~ Since the reaction ordinarily proceeds very rapidly, long reaction times are not required. The reaction will usually be completed within a ma~ter of minutes or a few hours at ambient temperatures.
When derivatives of the nitroaralkyl cyanides 5 are desired, they may be prepared by employing conventional techniques to convert to the desired derivatives the nitroaralkyl cyanides made in .
accordance with the present invention. Thus, for example:
(A) 2-(4-nitrophenyl)propionitriIe synthesized by the process of the invention may be hydrolyzed to 2-(4-nitrophenyl)propionlc acid, which in turn may be hydrogenated to 2-(4-aminophenyl)propionic acid, reacted with phthalic anhydride to form 2-(4-phthal-15 imidophenyl)propionic acid, and reduced to indoprofen, (B) 2-(4-nitrophenyl)propionitrile synthesized by the process of the invention may be hydrogenated to 2-(4-amino-phenyl)propionitrile, hydrolyzed to 2-(4-aminophenyl)propionic acid, reacted with phthalic 20 anhydride to form 2-(4-phthalimidophenyl)propionic acid, and reduced to lndoprofen, (C) 2-(4-nitrophenyl)propionitrile synthesized by the process of the invention may be hydrogenated to 2-(4-aminophenyl)propionitrile, reacted with phthalic 25 anhydride to form 2-(4-phthalimidophenyl)propionitrile, and hydrolyzed and reduced (in either order) to indoprofen, ~ ~ 7'7~

(D) 2-(4-nitrophenyl)bu~yronitrile synthesized by the process of the invention may be-subjected to the same reactions to prepare indobu:Een or indobufen intermediates, .5 (E) 2-(3-chloro-4-nitrophenyl)propionitrile synthesized by tbe process of the invention may be reduced to 2-(4-ami~o-3-chlorophenyl)propionitrile, reacted witb a 1,4-dihalo-2-butene to form ~-[3-ch.loro-4-(3-pyrrolinyl)phenyl]propionitrile, and lO then converted into 2-[3-chloro-4-(3-pyrrolinylphenyl]-propionic acid, and (F) 2-(3-fluoro-4-nitrophenyl)propionitrile synthesized by the process of the invention may be reduced to 2-(4-amino-3-fluorophenyl)propionitrile, 15 converted into (2-fluoro~4-biphenylyl)propionitrile by means of a Gomberg-Bachmann reaction with benzene, and then converted into 2-(2-fluoro-4-biphenylyl)propionic acid.
The particular conventional techniques used to 20 convert the nitroaralkyl cyanides into their various derivatives are not critical. It may sometimes be desirable to use certain particular techniques for the preparation of the derivatives, e.g., (a) the reduction and/or hydrolysis techniques taught in March, Advanced 25 Organic Chemistry, McGraw-Hill, New York, 1977, pages 809-10, 1125~6, and the references cited ~ ~t~7~ ~ ~

therein; (b) the Gomberg-Bachmann techniques taught in March, pages 653-4, and in Organic Reactions, Vol. 2, page 224 (1944); JournaL of_the American Chemical y, Vol. 46, page 2339 (1924); Chemical RevO ~ Vol.
~ 5 57, page 77 (1957), an~ Journal of_the Ch~mical Society~ Vol. D 1971, page 4il, and (c) the techniques taught in Adria Laboratories, Inc.'s NDA on Indoprofen Capsules, Section No. 8~c), pages 2-11, which is on file with the Federal Drug Administration. However, - 10 the overall processes for preparing the derivatives are simplified and made more efficient and economical by the present simplification of the synthesis of the nitroaralkyl cyanides regardless of the particular techniques used to convert them into their various 15 derivatives.
As indicated above, the present invention is particularly advantageous in providing a readier and more economical route to the synthesis of pharma-ceuticals and other chemica:L products that can be 20 prepared from nitroaralkyl cyanides. Such products include, not only those mentioned above, but a variety of products, such as products disclosed in U.S. Patents 3,641,040, 3,657,230, 3,767,805, 3,868,391., 3,936,467, 3,993,763, 3,997,669, 4,010,274, 4,118,504 9 ~ ~ 126,691, 25 4,163,788, and 4,239,901.

1~7~7~

The following examples are giver- to illus~rate the invention and are not intended as a limitation thereo~.
~e~
' 5^' 'Into a flame dried flask under nitrogen was placed 1.3 grams (0.026 mol) of NaH (50% dispersion in mineral oil). This was washed twice'with 10 ml portions of petroleum ether (b.p. 35-60C) and dried in a ni,trogen stream. Then 25 ml of N,N-dimethyl-10 formamide (DMF; dried over 3 Angstrom molecular sieves)was added followed by dropwise addition (over 20 minutes) of a solution of 2.2 ml (0.021 mol) of 2-fluoronitrobenzene and 1.9 ml (0.023 mol) of 2-chloro-propionitrile in lO ml of DMF. The mixture became red 15 and hot during the dropwise addition. A small portion of the reaction mixture was worked up by partitioning between lN HCl and diethyl ether, and analysis of the ether layer by gas chromatography (GC) indicated some starting material had not reacted. A second (0.40 g, 20 0.008 mol) and third (0.80 g, 0.017 mol) portion oE 50%
NaH were added so that workup of a reaction mixture sample Eollowed by GC analysis indicated that no starting material remained. The reaction mixture was poured into 250 ml of lN HCl and extracted with six 25 200 ml portions of ether. The ether layers were combined, dried (MgS04), and concentrated to give a black oil which was adsorbed on 15 g of Silica Gel 60 (230-400 mesh) and loaded on a column of 150 g Silica Gel 60 packed in 40% CH2C12/60% petroleum ether (bp 35-60C). Elution with the same solvent mixture 5 afforded four fractions which, by GC area %, contain 1.8 g (44%) of 2-(3-fluoro-4-nitrobenzene)propionitrile.
This compound was characterized by NMR, IR, and mass . .
spectrometry.

A slurry of 240 mg (5.0 mmols) of NaH (50% in mineral oil) in 2 ml of pyridine was treated dropwise, under nitrogen, with 0.26 ml (0.35 g, 2.5 mmols) of 2-fluoronitrobenzene followed by 0.22 ml (0.23 g, 2.6 mmols) of 2-chloropropionitrile. The purple reaction 15 mixture was stirred at room temperature under nitrogen for 15 minutes, then was poured into an equal volume of 5% HCl and extracted with an equal volume of CH2C12. The organic phase was shown by gas chromatography-mass spectral analysis tGC-MS) to 0 contain 2-(3~Eluoro-4-nitrobenzene)propionitrile.
Example Ill A solution of 0.61 g (3.1 mmol) of 2-(3-fluoro-4-nitrobenzene)propionitrile in lO ml of absolute ethanol was treated with 0.03 g of 7%
25 palladium on carbon and hydrogenated at 45 psi of hydrogen (Parr apparatus) for 1 hour. The reaction ~ ~7~7~ ~ ~

mixture was Eiltered and concentrated to give 0.54 g of an oil which darkened on standing. A portion of this oil was purified on 1 mm silica gel plates (developed with CH2C12) to give 2-(4-amino-3-fluorobenzene)-5 propionitrile, which was characterized by NMR, IR, andmass spectrometry.
Example_IV
A solution of 1.2 g (6.2 mmol) of 2-(3-fluoro-4-nitrobenzene)propionitrile in 24 ~1 of absolute ethanol 10 was treated with 0.06 g of 7% palladium on carbon and hydrogenated at 40-45 psi hydrogen pressure (Parr apparatus) for 1 hour. Th~e reaction mixture was filtered and the filtrate was shown to contain, by GC
analysis (area percent) 99% 2-(4-amino-3-fluorobenzene)-15 propionitrile. Removal of the solvent in a rotaryevaporator gave 1.1 gram of a yellow oil which quickly darkened on standing.

A solution oE 25 mg (0~15 mmol) of 2-(4-amino-3-20 fluorobenzene)propionitrile, 0.2 ml of benzene, and 0.03 ml (0.25 mmol) of isoamyl nitrite was heated at reflux for 1.5 hours. GC analysis ~area percent) of the reaction mixture indicated the presence of 23%
unreacted starting material and 60% of a product which 25 was identified by GC-MS to be 2-(2-fluoro-4-biphenylyl)-propionitrile.

~. ~'7'7~

To a slurry of 0.50 g (1~ mmols) of NaH (50~/~
dispersion in mineral oil) in 2 ml of NJN-dimethyl-formamide (DMF, dried over 3 Angstrom moIecular sieves) 5 under nitrogen was added dropwise1 over a period of 10 minutes, a solution of 0.60 ml (5.1 mmols) of 2-chloro-nitro~enzene and 0.42 ml (5.1 mmols) of 2 chloro~
- ., , - .
propionitrile in 1 ml of DMF~ During the addition, the mixture became purple and an exotherm was-observed.
10 The reaction mixture was stirred under nitrogen for 15 minutes, poured into 30 ml of lN HCl and extracted with four 30 ml portions of diethyl ether. The organic layers were combined, dried using MgS04, and concentrated to give 1.2 g of a black oil. Preparative 15 thin layer chromatography of 0.20 g of this oil (one 2mm silica gel plate developed with 50% CH2C12/50%
petroleum ether) afforded 0.088 gram of 2-(3-chloro-4-nitrobenzene)ptopionitrile which was characterized by means oE N~R and mass spectrometry.
EXAMPLE VII
_ _ _ _ Into a flask under nitrogen was placed 4.0 g oE
60% sodium hydride in mineral oil (0.10 mole). The sodium hydride was washed with three 10 ml portions of petroleum ether (b.p. 35-60C) and was slurried in 25 50 ml of N,N-dimethylformamide (DMF). A solution of 12.3 g of nitrobenzene (0.10 mole) and 9.0 g of ~ 7 7!C~

. 2-chloropropionitrile (O,10 mole) in 10 ml of DMF was added dropwise to the slurry. An ice water bath was applied to the mixture periodically so that the temperature did not exceed 45C. After the addition - 5 was complete (30 minutes) the purple m;xture was allowed to react for 30 minutes and was poured into 200 ml of cold 10% HCl. The aqueous mixture was extracted with three 100 ml portions of diethyl ether and the ether layers were combined, dried (MgSO~), and 10 concentrated to give a dark oil. Excess nitrobenzene and DMF were removed From thls oil at 50C (at 1 mm pressure) and the residue was chromatographed on a column of 400 g o silica gel which was eluted with dichloromethane. A fraction was collected containing 15 2.9 g of 2-(4-nitrobenzene)propionitrile (16.5% yield).
EXAMPLE VIII
Into a flame dried flask under nitrogen was placed 500 mg of 60% sodium hydride in mineral oil (12.5 mmole). The sodium hydride was washed with three 20 5 ml portions of petroleum ether (b.p. 35-60C) and was slurried in 4 ml of N,N-dimethylformamide (D~IF).
One drop of a solution of 770 mg of nitrobenzene (6.25 mmole) and 600 mg of 2 chloropropionitrile (6.70 mmole) in 1 ml of DMF was added to the sodium hydride slurry 25 to give a deep purple solution. After one minute the mixture was placed in an ice water bath and the rest of ~'7~7~g8~

the reactant solution was added dropwise. The resulting mixture was stirred at 0C for 15 minutes and was poured into 50 ml of lN HCl. The aqueous mixture was extracted with three 40 ml portions of 5 dlethyl ether and the ether layers were combined, dried (MgSO4), and concentrated to give 880 mg of black oil. Purification of 208 mg of this oil on one 2 mm silica gel plate eluted with 50% dichloromethane/50%
petroleum ether afforded 51.2 mg (20% yield) of lO 2-(4-nitrobenzene)propionitrile.
- EXAMPLE IX
Into a flame dried flask under nitrogen was placed 176 mg of potassium tert-butoxide (1.57 mmoles) J
23 mg of dibenzo 18-crown-6 ether (0.064 mmole), and 15 l.O ml of toluene, While this mixture was vigorously stirred in a room temperature water bath a solution of 106 mg of 1,3-dinitrobenzene (0.631 mmole) and 71 mg of 2-chloropropionitrile (0.79 mmole) in 0.5 ml oE toluene was added dropwise. The resulting purple mixture was 20 stirred for 15 minutes and poured into 20 ml of lN
HCl. The aqueous mixture was extracted with three 20 ml portions of diethyl ether and the ether layers were combined, dried (MgS04), concentrated, and placed on one 2 mm silica gel TLC plate. One development with 25 50% petroleum ether (bp35-60C~/50~/o dichloromethane afforded 10 mg of 1,3-dinitrobenzene (9% recovery) and :~ a~7¢~

25 mg of 2-(2~4-di-nitrobenzene)propionitrile (18V/o yield).
The preceding examples demonstrate the utility of alpha, alpha-disubstituted acetonitriles in the 5 preparation of nitroaralkyl cyanides. The following example shows that similar results are not achieved when an acetonitrile having only one alpha-sub5tituent ` ` is substituted for the alpha,alpha-disubstituted acetonitriles.
COMPARATIVE EXAMPLE
Into a flame dried fl~sk under nitrogen was placed 500 mg of 60% sodium hydride in mineral oil (12.5 mmole). The sodium hydride was washed with three 5 ml portions of petroleum ether (b.p. 35-60C), 15 slurried in 4 ml of N,N-dimethylformamide (DMF), and cooled in an ice water bath. A solution of 770 mg of nitrobenzene (6.25 mmole) and 500 mg of chloro-acetonitrile (6.62 mmole) in 1 ml of DMF was added dropwise. The resulting brown mixture was stirred at 20 0C for 15 minutes and was poured into 50 ml of lN
HCl. The aqueous mixture was extracted with three 40 ml portions of diethyl ether and the ether layers were combined, dried (MgSO4), and concentrated to give 1.02 g of black oil. Thin layer chromatographic 25analysis of this o;l revealed no substitution product;
only nitrobenzene and an immobile brown spot were observed.

~ 24 -

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process which comprises reacting a fluoronitroaromatic compound or a nitroaromatic compound devoid of halogen on the aromatic ring carrying a nitro group with an alpha,alpha-substituted acetonitrile in a substantially anhydrous aprotic solvent and in the presence of a base so that the nitrile undergoes a nucleophiiic substitution on an unsubstituted ring carbon of the nitroaromatic compound during which an alpha-substituent functions as a leaving group thereby forming a nitroarylacetonitrile.

2. The process as claimed in Claim 1 wherein the nitroaromatic compound is a compound which is devoid of halogen on the aromatic ring carrying a nitro group.

3. The process as claimed in Claim 1 wherein the nitroaromatic compound is a mononitrobenzene having an unsubstituted position para to the nitro group.

4. The process as claimed in Claim 3 wherein the mononitrobenzene is nitrobenzene.

5. The process as claimed in Claim 1 wherein the nitroaromatic compound is a fluoronitroaromatic compound.

6. The process as claimed in Claim 5 wherein the fluoronitroaromatic compound is a 2-fluoronitro-benzene.

7. The process as claimed in Claim 1 wherein the alpha, alpha-disubstituted acetonitrile is an alpha-haloalkyl cyanide containing at least three carbons.

8. The process as claimed in Claim 1 wherein (a) the nitroaromatic compound is a mononitrobenzene having an unsubstituted position para to the nitro group, (b) the alpha,alpha-disubstituted acetonitrile is an alphahaloalkyl cyanide containing at least three carbons, (c) the solvent is a dipolar aprotic solvent, (d) the base comprises an alkali metal compound, and (e) the nitroarylacetonitrile is a 2-(4 nitrophenyl)-acetonitrile.

9. The process as claimed in Claim 8 wherein (a) the mononitrobenzene is nitrobenzene, (b) the alpha, alpha-disubstituted acetonitrile is an alkyl alpha-chloro- or alpha-bromopropionitrile, (c) the base is sodium hydride or potassium hydride, and (d) the nitroarylacetonitrile is a 2-(4-nitrophenyl)-propionitrile.

10. The process as claimed in Claim 1 wherein (a) the nitroaromatic compound is a 2-fluoronitro-benzene, (b) the alpha,alpha-disubstituted acetonitrile is an alpha-chloro- or alpha-bromopropionitrile, (c) the base is sodium hydride or potassium hydride, and (d) the nitroarylacetonitrile is a 2-(3-fluoro-4-nitro-phenyl)propionitrile.

11. 2-(3-Fluoro-4-nitrophenyl)propioni-trile, when prepared by the process defined in claim 10 or an obvious chemical equivalent thereof.

12. The process as claimed in claim 1 wherein (A). nitrobenzene is reacted with an alpha-chloro-or alpha-bromopropionitrile to form 2-(4-nitrophenyl)-propionitrile, (B) the 2-(4-nitrophenyl)propionitrile is converted to 2-(4-aminophenyl)propionic acid by (1a) hydrolyzing the 2-(4-nitrophenyl)propionitrile to 2-(4-nitrophenyl)propionic acid and (1b) reducing the 2-(4-nitrophenyl)propionic acid or (2a) reducing the 2-(4-nitrophenyl)propionitrile to 2-(4-aminophenyl)propionitrile and (2b) hydrolyzing the 2-(4-aminophenyl)propionitrile, (C) the 2-(4-aminophenyl)propionic acid is reacted with phthalic anhydride to form 2-(4-phthalimidophenyl)-propionic acid, and (D) the 2-(4-phthalimidophenyl)propionic acid is reduced to 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]propionic acid.

13. The process as claimed in claim 1 wherein (A) nitrobenzene is reacted with an alpha-chloro-or alpha-bromopropionitrile to form 2-(4-nitrophenyl)-propionitrile, (B) the 2-(4-nitrophenyl)propionitrile is reduced to 2-(4-aminophenyl)propionitrile, (C) the 2-(4-aminophenyl)propionitrile is reacted with phthalic anhydride to form 2-(4-phthalimidophenyl)propionitrile, and (D) the 2-(4-phthalimidophenyl)propionitrile is converted into 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]propionic acid by (1a) hydrolyzing the 2-(4-phthalimidophenyl)-propionitrile to 2-(4-phthalimidophenyl)propionic acid and (1b) reducing the 2-(4-phthalimidophenyl)propionic acid or (2a) reducing the 2-(4-phthalimidophenyl)propionitrile to 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-phenyl]propioni-trile, and (2b) hydrolyzing the resulting nitrile.

14. The process as claimed in claim 1 wherein (A) 2-fluoronitrobenzene is reacted with an alpha-chloro- or alpha-bromopropionitrile to form 2-(3-fluoro-4-nitrophenyl)propionitrile, (B) the 2-(3-fluoro-4-nitrophenyl)propionitrile is reduced to 2-(4-amino-3-fluorophenyllpropionitrile, (C) the 2-(4-amino-3-fluoro-phenyl)propionitrile is converted into 2-(2-fluoro-4-biphenylyl)propionitrile by means of a Gomberg-Bachmann reaction with benzene, and (D) the 2-(2-fluoro-4-biphenylyl)-propionitrile is hydrolyzed to 2-(2-fluoro-4-biphenylyl)-propionic acid.

15. The process as claimed in claim 1 wherein (A) 2-fluoronitrobenzene is reacted with an alpha-chloro- or alpha-bromopropionitrile to form 2-(3-fluoro-4-nitrophenyl)propionitrile, and (B) the 2-(3-fluoro-4-nitrophenyl)propionitrile is reduced to 2-(4-amino-3-fluorophenyl)propionitrile.

16. 2-(4-Amino-3-fluorophenyl)propionitrile, wherein prepared by the process defined in claim 15 or an obvious chemical equivalent thereof.