CN115340485B - Method for synthesizing indole terpene analogues by palladium-catalyzed cascade Heck/carbonyl ortho-alkylation reaction - Google Patents
Method for synthesizing indole terpene analogues by palladium-catalyzed cascade Heck/carbonyl ortho-alkylation reaction Download PDFInfo
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Abstract
The invention discloses a method for synthesizing indole terpene analogues by palladium-catalyzed serial Heck/carbonyl ortho-alkylation, belonging to the technical field of organic chemistry. Benzocyclic ketone and N-o-iodophenyl binaphthyl amine are used as raw materials, indole terpene analogues are obtained through a serial Heck/carbonyl ortho-alkylation reaction in the presence of a palladium catalyst, a phase transfer catalyst and alkali, and then ring closure is performed through derivatization to obtain the condensed ring indole terpene analogues. The method has the advantages of good chemical selectivity and high yield, and the product contains chiral quaternary carbon centers.
Description
Technical Field
The invention relates to a method for synthesizing indole terpene analogues by palladium-catalyzed serial Heck/carbonyl ortho-alkylation, belonging to the technical field of asymmetric synthesis in organic chemistry.
Background
In recent decades, the ortho (alpha-position) asymmetric alkylation of carbonyl compounds has been well explored using transition metal catalysis, organocatalysis and synergistic catalysis, respectively. For example: in 2001, the chiral phase transfer catalyst/palladium catalyst synergistic catalysis concept was introduced into the research of asymmetric allylic alkylation of carbonyl ortho carbon. The Gong group of topics first described asymmetric allylation of glycinamide esters with allyl acetate under co-catalysis of palladium catalysts with cinchona alkaloid ammonium salts (formula a); the Takemoto group of topics discloses that nearly identical strategies perform similar reactions (formula b), expressed using the reaction equation:
recently, the Lin group of topics reported that palladium catalyzed allylation of tandem Heck/allylamine with active methyl compounds produced a single linear allylation product (formula a); guo et al report a new class of palladium-catalyzed asymmetric tandem Heck cyclization/dearomatization reactions of beta-naphthol and N- (2-iodophenyl) enamide for the construction of indole terpene analogues (formula b); the reaction equation is used to represent:
however, N- (2-iodophenyl) enamide tandem Heck/carbonyl α -allylalkylation under synergistic catalysis of palladium catalyst/PTC phase transfer catalyst has not been fully disclosed.
Disclosure of Invention
In order to solve the technical problems, the invention discloses a method for synthesizing indole terpene analogues by palladium-catalyzed cascade Heck/carbonyl ortho-alkylation. The indole terpene analogue 3 containing quaternary carbon center is obtained by adopting substituted N-phenyl-binaphthyl amine 1 and 2-methylbenzene cyclic ketone 2 as raw materials and carrying out serial Heck/carbonyl ortho-position alkylation reaction under the synergistic catalysis of a palladium catalyst and a PTC catalyst. The method provides a mild, simple and efficient way for synthesizing the product.
The invention relates to a method for synthesizing indole terpene analogues by palladium-catalyzed cascade Heck/carbonyl ortho-alkylation reaction, which comprises the following steps:
wherein: X=N-P, P is selected from Ac, boc, bz, bn, cbz, ts, 4- t Bu-C 6 H 4 SO 2 、3,5-Me 2 -C 6 H 3 SO 2 、2,4,6-Me 3 -C 6 H 2 SO 2 The method comprises the steps of carrying out a first treatment on the surface of the R is selected from H, C-C4 alkyl, C1-C4 alkoxy and halogen; r is R 1 Selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxycarbonyl, phenyl.
The method comprises the following steps: the method is characterized in that substituted N-phenyl-binaphthyl amine 1 and 2-methylbenzene cyclic ketone 2 are used as raw materials, and in the presence of a palladium catalyst, a PTC catalyst and alkali, a serial Heck/carbonyl ortho-alkylation reaction is carried out, so that an indole terpene analogue 3 containing a quaternary carbon center is generated.
Further, in the above technical scheme, the palladium catalyst is Pd (PPh 3 ) 4 Or Pd (PPh) 3 ) 2 Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The PTC catalyst is selected from Et 4 NCl、Bu 4 NCl、Bu 4 NI、Bu 4 NBr、Bu 4 NHSO 4 、TEBAC。
Further, in the above technical scheme, the base is selected from CsOH.H 2 O、NaOH、Cs 2 CO 3 。
Further, in the above technical scheme, the reaction is performed in an organic solvent, and the organic solvent is selected from one or more of dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile and chlorobenzene. Preferably the solvent is methylene chloride.
Further, in the technical scheme, the molar ratio of the N-phenyldienamine 1, the benzocyclic ketone 2, the palladium catalyst and the PTC catalyst to the alkali is 1:2:0.2-0.1:0.2-0.1:2.
Further, in the above technical scheme, the reaction temperature is selected from 0-50 ℃. The preferred temperature is 25 ℃.
Further, in the above technical scheme, the whole reaction process needs to be operated under the protection of inert gas, and the inert gas is preferably nitrogen.
Further, the product indole terpene analogue 3 is further derived to obtain different types of derived products, the products are reduced by adopting a reducing agent, and the condensed ring indole terpene analogue 6, the condensed ring indole terpene analogue 9 and the condensed ring indole terpene analogue 11 are obtained by controlling different reaction temperatures.
Derivative a: the indole terpene analogue 3ad reacts in the presence of magnesium metal and ammonium chloride to obtain a compound 5, and then cyclizes in the presence of indium chloride to obtain a condensed ring indole terpene analogue 6.
Derivative B: indole terpene analogue 3ad is reacted in the presence of a methyl grignard reagent to give intermediate 7, followed by reaction in the presence of magnesium metal and ammonium chloride to give compound 8, which is then cyclized in the presence of indium chloride to give fused ring indole terpene analogue 9.
Derivative C: indole terpene analog 3ma was taken in the presence of sodium borohydride to give compound 10, followed by cyclization in the presence of indium chloride to give fused ring indole terpene analog 11.
The invention has the beneficial effects that:
1. the indole terpene analogue 3 can be obtained by one step after the o-alkylation reaction of serial Heck/carbonyl under the synergistic catalysis of Pd/phase transfer catalyst by taking benzocyclic ketone and N-phenyl-binaphthyl amine as raw materials, and has chiral quaternary carbon centers, so that the reaction is novel.
2. The method has the advantages of easily obtained reaction raw materials, high product selectivity and highest reaction yield which can reach 95 percent respectively. The products are reduced and derived to obtain different condensed ring indole terpene analogues 6, 9 and 11.
Drawings
FIG. 1 is a single crystal X-ray diffraction chart of compound 3ga in example 2;
FIG. 2 is a single crystal X-ray diffraction pattern of compound 3ha of example 3;
FIG. 3 is an X-ray diffraction pattern of compound 3ia single crystal of example 1;
FIG. 4 is an X-ray diffraction pattern of compound 3al single crystal in example 10.
Detailed Description
Example 1
Taking N-phenyldienamine 1a and benzocyclopentanone 2a as an example, 3aa is generated, the reaction condition is optimized, and the reaction equation is as follows:
a unless otherwise indicated, the steps of the reaction are as follows: 1a (0.1 mmol), 2a (0.2 mmol), pd (PPh) 3 ) 4 (20 mol%) base (2 equiv), 1.0mL solvent in N 2 The reaction was carried out for 3 hours under protection. b1 The yield of H NMR was that, c the yield was isolated. d 20 equivalents of alkali. e 1equiv. base. f 10mol％of Et 4 NCl.。
In the reaction condition screening process, the effect of PTC on the reaction was first examined (entries 1-7). At the same time, the influence of different alkalis and organic solvents on the reaction is examined, and finally Et is determined 4 NCl is the best PTC and methylene chloride is the best reaction solvent.
Reaction conditions examine typical operation: n- (2-iodophenyl) allylamine 1a (0.2 mmol,1.0 eq), pd (PPh) 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2 eq) was added to the packageThere are magnetic seeds in Schlenk tube. The reaction tube is sealed by a threaded rubber plug, vacuumized and refilled with N 2 (repeated 3 times). A solution of benzocyclopentanone 2 (0.4 mmol,2 eq)/DCM (2.0 mL) was then injected using a syringe. The reaction mixture was stirred at room temperature for 3 hours. The reaction was complete, the reaction mixture was diluted with DCM, filtered through a short silica gel column and washed with DCM/MeOH (20:1, 20 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give 3aa as a white solid in 95% yield. M.p. =112.1-115.1 ℃ TLC: R f ＝0.4(PE/EA＝5:1). 1 HNMR(600MHz,CDCl 3 )δ7.90(d,J＝8.1Hz,1H),7.73(d,J＝7.6Hz,1H),7.54(d,J＝8.2Hz,2H),7.50(t,J＝7.8Hz,2H),7.32(t,J＝7.4Hz,1H),7.30(s,1H),7.29–7.23(m,2H),7.21(t,J＝7.5Hz,1H),7.03(d,J＝8.2Hz,2H),3.11(d,J＝17.0Hz,1H),3.08(d,J＝14.6Hz,1H),2.92(d,J＝14.5Hz,1H),2.78(d,J＝17.0Hz,1H),2.24(s,3H),1.27(s,3H). 13 C NMR(150MHz,CDCl 3 )δ210.5,152.6,144.7,135.6,135.0,134.9,134.8,131.8,129.7,127.5,126.6,126.6,124.7,124.6,124.3,123.2,119.7,119.1,113.6,50.2,39.5,31.9,25.0,21.5.HRMS(ESI)m/z:[M+Na] + calcd for C 26 H 23 NNaO 3 S 452.1291；found 452.1290.
Example 2:
4-bromo-N- (2-iodophenyl) dienamine (0.2 mmol), pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq). The reaction tube was sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and a solution of benzocyclopentanone (0.4 mmol,2 eq)/DCM (2.0 mL) was injected into the reaction tube with a syringe and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as an eluent, the reaction solution was rapidly passed through a short silica gel column, and the solution was concentrated in vacuo, and the crude product was further purified by silica gel column chromatography to give 3ga as a white solid in 82% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ7.69–7.63(m,2H),7.54(d,J＝2.0Hz,1H),7.47–7.39(m,3H),7.29–7.16(m,4H),6.97(d,J＝8.1Hz,2H),3.00–2.91(m,2H),2.79–2.69(m,2H),2.19(s,3H),1.17(s,3H). 13 C NMR(101MHz,CDCl 3 )δ210.4,152.5,145.1,135.7,135.1,134.8,133.7,133.6,129.9,127.7,127.6,126.73,126.65,125.9,124.5,122.5,118.5,117.0,115.2,50.3,39.6,31.9,25.1,21.7.HRMS(ESI)m/z:[M+Na] + calcd for C 26 H 25 BrNNaO 3 S 530.0393；found 530.0393.
Example 3:
4-methyl-N- (2-iodophenyl) diene (0.2 mmol) and Pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) and the reaction tube were sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and a solution of benzocyclopentanone (0.4 mmol,2 eq)/DCM (2.0 mL) was injected into the reaction tube by a syringe and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as eluent, the reaction solution was passed through a short silica gel column rapidly, and the solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography to give 3ha as a white solid in 88% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ7.77(t,J＝7.6Hz,2H),7.59–7.48(m,3H),7.36(t,J＝7.4Hz,1H),7.33–7.27(m,2H),7.24(s,1H),7.08(dd,J＝8.5,1.6Hz,1H),7.05(d,J＝8.1Hz,2H),3.12(d,J＝17.1Hz,1H),3.04(d,J＝14.5Hz,1H),2.90(d,J＝14.5Hz,1H),2.79(d,J＝17.1Hz,1H),2.41(s,3H),2.27(s,3H),1.28(s,3H). 13 C NMR(101MHz,CDCl 3 )δ210.6,152.7,144.6,135.8,135.1,134.9,133.2,132.9,132.2,129.8,127.6,126.7,126.6,126.1,124.8,124.5,119.6,119.0,113.4,50.3,39.6,31.8,25.0,21.6,21.5.HRMS(ESI)m/z:[M+Na] + calcd for C 27 H 25 NNaO 3 S 466.1448；found 466.1448.
Example 4:
4-methoxy-N- (2-iodophenyl) dienamine (0.2 mmol), pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) was sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and a solution of benzocyclopentanone (0.4 mmol,2 eq)/DCM (2.0 mL) was injected into the reaction tube with a syringe and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as eluent, the reaction solution was passed through a short silica gel column rapidly, and after concentration of the solution in vacuo, the crude product was further purified by silica gel column chromatography to give 3ia as a white solid in 80% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(400MHz,CDCl3)δ7.78(d,J＝9.0Hz,1H),7.73(d,J＝7.6Hz,1H),7.55–7.50(m,3H),7.34(t,J＝7.6Hz,1H),7.30(d,J＝7.7Hz,1H),7.25(s,1H),7.05(d,J＝8.2Hz,2H),6.93(d,J＝2.5Hz,1H),6.86(dd,J＝9.0,2.5Hz,1H),3.82(s,3H),3.12(d,J＝17.1Hz,1H),3.05(d,J＝14.5Hz,1H),2.86(d,J＝14.5Hz,1H),2.79(d,J＝17.1Hz,1H),2.28(s,3H),1.28(s,3H). 13 C NMR(101MHz,CDCl 3 )δ210.6,152.7,144.6,135.8,135.1,134.9,133.2,132.9,132.2,129.8,127.6,126.7,126.6,126.1,124.8,124.5,119.6,119.0,113.4,50.3,39.6,31.8,25.0,21.6,21.5.HRMS(ESI)m/z:[M+Na] + calcd for C 27 H 25 NNaO 3 S 466.1448；found 466.1448.
Example 5:
n- (2-iodophenyl) dienamine (0.2 mmol), fluorobenzocyclohexanone (0.4 mmol,2.0 eq), pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) and the reaction tube was sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and then a solution of DCM (2.0 mL) was injected into the reaction tube with a syringe and stirred at room temperature for 3 hours. After the reaction, DCM/MeOH=15/1 is used as eluent, the reaction liquid is quickly passed through a short silica gel column and dissolvedAfter the liquid was concentrated in vacuo, the crude product was further purified by silica gel column chromatography to give 3ab as a white solid in 87% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(600MHz,CDCl 3 )δ7.91(d,J＝8.2Hz,1H),7.61–7.57(m,2H),7.50(d,J＝7.3Hz,1H),7.35(dd,J＝7.4,2.4Hz,1H),7.30–7.26(m,2H),7.25–7.19(m,3H),7.10(d,J＝8.2Hz,2H),3.10(d,J＝10.6Hz,1H),3.08(d,J＝8.3Hz,1H),2.92(d,J＝14.6Hz,1H),2.76(d,J＝16.5Hz,1H),2.30(s,3H),1.29(s,3H). 13 C NMR(150MHz,CDCl 3 )209.77,162.4(d,J C-F ＝247.7Hz),148.03,144.89,137.5(d,J C-F ＝7.6Hz),135.1(d,J C-F ＝45.1Hz),131.73,129.87,128.1(d,J C-F ＝7.5Hz),126.74,124.80,124.73,123.33,122.7(d,J C-F ＝24.1Hz),119.77,118.81,113.77,110.2(d,J C-F ＝21.0Hz),51.4,39.1,32.1,25.0,21.7. 19 F NMR(565MHz,CDCl 3 )δ-114.21.HRMS(ESI):m/z:[M+Na] + calcd for C 26 H 22 FNNaO 3 S 470.1197；found 470.1193.
Example 6:
n- (2-iodophenyl) dienamine (0.2 mmol) and Pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) and the reaction tube were sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and then a solution of benzocyclohexanone 2d (0.4 mmol,2 eq)/DCM (2.0 mL) was injected into the reaction tube with a syringe and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as eluent, the reaction solution was passed through a short silica gel column rapidly, and after concentration of the solution in vacuo, the crude product was further purified by silica gel column chromatography to give 3ad as a white solid in 75% yield. TLC: R f ＝0.4(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ8.08(d,J＝7.7Hz,1H),7.93(d,J＝8.1Hz,1H),7.58(d,J＝8.1Hz,2H),7.44(t,J＝8.3Hz,2H),7.34–7.27(m,2H),7.23(d,J＝7.4Hz,1H),7.19(d,J＝7.5Hz,1H),7.15(d,J＝7.6Hz,1H),6.96(d,J＝8.0Hz,2H),3.22(d,J＝14.3Hz,1H),3.02–2.90(m,1H),2.83(d,J＝14.2Hz,1H),2.81–2.73(m,1H),2.20(s,3H),1.89–1.75(m,2H),1.19(s,3H). 13 C NMR(101MHz,CDCl 3 )δ201.8,144.7,143.3,135.0,133.3,132.5,131.7,129.7,128.8,128.1,126.9,126.7,125.6,124.5,123.2,120.0,119.4,113.9,46.4,33.2,32.1,25.4,22.6,21.6.HRMS(ESI)m/z:[M+Na] + calcd for C 27 H 25 NNaO 3 S 446.1447；found 446.1447.
Example 7:
n- (2-iodophenyl) dienamine (0.2 mmol), ester-based benzocyclohexanone (0.4 mmol,2.0 eq), pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) was sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and methylene chloride (2.0 mL) was added to the reaction tube and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as eluent, the reaction solution was passed through a short silica gel column rapidly, and after concentration of the solution in vacuo, the crude product was further purified by silica gel column chromatography to give 3ae as a white solid in 96% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝8.2Hz,1H),7.95(d,J＝8.0Hz,1H),7.59(d,J＝8.4Hz,2H),7.53(d,J＝7.7Hz,1H),7.47(td,J＝7.5,1.5Hz,1H),7.41(s,1H),7.34(t,J＝7.6Hz,1H),7.30–7.21(m,2H),7.14(d,J＝7.6Hz,1H),6.96(d,J＝8.1Hz,2H),3.62(s,3H),3.58(d,J＝14.4Hz,1H),3.30(d,J＝14.4Hz,1H),3.07–2.95(m,3H),2.77–2.67(m,1H),2.50–2.41(m,1H),2.22(s,3H),1.89–1.77(m,1H). 13 C NMR(101MHz,CDCl 3 )δ194.6,172.2,144.7,143.4,135.0,134.9,133.7,132.27,132.21,129.7,128.8,128.3,127.0,126.7,126.4,124.7,123.3,119.7,118.0,114.0,59.0,52.8,31.0,29.1,26.2,21.6.HRMS(ESI)m/z:[M+Na] + calcd for C 28 H 25 NNaO 5 S 510.1346；found 510.1346.
Example 8:
n- (2-iodophenyl) dienamine (0.2 mmol) and Pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) was sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and a solution of benzolactone (0.4 mmol,2 eq)/DCM (2.0 mL) was injected into the reaction tube with a syringe and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as eluent, the reaction solution was passed through a short silica gel column rapidly, and after the solution was concentrated in vacuo, the crude product was further purified by silica gel column chromatography to give a white solid 3ag in 92% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝8.2Hz,1H),7.51(d,J＝8.5Hz,2H),7.37(d,J＝7.8Hz,1H),7.26–7.11(m,7H),6.92(s,1H),6.84(d,J＝7.9Hz,1H),3.34(d,J＝14.4Hz,1H),3.19(d,J＝14.3Hz,1H),2.34(s,3H),2.26–2.12(m,1H),2.08–1.94(m,1H),0.72(t,J＝7.4Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ179.3,153.5,144.9,135.1,134.6,130.7,129.9,129.4,128.9,126.8,125.1,124.7,124.3,123.8,123.2,119.8,116.5,113.4,110.6,54.2,33.1,31.4,21.7,9.2.HRMS(ESI)m/z:[M+Na] + calcd for C 26 H 23 NNaO 4 S 468.1240；found 468.1240.
Example 9:
n- (2-iodophenyl) dienamine (0.2 mmol,1.0 eq), 2-phenylcyclohexanone (0.4 mmol,2.0 eq) and Pd (PPh) were added successively to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) was sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and then a DCM (2.0 mL) solution was poured into the reaction tube and stirred at room temperature for 3 hours. After the reaction, DCM/MeOH=15/1 is used as eluent, the reaction solution is quickly passed through a short silica gel column, and after the solution is concentrated in vacuo, the crude product is further purified by a silica gel columnChromatography gave 3aj as a white solid in 97% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ7.90(d,J＝8.3Hz,1H),7.66(d,J＝8.3Hz,2H),7.23–7.16(m,6H),7.05–6.98(m,1H),6.94–6.88(m,3H),6.78(s,1H),3.11(d,J＝14.4Hz,1H),3.06(d,J＝14.5Hz,1H),2.53–2.43(m,1H),2.38–2.36(m,1H),3.34(s,3H),2.33–2.29(m,1H),1.97–1.89(m,1H),1.73–1.62(m,4H). 13 C NMR(101MHz,CDCl 3 )δ213.2,144.8,140.1,135.4,134.7,132.3,129.8,128.9,127.3,127.2,126.9,125.4,124.2,122.9,119.7,118.5,113.5,58.0,40.2,35.3,35.1,28.3,21.7,21.6.HRMS(ESI)m/z:[M+Na] + calcd for C 28 H 27 NNaO 3 S 480.1604；found 480.1598
Example 10:
n- (2-iodophenyl) dienamine (0.2 mmol) and Pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) and the reaction tube were sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and a solution of 2-phenylpropionaldehyde (0.4 mmol,2 eq)/DCM (2.0 mL) was injected into the reaction tube with a syringe and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as eluent, the reaction solution was passed through a short silica gel column rapidly, and after concentration of the solution in vacuo, the crude product was further purified by silica gel column chromatography to give 3al as a white solid in 86% yield. TLC: R f ＝0.3(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.92(d,J＝8.3Hz,1H),7.59(d,J＝8.4Hz,2H),7.37–7.29(m,3H),7.25–7.21(m,1H),7.19(d,J＝8.1Hz,2H),7.15–7.08(m,4H),6.88(s,1H),3.27(d,J＝14.8Hz,1H),3.22(d,J＝14.8Hz,2H),2.34(s,3H),1.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ201.7,144.9,139.2,135.2,134.8,131.9,129.8,129.0,127.8,127.6,126.9,125.2,124.5,123.1,119.6,118.0,113.7,77.5,77.2,76.8,55.0,31.6,21.7,18.7.HRMS(ESI)m/z:[M+Na] + calcd for C 25 H 23 NNaO 3 S 440.1291；found 440.1284.
Example 11:
n- (2-iodophenyl) dienoyl (0.2 mmol), pd (PPh) were added sequentially to a Schlenk tube 3 ) 4 (10mol％)、Et 4 NCl (20 mol%) and CsOH.H 2 O (0.4 mmol,2.0 eq) was sealed with a screw-threaded rubber plug, replaced with nitrogen three times, and a solution of ethyl phenylcyanoacetate (0.4 mmol,2 eq)/DCM (2.0 mL) was injected into the reaction tube with a syringe and stirred at room temperature for 3 hours. After the reaction was completed, DCM/meoh=15/1 was used as eluent, and the reaction solution was passed through a short silica gel column rapidly, and the solution was concentrated in vacuo to give a crude product. The crude product was further purified by silica gel column chromatography to give 3lr as a colorless oil in 72% yield. TLC: R f ＝0.1(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝7.9Hz,1H),7.56–7.35(m,8H),6.96(s,1H),4.24(qd,J＝7.1,2.0Hz,2H),3.79(d,J＝14.9Hz,1H),3.53(s,3H),3.47(d,J＝14.9Hz,1H),1.20(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ167.6,162.2,136.5,134.4,134.3,131.8,129.34,129.27,128.3,126.9,126.4,126.0,123.0,118.2,109.0,63.8,55.2,37.1,37.0,13.9.HRMS(ESI)m/z:[M+Na] + calcd for C 22 H 20 N 2 O 3 383.1366；found 383.1363.
Example 12:
in a 50mL reaction tube was added compound 3ad (177.5 mg,0.4 mmol). After evacuating, the mixture was backfilled 3 times with nitrogen and then injected into the methanol-benzene mixture (1:1, 15 mL) with a syringe. Activated magnesium powder (98 mg,4.0 mmol) and ammonium chloride (214 mg,4.0 mmol) were added sequentially at room temperature under nitrogen. The reaction mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride. Ethyl acetate extraction, washing with saturated sodium chloride, na 2 SO 4 DryingAfter concentration in vacuo, purification by column chromatography on ethyl acetate/petroleum ether (10/1) on silica gel afforded product 5 (84%, dr=1:5.8). TLC: R f ＝0.5(PE/EA＝5:1). 1 H NMR(400MHz,CDCl 3 ,1:4mixture)δ8.10(s,1H),7.70(d,J＝7.8Hz,1H),7.63(d,J＝8.0Hz,0.2H),7.52(d,J＝7.6Hz,1H),7.38(d,J＝8.1Hz,1H),7.31(dd,J＝7.3,1.8Hz,1H),7.25–7.08(m,7.2H),7.63(d,J＝8.0Hz,0.2H),4.56(d,J＝7.2Hz,0.2H),4.29(d,J＝4.8Hz,1H),3.06(d,J＝14.1Hz,1H),2.98–2.71(m,4H),2.15–2.00(m,1H),1.85–1.79(m,0.2H),1.74–1.55(m,3.6H),1.02(s,0.6H),0.86(s,3H). 13 C NMR(101MHz,CDCl 3 )δ139.1,138.5,136.3,136.1,130.2,129.3,129.2,128.7,128.1,127.9,127.2,126.3,126.3,123.9,123.6,121.9,121.8,119.8,119.6,119.5,119.4,112.6,112.5,111.1,111.1,75.2,74.7,38.2,38.0,34.4,32.8,31.3,29.0,26.1,25.9,21.2,19.1.HRMS(ESI)m/z:[M+Na] + calcd for C 20 H 21 NO 314.1516；found 314.1513.
Example 13:
in a 25mL reaction tube, compound 5 (72.8 mg,0.25 mmol), inCl was added 3 (5.8 mg,10 mol%). Vacuum was applied, nitrogen was backfilled 3 times, and DCE (5.0 mL) was then added to the tube with a syringe. The reaction was stirred at 80℃for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was then purified by silica gel column chromatography (10/1) to give product 6 (74%, dr)>20:1)。TLC:R f ＝0.5(PE/EA＝5:1). 1 H NMR(600MHz,CDCl 3 )δ7.71(s,1H),7.45–7.40(m,1H),7.35(d,J＝7.5Hz,1H),7.25–7.23(m,1H),7.17–7.11(m,2H),7.09–7.04(m,2H),4.09(s,1H),2.88(dd,J＝14.3,1.8Hz,1H),2.80(d,J＝14.4Hz,1H),2.04–1.97(m,1H),1.70–1.63(m,1H),7.09–7.04(m,2H),1.45(s,3H). 13 C NMR(150MHz,CDCl 3 )δ144.3,140.6,137.9,137.0,129.2,128.4,126.5,126.3,125.3,120.8,119.7,118.8,116.4,111.6,50.4,48.2,39.3,35.9,29.0,27.0.HRMS(ESI)m/z:[M+Na] + calcd for C 20 H 19 N 296.1410；found 296.1413.
Example 14:
compound 3ad (116.9 mg,0.25 mmol) was added to a 10mL reaction tube. After evacuating, nitrogen was backfilled 3 times, and dry THF (1.0 mL) was injected with a syringe. To the above stirred solution was added MeMgI (0.5 mL 3.0M Et) at room temperature 2 O solution, 6.0 eq) and then stirred at 60 ℃ for 1 hour. After the reaction is completed, saturated NH 4 Quench with Cl and extract with ethyl acetate. Anhydrous Na 2 SO 4 Drying and vacuum concentration were carried out directly for the next step.
After evacuating, the mixture was backfilled 3 times with nitrogen and then injected into the methanol-benzene mixture (1:1, 15 mL) with a syringe. Activated magnesium powder (98 mg,4.0 mmol) and ammonium chloride (214 mg,4.0 mmol) were added sequentially at room temperature under nitrogen. The reaction mixture was stirred at the same temperature for 1 hour. After the reaction was completed, saturated ammonium chloride was quenched. Ethyl acetate extraction, washing with saturated brine, na 2 SO 4 After drying and concentration in vacuo, purification by column chromatography on ethyl acetate/petroleum ether (10/1) silica gel afforded product 8 (yield 81%, dr=1:1.3). 8 major (Rf＝0.6,PE/EA＝5:1)； 1 H NMR(400MHz,CDCl 3 )δ8.07(s,1H),7.70(d,J＝7.5Hz,1H),7.53(d,J＝8.0Hz,1H),7.36(d,J＝8.1Hz,1H),7.25–7.15(m,3H),7.14–7.08(m,2H),7.03(d,J＝2.4Hz,1H),3.03(d,J＝14.2Hz,1H),3.01–2.93(m,1H),2.82–2.75(m,2H),1.91(br,1H),1.87–1.82(m,1H),1.75–1.68(m,1H),1.56(s,3H),1.06(s,3H). 13 C NMR(101MHz,CDCl 3 )δ143.9,136.1,135.4,129.2,128.8,126.9,126.5,126.1,123.3,121.9,119.8,119.4,113.3,111.1,76.4,40.8,29.7,28.9,27.0,25.8,21.2.8 minor (Rf＝0.4,petroleum ether/ethyl acetate＝5:1)； 1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),7.70(d,J＝7.8Hz,1H),7.67(d,J＝7.9Hz,1H),7.38(d,J＝7.9Hz,1H),7.25–7.10(m,4H),7.06–7.01(m,2H),3.19(d,J＝13.9Hz,1H),2.84(d,J＝13.9Hz,1H),2.78–2.64(m,2H),1.99–1.88(m,1H),1.87–1.83(m,2H),1.82(br,1H),1.63(s,3H),0.90(s,3H). 13 C NMR(101MHz,CDCl 3 )δ144.9,136.1,135.2,129.3,128.5,126.7,126.5,126.3,123.6,121.9,119.8,119.5,113.2,111.1,40.7,31.2,30.8,27.7,25.7,18.8.HRMS(ESI)m/z:[M+Na] + calcd for C 21 H 23 NO 328.1672；found 328.1675.
Example 15:
to a solution of 3ma (99.8 mg,0.36 mmol) in anhydrous MeOH (18.0 mL) at room temperature was added NaBH 4 (36 mg,0.9 mmol). The reaction was stirred until the starting material disappeared (TLC monitoring). Solvent was removed in vacuo and the crude reaction mixture dr was used 1 HNMR assay. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give product 10 (yield 97%, dr=1:2.2). 10 major (R f ＝0.35,PE/EA＝5:1)； 1 H NMR(600MHz,CDCl 3 )δ8.06(s,1H),7.57(d,J＝7.9Hz,1H),7.41(d,J＝7.1Hz,1H),7.34(d,J＝8.1Hz,1H),7.29–7.16(m,1H),7.25–7.17(m,3H),7.11(t,J＝7.5Hz,1H),7.07(d,J＝2.2Hz,1H),4.75(s,1H),3.07(d,J＝15.7Hz,1H),3.00(d,J＝14.2Hz,1H),2.87(d,J＝14.2Hz,1H),2.46(d,J＝15.6Hz,1H),1.86(br,1H),1.08(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.8,142.6,136.0,129.1,128.5,126.8,125.5,124.8,123.5,121.8,119.5,119.4,113.3,111.1,83.5,48.9,42.7,29.0,24.5.10 minor (Rf＝0.3,PE/EA＝5:1)； 1 H NMR(600MHz,CDCl 3 ,1:5mixture)δ8.07(s,1H),7.61(d,J＝7.9Hz,1H),7.57(d,J＝7.8Hz,0.2H),7.41(d,J＝7.2Hz,0.2H),7.36–7.31(m,2.2H),7.29–7.24(m,0.6H),7.21–7.17(m,3H),7.16–7.09(m,2.4H),7.08(d,J＝2.4Hz,0.2H),7.03(d,J＝2.4Hz,1H),5.02(s,1H),4.75(s,0.2H),3.07(d,J＝15.0Hz,0.2H),3.02–2.96(m,2.2H),2.92(d,J＝15.4Hz,1H),2.65(d,J＝15.4Hz,1H),2.46(d,J＝15.6Hz,1H),1.81(br,0.2H),1.63(br,1H),1.08(s,0.6H),1.06(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.4,142.6,141.3,136.1,136.0,129.1,128.7,128.5,128.0,126.8,126.7,125.5,125.2,124.8,124.3,123.5,123.3,122.0,121.8,119.7,119.5,119.4,119.3,113.4,111.2,111.1,83.5,81.6,50.0,48.9,43.0,42.7,34.4,29.0,24.5,19.9.HRMS(ESI)m/z:[M+Na] + calcd for C 19 H 19 NO 300.1359；found 300.1362.
The foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
Claims (8)
1. The method for synthesizing the indole terpene analogues by palladium-catalyzed serial Heck/carbonyl ortho-alkylation reaction is characterized by comprising the following steps of: taking substituted N-phenyl-binaphthyl amine 1 and 2-methylbenzene cyclic ketone 2 as raw materials, and carrying out a serial Heck/carbonyl ortho-alkylation reaction in the presence of a palladium catalyst, a PTC catalyst and alkali to generate indole terpene analogues 3 containing quaternary carbon centers;
the reaction equation is expressed as:
wherein: X=N-P, P is selected from Ac, boc, bz, bn, cbz, ts, 4- t Bu-C 6 H 4 SO 2 、3,5-Me 2 -C 6 H 3 SO 2 、2,4,6-Me 3 -C 6 H 2 SO 2 The method comprises the steps of carrying out a first treatment on the surface of the R is selected from H, C-C4 alkyl, C1-C4 alkoxy and halogen; r is R 1 Selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxycarbonyl, phenyl.
2. The method for synthesizing an indole terpene analog according to claim 1, wherein: the palladium catalyst is Pd (PPh) 3 ) 4 Or Pd (PPh) 3 ) 2 Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The PTC catalyst is selected from Bu 4 NHSO 4 、Et 4 NCl、Bu 4 NCl、Bu 4 NI、Bu 4 NBr or TEBAC.
3. The method for synthesizing an indole terpene analog according to claim 1, wherein: the reaction is carried out in an organic solvent selected from dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile or chlorobenzene.
4. The method for synthesizing an indole terpene analog according to claim 1, wherein: the base is selected from CsOH.H 2 O, naOH or Cs 2 CO 3 。
5. The method for synthesizing an indole terpene analog according to claim 1, wherein: the molar ratio of the N-phenyldienamine 1, the benzocyclic ketone 2, the palladium catalyst and the PTC catalyst to the alkali is 1:2:0.2-0.1:0.2-0.1:2.
6. The method for synthesizing an indole terpene analog according to claim 1, wherein: the reaction temperature is 0-50 ℃.
7. The synthesis of the condensed ring indole terpene analogue 6 is characterized by comprising the following steps:
the indole terpene analogue 3ad obtained by any one of claims 1-6 is then reacted with indole terpene analogue 3ad in the presence of magnesium metal and ammonium chloride to give compound 5, which is cyclized in the presence of indium chloride to give the condensed ring indole terpene analogue 6.
8. The synthesis of the condensed ring indole terpene analogue 9 is characterized by comprising the following steps:
the use of any one of claims 1-5 to provide indole terpene analogues 3ad, followed by reaction of indole terpene analogues 3ad in the presence of a methyl grignard reagent to provide intermediate 7, followed by reaction in the presence of magnesium metal and ammonium chloride to provide compound 8, followed by cyclization in the presence of indium chloride to provide fused ring indole terpene analogues 9.
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| "Asymmetric Domino Heck/Dearomatization Reaction of β‑Naphthols to Construct Indole−Terpenoid Frameworks";Dong-Chao Wang et al.;《Organic Letters》;第23卷;第7865-7872页 * |
| "Chiral Spiro Phosphoric Acid-Catalyzed Friedel−Crafts Conjugate Addition/Enantioselective Protonation Reactions";Yi-Pan Li et al.;《ACS Catalysis》;第9卷;第6522-6529页 * |
| "Palladium-Catalyzed Allenamide Carbopalladation/Allylation with Active Methine Compounds";Xiaoyi Zhu et al.;《Organic Letters》;第23卷;第4630-4634页 * |
| "Substrate-Dependent Regioselectivity: Pd/PTC Cooperatively Catalyzed Domino Heck/Allylation of Allenamides with α‑Carbon of Carbonyl Compounds";Dong-Chao Wang et al.;《The Journal of Organic Chemistry》;第87卷;第14284-14298页 * |
| "Synthesis of cyclopent[b]indoles by formal [3+2]-addition of indolylmethyl cations to alkenes";Carrie-Ann Harrison et al.;《Tetrahedron Letters》;第34卷(第52期);第8527-8530页 * |
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| CN115340485A (en) | 2022-11-15 |
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