CN108003160A - The method of one kind synthesis [a]-ring annulated indole analog derivative - Google Patents

The method of one kind synthesis [a]-ring annulated indole analog derivative Download PDF

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CN108003160A
CN108003160A CN201610961417.3A CN201610961417A CN108003160A CN 108003160 A CN108003160 A CN 108003160A CN 201610961417 A CN201610961417 A CN 201610961417A CN 108003160 A CN108003160 A CN 108003160A
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indole
synthetic method
mole
reaction
substituted indole
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CN108003160B (en
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姜超
高亚东
李建华
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Nanjing University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
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Abstract

The invention discloses a kind of method of synthesis [a] ring annulated indole class compound.Under the action of palladium catalyst, using norbornene as transient state left hand material, using alkylene dihalide as alkylating reagent, under the action of alkali, treat different things alike and successively realize the Domino reaction of C2 alkylations of substituted indole and N H cyclizations, effectively synthesize [a] cyclisation substituent indole compound.The method mild condition, directly using commercially available substituted indole as substrate, eliminate pre- function dough process, reduce reactions steps, with higher Atom economy, simple indoles small molecule structure is modified, [a] ring annulated indole analog derivative can be further used for the research such as medical or fully synthetic, have higher potential value and wide application prospect in fields such as pharmaceutical chemistry.

Description

The method of one kind synthesis [a]-ring annulated indole analog derivative
Technical field
The invention belongs to technical field of organic synthetic chemistry, and in particular to one kind synthesis [a]-ring annulated indole analog derivative Method.
Background technology
All contain indoles skeleton in many biologically active natural and non-natural compounds.Such as in numerous biologies In alkaloid compound, indoles alkaloid just account for a quarter.The Benzazole compounds organic compound important as one kind, It is widely used in the fields such as medicine, pesticide, food, feed addictive and dye industry.The nuclear structure of [a]-ring annulated indole is deposited It is many biologically active indole derivatives such as mitomycins and pervone etc., in materials chemistry, medical chemistry, dyestuff It is widely used Deng field.The only a small amount of report of the method for synthesis [a]-ring annulated indole at present, such as utilize indoles organoboron reagent Intramolecular alkyl transport reaction method for the treatment of different things alike, (Ishikura M, Terashima shown in the A in following route M.Tetrahedron letters,1992,33(45):6849-6852.Ishikura M,Ida W,Yanada K.Tetrahedron,2006,62(5):1015-1024.)；Wittig methods as shown in the B in route (Schweizer E E, Light K K.The Journal of Organic Chemistry,1966,31(3):870-872.)；Freely it is cyclization and Substitution technique, (Ziegler F E, the Jeroncic L O.The Journal of Organic as shown in the C 1 in route Chemistry,1991,56(11):3479-3486.Caddick S,Aboutayab K,West R.Synlett,1993, 1993(03):231-232.Caddick S,Aboutayab K,West R I.Journal of the Chemical Society,Chemical Communications,1995(13):1353-1354.) and transition metal-catalyzed hydrocarbon work Change method, (Artis D R, Cho I S, Jaime-Figueroa S, the et al.The as shown in C 2 and D in route Journal of Organic Chemistry,1994,59(9):2456-2466.Venning A R O,Bohan P T, Alexanian E J.Journal of the American Chemical Society,2015,137(11):3731- 3734.Kaldas S J,Cannillo A,McCallum T,et al.Organic letters,2015,17(11):2864- 2866.Siebeneicher H,Bytschkov I,Doye S.Angewandte Chemie International Edition,2003,42(26):3042-3044.) etc..However, the method for these conventional synthesis [a]-ring annulated indole compounds is led to Often need to indole substrate pre-activate, by the synthetic route of multistep, often also can only obtain relatively low yield.
The content of the invention
It is an object of the invention to provide a kind of mild condition, higher yields, environmentally protective synthesis [a]-ring annulated indole The method of derivative.
To achieve these goals, technical scheme is as follows：Logical formula (I) [a]-ring annulated indole of one kind synthesis derives The method of thing,
It is by leading to the substituted indole of formula (II) and the alkylene dihalide of logical formula (III)
In palladium catalyst, norbornene, under the participation of alkali and water, realizes C2 alkylations of substituted indole and N-H cyclizations Domino reaction, its reaction expression are：
Wherein, R bases are selected from hydrogen, alkoxy, nitro, cyano group, halogeno-group, methyl, amino, acyl group etc., and R bases are replaced in indoles C3, C4, C5, C6 or C7 position of ring；
Wherein, X1Selected from bromine, X2Selected from chlorine, bromine；
Wherein, n is selected from 1,2,3 ...
Comprise the following steps that：
By substituted indole, alkylene dihalide, palladium catalyst, norbornene, alkali soluble in the mixed solvent, after mixing instead When answering 12-36 small, reaction temperature is set as 80 ± 20 DEG C, and short silica gel is filtered to remove indissoluble impurity after reaction, with acetic acid second Ester and water extract 3 times, are extracted 1 time with bittern, and organic phase removes solvent and obtains crude product, up to mesh after crude by column chromatography separation Mark compound.
In one embodiment of the invention, alkylene dihalide selects 1,3- dibromopropanes, and mole is rubbed for substituted indole 2.5 times of that amount.
In one embodiment of the invention, for palladium catalyst using double acetonitrile palladium chlorides, its mole is substituted indole 0.1 times of mole.
In one embodiment of the invention, norbornene mole is 5 times of substituted indole mole.
In one embodiment of the invention, alkali selects cesium carbonate or potassium carbonate, its mole to rub for Benzazole compounds 2-4 times of that amount.
In one embodiment of the invention, solvent selects the mixed solvent of DMA or DMF and water, and water is in the mixed solvent Concentration be 0.5M.
Compared with prior art, remarkable result of the invention is as follows：
(1) use is easy to get extensively, cheap indoles synthesizes [a]-ring annulated indole class as starting material, a step cascade reaction Compound, it is more efficient than traditional multi-step synthetic methods.
(2) with the reaction method of hydrocarbon activation, the pre-activate that conventional synthetic method is reacted, Atom economy are avoided Height, method green are easy.
Embodiment
The present invention is described in further detail below by way of illustrative example.
Experimental example 1
The synthesis of 2,3- dihydro -1H- pyrroles [1,2-a] indoles
Precise 1H- indole reactions thing (0.2mmol, 23.4mg), is transferred to reaction vessel, and 1 is added to reaction vessel, 3- dibromopropanes (0.5mmol, 50 μ L), PdCl2(MeCN)2(10%mmol, 5.2mg), norbornene (1.0mmol, 94.2mg), cesium carbonate (0.8mmol, 260.7mg), is added dropwise 1mLDMA and 9 μ L water in heavy wall pressure pipe, screws reaction pipe close Reaction system is sealed, 80 DEG C is heated to, reacts 12h under oil bath stirring condition.After reaction, reaction solution is cooled to room Temperature, short silica gel are filtered to remove indissoluble impurity, are extracted 3 times with ethyl acetate and water, are extracted 1 time with bittern, and organic phase removes solvent Crude product is obtained, crude product carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50) production of clean dry, is obtained Thing, yield 60%.1H NMR (300MHz, CDCl3) δ 7.55 (d, J=7.9Hz, 1H), 7.25 (d, J=9.2Hz, 1H), 7.09 (dtd, J=14.6,7.0,1.1Hz, 2H), 6.17 (d, J=0.8Hz, 1H), 4.13-4.01 (m, 2H), 3.03 (t, J= 7.4Hz, 2H), 2.61 (dd, J=14.2,7.2Hz, 2H) spectrograms are consistent with the data of document report.(Ishikura M,Ida W,Yanada K.Tetrahedron,2006,62(5):1015-1024.)
Experimental example 2
The synthesis of 2,3- dihydro -1H- pyrroles [1,2-a] indoles
Precise 1H- indole reactions thing (0.2mmol, 23.4mg), is transferred to reaction vessel, and 1- is added to reaction vessel Bromo- 3- chloropropanes (0.5mmol), PdCl2(MeCN)2(10%mmol, 4.48mg), norbornene (0.2mmol, 55mg), carbon Sour caesium (0.8mmol, 10.8mg), is added dropwise 1mLDMA and 9 μ L water in heavy wall pressure pipe, and screwing reaction pipe close makes reaction system close Envelope, is heated to 80 DEG C, reacts 12h under oil bath stirring condition.After reaction, reaction solution is cooled to room temperature, short silica gel filtering Indissoluble impurity is removed, is extracted 3 times with ethyl acetate and water, is extracted 1 time with bittern, organic phase removes solvent and obtains crude product, thick production Thing carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50) product of clean dry, yield 34%, are obtained.1H NMR (300MHz, CDCl3) δ 7.55 (d, J=7.9Hz, 1H), 7.25 (d, J=9.2Hz, 1H), 7.09 (dtd, J=14.6, 7.0,1.1Hz, 2H), 6.17 (d, J=0.8Hz, 1H), 4.13-4.01 (m, 2H), 3.03 (t, J=7.4Hz, 2H), 2.61 (dd, J=14.2,7.2Hz, 2H) spectrograms are consistent with the data of document report.(Ishikura M,Ida W,Yanada K.Tetrahedron,2006,62(5):1015-1024.)
Experimental example 3
The synthesis of 2,3- dihydro -1H- pyrroles [1,2-a] indoles
Precise 1H- indole reactions thing (0.2mmol, 23.4mg), is transferred to reaction vessel, and 1 is added to reaction vessel, 3- dibromopropanes (0.5mmol, 50 μ L), PdCl2(MeCN)2(10%mmol, 5.2mg), norbornene (1.0mmol, 94.2mg), cesium carbonate (0.8mmol, 260.7mg), is added dropwise 1mLDMF and 9 μ L water in heavy wall pressure pipe, screws reaction pipe close Reaction system is sealed, 80 DEG C is heated to, reacts 12h under oil bath stirring condition.After reaction, reaction solution is cooled to room Temperature, short silica gel are filtered to remove indissoluble impurity, are extracted 3 times with ethyl acetate and water, are extracted 1 time with bittern, and organic phase removes solvent Crude product is obtained, crude product carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50) production of clean dry, is obtained Thing, yield 49%.1H NMR (300MHz, CDCl3) δ 7.55 (d, J=7.9Hz, 1H), 7.25 (d, J=9.2Hz, 1H), 7.09 (dtd, J=14.6,7.0,1.1Hz, 2H), 6.17 (d, J=0.8Hz, 1H), 4.13-4.01 (m, 2H), 3.03 (t, J= 7.4Hz, 2H), 2.61 (dd, J=14.2,7.2Hz, 2H) spectrograms are consistent with the data of document report.(Ishikura M,Ida W,Yanada K.Tetrahedron,2006,62(5):1015-1024.)
Experimental example 4
The synthesis of 5- methoxyl groups -2,3- dihydro -1H- pyrroles [1,2-a] indoles
Precise 5- methoxyl group -1H- indole reactions things (0.2mmol, 29.4mg), are transferred to reaction vessel, to reaction Container adds 1,3- dibromopropanes (0.5mmol, 50 μ L), PdCl2(MeCN)2(10%mmol, 5.2mg), norbornene (1.0mmol, 94.2mg), cesium carbonate (0.8mmol, 260.7mg), is added dropwise 1mLDMA and 9 μ L water in heavy wall pressure pipe, screws Reaction pipe close seals reaction system, is heated to 80 DEG C, reacts 12h under oil bath stirring condition.After reaction, it is reaction solution is cold But indissoluble impurity is filtered to remove to room temperature, short silica gel, is extracted 3 times with ethyl acetate and water, extracted 1 time with bittern, organic phase is gone Except solvent obtains crude product, crude product carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50), obtain pure dry Dry product, yield 57%.1H NMR (300MHz, CDCl3) δ 7.13 (d, J=8.8Hz, 1H), 7.04 (d, J=2.2Hz, 1H), 6.78 (dd, J=8.7,2.3Hz, 1H), 6.09 (s, 1H), 4.03 (t, J=6.9Hz, 2H), 3.85 (s, 3H), 3.01 (t, J=7.3Hz, 2H), 2.67-2.54 (m, 2H) spectrograms are consistent with the data of document report.(Ishikura M,Ida W, Yanada K.Tetrahedron,2006,62(5):1015-1024.)
Experimental example 5
The synthesis of chloro- 2,3- dihydros -1H- pyrroles [1,2-a] indoles of 6-
The chloro- 1H- indole reactions things (0.2mmol, 30.3mg) of precise 6-, are transferred to reaction vessel, to reaction vessel Add 1,3- dibromopropanes (0.5mmol, 50 μ L), PdCl2(MeCN)2(10%mmol, 5.2mg), norbornene (1.0mmol, 94.2mg), cesium carbonate (0.4mmol, 130.3mg), is added dropwise 1mLDMA and 9 μ L water in heavy wall pressure pipe, screws reaction pipe close Reaction system is sealed, 80 DEG C is heated to, reacts 24h under oil bath stirring condition.After reaction, reaction solution is cooled to room Temperature, short silica gel are filtered to remove indissoluble impurity, are extracted 3 times with ethyl acetate and water, are extracted 1 time with bittern, and organic phase removes solvent Crude product is obtained, crude product carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50) production of clean dry, is obtained Thing, yield 47%.1H NMR (300MHz, CDCl3) δ 7.43 (d, J=8.4Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J= 8.4,1.8Hz, 1H), 6.13 (s, 1H), 4.01 (d, J=6.9Hz, 2H), 3.00 (d, J=7.7Hz, 2H), 2.64-2.58 (m, 2H).13C NMR(75MHz,CDCl3)δ145.37,132.94,131.74,125.85,120.95,119.57,109.33, 92.53,43.54,27.68,24.15.
Experimental example 6
The synthesis of iodo- 2,3- dihydros -1H- pyrroles [1,2-a] indoles of 5-
The iodo- 1H- indole reactions things (0.2mmol, 48.6mg) of precise 5-, are transferred to reaction vessel, to, answer container to add Enter 1,3- dibromopropanes (0.5mmol, 50 μ L), PdCl2(MeCN)2(10%mmol, 5.2mg), norbornene (1.0mmol, 94.2mg), cesium carbonate (0.4mmol, 130.3mg), is added dropwise 1mLDMA and 9 μ L water in heavy wall pressure pipe, screws reaction pipe close Reaction system is sealed, 80 DEG C is heated to, reacts 12h under oil bath stirring condition.After reaction, reaction solution is cooled to room Temperature, short silica gel are filtered to remove indissoluble impurity, are extracted 3 times with ethyl acetate and water, are extracted 1 time with bittern, and organic phase removes solvent Crude product is obtained, crude product carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50) production of clean dry, is obtained Thing, yield 52%.1H NMR (300MHz, CDCl3) δ 7.66 (d, J=1.6Hz, 1H), 7.19 (dd, J=8.5,1.8Hz, 1H), 7.09 (d, J=8.5Hz, 1H), 6.11 (d, J=0.6Hz, 1H), 4.03 (t, J=7.0Hz, 2H), 3.02 (t, J= 7.5Hz,2H),2.66–2.57(m,2H).13C NMR(75MHz,CDCl3)δ145.89,134.81,131.26,122.74, 122.60,112.29,110.61,92.05,43.70,27.69,24.29.
Experimental example 7
The synthesis of 2- nitro -6,7,8,9- tetrahydropyridines simultaneously [1,2- α] indoles
5 nitro -1H- indole reactions thing (0.2mmol, 32.4mg) of precise, is transferred to reaction vessel, to reaction vessel Add 1,4- dibromobutanes (0.5mmol, 60 μ L), PdCl2(MeCN)2(10%mmol, 5.2mg), norbornene (1.0mmol, 94.2mg), potassium carbonate (0.8mmol, 110.6mg), is added dropwise 1mLDMA and 9 μ L water in heavy wall pressure pipe, screws reaction pipe close Reaction system is sealed, 80 DEG C is heated to, reacts 36h under oil bath stirring condition.After reaction, reaction solution is cooled to room Temperature, short silica gel are filtered to remove indissoluble impurity, are extracted 3 times with ethyl acetate and water, are extracted 1 time with bittern, and organic phase removes solvent Crude product is obtained, crude product carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50) production of clean dry, is obtained Thing, yield 30%.1H NMR (500MHz, CDCl3) δ 8.46 (d, J=2.1Hz, 1H), 8.04 (dd, J=8.9,2.2Hz, 1H), 7.24 (s, 1H), 6.36 (s, 1H), 4.10 (t, J=6.2Hz, 2H), 3.01 (t, J=6.3Hz, 2H), 2.14-2.09 (m,2H),1.94–1.90(m,2H).
Experimental example 8
The synthesis of 5- cyano group -2,3- dihydro -1H- pyrroles [1,2-a] indoles
Precise 5- cyano-1 H-indols reactant (0.2mmol, 36.4mg), is transferred to reaction vessel, to, answer container Add 1,3- dibromopropanes (0.5mmol, 50 μ L), PdCl2(MeCN)2(10%mmol, 5.2mg), norbornene (1.0mmol, 94.2mg), potassium carbonate (0.8mmol, 110.6mg), is added dropwise 1mLDMA and 9 μ L water in heavy wall pressure pipe, screws reaction pipe close Reaction system is sealed, 80 DEG C is heated to, reacts 24h under oil bath stirring condition.After reaction, reaction solution is cooled to room Temperature, short silica gel are filtered to remove indissoluble impurity, are extracted 3 times with ethyl acetate and water, are extracted 1 time with bittern, and organic phase removes solvent Crude product is obtained, crude product carries out column chromatography for separation (eluant, eluent：Ethyl acetate/petroleum ether=1:50) production of clean dry, is obtained Thing, yield 47%.1H NMR (500MHz, CDCl3) δ 7.84 (s, 1H), 7.32 (ddd, J=8.4,2.3,1.3Hz, 1H), 7.23 (dd, J=8.4,2.1Hz, 1H), 6.22 (s, 1H), 4.09 (td, J=7.0,2.2Hz, 2H), 3.04 (dd, J=7.8, 7.1Hz,2H),2.68–2.61(m,2H).13C NMR(126MHz,CDCl3)δ147.25,134.23,132.94,125.59, 123.28,121.29,110.14,101.83,93.63,77.44,77.19,76.94,43.89,27.84,24.31.。

Claims (10)

1. the synthetic method of logical formula (I) [a]-ring annulated indole derivatives,
It is by logical formula (II) substituted indole and logical formula (III) alkylene dihalide
In palladium catalyst, norbornene, under the participation of alkali and water, realize C2 alkylations of substituted indole and N-H cyclizations more meters Promise is reacted,
Wherein, R bases are selected from hydrogen, alkoxy, nitro, cyano group, halogeno-group, methyl, amino or acyl group, and R bases are replaced in indole ring C3, C4, C5, C6 or C7；
X1Selected from bromine, X2Selected from chlorine, bromine；
N is selected from 1,2,3 ....
2. synthetic method as claimed in claim 1, it is characterised in that R bases are selected from hydrogen, alkoxy, nitro, cyano group, halogeno-group.
3. synthetic method as claimed in claim 1, it is characterised in that n is selected from 1 or 2.
4. synthetic method as claimed in claim 1, it is characterised in that alkylene dihalide selects 1,3- dibromopropanes, mole For 2.5 times of substituted indole mole.
5. synthetic method as claimed in claim 1, it is characterised in that palladium catalyst is using double acetonitrile palladium chlorides, its mole Measure as 0.1 times of substituted indole mole.
6. synthetic method as claimed in claim 1, it is characterised in that it is Yin that alkali, which selects cesium carbonate or potassium carbonate, its mole, 2-4 times of diindyl class compound mole.
7. synthetic method as claimed in claim 1, it is characterised in that norbornene mole is the 5 of substituted indole mole Times.
8. synthetic method as claimed in claim 1, it is characterised in that solvent selects the mixed solvent of DMA or DMF and water, water It is 0.5M in the concentration of in the mixed solvent.
9. synthetic method as claimed in claim 1, it is characterised in that reaction temperature is 60-100 DEG C.
10. synthetic method as claimed in claim 1, it is characterised in that when the reaction time is 12-36 small.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110437068A (en) * 2019-07-30 2019-11-12 武汉大学 A kind of preparation method of aromatic hydrocarbons methylation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110437068A (en) * 2019-07-30 2019-11-12 武汉大学 A kind of preparation method of aromatic hydrocarbons methylation
CN110437068B (en) * 2019-07-30 2020-11-03 武汉大学 Preparation method of aromatic methylation

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