Genre: Information/Explanation

Base-Promoted Intermolecular Cyclization of Substituted 3-Aryl ( Heteroaryl ) - 3-chloroacrylaldehydes and Tetrahydroisoquinolines : An Approach to Access Pyrrolo [ 2 , 1-a ] isoquinolines Ziqi Yang , Ning Lu , Zhonglin Wei , Jungang Cao , Dapeng Liang , Haifeng Duan * , and Yingjie Lin * Department of Organic Chemistry , College of Chemistry , Jilin University , Changchun 130012 , P. R. China J. Org . Chem . , Article ASAP DOI : 10.1021 / acs . joc . 6b01781 Publication Date ( Web ) : November 1 , 2016 Copyright © 2016 American Chemical Society OpenURL MASARYK UNIV Abstract We have developed a new base-promoted intermolecular cascade cyclization reaction of substituted 3-aryl ( heteroaryl ) - 3-chloroacrylaldehydes and tetrahydroisoquinolines in one pot . The reaction provides a facile and practical synthesis of pyrrolo [ 2 , 1-a ] isoquinolines . A number of pyrrolo [ 2 , 1-a ] isoquinolines were synthesized in moderate to high yields ( up to 97 % ) . Pyrrolo [ 2 , 1-a ] isoquinoline ( 1-4 ) ( Scheme 1a ) framework is ubiquitous in various natural products and some biologically active molecules . Representative compounds such as lamellarin D , lamellarin a 20-sulfate , and derivatives crispine A , trolline , and oleracein E are depicted in Scheme 1 . Among them , lamellarin D is a potent inhibitor of human topoisomerase I , ( 5 ) lamellarin a 20-sulfate is an inhibitor of HIV integrase , ( 6 ) and even other lamellarins exhibit anticancer activity ; ( 7-9 ) in addition , crispine A emerged as a target of great interest , due to potential biological and pharmaceutical activities . ( 10 , 11 ) The synthesis of pyrolo [ 2 , 1-a ] isoquinoline derivatives has been the focus of organic chemists' research for a long time . ( 12-18 ) Accordingly , a number of synthetic methods which include metal and metal-free catalysis have been reported . Sequential elegant studies ( Scheme 2 ) using metal catalysis ( e.g. , Ir , Ru , Rh , Ag , Cu , etc. ) were accomplished by several research groups . ( 19-27 ) Scheme 1 . Representative Natural Products Scheme 2 . Existing Strategies for the Synthesis of Pyrrolo [ 2 , 1-a ] isoquinolines In recent years , metal-free catalysis has been of great interest in the construction of the pyrrolo [ 2 , 1-a ] isoquinoline framework . These metal-free catalysis pathways involve stepwise coupling of radicals , which were in situ formed in the presence of t-BuOK / DMF , ( 28 ) or a concerted reaction followed by oxidation in the I2 / H2O2 , ( 29 ) KI / TBHP , ( 30 ) or TBAI / TBHP ( 31 ) system , such as [ 3 + 2 ] cycloaddition between 1 , 4-dicarbonyl-2-butenes and alkyl 2 - ( 3 , 4-dihydroisoquinolin-2 ( 1H ) - yl ) acetates . Although aforementioned successful synthetic methods have been developed , new and facile approaches are still desirable in terms of great structural diversity of pyrrolo [ 2 , 1-a ] isoquinoline derivatives . In this context , we developed a new and facile synthetic method for pyrrolo [ 2 , 1-a ] isoquinolines which include an intermolecular cascade cyclization of substituted 3-aryl ( heteroaryl ) - 3-chloroacrylaldehydes and tetrahydroisoquinolines in a one-pot reaction promoted by Et3N / DMF . Initially , the optimal reaction conditions in Yan's work ( 28 ) were also used to examine the reaction of ( Z ) - 3-chloro-3-phenylacrylaldehyde ( 1a ) with THIQ ( 1 , 2 , 3 , 4-tetrahydroisoquinoline , 2a ) . Unfortunately , 3-phenyl-5 , 6-dihydropyrrolo [ 2 , 1-a ] isoquinoline ( 4a ) has not been detected , and the substrate 1a was transformed to complex byproducts ( Table 1 , entry 1 ) . Surprisingly , reducing the basicity of inorganic bases is beneficial to the reaction ; for example , when NaOH or K2CO3 was used as the base , the product 4a was obtained in 34 % and 42 % isolated yields respectively ( entries 2 and 3 ) , and 4a was confirmed by crystal structure ( CCDC : 1421171 ; ( 32 ) for more details please see Supporting Information ) . Encouraged by these preliminary results , a variety of organic bases such as DBU ( 1 , 8-diazabicyclo [ 5 . 4 . 0 ] undec-7-ene ) , DABCO ( 1 , 4-diazabicyclo [ 2 . 2 . 2 ] octane ) , DIPEA ( N , N-diisopropylethylamine ) , DMAP ( 4-dimethylaminopyridine ) , TMEDA ( tetramethylethylenediamine ) , and TEA ( trimethylamine ) were used instead of K2CO3 . Obviously , among these bases , TEA gave the best yield ( 56 % , entry 4 ) , and remarkably , DMAP gave us an extreme decrease in yield ( 26 % , entry 8 ) , which might due to DMAP being a weak nucleophile but a strong base . ( 33 ) Thus , we used TEA as the optimal base for further optimization including in the screening of solvents , reaction temperature , additives , and the loading of substrates . As results show in Table 1 , compared with DMF , the high polarity of solvents such as DMSO was also beneficial to the reaction ( 48 % , entry 10 ) ; however , compared with DMF or DMSO , other solvents of relatively low polarity , such as , CH2Cl2 , THF , and CH3CN ( entries 11 , 12 , and 13 ) , gave a trace amount of product 4a . The results showed that the reaction temperature has an apparent effect on the reaction ; both a lower and higher temperature would depress the conversion of substrates ( entries 14 and 15 ) . In addition , some additives such as activated 4 Å molecular sieves and silica or the oxidant MnO2 could not apparently improve the yields ( separately 55 % , 55 % , entries 16 , 17 , and 18 ) ; Gratifyingly , increasing the amount of THIQ and TEA led to a high yield ( 93 % , entry 19 ; for more details , see SI Table 1 ) ; Further experiments exhibited that oxygen had no impact on this reaction in which a radical pathway might not be involved . Ultimately , the optimal reaction conditions identified were as follows : 2.5 equiv of TEA , 4 equiv of THIQ , DMF used as solvent , and a reaction temperature of 120 ° C. Table 1 . Optimization of Reaction Conditionsa entry T ( ° C ) base additive solvent yieldb ( % ) 1 90 / 120 t-BuOK – DMF N.D. c 2 120 NaOH – DMF 34 3 120 K2CO3 – DMF 42 4 120 TEA – DMF 56 5 120 DBU – DMF 31 6 120 DABCO – DMF 45 7 120 DIPEA – DMF 50 8 120 DMAP – DMF 26 9 120 TMEDA – DMF 47 10 120 TEA – DMSO 48 11 reflux TEA – DCE traced 12 reflux TEA – THF trace 13 reflux TEA – MeCN trace 14 100 TEA – DMF 38 15 150 TEA – DMF 42 16 120 TEA 4 Å DMF 55e 17 120 TEA silica DMF 55e 18 120 TEA MnO2 DMF 38e 19 120 TEA – DMF 93f 20 120 TEA – DMF 92g aReaction conditions : 1a ( 1 . 20 mmol ) , 2a ( 1 . 80 mmol ) , 3a ( 1 . 80 mmol ) , solvent ( 3 mL ) , at 120 ° C 16 h , under Ar protection . bIsolated yield of 4a . cNo desired product ; detected by HRMS . dDetected by HRMs . eAdditive / 1a ( m / m = 1 : 1 ) . f1a ( 1 . 20 mmol ) , 2a ( 4 . 80 mmol ) , 3a ( 3 . 00 mmol ) . g1a ( 1 . 20 mmol ) , 2a ( 4 . 80 mmol ) , 3a ( 3 . 00 mmol ) , without Ar protection . With optimized conditions in hand ( Table 1 , entry 20 ) , we next explored the scope and limitations of this reaction by employing various ( Z ) - 3-aryl ( heteroaryl ) - 3-chloroacrylaldehydes 1 and THIQs 2 ( Scheme 2 ) . An assembly of 20 compounds were synthesized using this protocol and gave the best yield up to 97 % . The results indicated that compounds 1 with electron-withdrawing ( F , Cl , Br , and NO2 ) or electron-donating groups ( Me and OMe ) were well tolerated and provided the corresponding products in moderate to high yields . As shown in Table 2 , when R1 is a meta - or para-substituted group on the phenyl ring , the corresponding product was obtained in a high yield ( up to 97 % , 4e ) . However , ortho-substituents such as F and Br due to their steric hindrance are not beneficial to the reaction ( 34 % 4g and 43 % 4k ) ; surprisingly the substrate which involves ortho-substituent OMe gave a satisfying yield of 71 % ( 4b ) . Substrates with the substituent R2 such as Me and phenyl all provided corresponding products in good to excellent yields respectively ( 84 % 4o and 61 % 4q ) . Table 2 . Scope of Tandem Reactiona Table aReaction conditions : 1a ( 1 . 20 mmol ) , 2a ( 4 . 80 mmol ) , 3a ( 3 . 00 mmol ) , solvent ( 3 mL ) , at 120 ° C 16 h , without Ar protection . Similarly , 1-chloro-3 , 4-dihydronaphthalene-2-carbaldehyde also gave corresponding product 4p in 41 % yield . Subsequently , when condensed 3-aryl - and 3-heteroaryl-substituted 3-chloroacrylaldehydes including naphthalene and thiophene frameworks were subjected to the optimized conditions , products 4r and 4s were obtained in excellent isolated yields ( 89 % and 95 % ) . Finally , 6 , 7-dimethoxy-1 , 2 , 3 , 4-tetrahydroisoquinoline in place of THIQ reacted with 1a ; this reaction also led to the corresponding product 4t in a satisfactory yield ( 77 % ) . Unfortunately , while N-methylbenzylamine and piperidine were used , corresponding products were not detected . To gain insight into the reaction mechanism we performed some additional experiments ( Scheme 3 ) . In experiment A , a mixture of Z and E isomers of 3-chloro-3 - ( 2-fluorophenyl ) acrylaldehyde ( 1gg , Z / E = 1.5 : 1 detected by 1H NMR see SI ) in place of 1g was used to investigate the effect of the E / Z configuration on the reaction . Interestingly , product 4g was obtained in 34 % yield ( Scheme 3A ) . The result is similar to the data for 4g which derived from ( Z ) - 3-chloro-3 - ( 2-fluorophenyl ) acrylaldehyde ( 1g ) used as the substrate in Table 2 and showed that the geometric configuration might have no effect on the reaction result . Compared with ( Z ) - 3-chloro-3-phenylacrylaldehyde ( 1a ) , ( Z ) - 3-bromo-3-phenylacrylaldehyde ( 1aa ) also might undergo the same intermediate step in this protocol and give 4a in a similarly high yield ( 92 % , Scheme 3B ) . In Yan's work , ( 28 ) intramolecular dehydrative coupling of tertiary amines and ketones was promoted by t-BuOK / DMF through a radical process ; ( 34 ) however , under the same conditions , the reaction of ( Z ) - 3-chloro-3-phenylacrylaldehyde ( 1a ) with tetrahydroisoquinoline could not afford corresponding product 4a ( Table 1 , entry 1 ) . In addition , another investigation using TEMPO to catch a possible radical intermediate under an argon atmosphere was not successful , and the product was still obtained in a high yield ( 90 % , Scheme 3C ) . Scheme 3 . Mechanistic Studies Thus , based on these experiment results , a plausible mechanism for this reaction is tentatively proposed in Scheme 4 . Initially , intermediate A was first formed from compounds 1 and 2 via a Michael addition , then nucleophilic substitution between A and THIQ gave an intermediate B under basic conditions . B prompted by TEA was transformed to intermediate C in situ , and then D was generated by 6π-electrocyclization and subsequent elimination of THIQ ( path a ) . Through path b , A was first prompted by TEA to give intermediate E , and then F might be formed through a nucleophilic addition . Final product 4 was generated after the dehydration of F. Scheme 4 . Suggested Mechanism In conclusion , we have developed a new TEA-prompted intermolecular cascade cyclization reaction of substituted 3-aryl ( heteroaryl ) - 3-chloroacrylaldehydes and tetrahydroisoquinolines in one pot . The reaction provides a facile and practical synthesis of pyrrolo [ 2 , 1-a ] isoquinolines . A number of pyrrolo [ 2 , 1-a ] isoquinolines were synthesized in moderate to high yields , and the mechanism of the reaction was tentatively proposed .