Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of 4‑Difluoromethylquinolines by NHC-Catalyzed Umpolung of Imines Atanu Patra,†,‡ Fabien Gelat,§ Xavier Pannecoucke,§ Thomas Poisson,§,∥ Tatiana Besset,§ and Akkattu T. Biju*,†,⊥ †
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India § Normandie Université, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France ∥ Institut Universitaire de France, 103 boulevard Saint-Michel, 75005 Paris, France ‡
S Supporting Information *
ABSTRACT: The N-heterocyclic carbene (NHC)-catalyzed umpolung of aldimines for the synthesis of 4-difluoromethylquinoline derivatives is reported. In the presence of NHCs, the intramolecular cyclization of aldimines bearing a moderately electron-poor double bond due to the presence of the −CF3 group likely proceeds via the intermediacy of the aza-Breslow intermediate. The key to the success of this aza-Stetter type transformation is the NHC generated from the bicyclic triazolium salt using DBU as the base.
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for organocatalytic applications was extended to Michael acceptors by Fu in 2006 (intramolecular version; Scheme 1, eq 2)7 and later independently by Matsuoka8 and Glorius9 (intermolecular version).10 Apart from the umpolung of aldehydes and Michael acceptors using NHCs, the polarity reversal of other electrophiles using NHCs has received only limited attention.11 The synthesis of deoxy-Breslow intermediates by the addition of NHCs to alkyl halides was uncovered by Jacobi von Wangelin11 and Mayr.12 However, catalysis using these intermediates has not been explored. Moreover, the intramolecular addition of an NHC to an aldimine leading to the generation of aza-Breslow intermediate A was disclosed by Douthwaite in 2009 (Scheme 2, eq 1).13 Subsequently, the Rovis group reported the isolation of aza-Breslow intermediate B by the addition of an NHC to an iminium salt.14 During the course of our studies on organocatalytic umpolung using NHCs,15 we recently reported the umpolung of aldimines for the synthesis of N-unprotected 2,3-disubstituted indoles, which likely proceeded via an aza-Breslow intermediate (Scheme 2, eq 2).16−18 In an effort to extend the scope of NHC-catalyzed umpolung of imines,19 herein we report the synthesis of 2-aryl-4difluoromethylquinolines by the NHC-catalyzed intramolecular cyclization of aldimines bearing a moderately electron-poor double bond due to the presence of the CF3 group. It may be mentioned that the synthesis of related quinoline derivatives using cyanide catalysis has been reported.20 Given the importance of the CF2H group21 due to their H-bond-donor
rganocatalysis using N-heterocyclic carbenes (NHCs) has been widely employed for the synthesis of various five- and six-membered heterocycles.1 The primary mode of reactivity of NHCs in organocatalysis is via the umpolung of aldehydes to generate nucleophilic Breslow intermediates (acyl anion equivalents).2 The two important transformations proceeding via the umpolung of aldehydes are the benzoin condensation3 and the Stetter reaction (Scheme 1, eq 1).4 The addition of NHCs to α,β-unsaturated aldehydes can transform either the carbonyl position nucleophilic (normal umpolung) or the βposition nucleophilic (conjugate umpolung: generation of homoenolate equivalents) depending on the steric nature of the carbene employed.5,6 The concept of umpolung using NHCs Scheme 1. NHC-Catalyzed Umpolung of Aldehydes and Michael Acceptors
Received: December 29, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b04055 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Scheme 2. NHC-Catalyzed Umpolung of Imines
ability and high lipophilicity combined with the biological relevance of substituted quinolines, the 4-difluoromethylquinoline analogues are likely to have potential biological properties. Driven by our recent synthesis of indoles by NHC-catalyzed umpolung of imines,16a the present study was initiated by treating aldimine 1a22 with the carbene generated from bicyclic triazolium salt 3 using DBU as the base in DMF at 100 °C. To our delight, under these conditions the reaction afforded difluoromethylquinoline 2a in 75% yield (Table 1, entry 1). The NHCs generated from other triazolium salts 4 and 5 furnished 2a in reasonable yields (entries 2 and 3), whereas the carbenes derived from common thiazolium salt 6 and imidazolium salt 7 are not reactive for this imine umpolung (entries 4 and 5). Heating 1a in DMF in the absence of 3 and DBU did not afford 2a (entry 6), ruling out the possibility of 6π electrocyclization in the present case.23 DBU was found to be the optimal base for this reaction, as the transformations performed using organic bases (e.g., DMAP and DABCO) and inorganic bases (e.g., t-BuOK and K2CO3) returned inferior results (entries 7−10). The reactions carried out in DMSO and chlorobenzene furnished 2a in 48% and 41% yield, respectively (entries 11 and 12). In 1,4-dioxane, 2a was isolated in 63% yield, and the reaction did not proceed in toluene (entries 13 and 14). The reaction afforded reduced yields of 2a when performed at a lower temperature of 80 °C and when the reaction time was reduced to 24 h (entries 15 and 16). Moreover, an excess of DBU was required for good conversion into 2a, and the reaction provided only a 51% yield of 2a when performed using 15 mol % 3 (entries 17 and 18).24 With the optimized reaction conditions in hand, we then examined the substrate scope of this quinoline synthesis (Scheme 3). A series of trifluoromethylated aldimines synthesized from the corresponding aromatic amine and various aromatic aldehydes having electron-neutral, -releasing, and -withdrawing groups at the 4-position of the ring underwent smooth annulation via the NHC-catalyzed umpolung, leading to the synthesis of 2-aryl-4-difluoromethylquinolines in good yields (2a−g). Moreover, aldimines derived from aromatic aldehydes having substitution at C3 or C2 as well as disubstitution at C3 and C4 were well-tolerated, and the corresponding quinolines were formed in generally high yields (2h−m). In addition, aldimines derived from heteroaromatic aldehydes worked well under the present conditions, and the 2-heteroaryl-function-
entry
variation of the standard conditionsa
yield of 2a (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
none 4 instead of 3 5 instead of 3 6 instead of 3 7 instead of 3 no 3 and DBU DMAP instead of DBU DABCO instead of DBU t-BuOK instead of DBU K2CO3 instead of DBU DMSO instead of DMF chlorobenzene instead of DMF 1,4-dioxane instead of DMF toluene instead of DMF 80 °C instead of 100 °C run for 24 h instead of 36 h 2.0 equiv of DBU instead of 3.0 equiv 15 mol % of 3 instead of 20 mol %
75 70 59
