Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective N‑Heterocyclic Carbene-Catalyzed Cascade Reaction for the Synthesis of Pyrroloquinolines via N−H Functionalization of Indoles Subrata Mukherjee,†,‡ Sayan Shee,§ 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), Ghaziabad 201002, India § Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India ∥ Normandie Université, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France ⊥ Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France
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‡
S Supporting Information *
ABSTRACT: Functionalization of the indole N−H bond for enantioselective synthesis of biologically important pyrroloquinoline derivatives has been reported under oxidative N-heterocyclic carbene catalysis conditions. The interception of catalytically generated chiral α,β-unsaturated acylazoliums with the indole derivatives proceeds in an aza-Michael/Michael/ lactonization sequence to deliver the pyrroloquinoline derivatives in good yields, diastereoselectivities, and enantioselectivities. The simultaneous enhancement of reactivity and selectivity observed in polar aprotic solvents is noteworthy.
T
he indole ring system is a ubiquitous heterocyclic moiety that is present in many biologically active natural products and drugs.1 Hence, mild and selective functionalization of the indole ring has attracted increasing interest among synthetic organic chemists. Although methods are available for the selective functionalization of indoles at the C-2 and C-3 positions, the enantioselective functionalization of indoles at the N−H bond is relatively limited.2 Recently, many methods have been developed for the synthesis of ring-fused indole systems. Among the various annulated indoles, pyrroloquinolines (1,7-annulated indoles) are important because these structural motifs are found in many natural products. For example, the substituted pyrroloquinoline KC 11404 is a promising molecule for the treatment of asthma (Figure 1).3 Moreover, DCQTB has been explored as red light-emitting dopants in organic light-emitting diodes (OLEDs)4 and PHA529311 is known for its inhibitory activity against herpes virus DNA polymerases.5 In addition, murrayazoline is a carbazole alkaloid, which is a widely used drug due to its potent antiplatelet aggregation activity.6 Consequently, the development of enantioselective routes to pyrroloquinolines is of great importance. Given the importance of indole derivatives, selective functionalization of this nucleus using N-heterocyclic carbene © XXXX American Chemical Society
Figure 1. Selected biologically important pyrroloquinolines.
(NHC) catalysis has been gaining more interest recently.7 In 2013, Chi and co-workers developed the NHC-catalyzed [4 + 2] annulation of indole 3-carboxaldehydes with trifluoroacetophenones leading to the enantioselective synthesis of tricyclic Received: September 4, 2018
A
DOI: 10.1021/acs.orglett.8b02820 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters δ-lactones and that the reaction proceeds via NHC-bound dienolate intermediates (Scheme 1, eq 1).8 Independently,
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. NHC-Catalyzed Indole Functionalization
entry
(1)
base
solvent
yield 3 (%)b
drc
erd
1 2 3 4 5 6 7 8 9 10 11 12e
1a 1b 1c 1d 1d 1d 1d 1d 1d 1d 1d 1d
DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO K2CO3 Cs2CO3 DMAP DABCO
DMSO DMSO DMSO DMSO toluene CH2Cl2 THF DMF DMSO DMSO DMSO DMSO
20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
nd nd 77:23 95:5 56:44 70:30 73:27 93:7 95:5 95:5 95:5 95:5
a
Conditions: 1 (0.125 mmol), 2a (0.125 mmol), 4 (10 mol %), 5 (1.0 equiv), base (1.0 equiv), solvent (1.0 mL), 25 °C, and 12 h. bThe yields were determined by 1H NMR analysis of crude product using CH2Br2 as the internal standard. cDetermined by 1H NMR spectroscopy prior to purification. dDetermined by HPLC analysis on a chiral stationary phase. eUsing 1.5 equiv each of 2a and 5 and 15 mol % of 4.
Enders and co-workers demonstrated the enantioselective synthesis of pyrroloindolones by the NHC-catalyzed [2 + 3] annulation of α-functionalized aldehydes with 2-nitrovinylindoles, and the reaction proceeds via the NHC-bound enolate intermediates (eq 2).9 Very recently, Studer and co-workers have disclosed the NHC-catalyzed dearomatization of indoles for the enantioselective synthesis of spirocyclic indolenines (eq 3).10 This reaction proceeds through indole 3-acylation using the in situ-generated NHC-bound acylazolium intermediates under oxidative conditions. In light of our interest in the NHCcatalyzed reactions proceeding via the chiral α,β-unsaturated acylazoliums,11 we envisioned that the reaction of Nunsubstituted indoles bearing a Michael acceptor at the 7position with catalytically generated chiral α,β-unsaturated acylazoliums under oxidative conditions could result in the synthesis of tetracyclic δ-lactones. Herein, we report the enantioselective synthesis of pyrroloquinoline-fused δ-lactones by the reaction of indole derivatives with enals under oxidative conditions (eq 4). The present studies were initiated by treating the N−H indole derivative bearing a Michael acceptor moiety at the 7position (1a) and cinnamaldehyde 2a in the presence of the carbene generated from the chiral aminoindanol-derived triazolium salt 412 using DABCO and the bisquinone 5 as the oxidant. Disappointingly, under these conditions, the desired tetracyclic δ-lactone product 3a was not formed (Table 1, entry 1). As the reaction design first involved an aza-Michael addition, we reasoned that the N−H acidity of the indole substrate was the reason for the inferior reactivity. Hence, we attempted the reaction with electron-withdrawing groups such as Cl (1b) and CHO (1c) at the 3-position to increase the N−
H acidity. Although the substrate 1b was unreactive under the present conditions (entry 2), the reaction using 1c afforded the expected pyrroloquinoline 3c in 42% yield, >20:1 dr, and 77:23 er (entry 3).13,14 Gratifyingly, performing the reaction using substrate 1d having a COCF3 group at the 3-position improved the reactivity and selectivity to furnish 3d in 60% yield, >20:1 dr, and 95:5 er (entry 4). A rapid solvent screening revealed that polar aprotic solvents such as DMF and DMSO were useful for this cascade reaction (entries 5−8). Among the various bases screened in DMSO, K2CO3, Cs2CO3, and DMAP afforded 3a in moderate yields, maintaining the high er values (entries 9−11). Finally, employing 1.5 equiv of both 2a and 5 in DMSO afforded 3d in 84% yield, >20:1 dr, and 95:5 er (entry 12).15 With these optimized reaction conditions in hand, the scope and limitations of this tetracyclic δ-lactone synthesis were studied. Initially, the variation on α,β-unsaturated aldehydes was evaluated (Scheme 2). The unsubstituted parent system worked well, and a series of electron-donating/neutral and -withdrawing groups at the 4-position of the β-aryl ring of enals was well tolerated, and in each case, the 1,7-annulated indole (pyrroloquinolines) derivative was formed in a high yield, excellent dr, and good er values (3d−3k). In the case of the chloro derivative 3h, the structure and stereochemistry was unambiguously confirmed by single-crystal X-ray analysis. Moreover, enals having substituents at the 3- and 2-positions of the β-aryl ring did not affect the reactivity, and the desired products were isolated in high yields and selectivities (3l−3p). In addition, disubstitution at the β-aryl ring of 2 resulted in the B
DOI: 10.1021/acs.orglett.8b02820 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scope of the Reactiona
A plausible mechanism of the present cascade reaction is illustrated in Scheme 3. The reaction proceeds via the Scheme 3. Proposed Mechanism of the Reaction
General reaction conditions: 1d (0.25 mmol), 2 (0.375 mmol), 4 (15.0 mol %), 5 (0.375 mmol), DMSO (2.0 mL), 25 °C, and 12 h. Yields of isolated products are given, and the er value was determined by HPLC analysis on a chiral stationary phase.
nucleophilic attack of NHC generated from 4 onto enal 2, generating the tetrahedral intermediate (I), which on proton transfer generates the nucleophilic Breslow intermediate (II).16 In the presence of the bisquinone oxidant 5, intermediate II is oxidized to the key α,β-unsaturated acyl azolium intermediate (III). The nucleophilic attack of 1 to intermediate III via the N−H indole moiety (aza-Michael addition) provides the NHC-bound enolate intermediate IV, which undergoes an intramolecular Michael addition to the vinyl ketone moiety to give the enolate intermediate V bearing an NHC-azolium moiety. Finally, intramolecular acylation of V affords the pyrroloquinoline product 3 with regeneration of the NHC catalyst. During the optimization of the reaction conditions, we observed a simultaneous enhancement in reactivity and selectivity for the formation of 3d in polar aprotic solvents, such as CH3CN, DMF, DMSO, and so forth. For this to be validated, the reaction was performed in various solvents, and the dielectric constant (DEC) of the solvent was plotted against the yield/ee of 3d obtained (Figure 2).15 For instance,
smooth conversion to the products in good yields and enantioselectivities (3q−3s). Additionally, heterocyclic α,βunsaturated aldehydes underwent an efficient cascade reaction, furnishing the target products in good yields and good er values (3t, 3u). Furthermore, the dienal having a δ-aryl group also furnished the tetracyclic indole 3v in 93% yield, >20:1 dr, and 96:4 er, thus demonstrating the versatility of the present cascade reaction. Interestingly, the methyl group at the Michael acceptor moiety could be varied with cyclic and acyclic alkyl groups without affecting the reactivity/selectivity. Finally, the presence of Br in the indole ring was also well tolerated and furnished the corresponding product 3y in 76% yield, >20:1 dr, and 99:1 er value, thus expanding the scope of this cascade reaction.
Figure 2. Variation of yield/ee of 3d with polarity of solvent (dielectric constant).
a
C
DOI: 10.1021/acs.orglett.8b02820 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters the reaction afforded poor yield/ee when performed in toluene (DEC: 2.38), moderate yield/ee in THF (DEC: 7.58), and high yield/ee in DMF (DEC: 36.7). Although a general linear relationship was not observed, the overall trend observed was that the reactivity/selectivity was improved in polar aprotic solvents. It should be noted that the reactivity in highly polar solvents was not only because of the solubility of the reactants, as the reactants are soluble in THF, but that the reactivity/ selectivity was only moderate. Moreover, polar aprotic solvents are known to stabilize zwitterionic intermediates. Finally, the functionalization of the tetracyclic δ-lactones was carried out. Ring-opening of the unsaturated lactone moiety in 3d using MeOH furnished the pyrroloquinoline 6d in 76% yield and 95:5 er value (Scheme 4). Similarly, the ring-opening
Details on experimental procedures, characterization, NMR spectra and HPLC traces of pyrroloquinolines derivatives (PDF) Accession Codes
CCDC 1863110 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
Scheme 4. Functionalization of Pyrroloquinoline 3d
ORCID
Thomas Poisson: 0000-0002-0503-9620 Tatiana Besset: 0000-0003-4877-5270 Akkattu T. Biju: 0000-0002-0645-8261 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Generous financial support by IFCPAR-CEFIPRA (no. 55051) is gratefully acknowledged. S.M. thanks UGC for a fellowship, and S.H. thanks IISc for a fellowship. We thank Mr. Rupak Saha (IPC, IISc) for the X-ray data.
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of 3d using BnNH2 afforded the corresponding amide derivative 7d in 81% yield, maintaining the high er value. Moreover, the selective olefination at the C-4 position of 3d was achieved by a Rh(III)-catalyzed reaction with methyl acrylate, leading to the formation of the C-4-functionalized product 8d in 79% yield and 97:3 er value.17 In addition, the Rh(III)-catalyzed reaction of 3d with N-benzyl maleimide resulted in the hydroarylation at the C-4 position, affording 9d as an inseparable mixture of diastereomers in 81% yield, 2:1 dr, and 95:5 er (for both diastereomers).18 In conclusion, we have developed the enantioselective synthesis of pyrroloquinolines bearing three contiguous stereocenters by the NHC catalyzed N−H functionalization of indoles. The reaction of enals with indole derivatives proceeded via the generation of the α,β-unsaturated acylazoliums, and the desired products were formed in a cascade reaction following the aza-Michael−Michael lactonization. Excellent levels of diastereoselectivity and enantioselectivity, atom-economy, and tolerance with a broad range of functional groups and mild reaction conditions are the notable features of the present annulation. Further studies on related cascade reactions are ongoing in our laboratory.
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DOI: 10.1021/acs.orglett.8b02820 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (g) De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Chem. - Eur. J. 2013, 19, 4664. (h) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906. (i) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (j) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. (k) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686. (l) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53. (m) Vora, H. U.; Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617. (n) Chiang, P.-C.; Bode, J. W. In NHeterocyclic Carbenes; The Royal Society of Chemistry: London, 2011; p 399. (o) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336. (p) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (8) (a) Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52, 11134. See also: (b) Cheng, J.; Sun, J.; Yan, J.; Yang, S.; Zheng, P.; Jin, Z.; Chi, Y. R. J. Org. Chem. 2017, 82, 13342. (9) (a) Ni, Q.; Zhang, H.; Grossmann, A.; Loh, C. C. J.; Merkens, C.; Enders, D. Angew. Chem., Int. Ed. 2013, 52, 13562. For a related homoenolate reaction, see: (b) Yang, Y.-J.; Ji, Y.; Qi, L.; Wang, G.; Hui, X.-P. Org. Lett. 2017, 19, 3271. (10) (a) Bera, S.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed. 2017, 56, 7402. For the pioneering report on the use of 5 in oxidative NHC-catalysis, see: (b) De Sarkar, S.; Grimme, S.; Studer, A. J. Am. Chem. Soc. 2010, 132, 1190. (11) For reports from our group, see: (a) Mondal, S.; Ghosh, A.; Mukherjee, S.; Biju, A. T. Org. Lett. 2018, 20, 4499. (b) Mukherjee, S.; Ghosh, A.; Marelli, U. K.; Biju, A. T. Org. Lett. 2018, 20, 2952. (c) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A. T. Angew. Chem., Int. Ed. 2016, 55, 268. (d) Yetra, S. R.; Mondal, S.; Suresh, E.; Biju, A. T. Org. Lett. 2015, 17, 1417. (e) Yetra, S. R.; Bhunia, A.; Patra, A.; Mane, M. V.; Vanka, K.; Biju, A. T. Adv. Synth. Catal. 2013, 355, 1089. (f) Yetra, S. R.; Roy, T.; Bhunia, A.; Porwal, D.; Biju, A. T. J. Org. Chem. 2014, 79, 4245. (g) Yetra, S. R.; Kaicharla, T.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013, 15, 5202. (12) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362. (13) For an organocatalytic synthesis of pyrroloquinolines, see: Giardinetti, M.; Moreau, X.; Coeffard, V.; Greck, C. Adv. Synth. Catal. 2015, 357, 3501. (14) For related reports on NHC-catalyzed aza-Michael reaction, see: (a) Zhang, H.-R.; Dong, Z.-W.; Yang, Y.-J.; Wang, P.-L.; Hui, X.P. Org. Lett. 2013, 15, 4750. (b) Wu, X.; Hao, L.; Zhang, Y.; Rakesh, M.; Reddi, R. N.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int. Ed. 2017, 56, 4201. (15) For details, see the Supporting Information. (16) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (17) For a related report, see: Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2016, 18, 5496. (18) For a related report, see: Sherikar, M. S.; Kapanaiah, R.; Lanke, V.; Prabhu, K. R. Chem. Commun. 2018, 54, 11200.
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DOI: 10.1021/acs.orglett.8b02820 Org. Lett. XXXX, XXX, XXX−XXX
