Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene-Catalyzed Michael−Michael−Lactonization Cascade for the Enantioselective Synthesis of Tricyclic δ‑Lactones Subrata Mukherjee,†,‡ Arghya Ghosh,§ Udaya Kiran Marelli,†,‡ 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 § Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India ‡
S Supporting Information *
ABSTRACT: Enantioselective synthesis of tricyclic δ-lactones with three contiguous stereocenters has been demonstrated by the N-heterocyclic carbene (NHC)-catalyzed functionalization of benzylic C(sp3)−H bonds. The NHC-catalyzed reaction of enals with dinitrotoluene derivatives under oxidative conditions proceeds via the chiral α,β-unsaturated acylazoliums and produces the δ-lactones in good yields and excellent diastereoselectivity and enantioselectivity. This mild and atom-economic cascade reaction takes place in a Michael/Michael/lactonization sequence and tolerates a broad range of functional groups.
N
-Heterocyclic carbene (NHC)-catalyzed cascade reactions are highly valuable for the stereoselective construction of complex organic compounds.1,2 In most of the NHC-catalyzed cascade transformations, the reaction is initiated by the generation of NHC-bound intermediates (mainly the Breslow intermediates, homoenolates, and α,βunsaturated acylazoliums), followed by a sequence of reactions leading to multiple carbon−carbon and carbon−heteroatom bond formations in one pot.3 A series of cyclic compounds, where a carbocycle is fused to a heterocyclic system is accessible in enantiomerically pure form using cascade reactions catalyzed by NHCs.4 The Michael addition is commonly employed in NHC-catalyzed cascade processes proceeding via the α,βunsaturated acylazoliums. The NHC-catalyzed cascade reaction for the enantioselective synthesis of bicyclic δ-lactones proceeding via the chiral α,β-unsaturated acylazoliums was uncovered by the Studer,5 Ye,6 and Chi groups.7 In 2013, Hui and co-workers demonstrated the NHCcatalyzed cascade reaction of 2-bromoenals with 2′-aminophenylenones proceeding via the chiral α,β-unsaturated acylazoliums and progressing in an aza-Michael−Michael− lactonization sequence for the enantioselective synthesis of tetrahydroquinoline-fused δ-lactones (eq 1).8 Moreover, Xu and co-workers reported the enantioselective construction of C−S bonds for the synthesis of thiochromane-fused δ-lactones by the NHC-catalyzed cascade reaction of unsaturated thioesters proceeding in a thia-Michael−Michael−lactonization sequence where chiral α,β-unsaturated acylazoliums are the key intermediate (eq 2).9 In the context of our studies on NHC-catalyzed reactions proceeding via the chiral α,β-unsaturated acylazoliums,10 we envisioned that the catalytically generated chiral α,β-unsaturated azoliums11 from enals could be intercepted with toluene derivatives bearing electron-withdrawing groups on the benzene ring via the activation of the benzylic C(sp3)−H © XXXX American Chemical Society
bonds. Herein, we report a cascade reaction of dinitrotoluene derivatives with enals under oxidative NHC catalysis, leading to the highly selective synthesis of tricyclic δ-lactones proceeding in a Michael/Michael/lactonization sequence (eq 3).12 Notably, Chi and co-workers reported a mechanistically different NHC-catalyzed C(sp3)−H activation of 2-methylindole 3-carboxaldehydes and subsequent interception with an activated carbonyl group of trifluoromethyl ketones/isatins for the enantioselective synthesis of functionalized lactones.13 The present studies were initiated by treating the dinitrotoluene derivative 1a and cinnamaldehyde 2a with the Received: March 28, 2018
A
DOI: 10.1021/acs.orglett.8b00998 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Scope of the α,β-Unsaturated Aldehydesa
carbene generated from the chiral aminoindanol-derived triazolium salt 4,14 using DBU as the base under oxidative conditions using quinone 5. Interestingly, under these conditions, the tricyclic δ-lactone 3a was formed in 51% yield in high diastereoselectivity (>20:1) and an excellent enantioselectivity of 98% (Table 1, entry 1). With this initial result, we Table 1. Optimization of the Reaction Conditionsa
entry
variation of the standard conditionsa
1 2 3 4 5 6 7 8 9 10 11 12
none Cs2CO3 instead of DBU KOt-Bu instead of DBU DMAP instead of DBU Et3N instead of DBU DABCO instead of DBU toluene instead of THF CH2Cl2 instead of THF 1,4-dioxane instead of THF DME instead of THF 10 mol % of 4 instead of 15 mol % DABCO instead of DBU, 2.0 equiv of 2a and 5
yield of 3a (%)c
ee of 3a (%)d
51 41 51 49 28 58 33 26 29 45 43 65 (64)
98 60 98 98 98 98 99 99 99 93 98 98
a Standard conditions: 1a (0.25 mmol), 2a (0.375 mmol), 4 (15 mol %), DBU (20 mol %), 5 (1.5 equiv), THF (2.0 mL), 30 °C and 12 h. b Determined using 1H NMR. cThe yield was determined by 1H NMR analysis (CDCl3) of the crude products using CH2Br2 as the internal standard. Yield of isolated product in 0.5 mmol scale is given in parentheses. dDetermined by HPLC analysis on a chiral column.
a General reaction conditions: 1a (0.25 mmol), 2 (0.50 mmol), 4 (15 mol %), 5 (0.50 mmol), THF (2.0 mL), 30 °C and 12 h. Yields of isolated products are given, and the ee value was determined by HPLC analysis on a chiral column. bThe reaction was performed on a 0.5 mmol scale.
proceeded with the optimization of the reaction conditions. When the reaction was performed using Cs2CO3 instead of DBU, it returned inferior results; however, the use of KOt-Bu generated comparable results, maintaining high dr and ee values (entries 2 and 3). The use of organic bases such as DMAP and Et3N was not beneficial in this reaction (entries 4 and 5), whereas the reaction carried out using DABCO afforded 3a in an improved yield of 58% preserving the high dr and ee values (entry 6). The solvent screening indicated that the 3a was furnished in lower yields when the reaction was carried out in solvents such as toluene, CH2Cl2, 1,4-dioxane, DME, etc. (entries 7−10). For good converstion to 3a, 15 mol % of 4 was required, as the attempted reaction using 10 mol % of 4 resulted in only 43% yield of 3a (entry 11). Finally, use of DABCO as the base and employing 2.0 equiv of both 2a and 5 afforded 3a in 64% yield, >20:1 dr, and 98% ee (entry 12).15 With the optimized reaction conditions in hand, we then examined the scope and limitations of this methodology. First, the tolerance of aldehydes was evaluated (Scheme 1). A series of α,β-unsaturated aldehydes bearing electron-releasing, -neutral, and -withdrawing groups at the 4-position of the β-aryl ring underwent a smooth Michael/Michael/lactonization sequence upon treatment with the dinitrotoluene derivatives under the
present reaction conditions, and in all cases, the tricyclic δlactones are formed in moderate to good yields and excellent dr and ee values (3a−3h). Notably, with electron-withdrawing substituents, the yields were only moderate under the optimized conditions. Moreover, enals having substituents at the 3-position of the β-aryl ring as well as at the 2-position underwent a smooth annulation reaction, leading to the formation of the tricyclic products in moderate to good yield and excellent dr and ee values (3i−3m). In the case of the reaction performed using 2-chlorocinnamaldehyde, the structure and stereochemistry of the δ-lactone 3l were confirmed using X-ray analysis. In addition, disubstituted cinnamaldehydes also worked under the optimized reaction conditions (3n−3p). Furthermore, β-heteroaryl enals worked well under the present reaction conditions to afford the desired products (3q, 3r) in good yields and excellent dr and ee values, thus demonstrating the versatile nature of the present annulation. It is noteworthy that when the β-aryl moiety was changed to substrate with extended conjugation, the selectivity was not significantly affected, and the corresponding product 3s was formed in 98% ee. Disappointingly, reactions performed using β-alkyl-subB
DOI: 10.1021/acs.orglett.8b00998 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters stituted aldehydes furnished only traces of the expected tricyclic δ-lactones under the present conditions. Next, we studied the variation on the dinitrotoluene moiety (Scheme 2). It was found that the presence of two nitro groups
Scheme 3. Proposed Mechanism of the Reaction
Scheme 2. Variation of the Dinitrotoluene Moietya
a General reaction conditions: 1a (0.25 mmol), 2 (0.50 mmol), 4 (15 mol %), 5 (0.50 mmol), THF (2.0 mL), 30 °C and 12 h. Yields of isolated products are given, and the ee value was determined by HPLC analysis on a chiral column. bThe reaction was performed on a 0.5 mmol scale.
is essential for this reaction, as the reaction carried out with substrate without nitro groups afforded only traces of the δlactone product. The nitro groups will increase the acidity of the benzylic C−H protons, making it more reactive toward the α,β-unsaturated acylazoliums. The methyl vinyl ketone moiety in 1 could be varied with ethyl and cyclopropyl groups, and it did not affect the selectivity of the reaction (3t, 3u). Moreover, the presence of Cl in the ring was tolerated, and the target product 3v was formed in 51% yield and >99% ee. A plausible mechanism of the present NHC-catalyzed Michael−Michael−lactonization cascade annulation is presented in Scheme 3. The reaction proceeds via the nucleophilic attack of NHC generated from 4, onto the enal 2, generating the tetrahedral intermediate (I). Rapid proton transfer could lead to the generation of nucleophilic Breslow intermediate (II),16 which in the presence of the quinone oxidant 5 forms the key chiral α,β-unsaturated acylazolium intermediate (III). The nucleophilic attack of 1 (1,4-addition) from the si face of the azolium III could result in the formation of the NHCbound enolate intermediate IV, which undergoes an intramolecular Michael addition to the vinyl ketone moiety and generates the enolate intermediate V. Intramolecular acylation of V affords the tricyclic δ-lactone with the regeneration of the NHC catalyst.17 We also performed the functionalization of the tricyclic δlactones (Scheme 4). Ring opening of the unsaturated lactone 3a using MeOH afforded the highly substituted tetraline derivative 6a in 85% yield and 99% ee. Moreover, the reduction of both NO2 groups in 3a was accomplished using Zn/HCl, and the corresponding diamino derivative 7a was obtained in 40% yield and 93% ee. Reduction of the C−C double bond in lactone 3a was carried in a one-pot operation, resulting in the formation of the saturated δ-lactone 8a in 91% yield, 1:1 dr, and high ee values. Additionally, the ring opening of 3a using BnNH2 furnished functionalized tetraline derivative 9a in 83% yield and 99% ee as a single diastereomer. Furthermore, ring contraction of the δ-lactone was realized in a one-pot operation using m-CPBA and PTSA via the epoxidation, ring opening,
Scheme 4. Functionalization of Tricyclic δ-Lactones
ring closure sequence in tandem, and the expected tricyclic γlactone 10a was isolated in 51% yield, 99% ee and in excellent dr. In conclusion, we have developed the enantioselective synthesis of tricyclic δ-lactones bearing three contiguous stereocenters by the NHC-catalyzed cascade reaction of enals with dinitrotoluene derivatives under oxidative conditions. The reaction proceeds via the generation of chiral α,β-unsaturated acylazoliums and resulted in the functionalization of benzylic C(sp3)−H bonds in a Michael/Michael/lactonization sequence and tolerates a broad range of functional groups. Mild reaction conditions, atom-economy, and excellent diastereo- and enantioselectivity are the notable features of the present C
DOI: 10.1021/acs.orglett.8b00998 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Biomol. Chem. 2008, 6, 2037. (d) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 2007, 1477. (e) Enders, D.; Grondal, C.; Huttl, M. R. Angew. Chem., Int. Ed. 2007, 46, 1570. (3) For a review on NHC-catalyzed domino reactions, see: (a) Chen, X.-Y.; Li, S.; Vetica, F.; Kumar, M.; Enders, D. iScience 2018, 2, 1. (b) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (4) For selected recent reports, see: (a) Gillard, R. M.; Fernando, J. E. M.; Lupton, D. W. Angew. Chem., Int. Ed. 2018, 57, 4712. (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. (c) Zhang, C.; Lupton, D. W. Org. Lett. 2017, 19, 4456. (d) Yang, Y.-J.; Ji, Y.; Qi, L.; Wang, G.; Hui, X.-P. Org. Lett. 2017, 19, 3271. (e) Perveen, S.; Zhao, Z.; Zhang, G.; Liu, J.; Anwar, M.; Fang, X. Org. Lett. 2017, 19, 2470. (f) Shu, T.; Ni, Q.; Song, X.; Zhao, K.; Wu, T.; Puttreddy, R.; Rissanen, K.; Enders, D. Chem. Commun. 2016, 52, 2609. (g) Levens, A.; Ametovski, A.; Lupton, D. W. Angew. Chem., Int. Ed. 2016, 55, 16136. (5) Bera, S.; Daniliuc, C. G.; Studer, A. Org. Lett. 2015, 17, 4940. (6) Liang, Z.-Q.; Wang, D.-L.; Zhang, H.-M.; Ye, S. Org. Lett. 2015, 17, 5140. (7) Fu, Z.; Wu, X.; Chi, Y. R. Org. Chem. Front. 2016, 3, 145. (8) Zhang, H.-R.; Dong, Z.-W.; Yang, Y.-J.; Wang, P.-L.; Hui, X.-P. Org. Lett. 2013, 15, 4750. (9) Lu, H.; Zhang, J.-L.; Liu, J.-Y.; Li, H.-Y.; Xu, P.-F. ACS Catal. 2017, 7, 7797. (10) For reports from our group, see: (a) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A. T. Angew. Chem., Int. Ed. 2016, 55, 268. (b) Yetra, S. R.; Mondal, S.; Suresh, E.; Biju, A. T. Org. Lett. 2015, 17, 1417. (c) Mondal, S.; Yetra, S. R.; Patra, A.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Chem. Commun. 2014, 50, 14539. (d) Yetra, S. R.; Roy, T.; Bhunia, A.; Porwal, D.; Biju, A. T. J. Org. Chem. 2014, 79, 4245. (e) Yetra, S. R.; Kaicharla, T.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013, 15, 5202. (f) Yetra, S. R.; Bhunia, A.; Patra, A.; Mane, M. V.; Vanka, K.; Biju, A. T. Adv. Synth. Catal. 2013, 355, 1089. (11) For pioneering reports, see: (a) De Sarkar, S.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, 9266. (b) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010, 132, 8810. (c) Ryan, S. J.; Candish, L.; Lupton, D. W. J. J. Am. Chem. Soc. 2009, 131, 14176. (d) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371. (e) Zeitler, K. Org. Lett. 2006, 8, 637. (12) For related reports, see: (a) Bera, S.; Samanta, R. C.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed. 2014, 53, 9622. (b) Biswas, A.; De Sarkar, S.; Frohlich, R.; Studer, A. Org. Lett. 2011, 13, 4966. (13) Chen, X.; Yang, S.; Song, B. A.; Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52, 11134. Notably, the activation of 2-methyl benzaldehyde was not successful using this procedure. (14) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362. (15) See the Supporting Information for details. (16) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (17) Reactions performed under the optimized conditions in the presence of TEMPO and BHT afforded 3a in 47 and 51% yield, respectively, ruling out the involvement of radical species in the present reaction.
reaction. Further studies on related cascade reactions proceeding via chiral α,β-unsaturated acylazoliums are ongoing in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00998. Details on experimental procedures, characterization, and NMR spectra of functionalized tricyclic δ-lactone (PDF) Accession Codes
CCDC 1817828 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 data_
[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]. ORCID
Akkattu T. Biju: 0000-0002-0645-8261 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Generous financial support from the Board of Research in Nuclear Sciences (BRNS), the Government of India (Grant No. 37(2)/14/49/2014-BRNS/), and the Indian Institute of Science (start-up grant for A.T.B.) is gratefully acknowledged. S.M. thanks UGC for the senior research fellowship, and A.G. thanks CSIR for the junior research fellowship. We thank Mr. Rupak Saha (IPC, IISc) for the X-ray data.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00998 Org. Lett. XXXX, XXX, XXX−XXX
