Letter pubs.acs.org/OrgLett
Organocatalytic β‑Azidation of Enones Initiated by an ElectronDonor−Acceptor Complex Rajendra P. Shirke and S. S. V. Ramasastry* Organic Synthesis and Catalysis Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Mohali, Sector 81, Manauli P.O., S. A. S. Nagar, Punjab 140306, India S Supporting Information *
ABSTRACT: An operationally straightforward organocatalytic β-azidation of α,β-unsaturated ketones is described. Reaction of the Zhdankin azidoiodane with enones in the presence of a catalytic amount of an amine provides β-azido ketones via the formation of an electron-donor−acceptor complex. The application of this protocol is demonstrated through one-step elaborations leading to the synthesis of unprecedented classes of 1,2,3-triazoles. Scheme 1. Existing β-Azidation Strategies and Our Work
O
rganic azides are versatile intermediates in organic synthesis.1 It is due to their versatility in providing access to valuable functional groups (such as amines, amides, etc.) and also because of their worthiness in the synthesis of privileged heterocycles (such as pyrroles, pyridines, 1,2,3triazoles, and tetrazoles). The thriving field of “click chemistry” further established the relevance of organic azides in various drug discovery programs and also in the development of new materials.2 Therefore, the prominence of organic azides in medicinal chemistry, chemical biology and materials science attracted the development of numerous synthetic methods.1 Due to the ready availability of nucleophilic azidation agents such as NaN3, TMSN3, etc., a majority of the synthetic approaches for organic azides were centered around the substitution of organic (pseudo)halides, Mitsunobu reaction of alcohols, ring opening of epoxides, acid-mediated βazidations, to mention a few.1,3 With the advent of the Zhdankin azidoiodane reagent 1,4 electrophilic and radical azidation modes have received tremendous attention. Among them, the strategy to introduce azide via the β-azidation of activated alkenes has emerged only recently.5 In 2014, Nevado reported6 a cascade reaction initiated by the radical β-azidation of α-substituted acrylsulfonamides A and Zhdankin reagent 1 in the presence of a stoichiometric amount of a base such as 1,10phenanthroline (phen) (Scheme 1, eq 1). However, sufficient clarity was not provided on the role of “phen” in the transformation of A to B. Subsequent to Nevado’s work, a few metal-mediated βazidations of α-substituted-α,β-unsaturated amides were reported. Song and Li described a Cu-catalyzed radical [2 + 2 + 1]-annulation of 1,n-enynes C for the synthesis of a variety of fused pyrroline derivatives D (Scheme 1, eq 2).7 On the other hand, Jiang and Yang reported a one-pot chloroazidation of α,β-unsaturated amides E (Scheme 1, eq 3).8 An interesting Cu-catalyzed β-azidation strategy for the construction of quinoxalin-2-ones H was reported by Yu and co-workers (Scheme 1, eq 4).9 © 2017 American Chemical Society
It is important to note that the aforementioned studies are restricted only to the α-substituted acrylamides, which significantly limits the scope and applicability of these methods. Further, the development of catalytic and metal-free reactions should be of priority from a green chemistry point-of-view. Received: September 13, 2017 Published: September 26, 2017 5482
DOI: 10.1021/acs.orglett.7b02861 Org. Lett. 2017, 19, 5482−5485
Letter
Organic Letters
12). The successful β-azidation methods described for acrylamides5−9 were verified in the conversion of 2a to 3a. Interestingly, only poor yields of 3a were realized (Table 1, entries 13−16), highlighting the selectivity and efficiency of the DABCO-mediated process. As expected, no product formation was observed when the reaction was carried out only in the presence of o-iodobenzoic acid (Table 1, entry 17). With the optimized conditions in hand, the scope and generality of the reaction were subsequently investigated, and the representative results are summarized in Scheme 2. A
Moreover, performing the reactions involving azides at elevated temperatures can be detrimental, and maintaining inert atmosphere throughout the reaction can be impractical and expensive. In an attempt to address these concerns, we commenced our efforts for the development of an organocatalytic β-azidation of ubiquitous α,β-unsaturated ketones with Zhdankin’s reagent under practical and straightforward conditions (Scheme 1, eq 5). Toward this end, various combinations of Zhdankin’s reagent 1 and additives were investigated with the enone 2a as the model substrate (Table 1). Table 1. Optimization of the Reaction Parameters
entry 1 2 3 4 5 6 7 8 9 10d 11e 12f 13 14 15 16 17g
additive/catalyst (20 mol %) − imidazole DBU DMAP DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO 1,10-phenanthroline 2,6-di-tert-butyl-4methylpyridine CuI Cu(OAc)2 −
Scheme 2. Substrate Scopea,b
a,b
solvent
time (h)
yieldc (%)
toluene toluene toluene toluene toluene CH2Cl2 THF CH3CN (CH3)2SO toluene toluene toluene toluene toluene
96 18 13 13 8 12 12 17 20 2 9 8 48 48
− 51 85 63 94 83 73 71 47 35 90 96 40
