Synthetic Methods DOI: 10.1002/anie.201100375 Tandem Ring Opening/Cyclization of Vinylcyclopropanes: A Facile Synthesis of Chiral Bicyclic Amidines** Venkataraman Ganesh, Devarajulu Sureshkumar, and Srinivasan Chandrasekaran* Vinylcyclopropanes (VCP) are important synthons in organic synthesis because of the presence of a highly strained ring system in conjugation with a carbon–carbon double bond, thus enabling these compounds to participate in a wide range of reactions. This structural motif is found in numerous naturally occurring optically active compounds that are important intermediates in the biosynthesis of terpenes. [1] Furthermore, these compounds are prone to pyrolysis, electrophilic ring opening, and acid-catalyzed rearrangement, thus leading to structurally interesting compounds. [2, 3] Herein, a one-pot synthesis of enantiomerically pure bicyclic amidines from bicyclic vinylcyclopropanes is reported (Scheme 1). Amidines have attracted considerable interest owing to their diverse applications in the fields of chemistry and biology. [4] Chiral amidine scaffolds are efficient organo- catalysts and excellent ligands for transition-metal-based asymmetric catalysis, thus providing good enantioselectivity. [5] However, only a few methods are available for the synthesis of amidines with a wide range of structures. [6] Shibasaki and co-workers reported an interesting intramo- lecular cyclization for the efficient synthesis of bicyclic amidines [6a] and highlighted the challenge in synthesizing chiral bicyclic amidines. The present study focuses on a ring opening of the VCP, a Ritter-type reaction, and a subsequent cyclization in one pot to obtain enantiomerically pure amidines. In our preliminary studies, we investigated the reaction of (+)-2-carene (3) with chloramine-T (1) in the presence of a catalytic amount of phenyltrimethylammonium tribromide (2 ; PTAB) using acetonitrile as the solvent (Scheme 1). It resulted in the serendipitous formation of the optically pure [4.4.0] bicyclic amidine 4a in good yield, rather than the expected aziridine derivative A. [7, 8] The structure of 4a was confirmed unambiguously by X-ray crystallography (see Scheme 4). Although, VCP derivatives have been shown to undergo a Ritter-type reaction under strongly acidic conditions, [8] the reaction has not been utilized as an approach for the synthesis of amidines. The reaction was optimized by varying the electrophilic halogen source, which was used as the catalyst, to get the bicyclic amidine 4a as the exclusive product. With iodine [7] and other electrophilic halogen sources, such as N-bromosuccinimide and N-iodosuccinimide, the reaction afforded the product in only a moderate yield. When the reaction was carried out with 10 mol % of pyridinium hydrobromide perbromide, [9a] the yield of 4a went up to 73 % and further improvement in yield (82 %) was achieved when PTAB [9b] was used as the catalyst (see the Supporting Information). To demonstrate the versatility of the reaction as a general method towards the synthesis of chiral bicyclic amidine derivatives, it was carried out using various nitriles as the solvent. In all cases, the reaction proceeded smoothly leading to the corresponding nitrile-inserted compounds (4b–d) in good yields (Table 1, entries 2–4). Even with the electron-deficient nitrile pentafluoroben- zonitrile (Table 1, entry 5), the reaction afforded 4e, albeit in low yield (25 %). Cis- and trans-4-carene (5 and 7, respec- tively), when treated under similar reaction conditions, underwent rearrangement readily in acetonitrile to yield the corresponding amidines 6 and 8 in good yields (Table 1, entries 6 and 7). The study was then extended to other VCP derivatives, such as (S)-(+)-caren-5-ol (9) and 5-acetylcarene (11), [10] which yielded the corresponding amidines 10 (83 %) and 12 (76%) in good yields (Table 1, entries 8 and 9). The reaction scope was further extended by the study of the fused five-membered bicyclic VCP 17 to achieve the synthesis of chiral [4.3.0] bicyclic amidines (see Table 2). Therefore, 17 was synthesized starting with the dihydroxyla- tion of 2-carene (3) using OsO 4 and NMMO in tBuOH to give the corresponding cis-diol 13 in 86 % yield (Scheme 2). [11a] The diol was subsequently treated with NaIO 4 /silica gel [11b] to furnish the keto aldehyde 14 (97 % yield), which after an intramolecular Aldol reaction gave the corresponding five- membered a,b-unsaturated ketone 15. [11c] The ketone 15 was reduced with NaBH 4 /CeCl 3 under Luche conditions to yield the alcohol 16 as a diastereomeric mixture (85:15). The diastereomers were separated after conversion into the benzyl ether (NaH, BnBr and DMF) and the major isomer 17 was used for further studies. Scheme 1. Reaction of VCP 3 with chloramine-T. Ts = p-toluenesulfonyl. [*] V. Ganesh, [+] Dr. D. Sureshkumar, [+] Prof. S. Chandrasekaran Department of Organic Chemistry, Indian Institute of Science Bangalore-560 012, Karnataka (India) Fax: (+ 91) 80-2360-2423 E-mail: scn@orgchem.iisc.ernet.in [ + ] These authors contributed equally. [**] We thank the CSIR (New Delhi) for the Shyama Prasad Mukherjee Fellowship (V.G.) and DST for the JC Bose National Fellowship (S.C.). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201100375. Communications 5878  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 5878 –5881