Catalytic One-Pot Synthesis of Cyclic Amidines by Virtue of Tandem Reactions Involving Intramolecular Hydroamination under Mild Conditions Sukbok Chang,* Minjae Lee, Doo Young Jung, Eun Jeong Yoo, Seung Hwan Cho, and Sun Kyu Han Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and School of Molecular Science (BK21), Korea AdVanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea Received July 6, 2006; E-mail: sbchang@kaist.ac.kr A range of multicomponent reactions, especially consisting of multiple reversible steps, are often favorably driven by a certain irreversible step to facilitate the whole transformation. 1 For example, release of stable molecules such as N 2 , CO, or CO 2 can serve as a driving force, thereby enabling the reactions to be carried out under mild conditions. Recently, we have reported highly efficient Cu- catalyzed three component reactions, 2 in which terminal alkynes and sulfonyl azides are coupled with amines, alcohols, and water to give amidines, imidates, and amides, respectively. Although the mechanistic details are not fully described yet, it is presumed to proceed via a ketenimine intermediate, which has been also proposed by Fokin et al. 3 To expand the scope of these novel couplings, we envisioned that the reaction of 1,n-aminoalkynes with sulfonyl azides could provide cycloamidines, 4 which are highly useful in medicinal and coordination chemistry as well as materials science. 5 When 1-(N- benzyl)amino-4-pentyne (1) was treated with TsN 3 (2), to our surprise, 5-membered amidines were obtained as a mixture of 3 and 4 using CuI catalyst (eq 1). The outcome was unexpected in that the intramolecular attack of amino group into the putative tethered ketenimine (5) should lead to a six-membered amidine (6) if it follows the same pathway as in the intermolecular version. We immediately found that several significant differences exist between the inter- and intramolecular reactions. First, whereas only a few copper salts, representatively CuI, perform the interreactions, the intramolecular version could be catalyzed with a range of metal species including Pd(II), Pt(II), Au(III), Ru(0, III) as well as Cu- (I), although the catalytic activity and selectivity were dependent on the metals employed. 6 Among those, Ru 3 (CO) 12 displayed notably high efficiency in THF. Second, while sulfonyl azides were the only efficiently viable substrates in the interreactions, a range of electron-deficient azides readily participated in the intraversion of amidine synthesis (Table 1). When 1,5-aminoalkyne (7) was reacted with p-toluenesulfonyl azide at ambient temperature, two cycloamidine products 8 and 9 (8.0:1) were produced in high yield by virtue of Ru 3 (CO) 12 (entry 1). 7 The yield was slightly improved by the presence of Et 3 N while the selectivity was not significantly changed (entry 2). The reaction proceeded smoothly with various sulfonyl azides (entries 3-4). Noticeably, only one compound 8 having a R-methyl group was produced exclusively in good yields when 7 was reacted with benzoyl azides, irrespective of the electronic nature of the substit- uents (entries 5-7). Additionally, phosphoryl- and benzyloxycar- bonyl azide could be also employed as reacting counterparts (entries 8-9). 8 However, relatively electron-rich azides such as alkyl or aryl variants did not react (entry 10). On the basis of the product distribution and precedents that electron-deficient azides react with activated olefins including enamines, 9 a plausible pathway for the present reaction is depicted in Scheme 1. The transformation is assumed to be initiated by the intrahydroamination by the assistance of a metal catalyst. 10 While the emerging enamine exists as an isomeric mixture, 11 the more stable exo-methylene pyrrolidine adduct (10) is preferentially cyclized with azides giving a spiro triazoline (11), which is then rearranged to cycloamidine 3 upon release of diazomethane. In fact, we were able to capture in situ CH 2 N 2 from a reaction in the presence of 4-phenylbenzoic acid. 12 In the case of 1,5-aminoalkynes, endo-adduct 12 rather than its exo-isomer reacts more readily with azides. 11 Rearrangement of the resultant triazoline (14) is postulated to lead to 8a upon the migration of a Me group and release of N 2 . 13 It is noteworthy that the present reactions include a mild intramolecular hydroamination as the most probable key pathway, which normally takes place under much harsher conditions using late transition metal catalysts. 14 The mechanistic interpretation gains credence by several experi- ments in addition to the product distribution and capture of released CH 2 N 2 . First, treatment of TsN 3 with an independently prepared cyclic enamines from 1-benzyl-2-pyrrolidinone using Tebbe reagent Table 1. Scope of Azides in the Reaction with Aminoalkyne 7 a entry R 2 ratio (8/9) b yield (%) c 1 (4-Me)C6H4SO2 8.0:1 75 2 d (4-Me)C6H4SO2 8.1:1 81 3 MeSO2 6.5:1 81 4 2-PySO2 11:1 66 5 C6H5CO >25:1 65 6 (4-O2N)C6H4CO >25:1 80 7 (4-Me)C6H4CO >25:1 65 8 (PhO)2PO >25:1 69 9 PhCH2OCO >25:1 74 10 PhCH2 <5 a Azide (0.24 mmol) and 7 (0.2 mmol) in THF (2.0 mL). b 1 H NMR ratio of crude mixture. c Combined yield. d Et3N (1.2 equiv) was used. Published on Web 09/01/2006 12366 9 J. AM. CHEM. SOC. 2006, 128, 12366-12367 10.1021/ja064788i CCC: $33.50 © 2006 American Chemical Society