Intramolecular Alkynylcyclopropanation of Olefins Catalyzed by Bi(OTf)<sub>3</sub>: Stereoselective Synthesis of 1‐Alkynyl‐3‐azabicyclo[3.1.0]hexanes (2009)

The postman always rings twice: 1-Alkynyl-3-azabicyclo[3.1.0]hexanes 2 were obtained in good to excellent yields from the stereoselective Bi(OTf)3-catalyzed dehydrative alkynylcyclopropanation of azaenynols 1, in which the propargyl alcohol motif of 1 acted as a propargyl carbene synthetic equivalent. The development of efficient cyclization methods for the construction of nitrogen-containing heterocycles constitutes an ongoing challenge in the construction of natural and pharmaceutical materials. The cycloisomerization of enynes is one such method, for which transition metal catalysts, such as palladium, platinum, gold, ruthenium, and rhodium, have been found to effectively promote the reaction.1 However, most of these procedures require high loading of expensive metal catalysts and ligands; moreover, accessible heterocyclic skeletons are limited. Therefore, the development of more practical catalyst systems for the synthesis of new heterocycles is desirable. To this end, we have recently reported the iron-catalyzed or bismuth-catalyzed intramolecular heterofunctionalization of olefins and alkynes; this provides various types of heterocycles in both an environmentally friendly and atom efficient manner.2 Nitrogen-containing heterocycles, such as 3-azabicyclo[3.1.0]hexanes, are core structures of a variety of biologically active compounds.3 Some efficient synthetic routes to this skeleton have been reported, which use stoichiometric quantities of organometallic reagents.4 Recently, catalytic approaches to 3-azabicyclo[3.1.0]hexanes, which contain a vinylcyclopropane motif, have been developed using the transition-metal-catalyzed tandem carbometalation of 1,6-enynes with organotin5 or diazoalkane6 (Scheme 1). These vinylcyclopropane motifs are prized for their utility in ring-expansion reactions, affording a variety of heterocyclic ring sizes.7 In contrast, the synthesis of analogous azabicyclohexanes with alkynyl substituents have been scarcely reported,8 even though the alkynylcyclopropanes are versatile units for numerous chemical transformations9 and are substructures in many natural products.10 Tandem carbometalation of 1,6-enynes using ruthenium or palladium catalysts. Propargyl alcohol acting as a synthetic carbene equivalent for the alkynylcyclopropanation of olefins. Next, with our optimized conditions in hand, we investigated the tolerance of the Bi(OTf)3-catalyzed alkynylcyclopropanation with various azaenynols 1b–1w (Table 1). Internal olefins 1 b, 1 e, 1 h, 1 j, 1 l, 1 n, 1 o, and 1 q reacted more efficiently under the optimized reaction conditions than terminal ones (1 d, 1 g, 1 i, 1 m, and 1 p). Notably, these internal E-olefins provided only the cis-2 stereoisomer between γ-alkynyl and ω-alkyl moieties (see Eq. (1) for assignment). The stereochemistry was determined from the coupling constant between the C(δ)H and C(ω) protons in the product (3JH(δ)-H(ω)=ca. 4.0 Hz),5b and confirmed by an X-ray structure of the representative product 2 l (Figure 1). Furthermore, electron-rich olefins 1 c, 1 f, and 1 k enhanced the reaction efficiency, which proceeded at lower temperature (25 °C) and in the absence of an additive (Table 1, entries 2, 5, and 10). Alkyl substituents at the α-position of 1 inhibited the reaction, but a wide range of aryl attachments could successfully participate in the reaction; electron-withdrawing groups on the aryl ring were superior to electron-donating ones (Table 1, entries 3–7 vs. 8–11). Moreover, ortho-substitution of the aromatic ring did not interfere with the transformation (Table 1, entries 12–16). ORTEP showing two orthogonal views of 2 l. Ellipsoids are shown at 50 % probability. Hydrogen atoms are omitted for clarity. Entry Substrate t [h] Product Yield [%][a] 1 2[b] R=Me R=Pr 1 b 1 c 1 1 2 b 2 c 80 85 3 4 5[b] R=H R=Me R=Pr 1 d 1 e 1 f 4 5 10 2 d 2 e 2 f 52 77 80 6 7 R=H R=Me 1 g 1 h 24 5 2 g 2 h 36 80 8 9 10[b] R=H R=Me R=Pr 1 i 1 j 1 k 24 2 3 2 i 2 j 2 k 26 65 70 11 1 l 10 2 l 52 12 13 R=H R=Me 1 m 1 n 12 5 2 m 2 n 31 67 14 1 o 3 2 o 67 15 16 R=H R=Me 1 p 1 q 3 7 2 p 2 q 36 62 17 1 r 2 2 r 23 18 1 s 4 2 s 48 19 1 t 12 2 t 54 20[c] 1 u 18 2 u 33 21[d] 1 v 1 week 2 v 33 22[b] 1 w 24 2 w 75 This transformation is not limited to substrates have simple aryl attachments at the α-position. Valuable functional groups, such as heteroaryl (Table 1, entries 17 and 18), vinyl (entries 19 and 20), and alkynyl substituents (entry 21), could be introduced into the 1-alkynyl-3-azabicyclo[3.1.0]hexane framework in satisfactory yields. Furthermore, this procedure was extended to the formation of 1-alkynyl-3-azabicyclo[4.1.0]heptane 2 w (Table 1, entry 22). On the basis of these mechanistic studies, we propose a mechanism for the dehydrative alkynylcyclopropanation as follows (Scheme 3): a) Dual coordination of the alkyne and the oxygen of the hydroxy group to the bismuth catalyst gives complex C.2f, 15 b) Nucleophilic addition of the pendant olefin to the activated propargyl alcohol produces carbocation D, which contains a vinylidene moiety;16 in the intermediate D, RE and RZ substituents would sit equatorially and axially, respectively.17 c) A second cyclization from the vinylidene to the neighboring carbocation affords vinyl cation E; deprotonation gives 1-alkynyl-3-azabicyclo[3.1.0]alkane 2 with expulsion of water. Plausible reaction mechanism. In conclusion, we have reported a bismuth-catalyzed dehydrative alkynylcyclopropanation of azaenynols to give 1-alkynyl-3-azabicyclo[3.1.0]hexanes in good yield, wherein the propargyl alcohol unit formally acts as a propargyl carbene equivalent. This reaction tolerates a wide range of substituents at the propargyl position, including aryl, heteroaryl, vinyl, and alkynyl functional groups. Remarkably, the stereochemistry of theses products strongly depends on that of the starting azaenynols, that is, cis- and trans-1-alkynyl-3-azabicyclo[3.1.0]hexanes were obtained stereoselectively from the reaction of E- and Z-azaenynols, respectively. Although the exact roles of the bismuth catalyst and bipyridine additive are not yet fully clear, the reaction proceeds efficiently only in the presence of bismuth triflates or iron triflates. Consequently, we concluded that the simple Lewis acid catalyzed pathway does not contribute to the present reaction. Mechanistic studies, and the extension of this procedure to other types of alkynylcyclopropanation reactions are in progress. General procedure for the reaction of 1 b with Bi(OTf)3 catalyst: A solution of azaenynol 1 b (55.5 mg, 0.14 mmol) in 1,2-dichloroethane (0.7 mL) was added into a mixture of Bi(OTf)3 (4.6 mg, 7.0 μmol), bipyridine (1.1 mg, 7.0 μmol), and 1,2-dichloroethane (0.7 mL) under N2. After stirring for 1 h at 80 °C, the reaction mixture was cooled to room temperature, passed through a short silica gel column, and then concentrated. The crude product was purified by column chromatography on silica gel (60–230 mesh) with a hexanes/ethyl acetate eluent (5:1) to afford pure 1-phenylethynyl-6-methyl-3-tosyl-3-azabicyclo[3.1.0]hexane (2 b) in 80 % yield (39.3 mg). 2 b was isolated as a white solid; m.p. 96.0–96.5 °C; Rf (SiO2, hexanes/EtOAc=5:1)=0.28; 1H NMR (CDCl3, 270.05 MHz): δ=1.22 (3 H, t, J=5.9 Hz), 1.29–1.35 (1 H, m), 1.45 (1 H, t, J=4.1 Hz), 2.45 (3 H, s), 3.12 (1 H, dd, J=9.2, 4.1 Hz), 3.15 (1 H, d, J=9.1 Hz), 3.59 (1 H, d, J=9.1 Hz), 3.71 (1 H, d, J=9.1 Hz), 7.27–7.36 (7 H, m), 7.69 ppm (2 H, d, J=8.2 Hz); 13C NMR (CDCl3, 67.80 MHz): δ=13.6, 21.3, 21.5, 23.9, 32.8, 49.6, 52.9, 81.2, 87.0, 123.0, 127.6, 128.0, 128.2, 129.7, 131.6, 133.0, 143.7 ppm; HRMS: m/z calc. for C21H21NO2S: 351.1293, found: 351.1300. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. 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