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Treatment of an internal acetylene such as 1-silyl-1-octyne (3) with a low-valent titanium reagent, (η 2 -propene)Ti(O-i-Pr) 2 (1) readily prepared from Ti(O-i-Pr) 4 and i-PrMgCl in situ, generates an acetylenetitanium complex. This complex was allowed to react with a terminal acetylene, 4-(benzyloxy)-1-butyne (5), to give the intermediate titanacyclopentadiene (6) which, upon hydrolysis, deuteriolysis, or iodinolysis, gave diene 8, or its bis-deuterated (>99% d 2 ) and bis-iodinated counterparts (9 and 10), in good yields and with high selectivities. This reaction is applicable to the cross-coupling reaction of functionalized acetylenes such as 2-alkynoates and 2-alkynamides 12-18 and a variety of terminal acetylenes 24-28 to give dienes 36-50 in good yields. A terminal acetylene 28 carrying an olefinic bond at the other terminus reacted with a silylpropiolate to afford the expected diene 42 without any complication.

Unsaturated heterocyclic compounds are useful synthetic intermediates as well as important structural units found in natural and artificial products. 1 Their synthesis requires proper alignment of heteroatoms as well as unsaturation at a defined position in the ring system. This is often a critical issue, especially when the heterocycle has multiple heteroatoms. 1 Here we report a concise preparation of 1,4-diaza(or partially oxa)-2-cycloalkenes based on a new copper-catalyzed double amination of haloacetylenes, as formulated in eq 1 (X ) N; Y ) N or O). 2,3 While investigating copper-catalyzed coupling of sulfonamides and haloacetylenes, 4 we attempted N,N′-dialkynylation of diamine derivative 3 (see eq 2, Ts ) p-MeC 6 H 4 SO 2 -). However, we were unable to obtain more than a trace amount of the expected dialkynylated product, and the actual isolated product was a 1,2,3,4tetrahydropyrazine derivative 4. Equation 2 shows the representative reaction conditions for the preparation of 4 and 5 from aliphatic and aromatic acetylenes 1 and 2, respectively. The structure of 5 was confirmed by comparison with an authentic sample prepared by an alternative method. 5 As unprotected 1,2,3,4-tetrahydropyrazines, which are enamines doubly activated by two nitrogen atoms, are unstable compounds, this simple one-step method is suitable for the direct preparation of their protected surrogates. 6

tert-Butyl 2-en-7-ynoate 6 was treated with (η2-propene)Ti(O-i-Pr)2 (3), generated in situ from Ti(O-i-Pr)4 or Ti(O-i-Pr)3Cl and i-PrMgCl, in ether at −50 to −20 °C to afford the product 8 in good yield. The presence of the intermediate titanabicycle 7 was verified by bis-deuterolysis with excess D2O. When the titanabicycle 7 was treated with 1.1 equiv of i-PrOD and then worked up as usual, the monodeuterated product 10 was obtained with high site selectivity and stereoselectivity. Other electrophiles such as aldehydes and ketones also reacted with the titanabicycle in a highly stereoselective manner to give cyclopentanes having a stereo-defined side chain. On the contrary, treatment of the corresponding ethyl ester, ethyl 8-(trimethylsilyl)-(E)-2-octen-7-ynoate (28), with 3 under the same conditions followed by the addition of 1.1 equiv of s-BuOH afforded 2-(trimethylsilyl)-1-bicyclo[3.3.0]octen-3-one (32) in 80% yield. Quenching the same reaction mixture with i-PrOD, EtCHO, and Et2CO in place of s-BuOH gave 4-deuterio (with exclusive deuterium incorporation), 4-(1-hydroxypropyl), and 4-(1-ethyl-1-hydroxypropyl) derivatives of the above bicyclic ketone (34, 35, and 36) in good yields. These electrophiles were always introduced from the convex face of the bicyclic skeleton. The stereochemistry of the cyclization could be controlled by an allylic substituent such as (tert-butyl)dimethylsiloxy or butyl group to a high degree yet with a reversal diastereoselection to give 45 or 47. The reaction of ethyl 7-octen-2-ynoate (56) and 3 at −50 to 0 °C took place in a quite different way to afford 1-[(ethoxycarbonyl)methyl]bicyclo[3.1.0]hexane (64) in 74% yield after hydrolysis. If the simple hydrolysis is replaced by deuterolysis or the action of diethyl ketone, 1-[(ethoxycarbonyl)dideuteriomethyl] (with 99% deuterium incorporation), or 1-[(ethoxycarbonyl)(3-pentylidene)methyl] derivative of the above product (65 or 66) was obtained in good yields. A 7-en-2-ynoate having an internal Z-double bond such as 80 afforded a single stereoisomer 82 with the substituent at the endo position of the bicyclic skeleton, suggesting that the stereochemical integrity of the Z-double bond of the starting material was retained in the product. An alkyl substituent at the allylic position of the substrates like 74 and 76 nicely controlled the stereochemistry of the cyclization to afford single products 75 and 77 with the substituent being placed in the exo orientation of the bicyclic structure. This high diastereoselectivity was successfully applied to an enantioselective synthesis of d-sabinene from an optically active enynoate via nearly complete chirality transfer.

Hydrometalation of acetylenes illustrated in eq 1 is a superior method for preparing stereodefined alkenylmetal species, which are particularly useful for the construction of olefinic linkages with predictable stereochemistry. Hydrometalation reactions1 including hydroboration,18 -alumination,lb -magnesation,lc -silylation,ld -stannation,18 and -zirconation,lf etc., have been routinely utilized in the synthesis of complex natural products. Herein we report a new entry to this series of reactions, namely the first hydrozincation of acetylenes, and demonstrate its application to further synthetic transformations.Recently, organozinc compounds of the type RZnX (R = alkyl; X = halogen, R, etc.) have been widely recognized as versatile carbon nucleophiles in organic synthesis owing to their selective reactivities.2 Alkenylzinc compounds are usually prepared via transmetalation of appropriate organometallic reagents, typically organolithium, -magnesium, or -boron compounds, with zinc salts or diethylzinc.2a-C|3 Direct reductive metalation of alkenyl halides with zinc metal can also be effected, but the stereochemical integrity of the starting alkenyl halide is not always retained in the zinc reagent.4 If hydrozincation of acetylenes (eq 1, "M-H" = "ZnHX") could be executed in a stereoselective manner, this reaction could become a straightforward method to prepare stereochemically defined alkenylzinc reagents. While hy-

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Treatment of a variety of 1,2-dien-7-ynes with a slight excess of (η2-propene)Ti(O-i-Pr)2 (1), prepared in situ from Ti(O-i-Pr)4 and 2 equiv of i-PrMgCl in ether, afforded 1-alkenyl-2-alkylidenecyclopentanes in moderate to good yields after aqueous workup. The intermediate titanabicycle such as 7 was identified by deuterolysis, which gave d 2-8 with exclusive deuterium incorporation. The use of an optically active allene such as 19 (≤83% ee) realized a highly efficient axial to centered chirality transfer to give 21 (80−83% ee). Analogously, the cyclization of 22 (≤86% ee) with 1 followed by carbonylation (under ca . 1 atm of CO) afforded the optically active bicyclic ketone 25 (86% ee). When a homologous 1,2-dien-6-yne 27 was subjected to the cyclization as above, a different type of titanabicycle 28 was generated, which was identified by hydrolysis giving 29 or the following carbonyl addition. Upon reaction with nonanal, 28 afforded the alcohol 32 with very high regio- (with respect to the allylic system), stereo- (the diene moiety), and diastereoselectivities (the hydroxy group). Various 1,2-dien-6-ynes underwent the cyclization followed by the addition to carbonyl compounds in comparable selectivities as above. Chiral 1,2-dien-6-ynes 46 (≤83% ee) achieved a nearly complete chirality transfer to generate a chiral titanabicycle 48, which, in turn, reacted with nonanal, acetone, or N-benzylidenepropylamine to afford the alcohols 51 and 52 (both in 80% ee) or the amine 53 (81% ee) in good yields with a very small loss of the enantiopurity.