Arylethyne Bromoboration–Negishi Coupling Route to E- or Z-Aryl-Substituted Trisubstituted Alkenes of ≥98% Isomeric Purity. New Horizon in the Highly Selective Synthesis of Trisubstituted Alkenes

Despite major advances in the syntheses of strictly (≥98%) regio- and stereodefined alkenes via “elementometalation”[1]–Pd- or Ni-catalyzed cross-coupling developed since 1976,[2]-[4] efficient and highly (≥98%) selective syntheses of tri- and tetrasubstituted alkenes continue to provide major synthetic challenges. The Zr-catalyzed alkyne carboalumination–Negishi coupling[3][4] (Eq. 1 in Scheme 1) has provided a highly selective and widely used method for the synthesis of trisubstituted alkenes.[4b] Although this method is broad in synthetic scope with respect to R1 of the starting alkyne (R1C≡CH), the R2 group of the organoalanes to be added to R1C≡CH has been practically limited to Me, and a limited number of alkyl groups including allyl and benzyl groups.[3–6] On the other hand, in an alkyne bromoboration–Negishi-Suzuki tandem cross-coupling process (Eq. 2 in Scheme 1) reported by Suzuki in 1988,[7] bromoboration of R1C≡CH is followed by incorporation of both R2 and R3 groups by Pd-catalyzed cross-coupling reactions of wide synthetic scopes, thereby promising to provide a method of very wide applicability for synthesizing trisubstituted alkenes. In reality, however, all reported examples[7] of Eq. 2 in Scheme 1 and of its modification involving double Negishi coupling reactions[8,9] (Eq. 3 in Scheme 1) involve the use of only alkylethynes, even though haloboration of aryl- and alkenyl-substituted ethynes are known to proceed well.[10] Scheme 1 Highly (≥98%) selective “elementometalation” –Pd-catalyzed cross-coupling routes to trisubstituted alkenes. As readily suspected, competitive debromoboration of 2 to revert to the starting alkynes would be the main cause of difficulty in the Pd-catalyzed cross-coupling of 2, and the fact that those derived from aryl- and alkenyl-substituted ethynes are benzylic and allylic bromides, respectively, besides being alkenyl bromides must undoubtedly be responsible for their significantly higher propensity to undergoing debromoboration, as compared with that of alkylethyne-derived 2. Thus, for example, the reaction of 2a, generated by bromoboration of phenylethyne followed by treatment with pinacol, with (E)-1-octenylzinc bromide in the presence of Pd(DPEphos)Cl2 (0.5 mol %) at 23 °C for 2 h led to the formation of the desired 3a in <2% yield along with PhC≡CH (20%) and the unreacted 2a (67%). The results indicate that the reaction not only is slow but also produces at least ten times as much PhC≡CH as 3a. To our delight, however, the use of highly active Pd catalysts, such as Pd(tBu3P)2[11,12] and PEPPSI™-IPr (5),[12c,13,14] almost fully suppressed debromoboration of 2a and led to the production of the desired 3a of ≥98% isomeric purity in high yields along with only traces (<2%) of PhC≡CH and the unreacted starting compound 2a (Eq. 1 in Scheme 2). Earlier in this study, we treated 2b (Y = Br) with nHexZnBr in THF in the presence of 0.5 mol % of Pd(tBu3P)2 and obtained, after iodinolysis, the desired (E)-α-(n-hexyl)-β-iodostyrene (4b) only in 14% yield along with PhC=CH formed in 78% yield (Eq. 2 in Scheme 2). However, the use of Pd(tBu3P)2 as a catalyst later proved to be appropriate, since its use along with 2a in place of 2b gave 4b in 86% yield (Eq. 3 in Scheme 2). The results shown in Scheme 2 clearly indicate that proper selection of not only Pd catalysts, e.g., Pd(tBu3P)2 and PEPPSI™-IPr (5), but also boryl groups, e.g., pinacolboryl rather than dibromoboryl, is critically important. Scheme 2 Pd-Catalyzed cross-coupling reactions of (Z)-β-bromo-β-phenylethenylboranes (2a and 2b). Effects of Pd catalysts and boryl groups. Cond. I: i) BBr3 (1.1 equiv), CH2Cl2, −78 °C, 1 h; ii) pinacol (1.2 equiv), iPr2NEt (2.4 ... As summarized in Table 1, a wide range of R2 groups including alkyl, alkenyl, aryl, and alkynyl may now be introduced into 3 and 4 derived from aryletheynes, such as phenylethyne, p-chlorophenylethyne, and p-tolylethyne, by using (i) (Z)-β-aryl-β-bromoalkenyl(pinacol)boranes (2), (ii) either Pd(tBu3P)2 or PEPPSI™-IPr (5). Since a wide range of Pd-catalyzed alkenylation reactions are known to selectively and satisfactorily convert alkenylmetals and/or alkenyl halides represented by 3 and 4 into the corresponding trisubstituted alkenes 1[4,15] our attention in this study is focused on the synthesis of 3 and 4. Many of the alkenes represented by 3 and 4 shown in Table 1 are very difficult to prepare in a highly (≥98%) selective manner by any previously known methods except for those that are accessible by Zr-catalyzed carboalumination[5] and carbocupration[16] of alkynes. To demonstrate the synthetic utility of the alkyne bromoboration–Pd-catalyzed cross-coupling route to 3 and 4, a pair of (E)- and (Z)-2-iodo-1,1-diarylethenes 4h and 4i were synthesized as ≥98% stereoisomerically pure compounds in 42% and 46% yields in two steps from PhC≡CH and p-ClC6H4C≡CH, respectively (Scheme 3). Scheme 3 Highly selective (≥98%) synthesis of (E)- and (Z)-α -(p-chlorophenyl)-β-iodostyrenes (4h and 4i) via arylethyne bromoboration–Negishi coupling–iodinolysis. Table 1 Arylethyne bromoboration–Negishi coupling route to β,β-disubstituted alkenyl(pinacol)boranes (3) and the corresponding iodides (4). In summary, the following findings have significantly contributed to the development of the widely applicable and highly selective route to trisubstituted alkenes via alkyne elementometalation–Pd-catalyzed cross-coupling. (1) (Z)-β-Bromo-β-arylethenyldibromoboranes, readily preparable by treatment of arylethyne with BBr3,[10] do not satisfactorily undergo Pd-catalyzed cross-coupling due to competitive β-debromoboration under all conditions tested thus far. However, the combined use of the corresponding (Z)-β-bromo-β-arylethenyl(pinacol)boranes and highly active Pd catalysts, such as Pd(tBu3P)2[11,12] and PEPPSI™-IPr (5),[13] leads to highly (≥98%) regio- and stereoselective syntheses of the corresponding trisubstituted alkenyl(pinacol)boranes (3) in one or two steps from arylethynes via Negishi coupling in 53 to 66% isolated overall yields. The corresponding alkenyl iodides (4) can be obtained as ≥98% isomerically pure compounds by known iodinolysis of 3 with I2 and NaOH in 80–86% isolated yields from 3. In a couple of cases, the feasibility of one-pot conversion of arylethynes to 4 in ca. 60% overall yields has also been demonstrated (Table 1). (2) The arylethyne bromoboration–Negishi coupling protocol reported herein makes available 3 and 4, and hence their fully carbotrisubstituted derivatives as well,[4,15] many of which have been very difficult to prepare as highy (≥98%) isomerically pure compounds by any other known methods. Together with the related alkylethyne-based protocols,[7–9] the alkyne bromoboration–Negishi coupling protocol represents the hitherto most widely applicable and highly (≥98%) selective route to trisubstituted alkenes. Further development with the use of conjugated 1,3-enynes and 1,3-diynes is currently in progress.