Highly selective cross-coupling reactions of 1,1-dibromoethylenes with alkynylaluminums for the synthesis of aryl substituted conjugated enediynes and unsymmetrical 1,3-diynes

A highly efficient method for the synthesis of aryl substituted conjugated enediynes and unsymmetrical 1,3-diynes via selective cross-coupling reactions of 1,1-dibromoethylenes with alkynylaluminums using the Pd(OAc)2–DPPE and Pd2(dba)3–TFP complexes as catalysts, respectively, has been successfully developed. Though the alkyl substituted conjugated enediynes and unsymmetrical 1,3-diynes were not obtained, this case is also remarkable as the same starting materials could selectively produce either aryl substituted conjugated enediynes or unsymmetrical 1,3-diynes in moderate to excellent yields (up to 99%) in the different Pd–phosphine catalytic systems.


Introduction
The conjugated enynes 1 and diynes, 2 which play important roles in organic synthesis, have been widely used in the preparation of natural products, 3 pharmaceuticals 4 and advanced materials. 5 Particularly, the conjugated enediynes are usually used for synthesis of electronic and optical materials. 6 Meanwhile, the 1,3-diynes are common structural motifs found in biologically active and pharmaceutical compounds, which are known to have anti-HIV, 7 anticancer, 8 antibacterial, 9 and anti-inammatory properties. 10 Though several kinds of typical synthetic processes, including homo-11 or cross-coupling, 12,13 diynone decarbonylation, 14 oxidative coupling 15 and oxidative decarboxylative homo-coupling, 16 have been realized, developing some efficient methods for accessing such frameworks from easily available organic compounds is very desirable and important.
The 1,1-dibromoethylenes, which are readily available from aldehydes, have attracted some attention due to their potentialities in the construction of conjugated enediynes and 1,3diynes. Compared with the mature cases for constructing of symmetric conjugated 1,3-diynes, which are mostly from homocoupling of 1,1-dibromoethylenes (Scheme 1a), 17 the applications of 1,1-dibromoethylenes for synthesizing of conjugated enediynes and unsymmetrical 1,3-diynes are very rare. In 2005, Kabalka et al. reported a highly efficient Suzuki-Miyaura coupling of 1,1-dibromo-1-olen with potassium alkynyl tri-uoroborate to provide conjugated enediynes (Scheme 1b). 18 Besides, they have been successfully applied to the crosscoupling reaction of terminal alkynes to produce unsymmetrical conjugated 1,3-diynes (Scheme 1c). 19 Obviously, the crosscoupling reactions of 1,1-dibromoethylenes with organometal reagents is one of the most generally useful. However, this type of reactions has been less explored due to a complication of three competitive pathways (Scheme 1a-c). A key success of this reaction relies mainly on suitable catalytic systems and/or appropriate organometallic reagents that can selectively produce either conjugated enediynes or 1, 3-diynes. To the best of our knowledge, the cross-coupling reaction of 1,1-dibromoethylenes with alkynylaluminums, which have been extensively used in organic synthesis, 20 has not been achieved. Herein, we would like to describe the novel Pd-phosphine complexes catalyzed selective cross-coupling reactions of 1,1dibromoethylenes 1 with alkynylaluminums 2 to provide the aryl substituted conjugated enediynes 3 and unsymmetrical 1,3diynes 4, respectively (Scheme 1d).
Under the optimal conditions (Table 1, entry 11), various 1,1dibromoethylenes 1 and alkynylaluminum reagents 2 were evaluated, affording the corresponding aryl substituted conjugated enediynes 3 with moderate to good yields (up to 93%) and the trace of 1,3-diyne byproducts 4 and 5 were not isolated. As shown in Table 2, the reactivity of the cross-coupling was sensitive to the steric hindrance rather than to the electronic property of substituents on the phenyl ring of 1,1-dibromoethylenes 1. The substrates 1 with ortho-substituents gave lower yields than those with para ones (Table 2, entries 2 vs. 1, 6 vs. 5 and 8 vs. 7). Meanwhile, the fused-ring and heteroaromatic substrates (1m, 1n and 1o) were also tolerable, giving the desired products with 51% to 93% yields (Table 2, entries 11, 12, 13, 16, 19, 20, 24 and 28). On the other hand, the reactivity of this reaction was sensitive to neither the electronic properties nor the steric hindrance of substituents on the phenyl ring of alkynylaluminums 2. Generally, the desired conjugated enediynes 3 were isolated with good to excellent yields (up to 93%) except 3fa and 3oa (53% and 51% yields, Table 2, entries 6 and 13). Moreover, the 2-thienyl substituted substrate 2g also successfully afforded the desired products with good yields ( Table 2, entries 26-28). 22 Inspired by the previous discovery (Table 1, entry 5), it was envisioned that the aryl substituted unsymmetrical 1,3-diynes 4 could be achieved via cross-coupling reaction of 1,1-dibromoethylenes 1 with alkynylaluminums 2 in the presence of Pd 2 (dba) 3 . Thus, we then restarted to optimize the reaction conditions of this Pd 2 (dba) 3 catalyzed cross-coupling using 1a 21 and 2a as the model substrates, respectively, in which the conjugated enediyne 3aa and homo-coupling byproduct 1,4diphenylbuta-1,3-diyne 5aa were not determined. Performing the reaction in THF at higher temperature afforded the desired product 4aa with higher yield [ Table 3, entries 2 (80 C) vs. 1 (60 C)]. To improve the reactivity, the efficiency of solvent was then examined and it was found that the polar aprotic solvents were benecial (Table 3, entries 3 and 4). Further optimization of the reaction conditions was then aimed at exploring the efficiency of Pd 2 (dba) 3 with various P-ligands. The addition of DPPE, which had been proved to be the most effective ligand in the synthesis of conjugated enediyne 3aa, could hardly provide the target product 4aa (Table 3, entry 5). Delightedly, when the reaction was carried out with 5.0 mol% of tri(2-furyl)phosphine (TFP , Table 1) as ligand, the desired 1,3-diyne 4aa could be isolated in 45% yield ( Table 3, entry 8). Increasing the amount of TFP to 15.0 mol% could greatly improve the yield to 60% (Table 3, entry 9). The addition of 1.5 equiv. of diisopropyl ethylamine (DIPEA) could further enhance the yield to 74% (Table 3, entry 10). Thence, the optimal conditions were iden-tied as 2.5 mol% of Pd 2 (dba) 3 with 15.0 mol% of TFP, 1.5 equiv. of DIPEA in DMF at 80 C for 10 h.
With the optimal reaction conditions in hand (Table 3, entry 10), the substrate scope of 1,1-dibromoethylenes 1 with alkynylaluminums 2 was next examined and also the conjugated enediynes 3 and homo-coupling byproducts 1,3-diynes 5 were   not determined. As shown in Table 4, the electronic or positional nature of the substituents either in 1,1-dibromoethylenes 1 or in alkynylaluminums 2 had nearly no effect on the efficiency of this cross-coupling reaction, affording the aryl substituted unsymmetrical 1,3-diynes 4 with good to excellent yields (up to 99%). For the fused-ring substrate 1m, the expected products 4ma and 4mb were obtained in good yields (Table 4, entries 6 and 11). Especially, the 2-thienyl or 2-furyl substituted substrates successfully afforded the unsymmetrical 1,3-diynes 4ob, 4oc and 4cg in good yields (Table 4, entries 12, 16 and 21). 22 According to the previous studies on the palladium catalyzed cross-coupling reactions 11-13 and our previous works about organoaluminums, 20g-l two reasonable catalytic cycles are proposed in Scheme 2. The possible mechanism of the crosscoupling for producing enediynes 3 is shown in path A. First, the oxidative additions of 1,1-dibromoethylenes 1 to Pd-DPPE complex generate the organopalladium(II) bromide intermediates I. Then, the transmetalations of alkynylaluminums 2 with intermediates I give complex intermediates II and Me 2 AlBr. The intermediates II with another alkenyl bromide could isomerize into complex intermediates III via intramolecular Pd II -translation. Next, the transmetalation of alkynylaluminums 2 with intermediates III provided complex intermediates IV and another Me 2 AlBr again. Finally, intermediates IV under goes reductive eliminations to afford the desired aryl substituted conjugated enediynes 3 and regenerate the active Pd-DPPE species for the next catalytic cycle. Similar to path A, the possible mechanism of the cross-coupling for producing unsymmetrical 1,3-diynes 4 is shown in path B. Oxidative additions of 1,1-dibromoethylenes 1 to Pd-TFP generate the organopalladium(II) bromide intermediates V and transmetalations of alkynylaluminums 2 with intermediates V give intermediates VI and Me 2 AlBr. Elimination of the b-H in intermediates VI, in which the acidities of b-H of intermediates VI could probably be stronger than those of intermediates II so that this elimination could be promoted by an equiv. amount of DIPEA, generate intermediates VII and HBr$DIPEA. Finally, intermediates VII also under goes reductive eliminations to afford the desired aryl substituted unsymmetrical 1,3-diynes 4 and regenerate the active Pd-TFP species for the next catalytic cycle.

Conclusions
Though the specic mechanism and reason why the same starting materials could selectively produce either conjugated enediynes or unsymmetrical 1,3-diynes in analogous Pd-phosphine catalytic system were unclear, we have successfully developed a highly efficient method for the synthesis of aryl substituted conjugated enediynes and unsymmetrical 1,3diynes via selective cross-coupling reactions of 1,1-dibromoethylenes with alkynylaluminums using Pd(OAc) 2 -DPPE and Pd 2 (dba) 3 -TFP complexes as catalysts, respectively. A series of aryl substituted conjugated enediynes 3 and unsymmetrical 1,3diynes 4 have been obtained in moderate to excellent yields (up to 99%). To the best of our knowledge, there is no precedent for the application of 1,1-dibromoethylenes and alkynylaluminums in cross-coupling reaction to date. Further mechanistic studies of these selective cross-coupling reactions are still in progress.

Conflicts of interest
There are no conicts to declare.