Background and Originality Content
Conjugated dienes possess unique electronic structures and exhibit rich reactivity,[1] which make them important building blocks in fields of pharmaceuticals,[2] optical materials,[3] and polymer chemistry.[4] Moreover, many natural products contain structural units of conjugated olefins.[5]Therefore, the synthesis of conjugated dienes has been of great interest.[6] However, the synthesis of multi-substituted conjugated olefins is highly challenging due to the difficulty in controlling the Z /Eselectivity.[7]
The alkenylzincation of alkynes represents a powerful strategy for the synthesis of conjugated dienes. This reaction enables facile control over the stereo- and regioselectivity of the newly formed olefins, making it a highly advantageous method. While alkenylzincation of terminal alkynes has been well established recently,[8] the corresponding reactions with internal alkynes remains underdeveloped, as evidenced by only two reported examples with significant limitations in substrate scope and selectivity control (Scheme 1A). In 2009, Lam and co-workers[9] developed a directed carbozincation of ynamides using Rh(cod)(acac) as the catalyst, where the zinc group is selectively added to the proximal side of the amide. One example of vinylzincation was achieved, leading to the synthesis of functionalized conjugated diene in moderate yield (66%) and regioselectivity (7:1). In 2016, Yoshikai and co-workers[10] used CoF2/t Bu-Xantphos as a catalyst for the alkenylzincation of unactivated internal alkynes and obtained corresponding conjugated dienyl zinc products with moderate to good yields (34–95%). However, the reaction suffered from competing 1,4-cobalt migration, which leaded to uncontrollable regio- and chemoselectivity. Furthermore, this Co catalyst system was not effective for vinylzincation, probably due to the high reactivity of the vinylzinc reagent towards undergoing its own addition reaction in the presence of the catalyst.[11] In view of these challenges in substrate scope and selectivity control, the development of efficient new catalysts for alkenylzincation of internal alkynes is highly desired.
Scheme 1 Catalytic alkenylzincation of internal alkynes
As our continuous efforts on the development of iron catalysis,[12] we herein report an iron-catalyzed alkenylzincation of internal alkynes that exhibits exceptional reaction activity (up to 11500 turnover numbers), high stereo- and regioselectivity (E /Z > 95:5; regioisomeric ratios, rr > 95:5), and a wide range of substrate applicability (Scheme 1B). Notably, the reaction also shows excellent functional group tolerance, and enables for the first time the highly selective vinylzincation of unfunctionalized internal alkynes as well as carbozincation of unsymmetrical diarylacetylenes and dialkyl acetylenes. This reaction provides a competitive approach to the synthesis of structurally diverse multi-substituted conjugated dienes.
Results and Discussion
We began by the reaction of 4-methoxyphenylacetylene 1aa with divinylzinc reagent in THF at room temperature (Table 1). Initially, the catalysts reported in literature for carbozincation of internal alkynes were investigated,[13] but none of them provided satisfactory results (entries 1–7). Subsequently, we systematically evaluated iron complexes bearing various types of ligands. The tridentate phenanthroline-imine iron complexesL1-FeCl2 and L2-FeCl2 , with the 9-position of the ligand substituted with 2,4,6-triisopropylphenyl, exhibited high activity and complete conversion of the alkyne was achieved (entries 8 and 9). The tridentate pyridine-diimine iron complexes also showed high catalytic activity, and the catalysts L3-FeCl2 ,L4-FeCl2 , and L5-FeCl2produced the conjugated diene product 2aa in high yield and with exclusive selectivity (entries 10–12). Although iron complexes bearing bidentate phenanthroline ligands (L6-FeCl2 andL7-FeCl2 ) showed good activity, reactions catalyzed by these complexes gave moderate regioselective and stereoselective (entries 13 and 14). Furthermore, other iron/bidentate nitrogen complexes with different backbones showed poor reaction results (entries 15–17). When the bidentate α-diimine iron complexL9-FeCl2 was evaluated, the results showed 22% of the desired carbozincation product and 30% of the secondary carbozincation product 4,4’-((1E ,3E )-2,4-dimethylhexa-1,3,5-triene-1,3-diyl)bis(methoxybenzene) (entry 16), which was due to the excessively high activity of the catalyst towards the secondary carbozincation of product 2aa . Other bidentate nitrogen ligands, tridentate nitrogen ligands and diphosphine ligands, were also evaluated but showed no significant improvement in activity or selectivity (see Table S1 for details). After comprehensive consideration, L3-FeCl2 was selected as the optimal catalyst for the following studies. Control experiments demonstrated that the reaction did not occur when FeCl2 was used as the catalyst or when only theL3 ligand was added (entries 18, 19). Furthermore, the purity of the complexes L3 -FeCl2 andL5-FeCl2 were analyzed and a series of control experiments were carried out to exclude the influence of impurities on the reaction. Replacement of the central iron atom by other metals resulted in no reaction (see Tables S2 and S3 for details).
After obtaining the optimal reaction conditions (Table 1, entry 10), we investigated substrate scope of aryl-alkyl acetylenes (Scheme 2). First, we examined the effect of substituents on the benzene ring of the alkynes. The electronic effects of substituents on the phenyl ring had a small effect on the yield. When the phenyl ring was substituted with electron-donating groups, methoxy (2aa ) or dimethylamino (2ad ) at the para -position, the corresponding conjugated diene products were obtained in 91% and 96% yields, respectively. When the phenyl rings of the alkynes substituted with electron-withdrawing groups, the corresponding vinylzincation products (2ah2aq ) were obtained with satisfactory yields and selectivity under standard conditions, albeit those containing ester (2ah ) and cyano (2aj ) groups exhibited slightly reduced stereoselectivities with unidentified reasons. In addition, steric effects of substituent on the phenyl ring of the alkyne slightly affect the reaction. The alkynes having ortho - ormeta -substituted phenyl rings gave high yield and selectivity (2ao , 2as , 2au ). In addition to phenyl, the aryl group of the alkynes 1 could also be benzodioxole (2ba ), naphthalene (2bb ) and heteroaromatics (benzofuran 2bc , indole 2bd , thiophene 2be , furan 2bf , pyridine 2bg ). Note that the reaction exhibited excellent functional group tolerance, as methoxy (2aa ), silyl (2ac ), amino (2ad ), methylthio (2ae ), ester (2ah ), amide (2ai ), cyano (2aj ), sulfonyl (2ak ), acetal (2al ), trifluoromethyl (2am ), halogen (2an2aq ,2as , 2au ), and hydroxy (2cg ) groups were all tolerated.
Table 1 Catalytic vinylzincation of an internal alkyne1aa : optimizing reaction conditions a