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
(2ah –2aq ) 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 (2an –2aq ,2as , 2au ), and hydroxy (2cg ) groups were all
tolerated.
Table 1 Catalytic vinylzincation of an internal alkyne1aa : optimizing reaction conditions a