Iridium-catalyzed enantioselective hydroalkynylation via alkene isomerization

Article abstract of DOI:10.1016/j.tetlet.2021.153108

An iridium-catalyzed enantioselective alkynylation of methylene C–H bonds γ to the amide group is developed. The reaction proceeds through alkene isomerization followed by regioselective hydroalkynylation. This method provides rapid access to a wide range of stereodefined alkynylated compounds in good yields and good enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2021.153108

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iridium-catalyzed enantioselective hydroalkynylation via alkene
isomerization
⇑
Wen-Wen Zhang, Bi-Jie Li
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An iridium-catalyzed enantioselective alkynylation of methylene CAH bonds
c to the amide group is
Received 26 February 2021
Revised 15 April 2021
Accepted 18 April 2021
Available online xxxx
developed. The reaction proceeds through alkene isomerization followed by regioselective hydroalkyny-
lation. This method provides rapid access to a wide range of stereodefined alkynylated compounds in
good yields and good enantioselectivities.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Hydroalkynylation
Iridium catalysis
Alkene isomerization
Transition metal catalyzed enantioselective functionalization of
C(sp3)-H bond has been proved to be one of the most effective and
powerful methods for constructing carbon–carbon and carton-het-
eroatom bonds [1]. Therefore, significant efforts have been made
by chemists over the last few decades. Diverse transformations
enabled by enantioselective C(sp3)-H functionalization have been
documented, including arylation [2], olefination [3] and alkylation
[4]. In comparison, methods for enantioselective C(sp3)-H bond
alkynylation are relatively rare [5]. Such methods would enable
access to chiral alkynylated compounds which are valuable inter-
mediates for the synthesis of natural products and bioactive mole-
cules [6].
So far, the majority of methylene CAH alkynylation reactions
mainly rely on cross-dehydrogenative coupling reactions, in which
the methylene CAH bonds are adjacent to heteroatoms [7]
(Scheme 1A). Recently, the Liu group and the Wang group indepen-
dently developed enantioselective alkynylations of benzylic CAH
bonds via hydrogen atom transfer (HAT) [8]. In addition, Liu and
Lin reported a copper-catalyzed asymmetric alkynylation of ben-
zylic CAH bonds via radical relay [9] (Scheme 1B). Another impor-
tant advance was made by Shi and co-workers. They demonstrated
that the combination of a PIP (pyridinylisopropyl) directing group
and 3,30-fluorinated-BINOL ligand could enable the palladium-cat-
alyzed enantioselective alkynylation of unbiased methylene CAH
bond b to the carbonyl group [10] (Scheme 1C). Despite these
advances, catalytic enantioselective alkynylation of methylene
CAH bond remote to a functional group still remains underdevel-
oped [2h,11].
Transition metal-catalyzed isomerization of alkenes provides a
new strategy to prepare useful products in an atom- and redox-
economical manner [12,13]. We envisioned that alkene isomeriza-
tion could provide a potential solution to catalytic enantioselective
alkynylation of remote methylene CAH bonds. In our previous
work, we have developed an iridium-catalyzed
c
-alkynylation of
a, b-unsaturated amide [14]. Experimental data suggest that the
reaction proceeds through isomerization of a, b-unsaturated amide
to b, c- unsaturated amide followed by hydroalkynylation. We rea-
soned that if the catalyst could affect the isomerization of an
alkene remote to the amide group, we would be able to achieve
an enantioselective hydroalkynylation of remote methylene CAH
bond. Herein, we reported an enantioselective alkynylation of
methylene CAH bonds
c to the amide group through iridium cat-
alyzed alkene isomerization followed regioselective hydroalkyny-
lation .
Initial assessment of the reactivity revealed that the
hydroalkynylation of amide 1a catalyzed the combination of Ir
(COD)2OTf and (R)-DM-Segphos afforded the alkynylation product
3a as a single regioisomer. In addition, the ee observed was similar
to that observed by the hydroalkynylation of
a, b-unsaturated
amide (Scheme 2). However, only moderate yield was obtained,
indicating that the isomerization of compound 1a is more difficult
than that of the corresponding a, b-unsaturated amide. To increase
the yield, various additives were tested. Finally, we found that the
addition of an Brønsted acid could improve the yield without
affecting the enantioselectivity [15].
⇑
Corresponding author.
E-mail address: bijieli@mail.tsinghua.edu.cn (B.-J. Li).
https://doi.org/10.1016/j.tetlet.2021.153108
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Wen-Wen Zhang and Bi-Jie Li, Iridium-catalyzed enantioselective hydroalkynylation via alkene isomerization, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2021.153108

Wen-Wen Zhang and Bi-Jie Li
Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Enantioselective alkynylation of CAH bond.
Scheme 2. Additives in enantioselective alkynylation.
The reactivities of a range of N-alkyl substituted amides were
tested (Table 1). Hydroalkynylations of a series of aliphatic amides
with various linear chains and steric hindrance gave the corre-
sponding products in good yields and high enantioselectivities
(3b-3e). The indole substituted substrate was tolerated (3f). The
reaction was also applicable to tertiary amides although higher
catalyst loading was necessary (3g-3h).
Fig. 1. Kinetic profile of the reaction 1a with 2.
To gain some preliminary insight into the reaction mechanism,
We next tested the substrate containing an alkene further
remote from the amide group. When 1i as used as a substrate,
the reactivity was lower and the corresponding product 3i was
generated in moderate yield and enantioselectivity by switching
to DTBM-Garphos as a ligand (Eq. 1). Further improvement of the
catalyst activity is necessary.
kinetic profile of the reaction 1a with 2 was conducted (Fig. 1).
unsaturated amide 1a-1, b, - unsaturated amide 1a-2 and
c
, d-
c
a, b-
unsaturated amide 1a-3 were all observed throughout the reaction
progress. These results suggest that the regioselectivity is not
determined by alkene isomerization but rather by a
hydroalkynylation of b, - unsaturated amide.
c-selective
c
2

Wen-Wen Zhang and Bi-Jie Li
Tetrahedron Letters xxx (xxxx) xxx
Table 1
and the alkene. High yields and enantioselectivities were obtained
under the standard conditions (3k-3o). Amides containing func-
tional groups including halide and phenol underwent regioselec-
tive alkynylations to give the products in moderate to good
yields and high enantioselectivities (3l-3n). In addition, silyl ether,
acetal, ester and hydroxyl group were tolerated (3p-3s). Under
these conditions, no hydroalkynylation product was observed for
tri-substituted alkenes. Furthermore, aryl and alkyl alkynes did
not work due to the competing alkyne dimerization.
Scope of enantioselective alkynylation of methylene C(sp3)-H bond.a
The co-existence of
rated amide 1a-2 and
c
, d- unsaturated amide 1a-1, b,
c- unsatu-
a, b-unsaturated amide 1a-3 in the reaction
indicated that it is possible to use a mixture of these substrates to
generate a single isomeric product. To do so, we tested the
hydroalkynylation of a mixture of 1a and 1a-3 with 2 in the pres-
ence of Ir(COD)2OTf and (R)-DM-Segphos. As we expected, product
3a was afforded in high yield and high enantioselectivity (Eq. 2).
Similarly, catalytic hydroalkynylation of a mixture of 1a, 1a-2
and 1a-3 generated similarly good yield and high enantioselectiv-
ity (Eq. 3). These results showed potential application of industrial
material by using isomeric unsaturated carboxylic acid derivatives
without prior separation.
aReactions were conducted at 0.10 mmol scale. Isolated yields were reported. The er
values were determined by chiral HPLC. b10 mol% catalyst.
In conclusion, we have developed an iridium-catalyzed alkyny-
lation of methylene CAH bonds remote to the amide group.
Through a combination of iridium-catalyzed alkene isomerization
and hydroalkynylation, the alkynylation occurred regio- and enan-
Substrates containing an alkene closer to the amide group
tioselectively at the
c position. Further efforts to improve the cat-
exhibited higher activity. For hydroalkynylation of
c,d- unsatu-
alytic activity is ongoing in our laboratory.
rated amide, the product 3 could be obtained through effective iso-
merization in the absence of 1,4-dihydroxynathalene (Table 2). The
methylene CAH bonds b to the amide group were cleaved, and the
Declaration of Competing Interest
alkynylation occurred regioselectively at the
c position. The func-
tional group compatibility of this catalytic hydroalkynylation was
investigated. As shown in Table 2, the alkynylation was not sensi-
tive to the chain length and the substituents on the nitrogen atom
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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