Tetrasubstituted 1,3-Enynes by Gold-Catalyzed Direct C(sp2)-H Alkynylation of Acceptor-Substituted Enamines

Article abstract of DOI:10.1021/acs.orglett.1c01486

A gold-catalyzed synthesis of tetrasubstituted 1,3-enynes from hypervalent iodine(III) reagents and activated alkenes is reported. This reaction involves an in situ formed alkynyl Au(III) species and a subsequent direct C(sp2)-H functionalization of alkenes, offering 26 enynes in 62-92% yield with excellent functional group tolerance.

Full text of DOI:10.1021/acs.orglett.1c01486

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Letter
2
Tetrasubstituted 1,3-Enynes by Gold-Catalyzed Direct C(sp )−H
Alkynylation of Acceptor-Substituted Enamines
Chunyu Han, Xianhai Tian,* Huili Zhang, Frank Rominger, and A. Stephen K. Hashmi*
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ABSTRACT: A gold-catalyzed synthesis of tetrasubstituted 1,3-enynes from hypervalent iodine(III) reagents and activated alkenes
2
is reported. This reaction involves an in situ formed alkynyl Au(III) species and a subsequent direct C(sp )−H functionalization of
alkenes, offering 26 enynes in 62−92% yield with excellent functional group tolerance.
1
,3-Enynes are important subunits present in natural products,
Scheme 1. Metal-Catalyzed Alkynylations of Alkenes
1
pharmacologically active molecules, and functional materials.
They also serve as highly valuable synthetic intermediates
participating in diverse organic transformations. Thus, it is not
2
surprising that considerable efforts have been expended in
seeking methods for the preparation of conjugated 1,3-enynes.
Classical synthetic strategies for the construction of 1,3-enynes
3
include Wittig olefinations of propynals or ynones,
4
dehydrations of propargyl alcohols, cross-dimerizations of
alkynes, and Sonogashira as well as Suzuki-Miyaura coupling
2
a,5
reactions.
Over the past decade, the direct alkynylation of
6
alkenes has gained more attention. Usually, the alkynylation of
C(sp )−H bonds to give 1,3-enynes is limited to activated
olefins or substrates bearing a proper directing group.
2
7
Consequently, there is still a high demand to develop efficient
and simple methods for the direct stereo- and regioselective
synthesis of highly substituted enynes.
1
4
cycles, and we recently reported Au-catalyzed domino
1
5
cyclization/alkynylation reactions, dual Au/Ag catalyzed
On the other hand, owing to the nonclassical bond character
16
8
direct alkynylations of cyclopropenes, and C−H alkynyla-
and the excellent reactivity, alkynyl-substituted hypervalent
17
tions/oxy-alkynylations of phenols. Our previous in-depth
mechanistic studies have demonstrated that Au(III) species are
key intermediates for the formation of C−C bonds. We herein
iodine reagents have attracted increasing attention from many
9
organic chemists. For instance, Waser’s group reported several
direct alkynylations of heterocycles using alkynyl-substituted
2
10
report the first gold-catalyzed C(sp )−H alkynylation of
hypervalent iodine reagents. Patil’s group disclosed a gold-
acceptor-substituted enamines with hypervalent iodine re-
catalyzed aminoalkynylation reaction of alkynes using the
11
TIPS-EBX agent. Liu’s group developed a new method for
Received: April 30, 2021
Published: June 9, 2021
the synthesis of unsymmetrical 1,3-butadiynes by a gold-
12
catalyzed C−H alkynylation reaction of terminal alkynes. To
date, alkynylations of alkenes for the synthesis of 1,3-enynes
using TIPS-EBX are viable only by employing rhodium or
7b,13
iridium catalysts (Scheme 1a).
Our group has been
interested in reactions involving Au(I)/Au(III) catalytic
©
2021 American Chemical Society
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Letter
Scheme 2. Reaction Scope ,
a b
agents for the synthesis of tetrasubstituted 1,3-enynes (Scheme
1
b).
We initially optimized the reaction conditions by employing
-aminoacrylate 1a and TIPS-EBX 2a as model substrates
3
(Table 1). As expected, the desired product 3aa was isolated in
Table 1. Optimization of the Reaction Conditions ,
a b
c
Entry
Catalyst
Ligand
Solvent
Yield (%)
d
e
1
2
3
4
5
6
7
8
9
Ph PAuNTf /AgNTf
Phen
CH CN
87 (88)
3
2
2
2
3
Ph PAuNTf
Phen
Phen
−
CH CN
90
n.d.
3
3
f
−
CH CN
3
Ph PAuNTf
CH CN
31
84
81
12
3
2
3
Ph PAuCl
3
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
CH CN
3
(C F ) PAuNTf
CH CN
6
5
3
2
3
IPrAuCl
CH CN
3
f
JohnPhosAuCl
Ph PAuNTf
CH CN
n.d.
3
g
DCE
76
56
83
42
85
3
2
2
2
2
2
10
11
12
13
Ph PAuNTf
3
CH Cl
3
h
Ph PAuNTf
3
THF
Ph PAuNTf
3
Toluene
CH Cl
Ph PAuNTf
3
2
2
a
1
a (0.10 mmol), 2a (0.12 mmol), catalyst (5 mol %), Phen (20 mol
b
%
) in solvent (1 mL) at 50 °C. Replacing 1a by the corresponding
silylenol ether of ethyl acetylacetate did not show conversion under
c
these conditions. NMR yield with CH Br as an internal standard.
2
2
d
e
f
Phen: 1,10-phenanthroline. Isolated yield. n.d.: not detected.
g
h
DCE: 1,2-dichloroethane. THF: tetrahydrofuran.
8
8% yield when the reaction was performed at 50 °C in the
presence of 5 mol % Ph PAuNTf , 5 mol % AgNTf , and 20
3
2
2
mol % 1,10-phenanthroline in CH CN (entry 1). Different
3
16a,17
from our previous work,
silver is not essential (entry 2).
Control experiments showed that gold is key to the formation
of product 3aa (entries 3 and 4). The product yield decreased
dramatically in the absence of Phen ligand (entry 4). Other
gold catalysts did not improve the reaction (entries 5−8); no
product was detected when JohnPhosAuCl was used as catalyst
a
Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), Ph PAuNTf
3
2
b
(5 mol %), Phen (20 mol %) in CH CN (1.0 mL) at 50 °C. Isolated
3
yield.
(
entry 8). Other solvents were found to be less efficient than
CH CN (entries 9−13). Other transition metal catalysts
3
proved ineffective (see Table S1 in the Supporting
Information), as well as aryl- and alkyl-substituted alkynes.
Under the optimized reaction conditions (Table 1, entry 2),
we investigated the reaction scope. We first tested different
1
enamines. As shown in Scheme 2, a series of alkyl (R = Me,
Et, Bu, i-Pr, cyclopropyl) substituents were tolerated (3aa−
ea). The structure of 3aa was confirmed by single-crystal X-ray
structure analysis (Figure 1). Phenyl-substituted alkyl 3-
aminoacrylates 1f delivered product 3fa in 89% yield.
Substrates containing electron-donating groups such as Me−,
t-Bu−, MeO−, and cyclopentane− on the arene rings were
smoothly converted to the corresponding products (3ga−ia,
3
oa) in 80−92% yield. 3-Aminoacrylates bearing aryl halides at
the 3-position afforded the target products (3ja−na) in 63−
Figure 1. Solid state molecular structure of 3aa.
9
2% yield. Furthermore, heteroaryl-derived products (3pa−ra)
were readily prepared in moderate to good yield under the
standard conditions. Notably, replacements of the ethoxycar-
bonyl group in substrate 1f with other electron-withdrawing
groups, including COOMe, CN, Ac, Ts, and NO groups, gave
the corresponding functionalized products (3sa−wa) in good
47−90% yield. N-Phenyl and -cyclopropyl substituted
2
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enamines 1x and 1y were well-tolerated, affording the desired
products 3xa and 3ya in good yield. Replacement of the TIPS
group of 2a by TBDPS gave product 3ab in 85% yield.
Furthermore, the gram-scale synthesis of 3aa was efficiently
executed (Scheme 3); other alkenes than the ones shown in
Scheme 2 could not be used (e.g., ethyl acrylate or styrene).
Experimental procedures and compound characteriza-
tion (PDF)
Accession Codes
CCDC 2080692 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 3. Gram-Scale Synthesis
AUTHOR INFORMATION
Corresponding Authors
■
Xianhai Tian − Organisch Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany;
Email: xhtian1013@outlook.com
A plausible mechanism is described in Scheme 4 on the basis
16a,17
A. Stephen K. Hashmi − Organisch Chemisches Institut,
Heidelberg University, 69120 Heidelberg, Germany;
Chemistry Department, Faculty of Science, King Abdulaziz
University, Jeddah 21589, Saudi Arabia; orcid.org/0000-
of previous reports.
First, Au(I) species A is formed under
Scheme 4. Proposed Reaction Mechanism
0002-6720-8602; Email: hashmi@hashmi.de
Authors
Chunyu Han − Organisch Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany
Huili Zhang − Organisch Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany
Frank Rominger − Organisch Chemisches Institut, Heidelberg
University, 69120 Heidelberg, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01486
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
C.H., X.T., and H.Z. are grateful to the CSC (China
Scholarship Council) for a PhD fellowship.
■
the optimized reaction conditions. Subsequently, species A
undergoes an oxidative addition with hypervalent iodine
reagent 2 to produce alkynyl Au(III) complex B. In
comparison with simple olefins, the carbon−carbon double
bond of enamine 1 is more electron-rich because of the
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