Chloride-tolerant gold(I)-catalyzed regioselective hydrochlorination of alkynes

Article abstract of DOI:10.1021/acscatal.7b02567

We have developed a highly regioselective homogeneous gold(I)-catalyzed anti-hydrochlorination of unactivated alkynes at room temperature. We have overcome the incompatibility between conventional cationic gold catalysts and chloride by using a hydrogen-b

Full text of DOI:10.1021/acscatal.7b02567

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Letter
Chlorine-Tolerant Gold(I) Catalyzed
Regioselective Hydrochlorination of Alkynes
Rene Ebule, Shengzong Liang, Gerald B. Hammond, and Bo Xu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02567 • Publication Date (Web): 07 Sep 2017
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ACS Catalysis
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Chloride-Tolerant Gold(I) Catalyzed Regioselective
Hydrochlorination of Alkynes
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Rene Ebule,[a]† Shengzong Liang,[a]† Gerald B. Hammond, [a]* Bo Xu [b]
[a] Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States; [b] College of
Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai, China
† These authors contributed equally to this work
*
Supporting Information Placeholder
for manufacture of vinyl chloride monomer (VCM) is a well-
studied process,12 and has been industrialized recently
(Scheme 1d).13 Recently, and independently, Corma group14
and our group15 reported a heterogeneous gold (TiO2/Au)
catalyzed hydrochlorination reaction of alkynes. Although
good syn-addition selectivity was observed, high
temperatures were needed (Scheme 1d).
ABSTRACT: We have developed a highly regioselective
homogeneous gold(I)-catalyzed anti-hydrochlorination of
unactivated alkynes at room temperature. We have overcome
the incompatibility between conventional cationic gold
catalysts and chloride by using a hydrogen bonding activation
of Au-Cl bond. This approach is scalable, exhibits excellent
functional group tolerance, and can be conducted in open air.
KEYWORDS: gold catalysis, hydrochlorination, chloride-
tolerant, alkyne, HCl/DMPU
Chlorination is one of the most important transformations in
organic synthesis because of the biological activities and
synthetic value of the chlorinated products.1 More specifically,
vinylchloride is one of the most important group of chlorine-
containing compounds. Vinylchlorides are widely found in
natural products, pharmaceuticals and agrochemicals,1-2 and
also are valuable coupling partners in coupling reactions such
as Buchwald-Hartwig amination3 and Suzuki-Miyaura
coupling.4 Compared to the traditional syntheses of
vinylchlorides, such as halogenations of carbonyl compounds5
and electrophilic chlorination of alkynes,6 the direct
hydrochlorination of alkynes from HCl is a straightforward
and atom-economic method. However, given that HCl itself is
a
dangerous gas and handling is problematic, synthetic
chemists have focused on indirect hydrochlorination
strategies for activated alkynes,7 using RCOCl, TMSCl or metal
chlorides as chlorine sources (Scheme 1a).8 One notable
example is the recent work by Engle and coworkers on the
palladium-catalyzed anti-hydrochlorination of alkynes using a
directing group (Scheme 1b).9 The direct hydrochlorination of
unactivated alkynes using HCl has been rarely reported. Dai
and coworkers found that gaseous HCl could hydrochlorinate
electron-rich phenylacetylenes but the use of gaseous HCl, and
hydration side products present major drawbacks.10 Derien
Scheme 1. Major synthetic methods for chlorination of alkynes to
synthesize vinylchlorides.
Although homogeneous cationic gold catalysts are considered
as the most powerful catalysts for the electrophilic activation
of alkynes,16 the cationic gold-catalyzed hydrochlorination of
alkynes has not been reported because of the high affinity
between cationic gold and chloride.17 Indeed, commonly used
gold pre-catalysts, such as PPh3AuCl, usually need silver salts
to break the strong Au-Cl bond and release an active cationic
gold species and chloride is known to easily poison cationic
gold species (Scheme 2a).18 We are now pleased to report a
and
coworkers
developed
a
ruthenium-catalyzed
hydrochlorination of alkynes that gave good yields (Scheme
1c).11 Although this method works well for terminal alkynes,
higher temperature was needed and low stereoselectivity was
observed for internal alkynes (Scheme 1c). Moreover, a
restrictive Schlenk environment was essential. The
heterogeneous gold catalyzed hydrochlorination of acetylene
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16b, d
L6
1.2
HCl/DMPU
HFIP/ DMF
93
98:2: -
homogenous gold-catalyzed alkyne hydrochlorination with
aYields were determined by GC-MS using dodecane as internal standard.
bReaction run at rt for 24 h. cKetone product formed (accounts for the remaining
ratio of product). dSolvent mixture is 1:1 by volume.
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exclusive anti-selectivity that overcomes the incompatibility
between cationic gold catalysts and chloride (Scheme 1e).
We proposed that a combination of strong hydrogen bond
donor solvents such as hexafluoroisopropanol (HFIP), and HCl
would generate a strong hydrogen bonding donor network A,
and that the hydrogen bonding between chlorine in L-Au-Cl
and A might weaken the Au-Cl bond (Scheme 2b). This would
generate a partially cationic gold species B via hydrogen
bonding interaction. This strategy would avoid the use of a
silver salt to activate the gold pre-catalyst, a step that is
known to exert negative effects in gold catalysis.19
Due to its high hydrogen bond basicity but low Brønsted
basicity,20,21 DMPU is able to form a stable and highly
concentrated complex with hydrogen chloride (HCl).15 Using
1.5 equiv of HCl/DMPU and 2 mol % of gold catalyst and
various ligands (L1-L6) led to high yields of product (Table 1,
entries 1-6). However, the anti-Markovnikov and
dichlorinated products were also obtained in varying amounts.
The use of L5 improved the selectivity of the produced
vinylchloride to 95 % yield, needing only 1.2 equiv of
HCl/DMPU (Table 1, entry 7). Formation of the dichlorinated
byproduct was avoided by running the reaction at ambient
temperature (Table 1, entry 8-9), with both L5 and L6
working equally well. A poor yield was obtained in the
absence of gold (Table 1, entry 10). Notably, lower selectivity
and poor yields were observed when commercially available
HCl sources (HCl/iPrOH and HCl/ether) were used (Table 1,
entries 11 and 12). We screened other solvents to further
optimize the regioselectivity. We found that a 1:1 HFIP:
CH3NO2 mixture provided optimal conditions. It is worth
noting that tert-butanol and THF gave substantial amounts to
the corresponding ketone. A 1:1 HFIP: DMF combination
worked well also (Table 1, entry 16).
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Scheme 2. Conventional cationic gold catalysis and chloride-
tolerant homogenous gold catalysis.
With optimized conditions in hand, we investigated the
substrate scope (Table 2). We first examined the scope of
aliphatic alkynes. A wide variety of terminal alkynes reacted
smoothly to give the corresponding vinylchlorides in good to
excellent yields.
We used 4-phenylbutyne 1a as the model substrate for
reaction optimization. We screened various ligands, HCl
sources and solvents (Table 1).
Table 1. Screening of homogeneous gold catalyzed
hydrochlorination of alkynes.
Table 2. Substrate scope of homogeneous gold
catalyzed hydrochlorination of alkynes.a
HCl/DMPU ( m equiv.)
Cl
LAuCl (2 mol %)
Ph
Ph
Ph
+
Ph
+
Solvent (0.4 mL)
75 oC, 6 h
Cl Cl
Cl
1a
2a
2a'
3a
Me(OMe)
F3C
iPr
O
O
CF3
MeO(Me)
F3
C
iPr
iPr
P(tBu)2
iPr
P
O
iPr
Ph
O
O
P
JohnPhos
P
O
L1
iPr
F3
C
P
O
O
Ph
iPr
L6
iPr
O
iPr
L5
L3
L4
L2
Entry
L
m
HCl
Solvent
Yield
(%)a
Ratio of
2a:2a’:3a
1
2
L1
L2
L3
L4
L5
L6
L5
L5
L6
-
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
2.4
1.2
1.2
1.2
1.2
1.2
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/DMPU
HCl/iPrOH
HCl/Et2O
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
tBuOH
THF
80
55
65
38
95
96
95
98
95
34
72
<5
85
78
97
75:8:17
76:9:15
90:8:2
82:9:9
93:4:3
90:7:3
95:4:1
97:3: -
97:3: -
59:16:25
88:12: -
n. a.
3
4
5
6
7
8b
9b
10
11b
12b
13b, c
14b, c
15b, d
L5
L5
L6
L6
L6
aReaction conditions: alkyne 1 (0.5 mmol), HCl/DMPU (1.2 equiv), L6AuCl (2
mol %), HFIP:CH3NO2 (0.125 mL) at rt for 16-36 h. Isolated yields. b75 oC was
used.
HCl/DMPU
HCl/DMPU
HCl/DMPU
51: -: -
82:8: -
99:1: -
HFIP/MeNO2
2
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Nitrile (2b), ester (2d), imide (2e), sulfide (2f), amide (2u),
In conclusion, we have reported the first efficient
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and ketone ether (2v) functional groups were well tolerated
under the standard conditions. The reaction with derivatized
amino acid (2u) and the natural product estrone (2v) led
toteh corresponding products in 69 % and 95 % yield,
respectively. The internal alkyne 4-octyne (2c) also worked
well, although higher temperature and longer reaction time
were needed. When we explored the scope of arylacetylenes
we found good to excellent yields using electron-rich and
electron-deficient arylacetylenes. Para (1h), meta (1i) and
ortho (1j) tolylacetylenes furnished the corresponding
vinylchlorides in excellent yields. It is worth noting that
electron deficient arylacetylenes gave increasing amounts of
the anti-Markovnikov products (2n, 2o, 2p, and 2q). A
remarkable example was the heteroaromatic alkyne 2-
ethynylpyridine (1r), which was expected to quench the
reactivity of homogenous cationic gold due to its basic nature,
but under our conditions, 1r furnished the anti-Markovnikov
vinylchloride (2r) in 70 % yield.
regioselective homogeneous gold-catalyzed hydrochlorination
of unactivated alkynes. We have overcome the traditional
incompatibility between conventional cationic gold catalysts
and chloride. This method can be easily scaled up, and the
reactions can be conducted in the open air.
ASSOCIATED CONTENT
AUTHOR INFORMATION
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Corresponding Author
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gb.hammond@louisville.edu; bo.xu@dhu.edu.cn
Notes
The authors declare no competing financial interests.
Supporting Information
Experimental procedures and characterization data of
products. This material is available free of charge via the
internet at http://pubs.acs.org.
The change of regioselectivity in 2r could have been caused
by the pyridinyl nitrogen acting as a directing group and
coordinating with HCl or gold. 3-Ethynylthiophene (1s) gave
an excellent yield of the corresponding chloro product. The
electron deficient internal alkyne ethylphenylpropiolate (1t)
also worked well, albeit a higher temperature (75oC) was
needed, and the yield was modest (66%). In this case, a
mixture of E/Z isomers was obtained, possibly due to the
isomerization caused by the elevated temperature.
ACKNOWLEDGMENT
We are grateful to the National Institutes of Health for
financial support (1R01GM121660-01). Bo Xu is grateful to
the National Science Foundation of China for financial support
(NSFC-21472018).
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It should be noted that our homogenous gold catalyzed
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the recently reported heterogeneous gold catalyzed process,
and that the stereochemistry of the addition was different.14
Due to the milder conditions of our reaction, we expected
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typical homogeneous gold catalysis where cationic gold
activates alkyne substrates. On the other hand, the nanogold
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