A Chlorinating Reagent Yields Vinyl Chlorides with High Regioselectivity under Heterogeneous Gold Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b02101

A novel chlorinating reagent with a high concentration of HCl has enabled the highly regioselective hydrochlorination of unactivated alkynes using a commercial nanogold catalyst. No overchlorination or hydration products were formed, and various functional groups were tolerated. This hydrochlorination method could be conducted under open air.

Full text of DOI:10.1021/acs.orglett.7b02101

Letter
pubs.acs.org/OrgLett
A Chlorinating Reagent Yields Vinyl Chlorides with High
Regioselectivity under Heterogeneous Gold Catalysis
Shengzong Liang,†,§ Rene Ebule,†,§ Gerald B. Hammond,*,† and Bo Xu*,‡
†Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
‡College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
S
* Supporting Information
ABSTRACT: A novel chlorinating reagent with a high
concentration of HCl has enabled the highly regioselective
hydrochlorination of unactivated alkynes using a commercial
nanogold catalyst. No overchlorination or hydration products
were formed, and various functional groups were tolerated.
This hydrochlorination method could be conducted under
open air.
Scheme 1. Comparison of Different Formulations of HCl
Solutions
hlorine-containing compounds are prevalent in natural
1
Cproducts, pharmaceuticals, and agrochemicals. They also
play a significant role in organic synthesis because of their
broad applications as useful intermediates for transition-metal-
catalyzed carbon−carbon and carbon−heteroatom coupling
reactions such as Buchwald−Hartwig amination2 and Suzuki−
Miyaura coupling.3 Among various chlorinated compounds,
vinyl chlorides stand out as an important group. Compared to
traditional synthesis of vinyl chlorides from carbonyl
compounds,4 the direct hydrochlorination of alkynes from
HCl is a more straightforward and higher atom-efficiency
method. Indeed, several hydrochlorinations of alkynes have
been developed using LiCl, MgCl2, AcCl, and TMSCl as a
chloride source.5 However, the direct hydrochlorination of
unactivated alkynes using HCl as a chlorine source has been
rarely reported. Dai’s group found that HCl gas could
hydrochlorinate electron-rich phenylacetylenes, although hy-
drated products were also formed.6 One remarkable hydro-
chlorination of alkyne was reported by Derien’s group. They
developed a highly efficient ruthenium-catalyzed hydrochlori-
nation of alkynes. Both good yield and selectivity were
achieved, although strict oxygen- and water-free operation
was needed in this strategy.7 More recently, Corma and co-
workers reported a hydrochlorination of alkynes using
hydrogen chloride in dioxane and catalytic amounts of gold
nanoparticles, but functional group tolerance was not deeply
explored.8
is weakly basic and weakly nucleophilic and is a strong
hydrogen-bond acceptor, we assumed that it would be also an
ideal chlorinating reagent carrier for organic reactions. To our
delight, the synthesized HCl/DMPU presents an extraordi-
narily high mole ratio (2.65) between HCl and DMPU. In
contrast, other commercially available HCl solutions have a
much lower mole ratio, such as 0.21 for HCl/water, 0.22 for
HCl/ether, 0.34 for HCl/dioxane, and 0.42 for HCl/iPrOH.
The molarity of HCl/DMPU (43% w/w) is 14 M, which is also
higher than other commercially available HCl solutions,
indicating that HCl/DMPU might exhibit higher activity for
nucleophilic chlorination reactions. In addition, as compared
with the pKBHX of other HCl solutions such as 0.65 for HCl/
water, 1.01 for HCl/ether, 0.73 for HCl/dioxane, and 1.06 for
HCl/iPrOH, the larger hydrogen-bond basicity (pKBHX) of
DMPU (2.79) would also increase the nucleophilicity of
Searching for an appropriate HCl-based chlorinating reagent
is crucial for a direct hydrochlorination reaction. The
commercial sources of HCl are usually not very effective
chlorinating reagents due to the low activity caused by the
relatively low concentration of HCl (Scheme 1). Moreover, the
nucleophilicity of chloride in protic mediums such as water and
alcohol is greatly reduced.9 Our group has previously developed
a novel nucleophilic fluorinating reagent HF/DMPU based on
the concept of hydrogen bond basicity (pKBHX).10 Considering
that DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone)
Received: July 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02101
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Organic Letters
Letter
a
Table 1. Screening of Hydrochlorination of 1-Octyne
entry
HCl (equiv)
solvent
temp (°C)
time (h)
2/2′
yield (%)
1
2
HCl/Et2O (2)
DCE
80
80
5
5
100/0
100/0
100/0
90/10
88/12
87/13
92/8
99/1
98/2
98/2
98/2
98/2
98/2
99/1
98/2
98/2
98/2
98/2
100/0
100/0
99/1
8
15
4
HCl/iPrOH (2)
HCl/H2O (2)
DCE
3
DCE
80
5
4
HCl/DMPU (2)
HCl/DMPU (2)
HCl/DMPU (2)
HCl/DMPU (2)
HCl/DMPU (2)
HCl/DMPU (2)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
HCl/DMPU (4)
DCE
80
5
90
67
93
80
23
55
66
83
85
77
45
68
57
91
71
9
5
tol
80
5
6
dioxane
MeCN
t-BuOH
DMF
DMF
DMF
DMF
DMA
NMP
DMF
DMF
DMF
DMF
DMF
DMF
80
5
7
80
5
8
80
5
9
80
5
10
80
14
14
14
14
14
14
14
7
b
11
80
12
13
14
100
100
100
100
100
100
100
100
100
100
c
15
d
16
e
17
f
18
14
14
14
g
19
h
20
10
46
i
21
DMF
14
a
b
c
d
e
f
1
Both regioselectivity and yield were determined by H NMR. Au/TiO2 (4 mol %) was used. [1a] = 0.5 M. [1a] = 0.2 M. [1a] = 2 M. Au/
g
h
i
Al2O3 (2 mol %) was used. No Au/TiO2 was used. TiO2 (1 equiv) was used. PPh3AuCl (2 mol %) and AgOTf (2 mol %) were used.
chloride and, meanwhile, form a stable and highly concentrated
complex with HCl. Moreover, even at a high mole ratio, we
found that the HCl/DMPU complex exhibited less fuming than
the common concentrated HCl water solution (HCl/water =
0.21).
To further increase the regioselectivity, we screened different
solvents. Nonpolar or less polar solvents such as toluene,
dioxane, and acetonitrile did not improve the selectivity (Table
1, entries 5−7). t-BuOH provided the desired product with
better selectivity yet much poorer yield (Table 1, entry 8).
DMF was ultimately considered as the best solvent because of
its moderate yield and higher regioselectivity (Table 1, entry 9).
More HCl/DMPU (4 equiv) could increase the yield to 66%
(Table 1, entry 10). And with more Au/TiO2 (4 mol %), the
yield could be further enhanced to 83% (Table 1, entry 11). We
found that a higher reaction temperature works equally well
(Table 1, entry 12). We also tested other amide types of solvent
such as DMA and NMP, but they were inefficient (Table 1,
entries 13 and 14). Different reaction concentrations were also
screened (Table 1, entries 15−17), and a higher concentration
(2 M) gave a 91% yield. Au/Al2O3 was also used in this
hydrochlorination reaction, but its efficiency was not as good as
Au/TiO2 (Table 1, entry 18). Au/TiO2 was essential for
achieving high efficiency for this transformation because when
no Au/TiO2 was used or just the support TiO2 was used, only
9% and 10% of products were observed, respectively (Table 1,
entries 19 and 20). We found that a homogeneous gold
catalyst, using our optimal conditions, was much less effective
than heterogeneous gold nanoparticles (Table 1, entry 21).
With optimized conditions in hand, we evaluated the
substrate scope. The vinyl chlorides derived from aliphatic
terminal alkynes were obtained in good yields and regiose-
lectivities (Scheme 2, 2a−2c). Our hydrochlorination method
also exhibited excellent functional group tolerance. Both cyano
and carboxylic acid groups could be tolerated (Scheme 2, 2d
and 2e). A chloro-containing alkyne also provided a
corresponding Markovnikov vinyl chloride product in good
yield (Scheme 2, 2f). Both benzyl ether and allyl ether
Gold catalysis is well-known for its excellent ability to
activate C−C unsaturated bonds, thus allowing the generation
of a heteroatom−carbon bond via the nucleophilic addition
onto the gold-bound π-bond intermediate.11 Commercially
available gold catalysts such as PPh3AuCl are usually stabilized
through formation of Au−Cl complexes due to the relatively
strong bond energy between gold and chlorine.12 Thus, silver
salts are usually needed to break the strong Au−Cl bond to
release active cationic gold species. In our previous work, gold
nanoparticles have been successfully used as catalysts for
various organic transformations.13 In particular, we found that
the weaker cationic character of gold nanoparticles allowed
them to tolerate a strong basic environment, leading, for
example, to the hydration of alkynes under basic conditions
without affecting acid-sensitive functionalities.13d Therefore, we
hypothesized that this property may also enable the chloride
compatibility of gold nanoparticles. Herein, we are glad to
report the first commercially available gold nanoparticle-
catalyzed hydrochlorination of unactivated alkynes with HCl/
DMPU.
To test the feasibility of our hypothesis, we chose the
hydrochlorination of 1-octyne as a model reaction with Au/
TiO2 (2 mol %) as the catalyst. Not surprisingly, three
commercially available HCl solutions were ineffective for this
transformation because of the low concentration of HCl (Table
1, entries 1−3). However, when HCl/DMPU was used, a very
high yield of hydrochlorinated product (90%) was observed,
and good regioselectivity was also achieved (Table 1, entry 4).
B
DOI: 10.1021/acs.orglett.7b02101
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Organic Letters
Letter
Finally, to demonstrate the applicability of our strategy to
gram-scale synthesis, we conducted the hydrochlorination of 10
mmol of 1a under standard condtions; after 7 h, the same yield
as that for the reaction in small scale was observed, and the
regioselectivity was also not influenced (eq 1).
Scheme 2. Au/TiO2 Catalyzed Hydrochlorination of Alkynes
with HCl/DMPU
a b
,
In summary, we have found a highly efficient chlorinating
reagent in a nonprotic, weakly basic, and weakly nucleophilic
medium, DMPU. It has a higher concentration of HCl than
commercial HCl sources. These features may be useful in other
organic transformations involving HCl. HCl/DMPU was an
effective reagent for the synthesis of vinyl chlorides from
alkynes using heterogeneous nanogold catalysis. Good yields
and regioselectivity were observed, and a variety of function-
alities were compatible with this hydrochlorination process.
Moreover, this method was easily scaled up and did not require
strict oxygen- and water-free conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Experiments were performed with 1 (0.4 mmol), HCl/DMPU (43%
w/w, 1.6 mmol), Au/TiO2 (2 mol %) in DMF (0.2 mL) at 100 °C.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02101.
b
c
1
Isolated yields. Not isolated; yields were determined by H NMR
using 1,3,5-trimethoxybenzene as internal standard. Regioselectivity
d
e
was dertemined by GCMS. HCl/DMPU (3.2 mmol) was used. Au/
Experimental detail and copies of NMR spectra (PDF)
TiO2 (4 mol %) was used at 120 °C for 16 h.
AUTHOR INFORMATION
Corresponding Authors
■
substrates worked very well under standard condition (Scheme
2, 2g and 2h). Both ester and imide groups remained intact
during the hydrochlorination process (Scheme 2, 2i and 2j).
Sulfane- and sulfone-containing substrates also gave good yields
and selectivity without any problem (Scheme 2, 2k and 2l).
Aromatic terminal alkynes were also examined; however, more
anti-Markovnikov products were formed (Scheme 2, 2m and
2n). To test the potential of this strategy in the late-stage
hydrochlorination of complex molecules, the terminal alkynes
attached to biomolecular scaffolds were then examined. A
structurally complex glycoside could give corresponding vinyl
chloride 2o without loss of the glycosyl linkage (Scheme 2, 2o).
Protected amino acids such as a phenylalanine derivative were
also able to undergo hydrochlorination with a moderate yield
(Scheme 2, 2p). An estrone derivative bearing an alkyne moiety
was also a suitable substrate for such a transformation (Scheme
2, 2q). Lastly, a cholesterol ester derivative could smoothly
provide the desired vinyl chloride 2r with excellent yield and
selectivity as well (Scheme 2, 2r). In addition, we also tried 1,6-
heptadiyne, which led to the formation of a divinyl chloride
product (Scheme 2, 2s). Finally, an internal alkyne diphenyl-
acetylene was also examined, which provided the cis-vinyl
chloride in 33% yield (Scheme 2, 2t).
*E-mail: bo.xu@dhu.edu.cn.
*E-mail: gb.hammond@Louisville.edu.
ORCID
Gerald B. Hammond: 0000-0002-9814-5536
Author Contributions
§S.L. and R.E. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health for financial
support (1R01GM121660-01) and to the National Science
Foundation (CHE-1401700) for supporting the preliminary
phase of this research. B.X. is grateful to the National Science
Foundation of China for financial support (NSFC-21472018).
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