Palladium-Catalyzed Nitrile-Assisted C(sp3)-Cl Bond Formation for Synthesis of Dichlorides

Article abstract of DOI:10.1021/acs.orglett.9b03066

A palladium-catalyzed coupling procedure of alkenes with alkynylnitriles has been demonstrated for the synthesis of dichlorides. The reaction is the first example of nitrile-assisted C(sp³)-Cl formation promoted by coordination of a cyano group with an alkylpalladium(II) complex. The construction of a five-membered cycle intermediate successfully inhibits the β-hydride abstraction, resulting in direct C-Cl bond reductive elimination of alkylpalladium(II) chloride.

Full text of DOI:10.1021/acs.orglett.9b03066

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Nitrile-Assisted C(sp3)−Cl Bond Formation for
Synthesis of Dichlorides
Dandan He, Liangbin Huang, Jianxiao Li, Wanqing Wu,* and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed coupling procedure of
alkenes with alkynylnitriles has been demonstrated for the
synthesis of dichlorides. The reaction is the first example of
nitrile-assisted C(sp3)−Cl formation promoted by coordina-
tion of a cyano group with an alkylpalladium(II) complex. The
construction of a five-membered cycle intermediate success-
fully inhibits the β-hydride abstraction, resulting in direct C−
Cl bond reductive elimination of alkylpalladium(II) chloride.
hlorine-containing organic molecules exist ubiquitously
in natural products,1 pharmaceuticals,2 agricultural
Scheme 1. Suppressive Strategies for β-Hydride Elimination
C
chemicals,3 and functional materials.4 For example, the
reported data show that over 2000 chlorine-containing
compounds have been found in natural products, and many
of them display significant antibiotic or cytotoxic properties.1
Due to the continued widespread utilization of organo-
chlorides, their synthesis is greatly pursued by organic
researchers over the past decades and great synthetic efforts
have been exerted.
Currently, the reported methods are mostly about the
synthesis of aryl chlorides and vinyl chlorides.5 For the
preparation of aryl chlorides, many successful traditional
reactions including Friedel−Crafts-type electrophilic halogen-
ation,6a Sandmeyer-type reactions of diazonium salts,6b
halogenations of preformed organometallic reagents, etc.6c
and subsequent transition-metal-catalyzed strategies7 have
been developed. Vinyl chlorides were commonly constructed
by hydrohalogenation of alkynes,8 carbohalogenation of
alkynes,9 and other reaction types.10 For the synthesis of
alkyl chlorides, transition-metal-catalyzed cross-coupling re-
actions have recently become synthetically useful through high
valent metal centers. Nevertheless, the direct C(sp3)−Cl bond
formation by a transition-metal-catalyzed reductive elimination
process remains a challenge in modern homogeneous catalysis.
This is owing to the competitive reaction of β-hydride
abstraction. To address this issue, two strategies are typically
employed: (i) One is to design a series of substrates without β-
hydrogen atoms reported by Lautens11 and other groups12
(Scheme 1a). In their strategy, bulky trialkylphosphine ligands
or other additives were required. (ii) The other, mainly for the
case that contains a β-hydrogen atom, has been developed by
Lu,13 Liu,14 Sridharan,15 and our group.16 In these methods,
introducing a rigid cycle structure to the β-site is the key to the
increase in difficulty of β-hydride elimination from
alkylpalladium(II) halides (Scheme 1b). However, all reactions
are limited to intramolecular cyclization, in which the substrate
compatibility is limited. To facilitate advances in this field,
novel design and direct synthetic methods are highly sought.
Nitriles are often used to assist organometallic reactions due
to the stability and coordination performance of the carbon−
nitrogen triple bond.17 While nitrile templates have served as
powerful end-on directing groups in the realm of C−H
activation,18 side-on π-bond interaction is another mode of
binding that can be productive in catalysis.19 Knochel and co-
workers19a have developed an efficient nickel-catalyzed cross-
coupling reaction between two C(sp3) centers, which
Received: August 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03066
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
demonstrates that coordination to the π-system of cyano
groups can facilitate C(sp3)−C(sp3) reductive elimination.
Aside from this, nitriles are also utilized for some allylic
alkylation via π-conjugation.19b Herein, we report the first
example of nitrile-assisted reductive elimination of alkyl
chlorides from alkylpalladium(II) chlorides containing two β-
hydrogen atoms. As illustrated in Scheme 1c, we hypothesized
that interaction with a pendant nitrile could promote C−Cl
reductive elimination.
Scheme 2. Scope of Alkenes
Based on many chloropalladation initiated reactions
reported by our group,20 the reaction was initially carried
out with 3-phenylpropiolonitrile (1a) and butyl acrylate (2a)
in the presence of CuCl2 and PdCl2 in MeCN at 80 °C.
Pleasantly, the desired product 3a was detected in 38% yield by
1H NMR analysis (Table 1, entry 1), and only a trace amount
a
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), PdCl2 (10 mol
%), CuCl2 (4 equiv), MeCN (0.5 mL), 50 °C, 12 h. Yields of isolated
CuCl2
yield of 3a
a
a
b
entry
catalyst
PdCl2
Pd(OAc)2
Pd(dppe)Cl2
Pd(PhCN)2Cl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
(x equiv)
T/°C
(%)
Z/E
products are given. Total NMR yield of Z- and E-products.
1
2
3
4
5
6
7
8
2
2
2
2
3
4
5
6
4
4
4
4
4
4
4
80
80
80
80
80
80
80
80
70
60
55
50
45
40
35
38
36
37
35
48
66
67
66
80
81
83
84 (81)
70
4:1
3:1
4:1
5:1
4:1
5:1
6:1
6:1
7:1
crystallographic analysis (CCDC 1915234; see the Supporting
Information for details). Gratifyingly, conjugate alkene
acrylonitrile could be also smoothly transformed to the desired
product 3g after slightly changing the reaction conditions.
Notably, product 3h was constructed through the cleavage of
the carbon−carbon bond with the “bridging” palladium
intermediate,16,21 when the reaction was operated using
norbornene as substrute. Its structure has been confirmed by
X-ray structure analysis (CCDC 1915236; see the Supporting
Information for details). In addition, the reactivity of some aryl
alkenes were examined in the system. The results showed that
styrene and p-bromostyrene were applicable to the standard
conditions, and the corresponding products 3i and 3j were
obtained in 61% yield with a Z/E ratio of 8:1 and 68% yield
with a Z/E ratio of 9:1, respectively.
To further define the generality of this protocol, we then
turned our attention to different 3-arylpropiolonitriles
(Scheme 3). Pleasingly, the tested substrates with electron-
donating (Me, Et, and OMe) and electron-withdrawing (F, Br,
CF3, CN, NO2, CHO, COCH3, and COOMe) groups at the
C-4 position of the aryl ring smoothly underwent this reaction
and afforded the corresponding products 3l−3v in 40−83%
isolated yields. All results revealed that the Z/E selectivities
were obviously better for the substrates with electron-
withdrawing groups than those with electron-donating groups.
Simultaneously, 3-phenylpropiolonitriles substituted by −Me
and −F at the C-3 position of the aryl ring also reacted well in
the system to provide the desired products 3v and 3w in high
yields with different Z/E ratios, indicating that this reaction
was not sensitive to the steric hindrance. Furthermore, the
reaction was compatible with both disubstituted or trisub-
stituted 3-phenylpropiolonitriles to give the desired products
(3x−3z) in good to high yields and Z/E ratios of large
differences. In order to expand the molecular library of
dichlorides, the substrates were successfully extended to the
heteroaryl alkynylnitriles, such as 3-(thiophen-2-yl)propiolo-
nitrile and 3-(3,5-dimethylisoxazol-4-yl)propiolonitrile, for the
synthesis of 3ab and 3ac, respectively.
9
10
11
12
13
14
15
9:1
10:1
11:1
11:1
10:1
10:1
60
53
a
All reactions were performed with 1a (0.10 mmol), 2a (0.20 mmol),
[Pd] catalyst (10 mol %), CuCl2 (x equiv), MeCN (0.5 mL) under air
for 12 h. Determined by H NMR using CH2Br2 as the internal
standard.
b
1
of previous diolefin product from the β-hydride elimination
process was obtained. Subsequently, a variety of different
palladium catalysts were tested, but all were ineffective for yield
improvement (entries 2−4). Next, the screening of the amount
of CuCl2 revealed that the yield of 3a and the Z/E ratio
increased with the amount of copper (entries 5−8). And a 4
equiv amount of CuCl2 was defined as the most appropriate for
the reaction (entry 6). We further investigated the effects of
temperature (entries 9−15) and found it is a crucial factor for
this transformation. Finally, 50 °C was proved to be the
optimal temperature for the catalytic system, and product 3a
was obtained in 84% NMR yield and 81% isolated yield with a
Z/E ratio of 11:1 (entry 12).
Under the optimized reaction conditions, the scope of this
method was investigated with a variety of alkene substrates,
and the results were outlined in Scheme 2. The reaction is
compatible with various acrylates and acrylamides to afford
different dichlorinated products with good yields and moderate
E/Z isomer selectivity (3a−3f). Significantly, the structure and
relative stereochemistry of 3e were determined by X-ray
B
DOI: 10.1021/acs.orglett.9b03066
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Alkynylnitriles
Scheme 5. Mechanistic Studies
Scheme 6. Initially, vinylpalladium(II) intermediate A is
generated by anti-chloropalladation of alkynylnitrile 1 with
Scheme 6. Plausible Mechanistic Pathway
a
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), PdCl2 (10 mol
%), CuCl2 (4 equiv), MeCN (0.5 mL), 50 °C, 12 h. Yields of isolated
b
1
products are given. Total H NMR yield of Z- and E-products.
To demonstrate the potential utility of this reaction,
compound 3u was synthesized in gram scale in 71% isolated
yield with Z/E > 20:1 under the standard reaction conditions
(Scheme 4).
PdCl2, which successively undergoes insertion of alkene 2 and
affords alkylpalladium(II) complex B. And the intramolecular
coordination of palladium(II) species with the carbon−
nitrogen triple bond forms a stable five-membered ring,
which in turn facilitates the direct C−Cl bond reductive
elimination to deliver the dichlorinated product 3. The
generation of 3 rather than products arising from the β-
hydride elimination process suggested that the coordinated
five-membered ring should be crucial for C(sp3)−Cl formation
by inhibiting β-hydride abstraction.
Scheme 4. Gram-Scale Synthesis
In conclusion, we have developed the first palladium-
catalyzed nitrile-assisted method to prepare a series of alkyl
chlorides. The reaction exhibits various advantages including
excellent functional group compatibility, providing the desired
products in good yield and high Z/E ratio when the substrates
with strongly electron-withdrawing groups were utilized.
Mechanistic studies provide insights into the reaction pathway
and suggest that the presence of the cyano group was critical
for C(sp3)−Cl formation. The protocol showcases a potential
opportunity for systematic development of various carbon−
heteroatomic bonds using a nitrile-assisted strategy.
To gain more insight into the mechanism of C(sp3)−Cl
bond formation, a series of control experiments were
performed. First, the substrate 5 with an extended carbon
chain was prepared and subjected to the reaction with 2a
(Scheme 5, eq 1). The desired product 6 was not detected,
whereas usual product 7 from β-hydride elimination was
collected in 83% yield. It is suspected that the extended carbon
chain separating the cyano group from alkylpalladium(II) led
to the coordination failure of Pd(II) and the carbon−nitrogen
triple bond. Considering the interaction between Pd(II) and
the oxygen atom, the substrates 8 and 11 were respectively
employed in the system (Scheme 5, eqs 2 and 3). In the former
system, the desired product 10 was detected in 11% GC-MS
yield, and most of the raw material was converted to the
previously reported product 9.20d In the latter system, product
12 from dichlorination of alkynes was isolated in 63% yield
without compound 13 being detected.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03066.
Experimental procedures, condition screening table,
characterization data, and copies of NMR spectra for
all products (PDF)
Based on the above-mentioned investigations and previous
reports, a plausible mechanism for the reaction is postulated in
C
DOI: 10.1021/acs.orglett.9b03066
Org. Lett. XXXX, XXX, XXX−XXX

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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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
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ORCID
Wanqing Wu: 0000-0001-5151-7788
Huanfeng Jiang: 0000-0002-4355-0294
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology of
the People’s Republic of China (2016YFA0602900) and the
National Natural Science Foundation of China (21490572 and
21871095) for financial support.
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DOI: 10.1021/acs.orglett.9b03066
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