Selective activation of 1,2-dichloroethane for access to β-chloroethylarenes enabled by nickel-catalyzed suzuki-type couplings

Article abstract of DOI:10.1016/j.tetlet.2019.03.040

The selective conversion of one inactive C(sp³)-Cl bond of 1,2-dichloroethane (DCE) into C(sp³)-C(sp²) linkages for access to β-chloroethylarenes is presented here. The key to achieve the required reactivity and chemoselectivity in this synthetic method was the utilization of nickel and combinatorial nitrogen ligands as catalytic system. Synthetic advantages of this coupling chemistry included the step-simplicities to β-chloroethylarenes, the mildness and effectiveness of coupling conditions, together with the convenience for allowing further functional group transformations of the retained homobenzylic C–Cl bonds.

Full text of DOI:10.1016/j.tetlet.2019.03.040

Accepted Manuscript
Selective Activation of 1,2-Dichloroethane for Access to β-Chloroethylarenes
Enabled by Nickel-Catalyzed Suzuki-type Couplings
Yi Yang, Junjie Cai, Gen Luo, Xia Tong, Yumei Su, Yan Jiang, Yingle Liu,
Yubin Zheng, Jijiao Zeng, Chaolin Li
PII:
S0040-4039(19)30257-6
https://doi.org/10.1016/j.tetlet.2019.03.040
TETL 50681
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 January 2019
23 February 2019
15 March 2019
Please cite this article as: Yang, Y., Cai, J., Luo, G., Tong, X., Su, Y., Jiang, Y., Liu, Y., Zheng, Y., Zeng, J., Li,
C., Selective Activation of 1,2-Dichloroethane for Access to β-Chloroethylarenes Enabled by Nickel-Catalyzed
Suzuki-type Couplings, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.040
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Selective Activation of 1,2-Dichloroethane
for Access to β-Chloroethylarenes Enabled
by Nickel-Catalyzed Suzuki-type Couplings
Leave this area blank for abstract info.
Yi Yanga, , Junjie Caia, Gen Luoa, Xia Tonga, Yumei Sua, Yan Jianga, Yingle Liua, , Yubin Zhenga,b, Jijiao
Zenga and Chaolin Lia
N
N
N


Nickel
Ar-CH2CH2-Cl
+
Cl-CH2CH2-Cl
Ar-B(OH)2
Suzuki coupling
homobenzylic chloride
vicinal dihalide
X
inert C-Cl
activation
aryl-alkyl
linkage
-Cl or H
elimination

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Selective Activation of 1,2-Dichloroethane for Access to β-Chloroethylarenes
Enabled by Nickel-Catalyzed Suzuki-type Couplings
Yi Yanga, , Junjie Caia, Gen Luoa, Xia Tonga, Yumei Sua, Yan Jianga, Yingle Liua, , Yubin Zhenga,b, Jijiao
Zenga, and Chaolin Lia
a Key Laboratory of Green Catalysis of Higher Education Institutes of Sichuan, Sichuan University of Science & Engineering, Zigong 643000, China
b Shandong Jinjing Biological Technology Co., Ltd, Weifang 261313, China
———
ARTICLE INFO
ABSTRACT
 Yi Yang. Tel.: +86-813-550-5606; e-mail: yangyiyoung@163.com
 Yingle Liu. Tel.: +86-813-550-5606; e-mail: liuyingleyou@163.com
Article history:
Received
Received in revised form
Accepted
The selective conversion of one inactive C(sp3)-Cl bond of 1,2-dichloroethane (DCE) into
C(sp3)-C(sp2) linkages for access to β-chloroethylarenes is presented here. The key to achieve
the required reactivity and chemoselectivity in this synthetic method was the utilization of nickel
and combinatorial nitrogen ligands as catalytic system. Synthetic advantages of this coupling
chemistry included the step-simplicities to β-chloroethylarenes, the mildness and effectiveness
of coupling conditions, together with the convenience for allowing further functional group
transformations of the retained homobenzylic C-Cl bonds.
Available online
Keywords:
Nickel
Combined ligands
Suzuki coupling
Chloroethylation
2009 Elsevier Ltd. All rights reserved.
1. Introduction
a. Rotational isomers of 1,2-dichloroethane
Cl
Cl
The chemical transformations of alkyl halides have received
substantial attention in the synthetic community over the past few
decades because the polarized C-X bond provides interesting
reactivities upon its cleavage [1]. Various chemical reactions
starting from the alkyl halide feedstocks, such as nucleophilic
substitutions [2], β-eliminations [3], Grignard reactions [4], and
radical reactions [5] are well established for the synthesis of
value-added organic compounds. Despite the great progress on
the functionalizations of alkyl halides, the conversion of vicinal
dihalides to generate new C-C linkages remains considerably
underdeveloped and poses formidable synthetic challenges due to
the difficulties in regulating the isomeric conformational
rotations and involved chemoselectivities [6]. The representative
example is 1,2-dichloroethane (DCE) in which the gauche effect
plays important role in stabilizing the C-Cl covalence (Figure 1a)
[7], thus making DCE widely used as an inert organic solvent and
being difficult to serve as a C2 synthetic building blocks for
forging C-C bonds. Recently, Hu group disclosed the first
example of stoichiometric reaction between DCE and pincer-
H
H
H
H
H
H
Cl
H
trans
gauche
Cl
H
b. Stoichiometric reaction between DCE and [(MeNN2)NiIIMe] complex
NMe2
N Ni Me
NMe2
CH2CH2Cl
CH3
100 o
24 h
C
5%
+
CH2=CH2
ClCH2CH2Cl
+
6%
c. This work: Suzuki-type direct chloroethylation of arylboronic acids
Nickel Catalysis
(Het)Ar-B(OH)2 + ClCH2CH2Cl
CH CH Cl
(Het)Ar-
2
2
 broad substrate scope
 activation of inert 1,2-dichloroethane
 mild conditions and synthetic simplicity  circumventing -Cl/H elimination
Figure 1. Strategy for the direct Suzuki-type chloroethylation.
o
ligated [(MeNN2)NiIIMe] complex at 100 C and found that DCE
β-chloroethylarenes products (ArCH2CH2Cl) via
a nickel-
catalyzed C(sp3)-C(sp2) bonding methodology (Figure 1c).
was dechloro/methylated to afford ClCH2CH2CH3 in 5% yield
with a concurrent formation of E1cb product ethylene (Figure 1b)
[8]. Based on this seminal result and the power of nickel coupling
chemistry [9-12], we envisage the feasibility of Suzuki-type cross
couplings between ClCH2CH2Cl and arylboronic acids to deliver
On the other hand, although the nickel catalysis have lots of
merits in the aspect of utilizing sp3-centered alkyl halides as
coupling partners [13-14], the designed reaction system still
needs to meet these requirements: (i) The catalytic species should
be active enough to insert into the inert C-Cl bond of DCE and
fulfill the successive steps of catalytic cycle [15]; (ii) The
competitive
β-chloride/hydride
elimination
and
hydrodehalogenation of DCE should be inhibited for productive

2
Tetrahedron Letters
synthetic outcomes [3a, 16-17]; (iii) The catalytic system needs
cReaction conditions for ClCH2CH2Br 2b as electrophile: 1a (0.3 mmol, 1.5
equiv), 2b (0.2 mmol, 1.0 equiv), K3PO4 (0.6 mmol, 3.0 equiv), dtbpy (0.02
mmol, 0.1 equiv), 4-MeO-Py (0.06 mmol, 0.3 equiv), DME (1.0 mL), 24 h.
to be compatible with the homobenzylic chloride ArCH2CH2Cl
and leaves the reserved C-Cl intact. Accordingly, we hypothesize
that the above required catalytic factors would be achieved by
tuning the electronic and steric factors of the nickel complex via
heteroleptic ligand combinations (N,N-bidentate ligand plus N-
monodentate ligand) [18] as the surrogate of the complicated
tridentate N,N,N-pincer ligand in Hu’s chloroethylation [8]. With
these synthetic strategies in mind, we began the exploration of
the selective activation of 1,2-dichloroethane for access to β-
chloroethylarenes under a combinatorial ligands/nickel catalysis
system which were expected to provide remarkable synthetic
simplicities in contrast with the classical β-hydroxyethyl
prefunctionalization/deoxychlorination sequence [19-21].
With the optimized reaction conditions in hand, the scope of
this Suzuki-type chloroethylation protocol with respect to the
substituents on the (hetero)arylboronic acids was examined.
Substrates 1 with electron-donating or eletron-withdrawing
groups at the para site were coupled smoothly with either
ClCH2CH2Cl 2a (Table 1, entry 9, abbreviated as condition A) or
ClCH2CH2Br 2b (Table 1, entry 10, abbreviated as condition B)
to afford β-chloroethylarenes 3. Overall, various functional
groups like ester (1b), nitrile (1c), ketone (1d), aldehyde (1e),
and ether (1g) were well tolerated and the para electron-
withdrawing arylboronic acids gave better yields than the
electron-rich cases [24]. Additionally, several meta-substituted
arylboronic acids (1j, 1k, 1l, 1m) were also proved to be
effective in this transformation. However, the ortho-substituted
arylboronic acids (1q, 1r) failed to give the corresponding
product which might be explained by the unsuccessful Ni-B
transmetalation resulted by the increased steric hindrance.
Interestingly, the heteroarylboronic acids (1n, 1o, 1p) bearing the
ortho coordination heteroatoms were viable substrates for
incorporating fluoroethyl motifs. We speculated that the transient
coordination of these heteroatoms (proximal to C-B bond of 1)
towards Ni could be responsible for enhancing the interaction
between nickel catalytic species and arylboronic acids, thus
facilitating the transmetalation step. Further extension of this
C(sp3)-C(sp2) coupling methodology to the functionalization of
other vicinal multi-chlorides was conducted. It was found that the
reaction conditions can be amenable to 1,2-dichloropropane 2c
and 1,2,3-trichloropropane 2d albeit the concurrent competitive
protodeboronation of arylboronic acids decreased the coupling
efficiencies partly [25]. Interestingly, the secondary C(sp3)-Cl
reaction sites displayed superior selectivity over the primary
C(sp3)-Cl which could allow further transformations of the
remaining steric-uncongested C-Cl bonds.
2. Result and Discussion
We initiated the investigation with 4-biphenylboronic acid and
1,2-dichloroethane as the coupling partners in the presence of
NiBr2 (10 mol%), electron-rich bidentate 4,4-di-tert-butyl
bipyridine (dtbpy, 10 mol%), monodentate 4-methoxypyridine
(4-MeO-Py, 30 mol%) and K3PO4 as arylboronic acid activator in
DME at 70 oC (see SI for detailed reaction parameters
optimization). To our delight, the coupling product 3a was
formed in 37% yield without detection of the repetitive coupling
product ArCH2CH2Ar (Table 1, entry 1). The absence of
bidentate bipyridinyl ligand (L-a) or monodentate pyridinyl
ligand (L-b) verified the cooperative roles of the designed
combined ligands in this catalytic coupling system (Table 1,
entry 2-3) [22]. Further screening of the auxiliary monodentate
ligands proved that 4-CN-Py (4-cyanopyridne) displayed unique
activity as the mediator which was superior to electron-rich 4-
MeO-Py, DMAP (4-dimethylaminopyridine) and electron-poor
2-CN-Py (2-cyanopyridne), pyrazine (Table 1, entries 4-8).
Interestingly, further adjustment of the NiBr2/bidentate ligand
ratio from 1:1 to 1:0.5 improved the yield from 51% to 65%
which corresponded with an irregular Ni/ligand ratio in Zhang’s
reductive difluoromethylation [23] (Table 1, entry 9).
Replacement of the auxiliary ligand 4-CN-Py with electron-rich
4-MeO-Py also delivered the coupling product successfully in
76% yield when utilizing the sibling ClCH2CH2Br as the
coupling electrophile (Table 1, entry 10).
To test the synthetic utility of this direct chloroethylation
method, the reaction between 4-biphenylboronic acid and
ClCH2CH2Cl (DCE) was conducted on a gram scale under the
standard conditions (condition A). An isolated yield of 57% was
furnished comparable to that of small-scale experiment (Table
1, entry 9, 65% yield) with providing 3a in 1.23 gram.
Compound 3a retained with homobenzylic C-Cl bond was further
converted into diverse organic compounds [26] via β-elimination
and nucleophilic substitutions (Table 3). A series of N, O, S and
C-centered nucleophiles (H-Nu) proved to be viable for
producing ArCH2CH2Nu molecules under weak basic conditions.
For instance, Chlorzoxazone (a central muscle relaxant)
containing carbamate N-H can be efficiently transformed to the
alkylated N-CH2CH2Ar pattern in 63% yield. These synthetic
examples demonstrated the potential of DCE as an ethylene (-
CH2CH2-) linker under the developed protocol which might
found potential applications in drug modifications.
Table 1. Reaction condition optimizationa.
NiBr2 (10 mol%)
(N,N-ligand, 10 mol%)
CH2CH2Cl
B(OH)2
L-a
L-b
ClCH2CH2X
or additive (30 mol%)
Ph
2a
2b
Ph
(X= Cl)
(X= Br)
K3PO4, DME, 70 o
C
1a
3a
L-b or additive
(y mol%)
Entry
L-a (x mol%)
Yieldb
1
2
dtbpy (10 mol%)
dtbpy (10 mol%)
none
4-MeO-Py (30 mol%)
none
37%
23%
N.D.
42%
28%
51%
9%
3
4-MeO-Py (30 mol%)
DMAP (30 mol%)
Pyridine (30 mol%)
4-CN-Py (30 mol%)
2-CN-Py (30 mol%)
Pyrazine (30 mol%)
4-CN-Py (30 mol%)
4-MeO-Py (30 mol%)
4
dtbpy (10 mol%)
dtbpy (10 mol%)
dtbpy (10 mol%)
dtbpy (10 mol%)
dtbpy (10 mol%)
dtbpy (5 mol%)
5
6
7
8
32%
65%
76%
9
10c
dtbpy (10 mol%)
aReaction conditions for DCE 2a as electrophile (unless stated otherwise): 1a
(0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), K3PO4 (0.4 mmol, 2.0
equiv), L-a (N,N-ligand) (0.02 mmol, 0.1 equiv), L-b or additive (0.04 mmol,
0.3 equiv), DME (1.0 mL), 24 h.
Table 2. Substrate scope investigation a.
bIsolated yield.

3
cReaction condition for using Chlorzoxazone as nucleophile: 3a (0.20
A
2
Conditions for (X=Cl)
mmol, 3.0 equiv), Chlorzoxazone (1.0 equiv), K2CO3 (0.20 mmol, 3.0 equiv.),
DMF (1.0 mL), 60 oC.
(Het)Ar-B(OH)2
RCHClCH2X
Ar-CH(R)CH2Cl
+
B
2
Conditions for (X=Br)
3
1
2a; 2b; 2c; 2d
Base on the related literatures of nickel-catalyzed Suzuki-type
C(sp3)-C(sp2) couplings [18d, 27] and the experimental
observation from the radical inhibition tests (Scheme 1), a
plausible mechanism involving NiI/NiII/NiIII catalytic cycle was
proposed for the current chloroethylations (Figure 2). The NiI
catalytic species A was supposed to be produced from a
comproportionation between NiII and Ni0 species [23] (Figure 2a).
Upon the participation of NiI catalytic species A into catalytic
cycle, it underwent a Ni-B transmetalation to generate [LnNiIAr]
B. Subsequent oxidative addition between B and ClCH2CH2X
took place via halogen abstraction and consecutive radical
rebound process to deliver [LnNiIII(Ar)(CH2CH2Cl)(X)] D. Final
reductive elimination of D furnished the coupling product
ArCH2CH2Cl and regenerated A to complete the catalytic cycle.
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
Ph
MeO2C
NC
b
c
b
c
b
c
3a
3d
3b
3c
, 42% (61% )
, 65% (76% )
, 51% (70% )
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
tBu
OHC
b
c
O
b
c
b
c
3f
3i
, 38% (46% )
3e
3h
, 57% (55% )
, 65% (94% )
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
MeO
Ph
b
c
b
c
b
c
, 45% (73% )
, 26% (29% )
3g
, 41% (47% )
CH2CH2Cl
CH2CH2Cl
Ac
CH2CH2Cl
OHC
CH2CH2Cl
B(OH)2
TEMPO (1.0 equiv)
a
ClCH2CH2X
(X= Cl or Br)
A
B
standard conditions or
Ph
Ph
b
c
b
c
b
c
3a
, ND
3j
, 37% (46% )
1
3k
3n
, 41% (52% )
3l
, 39% (51% )
1,4-dinitrobenzene
(1.0 equiv)
CH2CH2Cl
CH2CH2Cl
MeO2C
B(OH)2
CH2CH2Cl
b
ClCH2CH2X
(X= Cl or Br)
A
B
standard conditions or
O
N
OCH3
Ph
Ph
CH2CH2Cl
1
3a
, ND
b
c
b
c
b
c
3m
, 40% (45% )
, 37% (46% )
3o
, 26% (55% )
R
Scheme 1. Radical inhibition experiments.
CH2CH2Cl
Cl
1
3q
3r
(R = Ph)
3s
3t
(R = CH3)
(R = CH2Cl)
S
R1
Ph
1
(R = Et)
CH2CH2Cl
a. Generation of NiI catalytic species
b,c
b
c
d
e
3q 3r,
or
3p
N.D.
3s
3t
, 45% (53% )
, 20% ; , 19%
Ar-Ar
aOrganohalides: ClCH2CH2Cl 2a; ClCH2CH2Br 2b; CH3CH(Cl)CH2Cl 2c;
ClCH2CH(Cl)CH2Cl 2d. Reaction condition A for 2a, 2c, 2d. Reaction
condition B for 2b. Coupling reactions were run on a 0.20 mmol scale.
2ArB(OH)2
LnNiX2
LnNiIIAr2
LnNiIIX2
[LnNi0]
LnNiIX
base
RE
b. Proposed catalytic cycle
Ln = combined ligands
bIsolated yield for using ClCH2CH2Cl 2a as electrophile.
LnNiIX
(A)
cIsolated yield in the parenthesis for using ClCH2CH2Br 2b as electrophile.
dIsolated yield for using CH3CH(Cl)CH2Cl 2c as electrophile.
CH3CH(Ar)CH2Cl and CH3CH(Cl)CH2Ar were obtained as an inseparable
mixture in a ratio of ca. 1.6:1 determined by 1H NMR.
ArCH2CH2Cl
ArB(OH)2
base
transmetalation
reductive
elimination
eIsolated yield for using ClCH2CH(Cl)CH2Cl 2d as electrophile.
ClCH2CH(Ar)CH2Cl and ClCH2CH(Cl)CH2Ar were obtained as an
inseparable mixture in a ratio of ca. 6.7 : 1 determined by 1H NMR.
CH2CH2Cl
Ar
(B) LnNiIAr
NiI/NiII/NiIII shuttle
IIINi
Ln
X
(D)
Table 3. Derivatization on the scaffold of ArCH2CH2Cl 3a
ClCH2CH2
+
LnNiII(Ar)(X)
CH2CH2Cl
CH2CH
2Nu
ClCH2CH2X
halogen
abstraction
-HCl
H-Nu
radical
rebound
elimination
substitution
Ph
Ph
Ph
3a (
gram-synthesized)
(C)
Figure 2. Proposed reaction mechanism.
N
N
CH2S
CH2
Ph
Ph
a
b
3. Conclusion
4
5
, 51%
, 61%
O
In conclusion, we have developed an efficient
nickel/combinatorial nitrogen ligands system for incorporation of
β-chloroethyl into aromatic rings from readily available
(hetero)arylboronic acids and vicinal dihalides ClCH2CH2X (X =
Cl or Br). This method was highlighted by the selective
activation of proximal inactive C-X bond for Suzuki-type C(sp3)-
C(sp2) linkages and the successful suppression of β-chloride or
hydride side eliminations as well as the compatibility for
retention of the homobenzyllic C-Cl bond in the coupling
products. The conversions of these homobenzylic chlorides (Ar1-
CH2CH2Cl) into Ar1-CH2CH2-R structures demonstrated the
potential of the ethylene (-CH2CH2-) linker in merging different
bioactive molecular moieties for drug modifications. Further
explorations of the mechanistic details and extension of this
protocol to more complicated secondary or tertiary vicinal
CH2CH
2OPh
CH2CH2
N
Ph
Ph
b
Ph
b
6
, 18%
O
7
, 31%
CH2CH2
CH2CH
2CH(CO2Me)2
Cl
N
O
O
Ph
b
c
8
9
, 63%
, 19%
aReaction condition for elimination: 3a (0.20 mmol, 1.0 equiv), NaOH (0.24
mmol, 1.2 equiv), DMF (1.0 mL), 90 oC.
bReaction condition for nucleophilic substitutions (5-8): 3a (0.20 mmol, 1.0
equiv), nucleophile (H-Nu, 1.0 equiv), K2CO3 (0.20 mmol, 3.0 equiv.), DMF
(1.0 mL), 60 oC.

4
Tetrahedron Letters
dihalides are still undergoing, and the results will be reported in
due course.
Acknowledgments
The National Natural Science Foundation of China
(21502131), Science & Technology Department of Sichuan
Province (2018JZ0061, 2018HH0128), Education Department of
Sichuan Province (18CZ0024), Sichuan University of Science
and Engineering (2017RCL03) and Sichuan Youth Plan (2017,
2018) are greatly acknowledged for funding this work.
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5
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Supplementary Material
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