Nickel-Catalyzed Regioselective Reductive Cross-Coupling of Aryl Halides with Polysubstituted Allyl Halides in the Presence of Imidazolium Salts

Article abstract of DOI:10.1055/s-0035-1560531

The nickel-catalyzed direct reductive cross-coupling of aryl halides with readily accessible polysubstituted allyl halides provides an efficient method for preparing diverse allylated arenes under mild conditions. Both allyl bromides and allyl chlorides are compatible with the transformation.

Full text of DOI:10.1055/s-0035-1560531

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2784–2788
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Z. Zhang et al.
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Nickel-Catalyzed Regioselective Reductive Cross-Coupling of Aryl
Halides with Polysubstituted Allyl Halides in the Presence of Imid-
azolium Salts
Zhan Zhang
Lijun Xu
X
R1
Mg (3.0 equiv)
NiI2 (5 mol%)
ligand (10 mol%)
R2
Zhengkai Chen
Zhubo Liu
N
N
+
R3
R1
Maozhong Miao
Jinyu Song
R2
LiCl (3 equiv)
THF, 0 °C, 12 h
Cl
ligand
X
R3
Hongjun Ren*
X = Cl, Br
19 examples (29–69%)
Department of Chemistry, Zhejiang Sci-Tech University,
Hangzhou 310018, P. R. of China
renhj@zstu.edu.cn
Received: 21.09.2015
Accepted after revision: 26.10.2015
Published online: 13.11.2015
Negishi coupling reaction of 3,3-disubstituted allylzinc re-
agents with aryl, hetaryl, or vinyl halides with completely
linear selectivity (Scheme 1, a).5 Although these methods
are efficient and highly selective, they have some draw-
backs, especially in the case of the preparation of polysub-
stituted allyl–metal reagents, such as polysubstituted allyl-
boronates6a–c or zinc reagents.6d–e The development of strat-
egies for the synthesis of diverse allylated arenes that are
more convenient and more economic is still desirable.
DOI: 10.1055/s-0035-1560531; Art ID: st-2015-s0755-c
Abstract The nickel-catalyzed direct reductive cross-coupling of aryl
halides with readily accessible polysubstituted allyl halides provides an
efficient method for preparing diverse allylated arenes under mild con-
ditions. Both allyl bromides and allyl chlorides are compatible with the
transformation.
Key words nickel, catalysis, cross-coupling, aryl halides, allylarenes,
imidazolium salts
(a) Organ and Buchwald's work:
R2
R2
X
R3
Pd/L
Considerable attention has recently been paid to the
synthesis of allylarene derivatives, which can serve as ver-
satile synthetic intermediates and useful chemicals.1
Among this important group of compounds are the pre-
nylated arenes, which are especially worthy of attention be-
cause of their widespread distribution in synthetic and nat-
ural bioactive products and their privileged position in
drug discovery.2 Generally, the preparation of allylarenes,
especially prenylated arenes, involves the introduction of
prenyl or related 3,3-disubstituted allyl groups onto func-
tionalized aromatic systems. In this context, the exclusive
control of regioselectivity remains a great challenge.
Organ and co-workers developed cross-coupling reac-
tions of 3,3-disubstituted allylboronates with aryl or het-
aryl halides in the presence of N-heterocyclic carbene
(NHC)-based palladium catalysts to give linear allylated
products with high selectivity (Scheme 1, a).3 Yang and
Buchwald subsequently demonstrated a phosphine-ligand-
controlled regiodivergent Suzuki–Miyaura coupling of allyl-
boronates with (het)aryl halides (Scheme 1, a).4 This ele-
gant protocol provides an efficient approach to the highly
selective construction of linear or branched allylated
arenes. Buchwald and co-workers also reported a practical
M
R3
R1
R1
+
M = ZnBr, Bpin
(b) Gong and Weix's work:
X
Ni/L
R2
R1
R1
AcO
+
R2
Zn or Mn
40 °C
(c) our previous work: copper-free arylation of 3,3-disubstituted allylic halides with
triazene-softened aryl Grignard reagents
mask
Me
Me
R
γ
Ar
X = Cl
+
α
X = Br
MgX
Me
X
Me
Ar
Me Me
softened Grignard
reagents
α-selective
γ-selective
(d) this work: direct aryl–allylic cross-coupling
R2
R2
X
Ni/L
Mg, 0 °C
R3
R1
+
R3
X = Cl, Br
R1
X
γ-selective
Scheme 1 Various strategies for the preparation of allylated aromatic
compounds
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2784–2788

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Z. Zhang et al.
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From the point of view of environmental and economic
sustainability, nickel catalysts are less expensive and more
sustainable than palladium catalysts. Nickel has been wide-
ly used in organic synthesis as a catalyst for the formation
of carbon–carbon and carbon–heteroatom bonds.7 A nickel-
catalyzed direct reductive cross-coupling reaction to con-
struct C–C bonds has recently received significant atten-
tion.8 Nickel catalyst have also been applied in a synthesis
of various allylated arenes. Gong9a,b and Weix9c and their re-
spective co-workers have individually disclosed general
nickel-catalyzed selective coupling reactions of organic ha-
lides with allylic acetates under mild conditions (Scheme 1,
b). Apart from these contributions, there are few reported
examples of successful nickel- or cobalt-catalyzed transfor-
mations that generate allylated motifs.10 The nickel-cata-
lyzed direct reductive coupling of aryl halides with 3,3-
disubstituted allyl halides remains rare, presumably due to
issues of regioselectivity and, especially, homocoupling. We
recently developed a copper-free arylation of 3,3-disubsti-
tuted allyl halides with triazene-softened aryl Grignard re-
agents, which provides an efficient way to construct both
the α- and γ-isomers of prenylated arenes (Scheme 1, c).11
Here we report a nickel-catalyzed direct reductive
cross-coupling reaction of aryl halides with readily accessi-
ble polysubstituted allyl halides for the rapid assembly of a
wide range of allylated arenes under mild conditions
(Scheme 1, d).
We began by examining the reaction of 4-bromobiphe-
nyl (1a) with 1-bromo-3-methylbut-2-ene (prenyl bro-
mide; 2a) in the presence of magnesium in tetrahydrofuran
with various nickel salts as catalysts (Table 1). When nick-
el(II) fluoride or bromide was chosen as the catalyst, none
of the desired cross-coupling product was obtained (Table
1, entries 1 and 2). Gratifyingly, the use of nickel(II) iodide
as a catalyst gave the linear coupling product 3a in 25%
yield (entry 3). Because of the significant effects of N-het-
erocyclic carbene on coupling reactions,12 we surmised that
an N-heterocyclic carbene precursor might improve the ef-
ficiency of our reaction. Unexpectedly, the reaction pro-
ceeded smoothly with nickel(II) fluoride or bromide as cat-
alyst in the presence of imidazolium salt L1 (Figure 1) to
give the desired coupling product 3a in 22 or 23% yield, re-
spectively, demonstrating that the imidazolium salt has a
positive effect on the transformation (entries 4 and 5). A
combination of nickel(II) iodide (5 mol%) and L1 (10 mol%)
gave 3a in 37% yield (entry 6). Note that the yield increased
to 41% or 62% with the addition of LiI (10 mol%) or LiCl (3.0
equiv) to the reaction system (entries 7 and 8, respectively).
Various imidazolium salts were tested, but the promoting
effect of imidazolium salts L2–L6 was found to be inferior
to that of L1 (entries 9–13). Screening of other commercial-
ly available metal salts, such as iron(III) chloride,
tris(acetylacetonato)iron(III) [Fe(acac)3], cobalt(II) chloride,
or bis(acetylacetonato)cobalt(II), gave poor yields and poor
regioselectivities, showing that their catalytic activity was
inferior to that of nickel(II) iodide (entries 14–17).
Table 1 Optimization of the Reaction Conditionsa
Me
Mg (3.0 equiv)
cat. (5 mol%)
Br
Me
ligand (10 mol%)
1a
3a
additive (3.0 equiv)
THF, 0 °C, N2
+
+
Br
Me
Me
Me
Me
2a
3a'
Entry
Catalyst
Ligand
Additive
Yieldb (%) of 3a
1
2
NiF2
NiBr2
NiI2
–
–
–
–
–
–
3
–
–
25
22
23
37
41
62
40
28
46
46
50
40e
38e
39e
32e
4
NiF2
NiBr2
NiI2
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
–
5
–
6
–
7
NiI2
LiIc
8
NiI2
NiI2
LiCld
LiCld
LiCld
LiCld
LiCld
LiCld
LiCld
LiCld
LiCld
LiCld
9
10
11
12
13
14
15
16
17
NiI2
NiI2
NiI2
NiI2
FeCl3
Fe(acac)3
CoCl2
Co(acac)2
a Reaction conditions: 4-bromobiphenyl (1a; 1.0 mmol), 2a (3.0 mmol),
catalyst (5 mol%), Mg (3.0 mmol), ligand (10 mol%), additive, THF (3.0 mL),
under N2, 0 °C, 12 h.
b Yield of the isolated product.
c 10 mol%.
d 3 equiv.
e The γ-selective product 3a′ was also obtained in 5–10% yield.
Having identified the optimal reaction conditions, we
examined the scope of nickel-catalyzed reductive cross
coupling reaction with various aryl halides and allyl halides
(Scheme 2). 2-Bromobiphenyl and 3-bromobiphenyl react-
ed well with bromide 2a under the standard conditions to
give the desired coupling products 3b and 3c in moderate
yields (52 and 50%, respectively).13 The reactivity of 1-bro-
mo-4-methoxybenzene (2d) and 1-bromo-3-methoxyben-
zene (2f) was similar to that of 1-bromo-2-methoxyben-
zene (2e), indicating that the orientation of the substi-
tuents has only a weak effect on this transformation.
1-Bromo-2-(methoxymethyl)benzene (2k) and 4-bromo-
2,5-dimethylbiphenyl (2l) also reacted to give the corre-
sponding coupling product 3k and 3l in 49 and 54% yield,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2784–2788

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R2
R3
Mg (3.0 equiv)
NiI2 (5 mol%)
L1 (10 mol%)
R2
N
N
Br
N
N
Br
R1
+
R1
LiCl (3 equiv)
THF, 0 °C, 12 h
R3
2
BF4
L2: IMes⋅HBF4
1
3b–q, 29–69%
Cl
L1: IPr⋅HCl
Me
Me
Me
Me
Me
Me
MeO
Ph
Ph
N
N
N
N
3b, 52%
3c, 50%
3d, 40%
Me
Me
Me
Cl
Cl
L4: SIMes⋅HCl
Ph
CH3
Ph
L3: ICy⋅HCl
MeO
OMe
MeO
3e, 48%
3f, 43%
3g, 49%
N
N
N
N
Ph
Ph
BF4
Cl
L5; SIPr⋅HCl
Ph
OMe
MeO
3i, 69% (E/Z > 99:1)
L6: IAd⋅HBF4
Figure 1 NHC ligands L1–L6
3j, 44% (E/Z > 99:1)
3h, 51% (E/Z > 99:1)
Me
Me
OMe
Me
OMe
Me
respectively. Notably, [(1E)-3-bromoprop-1-en-1-yl]ben-
zene reacted with various aryl halides to give the corre-
sponding coupling products 3g–j and 3m in 44–69% isolat-
ed yield. It is worth mentioning that the reaction also pro-
ceeded smoothly with the series of substituted allyl
bromides 2n–p, and that the configuration of the alkenes
was retained in the corresponding products 3g–j, 3m, and
3o–p. Furthermore, the dicoupling product 3q was success-
fully obtained with the current catalytic system, albeit in a
lower yield.
To extend the applicability of the reaction, we next
turned our attention to the possibility of using cyclic allylic
chlorides in the nickel-catalyzed reductive cross-coupling
reaction (Scheme 3). To our delight, when we used 1-bro-
mo-4-methoxybenzene or 1-bromo-3-methoxybenzene
with 3-chloro-1,5,5-trimethylcyclohex-1-ene (4) as sub-
strates under the nickel-catalyzed reductive cross-coupling
conditions, we obtained the desired α-selective coupling
product 5a and 5b, respectively, albeit with relatively low
yields. However, the desired product 5c was not obtained
from 1-bromo-2-methoxybenzene, indicating that steric
interference between the ortho-substituent and the bulky
3-chloro-1,5,5-trimethylcyclohex-1-ene (4) had an obvious
influence on the reactivity of the substrate in this case.
Next, we attempted to exploit the full potential of our
nickel-catalyzed reductive cross-coupling by synthesizing a
complex molecule. The diprenyl derivative of curcumin
(PCRM) is a useful probe for investigating the antioxidant
pharmacophore of natural curcuminoids, and it possesses
excellent anticarcinogenic and antiinflammatory proper-
ties.14 The usual synthesis of diprenylated curcumin re-
quired intricate procedures for the installation of the prenyl
moiety.15 By using our method, we obtained the key PCRM
Ph
Me
Me
Ph
3k, 49%
3l, 54%
3m, 53% (E/Z > 99:1)
Me
Me
Me
Me
MeO
MeO
Me
3n, 45%
3o, 49% (E/Z > 99:1)
Me
Me
Me
Me
OMe
Me
Me
Me
MeO
Me
MeO
3q, 29%a
3p, 46% (E/Z > 99:1)
Scheme 2 The scope of nickel-catalyzed reductive cross-coupling. Re-
agents and conditions: aryl bromide 1 (1.0 mmol), allyl bromide 2 (3.0
mmol), NiI2 (5 mol%), Mg (3.0 mmol), L1 (10 mol%), LiCl (3.0 equiv),
THF (3.0 mL), stirring, under N2, 0 °C, 12 h. The yields refer to the isolat-
ed products. a Reagents and conditions: aryl bromide 1 (1.0 mmol), allyl
bromide 2 (5.0 mmol), NiI2 (5 mol%), Mg (5.0 mmol), L1 (10 mol%), LiCl
(5.0 equiv), THF (3.0 mL), stirring, under N2, 0 °C, 12 h.
precursor 6e smoothly from readily available starting mate-
rials, thereby providing straightforward access to the useful
bioactive molecule (Scheme 4).
In summary, we have developed an efficient pathway
for the preparation of a range of allylated arenes by nickel-
catalyzed reductive cross-coupling of aryl halides with
polysubstituted allyl halides. Notable features of this trans-
formation include the mild reaction conditions, the readily
available starting materials, and a broad substrate scope.
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References
Me
Cl
Mg (3.0 equiv)
NiI2 (5 mol%)
L1 (10 mol%)
Br
(1) (a) Manitto, P. Biosynthesis of Natural Products; Ellis Horwood:
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Me
Me
MeO
+
Me
Me
MeO
LiCl (3 equiv)
THF, 0 °C, 12 h
Me
1
5
4
Me
Me
Me
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Me
Me
Me
Me
Me
Me
MeO
OMe
OMe
5a, 33%
5b, 35%
5c, 0%
Scheme 3 The coupling reaction of a cyclic allylic chloride with various
aryl bromides. Reagents and conditions: aryl bromide 1 (1.0 mol), 1,5,5-
trimethylcyclohex-1-ene (4; 3.0 mol), NiI2 (5 mol%), Mg (3.0 mol), L1
(10 mol%), LiCl (3.0 equiv), THF (3.0 mL), stirring, under N2, 0 °C, 12 h.
Yields are those of the isolated products.
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Further studies to elucidate the mechanism of the reaction
and to extend the range of practical applications of this
method are in progress in our laboratory.
Acknowledgements
We are grateful for financial support from the National Nature Sci-
ence Foundation of China (21272003) and from the Zhejiang Provin-
cial Top Key Academic Discipline of Chemical Engineering and
Technology of Zhejiang Sci-Tech University.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560531.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
Br
Br
OMe
a) (HCHO)n, H2SO4, DDQ
OMe
OMe
OMe
c) 2,2-dimethyl-
propan-1,3-diol
d) standard
conditions
MeCN, 80 °C, 5 h
O
OMe
TsOH⋅H2O
toluene, reflux
b) NBS, MeCN, r.t., 4 h
OHC
Me
Me
OMe
O
6a, 85%
6b, 86%
Me
Me
Me
Me
Me
O
O
Me
Me
Me
f) B2O3, pentane-2,4-dione
B(OMe)3, DMF, 90 °C, 1 h
OMe
OMe
e) HCl, THF, 1 h
OMe
OMe
MeO
OMe
O
AcOH, 60 °C, 3 h
OMe
OMe
Me
Me
O
OHC
6e, 56%
6c, 47%
6d, 89%
Scheme 4 Application in the synthesis of a diprenyl derivative of curcumin. Reagents and conditions: (a) (HCHO)n (4.0 equiv), H2SO4 (cat.), DDQ (2.0
equiv), MeCN, 80 °C, 5 h; (b) NBS (2.0 equiv), MeCN, r.t., 4 h; (c) 2,2-dimethylpropane-1,3-diol (1.05 equiv), TsOH·H2O (0.1 equiv), toluene, reflux, 12 h;
(d) standard Ni-catalyzed conditions; (e) concd aq HCl (2.0 equiv), THF, r.t., 1 h; (f) B2O3 (0.47 equiv), pentane-2,4-dione (0.5 equiv), B(OMe)3 (3.3
equiv), DMF, 90 °C, 1 h, then AcOH (0.05 equiv), 60 °C, 3 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2784–2788

2788
Z. Zhang et al.
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(9) (a) Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012, 14, 3352. (b) Cui,
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(13) 2-(3-Methylbut-2-en-1-yl)biphenyl (3b); Typical Example
A dry, N2-flushed, 25 mL Schlenk tube equipped with a mag-
netic stirrer was charged with Mg (3.5 mmol, 3.5 equiv) and
anhyd LiCl (3 mmol, 3.0 equiv), which were covered with anhyd
THF (3 mL) and activated by the addition of a few drops of
TMSCl. The mixture was stirred for 30 min, then ligand L1 (0.1
mmol, 0.1 equiv) and NiI2 (0.05 mmol, 0.05 equiv) were added,
and the mixture was stirred at 0 °C. A solution of 4-bromobi-
phenyl (1b; 1.0 mmol, 1.0 equiv) and bromide 2a (3.0 mmol, 3.0
equiv) in THF (2 mL) was slowly added from a syringe pump at
0 °C (flow rate: 3 mL/h). The resulting mixture was stirred
under N2 at 0 °C for 12 h. Sat. aq NH4Cl (10 mL) was added, and
the mixture was extracted with EtOAc (3 × 30 mL). The com-
bined organic fractions were dried (Na2SO4), concentrated in
vacuo, and purified by chromatography [silica gel (200–300
mesh), PE] to give a colorless oil; yield: 115 mg (52%); Rf = 0.58
(PE). IR (ATR–FTIR): 2969, 1479, 1047, 738, 700 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.43–7.38 (m, 2 H), 7.36–7.29 (m, 5 H),
7.25–7.21 (m, 2 H), 5.19 (t, J = 7.2 Hz, 1 H), 3.28 (d, J = 7.2 Hz, 2
H), 1.68 (s, 3 H), 1.51 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ =
141.84, 141.76, 139.2, 131.9, 130.0, 129.33, 129.25, 128.0,
127.4, 126.7, 125.7, 123.7, 32.0, 25.7, 17.7. MS (ES+): m/z (%) =
223 (8) [M + H]+, 195 (28), 177 (21), 168 (25), 133 (100), 117
(35), 105 (12). HRMS (ES+–TOF): m/z [M + H]+ calcd for C17H19
:
223.1487; found: 223.1474.
(14) (a) Koeberle, A.; Muñoz, E.; Appendino, B.; Minassi, A.; Pace, S.;
Rossi, A.; Weinigel, C.; Barz, D.; Sautebin, L.; Caprioglio, D.;
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2784–2788