N-heterocyclic carbene-assisted, Bis(phosphine)nickel-catalyzed cross-couplings of diarylborinic acids with aryl chlorides, tosylates, and sulfamates

Article abstract of DOI:10.1021/jo501291y

Efficient bis(phosphine)nickel-catalyzed cross-couplings of diarylborinic acids with aryl chlorides, tosylates, and sulfamates have been effected with an assistance of N-heterocyclic carbene (NHC) generated in situ from N,N′-dialkylimidazoliums, e.g., N-butyl-N′-methylimidazolium bromide ([Bmim]Br), in toluene using K₃PO₄·3H₂O as base. In contrast to bis(NHC)nickel-catalyzed conventional Suzuki coupling of arylboronic acids, mono(NHC)bis(phosphine)nickel species generated in situ from Ni(PPh₃)₂Cl₂/[Bmim]Br displayed high catalytic activities in the cross-couplings of diarylborinic acids. The structural influences from diarylborinic acids were found to be rather small, while electronic factors from aryl chlorides, tosylates, and sulfamates affected the couplings remarkably. The couplings of electronically activated aryl chlorides, tosylates, and sulfamates could be efficiently effected with 1.5 mol % NiCl₂(PPh₃)₂/[Bmim]Br as catalyst precursor to give the biaryl products in excellent yields, while 3-5 mol % loadings had to be used for the couplings of non- and deactivated ones. A small ortho-substitutent on the aromatic ring of aryl chlorides, tosylates, and sulfamates was tolerable. Applicability of the nickel-catalyzed cross-couplings in practical synthesis of fine chemicals has been demonstrated in process development for a third-generation topical retinoid, Adapalene.

Full text of DOI:10.1021/jo501291y

Article
pubs.acs.org/joc
N‑Heterocyclic Carbene-Assisted, Bis(phosphine)nickel-Catalyzed
Cross-Couplings of Diarylborinic Acids with Aryl Chlorides, Tosylates,
and Sulfamates
Haihua Ke, Xiaofeng Chen, and Gang Zou*
Department of Fine Chemicals, East China University of Science & Technology, 130 Meilong Road, Shanghai 200237, China
S
* Supporting Information
ABSTRACT: Efficient bis(phosphine)nickel-catalyzed cross-
couplings of diarylborinic acids with aryl chlorides, tosylates, and
sulfamates have been effected with an assistance of N-heterocyclic
carbene (NHC) generated in situ from N,N′-dialkylimidazoliums,
e.g., N-butyl-N′-methylimidazolium bromide ([Bmim]Br), in tolu-
ene using K3PO4·3H2O as base. In contrast to bis(NHC)nickel-
catalyzed conventional Suzuki coupling of arylboronic acids, mono-
(NHC)bis(phosphine)nickel species generated in situ from Ni(PPh3)2Cl2/[Bmim]Br displayed high catalytic activities in the
cross-couplings of diarylborinic acids. The structural influences from diarylborinic acids were found to be rather small, while
electronic factors from aryl chlorides, tosylates, and sulfamates affected the couplings remarkably. The couplings of electronically
activated aryl chlorides, tosylates, and sulfamates could be efficiently effected with 1.5 mol % NiCl2(PPh3)2/[Bmim]Br as catalyst
precursor to give the biaryl products in excellent yields, while 3−5 mol % loadings had to be used for the couplings of non- and
deactivated ones. A small ortho-substitutent on the aromatic ring of aryl chlorides, tosylates, and sulfamates was tolerable.
Applicability of the nickel-catalyzed cross-couplings in practical synthesis of fine chemicals has been demonstrated in process
development for a third-generation topical retinoid, Adapalene.
catalysts for Suzuki coupling of aryl chlorides, while bis(NHC)
palladium species seemed too stable to be active. In sharp
contrast, bis(NHC)nickel species have appeared to be more
catalytically active than the mono(NHC)nickel ones in Suzuki
coupling, although the NHC/nickel catalyst systems are still far
away from being established.4,11−17 For example, bis(NHC)
nickel species had been identified by in situ NMR and EXAFS
and proposed to be true catalysts in a nickel ion-containing ionic
liquid, bis(N-butyl-N′-methylimidazolium)tetrachloronickelate
([Bmim]2NiCl4), catalyzed Suzuki coupling.12 Radius et al. even
reported selective Suzuki coupling of perfluorinated arenes by
using a bis(NHC)nickel complex of 1,3-di(isopropyl)imidazol-
2-ylidene, [Ni2(diiPrim)4(COD)].13a Nickel complexes (I−IV)
supported by bridged chelating bis(NHC) ligands had been
further designed and used as catalyst precursors in Suzuki coup-
ling, which showed good catalytic efficiencies if in the presence
of 2−5 equiv of phosphine coligand (Figure 1).17
As a part of our ongoing efforts to develop practical arylation
methods using diarylborinic acids, we report herein efficient
cross-couplings of diarylborinic acids with aryl chlorides,
tosylates, and sulfamates catalyzed by mono(NHC), bis-
(phosphine) coligated nickel catalysts generated in situ from
bis(phosphine)nickel chloride and N,N′-dialkylimidazoliums,
such as [Bmim]Br or [diBim]Br, etc., and its application in
practical synthesis of a third-generation topical retinoid,
Adapalene.
INTRODUCTION
■
Chemistry of palladium-catalyzed Suzuki coupling of arylbor-
onic acids has been well-established.1 However, its applications
in large scale production are still hampered by the costs of pal-
ladium catalysts and/or expensive substrates, especially aryl-
boronic acids. Developments of efficient nickel catalysts pio-
neered by Percec2 and Fu3 et al. have promised great potentials
not only in reducing the catalyst costs but also in taking
advantage of electrophiles that are challengeable to palladium-
catalyzed Suzuki coupling, such as a variety of phenol deri-
vatives and alkyl halides.2−4 Comparably, it is still undeveloped
to use high-order arylborons (Ar2B(OH), Ar3B and [Ar4B]M)
in Suzuki coupling, although they not only have higher atom
economies but also could be more economically prepared than
the corresponding arylboronic acids.5 We recently have effected
cross-couplings of diarylborinic acids (Ar2B(OH)) with aryl
(pseudo)halides by using a phosphine/nickel catalyst system
(NiCl2(PAr3)2/2PAr3) in developing cost-effective Suzuki
coupling.6 However, similar to most phosphine/nickel catalyst
systems for Suzuki coupling, four or more equivalents of
phosphine ligand relative to nickel had to be used to maintain
an acceptable catalytic efficiency because of dissociation and de-
composition of phosphines. N-Heterocyclic carbenes (NHCs)
have been well-known to be better supporting ligands than
phosphines for robust transition metal complexes.7 In fact,
mono(NHC)palladium complexes of sterically demanding
N-heterocyclic carbenes, e.g., 1,3-di[2,6-(diisopropyl)phenyl]-
imidazolylidene (IPr) etc., have been elegantly established by
Nolan,8 Organ9 and Glorius10 et al. to be the most efficient
Received: June 10, 2014
Published: July 15, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Article
reaction was run in toluene, the yield of 3aa remarkably
increased to 77%. The preformation of catalytically active nickel
species proved crucial for the model reaction to take place
efficiently since 3aa was isolated in only 10% yield when all
components of the catalyst system and substrates were added
simultaneously (Table 1, entries 3 and 4). When NiCl2(PPh3)2
was used in placement of NiCl2 and PPh3, it was not necessary
any more to preform the catalytic species (Table 1, entry 5). An
increase in the mole ratios of [Bmim]Br to NiCl2(PPh3)2, thus
NHC to Ni, from 2/1 to 3/1 and 4/1 decreased the yields of
product 3aa significantly from 78 to 64 and 43%, respectively.
In contrast, use of 3 mol % NiCl2(PPh3)2 with 3 mol %
[Bmim]Br, namely equivalent NHC to Ni, gave an excellent
yield (93%) for 3aa under otherwise identical conditions
(Table 1, entry 8). These results implied that some mono-
(NHC), bis(phosphine) coligated nickel species generated in
situ, e.g., Ni(PPh3)2(NHC), should be more catalytically active
in the cross-coupling of diarylborinic acids with aryl chlorides
although bis(NHC)nickel complexes have been generally used
as catalytic precursors or even proposed to be the active species
in NHC/nickel catalyst systems for the conventional Suzuki
coupling of arylboronic acids. The yield of 3aa failed to further
increase upon increasing the catalyst loading to 4 mol % while a
lower yield (56%) was obtained with 2 mol % NiCl2(PPh3)2/
[Bmim]Br (Table 1, entries 9 and 10).
RESULTS AND DISCUSSION
■
Cross-Coupling of Aryl Chlorides. Cross-coupling of
bis(p-tolyl)borinic acid (1a) with electronically deactivated aryl
chloride, 4-(benzyloxy)phenyl chloride (2a), was chosen as
model reaction to evaluate NHC/Ni catalyst systems since the
reaction has been recently effected in our laboratory by using
Pd/(POR)3/IPr5d and NiCl2(PAr3)2/2PAr3 catalyst systems.
6a
No reaction was observed with the [Bmim]2NiCl4 catalyst
system reported for Suzuki coupling of arylboronic acids with
aryl chlorides under otherwise identical conditions.12 Consid-
ering bis(NHC)nickel complexes, e.g., NiCl2(NHC)2, had been
identified in the [Bmim]2NiCl4 catalyst system, a combination
of NiCl2 with 2 equiv of [Bmim]Br in the presence of K3PO4·
3H2O, which was heated prior to addition of substrates to in
situ generate NHC nickel species, was tested subsequently. The
reaction did occur with 3 mol % NiCl2 and 6 mol % [Bmim]Br,
but sluggishly even in the presence of 6 mol % PPh3 as coli-
gand for nickel (Table 1, entries 1 and 2). However, when the
The control experiments in the absence of a phosphine or
NHC precursor indicated that phosphines should be more
important than NHCs in the NHC/phosphine coligated nickel
catalysts although NHCs have generally played a major role in
transition metal catalysts mixed-ligated by NHC and other
ligands (Table 1, entries 11−13).9,18−20 Screening of phosphine
ligands showed that the electron-rich triarylphosphine P(4-
MeOPh)3 performed comparably to PPh3 while tricyclohex-
ylphosphine (PCy3) showed almost no activity in the
Figure 1. Selected bis(NHC)nickel catalyst precursors in Suzuki coupling.
a
Table 1. Optimization of the Nickel-Catalyzed Cross-Coupling of Diarylborinic Acid with Aryl Chloride
yield
(%)
b
entry
Ni(II) (mol %)
L (mol %)
base
solvent
20 NiCl2(dppf) (3)
21 NiCl2(PPh3)2 (3)
22 NiCl2(PPh3)2 (3)
23 NiCl2(PPh3)2 (3)
24 NiCl2(PPh3)2 (3)
25 NiCl2(PPh3)2 (3)
26 NiCl2(PPh3)2 (3)
27 NiCl2(PPh3)2 (3)
28 NiCl2(PPh3)2 (3)
29 NiCl2(PPh3)2 (3)
30 NiCl2(PPh3)2 (3)
31 NiCl2(PPh3)2 (3)
32 NiCl2(PPh3)2 (3)
33 NiCl2(PPh3)2 (3)
34 NiCl2(PPh3)2 (3)
35 NiCl2(PPh3)2 (3)
36 NiCl2(PPh3)2 (3)
37 NiCl2(PPh3)2 (3)
38 NiCl2(PPh3)2 (3)
39 NiCl2(PPh3)2 (3)
40 NiCl2(PPh3)2 (3)
41 NiCl2(PPh3)2 (3)
[Bmim]Br (3) K3PO4·3H2O toluene
[tBumim]I (3) K3PO4·3H2O toluene
[Emim]Br (3) K3PO4·3H2O toluene
[Pmim]Br (3) K3PO4·3H2O toluene
[Hmim]Br (3) K3PO4·3H2O toluene
[diBim]Br (3) K3PO4·3H2O toluene
[ditBuim]Cl (3) K3PO4·3H2O toluene
[diEim]Br (3) K3PO4·3H2O toluene
84
78
82
87
81
90
75
83
80
71
59
56
66
44
34
64
42
69
11
30
19
58
yield
(%)
b
entry
Ni(II) (mol %)
NiCl2 (3)
L (mol %)
base
solvent
c
1
[Bmim]Br (6) K3PO4·3H2O dioxane
12
35
77
10
78
64
43
93
94
56
trace
48
55
91
c
2
NiCl2 (3)/PPh3 (6) [Bmim]Br (6) K3PO4·3H2O dioxane
NiCl2 (3)/PPh3 (6) [Bmim]Br (6) K3PO4·3H2O toluene
NiCl2 (3)/PPh3 (6) [Bmim]Br (6) K3PO4·3H2O toluene
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (4)
c
3
4
5
6
7
8
9
[Bmim]Br (6) K3PO4·3H2O toluene
[Bmim]Br (9) K3PO4·3H2O toluene
[Bmim]Br (12) K3PO4·3H2O toluene
[Bmim]Br (3) K3PO4·3H2O toluene
[Bmim]Br (4) K3PO4·3H2O toluene
[Bmim]Br (2) K3PO4·3H2O toluene
[Bmim]Br (6) K3PO4·3H2O toluene
[diMim]I (3)
[Phmim]I (3) K3PO4·3H2O toluene
IPr·HCl (3) K3PO4·3H2O toluene
IMes·HCl (3) K3PO4·3H2O toluene
IPh·HCl (3) K3PO4·3H2O toluene
K3PO4·3H2O toluene
10 NiCl2(PPh3)2 (2)
11 NiCl2 (3)
[Mesmim]I (3) K3PO4·3H2O toluene
[Bmim]Br (3) K3PO4·3H2O dioxane
[Bmim]Br (3) K3PO4·3H2O THF
[Bmim]Br (3) K3PO4·3H2O CH3CN
[Bmim]Br (3) K3PO4·3H2O DMF
[Bmim]Br (3) K3PO4·3H2O EtOH
12 NiCl2(PPh3)2 (3)
13 NiCl2(PPh3)2 (3)
−
K3PO4·3H2O toluene
K3PO4·3H2O toluene
TBAB (3)
14 NiCl2[P(4-
MeOPh)3]2 (3)
[Bmim]Br (3) K3PO4·3H2O toluene
15 NiCl2(PCy3)2 (3)
16 NiCl2(dppm) (3)
17 NiCl2(dppe) (3)
18 NiCl2(dppp) (3)
19 NiCl2(dppb) (3)
[Bmim]Br (3) K3PO4·3H2O toluene
[Bmim]Br (3) K3PO4·3H2O toluene
[Bmim]Br (3) K3PO4·3H2O toluene
[Bmim]Br (3) K3PO4·3H2O toluene
[Bmim]Br (3) K3PO4·3H2O toluene
8
[Bmim]Br (3) K2CO3
[Bmim]Br (3) Na2CO3
[Bmim]Br (3) NaOH
toluene
toluene
toluene
20
24
23
69
a
b
c
Reaction conditions: 1a (1.3 mmol), 2a (2 mmol), base (5.2 mmol), solvent (5 mL), N2, 10 h, reflux. Isolated yields. Preformation of Ni/NHC/
PPh3 complex before addition of substrates.
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NiCl2(PR3)2/imidazolium catalyst system. Among the common
bidentate phosphines tested, only 1,1′-bis(diphenylphosphino)-
ferrocene (dppf) showed an acceptable performance, but still
poorer than those of PPh3 and P(4-MeOPh)3. The structure
of imidazoliums also remarkably affected the activities of
the NiCl2(PPh3)2/imidazolium catalyst system. Use of either
more or less sterically demanding dialkylimidazoliums, such as
N-tert-butyl-N′-methylimidazolium iodide ([tBumim]I) and
N,N′-di(tert-butyl)imidazolium chloride ([ditBuim]Cl), or
N-ethyl-N′-methylimidazolium bromide ([Emim]Br) and N,N′-
di(methyl)imidazolium iodide ([diMim]I) in the NiCl2-
(PPh3)2/imidazolium system led to slightly lower yields
(75−82%) for 3aa, while N,N′-di(butyl)imidazolium bromide
([diBim]Br) gave a comparable yield (90%) to that (93%) of
[Bmim]Br (Table 1, entries 21−28). N-Aryl imidazoliums, such
as N-Ph, mesityl, or 2,6-diisopropylphenyl ones, displayed
poor performances in the NiCl2(PPh3)2/imidazolium system
(Table 1, entries 29−33). The other common solvents (THF,
DMF, CH3CN, EtOH and dioxane) and bases (K2CO3,
Na2CO3 and NaOH) provided 3aa in lower yields (11−69%)
than the combination of toluene with K3PO4·3H2O for the
model reaction. Finally, an optimal catalyst system and reac-
tion conditions were set as NiCl2(PPh3)2/[Bmim]Br in toluene
using K3PO4·3H2O as base, under which scope of the
mono(NHC)bis(phosphine)nickel-catalyzed cross-coupling of
aryl chlorides with diarylborinic acids was explored (Table 2).
Similar to the model reaction, electron-neutral or -rich aryl
chlorides reacted with 1a to give products 3ab, 3ae and 3ah
in 92−98% yields with 3 mol % catalyst loading (Table 2,
entries 1, 4 and 7). Aryl chlorides activated by an electron-
withdrawing group, e.g., CHO, CN, CO2Me and COCH3,
at para- or meta-position of aromatic ring were more reactive
and excellent yields could be obtained for the corresponding
coupling products 3ak, 3al, 3ao, 3ap, and 3aq even with a
lower (1.5 mol %) catalyst loading in shorter reaction
time (Table 2, entries 10, 11 and 15−17). A small ortho-
substituent on the aromatic ring of aryl chlorides was tolerable
although a large one significantly hampered their couplings
with diarylborinic acids. For example, aryl chlorides bearing an
ortho-methyl (2c), -methoxy (2f) or -cyano (2m) substituent
could be effectively coupled to give the corresponding products
3ac (95%), 3af (93%) or 3am (97%) in high yields (Table 2,
entries 2, 5 and 12) while the ones bearing 2,6-dimethyl
groups (2d), an ortho-isopropoxy (2g) or -acetyl (2n) group
afforded the products 3ad (33%), 3ag (63%) or 3an (45%)
in significantly lower yields (Table 2, entries 3, 6 and 13). For
2-chloroacetophenone (2n), 3 mol % catalyst loading could
afford a satisfactory yield (94%) for 3an (Table 2, entries 13
and 14).21 Aryl chlorides with a free amino group appeared
to be tolerable although the yields slightly decreased for
both 4-chloroaniline (2i, 83%) and its ortho-isomer (2j, 79%)
(Table 2, entries 8 and 9). Investigation of structural effects
of diarylborinic acids on the NHC assisted, NiCl2(PPh3)2-
catalyzed cross-coupling reaction showed that influences of
both electronic and steric factors were negligible. For example,
the cross-couplings of 4-(benzyloxy)phenyl chloride (2a) with
diarylborinic acids with an electron-withdrawing (4-F, 1d) or
-donating (4-OMe, 1c; 2-Me, 1e; 2-Et, 1f; 2-OMe, 1g; and
2-OiPr, 1h) substituent at either para- or ortho-position of
aromatic rings afforded the corresponding biaryls 3ca−3ha in
good to excellent yields (Table 2, entries 19−24). However, an
accumulative effect of steric hindrance of diarylborinic
acids and aryl chlorides was observed for the reactions of
Table 2. Scope of the Cross-Coupling of Diarylborinic Acids
with Aryl Chlorides
a
b
entry
R1 (1)
R2 (2)
cat (mol %) t (h) yield (%)
1
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
H (1b)
4-Me (2b)
3
10
10
10
10
10
10
10
10
10
6
98 (3ab)
95 (3ac)
33 (3ad)
96 (3ae)
93 (3af)
63 (3ag)
92 (3ah)
83 (3ai)
79 (3aj)
95 (3ak)
93 (3al)
97 (3am)
45 (3an)
94 (3an)
98 (3ao)
96 (3ap)
95 (3aq)
94 (3ba)
90 (3ca)
88 (3da)
90 (3ea)
84 (3fa)
88 (3ga)
89 (3ha)
72 (3ef)
54 (3ff)
2
2-Me (2c)
3
3
2,6-diMe (2d)
4-OMe (2e)
2-OMe (2f)
2-OiPr (2g)
4-NMe2 (2h)
4-NH2 (2i)
2-NH2 (2j)
4-CN (2k)
3-CN (2l)
3
4
3
5
3
6
3
7
3
8
3
9
3
10
11
12
13
14
15
16
17
1.5
1.5
1.5
1.5
3
6
2-CN (2m)
2-Ac (2n)
6
10
10
6
2-Ac (2n)
4-Ac (2o)
1.5
1.5
1.5
3
4-CO2Me (2p)
4-CHO (2q)
4-OBn (2a)
4-OBn (2a)
4-OBn (2a)
4-OBn (2a)
4-OBn (2a)
4-OBn (2a)
4-OBn (2a)
2-OMe (2f)
2-OMe (2f)
2-OMe (2f)
2-OMe (2f)
7
8
c
18
10
10
10
10
10
10
10
10
10
10
10
19
20
21
22
23
24
25
26
27
28
4-OMe (1c)
4-F (1d)
3
3
2-Me (1e)
2-Et (1f)
3
3
2-OMe (1g)
2-OiPr (1h)
2-Me (1e)
2-Et (1f)
3
3
3
3
2-OMe (1g)
2-OiPr (1h)
3
71 (3gf)
65 (3hf)
3
a
Reaction conditions: 1 (1.3 mmol), 2 (2 mmol), K3PO4·3H2O (5.2
b
c
mmol), toluene (5 mL), N2, 10 h. Isolated yield. 0.65 mmol of
diphenylborinic anhydride was used.
2-methoxyphenyl chloride (2f) with ortho-substituted diary-
lborinic acids 1e−1h, affording 3ef−3hf in just modest yields
(Table 2, entries 25−28).
Cross-Couplings of Aryl Tosylates and Sulfamates.
Phenols are the most abundant naturally occurring aryl
sources.22 Therefore, it is important to take advantage of
readily available phenol derivatives, such as tosylates and
sulfamates, as the electrophile counterparts in transition metal-
catalyzed cross-couplings.2,4,23 Using the established catalyst
system, NiCl2(PPh3)2/[Bmim]Br, for cross-coupling of aryl
chlorides with diarylborinic acids, reaction of aryl tosylates was
investigated at first considering their ready availability at low
cost and easy to handle properties (Table 3). A lower reactivity
but with a larger electronic effect was observed from aryl
tosylates than that from aryl chlorides in their cross-couplings
with diarylborinic acids. For example, reaction of 4-methox-
yphenyl tosylate (4a) with bis(p-tolyl)borinic acid (1a) gave
biaryl 3ae in only 47 and 68% yields with 3 and 5 mol %
catalyst loadings, respectively, significantly lower than that
(96%) of 4-methoxyphenyl chloride (2e) with 3 mol % catalyst
loading (Table 3, entries 1 and 2 vs Table 2, entry 4). However,
electron-neutral and -deficient aryl tosylates coupled much
more effectively with diarylborinic acids. For example, electron-
neutral phenyl (4c) and p-tolyl (4d) tosylates reacted with 1a
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afforded the corresponding biaryls 6ac and 3ab in 87 and 88%
yields, respectively (Table 3, entries 4 and 5). The reaction of
4-acetylphenyl tosylate (4f) occurred to afford 3ao in 88
and 93% yields with 1.5 or 3 mol % NiCl2(PPh3)2/[Bmim]Br,
respectively, just slightly lower than that (98%) of 4-
acetylphenyl chloride (2o) (Table 3, entries 7 and 8 vs Table 2,
entry 15). The steric effects observed for both aryl tosylates
and diarylborinic acids bearing a small ortho-substituent were
negligible. For example, the reactions of bis(p-tolyl)borinic acid
(1a) with 2-methoxyphenyl tosylate (4b) and 2-methylphenyl
tosylate (4e) gave products 3af (62%) and 3ac (85%) in yields
comparable to those (68%, 4a and 88%, 4d) with a para-
substituent (Table 3, entries 2, 3, 5 and 6). Similarly, diary-
lborinic acids with an ortho-substituent at aromatic rings,
such as o-methyl (1e), o-ethyl (1f), o-methoxy (1g) or even
o-isopropoxy (1h) reacted with 4-acetylphenyl tosylate (4f) as
well as those without an ortho-substituent 1a and 1c (Table 3,
entries 8, 10 and 13−16).
Aryl dimethylsulfamates coupled with diarylborinic acids
similarly to tosylates under the above established conditions
although sulfamates are generally believed to be more stable.
Electronically deactivated aryl sulfamates reacted even more
smoothly than the corresponding tosylates. For example,
reaction of bis(p-tolyl)borinic acid (1a) with electron-rich
aryl sulfamate, 4-methoxyphenyl dimethylsulfamate (5a), could
afford 4-methoxy-4′-methyl biphenyl 3ae in 79% yield with
5 mol % catalyst loading, slightly higher than that (68%) of
aryl tosylate 4a under otherwise identical conditions (Table 3,
entries 2 and 17). The higher reactivity of sulfamates over
tosylates could be possibly attributed to an intramolecular
N−Ni coordination between the sulfamate group and the
catalyst, which should facilitate the oxidative addition of Aryl-
OSO2NMe2. For electron-deficient aryl sulfamates, such as
4-acetylphenyl dimethylsulfamate 5f, 1.5 mol % catalyst loading
proved enough for it to couple with bis(p-tolyl)borinic acid 1a,
affording the desired product 3ao in an excellent yield (91%)
(Table 3, entry 23). Similar to the reaction of aryl tosylates,
steric effects from both aryl sulfamates and diarylborinic acids
with a small ortho-substituent on the aromatic rings appeared to
be negligible since all of the investigated substrates with an
ortho-substituent, e.g., diarylborinic acids 1e (2-Me), 1f (2-Et),
1g (2-OMe), or 1h (2-OiPr), and aryl sulfamates 5b (2-OMe)
and 5e (2-Me) reacted comparably to those without an ortho-
substituent to give the desired biaryls (3af, 3ac and 6ea−6hf)
in good to excellent yields (Table 3, entries 18, 21 and 26-31).
Application Exploration. Synthesis of Adapalene, a
member of the new generation synthetic receptor-selective
retinoids,24 is taken here as an illustrative example for appli-
cation of the NiCl2(NHC)(PPh3)2-catalyzed cross-couplings of
aryl tosylates and sulfamates with diarylborinic acids in practical
synthesis of biaryl fine chemicals (Scheme 1).25 The key in
synthesis of Adapalene is the connection between 2-(1-
adamantyl)anisole and 2-naphthoic acid moieties, which has
been effected by cross-coupling of zincate (Negishi),26
Grignard reagent (Kumada),27 or boronic acid derivatives
(Suzuki)28 of 2-(1-adamantyl)-4-bromoanisole with 6-bromo-2-
naphthoate or 6-tosyloxy-2-naphthoate. Unfortunately, the
environmentally friendly Suzuki coupling processes have to
be abandoned in commercial production of Adapalene because
of the high cost of 3-(1-adamantyl)-4-methoxyphenyl boronic
acid, which has to be prepared using either cryogenic con-
ditions or expensive borylation reagents, such as catecholborane
or bis(pinacolato)diboron.
Table 3. Scope of the Couplings of Diarylborinic Acids with
Aryl Tosylates and Dimethylsulfamates
a
cat
(mol %)
yield
b
entry
R1 (1)
X
R2 (4/5)
(%)
1
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
4-OMe (4a)
4-OMe (4a)
2-OMe (4b)
H (4c)
3
47 (3ae)
68 (3ae)
62 (3af)
87 (6ac)
88 (3ab)
85 (3ac)
93 (3ao)
88 (3ao)
75 (3ao)
90 (6cf)
65 (6ea)
83 (6ec)
92 (6ef)
89 (6ff)
91 (6gf)
89 (6hf)
79 (3ae)
80 (3af)
89 (6ac)
83 (3ab)
81 (3ac)
95 (3ao)
91 (3ao)
77 (3ao)
87 (6cf)
86 (6ea)
90 (6ec)
95 (6ef)
93 (6ff)
90 (6gf)
86 (6hf)
2
5
3
5
4
5
5
4-Me (4d)
2-Me (4e)
4-Ac (4f)
4-Ac (4f)
4-Ac (4f)
4-Ac (4f)
4-OMe (4a)
H (4c)
5
6
5
7
3
8
1.5
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4-OMe (1c) OTs
1.5
5
2-Me (1e)
2-Me (1e)
2-Me (1e)
2-Et (1f)
OTs
OTs
OTs
OTs
5
4-Ac (4f)
4-Ac (4f)
4-Ac (4f)
4-Ac (4f)
1.5
1.5
1.5
1.5
5
2-OMe (1g) OTs
2-OiPr (1h)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
4-Me (1a)
OTs
OSO2NMe2 4-OMe (5a)
OSO2NMe2 2-OMe (5b)
OSO2NMe2 H (5c)
5
5
OSO2NMe2 4-Me (5d)
OSO2NMe2 2-Me (5e)
OSO2NMe2 4-Ac (5f)
OSO2NMe2 4-Ac (5f)
OSO2NMe2 4-Ac (5f)
5
5
3
1.5
1
4-OMe (1c) OSO2NMe2 4-Ac (5f)
1.5
5
2-Me (1e)
2-Me (1e)
2-Me (1e)
2-Et (1f)
OSO2NMe2 4-OMe (5a)
OSO2NMe2 H (5c)
5
OSO2NMe2 4-Ac (5f)
OSO2NMe2 4-Ac (5f)
1.5
1.5
1.5
1.5
2-OMe (1g) OSO2NMe2 4-Ac (5f)
2-OiPr (1h)
OSO2NMe2 4-Ac (5f)
a
Reaction conditions: 1 (1.3 mmol), 4/5 (2 mmol), K3PO4·3H2O (5.2
b
mmol), toluene (5 mL), N2, 10 h. Isolated yield.
In contrast, di(3-(1-adamantyl)-4-methoxyphenyl)borinic
acid (10) could be readily prepared in 80% yield via one-pot
reaction from 2-(1-adamantyl)-4-bromoanisole, 1.1 equiv of
magnesium and 0.5 equiv of tributylborate in THF at 40−
60 °C. The advantages of using β-naphthalenyl tosylates and
sulfamates over halides in transition metal-catalyzed cross-
coupling are obvious because β-naphthalenylols are readily avail-
able while tedious procedures are often necessary for synthesis of
β-halonaphthalene derivatives. For example, because of the
overwhelming α-selectivity in direct halogenation of naphtha-
lenes, β-naphthalenyl bromides had to be prepared from
β-naphthalenylols via bromination using P(Br2)Ph3 at >250 °C29
or Na2S2O5-mediated OH-NH2 exchange with NH4OH (aq.)
in autoclave followed by diazotization-bromination with CuBr
(Sandmeyer reaction).30 Methyl 6-tosyloxy-2-naphthoate (8)
and methyl 6-(dimethylsulfamayl)oxy-2-naphthoate (9) were
prepared in 82 and 81% yields, respectively, from commercially
available 1-(6-methoxynaphthalen-2-yl)ethanone31 via a 4-step,
chromatography-free process consisting of chloroform reaction,
demethylation in HBr/AcOH, esterization and tosylation or
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Scheme 1. Scalable and Cost-Effective Process for Synthesis of Adapalene
sulfamation. The cross-coupling of di(3-(1-adamantyl)-4-
methoxyphenyl)borinic acid (10) with methyl 6-tosyloxy-2-
naphthoate (8) or methyl 6-(dimethylsulfamayl)oxy-2-naph-
thoate (9) proceeded smoothly to provide methyl ester of
Adapalene (11) in 95 and 93% yields, respectively, with 1 mol
% NiCl2(PPh3)2/[Bmim]Br as catalyst precursor in 0.1 mol
scale, from which Adapalene (12) could be readily obtained
after hydrolysis.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a N2
atmosphere unless otherwise stated. Commercially available chemicals
were used as received. Nickel complexes of NiCl2(PPh3)2,32 NiCl2[(4-
MeOPh)3P]2,32 NiCl2(PCy3)2,23a NiCl2(dppm),33 NiCl2(dppe),33
NiCl2(dppp),33 NiCl2(dppb),33 and NiCl2(dppf);34 N-heterocyclic
carbene precursors of [Bmim]Br,35 [Emim]Br,35 [Pmim]Br,35
[Hmim]Br,35 [diMim]I,35 [diBim]Br,35 [ditBuim]Cl,35 [tBumim]I,35
IPr·HCl,8a IMes·HCl,8a IPh·HCl,36 [Phmim]I,37 and [Mesmim]I,37
diarylborinic acids,6a aryl tosylates,23b aryl sulfamates2e and 2-(1-
adamantyl)-4-bromoanisole38 were prepared according to previously
reported procedures. 1H and 13C NMR spectra were recorded in
CDCl3 or DMSO-d6 at ambient temperature. Chemical shifts in NMR
are reported in ppm (δ), relative to the internal standard of tetra-
methylsilane (TMS). The signals observed are described as s (singlet),
d (doublet), t (triplet), dd (double doublet), m (multiplets). The
number of protons (n) for a given resonance is indicated as nH.
Coupling constants are reported as J in Hz.
General Procedure for Cross-Couplings of Aryl Chlorides,
Tosylates, and Sulfamates. For Aryl Chlorides. To a 10 mL flask
were added aryl chloride (2.0 mmol), diarylborinic acid (1.3 mmol),
1.5−3 mol % NiCl2(PPh3)2 (0.03−0.06 mmol), 1.5−3 mol % [Bmim]
Br (0.03−0.06 mmol), K3PO4·3H2O (5.2 mmol), and toluene (5 mL).
The mixture was stirred at 110 °C for a given time or monitored by
TLC until the starting material was completely consumed. The
reaction mixture was diluted with CH2Cl2 (15 mL). The organic layer
was separated and washed with H2O (10 mL × 2), followed by drying
over Na2SO4, filtering and removal of solvents under reduced pressure
to give the crude product, which was purified by column chro-
matography on silica gel with EtOAc/petroleum ether.
CONCLUSION
■
In summary, cross-couplings of diarylborinic acids with aryl
chlorides, tosylates, and sulfamates have been efficiently ef-
fected by using a simple mono(NHC)bis(phosphine)nickel
catalyst system generated in situ from NiCl2(PPh3)2 and dia-
lkylimidazoliums in the presence of K3PO4·3H2O as base in
toluene. In contrast to bis(NHC)nickel-catalyzed conventi-
onal Suzuki coupling of arylboronic acids, mono(NHC)bis-
(phosphine)nickel species of sterically undemanding N,
N′-dialkylimidazolylidene displayed high catalytic activities in
the cross-couplings of diarylborinic acids. Scope and limitation
of the mono(NHC)bis(phosphine)nickel-catalyzed couplings
have been briefly explored. Structural influences from diary-
lborinic acids appeared to be negligible in the cross-couplings
while remarkable electronic effects have been observed from
aryl chlorides, tosylates, and sulfamates. For electronically acti-
vated aryl chlorides, 1.5 mol % catalyst loading proved enough
in their couplings with diarylborinic acids to give the biaryl
products in excellent yields while 3 mol % NiCl2(PPh3)2/
[Bmim]Br had to be used for the coupling of deactivated ones.
For aryl tosylates and sulfamates, a larger electronic influence
than that from aryl chlorides was observed in their couplings. A
higher catalyst loading (5 mol %) had to be used to obtain the
biaryl products in modest to good yields for non- or deactivated
tosylates and sulfamates while 1.5 mol % loading worked well in
the couplings of those bearing an electron-withdrawing group.
A small ortho-substitutent on the aromatic ring of aryl chlorides,
tosylates, and sulfamates showed negligible influences on their
cross-coupling reactions. Features of the mono(NHC)bis-
(phosphine)nickel-catalyzed cross-couplings include high
atom and process economies of diarylborinic acids, readily
available aryl (pseudo)halides and cost-effectiveness of nickel
catalyst system, which have been demonstrated in development
of practical processes for synthesis of a third-generation topical
retinoid, Adapalene.
For aryl Tosylates and Sulfamates. A procedure similar to that for
the cross-coupling of aryl chlorides was adopted with aryl tosylates and
dimethylsulfamates using 1−5 mol % catalyst loadings.
4-Benzyloxy-4′-methylbipheny (3aa).6a White solid (0.510 g,
1
93%): mp 140−142 °C; H NMR (400 MHz, CDCl3) δ 7.44−7.36
(m, 6H), 7.32 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.0 Hz, 1H), 7.14 (d, J =
8.0 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 5.01 (s, 2H), 2.30 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.2, 138.0, 137.1, 136.4, 134.0, 129.5,
128.7, 128.0, 127.6, 126.7, 115.2, 70.1, 21.2.
4,4′-Dimethylbiphenyl (3ab).6a White solid (0.357 g, 98% from
aryl chloride 2b, 0.320 g, 88% from aryl tosylate 4d, 0.302 g, 83% from
1
aryl sulfamate 5d): mp 122−123 °C; H NMR (400 MHz, CDCl3) δ
7.47 (d, J = 8.0 Hz, 4H), 7.22 (d, J = 8.0 Hz, 4H), 2.37 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 138.4, 136.8, 129.5, 126.9, 21.2.
2,4′-Dimethylbiphenyl (3ac).6a Colorless oil (0.346 g, 95% from
aryl chloride 2c, 0.309 g, 85% from aryl tosylate 4e, 0.295 g, 81% from
aryl sulfamate 5e): 1H NMR (400 MHz, CDCl3) δ 7.26−7.22
(m, 8H), 2.40 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
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1
141.9, 139.0, 136.4, 135.4, 130.3, 129.9, 129.1, 128.8, 127.1, 125.8,
21.2, 20.5.
4f, 0.399 g, 95% from aryl sulfamate 5f): mp 118−119 °C; H NMR
(400 MHz, CDCl3) δ 8.02 (dd, J = 2.0, 8.4 Hz, 2H), 7.66 (dd, J = 2.0,
8.4 Hz, 2H), 7.53 (dd, J = 2.0, 8.0 Hz, 2H), 7.28 (d, J = 6.4 Hz, 2H),
2.63 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.8,
145.7, 138.3, 136.9, 135.6, 129.7, 129.0, 127.1, 126.9, 26.7, 21.2.
Methyl 4-methylbiphenyl-4′-carboxylate (3ap).6a White solid
(0.434 g, 96%): mp 115−116 °C; 1H NMR (400 MHz, CDCl3) δ 8.08
(d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H),
7.26 (d, J = 7.6 Hz, 2H), 3.92 (s, 3H), 2.40 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 167.1, 145.6, 138.1, 137.1, 130.1, 129.7, 128.6, 127.1,
126.8, 52.1, 21.2.
2,6,4′-Trimethylbiphenyl (3ad).39 Colorless oil (0.129 g, 33%):
1H NMR (400 MHz, CDCl3) δ 7.29−7.25 (m, 3H), 7.21−7.13 (m,
3H), 7.07 (d, J = 8.0 Hz, 1H), 2.44 (s, 3H), 2.07 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 141.9, 138.0, 136.3, 136.1, 129.1, 128.9, 127.2,
126.9, 21.3, 20.9.
4-Methoxy-4′-methylbiphenyl (3ae).6a White solid (0.380 g,
96% from aryl chloride 2e, 0.269 g, 68% from aryl tosylate 4a, 0.313 g,
1
79% from aryl sulfamate 5a): mp 111−112 °C; H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.21 (d,
J = 8.0 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.37 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.0, 138.0, 136.4, 133.8, 129.5,
128.0, 126.6, 114.2, 55.4, 21.1.
4-Methylbiphenyl-4′-carboxaldehyde (3aq).6a White solid
1
(0.372 g, 95%): mp 105−107 °C; H NMR (400 MHz, CDCl3) δ
10.03 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53
(d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 192.0, 147.2, 138.6, 136.8, 135.0, 130.3, 129.8,
127.4, 127.2, 21.2.
2-Methoxy-4′-methylbiphenyl (3af).6a White solid (0.368 g,
93% from aryl chloride 2f, 0.246 g, 62% from aryl tosylate 4b, 0.317 g,
1
80% from aryl sulfamate 5b): mp 79−80 °C; H NMR (400 MHz,
4-Benzyloxybiphenyl (3ba).6a White solid (0.489 g, 94%): mp
CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.21 (d,
J = 8.0 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 3.79
(s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.5, 136.6,
135.6, 130.8, 130.7, 129.5, 128.8, 128.4, 120.8, 111.2, 55.6, 21.3.
2-Isopropoxy-4′-methylbiphenyl (3ag). Colorless oil (0.284 g,
1
131−133 °C; H NMR (400 MHz, CDCl3) δ 7.55−7.51 (m, 4H),
7.45−7.37 (m, 6H), 7.34−7.27 (m, 2H), 7.04 (d, J = 8.4 Hz, 2H), 5.09
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 157.3, 139.7, 135.9, 133.0,
127.7, 127.6, 127.1, 126.9, 126.4, 125.7, 125.6, 114.1, 69.0.
4-Benzyloxy-4′-methoxybiphenyl (3ca).6a White solid (0.522 g,
1
63%): H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.38
1
90%): mp 172−174 °C; H NMR (400 MHz, CDCl3) δ 7.41−7.37
(dd, J = 1.6, 7.6 Hz, 1H), 7.33−7.29 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H),
7.08−7.02 (m, 2H), 4.52−4.46 (m, 1H), 2.45 (s, 3H), 1.31 (d, J =
6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 154.9, 136.3, 136.0,
132.0, 131.1, 129.5, 128.6, 128.2, 121.0, 115.2, 70.9, 22.1, 21.3; HRMS
(ESI-TOF) m/z [M+1]+ calcd for C16H19O 227.1436, found
227.1436.
(m, 6H), 7.32 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 6.95 (d, J =
8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.02 (s, 2H), 3.76 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 157.7, 156.9, 136.0, 132.7, 132.4, 128.3,
127.6, 126.9, 126.7, 126.5, 114.1, 113.1, 69.1, 54.3.
4-Benzyloxy-4′-fluorobiphenyl (3da).6a White solid (0.489 g,
1
88%): mp 139−140 °C; H NMR (400 MHz, CDCl3) δ 7.41−7.36
N,N,4′-Trimethylbiphenyl-4-amine (3ah).6a Yellow solid
(m, 6H), 7.31 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.00 (t, J =
8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.02 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 161.1 (d, J = 250 Hz), 157.3, 135.9, 132.0, 127.6,
127.2, 127.1, 127.0, 126.4, 114.5 (d, J = 21 Hz), 114.1, 69.0.
1
(0.388 g, 92%): mp 149−152 °C; H NMR (400 MHz, CDCl3) δ
7.49−7.44 (m, 4H), 7.20 (d, J = 7.6 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H),
2.97 (s, 6H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.8,
138.4, 135.7, 129.4, 127.6, 126.2, 113.0, 40.7, 21.1.
4-Benzyloxy-2′-methylbiphenyl (3ea).6a White solid (0.493 g,
4-Methyl-4′-aminobiphenyl (3ai).6a Yellow solid (0.304 g,
1
90%): mp 62−63 °C; H NMR (400 MHz, CDCl3) δ 7.46 (d, J =
1
83%): mp 92−94 °C; H NMR (400 MHz, CDCl3) δ 7.42 (d, J =
7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.35−7.31 (m, 1H), 7.26−7.21
(m, 6H), 7.02 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 2.28 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 156.6, 140.4, 135.9, 134.3, 133.5, 129.2,
129.1, 128.8, 127.5, 126.8, 126.4, 125.9, 124.7, 113.3, 68.8, 19.5.
4-Benzyloxy-2′-ethylbiphenyl (3fa).6a Colorless oil (0.484 g,
84%): 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 2H), 7.42−
7.38 (m, 2H), 7.35−7.33 (m, 1H), 7.29−7.28 (m, 2H), 7.24−7.17 (m,
4H), 7.01 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H),
1.10 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.8, 141.8,
141.3, 137.1, 134.7, 130.3, 130.2, 128.7, 128.6, 128.1, 127.6, 127.3,
125.6, 114.4, 70.1, 26.2, 15.7.
8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.69
(d, J = 8.4 Hz, 2H), 3.63 (br, 2H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 145.7, 138.4, 136.0, 131.6, 129.5, 127.9, 126.4, 115.5, 21.1.
4-Methyl-2′-aminobiphenyl (3aj).6a Colorless oil (0.289 g,
1
79%): H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 2H),
7.24 (d, J = 8.0 Hz, 2H), 7.14−7.10 (m, 2H), 6.80 (t, J = 7.2 Hz, 1H),
6.74 (d, J = 7.6 Hz, 1H), 3.51 (br, 2H), 2.39 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.6, 136.9, 136.6, 130.5, 129.6, 129.0, 128.4,
127.7, 118.7, 115.6, 21.2.
4-Cyano-4′-methylbiphenyl (3ak).6a White solid (0.367 g,
1
4-Benzyloxy-2′-methoxybiphenyl (3ga).6a Colorless oil (0.510 g,
95%): mp 110−111 °C; H NMR (400 MHz, CDCl3) δ 7.70−7.64
(m, 4H), 7.48 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 2.41
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.6, 138.8, 136.3, 132.6,
129.9, 127.5, 127.1, 119.1, 110.5, 21.2.
1
88%): H NMR (400 MHz, CDCl3) δ 7.45 (t, J = 8.2 Hz, 4H), 7.38
(t, J = 7.4 Hz, 2H), 7.33−7.26 (m, 3H), 7.02−6.94 (m, 4H), 5.08
(s, 2H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.0, 156.5,
137.2, 131.2, 130.8, 130.7, 130.3, 128.7, 128.3, 128.0, 127.6, 120.9,
114.5, 111.2, 70.1, 55.6.
3-Cyano-4′-methylbiphenyl (3al).6a Yellow solid (0.359 g,
1
93%): mp 73−74 °C; H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H),
4-Benzyloxy-2′-isopropoxybiphenyl (3ha).6a Colorless oil
(0.566 g, 89%): 1H NMR (400 MHz, CDCl3) δ 7.51−7.45 (m,
4H), 7.39 (t, J = 7.4 Hz, 2H), 7.34−7.29 (m, 2H), 7.25−7.21 (m, 1H),
7.02−6.95 (m, 4H), 5.09 (s, 2H), 4.47−4.37 (m, 1H), 1.24 (d, J =
6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.8, 154.9, 137.2,
131.7, 131.6, 130.9, 130.7, 128.6, 128.0, 127.6, 121.1, 115.4, 114.2,
70.9, 70.0, 22.1.
7.79 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz,
1H), 7.45 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 142.4, 138.4, 136.0, 131.3, 130.5,
130.4, 129.9, 129.6, 126.9, 119.0, 112.9, 21.2.
2-Cyano-4′-methylbiphenyl (3am).6a White solid (0.374 g,
1
97%): mp 49−50 °C; H NMR (400 MHz, CDCl3) δ 7.74 (d, J =
7.6 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.51−7.39 (m, 4H), 7.30 (d, J =
8.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.5,
138.7, 135.3, 133.8, 132.9, 130.1, 129.5, 128.7, 127.4, 119.0, 111.1,
21.3.
2-Methoxy-2′-methylbiphenyl (3ef).6a Colorless oil (0.285 g,
72%): 1H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 8.4 Hz, 1H), 7.24−
7.13 (m, 5H), 6.99 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 3.73
(s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 138.7,
136.9, 131.1, 130.9, 130.1, 129.6, 128.6, 127.4, 125.5, 120.5, 110.7,
55.4, 20.0.
1-(4′-Methylbiphenyl-2-yl)ethanone (3an).6a Colorless oil
(0.395 g, 94%): 1H NMR (400 MHz, CDCl3) δ 7.54−7.48 (m,
2H), 7.39 (t, J = 7.6 Hz, 2H), 7.23 (s, 4H), 2.41 (s, 3H), 2.01 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 205.2, 140.9, 140.5, 137.8, 130.7,
130.2, 129.4, 128.8, 127.8, 127.2, 30.5, 21.2.
2-Methoxy-2′-ethylbiphenyl (3ff).6a Colorless oil (0.229 g,
54%): 1H NMR (400 MHz, CDCl3) δ 7.34−7.29 (m, 3H), 7.24−7.19
(m, 1H), 7.15−7.13 (m, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.93 (d, J =
8.0 Hz, 1H), 3.71 (s, 3H), 2.50−2.41 (m, 2H), 1.06 (t, J = 7.4 Hz,
1-(4′-Methylbiphenyl-4-yl)ethanone (3ao).6a White solid
(0.412 g, 98% from aryl chloride 2o, 0.391 g, 93% from aryl tosylate
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3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 142.8, 138.1, 131.3,
130.8, 130.2, 128.6, 127.9, 127.6, 125.5, 120.4, 110.7, 55.4, 26.2, 15.1.
2,2′-Dimethoxybiphenyl (3gf).40 White solid (0.304 g, 71%):
mp 153−155 °C; 1H NMR (400 MHz, CDCl3) δ 7.42−7.38 (m, 2H),
7.34−7.31 (m, 2H), 7.10−7.04 (m, 4H), 3.84 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 157.1, 131.5, 128.7, 127.8, 120.4, 111.1, 55.7.
2-Methoxy-2′-isopropoxybiphenyl (3hf).6a Colorless oil (0.315 g,
65%): 1H NMR (400 MHz, CDCl3) δ 7.38−7.28 (m, 4H), 7.06−6.98
(m, 4H), 4.47−4.38 (m, 1H), 3.81 (s, 3H), 1.22 (d, J = 6.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 157.0, 155.5, 131.7, 131.6, 129.4,
128.4, 128.3, 128.2, 120.5, 120.1, 114.9, 110.7, 70.8, 55.5, 22.1.
4-Methylbiphenyl (6ac).5d White solid (0.292 g, 87% from aryl
Methyl 6-tosyloxy-2-naphthoate (8).45 White solid (58.7 g,
98%): mp 102−104 °C; H NMR (400 MHz, CDCl3) δ 8.57(s, 1H),
1
8.07 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz,
1H), 7.74 (d, J = 8.4 Hz, 2H), 7.53 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H),
7.16 (dd, J = 2.0, 8.8 Hz, 1H), 3.98 (s, 3H), 2.45 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.8, 148.9, 145.7, 135.7, 132.3, 131.3, 130.9,
130.7, 129.9, 128.5, 128.1, 128.0, 126.3, 122.1, 119.9, 52.4, 21.7.
Methyl 6-(dimethylsulfamayl)oxy-2-naphthoate (9).23g
1
White solid (49.9 g, 96%): mp 115−117 °C; H NMR (400 MHz,
DMSO-d6) δ 8.71(s, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 8.8 Hz,
1H), 8.05 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.59 (dd, J =
2.0, 8.8 Hz, 1H), 3.94 (s, 3H), 2.98 (s, 6H); 13C NMR (100 MHz,
DMSO-d6) δ 166.1, 149.2, 135.5, 131.8, 130.5, 130.4, 128.4, 127.3,
125.8, 122.0, 118.9, 52.3, 38.3.
1
tosylate 4c, 0.299 g, 89% from aryl sulfamate 5c): mp 45−48 °C; H
NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6
Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.24 (d, J =
7.6 Hz, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.3,
138.5, 137.1, 129.6, 128.8, 127.1, 21.2.
Synthesis of Di(3-(1-adamantyl)-4-methoxyphenyl)borinic
acid (10). Under a N2 atmosphere, a mixture of B(OBu)3 (23.02 g,
100 mmol) and 2-(1-adamantyl)-4-bromoanisole (64.25 g, 200 mmol)
in 100 mL of THF was added dropwise to a stirred mixture of
magnesium turnings (5.28 g, 220 mmol) and a small crystal of I2 in
THF (50 mL) at 40 °C over a period of 30 min. The reaction was
maintained at 40−60 °C for an additional 2 h and then hydrolyzed by
the addition of 200 mL of 5% HCl (aq.) after being cooled to room
temperature. The mixture was extracted with EtOAc and then
concentrated to 40 mL before 2-ethanolamine (9.16 g, 150 mmol)
was added. The resulting solution was stirred at room temperature for
2 h and then washed with water. The organic layer was concentrated
under a vacuum to obtain the crude product of 2-aminoethoxydi(3-(1-
adamantyl)-4-methoxyphenyl)borate, which was recrystallized in
ethanol and then acidified with 100 mL of 10% HCl (aq). The
mixture was extracted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under a vacuum to afford di(3-(1-
adamantyl)-4-methoxyphenyl)borinic acid 39.2 g (80%) as a white
1-(4′-Methoxybiphenyl-4-yl)ethanone (6cf).5d White solid
(0.407 g, 90% from aryl tosylate 4f, 0.394 g, 87% from aryl sulfamate
1
5f): mp 156−158 °C; H NMR (400 MHz, CDCl3) δ 8.00 (d, J =
8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 6.99
(d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.62 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.8, 159.9, 145.3, 135.2, 132.2, 129.0, 128.4, 126.6, 114.4,
55.4, 26.7.
4-Methoxy-2′-methylbiphenyl (6ea).41 White solid (0.257 g,
65% from aryl tosylate 4a, 0.341 g, 86% from aryl sulfamate 5a): mp
1
51−52 °C; H NMR (400 MHz, CDCl3) δ 7.27−7.21 (m, 6H), 6.95
(d, J = 8.4 Hz, 2H), 3.85 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.5, 141.6, 135.5, 134.4, 130.31, 130.27, 129.9, 127.0,
125.8, 113.5, 55.3, 20.6.
2-Methylbiphenyl (6ec).41 Colorless oil (0.279 g, 83% from
aryl tosylate 4c, 0.302 g, 90% from aryl sulfamate 5c): 1H NMR
(400 MHz, CDCl3) δ 7.40 (t, J = 7.2 Hz, 2H), 7.34−7.31 (m, 3H),
7.26−7.23 (m, 4H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
142.0, 135.4, 130.4, 129.9, 129.3, 128.2, 127.3, 126.8, 125.9, 20.6.
1-(2′-Methylbiphenyl-4-yl)ethanone (6ef).5d Colorless oil
(0.386 g, 92% from aryl tosylate 4f, 0.399 g, 95% from aryl sulfamate
5f): 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.43 (d,
J = 8.4 Hz, 2H), 7.31−7.21 (m, 4H), 2.65 (s, 3H), 2.27 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 197.9, 147.0, 140.8, 135.6, 135.2, 130.6,
129.6, 129.5, 128.3, 128.0, 126.0, 26.7, 20.5.
1
crystalline solid: mp 166−168 °C; H NMR (400 MHz, CDCl3) δ
7.74 (s, 2H), 7.69 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.54
(s, 1H), 3.89 (s, 6H), 2.13 (s, 12H), 2.06 (s, 6H), 1.77 (s, 12H); 13C
NMR (100 MHz, CDCl3) δ 161.2, 137.5, 134.1, 133.8, 111.1, 54.9,
40.7, 37.2, 37.1, 29.1; HRMS (ESI-TOF) m/z [M]+ calcd for
C34H43BO3 510.3305, found 510.3336.
Methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoate
(11).27b White solid (40.5 g, 95% from aryl tosylate 8, 39.7 g, 93%
from aryl sulfamate 9): mp 226−229 °C; 1H NMR (400 MHz,
CDCl3) δ 8.61 (s, 1H), 8.07 (dd, J = 1.2, 8.4 Hz, 1H), 8.01−7.98 (m,
2H), 7.92 (d, J = 8.8 Hz, 1H), 7.79 (dd, J = 1.6, 8.8 Hz, 1H), 7.60 (d,
J = 2.0 Hz, 1H), 7.54 (dd, J = 2.4, 8.4 Hz, 1H), 7.00 (s, 1H), 3.99 (s,
3H), 3.90 (s, 3H), 2.18 (s, 6H), 2.10 (s, 3H), 1.80 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 167.4, 158.9, 141.4, 139.0, 136.0, 132.6, 131.3,
130.9, 129.7, 128.2, 126.9, 126.5, 126.0, 125.8, 125.6, 124.8, 112.1,
55.2, 52.2, 40.6, 37.23, 37.16, 29.1.
1-(2′-Ethylbiphenyl-4-yl)ethanone (6ff).42 Colorless oil (0.399 g,
1
89% from aryl tosylate 4f, 0.417 g, 93% from aryl sulfamate 5f): H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.42 (d, J =
8.4 Hz, 2H), 7.34−7.33 (m, 2H), 7.27−7.23 (m, 1H), 7.18 (d, J =
7.6 Hz, 1H), 2.65 (s, 3H), 2.59 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 197.9, 147.1, 141.4, 140.5,
135.6, 129.6, 129.5, 128.8, 128.2, 128.1, 125.8, 26.7, 26.1, 15.7.
4-Acetyl-2′-methoxybiphenyl (6gf).43 White solid (0.411 g,
91% from aryl tosylate 4f, 0.407 g, 90% from aryl sulfamate 5f): mp
105−106 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H),
7.63 (d, J = 8.4 Hz, 2H), 7.38−7.32 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H),
7.00 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 2.63 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 198.0, 156.5, 143.6, 135.5, 130.7, 129.8, 129.5,
129.4, 128.1, 121.0, 111.3, 55.6, 26.7.
0.1 Mole Scale Synthesis of Adapalene (12).27b Under a N2
atmosphere, to a 500 mL flask were added methyl 6-tosyloxy-2-
naphthoate (35.6 g, 0.1 mol), di(3-(1-adamantyl)-4-methoxyphenyl)-
borinic acid (33.2 g, 0.065 mol), NiCl2(PPh3)2 (0.65 g, 0.001 mol),
[Bmim]Br (0.22 g, 0.001 mol), K3PO4·3H2O (53.3 g, 0.2 mol), and
toluene (250 mL). The mixture was stirred at 110 °C for 10 h. The
solid materials were filtrated off while keeping hot and washed with
100 mL of toluene. The filtrate was cooled to give methyl ester of
Adapalene as a white solid (40.5 g, 95%), which was hydrolyzed with
NaOH (10% aq.) and acidified with dilute HCl (5% aq.) to afford the
desired product Adapalene as a white crystalline solid (37.6 g, 96%):
4-Acetyl-2′-isopropoxybiphenyl (6hf). White solid (0.452 g,
89% from aryl tosylate 4f, 0.437 g, 86% from aryl sulfamate 5f): mp
1
75−77 °C; H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H),
7.66 (d, J = 8.4 Hz, 2H), 7.35−7.29 (m, 2H), 7.04−6.99 (m, 2H),
4.54−4.44 (m, 1H), 2.63 (s, 3H), 1.26 (d, J = 6.0 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 198.0, 154.9, 144.0, 135.3, 131.0, 130.6, 129.8,
129.3, 128.0, 121.0, 114.8, 70.9, 26.7, 22.0; HRMS (EI-TOF) m/z
[M]+ calcd for C17H18O2 254.1307, found 254.1306.
1
mp 320−321 °C; H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H),
Methyl 6-hydroxy-2-naphthoate (7).44 White solid (34.0 g,
84% from 1-(6-methoxynaphthalen-2-yl)ethanone (0.2 mol scale)):
8.22 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.00
(d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H),
7.58 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 2.14 (s, 6H), 2.07
(s, 3H), 1.76 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 167.6, 158.5,
140.1, 138.0, 135.4, 131.5, 130.9, 130.1, 129.7, 128.2, 128.1, 125.8,
125.7, 125.6, 125.0, 124.0, 112.6, 55.3, 40.0, 36.5, 28.4.
1
mp 168−170 °C; H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H),
8.52 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 1.2, 8.8 Hz, 1H),
7.79 (d, J = 8.8 Hz, 1H), 7.23−7.19 (m, 2H), 3.90 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 166.5, 157.7, 137.1, 131.2, 130.5, 126.6,
126.4, 125.0, 123.6, 119.6, 108.7, 51.9.
7138
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Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem., Int. Ed. 2009, 48,
2383−2387. (c) Nasielski, J.; Hadei, N.; Achonduh, G.; Kantchev, E.
A. B.; O’Brien, C. J.; Lough, A.; Organ, M. G. Chem.Eur. J. 2010, 16,
10844−10853. (d) Farmer, J. L.; Hunter, H. N.; Organ, M. G. J. Am.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds reported. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Chem. Soc. 2012, 134, 17470−17473. (e) Valente, C.; Çalimsiz, S.;
Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem., Int. Ed.
2012, 51, 3314−3332.
(10) (a) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F.
Angew. Chem., Int. Ed. 2003, 42, 3690−3693. (b) Altenhoff, G.;
Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126,
AUTHOR INFORMATION
Corresponding Author
*E-mail: zougang@ecust.edu.cn.
Notes
■
15195−15201. (c) Wurtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41,
̈
1523−1533.
The authors declare no competing financial interest.
(11) McGuinness, D. S.; Cavell, K. J.; Skelton, B. W.; White, A. H.
Organometallics 1999, 18, 1596−1605.
ACKNOWLEDGMENTS
We are grateful for financial support provided by the National
Science Foundation of China (No. 20972049).
■
(12) Zhong, C.; Sasaki, T.; Tada, M.; Iwasawa, Y. J. Catal. 2006, 242,
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