Methylation of arenes via Ni-catalyzed aryl C-O/F activation

Article abstract of DOI:10.1039/b718998b

Aryl C-O and C-F can be transformed into C-Me via Ni-catalyzed coupling with MeMgBr under mild conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718998b

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Methylation of arenes via Ni-catalyzed aryl C–O/F activationw
Bing-Tao Guan,a Shi-Kai Xiang,ab Tao Wu,c Zuo-Peng Sun,ab Bi-Qin Wang,ab
Ke-Qing Zhaob and Zhang-Jie Shi*a
Received (in Cambridge, UK) 10th December 2007, Accepted 4th January 2008
First published as an Advance Article on the web 25th January 2008
DOI: 10.1039/b718998b
Aryl C–O and C–F can be transformed into C–Me via
reflux (entry 18). However, relatively polar solvents, such as
Ni-catalyzed coupling with MeMgBr under mild conditions.
dioxane and THF, dramatically diminished the efficiency.
Different substrates were further investigated (Table 2).
With different alkoxy groups, the methylation took place
smoothly (entries 1–5, Table 2). However, steric hindrance
slightly decreased the efficiency of the reaction. MOM and
TMS protected 2-naphthol could also be transformed into the
methylated products in good yields (entries 6 and 7, Table 2).
Interestingly, when phenyl 2-naphthyl ether was applied as the
substrate, the methylation only occurred on the naphthyl
scaffold, with phenol as a by-product. It indicated that differ-
ent sp2 C–O bonds of hetero diaryl ethers could be differen-
tiated in the reaction, which offered the chance to control the
chemo- and regioselectivity of the methylation. However, only
2-naphthol was isolated as the main product from 2-naphthyl
acetate, arising from the high reactivity of Grignard reagents
toward the addition to esters. In addition, free naphthol is not
a suitable substrate for this transformation.
An alkoxy arene is a common structural unit in various
natural products, biologically active compounds and organic
functional materials.1 Direct functionalization of alkoxy are-
nes offers a new pathway to readily broaden the diversity of
functional molecules, and could thus be utilized to construct
libraries for the discovery of new features. However, the
activation of aryl C–OR (R = alkyl) bonds is a challenging
task for organic chemists due to their relatively high bond
energy and the selectivity issues arising from the two different
types of C–O bonds (aromatic C–O and alkyl C–O). Com-
pared with the wide utilization of aryl halides in coupling
chemistry,2 studies on alkoxy arenes are rare. Kakiuchi and
co-workers reported the functionalization of methoxy arenes
catalyzed by Ru(0) species, assisted by a carbonyl group as a
directing group.3 Direct arylation of C–OMe has recently been
reported with a large excess of aryl Grignard reagents.4
However, no efficient method to methylate anisole and its
derivatives was reported.5 Herein, we report a practical methy-
lation of aryl C–O/F via Ni(0)-catalysis.
Furthermore, the coupling of 2-naphthol derivatives was
performed very well to afford the desired products in excellent
Table 1 Methylation of 1a under different conditionsa
Traditionally, formation of aryl–Me took place by transi-
tion metal catalyzed coupling reactions from aryl halides.6
Starting from aryl C–OMe, methylation could perform
through the sequential reactions of deprotection, triflation
and coupling.7 We initiated this project by studying the direct
transformation of the methoxy group to the methyl group,
starting from 2-methoxynaphthalene and methyl Grignard
reagent. Various conditions were screened (Table 1). NiCl2
and NiCl2(PPh3)2 gave very low yields for this reaction in
toluene (entries 1 and 5). Gratifyingly, the efficiency can be
improved by varying ligands, solvent, and reaction tempera-
ture. PCy3 was the best ligand to support different Ni(II)
catalysts. Catalyst loading could be decreased to 2.0 mol%
(entry 4). Diethyl ether also served as a good solvent under
Entry
Cat.
L (mol%)
Solvent
Yield (%)
1
2
NiCl2
NiCl2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PPh3)2
NiCl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
THF
Trace
22
96 (92)
93
PCy3 (10.0)
3b
4c
5
4
0
6
7
8
9
PPh3 (10.0)
PCy3 (10.0)
PCy3 (10.0)
NiBr2
NiBr2
Trace
60
10
Ni(acac)2
Ni(acac)2
NiCl2(dppe)
NiCl2(dppf)
PdCl2
CoCl2
FeCl2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
10
11
12
13
14
15
16
17d
18d
a
90
4
7
PCy3 (20.0)
PCy3 (20.0)
PCy3 (20.0)
Trace
Trace
Trace
49
a Beijing National Laboratory of Molecular Sciences (BNLMS),
PKU Green Chemistry Centre and Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China.
E-mail: zshi@pku.edu.cn; Fax: +86 10 62760890; Tel: +86 10
62760890
62
90
Et2O
b College of Chemistry and Material Sciences, Sichuan Normal
University, Chengdu, Sichuan 610066, China
1.2 Equiv. of Grignard reagent were used and GC yields were
determined with the use of n-dodecane as an internal standard if
b
without further note. Isolated yield reported in the parentheses.
c Department of Chemistry, Beijing Normal University, Beijing
100875, China
c
d
2.0 mol% of NiCl2(PCy3)2 was used as the catalyst. The reaction
was carried out under reflux for 1 h.
w Electronic supplementary information (ESI) available: Experimental
and spectral data. See DOI: 10.1039/b718998b
ꢀc
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Table 2 Methylation of different alkoxy naphthalenes 1a
Table 4 Methylation of different dialkoxy naphthalenes 1
Entry
1
R
3a (%)b
Entry
1
2
3
4
5
6
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
92
92
96
91
88
69
95
95
1
1s
Br
91
1t
OMe
99
1u
1v
1w
1x
OPh
96
X =
3g (%)
OBun
99
OPri
97
OBut
97
Et
Bun
Bui
But
MOM
TMS
Ph
step with an excess amount of MeMgBr. Serving as protecting
groups for 2,6-naphthalenediol, methyl and phenyl could not
be discriminated under these coupling conditions either (entry
6, Table 4).
9c
10c
a
OAc
H
o5
1j
o5
To further clarify the reactivity of different methoxy groups
under the same conditions, we tested the methylation of
dimethoxy ether 1y. We found that monomethylation took
place in 90% isolated yield in the presence of 1.3 equiv. of
MeMgBr, with a small amount of dimethylated product as the
by-product [eqn (1)]. It indicated that the different methoxy
groups in the same molecule could be well differentiated.
Moreover, it is noteworthy that a free hydroxy group is
compatible under these conditions, and did not affect the
methylation of the methoxy group with an excess amount of
MeMgBr, and the hydroxy group could be further trans-
formed into other functionalities [eqn (2)]. Finally, methyla-
tion of the C–F bond also took place under these conditions
although C–F is very stable.8 Simple aryl fluorides 4a and 4b
were tested and the desired methylated products were obtained
in excellent conversions under these conditions [eqn (3)].
All the reactions were carried out on the scale of 0.5 mmol of 1, 0.6
b
mmol of 2, 5.0 mol% NiCl2(PCy3)2 in 4 mL of toluene. Isolated
c
yields if without further note. GC yields with the use of n-dodecane
as an internal standard.
efficiency, no matter whether the ether was located at 1- or 2-
positions (entries 1 and 2, Table 3). Alkenyl and aryl groups
did not affect this transformation (entries 3–5, Table 3). When
derivatives of anisole were submitted to this transformation,
the temperature of the reaction needed to be increased to
110 1C to facilitate the reaction. MeMgBr reacted with anisole
to afford toluene in a good conversion without observation of
any by-products by GC spectroscopy (entry 7, Table 3). It was
noteworthy that steric effects in the aromatic ring did not play
a critical role (cf. entries 8 and 9, Table 3).
Highly reactive C–Br could not be tolerated. Such function-
ality was transformed into a methyl group along with C–OMe
in an excess amount of MeMgBr (entry 1, Table 4). Different
dialkyl ethers located at both the 2- and 6-positions on the
same naphthalene could not be functionalized stepwise ac-
cording to their steric effects (entries 2–5, Table 4). Instead,
these substituted naphthalenes could be dimethylated in one
Table 3 Methylation of different methoxy arenes 1a
In summary, we have developed a practical way to construct
aryl C–Me bonds by methylating aromatic C–OR (R = alkyl,
aryl) and C–F via Ni(0) catalysis under mild conditions.
Further study to apply this transformation is under way.
Entry
1
Ar
3 (%)b
1c
1a
1k
1l
1m
1n
1o
1p
1q
1r
2-Naphthyl
1-Naphthyl
3a (93)
3b (92)
3c (98)
3d (94)
3e (93)
3f (92)
(62)
2c
3c
6-Phenyl-2-naphthyl
(E)-6-Styryl-2-naphthyl
(E)-4-Styrylphenyl
4-Phenylphenyl
Phenyl
4c
5d
Notes and references
6d,e
7d,f
8d,f
9d,f
a
1 (a) B. M. Trost and I. Fleming, in Comprehensive Organic Synth-
esis, ed. B. M. Trost and I. Fleming, Pergamon Press, New York,
1991, vol. 4, pp. 585–661; (b) R. C. Larock, Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, Wiley-
VCH, Weinheim, 1989; (c) S. Yonezawa, T. Komurasaki, K.
Kawada, T. Tsuri, M. Fuji, A. Kugimiya, N. Haga, S. Mitsumori,
M. Inagaki, T. Nakatani, Y. Tamura, S. Takechi, T. Taishi and M.
Ohtani, J. Org. Chem., 1998, 63, 5831–5387; (d) M. K. Gurjar, B.
Karumudi and C. V. Ramana, J. Org. Chem., 2005, 70, 9658–9661.
2 (a) Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich
and P. J. Stang, Wiley-VCH, New York, 1998; (b) Metal-Catalyzed
Cross-Coupling Reactions, ed. F. Diederich and A. de Meijere,
4-Tolyl
2-Tolyl
(74)
(71)
All the reactions were carried out on the scale of 0.5 mmol of 1, 0.75
b
mmol of 2, and 5.0 mol% of Ni(PCy3)2Cl2. Isolated yields if without
c
d
further note. The reaction was carried out at 80 1C. The reaction
was carried out at 110 1C. tert-Butyl phenyl ether was used as a
substrate. The reaction was carried out in mesitylene and the yield
e
f
was determined by GC with the use of n-dodecane as an internal
standard.
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Wiley-VCH, New York, 2004; (c) A. F. Littke and G. C. Fu,
Angew. Chem., Int. Ed., 2002, 41, 4176–4211.
3 (a) F. Kakiuchi, M. Usui, S. Ueno, N. Chatani and S. Murai, J.
Am. Chem. Soc., 2004, 126, 2706–2707; (b) S. Ueno, E. Mizushima,
N. Chatani and F. Kakiuchi, J. Am. Chem. Soc., 2006, 128,
16516–16517.
L. Barre, F. Sobrio, E. Fouquet and C. Perrio, Chem. Commun.,
2006, 97–99; (h) J. Blum, D. Gelman, W. Baidossi, E. Shakh, A.
Rosenfeld, Z. Aizenshtat, B. C. Wassermann, M. Frick, B. Hey-
mer, S. Schutte, S. Wernik and H. Schumann, J. Org. Chem., 1997,
62, 8681–8686; (i) D. Gelman, H. Schumann and J. Blum, Tetra-
hedron Lett., 2000, 41, 7555–7558.
4 J. W. Dankwardt, Angew. Chem., Int. Ed., 2004, 43, 2428–2432.
5 E. Wenkert, E. L. Michelotti, C. S. Swindell and M. Tingoli, J.
Org. Chem., 1984, 49, 4894–4899.
7 (a) J. E. McMurry and S. Mohanraj, Tetrahedron Lett., 1983, 24,
2723–2726; (b) T. Cooper, A. Novak, L. D. Humphreys, M. D.
Walker and S. Woodward, Adv. Synth. Catal., 2006, 348, 686–690;
(c) J. W. Han, N. Tokunaga and T. Hayashi, Synlett, 2002,
871–874; (d) J. Blum, J.A. Katz, N. Jaber, M. Michman, H.
Schumann, S. Schutte, J. Kaufmann and B. C. Wassermann, J.
Mol. Catal. A: Chem., 2001, 165, 97–102.
8 (a) A. L. Keen and S. A. Johnson, J. Am. Chem. Soc., 2006, 128,
1806–1807; (b) K. Fuchibe and T. Akiyama, J. Am. Chem. Soc.,
2006, 128, 1434–1435; (c) T. Schaub, M. Backes and U. Radius, J.
Am. Chem. Soc., 2006, 128, 15964–15965.
6 (a) M. K. Hossain and K. Takagi, Chem. Lett., 1999, 28,
1241–1242; (b) Y. Kondo, T. Matsudaira, J. Sato, N. Murata
and T. Sakamoto, Angew. Chem., Int. Ed. Engl., 1996, 35, 736–738;
(c) E. Vedejs, A. R. Haight and W. O. Moss, J. Am. Chem. Soc.,
1992, 114, 6556–6558; (d) T. Kauffmann and H. Nienaber, Synth-
esis, 1995, 207–211; (e) T. Hirao, T. Takada and A. Ogawa, J. Org.
Chem., 2000, 65, 1511–1515; (f) T. Takada, H. Sakurai and T.
Hirao, J. Org. Chem., 2001, 66, 300–302; (g) M. Huiban, A. Huet,
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