Copper(II)-catalyzed ortho-functionalization of 2-arylpyridines with acyl chlorides

Article abstract of DOI:10.1039/c0cc05557c

Copper-catalyzed ortho-benzoxylation of 2-arylpyridine sp² C-H bonds with acyl chloride is described. Notably, switching the base from t-BuOK to Li₂CO₃ causes chlorination of the C-H bond to take place. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc05557c

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Copper(II)-catalyzed ortho-functionalization of 2-arylpyridines with acyl
chloridesw
Wenhui Wang,a Changduo Pan,b Fan Chen*a and Jiang Cheng*a
Received 14th December 2010, Accepted 14th February 2011
DOI: 10.1039/c0cc05557c
Copper-catalyzed ortho-benzoxylation of 2-arylpyridine sp2
C–H bonds with acyl chloride is described. Notably, switching
the base from t-BuOK to Li2CO3 causes chlorination of the
C–H bond to take place.
suggested that the oxygen played a significant role in the
reaction. In addition, the amount of Cu(OAc)2 had little effect
on the reaction (Table 1, entries 7, 9 and 10). To reduce the
catalyst loading, we finally chose 20 mol% of Cu(OAc)2 as the
catalyst. Several copper sources were also examined, however,
the use of Cu(OTf)2, Cu(acac)2, CuO, and CuCl2 as the
catalyst precursors resulted in trace formation of 3aa
(Table 1, entries 11, 12, 14 and 15). The solvent was also
crucial for this transformation and the low-polar solvent
toluene was the best. Increasing the amount of benzoyl
chloride slightly did not change the yield obviously (Table 1,
entry 8). The reaction conducted on a 1 mmol scale provided
3aa in an acceptable 78% yield.
The direct conversion of carbon–hydrogen bonds into carbon–
carbon, carbon–halogen, carbon–nitrogen and carbon–sulfur
bonds is a very powerful methodology for building complex
molecules.1 Recently, carbon–oxygen bond formation via C–H
bond functionalization has attracted much attention.2 In 2005,
Yu reported a Pd-catalyzed stereoselective oxidation of methyl
groups by carboxylic anhydrides.3 In 2006, Yu described an
elegant example of Cu(OAc)2-catalyzed oxidative acetoxylation
of arene C–H bonds in HOAc/Ac2O using oxygen as a clean
oxidant (Scheme 1, eq (1)).4 In 2009, we developed an efficient
rhodium-catalyzed ortho-benzoxylation of an sp2 C–H bond
(Scheme 1, eq (2)).5 Subsequently, we demonstrated a copper-
catalyzed ortho-acyloxylation reaction of an sp2 C–H bond
(Scheme 1, eq (2)).6 However, transition-metal-catalyzed
benzoxylation of a C–H bond is not common, and sometimes,
the carboxylic anhydrides are not commercially available.
Thus, the need for new methodology for such a transformation
still exists. Our interest in C–H functionalization led us to
explore the possibility of using readily available acyl chlorides
as the reaction partners for such transformations.5–7 Herein,
we report a chelation-assisted copper(II)-catalyzed ortho-
acyloxylation of the sp2 C–H bond of 2-arylpyridine by acyl
chloride, employing O2 as the terminal oxidant (Scheme 1, eq (3)).8
Initial studies were performed using the reaction of
2-o-tolylpyridine with benzoyl chloride under oxygen as the
model reaction, employing Cu(OAc)2 as the catalyst in a
sealed tube (Table 1). The results suggested that the base
was important for this transformation and t-BuOK appeared
to be the best among the screened bases, delivering the
product in 85% yield (Table 1, entry 7). Under air, the yield
dramatically decreased to 57%, while no desired product was
detected under nitrogen (Table 1, entry 7). These results
Encouraged by these results, we further pursued the scope
of the process with respect to acyl chlorides. As expected, the
reaction proceeded smoothly, with yields ranging from
moderate to good, and tolerated various functional groups,
such as ethoxyl, chloro, fluoro and trifluoromethyl groups.
The hindrance on the phenyl of acyl chloride had some effect
on the reaction. For example, 3ac and 3ad were isolated in
90% and 87% yields, respectively (Table 2, entries 3 and 4),
while 3ab was obtained in 72% yield (Table 2, entry 2).
The electronic effect of the substituent on the phenyl of the
acyl chloride is not obvious in the reaction. Evidently, the
regioselectivity of the meta-substituted substrates was domi-
nated by steric effects, and the less hindered ortho-position of
a College of Chemistry & Materials Engineering, Wenzhou University,
Wenzhou 325000, People’s Republic of China.
E-mail: jiangcheng@wzu.edu.cn, fanchen@wzu.edu.cn
b Wenzhou Institute of Industry & Science, Wenzhou 325000,
People’s Republic of China
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc05557c
Scheme 1 Acyloxylation of the 2-phenylpyridine C–H bond.
c
3978 Chem. Commun., 2011, 47, 3978–3980
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Table 1 Selected results of reaction parameters screeninga
Interestingly, when Li2CO3 was used in the procedure
instead of t-BuOK, ortho-chlorination of 2-arylpyridine
occurred (Table 3). For 1f, the reaction gave the dichlorinated
product in 99% yield with a longer reaction time. However, if
we blocked one ortho position of 2-arylpyridine or increased
the hindrance either on the phenyl or pyridinyl ring, the
mono-chlorination took place smoothly using the procedure.
Obviously, the chloride source was derived from the benzoyl
chloride. In 2009, Dong reported a similar work in the
palladium-catalyzed C–H bond functionalization with aryl-
sulfonyl chlorides.10 It is a novel approach of providing
chlorinated arylpyridine.4,10,11
Entry Cu source (equiv.) Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.1)
Cu(OTf)2 (0.2)
Cu(acac)2 (0.2)
CuI (0.2)
NaHCO3 toluene
KHCO3 toluene
Na2CO3 toluene
Ag2CO3 toluene
56
81
66
80
Li2CO3
NaOAc
toluene
toluene
o5
During the reaction, carboxylic anhydride was detected by
GC-MS. The acyl chloride may readily form carboxylic
anhydride in the presence of a base and moisture.12 Moreover,
PhCOOtBu, which may be formed by the reaction of acyl
chloride with t-BuOK, was subjected to the procedure, and no
benzoxylation product was formed. Based on the experimental
results and our previous work,6 we reasoned carboxylic
anhydride was the intermediate in this tranformation.
o5
t-BuOK toluene
t-BuOK toluene
t-BuOK toluene
t-BuOK toluene
t-BuOK toluene
t-BuOK toluene
t-BuOK toluene
t-BuOK toluene
t-BuOK toluene
t-BuOK xylene
t-BuOK DMF
85 (57b,o5c)
86d
83
9
10
11
12
13
14
15
16
17
18
19
20
80
o5
o5
60
o5
o5
76
o5
o5
59
CuO (0.2)
CuCl2 (0.2)
A plausible mechanism for this transformation is outlined in
Scheme 2. In step (i), carboxylic anhydride was formed in situ
from acyl chloride in the presence of a base and moisture.12 In
fact, the reaction is inhibited in the presence of molecular
sieves. This result is consistent with step (i). In step (ii), the
reaction of Cu(OAc)2 with benzoic anhydride 5 affords Cu(II)
benzoate and acetic anhydride as a byproduct. Step (iii)
involves the electrophilic attack of Cu(II) on the phenyl ring
of 1 to afford a cyclometallated Cu(II) intermediate A. Then,
the Cu(II) intermediate A is oxidized to a Cu(III) intermediate B
in the presence of Cu(II).13 In the final step, the reductive
elimination of Cu(III) intermediate B takes place immediately
to deliver the product 3 along with a Cu(i) species, which is
oxidized by O2 to regenerate the Cu(II) benzoate in the
presence of benzoic anhydride 5.
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
t-BuOK NMP
t-BuOK chlorobenzene
t-BuOK CH3CN
18
a
Reaction conditions: 2-o-tolylpyridine (0.2 mmol), benzoyl chloride
(0.4 mmol), base (2 equiv.), Cu source in dry solvent (2 mL) in a sealed
b
c
tube, 145 1C, 48 h, under O2. Isolated yield. Under air. Under N2.
Benzoyl chloride (0.6 mmol).
d
Table 2 Ortho-chlorination of 2-arylpyridines with acyl chloridesa
In conclusion, we have developed a copper-catalyzed
ortho-benzoxylation of 2-arylpyridine C–H bonds using the
commercially available acyl chlorides. The procedure tolerates
a series of functional groups, such as ethoxyl, chloro, fluoro
and trifluoromethyl groups. Notably, switching the base from
Entry
R1, R2
R3
Yieldb (%)
1
2
3
4
5
6
7
8
R1 = 2-Me, R2 = H (1a)
1a
1a
1a
1a
1a
1a
H (2a)
83 (3aa)
72 (3ab)
90 (3ac)
87 (3ad)
83 (3ae)
60 (3af)
89 (3ag)
86 (3ah)
76 (3ba)
54 (3ca)
52 (3da)
81 (3ea)
2-Me (2a)
3-Me (2c)
4-Me (2d)
4-F (2e)
2-Cl (2f)
3-CF3 (2g)
2-OEt (2h)
H (2a)
Table 3 Ortho-chlorination of 2-arylpyridines with acyl chloridesa
1a
9
R1 = 2-OMe, R2 = H (1b)
R1 = 3-Me, R2 = H (1c)
R1 = 3,5-Me, R2 = H (1d)
R1 = H, R2 = Me (1e)
10
11
12
H (2a)
H (2a)
H (2a)
a
Reaction conditions:
(20 mol%), and t-BuOK (0.4 mmol) in dry toluene (2 mL) under O2
1 (0.2 mmol), 2 (0.4 mmol), Cu(OAc)2
b
Entry
1
Yieldb (%)
at 145 1C for 48 h. Isolated yield.
1
2
3
4
5
1a
1b
1d
1e
80 (4aa)
77 (4ba)
65 (3da)
51 (3ea)
99 (3fa)c
2-arylpyridine was acylated with good selectivity (495: 5).
Meanwhile, presumably as a result of steric hindrance, the
monofunctionalized product was observed using substrate 1e
(Table 2, entry 12).9 Disappointingly, the feasibility of accessing
the acetoxylated product using acetyl chloride was poor. In
comparison with our previous work, this methodology is more
practical since most acyl chlorides are commercially available.
R1 = H, R2 = H (1f)
a
Reaction conditions: 2-arylpyridine 1 (0.2 mmol), benzoyl chloride
2a (0.6 mmol), Li2CO3 (0.4 mmol) and Cu(OAc)2 (20 mol%) in dry
b
toluene (2 mL) in a sealed tube, 145 1C, 48 h, under O2. Isolated
yield. 60 h.
c
c
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3 R. Giri, J. Liang, J.-G. Lei, J.-J. Li, D.-H. Wang, X. Chen,
I. C. Naggar, C. Guo, B. M. Foxman and J.-Q. Yu, Angew. Chem.,
Int. Ed., 2005, 44, 7420.
4 X. Chen, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem.
Soc., 2006, 128, 6790.
5 Z. Ye, W. Wang, F. Luo, S. Zhang and J. Cheng, Org. Lett., 2009,
11, 3974.
6 W. Wang, F. Luo, S. Zhang and J. Cheng, J. Org. Chem., 2010, 75,
2415.
7 (a) X. Jia, S. Zhang, W. Wang, F. Luo and J. Cheng, Org. Lett.,
2009, 11, 3120; (b) X. Jia, D. Yang, S. Zhang and J. Cheng, Org.
Lett., 2009, 11, 4716; (c) X. Jia, D. Yang, W. Wang, F. Luo and
J. Cheng, J. Org. Chem., 2009, 74, 9470; (d) S. Zhang, F. Luo,
W. Wang, M. Hu, X. Jia and J. Cheng, Tetrahedron Lett., 2010, 51,
3317; (e) S. Zhang, P. Qian, M. Zhang, M. Hu and J. Cheng,
J. Org. Chem., 2010, 75, 6732.
8 For selected copper-catalyzed C–H functionalization reaction,
please see: (a) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc.,
2007, 129, 12404; (b) H.-Q. Do and O. Daugulis, J. Am. Chem.
Soc., 2008, 130, 1128; (c) R. J. Phipps and M. J. Gaunt, Science,
2009, 323, 1593; (d) J. M. Lee, E. J. Park, S. H. Cho and S. Chang,
J. Am. Chem. Soc., 2008, 130, 7824; (e) O. Basle and C.-J. Li, Org.
Lett., 2008, 10, 3661; (f) G. Brasche and S. L. Buchwald, Angew.
Chem., Int. Ed., 2008, 47, 1932; (g) S. Usui, Y. Hashimoto,
J. V. Morey, A. E. H. Wheatley and M. Uchiyama, J. Am. Chem.
Soc., 2007, 129, 15102; (h) R. Bernini, G. Fabrizi, A. Sferrazza and
S. Cacchi, Angew. Chem., Int. Ed., 2009, 48, 8078; (i) S. Ueda and
H. Nagasawa, Angew. Chem., Int. Ed., 2009, 47, 6411; (j) I. Ban,
T. Sudo, T. Taniguchi and K. Itami, Org. Lett., 2008, 10, 3607;
(k) Q. Wang and S. L. Schreiber, Org. Lett., 2009, 11, 5178;
(l) S. Yotphan, R. G. Bergman and J. A. Ellman, Org. Lett.,
2009, 11, 1511; (m) H. Wang, Y. Wang, C. Peng, J. Zhang and
Q. Zhu, J. Am. Chem. Soc., 2010, 132, 13217; (n) L. Zhang,
J. Cheng, T. Ohishi and Z. Hou, Angew. Chem., Int. Ed., 2010,
49, 8670; (o) L. Ackermann, H. K. Potukuchi, D. Landsberg and
R. Vicente, Org. Lett., 2008, 10, 3081; (p) F. Besselievre and
S. Piguel, Angew. Chem., Int. Ed., 2009, 48, 9553.
9 (a) D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford,
J. Am. Chem. Soc., 2005, 127, 7330; (b) Y. Matsuura, M. Tamura,
T. Kochi, M. Sato, N. Chatani and F. Kakiuchi, J. Am. Chem.
Soc., 2007, 129, 9858; (c) Y. Zhang, J. Feng and C.-J. Li, J. Am.
Chem. Soc., 2008, 130, 2900; (d) J. Norinder, A. Matsumoto,
N. Yoshikai and E. Nakamura, J. Am. Chem. Soc., 2008, 130,
5858; (e) D. Kalyani and M. S. Sanford, Org. Lett., 2005, 7, 4149.
10 X. Zhao, E. Dimitrijevic and V. M. Dong, J. Am. Chem. Soc.,
2009, 131, 3466.
Scheme 2 A possible mechanism for the transformation via Cu(II) (A)
and Cu(III) (B) intermediates.
t-BuOK to Li2CO3 causes chlorination of the C–H bond to
take place. Ongoing work seeks to gain further insights into
the mechanism of this reaction and to expand the scope to the
acylation of unactivated sp3 C–H bonds.
This work was financially supported by the National
Natural Science Foundation of China (No. 20972115) and the
Key Project of Chinese Ministry of Education (No. 209054).
Notes and references
1 (a) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147;
(b) I. A. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and
J. F. Hartwig, Chem. Rev., 2010, 110, 890; (c) D. A. Colby,
R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624;
(d) O. Daugulis, H.-Q. Do and D. Shabashov, Acc. Chem. Res.,
2009, 42, 1074; (e) X. Chen, K. M. Engle, D.-H. Wang and
J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094;
(f) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem.,
Int. Ed., 2009, 48, 9792; (g) B.-J. Li, S.-D. Yang and Z.-J. Shi,
Synlett, 2008, 949; (h) C. I. Herrerıas, X. Yao, Z. Li and C.-J. Li,
´
Chem. Rev., 2007, 107, 2546; (i) D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174; (j) T. Nishikata,
A. R. Abela, S. Huang and B. H. Lipshutz, Angew. Chem., Int.
Ed., 2010, 49, 781; (k) B. Haffemayer, M. Gulias and M. J. Gaunt,
Chem. Sci., 2011, 2, 312.
2 (a) A. R. Dick, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc.,
2004, 126, 2300; (b) D. Kalyani and M. S. Sanford, Org. Lett.,
2005, 7, 4149; (c) L. V. Desai, K. L. Hull and M. S. Sanford, J. Am.
Chem. Soc., 2004, 126, 9542; (d) L. V. Desai, H. A. Malik and
M. S. Sanford, Org. Lett., 2006, 8, 1141; (e) B. V. S. Reddy,
L. R. Reddy and E. J. Corey, Org. Lett., 2006, 8, 3391;
(f) K. L. Hull, E. L. Lanni and M. S. Sanford, J. Am. Chem.
Soc., 2006, 128, 14047; (g) G.-W. Wang, T.-T. Yuan and X.-L. Wu,
J. Org. Chem., 2008, 73, 4717; (h) Y. Fu, Z. Li, S. Liang,
Q.-X. Guo and L. Liu, Organometallics, 2008, 27, 3736;
(i) D.-H. Wang, X.-S. Hao, D.-F. Wu and J.-Q. Yu, Org. Lett.,
2006, 8, 3387.
11 Transformation of sp2-hybridized C–H bond to C–X, please see:
(a) D. Kalyani, A. R. Dick, W. Q. Anani and M. S. Sanford,
Org. Lett., 2006, 8, 2523; (b) X. B. Wan, Z. X. Ma, B.-J. Li,
K. Y. Zhang, S. K. Cao, S. W. Zhang and Z.-J. Shi, J. Am. Chem.
Soc., 2006, 128, 7416; (c) T.-S. Mei, R. Giri, N. Maugel and
J.-Q. Yu, Angew. Chem., Int. Ed., 2008, 47, 5215.
12 (a) I. Dhimitruka and Jr. J. SantaLucia, Org. Lett., 2006, 8, 47;
(b) W. K. Fife and Y. Xin, J. Am. Chem. Soc., 1987, 109, 1278;
(c) C.-S. Kuo and J.-J. Jwo, J. Org. Chem., 1992, 57, 1991;
(d) H. Adkins and Q. E. Thompson, J. Am. Chem. Soc., 1949, 71, 2242.
13 (a) A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc.,
2009, 131, 5044; (b) A. E. King, L. M. Huffman, A. Casitas,
M. Costas, X. Ribas and S. S. Stahl, J. Am. Chem. Soc., 2010, 132,
12068; (c) B. Yao, D.-X. Wang, Z.-T. Huang and M.-X. Wang,
Chem. Commun., 2009, 2899.
c
3980 Chem. Commun., 2011, 47, 3978–3980
This journal is The Royal Society of Chemistry 2011