Copper-catalyzed N-methylation of amides and O-methylation of carboxylic acids by using peroxides as the methylating reagents

Article abstract of DOI:10.1021/ol401362k

The copper-catalyzed N-methylation of amides and O-methylation of carboxylic acids by using peroxides as the methylating reagent are described. Various amides and carboxylic acids were methylated affording N-substituted amides and esters. Tentative mechanistic studies suggest that this reaction is likely to involve a radical process.

Full text of DOI:10.1021/ol401362k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Copper-Catalyzed N‑Methylation of
Amides and O‑Methylation of Carboxylic
Acids by Using Peroxides as the
Methylating Reagents
000–000
†
Qinqin Xia, Xiaolong Liu, Yuejiao Zhang, Chao Chen, and Wanzhi Chen*
†
†
†
,†,‡
Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. China,
State Key Laboratory of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
chenwzz@zju.edu.cn
Received May 15, 2013
ABSTRACT
The copper-catalyzed N-methylation of amides and O-methylation of carboxylic acids by using peroxides as the methylating reagent are
described. Various amides and carboxylic acids were methylated affording N-substituted amides and esters. Tentative mechanistic studies
suggest that this reaction is likely to involve a radical process.
3
Amides are present in many natural organic compounds
1
and medicinally relevant compounds. N-Alkylation of
alternative for N-alkylation of amides. This strategy is
an important method for the synthesis of valuable amide
derivatives without the need for prefunctionalized starting
amides is an efficient way to prepare more substituted
analogues. Typical approaches to N-substituted amides
generally involve nucleophilic substitution with alkyl
3
materials (Scheme 1a). However, only specific sp CÀH
bonds such as benzylic CÀH bonds were suitable for the
direct amidation.
In the past decade, organic peroxides were widely used
2
halides under basic conditions which suffers from the use
of alkyl halides and strong bases. Recently, direct amida-
3
3
tion of sp CÀH bonds has emerged as an attractive
in sp CÀH bond activation processes, especially in the
4
cross-dehydrogenative coupling (CDC) reactions. In
†
these reactions, organic peroxides were usually used as
H-acceptors to activate CÀH bonds. Herein, we report
Cu-catalyzed N-methylation of amides in which organic
peroxide serves as the methylating reagent, thus offering
a new convenient pathway for the synthesis of various
N-substituted amides (Scheme 1b). Compared with nu-
cleophilic substitution, the new method was carried out
under neutral conditions and the overalkylation of pri-
mary amides could be suppressed.
Zhejiang University.
Nankai University.
‡
(
1) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
243. (b) Fletcher, M. D.; Campbell, M. M. Chem. Rev. 1998, 98, 763.
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4, 1010. (b) Isele, G. L.; Luttring, A. Synthesis 1971, 266. (c) Johnstone,
2
(
7
R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169. (d) Gajda, T.;
Zwierzak, A. Synthesis 1981, 1005.
(3) (a) Pelletier, G.; Powell, D. A. Org. Lett. 2006, 8, 6031. (b) Liu,
X. W.; Zhang, Y. M.; Wang, L.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. J. Org.
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Zhao, Y. F. Org. Lett. 2008, 10, 1863. (d) Fan, R. H.; Li, W. X.; Pu,
D. M.; Zhang, L. Org. Lett. 2009, 11, 1425. (e) Cundari, T. R.; Wiese, S.;
Badiei, Y. M.; Gephart, R. T.; Mossin, S.; Varonka, M. S.; Melzer,
M. M.; Meyer, K.; Warren, T. H. Angew. Chem., Int. Ed. 2010, 49, 8850.
f) Powell, D. A.; Fan, H. J. Org. Chem. 2010, 75, 2726. (g) Ye, Y. H.;
Zhang, J.; Wang, G.; Chen, S. Y.; Yu, X. Q. Tetrahedron 2011, 67, 4649.
h) Gephart, R. T.; Huang, D. L.; Aguila, M. J. B.; Schmidt, G.; Shahu,
(4) For reviews on CDC reactions, see: (a) Li, C. J. Acc. Chem. Res.
2009, 42, 335. (b) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540. (c)
Scheuermann, C. J. Chem.;Asian J. 2010, 5, 436. (d) Yoo, W. J.; Li,
C. J. Top. Curr. Chem. 2010, 292, 281. (e) Cho, S. H.; Kim, J. Y.; Kwak,
J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (f) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (g) Jones, K. M.; Klussmann, M.
Synlett 2012, 23, 159.
(
(
A.; Warren, T. H. Angew. Chem., Int. Ed. 2012, 51, 6488. (i) Mao, X.;
Wu, Y.; Jiang, X.; Liu, X.; Cheng, Y.; Zhu, C. RSC Adv. 2012, 2, 6733.
1
0.1021/ol401362k r XXXX American Chemical Society

a
Scheme 1. N-Alkylation of Amides
Table 1. Optimization of Reaction Conditions
yield of
b
entry
catalyst
CuCl
peroxide
2a (%)
1
2
3
4
5
6
7
8
9
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBPB
TBHP
DCP
72
29
64
41
63
19
57
À
CuBr
CuI
Cu(OTf)
2
Cu(OAc)
2
3 H2
O
3
CuSO
4
5H O
2
In a study of N-alkylation of amides with sp CÀH
3
5
bonds using peroxide as the oxidant, we occasionally
2
CuCl2 2H O
3
FeCl
2
observed the formation of the N-methylation product as
an insignificant amount of byproduct. This inspired us to
further investigate the reaction of benzamide (1a) with di-
tert-butyl peroxide (DTBP) in chlorobenzene in the pre-
sence of CuCl. When the reaction was carried out at 130 °C
for 12 h, N-methylbenzamide (2a) was obtained in 72%
yield together with a trace amount of N,N-dimethylbenza-
mide (4a) (Table 1, entry 1). Obviously, the methyl group
originates from the decomposition of peroxide. Actually,
Li et al. reported the Pd-catalyzed directed methylation of
Pd(OAc)
À
2
À
10
À
11
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
48
À
12
13
90
c
14
15
16
17
18
DCP
63
d
DCP
82
e
DCP
82
f
DCP
81
g
DCP
À
a
Reaction conditions: benzamide (0.5 mmol), peroxide (1.0 mmol),
2
-phenylpyridine through aryl CÀH bond activation by
b
. Yield of
6
catalyst (0.05 mmol), C
isolated product. CuCl (0.025 mmol). DCP (0.75 mmol). Under air.
6
H
5
Cl (1.0 mL), 130 °C, 12 h, under Ne
2
using peroxides. Further investigation indicated that
other copper salts are also active regardless of their oxida-
tion states but show lower catalytic efficiency than CuCl
c
d
f
g
The reaction was carried out at 110 °C. The reaction was carried out
at 80 °C.
(
entries 2À7). However, when FeCl and Pd(OAc) were
2
2
used as the catalysts, no product was observed (entries 8
and 9). In addition, no N-methylation occurred in the
absence of a Cu-catalyst (entry 10). Therefore, a Cu-
catalyst is crucial for this transformation. We also found
that other organic peroxides suchas tert-butyl perbenzoate
reactions, only trace amounts of double methylation prod-
ucts were obtained. The reaction of 4-methylbenzamide
afforded the desired product in 83% yield (2b). The reac-
tion of 4-tert-butylbenzamide also proceeded well giving
the coupling product in 81% yield (2c). Substrates bearing
strong electron-donating substituents worked well under
the standard conditions (2d and 2e). Halogen substituents
could be well tolerated, and 4-halobenzoamides were iso-
lated in good yields (2fÀ2h). Moreover, benzamides bear-
ing strong electron-withdrawing groups also display high
activities (2i and 2j). The results implied that the electronic
effect is not critical for this transformation. N-Methylation
of 2,6-difluorobenzamide afforded a slightly lower yield
compared to benzamide (2k). The hydroxy group was well
tolerated under the oxidation conditions (2l). Heteroaryl
amides could also be transformed to N-methylated amides
in good yields (2m and 2n). Furthermore, cinnamamide
was also a compatible substrate for this transformation
and gave the desired product in good yield (2o).
(
TBPB) showed lower reactivity than DTBP (entry 11).
The reaction did not proceed when tert-butyl hydroper-
oxide (TBHP) was used (entry 12). Among the peroxides
tested, dicumyl peroxide (DCP) provided relatively higher
yields of the product; the N-methylated product was
isolated in 90% yield (entry 13). In addition, 2-phenylpro-
pan-2-ol and acetophenone were simultaneously isolated
in 78% and 73% yields, respectively. A lower loading of
CuCl or DCP led to decreased yields (entries 14 and 15).
The reaction could proceed in air, but the yield is slightly
lower (entry 16). When we decreased the temperature to
1
10 °C, the yield was decreased to 81% (entry 17). A
further decrease of the temperature to 80 °C resulted in no
reaction indicating that the decomposition of peroxides
requires a higher temperature (entry 18).
With the above optimized reaction conditions, a variety
of primary amides were tested (Scheme 2). In all the
We found that double methylation of primary aromatic
amides to N,N-dimethylamides was hard under the opti-
mized conditions. N-Methyl- and N-phenylbenzamide
showed relatively lower activity compared to benzamide
3
(
Scheme 3, 4a and 4b). However, the secondary amides
(
5) For our previous work on direct CÀN bonds fomation via sp
CÀH bonds activation, see: (a) Xia, Q. Q.; Chen, W. Z.; Qiu, H. Y.
derived from aliphatic acids could be smoothly transfor-
medinto theircorrespondingproducts. AslistedinScheme3,
N-phenylacetamide worked well under the standard
J. Org. Chem. 2011, 76, 7577. (b) Xia, Q. Q.; Chen, W. Z. J. Org. Chem.
2
012, 77, 9366.
(
6) Zhang, Y. H.; Feng, J. Q.; Li, C. J. J. Am. Chem. Soc. 2008, 130, 2900.
B
Org. Lett., Vol. XX, No. XX, XXXX

a
a
Scheme 2. N-Methylation of Various Primary Amides
Scheme 3. N-Methylation of Various Secondary Amides
a
a
Reaction conditions: 3 (0.5 mmol), DCP (1.0 mmol), CuCl
b
Reaction conditions: 1 (0.5 mmol), DCP (1.0 mmol), CuCl
Cl (1.0 mL), 130 °C, 12 h, under N
(
0.05 mmol), C
6
H
5
2
Cl (1.0 mL), 130 °C, 12 h, under N . 24 h.
(
0.05 mmol), C
6
H
5
2
.
acid were suitable for this transformation giving the corre-
sponding products (6k and 6l) in 63% and 76% yields,
respectively. A moderate yield was obtained when cinnamic
acid was served as the substrate (6m). Most importantly,
alkyl acids could also be methylated and the desired esters
were isolated in good yields (6n and 6o).
conditions (4c). A halogen group such as Cl is also well
tolerated, which offers further possibility for additional
functionalization through cross-coupling reactions (4d).
In general, the amides bearing both electron-donating
and -withdrawing substituents could be methylated under
the oxidation conditions. The strong electron-donating
groups slightly decrease the yields (4eÀ4h). The reactions
of N-benzyl- and N-butylacetamide produced the corre-
sponding products in 66% and 65% yield, respectively
Esters are one of the most important intermediates in
chemical and pharmaceutical industries and have been
widely used in the production of valuable compounds such
7
as polymers, fragrances, or fatty acids. Esterification is
8
one of the fundamental reactions in organic synthesis.
(
4i and 4j). N-Phenylpropionamide could also be methy-
lated in good yield similar to acetamides (4k). Moreover,
the lactams could also be methylatedand showed relatively
higher reactivity than linear amides (4l and 4m).
Traditionally, esters are prepared from carboxylic acids
and alcohols catalyzed by Bronsted or Lewis acids. Other
attractive approaches include transition-metal-catalyzed
The present methylation reaction is not suitable for the
methylation of phenols under the oxidation conditions.
However, the methylation of a variety of carboxylic acids
could proceed smoothly affording the corresponding
esters. Both DTBP and DCP were good methylating re-
agents, and they reacted with various acids giving esters in
similar yields. The results by using DTBP were summarized
in Scheme 4. Methyl benzoate could be easily obtained in
9
oxidative esterification of aldehydes and direct CÀH
1
0
functionalization. The present protocol provides an al-
ternative route for the synthesis of methyl esters.
(
7) Otera, J. Esterification: Methods, Reactions and Applications;
Wiley-VCH: Weinheim, 2003.
(8) (a) Larock, R. C. Comprehensive Organic Transformation; VCH:
NewYork, 1999. (b) Otera, J. Chem. Rev. 1993, 93, 1449. (c) Otera, J.
Angew. Chem., Int. Ed. 2001, 40, 2044.
76% yield (6a). Again, the halogen group is well tolerated (6b
and 6c). Unlike amides, strong electron-withdrawing sub-
(9) Selected examples: (a) Rosa, J. N.; Reddy, R. S.; Candeias, N. R.;
Cal, P. M. S. D.; Gois, P. M. P. Org. Lett. 2010, 12, 2686. (b) Liu, C.; Wang,
J.; Meng, L. K.; Deng, Y.; Li, Y.; Lei, A. W. Angew. Chem., Int. Ed. 2011,
stituents at the para-position significantly lower the yields
(
5
1
0, 5144. (c) Tejel, C.; Ciriano, M. A.; Passarelli, V. Chem.;Eur. J. 2011,
7, 91. (d) Liu, C.; Tang, S.; Zheng, L. W.; Liu, D.; Zhang, H.; Lei, A. W.
6d and 6e). However, benzoic acids having electron-with-
Angew. Chem., Int. Ed. 2012, 51, 5662. (e) Meng, J. J.; Gao, M.; Wei, Y. P.;
Zhang, W. Q. Chem.;Asian. J. 2012, 7, 872. (f) Rout, S. K.; Guin, S.;
Ghara, K. K.; Banerjee, A.; Patel, B. K. Org. Lett. 2012, 14, 3982.
drawing substituents at the ortho-positions showed even
higher activity compared to unsubstituted benzoic acid (6f
and 6g), where it seems that steric hindrance has little effect
on the reaction. Electron-donating groups such as methyl,
tert-butyl, and methoxy substituents of benzoic acids sur-
vived, and the desired products were obtained in good yields
(
10) Selected examples: (a) Zhang, S.; Luo, F.; Wang, W.; Jia, X.;
Hu, M.; Cheng, J. Tetrahedron Lett. 2010, 51, 3317. (b) Chen, L.; Shi,
E. B.; Liu, Z. J.; Chen, S. L.; Wei, W.; Li, H.; Xu, K.; Wan, X. B.
Chem.;Eur. J. 2011, 17, 4085. (c) Feng, J.; Liang, S.; Chen, S. Y.;
Zhang, J.; Fu, S. S.; Yu, X. Q. Adv. Synth. Catal. 2012, 354, 1287. (d) Shi,
E. B.; Shao, Y.; Chen, S. L.; Hu, H. Y.; Liu, Z. J.; Zhang, J.; Wan, X. B.
Org. Lett. 2012, 14, 3384.
(
6h, 6i, and 6j). 4-Biphenylcarboxylic acid and 1-naphthoic
Org. Lett., Vol. XX, No. XX, XXXX
C

a
Scheme 4. O-Methylation of Various Carboxylic Acids
Scheme 5. Radical Trapping Experiment
Scheme 6. Proposed Mechanism
a
Reaction conditions: 5 (0.5 mmol), DTBP (1.0 mmol), CuCl
Cl (1.0 mL), 130 °C, 12 h, under N
(
0.05 mmol), C
6
H
5
2
.
Althougha metal insertion mechanism was proposedfor
6
the Pd-catalyzed C-methylation of 2-phenylpyridine, the
present N- and O-methylation was assumed to proceed via
a radical mechanism. We observed that in both N- and
O-methylation reactions, with the addition of the 2,2,6,6-
tetramethylpiperidine-1-oxyl radical (TEMPO), a radical-
trapping reagent, the formation of the desired products
was completely suppressed under the standard reaction
conditions and 1-methoxy-2,2,6,6-tetramethylpiperidine
II
I
would reduce the [Cu ] intermediate C to [Cu ] and
simultaneously afford the N- or O-methylation product.
In summary, the Cu-catalyzed N-methylation of amides
and O-methylation of carboxylic acids by using peroxides
as the methylating reagents have been developed. A variety
of amides and carboxylic acids were suitable substrates
for the reaction. This transformation provides a new and
effective protocol toward the synthesis of N-substituted
amides and esters. Tentative mechanistic studies suggest
that this reaction is likely to involve a radical process.
Further studies on the mechanistic details and expansion
of the scope of the reaction are currently underway in our
laboratory.
(
7) was detected (Scheme 5). Furthermore, the reaction
of TEMPO with DCP even without CuCl gave 7 in 87%
yield. In the absence of a copper salt, 2-phenylpropan-2-ol
and acetophenone could also be isolated. The results
suggest that the reaction might proceed via the methyl
radical. In addition, the generation of the methyl radical
from DCP does not require copper.
3
e,h,6,11
Based on previous reports
proposed reaction pathway is depicted in Scheme 6. In-
and the above results, a
I
itially, the reaction between [Cu ] and dialkyl peroxide
would give copper(II) alkoxide A and alkoxy radical B.
Metathesis of A in the presence of amides or carboxylic
acids would then form intermediate C and alcohol D.
Thermal β-methyl elimination from alkoxy radical B
would generate ketone E and a methyl radical which can
be quantitatively trapped by a TEMPO. Both alcohol D
and ketone E have been isolated in stoichiometric amounts
and determined by NMR. Finally, the methyl radical
Acknowledgment. The work was supported by Na-
tional Natural Science Foundation of China (21072170
and J1210042).
Supporting Information Available. Experimental de-
tails and characterization data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Kochi, J. K. J. Am. Chem. Soc. 1962, 84, 1193. (b) Gephart,
R. T.; McMullin, C. L.; Sapiezynski, N. G.; Jang, E. S.; Aguila, M. J. B.;
Cundari, T. R.; Warren, T. H. J. Am. Chem. Soc. 2012, 134, 17350.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX