Copper-catalyzed methyl esterification of aromatic aldehydes and benzoic alcohols by TBHP as both oxidant and methyl source

Article abstract of DOI:10.1016/j.tetlet.2013.11.040

A copper-catalyzed synthesis of methyl esters from aromatic aldehydes in the presence of tert-butyl hydrogen peroxide (TBHP) was developed via a radical reaction mechanism. TBHP acts not only as an efficient oxidant, but also as a green methyl source in such transformation. Moreover, this method could also be efficiently extended to the methyl esterification of benzylic alcohols.

Full text of DOI:10.1016/j.tetlet.2013.11.040

Tetrahedron Letters 55 (2014) 390–393
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed methyl esterification of aromatic aldehydes
and benzoic alcohols by TBHP as both oxidant and methyl source
Pan Li a,b, Jingjing Zhao a, Rui Lang a, Chungu Xia a, Fuwei Li a,
⇑
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
b Graduate University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed synthesis of methyl esters from aromatic aldehydes in the presence of tert-butyl
hydrogen peroxide (TBHP) was developed via a radical reaction mechanism. TBHP acts not only as an effi-
cient oxidant, but also as a green methyl source in such transformation. Moreover, this method could also
be efficiently extended to the methyl esterification of benzylic alcohols.
Received 5 September 2013
Revised 2 November 2013
Accepted 11 November 2013
Available online 27 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Methyl esterification
Aromatic aldehydes
Benzoic alcohols
Methyl source
Free radical
Classical methyl sources are mainly originated from methyl
iodide (MeI), methyl sulfofluoridate (MeSO3F), trifluoromethane-
sulfonate (MeOTf), dimethyl sulfate (Me2SO4), methyl carbonate
(Me2CO3), diazomethane (CH2N2), and methyl organometallic
reagents. Nevertheless, these reactive methylating agents more
or less face some application limitations owing to their unfriendly
properties (such as toxicity and causticity). Recently, the develop-
ment of a green and efficient methyl source for specific molecular
functionalization has received much attention. Augusto and
coworkers reported Fe-catalyzed DNA methylation by TBHP as a
methylation source.1 Later on, Li et al. discovered a Pd-catalyzed
direct methylation of aryl C–H bond using peroxides as both
methyl reagent and oxidant.2 More recently, Chen and co-workers
described methylation of amides and carboxylic acids by using per-
oxides as the methylating reagents.3 In addition, TBHP has been
proved to be an efficient oxidant in the direct functionalization
of aldehyde C–H bond to synthesize aryl ketones via an acyl radical
intermediate,4 but metal-catalyzed methyl esterification of
aldehyde by dual TBHP has not been reported.
have been extensively studied and afforded facile alternatives for
the direct synthesis of ester from more simple substrates.6 Mecha-
nistically, the oxidation of hemiacetal intermediate, in situ gener-
ated from the condensation of alcohol with aldehyde, is the key
step for these conversions.7 Herein, we wish to report a novel
and non-precious metal-catalyzed methyl esterification procedure
through direct oxidative functionalization of aldehydes and alco-
hols with peroxides as both the methyl source and the oxidant.
To achieve this goal, appropriate peroxides that could act as an
efficient oxidant and provide methyl source were initially screened
in the CuBr2-catalyzed oxidative esterification of anisaldehyde (1a)
in DMSO at 100 °C. As shown in Table 1, 16% HPLC yield of the
methyl ester product, methyl 4-methoxybenzoate (2a), was ob-
tained in the presence of TBHP (Table 1, entry 3), and no reaction
or only trace amount of 2a was observed when using tert-butyl
peroxide (TBP) or tert-butyl peroxybenzoate8 (TBPB) as the oxidant
and the methyl feedstock (Table 1, entries 1 and 2), respectively. To
our delight, by increasing the amount of TBHP, the yield of desired
product could be raised to 53% (Table 1, entries 4 and 5). Subse-
quently, various copper catalysts were examined under the same
reaction conditions (Table 1, entries 6–14). It should be mentioned
that all the frequently-used copper sources were effective in gener-
ating the expected methyl 4-methoxybenzoate, but CuF2 showed
the best activity toward this direct esterification of 1a, affording
69% isolated yield of 2a (Table 1, entry 7). However, other repre-
sentative metal oxidation catalysts, such as iron and silver as well
as palladium, ruthenium, and rhodium catalysts, were found to be
ineffective for this oxidative transformation (Table 1, entries
Methyl esterification is one of the most fundamental transfor-
mations in organic synthesis.5 The common synthetic routes to
methyl esters are the reactions of carboxylic acids (or their deriv-
atives) with methanol in the presence of acid or base. Recently,
Pd-catalyzed direct oxidative esterifications of aldehydes (or alco-
hols), with the necessary presence of silver salt or base additives,
⇑
Corresponding author.
E-mail address: fuweili@licp.cas.cn (F. Li).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.040

P. Li et al. / Tetrahedron Letters 55 (2014) 390–393
391
Table 1
15–20). The present esterification was very sensitive to the reac-
tion temperature, and a much lower yield (28%) was obtained
when temperature was reduced from 100 °C to 80 °C (Table 1, en-
try 21). When the reaction was performed under argon in DMSO,
the isolated yield could be further enhanced to 75% (Table 1, entry
22). Similar to peroxide, solvent also played an important role in
controlling the catalytic reactivity. Only low yields (<5%) were ob-
tained when DMSO was replaced by DMAc or DMF, and no target
product was observed in other solvents such as CH3CN, THF, DCE,
and dioxane. In addition, we obtained trace amount of byproduct
methylsulfinylmethyl 4-methoxybenzoate9 which could be formed
Reaction optimizationa
MeO
MeO
peroxide catalyst
DMSO
CHO
COOMe
1a
2a
Entry
Peroxide (equiv)
Catalyst (5%)
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
TBP(2)
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl2
CuF2
Cu(OAc)2
Cu(OTf)2
CuO
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
0
TBPB(2)
TBHP(2)
TBHP(4)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(6)
TBHP(8)
Trace
16
36
62 (53)
58
78 (69)
54
53
73 (63)
76 (65)
63
58
67
0
0
0
Å 11
by the cross-coupling of PMPCOOÅ10 and CH3SOCH2 . Interest-
ingly, the byproduct disappeared when using mixed solvent
(DMSO/H2O = 1:1). Yield of 2a could be improved to 85% by
increasing CuF2 loading to 10 mol % and the reaction temperature
to 120 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22c
23c,d
Cu2O
CuBr
CuI
With these satisfactory conditions in hand, we then turned to
examine the scope of aldehydes (Table 2). As illustrated in
Scheme 1, benzaldehyde itself (2b) and its derivatives (2a, 2c–
2e) with methoxyl groups at different positions on the phenyl ring
all worked smoothly under CuF2/TBHP catalytic system, giving 54–
85% yields of the desired methyl benzoates. The aldehydes (2f–2k)
substituted with electron-withdrawing groups (Cl, Br, CN, NO2) at
the ortho- or para-position could also be efficiently converted to
the expected methyl esters in 65–75% yields. However, phthalalde-
hyde only afforded 44% yield of dimethyl phthalate (2h). Obvi-
ously, sterically hindered aldehydes (2d–2h) afforded relatively
lower yields. Notably, the system also showed excellent activity to-
ward the oxidative esterification of other representative aromatic
aldehydes, such as 2-naphthaldehyde and thiophene-2-carbalde-
hyde, affording the desired ester products in 63% and 90% yields,
respectively, (2l–2m). It was surprising that 4-hydroxybenzalde-
Cu
FeCl3
FeBr2
AgOAc
PdCl2
RuCl3
RhCl3
CuF2
0
0
0
37 (28)
85 (75)
94 (85)
CuF2
CuF2
100
120
a
b
c
Reaction conditions: 0.5 mmol scale in 3 mL of DMSO for 12 h.
Yields determined by HPLC analysis, isolated yield in parentheses.
Under argon in pressure tubes.
d
DMSO/H2O = 1:1; CuF2 was increased to 10 mol %.
Table 2
Copper-catalyzed methyl ester of aldehydea
TBHP, CuF2
DMSO:H2O = 1:1
120 oC
RCHO
1
RCOOMe
2
Entry
1
R
Product
Yield (%)
Entry
8
R
Product
Yield (%)
70c
NC
R = Ph (1b)
65
71
R = 4-NCC6H4 (1i)
COOMe
2b
COOMe
2i
OMe
Br
Cl
COOMe
2
3
4
R = 3,5-(MeO)2C6H3 (1c)
R = 2-MeOC6H4 (1d)
9
10
11
R = 4-BrC6H4 (1j)
75
85
MeO
MeO
COOMe
2j
2c
OMe
67
54
R = 4-ClC6H4 (1k)
COOMe
COOMe
2d
2k
2l
OMe
COOMe
COOMe
R = 2,4,6-(MeO)3C6H2 (1e)
R = 2-naphthaleneyl (1l)
63
90
OMe
2e
Br
S
COOMe
5
6
R = 2-BrC6H4 (1f)
65
67
12
13
R = 2-thiophenyl (1m)
R = 4-HOC6H4 (1n)
COOMe
2m
2f
NO2
HO
R = 2-NO2C6H4 (1g)
44
COOMe
COOMe
2g
2n
(continued on next page)

392
P. Li et al. / Tetrahedron Letters 55 (2014) 390–393
Table 2 (continued)
Entry
R
Product
COOMe
Yield (%)
44b
Entry
14
R
Product
Yield (%)
44
Me
7
R = 2-(CHO)C6H4 (1h)
R = 4-MeC6H4 (1o)
COOMe
COOMe
2h
2o
a
A mixture of aldehyde (0.5 mmol), CuF2 (0.05 mmol), and TBHP (4 mmol) in 3 mL solvent (DMSO/H2O = 1:1) was stirred under argon in Schlenk tubes at 120 °C for 12 h.
Isolated yields.
b
TBHP (6 mmol) was added.
Reaction was performed at 100 °C for 12 h.
c
tBuOOH
tBuO
Comparing with aldehydes, oxidative methyl esterification of
benzoic alcohols13 represents a more sustainable alternative. To
our delight, the direct methyl esterification of benzylic alcohols,
substituted with electron-donating or -withdrawing groups at dif-
ferent positions, also proceeded efficiently under CuF2/TBHP sim-
ple catalyst system, affording 60–85% yields of desirable esters
(Table 3).
+
OH
Cu [X]
Cu [X+1]
tBuOOH
tBuOO
tBuO
_tBuOH
+
+
OH
H2O
RCHO
Deng and co-workers reported that DMSO could be a methyl
source for the methylation reaction.14a Coincidently, our highest
esterification yield was achieved in DMSO. In order to figure out
whether the methyl came from TBHP or DMSO, we carried out
the control reaction in DMSO-d6 with TBHP (5.5 M in decane)
instead of its aqueous solution (70 wt % TBHP). A 93% yield of 2a
was obtained with no deuterated ester detected, thus demonstrat-
ing the methyl group came from TBHP. Besides, 1-methoxy-2,2,6,6-
tetramethylpiperidine was detected by NMR and GC–MS in the
reaction of TEMPO with TBHP under the standard reaction condi-
tions.15 It was noteworthy that the expected methyl ester was
not observed when anisaldehyde was replaced with the corre-
sponding anisic acid, suggesting this transformation did not
proceed via an acid intermediate.3 This result ruled out forming
methyl ester via copper carboxylate intermediate.16 In addition,
when 3 equiv of TEMPO was added into the reaction as radical
scavenger, the yield sharply declined from 85% to 13%, possibly
indicating that radical intermediates were involved in the catalytic
cycle.
tBuOO
RCOOOtBu
RCO
(a)
(b)
O_O cleavage
RCOOOtBu
tBuO
tBuO
+
RCOO
(c)
(d)
+
CH3
CH3COCH3
RCOOCH3
+
RCOO
CH3
Scheme 1. Plausible reaction mechanism.
hyde could not only afford 44% yield of 2n, but also gave a certain
amount (5%) of 2a produced by further methylation on the hydro-
xyl group of 2n. Interestingly, 4-methylbenzaldehyde could not
only generate the desired product 2o in 44% yield, but also undergo
further oxidation of the methyl group of 2o to achieve 20% yield of
dimethyl terephthalate (2p). Similarly, 1-bromo-2-methylbenzene
could also afford 25% yield of the corresponding ester 2f. These
experimental results possibly suggested that such CuF2/TBHP sys-
tem could catalyze not only oxidative methyl esterification of the
aldehyde C–H bond, but also the methyl C(sp3)–H bond.12
Based on above experimental results and the related reports,17
a
plausible catalytic cycle is proposed in Scheme 1. Initially, the low-
valent copper species donated an electron to TBHP to generate a
Table 3
Copper-catalyzed methyl ester of benzoic alcohola
CuF2, TBHP
DMSO:H2O = 1:1
R
R
OH
COOMe
120 oC
3
2
Entry
1
R
Product
Yield (%)
Entry
4
R
Product
Br
Yield (%)
72
MeO
COOMe
2a
COOMe
R = 4-MeO (3a)
70
60
70
R = 2-Br (3d)
2f
Br
COOMe
2
3
R = H (3b)
5
6
R = 4-Br (3e)
77
85
COOMe
2j
2b
OMe
Cl
Cl
COOMe
R = 3,5-(MeO)2 (3c)
R = 3,4-Cl2 (3f)
MeO
COOMe
2q
2c
a
A mixture of benzoic alcohol (0.5 mmol), CuF2 (0.05 mmol), and TBHP (6 mmol) in 3 mL solvent (DMSO/H2O = 1:1) was stirred under argon in Schlenk tubes at 120 °C for
12 h. All yields were isolated yields.

P. Li et al. / Tetrahedron Letters 55 (2014) 390–393
393
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tert-butoxyl radical and a high-valent copper species. The latter
absorbed an electron from another molecule of TBHP and switched
back to the original low valent copper species along with the
production of tert-butyl peroxy radical. Tert-butoxyl radical could
abstract a hydrogen atom from aldehyde to generate the acyl rad-
ical,18 which coupled with tert-butyl peroxy radical, affording a
perester intermediate.10 This intermediate underwent a homolytic
cleavage to generate the acyloxyl radical and tert-butoxyl radical.19
It is known that tert-butoxyl radical could produce the methyl rad-
ical and acetone,1,3,20 these were successfully detected by NMR and
GC–MS. Ultimately, the desired methyl ester could be formed by
the cross-coupling of acyloxyl and methyl radicals.
In summary, we have developed a Cu-catalyzed methyl esterifi-
cation of aldehydes and alcohols utilizing TBHP as the oxidant and
methyl source. A radical reaction mechanism was proposed. Com-
pared with previous esterifications of aldehydes and alcohols, this
catalytic procedure represents a more sustainable alternative with-
out the use of noble metal and base. Further explorations about the
acyl radical and the methyl source are under investigation in our
laboratory.
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data.
10. Wei, W.; Zhang, C.; Xu, Y.; Wang, X. Chem. Commun. 2011, 10827.
11. Salamone, M.; DiLabio, G. A.; Bietti, M. J. Org. Chem. 2012, 77, 10479.
12. Methyl benzenes generated aromatic aldehydes, see recent examples: (a) Wu,
Y.; Choy, P. Y.; Mao, F.; Kwong, F. Y. Chem. Commun. 2013, 689; (b) Xu, Z.;
Xiang, B.; Sun, P. RSC Adv. 2013, 3, 1679; (c) Yin, Z.; Sun, P. J. Org. Chem. 2012,
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Acknowledgments
13. Benzoic alcohols generated aromatic aldehydes, see recent examples: (a) Li, H.;
Xie, J.; Xue, Q.; Cheng, Y.; Zhu, C. Tetrahedron Lett. 2012, 53, 6479; (b) Xu, K.;
Hu, Y.; Zhang, S.; Zha, Z.; Wang, Z. Chem.-Eur. J. 2012, 18, 9793; (c) Xiao, F.;
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Yuan, Y.; Chen, D.; Wang, X. Adv. Synth. Catal. 2011, 353, 3373; (e) Park, J.; Kim,
A.; Sharma, S.; Kim, M.; Park, E.; Jeon, Y.; Lee, Y.; Kwak, J. H.; Jung, Y. H.; Kim, I.
S. Org. Biomol. Chem. 2013, 11, 2766; (f) Gaspa, S.; Porcheddu, A.; Luca, L. D. Org.
Biomol. Chem. 2013, 11, 3803.
We thank The Chinese Academy of Sciences and the National
Natural Science Foundation of China (21002106 and 21133011)
for financial support.
Supplementary data
14. DMSO as methyl source, see recent examples: (a) Yao, B.; Song, R.-J.; Liu, Y.;
Xie, Y.-X.; Li, J.-H.; Wang, M.-K.; Tang, R.-Y.; Zhang, X.-G.; Deng, C.-L. Adv. Synth.
Catal. 1890, 2012, 354; (b) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun.
2011, 6725.
15. The detailed information of experiments see Supplementary data.
16. Although our reaction condition is similar to Chen’s report, the mechanism is
apparently different (see Ref. 3).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
11.040.
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