Copper catalyzed oxidative esterification of aldehydes with alkylbenzenes via cross dehydrogenative coupling

Article abstract of DOI:10.1021/ol301756y

Copper(II) as the catalyst in a cross dehydrogenative coupling (CDC) reaction has been demonstrated for the synthesis of benzylic esters using aldehydes and alkylbenzenes as coupling partners.

Full text of DOI:10.1021/ol301756y

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3982–3985
Copper Catalyzed Oxidative Esterification
of Aldehydes with Alkylbenzenes
via Cross Dehydrogenative Coupling‡
Saroj Kumar Rout, Srimanta Guin, Krishna Kanta Ghara, Arghya Banerjee, and
Bhisma K. Patel*
Department of Chemistry, Indian Institution of Technology, Guwahati,
Guwahati 781 039, India
patel@iitg.ernet.in
Received June 27, 2012
ABSTRACT
Copper(II) as the catalyst in a cross dehydrogenative coupling (CDC) reaction has been demonstrated for the synthesis of benzylic esters using
aldehydes and alkylbenzenes as coupling partners.
The upsurge in interest in the transition metal catalyzed
reactions via the cleavage of an ubiquitous CÀH bond has
been creating a renaissance in the construction of a diverse
array of CÀC and CÀX (X = heteroatom) bonds.1 The
two most popular approaches are chelation assisted CÀH
bond functionalization2 and the cross dehydrogenative
coupling (CDC).3 This field of synthesis has advanced to
suchanextent thateventheotherwiseinert sp3 CÀH bonds
could now be functionalized.3,4 The CDC approach is
attractive because it does not require substrate prefunctio-
nalization and it is atom economic.1d,5 As evident from the
literature, CDC has been widely investigated for the for-
mation of CÀC bonds3a,6 albeit the concept has rarely been
explored regarding CÀO bond formation. The relevance
of CÀO bonds in organic chemistry has resulted in the
emergence of various transition metal based methodolo-
gies via CÀH bond activation.7 In this regard the ester
functionality has been the common target. Some recent
metal catalyzed CDC based transformations for the synthe-
sis of esters involve acid and cyclic ethers where the
functionalization occurs selectively at the sp3 carbon atom
R totheetherealoxygen.8 Focusing on the protocolsfor the
synthesis of benzylic esters, besides the traditional methods,
a number of CDC based approaches employing metal cata-
lysts such as Ru,9 Rh,10 Ir,11 and Pd12 have been developed.
‡ Dedicated to Prof. Bijay Kumar Mishra on the occasion of his 60th
Birthday.
(1) (a) Handbook of CÀH transformations; Dyker, G., Ed.; Wiley-
VCH: Weinheim, 2005. (b) Shilov, A. E.; Shulpin, G. B. Chem. Rev. 1997,
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T. H. Acc. Chem. Res. 1995, 28, 154. (d) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215.
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2004, 126, 2300. (b) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2004, 126, 9542. (c) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.;
Wang, D.-H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu,
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Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (e) Ye, Z.;
Wang, W.; Luo, F.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 3974.
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Soc. 2005, 127, 10840. (b) Zhang, J.; Gandelman, M.; Shimon, L. J. W.;
Milstein, D. Dalton Trans. 2007, 107, 113. (c) Gunanathan, C.; Shimon,
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J.; Muzart, J. Chem. Rev. 2011, 111, 1170.
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50, 2178. (b) Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem., Int.
Ed. 2010, 49, 6169. (c) Deng, G.; Zhao, L.; Li, C. J. Angew. Chem., Int.
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r
10.1021/ol301756y
Published on Web 07/20/2012
2012 American Chemical Society

Most of these transition metal catalyzed formations of
benzylic esters invoke the concept of a hydrogen borrow-
ing13 or hydrogen autotransfer process14 where benzylic
alcohols serve as a precursor. The other methodology that
has recently been developed uses the advantage of metal-
free conditions for the synthesis of benzylic esters via
oxidative CÀO bond formation at the sp3 benzylic carbon
of various alkylbenzenes with carboxylic acids.15
Table 1. Substrate Scope for Benzylic Estersa,b
Extensive use and exploration of copper in CÀH activa-
tion is a promising area in organic synthesis because of its
high efficiency as a catalyst.16 The use of various copper
salts in combination with peroxides as an oxidant is known
to work effectively in facilitating functionalizations at the
relatively inert sp3 carbon.3a,17 However, most of these
methodologies concentrate on CÀH bond functionaliza-
tion at the sp3 carbon atom R to heteroatoms. A direct
functionalization at the relatively nonactivated alkylben-
zenes has rarely been explored. To date, there is no
precedence of copper catalyzed methodology with alkyl-
benzenes and aldehydes as precursors for the synthesis of
benzylic esters via a CDC approach. With this motivation
we initiated our investigation by reacting benzaldehyde
(1 equiv) (a) with toluene (5 equiv) (1) in the presence
copper(I) bromide (20 mol %) and aqueous TBHP
(1 equiv) at 80 °C which provided the expected (1b) ester
but in a mere yield of 22%. The hydrated copper(II)
acetate provided a superior yield (48%) compared to other
Cu salts such as CuBr2, CuCl, CuCl2, and Cu(OTf)2 tested.
The use of a decane solution of TBHP instead of aqueous
TBHP improved the yield up to 65%. Interestingly, an
identical yield was observed using 10 mol % of the catalyst
when TBHP in decane (5À6 M) was used. A complete
disappearance of the substrate (1a) was observed with an
isolated yield of 74% when the oxidant quantity was
increased by 2-fold at a temperature of 100 °C. A further
decrease in catalyst loading (5 mol %) had an adverse
effect on product yield. No desired product was obtained
when oxidant H2O2 was used instead of TBHP. The
control experiments carried out with either a copper
€
(10) Zweifel, T.; Naubron, J.-V.; Grutzmacher, H. Angew. Chem.,
Int. Ed. 2009, 48, 559.
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2003, 68, 1601. (b) Dam, J. H.; Osztrovszky, G.; Nordstrøm, L. U.;
Madsen, R. Chem.;Eur. J. 2010, 16, 6820. (c) Watson, A. J. A.;
Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667. (d) Shimizu,
K. -i.; Ohshima, K.; Satsuma, A. Chem.;Eur. J. 2009, 15, 9977.
(12) (a) Gowrisankar, S.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2011, 50, 5139. (b) Liu, C.; Wang, J.; Meng, L.; Deng, Y.; Li, Y.;
Lei, A. Angew. Chem., Int. Ed. 2011, 50, 5144. (c) Liu, C.; Tang, S.;
Zheng, L.; Liu, D.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2012,
51, 5662.
(13) (a) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton
Trans. 2009, 753. (b) Lamb, G. W.; Williams, J. M. J. Chim. Oggi. 2008,
26, 17. (c) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv.
Synth. Catal. 2007, 349, 1555.
(14) Ramon, J.; Yus, M.; Guillena, G. Angew. Chem., Int. Ed. 2007,
46, 2358.
(15) Feng, J.; Liang, S.; Chen, S.-Y.; Zhang, J.; Fu, S.-S.; Yu, X.-Q.
Adv. Synth. Catal. 2012, 354, 1287.
(16) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
(b) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607. (c) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y.
Org. Lett. 2007, 9, 3469. (d) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed.
2008, 47, 7075.
a Reaction conditions: aldehyde (1 mmol), alkylbenzene (5 mmol),
Cu(OAc)2 2H2O (0.1 mmol), TBHP (2 mmol), 100 °C, time 1.5À7 h.
3
b Reactions were monitored by TLC. Confirmed by spectroscopic
analysis. Yield of isolated pure product reported.
(17) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
Org. Lett., Vol. 14, No. 15, 2012
3983

catalyst or TBHP alone did not serve the purpose, as no
desired product could be detected.
alkyl (1°) position. The use of benzylic alcohols such as
p-methoxybenzyl and p-nitrobenzyl alcohols (as latent alde-
hydic functionality) with alkylbenzenes is expected to give
the aforementioned unsymmetrical esters. However, when
p-methoxybenzyl and p-nitrobenzyl alcohols were treated
separately with toluene (1) under the present experimental
conditions, only self-coupled symmetrical benzylic esters,
viz. 4-nitrobenzyl-4-nitrobenzoate and 4-methoxybenzyl-4-
methoxybenzoate, were obtained and no traces of unsym-
metrical esters benzyl-4-nitrobenzoate and benzyl-4-
methoxybenzoate could be found. Thus, the present methodol-
ogy is most suitable for the preparation of unsymmetrical esters.
Encouraged by the outcome of the above experiments,
the suitability of this protocol was examined toward the
synthesis of benzylic esters employing various alkylben-
zenes with a set of aldehydes as coupling partners. The
optimized conditions were initially applied to the coupling
of toluene (1, Table 1) with a set of aromatic aldehydes
(aÀe, Table 1) having both electron-donating (b and c) and
electron-withdrawing (d) substituents. It was observed
that, under the present conditions, toluene smoothly un-
derwent reactions with various aldehydes to afford the
desired benzylic esters (1aÀ1d) in good to excellent yields
as shown in Table 1. Reaction with p-phenyl benzaldehyde
(e) gave a fairly good yield of the corresponding benzylic
ester (1e). As evident from the results in Table 1, the
electronic effects of the substituent in the aryl ring bearing
the aldehyde functionality played a role in controlling the
product yields. With electron-donating substituents (bÀc,
Table 1), high yields of the benzylic esters (1bÀ1c, Table 1)
were obtained in a shorter span while those with electron-
withdrawing substituents (d, Table 1) proceeded a bit
sluggishly providing moderate yields. To further unravel
the potentiality of this approach, other target alkylben-
zenes, viz. p-xylene (2), o-xylene (3), and mesitylene (4)
(Table 1), were examined, all of which possess more than
one benzylic carbon. A query arises as to whether their
reactions would provide mono, bis, or tri esters. However,
the most appealing outcome in all their reactions were the
selective formation of the corresponding monoester with
the other alkyl (methyl) groups remaining intact besides
undergoing a smooth reaction with their corresponding
coupling aldehyde partners. Specifically, the reaction of
p-xylene (2) when treated witha diverse array of aldehydes,
viz. aromatic (aÀb, eÀh, Table 1) aliphatic (i), hetero-
atomic (j), and RÀβ unsaturated (k), provided satisfactory
results (Table 1). The formations of the benzylic esters
(2aÀ2k, Table 1) were unaffected by the influence of any
groups present within the aldehydic moiety. This meth-
odology was also equally successful toward the monoester-
ification of o-xylene (3) and mesitylene (4) with various
aldehydes as shown in Table 1. Noteworthy, the reactivity
trends observed for these di- or trialkylatedbenzenes with
aromatic aldehydes were the same as was observed with
toluene (1). Next we turned our attention to study the
reactivity of benzylic CÀH of 2,4-dichloromethylbenzene
(5, Table 1) with aromatic aldehydes (a, b, and l, Table 1).
In all these cases the reactions proceeded rather sluggishly
to afford the desired products (5a, 5b, and 5l) in moderate
to good yields depending on the substituent present in the
aldehydes. The slow reactivity of 2,4-dichloromethylben-
zene (5) could be attributed to the reluctance of the methyl
group toward the CÀO bond formation with Cu/TBHP.
The reaction of ethylbenzene (6, Table 1) with p-methoxy-
benzaldehyde (b) proceeded smoothly to form the CÀO
bond selectively at the 2° benzylic carbon to form the
corresponding benzylic ester (6b, Table 1). This observa-
tion shows that benzylic carbon is more susceptible toward
an oxidative CÀO bond formation rather than another
Scheme 1. A Crossover Experiment
To probe the mechanism of the reaction, several control
experiments were performed. During the reaction of ben-
zaldehyde (a) with p-xylene (2), along with the desired
product (2a), formation of p-methylbenzyl alcohol was
observed with a trace amount of benzoic acid (oxidation
of benzaldehyde). p-Methylbenzyl alcohol formed by the
oxidation of a combination of p-xylene (2) withCu/TBHP.18
Thus ambiguity appears in whether the esterification oc-
curred via a reaction of in situ generated benzyl alcohol with
benzaldehyde (a) by an oxidative process19 or by the radical
coupling of the in situ generated benzoic acid (from
benzaldehyde) with p-xylene (2) as has been reported.15 To
ascertain the exact coupling partners a crossover experiment
was performed in which p-methoxybenzaldehyde (b) and
benzoic acid were reacted with p-xylene (2) under the present
experimental conditions (Scheme 1). No formation of
4-methylbenzyl benzoate (2a) and exclusive formation of
4-methylbenzyl-4-methoxy benzoate (2b) ruled out the usual
esterification of acid and alcohol (generated in situ from
p-xylene) or the radical pathway between acid and
alkylbenzene.15 This reaction, rather, occurs via the cou-
pling of aldehyde and the in situ generated alcohol (from
alkylbenzene) via a hemiacetal intermediate12,19 as shown in
Scheme 2. No kinetic isotope effect (KH/KD ∼1) was observed
when the reaction of deuterated benzaldehyde was carried out
with toluene (1) suggesting that hydride transfer is not the
rate-determining step. Considerable rate retardation asso-
ciated with the poor yield of product in the presence of a
radical scavenger such as 2,2,6,6-tetramethylpyridine
N-oxide (TEMPO) suggests inhibition of oxidation at the
benzylic carbon leading to the formation of alcohol which is
possibly the rate-determining step.18
(18) Rothenberg, G.; Feldberg, L.; Wiener, H.; Sasson, Y. J. Chem.
Soc., Perkin. Trans. 2 1998, 2429.
(19) Gopinath, R.; Patel, B. K. Org. Lett. 2000, 2, 577.
3984
Org. Lett., Vol. 14, No. 15, 2012

observed for polyalkylated benzenes indicating a high
degree of selectivity. This methodology provides an ave-
nue to the synthesis of various unsymmetrical benzylic
esters from diverse alkylbenzenes and aldehydes. Hence
this protocol is yet another novel addition to the existing
methods.
Scheme 2. Proposed Mechanism of the Oxidative Esterification
Acknowledgment. B.K.P. acknowledges the support of
this research by the Department of Science and Technol-
ogy (DST) (SR/S1/OC-79/2009), New Delhi, and the
Council of Scientific and Industrial Research (CSIR)
(01(2270)/08/EMR-II). S.K.R., S.G., and A.B. thank
CSIR for fellowships. Thanks are due to Central Instru-
ments Facility (CIF) IIT Guwahati for NMR spectra.
Supporting Information Available. General informa-
tion, experimental procedures, spectral data, and copies
of 1H NMR and 13C NMR spectra for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion we have developed a new and efficient
catalytic approach for the synthesis of benzylic ester from
aldehydes and alkylbenzenes. This reaction proceeds via
benzylic sp3 CÀH bond activation of alkylbenzenes in the
presence of an inexpensive copper catalyst and TBHP
combination. Exclusive formation of monoesters was
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
3985