Easy access to benzylic esters directly from alkyl benzenes under metal-free conditions

Article abstract of DOI:10.1039/c3cc40832a

An efficient metal free protocol has been developed for the synthesis of benzylic esters via a cross dehydrogenative coupling (CDC) involving alkylbenzene(s) as a self- or as a cross-coupling partner(s) via the intermediacy of Ar-COOH and the benzylic carbocation obtained from the other half of the alkylbenzene; both symmetrical as well as unsymmetrical esters can be prepared using Bu₄NI and TBHP. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc40832a

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Easy access to benzylic esters directly from alkyl
benzenes under metal-free conditions†‡
Cite this: Chem. Commun., 2013,
49, 3031
Ganesh Majji, Srimanta Guin, Anupal Gogoi, Saroj Kumar Rout and
Bhisma K. Patel*
Received 31st January 2013,
Accepted 25th February 2013
DOI: 10.1039/c3cc40832a
www.rsc.org/chemcomm
An efficient metal free protocol has been developed for the synthesis protocols have been developed lately. Catalysts such as Ru, Rh, Ir, Pd
of benzylic esters via a cross dehydrogenative coupling (CDC) invol- and V have been employed for the cross dehydrogenative coupling
ving alkylbenzene(s) as a self- or as a cross-coupling partner(s) via (CDC) between aldehydes or the in situ generated aldehydes and
the intermediacy of Ar–COOH and the benzylic carbocation obtained alcohols (paths II and III, Scheme S1, ESI‡) for the synthesis of
from the other half of the alkylbenzene; both symmetrical as well as benzylic esters.11 Most of these processes rely on the concept of
unsymmetrical esters can be prepared using Bu4NI and TBHP.
either hydrogen borrowing12 or a hydrogen auto transfer process.13
Recently, a CDC based approach has been developed by our group
The selective oxidative cleavage of the sp3 C–H bond is of for the synthesis of benzylic esters from aryl aldehydes and alkyl-
paramount interest to both academic and industrial research.1 benzenes using Cu(II) as the catalyst and tert-butyl hydroperoxide
The two most common strategies adopted for the C–H bond (TBHP) as the oxidant (path IV, Scheme S1, ESI‡).6e Efficient
activation processes rely on the concept of chelation assisted C–H coupling of carboxylic acids or the in situ generated carboxylic acids
bond functionalization2 and cross dehydrogenative coupling and alkylbenzenes has also been reported under metal free condi-
(CDC).3 CDC based methodologies are highly appreciable because tions using tetra n-butylammonium iodide (Bu4NI) as the catalyst
it does not require substrate prefunctionalisation. Besides being and TBHP as the oxidant (path V, Scheme S1, ESI‡).8c–d
atom and step economic, these reactions are often air and
During the course of our investigations on CDC coupling
moisture insensitive, and thereby can be performed in an aqueous between benzaldehyde and p-methoxytoluene, the formation of
environment or an air atmosphere.4 The CDC approach has been benzoic acid and p-methoxybenzyl alcohol originating respectively
mainly exploited towards the C–C bond formations,3a,5 but of late from benzaldehyde and p-methoxytoluene was observed. The in situ
the number of C–O bond forming reactions are also increasing.3e,6 generated p-methoxybenzyl alcohol can be further converted to its
The CDC based protocols in the construction of a C–O bond aldehyde and subsequently to carboxylic acid under the oxidative
have been achieved using transition metal catalysts such as Cu, reaction conditions. Thus, the in situ formed aldehyde or acid can in
Fe, Ru, Rh, Ir, and Pd in combination with various oxidants.7 turn couple with the unreacted alkylbenzene in the medium to give
However, the disadvantages associated with these method- an ester via a CDC approach (Scheme S1, ESI,‡ paths IV and V).6e,8c–d
ologies, owing to the use of expensive metal catalysts, elevated Hence, we envisaged a self-coupling of an alkylbenzene or a cross-
reaction temperature, and the problems associated with the coupling between two different alkylbenzenes to obtain a symme-
removal of metal residues limit their practical applicability. trical or an unsymmetrical ester (Scheme S1, ESI,‡ path VI).
Therefore, increasing interest has been focused on metal free
In pursuit of the above objective when toluene (a) was treated
catalysts, particularly towards the formation of a C–O bond.6a–c,8 with Cu(OAc)2Á2H2O (0.1 equiv.) and TBHP (4 equiv.), a condition
Selective to the C–O bond formation, the ester functionalities, similar to our previous report, only a trace (o3%) of benzylbenzoate
particularly the benzylic esters, are common target because of their (aa) was formed (entry 1, Table S1, see ESI‡) along with substantial
applications in synthetic organic and medicinal chemistry.9 Besides formation of benzoic acid.6e In spite of the presence of significant
the traditional esterification reactions involving alcohols and acids amount of benzoic acid in the medium, the amount of ester (aa)
(or their equivalents) (path I, Scheme S1, ESI‡),10 several elegant formed was negligible as the Cu(II)/TBHP condition is perhaps not
conducive for the coupling between an acid and an alkylbenzene.6e
Traces of the ester (aa) formed is possibly due to the less concen-
tration of benzaldehyde and benzyl alcohol present in the medium,
Department of Chemistry, Indian Institute of Technology Guwahati,
781 039, Assam, India. E-mail: patel@iitg.ernet.in; Fax: +91-3612690762
while most of the benzaldehyde gets rapidly oxidised to benzoic
† We would like to dedicate this manuscript to Prof. Dr. Fritz Eckstein on the
acid.6e Metal free catalyst Bu4NI in combination with oxidant TBHP
occasion of his 80th birthday.
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc40832a is not only an efficient reagent for the oxidation of alkylbenzenes to
c
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acids but is also equally effective towards cross dehydrogenative
In light of these novel observations the optimised conditions
coupling between acids and alkylbenzenes.8c–d With this inspiration, were subsequently applied to m-methoxy (b), p-methoxy (c),
further optimisation was undertaken towards a metal free sp3 C–H p-chloro (d), p-bromo (e), and p-nitro (f) toluenes towards self-
bond oxidative esterification using toluene (a) as the self-coupling oxidative esterification. It was observed that, under the present
partner. Toluene (a) (1 mL) was treated with 10 mol% of Bu4NI and conditions, toluene with electron-donating substituents (b and c),
TBHP (5–6 M in decane) (4 equiv.) at room temperature, which the reactions proceeded smoothly to afford the desired self-
afforded benzylbenzoate (aa) in 30% isolated yield (entry 2, Table S1, coupled benzylic esters (bb, cc) in excellent yields (Scheme 1).
see ESI‡). Here the alkylbenzene (toluene) acts as reactant(s) i.e. self- For toluenes possessing electron-withdrawing substituents
coupling partner(s) as well as a solvent.
(d, e), the reaction provided the desired benzylic esters (dd, ee)
Taking cues from the literature and the controlled experiments in good yields but the reactions were a bit sluggish (Scheme 1).
carried out, a mechanism similar to the one proposed by Yu et al.8c The sluggishness was quite pronounced with the substrate bear-
and Wan et al.8d could be suggested for this transformation as well. ing strongly electron withdrawing –NO2 (f) in toluene under the
The oxidant TBHP is known to oxidize the catalyst Bu4N+IÀ to either present reaction conditions, giving a poor yield of 25% of the
[Bu4N+][IO]À or [Bu4N+][IO2]À.14 However, we have observed the desired ester (ff). For such a deactivated substrate, an improved
formation of [IO]À i.e. [Bu4N+][IO]À by ESI mass analysis of the yield (80%) was obtained when the reaction was performed at
reaction mixture. This active hypoiodite [Bu4N+][IO]À species would 110 1C (Scheme 1). These results imply that the electronic effects
initiate a homolytic cleavage at the benzylic C–H bond of the toluene of the substituents in the methyl benzene affect the reaction rates
to give a benzyl radical (I).8c–d,15 Formation of a benzyl radical (I) and the product yields.
could be the rate determining step in the entire reaction. The
The synthetic utility of this approach was then applied to
benzylic radical (I) is further oxidised by the hypoiodite species various di-alkylatedbenzenes such as o-xylene (g), m-xylene (h),
[Bu4N+][IO]À to a benzyl cation (II). Alternatively, some of the and p-xylene (i), all of which gave self-coupled monoesters (gg),
alkylbenzene could be converted to its alcohol via a radical oxidation (hh), and (ii) in excellent yields (Scheme 1). Only monoesters were
path and subsequently to corresponding acid (III) via an aldehyde obtained in these cases and no traces of diesters were detected.
intermediate (see Scheme S2, ESI‡). After the formation of the acid Symmetrical trialkylatedbenzene such as mesitylene (j) yielded
(III), the oxygen atom of the hypoiodite species [IO]À removes the the corresponding self-coupled monoester (jj) (Scheme 1).
acidic proton from the benzoic acid, giving a benzoate ion (IV).
Finally, the coupling between the in situ generated benzoate ion (IV)
and the benzyl cation (II) would give the desired ester as shown in
Scheme S2 (ESI‡). As per the mechanism, four equivalents of the
oxidant (TBHP) get consumed, forming an equivalent of the benzo-
ate ion (IV) and further two equivalents are required for the
formation of the benzyl cation (II) from alkylbenzene. Thus, a total
of six equivalents of TBHP is essential for the coupling of two
equivalents of alkylbenzene, giving an equivalent of ester.
Moving further onto the optimization, when the same reaction
was performed using 6 equivalents of TBHP at 80 1C the yield
improved upto 90% (entry 3, Table S1, see ESI‡). Gratifyingly, the
use of aqueous TBHP (70%) instead of a decane solution of TBHP
(5–6 M) improved the yield upto 95% (entry 4, Table S1, see ESI‡).
Upon increasing the reaction temperature to 100 1C or increasing
the catalyst quantity to 20 mol%, no further improvement in the
yield was observed (entries 5–6, Table S1, ESI‡). However a
decrease in the catalyst loading (5 mol%) and oxidant quantity
(5 equiv.) reduced the product yield (entries 7–8, Table S1, ESI‡).
No desired product could be obtained when oxidants H2O2, DDQ,
PhI(OAc)2 (entries 9–11, Table S1, ESI‡) were used instead of
TBHP. Other halogen species such as Bu4NBr, KI and I2 (entries
12–14, Table S1, ESI‡) were found to be completely ineffective.
Control experiments carried out in the absence of either the
catalyst (Bu4N+IÀ) or the oxidant (TBHP) failed to bring about the
desired transformation, suggesting the requirement of this parti-
cular combination.
It may be mentioned here that recently Luque et al. have
reported a Au–Pd system for the selective oxidation of alkyl-
Scheme 1 Substrate scope for the synthesis of benzylic esters via metal free
benzenes to esters.16 The method mentioned not only uses
C–H functionalization. aReaction conditions: alkylbenzene (1 mL), Bu4N+IÀ
(0.1 mmol), TBHP (6 mmol), 80 1C, time 6 h. bReactions were monitored by TLC,
expensive catalyst but also gives multitudes of other products
and hence is of little industrial significance.
confirmed by spectroscopic analysis. Yield of the isolated pure product reported.
c
3032 Chem. Commun., 2013, 49, 3031--3033
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As depicted in the mechanism (Scheme S2, ESI‡), during the
formation of a symmetrical ester, one half of the alkylbenzene
is transformed to acid, which couples with the in situ generated
benzyl cation derived from the other half of the alkylbenzene.
Ethylbenzene is expected to form a more stable carbocation
than the methylbenzene and the latter is more susceptible to
oxidation, giving acid. Thus, if an equimolar mixture of ethyl
and methylbenzene is treated under the present reaction con-
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prepared from alkylbenzenes as the only precursor via a cross
dehydrogenative coupling (CDC) under metal free conditions
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self-coupled product for mono or poly methylatedbenzenes.
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and methylbenzene where the acid part is derived from methyl-
benzene and the benzyl cation is derived from ethylbenzene.
Various functional groups are tolerated under the present
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B. K. P. acknowledges the support of this research by the
Department of Science and Technology (DST) (SR/S1/OC-79/2009),
New Delhi, and the Council of Scientific and Industrial Research
(CSIR) (02(0096)/12/EMR-II). MG thanks UGC for fellowship.
Thanks are due to Central Instruments Facility (CIF) IIT Guwahati
for NMR spectra.
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c
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Chem. Commun., 2013, 49, 3031--3033 3033