Copper-catalyzed oxidative esterification of aldehydes with dialkyl peroxides: Efficient synthesis of esters of tertiary alcohols

Article abstract of DOI:10.1039/c3ra40246k

Copper-catalyzed oxidative esterification of aldehydes with dialkyl peroxides has been developed. This protocol affords a novel approach for the synthesis of carboxylic esters of tertiary alcohols under mild conditions. Depending on the catalyst system, a variety of tertiary esters were produced in good to excellent yields.

Full text of DOI:10.1039/c3ra40246k

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Copper-catalyzed oxidative esterification of aldehydes
with dialkyl peroxides: efficient synthesis of esters of
tertiary alcohols3
Cite this: RSC Advances, 2013, 3, 13668
Received 17th January 2013,
Accepted 21st June 2013
Yefeng Zhu and Yunyang Wei*
DOI: 10.1039/c3ra40246k
www.rsc.org/advances
Copper-catalyzed oxidative esterification of aldehydes with
dialkyl peroxides has been developed. This protocol affords a
novel approach for the synthesis of carboxylic esters of tertiary
alcohols under mild conditions. Depending on the catalyst system,
a variety of tertiary esters were produced in good to excellent
yields.
date, only a limited amount work has been published regarding
the formation of tertiary esters via the direct esterification of
aldehydes.5h,13 The problem was presumably due to the relative
bulkiness of tertiary alcohols compared with primary and
secondary alcohols. However, the high utility of tertiary esters,
especially as protecting groups for the free carboxylic acid, calls for
continuous development toward their synthesis.
In this paper, we report a new copper-catalyzed direct
esterification of aldehydes with dialkyl peroxides for the synthesis
of tertiary esters under mild conditions (Scheme 1, eqn (5)).13 In
contract to previous reports, the dialkyl peroxide plays a dual role
as an oxidant and a tertiary alcohol precursor in this reaction. To
the best of our knowledge, there is no precedence of copper
catalyzed synthesis of tertiary esters of carboxylic acids from
aldehydes and dialkyl peroxides.
Esters are important intermediates in organic chemistry. They can
be found in an array of drugs, synthetic materials, and polymers.1
Because of the importance of this structural motif, many practical
synthetic methods have been developed. Among them, the
reaction of carboxylic acid derivatives with alcohols, either in the
presence of a condensing agent or directly under harsh reaction
conditions, is perhaps the most commonly utilized method for the
synthesis of esters.2 In particular, recent developments in
palladium-catalyzed three component esterification of an alcohol,
aryl halide and CO have provided a more direct approach for ester
synthesis.3,14 However, high temperature and high CO pressure
are required for the reaction to proceed in a reasonable rate.4
Recently, the increasing upsurge in attention to the direct
esterification of aldehydes with alcohols in the presence of an
oxidant and catalyst has presented one of the most attractive and
powerful strategies for esters synthesis and many important
results have been achieved via this methodology during the past
ten years (Scheme 1, eqn (1)).5 Furthermore, a copper-catalyzed
process that utilizes t-butyl hydro-peroxide (TBHP) as oxidant to
produce esters from aldehydes and b-diketones or b-keto esters,
which serve as enolate precursors, has been developed by Li and
coworkers (Scheme 1, eqn (2)).6 Copper catalyzed methodology
with alkylbenzenes and aldehydes as precursors for the synthesis
of benzylic esters via a CDC approach (Scheme 1, eqn (3))7 and a
new type of transesterification for the synthesis of esters using
aldehydes as acyl donors (Scheme 1, eqn (4))8 have also been
reported. Although great progress has been achieved in this field,
the formation of tertiary esters remains a persistent challenge. To
We started our research with benzaldehyde as substrate and
the commercially available di-t-butyl peroxide (DTPB) as oxidant
and t-butyl alcohol precursor (Table S1, ESI ). CuBr was initially
3
chosen as the copper source. In the absence of added ligands, we
could not observe the formation of the desired esterification
product 3a (Table S1, ESI, entry 1). Ligands such as tetramethy-
3
lethylenediamine (L1), 2-picolinic acid (L2), 2,29-bipyridyl (L3),
1,10-phenanthroline (L4) and triphenylphosphine (L5) are not
School of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing 210094, China. E-mail: ywei@mail.njust.edu.cn
Scheme 1 Direct esterification of aldehydes for the synthesis of esters.
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Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra40246k
3
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efficient in the reaction (Table S1, ESI, entries 2–6). With the use
of CuBr and Mannich base L6, which has been proved to be an
3
Table 1 Copper-catalyzed direct esterification of different aldehydes with
DTPBa,b
efficient catalyst in copper catalyzed C–N cross-coupling reactions
by us,9 only trace amount of 3a was detected (Table S1, ESI, entry
3
7). Other Mannich bases, such as L7, L8 and L9 gave similar
results as L6 (Table S1, ESI, entries 8–10). With dppp (L10) or
3
b-diketones (L11, L12) as ligand, t-butyl benzoate was obtained in
15% to 26% yield (Table S1, ESI, entries 11–12). Encouraged by
3
these results, imine L1310 was synthesis from diketone L11 and
2,6-dimethylbenzenamine and used as ligand in the copper
catalyzed esterification of benzaldehyde. To our delight the
desired product t-butyl benzoate was obtained in 92% yield
(Table S1, ESI, entry 13).
3
With L13 as ligand, we then examined the effectiveness of
various copper sources and solvents for the reaction (Table S2,
ESI ). As shown in Table S2, ESI, in the absence of any copper
3
3
source, no product was obtained (Table S2, ESI, entry 1). When
3
CuI, CuBr, CuCl or CuCl2 were used as catalyst, the desired
product was obtained in 82%, 85%, 87%, and 78% yield,
respectively (Table S2, ESI, entries 2–4, 8). However, employment
3
of Cu2O, Cu(OAc)2, or Cu(acac)2 as catalyst resulted in lower yields
(Table S2, ESI, entries 6–7, 9). It is worth to point out that the
3
choice of solvent was very important for the reaction. n-Hexane
was proved to be the proper solvent. Only trace amount of product
was observed when the reaction was conducted in other solvents
(Table S2, ESI, entries 10–13). Other t-butyl peroxide or
3
a
Reaction conditions: a mixture of aldehyde (1, 0.5 mmol), CuBr (20
combination of t-butanol and oxidants were then tested for the
reaction. Using of TBHP or t-butyl perbenzoate as t-butyl source
and oxidant instead of DTBP resulted in decreased yield (Table S2,
mol%), L13 (20 mol%), DTBP (2a, 0.3 mL) in n-hexane (3 mL) was
stirred at 90 uC for 5 h under N2. Isolated yield.c Yield determined
b
by GC-MS.d Reaction time was 12 h.e The reaction temperature was
110 uC.
ESI, entries 14–15). Combination of t-butanol and oxidant such as
3
O2, H2O2, K2S2O4 or NHPI led to no product formation (Table S2,
ESI, entries 16–19). Temperatures lower than 90 uC or decreased
3
the amount of peroxide DTBP will decelerate the reaction rates
delight, the aliphatic aldehydes could also be applied in this
reaction and provide the products in moderate yields (3q and 3r).
In an endeavor to expand the scope of the methodology, this
new catalytic system was applied to other dialkyl peroxides. To our
delight, dicumyl peroxide also worked well with aryl aldehydes,
affording the desired products in good yields (Table 2, 3s–3v).
However, when trityl peroxide, a more sterically bulky dialkyl
peroxide was used, no products were isolated (Table 2, 3w and 3x).
Although the detailed mechanism for the present transforma-
tion is not clear, a possible mechanism may includes the following
steps: the reaction of peroxide with copper(I) complex A formed
and lead to lower yields (Table S2, ESI, entries 20–21). Therefore,
3
the optimized reaction conditions is as follows: reacting 0.5 mmol
benzaldehyde with 0.3 mL DTBP in 3 mL n-hexane at 90 uC for 5 h
in the presence of 20 mol% of CuBr and L13.
With the above optimized conditions in hand, the scope of the
oxidative esterification was tested with other aromatic aldehydes
as coupling partners and the results was listed in Table 1. On the
whole, the reaction was benefited by electron donating groups and
hindered by electron withdrawing groups attached to the aromatic
ring. Aromatic aldehydes bearing electron donating groups or
weak electron withdrawing groups reacted smoothly under the
optimized conditions to form the corresponding esters in high
yields (3a–3i). With strong electron withdrawing groups the yield
of the product decreased remarkably. For example, when
4-nitrobenzaldehyde was used as substrate only 21% esterification
product 3j was detected by GC-MS even for a longer reaction time
of 12 h. Using of heteroaromatic aldehydes, such as furan-2-
carbaldehyde or 2-thenaldehyde as substrate, resulted in desired
product in good yields of 83% and 86% respectively (3o and 3p).
When o-tolualdehyde was used, corresponding ester was obtained
in 78% yield (3l) while no corresponding ester (3m and 3n) was
obtained even at 110 uC for 12 h when two ortho withdrawing
group substituted aryl aldehydes were used as substrate. To our
from CuBr and L13 generates intermediate LnCuII–OtBu (B)11c
,
coordination and subsequent insertion of aldehyde with inter-
mediate B to form a hemiacetal copper intermediate C12 which
then released the final product 3 and the copper hydride
intermediate D. Then the intermediate D undergoes oxidative
dehydrogenation to regenerate the LnCuI species (Scheme 2).
In conclusion, a novel copper-catalyzed oxidative esterification
procedure of aldehydes with dialkyl peroxides was developed. This
transformation provides an effective and practical protocol
towards the synthesis of t-alkyl, especially t-butyl esters. The
peroxide plays a dual role as an oxidant and a tertiary alcohol
precursor in this transformation and without the need of
additional oxidant, base or other additives. Further investigations
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13670 | RSC Adv., 2013, 3, 13668–13670
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