Bu4NI-catalyzed benzylic acyloxylation of alkylarenes with aromatic aldehydes

Article abstract of DOI:10.1039/c2cc35450k

An nBu₄NI-catalyzed benzylic C-H acyloxylation of alkylarenes with readily available aromatic aldehydes has been developed. These reactions occur under mild and clean reaction conditions using tert-butyl hydroperoxide as the green terminal oxid

Full text of DOI:10.1039/c2cc35450k

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COMMUNICATION
Bu4NI-catalyzed benzylic acyloxylation of alkylarenes with aromatic
aldehydesw
Juan Huang, Lan-Tao Li, Hong-Ying Li, Ezizjan Husan, Peng Wang and Bin Wang*
Received 24th May 2012, Accepted 30th August 2012
DOI: 10.1039/c2cc35450k
An nBu4NI-catalyzed benzylic C–H acyloxylation of alkylarenes
with readily available aromatic aldehydes has been developed.
These reactions occur under mild and clean reaction conditions
using tert-butyl hydroperoxide as the green terminal oxidant.
sp3 C–H bonds.5 We reasoned that the methyl group of 1a would
also be amenable to esterification under suitable conditions. As
shown in Table 1, 2-methylquinoline 1a was treated with 2 equiv.
of benzaldehyde 2a and 40 mol% of catalyst at 80 1C for 12 h
under a nitrogen atmosphere. When 4 equiv. of H2O2 was used
as a terminal oxidant, the acyloxylation of 1a with 2a only gave
traces of the desired product 3a in the presence of nBu4NI
(Table 1, entry 1). We found that changing the oxidant from
H2O2 to TBHP provided the superior conversion of 1a, giving
product 3a in 76% isolated yield (Table 1, entry 2). In contrast,
potassium iodide was completely ineffective under the same
conditions as those of entry 2 (Table 1, entry 3). We speculate
that the potassium ion may inhibit the present acyloxylation. The
reaction did not occur with I2 as the catalyst (Table 1, entry 4).
When the acyloxylation was performed in ethyl acetate, the
yield was only slightly lower than that obtained with water as
the solvent (Table 1, entry 5). Although copper(I) salts can be
efficiently used in the Kharasch–Sosnovsky reaction,2b the
present reaction did not occur with CuBr and the starting
materials were fully recovered from the reaction mixture
(Table 1, entry 6). The desired product 3a was not detected
in the absence of nBu4NI, and a trace amount of 2-quinoline-
carboxaldehyde was formed (Table 1, entry 7). The reaction
was also performed under anhydrous conditions by using dry
EtOAc as the solvent, and 3a was obtained in 70% yield.
Benzyl esters are valuable building blocks in organic synthesis
due to their analogy with allyl esters and they have frequently
been employed for decarboxylative benzylations and acyl C–O
bond activations.1 Traditional approaches for the formation
of benzyl esters rely on prefunctionalized starting materials,
including benzyl alcohols, carboxylic acids and acyl chlorides.
The synthesis of benzyl esters can also be achieved via copper-
catalyzed Kharasch–Sosnovsky reaction.2 However, it suffers from
several drawbacks, such as long reaction time, requirement for
high alkene concentrations, and substrate restrictions. Recently,
the direct and catalytic transformation of benzylic C–H bonds to
benzyl esters via C–H activation has attracted much attention. In
particular, Pd-catalyzed oxidative coupling reactions have been
well studied and effectively promote the benzylic C–H bond
acyloxylation with carboxylic acids.3 Although significant effort
has been devoted toward developing atom economical methods
for synthesis of benzyl esters, use of expensive palladium species,
toxic heavy metal oxidants and excess acids is required in these
transformations. To date synthesis of benzyl esters from aldehydes
via the direct acyloxylation of benzylic sp3 C–H bonds has not
been exploited. As part of a program aimed at developing
metal-free methods for the functionalization of sp3 C–H bonds,4
we report herein an nBu4NI-catalyzed direct acyloxylation of
benzylic C–H bonds with readily available aromatic aldehydes
and alkylarenes as coupling partners. This transformation utilizes
tert-butyl hydroperoxide (TBHP) as the green terminal oxidant
and proceeds efficiently with a series of different alkylarenes and
aromatic aldehydes under mild and clean conditions.
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Oxidant
Solvent
Yield
1
2
3
4
5
6
7
8b
nBu4NI
nBu4NI
KI
H2O2
H2O
H2O
H2O
H2O
EtOAc
H2O
H2O
Trace
76
0
0
71
0
Our initial efforts toward benzylic C–H acyloxylation focused
on the reaction of 2-methylquinoline 1a and benzaldehyde 2a.
Previous work from other groups has shown that 2-methyl
azaarenes are effective chelating units for alkylation of benzylic
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
I2
nBu4NI
CuBr
—
0
70
nBu4NI
EtOAc
State Key Laboratory of Medicinal Chemical Biology, College of
Pharmacy, Nankai University, 94 Weijin Road, Tianjin 300071,
China. E-mail: wangbin@nankai.edu.cn; Fax: +86-22-23507760;
Tel: +86-22-23506290
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc35450k
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst
(0.2 mmol), oxidant (2.0 mmol), TBHP (70% aqueous), solvent
b
(4 mL), 80 1C, 12 h, under nitrogen, isolated yield. TBHP (5.5 M
in decane).
c
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Table
2
Acyloxylation of 2-methyl azaarenes with aromatic
Table 3 Acyloxylation of inert alkylarenes with aromatic aldehydesa
aldehydesa
a
Reaction conditions: 4a–l (10.0 mmol), 2a (1.0 mmol), nBu4NI
(0.2 mmol), TBHP (4.0 mmol), 80 1C, 17 h, under nitrogen, isolated yield.
that the reaction proceeded well with inert alkylarenes, providing
the corresponding product in 15–72% yield (Table 3). The
reaction of diphenylmethane 4h gave the highest yield (72%)
due to the activation of another phenyl group. Notably, when
xylene was employed as a substrate, the corresponding mono-
ester was obtained as a single product (Table 3, 5b–d). In the
case of alkylarene with two potential sites of acyloxylation (5g,
5l, methyl vs. methoxyl; 5j, 5k, 11 C–H bond vs. 21 C–H bond),
the reaction showed complete regioselectivity for acyloxyla-
tion at benzylic C–H bonds. Unfortunately, attempts to
perform the acyloxylation of 2-methylpyridine using this
method failed even using 10 equiv. of 2-methylpyridines.
Several recent reports have proposed that a radical path-
way6 and in situ generated (hypo)iodites ([IO]ꢀ and [IO2]ꢀ)7
are involved in this catalysis system. At the beginning of this
study, benzoic acid was assumed to be a potential intermediate
in the present benzoyloxylation.8 A control experiment
revealed that benzoic acid was not observed in this trans-
formation (eqn (1)). We think that the benzoic acid may be
transformed to the benzoate anion quickly under the standard
conditions.8b When the reaction of 1a and benzaldehyde 2a
was quenched after 2 h, tert-butyl peroxybenzoate (TBPB) was
isolated in 30% yield, together with 10% of ester 3a (eqn (2)).
The reaction of 1a was further performed by using TBPB
instead of benzaldehyde in the absence of TBHP under
standard conditions, and 3a was obtained in 70% isolated
yield after 4 h (eqn (3)). From the above results we speculate
that the in situ generated TBPB may be the key intermediate
of this benzoyloxylation. More recently, Wan and co-workers
have developed an nBu4NI-catalyzed synthesis of TBPB
with benzaldehyde and TBHP. A radical pathway has
been proposed for their transformation (Scheme 1a).6b The
present reaction could also be inhibited by the radical scavenger
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (eqn (4)). Thus,
we reason that TBPB is formed at the initial stage of the
reaction via a radical process (Scheme 1a). In addition, the
reactions of benzylic alcohol with 2-methylquinoline or p-xylene
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), nBu4NI (0.2 mmol),
TBHP (2.0 mmol), H2O (4 mL), 80 1C, 12 h, under nitrogen, isolated
yield. Aldehyde (0.5 mmol), 7 h. 7 h.
b
c
Using the optimized reaction conditions uncovered in Table 1,
entry 2, we subsequently explored the reaction scope by using
substituted 2-methyl azaarenes 1 and aromatic aldehydes 2
(Table 2). A variety of 2-methyl azaarenes afforded the acyloxy-
lation products in 41–96% isolated yields (Table 2, 3a–t). When
2,4-dimethylquinoline was subjected to the optimized conditions,
the selective esterification of 2-methyl group was observed
(Table 2, 3b). Functional groups such as fluoro, chloro, bromo,
methoxy, nitro, and methyl group are compatible with the
reaction conditions. The electron donating substitute on alde-
hydes seems to promote the outcome of the reaction (Table 2, 3n
and 3o). Successful benzoyloxylation of 2-methylquinoxaline was
also achieved (Table 2, 3d). Notably, 2-naphthaldehyde,
4-methylbenzaldehyde and 3-bromobenzaldehyde gave the
corresponding benzyl esters in high yields (Table 2, 3k, 3n
and 3s). This method was further expanded to the hetero-
aromatic aldehyde by shortening the reaction time and reducing
the amount of aldehyde (Table 2, 3t). Encouraged by our success
in benzylic esterification of 2-methylquinolines (Table 2), we
hypothesized that we could develop a generally applicable
acyloxylation protocol using inactivated benzylic C–H bonds.
Gratifyingly, by increasing the amount of alkylarene, we found
c
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Scheme 1 Proposed TBPB formation pathway.
TBHP ð4:0 eq:Þ=nBu4NI ð0:4 eq:Þ
Scheme 2 A plausible pathway for the reaction.
Ph-CHO
Ph-COOH 0% ð1Þ
H2O; 80 ꢁC; 12 h; N2
C–H bond of alkylarene to afford benzylic radical 6, which is
re-oxidized quickly by (hypo)iodites to provide benzyl cation
7.8b,11 Finally, the reaction of 7 with the benzoate anion affords
the ester. It has been reported that the reaction of 2-picoline
N-oxide with acetic anhydride yields the 2-pyridylcarbinol
acetate, together with some sp2 C–H acyloxylation products.12
In the case of 2-methylquinolines, neither 2-methylquinoline
N-oxide nor the sp2 C–H acyloxylation product was detected.
In summary, we have developed a metal-free approach for
the direct acyloxylation of benzylic C–H bonds using aromatic
aldehydes under mild and clean conditions. Further investiga-
tions of the detailed mechanism are underway.
TBHP ð4 eq:Þ=nBu4NI ð0:1 eq:Þ
H2O; 80 ꢁC; 2 h; N2
1a Ph-CHO
0:5 mmol 1 mmol
TBPB 3a
30% 10%
þ
þ
ð2Þ
nBu4NI ð0:1 eq:Þ
H2O; 80 ꢁC; 4 h; N2
1a TBPB
0:5 mmol 1 mmol
þ
3a 70%
ð3Þ
TBHP ð4:0 eq:Þ=nBu4NI ð0:4 eq:Þ
TEMPO ð2:0 eq:Þ H2O; 80 ꢁC; 12 h; N2
1a Ph-CHO
0:5 mmol 1 mmol
þ
N: R:
ð4Þ
Financial support from the National Natural Science
Foundation of China (No. 21172120, 20902050) is greatly
appreciated.
I2 ð0:1 eq:Þ=nBu4NOH ð0:1 eq:Þ
1a Ph-CHO
0:5 mmol 1 mmol
þ
N: R: ð5Þ
H2O; 80 ꢁC; 2 h; N2
l2 ð0:1 eq:Þ=nBu4NOH ð0:1 eq:Þ
H2O; 80 ꢁC; 4 h; N2
1a TBPB
0:5 mmol 1 mmol
þ
3a 60%
ð6Þ
Notes and references
1 (a) J. D. Weaver, A. Recio, III, A. J. Grenning and J. A. Tunge,
Chem. Rev., 2011, 111, 1846; (b) R. Kuwano, Synthesis, 2009, 1049.
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TBHP ð4:0 eq:Þ=nBu4NI ð0:4 eq:Þ
H2O; 80 ꢁC; 12 h; N2
1a
0:5 mmol
PhCOONa
1 mmol
þ
3a 60%
ð7Þ
proceeded smoothly to give the corresponding esters.9
Moreover, benzylic alcohol can be oxidized to TBPB under
the present conditions.9 The results indicate that Cannizaro
reaction may also be involved as an alternative pathway for
the formation of TBPB. As shown in Scheme 1b, TBHP
induces the disproportionation of benzaldehyde to give TBPB
and benzyl alcohol. The thus-generated benzyl alcohol is
re-oxidized to benzaldehyde, which subsequently reacts with
TBHP to form TBPB. We next investigated whether in situ
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species.7a The reaction of 1a with benzaldehyde gave no
product in the presence of a catalytic amount of I2 and
NH4OH ([IO]ꢀ and [IO2]ꢀ generated in situ) (eqn (5)).8b In
sharp contrast, reaction of 1a with TBPB afforded 3a in 60%
yield under the similar conditions to those of eqn (5) (eqn (6)).
These results seem to indicate that [IO]ꢀ or [IO2]ꢀ may be
ineffective for the formation of TBPB at the initial stage of the
reaction but that they play a key role in the subsequent C–O
bond forming step. When sodium benzoate was subjected to the
reaction conditions, 60% of ester was isolated (eqn (7)). It is
evident that a benzyl cation is involved in this reaction.10 As
shown in Scheme 2, first, TBHP and TBPB can be decomposed
by the iodide ion to generate a tert-butoxyl radical and benzoic
acid. The iodide ion is oxidized to corresponding (hypo)iodites
([IO]ꢀ or [IO2]ꢀ). Subsequently, the tert-butoxyl radical or
(hypo)iodites abstract a hydrogen atom from the benzylic
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c
10206 Chem. Commun., 2012, 48, 10204–10206
This journal is The Royal Society of Chemistry 2012