Bu4NI-catalyzed decarboxylative acyloxylation of an sp 3 C-H bond adjacent to a heteroatom with α-oxocarboxylic acids

Article abstract of DOI:10.1039/c3ob40748a

A novel metal-free decarboxylative acyloxylation of an sp³ C-H bond in formamides and ethers has been explored. A variety of N-acyloxymethylamides and α-acyloxy ethers could be easily synthesized by this method. Preliminary mechanistic studies have shown that the reaction proceeded via a radical process. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40748a

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Biomolecular Chemistry
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Bu4NI-catalyzed decarboxylative acyloxylation of an
sp3 C–H bond adjacent to a heteroatom with
α-oxocarboxylic acids†
Cite this: Org. Biomol. Chem., 2013, 11,
4308
Received 15th April 2013,
Accepted 9th May 2013
Shuai Zhang, Li-Na Guo,* Hua Wang and Xin-Hua Duan*
DOI: 10.1039/c3ob40748a
www.rsc.org/obc
A novel metal-free decarboxylative acyloxylation of an sp3 C–H
bond in formamides and ethers has been explored. A variety of
N-acyloxymethylamides and α-acyloxy ethers could be easily syn-
thesized by this method. Preliminary mechanistic studies have
shown that the reaction proceeded via a radical process.
ð1Þ
Transition-metal-catalyzed decarboxylative cross-coupling reac-
tions are of great interest in modern organic synthesis because
the reactions show an advantage in using simple and readily
available carboxylic acids as reactants compared to related
cross-coupling with sensitive organometallic reagents.1 For
example, the direct olefination of arene carboxylates with
olefins via decarboxylative cross-coupling has emerged as an
attractive alternative to traditional Heck coupling methods.2 In
addition, the decarboxylative cross-coupling reactions of
various carboxylic acids with organo halides also represented
particularly powerful C–C bond formation strategies.3 Very
recently, more challenging decarboxylation/C–H activation of
simple unactivated (hetero)arenes and alkenes has been deve-
loped, affording various biaryl or diaryl ketone products (eqn
(1a)).4 Additionally, the copper-catalyzed oxidative functionali-
zation of unactivated C(sp)–H5 and C(sp3)–H6 bonds through
decarboxylative cross-coupling of carboxylic acids has also
been reported (eqn (1b) and (1c)). Obviously, the direct decar-
boxylative dehydrogenative cross-coupling may provide a more
appealing synthetic method because neither organohalides
nor sensitive organometallics are required for these processes.
Although some excellent pioneering progress has been made
on this subject,4–6 exploitation of the new catalytic decarboxyl-
ative/C–H functionalization reaction still remains a major
challenge for synthetic chemists.
On the other hand, transition-metal-catalyzed oxidative
functionalization of an sp3 C–H bond is a challenging and
powerful method to the formation of C–C and C–heteroatom
bonds from simpler starting materials.7 In this context, sub-
strates which contain an sp3 C–H bond adjacent to a hetero-
atom have been extensively examined in comparison with the
analogous reactant.7f–h In addition, the metal-free oxidative
functionalization of an sp3 C–H bond adjacent to a nitrogen or
an oxygen atom has also been reported.8 However, to date, the
metal-free decarboxylative functionalization of an sp3 C–H
bond adjacent to a heteroatom with stable carboxylic acids has
been scarcely studied.1 In connection with our recent efforts
on transition-metal catalyzed decarboxylative C–H bond acyla-
tion,4k we envisioned that the use of readily available α-oxocar-
boxylic acids for catalytic decarboxylative sp3 C–H bond
acylation of formamides and ethers might be a useful method
for the synthesis of various ketones (eqn (2)).
ð2Þ
We first investigated the reaction of phenylglyoxylic acid
(1a) with N,N-dimethylformamide (DMF, 2a) in the presence of
20 mol% of CuO and 2 equiv. of di-tert-butyl peroxide (DTBP)
as an oxidant at 80 °C for 3 h. Surprisingly, the expected
product
N-benzoylmethyl-N-methylformamide
was
not
observed. Instead,
a
new product N-benzoyloxymethyl-N-
Department of Chemistry, School of Science and MOE Key Laboratory for
Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong
University, Xi’an 710049, China. E-mail: duanxh@mail.xjtu.edu.cn,
guoln81@mail.xjtu.edu.cn
methylformamide 3a was obtained. Although Bamford and co-
workers have found that DMF could be converted to 3a in the
presence of benzoyl peroxide, however, only this product was
reported therein.9 Given that N-acyloxymethylamides are valu-
able synthetic intermediates and important structural units
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40748a
4308 | Org. Biomol. Chem., 2013, 11, 4308–4311
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Table 1 Optimization of the direct decarboxylative C–H acyloxylation of DMF
with phenylglyoxylic acida
Table 2 Decarboxylative C–H acyloxylation of amides with various phenyl-
glyoxylic acidsa
Entry
Catalyst (mol%)
Oxidant (equiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
CuO (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
Bu4NBr (20)
KI (20)
DTBP (2)
DTBP (2)
DCP (2)
<5c
12c
18c
TBHPd (2)
TBHPe (2)
TBHPe (2)
TBHPe (2)
TBHPe (1.2)
TBHPe (2)
TBHPe (2)
TBHPe (2)
TBHPe (2)
30c
48c
62
20f
21
9
Trace
11
Trace
Trace
10
11
12
I2 (20)
—
a Reaction conditions: 20 mol% of catalyst, 1a (0.2 mmol, 1 equiv.),
DMF (2 mL), oxidant (2 equiv.), 80 °C, 3 h. b Yield of the isolated
product. c At 110 °C. d TBHP (70% aqueous). e TBHP (tert-butyl
hydroperoxide, 5–6 M in decane). f At 60 °C.
found in numerous natural products and pharmaceuticals,10
efforts were then made to improve the yield of this novel decar-
boxylative coupling reaction (Table 1). However, other metal
catalysts did not show any catalytic activity for this decarboxy-
lative acyloxylation reaction.11 Very recently, tetrabutyl-
ammonium iodide (TBAI) catalyzed oxidative C–H activation
reaction has attracted much attention in synthetic organic che-
mistry.8c,12 However, when TBAI was used as a catalyst, only
a All reactions were performed with 1 (0.2 mmol) and formamides 2
(2 mL), under standard conditions (Table 1, entry 6) at 80 °C, 3 h.
Yields are of the isolated products. b An inseparable byproduct was
observed.
12% yield of the desired product was obtained (Table 1, entry coupling of α-oxocarboxylic acids with ethers. As expected, the
2). The use of dicumyl peroxide (DCP) instead of DTBP has no various phenylglyoxylic acids reacted with 1,4-dioxane leading
significant influence on the yield (entry 3). When TBHP was to the desired α-acyloxy ethers 5 in good to excellent yields
employed as an oxidant, the yield could be improved to 48% (Table 3). A variety of electron-donating and electron-withdraw-
(entry 5). Screening revealed that 80 °C was the optimal temp- ing groups could be tolerated in this reaction (5b–h). Addition-
erature, giving a moderate result (entry 6). Variation of the cata- ally, the furoylformic acid and 2-thienylglyoxylic acid also
lysts showed that TBAI was the best one (entries 9–11).
proceeded smoothly to give the desired products 5k and 5l in
Table 2 summarizes the application of the optimized reac- 98% and 92% yields, respectively.
tion conditions to a range of phenylglyoxylic acids. Phenyl-
For the TBAI-catalyzed decarboxylative acyloxylation reac-
glyoxylic acids with p-substituted electron-rich or -poor groups tion reported above, the corresponding arenecarboxylic acids
proved to be good substrates for this transformation, affording were also observed in some cases. The result suggested that
the corresponding N-acyloxymethylamides in moderate yields arenecarboxylic acid might be a potential intermediate in this
(3b–g). Phenylglyoxylic acids bearing an ortho-substituent such reaction. It is known that the α-oxocarboxylic acids could easily
as o-methylphenylglyoxylic acid also gave the desired product undergo oxidative decarboxylation to homologous carboxylic
3h in moderate yield, but along with a small amount of inse- acids in the presence of various oxidants.13 In fact, when ethyl
parable byproduct, which indicated that steric hindrance dis- acetate was used instead of DMF, under the same conditions
favored this acyloxylation reaction. In addition, when the benzoic acid 6 was isolated in 97% yield, which indicated
β-naphthyloxoacetic acid and furoylformic acid were used, the that phenylglyoxylic acid also oxidatively degraded to 6 under
desired products of 3i and 3j were obtained in 58% and 42% the TBAI/TBHP (eqn (3)). On the other hand, the reaction of 6
isolated yields, respectively. However, other N,N-disubstituted with DMF 2a also gave the N-acyloxymethylamide 3a in 62%
formamides, such as N-formylpiperidine, were inefficient for isolated yield (eqn (4)). So, we proposed that the benzoic acid
this decarboxylative coupling reaction (3k). The acetamide also should be the key intermediate of this oxidative decarboxyla-
gave the corresponding product in 63% yield (3l).
tive C–H acyloxylation reaction.14 Furthermore, the reaction
To further expand the scope of this acyloxylation reaction to was also suppressed by addition of a radical scavenger, such as
other substrates, we next investigated the decarboxylative TEMPO. Thus, we speculated that the reaction proceeds via a
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system, respectively. Both the starting materials are simple and
easily available.
Table 3 Decarboxylative C–H acyloxylation of 1,4-dioxane with various
phenylglyoxylic acidsa
Acknowledgements
Financial support from National Natural Science Foundation
of China (Nos. 21102110, 21102111), the Doctoral Fund of the
Ministry of Education of China (No. 20110201120076), and the
Fundamental Research Funds of the Central Universities is
greatly appreciated.
Notes and references
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ð3Þ
ð4Þ
In summary, we have demonstrated that the C(sp3)–H bond
acyloxylation of formamides and ethers with α-oxocarboxylic
acids can be achieved using metal-free catalytic systems. This
operationally simple and efficient method provides a new
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277.
reviewers for the reaction mechanism.
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