Copper-catalyzed oxidative C-O coupling by direct C-H bond activation of formamides: Synthesis of enol carbamates and 2-carbonyl-substituted phenol carbamates

Article abstract of DOI:10.1002/anie.201105020

Formamide C-H bond activation has been achieved under oxidative conditions, using a copper catalyst and tert-butyl hydroperoxide (TBHP) as the external oxidant (see scheme). This oxidative coupling of a range of dialkyl formamides provides an easy, phosge

Full text of DOI:10.1002/anie.201105020

Communications
DOI: 10.1002/anie.201105020
Oxidative Coupling
À
À
Copper-Catalyzed Oxidative C O Coupling by Direct C H Bond
Activation of Formamides: Synthesis of Enol Carbamates and
2-Carbonyl-Substituted Phenol Carbamates**
G. Sathish Kumar, C. Uma Maheswari, R. Arun Kumar, M. Lakshmi Kantam, and
K. Rajender Reddy*
Coupling chemistry is an important synthetic strategy, widely
used in both industry and academia for the formation of
[1]
À
À
carbon carbon and carbon heteroatom bonds. The tradi-
tional coupling procedures involve either the use of stoichio-
metric organometallic reagents, such as Grignard and organo-
lithium reagents, or the transition-metal-catalyzed coupling of
functionalized hydrocarbons. There has been substantial
progress in these methods over the last few decades, and
they are successfully applied in the synthesis of commercially
important products.[2] However, the use of prefunctionalized
starting materials in these methods, thus adding steps towards
the formation of desired chemical bond, is a major concern
for the synthetic chemist from an atom-economical and
environmental point of view. The best way to address this
issue is to utilize unfunctionalized starting materials by the
À
Scheme 1. a) ortho-Assisted C H bond functionalization b) CDC reac-
À
tions for C C bond formation. DG=directing group.
turn are prepared by employing phosgene or its substitutes.[8]
To avoid the use of toxic and harmful reagents, phosgene-free
routes involving the oxidative carbonylation of amines using
Nobel metal catalysts have been reported.[9] The other
environmentally benign route is the utilization of CO2 as a
safe and abundant reagent for the synthesis of carbamates.[10]
We have been working on iodide-mediated catalytic oxidative
organic transformations using TBHP as an external oxi-
dant,[11] and in this context, we were interested to develop
useful coupling protocols under oxidative conditions using
transition metal and non-transition metal catalysts.
Formamides are known to react differently under differ-
ent reaction conditions. For example, Muzart summarized in
his recent review that N,N-dimethylformamide (DMF), which
is one of the most widely used formamide derivatives, could
be a source of CO, Me2N, Me2NCO, oxygen, etc., depending
on the reaction conditions.[12] Recent studies on the amino-
carbonylation of aryl halides with DMF using transition metal
À
direct activation of C H bonds. Several reports have
À
appeared in the literature on transition-metal-catalyzed C
À
H bond activation and its further application to carbon
carbon and carbon heteroatom bond formations.[3] In recent
À
years, more systematic and concerted efforts have been made
in C H bond activation and its application in coupling
chemistry. As a result exceptionally useful methods for
organic synthesis have been developed, such as, the tran-
sition-metal-catalyzed functional-group-directed C H bond
functionalization to achieve C C and C X bonds, and
pioneering work by Li in the area of cross-dehydrogenative
couplings (CDC), where the activation of two different C H
À
À
[4]
À
À
À
bonds under oxidative conditions have been achieved
(Scheme 1).[5]
Organic carbamates are valuable agricultural chemicals,
largely used as pesticides, fungicides, and herbicides.[6] They
have also played an important role in synthetic organic
chemistry, primarily as intermediates or as novel protecting
groups.[7] The conventional synthesis of carbamates involves
intermediates such as chloroformates or isocyanates, which in
catalysts have shown the possibility of the direct activation of
[13]
À
the formamide C H bond. A few reports are available on
À
the direct activation of the formamide C H bond in the
intermolecular addition to alkenes and alkynes.[14] Very
recently, direct amidation of azoles with formamides by
À
metal-free C H bond activation has been achieved using tert-
butyl perbenzoate.[15] To the best of our knowledge, this is the
first report in which b-dicarbonyl- or 2-carbonyl-substituted
phenols are directly coupled with N,N’-disubstituted forma-
mides under oxidative conditions to yield carbamates
(Scheme 2).
[*] G. S. Kumar, C. U. Maheswari, R. A. Kumar, Dr. M. L. Kantam,
Dr. K. R. Reddy
Inorganic and Physical Chemistry Division
Indian Institute of Chemical Technology
Tarnaka, Hyderabad-500 607 (India)
E-mail: rajender@iict.res.in
The direct coupling of formamide with aryl halides has
been postulated to proceed by the Heck-type addition of aryl
halides to the iminium species, which is produced from a
mixture of DMF and POCl3.[13a] In their recent report on the
direct amidation of azoles with formamides, Wang and co-
workers have proposed the possible formation of a free
radical of DMF under the peroxide conditions.[15] Similarly,
rajenderkallu@yahoo.com
[**] G.S.K., C.U.M., and R.A.K. thank the Council of Scientific and
Industrial Research (CSIR), India, for their fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105020.
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enol carbamate. Having observed the coupled product,
optimization of the reaction conditions was carried out
(Table 1). An increase in reaction temperature greatly
improved the product yield (Table 1, entry 2). The absence
of any coupled product in control experiments clearly shows
the importance of the catalyst in this reaction (Table 1,
entries 3 and 4). Both the CuI and CuII salts were quite active
for this coupling reaction (Table 1, entry 5–12). Among the
different copper salts, CuBr2 provided relatively higher yields
of the product. The lower activity observed with CuO could
be because of the insoluble nature of the metal oxide (Table 1,
entry 13). We did not observe any product formation, when
one equivalent of ethyl benzoylacetate and one equivalent of
DMF were reacted in a variety of solvents.[17] Next we
evaluated the role of the oxidant; no product formation was
observed with H2O2, UHP, mCPBA, and NaOCl as the
oxidant. Further substrate screenings were done using
5 mol% of CuBr2 at 808C with the respective formamide as
the solvent and TBHP as the external oxidant (Scheme 3).
Under the standard reaction conditions, various b-
ketoesters were used as substrates for the formation of enol
Scheme 2. Synthesis of enol and phenol carbamates by oxidative
coupling. TBHP=tert-butyl hydroperoxide.
the copper-catalyzed oxidative coupling with peroxides has
been proposed to proceed by a radical mechanism.[5] We
initiated this work with the anticipation that DMF can be
activated under oxidative conditions to yield the coupled
product with carbon nucleophiles. For our initial experiments,
ethyl benzoylacetate was chosen as the carbon nucleophile
and treated with an excess of DMF, using 5 mol% of CuI as a
catalyst and TBHP (70 wt% in water) as an external oxidant
(Table 1, Entry 1). To our surprise, at room temperature we
Table 1: Optimization of reaction conditions.[a]
Entry
Catalyst
Yield [%][b]
1
2
3
4
CuI
CuI
–
CuI
16[c]
67
n.r.[d]
n.r.[e]
76
5
CuBr
6
CuCl
78
7
CuSCN
76
8
CuBr2
84
9
CuCl2·2H2O
Cu(ClO4)2·6H2O
CuSO4·5H2O
Cu(CH3COO)2·H2O
CuO
79
65
71
81
10
11
12
13
8
[a] Reaction conditions: 1a (1 equiv), catalyst (5 mol%), DMF (2 mL,
27 equiv), TBHP (70 wt% in water, 1.5 equiv), 808C, 3 h. [b] Yields of the
isolated products. [c] Reaction carried out at room temperature.
[d] Without catalyst. [e] Without TBHP.
observed a small amount of carbamate product, in which the
enol hydroxy group had participated in the oxidative coupling
instead of active methylene group. This result is similar to that
observed in the oxidative esterification of aldehydes to give b-
dicarbonyl products.[16] Purification of the product and
analysis by 1H and 13C NMR spectroscopy, and ESI mass
spectrometry revealed that the coupled product is indeed the
Scheme 3. Oxidative coupling of formamides with b-ketoesters.
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Communications
carbamates. In general, the desired enol carbamates were
activated esters with phenols. However, recently N-hetero-
cyclic-based ligands have been successfully utilized for
oxidative esterifications of aldehydes with phenols using
palladium or iron catalysts.[19] Use of these ligands involves a
multistep synthesis and moreover, poor yields were observed
for ortho-substituted phenols. In the present case, the reaction
between 2-acetyl phenol with various aldehydes, using DMSO
as the solvent under the standard reaction conditions,
provided the phenol esters in very good yields (Scheme 5).
obtained in good yields with high stereoselectivity towards
the Z isomer (Scheme 3). We did not observe any E isomer in
these reactions, as confirmed by NOE experiments of product
3c. The nature of the b-ketoesters and dialkyl formamides did
not have any profound influence on the reactivity.
Next we looked at extending the above method to ortho-
substituted phenolic compounds, which have structural sim-
ilarities to the enol tautomer of the diketone moiety. Avariety
of 2-acyl and 2-benzoyl phenolic compounds, substituted with
electron-withdrawing and electron-donating groups were
subjected to oxidative coupling with N,N’-dialkyl formamides
under the standard reaction conditions, which include
5 mol% of Cu(OAc)2 as a catalyst (Scheme 4).[18] In all
Scheme 5. Oxidative coupling of aldehydes with phenols.
The coordinating ability of the dicarbonyl compounds
with the metal could be one of the key factors for the
formation of carbamates (3 and 5) and esters (6). Moreover,
the lack of the formation of any phenol carbamates (5) with
simple phenols also supports this hypothesis. Similarly, the
lack of product for the reaction between DMF and 2-acetyl
phenol in the presence of the radical scavenger TEMPO,
supports the hypothesis that the present coupling proceeds by
a radical mechanism, which is often invoked for metal-
catalyzed oxidation reactions involving peroxides. Based on
these observations, we speculate that formamide radicals,
analogous to the acyl radicals proposed in the copper-
catalyzed oxidative esterification of aldehydes with b-dicar-
bonyl compounds in the presence of TBHP, could be one of
the active species.[16] Moreover, the formation of such a
formamide radical has been postulated recently in the direct
amidation of azoles with formamides using tert-butyl perben-
zoate as the oxidant.[15] These mechanisms are speculative and
many other possible mechanisms exist, further comprehen-
sive studies are required to elucidate the mechanism of
À
oxidative cross-coupling chemistry involving C H bond
activations.
In summary, we have developed a novel copper-catalyzed
À
oxidative C O coupling reaction for the efficient synthesis of
enol and phenol carbamates. Advantages of our procedure
include the simplicity of operation and the fact that it is a
phosgene-free route, thus avoiding the use of toxic and
harmful reagents. Moreover, a high stereoselectivity was
achieved for enol carbamates and the present strategy was
also extended to oxidative esterification of carbonyl-substi-
tuted phenols. The scope of this reaction is under investiga-
tion and the results will be discussed in due course.
Scheme 4. Oxidative coupling of formamides with phenols.
cases, we observed the formation of phenol carbamates in
good yield. We did not observe any correlation between the
yields and the electronic nature of the phenol substituents.
This demonstrates that the substitution on the phenolic group
has a negligible influence on the product conversion. Reac-
tions of simple phenol or p-bromophenol with DMF did not
provide the desired coupled product.
The success of the oxidative coupling of formamides with
phenols having carbonyl functionality at the ortho-position
encouraged us to investigate the corresponding oxidative
esterifications with aldehydes. Generally aryl benzoates are
prepared by the reaction of acyl halides, anhydrides, or
Experimental Section
General procedure: TBHP (70 wt% in water) was added dropwise,
with stirring over a period of 5 min, to a mixture of b-ketoester (1) or
phenol (4), copper salt (5 mol%; CuBr2 for b-ketoesters and Cu-
(OAc)2 for phenols), and formamide (2 mL). Then the reaction
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temperature was increased to 808C and the reaction mixture was
stirred for three hours. After cooling to RT, the reaction mixture was
extracted with ethyl acetate and dried over anhydrous Na2SO4.
Removal of the solvent under vacuum afforded the crude product,
which was purified by column chromatography on silica gel (ethyl
acetate/hexane 1:9) to afford the required product (3 and 5).
A slightly modified procedure, in which DMSO was used as the
solvent and the reaction time increased to 6 h, was employed for the
oxidative esterification reactions resulting in the formation of product
6.
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CuBr2 (75%).
Received: July 18, 2011
Published online: October 12, 2011
Keywords: carbamates · copper · homogeneous catalysis ·
.
oxidative coupling · synthetic methods
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