Temperature-controlled NaI-mediated α-oxybenzoylation or oxyacylation-decarboxylation reactions of dimethyl malonate with carboxylic acids

Article abstract of DOI:10.1016/j.catcom.2015.07.013

A NaI-mediated α-functionalization of dimethyl malonate and its derivatives with carboxylic acids has been developed. Two different reaction routes based on the same substrates and reaction conditions by simply altering the reaction temperature have been

Full text of DOI:10.1016/j.catcom.2015.07.013

Catalysis Communications 70 (2015) 62–65
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Temperature-controlled NaI-mediated α-oxybenzoylation or
oxyacylation–decarboxylation reactions of dimethyl malonate with
carboxylic acids
b
a
a
b
b
Jincheng Mao a,b, , Defu Liu , Yongming Li , Jinzhou Zhao , Guangwei Rong , Hong Yan , Guoqi Zhang
⁎
c,⁎⁎
a
State Key Laboratory of Oil and Gas Reservoir Geology and Exploitation, Southwest Petroleum University, Chengdu 610500, PR China
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
Department of Sciences, John Jay College and The Graduate Center, The City University of New York, New York, NY 10019, USA
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 May 2015
Received in revised form 17 July 2015
Accepted 21 July 2015
Available online 29 July 2015
A NaI-mediated α-functionalization of dimethyl malonate and its derivatives with carboxylic acids has been
developed. Two different reaction routes based on the same substrates and reaction conditions by simply altering
the reaction temperature have been observed, which led to the synthesis of two types of products in good to high
yields. The scope of substrates was investigated for both types of reactions, respectively, and possible reaction
mechanisms were suggested.
© 2015 Elsevier B.V. All rights reserved.
Keywords:
α-Oxybenzoylation
Oxidative decarboxylative
Dimethyl malonate
Carboxylic acids
Temperature-controlled
1. Introduction
To develop a ‘greener’ and atom-economic methodology for the
α-carboxyl functionalizations of a class of important β-dicarbonyl
β-Dicarbonyl compounds are crucial structural units that have
found widespread applications in synthetic chemistry [1–3]. The
functionalization of β-dicarbonyl compounds at the α-position with
heteroatomic groups, in particular α-oxygen functionalization, is one
of the most promising transformations for this type of compounds, as
it provides key intermediates for the synthesis of a variety of heterocy-
clic and natural products that adopt unique interests in medicinal
chemistry [4–10]. Recently, a range of α-oxygen functionalizations of
β-dicarbonyl compounds including the oxyacylation, oxybenzoylation,
oxytosylation, oxyphosphorylation and oxyalkylation have been
approached by stoichiometric or catalytic reactions [11–23]. However,
the majority of the reported protocols utilized stoichiometric polyvalent
iodine reagents which are considered environmentally unfriendly
[24–29].
compounds, malonate esters, we investigated the reaction between
dimethyl malonate and carboxylic acid mediated by a catalytic amount
of iodide salt in the presence of an oxidant, and report herein our results
on the NaI-catalyzed α-oxybenzoylation of dimethyl malonate with
a variety of carboxylic acids in high yield under mild conditions.
Interestingly, an oxyacylation–decarboxylation product, α-carboxylic
ester resulting from the same reaction, yet at higher temperature was
observed and its substrate scope was preliminarily explored.
2. Experimental
2.1. General procedure for preparation of α-oxybenzoylative products
through the reaction between dimethyl malonate and carboxylic acids at
60 °C
To a reaction tube equipped with a magnetic stir bar cinnamic acid
(0.3 mmol), dimethyl malonate (0.9 mmol), NaI (20 mol%) TBHP (1.5
equiv.) in DMF (2 mL). The resulting reaction mixture was kept stirring
at 60 °C for 12 h. At the end of the reaction, the reaction mixture was
⁎
Correspondence to: J. Mao, State Key Laboratory of Oil and Gas Reservoir Geology and
Exploitation, Southwest Petroleum University, Chengdu 610500, PR China.
⁎⁎ Corresponding author.
E-mail addresses: jcmao@suda.edu.cn (J. Mao), guzhang@jjay.cuny.edu (G. Zhang).
http://dx.doi.org/10.1016/j.catcom.2015.07.013
1566-7367/© 2015 Elsevier B.V. All rights reserved.

J. Mao et al. / Catalysis Communications 70 (2015) 62–65
63
cooled to room temperature. After the removal of the solvent, the resi-
due was subjected to column chromatography on silica gel using ethyl
acetate and petroleum ether mixtures to afford the desired product in
high purity.
and DTBP were examined, yet none of them led to the formation of
4a, although product 3a was unfavorable as well (entries 4 and 5,
Table 1). Attempts to replace NaI with other catalysts such as KI, iodine,
TBAI (tert-butylammonium iodide) or TBAB (tert-butylammonium
bromide) were unsuccessful, providing either 3a as the only product
in low to moderate yields (entries 6–9, Table 1). Increasing the loading
of catalyst NaI to 50 mol% did not improve the results (entry 10,
Table 1). However, shortening the reaction time to 1 h favored the for-
mation of 4a in 28% yield (entry 11, Table 1). Finally, temperature was
found to be a determining factor for controlling the formation of 3a
and 4a in this reaction. Although the temperature above 100 °C has a
little influence on the reaction, a lower reaction temperature (60 °C)
completely inhibited the decarboxylation process and pleasingly, the
α-oxybenzoylation product 4a was isolated as the only product in 94%
yield, which drastically dropped to 50% when the reaction was run at
40 °C (entries 12–15, Table 1). As it was known that a decarboxylation
process might occur from β-diesters with heat, we performed an addi-
tional experiment to ascertain whether or not 3a was formed following
decarboxylation from 4a. Interestingly, heating pure 4a in DMF to
120 °C for 12 h led to the isolation of 3a in 43% yield, indicating that
3a was probably generated from 4a.
2.2. General procedure for preparation of oxyacylation–decarboxylation
products through the addition reaction between dimethyl malonate and
carboxylic acids at 120 °C
To a reaction tube equipped with a magnetic stir bar cinnamic acid
(0.3 mmol), dimethyl malonate (0.9 mmol), NaI (20 mol%), TBHP (1.5
equiv.) and DMF (2 mL) was added under air. The resulting reaction
mixture was kept stirring at 120 °C for 12 h. At the end of the reaction,
the reaction mixture was cooled to room temperature. After the
removal of the solvent, the residue was subjected to column chromatog-
raphy on silica gel using ethyl acetate and petroleum ether mixtures to
afford the desired product in high purity.
3. Results and discussions
Our initial studies began with a model reaction between cinnamic
acid and dimethyl malonate. It was interesting to note when the mix-
ture of cinnamic acid and dimethyl malonate (1.0 equiv.) was heated
in the presence of catalytic amount of sodium iodide and a common
oxidant TBHP in DMF at 120 °C for 12 h (TBHP = tert-butyl
hydroperoxide), the product 3a, resulting from the sequential oxidative
coupling and decarboxylation reaction, was isolated in 43% yield
(entry 1, Table 1). Although the formation of 3a was deviated from
our goal of gaining a direct oxidative coupling of dimethyl malonate
with cinnamic acid at the α-position, the fact that the α-oxygen
functionalization of dimethyl malonate did occur certainly warrants
further investigation. Therefore, a thorough screening on the reaction
conditions was carried out in order to suppress the production of 3a,
while pursuing the desired 4a from the direct oxidative coupling
without decarboxylation. Increasing the loading amount of dimethyl
malonate resulted in the isolation of 3a in moderate yields, whereas
4a was still not obtained (entry 2, Table 1). It was found that 3a could
be isolated in 70% yield when the amount of dimethyl malonate was
increased to 3.0 equiv. (entry 3, Table 1). Other oxidants such as DCP
With the above optimized reaction conditions for 4a in hand,
the scope of substrates was further examined and the results were
listed in Table 2. First, a variety of cinnamic acid derivatives with
substituents on the aromatic ring were tested. Cinnamic acids with
electron-donating groups including methyl, methoxyl, isopropyl, or
N,N′-dimethylamino units reacted with dimethyl malonate (3.0 equiv.)
smoothly at 60 °C in the presence of NaI (20 mol%) and TBHP (1.5
equiv.), affording the corresponding products 4b–4e in 80–95% yields.
The reactions were equally efficient when some cinnamic acids having
electron-withdrawing substituents were employed. In addition, the het-
erocyclic analogue of cinnamic acid, 3-(3-pyridyl)acrylic acid also
furnished the reaction, giving 4j in 97% yield. At this end, several general
carboxylic acids including benzoic acid and 5-bromo-2-furoic acid were
utilized for the reactions with dimethyl malonate under the optimal
Table 2
α-Oxybenzoylation of dimethyl malonatea.
Table 1
Screening of reaction conditions.a
Entry
Catalyst
(equiv.)
Oxidant
Temp. (°C)
Time (h)
Yieldb
(%, 3a)
Yieldb
(%, 4a)
1c
2d
3
4
5
6
7
8
9
10
11
12
13
14
15
NaI (0.2)
NaI (0.2)
NaI (0.2)
NaI (0.2)
NaI (0.2)
TBAI (0.2)
KI (0.2)
TBHP
TBHP
TBHP
DCP
120
120
120
120
120
120
120
120
120
120
120
130
100
60
12
12
12
12
12
12
12
12
12
12
1
43
58
70
20
62
65
52
b5
b5
71
52
55
50
N.D.
N.D.
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
28
DTBP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
I2 (0.2)
TBAB (0.2)
NaI (0.5)
NaI (0.2)
NaI (0.2)
NaI (0.2)
NaI (0.2)
NaI (0.2)
12
12
12
12
Trace
30
94
40
50
N.D.: Not detected. DCP: dicumyl peroxide; DTBP: di-t-butyl peroxide.
a
Unless otherwise stated, all reactions were carried out with 1a (0.3 mmol), 2a
(0.9 mmol), a catalyst (0.2–0.5 mol%) and an oxidant (0.45 mmol) in DMF in the air.
aReaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), NaI (0.2 mol%) and TBHP (0.45 mmol)
in DMF at 60 °C in the air.
bIsolated yield.
c16 h.
b
Isolated yield.
0.3 mmol of 2a was used.
c
d
0.6 mmol of 2a was used.

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J. Mao et al. / Catalysis Communications 70 (2015) 62–65
Table 3
The oxyacylation–decarboxylation reaction of dimethyl malonate with carboxylic acids at
120 °Ca.
Entry
1
Product
Yieldb (%)
70
Scheme 1. The oxidative coupling of cinnamic acid with diethyl malonate or ethyl
acetylacetate.
2
3
68
35
conditions, and the desired α-oxybenzoylation products 4k and 4l were
obtained in good yields. It was further observed that diethyl malonate
was also suitable substrate for this reaction, despite a slightly lower
yield for the functionalized diester 4m (Scheme 1). In contrast, the β-
ketoester, ethyl acetylacetate was a less effective substrate than dimeth-
yl malonate, giving α-carboxylic-β-ketoester 4n in moderate yield
(Scheme 1).
Subsequently, the oxidative couplings of diethyl malonate
with phenylpropiolic acid and phenylacetic acid were investigated,
respectively. As shown in Scheme 2, it can be seen that the desired
product 4o was obtained in 40% yield, while the corresponding product
could not be acquired for the reaction with phenylacetic acid.
4
5
45
32
6
55
Having revealed the temperature-dependent formation of 3a
and 4a in Table 1 and the successful preparation of a variety of
α-oxybenzoylation products by the NaI-catalyzed reaction under mild
conditions, we were also interested to test the substrate scope for the
oxyacylation–decarboxylation reaction under the optimal conditions
for 3a. Thus, several carboxylic acids were chosen to react with dimethyl
malonate (3.0 equiv.) in the presence of NaI (20 mol%) and TBHP (1.5
equiv.) at 120 °C, and the results were summarized in Table 3.
Moderate to good yields were obtained for substituted cinnamic acids,
and the substrates with electron-donating groups were superior to that
with an electron-withdrawing group. Benzoic acid and 2-naphthoic
acid also proceeded well in 69% and 70% yields, respectively, while
5-bromofuroic acid was found to be slightly less reactive.
To extend the applications of the oxyacylation–decarboxylation cou-
pling reaction, we examined several new substrates for the reactions at
120 °C as shown in Scheme 3. First, the reaction of cinnamic acid with
ethyl acetylacetate was tested, only the α-oxybenzoylation product 4n
was isolated in 36% yield and no desired oxyacylation–decarboxylation
product was detected. Phenylpropiolic acid was then chosen to react
with dimethyl malonate, however, no coupling products were observed,
which is in strong contrast with the previous results at 60 °C.
7
8
69
70
9
58c
a
Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), NaI (0.2 mol%) and TBHP (0.45 mmol)
in DMF at 60 °C in the air.
b
Isolated yield.
16 h.
c
(60 °C), releasing the catalyst precursor Na[IO]−. Alternatively, the
product 4 could be decarboxylated at higher temperature (120 °C) to
form the α-carboxylic ester 3 [35].
On the basis of previous work in the literature [30–32] and our own
results described above, we proposed a plausible mechanism for the
present reactions, which is shown in Scheme 4. Iodide was initially
oxidized by TBHP to Na[IO]−, which was further oxidized to a key inter-
mediate hypoiodite Na[IO2]− (A) with one more equivalent of TBHP
[33,34]. The oxidative addition of 2 at the α-position by A would give
a key β-diester intermediate B, which readily experienced substitution
by 1 to give the α-oxybenzoylation product 4 under mild conditions
4. Conclusion
In conclusion, we have described a facile NaI-mediated oxidative
coupling of dimethyl malonate with carboxylic acids. Two types of
products resulting from two different reaction pathways, i.e. the direct
Scheme 2. The oxidative coupling of diethyl malonate with phenylpropiolic acid or
Scheme 3. The reactions between cinnamic acid and methyl acetylacetate or
phenylacetic acid.
phenylpropiolic acid and dimethyl malonate under NaI/TBHP/DMF/120 °C system.

J. Mao et al. / Catalysis Communications 70 (2015) 62–65
65
Petroleum Research Fund (#54247-UNI3) and the PSC-CUNY award
(#67312-0045) from the City University of New York for support.
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versatile temperature-controlled α-functionalization of readily avail-
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