Nucleophilic imidoesterification of dicarbonyl compounds with cyanatobenzenes through CC bond formation

Article abstract of DOI:10.1016/j.cclet.2014.06.008

Under neat conditions, an efficient method for synthesis of imidoesters has been developed using cyanatobenzenes and dicarbonyl compounds. Nucleophilic addition spontaneously occurred between the two kinds of materials at room temperature with yields of up to 90%. A mechanism directed towards to the imidoester formation has been proposed.

Full text of DOI:10.1016/j.cclet.2014.06.008

Chinese Chemical Letters 25 (2014) 1327–1330
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Nucleophilic imidoesterification of dicarbonyl compounds
with cyanatobenzenes through C–C bond formation
Hang Ma a, Yang He a, Ruo-Feng Huang a, Xiao-Hui Zhang a, Jing Pan a,
Jia-Qiang Li a, Chao He a, Xue-Ge Ling a, Xuan-Lun Wang c, Yan Xiong a,b,
*
a School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, China
b Chongqing Key Laboratory of Chemical Process for Clean Energy and Resource Utilization, Chongqing University, Chongqing 400044, China
c College of Materials Science and Engineering, Chongqing University of Technology, Chongqing 400054, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Under neat conditions, an efficient method for synthesis of imidoesters has been developed using
cyanatobenzenes and dicarbonyl compounds. Nucleophilic addition spontaneously occurred between
the two kinds of materials at room temperature with yields of up to 90%. A mechanism directed towards
to the imidoester formation has been proposed.
Received 22 May 2014
Received in revised form 4 June 2014
Accepted 10 June 2014
Available online 13 June 2014
ß 2014 Yan Xiong. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
Imidoesters
Cyanatobenzenes
Dicarbonyl compounds
Imidoesterification
Nucleophilic addition
1. Introduction
amine-catalyzed aldol condensation, synthesis of bis(indolyl)-
methanes, theoretical halo-exchange SN2 reactions, iodination of
Imidoesters have been widely used in the synthesis of nitrogen-
containing organic compounds, and frequently used as cross-linking
reagents as well as drugs participation in the human body reactions
[1–6]. In 1883, Pinner reported the first synthesis of imidoesters
with nitrile and alcohol in the presence of dry hydrochloride [7].
Various kinds of methods have been developed in synthesizing
imidoesters since Pinner’s seminal work, using cyanates [8–10],
aldehydes [11], N-hydroxypyridine-2-thioketone sodium salt [12],
and aniline [13] as starting materials. However, the synthetic of
structurally diverse imidoesters need to be developed regardless of
these tremendous efforts devoted to this area.
sp3 C–H with hypervalent iodide, Fe(III)-promoted oxidative free
radical coupling of anilines, and superacid promoted benzylation
of arenes [15]. Herein we are pleased to report a new method for
neat atom-economical synthesis of imidoesters employing
cyanatobenzenes and dicarbonyl compounds as starting materi-
als under additive-free conditions.
2. Experimental
Ethyl acetoacetate 2a (126
solution of cyanatobenzene 1a (130
m
L, 1.0 mmol) was added to the
L, 1.2 mmol) in diethyl ether
m
In Buttke’s report, the treatment of dicarbonyl compounds and
cyanatobenzenes produces 2-cyano-1,3-diketones under ice-bath
conditions in the presence of sodium ethoxide [14]. When we
carried out these reactions in the absence of additives, imidoesters
were obtained instead of 2-cyano-1,3-diketones (Scheme 1).
In our former work, we have reported on theoretical cyana-
tion of aldimine, Cs2CO3-catalyzed transesterification, primary
(2 mL). The reaction mixture was stirred at room temperature for
40 h in the atmosphere and monitored by TLC. After completion of
the reaction, the volatile components were removed using a
vacuum rotary evaporator. The resulting residue was purified by
column chromatography on silica gel column using EtOAc/
petroleum ether (1:20 to 1:4, v/v) as eluent to afford the desired
product ethyl 3-hydroxy-2-(imino(phenoxy)methyl)but-2-enoate
3a. Products were recorded by NMR spectra on a 500 spectrometer
(500 MHz for 1H, 125 MHz for 13C) with deuterated chloroform
(CDCl3) as a solvent at 20–25 8C. For detailed experimental
procedure, characterization data of the products, and copies of
1H NMR and 13C NMR spectra, see Supporting information.
*
Corresponding author at: School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China.
E-mail address: xiong@cqu.edu.cn (Y. Xiong).
http://dx.doi.org/10.1016/j.cclet.2014.06.008
1001-8417/ß 2014 Yan Xiong. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

1328
H. Ma et al. / Chinese Chemical Letters 25 (2014) 1327–1330
Scheme 1. Reported cyanation and proposed imidoesterification of dicarbonyl compounds with cyanatobenzenes.
O
O
O
CN
OH
NH
diethyl ether
r.t., 40 h
R
R
R1
R2
+
O
COOEt
1
2
3
COOEt
OH
C(CH3)3
O
OH
NH
OH
NH
NH
OH
NH
OH
OH
NH
O
O
O
I
O
O
COOEt
COOEt
C(CH3)3
COOEt
COOEt
3b, 42% (26%) b
3d, 33%
3c, 76%
3a, 90%
Br
F
NH
OH
OH
NH
OH
OH
OH
NH
NH
O
O
O
O
COMe
, 76%
COOEt
COOEt
COOEt
3f, 52% (21%) b
, 75%
3g
3e, 90%, (69%)a (43%) b
3h
NH
OH
NH
OH
NH
NH
NH
OH
F
O
O
F
O
O
O
COMe
COOMe
COOMe
COOMe
COOMe
, 7% (70% c) b
, 16% (43% c
)
b
, 32% (46% c
)
b
3k
3l, 25%
3m
3j
, 70%
3i
Scheme 2. Expansion of cyanatobenzenes and dicarbonyl compounds. Reaction conditions: dicarbonyl compounds 2 (1.0 mmol), cyanatobenzenes 1 (1.2 equiv.) in diethyl
ether (2 mL) at room temperature for 40 h. (aIn the presence of triethylamine (0.2equiv.); bIn the presence of pyrrole (0.2 equiv.); cDicarbonyl compounds 2 (2.0 mmol),
cyanatobenzenes 1 (1.2 equiv.) in diethyl ether (2 mL) at room temperature.)
3. Results and discussion
Under the solvent-free conditions, the imidoester 3a was obtained
in 62% yield in the absence of additive (entry 1), while the usage of
Et2O as solvent led to better yield of 90% at room temperature
(entry 2). Other common solvents such as THF, DCM, toluene,
EtOAc, dioxane, acetonitrile and DMSO generally resulted in the
decrease of yields to some different extent (entries 3–9). In the
examination of temperature, either high or low temperature was
found to be unbeneficial to imidoesterification compared with the
result obtained at the room temperature (entries 10 and 11). The
alternation of the proportion of 1a in the range of 1.0–1.5 equiv. to
ethyl acetoacetate 2a was investigated as well. As a result, both less
and excessive amount of 2a led to lower yields and 1.2 equiv. of 2a
was most appropriate to this transformation (entries 12 and 13).
Therefore, the optimal reaction conditions were established:
dicarbonyl compounds (1.0 mmol) and cyanatobenzenes
(1.2 equiv.) in diethyl ether at room temperature.
We firstly aimed at the optimization of reaction conditions for
the synthesis of imidoesters. The treatment of cyanatobenzene 1a
with ethyl acetoacetate 2a was chose as a model reaction to screen
various kinds of solvents, temperature and material ratio (Table 1).
Table 1
Optimization of reaction conditions.a
.
Entry
Solvent
Temperature
1a (mmol)
Yield of 3a (%)b
With the established optimal conditions in hand, the scope of
cyanatobenzenes was then investigated. Ethyl acetoacetate 2a
was used as nucleophile and ethyl 3-hydroxy-2-(imino(phenox-
y)methyl)but-2-enoate 3a was obtained providing a high yield up
to 90% (Scheme 2). These results showed that the reactivity is
1
2
–
RT
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.5
62
90
32
43
67
59
47
17
15
40
69
53
86
Et2O
RT
3
THF
RT
4
DCM
Toluene
EtOAc
Dioxane
CH3CN
DMSO
Et2O
RT
5
RT
6
RT
7
RT
8
RT
9
RT
10
11
12
13
0 8C
60 8C
RT
Et2O
Et2O
Et2O
RT
a
Reaction conditions: cyanatobenzene 1a (specified), ethyl acetoacetate 2a
(1.0 mmol) in solvent (2 mL) at temperature (specified) for 40 h.
b
Isolated yields.
Scheme 3. Two types of activation of dicarbonyl compounds.

H. Ma et al. / Chinese Chemical Letters 25 (2014) 1327–1330
1329
Scheme 4. A proposed mechanism.
independent to electron nature of cyanatobenzenes. With electro-
Acknowledgments
donating substitutions on benzene ring of cyanatobenzenes, ethyl
2-((4-ethylphenoxy)(imino)methyl)-3-hydroxybut-2-enoate 3b
was gotten in a yield of 42%, while ethyl 3-hydroxy-2-(imi-
no(3-methoxyphenoxy)methyl)but-2-enoate 3c was produced
in a higher yield of 76%. Regarding to the dicyanato material 1,4-
We gratefully acknowledge for funding from the SRTP of
Chongqing University for undergraduate cultivation (H. Ma and
Y. He), the National Natural Science Foundation of China
(Nos. 21372265 and 61271059), the Scientific Research Founda-
tion for the Returned Overseas Chinese Scholars, State Education
Ministry, the Natural Science Foundation Project of CQ CSTC
(Nos. CSTC2013jcyjA0217 and CSTC2010BB4086), and the Funda-
mental Research Funds for the Central Universities (Nos. CQDXWL-
2013-Z012 and CDJZR-14225502).
di-tert-butyl-2,5-dicyanatobenzene 1d,
a low yield of 33%
was provided furnishing diimidoesterified adduct. With
a
electro-withdraw halogenated substitutions on benzene ring of
cyanatobenzenes, ethyl 2-((4-fluorophenoxy)(imino)methyl)-3-
hydroxybut-2-enoate 3e was obtained in an excellent yield of 90%,
whereas ethyl 2-((4-bromophenoxy)(imino)methyl)-3-hydroxy-
but-2-enoate 3f and ethyl 3-hydroxy-2-(imino(4-iodophenoxy)-
methyl)but-2-enoate 3g were obtained in good yields of 52% and
75%, respectively. With an attempt to improve the reactivity
through the enamine and enol anion activation (Scheme 3),
secondary and tertiary amines such as pyrrole and triethylamine
served as additives. As a result, they failed to afford 3b, 3e and 3f in
comparative yields. In the presence of pyrrole, the decreased
conversions of 26%, 43% and 21% into 3b, 3e and 3f occurred.
Likewise, triethylamine had the similar negative effects as well,
resulting in a decreased yield of 69% into 3e.
To further explore the scope of dicarbonyl compounds, a
variety of dicarbonyl compounds were then examined. Reacted
with electrophilic cyanatobenzene 1a, desired adducts of phenyl
2-acetyl-3-hydroxybut-2-enimidate 3h and methyl 3-hydroxy-2-
(imino(phenoxy)methyl)but-2-enoate 3i in 76% and 70% yields
were obtained, respectively, whereas lower yields of 32% and
7% were produced for methyl 2-((4-fluorophenoxy)(imino)-
methyl)-3-hydroxypent-2-enoate 3j and methyl 3-hydroxy-2-
(imino(phenoxy)methyl)-4-methylpent-2-enoate 3k. Whereas
4-fluorophenyl 2-acetyl-3-hydroxybut-2-enimidate 3l and meth-
yl 2-((4-fluorophenoxy)(imino)methyl)-3-hydroxybut-2-enoate
3m were assembled in lower yields of 25% and 16%, respectively. It
is worthy noting that in the imidoesterifications of 3j, 3k and 3m,
the yields of imidoesters were improved to some different extent
oppositely in the presence of pyrrole.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.06.008.
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