SeO2-Mediated One-Pot Synthesis of 3-Cyanofurans from 3-Oxo-3-arylpropanenitriles and Substituted Acetaldehydes

Article abstract of DOI:10.1002/ejoc.201700383

An SeO₂-mediated one-pot method was established for the synthesis of 3-cyanofurans from 3-oxo-3-arylpropanenitriles and substituted acetaldehydes. The generality of the reaction was explored, and a plausible mechanism is proposed.

Full text of DOI:10.1002/ejoc.201700383

A Journal of
Accepted Article
Title: SeO2-mediated One-pot Synthesis of 3-Cyanofurans from 3-
Oxo-3-arylpropanenitrile and Substituted Acetaldehyde
Authors: Yiqian Wan, Jie Zhou, Xinhai Zhu, and Manna Huang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700383
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700383
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700383
COMMUNICATION
SeO -mediated One-pot Synthesis of 3-Cyanofurans from 3-Oxo-
2
3
-arylpropanenitrile and Substituted Acetaldehyde
[
a]
[a]
[a]
[a]
Jie Zhou, Xinhai Zhu, Manna Huang,* and Yiqian Wan*
Abstract:
A
novel SeO
2
-mediated one-pot method has been
metal silver together with the limited performance of the alkyl
terminal alkynes made it less practical in some cases. Copper-
established for the synthesis of 3-cyanofurans from 3-oxo-3-
[
15]
arylpropanenitrile and substituted acetaldehyde. The generality of
catalyzed β-diketones reacting with propargyl bromide
or
[
16]
the reaction was explored and a plausible mechanism was proposed. acetoacetonitriles with gem-difluoroalkene
represented
another one-pot way to 3-cyanofurans. However the
corresponding substrate limitation of both gem-difluoroalkenes
and propargyl bromides alleviated their wide application.
Introduction
Furans are ubiquitously found as core moieties present in a
[
1]
[1b,
variety of natural products, medicinally relevant compounds,
1
d, 2]
[3]
advanced materials and as versatile building blocks in
organic synthesis. Consequently many methodologies have
been developed for the selective and effective preparation of
diversely substituted furan cores during the past few decades
In particular, a number of synthetic strategies toward 3-
cyanofurans have been developed owing to the well-known
[4]
[
1c,
4
b, 5]
[
6]
versatile transformations of the cyano functionality.
As
depicted in Scheme 1, direct cyanation of parent furan ring to 3-
cyanofurans has been extensively explored, including: the
[
7]
transition-metal catalyzed C-halide or C-H cyanations, the
[
8]
reduction of furan-3-carboxylic acids, and the transformation of
[9]
aldehydes to nitriles. However, the shortage of the starting
materials and usually the requisite of harsh reaction conditions
limited their applications. In contrast, more attractive and
challenging routes to 3-cyanofuran framework have been
[
10]
established by cyclization of precursors bearing a “CN” moiety
or that being generated in situ.
Scheme 1. Synthesis of 3-cyanofurans.
[11]
To overcome the
inconvenience of the classical stepwise methodology, a series of
simpler, and more efficient one-pot procedures were developed
recently. In more detail, Li’s group developed a facile synthetic
pathway to 2, 3, 4-tricyanofurans from α-cyano ketones using
Here, we revealed a facile and efficient one-pot pathway to the
synthesis of 3-cyanofurans via SeO -mediated cyclization of 3-
2
oxo-3-arylpropanenitrile and substituted acetaldehyde.
As well known, the aldol reaction of 3-oxo-3-arylpropanenitrile
and aldehyde could take place under acidic condition. We
envisioned that the corresponding aldol type product might
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)
as
maleonitrile building block at room temperature with good
functional-group tolerance, although requisite 3 equivalents of
[
12]
DDQ impaired its atom economy. Slightly later, Deng and his
coworkers developed a facile oxidative coupling of α-carbonyl
radicals to DDQ for the synthesis of 2,3-dicyanofurans from
readily available β-diketones and simple ketones in one step
afford 3-cyanofurans after a key step of allylic oxidation using
[17]
2
SeO .
[
13]
with some limitation of atom economy. Lei’s group reported a
novel and effective one-pot protocol for the synthesis of
polysubstituted furans by silver-mediated highly selective
oxidative C−H/C−H functionalization of 1, 3-dicarbonyl
Results and Discussion
Initially, the reaction of 2-chlorobenzoylacetonitrile 1a (0.5 mmol)
with isopentaldehyde 2a was selected as the model reaction to
optimize the conditions. The furan product 3a was obtained in
[
14]
compounds with terminal alkynes.
But the cost of precious
3
5% yield by the use of 1.1 equiv of SeO
2
as oxidant in ethanol
O,
3
exhibited no reactivity for the reaction (Table 1,
at 100 C for 4h (Table 1, entry 1). Other oxidants such as Cu
CuI and FeCl
entries 4-6).
2
[
a]
J. Zhou, X. Zhu, M. Huang* and Y. Wan*
School of Chemical Engineering and Technology
Sun Yat-sen University
Guangzhou 510275, P.R. China
E-mail: ceswyq@mail.sysu.edu.cn; huangmn25@mail.sysu.edu.cn;
http://cet.sysu.edu.cn/User/7.aspx
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201700383
COMMUNICATION
[a]
Table 1. Optimization of the reaction conditions.
A control experiment verified the requirement of SeO
entries 3 and 31). Then, a series of additives (morpholine,
NH PO , HOAc and Pyridine, Table 1, entries 7-11) were
evaluated, wherein NH PO was the most effective (Table 1,
entry 8). Furthermore, several solvents including DMF, toluene,
CH CN, H O, DCE and NMP were tested for this transformation
Table 1, entries 12-17). To our delight, the mixture solvents of
ethanol and water proved to be the most suitable for this
transformation (Table 1, entry 18), given 3a in 66% yield. We
then turned our attention to the effect of temperature. As
illustrated in Table 1, entries 21-23, we found that the reaction
proceeded efficiently at 100 °C. In addition, the optimization on
2
(Table 1,
4
H
2
4
4
H
2
4
Oxidants
equiv)
SeO (1.1)
Solvent
(v/v)
Additives
Yield
entry
2a/1a
[
b]
(
(1.1 equiv)
(%)
3
2
1
2
3
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
0.67
0.33
1.1
1.1
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
-
35
(
[
[
h]
Se(1.1)
-
-
n. d.
n. d.
h]
-
[
h]
FeCl
Cu O (1.1)
CuI (1.1)
3
(1.1)
-
trace
[
h]
h]
2
-
n. d.
n. d.
39
different concentrations of selenium dioxide and NH
4 2 4
H PO
[
-
(
Table 1, entries 24−27) indicated that the best results were all
at 0.55 mmol (Table 1, entry 18). Hereto, the optimum conditions
for the reaction were as follow: 0.5 mmol of 1a was treated with
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
SeO
-
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(0.2)
(2.0)
(1.1)
(1.1)
(1.1)
morpholine
NH
HOAc
Pyridine
KH PO
4
H
2
PO
4
51
0
.55 mmol of 2a and 0.55 mmol of SeO
mL) in the presence of 0.55 mmol of NH
, entry18) for 4 h.
2
in ethanol/H
2
O (1 mL/1
39
4
H
2
PO at 100 C (Table
4
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
21
To understand the reaction in more detail, we run the model
reaction under the monitor of UV-Vis spectrometer. As shown in
fig S1, some reactions were occurring shortly after heating of the
mixture of 1a and 2a to provide a intermediate, which was
interestingly converted to another one in 5 min according to its
corresponding intensity of absorbance. Therefore, we quenched
the reaction within 3 min and 5 min respectively to identified
them. Intermediate 4a, an interesting trimer of 2-
chlorobenzoylacetonitrile, was successfully identified by X-ray
single crystal diffraction analysis and NMR technique, although
corresponding intermediates occuring at 5 min did not isolate
and characterize unfortunatelly because of the complicated
reaction spectrum. Further, 4a reacting with 1a did not afford the
target compound 3a but also provided much complicated
outcome of the reaction. This suggested that the formation of 4a,
a main side reaction, deteriorated the reaction outcome.
2
4
40
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
-
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
2
PO
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
32
[
h]
Toluene
trace
[
h]
CH
3
CN
n. d.
2
H O
37
[
[
h]
DCE
trace
trace
66
h]
NMP
EtOH/ H
2
O (1/1)
O (2/1)
O (1/2)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
O (1/1)
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
EtOH/ H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
58
54
[
[
[
[
[
c]
d]
e]
f]
[h]
trace
62
58
59
g]
61
15
55
63
63
61
[
h]
n. d.
Scheme 2. A main side reaction.
SeO
2
(1.1)
32
With the optimized reaction conditions in hand, we explored the
scope of substrates of this reaction. As shown in Figure 1, all the
tested 3-oxo-3-arylpropanenitriles bearing both electron-
donating and -withdrawing substituents either on the ortho- (3a,
[
a] Reaction conditions: 1a (1.0 mmol), 2a, oxidant, additive, solvent (2 mL) ,
sealed tube, at 100 °C for 4 h. [b] Isolated yield; [c] 50 °C; [d] 80 °C; [e]
20 °C; [f] NH PO (0.5 equiv); [g] NH PO (2 equiv). [h] Detected by
TLC.
1
4
H
2
4
4
H
2
4
3d, 3h-3o), meta- (3e), or para- (3b-3c) position, afforded 3-
cyanofurans in moderate yield. Besides, either the alkyl
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European Journal of Organic Chemistry
10.1002/ejoc.201700383
COMMUNICATION
acetaldehydes (3a-3j, 3o) or the aromatic acetaldehydes (3k-3n)
performed the reaction well no matter how the electronic effect is
(
3k, 3n). However, ketones and esters analogus to nitriles as
substrates did not work successfully under the experimental
conditions (3r, 3s).
Scheme 3. Proposed mechanism.
Conclusions
In summary, we developed a novel one-pot approach to 3-
cyanofurans via SeO -mediated cyclization of 3-oxo-3-
2
arylpropanenitriles and acetaldehydes. A variety of 3-oxo-3-
arylpropanenitriles reacted with alkyl acetaldehydes or the
aromatic acetaldehydes afforded 3-cyanofurans in moderate
yield, no matter what positions the substituents were on and how
the electronic effect was.
Experimental Section
General procedure for 3a-3s:
To a 10 mL of sealed vial was added 3-oxo-3-arylpropanenitrile 1 (0.5
mmol), acetaldehydes derivatives 2 (0.55 mmol), SeO (61.1mg, 0.55
2
mmol), NH PO (63.3 mg, 0.55 mmol), EtOH (1 mL), H O (1 mL) and a
2
H
4 2
4
magnetic stir bar. The reaction mixture was stirred in an oil bath
preheated to 100 C for 4 h. After allowing the mixture to cool to room
temperature, the reaction mixture was filtered, and the residue was
extracted with ethyl acetate (3 × 15 mL). The combined organic phase
Figure 1. Products and isolated yields for the synthesis of substituted furans.
Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol) and NH
4 2 4
H PO (0.55 mmol)
in EtOH/H O (1.0 mL/1.0 mL) at 100 °C for 4 h; Isolated yields.
2
2 4
was washed with brine (45 mL), dried over anhydrous Na SO , and
concentrated in vacuo. The residue was purified by flash column
chromatograph on silica gel to afford the desired product.
To explore a plausible mechanism, the model reaction was run
under the same conditions as the optimum but without SeO to
2
1
2
afford 5a (R =2Cl, R = isopropyl), which was identified to be the
Acknowledgments
-
product of aldol type condensation by ESI-MS ([M-H] = 246). 5a,
obtained from the reaction of 1a and 2a using FeCl
was further treated with SeO under the optimum conditions
directly to provide 3a in 49% isolated yield. This would result
from allylic oxidation of 5 by SeO according to Rosenblum’s
work, successive cyclization and aromatization of 6. Thus, a
proposed mechanism for our reaction was suggested as in
Scheme 3.
3
as catalyst,
This work was supported financially by grants from the
National Natural Science Foundation of China (21272287) and
the Fundamental Research Funds for the Central Universities
(16lgpy16).
2
2
[18]
Keywords: 3-Oxo-3-arylpropanenitrile • Substituted
acetaldehyde • Selenium dioxide • 3-Cyanofurans
References and notes
[
1] a) A. Boto, L. Alvarez, Furan and Its Derivatives in :Heterocycles in
Natural Product Synthesis, Ed by Edited by K. C. Majumdar and S. K.
Chattopadhyay, Wiley-VCH Verlag & Co. KGaA, 2011; b) B. A. Keay, J.
M. Hopkins, P. W. Dibble, Furans and their Benzo Derivatives:
Applications in "Comprehensive Heterocyclic Chemistry III" , Vol. 3, ed.
by G. Jones and C. A. Ramsden Elsevier, Amsterdam, 2008; c) X.-F. Wu,
Transition Metal Catalyzed Furans Synthesis, Elsevier Inc., 2016; d) H.
Bao, Q. Zhang, Y. Ye, L. Lin, Phytochem. Rev. 2016, Ahead of Print.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700383
COMMUNICATION
[
[
[
[
2] a) B. E. Love, Eur. J. Med. Chem. 2015, 97, 377-387; b) S. L. Greene,
Novel Psychoact. Subst. 2013, 383-392; c) Y.-J. Wu, Prog. Heterocycl.
Chem. 2012, 24, 1-53; d) J. Vranova, Z. Ciesarova, Czech J. Food Sci.
2009, 27, 1-10.
3] a) P. Huang, J. Du, M. C. Biewer, M. C. Stefan, J. Mater. Chem. A 2015,
3, 6244-6257; b) H. Wang, J. Male, Y. Wang, ACS Catal. 2013, 3, 1047-
1070; c) Z. Xu, Y. Zhao, X. Wang, T. Lin, Chem. Commun. 2013, 49,
6755-6757.
4] a) S. F. Kirsch, Org. Biomol. Chem. 2006, 4, 2076-2080; b) B. H.
Lipshutz, Chem. Rev. 1986, 86, 795-819; c) A. Bartoli, F. Rodier, L.
Commeiras, J. L. Parrain, G. Chouraqui, Nat. Prod. Rep. 2011, 28, 763-
782.
5] a) A. Blanc, V. Beneteau, J.-M. Weibel, P. Pale, Org. Biomol. Chem.
2016, 14, 9184-9205; b) M. Egi, S. Akai, Heterocycles 2015, 91, 931-
958; c) C. Song, J. Wang, Z. Xu, Org. Biomol. Chem. 2014, 12, 5802-
5806; d) A. V. Gulevich, A. S. Dudnik, N. Chernyak, V. Gevorgyan,
Chem. Rev. 2013, 113, 3084-3213; e) T. J. Donohoe, J. F. Bower, L. K.
Chan, Org. Biomol. Chem. 2012, 10, 1322-1328; f) B. Crone, S. F.
Kirsch, Chem. -Eur. J. 2008, 14, 3514-3522; g) S. F. Kirsch, Org. Biomol.
Chem. 2006, 4, 2076-2080; h) R. C. Brown, Angew. Chem. Int. Ed. Engl.
2005, 44, 850-852; i) X. L. Hou, H. Y. Cheung, T. Y. Hon, P. L. Kwan, T.
H. Lo, S. Y. Tong, H. N. C. Wong, Tetrahedron 1998, 54, 1955-2020; j)
X.-L. Hou, Z. Yang, H. N. C. Wong, Prog. Heterocycl. Chem. 2001, 13,
130-166; k) X.-L. Hou, Z. Yang, K.-S. Yeung, H. N. C. Wong, Prog.
Heterocycl. Chem. 2008, 19, 176-207.
[
[
6] a) Y. Ping, Q. Ding, Y. Peng, ACS Catal. 2016, 6, 5989-6005; b) S. J.
Collier, P. Langer, Sci. Synth. 2004, 19, 403-425.
7] a) M. Beller, T. Schareina, A. Zapf, A. Cotté, N. Müller, Synthesis 2008,
20, 3351-3355; b) T. Schareina, A. Zapf, W. Magerlein, N. Muller, M.
Beller, Chemistry 2007, 13, 6249-6254; c) D. Z. Steven A. Weissman,
and Cheng Chen, J. Org. Chem. 2005, 70, 1508-1510; d) L. F. a. H.
Shechter, J. Org. Chem 1960, 25, 877; e) W. Liu, L. Ackermann, Chem.
Commun. 2014, 50, 1878-1881.
[
[
[
8] a) D. Cantillo, C. O. Kappe, J. Org. Chem. 2013, 78, 10567-10571; b) Y.-
Q. Cao, A.-L. Qu, R.-Y. Liu, C.-M. Duan, J. Chem. Res. 2010, 34, 414-
415.
9] a) M. Carmeli, N. Shefer, S. Rozen, Tetrahedron Lett. 2006, 47, 8969-
8972; b) B. Movassagh, S. Shokri, Tetrahedron Lett. 2005, 46, 6923-
6925.
10] a) S.-e. S. Tzu-Ting Kao, Yi-Wun Jhang, and Wenwei Lin, Org. Lett.
010, 12, 3066-3069; b) C. K. Chan, Y. L. Chan, Y. L. Tsai, M. Y. Chang,
2
J. Org. Chem. 2016, 81, 8112-8120; c) C. J. Lee, T. H. Chang, J. K. Yu,
G. Madhusudhan Reddy, M. Y. Hsiao, W. Lin, Org. Lett. 2016, 18, 3758-
3761.
[
[
[
[
[
11] a) H. Jiang, Y. Yu, Y. Chen, W. Wu, Chem. Commun. 2016; b) L. Wang,
X. Liu, M. Wang, J. Liu, Org. Lett. 2016, 18, 2162-2165.
12] W. Wu, X.-L. Li, X.-H. Fan, L.-M. Yang, Eur. J. Org. Chem. 2013, 2013,
862-867.
13] Z. L. Wang, H. L. Li, L. S. Ge, X. L. An, Z. G. Zhang, X. Luo, J. S.
Fossey, W. P. Deng, J. Org. Chem. 2014, 79, 1156-1165.
14] C. He, S. Guo, J. Ke, J. Hao, H. Xu, H. Chen, A. Lei, J. Am. Chem. Soc.
2012, 134, 5766-5769.
15] A. Arcadi, G. Cerichelli, M. Chiarini, S. Di Giuseppe, F. Marinelli,
Tetrahedron Lett. 2000, 41, 9195-9198.
[
[
16] X. Zhang, W. Dai, W. Wu, S. Cao, Org. Lett. 2015, 17, 2708-2711.
17] K. J. Fraunhoffer, in Compr. Org. Synth. (2nd Ed.), Vol. 7, 2014, pp. 145-
177.
[
[
18] M. Rosenblum, J. Am. Chem. Soc. 1957, 79, 3179-3181.
19] CCDC 1526129 (3m) and CCDC 1526130 (4a) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Center
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European Journal of Organic Chemistry
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COMMUNICATION
Layout 2:
COMMUNICATION
Synthesis of 3-Cyanofurans
Jie Zhou, Xinhai Zhu, Manna Huang*
and Yiqian Wan*
Page 1 – Page 4.
SeO
3-Cyanofurans
2
-mediated One-pot Synthesis of
from 3-Oxo-3-
2
A novel method for the synthesis of 3-cyanofurans in one pot via SeO -mediated
cyclization of 3-oxo-3-arylpropanenitriles and acetaldehydes has been established.
arylpropanenitrile and Substituted
Acetaldehyde
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