An Efficient synthesis of 2-aminofuran-3-carbonitriles via cascade Stetter-γ-ketonitrile cyclization reaction catalyzed by N-heterocyclic carbene

Article abstract of DOI:10.1055/s-0030-1259945

An efficient method for the synthesis of 4,5-disubstituted 2-aminofuran-3-carbonitriles via a cascade Stetter-γ-ketonitrile cyclization reaction of aromatic aldehydes with acylidenemalononitriles, catalyzed by N-heterocyclic carbenes, has been developed.

Full text of DOI:10.1055/s-0030-1259945

LETTER
1133
An Efficient Synthesis of 2-Aminofuran-3-carbonitriles via Cascade Stetter–
g-Ketonitrile Cyclization Reaction Catalyzed by N-Heterocyclic Carbene
2
-Aminofuran
e
-3-carbonit
n
a
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
Fax +86(21)64253691; E-mail: malei@ecust.edu.cn
b
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica,
Shanghai, 201203, P. R. of China
E-mail: simmhulh@mail.shcnc.ac.cn
Received 14 January 2011
et al.12 reported a cascade Stetter–Aldol reaction for the
synthesis of 4-hydroxytetralones. In both cases, the inter-
mediates formed by the addition of aldehydes to Michael
acceptors were used to attack another electrophile to com-
Abstract: An efficient method for the synthesis of 4,5-disubstituted
2-aminofuran-3-carbonitriles via a cascade Stetter–g-ketonitrile
cyclization reaction of aromatic aldehydes with acylidenemalono-
nitriles, catalyzed by N-heterocyclic carbenes, has been developed.
This procedure provides the corresponding products in moderate to plete the cascade reactions. We hypothesized the Stetter
high yields under mild conditions.
intermediates might attack electrophiles of Michael ac-
ceptors and cyclize to 2-aminofurans when a,b-unsaturat-
ed nitriles are used as Michael acceptors (Scheme 2).
Key words: N-heterocyclic carbenes (NHCs), umpolung, cascade
reaction, Stetter reaction, 2-aminofuran
2-Aminofurans and their derivatives are useful intermedi-
ates in the synthesis of several heterocyclic compounds,
such as 4H-furo[2,3-f]-pyrrolo[1,2-a][1,4]diazepines13
and isoindolinedinones.14 Several approaches have been
developed for the synthesis of 2-aminofurans, including
the reaction of a-hydroxyketone with malononitrile15 and
the acid-catalyzed cyclization of phenacylmalononi-
triles.16 In general, however, the previous methods using
a-hydroxyketone and malononitrile are limited to the
preparation of only a few compounds because cyclization
to the corresponding hydroxypyrroles was likely to take
place in many cases.15 In order to access a variety of 2-
aminofurans, the phenacylmalononitriles need to be syn-
thesized beforehand, and this method often leads to low
yields.16 Therefore, more efficient methods are required to
synthesize this motif from simple and readily available
starting materials. We, herein, wish to develop an efficient
cascade Stetter–g-keto nitrile cyclization reaction from ar-
omatic aldehydes 1 and acylidenemalononitriles 2 to gen-
erate 2-aminofuran-3-carbonitriles 3 catalyzed by NHCs
(Scheme 2).
Ever since the discovery of a stable carbene,1 the N-het-
erocyclic carbenes (NHCs) have attracted considerable at-
tention due to their inversion of the classical reactivity
(umpolung).2 It is generally accepted that these umpolung
reactions proceed with the addition of a Breslow interme-
diate (Scheme 1) to various electrophilic reagents, such as
aldehydes3 and Michael acceptors.4 Recently, the use of
some new electrophilic reagents as acceptors have been
reported in umpolung reactions involving ketones,5 aziri-
dines,6 nitroalkenes,7 and imines.8
Me
Me
I–
Me
N
OH
R
N
N
+
base
HO
S
S
S
HO
HO
Breslow intermediate
NHC
Scheme 1 NHC and a Breslow intermediate
Cascade reactions, which allow two or more reactions to
occur consecutively in one-pot, have attracted intense in-
terest in recent years.9 The products of the Stetter reaction
are usually 1,4-bifunctional molecules,4 such as 1,4-dike-
tones, 4-keto esters, and 4-keto nitriles, which are useful
in many synthetic transformations.10 However, to the best
of our knowledge, few cascade reactions involving the
Stetter reaction have been reported. Very recently, Gravel
et al.11 reported an NHC-catalyzed cascade Stetter–
Michael reaction for the synthesis of indanes and cascade
Stetter–aldol–Michael (SAM) and Stetter–aldol–aldol
(SAA) reactions for the synthesis of spiro bis-indanes; Ye
Me
I–
N
O
R1
NH2
S
CN
R2
HO
R1CHO
+
t-BuOK (100 mol%)
EtOH, r.t.
CN
R2
CN
1
2
3
Scheme 2 Cascade Stetter–g-keto nitrile cyclization of aromatic
aldehydes and acylidenemalononitriles
To test the feasibility of our envisaged approach, we ini-
tially examined the reaction of benzaldehyde (1a) and 2-
benzylidenemalononitrile (2a) catalyzed by NHC gener-
ated from thiazolium salt 4c in the presence of the base
t-BuOK in tetrahydrofuran (THF). We were delighted to
obtain the desired product 3a in 38% yield. A series of
SYNLETT 2011, No. 8, pp 1133–1136
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.04.2011
DOI: 10.1055/s-0030-1259945; Art ID: W00511ST
© Georg Thieme Verlag Stuttgart · New York

1134
P. Liu et al.
LETTER
thiazolium salts 4a–d, 6 and imidazolium salt 5 were then reaction resulted in lower yield (Table 1, entry 7), but the
tested (Table 1, entries 1–6). The results showed that by employment of 60% 4c did not increase the yield
using imidazolium 5 (Table 1, entry 5) as a precursor, the (Table 1, entry 8).
reaction did not give any observable product. A slightly
lower yield of the desired product 3a was isolated when
thiazolium salt 4d (Table 1, entry 4) was used in the reac-
tion. However, the catalysts derived from thiazolium salts
4a and 4b (Table 1, entries 1 and 2) failed to give any
product, despite the structural similarity of 4a, 4b, and 4c.
From the point of view of economy and yield, thiazolium
salt 4c was chosen to be the precatalyst for the further re-
As summarized in Table 1, different solvents and bases
were examined for the reaction. Among the bases tested
(NaH, K2CO3, Et3N, and DBU) in this reaction (Table 1,
entries 9–12), t-BuOK was found to be optimal in terms of
yield. Several polar solvents (MeOH, MeCN and EtOH)
all led to good yields (Table 1, entries 13, 14, and 17) and
the reaction in EtOH gave the best yield (65%). According
to the above results, the optimal reaction conditions were
actions. The catalyst loading was also investigated. When
the amount of precatalyst 4c was reduced to 40%, the
obtained as follows: in the presence of thiazolium salt 4c
(50 mol%) and t-BuOK (100 mol%), the reactions were
carried out in EtOH at room temperature.
Table 1 Optimization of Reaction Conditions for the Formation of
Representative Compound 3aa
O
catalyst
base
NH2
Ph
Table 2 Reaction of Aromatic Aldehydes with Acylidenemalono-
CN
+
PhCHO
Ph
nitriles to Generate 2-Aminofuran-3-carbonitrilesa
solvent
CN
1a
2a
Ph
CN
3a
Me
I–
R1
X–
4a R1 = Bn, R2 = CH2CH2OH, X = Cl
4b R1 = n-Bu, R2 = CH2CH2OH, X = Br
4c R1 = Me, R2 = CH2CH2OH, X = I
4d R1 = Me, R2 = H, X = I
N
+
N
+
S
O
R1
R2
NH2
HO
CN
S
(50 mol%)
R2
R1CHO
+
4
t-BuOK (100 mol%)
EtOH, r.t.
Me
I–
CN
R2
CN
+N
3
1
2
N
N+
I–
Entry R1
R2
Product 3 Yield (%)b
Me
Me
S
5
6
1
2
Ph
Ph
3a
3b
3c
3d
3e
3f
65c
34d
68
75
73
74
77
69
80
82
62c
75
82
85
68c
77
83
85
Entry
1
Precat. (mol%) Base
Solvent
THF
Yield (%)b
4-MeOC6H4
2-Furyl
Ph
c
4a (50)
4b (50)
4c (50)
4d (50)
5 (50)
t-BuOK
–
3
Ph
c
2
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
K2CO3
NaH
THF
–
4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
4-CNC6H4
Ph
Ph
3
THF
38
25
5
Ph
4
THF
6
Ph
c
5
THF
–
7
Ph
3g
3h
3i
c
6
6 (50)
THF
–
8
Ph
7
4c (40)
4c (60)
4c (50)
4c (50)
4c (50)
4c (50)
4c (50)
4c (50)
4c (50)
4c (50)
4c (50)
THF
15
9
Ph
8
THF
32
10
11
12
13
14
15
16
17
18
Ph
3j
9
THF
trace
20
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3k
3l
10
11
12
13
14
15
16
17
THF
4-ClC6H4
2,4-Cl2C6H3
4-CNC6H4
Ph
Et3N
THF
trace
30
3m
3n
3o
3p
3q
3r
DBU
THF
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
MeOH
MeCN
CH2Cl2
Toluene
EtOH
42
46
4-ClC6H4
2,4-Cl2C6H3
4-CNC6H4
c
–
trace
65
a Reaction conditions: 1/2/t-BuOK = 1:1:1 mmol, EtOH (5 mL), r.t.,
a Reaction conditions: benzaldehyde (1.0 mmol), 2-benzylidene-
malononitrile (1.0 mmol), base (1.0 mmol), solvent (5.0 mL), r.t., 1 h.
b Isolated yield.
0.5 h.
b Isolated yield.
c Reaction time: 1 h.
d Reaction time: 2 h.
c No products were detected.
Synlett 2011, No. 8, 1133–1136 © Thieme Stuttgart · New York

LETTER
2-Aminofuran-3-carbonitriles
1135
O
CN
Me
CN
R3
OH
Ph
N
R2
CN
NHC
pathway A
NC
2
R3
9
S
base
R1
CN
R3
CN
Me
CN
R3
R2
S
O
N
NH2
R2CHO
1
O
R2
3
R1
7
NH2
NC
R3
NHC
Me
pathway B
O
N
R2
R1
S
Me
N
S
R1
8
Scheme 3 Two possible pathways to product 3
With the optimal reaction conditions identified, we then nitriles has been developed to synthesize 4,5-disubstituted
examined the use of a variety of functionalized aldehydes 2-aminofuran-3-carbonitriles.18 Aromatic and heteroaro-
1 and acylidenemalononitriles 2 to assess the generality matic aldehydes are successfully employed to afford 2-
and scope of this reaction. The reactions of various aro- aminofuran-3-carbonitriles 3 in moderate to good yields
matic aldehydes 1 (Table 2, entries 1–9) with 2-benz- by using an inexpensive catalyst under mild conditions.
ylidenemalononitrile (2a) were examined under the
optimal conditions mentioned above. It was found that the
use of aldehydes with electron-withdrawing substituents
(Table 2, entries 4-10) usually led to good yields. On the
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
other hand, aldehydes bearing electron-donating groups
(Table 2, entry 2) gave low yield. It was interesting to find
that 2-chlorobenzaldehyde (Table 2, entry 5) proved to be
slightly less reactive than 4-chlorobenzaldehyde (Table 2,
entry 7), which meant that steric factors did not affect the
reactivity greatly.
Primary Data for this article are available online at http://
www.thieme-connect.com/ejournals/toc/synlett and can be cited
using the following DOI: 10.4125/pd0010th.
Acknowledgment
This work was supported by the Chinese National Science and
Technology Major Project ‘Key New Drug Creation and Manufac-
turing Program’ (Grants 2009ZX09301-001, 2009ZX09102-022),
the National Natural Science Foundation of China (Grants
21002027, 90713046, 30772638 and 30925040) and the CAS Foun-
dation (Grant KSCX2-YW-R-179).
Various acylidenemalononitriles 2 (Table 2, entries 11
and 15), which were easily prepared by Knoevenagel con-
densation,17 bearing halogen or alkoxyl substituents in the
para position of the phenyl ring were also tested in the re-
action, and the results showed that the nature of the sub-
stituents did not affect the yields greatly.
References and Notes
On the basis of the above results, a tentative mechanism is
depicted in Scheme 3. Aldehyde 1 reacts with carbene to
give the Breslow intermediate, which attacks the
acylidenemalononitrile 2 to afford the Stetter intermediate
7. This intermediate then releases the NHC to generate the
Stetter product 9. Finally, the Stetter product 9 cyclizes to
form the final product 3 in the presence of a base
(Scheme 3, pathway A). Besides this mechanism, there
may be an alternative pathway (Scheme 3, pathway B),
starting from the Stetter intermediate 7 that generates the
product 3 in a manner similar to that reported by Ye and
co-workers.12 In this pathway, intermediate 7 undergoes
the cyclization reaction with NHC attached, followed by
release of NHC to generate the final product 3.
(1) Arduengo, A. J. III.; Harlow, R. L.; Kline, M. K. J. Am.
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In conclusion, a cascade Stetter–g-keto nitrile cyclization
reaction of aromatic aldehydes and acylidenemalono-
Synlett 2011, No. 8, 1133–1136 © Thieme Stuttgart · New York

1136
P. Liu et al.
LETTER
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(18) General procedure for the synthesis of 4,5-disubstituted 2-
aminofuran-3-carbonitriles 3: A flame-dried, round-bottom
flask was charged with thiazolium salt 4c (0.5 mmol),
aromatic aldehyde 1 (1.0 mmol), acylidenemalononitrile 2
(1.0 mmol), and EtOH (5 mL) under a positive pressure of
nitrogen, followed by addition of t-BuOK (1.0 mmol).
The resulting solution was stirred for 0.5–2 h at r.t. After
completion of the reaction (monitored by TLC), the reaction
mixture was concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel (petroleum ether–EtOAc, 6:1) to afford the product 3.
Synlett 2011, No. 8, 1133–1136 © Thieme Stuttgart · New York

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