Reactions of heterocyclic ketene aminals with 2-[3-oxoisobenzofuran-1(3 h)-ylidene]malononitrile: Synthesis of novel polyfunctionalized 1,4-dihydropyridine-fused 1,3-diazaheterocycles

Article abstract of DOI:10.1055/s-0029-1220126

An efficient method has been developed for the synthesis of a novel kind of polyfunctionalized 1,4-dihydropyridine-fused 1,3-diazaheterocycles via the reactions of heterocyclic ketene aminals (HKAs) with 2-[3-oxoisobenzofuran-1(3H) -ylidene]malononitrile. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1220126

1682
LETTER
Reactions of Heterocyclic Ketene Aminals with 2-[3-Oxoisobenzofuran-
1(3H)-ylidene]malononitrile: Synthesis of Novel Polyfunctionalized
1,4-Dihydropyridine-Fused 1,3-Diazaheterocycles
S
ynthesis of
N
ovel Poly
e
functionaliz
n
ed 1,4-Dihy
-
dropyrid
Y
ine-Fused 1,3-Dia
u
zaheterocycl
a
e
s
n Xu,a,b Yue-Mei Jia,b Jing-Kui Yang,*a Zhi-Tang Huang,*b Chu-Yi Yu*b
a
b
Received 8 April 2010
satile functionalities, which makes it a good biselectro-
philic reagent to construct the titled compounds with
bisnucleophilic HKAs 1.
Abstract: An efficient method has been developed for the synthesis
of a novel kind of polyfunctionalized 1,4-dihydropyridine-fused
1,3-diazaheterocycles via the reactions of heterocyclic ketene ami-
nals (HKAs) with 2-[3-oxoisobenzofuran-1(3H)-ylidene]malono-
nitrile.
As was expected, HKAs 1 reacted with 2-[3-oxoisobenzo-
furan-1(3H)-ylidene]malononitrile 2 smoothly to afford
the novel structures of polyfunctionalized 1,4-dihydropy-
ridine-fused 1,3-diazaheterocycles 3, i.e. spiro(imida-
zo[1,2-a]pyridine-7,1¢-isobenzofuran)-6¢-carbonitriles and
spiro(isobenzofuran-1,8¢-pyrido[1,2-a]pyrimidine)-7¢-car-
bonitriles (Scheme 1).22
Key words: heterocyclic ketene aminals, polyfunctionalized, 1,4-
dihydropyridine-fused 1,3-diazaheterocycles, synthesis
Heterocyclic ketene aminals (HKAs), also known as cy-
clic 1,1-enediamines, are versatile starting materials for
the syntheses of a wide variety of heterocycles.1,2 Since
both the a-carbon and the secondary amino group in
ketene aminals could be involved in the reactions with
electrophiles, HKAs have been used as bisnucleophiles to
construct fused azaheterocycles.3–6 Furthermore, some
HKAs and their derivatives might be used as pesticides,7
antibacterial agents,8 antianxiety agents,9 antileishmanial
agents10 and anticancer agents.11
CN
CN
H
R
O
N
O
H
N
n
R
H
DMF
n
+
N
120 °C
O
N
H
O
H2N
CN
1
2
3
n = 1, 2; R = CN, NO2, CO2Et, 4-XPh-CO; X = H, Me, OMe, Cl, Br, F, Ph
Scheme 1 Reactions of HKAs with 2-[3-oxoisobenzofuran-1(3H)-
Spiro compounds are of recent interest due to their many
uses in material sciences12 and asymmetrical catalysis13
and their prevalence in naturally occurring molecules.14,15
Therefore, the syntheses of spiro compounds have been of
intensive interest in recent years.16
ylidene]malononitrile
2-[3-Oxoisobenzofuran-1(3H)-ylidene]malononitrile (2),
prepared according to the literature,21a was stirred with
HKAs 1 in N,N-dimethylformamide at 120 °C to give 3
1,4-Dihydropyridines are kinds of important compounds (Table 1). Most of the reactions proceeded well and re-
that have wide uses as pharmaceuticals17,18 and synthetic sulted in the formation of the desired products in excellent
intermediates.19 The construction of multisubstituted di- yields. The relatively lower yield of 3b, 3f and 3n was as-
hydropyridines has attracted considerable attention in cribed to the partial decomposition of the final products
synthetic organic chemistry since Hantzsch’s pioneering upon workup. It is noteworthy that compounds 3 were
work more than one century ago.20
formed at temperatures over 120 °C, but deteriorated at
temperature above 130 °C under the same reaction condi-
tions. Therefore, the reactions should be conducted at
around 120 °C.
In the context of our continuing efforts in diversity-orient-
ed synthesis of 1,4-dihydropyridine-fused 1,3-diazahet-
erocycles, we envisaged that it could be possible to
develop a simple and novel method to construct the highly The structures of compounds 3a–o were determined by
functionalized 1,4-dihydropyridine-fused 1,3-diazahet- spectroscopic data and high-resolution mass spectrosco-
1
erocycles 3 via the reaction of HKAs 1 and 2-[3- py. IR, H NMR and 13C NMR indicated that 3a–o were
oxoisobenzofuran-1(3H)-ylidene]malononitrile
(2).21
highly substituted with a number of functional groups, in-
Compound 2 is an ideal exocyclic double-bond compound cluding two amino groups, a cyano group, and a lactone
for the synthesis of spiro compounds as it possesses ver- substructure. The absorption in IR at about 3300, 2190–
2224 and 1630–1651 cm–1 indicated the existence of ami-
no, cyano and carbonyl groups. Furthermore, for some
products, a signal appeared at d = 10.77–8.90 ppm in 1H
NMR, which was attributed to the amino group, which in
turn was ascribed to the intramolecular hydrogen bond be-
SYNLETT 2010, No. 11, pp 1682–1684
Advanced online publication: 01.06.2010
DOI: 10.1055/s-0029-1220126; Art ID: W05610ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

LETTER
Synthesis of Novel Polyfunctionalized 1,4-Dihydropyridine-Fused 1,3-Diazaheterocycles
1683
Table 1 Synthesis of 1,4-Dihydropyridine-Fused 1,3-Diazaheterocycles 3
Entry
HKA 1
1a
R
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Temp (°C)
120
n
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
Product
3a
Yield (%)a
1
PhC=O
95
89
96
90
91
87
98
98
99
99
95
90
96
88
94
2
1b
1c
4-MeC6H4C=O
4-MeOC6H4C=O
4-ClC6H4C=O
4-FC6H4C=O
4-PhC6H4C=O
NO2
120
3b
3c
3
120
4
1d
1e
120
3d
3e
5
120
6
1f
120
3f
7
1g
120
3g
8
1h
1i
CN
120
3h
3i
9
CO2Et
120
10
1j
NO2
120
3j
11
1k
1l
PhC=O
120
3k
3l
12
4-MeC6H4C=O
4-MeOC6H4C=O
4-ClC6H4C=O
4-BrC6H4C=O
120
13
1m
1n
1o
120
3m
3n
3o
14
120
15
120
a Isolated yield.
tween amino and benzoyl carbonyl group.23 The a-H and isobenzofuran-1(3H)-ylidene]malononitrile (2) undergo
one of NH signals related with 1a–o disappeared in final an aza-ene reaction to give the intermediate 4, which un-
1
products 3a–o as shown by H NMR. One of the cyano dergoes successive imine-enamine tautomerization, fol-
groups in compound 2 disappeared and only one cyano lowed by nucleophilic addition of the secondary amino
signal (d = 115.5–117.8 ppm) remained in the final prod- group to the cyano group, resulting in the formation of in-
ucts 3a–o as shown by 13C NMR, except for 3h which had termediate 5. Consecutive 1,3-H migration or imine-
another cyano group derived from substrate 1h. A pair of enamine tautomerization gives the relatively more stable
downfield shift signals (d = 150.1–155.9 ppm) and anoth- dihydropyridines 3.
er pair of upfield shift signals (d = 77–89.8 ppm) indicated
In conclusion, a simple and easy method has been devel-
that this pair of double bonds was highly polarized, which
oped for the quick construction of a novel kind of poly-
further proved the product’s structures.
functionalized 1,4-dihydropyridine-fused 1,3-diaza-
A plausible mechanism of the reaction is depicted in heterocycles by the reaction of HKAs 1 with 2-[3-ox-
Scheme 2. The reaction proceeds in a cascade way. First- oisobenzofuran-1(3H)-ylidene]malononitrile (2). These
ly, the ene-component HKAs 1 and the enophile 2-[3-oxo- types of heterocycles contain a number of functional
groups and are therefore valuable precursors for diversity-
H
oriented synthesis of pyridine-fused 1,3-diazaheterocy-
R
R
N
n
H
cles libraries, which are of potential uses in the facile
preparation of biologically active molecules. Further
work on the reactions of compounds 3 and 5 is under way.
N
aza-ene reaction
N
O
H
n
N
O
O
O
H
CN
CN
N
CN
1
2
4
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
H
R
N
imine–enamine
tautomerization
n
imine–enamine
tautomerization
3
N
nucleophilic additon
O
O
Acknowledgment
HN
CN
H
5
This work was supported by The Ministry of Science and Techno-
logy and the Ministry of Health of the P. R. of China (No.
2009ZX09501-006), and The Chinese Academy of Sciences.
Scheme 2 Mechanism of the formation of 1,4-dihydropyridine-
fused 1,3-diazaheterocycles 3
Synlett 2010, No. 11, 1682–1684 © Thieme Stuttgart · New York

1684
W.-Y. Xu et al.
LETTER
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(22) General Procedure for the Synthesis of 3: Heterocyclic
ketene aminals 1 (1 mmol) and 2-[3-oxoisobenzofuran-1
(3H)-ylidene]malononitrile (2; 1 mmol) were stirred in
DMF (5 mL) at 120 °C until the reaction was complete as
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heterospiro compounds 3.
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Compound 3f: yellow solid; mp 306–307 °C. IR (KBr): 3363
(m), 3331 (m), 2211 (m), 1633 (s), 1603 (s), 1582 (s), 1558
(s), 1508 (m), 1370 (s), 1311 (s), 931 (m), 849 (w), 763 (m),
732 (m), 678 (m), 652 (m) cm–1. 1H NMR (300 MHz,
DMSO-d6): d = 7.73 (d, J = 7.5 Hz, 1 H), 7.53–7.63 (m, 4 H),
7.44–7.47 (m, 4 H), 7.30–7.40 (m, 2 H), 7.20–7.25 (m, 1 H),
7.04 (d, J = 7.2 Hz, 1 H), 4.03–4.22 (m, 2 H), 3.79–3.94 (m,
2 H). 13C NMR (75 MHz, DMSO-d6): d = 192.0, 166.8,
154.4, 152.7, 142.9, 139.2, 137.7, 132.5, 137.0, 130.6,
130.2, 129.5, 129.1, 128.9, 128.3, 128.0, 126.7, 125.8,
117.1, 105.1, 77.9, 48.6, 45.4. HRMS (ESI): m/z [M + H]+
+
calcd for C28H21N4O3 : 461.1608; found: 461.1609.
Compound 3o: yellow solid; mp 205–207 °C. IR (KBr):
3282 (m), 3061 (m), 2212 (m), 1631 (s), 1604 (s), 1560 (s),
1528 (s), 1480 (m), 1376 (s), 1337 (s), 1280 (m), 1068 (m),
927 (m), 850 (m), 776 (m), 676 (m) cm–1. 1H NMR (300
MHz, DMSO-d6): d = 7.63 (d, J = 6.9 Hz, 1 H), 7.17–7.31
(m, 6 H), 7.00 (d, J = 6.6 Hz, 1 H), 4.01–4.02 (m, 2 H), 3.40–
3.42 (m, 2 H), 2.00–2.03 (m, 2 H). 13C NMR (75 MHz,
DMSO-d6): d = 192.7, 166.8, 156.1, 154.5, 152.1, 139.7,
137.2, 132.4, 130.6, 130.2, 130.1, 129.9, 128.5, 124.2,
117.2, 103.2, 83.5, 48.6, 42.8, 18.6. HRMS (ESI): m/z [M +
H]+ calcd for C23H18N4O3Br+: 477.0571; found: 477.0562.
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Synlett 2010, No. 11, 1682–1684 © Thieme Stuttgart · New York