Rearrangement of pyran derivatives obtained from vinyl malononitriles and aldehydes via vinylogous aldol reaction: A novel facile method for the synthesis of dienamides

Article abstract of DOI:10.1055/s-0030-1258522

A novel one-pot approach to a variety dienamides from vinyl malononitriles and aldehydes via vinylogous aldol reaction was achieved by the electrolytic ring opening of the initially formed pyran derivatives under mild basic catalysis with good diastereoselectivity. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258522

LETTER
2125
Rearrangement of Pyran Derivatives Obtained from Vinyl Malononitriles
and Aldehydes via Vinylogous Aldol Reaction: A Novel Facile Method for the
Synthesis of Dienamides
Synthesis of
D
ie
h
namides elagathoti Hari Babu, Sujeet Pawar, D. Muralidharan, Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute (a CSIR Laboratory), Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 15 May 2010
OH
Abstract: A novel one-pot approach to a variety dienamides from
vinyl malononitriles and aldehydes via vinylogous aldol reaction
was achieved by the electrolytic ring opening of the initially formed
pyran derivatives under mild basic catalysis with good diastereose-
lectivity.
O
O
H
O
N
N
H
O
O
OH
O
Key words: vinyl malononitrile, vinylogous aldol reaction, pyran
rearrangement, dienamides
OH
Me
O
OH
apicularen A
salicylihalamide A
(IC50 < 1 nM)
O
N
Dienamides have been long recognized as key reactive in-
termediates due to their great diversity, synthetic poten-
tial, and occurrence in nature. Dienamides have been
effectively used both as electron-rich and electron-poor
dienes in Diels–Alder reactions.1 Dienamide based Diels–
Alder reactions are regioselective and have also been used
recently in asymmetric cycloadditions.2 Acyclic diena-
mides are also the key constituents in a number of biolog-
ically active natural products and pharmaceutically
relevant units. Examples of these include apicularen A,
salicylihalamide A, zampanolide (Figure 1).3 Although a
number of preparative methods for dienamides have ap-
peared in the literature4–11 mainly employing isocyanates
as substrates and transition metals as catalysts, the devel-
opment of mild synthetic approaches enabling facile ac-
cess to these dienamides is desirable.
HO
O
H
O
O
H
O
H
zampanolide
Figure 1 Some natural products with dienamide unit
During our studies on the reactivity of vinyl malononi-
triles in Michael addition reaction,16 we found that the vi-
nyl malononitriles also undergo aldol reaction with isatin
derivatives forming aldol adducts which are susceptible to
intramolecular nucleophilic addition and isomerization
furnishing spirofused polyhydro isochromene derivatives
with good diastereoselectivity under mild basic cataly-
sis.17 The success of our efficient novel tandem synthesis
of spirofused polyhydroisochromenes encouraged us to
explore this methodology for aldehydes also.
The vinylogous aldol reaction of a,b-unsaturated carbonyl
compounds represents an extension of the classical aldol
condensation particularly important both from the prepar-
ative and stereochemical point of view.12
Recently, Chen et al. reported that a,a-dicyanoolefin
compounds can selectively behave as acceptors13 or viny-
logous donors14,15 in Michael reactions under easily con-
trollable conditions, and yet a simple tertiary amine can
smoothly catalyze the Michael addition of an a,a-dicya-
noolefin substrate to nitrostyrene by deprotonating the
acidic g-allylic C–H to generate the nucleophilic carban-
ion.14a,c However, vinyl malononitriles have been used ex-
tensively in Michael reactions as vinylogous donors, their
reactivity in aldol reaction has not yet been explored to
any great extent.
Interestingly the pyran derivatives obtained initially from
vinyl malononitriles and aldehydes by this methodology
underwent electrolytic ring opening to afford a variety of
five- to eight-membered stereodefined cyclic dienamides
in mild reaction conditions.18
The strategy we have developed begins with the reaction
of 1.5 mmol of cyclohexylidene malononitrile (1a,
Figure 2) and 1 mmol of 4-chlorobenzaldehyde (2a) in
ethylene glycol at room temperature (32 °C) in the pres-
ence of 1 mmol of triethylamine. The reaction undergoes
smoothly within 30 minutes yielding 50% of the product.
Elevation from room temperature to 40 °C increases the
yield upto 78% (Scheme 1). The product was isolated as a
SYNLETT 2010, No. 14, pp 2125–2129
x
x
.x
x
.2
0
1
0
Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258522; Art ID: G15910ST
© Georg Thieme Verlag Stuttgart · New York

2126
T. H. Babu et al.
LETTER
NC
CN
NH2
O
CHO
NC
NC
O
NH2
Et3N, 40 °C
+
ethylene glycol
Cl
Cl
Cl
1a
2a
3a
Scheme 1
NH2
O
CHO
NC
R1
NC
R1
O
NH2
NC
R1
CN
Et3N, 40 °C
ethylene glycol
R3
R3
+
R2
R3
R2
R2
2
1a–g
3a–k
Scheme 2
single diastereomer by column chromatography and as-
signed the structure 3a on the basis of spectroscopic da-
ta.19 In the 1H NMR spectra the olefinic proton appears at
d = 6.40 ppm, whereas the amide NH2 protons resonated
at d = 7.53 and 7.87 ppm as two singlets. The amide car-
bon in 13C signaled at d = 164.5 ppm. Further the stereo-
chemistry of 3a was determined as (2Z,4E) based on its
crystal structure (Figure 3).20
NC
CN
NC
CN
NC
CN
CN
NC
Figure 3 ORTEP diagram of compound 3a
1a
1b
1c
1d
NC
CN
Me
With the demonstration of the utility of this protocol in
general, we attempted a series of reactions with a variety
of vinyl malononitriles and aromatic aldehydes under
mild reaction conditions. It is note worthy that all diena-
mides showed excellent diastereoselectivity (Scheme 2
and Table 1). However, the reaction of vinyl malono-
nitriles with aliphatic aldehydes was unsuccessful.
NC
CN
Me
CN
Me
NC
Me
Me
Me
1e
1f
1g
Figure 2
To the best of our knowledge this is the first report of the
preparation of dienamides using vinyl malononitriles.
Similarly the stereochemistries of 3b–k were assigned
analogously to those of 3a. In the H NMR, the two ole-
1
finic protons of acyclic dienamides 3i–k showed the trans
coupling constant 16 Hz.
Table 1 Synthesis of Dienamides via Vinylogous Aldol Reaction
Entry
Vinyl malononitrile
R3
Dienamide
Time (min)
40
Yield (%)a
O
NC
NH2
1
1a
4-Cl
3a
78
Cl
Synlett 2010, No. 14, 2125–2129 © Thieme Stuttgart · New York

LETTER
Synthesis of Dienamides
2127
Table 1 Synthesis of Dienamides via Vinylogous Aldol Reaction (continued)
Entry
2
Vinyl malononitrile
R3
Dienamide
Time (min)
35
Yield (%)a
O
NC
NH2
1a
4-NO2
3b
81
75
75
NO2
O
O
O
NC
NH2 Cl
3
4
1a
1a
2-Cl
3-Br
3c
45
50
NC
NH2
3d
Br
NC
NH2
5
1a
C4H4
3e
60
70
O
NC
NH2
6
7
1b
1c
4-NO2
4-NO2
3f
35
45
80
75
NO2
O
NC
NH2
3g
NO2
NC
O
NH2
8
1d
4-NO2
3h
50
70
NO2
O
NC
NH2
9
1e
1f
4-NO2
4-NO2
3i
35
30
80
85
NO2
O
NC
Me
NH2
10
3j
Me
NO2
Synlett 2010, No. 14, 2125–2129 © Thieme Stuttgart · New York

2128
T. H. Babu et al.
LETTER
Table 1 Synthesis of Dienamides via Vinylogous Aldol Reaction (continued)
Entry
11
Vinyl malononitrile
R3
Dienamide
Time (min)
40
Yield (%)a
O
NC
NH2
1g
4-NO2
3k
80
Me
NO2
a Isolated yield.
When the reaction of 1a with 2a was carried out in ethanol Scheme 4. The first step involves facile deprotonation of
and in neat conditions, interestingly methylene hydrogen vinyl malononitrile to furnish a nucleophile that attacks
of intermediate 6 was isomerized resulting in the isolation the aldehyde via vinylogous aldol reaction and subsequent
of polyhydroisochromene derivative 8 in 60% yield by intramolecular nucleophilic addition and isomerization
simple filtration (Scheme 3). But when the reaction was resulted in the intermediate 5. Ultimately intermediate 5
carried out with other vinyl malononitriles (1b–g) a mix- furnished the electrolytic ring-opened cycloadducts (3a–
ture of inseparable products was obtained. Compound 8 k). During our investigations a small fraction of the inter-
was found to be stable even when heated in ethanol or eth- mediate 4 (reaction between 1a and 2a) was isolated and
ylene glycol as confirmed by NMR and IR spectroscopy. confirmed by 1H NMR spectroscopy.
Although the detailed mechanism of the above reaction Advantages of this method are mild reaction conditions,
has not been clarified, the formation of the products can short reaction times, and isocyanate-free synthesis of die-
be tentatively explained by the pathway presented in namides with good diastereoselectivity.
NH
NH2
NC
NC
O
O
path A
H
NC
CN
CHO
Cl
Cl
7
6
Et3N, r.t.
+
EtOH (or)
neat
NH2
NH
Cl
2a
NC
NC
O
O
1a
H
path B
H
Cl
Cl
6
8
Scheme 3
N
NC
R1
NC
CN
O
H
NC
R1
CN
R2
Et3N
R2
R1
R2
1a–g
2
R3
O
NH2
NH
NC
R1
NC
R1
NH2
O
H
NC
R1
O
R2
3a–k
R2
R3
R3
R2
5
R3
4
Scheme 4 Plausible mechanism
Synlett 2010, No. 14, 2125–2129 © Thieme Stuttgart · New York

LETTER
Synthesis of Dienamides
2129
(12) For a review, see: Casiraghi, G.; Zanardi, F.; Appendino, G.;
Rassu, G. Chem. Rev. 2000, 100, 1929.
(13) (a) Chen, Y.-C.; Xue, D.; Deng, J.-G.; Cui, X.; Zhu, J.; Jiang,
Y.-Z. Tetrahedron Lett. 2004, 45, 1555. (b) Xue, D.; Chen,
Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G. J. Org.
Chem. 2005, 70, 3584.
(14) (a) For similar work, see: Xue, D.; Chen, Y.-C.; Cun, L.-F.;
Wang, Q. W.; Zhu, J.; Deng, J.-G. Org. Lett. 2005, 7, 5293.
(b) Poulsen, T. B.; Alemparte, C.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 11614. (c) Poulsen, T. B.; Bell, M.;
Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63.
(15) For a recent review on vinylogous reactions, see: Denmark,
S. E. J. R.; Heemstra, J. R.; Beutner, G. L. Angew. Chem. Int.
Ed. 2005, 44, 4682.
In conclusion we have developed a novel simple method
for the formation dienamides from readily available start-
ing materials such as vinyl malononitriles and aldehydes
via vinylogous aldol reaction followed by the electrolytic
cleaveage of pyran ring in one-pot procedure. Further ex-
ploration of these dienamides is under way.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(16) Babu, T. H.; Joseph, A. A.; Muralidharan, D.; Perumal, P. T.
Tetrahedron Lett. 2010, 51, 994.
The authors thank the Council of Scientific and Industrial Research,
New Delhi, India for the financial assistance.
(17) Babu, T. H.; Karthik, K.; Perumal, P. T. Synlett 2010, 1128.
(18) The thermal electrocyclic isomerization of fused a-pyrans is
common, see: (a) Trost, B. M.; Rudd, M. T.; Costa, M. G.;
Lee, P. I.; Pomerantz, A. E. Org. Lett. 2004, 6, 4235.
(b) Marvell, E. N.; Chadwick, T.; Caple, G.; Gosink, T.;
Zimmer, G. J. Org. Chem. 1972, 37, 2992. (c) Kluge, A. F.;
Lillya, C. P. J. Org. Chem. 1971, 36, 1979. (d) Marvell,
E. N.; Caple, G.; Gosink, T. A.; Zimmer, G. J. Am. Chem.
Soc. 1966, 88, 619.
(19) General Procedure for the Synthesis of Dienamide 3a
The mixture of vinyl malononitrile 1a (1.5 mmol), aldehyde
2a (1 mmol), and Et3N (1 mmol) in ethylene glycol (7 mL)
was stirred at 40 °C for 40 min. After the reaction was
complete as indicated by TLC, the reaction mixture was
cooled to r.t. diluted with acid H2O (10 mL). The resulting
precipitate was filtered and subjected to chromatographic
purification over silica gel (Merck; 100–200 mesh; EtOAc–
hexane = 3:7) to obtain dienamide 3a (78%) as a single
diastereomer.
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Spectral Data of Dienamide 3a (Table 1, Entry 1)
Off-white solid; yield 78%; mp 392 °C. 1H NMR (500 MHz,
DMSO-d6): d = 1.55 (m, 2 H), 1.75 (m, 2 H), 2.53 (m, 4 H),
6.42 (s, 1 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 8.4 Hz,
2 H), 7.53 (s, 1 H, D2O exchangeable), 7.87 (s, 1 H, D2O
exchangeable). 13C NMR (125 MHz, DMSO-d6): d = 26.0,
26.4, 29.9, 35.1, 106.6, 116.8, 127.2, 128.9, 128.9, 130.1,
131.4, 132.6, 135.0, 139.3, 164.3, 164.5. IR (KBr): nmax
=
3397, 3385, 2935, 2216, 1673, 1388, 1092, 626 cm–1. ESI-
MS: 287 [M + 1]. Anal. Calcd (%) for C16H15ClN2O: C,
67.02; H, 5.27; N, 9.77. Found: C, 66.97; H, 5.21; N, 9.71.
Spectral Data of Dienamide 3k (Table 1, Entry 11)
Off-white solid; yield 80%; mp 364 °C. 1H NMR (500 MHz,
CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H), 1.32 (m, 4 H), 1.47 (m,
2 H), 1.64 (m, 2 H), 2.82 (t, J = 8.4 Hz, 2 H), 5.87 (s, 1 H,
D2O exchangeable), 6.33 (s, 1 H, D2O exchangeable), 7.17
(d, J = 16.9 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 2 H), 8.22 (d,
J = 8.4 Hz, 2 H), 8.58 (d, J = 16.1 Hz. 1 H). 13C NMR (125
MHz, CDCl3): d = 14.1, 22.5, 29.5, 30.3, 31.4, 33.8, 105.6,
117.8, 124.2, 124.2, 128.0, 128.7, 128.7, 137.1, 141.9,
148.2, 163.1, 166.0. IR (KBr): nmax = 3358, 3187, 2930,
2217, 1670, 1600, 1521, 1338 cm–1. ESI-MS: 328 [M + 1].
Anal. Calcd (%) for C18H21N3O3: C, 66.04; H, 6.47; N,
12.84. Found: C, 66.01; H, 6.43; N, 12.77.
(20) Crystallographic data for compound 3a in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplemental publication No. CCDC- 775677.
Copies of the data can be obtained, free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033 or email:
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Synlett 2010, No. 14, 2125–2129 © Thieme Stuttgart · New York