A new multicomponent reaction for the synthesis of pyridines via cycloaddition of azadienes and ketenimines

Article abstract of DOI:10.1016/j.tetlet.2011.04.007

The ketenimines resulting from a Nef isocyanide/Perkow sequence react with 1-azadienes to form pyridines or pyrimidines depending on their substitution pattern. The reaction is most efficient with ester-substituted ketenimines which leads to pyridines aft

Full text of DOI:10.1016/j.tetlet.2011.04.007

Tetrahedron Letters 52 (2011) 3023–3025
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Tetrahedron Letters
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A new multicomponent reaction for the synthesis of pyridines via
cycloaddition of azadienes and ketenimines
Didier Coffinier a, Laurent El Kaim a, , Laurence Grimaud a, , Eelco Ruijter b, Romano V. A. Orru b,
⇑
⇑
⇑
a Laboratoire Chimie et Procédés, DCSO, UMR 7652, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, Paris 75015, France
b Department of Chemistry & Pharmaceutical Sciences, VU University, de Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The ketenimines resulting from a Nef isocyanide/Perkow sequence react with 1-azadienes to form pyri-
dines or pyrimidines depending on their substitution pattern. The reaction is most efficient with ester-
substituted ketenimines which leads to pyridines after elimination of the phosphate group.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 February 2011
Revised 18 March 2011
Accepted 1 April 2011
Available online 9 April 2011
Keywords:
Isocyanides
Nef
Perkow
Azadiene
[4+2] Cycloaddition
Pyridine
Most medicinal compounds are small synthetic organic mole-
cules, many of which contain heterocyclic rings. In addition, the
most potent ligand systems in (transition) metal mediated (asym-
metric) catalysis are based on heterocyclic cores. However, the
range of easily accessible and suitably functionalized heterocyclic
building blocks is still surprisingly limited and the construction
of even a small array of relevant heterocyclic compounds is often
far from trivial. Heterocyclic chemistry, therefore, continues to at-
tract the attention of the chemistry community and the develop-
ment of novel methodologies to access heterocycles efficiently is
highly appreciated.1 In this context, methodology based on multi-
component reactions (MCRs) has received growing attention.2
Starting from three or more simple building blocks, complex (het-
ero)cyclic scaffolds can be constructed in a single operation. Rela-
tively unexplored building blocks in MCR chemistry are
ketenimines, which were first reported in 1919.3 Besides their
use as dehydrating agents, they have found many applications in
The resulting ketenimines are functionalized with a phosphate
moiety, which should have a strong influence on the reactivity of
these species. In cycloaddition reactions, the presence of the phos-
phate group could direct reactions with either the alkene or the
imine moiety. We have already explored the reactivity of these
intermediates toward several 1,3-dipoles.7 Taking into account
our interest in multicomponent reactions, we decided to further
examine these regio-selectivity issues using 1-azadienes as the
‘diene’. In earlier work, we showed that 1-azadienes are versatile
intermediates, formed via a one-pot reaction of phosphonates, ni-
triles, and aldehydes, which may be trapped in situ by a fourth
component (isocyanates, isothiocyanate, isocyanoesters) to obtain
complex heterocycles with high functional diversity (Scheme 2).8
When ketenimines are reacted with the in situ formed 1-azadienes,
pyridine or pyrimidine derivatives may be obtained depending on
the regio-selectivity of the reaction. Herein, we report our results
on this novel ketenimine/1-azadiene four-component reaction.
We started our study with the ketenimines obtained from oxa-
lic acid monoethyl ester chloride. These can be prepared directly
the synthesis of heterocycles by condensation with polar
p
bonds.4
Following our ongoing interest in isocyanide-based MCRs, we re-
cently disclosed a new solvent-free preparation of ketenimines
from isocyanides.5 This synthesis features a Nef coupling6 of an iso-
cyanide and an acid chloride followed by trapping the resulting
imidoyl chloride by a phosphite (Scheme 1).
R1
N
R1
O
R2
C
N
P(OR3)3
Nef
R2
R1 NC
R2
Cl
+
Cl
Δ
O
P(OR3)2
O
O
⇑
Corresponding authors.
E-mail addresses: laurent.elkaim@ensta.fr (L.E. Kaim), laurence.grimaud@ensta.
fr (L. Grimaud), orru@few.vu.nl (R.V.A. Orru).
Scheme 1. Formation of ketenimines by a Nef/Perkow sequence.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.007

3024
D. Coffinier et al. / Tetrahedron Letters 52 (2011) 3023–3025
R3
Ar1
N
Ar1
Ar1
NH
OPO(OR2)2
Ar2
R2
R1
R4
X
Cy
O
THF, rt
N
N
X
+
R3
Ar2
OPO(OR2)2
R3
H
O
P
CyN
Ph
N
Ph
NHCy
N
H
R3
R2
R4NCX
Ph
OMe
OMe
C
OPO(OR)2
Ar2
n-BuLi
R2
+
R1
R1 NH
Ar2= 4-FC6H4, R=i-Pr 2e
Ar2= 4-ClC6H4, R=Et 2f
Ar1= Ph 1a
Ar1= 4-ClC6H4 1b
N
R2
R1
25% (1.4/1)
27% (1/0.1)
23% (1/1)
21%(1/0.1)
O
NR4
P(OR6)2
N
H
N
R4
C
O
Scheme 4. Dihydropyridines and dihydropyrimidines from aryl ketenimines.
?
R5
R3
N
R3
N
OPO(OR6)2
R5
from the corresponding isocyanides and trialkyl phosphites and
can be used without any further purification in the subsequent
cycloadditions.
R2
R1
R4
R5
R2
R1
OPO(OR6)2
or
N
NR4
When ketenimine 2a was added to preformed azadiene 1a in
THF and the mixture stirred overnight at room temperature, the
dihydropyridine derivative 3a was formed as a single diastereomer
in 67% isolated yield (Scheme 3). Product 3a could be converted
quantitatively into pyridine 4a under basic treatment with DBU.
Assuming that changes in the nature of the initial substrates
might lead to dihydropyridines of moderate stability, we preferred
to avoid their isolation and performed subsequent phosphate elim-
ination by direct addition of DBU. Under these conditions, pyridine
4a was obtained in 68% isolated yield from diethyl methylphospho-
nate. Various ketenimines and azadienes reacted similarly to give
the corresponding pyridines in good to moderate yields (Table 1).
Besides carboethoxy substituted ketenimines 2a–d, the Nef/Per-
kow sequence was also efficient for the formation of aryl substi-
tuted ketenimines. Consequently, the cycloadditions with these
ketenimines and azadienes were studied under similar conditions.
However, these reactions proceeded with less regio- and diaste-
reo-selectivity than the MCR toward pyridines 4. Indeed when ket-
enimine 2e was added to azadiene 1a, two sets of diastereomers
were isolated in a moderate overall yield (Scheme 4). The two dihy-
dropyridine diastereomers were obtained in 25% yield as a 1.4/1
mixture. Their formation may be explained by cycloaddition of 1a
to the carbon–carbon double bond of the ketenimine. On the other
hand, formation of the dihydropyrimidine isomer (23% yield as a 1/
1 mixture) most likely proceeds via the competing cycloaddition
path involving the carbon–nitrogen double bond of 1a. Ketenimine
2f behaved similarly upon treatment with azadiene 1b, albeit form-
ing a mixture of regiomers with improved diastereo-selectivity
(Scheme 4).
Scheme 2. 1-Azadiene formation and trapping.
CyN
Ph
Ph
Ph
C
OPO(Oi-Pr)2
OPO(Oi-Pr)2
CO2Et
NHCy
2a
CO2Et
DBU
CO2Et
NHCy
THF
Ph
N
Ph
NH
Ph
N
THF, rt
67%
quant
1a
4a
3a
Scheme 3. Pyridine formation from 1a.
Table 1
Pyridine synthesis from ketenimines 1 and azadienes 29
R1NC
P(OR2)3
COCl
+
CO2Et
neat
N
R1
C
OPO(OR2)2
Ar2
N
Ar2
Ar2CHO
CO2Et
2
Ar1CN
CO2Et
n-BuLi
THF
+
Ar1
NHR1
1.THF, rt
2. DBU 1.5 equiv, rt
Ar1
NH
MePO(OMe)2
4
1
Entry
1
Azadiene
Keteniminea
Product (yield %)
In conclusion, we have coupled two multicomponent processes
to provide a new pyridine synthesis involving azadienes and keteni-
mines. Unifying different multicomponent reactions as a synthetic
strategy for the construction of heterocyclic cores is an interesting
approach to achieve complexity and diversity in synthesis.10 More
interestingly, we have shown that the regio-selectivity of the
cycloaddition between the ketenimine and the azadiene could be
controlled by the substitution pattern on the ketenimine with addi-
tions observed on the C@C and the C@N double bonds of the
ketenimine.
EtO2C
OPO(Oi-Pr)2
Ar1, Ar2 = Ph 1a
4a (68)
C
N
2a
Cy
EtO2C
OPO(Oi-Pr)2
C
N
2
3
1a
4b (58)
4c (37)
2b
OMe
OMe
EtO2C
OPO(Oi-Pr)2
C
N
1a
1a
2c
Acknowledgments
EtO2C
OPO(OEt)2
O
D.C. thanks GlaxoSmithKline and the Centre National pour la
Recherche Scientifique for a fellowship. Financial support was pro-
vided by ENSTA.
C
N
4
5
4d (39)
4e (48)
2d
Ar1 = Ph
Ar2 = 4-ClC6H4
1b
2a
References and notes
6
Ar1 = 4-MeOC6H4
Ar2 = Ph
1c
2a
4f (47)
1. See for example the May issue (5) of Chem. Rev. 2004, 104 (guest editor
Katritzky, A.R), which is devoted entirely to heterocyclic syntheses.
2. See for example: Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley:
Weinheim, 2005; Dömling, A. Chem. Rev. 2006, 106, 17–89; Orru, R. V. A.; de
Greef, M. Synthesis 2003, 1471. and references cited therein.
a
Except for 2a and 2c which were quantitatively formed, ketenimines were
purified on silica gel before use.

D. Coffinier et al. / Tetrahedron Letters 52 (2011) 3023–3025
3025
3. For reviews on ketenimines, see: Krow, G. R. Angew. Chem., Int. Ed. 1971, 10,
435–528; Barker, M. W.; McHenry, W. E. In The Chemistry of Ketenes, Allenes and
Related Compounds, Part 2; Patai, S., Ed.; John Wiley: New York, 1980; p 701.
4. Barbaro, G.; Battaglia, A.; Giorgianni, P.; Giacomini, D. Tetrahedron 1993, 49,
4293; Alajarin, M.; Molina, P.; Vidal, A.; Tovar, F. Tetrahedron 1997, 39, 13449;
Schmittel, M.; Steffen, J.-P.; Angel, M. A. W.; Engels, B.; Lennartz, C.; Hanrath, M.
Angew. Chem., Int. Ed. 1998, 37, 1562; Ruiz, J.; Marquinez, F.; Riera, V.; Vivanco,
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K.; Wu, S. H.; Wu, R. R.; Sun, S. Y. J. Org. Chem. 2002, 67, 4298; Giera, H.;
Huisgen, R.; Polborn, K. Eur. J. Org. Chem. 2005, 3781; Cheng, Y.; Ma, Y. G.;
Wang, X. R.; Mo, J. M. J. Org. Chem. 2009, 74, 850; Lu, P.; Wang, Y. Synlett 2010,
165.
(1.1 equiv) was then added and the mixture stirred at –78 °C for 45 min before
being stirred at –40 °C for 1 h. Benzaldehyde (1.1 equiv) was added and the
mixture stirred at –5 °C for 30 min before being stirred at room temperature for
90 min. A 1 M solution of keteneimine 2a (1.2 equiv) in THF was then added
and the mixture was stirred at room temperature overnight. The solvents were
removed in vacuo to afford dihydropyridine 3a as a brown oil after flash
chromatography (0.39 g, 67%). 1H NMR (CDCl3; 400 MHz) d 7.82 (d, J = 6.8 Hz,
2H), 7.40–7.32 (m, 4H), 7.26 (d, J = 6.8 Hz, 2H), 7.30–7.23 (m, 2H), 5.86 (d,
J = 6.6 Hz, 1H), 5.83 (d, J = 5.6 Hz, 1H), 4.51 (octuplet, JHÀH = JHÀP = 6.3 Hz, 2H),
4.41–4.32 (m, 1H), 4.27–4.15 (m, 2H), 4.17–4.06 (m, 1H), 2.22–2.12 (m, 1H),
2.09–1.99 (m, 1H), 1.83–1.59 (m, 4H), 1.53–1.15 (m, 4H), 1.24 (d, J = 6.3 Hz,
3H), 1.20 (d, J = 6.3 Hz, 3H), 1.18 (t, J = 5.1 Hz, 3H), 1.15–1.10 (m, 6H). 13C NMR
(CDCl3; 100.6 MHz) d 168.3 (d, JCÀP = 1.5 Hz), 153.7 (d, JCÀP = 4.4 Hz), 144.8,
139.3, 137.5, 130.5, 128.5, 128.4, 127.9, 127.8, 125.9, 104.0, 82.4 (d,
JCÀP = 8.1 Hz), 73.7 (d, JCÀP = 5.9 Hz), 73.5 (d, JCÀP = 5.9 Hz), 62.8, 50.0, 47.7 (d,
JCÀP = 5.1 Hz), 32.6, 32.5, 26.3, 25.1, 24.0 (d, JCÀP = 5.1 Hz), 23.7 (d, JCÀP = 5.1 Hz),
14.2. IR (thin film) 2932, 1680, 1575, 1546, 1266, 1227, 1129, 999. MS (DI, CIP
NH3) m/z 400 (M–HOPO(Oi-Pr)2). Typical procedure for 4a: The procedure for 3a
was initially followed. Then DBU (1.5 equiv) was added before purification and
the mixture was stirred at room temperature for 90 min. The solvents were
removed in vacuo to obtain pyridine 4a as a light yellow oil after flash column
chromatography (0.27 g, 68%). 1H NMR (CDCl3; 400 MHz) d 8.09 (d, J = 8.1, 2H),
7.51–7.37 (m, 7H), 7.35–7.30 (m, 2H), 6.96 (s, 1H), 4.34–4.22 (m, 1H), 3.93 (q,
J = 7.1 Hz, 2H), 2.21–2.13 (m, 2H), 1.87–1.78 (m, 2H), 1.73–1.65 (m, 1H), 1.56–
1.26 (m, 5H), 0.73 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3; 100.6 MHz) d 169.4,
158.0, 157.8, 154.6, 143.0, 139.4, 129.8, 128.9, 128.3, 127.9, 127.7, 127.5, 110.7,
105.4, 60.7, 49.8, 33.5, 26.5, 25.4, 13.5. IR (thin film) 2929, 1683, 1653, 1576,
1545, 1265. MS (DI, CIP NH3) m/z 400.
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mmol) in dry THF was added n-BuLi (1.2 equiv, 750
lL of a 1.6 M solution in
petroleum ether). The mixture was stirred at –78 °C for 90 min. Benzonitrile