Nef-Perkow access to indolizine derivatives

Article abstract of DOI:10.1055/s-0030-1258569

We present herein a new access to indolizine derivatives involving 1,3-dipolar cycloaddition of pyridinium ylides with phosphorylated hydroxyketenimines. These ketenimines are easily formed via a Nef-Perkow cascade involving isocyanides as starting material. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258569

2474
LETTER
Nef–Perkow Access to Indolizine Derivatives
N
ef–PerkowAcce
i
ss to
I
n
d
dolizine
D
er
i
ivativeser Coffinier,* Laurent El Kaim,* Laurence Grimaud*
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, 75739 Paris Cedex 15, France
Fax +33(1)45525587; E-mail: didier.coffinier@laposte.net; E-mail: laurent.elkaim@ensta.fr; E-mail: laurence.grimaud@ensta.fr
Received 2 August 2010
with other 1,3-dipoles, such as the one derived from py-
Abstract: We present herein a new access to indolizine derivatives
ridines. Pyridinium ylides have been widely used in dipo-
involving 1,3-dipolar cycloaddition of pyridinium ylides with phos-
phorylated hydroxyketenimines. These ketenimines are easily
lar cycloadditions with unsaturated compounds.7 These
dipolar species are easily prepared through the alkylation
of pyridine followed by a basic treatment of the resulting
pyridinium salt. The ylide 2a was prepared in acetonitrile
from pyridine and p-methoxybromoacetophenone. To this
in situ prepared ylide was directly added the ketenimine
1a. The resulting mixture was left overnight at room tem-
perature. After the usual treatment, the indolizine 3a was
obtained in a 71% isolated yield. This indolizine forma-
tion may be explained by a 1,3-dipolar cycloaddition in-
volving the alkene moiety of the ketenimine 1a, followed
by an aromatization of the fused-ring system through the
elimination of the phosphate (Scheme 2).
formed via a Nef–Perkow cascade involving isocyanides as starting
material.
Key words: Nef reaction, isocyanide, indolizine, pyridinium ylide,
cycloaddition
Best known for his discovery of the conversion of a nitro
to ketone functionality, Nef also disclosed an interesting
formation of imidoyl chlorides from the a-addition of acyl
chlorides onto isocyanides.1 In comparison with the more
recent Ugi and Passerini reactions,2 this reaction covers an
aspect of isocyanide reactivity that has remained largely
unexplored.3 Following our interest in isocyanide-based
multicomponent reactions, we recently revisited this reac-
tion with the idea of transforming it into a three-compo-
nent process by the final addition of various nontrivial
nucleophiles. Eventually, this process led us to disclose a
new solvent-free preparation of ketenimines by a two-step
procedure involving a Nef reaction followed by the trap-
ping of the resulting imidoyl chloride by a phosphite in a
Perkow-type reaction (Scheme 1).4 These ketenimines
were fairly stable and could be separated on silica gel
without extensive hydrolysis.
EtO2C
O
Cy
O
N
Ar
C
N
O
N
Ar
(Oi-Pr)2P
O
NCy
1a
r.t.
OPO(Oi-Pr)2
EtO2C
2a
1)
– HOPO(i-Pr)2
O
Br
O
Ar
Ar
2) K2CO3
N
NHCy
N
Ar =
OMe
R1
R1
CO2Et
R1 NC
3a (71%)
N
Nef
P(OR3)3
N
R2
C
+
R2
Cl
Δ
Scheme 2 Indolizine 3a formation from 1a
O
O
O
P(OR3)2
O
R2
Cl
As shown by the various examples reported in Table 1,
phosphorylated hydroxyketenimines 1 behave similarly
with various pyridinium ylides to form indolizine deriva-
tives 3 in good to moderate yields.
Scheme 1 Ketenimine formation
Ketenimines are known as reactive intermediates that can
be trapped by various nucleophiles or involved in differ-
ent cycloadditions.5 An interesting feature of the cycload-
ditions with these species is their ability to interact either
by their alkene or imine moiety.6 We previously reported
a 1,2,3-triazole formation through the reaction of phos-
When dealing with ketenimines 1, the best yields were ob-
tained with carboethoxy-substituted derivatives 1a and
1b. This is probably associated with a more efficient
control of the cycloaddition by
a HOMO(dipole)–
LUMO(ketenimine) interaction; the ketenimine reacting as an
electrophile with the initial bonding at the imine carbone
of 1. This is consistent with a weak coupling of 1a with the
electron-deficient ylide formed from bromopyruvic acid
derivatives (entry 9) as well as with the lack of reactivity
of 1f. The latter may be explained by the reduced efficien-
cy of nucleophilic additions onto the sterically hindered
N-tert-butylketenimine.
phorylated hydroxyketenimines
1
with silyldiazo-
methane.4 We were interested to explore further the
influence of the phosphorylated group on cycloadditions
SYNLETT 2010, No. 16, pp 2474–2476
x
x
.x
x
.2
0
1
0
Advanced online publication: 14.09.2010
DOI: 10.1055/s-0030-1258569; Art ID: D20810ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nef–Perkow Access to Indolizine Derivatives
2475
Table 1 Synthesis of Indolizine Derivatives 3
In conclusion, we have disclosed a new indolizine prepa-
ration from isocyanides. This synthesis features a new cy-
clization mode for phosphorylated hydroxy ketenimines
1. Beside its mechanistic interest, this study brings a new
access to scaffolds with significant biological interest.
Indeed, indolizines have found applications as phospho-
lipase A2 inhibitors,8 channel calcium antagonists,9 selec-
tive estrogen receptors modulators,10 or melatonin
receptors inhibitors.11 We are currently exploring further
the reactivity and synthetic potential of phosphorylated
hydroxy ketenimines 1.
O
N
R2
O
NHR4
R3
1)
2)
, K2CO3
Br
R2
R3
N
R4
R1
R1
O
C
N
3
(R5O)2P
O
1
Entry R1
R2
1a
Product, yield (%)
1
2
H
H
4-MeOC6H4
4-BrC6H4
1b
1a
1a
1c
1d
1e
1a
1d
1a
1f
3a 63
3b 51
3c 36
3d 61
3e 31
3f 37
3g 74
3h 23
–
3
4-O2NCH2C6H4 4-MeOC6H4
Typical Procedure for the Preparation of Compound 3a
Pyridine (1 mmol) and bromoacetophenone (1 mmol) were heated
in MeCN (0.3 M) at 60 °C for 30 min. Potassium carbonate (2
mmol) and a solution of 1a (1 mmol) in MeCN (1 mL) were then
added. The resulting mixture was left at r.t. overnight. Hydrolysis
followed by an extraction with CH2Cl2 and a flash chromatography
(EtOAc–PE) afforded 3a as a pale yellow solid (mp 136–138 °C,
299 mg, 71%).
4
H
H
H
H
H
H
H
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
MeO
5
6
7
Spectroscopic Data for Indolizine 3a
8
MeO
1H NMR (400 MHz, CDCl3): d = 9.58 (d, J = 7.1 Hz, 1 H), 8.07 (d,
J = 8.6 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 2 H), 7.32 (t, J = 8.1 Hz, 1 H),
6.96 (d, J = 8.8 Hz, 2 H), 6.85 (t, J = 7.1 Hz, 1 H), 6.56 (d, J = 10.4
Hz, 1 H), 4.43 (q, J = 7.3 Hz, 2 H), 3.89 (s, 3 H), 2.56 (br s, 1 H),
1.55–1.36 (m, 5 H), 1.48 (t, J = 7.3 Hz, 3 H), 1.10–0.98 (m, 1 H),
0.98–0.84 (m, 4 H). 13C NMR (100.6 MHz, CDCl3): d = 185.6,
166.7, 163.1, 150.5, 138.8, 133.4, 131.6, 128.2, 127.9, 118.2, 114.1,
113.7, 112.3, 93.9, 60.1, 58.5, 55.9, 33.8, 26.0, 25.3, 15.0. IR (thin
film): 2360, 1664, 1591, 1508, 1423, 1313, 1218, 1173 cm–1.
HRMS: m/z calcd for C25H28N2O4: 420.2049; found: 420.2062.
9
MeO2C
10
4-MeOC6H4
–
a For the different ketenimines 1 involved and the yields obtained for
their preparation from the corresponding isocyanide, acylchloride and
phosphite, see ref. 4.
EtO2C
O
Cy
EtO2C
O
Cy
C
N
C
N
(EtO)2P
O
(i-PrO)2P
O
Acknowledgment
1a (100%)
1b (65%)
Financial support was provided by GlaxoSmithKline, the CNRS
and ENSTA ParisTech.
EtO2C
O
C
N
Ph
O
Cy
(i-PrO)2P
O
OMe
OMe
O
C
N
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(i-PrO)2P
1c (85%)
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Synlett 2010, No. 16, 2474–2476 © Thieme Stuttgart · New York

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D. Coffinier et al.
LETTER
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Synlett 2010, No. 16, 2474–2476 © Thieme Stuttgart · New York