N-Heterocyclic carbene (NHC) catalyzed annulation of enals and vinyl ketones: A novel synthesis of [2H]-pyranones

Article abstract of DOI:10.1016/j.tetlet.2011.08.157

Homoenolate annulation of vinyl ketones led to the synthesis of dihydropyranones in contrast to cyclopentenes obtained by the homoenolate annulation of chalcones, another class of α,β-unsaturated ketones.

Full text of DOI:10.1016/j.tetlet.2011.08.157

Tetrahedron Letters 52 (2011) 5992–5994
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-Heterocyclic carbene (NHC) catalyzed annulation of enals and vinyl ketones:
a novel synthesis of [2H]-pyranones
⇑
Vijay Nair , Rony Rajan Paul, K.C. Seetha Lakshmi, Rajeev S. Menon, Anu Jose, C.R. Sinu
Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Homoenolate annulation of vinyl ketones led to the synthesis of dihydropyranones in contrast to cyclo-
Received 2 August 2011
Revised 26 August 2011
Accepted 27 August 2011
Available online 2 September 2011
pentenes obtained by the homoenolate annulation of chalcones, another class of
ketones.
a,b-unsaturated
Ó 2011 Elsevier Ltd. All rights reserved.
This paper is dedicated with best wishes to
Professor Gilbert Stork on the occasion of his
90th birthday
Keywords:
N-Heterocyclic carbene
Homoenolate
Vinyl ketone
[2H]-Pyranone
The quest for the discovery of efficient, ecofriendly catalysts for
the construction of carbon–carbon bonds is a perennial issue in or-
ganic synthesis. The renaissance of organocatalysis,1 in general,
and the recognition of the unique polarity reversal (umpolung)
property of N-heterocyclic carbenes (NHCs)2 in particular, amply
illustrate this point. Recent investigations in a number of laborato-
ries have uncovered a variety of catalytic processes initiated by
NHCs, the most interesting of these being the generation of homo-
enolates from enals, discovered by Glorius3 and Bode.4 Subsequent
reaction of enals with
respectively.
c
-ketoesters and alkylidene diketones,
In an initial experiment 4-methoxy cinnamaldehyde (1,
1.5 equiv), IMesCl (0.15 equiv), and methyl vinyl ketone were taken
in THF. After the addition of DBU (0.2 equiv), the solution was stirred
for 12 h. The reaction mixture on column chromatography yielded
the product as a pale brown colored liquid which was characterized
as
3-(4-methoxybenzyl)-6-methyl-3,4-dihydro-2H-pyran-2-one
(6) (Scheme 1).
to their original work on the synthesis of
c
-lactones, a multitude of
Subsequent to the preliminary experiments, it was found that
the reaction worked more efficiently when IMesCl (3b) is used as
the catalyst and DMAP (4b) as the base (Table 1).
The reaction was extended to a number of a,b-unsaturated
aldehydes and the results are summarized in Table 2.
NHC catalyzed homoenolate reactions have emerged.5 Inter alia,
the synthesis of c
-spirolactones,6 pyrazolidinones,7 pyridazininon-
es,8 spirocyclopentanones,9 lactams,10 and cyclopentanols11 are
noteworthy. Homoenolates have also been shown to add efficiently
to nitrostyrenes12 and sulfonimines leading to the precursors for
novel c
-aminobutyric acid derivatives.13 A reaction that intrigued
OMe
OMe
us most was the NHC mediated annulation of enals with chalcones
leading to cyclopentenes.14 Our early studies were confined to the
reaction of aryl enals and aryl enones. In the continuing efforts to
define the scope of this reaction, we investigated the annulations
of enals with vinyl ketones. To our surprise, this reaction followed
a different pathway to yield [2H]-pyranones exclusively.15 The re-
sults of these studies are presented in this Letter. Recently Bode16a
and Chi16b have reported the formation of d-enol lactones by the
Mes
N
CHO
X
Me
Cl
15 mol %
O
N
Mes
5
3b
Me
20 mol % DBU (4a)
Me
O
O
OMe
THF, rt, 12 h, 44%
2
1
6
⇑
Corresponding author. Tel.: +91 471 2490406; fax: +91 471 491712.
E-mail address: vijaynair_2001@yahoo.com (V. Nair).
Scheme 1. Reaction of enal 1 with methyl vinyl ketone.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.157

V. Nair et al. / Tetrahedron Letters 52 (2011) 5992–5994
5993
Table 1
R
N
R2
O
O
O
R1
R1
N
R
H
CHO
O
3
cat. (15 mol %)
Me
O
O
OMe
IV
Me
MeO
THF,12 h
4a or 4b (20 mol %)
1
6
2
R2
R2
O
R
N
O
R
N
R
N
O
Mes
N
Mes
O
III
C6F5
ClO4
Et
N
OH
Bn
N
Cl
N
N
N
Cl
I
N
Cl
Mes
3b
N
N
R
N
N
N
N
Et
R1
R
V
R1
R1
S
I
R
HO
Mes
3a
3c
3d
3e
4a = DBU, 4b = DMAP
DMAPH
DMAP
R
N
Entry
Catalyst
Base
Yield (%)
H
O
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3b
3c
4a
4a
4a
4a
4a
4b
4b
0
44
13
0
0
76
20
N
R1
O
R
II
R2
Scheme 2. Mechanistic rationalization.
OMe
O
Table 2
Ph
O
O
CHO
3b,
15 mol %
Substrate scope18
Ph
4b
20 mol % , THF
OMe
Mes
8
9
7
rt, 12 h, 30%
N
Cl
Scheme 3. Reaction of enal 7 with phenyl vinyl ketone.
15 mol %
N
O
Me
O
O
CHO
Mes
of the enol II is proposed here keeping in line with the observed
reactivity of related homoenolates.12
R1
Me
20 mol % DMAP
THF, rt, 12 h
R1
In the subsequent studies, it was found that phenyl vinyl ketone
also afforded an analogous product, albeit in low yield (Scheme 3).
In conclusion the homoenolate annulation to vinyl ketones
leads to the synthesis of dihydropyranone derivatives in contrast
to the cyclopentenes obtained by the homoenolate reaction of an-
2
6a-i
1a-i
Entry
R1
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Phenyl
6a
6b
6c
6d
6e
6f
6g
6h
6i
90
76
98
59
60
64
37
88
51
4-Methoxyphenyl
2-Methoxyphenyl
Methyl
4-Chlorophenyl
4-Methylphenyl
4-Fluorophenyl
2-Methylphenyl
Thienyl
other class of a,b-unsaturated ketones viz., chalcones.
Acknowledgments
V.N. acknowledges the Department of Science and Technology
for the Raja Ramanna Fellowship. The authors also thank the Coun-
cil of Scientific and Industrial Research, New Delhi for financial
assistance. Thanks are due to Mrs. Soumini Mathew, Mrs. Viji S.
and Mr. Vipin M. G. for spectral data.
A mechanistic rationalization for this unexpected reaction may
be postulated as follows. The use of a weak amine base such as
DMAP for the deprotonation of the NHC precatalyst generates a
stronger cojugate acid (DMAPH+). The homoenolate equivalent I
formed initially from the enal and NHC undergoes b-protonation
presumably by DMAPH+, to afford enol II.17 The latter on Michael
addition to the vinyl ketone affords species III which on intramo-
lecular O-acylation reaction delivers [2H]-pyranone (IV). It is note-
worthy that isomerisation of enolate III to a more stable enolate V
and subsequent intramolecular aldol-type reaction, analogous to
the events observed in the case of cyclopentene formation from
chalcone is precluded here since that would involve a four-mem-
bered intermediate (Scheme 2). Interestingly, no homoenolate-
type reactivity was observed even in the presence of DBU (Table
1, entry 2).
Supplementary data
Supplementary data (general remarks, experimental procedure,
spectral data, 1H NMR and 13C NMR are included) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.08.157.
References and notes
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prospect in this reaction. A Michael-initiated annulation reaction

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18. General experimental procedure: The
a,b-unsaturated aldehyde (1.5 equiv),
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IMesCl (0.15 equiv) and vinylketone (1 equiv) were taken in THF. After addition
of DMAP (0.2 equiv) the reaction mixture was allowed to stir at room
temperature for 12 h. The reaction mixture on column chromatography on
silica gel (100–200 mesh) using 1:20 ethylacetate:hexane mixture yielded the
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corresponding [2H]-pyranone as
representative compound: 3-benzyl-6-methyl-3,4-dihydro-2H-pyran-2-one
(6a): IR (Neat) mmax
1711, 1451, 1362, 1161 cmÀ1 1H NMR (300 MHz,
CDCl3): 7.29–7.14 (m, 5H), 4.89 (s, 1H), 3.33 (d, J = 9.6 Hz, 1H), 2.77–2.66 (m,
2H), 2.14–1.94 (m, 2H), 1.86 (s, 3H). 13C NMR (75 MHz, CDCl3): 170.7, 149.4,
138.3, 128.9, 128.4, 126.4, 99.3, 39.9, 35.6, 23.5, 18.4. MS (LR-FAB): m/z calcd
for C13H14O2 (M+H)+: 203.10, found: 203.74.
a pale brown liquid. Spectral data of a
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:
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