Synthesis of functionalized and fused furans and pyrans from the Morita-Baylis-Hillman acetates of nitroalkenes

Article abstract of DOI:10.1016/j.tetlet.2012.04.084

The Morita-Baylis-Hillman (MBH) acetates derived from nitroalkenes and ethyl glyoxylate have been transformed in one pot at room temperature to highly fused and functionalized furans and pyrans in good to excellent yield. The reaction involves a cascade M

Full text of DOI:10.1016/j.tetlet.2012.04.084

Tetrahedron Letters 53 (2012) 3349–3352
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Synthesis of functionalized and fused furans and pyrans from the
Morita–Baylis–Hillman acetates of nitroalkenes
⇑
Divya K. Nair, Shaikh M. Mobin, Irishi N.N. Namboothiri
Department of Chemistry, Indian Institute of Technology, Bombay, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The Morita–Baylis–Hillman (MBH) acetates derived from nitroalkenes and ethyl glyoxylate have been
transformed in one pot at room temperature to highly fused and functionalized furans and pyrans in good
to excellent yield. The reaction involves a cascade Michael–oxa-Michael addition of b-dicarbonyl com-
pounds to the MBH acetates in the presence of an amine base such as DABCO. An unusual switching of
selectivity in the oxa-Michael addition from 5-exo-trig to 6-endo-trig was observed when the b-dicarbonyl
compound was changed from acyclic or six-membered ring cyclic to five-membered ring cyclic system.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 March 2012
Revised 18 April 2012
Accepted 18 April 2012
Available online 25 April 2012
Keywords:
Furan
Pyran
Nitroalkene
Morita–Baylis–Hillman acetates
Cascade reaction
CH3COCl
pyridine
OHCCO2Et
Im or DMAP
ref 13
Functionalized and fused furans are fabulous heterocyclic scaf-
folds for the synthesis of numerous natural products and designed
molecules.1 The biological activities such as anti-microbial, anti-
cancer, and tubulin binding properties of furan containing com-
pounds are well-documented in the literature.2 This exceptional
ability of furans to function as synthetic intermediates and as
biological agents endowed them as one of the sought after heterocy-
cles in organic synthesis.3 The cyclocondensation of 1,4-dicarbonyl
NO2
R
NO2
R
ref 14
HO
CO2Et
1
3
2
CO2Et
NO2
R2
O
R2
NO2
NO2
+
CO2Et
R1
R
R
R
O
diarylprolinol-
TMS ether
kinetic resolution
ref 14
AcO
CO2Et
AcO
*
compounds (Paal–Knorr synthesis)4 and that of
a-haloketones or
3*
4
analogous compounds with b-dicarbonyl compounds (Feist–Benary
synthesis)5 is the classical method for the synthesis of furans. In
recent years, transition metal-mediated cycloisomerization of alky-
nyl and allenyl substrates has emerged as an efficient strategy.6
However, development of new protocols for the synthesis of furans
from readily available precursors under mild conditions is still an
attractive objective.
Although pyran skeleton is present in sugars, flavanoids, and
other natural products, 4H-pyrans received only a limited atten-
tion.7 Sporadic reports on the biological activities of 4H-pyrans indi-
cate theirability to functionas inhibitorsof influenza virus sialidases
and as plant growth stimulants.8 The well known methods of intra-
molecular cyclization of o-hydroxychalcones (Auwers synthesis),
rearrangement of aromatic o-ketoesters of phenols (Baker–Venka-
taraman synthesis), condensation of phenols with b-ketoesters
(von Pechman synthesis), and condensation of o-hydroxyarylke-
tones with enamines or carbonyl compounds (Kabe synthesis and
R1
Scheme 1. Previous work.
Robinson–Kostanecki synthesis) are all limited to the synthesis of
chromones (benzopyranones).9 To our knowledge, the available
methods for the synthesis of 4H-pyrans are too substrate specific7,10
and 4H-pyrans fused to other alicycles are relatively rare.11
The Morita–Baylis–Hillman (MBH) reaction between electron
deficient alkenes and suitable carbonyl compounds generates a
diverse array of allylic alcohols that are amenable for further
manipulation.12 Some time ago, we reported the MBH reaction of
nitroalkenes 1 with various activated non-enolizable carbonyl
compounds, for instance, ethyl glyoxylate, to generate alcohols 2
(Scheme 1).13 Recently, Chen and co-workers elegantly demon-
strated the kinetic resolution of corresponding acetates 3 using
aldehydes and ketones involving a Michael addition-elimination
sequence.14
We realized that at least two potential electrophilic sites open up
as in 5 or 8–9 after the first Michael addition to acetate 3 followed
⇑
Corresponding author.
E-mail address: irishi@iitb.ac.in (I.N.N. Namboothiri).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.084

3350
D. K. Nair et al. / Tetrahedron Letters 53 (2012) 3349–3352
Table 2
X
a
X
Y
X
Synthesis of fused furans 11 via addition of dimedone 10 to MBH acetates 3
Y
NO2
NO2
NO2
R
Y-
R
and/or
Michael
R
O
R
NO2
O
DABCO
THF, rt
R
CO2Et
CO2Et
CO2Et
b
5
6
7
AcO
CO2Et
O
EtO2C
O
10
Y-
Michael-
Y-
X-
X
X
3
11
Elimination
Y-
NO2
X-
NO2
and/
or
R
R
R
CO2Et
Michael-Elim-
CO2Et
Intra-Michael
NO2
Entry
R
11
Time (h)
% Yielda
CO2Et
AcO
3
8
9
1
2
3
4
5
6
7
8
9
10
11
12
13
3,4-(OMe)2Ph
2,5-(OMe)2Ph
11a
11b
11c
11d
11e
11f
11g
11h
11i
1
2.5
1
1
1
92
90
94
94
91
94
87
88
86
85
86
75
exo-trig
endo-trig
3,4-(OCH2O)Ph
3,4,5-(OMe)3Ph
4-OMePh
4-NMe2Ph
4-MePh
Ph
4-ClPh
2-Furyl
Scheme 2. Present work.
by elimination offering the possibility of further Michael addition
(Scheme 2). Such a second Michael addition in an intermolecular
fashion would provide 6 or 7 whereas its intramolecular version
would take place in an n-exo-trig fashion as shown in 8 and/or in
an n+1-endo-trig fashion as in 9. The intramolecular version would
be particularly attractive from the perspective of synthesis of den-
sely functionalized and fused heterocyclic scaffolds. We envisioned
that b-dicarbonyl compounds would be excellent nucleophiles to
test our hypothesis due to their proven ability to enolize and react
as C-nucleophiles and as oxygen nucleophiles under suitable
conditions.15
6
5
1.5
1.5
3
2.5
1
11j
11k
11l
2-Thienyl
2-MeOPhCH@CH
i-Pr
b
11m
1
—
a
Isolated yield after silica gel column chromatography.
Complex mixture.
b
important to note that the MBH acetates with strong single and
multiple electron donating groups on the aromatic rings 3a–3f pro-
vide the products 11a–f in excellent yield (>90%, Table 3, entries
1–6). The MBH acetates with aromatic rings possessing weakly acti-
vating and weakly deactivating substituents, 3g and 3i, respec-
tively, as well as those with phenyl and heteroaromatic rings, 3h
and 3j–k, respectively, delivered the desired furans in high yield
(85–88%, Table 2, entries 7–11). Marginally lower yield (75%) was
encountered when nitrodiene derived MBH acetate 3l was em-
ployed as the Michael acceptor (Table 2, entry 12). However, our
attempts to react the acetate 3m with dimedone 10 under the opti-
mized conditions provided only complex mixture (Table 2, entry
13).
The hallmark of the above strategy was the formation of regio-
isomerically pure products at rt in good to excellent yields in reac-
tion times not exceeding 6 h. The regiochemistry of the products
was confirmed by 1H–1H NOESY experiment. Thus a positive
NOE interaction was observed between CH2 appearing as a singlet
at d 3.69 and the aromatic protons in a representative compound
11d. The structure of furans 11a–l was further unambiguously
established by single crystal X-ray analysis of a representative
product 11j (see Supplementary data).
Initially, MBH acetate 3a and dimedone 10 were chosen as mod-
el substrates for our studies. Treatment of 3a with 10 in the pres-
ence of 1 equiv of amine bases such as DMAP, DBU, imidazole, and
Et3N in THF at room temperature provided unsatisfactory results
(Table 1, entries 1–4). However, when 3a was treated with 10 in
the presence of DIPA, we were pleasantly surprised to see the for-
mation of furan 11a in 52% yield (Table 1, entry 5). Further
improvement in the yield was observed in the presence of K2CO3
and EDIPA (63% and 70%, respectively, Table 2, entries 6–7). Finally,
a remarkable increase in the yield (92%) with decrease in reaction
time (1 h) was observed when the reaction was carried out in the
presence of 1 equiv of DABCO (Table 1, entry 8). Longer reaction
time (10 h) and substantial decrease in the yield (72%) were
encountered when the amount of DABCO was reduced to 0.5 equiv
(Table 1, entry 9).
The above optimized conditions, viz. 1 equiv of DABCO, in THF,
at rt, were employed to explore the scope of the reaction of
dimedone 10 with different MBH acetates 3b–m (Table 2). It is
Table 1
Screening of bases
MeO
MeO
Further scope of the above Michael–oxa–Michael-elimination
cascade was investigated by the addition of diverse acyclic and
six-membered cyclic b-dicarbonyl compounds 12a–f to a represen-
tative MBH acetate 3d under the optimized conditions (Table 3).
Thus b-diketones viz. cyclohexanedione 12a and acetylacetone
12b reacted with MBH acetate 3d to provide furans 13a and 13b
in yields of 88% and 92%, respectively (Table 3, entries 1–2). An
acyclic b-diketone with extended conjugation such as 12c (analog
of curcumin) afforded the embellished furan 13c though in lower
yield (54%) and a longer reaction time (48 h, Table 3, entry 3). Sim-
ilar reaction of b-ketoester 12d with MBH acetate 3d proceeded
well to provide furan 13d in good yield (Table 4, entry 4). However,
under our experimental conditions, the cyclic ester, Meldrum’s
acid, 12e did not add to MBH acetate 3d and the cyclic diamide,
barbituric acid, 12f, though reacted with 3d, gave an intractable
mixture on attempted purification (Table 3, entry 6).
Base
MeO
MeO
NO2
O
O
(1 equiv)
THF, rt
CO2Et
AcO
O
O
EtO2C
3a
10
11a
Entry
Base
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
DMAP
DBU
Imidazole
Et3N
6
1
16
30
4
1
5
1
10
Traces
Complex mixture
No reaction
Complex mixture
52
63
70
92
72
DIPA
K2CO3
EDIPA
DABCO
DABCOb
Surprisingly, reaction of a series of MBH acetates 3 with cyclop-
entanedione 14 under the above optimized conditions led to the
formation of fused pyrans 15 instead of furans as observed in the
a
Isolated yield after silica gel column chromatography.
0.5 equiv of DABCO was used.
b

D. K. Nair et al. / Tetrahedron Letters 53 (2012) 3349–3352
3351
Table 4
case of acyclic and six-membered cyclic b-dicarbonyl compounds
(Table 4). The MBH acetates with strongly electron donating aro-
matic rings 3a and 3c and those with heteroaromatic rings 3j
and 3k reacted with 14 to afford pyrans 15a, 15c, 15j, and 15k,
respectively, in good yield (72–81%, Table 4, entries 1, 2, 5, and
6). Although MBH acetate 3h with Ph group at the b-position of
the nitro group gave the product in moderate yield (53%, entry
3), the corresponding p-chlorophenyl analog 3i reacted well with
14 to give pyran 15i in good yield. The structure of pyrans 15a,
15c, and 15h–k was confirmed by single crystal X-ray analysis of
a representative product 15k (see Supplementary data).
The proposed mechanism involves DABCO mediated deprotona-
tion of b-dicarbonyl compound, for example, 12a or 14, and its
addition to MBH acetate 3 in a Michael fashion which is overall
an SN2’ substitution (Scheme 3). The intermediate I or III then
undergoes enolization followed by intramolecular oxa-Michael
addition in a regioselective fashion. In the case of dimedone 10
or six-membered cyclic or open chain b-dicarbonyl compound
Synthesis of fused pyrans 15 via reaction of cyclopentan-1,3-dione 14 with MBH
acetates 3
Ar
O
AcO
Ar
CO2Et
NO2
O
O
DABCO
THF, rt
EtO2C
O
3
14
15
Entry
Ar
15
Time (h)
% Yielda
1
2
3
4
5
6
3,4-(OMe)2Ph
3,4-(OCH2O)Ph
Ph
4-ClPh
2-Furyl
15a
15c
15h
15i
15j
15k
5
4
4
1
6
4
81
72
53
70
80
78
2-Thienyl
a
Isolated yield after silica gel column chromatography.
12, oxa-Michael addition in a 5-exo-trig fashion to the a,b-unsatu-
furan 11. In the case of cyclopentanedione 14, although the first
step is analogous to that in the furan formation, a dramatic change
in the reaction profile is observed in the second step (path B,
rated ester moiety affords intermediate II (path A, Scheme 3). The
DABCO mediated elimination of HNO2 from intermediate II com-
pletes the sequence to provide a highly functionalized and fused
Table 3
Scope of acyclic and six-membered cyclic 1,3-dicarbonyl compounds 12
OMe
MeO
MeO
MeO
NO2
O
O
O
DABCO
THF, rt
MeO
EtO2C
R2
R1
R1
R2
AcO
OMe
CO2Et
O
3d
12
13
Entry
1
12
1,3-Dicarbonyls
13
Furans
Time (h)
4
% Yielda
88
O
O
O
Ar
12a
13a
13b
EtO2C
EtO2C
O
O
Ar
2
3
12b
12c
R1, R2 = CH3
1
92
54
74
O
O
O
OMe
MeO
MeO
Ph
Ph
O
Ph
Ph
13c
48
EtO2C
O
O
Ar
OEt
4
5
12d
12e
R
1 = CH3, R2 = OEt
13d
13e
3
EtO2C
O
O
O
O
Ar
b
O
O
O
24
—
O
EtO2C
EtO2C
O
O
O
O
Ar
HN
NH
NH
c
6
12f
13f
4
—
O
O
N
H
O
a
b
c
Isolated yield after silica gel column chromatography.
No reaction.
Complex mixture.

3352
D. K. Nair et al. / Tetrahedron Letters 53 (2012) 3349–3352
n
O
O
O
O
O
H
R
5-exo-trig
n = 2
path A
O
O
DABCO
-HNO2
NO2
CO2Et
O
CO2Et
II
H
n
R
I
11
R
NO2
12a or 14
O
NO2
CO2Et
R
DABCO
CO2Et
R
O
n
AcO
O
O
O
6-endo-trig
n = 1
DABCO
-HNO2
O
3
H
H
R
CO2Et
EtO2C
CO2Et
R
path B
NO2
NO2
III
IV
15
Scheme 3. Proposed mechanism for the formation of furans 11, 13, and pyrans 15.
Anticancer: (c) Rao, R. R.; Chaturvedi, V.; Babu, K. S.; Reddy, P. P.; Rao, V. R. S.;
Sreekanth, P.; Sreedhar, A. S.; Rao, J. M. Med. Chem. Res. 2012, 21, 634; Tubulin
polymerization inhibitor: (d) Kerr, D. J.; Hamel, E.; Jung, M. K.; Flynn, B. L.
Bioorg. Med. Chem. 2007, 15, 3290.
Scheme 3). Thus the oxa-Michael addition in III is not to the
,b-unsaturated ester moiety, but to the nitroalkene moiety in a
6-endo-trig fashion. This dramatic change in the mode of cycliza-
tion is attributable to a combination of the geometry of the enolate
arising from III and the superior Michael acceptor ability of nitro-
alkene moiety (Scheme 3).
a
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In conclusion, highly regioselective cascade reactions of b-dicar-
bonyl compounds with Morita–Baylis–Hillman acetates of nitroal-
kenes led to functionalized and fused furans and pyrans in high
yield. The reaction mediated by DABCO proceeds in a cascade
Michael–5-exo-trig-oxa-Michael fashion in the case of open chain
and six-membered cyclic b-dicarbonyl compounds to afford fused
furans. On the other hand, a cascade Michael–5-endo-trig-oxa-
Michael reaction takes place in the case of five-membered cyclic
b-dicarbonyl compounds to afford fused 4H-pyrans.
Acknowledgment
I.N.N.N. thanks the DST India for financial assistance. D.K.N.
thanks the CSIR India for a senior research fellowship. The authors
thank the CRNTS, IIT Bombay for selected NMR data.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
084.
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