A simple protocol for the synthesis of a piperidine-2,6-dione framework from Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2009.03.038

3-Hydroxy-2-methylenealkanenitriles, the Baylis-Hillman alcohols, derived from various aldehydes and acrylonitrile, have been conveniently transformed into 3-arylidene(or alkylidene)piperidine-2,6-diones in an operationally simple one-pot multi-step process involving Johnson-Claisen (J-C) rearrangement, partial hydrolysis, and cyclization. Rearranged Baylis-Hillman alcohols, (E)-2-hydroxymethyl-3-arylprop-2-enenitriles, have been converted into 4-aryl-3-methylidenepiperidine-2,6-diones in a similar reaction sequence. 4-Aryl-3,5-dimethylidenepiperidine-2,6-dione derivatives have been synthesized from Baylis-Hillman compounds, 3-aryl-4-cyano-2-methoxycarbonylpenta-1,4-dienes, obtained via the Baylis-Hillman reaction of methyl (2Z)-2-(bromomethyl)-3-arylprop-2-enoates with acrylonitrile, in a one-pot process.

Full text of DOI:10.1016/j.tetlet.2009.03.038

Tetrahedron Letters 50 (2009) 3538–3542
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Tetrahedron Letters
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A simple protocol for the synthesis of a piperidine-2,6-dione framework
from Baylis–Hillman adducts
*
Deevi Basavaiah , Dandamudi V. Lenin, Badugu Devendar
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Hydroxy-2-methylenealkanenitriles, the Baylis–Hillman alcohols, derived from various aldehydes and
acrylonitrile, have been conveniently transformed into 3-arylidene(or alkylidene)piperidine-2,6-diones
in an operationally simple one-pot multi-step process involving Johnson–Claisen (J–C) rearrangement,
partial hydrolysis, and cyclization. Rearranged Baylis–Hillman alcohols, (E)-2-hydroxymethyl-3-aryl-
prop-2-enenitriles, have been converted into 4-aryl-3-methylidenepiperidine-2,6-diones in a similar
reaction sequence. 4-Aryl-3,5-dimethylidenepiperidine-2,6-dione derivatives have been synthesized
from Baylis–Hillman compounds, 3-aryl-4-cyano-2-methoxycarbonylpenta-1,4-dienes, obtained via the
Baylis–Hillman reaction of methyl (2Z)-2-(bromomethyl)-3-arylprop-2-enoates with acrylonitrile, in a
one-pot process.
Received 8 January 2009
Revised 2 March 2009
Accepted 5 March 2009
Available online 13 March 2009
Keywords:
Baylis–Hillman alcohols
Johnson–Claisen rearrangement
Partial hydrolysis
Cyclization
Ó 2009 Elsevier Ltd. All rights reserved.
Piperidine-2,6-diones
DABCO
The piperidine-2,6-dione framework is a prominent skeleton
present in a number of biologically active and natural products
such as thalidomide1a (sedative, drug to prevent morning sickness
of pregnant women), (+)-migrastatin1b,c (antitumor agent),
lactimidomycin1d,e (antibiotic), dorrigocins A and B1f,g (antifungal,
antibiotic), NK30424 A and B1h,i [inhibitors of lipopolysaccharide
A few years ago, we reported an interesting methodology for the
synthesis of functionalized alkenes, that is, ethyl (4Z)-4-cyanoalk-4-
enoates [with exclusive (Z)-selectivity] via the J–C rearrangement5s
of the 2-methylene-3-hydroxyalkanenitriles, the Baylis–Hillman
alcohols. We felt that the presence of two interesting functionalities
(ester and nitrile) in appropriate positions in ethyl (4Z)-4-cyanoalk-
4-enoates would make these derivatives attractive synthons for
obtaining piperidine-2,6-dione derivatives via the partial hydrolysis
of the cyano group into the amide group followed by cyclization. To-
day the science of synthesis demands the development of operation-
ally simple one-pot processes for obtaining important molecules of
medicinal relevance. We have, therefore, directed our attention to-
ward the development of one-pot processes for the synthesis of
piperidine-2,6-dione derivatives starting from the Baylis–Hillman
alcohols derived from acrylonitrile and aldehydes (see retro-syn-
thetic strategy: Scheme 1). In this direction, our real task would be
the selection of an appropriate reagent to transform the nitrile group
into the amide group, thus leading to cyclization.
The literature survey reveals that a combination of FeCl3/acetic
acid has been used for the preparation of cyclic amides from
ketonitriles and imides from the compounds containing the ester
and nitrile moieties in appropriate positions.6 Batra and co-work-
ers7 used the combination of FeCl3/propanonic acid for the con-
version of 2-methylidene-3-(cyanoethoxycarbonyl)methyl-3-
arylpropanoates, derived from the corresponding Baylis–Hillman
acetates, into 3-methylidene-2,5-piperidinedione derivatives in
two steps.
(LPS)-induced tumor necrosis factor (TNF)-
a promoter activity],
streptimidone1j,k (antibiotic), and sesbanimide1l,m (antitumor).
Therefore the development of simple and facile methodologies
for the synthesis of piperidine-2,6-dione frameworks represents
an attractive and challenging area in synthetic organic and medic-
inal chemistry.2 As part of our on-going research program on the
applications of Baylis–Hillman adducts in heterocyclic chemistry,3
we herein report a facile transformation of the Baylis–Hillman (B–
H) adducts (or rearranged B–H adducts) into substituted piperi-
dine-2,6-dione derivatives in an operationally simple procedure.
The Baylis–Hillman reaction has become a powerful synthetic
tool in organic chemistry for the preparation of densely functional-
ized molecules via the construction of carbon–carbon bonds in an
operationally simple one-pot atom economical procedure.4,5 These
densely functionalized molecules usually known as Baylis–Hillman
adducts have been systematically employed in various organic
transformations and also in the synthesis of natural products and
bioactive molecules.4,5
* Corresponding author. Tel.: +91 40 23134812; fax: +91 40 23012460.
E-mail address: dbsc@uohyd.ernet.in (D. Basavaiah).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.038

D. Basavaiah et al. / Tetrahedron Letters 50 (2009) 3538–3542
3539
(a)
(b)
(c)
Figure 1. ORTEP diagrams of compounds (a) 2b, (b) 2c, and (c) 6a11 (hydrogen atoms were omitted for clarity).
COOEt
O
Partial
Hydrolysis
OH
J-C
R
Cyclization
rearrangement
NH
R
R
C-OEt
R
O
Isomerization
CN
N
H2
CN
O
O
(Z)-isomer
(E)-isomer
Scheme 1. Retro-synthetic strategy for the synthesis of 3-arylidene-(alkylidene)piperidine-2,6-dione framework.
Therefore it occurred to us that FeCl3/acetic acid would serve
as an appropriate reagent for the transformation of ethyl (4Z)-
1, it is indeed, quite clear that the amount of FeCl3 directs the fate
of the stereochemistry of the product and we were pleased to
note that FeCl3 (5 mmol) (for 1 mmol of the Baylis–Hillman alco-
hol) provides 100% (E)-stereoselectivity.8,9 Another interesting
point in this strategy is that four steps (orthoester rearrangement,
partial hydrolysis of the cyano group, cyclization, and isomeriza-
tion) were performed in an operationally simple one-pot to pro-
duce 3-benzylidenepiperidine-2,6-dione (2a) with (E)-selectivity
in good yields.
With a view to understanding the generality of this reaction, we
subjected representative Baylis–Hillman alcohols (1b–g), obtained
via the reaction of acrylonitrile with various aldehydes, to this
reaction strategy to provide (E)-3-arylidene (or alkylidene)piperi-
dine-2,6-diones (2b–g) in 67-81% isolated yields (Scheme 1, Table
2). In order to extend the possibility of this strategy for obtaining
more substituted imide derivatives, we performed the J–C rear-
rangement of the Baylis–Hillman alcohols 1a and 1e with triethyl
orthopropanoate and then treated the in situ generated products
with FeCl3/acetic acid for 10 h under reflux to provide the com-
pounds (E)-3-benzylidene-5-methylpiperidine-2,6-dione (2h) and
(E)-3-(3-phenylpropylidene)-5-methylpiperidine-2,6-dione (2i) in
76% and 67% isolated yields, respectively (Table 2, entries 8 and
9). The structures of the compounds 2b and 2c were further con-
firmed by single crystal X-ray data.11
4-cyanoalk-4-enoates into
a 3-benzylidenepiperidine-2,6-dione
framework via selective hydrolysis and cyclization, in a one-pot
process. We have thus first selected 3-hydroxy-2-methylene-3-
phenylpropanoate (1a), the Baylis–Hillman alcohol obtained via
the coupling of acrylonitrile and benzaldehyde, as a substrate
for this purpose. In this direction, we have treated Baylis–Hillman
alcohol 1a (1 mmol) with triethyl orthoacetate (1 mL) at 146 °C in
the presence of propanoic acid (3 drops) for 2 h. The excess ortho-
ester and propanoic acid were removed under reduced pressure.
The residue thus obtained was treated with anhydrous FeCl3
(1 mmol) in acetic acid (5 mL) at reflux temperature for 10 h, to
provide 3-benzylidenepiperidine-2,6-dione (2a) as a mixture of
E:Z (78:22)8 isomers as a colorless solid in 44% isolated yield,
after work-up and purification by column chromatography
(Scheme 1, Table 1, entry 1). It is indeed interesting to note that
the (Z)-stereochemistry in the key intermediate (IA) has been
converted into (E)-stereochemistry in the final product. It oc-
curred to us that increasing the amounts of FeCl3 might result
in the total isomerization of the (Z)-double bond of the key inter-
mediate into an (E)-double bond in the product. We have there-
fore conducted
a number of experiments with increasing
quantities of FeCl3 to understand this aspect (Table 1). From Table
Table 1
Standardization of reaction conditionsa
O
CH C(OEt) / EtCO H (cat)
3
3
2
OH
CO2Et
FeCl
3
Ph
J-C rearrangement
Ph
NH
Ph
CN
CH CO H
CN
3
2
O
(Z)
2 h, 146 ºC
I A
1a
reflux
2a
b,c
Entry
FeCl3 (mmol)
Time (h)
2a (E:Z)8
Yield
2a (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
5
5
5
5
10
10
10
10
02
04
06
08
10
78:22
82:18
91:09
96:04
65:35
88:12
92:08
96:04
100:00
44
80
82
81
45
60
70
82
84
a
All reactions were carried out on a 1 mmol scale of B–H alcohol (1a).
The compound 2a was obtained as a colorless solid and fully characterized.
Isolated yields based on B–H alcohols.
b
c

3540
D. Basavaiah et al. / Tetrahedron Letters 50 (2009) 3538–3542
Table 2
followed by subsequent anti-elimination might provide (E)-imide.
In order to understand the possibility of (Z)-imide [(Z)-2a] convert-
ing into (E)-imide we have prepared (Z)-3-benzylidenepiperidine-
2,6-dione [(Z)-2a imide] via the treatment of the in situ generated
(4Z)-4-cyano-5-phenylpent-4-enoate (IA) (the J–C rearrangement
product) with H2SO4 [to provide-IIA amide (isolated)] followed
by subsequent cyclization using NaH. The treatment of (Z)-2a
(imide) with FeCl3/acetic acid under reflux for 10 h provided (E)-
3-benzylidenepiperidine-2,6-dione [(E)-2a] (probably thermody-
namically more stable product12) (Scheme 3). We have also ob-
served that the reaction of (4Z)-4-aminocarbonyl-5-phenylpent-
4-enoate (IIA) with FeCl3/acetic acid at reflux temperature for
10 h directly provided (E)-3-benzylidenepiperidine-2,6-dione
[(E)-2a] (Scheme 3). These experiments, to some extent, demon-
strate that the change of (Z)-stereochemistry into (E)-stereochem-
istry might be either due to the Michael addition of the acetate ion
onto the (Z)-ene-nitrile or on to the (Z)-ene-imide12 onto in situ
formed (Z)-ene-amide followed by anti-elimination (Transition
state models: TS-I and TS-II).
With a view to providing a simple method for the synthesis of
4-aryl-3-methylidenepiperidine-2,6-dione derivatives, we sub-
jected the rearranged Baylis–Hillman alcohols, (2E)-2-cyano-3-
arylprop-2-en-1-ols5r (3a–d) (which were obtained from 3-hydro-
xy-2-methylene-3-arylpropionitriles via the treatment with 20%
aq H2SO4 at reflux temperature for 2 h) to this strategy (the J–C
rearrangement followed by partial hydrolysis and cyclization).
The resulting products, 4-aryl-3-methylidenepiperidine-2,6-dione
(4a–d) (Table 3, entries 1–4), were obtained in 64–70% isolated
yields.
Synthesis of (E)-3-arylidene(alkylidene)piperidine-2,6-diones (2a–i) from Baylis–
Hillman alcohols (1a–g)a
1) R1CH2C(OEt)3 / EtCO2H (cat)
O
J-C rearrangement
146 ºC, 2 h
R
NH
OH
O
R
2) FeCl3 (5 eq.)
CH3CO2H, reflux, 10 h
R1
(E) - 2a-i
CN
1a-g
Entry
B–H alcohol
R
R1
Productb
Yieldc (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1a
1b
C6H5
H
H
H
H
H
H
2a9,10
2bd
2cd
2d
2e
2f
84
67
71
77
73
75
81
76
67
3-ClC6H4
4-ClC6H4
4-MeC6H4
C6H5CH2CH2
C7H15
C5H11
H
2g
C6H5
C6H5CH2CH2
CH3
CH3
2h
2i
a
All reactions were carried out on a 1 mmol scale of B–H alcohols (1a–g).
All the compounds (2a–i) were obtained as colorless solids and fully charac-
b
terized and the E-stereochemistry was assigned on the basis of 1H NMR spectral
analysis.8
c
Isolated yields based on B–H alcohols.
Structures of these molecules were also confirmed by single crystal X-ray data
d
(Fig. 1).11
A possible mechanism for the interesting reversal of (Z)-stereo-
chemistry in the key intermediate (IA) (J-C rearrangement prod-
uct) into (E)-stereochemistry in the final product (imide) is
presented in Scheme 2. FeCl3 might first coordinate with the nitro-
gen of the nitrile group thus making its carbon more electrophilic.
Then acetate ion might add on to the ene-nitrile via the 1,4-fashion
first and then 1,2-fashion (Path 1) leading to the formation of an
imide ring. Subsequent anti-elimination of the acetate might then
give (E)-imide. Alternatively the acetate ion might add first in 1,2-
fashion on to the ene-nitrile leading to the formation of (Z)-imide
and then 1,4 addition of the acetate ion on the (Z)-imide (Path 2)
We have recently developed a simple methodology for the
preparation of 4-cyano-2-methoxycarbonyl-3-arylpenta-1,4-die-
nes5p via the reaction of the Baylis–Hillman allyl bromides, that
is, methyl (2Z)-2-(bromomethyl)-3-arylprop-2-enoates with acry-
lonitrile in the presence of DABCO. It occurred to us that these mol-
ecules might be appropriate starting materials for obtaining 4-aryl-
3,5-dimethylidenepiperidine-2,6-dione derivatives. Accordingly
we have subjected a representative class of Baylis–Hillman prod-
AcO
R
O
O
AcO
CO2Et
C-OEt
R
Path 1
FeCl
OEt
Fe+3
R
CN
C
N
C
3
(Z)
I A
NH
acetic acid
FeCl
acetic acid
Path 2
3
anti-elimination
AcO
AcO
R
H
O
R
Fe+3
O
C-OEt
R
AcO
H
AcO
R
OEt
Fe+3
O
O
N
H
N
H
C
N
AcO
R
Favored
Disfavored
C
N
TS-I
TS-II
AcO
-EtOH
-EtOH
AcO
R
AcO
R
anti-elimination
N
O
AcO
N
O
AcO
N
O
Fe+3
AcO
R
O
N
H
O
(E)
Scheme 2. A plausible mechanism for the formation of the (E)-3-arylidene(alkylidene)piperidine-2,6-dione framework.

D. Basavaiah et al. / Tetrahedron Letters 50 (2009) 3538–3542
3541
NaH (4 eq.)
dry toluene
1) CH C(OEt) / EtCO H (cat)
3
3
2
Ph
J-C rearrangement
146 ºC, 2 h
CO 2Et
OH
Ph
N
atm, 1 h
2
O
N
H
O
CONH
(Z) -II A
2
Ph
2) H SO (excess),
(Z)-2a
2
4
CN
rt, 4h
FeCl (5 eq.)
CH CO H
3
FeCl (5 eq.)
3
reflux, 10 h
reflux, 10 h
3
2
CH CO H
3 2
(ref. 12)
Ph
O
O
NH
O
Ph
NH
O
(E)-2a
(E)-2a
Scheme 3. Conversion of (Z)-imide into (E)-imide and (Z)-amide into (E)-imide using FeCl3/CH3CO2H.
Table 3
(via the treatment with sulfuric acid and followed by the treatment
of the resulting amides with sodium bicarbonate in aqueous meth-
anol). Our results clearly indicate that our one-pot procedure using
FeCl3/acetic acid offers better results than the two-step process
mentioned above.
One-pot multi-step synthesis of 3-methylidene-4-arylpiperidine-2,6-diones (4a–d)
from rearranged Baylis–Hillman alcohols (3a–d)a
O
1) CH3C(OEt)3 / EtCO2H (cat)
J-C rearrangement
146 ºC, 3 h
NH
In conclusion, we have developed a convenient and simple one-
pot multi-step procedure for the synthesis of (E)-3-arylidene(or
R
OH
R
O
CN
3a-d
2) FeCl3 (5 eq.)
CH3CO2H
reflux, 10 h
4a-d
alkylidene)piperidine-2,6-diones,
4-aryl-3-methylidenepiperi-
dine-2,6-diones, and 4-aryl-3,5-dimethylidenepiperidine-2,6-
diones thus demonstrating the importance of Baylis–Hillman ad-
ducts in organic synthesis.
Entry
B–H rearranged alcohol
R
Productb
Yieldc(%)
1
2
3
4
3a
3b
3c
3d
C6H5
4a
63
70
67
64
2-MeC6H4
4-MeC6H4
4-iPrC6H4
4b
Acknowledgments
4c10
4d
We thank DST (New Delhi) for funding this project. D.V.L.
thanks UGC (New Delhi) for his fellowship. B.D. thanks CSIR
(New Delhi) for his fellowship. We thank UGC (New Delhi) for sup-
port and for providing some instrumental facilities. We thank the
National Single-Crystal X-ray facility funded by DST. We thank Pro-
fessor S. Pal, School of Chemistry, University of Hyderabad, for
helpful discussions regarding X-ray crystal structures.
a
All reactions were carried out on a 1 mmol scale of rearranged B–H alcohols
(3a–d).
b
All the compounds (4a–d) were obtained as colorless solids and fully
characterized.
c
Isolated yields based on rearranged B–H alcohols.
ucts, 4-cyano-2-methoxycarbonyl-3-arylpenta-1,4-dienes (5a–j) to
this reaction strategy to provide 4-aryl-3,5-dimethylidene-piperi-
dine-2,6-dione derivatives in 61–86% isolated yields (Table 4, en-
tries 1–10).
References and notes
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1111–1115; (j) Kondo, H.; Oritani, T.; Kiyota, H. Eur. J. Org. Chem. 2000, 3459–
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It is worth mentioning here that Kim and co-workers6a,13 re-
ported the synthesis of 3,5-dimethylidene-4-phenylpiperidine-
2,6-dione and 3,5-dimethylidenepiperidine-2,6-dione (two exam-
ples) from the corresponding Baylis–Hillman products in two steps
Table 4
Synthesis of 4-aryl-3,5-dimethylidenepiperidine-2,6-dione (6a–j) from Baylis–Hill-
a
man compounds (5a–j)
O
R
NH
NC
CO Me
2
FeCl (5 eq.)
3
R
O
CH CO H, 5 h , reflux
5a-j
3
2
6a-j
Entry
Substrate
R
Productb
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
6ad,10
6b
6c
6d
6e
6f
6g
6h
6i
82
80
86
61
75
76
63
85
70
84
3-ClC6H4
3-BrC6H4
3-OMeC6H4
4-ClC6H4
4-BrC6H4
4-OMeC6H4
4-MeC6H4
4-EtC6H4
4-iPrC6H4
5j
6j
a
All reactions were carried out on a 1 mmol scale of B–H compounds (5a–j).
All the products (6a–j) were obtained as colorless solids and fully characterized.
Isolated yields based on B–H products.
b
c
4. For leading reviews on the Baylis–Hillman reaction see: (a) Singh, V.; Batra,
S. Tetrahedron 2008, 64, 4511–4574; (b) Basavaiah, D.; Rao, K. V.; Reddy, R. J.
Chem. Soc. Rev. 2007, 36, 1581–1588; (c) Masson, G.; Housseman, C.; Zhu, J.
d
The structure of this molecule was also confirmed by single crystal X-ray data
(Fig. 1).11,14

3542
D. Basavaiah et al. / Tetrahedron Letters 50 (2009) 3538–3542
Angew. Chem., Int. Ed. 2007, 46, 4614–4628; (d) Basavaiah, D.; Rao, A. J.;
(1a, 1 mmol, 0.159 g) in triethyl orthoacetate (1 mL), propanoic acid (3
drops) was added and the reaction mixture was heated at 146 °C for 2 h. The
reaction mixture was cooled to room temperature and the excess orthoester
and propanoic acid were distilled off under reduced pressure. The residue,
thus obtained, was dissolved in acetic acid (5 mL). Anhydrous FeCl3 (5 mmol,
0.812 g) was added and the reaction mixture was heated under reflux for
10 h. Then the reaction mixture was cooled to room temperature and acetic
acid was removed under reduced pressure. The residue was dissolved in
dichloromethane (5 mL) and poured into aqueous 4 N HCl (5 mL). The
organic layer was separated and the aqueous layer was extracted with
dichloromethane (2 Â 10 mL). The combined organic layer was washed
successively with saturated NaHCO3 solution, water, and dried over
anhydrous Na2SO4. The solvent was removed and the residue was purified
by column chromatography (silica gel, 35% ethyl acetate in hexanes) to
Satyanarayana, T. Chem. Rev. 2003, 103, 811–891; (e) Ciganek, E.. In Organic
Reactions; Paquette, L. A., Ed.; Wiley: New York, 1997; Vol. 51, pp 201–350;
(f) Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R. Tetrahedron 1996, 52,
8001–8062; (g) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653–
4670.
5. (a) Jiang, Y-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202–7203; (b)
Amarante, G. W.; Rezende, P.; Cavallaro, M.; Coelho, F. Tetrahedron Lett.
2008, 49, 3744–3748; (c) Winbush, S. M.; Mergott, D. J.; Roush, W. R. J. Org.
Chem. 2008, 73, 1818–1829; (d) Chen, P-Y.; Chen, H.-M.; Chen, L.-Y.; Tzeng,
J.-Y.; Tasai, J.-C.; Chi, P.-C.; Li, S.-R.; Wang, E.-C. Tetrahedron 2007, 63, 2824–
2828; (e) Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2007,
129, 15513–15525; (f) Basavaiah, D.; Reddy, K. R.; Kumaragurubaran, N. Nat.
Protocols 2007, 2, 2665–2676; (g) Shanmugam, P.; Viswambharam, B.;
Madhavan, S. Org. Lett. 2007, 9, 4095–4098; (h) Kabalka, G. W.;
Venkataiah, B.; Chen, C. Tetrahedron Lett. 2006, 47, 4187–4189; (i) Acke, D.
R. J.; Stevens, C. V. Org. Process Res. Dev. 2006, 10, 417–422; (j) Buskens, P.;
Klankermayer, J.; Leitner, W. J. Am. Chem. Soc. 2005, 127, 16762–16763; (k)
Kataoka, T.; Kinoshita, H. Eur. J. Org. Chem. 2005, 45–58; (l) Turki, T.;
Villieras, J.; Amri, H. Tetrahedron Lett. 2005, 46, 3071–3072; (m) Luo, S.; Mi,
X.; Xu, H.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 8413–8422; (n)
Yang, K.-S.; Lee, W.-D.; Pan, J.-f.; Chen, K. J. Org. Chem. 2003, 68, 915–919;
(o) Pei, W.; Wei, H.-X.; Li, G. Chem. Commun. 2002, 1856–1857; (p)
Basavaiah, D.; Kumaragurubaran, N.; Sharada, D. S. Tetrahedron Lett. 2001,
42, 85–87; (q) Basavaiah, D.; Kumaragurubaran, N.; Padmaja, K. Synlett 1999,
1630–1632; (r) Basavaiah, D.; Pandiaraju, S.; Padmaja, K. Synlett 1996, 393–
395; (s) Basavaiah, D.; Pandiaraju, S. Tetrahedron Lett. 1995, 36, 757–758.
6. (a) Lee, M. J.; Kim, S. C.; Kim, J. N. Bull. Korean Chem. Soc. 2006, 27, 140–142; (b)
Wang, S.; Pan, J.; Hu, Y.; Hu, H. Synthesis 2005, 753–756; (c) Hong, W. P.; Lim, H.
N.; Park, H. W.; Lee, K. Bull. Korean Chem. Soc. 2005, 26, 655–657.
provide (E)-3-benzylidenepiperidine-2,6-dione (2a) as
(0.169 g) in 84% yield. Mp: 198–200 °C, (Lit.2f,10 209–210 °C) IR (KBr):
3200–2900 (multiple bands), 1730, 1691, 1624 cmÀ1 1H NMR (400 MHz,
a colorless solid
m
;
CDCl3): d 2.64 (t, 2H, J = 6.8 Hz), 2.98–3.06 (m, 2H)*, 7.37–7.50 (m, 5H), 7.90
(s, 1H), 8.03 (br s, 1H); 13C NMR (100 MHz, 20% DMSO-d6 in CDCl3): d 21.30,
30.29, 126.21, 127.43, 127.86, 128.55, 133.53, 137.26, 166.00, 171.37; LC–MS
(m/z): 200 (MÀH)À, Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96.
Found: C, 71.69; H, 5.56; N, 6.92. (* This multiplet almost looks like an
unresolved dd).
10. These compounds are known in the literature. Spectral data are reported. Our
spectral data are in agreement with those of the literature (for 2a see Ref. 2d,f,
for 4c see Ref. 7, for 6a see Ref. 6a).
11. Detailed X-ray crystallographic data are available from the CCDC, 12 Union
road, Cambridge CB2 1EZ, UK for compounds 2b (CCDC #689771), 2c (CCDC
#689772), 6a (CCDC #689773).
12. The plausible mechanism for the conversion of (Z)-imide into thermody-
namically more stable (E)-imide is shown below.
7. Batra prepared three 4-aryl-3-methylidenepiperidine-2,6-dione derivatives
following the procedure given below (Ref.: Singh, V.; Yadav, G. P.; Maulik, P.
R.; Batra, S. Tetrahedron 2006, 62, 8731–8739).
CNCH2CO2Et,
DABCO
FeCl3.6H2O
EtCO2H,
O
OH
THF:H2O, rt,
2h
EtO2C
R
CN
CO2Me
AcCl, pyridine,
CH2Cl2, rt, 4-6h
OAc
CO2Me
reflux, 2 h
NH
R
CO2Me
R
R
O
80-92%
58-65%
72-92%
R = 2-ClC6H4, 4-ClC6H4,4-MeC6H4
8. It has been well known in the literature that in the 1H NMR spectrum of the
trisubstituted alkenes the chemical shifts of the vinylic b-protons cis to the
carbonyl (ketone, ester, acid, and amide) group and those of the corresponding
vinylic b-protons trans to the carbonyl group are well differentiated. The
vinylic b-protons cis to the carbonyl group appear downfield in comparison
with that of trans b-protons. [see Ref: (a) Jackman, L. M.; Sternhell, S.
Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry,
2nd ed., Pergamon: Oxford, 1969; Vol. 5. (b) Tobey, S. W. J. Org. Chem. 1969, 34,
1281]. In the case of compound 2a (R = Phenyl) the E:Z ratio was determined by
the integration values of the singlets at d 7.90 [vinylic b-protons cis to the
carbonyl group (E-alkene) and d 6.97 [vinylic b-protons trans to the carbonyl
group (Z-alkene)]. In the case of 2a–d, h (R = aryl) vinylic b-protons appeared at
ꢀd 7.86 (as a singlet) while in the case of 2e–g, i (R = alkyl or 2-phenylethyl)
vinylic b-protons appeared at ꢀd 7.01 (as triplets).
FeCl (5 eq.)
3
AcO
Ar
O
AcO
O
CH CO H
3
2
anti-elimination
O
reflux, 10 h
Ar
NH
Ar
O
N
O
O
+3Fe
+3Fe
N
H
H
(E)-2a-i
(Z)-2a-i
13. Kim’s two-step procedure: two examples only reported (Ref: see 6a).
R
O
R
R
H O/MeOH
H SO (excess)
2
2
4
CO Me
2
CO Me
2
NC
NaHCO
MeOH, 0 ºC, 3h
3
H N
2
O
N
H
O
30-40 ºC, 72 h
9. Representative procedure: Synthesis of (E)-3-benzylidene-piperidine-2,6-dione
(2a): To a stirred solution of 3-hydroxy-2-methylene-3-phenylpropanenitrile
R= H, 75%
R= Ph 85%
R = H, 32%
R = Ph, 73%
14. The single crystal revealed the presence of two molecules in the asymmetric
unit. For clarity we have shown one molecule in the ORTEP diagram.