α-Amido sulfones: novel substrates for the practical and efficient aza-Morita-Baylis-Hillman reaction under neat conditions

Article abstract of DOI:10.1016/j.tet.2008.07.093

α-Amido sulfones undergo aza-Morita-Baylis-Hillman reaction efficiently with alkyl acrylates under neat conditions in the presence of DABCO at room temperature. These sulfones generate aryl imines in the presence of DABCO and form the corresponding adduct

Full text of DOI:10.1016/j.tet.2008.07.093

Tetrahedron 64 (2008) 9396–9400
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a
-Amido sulfones: novel substrates for the practical and efficient
aza-Morita–Baylis–Hillman reaction under neat conditionsq
*
Biswanath Das , Kongara Damodar, Nikhil Chowdhury, Darshanala Saritha,
Bommena Ravikanth, Maddeboina Krishnaiah
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road Hyderabad-500007, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2008
Received in revised form 21 July 2008
Accepted 23 July 2008
Available online 26 July 2008
a
-Amido sulfones undergo aza-Morita–Baylis–Hillman reaction efficiently with alkyl acrylates under
neat conditions in the presence of DABCO at room temperature. These sulfones generate aryl imines in
the presence of DABCO and form the corresponding adducts in high yields (85–94%) within 9–12 h.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
a
-Amido sulfones
aza-Morita–Baylis–Hillman reaction
-Methylene -amino esters
a
b
Elimination–addition reaction
DABCO–alkyl acrylate couple
X
1. Introduction
XH
z
Catalyst
+
z
R
H
R
The Morita–Baylis–Hillman reaction involves the coupling of an
activated vinylic system with an electrophile in the presence of
a catalyst, generally a phosphine or a tertiary amine, leading to the
formation of multifunctional molecule, known as adduct.1 The re-
action can also be catalyzed by a Lewis acid, such as TiCl4 without
direct use of a Lewis base.2 The original process uses an aldehyde as
an electrophile and appears as a useful carbon–carbon bond-
forming method. If the aldehyde is replaced by an imine the re-
action is known as the aza-Morita–Baylis–Hillman reaction3
X = O, NRI
R = Alkyl, Aryl
Z = Electron-withdrawing group
Catalyst = RII3N, RII3P
Scheme 1. Morita–Baylis–Hillman reaction and its aza-version.
The reactions between sulfonylimines and activated olefins in
the presence of DABCO as a catalyst required high temperatures
and long reaction times.3a–c Moreover, imines, in general, tend to be
unstable during purification process. Therefore, alternative
methods involving the in situ generation of imines from amines
and aldehydes are more attractive.6 However, still the harsh re-
action conditions, complex experimental procedures, long reaction
period and unsatisfactory yields are the drawbacks in many of these
methods.
(Scheme 1). This reaction results in the formation of an
a
a
-meth-
-meth-
ylene
ylene
b
b
-amino carbonyl compound and in particular, of an
-amino ester when an acrylate is employed as a Michael
acceptor.
The
thesis of various valuable compounds such as cinnamic acid de-
a
-methylene b-amino esters are highly useful in the syn-
rivatives, amino acid analogues, peptides,
b-lactams and other
nitrogen heterocycles.4,5 The aza-Morita–Baylis–Hillman reaction
is thus an important method for the preparation of the starting
materials for the synthesis of these compounds.
An alternative access to a-methylene b-amino carbonyl com-
pounds has been discovered starting from Morita–Baylis–Hillman
adducts by converting them to the corresponding allyl bromides,
acetates or related derivatives followed by treatment with amines.7
However, such conversions require multistep transformations
and in several cases the overall times are long, yields are low and
regioisomers are formed. Here, we wish to report a convenient and
q
Part 167 in the series, ‘Studies on Novel Synthetic Methodologies’.
* Corresponding author. Tel./fax: þ91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
efficient method for the preparation of a-methylene b-amino esters
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.093

B. Das et al. / Tetrahedron 64 (2008) 9396–9400
9397
Table 2
involving
niently prepared8 from aldehydes, sodium salt of p-toluene sulfinic
acid and benzylcarbamate. Most of the -amido sulfones are stable
solids and can be stored for prolonged times. A variety of nucleo-
philic reagents9 can be used for reactions with these
-amido sul-
a-amido sulfones. The a-amido sulfones can be conve-
Effect of catalyst on the aza-Morita–Baylis–Hillman reaction of
NHCbz O
Ph
a
-amido sulfonesa
O
a
NHCbz
SO2Tol
catalyst
OMe
2a
+
OMe
OMe
rt
Ph
a
1a
3a
+
fones including organometallic reagents, stable carbanions,
heteronucleophiles and reducing agents. Earlier, we have utilized
these compounds in Sakurai reactions for the synthesis of homo-
O
S
O
allylic amines.10 The
the synthesis of -methylene
a
-amido sulfones have been employed now for
-amino esters.
O
4a
a
b
Entry
Catalyst
Catalyst loading
(mmol)
Time (h)
Yieldb (%)
2. Results and discussions
In continuation of our work11 on the Morita–Baylis–Hillman
1
2
3
4
5
6
7
8
9
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
PPh3
PPh3
DMAP
0.25
0.50
0.75
0.75
1.00
1.00
1.00
1.00
1.00
24
24
11
24
11
24
11
24
24
35
50
60
75
90
55
65
85
35
reaction we have observed that -amido sulfones are novel sub-
a
strates for the aza-version of this reaction (Scheme 2). The reaction
was conducted in the presence of DABCO at room temperature. The
corresponding a-methylene b-amino esters were formed in high
yields (85–94%) within 9–12 h.
a
Reaction conditions: 1a (1 mmol) and 2a (25 mmol) at RT.
Yields of isolated, pure compounds after column chromatography.
b
O
NHCbz
O
NHCbz
DABCO, neat
rt 9 - 12 h
85 - 94 %
+
OR
Ar
3
OR
1a (Ar¼Ph) was treated with methyl acrylate in the presence of
DABCO (a general catalyst for Morita–Baylis–Hillman reaction) at
room temperature in various solvents as well as under neat
conditions.
Ar
SO2Tol
1
2
O
S
+
2a: R = Me
2b: R = Et
OR
The yield of the product 3a (Ar¼Ph) was found to be the best
(91%) when no solvent was used. Different other catalysts such as
DBU, PPh3 and DMAP were also used for the above reaction.
However, DABCO was found to be the most effective to carry out the
reaction. These results thus guided us to use DABCO under neat
conditions for the subsequent reactions. Recently, some aza-Mor-
ita–Baylis–Hillman reactions have also been carried out under neat
conditions.12
O
O
4
4a: R = Me
4b: R = Et
Scheme 2. aza-Morita–Baylis–Hillman reaction of
a
-amido sulfones.
Initially the effects of solvents (Table 1) and catalysts (Table 2)
on the above reaction were carefully studied. The a-amido sulfone
A series of adducts,
pared from various -amido sulfones by treatment with methyl ac-
rylate (Table 3). The amine group in these -amido sulfones was
protected by Cbz (benzyloxycarbonyl) group, which can more easily
be deprotected in the products compared to the tosyl group.13 The
amido sulfones derived from aromatic aldehydes containing both
electron–donating and electron–withdrawing groups underwent
the conversion smoothly. Different heterocyclic aldehydes were also
a-methylene b-amino esters have been pre-
Table 1
a
Effect of solvent on the aza-Morita–Baylis–Hillman reaction of a
-amido sulfonesa
a
NHCbz
O
O
NHCbz
SO2Tol
1a
DABCO
rt
+
Ph
OMe
OMe
a-
OMe
2a
Ph
3a
+
O
S
used to prepare these adducts. However, in the case of aliphatic a-
O
O
amidosulfones enecarbamates wasonlyformedandthis findingisin
4a
agreement with the earlier observation.14 Instead of methyl acrylate
Entry
Solvent
Methyl acrylate
Time (h)
Yieldb (%)
(x mmol)
Table 3
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CHCl3
CHCl3
THF
5
10
5
10
5
10
5
10
5
10
5
10
5
10
15
20
20
25
25
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
11
24
11
24
10
20
10
15
40
55
45
60
Trace
10
Trace
<10
10
20
35
60
80
90
92
The aza-Morita–Baylis–Hillman reaction of
(Scheme 2)a
a-amido sulfones with alkyl acrylate
Entry
a
-Amido sulfone
Alkyl acrylate Product 3b Time (h) Yieldc (%)
1
2
3
4
C6H5
C6H5
4-Cl–C6H4
4-MeO–C6H4
3,4-(MeO)2–C6H3
2a
2b
2a
2a
2a
3a
3b
3c
3d
3e
3f
11
11
10
9
90
89
92
93
92
90
91
85
88
91
90
88
93
94
THF
1,4-Dioxane
1,4-Dioxane
EtOAc
EtOAc
MeOH
MeOH
Neat
Neat
Neat
Neat
Neat
9
5
10
10
10
12
12
10
10
11
10
10
10
11
12
13
14
15
16
17
18
19
6
3,4,5-(MeO)3–C6H2 2a
7
8
9
10
11
12
13
14
Vanilyl
2a
2a
2a
2a
2a
2a
2a
2a
3g
3h
3i
3j
3k
3l
4-NO2–C6H4
3-NO2–C6H4
4-Tolyl
4-Isopropylphenyl
2-Napthyl
Furan-2-yl
Thiophene-2-yl
3m
3n
Neat
Neat
a
Reaction conditions: 1 (1 mmol), 2 (25 mmol) and DABCO (1 mmol) at RT.
a
b
Reaction conditions: 1a (1 mmol), 2a (x mmol) and DABCO (1 mmol) in solvent
Structures of these compounds were determined from their NMR (1H and 13C),
(5 mL) at RT.
MS and IR data.
b
c
Yields of isolated, pure compounds after column chromatography.
Yields of isolated, pure compounds after column chromatography.

9398
B. Das et al. / Tetrahedron 64 (2008) 9396–9400
when ethyl acrylate was used the conversion showed almost similar
results. For example, the reaction of 1a (Ar¼Ph) with methyl and
ethyl acrylates afforded the corresponding aza-adducts in the yields
of 91 and 89%, respectively, in 11 h (Table 3; entries 1 and 2).
The plausible mechanism of the conversion is discussed as fol-
instruments; IR: Perkin–Elmer RX1 FTIR spectrophotometer; NMR:
Varian Gemini 200 MHz (1H) and 50 MHz (13C) spectrometer;
FABMS: VG-Autospec micromass and HRMS: QSTAR XL, Hybrid MS
system (Applied Biosystems). Column chromatography was per-
formed with silica gel (BDH 100–200 mesh) and TLC with silica gel
GF254 pre-coated plates. Visualization was accomplished with UV
lamp or I2 stains. All chemicals were used as commercially avail-
lows. The reaction of a-amido sulfones (1) with DABCO produces
the Cbz-protected aryl imines along with p-toluenesulfinate ion.14
The latter undergoes the oxa-Michael addition with alkyl acrylate
to form the by-product, alkyl-3-(p-tolylsulfinyloxy) propanoate (4).
The Cbz-protected aryl imines, on the other hand, react with alkyl
acrylate in the presence of DABCO following the general mecha-
nism of the Morita–Baylis–Hillman reaction15 to form the adducts,
able. a
-Amido sulfones 1 have been prepared by reported method.8
Organic extracts were dried over anhydrous Na2SO4.
4.2. General experimental procedure
a
-methylene
b
-amino esters (3) (Scheme 3). The whole process can
To a mixture of a-amido sulfone 1 (1 mmol) and alkyl acrylate
be considered as tandem elimination–addition reaction that can be
carried out using DABCO–alkyl acrylate couple.
(2.15 g of methyl acrylate or 2.5 g of ethyl acrylate, 25 mmol)
DABCO (112 mg, 1 mmol) was added and the mixture was stirred at
room temperature. The reaction was monitored by TLC. After
completion 5% aqueous HCl (10 mL) was added and the mixture
was extracted with EtOAc (3ꢀ10 mL). The extract was dried over
anhydrous Na2SO4 and concentrated. The residue was subjected to
column chromatography over silica gel (EtOAc/hexane; 15:85 to
25:75) to obtain the adduct 3 and the by-product 4.
H
. .
NHCbz
SO2Tol
1
N
O
S
+
N
NCbz
+
+
_
+
O
Ar
N
Ar
. .
N
. .
4.3. Typical experimental procedure
OR
O
2
S
OR
O
4.3.1. Methyl 3-benzyloxycarbonylamino-3-phenyl-2-methylene
propanoate (3a)
O
O
O
H
4
+
Following Section 4.2,
a-amido sulfone 1a (395 mg, 1 mmol),
+
. .
N
S
OR
N
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (15% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3a (292.5 mg, 90%)
as a colourless liquid; Rf (30% EtOAc/hexane) 0.42; IR (neat): 3338,
+
O
O
_
N
. .
N
. .
1722,1500,1447,1230 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d 7.39–7.21
OR
(10H, m, Ar–H), 6.32 (1H, s, H2C]C), 5.91 (1H, s, H2C]C), 5.78 (1H,
d, J 8.8 Hz, –NH–), 5.69 (1H, d, J 8.8 Hz, –CH–NH–), 5.10 (2H, s,
O
_
–OCH2–Ph), 3.66 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d 166.2,
_
NCbz
NHCbzO
NCbz
O
N
H
O
N
156.4, 139.7, 136.5, 128.8, 128.7, 128.3, 127.8, 127.2, 126.6, 67.2, 56.9,
52.1; FABMS: m/z 326 [MH]þ, 348 [MNa]þ; HRMS (ESI): [MNa]þ,
found 348.1211. C19H19NO4Na requires 348.1211.
OR
OR
Ar
Ar
Ar
OR
3
+
N
+
. .
+
:
N
:
N
4.3.2. Ethyl 3-benzyloxycarbonylamino-3-phenyl-2-methylene
propanoate (3b)
N
. .
. .
N
Following Section 4.2,
a-amido sulfone 1b (395 mg, 1 mmol),
DABCO =
ethyl acrylate 2b (2.5 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (15% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3b (301.7 mg, 89%)
as a colourless liquid; Rf (30% EtOAc/hexane) 0.46; IR (neat): 3344,
N
. .
Scheme 3. Proposed reaction mechanism.
1718,1500,1232 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d 7.40–7.18 (10H,
In the present reaction if the sulfone 1 and the acrylate 2 were
used in 1:1 mole ratio, only thia-Michael addition product 4 was
formed.
m, Ar–H), 6.34 (1H, s, H2C]C), 5.89 (1H, s, H2C]C), 5.75 (1H, d, J
8.7 Hz, –NH–), 5.70 (1H, d, J 8.7 Hz, CH–NH–), 5.10 (2H, s, –OCH2–
Ph), 4.11 (2H, q, J 7.0 Hz, –OCH2CH3), 1.18 (3H, t, J 7.0 Hz, –OCH2CH3);
13C NMR (50 MHz, CDCl3):
d 165.8, 155.8, 140.2, 139.9, 136.6, 128.8,
3. Conclusions
128.7, 128.4, 127.8, 126.9, 126.7, 67.2, 61.1, 56.9, 14.2; FABMS: m/z
340 [MH]þ, 362 [MNa]þ; HRMS (ESI): [MNa]þ, found 362.1377.
In conclusion, we have developed a novel and efficient method
for the preparation of
Morita–Baylis–Hillman reaction involving
a
-methylene
b
-amino esters through the aza-
-amido sulfones and
C20H21NO4Na requires 362.1368.
a
alkyl acrylates in the presence of DABCO at room temperature. The
mild reaction conditions, solvent-free procedure, high yields, short
reaction times and the formation of single regioisomer are the
advantages of the method.
4.3.3. Methyl 3-benzyloxycarbonylamino-3-(4-chlorophenyl)-
2-methylene propanoate (3c)
Following Section 4.2, a-amido sulfone 1c (429.5 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3c (330.7 mg, 92%)
as a pale yellow colour solid; Rf (35% EtOAc/hexane) 0.52; mp: 61–
4. Experimental
4.1. General methods
63 ꢂC; IR (KBr): 3440, 1719, 1688, 1528, 1285 cmꢁ1
;
1H NMR
(200 MHz, CDCl3):
d 7.38–7.13 (9H, m, Ar–H), 6.32 (1H, s, H2C]C),
Melting points were measured on a Buchi-510 apparatus and are
uncorrected. The spectra were recorded with the following
5.91 (1H, s, H2C]C), 5.80 (1H, d, J 8.9 Hz, –NH–), 5.65 (1H, d, J
8.9 Hz, CH–NH–), 5.11 (1H, d, J 12.0 Hz, –OCH2–Ph), 5.04 (1H, d, J

B. Das et al. / Tetrahedron 64 (2008) 9396–9400
9399
12.0 Hz, –OCH2–Ph), 3.68 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d, J 8.9 Hz, CH–NH–), 5.49 (1H, br s, –OH), 5.11 (1H, d, J 12.0 Hz,
–OCH2–Ph), 5.06 (1H, d, J 12.0 Hz, –OCH2–Ph), 3.83 (3H, s, –OCH3),
d
166.0, 155.7, 139.4, 138.3, 136.3, 133.6, 128.9, 128.7, 128.4, 128.1,
127.9, 127.7, 67.3, 56.5, 52.2; FABMS: m/z 360, 362 [MH]þ, 382, 384
[MNa]þ; HRMS (ESI): [MNa]þ, found 382.0831. C19H18ClNO4Na re-
quires 382.0822.
3.69 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d 166.2, 155.5, 146.7,
145.3, 140.0, 136.4, 131.5, 128.5, 128.2, 126.3, 119.3, 114.5, 109.6, 67.0,
56.5, 55.9, 52.0; FABMS: m/z 394 [MNa]þ; HRMS (ESI): [MNa]þ,
found 394.1276. C20H21NO6Na requires 394.1266.
4.3.4. Methyl 3-benzyloxycarbonylamino-3-(4-methoxyphenyl)-
2-methylene propanoate (3d)
4.3.8. Methyl 3-benzyloxycarbonylamino-3-(4-nitrophenyl)-
Following Section 4.2,
a
-amido sulfone 1d (425 mg, 1 mmol),
2-methylene propanoate (3h)
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3d (330.2 mg, 93%)
as a white colour solid; Rf (35% EtOAc/hexane) 0.46; mp: 66–68 ꢂC;
Following Section 4.2, a-amido sulfone 1h (440 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (25% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3h (314.5 mg, 85%)
as a pale yellow colour solid; Rf (45% EtOAc/hexane) 0.50; mp: 72–
IR (KBr): 3344, 1720, 1509, 1245 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d
7.38–7.23 (5H, m, Ar–H), 7.14 (2H, d, J 8.0 Hz, Ar–H), 6.79 (2H, d, J
74 ꢂC; IR (KBr): 3346, 1722, 1521, 1348, 1236 cmꢁ1
;
1H NMR
8.0 Hz, Ar–H), 6.32 (1H, s, H2C]C), 5.88 (1H, s, H2C]C), 5.63 (2H, br
s, –NH– and CH–NH–), 5.08 (2H, s, –OCH2–Ph), 3.75 (3H, s, –OCH3),
(200 MHz, CDCl3): d 8.17 (2H, d, J 8.0 Hz, Ar–H), 7.45 (2H, d, J 8.0 Hz,
Ar–H), 7.40–7.22 (5H, m, Ar–H), 6.39 (1H, s, H2C]C), 6.02 (1H, s,
H2C]C), 5.98 (1H, d, J 8.8 Hz, –NH–), 5.73 (1H, d, J 8.8 Hz, CH–NH–),
5.12 (1H, d, J 12.0 Hz, –OCH2–Ph), 5.09 (1H, d, J 12.0 Hz, –OCH2–Ph),
3.67 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d 166.0, 158.9, 155.4,
139.9, 136.3, 131.5, 128.4, 128.1, 127.7, 126.3, 113.9, 66.9, 56.0, 55.1,
51.9; FABMS: m/z 356 [MH]þ, 378 [MNa]þ; HRMS (ESI): [MNa]þ,
found 378.1322. C20H21NO5Na requires 378.1317.
3.70 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d 165.8, 155.9, 147.5,
147.3, 138.2, 136.2, 129.2, 128.8, 128.6, 128.5, 127.3, 124.0, 67.6, 57.0,
52.5; FABMS: m/z 371 [MH]þ, 393 [MNa]þ; HRMS (ESI): [MNa]þ,
found 393.1055. C19H18N2O6Na requires 393.1062.
4.3.5. Methyl 3-benzyloxycarbonylamino-3-(3,4-dimethoxy-
phenyl)-2-methylene propanoate (3e)
Following Section 4.2,
a
-amido sulfone 1e (455 mg, 1 mmol),
4.3.9. Methyl 3-benzyloxycarbonylamino-3-(3-nitrophenyl)-
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3e (354.2 mg, 92%)
as a white colour solid; Rf (35% EtOAc/hexane) 0.39; mp: 76–78 ꢂC;
2-methylene propanoate (3i)
Following Section 4.2,
a-amido sulfone 1i (440 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (25% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3i (325.6 mg, 88%)
as a pale yellow colour solid; Rf (45% EtOAc/hexane) 0.55; mp: 69–
IR (KBr): 3351, 1722, 1513, 1459, 1258 cmꢁ1
CDCl3):
;
1H NMR (200 MHz,
d
7.41–7.24 (5H, m, Ar–H), 6.76 (3H, br s, Ar–H), 6.31 (1H, s,
H2C]C), 5.89 (1H, s, H2C]C), 5.63 (2H, br s, –NH– and CH–NH–),
5.10 (1H, d, J 12.0 Hz, –OCH2–Ph), 5.04 (1H, d, J 12.0 Hz, –OCH2–Ph),
3.85 (3H, s, –OCH3), 3.82 (3H, s, –OCH3), 3.69 (3H, s, –OCH3); 13C
72 ꢂC; IR (KB): 3338, 1721, 1530, 1349, 1232 cmꢁ1
;
1H NMR
(200 MHz, CDCl3):
d 8.18–8.09 (2H, m, Ar–H), 7.62 (1H, d, J 8.0 Hz,
Ar–H), 7.50 (1H, t, J 8.0 Hz, Ar–H), 7.40–7.24 (5H, m, Ar–H), 6.42 (1H,
s, H2C]C), 6.02 (1H, s, H2C]C), 6.01 (1H, d, J 8.7 Hz, –NH–), 5.79
(1H, d, J 8.7 Hz, CH–NH–), 5.15 (1H, d, J 12.0 Hz, –OCH2–Ph), 5.09
(1H, d, J 12.0 Hz, –OCH2–Ph), 3.71 (3H, s, –OCH3); 13C NMR (50 MHz,
NMR (50 MHz, CDCl3): d 166.1,155.5,149.1,148.6,140.0,136.4,132.2,
128.5, 128.2, 126.4, 118.7, 111.2, 110.2, 67.0, 56.4, 55.9, 51.9; FABMS:
m/z 408 [MNa]þ; HRMS (ESI): [MNa]þ, found 408.1429.
C
21H23NO6Na requires 408.1423.
CDCl3): d 165.6, 155.5, 148.5, 145.1, 142.1, 138.4, 136.0, 135.6, 132.4,
130.0, 129.6, 128.6, 128.4, 128.2, 67.4, 56.6, 52.3; FABMS: m/z 371
4.3.6. Methyl 3-benzyloxycarbonylamino-3-(3,4,5-trimethoxy-
[MH]þ, 393 [MNa]þ; HRMS (ESI): [MNa]þ, found 393.1081.
phenyl)-2-methylene propanoate (3f)
C19H18N2O6Na requires 393.1062.
Following Section 4.2,
a-amido sulfone 1f (485 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (25% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3f (373.5 mg, 90%)
as a white colour solid; Rf (45% EtOAc/hexane) 0.57; mp: 79–82 ꢂC;
4.3.10. Methyl 3-benzyloxycarbonylamino-3-(4-methylphenyl)-
2-methylene propanoate (3j)
Following Section 4.2,
a-amido sulfone 1j (409 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3j (308.5 mg, 91%)
as a white colour solid; Rf (35% EtOAc/hexane) 0.52; mp: 62–64 ꢂC;
IR (KBr): 3350, 1721, 1592, 1502, 1234 cmꢁ1
CDCl3):
;
1H NMR (200 MHz,
d
7.40–7.22 (5H, m, Ar–H), 6.45 (2H, s, Ar–H), 6.31 (1H, s,
H2C]C), 5.88 (1H, s, H2C]C), 5.73 (1H, d, J 8.8 Hz, –NH–), 5.61 (1H,
d, J 8.8 Hz, CH–NH–), 5.12 (1H, d, J 12.0 Hz, –OCH2–Ph), 5.05 (1H, d, J
12.0 Hz, –OCH2–Ph), 3.78 (6H, s, 2ꢀ–OCH3), 3.74 (3H, s, –OCH3),
IR (KBr): 3338, 1723, 1508, 1442, 1282, 1230 cmꢁ1
;
1H NMR
(200 MHz, CDCl3):
d 7.39–7.22 (5H, m, Ar–H), 7.12 (2H, d, J 8.0 Hz,
3.70 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d
166.1, 155.5, 153.3,
Ar–H), 7.04 (2H, d, J 8.0 Hz, Ar–H), 6.30 (1H, s, H2C]C), 5.87 (1H, s,
H2C]C), 5.73 (1H, d, J 8.8 Hz, –NH–), 5.61 (1H, d, J 8.8 Hz, CH–NH–),
5.05 (2H, s, –OCH2–Ph), 3.62 (3H, s, –OCH3), 2.29 (3H, s, Ar–CH3);
139.8, 137.5, 136.4, 135.2, 130.0, 128.5, 128.1, 126.7, 103.8, 66.9, 60.7,
56.7, 56.1, 52.0; FABMS: m/z 438 [MNa]þ; HRMS (ESI): [MNa]þ,
found 438.1539. C22H25NO7Na requires 438.1528.
13C NMR (50 MHz, CDCl3):
d 165.9, 155.4, 139.8, 137.1, 136.5, 136.3,
129.2, 128.4, 128.0, 126.3, 66.8, 56.3, 51.7, 20.9; FABMS: m/z 340
[MH]þ; HRMS (ESI): [MNa]þ, found 362.1373. C20H21NO4Na re-
quires 362.1368.
4.3.7. Methyl 3-benzyloxycarbonylamino-3-(4-hydroxy-3-
methoxyphenyl)-2-methylene propanoate (3g)
Following Section 4.2,
a-amido sulfone 1g (441 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (25% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3g (337.6 mg, 91%)
as a pale yellow colour liquid; Rf (50% EtOAc/hexane) 0.44; IR
4.3.11. Methyl 3-benzyloxycarbonylamino-3-(4-isopropylphenyl)-
2-methylene propanoate (3k)
Following Section 4.2,
a-amido sulfone 1k (437 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3k (330.3 mg, 90%)
as a colourless liquid; Rf (35% EtOAc/hexane) 0.46; IR (neat): 3341,
(neat): 3360, 1718, 1514, 1276 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d
7.35–7.23 (5H, m, Ar–H), 6.80–6.18 (3H, m, Ar–H), 6.30 (1H, s,
H2C]C), 5.87 (1H, s, H2C]C), 5.62 (1H, d, J 8.9 Hz, –NH–), 5.61 (1H,

9400
B. Das et al. / Tetrahedron 64 (2008) 9396–9400
1723, 1506, 1228 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
7.40–7.22 (5H,
128.2, 52.3, 51.5, 27.7, 21.7; FABMS: m/z 243 [MH]þ; HRMS (ESI):
m, Ar–H), 7.18 (2H, d, J 8.0 Hz, Ar–H), 7.11 (2H, d, J 8.0 Hz, Ar–H),
6.31 (1H, s, H2C]C), 5.88 (1H, s, H2C]C), 5.79 (1H, d, J 8.9 Hz, –NH–),
5.65 (1H, d, J 8.9 Hz, CH–NH–), 5.06 (2H, s, –OCH2–Ph), 3.63 (3H, s,
–OCH3), 2.84 (1H, m, –Ar–CH(CH3)2), 1.22 (6H, d, J 7.0 Hz, Ar–
[MNa]þ, found 265.0509. C11H14O4SNa requires 265.0510.
4.3.16. Ethyl-3-(p-tolylsufinyloxy) propanoate (4b)
Colourless solid; mp: 68–71 ꢂC; IR (KBr): 1735, 1597, 1316,
CH(CH3)2); 13C NMR (50 MHz, CDCl3):
d
166.1, 155.6, 148.2, 139.9,
1148 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d 7.77 (2H, d, J 8.0 Hz, Ar–H),
136.9, 136.4, 128.5, 128.2, 126.7, 126.5, 67.0, 56.5, 52.0, 33.7, 24.0;
FABMS: m/z 368 [MH]þ, 390 [MNa]þ; HRMS (ESI): [MNa]þ, found
390.1697. C22H25NO4Na requires 390.1681.
7.34 (2H, d, J 8.0 Hz, Ar–H), 4.05 (2H, q, J 7.0 Hz, –OCH2CH3), 3.31
(2H, t, J 7.0 Hz, –OCH2CH2–), 2.64 (2H, t, J 7.0 Hz, OCH2CH2–), 2.42
(3H, s, Ar–CH3), 1.21 (3H, t, J 7.0 Hz, –OCH2CH3); FABMS: m/z 279
[MNa]þ; HRMS (ESI): [MNa]þ, found 279.0678. C12H16O4SNa re-
quires 279.0667.
4.3.12. Methyl 3-benzyloxycarbonylamino-3-(2-naphthyl)-2-
methylene propanoate (3l)
Following Section 4.2,
a-amido sulfone 1l (445 mg, 1 mmol),
Acknowledgements
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3l (330.0 mg, 88%)
as a white colour solid; Rf (40% EtOAc/hexane) 0.49; mp: 99–101 ꢂC;
The authors thank CSIR and UGC, New Delhi for financial as-
sistance. They are also thankful to NMR, Mass and IR divisions of
IICT for spectral recording.
IR (KBr): 3426, 1720, 1502, 1225 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d
7.85–7.68 (5H, m, Ar–H), 7.50–7.22 (7H, m, Ar–H), 6.40 (1H, s,
Supplementary data
H2C]C), 5.98 (1H, s, H2C]C), 5.83 (2H, br s, –NH– and CH–NH–),
5.12 (2H, s, –OCH2–Ph), 3.64 (3H, s, –OCH3); 13C NMR (50 MHz,
Copies of 1H NMR spectra for all compounds, copies of 13C NMR
spectra for compounds 3a–3n and 4a and copies of HRMS spectra
for all compounds. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2008.07.093.
CDCl3):
d 166.1, 155.7, 139.8, 137.1, 136.4, 133.3, 132.9, 128.6, 128.2,
128.1, 127.7, 127.2, 126.3, 125.2, 124.8, 67.1, 56.8, 52.0; FABMS: m/z
376 [MH]þ, 398 [MNa]þ; HRMS (ESI): [MNa]þ, found 398.1351.
C
23H21NO4Na requires 398.1368.
References and notes
4.3.13. Methyl 3-benzyloxycarbonylamino-3-(furan-2-yl)-2-
methylene propanoate (3m)
1. (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815; (b)
Baylis, A. B.; Hillman, M. E. D. German patent 2155113, 1972; Chem. Abstr. 1972,
77, 34174q; (c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103,
811; (d) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581.
2. Li, G.; Wei, H.-X.; Gao, J. J.; Caputo, T. D. Tetrahedron Lett. 2000, 41, 1.
3. (a) Perlmutter, P.; Teo, C. C. Tetrahedron Lett. 1984, 25, 5951; (b) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521; (c) Matsui, K.; Takizawa, S.; Sasai,
H. Synlett 2006, 761; (d) Li, Q.; Shi, M.; Lyte, J. M.; Li, G. Tetrahedron Lett. 2006,
47, 7699.
4. (a) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905; (b) Masson, G.; Housseman,
C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614; (c) Kamimura, A.; Okawa, H.;
Morisaki, Y.; Ishikawa, S.; Uno, H. J. Org. Chem. 2007, 72, 3569.
5. (a) Lee, H. J.; Seong, M. R.; Kim, J. N. Tetrahedron Lett. 1998, 39, 6223; (b) Lee, H.
J.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 1998, 40, 4363; (c) Kundig, E. P.; Xu,
L.-H.; Romanens, P. Tetrahedron Lett. 1995, 36, 4047; (d) Sergeeva, N. N.;
Golubev, A. S.; Burger, K. Synthesis 2001, 281; (e) Dunn, P. J.; Hughes, M. L.;
Searle, P. M.; Wood, A. S. Org. Process Res. Dev. 2003, 7, 244; (f) Buchholz, R.;
Hoffmann, H. M. R. Helv. Chim. Acta 1991, 74, 1213; (g) Lee, H. S.; Kim, J. M.; Kim,
J. N. Tetrahedron Lett. 2007, 48, 4119.
Following Section 4.2, a-amido sulfone 1m (385 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3m (293.0 mg,
93%) as a pale yellow colour solid; Rf (35% EtOAc/hexane) 0.47; mp:
76–78 ꢂC; IR (KBr): 3338, 1723, 1504, 1231 cmꢁ1
;
1H NMR
(200 MHz, CDCl3):
d 7.37–7.25 (6H, m, Ar–H and furan–H), 6.33 (1H,
s, H2C]C), 6.28 (1H, m, furan–H), 6.13 (1H, d, J 2.0 Hz, furan–H),
5.91 (1H, s, H2C]C), 5.74 (2H, br s, –NH– and CH–NH–), 5.11 (2H, s,
–OCH2–Ph), 3.72 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d 165.8,
155.4, 152.3, 142.2, 137.8, 136.3, 128.5, 128.2, 127.5, 110.5, 106.8, 67.1,
52.0, 51.3; FABMS: m/z 316 [MH]þ, 338 [MNa]þ; HRMS (ESI):
[MNa]þ, found 338.0997. C17H17NO5Na requires 338.1004.
6. (a) Bertenshaw, S.; Kahn, M. Tetrahedron Lett. 1989, 30, 2731; (b) Richter, H.;
Jung, G. Tetrahedron Lett. 1998, 39, 2729; (c) Ribiere, P.; Enjalbal, C.; Aubagnac,
J.-L.; Yadav-Bhatgnagar, N.; Martinez, J.; Lamaty, F. J. Comb. Chem. 2004, 6, 464;
(d) Ribiere, P.; Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2006, 106, 2249.
7. (a) Brown, J. M.; James, A. P.; Prior, L. M. Tetrahedron Lett. 1987, 28, 2179; (b) Kim,
J. N.; Lee, H. J.; Lee, K. Y.; Gong, J. H. Synlett 2002, 173; (c) Rajesh, S.; Banerjee, B.;
Iqbal, J. J. Org. Chem. 2002, 67, 7852; (d) Galeazzi, R.; Mortelli, G.; Mobbili, G.;
Orena, M.; Rinaldi, S. Org. Lett. 2004, 6, 2571; (e) Chen, H.-Y.; Patkar, L. N.; Ueng,
S.-H.; Lin, C.-C.; Lee, A. S.-Y. Synlett 2005, 2035.
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(b) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970.
9. (a) Petrini, M. Chem. Rev. 2005, 105, 3949; (b) Petrini, M.; Torregiani, E. Synthesis
2007, 159 and references cited therein.
4.3.14. Methyl 3-benzyloxycarbonylamino-3-(thiophene-2-yl)-
2-methylene propanoate (3n)
Following Section 4.2,
a-amido sulfone 1n (401 mg, 1 mmol),
methyl acrylate 2a (2.15 g, 25 mmol) and DABCO (112 mg, 1 mmol)
gave, after purification by column chromatography (20% EtOAc/
hexane), the aza-Morita–Baylis–Hillman adduct 3n (311.1 mg, 94%)
as a pale yellow colour liquid; Rf (35% EtOAc/hexane) 0.53; IR
(neat): 3336, 1720, 1500, 1223 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d
7.35–7.22 (5H, m, Ar–H), 7.13 (1H, d, J 4.0 Hz, thiophene–H), 6.91–
6.80 (2H, m, thiophene–H), 6.32 (s, 1H, H2C]C), 5.97 (1H, d, J
8.8 Hz, –NH–), 5.91 (1H, s, H2C]C), 5.85 (1H, d, J 8.8 Hz, CH–NH–),
5.12 (1H, d, J 12.0 Hz, –OCH2–Ph), 5.04 (1H, d, J 12.0 Hz, –OCH2–Ph),
10. Das, B.; Damodar, K.; Saritha, D.; Chowdhury, N.; Krishnaiah, M. Tetrahedron
Lett. 2007, 48, 7930.
11. (a) Das, B.; Banerjee, J.; Mahender, G.; Majhi, A. Org. Lett. 2004, 6, 3349; (b) Das,
B.; Majhi, A.; Banerjee, J.; Chowdhury, N.; Venkateswarlu, K. Tetrahedron Lett.
2005, 46, 5713; (c) Das, B.; Chowdhury, N.; Banerjee, J.; Majhi, A.; Mahender, G.
Chem. Lett. 2006, 35, 358; (d) Das, B.; Chowdhury, N.; Damodar, K. Helv. Chim.
Acta 2007, 90, 2037.
12. (a) Aggarwal, V. K.; Castro, A. M. M.; Mereu, A.; Adams, H. Tetrahedron Lett.
2002, 43, 1577; (b) Wu, Z.; Zhou, G.; Zhou, J.; Guo, W. Synth. Commun. 2006, 36,
2491.
13. (a) Felix, M. J. Org. Chem. 1974, 39, 1427; (b) Meienhofer, J.; Kuromizu, K. Tet-
rahedron Lett. 1974, 3259; (c) Lott, R. S.; Chauhan, V. S.; Stammer, C. H. Chem.
Commun. 1979, 495; (d) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870; (e)
Beecher, J. E.; Tirrell, D. A. Tetrahedron Lett. 1998, 39, 3927.
14. (a) Mecozzi, T.; Petrini, M. Synlett 2000, 73; (b) Chemla, F.; Hebbe, V.; Normant,
J.-F. Synthesis 2000, 75.
3.68 (3H, s, –OCH3); 13C NMR (50 MHz, CDCl3):
d 166.0, 155.5, 144.0,
139.4, 136.4, 128.7, 128.4, 127.4, 127.2, 125.2, 124.9, 67.3, 53.4, 52.2;
FABMS: m/z 354 [MNa]þ; HRMS (ESI): [MNa]þ, found 354.0789.
C
17H17NO4SNa requires 354.0775.
4.3.15. Methyl-3-(p-tolylsufinyloxy) propanoate (4a)
Colourless solid; mp: 66–69 ꢂC; IR (KBr): 1737, 1597, 1411,
1285 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 7.79 (2H, d, J 8.0 Hz, Ar–
H), 7.34 (2H, d, J 8.0 Hz, Ar–H), 3.66 (3H, s, –OCH3), 3.32 (2H, t, J
7.0 Hz, –OCH2CH2–), 2.71 (2H, t, J 7.0 Hz, –OCH2CH2–), 2.47 (3H, s,
Ar–CH3); 13C NMR (50 MHz, CDCl3):
d
170.5, 145.1, 135.5, 130.0,
15. Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413.