A new method for the preparation of (E)-2-(styrylsulfonyl)acetic acid esters and their reactions with hydrazine hydrate

Article abstract of DOI:10.1055/s-0030-1259974

A new route to esters of (E)-2-(styrylsulfonyl)acetic acid has been developed. Treatment of the methyl ester with hydrazine hydrate gave the six-membered 4-amino-5-phenylthiomorpholine-3-one 1,1-dioxide (1), and not the seven-membered 6-phenyl-1,4,5-thiad

Full text of DOI:10.1055/s-0030-1259974

SHORT PAPER
1205
A New Method for the Preparation of (E)-2-(Styrylsulfonyl)acetic Acid Esters
and Their Reactions with Hydrazine Hydrate
(E
)-2-(Styryls
o
n
c
A
cid
E
sters T. Nguyen, Norton P. Peet*
Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA
Fax +1(508)7571999; E-mail: npeet@microbiotix.com
Received 18 December 2010; revised 18 February 2011
a lack of experimental details for the preparation of sodi-
um (E)-4-methylstyrylsulfinate. This problem prompted
us to design a new and more reliable synthesis of methyl
ester 6 and its analogues from the readily commercially
Abstract: A new route to esters of (E)-2-(styrylsulfonyl)acetic acid
has been developed. Treatment of the methyl ester with hydrazine
hydrate gave the six-membered 4-amino-5-phenylthiomorpholine-
3-one 1,1-dioxide (1), and not the seven-membered 6-phenyl-1,4,5-
thiadiazepane-3-one 1,1-dioxide (2) as previously described by oth- available starting materials methyl sulfanylacetate, dieth-
ers. In contrast, treatment of the ethyl ester with the same reagent
yl (chloromethyl)phosphonate, and benzaldehyde.
provided a separable 1:1.2 mixture of 1 and 2. The NMR spectra of
both 1 and 2 differed substantially from that described for 2 in the
previous report.
O
O
O
O
S
N
S
Key words: cyclizations, sulfones, heterocycles, esters
O
Ph
O
Ph
R
NH
N
NH2
H
In the course of our literature survey on diazepanes, we
were intrigued by a recently reported synthesis of 6-phe-
nyl-1,4,5-thiadiazepan-3-one 1,1-dioxide (2). Padmavathi
and co-workers reported that dioxide 2 was produced by
treatment of methyl (E)-2-(styrylsulfonyl)acetate with hy-
drazine hydrate in refluxing methanol.1 The reported for-
1
2
N
O
R
δNH (ppm)
2
3 H
4 Me
5 Ph
5.87
5.82
5.68
N
NH2
mation of this seven-membered ring was somewhat Figure 1
surprising to us, because previous experience seemed to
indicate that reactions of hydrazine with 1,5-dielectro-
O
O
K2CO3
philes strongly favors the formation of the six-membered-
+
SH
Cl
P
OEt
OEt
ring adducts.2 Furthermore, an examination of Padma-
MeO
60 °C
24 h
vathi’s 1H NMR data reinforced our concerns, in that one
8
7
62%
Oxone®
broad singlet at d = 10.58 ppm was assigned to two NH
protons. A single peak for both of these protons is not
O
O
P
S
OEt
OEt
RO
what one would expect, because the two NH groups in 2
are quite different. We suspected that the product might be
the isomeric six-membered 4-amino-5-phenylthiomor-
pholine-3-one 1,1-dioxide (1), the NH2 protons of which
would be expected to appear as a broad singlet. However,
a value of d = 10.58 ppm would be too high for such an
amino group by comparison with some known analogues
(Figure 1).2c,3 Because we were unable to contact the au-
thor, we decided to reinvestigate this reaction experimen-
tally to check the identity of the product.
MeOH, H2O
9 R = Me
11 R = Et
K2CO3, EtOH
95%
PhCHO
LiBr, Et3N
O
O
O
O
O
O
O
S
P
OEt
S
RO
Ph
OR
MeCN
OEt
6 R = Me 41%
13 R = Et 77%
10 R = Me 91%
12 R = Et 96%
Scheme 1
Padmavathi and co-workers did not report any experimen-
tal procedure for the preparation of their starting material,
methyl (E)-2-(styrylsulfonyl)acetate (6). The most closely
related substrate that has appeared in the literature is (E)-
2-(4-methylstyrylsulfonyl)acetic acid, which was pre-
pared by Bhaskar Reddy and co-workers from sodium
(E)-4-methylstyrylsulfinate and chloroacetic acid.4 Our
attempts to follow this route were unsuccessful because of
The synthesis began with treatment of methyl sulfanyl-
acetate (7) with diethyl (chloromethyl)phosphonate (8) to
give the sulfide 9 in 62% yield. Oxidation of 9 with Oxone
gave the corresponding sulfone 10 in 91% yield. Treat-
ment of 10 with benzaldehyde in the presence of triethyl-
amine and lithium bromide gave methyl ester 6 in 41%
yield. The corresponding ethyl ester 13 could also be con-
veniently prepared in good yield by the same route. We
believe that this route could be used to generate a library
of useful compounds simply by changing the aldehyde in
the last step. It was also possible to convert the methyl es-
SYNTHESIS 2011, No. 8, pp 1205–1207
x
x
.
x
x
.2
0
1
1
Advanced online publication: 25.03.2011
DOI: 10.1055/s-0030-1259974; Art ID: M54610SS
© Georg Thieme Verlag Stuttgart · New York

1206
S. T. Nguyen, N. P. Peet
SHORT PAPER
ter 6 into the ethyl ester 13 by treatment with potassium spectral data consistent with those previously reported for
carbonate and ethanol, albeit in a lower yield (48%).
compound 2 by Padmavathi and co-workers.1
Treatment of ester 6 or 13 with hydrazine hydrate provid-
ed interesting results. The six-membered-ring product 1
was obtained almost exclusively from the reaction of ester
6 with hydrazine hydrate, whereas a mixture of products
1 and 2 was obtained from the reaction of ester 13 with hy-
drazine hydrate (Scheme 2). The structures of 1 and 2
were elucidated by 1H NMR, 13C NMR, and IR spectros-
copy and by HRMS. The results matched our expectations
All commercially obtained solvents and reagents were used as re-
ceived. 1H (300 MHz) and 13C NMR (75 MHz) spectra were record-
ed on a Bruker 300 MHz instrument. Chemical shifts are given as d
values referenced to the internal standard TMS. Mass spectra were
recorded on an Agilent ESI-TOF instrument or a Waters Micromass
Quattro Ultima MS instrument, and HRMS spectra were recorded
on a Bruker Daltonic High Resolution Q-FTMS instrument. FTIR
spectra were recorded on a Perkin Elmer Spectrum 400 instrument.
1
in all respects. The H NMR spectrum of 1 showed a
Methyl {[(Diethoxyphosphoryl)methyl]sulfanyl}acetate (9)
broad singlet for two (exchangeable) NH protons at d =
4.65 ppm, whereas the spectrum of 2 showed two (ex-
changeable) NH signals at d = 9.42 ppm and d = 5.79 ppm.
At this point, the identity of the product reported by Pad-
mavathi and co-workers remains elusive, because the
NMR data in their report is not consistent with our NMR
results for either 1 or 2.
K2CO3 (5 g, 36.2 mmol) was added to
a mixture of
ClCH2P(O)(OEt)2 (8; 4.94 g, 26.5 mmol) and HSCH2CO2Me (7; 5
g, 47.1 mmol), and the mixture was stirred and heated at 70 °C for
24 h. The mixture was then diluted with CH2Cl2 (20 mL), filtered,
and concentrated by rotary evaporation. The residue was purified by
column chromatography (silica gel, 20–50% EtOAc–hexanes) to
give a colorless oil; yield: 4.22 g (62%); Rf = 0.28 (hexanes–EtOAc,
1:1).
1H NMR (CDCl3): d = 4.18 (m, 4 H), 3.74 (s, 3 H), 3.50 (s, 2 H),
2.89 (d, J = 12.9 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 6 H).
13C NMR (CDCl3): d = 170.4, 62.7, 52.4, 33.6, 24.8 (d, J = 149 Hz),
16.5.
O
O
.
O
O
O
S
N
NH2NH2 H2O
S
Ph
OMe
MeOH
65 °C
50%
Ph
O
6
NH2
HRMS (ESI): m/z [M + H]+ calcd for C8H18O5PS: 257.0607; found:
1
257.0613.
O
O
O
O
O
Ethyl {[(Diethoxyphosphoryl)methyl]sulfanyl}acetate (11)
K2CO3 (15 mg, 0.1 mmol) was added to a soln of ester 9 (1.78 g, 6.9
mmol) in EtOH (15 mL), and the mixture was stirred for 16 h then
filtered. The filtrate was concentrated by rotary evaporation. The
residue was dissolved in CH2Cl2 (10 mL) and filtered again to re-
move traces of K2CO3. The filtrate was concentrated by rotary evap-
oration and dried in a high vacuum to give a pale yellow oil; yield:
1.79 g (95%); Rf = 0.36 (hexanes–EtOAc, 1:1).
.
NH2NH2 H2O
S
S
Ph
OEt
O
1
+
EtOH
65 °C
48%
13
Ph
NH
N
H
O
O
2
S
(1.2:1)
O
R
O
Ph
NH
1H NMR (CDCl3): d = 4.18 (m, 6 H), 3.48 (s, 2 H), 2.89 (d, J = 12.9
Hz, 2 H), 1.35 (t, J = 7.2 Hz, 6 H), 1.29 (t, J = 7.2 Hz, 3 H).
NH2
HRMS (ESI): m/z [M + H]+ calcd for C9H20O5PS: 271.1; found:
271.0.
14 R = Me or Et
reaction intermediates
Scheme 2
Methyl {[(Diethoxyphosphoryl)methyl]sulfonyl}acetate (10);
Typical Procedure
A soln of Oxone (3.1 g, 5.0 mmol) in H2O (13 mL) was added drop-
wise to a soln of ester 9 (0.86 g, 3.35 mmol) in MeOH (10 mL) at
0 °C, and the resulting suspension was allowed to warm to r.t. over
1 h and then stirred for 16 h. The white solid was removed by filtra-
tion, and the filtrate was concentrated to about 10 mL by rotary
evaporation. The cloudy soln was extracted with EtOAc (4 × 30
mL), and the extracts were dried (MgSO4) and concentrated by ro-
tary evaporation. The residue was purified by gel column chroma-
tography (silica gel, 50–75% EtOAc–hexanes) to give a colorless
oil; yield: 0.88 g (91%); Rf = 0.32 (hexanes–EtOAc, 1:1).
1H NMR (CDCl3): d = 4.48 (s, 2 H), 4.25 (m, 4 H), 3.95 (d, J = 16.2
Hz, 2 H), 3.83 (s, 3 H), 1.38 (t, J = 7.2 Hz, 6 H).
13C NMR (CDCl3): d = 164.0, 63.8, 57.4, 53.3, 50.1 (d, J = 138 Hz),
49.2, 16.3.
Whereas we expected the formation of the six-membered-
ring product, we did not expect the formation of the seven-
membered ring, because the formation of the six-mem-
bered ring should be entropically favored. The change in
the product distribution caused by a subtle change in the
ester structure implies that the cyclization event occurs af-
ter the conjugate addition of hydrazine and that it is sensi-
tive to the steric bulk of the ester moiety. On the basis of
our results, we predict that the reaction of the correspond-
ing isopropyl ester should give 2 as the major product, but
we did not attempt this reaction.
In conclusion, we established a new and reliable route to
methyl (E)-2-(styrylsulfonyl)acetic acid methyl (6) and
the corresponding ethyl ester 13. 1,1-Dioxo-4-amino-5-
phenylthiomorpholine-3-one (1) and 1,1-dioxo-6-phenyl-
1,4,5-thiadiazepan-3-one (2) were prepared and fully
characterized; neither of these compounds displayed
HRMS (ESI): m/z [M + H]+: calcd for C8H18O7PS: 289.0505; found:
289.0518.
Ethyl {[(Diethoxyphosphoryl)methyl]sulfonyl}acetate (12)
Ester 12 was prepared by the same procedures as above, starting
from 11 (1.79 g, 6.63 mmol) and Oxone (6.11 g, 9.9 mmol).
Synthesis 2011, No. 8, 1205–1207 © Thieme Stuttgart · New York

SHORT PAPER
(E)-2-(Styrylsulfonyl)acetic Acid Esters
1207
Colorless oil; yield: 1.91 g (96%); Rf = 0.23 (hexanes–EtOAc, 1:1).
1H NMR (CDCl3): d = 4.45 (s, 2 H), 4.25 (m, 6 H), 3.95 (d, J = 16.2
Hz, 2 H), 1.40–1.30 (m, 9 H).
13C NMR (DMSO-d6): d = 160.5, 138.4, 128.5, 127.9, 127.2, 61.6,
55.3, 53.6.
HRMS (ESI): m/z [M + H]+ calcd for C10H13N2O3S: 241.0641;
found: 241.0643.
MS (ESI): m/z [M + H]+ calcd for C9H20O7PS: 303.1; found: 303.0.
6-Phenyl-1,4,5-thiadiazepan-3-one 1,1-Dioxide (2)
Methyl (E)-2-(Styrylsulfonyl)acetate (6); Typical Procedure
LiBr (0.38 g, 4.41 mmol) was added to a soln of ester 10 (0.85 g,
2.94 mmol), PhCHO (0.33 mL, 3.2 mmol), and Et3N (1.23 mL, 9.7
mmol) in MeCN (7 mL). The resulting suspension was stirred for
16 h at r.t. and then diluted with MeCN (10 mL). The white solid
was removed by filtration and rinsed with MeCN (5 mL). The com-
bined organic phases were concentrated by rotary evaporation and
the residue was purified by column chromatography (silica gel, 25–
50% EtOAc–hexanes) to give a waxy solid; yield: 0.29 g (41%);
Rf = 0.52 (hexanes–EtOAc, 1:1).
Thiadiazepan 2 was prepared as a mixture with 1 by using the same
procedures as above, starting from ester 13 (0.3 g, 1.18 mmol),
N2H4·H2O (86 L, 1.77 mmol), and EtOH (30 mL).
1: White solid; yield: 67 mg (24%).
2: White solid; yield: 85 mg (30%); mp 194–197 °C; Rf = 0.14 (hex-
anes–EtOAc 1:1).
FTIR (KBr): 3330.6 (m), 3285.7 (m), 3003.0 (w), 2942.6 (w),
1697.1 (br, vs), 1602.4 (vw), 1583.2 (vw) cm–1.
1H NMR (DMSO-d6): d = 9.42 [br s, 1 H, N(4)H, exch. D2O], 7.42–
7.28 (m, 5 H, Ph), 5.79 [br s, 1 H, N(5)H, exchangeable with D2O],
5.13 [br d, J = 13.8 Hz, 1 H, C(2)Ha], 4.33 [d, J = 11.7 Hz, 1 H,
C(6)H], 3.93 [dd, 1 H, J = 13.8, 11.7 Hz, C(7)Ha], 3.69 [br dd,
J = 13.8, 2.4 Hz, 1 H, C(2)Hb], 3.53 [dt, J = 13.8, 2.4 Hz, 1 H,
C(7)Hb].
1H NMR (CDCl3): d = 7.64 (d, J = 15.6 Hz, 1 H), 7.56–7.53 (m, 2
H), 7.47–7.43 (m, 3 H), 7.07 (d, J = 15.6 Hz, 1 H), 4.10 (s, 2 H),
3.82 (s, 3 H).
13C NMR (CDCl3): d = 163.4, 145.8, 132.0, 131.7, 129.2, 128.8,
124.5, 59.9, 53.3.
MS (ESI): m/z [M + Na]+ calcd for C11H12NaO4S: 263.0; found:
263.1.
13C NMR (DMSO-d6): d = 165.5, 139.1, 128.6, 127.9, 126.9, 62.9,
62.1, 59.6.
HRMS (ESI): m/z [M + H]+ calcd for C10H13N2O3S: 241.0641;
found: 241.0640.
Ethyl (E)-2-(Styrylsulfonyl)acetate (13)
Ester 13 was prepared by using the same procedures as above, start-
ing from 12 (1.0 g, 3.3 mmol), PhCHO (0.37 mL, 3.6 mmol), Et3N
(0.69 mL, 4.95 mmol), and LiBr (0.43 g, 4.95 mmol).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Viscous colorless oil; yield: 0.65 g (77%); Rf = 0.61 (hexanes–
EtOAc, 1:1).
1H NMR (CDCl3): d = 7.65 (d, J = 15.3 Hz, 1 H), 7.56–7.53 (m, 2
H), 7.48–7.43 (m, 3 H), 7.06 (d, J = 15.3 Hz, 1 H), 4.25 (q, J = 7.2
Hz, 2 H), 4.09 (s, 2 H), 1.29 (t, J = 7.2 Hz, 3 H).
Acknowledgment
We thank Dr Helena Majgier-Baranowska, Dr Bing Li, and Dr Min
Xie for their insightful discussions.
MS (ESI): m/z [M + H]+ calcd for C12H15O4S: 255.1; found: 255.0.
4-Amino-5-phenylthiomorpholine-3-one 1,1-Dioxide (1); Typi-
cal Procedure
References
N2H4·H2O (24 L, 0.50 mmol) was added to a cloudy soln of ester 6
(60 mg, 0.25 mmol) in MeOH (15 mL). The mixture was heated at
65 °C for 15 h and then concentrated by rotary evaporation. The res-
idue was purified by column chromatography (silica gel, 0–60%
EtOAc–hexanes) to give a white solid; yield: 30 mg (50%); mp
208–211 °C; Rf = 0.22 (hexanes–EtOAc, 1:1).
(1) (a) Padmavathi, V.; Thriveni, P.; Sudhakar Reddy, G.;
Deepti, D. Eur. J. Med. Chem. 2008, 43, 917.
(b) Padmavathi, V.; Thriveni, P.; Padmaja, A. J. Chem. Res.
2004, 556.
(2) (a) Peet, N. P. Synthesis 1984, 1065. (b) Peet, N. P.; Sunder,
S.; Trepanier, D. L. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 1976, 14, 701. (c) Kornet, M. J. J. Pharm.
Sci. 1973, 62, 834.
FTIR (KBr): 3305.0 (m), 2984.6 (m), 2933.5 (w), 2898.2 (w),
1639.1 (s), 1587.7 (s) cm–1.
(3) Scheiner, P.; Frank, L.; Giusti, I.; Arwin, S.; Pearson, S. A.;
Excellent, F.; Harper, A. P. J. Heterocycl. Chem. 1984, 21,
1817.
(4) Bhaskar Reddy, D.; Raman Reddy, P. V.; Vijayalakshmi, S.;
Raman Reddy, M. V. Phosphorus, Sulfur Silicon Relat.
Elem. 1993, 84, 63.
1H NMR (DMSO-d6): d = 7.39–7.28 (m, 5 H, Ph), 4.85 [dd,
J = 10.8, 5.1 Hz, 1 H, C(5)H], 4.80 [d, J = 15.8 Hz, 1 H, C(2)Ha],
4.65 (br s, 2 H, NH2, exch. D2O), 4.18 [dd, J = 15.8, 3.9 Hz,
C(2)Hb], 3.90 [ddd, J = 14.4, 4.8, 3.9 Hz, 1 H, C(6)Ha], 3.81 [dd,
J = 14.4, 10.8 Hz, 1 H, C(6)Hb].
Synthesis 2011, No. 8, 1205–1207 © Thieme Stuttgart · New York