Synthesis of Vinyl Sulfonamides Using the Horner Reaction

Article abstract of DOI:10.1055/s-2003-41059

A series of vinyl sulfonamides was synthesized using the Horner reaction of aldehydes and diphenylphosphorylmethane-sulfonamide. The sulfonamide reagent was easily prepared and can be stored indefinitely. The trans orientation about the double bond of the vinyl sulfonamides was the only isomer observed.

Full text of DOI:10.1055/s-2003-41059

PAPER
2321
Synthesis of Vinyl Sulfonamides Using the Horner Reaction
Synthesisof
Vinyl
e
S
ulfonami
b
des orah C. Reuter,* Joel E. McIntosh, Ashley C. Guinn,1 Ann Marie Madera
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Ave. R6E-3, Palo Alto, CA 94304, USA
Fax +1(650)3547363; E-mail: deborah.reuter@roche.com
Received 2 June 2003
sulfonamide was essential for substrate solubility and fac-
ile sulfonamide deprotonation. The synthesis of 3 was
straightforward starting with tert-butyl pyrocarbonate and
commercially available methyl sulfonamide9 (Scheme 1).
Abstract: A series of vinyl sulfonamides was synthesized using the
Horner reaction of aldehydes and diphenylphosphorylmethane-
sulfonamide. The sulfonamide reagent was easily prepared and can
be stored indefinitely. The trans orientation about the double bond
of the vinyl sulfonamides was the only isomer observed.
Treating the Boc-sulfonamide 3 with LDA in THF at –78
°C, followed by addition of diphenylphosphinic chloride
at the same temperature provided 4 as a crystalline solid
in 78% yield (Scheme 1). When the phosphoryl sulfona-
mide 4 was mixed with sodium hydride in DMF followed
by the addition of benzaldehyde, the only product ob-
served was the Boc-protected vinyl sulfonamide 5
(Scheme 2). This adduct was deprotected using TFA in
dichloromethane at room temperature to yield the vinyl
sulfonamide 6 in 82% yield (over the two steps).
Key words: sulfonamides, E-alkenes, Horner reaction, aldehydes,
ylides
Recently, we were interested in the synthesis of aromatic
vinyl sulfonamides as potential drug candidates for anti-
inflammatory programs.2 The sulfonamide is a useful
functionality because it can act as a carbonyl bioisostere3
making key interactions with receptor proteins as well as
providing aqueous solubility. Previous routes to vinyl sul-
fonamides have involved generating the vinyl sulfonate
ester,4 which is then converted to the sulfonyl chloride and
subsequently reacted with various amides.5 Other meth-
ods include Heck coupling of the ethylenesulfonamide
and aryl chlorides6 or a Peterson olefination reaction of a
silyl-substituted sulfonamide.7 After reviewing this litera-
ture, we found ourselves interested in developing a gener-
al route to vinyl sulfonamides that involved minimal steps
and utilized readily available starting materials. Herein,
we describe the synthesis of a phosphoryl sulfonamide
that reacts with aldehydes in a Horner8 reaction to gener-
ate vinyl sulfonamides. We anticipate that this facile
method will complement the existing sulfonamide proce-
dures.
NaH (2 eq)
SO2NHBoc
4
Ph-CHO
+
Ph
DMF
5
SO2NH2
TFA/CH2Cl2/rt
82%
6
Scheme 2
We then explored the generality of the reaction and found
that a variety of aldehydes yielded the respective vinyl
sulfonamides. Sodium hydride and potassium carbonate
are effective bases for the deprotonation of the phosphoryl
reagent. The Boc deprotection conditions were either TFA
in CH2Cl2 or hot DMSO,10 depending on the functionality
in the molecule. The overall yields of the sulfonamides for
the two step sequence were moderate11 to good (Table 1).
All sulfonamides isolated had the trans orientation about
the double bond as determined by NMR coupling con-
stants; the cis isomer was not observed in any of the ex-
amples described. We believe that the preference for the
trans vinyl sulfonamide is due to steric hindrance encoun-
tered in the transition state, which was also observed in
the synthesis of vinyl sulfones and sulfides via a phospho-
nate type reagent.12 Ketones did not react under these re-
action conditions with the phosphoryl reagent.
The synthesis of the sulfonamide reagent starts with the
generation of tert-butyl sulfonyl carbamate 3. We found
through initial experiments that a protecting group on the
Scheme 1
In conclusion, we have developed a novel and expedient
route to vinyl sulfonamides. The protected phosphoryl
sulfonamide 4 is easily prepared and following deprotona-
tion readily reacts with a variety of aldehydes. Removal of
the Boc group is straightforward using standard deprotec-
tion conditions. We anticipate that this procedure will
complement the existing methods for vinyl sulfonamide
SYNTHESIS 2003, No. 15, pp 2321–2324
Advanced online publication: 23.09.2003
DOI: 10.1055/s-2003-41059; Art ID: M02503SS
© Georg Thieme Verlag Stuttgart · New York
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x.
x
x
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D. C. Reuter et al.
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tert-Butyl[(diphenylphosphoryl)methyl]sulfonyl Carbamate (4)
To a solution of diisopropylamine (3.21 g, 31.76 mmol) in THF (32
mL) at –78 °C under N2 was added n-BuLi in hexanes (12.29 mL,
30.73 mmol). The mixture was warmed to 0 °C for 1 min, then re-
cooled to –78 °C. A solution of 3 (2.00 g, 10.24 mmol) in THF (22
mL) was added dropwise. After 8 min, diphenylphosphinic chloride
(2.42 g, 10.24 mmol) was added dropwise. After 90 min, H2O (100
mL) was added and the mixture was warmed to r.t. Additional H2O
(100 mL) was added and the mixture was washed with EtOAc (250
mL). The aqueous layer was brought to pH 5 with 5% aq HCl. The
white precipitate was filtered and dried in vacuo to yield 3.14 g of 4
(78%); mp 221.0–224.0 °C.
IR (KBr): 3434, 2980, 1730, 1140 cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.42 (9 H, s), 4.92 (2 H, d,
J = 9.7 Hz), 7.57 (6 H, m), 7.84 (4 H, m), 11.59 (1 H, s).
13C NMR (DMSO-d6, 300 MHz): = 27.6, 50.9, 51.7, 82.0, 128.5,
128.6, 130.4, 130.5, 130.6, 131.5, 132.0, 132.1, 132.9, 150.7.
Table 1 Synthesis of Vinyl Sulfonamides
Product
Deprotection Yield
Methoda
(%)b
SO2NH2
7
8
R =
OMe
A
54
R
R
R
R = Me
R = Cl
A
A
A
78
59
63
SO2NH2
SO2NH2
9
10
Cl
Cl
SO2NH2
LSI-MS: m/z = 396 (M + H)+.
11
B
74
SO2NH2
Anal. Calcd for C18H22NO5PS: C, 54.68; H, 5.61; N, 3.54. Found:
C, 54.84; H, 5.65; N, 3.58.
N
Ph
N
12
13
B
A
73
72
SO2NH2
Vinyl Boc-Sulfonamides; General Procedure
N
To a well–stirred solution of the reagent 4 (0.8 mmol) in DMF at
0 °C was added NaH (2.04 mmol). The reaction was allowed to
warm to r.t. and stirred for 30 min. The aldehyde (0.98 mmol) was
then added at once and the reaction was stirred overnight at r.t. H2O
(50 mL) was added to the reaction and the mixture was extracted
with EtOAc (50 mL). The organic solution was washed with 2% aq
HCl, H2O, brine, and dried (Na2SO4). The solvent was evaporated
in vacuo to give the crude product.
Cbz
OMe
SO2NH2
SO2NH2
N
MeO
Ph
N
14
15
A
B
46
26
Deprotection of Vinyl Boc-Sulfonamides; General Procedures
Method A: CH2Cl2 (20 mL) and TFA (6 mL) were added to the Boc-
sulfonamide (ca. 1 mmol) and the reaction mixture was stirred for
1–2 h (disappearance of the starting material was monitored by
TLC). The solvent and TFA were then removed via evaporation,
and H2O (30 mL) was added. The solution was neutralized with aq
20% NaOH solution and extracted with CH2Cl2. The resulting or-
ganic solution was washed with brine and dried (Na2SO4). Evapo-
ration of the solvent in vacuo, followed by purification via column
chromatography on silica gel (EtOAc–hexane, 40:60) provided the
respective vinyl sulfonamide.
SO2NH2
O
16
17
18
B
A
A
79
46
57
O
O
SO2NH2
O
SO2NH2
Method B: The Boc-sulfonamide (ca. 1 mmol) was dissolved in
DMSO (5 mL) and heated to 80 °C (disappearance of the starting
material was monitored by TLC). Upon completion, the reaction
was cooled, poured into H2O (25 mL) and extracted with EtOAc
(3 × 30 mL). Evaporation of the solvent in vacuo, followed by puri-
fication via column chromatography on silica gel (EtOAc–hexane,
50:50) provided the respective vinyl sulfonamide.
SO2NH2
a A = TFA/CH2Cl2, r.t.; B = DMSO/heat.
b Isolated yields after column chromatography on silica gel.
(E)-2-Phenylethenesulfonamide (6)
Solid; yield: 0.115 g (82%); mp 144 °C.
IR (KBr): 3337, 3240, 1624, 1450, 1284, 1194 cm–1.
synthesis providing an additional route to generate func-
tionally distinct molecules.
1H NMR (DMSO-d6, 300 MHz): = 7.10 (2 H, s), 7.22 (1 H, d,
J = 15.5 Hz), 7.3 (1 H, d, J = 15.5 Hz), 7.44 (3 H, m), 7.68 (2 H, m).
13C NMR (DMSO-d6, 300 MHz): = 128.1, 128.9, 130.1, 130.3,
Reagents and solvents were purchased from Aldrich as HPLC grade
whenever possible. NMR spectra were recorded on a Bruker DPX
300 spectrometer. Chemical shifts are reported in ppm downfield
from TMS with reference to internal solvent. Analytical TLC was
performed using Analtech silica gel plates (250 microns) with a flu-
orescent indicator present. Flash chromatography was conducted
using EM Science silica gel 60 (230–400 mesh).
132.9, 136.4;
HRMS (EI): m/z calcd for C8H9NO2S: 183.0354; found: 183.0359.
(E)-2-(4-Methoxyphenyl)ethenesulfonamide (7)
Solid; yield: 0.145 g (54%); mp 126–148 °C.
IR (KBr): 1514, 1312 cm–1.
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Synthesis of Vinyl Sulfonamides Using the Horner Reaction
2323
1H NMR (DMSO-d6, 300 MHz): = 3.80 (3 H, s), 6.98 (2 H, d,
J = 8.8 Hz), 7.03 (2 H, s), 7.07 (1 H, d, J = 15.4 Hz), 7.26 (1 H, d,
J = 15.5 Hz), 7.63 (2 H, d, J = 8.8 Hz).
Benzyl 4-[(E)-2-(aminosulfonyl)ethenyl]piperidine-1-carboxy-
late (12)
Solid; yield: 0.208 g (73%); mp 87 °C.
13C NMR (DMSO-d6, 300 MHz): = 55.7, 114.8, 125.7, 128.2,
IR (KBr): 3346, 1694, 1138 cm–1.
130.3, 136.7, 161.2.
EIMS: m/z = 213 (M)+.
1H NMR (CDCl3, 300 MHz): = 1.38 (2 H, m), 1.75 (2 H, m), 2.35
(1 H, m), 2.84 (2 H, m), 4.23 (2 H, m), 5.03 (2 H, s), 5.12 (2 H, s),
6.33 (1 H, dd, J = 15.2, 1.4 Hz), 6.73 (1 H, dd, J = 15.2, 6.4 Hz),
7.35 (5 H, m).
13C NMR (CDCl3, 300 MHz): = 30.3, 37.6, 43.5, 67.2, 127.9,
128.1, 128.5, 129.5, 136.7, 146.4, 155.2.
Anal. Calcd for C9H11NO3S: C, 50.69; H, 5.20; N, 6.57. Found: C,
50.36; H, 5.23; N, 6.69.
(E)-2-(4-Methylphenyl)ethenesulfonamide (8)
Solid; yield: 0.248 g (78%), mp 161.4–162.8 °C.
IR (KBr): 3328, 3244, 1606, 1315, 1132 cm–1.
HRMS (EI): m/z calcd for C15H20N2O4S: 324.1144; found:
324.1144.
1H NMR (DMSO-d6, 300 MHz): = 2.4 (3 H, s), 4.8 (2 H, br s),
6.88 (1 H, d, J = 15.4 Hz), 7.21 (2 H, d, J = 8.1 Hz), 7.38 (2 H, d,
J = 8.1 Hz), 7.51 (1 H, d, J = 15.4 Hz).
13C NMR (DMSO-d6, 300 MHz): = 21.9, 126.3, 128.7, 130.0,
130.2, 141.2, 142.0.
(E)-2-(2,4-Dimethoxypyrimidin-5-yl)ethenesulfon-amide (13)
Solid; yield: 0.138 g (72%); mp 172.6–173.4 °C.
IR (KBr): 3297, 3230, 2965, 1622, 1597, 1548, 1477 cm–1.
1H NMR (DMSO-d6, 300 MHz): = 3.95 (3 H, s), 4.04 (3 H, s),
7.08 (2 H, s), 7.25 (2 H, s), 8.70 (1 H, s).
13C NMR (DMSO-d6, 300 MHz): = 54.4, 54.9, 108.3, 127.9,
130.9, 160.2, 164.9, 168.1.
EIMS: m/z = 245 (M)+.
EI-MS: m/z = 197 (M)+.
Anal. Calcd for C9H11NO2S: C, 54.8; H, 5.62; N, 7.10. Found: C,
55.15; H, 5.61; N, 7.11.
(E)-2-(4-Chlorophenyl)ethenesulfonamide (9)
Solid; yield: 0.159 g (59%); mp 189.5–189.9 °C.
IR (KBr): 3374, 3262, 1329, 1136 cm–1.
HRMS (EI): m/z calcd for C8H11N3O4S (M)+: 245.0470; found
245.0471.
(1E,3E)-4-Phenylbuta-1,3-diene-1-sulfonamide (14)
Solid, yield: 0.123 g (46%); mp 194.2–195.4 °C.
IR (KBr): 3333, 3239, 1622, 1591, 1449, 1314 cm–1.
1H NMR (DMSO-d6, 300 MHz): = 7.16 (2 H, s), 7.25 (1 H, d,
J = 15.6 Hz), 7.35 (1 H, d, J = 15.6 Hz), 7.47 (2 H, d, J = 8.6 Hz),
7.73 (2 H, d, J = 8.6 Hz).
13C NMR (DMSO-d6, 300 MHz): = 128.9, 129.9, 131.1, 131.9,
134.6, 135.1.
1H NMR (DMSO-d6, 300 MHz): = 6.70 (1 H, m), 7.06 (5 H, m),
7.35 (3 H, m), 7.54, (2 H, br d, J = 6.9 Hz).
EI-MS: m/z = 217 (M)+.
13C NMR (DMSO-d6, 300 MHz): = 125.2, 127.5, 129.2, 129.3,
133.1, 136.3, 137.2, 140.0.
EI-MS: m/z = 209 (M)+.
Anal. Calcd for C8H8NClO2S: C, 44.14; H, 3.70; N, 6.43. Found: C,
44.43; H, 3.87; N, 6.27.
Anal. Calcd for C10H11NO2S: C, 57.39; H, 5.30; N, 6.69. Found: C,
57.64; H, 5.43; N, 6.58.
(E)-2-(2-Chlorophenyl)ethenesulfonamide (10)
Solid; yield: 0.172 g (63%); mp 132.0–134.2 °C.
IR (KBr): 3319, 3242, 1469, 1444 cm–1.
(E)-2-(2-Furyl)ethenesulfonamide (15)
To a well-stirred solution of 4 (1.02 g, 2.6 mmol) in H2O (8 mL)
were added K2CO3 (0.899 g, 6.5 mmol) and furfural (0.22 mL, 2.6
mmol) at r.t. The mixture was warmed to reflux and stirred over-
night. The mixture was cooled to r.t., diluted with EtOAc (50 mL)
and filtered through a plug of silica gel capped with anhyd MgSO4.
The filtrate was evaporated in vacuo to afford the crude product.
Method B was used for the deprotection of the Boc-sulfonamide
(0.117 g, 26%); mp 151.1–151.6 °C.
1H NMR (DMSO-d6, 300 MHz): = 7.27 (2 H, s), 7.37 (1 H, d,
J = 15.4 Hz), 7.45 (2 H, m), 7.57 (1 H, m), 7.63 (1 H, d, J = 15.5
Hz), 7.93 (1 H, dd, J = 7.2, 2.1 Hz).
13C NMR (DMSO-d6, 300 MHz): = 127.8, 128.4, 130.0, 130.6,
130.8, 131.6, 131.7, 133.3, 133.5.
EI-MS: m/z = 217 (M)+.
HRMS (EI): m/z calcd for C8H8ClNO2S (M)+: 216.9964; found:
IR (KBr): 3399, 3283, 1631, 1300, 1134 cm–1.
216.9965.
1H NMR (CDCl3, 300 MHz): = 5.45 (1 H, br s), 6.48 (1 H, dd,
J = 3.4, 1.8 Hz), 6.62 (1 H, d, J = 1.8 Hz), 6.83 (1 H, d, J = 15.1
Hz), 7.22 (1 H, d, J = 15.1 Hz)), 7.49 (1 H, d, J = 1.8 Hz).
13C NMR (DMSO-d6, 300 MHz): = 112.1, 115.0, 125.6, 125.9,
144.7, 148.6.
(E)-2-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)ethene-
sulfonamide (11)
Solid; yield: 0.273 g (74%); mp 176 °C.
IR (KBr): 3397, 3271, 1626, 1138 cm–1.
1H NMR (CDCl3, 300 MHz): = 2.43 (3 H, s), 6.41 (2 H, s), 6.9 (1
H, d, J = 15.7 Hz), 7.3 (1 H, d, J = 15.7 Hz), 7.47 (2 H, m), 7.52 (3
H, m).
13C NMR (CDCl3, 300 MHz): = 13.9, 111.8, 124.8, 126.9, 127.8,
128.6, 129.1, 137.4, 149.2.
EI-MS: m/z = 173 (M)+.
Anal. Calcd for C6H7NO3S: C, 41.61; H, 4.07; N, 8.09; Found: C,
41.88; H, 4.08; N, 8.09.
(E)-2-[5-(1,3-Benzodioxol-5-yl)-3-methyl-2-furyl]ethene-
sulfonamide (16)
Solid; yield: 0.2 g (79%); mp 199 °C.
HRMS (EI): m/z calcd for C12H12ClN3O2S: 297.0339; found
297.0338.
IR (KBr): 1501, 1479 cm–1.
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D. C. Reuter et al.
PAPER
1H NMR (DMSO-d6, 300 MHz): = 2.14 (3 H, s), 6.07 (2 H, s),
6.86 (1 H, d, J = 15.1 Hz), 6.89 (1 H, s), 6.98 (1 H, d, J = 8.1 Hz),
7.03 (2 H, s), 7.11 (1 H, d, J = 15.1 Hz), 7.32 (1 H, dd, J = 8.1, 1.7
Hz), 7.39 (1 H, d, J = 1.7 Hz).
Acknowledgment
The authors would like to express their gratitude to the Central
R&D Analytical group of Roche Palo Alto for their expertise in cha-
racterizing all of these compounds.
13C NMR (DMSO-d6, 300 MHz): = 9.79, 101.3, 104.5, 108.7,
109.5, 118.3, 121.7, 123.5, 125.1, 127.7, 143.6, 147.6, 147.8, 154.1.
EI-MS: m/z = 307 (M)+.
References
Anal. Calcd for C14H13NO5S: C, 54.7; H, 4.27; N, 4.56. Found: C,
54.49; H, 4.23; N, 4.49.
(1) Roche Bioscience Summer Intern Student; Current address:
Elan Pharmaceuticals, 800 Gateway Blvd., South San
Francisco, CA 94080.
(E)-4-(4-isopropylphenyl)-3-methylbut-1-ene-1-sulfonamide
(17)
Solid; yield: 0.156g (46%); mp 84–86 °C.
IR (KBr): 3327, 3241, 2957, 1321, 1131 cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.08 (3 H, d, J = 6.3 Hz), 1.23
(6 H, d, J = 6.9 Hz), 2.64 (4 H, m), 2.88 (1 H, m), 4.63 (2 H, br s),
6.25 (1 H, dd, J = 15.1, 1.0 Hz), 6.78 (1 H, dd, J = 15.1, 6.7 Hz),
7.04 (2 H, d, J = 8.1 Hz), 7.15 (2 H, d, J = 8.0 Hz).
13C NMR (DMSO-d6, 300 MHz): = 18.5, 24.0, 33.7, 37.6, 41.7,
126.5, 128.9, 129.1, 136.3, 147.0, 148.8.
(2) Lapierre, J.; Rotstein, D. M.; Sjogren, E. B. PCT Int. Appl.
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(3) (a) Thornber, C. W. Chem. Soc. Rev. 1979, 8, 563.
(b) Genmari, C.; Salom, B.; Potenza, D.; Williams, A.
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1969, 34, 1128. (b) Carretero, J. C.; Demillequand, M.;
Ghosez, L. Tetrahedron 1987, 43, 5125. (c) Musicki, B.;
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(5) Roush, W. R.; Gwaltney, S. L.; Cheng, J.; Scheidt, K. A.;
McKerrow, J. H.; Hansell, E. J. Am. Chem. Soc. 1998, 120,
10994.
EI-MS: m/z = 267 (M)+.
(6) Hirooka, S.; Tanbo, Y.; Takemura, K.; Nakahashi, H.;
Matsuoka, T.; Kuroda, S. Bull. Soc. Chem. Jpn. 1991, 64,
1431.
Anal. Calcd for C14H21NO2S: C, 62.88; H, 7.92; N, 5.24. Found: C,
62.64; H, 7.76; N, 5.18.
(7) Mladenova, M.; Gaudemar-Bardone, F. Phosphorous,
Sulfur Silicon Relat. Elem. 1991, 62, 257.
(8) (a) Horner, L.; Hoffman, H.; Wippel, H. G. Chem. Ber.
1958, 91, 64. (b) Horner, L.; Hoffman, H.; Wippel, H. G.;
Klahre, G. Chem. Ber. 1959, 92, 2499.
(9) (a) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379.
(b) Campbell, J. A.; Hart, D. J. J. Org. Chem. 1993, 58, 2900.
(10) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141.
(11) It is believed that the lower yields of products 14, 15, and 17
result from poor aldehyde purity.
(E)-2-Cyclohexylethenesulfonamide (18)
Solid; yield: 0.137 g (57%); mp 89–92 °C.
IR (KBr): 3349, 2923, 1324, 1137 cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.23 (5 H, m), 1.74 (5 H, m),
2.17 (1 H, m), 4.75 (2 H, br s), 6.31 (1 H, dd, J = 15.2, 1.5 Hz), 6.77
(1 H, dd, J = 15.2, 6.5 Hz).
13C NMR (DMSO-d6, 300 MHz): = 26.0, 26.2, 31.8, 40.0, 128.4,
149.8.
(12) (a) Shahak, I.; Almog, J. Synthesis 1969, 170. (b) Posner,
G. H.; Brunelle, D. J. J. Org. Chem. 1972, 37, 3547.
(c) Shahak, I.; Almog, J. Synthesis 1970, 145.
EI-MS: m/z = 189 (M)+.
Anal. Calcd for C8H15NO2S: C, 50.77; H, 7.99; N, 7.40. Found: C,
50.89; H, 7.95; N, 7.31.
Synthesis 2003, No. 15, 2321–2324 © Thieme Stuttgart · New York