Synthesis of ortho-Methoxyphenylsulfonylsemicarbazides

Article abstract of DOI:10.1081/SCC-120028635

The synthesis of a new series of phenylsulfonylsemicarbazide which was substituted in ortho position by a methoxy group is described. The protection of the phenyl ring by a bromine, in order to eliminate the obtention of undesired regioisomers, is necessa

Full text of DOI:10.1081/SCC-120028635

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 1041–1048, 2004
Synthesis of ortho-
Methoxyphenylsulfonylsemicarbazides
*
N. Lebegue, G. Bethegnies, and P. Berthelot
´ ´
Laboratoire de Chimie Therapeutique, Faculte des Sciences
Pharmaceutiques et Biologiques de Lille, Lille Cedex, France
ABSTRACT
The synthesis of a new series of phenylsulfonylsemicarbazide which was
substituted in ortho position by a methoxy group is described. The
protection of the phenyl ring by a bromine, in order to eliminate the
obtention of undesired regioisomers, is necessary to afford final
compounds.
Key Words: Phenylsulfonylsemicarbazide; Sulfonylurea; Ortho
position; Methoxy group.
Sulfonylurea derivatives are the most widely prescribed drugs for the
treatment of the maturity onset form of diabetes melitus.[1–3] Compounds 1
were also described in the literature like hypoglycemic agents[4] (Fig. 1).
*
´ ´
Correspondence: N. Lebegue, Laboratoire de Chimie Therapeutique, Faculte des
Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du Professeur Laguesse,
B.P. 83, 59006 Lille Cedex, France; E-mail: nlebegue@phare.univ-lille2.fr.
1041
DOI: 10.1081/SCC-120028635
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Lebegue, Bethegnies, and Berthelot
Figure 1. Compound 1 structure.
In regard with these structures, we decided to bring a sulfonylsemicarba-
zide moiety by replacement of the carboxylic acid (Fig. 2). Sulfonylureas are
well known to increase endogenous insulin secretion.[5] The difficulty of the
synthesis was to obtain sulfonylsemicarbazide substituted by a methoxy in
ortho position of the sulfonyl group in the phenyl ring.
The first step of the synthesis to obtain 2-piperidinobenzylamine
derivatives 2a–b are well known[4] (Sch. 1). Condensation of this amine with
3-methoxyphenylacetic acid, using dicyclohexylcarbodiimide (DCC) in
toluene, furnishes the corresponding amides 3a–b which are then treated
with chlorosulfonic acid in dichloromethane. 90% of the chlorosulfonylation
takes place at the 2-position (4a–b), which is more reactive than the
4-position (5a–b).
The blocking of this position by addition of bromine on 3-methoxy-
phenylacetic acid following by condensation with amines 2a–b affords the
amides 7a–b in 50–60% yield (Sch. 2). Addition of chlorosulfonic acid to
dichloromethane (stabilized with amylene) solution of amide 7 supplies the
chlorosulfonyl compound which is directly treated with gaseous ammonia.
The isomers 8a–b, bearing the sulfonamide group at the 4-position of the ring,
are obtained with 45–55% yield.
Displacement of the bromine is realized in the presence of ammonium
formate and Pd/C.[6,7] Synthesis of phenylsulfonylcarbazides from phenyl-
sulfonylisocyanate and the corresponding hydrazines is described in the
literature.[8] We have undertaken the synthesis by reacting sulfonamides 9a–b
Figure 2. Sulfonylsemicarbazide moiety by replacement of carboxylic acid.

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Synthesis of ortho-Methoxyphenylsulfonylsemicarbazides
1043

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1044
Lebegue, Bethegnies, and Berthelot
Scheme 2.
with carbamate 10 in the presence of NaOH in DMF to provide final
compounds 11a–b in 80–90% yield (Sch. 2).[9,10]
EXPERIMENTAL
Melting points were determined on a Bu¨chi B-540 apparatus and are
uncorrected. Infrared spectra were recorded as thin films on potassium
bromide disks on a Beckman Acculab IV spectrophotometer. Mass spectra
were performed on
(electrospray-ionspray method) (Laboratoire d’Application de Spectrometrie
a Applied Biosystems API 3000 LC/MS/MS
´
1
de Masse, Faculte de Medecine Henri Warembourg de Lille). H NMR spectra
´
were recorded on a Bruker AC 300 P and 2D NMR spectra on a Bruker DPX
300 (LARMN, Universite de Lille 2), using tetramethylsilane as internal

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Synthesis of ortho-Methoxyphenylsulfonylsemicarbazides
1045
standard. Elemental analyses were performed by C.N.R.S.—Vernaison, and
were in agreement with the calculated values within +0.4.
2-Bromo-3-methoxyphenylacetic acid (6). 1.7 mL of bromine (33 mmol)
was added at 08C to a solution of 5 g of 3-methoxyphenylacetic acid
(30 mmol) in 25 mL of dichloromethane and the mixture was stirred at room
temperature for 2 hr. The red solution was discolored with sodium thiosulfate,
washed with water and extracted with dichloromethane. The organic layers
were dried and evaporated under vacuo. Yield: 95%; mp ¼ 114–1158C (Lit.
1148C)[11]; IR (cm21): 3200–2600 (OH), 1700 (C55O), 1600, 1490 (C55C);
1H NMR (CDCl3): d (ppm) ¼ 3.77–3.82 (m, 5H), 6.75 (dd, 1H, J ¼ 8.8, 2.9),
6.85 (d, 1H, J ¼ 2.9), 7.45 (d, 1H, J ¼ 8.8). Anal. Calcd for C9H9BrO3
(M ¼ 245): C, 44.11; H, 3.7; Found: C, 44.23; H, 3.65.
General procedure for synthesis of amides (7). 1.9 g of 2a or 2.3 g of
2b (10 mmol) was added portionwise to a solution of 2.5 g of DCC (12 mmol)
and 2.7 g of 6 (11 mmol) in 100 mL of toluene at room temperature and stirred
for 10 hr. The reaction mixture was filtered, the filtrate was evaporated and the
residue was recrystallized from hexane. The following compounds were
obtained:
3-(2-Bromo-5-methoxyphenyl)-N-(2-piperidinobenzyl)acetamide (7a).
Yield 62%; mp ¼ 104–1058C; IR (cm21): 3300 (NH), 2900 (CH), 1650
(C55O), 1600, 1490 (C55C); 1H NMR (CDCl3): d (ppm) 1.48–1.62 (m, 6H),
2.72–2.80 (m, 4H), 3.72 (s, 2H), 3.75 (s, 3H), 4.51 (d, 2H, J ¼ 6.5), 6.55
(t, 1H, J ¼ 6.5), 6.72 (dd, 1H, J ¼ 8.7, 2.7), 6.89 (d, 1H, J ¼ 2.7), 7.05
(m, 2H), 7.25 (m, 2H), 7.45 (d, 1H, J ¼ 8.7). Anal. Calcd for
C21H25BrN2O2 (M ¼ 417.34): C, 60.44; H, 6.04; N, 6.71; Found: C,
60.19; H, 6.14; N, 6.84.
3-(2-Bromo-5-methoxyphenyl)-N-[1-(2-piperidinophenyl)-2-methyl-
propyl]acetamide (7b). Yield 52%; mp ¼ 128–1308C; IR (cm21): 3300
1
(NH), 2900 (CH), 1650 (C55O), 1600, 1490 (C55C); H NMR (CDCl3): d
(ppm) 0.73 (d, 3H, J ¼ 8.5), 0.95 (d, 3H, J ¼ 8.5), 1.50–1.75 (m, 7H), 1.95
(m, 1H), 2.62 (m, 2H), 2.95 (m, 2H), 3.65 (s, 2H), 3.7 (s, 3H), 4.98 (m, 1H),
6.70 (dd, 1H, J ¼ 8.5, 2.7), 6.88 (d, 1H, J ¼ 2.7), 6.95 (m, 1H), 7.05 (m, 2H),
7.23 (m, 2H), 7.45 (d, 1H, J ¼ 8.5). Anal. Calcd for C24H31BrN2O2
(M ¼ 459.42): C, 62.74; H, 6.80; N, 6.10; Found: C, 62.98; H, 6.84; N, 6.27.
General procedure for synthesis of sulfonamides (8). 4 mL of chloro-
sulfonic acid (60 mmol) was added dropwise to a solution of 4.2 g of 7a or
4.6 g of 7b (10 mmol) in 15 mL of CH2Cl2 (stabilized with amylene) at 08C.
The mixture was then refluxed for 5 hr. After cooling, 150 mL of CH2Cl2 was
added to the solution which was cooled to 08C and treated with gaseous
ammonia to form a white precipitate. The precipitate was filtered, washed with
CH2Cl2 and the filtrate was evaporated under vacuo and used without further
purification. The following compounds were obtained:

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Lebegue, Bethegnies, and Berthelot
3-(4-Aminosulfonyl-2-bromo-5-methoxyphenyl)-N-(2-piperidinoben-
zyl)acetamide (8a). Yield 53%; mp ¼ 187–1888C; IR (cm21): 3280, 3100
(NH), 2900 (CH), 1640 (C55O), 1600, 1490 (C55C), 1170, 1350 (SO2N); 1H
NMR (CDCl3): d (ppm) 1.62–1.79 (m, 6H), 2.71–2.83 (m, 4H), 3.73 (s, 2H),
3.95 (s, 3H), 4.55 (d, 2H, J ¼ 6.5), 5.09 (s, 2H), 7.12 (m, 3H), 7.25 (m, 2H),
8.05 (s, 1H). Anal. Calcd for C21H26BrN3O4S (M ¼ 496.42): C, 50.81; H,
5.28; N, 8.46; Found: C, 51.02; H, 5.34; N, 8.62.
3-(4-Aminosulfonyl-2-bromo-5-methoxyphenyl)-N-[1-(2-piperidino-
phenyl)-2-methyl-propyl]acetamide (8b). Yield 45%; mp ¼ 249–2508C;
IR (cm21): 3400, 3350 (NH), 2900 (CH), 1670 (C55O), 1600, 1500 (C55C),
1
1175, 1335 (SO2N); H NMR (CDCl3): d (ppm) 0.73 (d, 3H, J ¼ 8.5), 1.02
(d, 3H, J ¼ 8.5), 1.58–1.79 (m, 7H), 1.99 (m, 1H), 2.69 (m, 2H), 2.97 (m, 2H),
3.68 (m, 2H), 3.91 (s, 3H), 4.85 (m, 1H), 5.11 (s, 2H), 7.12 (m, 3H), 7.25
(m, 2H), 7.60 (m, 1H), 8.05 (s, 1H). Anal. Calcd for C24H32BrN3O4S
(M ¼ 538.5): C, 53.53; H, 5.99; N, 7.80; Found: C, 53.60; H, 5.79; N, 7.86.
General procedure for synthesis of (9). 1 g of 8a or 1.1 g of 8b
(2 mmol) and 130 mg of ammonium formate (2 mmol) were dissolved in
30 mL of methanol. 100 mg of palladium 10% on charcoal was then added and
the mixture was heated under reflux for 4 hr. After cooling, the palladium was
eliminated and the filtrate concentrated under reduced pressure. 50 mL of
NaOH 1 N was added to the residue and the solution was stirred for 1 hr at
room temperature. The resulting mixture was acidified with acetic acid 10%
until pH 6 and extracted twice with CHCl3. The combined extracts were dried,
concentrated under reduced pressure and recrystallized from ethanol. The
following compounds were obtained:
3-(4-Aminosulfonyl-3-methoxyphenyl)-N-(2-piperidinobenzyl)aceta-
mide (9a). Yield: 95%; mp ¼ 198–1998C; IR (cm21): 3400, 3300 (NH),
2950, 2850 (CH), 1655 (C55O), 1610, 1495 (C55C), 1160, 1345 (SO2N);
1H NMR (CD3OD): d (ppm) 1.64–1.82 (m, 6H), 2.91–3.08 (m, 4H), 3.84
(s, 2H), 4.05 (s, 3H), 4.65 (s, 2H), 7.12 (dd, 1H, J ¼ 8.1, 2.1), 7.23 (m, 2H),
7.35 (m, 3H), 7.95 (d, 1H, J ¼ 8.1); MS m/e 418.2. Anal. Calcd for
C21H27N3O4S (M ¼ 417.52): C, 60.41; H, 6.52; N, 10.06; Found: C, 60.52;
H, 6.48; N, 10.15.
3-(4-Aminosulfonyl-3-methoxyphenyl)-N-[1-(2-piperidinophenyl)-2
-
methylpropyl]acet-amide (9b). Yield: 90%; mp ¼ 205–2078C; IR (cm21):
3400, 3300 (NH), 2950, 2800 (CH), 1650 (C55O), 1600, 1500 (C55C), 1155,
1350 (SO2N); 1H NMR (CDCl3): d (ppm) ¼ 0.72 (d, 3H, J ¼ 8.5), 0.98 (d, 3H,
J ¼ 8.5), 1.56–1.80 (m, 7H), 1.95 (m, 1H), 2.63 (m, 2H), 2.90 (m, 2H), 3.56
(s, 2H), 3.91 (s, 3H), 4.85 (m, 1H), 5.08 (s, 2H), 6.91 (d, 1H, J ¼ 8.1), 7.02
(s, 1H), 7.09 (m, 2H), 7.25 (m, 2H), 7.52 (m, 1H), 7.85 (s, 1H); MS m/e 460.3.
Anal. Calcd for C24H3N3O4S (M ¼ 459.6): C, 62.72; H, 7.24; N, 9.14; Found:
C, 62.79; H, 7.09; N, 9.23.

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Synthesis of ortho-Methoxyphenylsulfonylsemicarbazides
1047
Phenyl hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamate (10). A
solution of 6.3 g of hexahydrocyclopenta[c]pyrrol-2(1H)-amine (50 mmol)
and 7 mL of triethylamine (50 mmol) was added dropwise to a solution of
7.5 mL of phenyl chloroformate (60 mmol) in 150 mL of CH2Cl2. The reaction
mixture was heated under reflux for 2 hr, evaporated, taken with water and the
resulting precipitate was filtered and washed with petroleum ether. Yield:
86%; mp ¼ 138–1408C; IR (cm21): 3260 (NH), 2900, 2840 (CH), 1730
(C55O), 1600, 1500 (C55C); 1H NMR (CDCl3): d (ppm) 1.45–1.71 (m, 6H),
2.45 (m, 2H), 2.65 (m, 2H), 3.35 (m, 2H), 5.82 (s, 1H), 7.15 (m, 3H), 7.35
(m, 2H). Anal. Calcd for C14H18N2O2 (M ¼ 246.3): C, 68.27; H, 7.37; N,
11.37; Found: C, 68.40; H, 7.32; N, 11.41.
General procedure for synthesis of sulfonylsemicarbazides (11).
80 mg of NaOH (2 mmol) dissolved in 5 mL of methanol was added to 0.83 g
of 9a or 0.92 g of 9b (2 mmol) in solution in 4 mL of DMF and the solution
was stirred at room temperature for 1 hr. The methanol was evaporated and
0.54 g of carbamate 10 (2.2 mmol) dissolved in 1 mL of DMF was added to the
resulting mixture which was stirred at 508C for 12 hr. After evaporation, the
residu was taken into 3 mL of CH2Cl2 and isopropylic ether was added until
precipitation of the sodium salt of the sulfonylsemicarbazide which was
filtered. The resulting powder was dissolved in CH2Cl2 and acidified with
acetic acid until pH 5 followed by addition of aqueous ammonia. The solution
was washed with water and the organic layers were dried, filtered and
evaporated. Recrystallization from acetone furnished the finals sulfonyl-
semicarbazides.
2-[4-[[[(hexahydrocyclopenta[c]pyrrol-2(1H)amino)carbonyl]amino]-
sulfonyl]-3-methoxy phenyl], N-(2-piperidinobenzyl)acetamide (11a).
Yield: 88%; mp ¼ 175–1768C; IR (cm21): 3390, 3340, 3100 (NH), 2950,
2860 (CH), 1700, 1660 (C55O), 1600, 1495 (C55C), 1160, 1330 (SO2N);
1H NMR (CDCl3): d (ppm) 1.52–1.76 (m, 12H), 1.98 (m, 1H), 2.61
(m, 2H), 2.84 (m, 6H), 3.32 (m, 1H), 3.63 (s, 2H), 3.92 (s, 3H), 4.56 (d, 2H,
J ¼ 6.3), 5.42 (m, 1H), 6.92 (d, 1H, J ¼ 8.0), 7.05 (m, 4H), 7.23 (m, 2H),
7.98 (d, 1H, J ¼ 8.0), 9.03 (m, 1H); MS m/e 570.2; Anal. Calcd for
C29H39N5O5S (M ¼ 569.7): C, 61.14; H, 6.9; N, 12.29; Found: C, 61.32; H,
6.84; N, 12.15.
2-[4-[[[(hexahydrocyclopenta[c]pyrrol-2(1H)amino)carbonyl]amino]
-
sulfonyl]-3-methoxy phenyl], N-[1-(2-piperidinophenyl)-2-methylpropyl]-
acetamide (11b). Yield: 78%; mp ¼ 198–2038C; IR (cm21): 3400, 3340,
3120 (NH), 2950, 2860 (CH), 1710, 1660 (C55O), 1600, 1490 (C55C), 1150,
1335 (SO2N); 1H NMR (CDCl3): d (ppm) 0.72 (d, 3H, J ¼ 8.1), 0.98 (d, 3H,
J ¼ 8.1), 1.48–1.72 (m, 13H), 1.99 (m, 1H), 2.53 (m, 4H), 2.84 (m, 4H), 3.31
(m, 1H), 3.55 (s, 2H), 3.85 (s, 3H), 4.82 (t, 1H, J ¼ 6.3), 5.33 (m, 1H), 6.92
(d, 1H, J ¼ 8.0), 7.01 (s, 1H), 6.98 (m, 2H), 7.22 (m, 2H), 7.48 (m, 1H), 7.98

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1048
Lebegue, Bethegnies, and Berthelot
(d, 1H, J ¼ 8.0), 9.03 (m, 1H); MS m/e 612.2; Anal. Calcd for C32H45N5O5S
(M ¼ 611.8): C, 62.82; H, 7.41; N, 11.45; Found: C, 62.78; H, 7.35; N, 11.53.
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Received in Poland July 5, 2003

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