Convenient Synthesis of Novel N -Acylsulfonamides Containing Phosphonate Moiety

Article abstract of DOI:10.1080/10426507.2014.931398

The present study describes a convenient method for the synthesis of new N-acylsulfonamides containing phosphonate moiety. The N-acylsulfonamides were prepared starting from chlorosulfonyl isocyanate (CSI) in four steps (carbamoylation, sulfamoylation, deprotection, and acylation). Trimethylphosphite has been used to introduce the phosphonate moiety into N-acylsulfonamides via Arbuzov reaction. GRAPHICAL ABSTRACT

Full text of DOI:10.1080/10426507.2014.931398

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Phosphorus, Sulfur, and Silicon and the Related
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Convenient Synthesis of Novel N-Acylsulfonamides
Containing Phosphonate Moiety
a
a
a
a
Wahida Boufas , Hadjer Cheloufi , Fouzia Bouchareb , Malika Berredjem & Nour-Eddine
a
Aouf
a
Laboratory of Applied Organic Chemistry, Synthesis of Biomolecules and Molecular
Modelling Group, Badji-Mokhtar. Annaba University, Box 12, 23000 Annaba, Algeria
Accepted author version posted online: 26 Jun 2014.
To cite this article: Wahida Boufas, Hadjer Cheloufi, Fouzia Bouchareb, Malika Berredjem & Nour-Eddine Aouf (2014):
Convenient Synthesis of Novel N-Acylsulfonamides Containing Phosphonate Moiety, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2014.931398
To link to this article: http://dx.doi.org/10.1080/10426507.2014.931398
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ACCEPTED MANUSCRIPT
Convenient Synthesis of Novel N-Acylsulfonamides Containing
Phosphonate Moiety
Wahida Boufas, Hadjer Cheloufi, Fouzia Bouchareb, Malika Berredjem*
and Nour-Eddine Aouf
Laboratory of Applied Organic Chemistry, Synthesis of Biomolecules and Molecular Modelling
Group, Badji-Mokhtar. Annaba University, Box 12, 23000 Annaba, Algeria.
E-mail: malika.berredjem@univ-annaba.org
Shortened title: N-Acylsulfonamides Containing Phosphonate Moiety
Abstract: The present study describes a convenient method for the synthesis of new N-
acylsulfonamides containing phosphonate moiety. The N-acylsulfonamides were prepared
starting from chlorosulfonyl isocyanate (CSI) in four steps (carbamoylation, sulfamoylation,
deprotection and acylation). Trimethylphosphite has been used to introduce the phosphonate
moiety into N-acylsulfonamides via Arbuzov reaction.
O
O
O
P
O
O
O O
P(OMe)3
OMe
OMe
R
S
Cl
R
S
N
N
N
N
H
H
H
H
Keywords: Sulfonamide; N-acylsulfonamide; phosphonate; Arbuzov reaction
1
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INTRODUCTION
N-acylsulfonamides derivatives are well known pharmaceutical agents since this group has been
the main functional part of most of the drug structures due to stability and tolerance in human
beings. These molecules have gained much attention due to their diverse biological activities in
1
2
pharmaceutical as antibacterial inhibitors of tRNA synthetases , antagonists for Angiotensin II
3
and Leukotriene D
4
-receptors . New N-acylsulfonamides were described such as 1 (Figure 1);
4
these compounds are the prodrugs of celecoxib non-steroidal anti-inflammatory and selective
COX-2 inhibitor used in the treatment of osteoarthritis and rheumatoid arthritis. Compound 2
5
(
Figure 1), which is a prodrug of valdecoxib that is marketed for the hospital treatment of
postoperative pain, also exemplifies this principle.
On the other hand, phosphonates have a variety of biological activities and may act as antibiotics
6
-7
and antiviral agents as well as insecticides and herbicides . The phosphonate functionality has
been incorporated into a range of clinically useful drugs. In addition, acyclic nucleoside
8
phosphonates have shown potential as therapeutics for pathogenic species . For example,
Tenofovir disoproxil fumarate (PMPA) is an approved agent for the treatment of HIV in humans,
9
and has shown efficacy in the treatment of hepatitis B (HBV) . The phosphonate moiety is also
found in HIV protease inhibitors showing an enhanced resistance profile compared to that of the
1
0
non-phosphonylated parent compounds . Phosphonate containing protease inhibitors also have
1
1
shown great potential for the treatment of Hepatitis C virus . Alafosfalin – an antibiotic with a
broad spectrum of activity – has been developed and demonstrates the ability to inhibit cell wall
2
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1
2
biosynthesis . It has proved to be potentially useful in the treatment of gastroenteritis and
1
3
bacterial urinary tract infections .
Introduction of phosphonate esters into a molecule intended as a possible drug candidate
enhances the water solubility, which changes its bioavailability. Such organophosphorus
1
4
15
16
compounds have found practical application in medicine , agriculture , industry , and organic
1
7
synthesis . In the literature novel phosphonates containing sulfonamide moiety have been
described and have interesting biological properties. New phosphonosulfonamides were
1
8
described such as compound 3, which is used in the treatment of HIV protease , and compound
1
9
4
, which was discovered to be potent inhibitor of protein tyrosine phosphatase 1B (Figure 2).
20-21
Several methods have been utilized by our group
for the synthesis of phosphonate esters 5 - 7
(
Figure 3), most notably the Michaelis-Arbuzov reaction.
Here we describe the synthesis of a new series of modified N-acylsulfonamides containing
phosphonate moiety starting from chlorosulfonyl isocyanate, primary amines and
trimethylphosphite.
RESULTS AND DISCUSSION
There are several approaches towards the synthesis of phosphonates, which focus on the
formation of the crucial C-P bond. Of these methods, the Abramov, Pudovik, Michaelis-Becker,
and Michaelis-Arbuzov (commonly called the “Arbuzov Reaction”) are the most well studied
3
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2
2
and documented . A search of the literature shows that the Arbuzov reaction is commonly used
2
3
to form phosphonates, and in fact is the most common method of phosphorylation employed .
The general method, which is employed to prepare the final compounds, is outlined in Scheme 1.
The N-acylsulfonamides presented here were obtained in four steps by a simple and efficient
methodology described below.
2
4
The sulfonamides (8a-f) were prepared by reaction of tert-butanol and chlorosulfonyl
isocyanate in anhydrous methylene chloride at 0 °C. After 30 min the N-chlorosulfonyl
carbamate and triethylamine were added to a solution of the primary amine in the same solvent.
After completion of the reaction, the mixture was washed with 0.1 N HCl and then with water.
The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to give
sulfonamides 8a-f as white powders in excellent yields. The deprotection reaction
of sulfonamides 8a-f was carried out in distilled water at 100 °C for 30-60 min to give
sulfonamides 9a-f in quantitative yields. Preparation of the N-acylsulfonamides 10a-f includes
the reaction of sulfonamides 9a-f with chloroacetyl chloride in toluene in the presence of a Lewis
acid catalyst at 110 °C for 3 h.
Phosphorylation of N-acylsulfonamides 10a-f was easily achieved by Arbuzov reaction in the
presence of a large excess of trimethylphosphite under reflux conditions.
In this study we obtained some new N-acylsulfonamides containing phosphonate moiety in good
to moderate yield. The structures of the synthesized compounds are confirmed by elemental
1
13
31
analysis as well as by IR and H, C and P NMR spectral data.
4
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CONCLUSION
In conclusion, a series of N-(aryl or alkyl)-(1-(2-dimethoxyphosphoryl) acetamide) sulfamides
4
a-f was synthesized with satisfactory yields. This synthesis has been performed easily starting
from the corresponding N-(aryl or alkyl) sulfamoyl-2-chloroacetamides 3a-f and trimethyl
phosphite using Michaelis-Arbuzov reaction.
EXPERIMENTAL PART
1
13
31
H, C and P NMR spectra were obtained with a Bruker AC 250 spectrometer in CDCl
3
as
PO
P) as external standard. All coupling constants (J) are reported in Hertz. Multiplicity is
1
13
solvent. Chemical shifts are refered to TMS ( H, C) as internal standard and to 85 % H
3
4
3
1
(
indicated as s (singlet), d (doublet), t (triplet), m (multiplet) and combination of these signals. IR
spectra were recorded in potassium bromide pellets with a Perkin-Elmer FT-600 spectrometer.
Melting points were measured in open capillary tubes on an Electro thermal apparatus and are
uncorrected. Elemental analyses were performed with a Perkin-Elmer 2400 C, H, N analyzer and
the determined values were within the acceptable limits of the calculated values. All reactions
were monitored by TLC on silica Merck h60 F254 (Art. 5554) precoated aluminum plates and
were developed by spraying with ninhydrin solution.
Preparation of N-acylsulfonamides 10a-f
In a three-neck round bottomed flask equipped with a magnetic stirring bar and reflux condenser,
sulfonamide (9a-f) (2 mmol) was dissolved in toluene (10 mL). Chloroacetyl chloride (0.41 g,
5
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0
.29 mL, 2 equiv., 4 mmol) and Lewis acid catalyst (0.4 g, 1.5 equiv., 3 mmol) were added
dropwise with stirring. The reaction mixture was kept at a temperature of 50 °C for 30 min and
then heated to reflux for 3 h. After completing the reaction the reaction mixture was cooled down
to room temperature. The excess of chloroacetyl chloride was washed with water and the organic
layer was separated. The solvent was removed under reduced pressure. The precipitated white
product was filtered and recrystallized from diethyl ether.
N-(Phenyl)-sulfamoyl-2-chloroacetamide (10a)
1
White solid; yield: 60 %; mp: 174-175 °C. R
f
= 0.7 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ
=
8.05 (s, 1H, NH-CO), 7.63-7.25 (m, 5H, arom-H), 4.25 (s, 2H, CH
2
-Cl); 4.00 (s, 1H, NH-Ar).
1
3
C NMR (CDCl
arom-C), 41.4 (CH
SO ). Anal. Calcd for C
.95; N, 11.35 %.
3
): δ = 160.1 (C=O), 136.6 (arom-C), 129.8 (arom-C), 125.9 (arom-C), 120.9
-1
(
(
2
-CO). IR (KBr): ν = 3350 (NH), 1725 (C=O), 1658 (C=C), 1365, 1159 cm
2
8
H
9
N
2
O
3
SCl (248): C, 38.64; H, 3.65; N, 11.26. Found: C, 38.75; H,
3
N-(3-Fluorophenyl)-sulfamoyl-2-chloroacetamide (10b)
White solid, yield: 55 %, mp: 184-185 °C. R = 0.75 (CH
δ = 8.20 (s, 1H, NH-CO), 6.91-7.23 (m, 4H, arom-H), 4.30 (s, 2H, CH2-Cl), 3.90 (s, 1H, NH-Ar).
1
f
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl ):
3
1
3
C NMR (CDCl
3
): δ = 166.7 (C=O), 163.0 (arom-C), 139.0 (arom-C), 129.6 (arom-C), 115.0
-CO). IR (KBr): ν = 3368 (NH), 1720.4
). Anal. Calcd for C SClF (266): C, 36.03; H,
.02; N, 13.29. Found: C, 36.19; H, 3.15; N, 13.05 %.
(
(
arom-C), 110.5 (arom-C), 105.0 (arom-C), 41.9 (CH
2
-1
C=O), 1658 (C=C), 1365, 1159 cm (SO
2
8
H
8
N
2
O
3
3
6
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N-(1-Phenylethyl)-sulfamoyl-2-chloroacetamide (10c)
1
White solid, yield: 65 %, mp: 175-176 °C, R
f
= 0.7 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ
=
8.69 (s, 1H, NH-CO), 7.50 (m, 5H, arom-H), 5.93 (d, J = 6.9 Hz, 1H, NH-CH), 4.67 (m, 1H,
1
3
CH), 3.92 (m, 2H, CH2-Cl), 1.57 (d, J = 6.9 Hz, 3H, CH
3
). C NMR (CDCl
3
): δ = 165.5 (C=O),
1
1
45.7 (arom-C), 125.1 (arom-C), 126.9 (arom-C), 126.5 (arom-C), 45.3, CH), 41.2 (CH
2
-CO),
). Anal.
SCl (276): C, 43.40; H, 4.73; N, 10.12. Found: C, 43.52.; H, 4.89; N, 10.20
-1
9.0 (CH
3
). IR (KBr): ν = 3260 (NH), 1710 (C=O), 1642 (C=C), 1360, 1153 cm (SO
2
Calcd for C10
H
13
N
2
O
3
%
.
N-(4-Methoxyphenyl)-sulfamoyl-2-chloroacetamide (10d)
White solid, yield: 60 %, mp: 184-185 °C, R = 0.8 (CH Cl
8.22 (s, 1H, NH-CO), 6.90-7.21 (m, 4H, arom-H), 4.28 (s, 2H, CH2-Cl), 4.00 (s, 1H, NH-Ar),
1
f
2
2
/ MeOH: 9 / 1). H NMR (CDCl ): δ
3
=
1
3
3
.91 (s, 3H, OCH
3
). C NMR (CDCl
3
): δ = 135.9, 129.7, 125.3, 150.7, 162.5 (C=O), 150.1 (C-
-Ar), 42.1 (CH -CO). IR (KBr): δ =
368 (NH), 1720.4 (C=O), 1658 (C=C), 1365, 1159 cm (SO ). Anal. Calcd for C SCl
277): C, 38.78; H, 3.98; N, 10.05. Found: C, 38.65; H, 4.05; N, 10.15 %.
Ar), 130.2 (C-Ar), 125.3 (C-Ar), 115.3 (C-Ar), 55.0 (OCH
3
2
-1
3
2
9
H
10
N
2
O
4
(
N-(Cyclohexyl)-sulfamoyl-2-chloroacetamide (10e)
White solid, yield: 87 %, mp: 178-179 °C, R = 0.7 (CH
1
f
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ
=
8.60 (s, 1H, NH-CO), 4.95 (d, J = 6.2 Hz, 1H, NH-cHex), 4.10 (s, 2H, CH
2
-Cl), 3,25 (m, 1H,
CH-NH), 1.85 (m, 2H, CH
2
of cHex), 1.55 (m, 2H, CH
2
of c-Hex), 1.35 (m, 2H, CH
2
of c-Hex),
7
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1
3
1
.27 (m, 4H, CH
CH -CO), 33.5 (CH
NH), 1700 (C=O), 1368, 1150 (SO
2
of c-Hex). C NMR (CDCl
of c-Hex), 25.9 (CH of c-Hex), 24.0 (CH
). Anal. Calcd for C
3
): δ = 159.2 (C=O), 43.8 (CH of c-Hex), 42.9
(
(
2
2
2
2
of c-Hex). IR (KBr): ν = 3269
2
8
H
15
N
2
O
3
SCl (254): C, 37.72; H, 5.94;
N, 11.00. Found: C, 37.65; H, 6.05; N, 11.15 %.
N-(Benzyl)-sulfamoyl-2-chloroacetamide (10f)
1
White solid, yield: 60 %, mp: 184-185 °C, R
f
= 0.65 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
):
-Cl),
): δ = 160.8 (C=O), 141.6 (arom-C), 128.5
arom-C), 126.9 (arom-C), 126.6 (arom-C), 43.7 (CH -NH), 41.4 (CH -CO). IR (KBr): ν = 3350
NH), 1725 (C=O), 1658 (C=C), 1365, 1159 cm (SO ). Anal. Calcd for C SCl (262):
δ = 8.10 (s, 1H, NH-CO), 7.65 (s, 1H, NH-Ar), 7.35-7.25 (m, 5H, arom-H), 4.25 (s, 2H, CH
2
1
3
3
.45 (d, J = 4.2 Hz, 2H, CH
2
-Ar). C NMR (CDCl
3
(
(
2
2
-1
2
9
H
11
N
2
O
3
C, 41.15; H, 4.22; N, 10.66. Found: C, 41.05; H, 4.35; N, 10.75 %.
General Procedure for the Arbuzov Reaction
The trimethylphosphite (5 equiv., 4.96 mmol) and the corresponding compound 10 (1.1 equiv.,
.96 mmol) were heated at 110 °C under argon and the resulting solution was heated to reflux for
4
additional 5 h. The undesired products were removed by distillation. The residue was then
purified by column chromatography on silica gel to give the corresponding compound 11 in good
yield.
8
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N-Phenyl-(1-(2-dimethoxyphosphoryl)-acetamide)-sulfamide (11a)
1
Yellow oil, yield: 65 %, R
f
= 0.4 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ = 9.32 (s, 1H,
), 3.01 (d, J =
): δ = 170.1 (C=O), 139.2 (arom-C), 129.6 (arom-C),
NH-CO), 7.12-7.50 (m, 4H, arom-H), 6.90 (m, 1H, arom-H), 3.82 (s, 6H, OCH
3
1
3
2
1
0.0 Hz, 2H, CH
2
-PO). C NMR (CDCl
3
3
1
25.3 (arom-C), 120.9 (arom-C), 52.0 (OCH
3
), 42.1 (CH
2
-PO). P NMR (CDCl ): δ = 27.3. IR
3
-1
(
KBr): ν = 3350 (NH), 1725 (C=O), 1658 (C=C), 1365, 1159 (SO
2
), 1251 cm (P=O). Anal.
Calcd for C10 SP (322): C, 37.26; H, 4.96; N, 8.69. Found: C, 37.35; H, 4.85; N, 8.75 %.
H
15
N
2
O
6
N-3-Fluorophenyl-(1-(2-dimethoxyphosphoryl)-acetamide)-sulfamide (11b)
1
Yellow oil, yield: 60 %, R
f
= 0.45 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ = 9.05 (s, 1H,
NH-CO), 7.65 (m, 1H, arom-H), 7.35 (m, 2H, arom-H), 6.90 (m, 1H, arom-H), 3.92 (s, 6H,
1
3
OCH
3
), 2.95 (d, J = 20.1 Hz, 2H, CH
2
-PO). C NMR (CDCl
3
): δ = 170.0 (C=O), 163.0 (arom-
C), 139.0 (arom-C), 129.6 (arom-C), 115.0 (arom-C), 110.5 (arom-C), 105.0 (arom-C), 52.7
3
1
(
OCH
3
), 42.0 (CH
658 (C=C), 1365, 1159 (SO
5.30; H, 4.15; N, 8.26. Found: C, 35.45; H, 4.05; N, 8.35 %.
2
-PO). P NMR (CDCl ): δ = 28.3. IR (KBr): ν = 3368 (NH), 1720.4 (C=O),
3
-
1
1
3
2
), 1245 cm (P=O). Anal. Calcd for C10
H
14
N
2
6
O SPF (340): C,
N-1-Phenylethyl-(1-(2-dimethoxyphosphoryl)-acetamide)-sulfamide (11c)
1
Yellow oil, yield: 70 %, R
f
= 0.42 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ = 8.62 (s, 1H,
NH-CO), 7.50 (m, 5H, arom-H), 5.55 (d, J = 6.2 Hz, 1H, NH-CH), 4.35 (m, 1H, CH), 3.80 (s,
1
3
6
H, OCH
3
), 2.92 (d, J = 19.1 Hz, 2H, CH
2
-PO), 1.28 (d, J = 6.9 Hz, 3H, CH ). C NMR
3
(
CDCl
3
): δ = 170.0 (C=O), 143.0 (arom-C), 128.1 (arom-C), 126.9 (arom-C), 126.5 (arom-C),
9
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3
1
5
3
2.7 (OCH
260 (NH), 1710 (C=O), 1642 (C=C), 1360, 1153 (SO
SP (350): C, 41.14; H, 4.15; N, 8.00. Found: C, 41.25; H, 4.19; N, 8.05 %.
3
), 46.0 (CH), 42.2 (CH
2
-PO), 19.0 (CH
3
). P NMR (CDCl ): δ = 27.9. IR (KBr): ν =
3
-
1
2
), 1250 cm (P=O). Anal. Calcd for
C
12
H
19
N
2
O
6
N-4-Methoxyphenyl-(1-(2-dimethoxyphosphoryl)-acetamide)-sulfamide (11d)
1
Yellow oil, yield: 75 %, R
NH-CO), 6.90-7.35 (m, 4H, arom-H), 3.90 (s, 9H, OCH
NMR (CDCl
C), 56.0 (OCH
368 (NH), 1720 (C=O), 1658 (C=C), 1365, 1159 (SO
SP (352): C, 37.50; H, 4.86; N, 7.95. Found: C, 37.55; H, 4.98; N, 7.85 %.
f
= 0.48 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ = 8.82 (s, 1H,
1
3
3
), 3.05 (d, J = 20 Hz, 2H, CH -PO). C
2
3
): δ = 170.5 (C=O), 153.0 (arom-C), 130.0 (arom-C), 125.0 (arom-C), 115.3 (arom-
3
1
3
-Ar), 52.3 (OCH
3
), 42.8 (CH
2
-PO). P NMR (CDCl ): δ = 28.1. IR (KBr): ν =
3
-1
3
2
), 1248 cm (P=O). Anal. Calcd for
C
11
H
17
N
2
O
7
N-Cyclohexyl-(1-(2-dimethoxyphosphoryl)-acetamide)-sulfamide (11e)
1
Yellow oil, yield: 70 %, R
NH-CO), 3.91 (s, 6H, OCH
H, CH of c-Hex), 1,55 (m, 2H, CH
of c-Hex). C NMR (CDCl
PO), 32.0 (CH of c-Hex), 25.0 (CH
9.8. IR (KBr): ν = 3269 (NH), 1700 (C=O), 1368, 1150 (SO
SP (328): C, 36.58; H, 3.45; N, 8.53. Found: C, 36.65; H, 3.25; N, 8.85 %.
f
= 0.50 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ = 8.65 (s, 1H,
3
), 3.66 (m, 1H, CH-NH), 2.80 (d, J = 10.1, 2H, CH
of c-Hex), 1,35 (m, 2H, CH of c-Hex), 1,28 (m, 4H, CH
): δ = 171.0 (C=O), 53.0 (OCH ), 43.0 (CH of c-Hex), 42.1 (CH
of c-Hex), 24.0 (CH
2
-PO), 1.85 (m,
2
2
2
2
2
1
3
3
3
2
-
3
1
2
2
2
of c-Hex). P NMR (CDCl
3
): δ =
-1
2
2
), 1245 cm (P=O). Anal. Calcd
for C10
H
21
N
2
O
6
1
0
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N-Benzyl-(1-(2-dimethoxyphosphoryl)-acetamide)-sulfamide (11f)
1
Yellow oil, yield: 65 %. R
f
= 0.42 (CH
2
Cl
2
/ MeOH: 9 / 1). H NMR (CDCl
3
): δ = 8.82 (s, 1H,
-Ar), 3.09 (d, J
): δ = 171.0 (C=O), 141.2 (arom-C), 128.6 (arom-C),
NH-CO), 7.25 (m, 5H, arom-H), 3.82 (s, 6H, OCH
3
), 3.75 (d, J = 4.2 Hz, 2H, CH
2
1
3
=
19.5 Hz, 2H, CH
26.9 (arom-C), 126.6 (arom-C), 52.2 (OCH
CDCl ): δ = 27.9. IR (KBr): ν = 3350 (NH), 1725 (C=O), 1658 (C=C), 1365, 1159 (SO
2
-PO). C NMR (CDCl
3
3
1
1
3
), 43.2 (CH
2
-NH), 41.2 (CH
2
-PO). P NMR
), 1249
SP (356): C, 41.25; H, 5.35; N, 8.75. Found: C, 41.35;
(
3
2
-1
cm (P=O). Anal. Calcd for C11
H
17
N
2
O
6
H, 5.25; N, 8.85 %.
FUNDING
This work was generously supported by the Direction Générale de la Recherche Scientifique et
du Développement Technologique, DGRS-DT, Algerian Ministry of Scientific Research.
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Me
O
O
O O
S
O O
S
R
N
Et
N
H
Na
N
N
N
O
1
2
Me
CF3
Figure 1 Some drugs with N-acylsulfonamide functionality
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R3
iPr
OH
H
O
N
N
S
O
O
R1
S
O
O
O
N
O
P
O
OH
OH
O
OR1
OR2
O
P
F
F
O
R2
3
4
Figure 2 Examples of phosphonates containing sulfonamide group
O
P
O
P
H
H
H
EtO
EtO
OEt
OEt
EtO
EtO
N
CO Me
N
N
2
P
(CH )
S
2 n
(CH )
2 n
O
O
R
O O
5
6
(
CH2)n
O
P
OEt
OEt
HN
N
S
(CH2)n
O
O
7
Figure 3 Examples of phosphonate esters
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7
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O
O
O
O O
tBuOH
S
R
O
S
tBu
Cl
NCO
RNH2, TEA
CH Cl , 0°C
N
N
O
H
H
2
2
8a-f
O
O
O
O
O
Cl
H O
Cl
AlCl3, toluene
2
R
S
R
S
Cl
8a-f
N
NH2
N
H
N
H
1
5-30 min
reflux
H
9a-f
10a-f
P(OMe)3
1
10 °C
O
O
P
O
O
OMe
OMe
R
S
R = Ph, CHMePh, 3-F-C H ,
N
N
6
4
H
H
4
-MeO-C H , cHex, CH Ph
6 4 2
11a-f
Scheme 1 Synthesis of N-acylsulfonamides containing phosphonate moiety
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