Efficient synthesis of arylsulfamides by reaction of amines with arylsulfamoyl imidazolium triflate

Article abstract of DOI:10.1016/j.tetlet.2005.08.092

Arylsulfamoyl imidazolium triflates, readily prepared from the corresponding chlorides, react with amines under neutral conditions to form arylsulfamides in high yields. This methodology, which contrasts with the slow and inefficient reactions of amines with arylsulfamoyl chlorides, is applied to the synthesis of arylsulfamide 3a, a bioisotere of muraglitazar.

Full text of DOI:10.1016/j.tetlet.2005.08.092

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 7139–7142
Efficient synthesis of arylsulfamides by reaction of amines with
arylsulfamoyl imidazolium triflate
Hyeon Kyu Lee,* Miyeon Bang and Chwang Siek Pak
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusung,
Taejon 305-606, Republic of Korea
Received 5 June 2005; revised 12 August 2005; accepted 19 August 2005
Available online 6 September 2005
Abstract—Arylsulfamoyl imidazolium triflates, readily prepared from the corresponding chlorides, react with amines under neutral
conditions to form arylsulfamides in high yields. This methodology, which contrasts with the slow and inefficient reactions of amines
with arylsulfamoyl chlorides, is applied to the synthesis of arylsulfamide 3a, a bioisotere of muraglitazar.
Ó 2005 Elsevier Ltd. All rights reserved.
The peroxisome proliferate-activated receptors (PPARs)
are membersof the nuclear receptor usperfamily that
play key rolesin the regulation of lipid metabolims
and storage.1 The three mammalian PPARs(PPAR a,
PPARc, and PPARd), identified thusfar, are important
molecular targetsfor the development of drugsfor the
treatment of human metabolic diseases, inflammation,
and cancer.1,2 A number of PPAR agonists (a-, c-,
and dual-a/c selective) have been identified for clinical
development.3–6 Two thiazolidinediones, rosiglitazone7
and pioglitazone,8 represent a novel class of insulin-sen-
sitizing PPARc agonists and are used clinically as anti-
diabetic drugs. Members of the fibrate drug class, such
asfenofibrate and bezafibrate, which lower triglycerides
and elevate HDL levels, are weak PPARa agonists and
are used for the treatment of dyslipidemia.1 Recently,
muraglitazar/BMS-298585 (Fig. 1), a novel non-thiazo-
lidinedione PPAR dual-a/c agonist with efficacious
glucose and lipid-lowering activities is in clinical
development for the treatment of type 2 diabetesand
dislipidemia.9
Aspart of recent studiestargeted at the development of
potent PPAR ligands, we identified arylsulfamide 3a, a
bioisotere of muraglitazar, as potential PPAR agonist.
In designing a synthesis of this substance, we recognized
that the preparation of alkylsulfamides is generally per-
formed by reacting the corresponding alkylsulfamoyl
chlorides with amines in the presence of base, the typical
Schotten-Bauman process.10 Following thisprotocol,
we attempted to prepare arylsulfamide 3a by reacting
amino ester 1a9 with arylsulfamoyl chloride 2a11 in the
presence of HunigÕsbase ( Scheme 1). However, the yield
of this process was disappointingly low (less than 10%).
Attemptsto improve the efficiency of thisreaction by
varying the base and solvent were unsuccessful. We be-
lieve that the low yield isdue in part to a side reaction
promoted by base or liberated chloride nucleophile. To
O
O
N
S
O
CO2H
CH3
N
CO2H
O
N
N
O
N
O
O
O
Muraglitazar
Sulfamide Bioisotere
Cl
OCH3
Figure 1. Muraglitazar and its sulfamide bioisotere.
Keywords: Arylsulfamide; Arylsulfamoyl chloride; Arylsulfamoyl imidazolium triflate; PPAR agonist.
*
Corresponding author. Tel.: +82 42 860 7016; fax: +82 42 861 0307; e-mail: leehk@krict.re.kr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.092

7140
H. K. Lee et al. / Tetrahedron Letters 46 (2005) 7139–7142
CH3
O
N
S
O
CO2Et
CH3
N
Cl
O
N
H
CO2Et
(i-Pr)2NEt
O
Ph
S
Ph
N
+
O
O
O
N
N
O
Cl
<10%
2a
1a
3a
Cl
Scheme 1.
O
O
O
N
O
N
S
O
CO2Et
S
N
H
CO2Et
S
O
N
Cl
Et3N
CH3CN
N
N
O
N
N
+
Ph
O
Ph
+
O
O
1b
2b
4b (8%)
5 (70%)
Scheme 2.
probe this issue further, reaction of arylsulfamoyl chlo-
ride 2b with amine 1b wascarried out ( Scheme 2). This
process produced a small amount of desired sulfamide
4b (8%) and the undesired symmetrical sulfamide 5 as
a major (70%) product.
$55 USD, Aldrich) and, asa result, it isnot applicable
to large scale syntheses. In addition, there are no
reported examplesof the preparation or reactionsof
arylsulfamoyl imidazolium triflates.
Consequently, studies to develop new methods to pre-
pare arylsulfamoyl imidazolium triflates were initiated.
We quickly found that arylsulfamoyl 2-methylimidazole
6a iseaisly prepared from the correpsonding, readily
available arylsulfamoyl chloride 2a by reaction with 2-
methylimidazole in acetonitrile (Scheme 3). Subsequent
methylation of the imidazole nitrogen of 6a with MeOTf
produced arylsulfamoyl imidazolium triflate 7a.14
Importantly, reaction of triflate 7a with amino ester 1a
proceeded to cleanly afford the desired arylsulfamide
3a in high yield (79%) (Scheme 4).15 Thisresult demon-
strates that a change of the sulfamoylating agent from
the arylsulfamoyl chloride 2a to the more reactive aryl-
sulfamoyl imidazolium triflate 7a greatly enhancesreac-
tivity toward the amine 1a.
The need for arylsulfamide 3a in our PPAR agonist
studies stimulated a search for an efficient procedure
for its preparation. Our observations suggested that it
would be advantageousto have a sulfamoylating agent
that does not possess a nucleophilic leaving group and
that reactswith aminesunder mild conditionsin the
absence of added base. A survey of the literature
revealed that arylsulfonyl imidazolium triflates are supe-
rior sulfamoylating agents as compared to arylsulfonyl
chlorides.12 A recent report, describing the synthesis of
alkylsulfamides, utilized highly reactive alkylsulfamoyl
0
imidazolium triflatesthat are prepared from 1,1 -sul-
fonyldiimidazole.13 Unfortunately, 1,10-sulfonyldiimi-
dazole is a very expensive starting material (1 g = ca.
Cl
Cl
CH3
N
Cl
CH3
N
CH3
N
O
N
O
O
N
O
O
N
O
TfO
CH3
MeOTf
99%
S
S
S
HN
HN
+
+
N
N
Cl
96%
90%
CH3
CH3
CH3
2a
6a
7a
CH3
N
CH3
N
CH3
O
N
O
O
O
O
S
N
O
TfO
CH3
MeOTf
99%
S
S
N
N
N
Cl
N
7b
6b
2b
Scheme 3.
O
Cl
N
S
O
CO2Et
CH3
CH3
N
CH3CN
reflux
O
O
N
O
O
Ph
N
H
CO2Et
TfO
CH3
S
N
+
O
N
Ph
N
N
O
CH3
3a
79%
1a
7a
Cl
Scheme 4.

H. K. Lee et al. / Tetrahedron Letters 46 (2005) 7139–7142
7141
In order to test the generality of the new methodology,
we studied reactions of arylsulfamoyl imidazolium
yields( Table 1). Tetrahydroquinolinesulfonyl imdazo-
lium triflate 7b wasalos prepared from the corre-s
ponding sulfamoyl chloride 2b by using the same reac-
tion conditionsemployed to form 7a. Reactionsof
triflate 7a with various amines. In nearly all cases, reac-
15
tionstook place to generate aryluslfamides
in high
Table 1. Syntheses of arylsulfamides by reactions of arylsulfamoyl imidazolium triflates with amines
CH
N
O
O
3
N
S
O
CO Et
2
N
S
O
CO Et
2
R
S
X
TfO
X
1
N
H
CO Et
O
CH CN
3
O
2
CH
3
N
R
N
X
or
CH
N
+
N
3
reflux
2
4b~e
3a~e
1a~e
7a,b
Cl
Entry
1
Amine
Sulfamoylating agent
Yielda of sulfamide (%)
O
Cl
1a
1a
N
CO2Et
CO2Et
3a (7)
O
N
O
H
S
N
O
Cl 2a
CH3
Cl
CH3
N
O
O
O
N
H
TfO
2
S
N
3a (79)
N
CH3
7a
N
O
CH3
1b
1c
N
H
CO2Et
N
3
4
7a
7a
3b (84)
3c (72)
O
O
O
H
N
CO2Et
N
O
N
H
CO2Et
1d
5
6
7a
7a
3d (72)
3e (76)
O
O
F3C
F3C
H
N
CO2Et 1e
O
N
O
1b
N
H
CO2Et
S
S
Cl 2b
N
7
4b (8)
O
O
CH3
N
O
N
O
TfO
CH3
N
H
CO2Et 1b
N
N
7b
8
9
4b (95)
4c (70)
O
O
O
H
N
CO2Et
1c
N
7b
O
1d
N
H
CO2Et
10
11
7b
7b
4d (79)
4e (75)
O
O
F3C
F3C
H
N
1e
CO2Et
a Isolated and purified yields with silica gel chromatography.

7142
H. K. Lee et al. / Tetrahedron Letters 46 (2005) 7139–7142
10. Reguerio-Ren, A.; Borzilleri, R. M.; Zheng, X.; Soong-
Hoon, K.; Johnson, J. A.; Fairchild, C. R.; Lee, F. Y. F.;
Long, B. H.; Vite, G. D. Org. Lett. 2001, 3, 2693.
11. (a) Kloeck, J. A.; Leschinsky, K. L. J. Org. Chem. 1976,
41, 4028; (b) Jager, U.; Sundermeyer, W.; Pritzkow, H.
Chem. Ber. 1987, 120, 1191; (c) Ducry, L.; Reinelt, S.;
Seiler, P.; Dietrich, F. Helv. Chim. Acta 1999, 82, 2432.
12. OÕConnell, J. F.; Rapoport, H. J. Org. Chem. 1992, 57,
4775.
7b with amines also provided sulfamides in high
yields.
In summary, the above studies have shown that aryl-
sulfamoyl imidazolium triflates can be readily prepared
from the corresponding chlorides and that they display
high reactivity with amines, in processes carried out
under neutral conditionsthat efficiently generate aryl-
sulfamide. Finally, this methodology was successfully
applied to the synthesis of arylsulfamide 3a, a potential
bioisotere of muraglitazar.
13. Beaudoin, S.; Kinsey, K. E.; Burns, J. F. J. Org. Chem.
2003, 68, 115.
14. (a) N-Methyl-N-(4-chlorophenyl)sulfamoyl-2-methylimid-
azole (6a): To a solution of 2-methylimidazole (5.5 g,
66 mmol) in CH3CN (50 mL) at 0 °C wasslowly added a
solution of N-methyl-N-(4-chlorophenyl)sulfamoyl chlo-
ride (2a) (7.2 g, 30 mmol) in CH3CN (15 mL). The mixture
waswarmed to room temperature and tsirred overnight,
and concentrated in vacuo. The residue was subjected to
silica gel chromatography (Hex–EA = 1:1) affording pure
Acknowledgements
We thank the Ministry of Science and Technology of
Korea and the Center for Biological Modulatorsfor
financial support.
1
6a as a white crystalline solid, 8.2 g (96%). Mp: 82 °C. H
NMR (500 MHz, CDCl3): d 2.15 (s, 3H), 3.33 (s, 3H), 6.91
(s, 1H), 7.03 (d, 2H, J = 6.60 Hz), 7.14 (s, 1H), 7.36 (d,
2H, J = 6.60 Hz). 13C NMR (125 MHz, CDCl3): d 15.13,
39.74, 119.63, 127.65, 128.40, 129.87, 134.99, 146.45.
(b) N-Methyl-N-(4-chlorophenyl)sulfamoyl-2,3-dimethyl-
imidazolium triflate (7a): To a solution of 6a (1.46 g,
5.1 mmol) in CH2Cl2 (20 mL) at 0 °C wasadded 0.61 mL
(5.36 mmol) of methyl triflate. After being stirred for 2 h
at 0 °C, the reaction mixture wasconcentrated in vacuo to
give 7a (2.29 g, 99%) asa white solid. 1H NMR (500 MHz,
CDCl3): d 2.70 (s, 3H), 3.55 (s, 3H), 3.96 (s, 3H), 7.19 (s,
1H), 7.30 (s, 1H), 7.43 (d, 2H, J = 6.70 Hz), 7.54 (d, 2H,
J = 6.70 Hz). 13C NMR (125 MHz, CDCl3): d 11.94,
36.59, 40.44, 120.68, 122.84, 129.14, 130.27, 136.00,
136.67, 146.50.
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15. Typical procedure for arylsulfamide from arylsulfamoyl
imidazolium triflate and amine: A solution of arylsulfa-
moyl imidazolium triflate 7a (4.95 g, 11 mmol) and amine
1b (3.80 g, 10 mmol) in CH3CN (40 mL) wastsirred
overnight at reflux. The mixture wasconcentrated in
vacuo giving a residue, which was subjected to silica gel
chromatography (Hex/EA = 4:1) affording sulfamide 3b
(4.91 g, 84%) asa white oslid.
1H NMR (500 MHz,
CDCl3): d 1.24 (t, 3H, J = 7.15 Hz), 2.44 (s, 3H), 3.27 (s,
3H), 3.81 (s, 2H), 4.16 (q, 2H, J = 7.15 Hz), 4.42 (s, 2H),
4.98 (s, 2H), 6.95–8.03 (m, 13H). 13C NMR (125 MHz,
CDCl3): d 10.54, 14.15, 38.82, 47.38, 52.00, 61.32, 62.30,
115.05, 126.14, 127.14, 127.34, 127.42, 128.02, 128.72,
129.19, 130.10, 130.15, 132.78, 136.64, 141.23, 147.15,
158.06, 160.06, 169.50. MS m/z 583 (M+, 3), 379 (6), 172
1
(100). Sulfamide 3c: H NMR (500 MHz, CDCl3): d 1.24
(t, 3H, J = 7.15 Hz), 2.24 (s, 3H), 3.28 (s, 3H), 3.85 (s, 2H),
4.16 (q, 2H, J = 7.15 Hz), 4.47 (s, 2H), 4.96 (s, 2H), 6.85–
8.02 (m, 13H). 13C NMR (125 MHz, CDCl3): d 10.53,
14.14, 38.83, 47.60, 52.55, 61.34, 62.21, 114.73, 114.89,
121.31, 126.16, 127.47, 128.00, 128.70.