Solid-phase synthesis of sulfamides

Article abstract of DOI:10.1016/S0040-4039(01)02327-9

A straightforward synthesis of diversely substituted sulfamides is described. The reaction of sulfamoylating agent 1 with solid-phase bound amines to give polymer bound BOC substituted sulfamides is described. Further N-alkylation is achieved under Mitsunobu conditions. Simultaneous deprotection and cleavage of the products leads to unsymmetrically substituted sulfamides.

Full text of DOI:10.1016/S0040-4039(01)02327-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1019–1021
Solid-phase synthesis of sulfamides
Cristina Esteve and Bernat Vidal*
Research Center, Almirall Prodesfarma, Cardener 68-74, E-08024 Barcelona, Spain
Received 29 November 2001; revised 5 December 2001; accepted 6 December 2001
Abstract—A straightforward synthesis of diversely substituted sulfamides is described. The reaction of sulfamoylating agent 1 with
solid-phase bound amines to give polymer bound BOC substituted sulfamides is described. Further N-alkylation is achieved under
Mitsunobu conditions. Simultaneous deprotection and cleavage of the products leads to unsymmetrically substituted sulfamides.
© 2002 Elsevier Science Ltd. All rights reserved.
In the area of combinatorial chemistry and solid-phase
synthesis there is a constant need for new methodolo-
gies. As part of our effort to develop synthetic strate-
gies for the preparation of diverse libraries for high
throughput screening, we became interested in the syn-
thesis of diversely substituted sulfamides.
Recently, Winum and co-workers have described the
preparation of a new stable and versatile sulfamoylat-
ing reagent 1 and described its reactivity in solution
towards various amines.6 We believed that a similar
strategy on a solid-support would prove very useful
because of the stability of reagent 1 with respect to CSI,
resulting in an easier adaptation to automated library
preparation.
Solution phase synthesis of unsymmetrically substituted
sulfamides has been performed by reaction of sulfamoyl
chlorides with amines,1 by transamidation of monosub-
stituted sulfamides,2 or by the stepwise addition of
tert-butanol and a primary amine to chlorosulfonyl
isocyanate (CSI), followed by Mitsunobu reaction and
removal of the BOC group.3
Our synthetic route, which is shown in Scheme 1,
begins by attachment of a primary amine to a backbone
amide linker (BAL) derivatised aminomethyl
polystyrene resin (0.8–1.4 mmol/g, 1% crosslinked with
Solid-phase synthesis of sulfahydantoins4 and
aminosulfonyl ureas5 have been recently described. In
the latter case, sulfamides were isolated as impurities.
Scheme 1. Reagents and conditions: (i) R1NH2, NaBH3CN, DMF–MeOH (8:2), 18 h, rt; (ii) 1, DCM, 18 h, rt; (iii) 6 equiv.
R2OH–Bu3P–ADDP, DMF, 18 h, rt; (iv) TFA–CHCl3–H2O (50:50:1).
Keywords: combinatorial chemistry; diversity; library; reductive amination; sulfamoylation; Mitsunobu reaction.
* Corresponding author. Fax: 34 932 913 420; e-mail: bvidal@almirallprodesfarma.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02327-9

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C. Este6e, B. Vidal / Tetrahedron Letters 43 (2002) 1019–1021
Table 1. Yields and purities of sulfamides prepared according to Scheme 1
Entry
Amine R1NH2
Alcohol R2OH
Purityb
Yieldc
1a
2
3
4
5
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
2-(2-Chlorophenyl)ethylamine
4-Methoxyaniline
–
80
88
92
95
75
80
88
75
50
80
90
75
93
90
95
45
61
42
45
51
40
50
40
38
48
38
45
55
58
55
Benzyl alcohol
4-Chlorobenzyl alcohol
3-Methoxybenzyl alcohol
2-Methoxybenzyl alcohol
3,4-Dimethoxybenzyl alcohol
2,6-Difluorobenzyl alcohol
sec-Phenethyl alcohol
Propargyl alcohol
3-Phenyl-2-propyn-1-ol
3-(3,4-Dimethoxyphenyl)propan-1-ol
–
6
7
8d
9
10d
11d
12a
13
14
15
4-Methoxyaniline
4-Methoxyaniline
4-Methoxyaniline
Benzyl alcohol
3-Methoxybenzyl alcohol
4-Chlorobenzyl alcohol
a Obtained after cleavage of the product from resin 2.
b Purity was determined by HPLC analysis of crude products at 210 nm. Products show satisfactory NMR and MS data, which are consistent
with the proposed structure.
c The crude yields were based on weight of crude samples and were relative to the initial loading of the BAL linked resin.
d The Mitsunobu protocol was repeated twice.
1
DVB) through a reductive amination to give 2.7 Con-
version to the BOC substituted sulfamide is accom-
plished by reaction with excess (5 equivalents)
sulfamoylating reagent 1 in DMF–DCM at room tem-
perature overnight.8 After a washing regimen, the prod-
ucts (5) were efficiently and simultaneously deprotected
and cleaved from the resin with TFA–CHCl3–H2O
(50:50:1). We found that either anilines or aliphatic
primary amines attached to the BAL linker were
efficiently sulfamoylated (entries 1 and 12).
ADDP related impurities. H NMR, HPLC and MS
were performed on all sulfamides to determine the
purity and confirm the structure.
N-Alkylation could not be achieved or gave products
with very low HPLC purity with heteroarylmethyl alco-
hols (2-thiophenemethanol, 3-pyridylcarbinol), or other
aliphatic alcohols such as 2-(N,N-dimethylamino)-
ethanol.
In summary, we describe an efficient and convenient
method for the solid-phase preparation of unsymmetri-
cally substituted sulfamides. Reaction of solid-phase
bound amines with the sulfamoylating reagent 1, fol-
lowed by N-alkylation under Mitsunobu conditions,
and deprotection and cleavage from the resin leads to
the target compounds with acceptable yields and good
purities. This method is presently being automatised for
the production of libraries of compounds.
Furthermore, we decided to explore the scope and
limitations of the Mitsunobu reaction on the resin
bound intermediate 3. The reaction of different poly-
mer supported BOC sulfamides with 6 equivalents of
the alcohol, tributylphosphine and 1,1%-(azodicar-
bonyl)dipiperidine (ADDP) in DCM provided cleanly
N-alkylated products (Scheme 1).9 Again, after a wash-
ing regimen and treatment with TFA–CHCl3–H2O
(50:50:1), unsymmetrically substituted sulfamides (6)
were obtained.
Acknowledgements
Further results, which illustrate the scope of this syn-
thesis, are listed in Table 1. As shown in Table 1,
benzylic alcohols substituted by either electron donat-
ing or electron withdrawing groups work well even in
hindered benzylic alcohols (entries 2–7). Analogously,
sulfamoylated anilines are also cleanly alkylated (entries
13–15).
The authors wish to thank Professor Fernando Alberi-
cio for helpful discussions during the preparation of the
manuscript. We wish to thank Dr. Mar´ıa-Jose´ Gonza´-
lez for supplying HPLC-MS data.
Secondary benzylic alcohols (entry 8), propargylic alco-
hols (entries 9–10) as well as aliphatic alcohols (entry
11) work equally well although a double Mitsunobu
treatment was required. This result provides a clear
advantage of the solid-phase approach with respect to
what we observed when we performed the same experi-
ment in solution phase where the final compound was
contaminated with a large excess of phosphine and
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mmol) was preswollen in CH2Cl2 (1.5 mL). A solution of
1 (0.15 g, 0.5 mmol, 5 equiv.) in DMF (1.5 mL) was
added, and the mixture was stirred at room temperature
for 20 h. The resin was filtered, washed sequentially with
DMF, MeOH, CH2Cl2 and THF, and dried.
9. General procedure for Mitsunobu reactions: PBu3 (148 mL,
0.6 mmol, 6 equiv.) followed by the corresponding alcohol
(0.6 mmol, 6 equiv.) were added to resin 3 (0.1 g, approx.
0.1 mmol) preswollen in CH2Cl2 (1 mL). The reaction was
cooled to 0°C and a solution of ADDP (0.15 g, 0.6 mmol,
6 equiv.) in CH2Cl2 (1 mL) was added. The reaction was
warmed to room temperature and stirred for 20 h. The
resin was filtered, washed sequentially with DMF, MeOH,
CH2Cl2 and THF, and dried.
The product was cleaved from the resin with TFA–
CHCl3–H2O (50:50:1).
8. General procedure for sulfamoylation of resin bound amines:
In a typical experiment, resin 2 (100 mg, approx. 0.1