Efficient general method for sulfamoylation of a hydroxyl group

Article abstract of DOI:10.1016/S0040-4039(00)01130-8

The application of N,N-dimethylacetamide or 1-methyl-2-pyrrolidone as solvent clearly accelerated the sulfamoylation reaction of a hydroxyl group compared with the solvents used so far. The target sulfamates were obtained in the highest yield without a base. It became clear that 2 equiv. of sulfamoyl chloride to the starting material was sufficient to complete the reaction. It was confirmed that this condition could be applied to extensive hydroxyl groups. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01130-8

Tetrahedron Letters 41 (2000) 7047±7051
Ecient general method for sulfamoylation of a hydroxyl
group
Makoto Okada,* Shigeki Iwashita and Naoyuki Koizumi
Organic Chemistry Research Department, Teikoku Hormone Mfg. Co. Ltd., 1604, Shimosakunobe, Takatu-ku,
Kawasaki 213-8522, Japan
Received 1 June 2000; accepted 30 June 2000
Abstract
The application of N,N-dimethylacetamide or 1-methyl-2-pyrrolidone as solvent clearly accelerated the
sulfamoylation reaction of a hydroxyl group compared with the solvents used so far. The target sulfamates
were obtained in the highest yield without a base. It became clear that 2 equiv. of sulfamoyl chloride to the
starting material was sucient to complete the reaction. It was con®rmed that this condition could be
applied to extensive hydroxyl groups. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: solvents and solvent e€ects; phenols; alcohols; sulfamoylation; sulfamic acid and derivatives.
Some important biological activities have been reported for the sulfamoyloxy group, for
example, potential antitumor in the steroid,1 antibiotic in the nucleoside2 and antiepilepsy in the
sugar.3 However, in the sulfamoylation so far, excessive base and sulfamoyl chloride4 were used
and the yields were often inadequate.1d,2a,d,3a,b Moreover, when N,N-dimethylformamide (DMF)
was used as a solvent, the undesired DMF adduct was obtained.1c This time we solved these
problems by using readily available and highly solubilizing N,N-dimethylacetamide (DMA) or
1-methyl-2-pyrrolidone (NMP) as a solvent (Eq. (1)). We optimized the reaction conditions and
found that the amounts of a base and sulfamoyl chloride were important to attain a high yield.
We con®rmed that this method could be applied to extensive alcohols and phenols.
ꢀ1†
* Corresponding author. Tel: +81 44 812 8634; fax: +81 44 833 5310; e-mail: okada-m1@kw.teikoku-hormone.co.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01130-8

7048
First, we examined the reaction of 4-hydroxyacetophenone (1) and sulfamoyl chloride in
various solvents (Eq. (2) and Table 1). We found that the solvent had great in¯uence on the rate
of reaction. The rate was slow in a previously reported solvent, 1,2-dimethoxyethane (DME),2a,d
dichloromethane1c or DMF1b,c,d,3b (runs 1±3). To the contrary, the rate in NMP or DMA was
faster with minimal by-product formation (runs 4 and 5). Considerable reaction progress in NMP
or DMA as well as in DMF probably reveals that these solvents work as moderate bases. The
diminished rate for DMF, compared with NMP or DMA, possibly attributes to a competing
reaction between DMF and sulfamoyl chloride. Formyl proton in DMF was changed to carbon
in DMA or NMP (Fig. 1), so DMA or NMP might have an inadequate reactivity for the
competing reaction.
ꢀ2†
Table 1
Conversion of 1 into 2 in various solventsa
Figure 1.
Next, we examined the amounts of the bases used (Table 2). Interestingly, elimination of a base
led to the highest yield (run 1). Probably DMA worked as a moderate base. When the base was
excessively used, the yield was diminished (runs 2±4). This was because further sulfamoylation of
the sulfamoyl group1c,5 and decomposition of sulfamoyl chloride6 might have occurred in the
presence of base. It has already been reported that sulfamoylation of estrone proceeded in DMF

7049
Table 2
Conversion of 1 into 2 with various amounts of triethylaminea
without any additional base.1c However, 5 equiv. of sulfamoyl chloride and 12 hours of reaction
time were needed for completion of the reaction. Our method needed only 2 equiv. of sulfamoyl
chloride and 3 hours of reaction time (Table 4, runs 3 and 4).
As for the amounts of sulfamoyl chloride, we found that the more sulfamoyl chloride was used,
the faster the rate was (Table 3, runs 1±3). Conventionally, 5±6 equiv. of sulfamoyl chloride have
been used.1c,d But our method needs only 2 equiv. of sulfamoyl chloride to the starting material
to complete the reaction, because our condition does not include any base and DMF, which
waste sulfamoyl chloride as we have mentioned above.
Table 3
Conversion of 1 into 2 with various amounts of sulfamoyl chloridea
An application of this reaction condition is summarized in Table 4.7 It was con®rmed that
phenols with an electron-withdrawing or donating group, ketone, lactone or ketal smoothly
reacted to give good yield (runs 1±6). Even fatty alcohols (primary, secondary) went well (runs 7±9).
But a tertiary alcohol did not a€ord the corresponding sulfamate,8 probably because of
occurrence of b-elimination. A reaction using NMP as a solvent gave a similar result to DMA
(runs 4 and 8).
In conclusion, we have developed a general method to e€ectively convert a hydroxyl group to a
sulfamoyloxy group using a minimum amount of the reagent. This method has the advantage of
being applicable to extensive alcohols and phenols at low cost and with a convenient operation as
compared with the former method. It was also successful in the scale-up to 21 g (75 mmol) of 5
(Table 4, run 5).9 This method will be useful not only in the laboratory but also for industrial
manufacture.

7050
Table 4
Application of this method to various substratesa
Acknowledgements
We thank Mrs. Nobuyoshi Minami, Takayoshi Nakagawa and Shigehiro Takegawa for helpful
discussions.
References
1. (a) Schwarz, S.; Weber, G. Z. Chem. 1974, 14, 15; (b) Nicola, M. H.; Atul, P.; Michael, J. R.; Barry, V. L. P.
J. Med. Chem. 1994, 37, 219; (c) Sigfrid, S.; Ina, T.; Margit, R.; Bernd, U.; Harry, H.; Walter, E. Steroids 1996, 61,
710; (d) Pui-Kai, L.; Guo-Hua, C.; JingPing, G.; Amy, P.; Kyle, W. S. Steroids 1998, 63, 425.

7051
2. (a) Dennis, A. S.; Morris, J. R.; Roland, K. R. J. Am. Chem. Soc. 1970, 92, 3434; (b) Jenkins, I. D.; Verheyden,
J. P. H.; Mo€att, J. G. J. Am. Chem. Soc. 1971, 93, 4323; (c) Block, A.; Coutsogeorgopoulos, C. Biochemistry
1971, 10, 4394; (d) Eileen, M.; Jay, B.; Robert, V. J. Med. Chem. 1992, 35, 3991.
3. (a) Michael, N. G.; Bruce, E. M. Tetrahedron Lett. 1992, 33, 5009; (b) Bruce, E. M.; Michael, J. C.; Samuel, O. N.;
Michael, N. G.; Richard, P. S.; James, J. S.; Marta, P. O.; Je€ry, L. V. J. Med. Chem. 1998, 41, 1315.
4. (a) Appel, R.; Berger, G. Chem. Ber. 1958, 91, 1339; (b) Kloek, J. A.; Leschinsky, K. L. J. Org. Chem. 1976, 41,
4028.
5. In the presence of base, sulfamoyl sulfamate (9) might have to be generated as a by-product:1c 4-
(H2NSO2NHSO2O)C6H4COMe (9).
6. Sulfamoyl chloride decomposed gradually in the presence of base in NMP. To the contrary, sulfamoyl chloride
hardly decomposed in only NMP.
7. General procedure: Sulfamoyl chloride (2.0 mmol) was added to a stirred mixture of a hydroxyl compound (1.0
mmol) and DMA (1.5 mL) on ice-cooling. The mixture was then stirred at room temperature for 3 hours. The
mixture was poured into cold brine, and the resulting solution was extracted with ethyl acetate (2Â20 mL). The
organic layer was separated, washed with brine (20 mL), dried (MgSO4), and concentrated under reduced
1
pressure. The product was puri®ed by TLC. 4-Acetylphenyl sulfamate: MS m/e: 215 (M+), 136, 121; H NMR
(DMSO-d6, ꢀ): 2.58 (3H, s), 7.3±7.5 (2H, m), 8.0±8.1 (2H, m), 8.15 (2H, s). 4-Methoxyphenyl sulfamate: MS m/e:
203 (M+), 123; 1H NMR (DMSO-d6, ꢀ): 3.76 (3H, s), 6.9±7.0 (2H, m), 7.1±7.3 (2H, m), 7.83 (2H, s). 17-Oxoestra-
1,3,5(10)-trien-3-yl sulfamate: MS m/e: 349 (M+), 270; 1H NMR (DMSO-d6, ꢀ): 0.84 (3H, s), 2.87 (2H, dd, J=3.8,
8.6 Hz), 6.98 (1H, d, J=2.4 Hz), 7.02 (1H, dd, J=2.4, 8.5 Hz), 7.35 (1H, d, J=8.5 Hz), 7.86 (2H, s). 17-Oxo-17a-
1
homo-17a-oxaestra-1,3,5(10)-trien-3-yl sulfamate: MS m/e: 365 (M+), 286; H NMR (DMSO-d6, ꢀ): 1.28 (3H, s),
1.4±1.7 (2H, m), 1.78 (1H, dt, J=3.5, 13.0 Hz), 1.9±2.1 (3H, m), 2.6±2.8 (1H, m), 2.7±3.0 (2H, m), 6.98 (1H, d,
J=2.6 Hz), 7.03 (1H, dd, J=2.6, 8.5 Hz), 7.36 (1H, d, J=8.6 Hz), 7.88 (2H, s). 17,17-(Ethylenedioxy)estra-
1,3,5(10)-trien-3-yl sulfamate: MS m/e: 393 (M+), 348, 314, 269; 1H NMR (DMSO-d6, ꢀ): 0.81 (3H, s), 2.1-2.3 (1H,
m), 2.3-2.4 (1H, m), 2.7-2.9 (2H, m), 3.7-3.9 (4H, m), 6.96 (1H, d, J=2.5 Hz), 7.01 (1H, dd, J=2.5, 8.5 Hz), 7.33
(1H, d, J=8.5 Hz), 7.85 (2H, s). 3-Phenylpropyl sulfamate: MS m/e: 215 (M+), 117; 1H NMR (DMSO-d6, ꢀ): 1.8±
2.0 (2H, m), 2.66 (2H, t, J=7.7 Hz), 4.02 (2H, t, J=6.4 Hz), 7.1±7.4 (5H, m), 7.41 (2H, s). 3-Oxoandrost-4-en-17ꢀ-
1
yl sulfamate: MS m/e: 367 (M+), 270; H NMR (DMSO-d6, ꢀ): 0.78 (3H, s), 1.16 (3H, s), 4.25 (1H, t, J=8.4 Hz),
5.62 (1H, s), 7.32 (2H, s).
8. The reaction of 2-phenyl-2-propanol showed conversion to a less-polar product (on TLC), but we could not isolate
any non-volatile materials.
9. Koizumi, N.; Takegawa, S.; Iwashita, S.; Fujii, T.; Kawachi, T.; Mieda, M. PCT intl Appl. WO 9811124, 19
March 1998.