A convenient preparation of heteroaryl sulfonamides and sulfonyl fluorides from heteroaryl thiols

Article abstract of DOI:10.1021/jo052164+

Heteroaromatic thiols may be oxidized to the sulfonyl chloride at low temperature (-25 °C) by using 3.3 equiv of aqueous sodium hypochlorite. The reaction is rapid, avoids the use of chlorine gas, and succeeds with substrates that have previously been found to afford little or none of the sulfonamide product with other procedures. The method allows the preparation of the sulfonyl fluorides, which are stable enough to be purified and stored, making them potentially useful monomers in parallel chemistry efforts.

Full text of DOI:10.1021/jo052164+

A Convenient Preparation of Heteroaryl Sulfonamides and Sulfonyl
Fluorides from Heteroaryl Thiols
Stephen W. Wright*,† and Kelly N. Hallstrom§,‡
Pfizer Global Research and DeVelopment, Eastern Point Road, Groton, Connecticut 06340, and Clark
UniVersity, Worcester, Massachusetts 01610
stephen.w.wright@pfizer.com
ReceiVed October 17, 2005
Heteroaromatic thiols may be oxidized to the sulfonyl chloride at low temperature (-25 °C) by using
3.3 equiv of aqueous sodium hypochlorite. The reaction is rapid, avoids the use of chlorine gas, and
succeeds with substrates that have previously been found to afford little or none of the sulfonamide
product with other procedures. The method allows the preparation of the sulfonyl fluorides, which are
stable enough to be purified and stored, making them potentially useful monomers in parallel chemistry
efforts.
Introduction
Unfortunately, as was indicated in the original papers and as
subsequently confirmed by others, this procedure has preparative
value only when the heterocycle is a pyridine. Other hetero-
cycles, for example, pyrimidine, frequently afford yields of 10%
or less, a result that we confirmed in our laboratories as well.
In addition, it has been reported that the use of exactly 3 equiv
of chlorine gas is required, although in the literature preparations
little effort has been made to actually limit the amount of
chlorine to 3 equiv.4 Other conditions that have been used to
effect this transformation include oxidation of the heteroaryl
thiol by chloramines to afford the sulfenamide, followed by
oxidation to the sulfonamide by mCPBA5 or potassium per-
manganate.6 The inadequate yield and lack of generality of these
methods, coupled with the hazards associated with chlorine gas
and chloramines, and the potential need to control the stoichi-
ometry of a gaseous reagent, led us to examine other conditions
for effecting the oxidation of 2a to 1a (Scheme 1). We reasoned
Sulfonamides play an important role in many medicinal
chemistry analogue programs. During the course of some recent
work, we wanted to prepare a number of heteroaryl sulfon-
amides. To prepare these analogues, we required access to the
corresponding heteroaryl sulfonyl chlorides such as 1a. Only a
very small number of these compounds are commercially
available due to their known instability.1 An examination of
the literature revealed that these compounds are generally
prepared by the oxidation of the corresponding heteroaryl thiol
such as 2a with chlorine gas in the presence of aqueous
hydrochloric acid. These conditions were first employed with
a heteroaryl thiol in 1942,2 and subsequent workers have
generally used these conditions with little or no modification.3
* Address correspondence to this author. Phone: 860-441-5831. Fax: 860-
715-4483.
† Pfizer Global Research and Development.
§ Pfizer Global Research and Development Summer Intern, 2004 and 2005.
‡ Clark University.
(4) (a) Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2000, 65, 2309. (b)
Vedejs, E.; Lin, S.; Klapars, A.; Wang, J. J. Am. Chem. Soc. 1996, 118,
9796. (c) Deeb, A.; Essawy, A.; El-Gendy, A. M.; Shaban, A. Monatsh.
Chem. 1990, 121, 281.
(5) (a) Ramasamy, K.; Imamura, N.; Hanna, N. B.; Finch, R. A.; Avery,
T. L.; Robins, R. K.; Revankar, G. R. J. Med. Chem. 1990, 33, 1220. (b)
Revankar, G. R.; Hanna, N. B.; Imamura, N.; Lewis, A. F.; Larson, S. B.;
Finch, R. A.; Avery, T. L.; Robins, R. K. J. Med. Chem. 1990, 33, 121. (c)
Revankar, G. R.; Hanna, N. B.; Ramasamy, K.; Larson, S. B.; Smee, D.
F.; Finch, R. A.; Avery, T. L.; Robins, R. K. J. Heterocycl. Chem. 1990,
27, 909.
(6) Woltersdorf, O. W., Jr.; Schwam, H.; Bicking, J. B.; Brown, S. L.;
DeSolms, S. J.; Fishman, D. R.; Graham, S. L.; Gautheron, P. D.; Hoffman,
J. M.; Larson, R. D.; Lee, W. S.; Michelson, S. R.; Robb, C. M.; Share, N.
N.; Shepard, K. L.; Smith, A. M.; Smith, R. L.; Sondey, J. M.; Strohmaier,
K. M.; Sugrue, M. F.; Viader, M. P. J. Med. Chem. 1989, 32, 2486.
(1) Johnson, T. B.; Sprague, J. M. J. Am. Chem. Soc. 1936, 58, 1348.
(2) (a) Caldwell, W. T.; Kornfeld, E. C. J. Am. Chem. Soc. 1942, 64,
1695. (b) Roblin, R. O.; Clapp, J. W. J. Am. Chem. Soc. 1950, 72, 4890.
(3) See, for example: (a) Skulnick, H. I.; Johnson, P. D.; Aristoff, P.
A.; Morris, J. K.; Kristine, D.;Lovasz, K. D.; Howe, W. J.; Watenpaugh,
K. D.; Janakiraman, M. N.; Anderson, D. J.; Reischer, R. J.; Schwartz, T.
M.; Banitt, L. S.; Tomich, P. K.; Lynn, J. C.; Horng, M.-M.; Chong, K.-T.;
Hinshaw, R. R.; Dolak, L. A.; Seest, E. P.; Schwende, F. J.; Rush, B. D.;
Howard, G. M.; Toth, L. N.; Wilkinson, K. R.; Kakuk, T. J.; Johnson, C.
W.; Cole, S. L.; Zaya, R. M.; Zipp, G. L.; Possert, P. L.; Dalga, R. J.;
Zhong, W.-Z.; Williams, M. G.; Romines, K. R. J. Med. Chem. 1997, 40,
1149. (b) Ager, E.; Iddon, B.; Suschitzky, H. J. Chem. Soc. C 1970, 1530.
(c) Bhattacharya, B. K. J. Heterocycl. Chem. 1986, 23, 113. (d) Marsais,
F.; Cronnier, A.; Trecourt, F.; Quequiner, G. J. Org. Chem. 1987, 52, 1133.
10.1021/jo052164+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/11/2006
1080
J. Org. Chem. 2006, 71, 1080-1084

Heteroaryl Sulfonamides and Sulfonyl Fluorides
SCHEME 1. Oxidation of Heteroaryl Thiol to Heteroaryl
Sulfonyl Chloridea
Under these conditions, 2b was transformed to 3b in 77% crude
yield and 64% yield following recrystallization. The addition
of calcium chloride to both the aqueous acid and the sodium
hypochlorite was necessary, otherwise the mixture began to
freeze as the sodium hypochlorite solution was added. Addition
of 25 wt % of anhydrous calcium chloride to the sodium
hypochlorite solution caused decomposition of the hypochlorite,
even with cooling in ice; therefore, calcium chloride hexahydrate
was added to the bleach in a quantity sufficient to be equivalent
to 25 wt % of anhydrous calcium chloride.
When the reaction was carried out on 2a at 5 to 10 °C
(internal temperature, ice water bath) and the dichloromethane
layer was washed with saturated sodium bicarbonate solution
prior to the trapping with benzylamine, the yield of 3a was
reduced to 25%. When brine was used in place of the sodium
bicarbonate solution, the yield of 3a was increased to 53%.
However, as dichloromethane dissolves very little water, and
the washing procedure appeared to provide no benefit, the
washing of the crude sulfonyl chloride solution was omitted
entirely. Instead, the crude sulfonyl chloride solution was
separated from the aqueous phase in a separatory funnel pre-
cooled with ice water, and the dichloromethane layer was
collected in a flask cooled in a dry ice-acetone bath. By this
means further decomposition of the crude sulfonyl chloride was
prevented and any aqueous phase entrained in the dichlo-
romethane was immobilized by freezing.
a Reagents and conditions: (a) Cl2 or NaOCl, HCl; (b) BnNH2 (excess);
(c) HCl, prolonged standing or increased temperature.
that aqueous sodium hypochlorite, which is inexpensive and of
easily determined molarity,7 would provide an alternative
oxidizing agent that would be more convenient to use and allow
much greater control of reactant stoichiometry. We also
anticipated that the use of a water-immiscible cosolvent such
as dichloromethane would be beneficial by allowing extraction
of the heteroaryl sulfonyl chloride as formed, thereby reducing
the exposure of the heteroaryl sulfonyl chloride to the aqueous
acid.
When only the theoretical amount of HCl required by the
reaction stoichiometry was used (6.6 mL of 1 M HCl, 2 equiv
to NaOCl used) at 5 to 10 °C (internal temperature, ice water
bath), the yield of 3a decreased slightly to 50%. The use of
ethyl acetate as cosolvent in the oxidation of 2a resulted in a
low recovery (30%) of 3a. Not surprisingly, if the dichlo-
romethane solution of 1a was allowed to warm to room
temperature, no 3a was obtained on trapping with benzylamine.
This method was then applied to a variety of commercially
available heteroaryl thiols (Table 1). As will be seen from the
results in Table 1, certain heteroaryl thiols afforded reasonable
yields of products at -10 to -5 °C (Method A), while other
heteroaryl thiols required reaction at -30 to -25 °C (Method
B) to afford acceptable yields of the sulfonamide products 3.
The limitations of the methods are apparent from Table 1 as
well. The imidazole substrates 2i and 2t required chromato-
graphic purification of the crude product mixtures and afforded
a low purified yield of the desired sulfonamides. In the case of
2t, the primary byproducts were identified as 2-chlorobenzimi-
dazole and 2-hydroxybenzimidazole by comparison to com-
mercial samples. The benzoxazole substrate 2r and 4-mercap-
toquinoline substrate 2j failed at either temperature, affording
only 2-chlorobenzoxazole (4r, identified by comparison to a
commercial sample) and 4-chloro-7-(trifluoromethyl)quinoline
Such a process would have significant advantages: (a) the
use of chlorine gas would be eliminated, resulting in a safer
and much more convenient procedure, and (b) the stoichiometry
of the oxidizing agent could be easily controlled, possibly
resulting in higher yields by preventing decomposition of the
heteroaryl sulfonyl chloride by excess chlorine or aqueous acid.
In view of the known instability of heteroaryl sulfonyl chlorides,
we elected to confirm their formation by trapping with an excess
of benzylamine, followed by isolation of the N-benzyl sulfon-
amide.
Results and Discussion
A preliminary experiment, using commercial bleach as a
source of sodium hypochlorite, showed that such a process was
possible, affording a 67% yield of the pyrimidine sulfonamide
3a. The reaction was run several times with 2-mercaptopyri-
midine (2a) to identify optimal conditions. The yield of product
was found to be dependent on four variables: (a) the temperature
of the oxidation reaction, (b) the procedure used to separate
the crude acid chloride, (c) the concentration of hydrochloric
acid, and (d) the reaction cosolvent.
When the reaction was run at 5 to 10 °C (internal temperature,
ice water bath), the yield of isolated 3a averaged at 64%. At
-10 to -5 °C internal temperature, the yield was almost
quantitative. However, other substrates (for example, 4,6-
dimethyl-2-mercaptopyrimidine, 2b) afforded much less product
at -10 to -5 °C internal temperature, yielding instead largely
the heteroaryl chloride (4b) resulting from decomposition of
the heteroaryl sulfonyl chloride. This difficulty was circum-
vented by carrying out the reaction at -30 to -25 °C internal
temperature. In these cases it was necessary to include 25 wt
% of calcium chloride in the aqueous phase to prevent freezing.8
1
(4j, identified by H NMR and GC-MS), respectively. The
4-trifluoromethylpyrimidine 2s returned only the disulfide upon
reaction at either -25 or -5 °C. Predictably, the 4-hydroxy-
pyrimidine substrate 2h underwent simultaneous nuclear chlo-
rination under the reaction conditions to afford product con-
taining a 5-chloro-4-hydroxypyrimidine. However, we were
pleased to find that certain substrates (2a, 2b, 2c, 2m) that had
been previously reported to give low yields2b gave much
improved yields using this procedure.
(8) Lide, D. R., Ed. CRC Handbook of Chemistry and Physics, Internet
Version 2005; http://www.hbcpnetbase.com; CRC Press: Boca Raton, FL,
2005.
(7) The United States Pharmacopeia USP 28; National Publishing:
Philadelphia, PA, 2005; p 1786.
J. Org. Chem, Vol. 71, No. 3, 2006 1081

Wright and Hallstrom
TABLE 1. Results of Conversion of Heteroaryl Thiols to Heteroaryl N-Benzyl Sulfonamides
entry
starting thiol
temp,a °C
product
yield,b %
mp, °C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2-mercaptopyrimidine (2a)
-5
-5
3a
3b
3b
3c
3d
3e
3f
94
19
64
74c
75c
90
98
53
22
9
117-118
129-130
129-130c
129-131
103-105
129-130e
102-103
97-98
4,6-dimethyl-2-mercaptopyrimidine (2b)
4,6-dimethyl-2-mercaptopyrimidine (2b)
5-mercapto-1-phenyl-1,2,3,4-tetrazole (2c)
2-mercapto-4-methylpyrimidine (2d)
2-mercaptobenzothiazole (2e)
-25
-25d
-25d
-5
2-mercaptopyridine (2f)
-5
methyl 2-mercaptonicotinate (2g)
4-hydroxy-2-mercapto-6-phenylpyrimidine (2h)
2-mercapto-1-methylimidazole (2i)
2-mercapto-7-(trifluoromethyl)quinoline (2j)
2-mercaptoquinoline (2k)
3-cyano-4,6-dimethyl-2-mercaptopyridine (2l)
2-mercaptothiazole (2m)
methyl 6-mercaptonicotinate (2n)
3-mercapto-6-methoxypyridazine (2o)
3-mercapto-5-methyl-4-phenyl-4H-1,2,4-triazole (2p)
4-mercaptopyridine (2q)
-5
3g
-5
5f
167-168
109-110
-25d
-25d
-5
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
0
80
80
93
57
64
76
39
0
106-107
157-158
98-99
115-116
181-183
221-223
163-166
-5
-5
-5
-25d
-25d
-25d
-25d
-25d
-25d
2-mercaptobenzoxazole (2r)
2-mercapto-4-trifluoromethylpyrimidine (2s)
2-mercaptobenzimidazole (2t)
0
16
217-218
a Maximum internal reaction temperature during oxidation by NaOCl. b Unoptimized yield of analytically pure isolated product. c Literature mp 130.5-
131 (see ref 16a). d Reaction was unsuccessful when carried out at -5 °C. e Literature mp 134 (see ref 16b). f Product was N-benzyl-4-hydroxy-5-chloro-
6-phenylpyrimidine-2-sulfonamide.
Having identified a convenient oxidation and trapping
procedure to prepare the desired heteroaryl sulfonamides, we
turned our attention to the identification and preparation of stable
heteroaryl sulfonyl derivatives that would serve as synthetic
equivalents to the unstable sulfonyl chlorides. Such derivatives
would be of great value in medicinal chemistry analogue
programs and parallel synthesis. Arylsulfonyl 1-hydroxyben-
zotriazole esters have been described as reactive sulfonylating
agents,9 as have heteroaryl benzotriazole sulfonamides.10 Aryl
sulfonyl 4-nitrophenyl esters have also been described;11
however, these appeared unsuitable for our purpose as they are
known to react with amine nucleophiles by two pathways: (a)
attack at the sulfonyl group to afford the sulfonamide and
4-nitrophenol and (b) attack at the 4-position of the nitrophenol
to afford the sulfonic acid and a 4-nitroaniline derivative by an
SN2Ar mechanism.12 Attempts to prepare either pyrimidine-2-
sulfonic acid benzotriazol-1-yl ester (6) or 1-(pyrimidine-2-
sulfonyl)-1H-benzotriazole (7) from dichloromethane solutions
of 1a were entirely unsuccessful, affording only 2-chloropyri-
midine.
fluoride at -10 to -5 °C using bleach as the oxidizing agent
in the presence of a tetralkylammonium salt. The identity of 8a
was confirmed by 1H, 13C, and 19F NMR, IR, elemental analysis,
and conversion to 3a by reaction with excess benzylamine in
CH2Cl2 at room temperature. We found that the inclusion of a
quaternary ammonium salt was crucial to obtain good yields of
the sulfonyl fluoride. With use of 2-mercaptobenzothiazole (2e)
as a model, tetrabutylammonium ion and tetraethylammonium
ion gave approximately a 2:1 ratio of the sulfonyl fluoride to
1
combined other products as judged by examination of the H
NMR spectra of the crude reaction products. Not surprisingly,
the tetraethylammonium ion was more easily washed out of the
crude sulfonyl fluoride product with water. Benzyltrimethyl-
ammonium ion was less satisfactory, affording approximately
a 1:1 ratio of the sulfonyl fluoride to combined other products
as judged by examination of the 1H NMR spectrum of the crude
reaction product. Somewhat surprisingly, the use of a methanol-
water mixture as reaction solvent generally gave poor results
in all cases, with the crude reaction products consisting largely
of disulfide and some 4.14 We therefore applied the biphasic
oxidation method to some commercially available heteroaryl
thiols (Table 2).
We found that in general the reaction afforded good yields
(>80%) of the heteroaryl sulfonyl fluorides following removal
of the tetraalkylammonium salt by washing with water. Further
purification, to remove the last traces of tetraalkylammonium
salt in order to afford analytically pure samples, was more
difficult. Not surprisingly, the heteroaryl sulfonyl fluorides were
(10) Katritzky, A. R.; Rodriguez-Garcia, V.; Nair, S. K. J. Org. Chem.
2004, 69, 1849.
(11) (a) Islam, A. M.; Bedair, A. H.; El-Maghraby, A. A.; Aly, F. M.;
Emam, H. A. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1982,
21B, 487. (b) Osman, A. M.; El-Sherief, H. A. H.; Mahmoud, A. M. J.
Indian Chem. Soc. 1979, 56, 293. (c) Wentworth, S. E.; Sciaraffa, P. L.
Org. Prep. Proced. Int. 1969, 1, 225.
(12) (a) Netscher, T.; Schwesinger, R.; Trupp, B.; Prinzbach, H.
Tetrahedron Lett. 1987, 28, 2115. (b) Takikawa, Y.; Yoshida, S.; Sato, R.;
Takizawa, S. Nippon Kagaku Kaishi 1976, 631 (Chem. Abstr. 1976, 85,
93352).
We therefore turned our attention to the preparation of
2-pyrimidinyl sulfonyl fluoride (8a).13 We were pleased to find
that we could obtain a nearly quantitative yield of the sulfonyl
(9) (a) Carpino, L. A.; Xia, J.; Zhang, C.; El-Faham, A. J. Org. Chem.
2004, 69, 62. (b) Kim, S. Y.; Sung, N.-D.; Choi J.-K.; Kim, S. S.
Tetrahedron Lett. 1999, 40, 117. (c) Itoh, M.; Notani, K. U.S. Patent
4,242,507, 1980 (Chem. Abstr. 1981, 95, 7290).
(13) Brown, D. J.; Hoskins, J. A. J. Chem. Soc., Perkin Trans. 1 1972,
522.
1082 J. Org. Chem., Vol. 71, No. 3, 2006

Heteroaryl Sulfonamides and Sulfonyl Fluorides
TABLE 2. Results of Conversion of Heteroaryl Thiols to Heteroaryl Sulfonyl Fluorides
entry
starting thiol
product
yield,a %
mp, °C
1
2
3
4
5
6
2-mercaptopyrimidine (2a)
8a
8b
8e
8f
8k
8o
73
79
42
70
49
73
58-60b
57-58c
95-96
25-28d
76-77
55-57e
4,6-dimethyl-2-mercaptopyrimidine (2b)
2-mercaptobenzothiazole (2e)
2-mercaptopyridine (2f)
2-mercaptoquinoline (2k)
3-mercapto-6-methoxypyridazine (2o)
a Unoptimized yield of analytically pure isolated product. b Literature mp 57 °C (see ref 13). c Literature mp 58 °C (see ref 13). d Product purified by
Kugelrohr distillation (oven temperature 125 °C, pressure 2 Torr). e See ref 16c.
hypochlorite solution was added by pipet and the liberated iodine
was titrated with 0.100 N standardized sodium thiosulfate solution,
adding a few milliliters of starch solution as the endpoint was
approached. Each milliliter of 0.100 N sodium thiosulfate required
is equivalent to 3.722 mg of NaOCl.
decomposed upon attempted chromatography on silica or
alumina. Distillation proved successful for sufficiently low
molecular weight compounds (8f). Recrystallization from etha-
nol or 2-propanol afforded analytically pure samples of crystal-
line products, but the relatively high solubility of the products
in these solvents resulted in low recovery of the products.
In summary, we have developed a general method for the
preparation of heteroaryl sulfonamides from the readily available
heteroaryl thiols by oxidation at lower temperatures than
previously employed and immediate trapping of the unstable
intermediate heteroaryl sulfonyl chloride with the desired amine.
The reaction uses readily available reagents, allows easy control
of stoichiometry, and avoids the use of chlorine gas. The reaction
conditions may be modified to afford the heteroaryl sulfonyl
fluorides, which are stable enough to isolate and store, yet
reactive enough toward amines to afford the corresponding
heteroaryl sulfonamides. These features make the heteroaryl
sulfonyl fluorides potentially useful fragments to consider in a
parallel medicinal chemistry effort. We hope that these proce-
dures may be of value to others seeking novel synthetic
fragments with unique properties for medicinal chemistry
programs.
Procedure A: Preparation of Heteroaryl Sulfonamides at
-10 to -5 °C. N-Benzyl Pyrimidine-2-sulfonamide (3a). 2-Mer-
captopyrimidine (2a, 0.561 g, 5 mmol) was stirred in a mixture of
25 mL of CH2Cl2 and 25 mL of 1 M HCl in a 125-mL Erlenmeyer
flask for 10 min at -10 to -5 °C (internal temperature). Cold (5
°C) sodium hypochlorite (6% solution, 0.68 M, 26 mL, 18 mmol,
3.3 equiv) was added dropwise with Very rapid stirring, maintaining
the internal temperature at -10 to -5 °C. The mixture was stirred
for 15 min at -10 to -5 °C (internal temperature) after the addition
was completed. The mixture was transferred to a separatory funnel
(pre-cooled with ice water) and the CH2Cl2 layer was rapidly
separated and collected in a clean 125-mL Erlenmeyer flask cooled
in a dry ice-acetone bath. Benzylamine (1.4 mL, 12.5 mmol) was
added with stirring, whereupon the CH2Cl2 layer became a white
suspension. The flask was removed to an ice-water bath and the
suspension was stirred for 30 min at 0 °C. The suspension was
then washed with 1 M phosphoric acid (all solids dissolved at once),
then with water and brine. Drying (Na2SO4) and concentration
afforded 1.171 g (94%) of 3a as a fine white powder, mp 117-
118 °C. 1H NMR (CDCl3) δ 8.87 (d, J ) 5 Hz, 2 H), 7.46 (t, J )
5 Hz, 1 H), 7.28 (m, 5 H), 5.14 (br t, 1 H), 4.41 (d, J ) 6 Hz, 2
H); 13C NMR (CDCl3) δ 158.7, 136.5, 129.0, 128.2, 123.3, 48.4.
APCI MS: m/z 250 (M + H)+. Anal. Calcd for C11H11N3O2S: C,
53.00; H, 4.45; N, 16.86. Found: C, 52.71; H, 4.40; N, 16.71.
Procedure B: Preparation of Heteroaryl Sulfonamides at
-30 to -25 °C. N-Benzyl 4,6-dimethylpyrimidine-2-sulfonamide
(3b): 4,6-Dimethyl-2-mercaptopyrimidine (2b, 0.701 g, 5 mmol)
was stirred in a mixture of 25 mL of CH2Cl2 and 25 mL of 1 M
HCl (25 wt % CaCl2) in a 125-mL Erlenmeyer flask for 10 min at
-30 to -25 °C (internal temperature, maintained by intermittent
cooling with a dry ice-acetone bath). Calcium chloride 6-hydrate
(19 g) was dissolved in sodium hypochlorite (6% solution, 0.74
M, 24 mL, 18 mmol, 3.3 equiv), and the resulting clear solution
was added dropwise with Very rapid stirring, maintaining the
internal temperature at -30 to -25 °C. The mixture was stirred
for 15 min at -30 to -25 °C (internal temperature) after the
addition was completed. The mixture was diluted with 25 mL of
ice water and transferred to a separatory funnel (pre-cooled with
ice water). The CH2Cl2 layer was rapidly separated and collected
in a clean 125-mL Erlenmeyer flask cooled in a dry ice-acetone
bath. Benzylamine (1.4 mL, 12.5 mmol) was added with stirring,
whereupon the CH2Cl2 layer became a white suspension. The flask
was removed to an ice-water bath and the suspension was stirred
for 30 min at 0 °C. The suspension was then washed with 1 M
phosphoric acid, then with water and brine. Drying (Na2SO4) and
Experimental Section
All oxidation reactions involving sodium hypochlorite were
carried with rapid continuous magnetic stirring in Erlenmeyer flasks
open to the atmosphere. Sodium hypochlorite was commercial
“ultra” laundry bleach containing a stated concentration of 6%
NaOCl. The actual concentration of hypochlorite was determined
by iodometric titration. Hydrochloric acid (ca. 1 M) containing 25
wt % of calcium chloride was prepared by dissolving 125 g of
anhydrous calcium chloride in 350 mL of water and cooling to
room temperature. Once the solution had cooled, 42 mL of
concentrated hydrochloric acid was added and the solution was
diluted to 500 mL with water. Methyl 2-mercaptonicotinate (2g)
and methyl 6-mercaptonicotinate (2n) were prepared by literature
procedures.15
Titration of Sodium Hypochlorite. Potassium iodide (2 g) and
3 mL of glacial HOAc were dissolved in 50 mL of H2O in an
Erlenmeyer flask. An accurately measured volume (3 mL) of
(14) Oxidation of 2a, 2b, and 2d with Cl2 in MeOH-H2O-KHF2 has
been reported to proceed in good yield; see ref 13. Oxidation of 2o under
similar conditions has been reported; see: Turck, A.; Ple, N.; Pollet, P.;
Queguiner, G. J. Heterocycl. Chem. 1998, 35, 429. These procedures use
chlorine gas in large excess as the oxidant. Presumably the use of
hypochlorite in stochiometeric amounts is unsatisfactory under the MeOH-
H2O conditions due to competing oxidation of MeOH by hypochlorite.
(15) Fibel, L. R.; Spoerri, P. E. J. Am. Chem. Soc. 1948, 70, 3908. Young,
R. N.; Gauthier, J. Y.; Coombs, W. Tetrahedron Lett. 1984, 25, 1753.
(16) (a) Clapp, J. W.; Roblin, R. O., Jr. U.S. Patent 2,577,231, 1951
(Chem. Abstr. 1952, 46, 32788). (b) Stanovnik, B.; Tisler, M. Arch. Pharm.
1965, 298, 357. (c) Mylari, B. L.; Armento, S. J.; Beebe, D. A.; Conn, E.
L.; Coutcher, J. B.; Dina, M. S.; O’Gorman, M. T.; Linhares, M. C.; Martin,
W. H.; Oates, P. J.; Tess, D. A.; Withbroe, G. J.; Zembrowski, W. J. J.
Med. Chem. 2003, 46, 2283.
1
concentration afforded 1.060 g of 3b as a fine white powder. H
NMR indicated the presence of about 5% of 2-chloro-4,6-dimeth-
ylpyrimidine. Recrystallization from 2-propanol gave 0.885 g (64%)
of 3b as white crystals, mp 129-130 °C. 1H NMR (CDCl3) δ 7.29-
7.20 (m, 5 H), 7.11 (s, 1 H), 5.24 (br t, 1 H), 4.37 (d, J ) 6 Hz, 2
H), 2.54 (s, 6 H); 13C NMR (CDCl3) δ 169.2, 165.3, 136.7, 128.8,
128.3, 128.2, 128.1, 122.4, 48.4, 24.1. APCI MS: m/z 278 (M +
J. Org. Chem, Vol. 71, No. 3, 2006 1083

Wright and Hallstrom
H)+. Anal. Calcd for C13H15N3O2S: C, 56.30; H, 5.45; N, 15.15.
Found: C, 56.28; H, 5.23; N, 15.13.
quickly. Recrystallization from EtOH gave 0.442 g (11%) of 8a as
1
white crystals, mp 58-60 °C. H NMR (CDCl3) δ 9.03 (d, 2 H),
Procedure C: Preparation of Heteroaryl Sulfonyl Fluorides.
Pyrimidine-2-sulfonyl Fluoride (8a): 2-Mercaptopyrimidine (2a,
2.803 g, 25 mmol) was stirred in a mixture of 100 mL of CH2Cl2
and 100 mL of water containing 19.55 g (250 mmol) of KHF2 and
8.48 g (25 mmol) of Bu4NHSO4 in a 500-mL polypropylene
Erlenmeyer flask for 30 min at 0 to -5 °C (internal temperature).
Cold (5 °C) sodium hypochlorite (6% solution, 0.68 M, 130 mL,
90 mmol, 3.6 equiv) was added dropwise with Very rapid stirring,
maintaining the internal temperature at 0 to -5 °C. The mixture
was stirred for 10 min at 0 to -5 °C (internal temperature) after
the addition was completed. The CH2Cl2 phase was separated,
washed with water and brine, dried (Na2SO4), and concentrated.
The residual oil (5.241 g) was dissolved in Et2O and washed twice
with water to remove the Bu4N salt, then dried (Na2SO4) and
concentrated to afford 3.210 g (79%) of 8a as an oil that crystallized
7.71 (t, 1 H); 13C NMR (CDCl3) δ 159.4, 125.5; 19F NMR (CDCl3)
Φ* -180.8; IR 1570, 1415, 1383, 1241, 1157 cm-1. EI MS: m/z
162 (M+). Anal. Calcd for C4H3FN2O2S: C, 29.63; H, 1.86; N,
17.28; F 11.72. Found: C, 29.67; H, 1.87; N, 17.07; F 11.53.
Acknowledgment. The authors thank the Pfizer Summer
Intern Program for a summer internship (K.N.H.) and their
support of this work.
Supporting Information Available: General experimental
1
procedures and H NMR, 13C NMR, 19F NMR, IR, MS data, and
elemental analyses for compounds 3c-3g, 3i, 3k-3q, 3t, 5, 8b,
8e, 8f, 8k, 8o. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO052164+
1084 J. Org. Chem., Vol. 71, No. 3, 2006