Preparation of 4,6-disubstituted 5-pyrimidinesulfonamides

Article abstract of DOI:10.1055/s-1998-1999

The first general synthesis of 4,6-disubstituted 5-pyrimidinesulfonamides is described. Treatment of 4,6-dichloro-5-benzylthiopyrimidine (3) with ethoxide or trifluoroethoxide, oxidation of the benzylthio group to a sulfonyl chloride and reaction with amm

Full text of DOI:10.1055/s-1998-1999

3
6
Short Papers
SYNTHESIS
Preparation of 4,6-Disubstituted 5-Pyrimidinesulfonamides
Wayne M, Best, Marie-Anne M. Fam, Martin J. Gregory, Bruno Kasum, Philip L. Keep, Sam Lazzaro, Nicole Osner,
1
*,2
Natasha Stewart, San H. Thang, Keith G. Watson
ICI Australia, Research Group, Newsom St. Ascotvale, Victoria 3032, Australia
Fax + 61(3)99054597; E-mail: k.watson@sci.monash.edu.au
Received 16 June 1997; revised 11 August 1997
The first general synthesis of 4,6-disubstituted 5-pyrimidinesulfona-
cleophilic replacement of the 4,6-dichloro substituents on
mides is described. Treatment of 4,6-dichloro-5-benzylthiopyrimi-
dine (3) with ethoxide or trifluoroethoxide, oxidation of the
benzylthio group to a sulfonyl chloride and reaction with ammonia
gave 4,6-dialkoxy-5-pyrimidinesulfonamides 5a,b. Stepwise dis-
compound 3 with 2,2,2-trifluoroethoxy or ethoxy groups
gave compounds 4a and 4b, and then oxidative
chlorination11 gave the corresponding sulfonyl chlorides,
placement of the trifluoroethoxy groups in 5a gave a variety of sym- which were immediately converted to the sulfonamides
metrical and non-symmetrical 4,6-disubstituted 5-pyrimidinesulfon-
amides 5b–-h.
5
a and 5b, in good overall yield (Scheme).
The sulfonylurea herbicides represent a major develop-
ment in agricultural chemistry, providing broad spectrum
weed control at field rates as low as 2 to 5 grams/hectare.
3
Since their discovery by DuPont chemists in 1976, more
than twenty different sulfonylurea herbicides have been
commercialized for weed control in many important
4
crops. The requirements for activity have been well de-
5
scribed by Levitt and most herbicidal sulfonylureas fall
into the general class of structure 1. For high herbicidal
activity it is important that the aryl ring contains a substit-
uent ortho to the sulfonylurea bridge, but no substituent
para to the bridge. There are commercial sulfonylurea her-
bicides in which the aryl ring in structure 1 is a substituted
benzene (11 examples), pyrazole (4 examples), pyridine
(
3 examples) or a thiophene ring.4
Arylsulfonylureas in which the aryl ring is pyrimidine are
6
disclosed in the patent literature, but the only example
given was prepared from a 2-pyrimidinesulfonamide and
is herbicidally inactive, probably because it has no substit-
uents ortho to the sulfonyl group. We believed that it
should be possible to achieve high herbicidal activity with
pyrimidylsulfonylureas of general structure 2, prepared
from either 4-substituted or 4,6-disubstituted 5-pyrim-
idinesulfonamides. However, the only reported prepara-
tion of a 5-pyrimidinesulfonamide lacking a 2-substituent
involved a low yielding and indirect synthesis of 4,6-di-
7
amino-5-pyrimidinesulfonamide. We have now devel-
oped a more general synthetic route for the preparation of
such pyrimidine derivatives and have confirmed that sul-
fonylureas prepared with these new sulfonamides have
high herbicidal activity.8
Chlorosulfonation would appear to be the most direct
method for the preparation of 5-pyrimidinesulfonamides.
Thus, uracil is known to react at high temperatures to give
9
5
-chlorosulfonyl-2,4-dihydroxypyrimidine, but we have
found that 4,6-dihydroxypyrimidine does not undergo
chlorosulfonation under similar conditions,
We have recently reported10 a convenient synthesis of 5-
benzylthio-4,6-dichloropyrimidine (3) from the readily
available 4,6-dihydroxypyrimidine and we now report
that compound 3 is a useful precursor to a wide range of
4
,6-disubstituted 5-pyrimidinesulfonamides. Thus, nu- Scheme

January 1998
SYNTHESIS
37
1
2
It is well known that activated 4-alkoxypyrimidines will
undergo reactions such as transalkoxylation, alkaline hy-
drolysis and aminolysis, though in general fairly harsh
C
15
H
18
N
2
O
2
S
calc.
found
C
62.06
62.19
H
6.25
6.03
N
9.65
9.51
(290.4)
1
H NMR (CDCl ): d = 1.35 (6 H, t, J = 7.1 Hz), 3.98 (2 H, s), 4.39
3
(
4 H, q, J = 7.1 Hz), 7.16 (5 H, s), 8.25 (1 H, s).
conditions such as elevated temperatures are necessary.
1
3
Trifluoroethoxy is known13 to be a better leaving group
C NMR: d = 14.50, 36.59, 63.13, 97.26, 126.99, 128.20, 128.82,
1
38.03, 155,94, 169.47.
than ethoxy and therefore we decided to test the use of
compound 5a as the key precursor to a variety of 4,6-di-
substituted 5-pyrimidinesulfonamides. We have found
that the bis(trifluoroethoxy)pyrimidinesulfonamide 5a
4
,6-Bis(2,2,2-trifluoroethoxy)-5-pyrimidinesulfonamide (5a);
Typical Procedure:
undergoes nucleophilic displacement of one or both of the A suspension of 4a (18.5 g, 47 mmol) in AcOH (270 mL) and H O
2
(
65 mL) was vigorously stirred and cooled to 5 °C. Cl gas was bub-
trifluoroethoxy substituents under mild conditions and we
have used 5a to prepare the various other sulfonamides
2
bled into the reaction mixture for 20 min and stirring was continued
while maintaining the reaction temperature below 10°C for a further
1
5
b–h shown in the Table.
5 min. The reaction mixture was poured onto ice water (600 mL) and
the crude sulfonyl chloride separated as a cream solid which was col-
lected by filtration (15.9 g, 91%). The sulfonyl chloride (15.9 g) was
dissolved in MeCN (160 mL) and the solution was cooled with ice
Table. Sulfonamides 5b–h Prepared from 5a by Reaction with Nu-
cleophiles
and treated with a stream of gaseous NH for 10 min. The mixture was
3
stirred at 5 °C for a further 15 min and then the solvent and excess
Product
A
B
Nucleophile Yield (%)
NH were removed on a rotary evaporator. The residue was stirred
3
with H O (50 mL) and filtered to give the product 5a as a cream solid
which gave colourless crystals (10.6 g, 71%) from EtOAc/hexane; mp
98–100°C.
2
5
5
5
5
5
5
5
b
c
d
e
f
OEt
OEt
SMe
SMe
HO
OEt
OCH CF3
OCH CF3
SMe
OCH CF3
OCH CF3
NH2
EtO–
EtO–
MeS–
72
52
73
72
86
59
45
2
2
C H F N O S calc.
C
27.05
27.20
H
1.99
1.95
N
11.82
11.57
–
8 7 6 3 4
MeS
(355.2)
found
–
HO
2
1
H NMR (CDCl ): d = 4.87 (4 H, q, J = 8.2 Hz), 6.3 (2 H, br s), 8.38
g
h
NH2
NH2
NH3
NH3
3
2
(1 H, s).
1
3
C NMR: d = 62.7 (q, JC,F = 37 Hz), 110, 123.3 (q, JC,F = 277 Hz),
1
57.9, 164,3.
Melting points were determined using a Gallenkamp MFB-595 appa-
1
13
ratus and are uncorrected. H and C NMR spectra were recorded on
a Bruker AC-200 spectrometer in DMSO-d as solvent (unless other-
4,6-Diethoxy-5-pyrimidinesulfonamide (5b):
6
wise specified), locked on solvent deuterium and referenced to resid-
ual solvent protons. Mass spectra were measured with a VG Trio-1
spectrometer at 70 eV. TLC was carried out on Whatman silica gel
Method A: Starting with compound 4b and following essentially the
typical procedure as described for compound 5a, the sulfonamide 5b
was obtained in 75% yield as colourless crystals; mp 158–159°C.
6
0A plates and Merck silica gel 60 (0.063-0.20 mm) was used for col-
C H N O S
calc.
found
C
38.86
38.82
H
5.30
5.13
N
17.00
16.77
8
13 3 4
umn chromatography. Commercially available solvents and reagents
were used without further purification.
(247.3)
1
H NMR : d = 1.35 (6 H, t, J = 7.2 Hz), 4.49 (4 H, q, J = 7.2 Hz), 7.25
2 H, br s), 8.52 (1 H, s).
(
5
-Benzylthio-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (4a):
13
C NMR : d = 14.39, 63.94, 109.07, 158.38, 165.67.
NaH (60% dispersion in oil, 1.8 g, 45 mmol) was added to a solution
of 2,2,2-trifluoroethanol (3.25 mL, 45 mmol) in dioxane (30 mL) and
the mixture was stirred at r.t. for 0.5 h, 5-Benzylthio-4,6-dichloropyr-
imidine (3; 3.0 g, 11 mmol) in dioxane (20 mL) was added slowly (15
min) and the resulting mixture was stirred for 3 h at 50°C. The solvent
was evaporated and the residue was partitioned between EtOAc and
Method B: Compound 5a was treated with a solution of excess
NaOEt in EtOH at r.t. following essentially the same procedure as de-
scribed for compound 4b from 3. The reaction was monitored by TLC
which showed complete reaction after 16 h and compound 5b was
isolated in 72% yield.
dil aq 5% citric acid. The organic layer was washed with H O, sepa-
2
rated, dried (MgSO ) and evaporated to give the product (4.3 g, 97%)
4
as a yellow oil which crystallized on standing to give compound 4a as
pale yellow crystals; mp 57–58 °C.
4
(
-Ethoxy-6-(2,2,2-trifluoroethoxy)-5-pyrimidinesulfonamide
5c):
Compound 5a (180 mg, 0,5 mmol) was added to a solution of Na
15 mg, 0.65 mmol) in EtOH and the solution was stirred at r.t. for 24
C H F N O S calc.
C
45.23
45.58
H
3.04
3.09
N
7.03
6.85
15 12 6 2 2
(
398.3)
found
(
1
H NMR (CDCl ): d = 4.05 (2 H, s), 4.78 (4 H, q, J = 8.3 Hz), 7.19
h. TLC showed the formation of compound 5b plus a second, faster
moving and major product. The solvent was evaporated and the resi-
due was partitioned between H O (15 mL) and CHCl (2 ´ 30 mL).
3
(5 H, s), 8.26 (1 H, s).
1
3
C NMR: d = 36.45, 62.90 (q, JC,F = 37 Hz), 98.85, 123.75 (q, JC,F
=
2
3
2
76 Hz), 127.27, 128.38, 128.66, 137.31, 155.73, 168.28.
The organic layers were combined. dried (MgSO ) and evaporated to
4
give a solid which was purified by chromatography on silica gel using
CHCl as eluent. Compound 5c was obtained as colourless crystals
5
5
-Benzylthio-4,6-bis(ethoxy)pyrimidine (4b):
-Benzylthio-4,6-dichloropyrimidine (3; 2.7 g, 10 mmol) was added
3
(80 mg, 52%); mp 88–89 °C.
to a solution of sodium metal (0.7 g, 30 mmol) in EtOH (50 ml) and
the solution was refluxed for 16 h. Most of the solvent was evaporated
and the residue was partitioned between dil HCl (1 M, 100 mL) and
CHCl3 (2 ´ 100 mL). The combined CHCl3 layers were dried
C H F N O S calc
C
31.89
32.00
H
3.35
3.52
N
13.95
13.76
8
10 3 3 4
(301.2)
found
1
H NMR (CDCl ): d = 1.46 (3 H, t, J = 7.1 Hz), 4.61 (2 H, q, J =
3
7
.1 Hz), 4.91 (2 H, q, J = 8.2 Hz), 5.4 (2 H, br s), 8.44 (1 H, s).
(
MgSO ) and evaporated to give the crude product which was purified
4
1
3
by chromatography on silica gel to afford 4b (2.6 g, 89%) as a pale
yellow solid; mp 59-61 °C.
C NMR: d = 14.30, 62.23 (q, JC,F = 37 Hz), 64.56, 109.52, 118.1 (q,
J
C,F = 256 Hz), 158.29, 163.94, 166.15.

3
8
Short Papers
SYNTHESIS
4
-Methylthio-6-(2,2,2-trifluoroethoxy)-5-pyrimidinesulfonamide C H F N O S calc.
C
26.48
26.61
H
2.59
2.53
N
20.58
20.59
6
7 3 4 3
(5d):
(272.2)
found
Compound 5a (710 mg, 2 mmol) was added to a stirred suspension of
NaOMe (140 mg, 2 mmol) in DMF (4 mL) at r.t. Stirring was contin-
ued for 4 h before the reaction mixture was poured into dil aq citric
acid (10%, 50 mL) and the precipitate collected by filtration to give
compound 5d as a near white solid (440 mg, 73%); mp 151–l52°C.
1
H NMR (acetone-d ): d = 5.13 (q, 2 H, J = 8.7 Hz), 6.63 (br s, 2 H),
6
7
.06 (br s, 1 H), 7.50 (br s, 1 H), 8.23 (s, 1 H).
1
3
C NMR : d = 61.53 (q, J = 35 Hz), 102.39, 123.59 (q, JC,F
=
C,F
2
78 Hz), 158.49, 160.36, 164.14.
C H F N O S calc.
C
27.72
27.93
H
2.66
2.64
N
13.85
13.70
4,6-Diamino-5-pyrimidinesulfonamide (5h):
7
8 3 3 3 2
(303.3)
found
NH OH (25%, 4 mL) was added with stirring to 5a (350 mg, 1 mmol).
4
1
The mixture was stirred and heated at 70°C for 6 h and then concen-
trated to dryness on a rotary evaporator. The residue was directly
chromatographed on silica gel (10 g), starting with EtOAc as eluent
to remove 5g (70 mg) and then using 10% MeOH/EtOAc to give 5h
H NMR : d = 2.48 (s, 3 H), 5.23 (q, 2 H, J = 8.3 Hz), 7.56 (br s, 2 H),
8
.77 (s, 1 H).
1
3
C NMR : d = 14.10, 61.80 (q, JC,F = 36 Hz), 120.19, 123.02 (q, JC,F
284), 156.86, 162.90, 169.65.
=
7
as a colourless solid (85 mg, 45%); mp 220–222°C (Lit. mp 221–
2
1
22°C).
4
,6-Dimethylthio-5-pyrimidinesulfonamide (5e):
H NMR : d = 7.0 (br s, 4 H), 7.45 (s, 2 H), 7.81 (s, 1 H).
A solution of 5a (355 mg, 1 mmol) in DMF (1 mL) was added to a
stirred suspension of NaOMe (220 mg, 3.1 mmol) in DMF (3 mL) at
r.t. The reaction mixture was stirred for 4 h and then poured into dil
aq citric acid (10%, 50 mL) and the creamy precipitate was collected
by filtration to give compound 5e (182 mg, 72%); mp 200-201 °C.
13
C NMR : d = 96.53, 158.94, 159.46.
(1) New address: CSIRO, Division of Chemicals & Polymers, Pri-
vate Bag 10, Clayton South MDC, Victoria 3169, Australia
C H N O S
9 3 2 3
calc.
found
28.67
28.57
H
3.61
3.48
N
16.71
16.41
(2) New address: Biota Chemistry Laboratory, Chemistry Depart-
ment, Monash University, Clayton, Victoria 3168, Australia
(3) Beyer, E.M,; Duffy, M. J.; Schlueter, D,D. In Herbicides: Chem-
istry, Degradation and Mode of Action; Vol. 3; Kearney, P. C.;
Kaufman, D. D., Eds.; Marcel Dekker, Inc.: New York, 1988;
p 117.
6
(
251.4)
1
H NMR : d = 2.49 (s, 6 H), 7.78 (br s, 2 H), 8.81 (s, 1H).
13
C NMR : d = 14.19, 131.66, 155.26, 167.86.
4-Hydroxy-6-(2,2,2-trifluoroethoxy)-5-pyrimidinesulfonamide(5f):
A solution of NaOH (0.91g, 23 mmol) in H O was added to 5a (2.01
(4) The Pesticide Manual, 10th ed., Tomlin, C., Ed.; British Crop
Protection Council: Bath, 1994; p 1340
(5) Levitt, G. In Synthesis and Chemistry of Agrochemicals II, ACS
Symposium Series No. 443, Baker, D. R.; Fenyes, J. G.;
Moberg, W. K., Eds.; American Chemical Society: Washing-
ton, DC, 1990; p 16.
2
g, 5.7 mmol). The suspension was stirred and heated to 90°C, giving
a clear solution which was heated for a further 2 h. The reaction mix-
ture was cooled, acidified to pH 6 with concd HCl, and after standing
at 0°C for 1 h the white precipitate was collected by filtration and air
dried to give 5f (1.33 g, 86%) as a colourless solid; mp 243.5–
2
44.5°C.
(6) Boehner, B.; Foery, W.; Schurter, R.; Pissiotas, G. U. S. Patent
4
707551, 1987; Chem. Abstr. 1984, 100, 139152
C H F N O S calc.
C
26.38
26.44
H
2.21
2.09
N
15,38
15.67
6
6 3 3 4
(
273.2)
found
(7) Gilow, H. M.; Jacobus, J. J. Org. Chem. 1963, 28, 1994
(8) Watson, K. G.; Best, W. M. U. S. Patent 5298480, 1994; Chem.
Abstr. 1992, 116, 83695.
1
H NMR : d = 5.09 (q, 2 H, J = 8.9 Hz), 6.96 (br s, 2 H), 8.42 (s, 2 H).
1
3
C NMR : d = 62.86 (q, JC,F = 35 Hz), 109.91, 123.54 (q, JC,F
=
Watson, K. G.; Keep, P. L, C.; Gregory, M. J.; Thang, S. H. PCT
Int. Appl. WO 9206,965; Chem. Abstr. 1992, 117, 111652.
2
77 Hz), 152.25, 159.57, 163.42.
(
9) Herr, R. R.; Enkoji, T.; Bardos,T. J. J. Am. Chem. Soc. 1956, 78,
4
-Amino-6-(2,2,2-trifluoroethoxy)-5-pyrimidinesulfonamide (5g):
4
4
01.
NH OH (15%, 5 mL) was added with stirring at r.t. to 5a (710 mg,
2
and excess NH were removed on a rotary evaporator and the residue
was partitioned between H O (5 mL) and EtOAc (3 ´ 30 mL). The
combined organic layers were dried (MgSO ), filtered and evaporated
to give a semi-crystalline solid which was purified by chromatogra-
phy on silica gel using 95% CHCl /MeOH as eluent. Compound 5g
(
10) Thang, S. H.; Watson. K. G.; Best, W. M.; Fam, M-A. M; Keep,
mmol). The reaction mixture was stirred for 15 h at r.t. and then H O
2
P. L. C. Synth. Commun. 1993, 23, 2363
3
(
(
11) Roblin, R. O.; Clapp, J. W. J. Am. Chem. Soc. 1950, 72, 4890
12) Brown, D. J. In The Chemistry of Heterocyclic Compounds;
Vol.16, Supplement II; Weissberger, A.; Taylor, E. C., Eds.;
Interscience: New York, 1985.
2
4
3
was obtained as colourless crystals (320 mg, 59%); mp 201–202°C.
(13) Rappoport, Z.; Peled, P. J. Am. Chem. Soc. 1979, 101, 2682