Expedient syntheses of sulfonylhydantoins and two six-membered analogues

Article abstract of DOI:10.1055/s-2005-863735

A range of α-amino esters can be turned into sulfonyl-hydantoins 2 in a single, atom-economic step using sulfamide and DBU. This procedure obviates the need for a three- or four-step sequence utilised by traditional procedures. Two new six-membered analogues 3 and 4 have also been prepared utilising novel synthetic protocols.

Full text of DOI:10.1055/s-2005-863735

834
LETTER
Expedient Syntheses of Sulfonylhydantoins and Two Six-Membered
Analogues
E
xpedient Synthe
s
n
es of Sulfon
d
AstraZeneca Research and Development, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Fax +44(1625)516667; E-mail: andrew.campbell2@astrazeneca.com
Received 26 October 2004
by basic cyclisation forms the desired sulfonylhydantoin.
Alternatively, the isocyanate is reacted with formic acid8
or water9 to generate ‘NH2SO2Cl’ which is subsequently
reacted with the amine and cyclised to form the same
Abstract: A range of a-amino esters can be turned into sulfonyl-
hydantoins 2 in a single, atom-economic step using sulfamide and
DBU. This procedure obviates the need for a three- or four-step se-
quence utilised by traditional procedures. Two new six-membered
analogues 3 and 4 have also been prepared utilising novel synthetic products. Although this route works, we believed this
protocols.
three- or four-step sequence could be improved and avoid
the use of the highly reactive chlorosulfonyl isocyanate.
Key words: amino acids, sulfonamides, heterocycles, medicinal
chemistry, phosphates
The first report of the 1,2,5-thiadiazolidin-3-one 1,1-diox-
ide moiety (‘sulfonylhydantoin’, 1) was in 1965 by the
group of Ziegler.1 Since then, this heterocycle has re-
ceived a lot of attention amongst the synthetic and medic-
inal chemistry community particularly in relation to serine
protease inhibitors,2 crop protection agents,3 antihyper-
tensives,4 artificial sweetners5 and others.6 More recently,
they have been described as PTB-1b inhibitors which may
have a role in controlling blood sugar in diabetes7a and as
anti-cancer compounds.7b We became interested in sulfo-
nylhydantoins such as 2 and their closely related but pre-
viously unknown analogues 3 (5-aryl-1,2,6-thiadiazinan-
3-one 1,1-dioxide) and 4 (5-aryl-1,2-thiazinan-3-one 1,1-
dioxide) as phosphate mimics (Figure 1). N-substituted
sulfonylhydantoins are usually prepared by one of two
general methods starting from N-substituted a-ami-
noesters.2b,5 Reaction of an alcohol with chlorosulfonyl
isocyanate generates the N-protected sulfonyl chloride
(Scheme 1), which is then reacted with the amine to form
the sulfamoyl group. Protecting group removal followed
Scheme 1 Standard methods for synthesising sulfonylhydantoins.
Reagents and conditions: i) ClSO2NCO, ROH then a-amino ester,
base; ii) deprotection of protecting group (PG); iii) NaH or NaOMe;
iv) ClSO2NCO, HCOOH or H2O then a-amino ester/base.
We hoped to react our amino esters with sulfamide
(NH2SO2NH2) in the presence of a base to effect a sulfa-
moylation and cyclisation in one pot. There is one litera-
ture example of this transformation being achieved
directly without the use of base,4 although the substrate
scope was not examined. The amino esters were either
commercially available or prepared by standard amine-
monoalkylation of methyl bromoacetate or reductive am-
ination with glycine methylester hydrochloride with the
corresponding aldehyde according to the procedure of
Groutas and co-workers.2b The reaction of amines with
sulfamide is well documented10 so we initially attempted
heating N-benzyl glycine ethyl ester with sulfamide at
160 °C in the absence of solvent for 15 minutes. Follow-
ing purification, we were pleased to isolate the desired
sulfamoylated product (addition of SO2NH2 to the amine)
in 65% yield. The same reaction was attempted with the
addition of one equivalent of DBU, and the required sul-
fonylhydantoin was isolated after acid/base work up in
good yield without the need for chromatography.11 This
procedure was then applied to a range of substituted gly-
cine derivatives (Table 1). Although the unoptimised
Figure 1 Examples of sulfonylhydantoins and analogues required.
SYNLETT 2005, No. 5, pp 0834–0838
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863735; Art ID: D32104ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Expedient Syntheses of Sulfonylhydantoins
835
yields are moderate in most cases, the one-step protocol (entry 8) and ester functionalities (entry 9). The reaction
allowed for a large range of sulfonylhydantoins to be with N-phenyl glycine methyl ester failed to give any
prepared in a time efficient manner without the need for product (entry 16) while dilution with solvent (entry 3)
chromatography in any example. The procedure tolerates and heating under microwave conditions also failed to
substitution at the a-carbon (entries 10, 13–15) and substi- give clean product formation.
tution a to the amine (entry 6) although the yield drops
considerably with gem-dimethyl substitution (entry 11).
The reaction also tolerates thiophene (entry 5), nitrile
Table 1 Results for the Reaction of a-Amino Esters with Sulfamide and DBU11
Entry
1
a-Amino ester
Product
Yield (%)a,b
65a,b
2
3
4
5
6
35
29c
45
43
26
7
8
9
47
36
55
Synlett 2005, No. 5, 834–838 © Thieme Stuttgart · New York

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A. D. Campbell, A. M. Birch
LETTER
Table 1 Results for the Reaction of a-Amino Esters with Sulfamide and DBU11 (continued)
Entry
10
a-Amino ester
Product
Yield (%)a,b
23
11
12
13
14
15
16
2
40
38
57
39
0
a Reaction without DBU gave uncyclised material in 65% isolated yield.
b If a salt is used in this reaction, a second equivalent of DBU was added. The yield was 65%.
c Heating at 160 °C in THF–H2O for 15 min gave an impure reaction mixture.
We next turned our attention to the hitherto unknown 5-
aryl-1,2,6-thiadiazinan-3-one 1,1-dioxide system 3 which
we hoped to make by the same method. Unfortunately,
when b-amino acid 5 was heated with sulfamide and
DBU, the only isolated product was methyl cinnamate 6
presumably formed by elimination in the basic conditions.
Heating with sulfamide in the absence of DBU did form
the desired product in low yield, however, by-products 6
and 8 were isolated as the major products (Scheme 2).
We therefore reverted to homologation using NH2SO2Cl.
The required starting b-amino esters were prepared by
Scheme 2 Reaction of b-amino ester with sulfamide with and
without added DBU. Reagents and conditions: i) NH2SO2NH2, DBU,
160 °C, 15 min, 55%; ii) NH2SO2NH2, 160 °C, 20 min, 7, 15%, 8,
22%, 6, 42%.
Rodionow reaction12 of 3-bromobenzaldehyde and 5-bro-
mo-2-methoxybenzaldehyde with ethyl hydrogen mal-
onate in the presence ammonium chloride (Scheme 3).
Although the yields were relatively low, the starting
Synlett 2005, No. 5, 834–838 © Thieme Stuttgart · New York

LETTER
Expedient Syntheses of Sulfonylhydantoins
837
materials were cheap, readily available and the amine rationale was substantiated by obtaining a 36% yield of
products easily purified. These amines were then reacted product 11 as the E-isomer (J = 15.6 Hz). Unfortunately,
with sulfamoyl chloride prepared from chlorosulfonyl on scale-up (8 mmol) the yield dropped to 23%.
isocyanate and water in THF. This revised procedure gave
Another strategy utilising a cross-metathesis between
much improved yields compared to the formic acid proce-
phenyl vinylsulfonate and 3-bromo styrene using Grubbs
dure.8 The sulfamoylated products underwent smooth cy-
second generation ruthenium catalyst failed to give any
clisation with NaOMe in MeOH to afford the novel
cross-metathesis product despite good precedent with vi-
substituted ring system. Both compounds were coupled
nyl phosphates and styrenes.16 Although alkenyl sulfonate
smoothly with phenyl boronic acid under Suzuki condi-
12 could be prepared and indeed reacted with dimethyl
tions to give homologated products and to exemplify that
malonate, the low yielding initial step meant that an alter-
these structures are amenable to palladium-catalyzed cou-
native strategy had to be followed.
pling protocols.
Our second option was to go via a Michael reaction of a
malonate anion to a b-substituted vinyl sulfonamide as the
key step (Scheme 4), a process that is not documented in
the literature. Thus N,N-bis(4-methoxybenzyl)methane-
sulfonamide was easily prepared by reaction of methane-
sulfonyl chloride with bis(4-methoxybenzyl)amine.
Alternatively, the same material could be prepared by
alkylation of methanesulfonamide with 4-methoxybenzyl
The final ring system (5-aryl-1,2-thiazinan-3-one 1,1-di-
oxide) 4 had not been prepared previously although the
work by Morris and Wishka13 gave us an insight into pre-
paring a regioisomeric aryl-substituted product. Our ini-
tial plan relied heavily on the preparation of vinyl
sulfonate ester 12 (Scheme 4) and a Michael addition of
the malonate anion to it.14 The phenyl sulfonate ester was
chosen due its lability to sulfur-oxygen cleavage com-
chloride albeit in lower yield. The sulfonamide was then
pared to an alkyl sulfonate ester, which may be prone to
treated with LiHMDS (2 equiv) followed by the addition
alkyl-oxy fission. Thus, phenyl methylsulfonate was
of diethyl chlorophosphate and quenched with 5-bromo-
treated with two equivalents of LiHMDS at –78 °C fol-
2-methoxybenzaldehyde to form alkenyl sulfonamide 14
in 80% yield. We were delighted to find that Michael ad-
lowed by addition of one equivalent of diethyl chloro-
phosphate to generate the Wadsworth–Emmons reagent
dition proceeded smoothly with dimethyl malonate to
in situ. Aldehyde 9 was added and warmed to room tem-
form the diester in 85% yield. Krapcho decarboxylation
perature. Unfortunately, no product was isolated from the
reaction. In order to ascertain why the reaction had failed,
carried out in DMF and sulfonamide deprotection in 1:1
13
TFA–CH2Cl2 formed the sulfonamide 15 in 46% yield
we attempted the same reaction using ethyl methane-
over two steps. Cyclisation using standard NaOMe in
sulfonate and were pleased to isolate the alkenyl product
MeOH conditions smoothly formed the novel 5-aryl-1,2-
11 in 85% yield solely as the E-isomer (J = 15.6 Hz).
thiazinan-3-one dioxide system in excellent yield. Suzuki
Hence, we assumed that during the generation of the anion
coupling with phenyl boronic acid formed the biaryl prod-
of phenyl methylsulfonate, elimination to sulfene and
uct 16 in 74% yield.
phenoxide was occurring15 prior to addition to diethyl
In conclusion, we have developed a novel one-step proto-
chlorophosphate. Therefore, we decided to carry out an in
col for the synthesis of sulfonylhydantoins from N-substi-
situ quench at low temperature, which might circumvent
tuted a-amino esters. The products are formed in high
sulfene formation. We were delighted to find that this
Scheme 3 Generation of the 5-aryl-1,2,6-thiadiazinan-3-one 1,1-dioxide ring system. Reagents and conditions: i) NH4Cl, ethyl hydrogen
malonate, EtOH, reflux 16 h, R = OMe, 25%; R = H, 13%; ii) ClSO2NCO, THF, H2O (1 equiv), 0 °C, 1 h, b-amino ester then Et3N, R = OMe,
57%; R = H, 67%; iii) NaOMe–MeOH, r.t., 1 h, R = OMe, 82%; R = H, 94%; iv) PhB(OH)2, DME–H2O (2:1), Pd(PPh3)4 (5 mol%), Cs2CO3
(4 equiv), R = OMe, 82%; R = H, 50%.
Synlett 2005, No. 5, 834–838 © Thieme Stuttgart · New York

838
A. D. Campbell, A. M. Birch
LETTER
Scheme 4 Generation of the 5-aryl-1,2-thiazinan-3-one 1,1-dioxide ring system. Reagents and conditions: i) ethyl methanesulfonate,
LiHMDS (2 equiv), –78 °C, 30 min then ClPO(OEt)2, 1 h then RCHO 9, –78 °C to r.t., 1 h, 85%; ii) phenyl methanesulfonate, LiHMDS (2
equiv), –78 °C, 30 min then ClPO(OEt)2, 1 h then RCHO 9, –78 °C to r.t., 1 h, 0%; iii) phenyl methanesulfonate, ClPO(OEt)2, LiHMDS (2
equiv), –78 °C, 1 h then RCHO 9, –78 °C to r.t. 1 h, 23–36%; iv) dimethyl malonate, NaOMe–MeOH, MeCN, 48 h, r.t., 85%; v) N,N-bis(4-
methoxybenzyl)methanesulfonamide, LiHMDS (2 equiv), –20 °C, 30 min then ClPO(OEt)2, 1 h then RCHO 10, –20 °C to r.t., 1 h, 80%; vi) a)
dimethyl malonate, NaOMe–MeOH, MeCN, 18 h, reflux, 85%; b) DMF, NaCl, H2O, reflux, 5h; c) TFA–CH2Cl2 (1:1), 18 h, r.t., 46% (2 steps);
vii) a) NaOMe–MeOH, r.t., 1 h, 93%; b) PhB(OH)2, DME–H2O (2:1), Pd(PPh3)4 (5 mol%), Cs2CO3 (4 equiv), 74%.
purity, quickly and without the need for chromatography.
The procedure should be readily applicable to the synthe-
sis of other sulfonylhydantoins. Two previously unde-
scribed six-membered analogues have also been prepared
using novel chemistry and have proved compatible to
further functionalisation.
(8) Lee, C.-H.; Korp, J. D.; Kohn, H. J. J. Org. Chem. 1989, 54,
3077.
(9) Graf, R. Chem. Ber. 1959, 92, 509.
(10) Lee, H.-C.; Kohn, H. J. J. Org. Chem. 1990, 55, 6098.
(11) Sulfamide (159 mg, 1.65 mmol) was added to methyl N-(2-
methoxybenzyl)glycinate (345 mg, 1.65 mmol) followed by
addition of DBU (0.25 mL, 1.65 mmol) in a 10 mL pyrex
tube under an argon stream. The reaction was then heated to
160 °C at which point the reaction became homogeneous
and bubbling was observed. After 15 min, the reaction was
cooled to r.t. and diluted with 1 M NaOH (40 mL) and Et2O
(20 mL) and shaken until all the gum dissolved. The aqueous
layer was separated, acidified with 6 M HCl until pH 1 and
then extracted with EtOAc (2 × 20 mL). The combined
EtOAc layers were dried (MgSO4), filtered and evaporated
to form a beige solid. Trituration with Et2O–hexanes (1:5, 5
mL) followed by filtration afforded the sulfonylhydantoin
product (Table 1 entry 4, 190 mg, 0.742 mmol, 45%) as an
off-white solid. 1H NMR (300 MHz, DMSO): d = 3.80 (s, 3
H), 4.00 (s, 2 H), 4.24 (s, 2 H), 6.93 (t, J = 7.5 Hz, 1 H), 7.01
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Synlett 2005, No. 5, 834–838 © Thieme Stuttgart · New York