Rapid and selective synthesis of substituted 1,2,5-thiadiazolidine 1,1-dioxides

Article abstract of DOI:10.1055/s-2006-939039

The reaction of N,N-dimethylsulfamoyl aziridines with primary amines gives direct access to substituted 1,2,5-thiadiazolidines in a regioselective manner. Furthermore, the product from reaction with 4-methoxybenzyl amine can be subsequently manipulated to give the alternative nitrogen substitution pattern in a controlled fashion. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939039

LETTER
833
Rapid and Selective Synthesis of Substituted 1,2,5-Thiadiazolidine
1,1-Dioxides
Synthesis
o
of Substitute
a
d
1,2,5-Thi
n
adiazolidine
n1,1-Dioxidese Hannam, Timothy Harrison, Felicity Heath, Andrew Madin,* Kevin Merchant
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
Fax +44(1279)440390; E-mail: a.madin@astex-therapeutics.com
Received 12 December 2005
O
R
Abstract: The reaction of N,N-dimethylsulfamoyl aziridines with
primary amines gives direct access to substituted 1,2,5-thiadiazol-
idines in a regioselective manner. Furthermore, the product from
reaction with 4-methoxybenzyl amine can be subsequently mani-
pulated to give the alternative nitrogen substitution pattern in a
controlled fashion.
O
O
S
NH2
N
a, b
c, d
H2N
HN
3
4
Key words: heterocycles, aziridines, cyclic sulfamides, regioselec-
tive
k
2
R
t
SOn Bu
HN
e, f (n = 1)
g, h (n = 2)
N
i, j
H2N
As part of a progamme to develop potent and selective in-
hibitors of g-secretase for the treatment of Alzheimer’s
disease, we identified a series of cyclic sulfamides1 with
the general structure shown in Figure 1. We herein report
an improved synthesis of substituted 1,2,5-thiadiazol-
idines, which facilitates rapid exploration of structure–
activity relationships for this class of compounds.
(n = 2)
5 n = 1
6 n = 2
7
Scheme 1 Reagents and conditions: a) NH4OH, NaCN, NH3,
MeOH, 0 °C, 70%; b) LiAlH4, THF, r.t., 77%; c) SO2(NH2)2, pyri-
dine, reflux, 85%; d) NaH, RBr, DMF, r.t.; e) ( )-t-BuS(O)NH2,
Ti(OEt)4, THF, reflux, 72%; f) Me3S(O)I, NaH, DMSO, 81%; g) t-
BuSO2NH2, TiCl4, Et3N, (ClCH2)2, reflux, 83%; h) Me3S(O)I, NaH,
DMSO, 48%; i) RNH2, DMSO, 100 °C, 55–90%; j) CF3SO3H, ani-
sole, CH2Cl2, 0 °C to r.t.; k) SO2(NH2)2, pyridine, reflux, 36–67%, 2
steps.
H
O
R'
N
O
S
N
R
a tert-butylsulfonyl group requires strongly acidic condi-
tions that are often incompatible with many functional
groups.
Figure 1
Our initial approach introduced the nitrogen substituent,
R, by alkylation of the parent heterocycle, which in turn
was prepared by reaction of the appropriate diamine with
sulfamide (Scheme 1).2
We speculated that it may be possible to activate aziridine
opening with a sulfonyl group in which the tert-butyl
group is replaced with a moiety that could function as a
leaving group, thus facilitating in situ cyclisation to give
the cyclic sulfamide in one step (Scheme 2). This would
give the desired heterocycle directly, with the required
substitution pattern, and negate the need for harsh condi-
tions in either the opening of the aziridine or removal of
the activating group.
However, in some cases bis-alkylation led to a significant
reduction in yield of the required product, despite the use
of stoichiometric amounts of electrophile. This led us to
examine aziridine opening with primary amines as an al-
ternative method to create and control the desired substi-
tution pattern of the final heterocycle. Ellman and others3
have demonstrated the utility of the tert-butylsulfinyl
group in amine synthesis. An attractive feature is that it
can be removed under mild conditions, but opening of a
tert-butylsulfinyl aziridine4 with an amine requires some-
what elevated temperatures.5 Therefore, we first targeted
the tert-butylsulfonyl analogue. In accordance with litera-
ture precedent,6 the reaction of 6 with an amine proceeds
smoothly and with complete regiocontrol, but removal of
O
X
O
S
SO2X
RNH2
HN
N
A
NHR
A
B
B
O
R
– XH
O
S
N
HN
A
B
SYNLETT 2006, No. 6, pp 0833–0836
Advanced online publication: 14.03.2006
0
4.
0
4.
2
0
0
6
Scheme 2
DOI: 10.1055/s-2006-939039; Art ID: D37005ST
© Georg Thieme Verlag Stuttgart · New York

834
J. Hannam et al.
LETTER
O
O
To test this possibility we chose to examine the reactivity
of N,N-dimethylsulfamoyl aziridines (X = NMe2). These
may be accessed from the tert-butylsulfinyl aziridine by
deprotection with HCl in methanol followed by reaction
with dimethylsulfamoyl chloride (Scheme 3). Alterna-
tively, they can be constructed from an amino alcohol in a
straightforward manner as shown in Scheme 4. The di-
methylsulfamoyl group can be introduced either follow-
ing Mitsunobu reaction7 or prior to conversion of the
alcohol to a leaving group. Both options serve as effective
routes to the desired heterocycle.
S
O
Me2N
N
a
13
14
NMe2
S
O
N
b
O
tBu
S
Me2N
15
S
N
O
Scheme 5 Reagents and conditions: a) Me2NSO2NH2, Ti(OEt)4,
THF, reflux, 50%; b) Me3S(O)I, NaH, DMSO, 87%.
N
O
O
a, b
O
O
Me2N
N
O
S
S
R
HN
Me
Ph
16 R = n-propyl
17 R = 4-methoxybenzyl
N
Me
O
a
5
8
Ph
(±)
Scheme 3 Reagents and conditions: a) HCl, dioxane, MeOH, 0 °C,
76%; b) Me2NSO2Cl, Et3N, CH2Cl2, r.t., 63%.
10
Me2N
Scheme 6 Reagents and conditions: a) RNH2, DMSO, 100 °C (16:
80%; 17: 90%).
O
S
O
NH2
Me
Me
a–c
N
Ph
OH
Ph
Table 1 Reaction of Aziridines 12 and 15 with Amines11
9
10
(±)
(±)
O
O
O
Me2N
S
N
O
S
RNH2
R
HN
N
Me2N
N
O
S
DMSO
100 °C
A
NH2
A
B
O
d, e
B
Ph
OH
Ph
12 or 15
11
12
O
NH
S
O
S
Entry RNH2
Scheme 4 Reagents and conditions: a) Me2NSO2Cl, Et3N, CH2Cl2,
r.t., 91%; b) MsCl, Et3N, CH2Cl2, r.t., 86%; c) NaH, THF, 0 °C, 83%;
d) DIAD, PPh3, PhMe, reflux, 62%; e) Me2NSO2Cl, Et3N, CH2Cl2,
r.t., 78%.
O
O
HN
N
N
Ph
R
R
1
2
18a, 87%
18b, 78%
19a, 87%12
19b, 66%
NH2
NH2
A more concise synthesis of N,N-dimethylsulfamoyl azir-
idines,8 starting from a carbonyl group, was developed
through adaptation of the sulfinyl imine chemistry de-
scribed in Scheme 1. Substituting dimethylsulfamide for
tert-butylsulfinamide affords the N,N-dimethylsulfamoyl
imine in modest yield9 (Scheme 5); subsequent reaction
with trimethylsulfoxonium ylide10 proceeds well to give
the activated aziridine in comparable overall yield to the
other routes described.
3
18c, 72%
19c, 67%
NH2
4
5
6
18d, 66%
18e, 79%
18f, 76%
19d, 77%
19e, 81%
19f, 64%
NH2
NH2
O
MeO
N
NH2
We found that simply heating 10 in DMSO at 100 °C with
five equivalents of a primary amine affords the desired cy-
clic sulfamide directly and in good yield (Scheme 6).
7
18g, 60%
19g, 66%
NH2
Aziridines 12 and 15 were then employed to test a range
of amines in this transformation (Table 1). Good yields
and regioselectivity were observed with allylic, benzylic
and sterically demanding aliphatic amines. Aliphatic
amines with heteroatoms, and heteroaromatic benzylic
Synlett 2006, No. 6, 833–836 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 1,2,5-Thiadiazolidine 1,1-Dioxides
835
NMe2
References and Notes
O
S
(1) (a) Sparey, T.; Beher, D.; Best, J.; Biba, M.; Castro, J. L.;
Clarke, E.; Hannam, J.; Harrison, T.; Lewis, H.; Madin, A.;
Shearman, M.; Sohal, B.; Tsou, N.; Welch, C.; Wrigley, J.
Bioorg. Med. Chem. Lett. 2005, 15, 4212. (b) Collins, I. J.;
Hannam, J. C.; Harrison, T.; Lewis, S. J.; Madin, A.; Sparey,
T. J.; Williams, B. J. WO 2002036555, 2004. (c) Collins, I.
J.; Cooper, L. C.; Harrison, T.; Keown, L. E.; Madin, A.;
Ridgill, M. P. WO 2003093252, 2003. (d) Collins, I. J.;
Hannam, J. C.; Harrison, T.; Madin, A.; Ridgill, M. P. WO
2004039800, 2004.
(2) Some other recent approaches to cyclic sulfamides:
(a) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem.
Soc. 2005, 127, 11250. (b) Espino, C. G.; Williams Fiori,
K.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126,
15378. (c) Nicolaou, K. C.; Longbottom, D. A.; Snyder, S.
A.; Nalbanadian, A. Z.; Huang, X. Angew. Chem. Int. Ed.
2002, 41, 3866.
(3) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984. (b) Ellman, J. A. Pure Appl. Chem. 2003, 75,
39.
(4) Preparation of tert-butyl sulfinyl aziridines: Morton, D.;
Pearson, D.; Field, R. A.; Stockman, R. A. Synlett 2003, 13,
1985.
(5) Campbell, A. Merck Sharp and Dohme, Terlings Park.
Personal communication: tert-butyl sulfinyl aziridines
derived from benzaldehydes undergo reaction with amines
at 150 °C in DMSO under microwave irradiation to give a
mixture of regioisomers.
NH
O
H
Ph
N
Ph
Figure 2 Structure of the product from the reaction of 12 with
aniline.
amines also performed well. Interestingly, the reaction of
12 with aniline, under the standard conditions, failed to
give the desired cyclic sulfamide. Instead, the product of
simple aziridine opening (Figure 2) was isolated in good
yield (90%).
The product from reaction with 4-methoxybenzylamine
can be further manipulated to access alternatively substi-
tuted analogues (Scheme 7). The sulfamide reacts
smoothly with simple alkyl halides after deprotonation
with sodium hydride,13 and the 4-methoxybenzyl group
can then be removed by treatment with trifluoroacetic acid
at room temperature.14
Me2N
O
S
O
O
O
S
HN
N
a
N
Ph
Ph
12
19a
(6) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999,
1, 783.
a
(7) Jiaxi, X. Tetrahedron: Asymmetry 2002, 13, 1129.
(8) Alternative synthesis of dimethylsulfamoyl aziridines from
alkenes: Greatbanks, D.; Seden, T. P.; Turner, R. W.
Tetrahedron Lett. 1968, 9, 4863.
O
S
O
S
O
O
b
HN
N
N
N
R
Ph
Ph
PMB
(9) N¢-{Bicyclo[4.2.1]non-3-en-9-ylidene}-N,N-dimethyl-
sulfamide (14). Titanium(IV) ethoxide (12.6 mL, 60 mmol)
was added to a solution of bicyclo[4.2.1]non-3-en-9-one15
(13, 2.72 g, 20 mmol) and N,N-dimethylsulfamide (12.4 g,
100 mmol) in dry THF (20 mL) at r.t. under N2. The dark red
solution was stirred and heated at reflux for 16 h, then
allowed to cool to r.t. The reaction mixture was poured into
brine (120 mL) with rapid stirring. After 20 min the solid
was removed by filtration through Hyflo®, washing with
EtOAc. The layers were separated and the aqueous layer was
extracted with EtOAc (2 × 200 mL). The combined extracts
were washed with half-sat. aq NaHCO3, then dried (MgSO4),
filtered and evaporated. The residue was purified by
chromatography (silica, 5% EtOAc–isohexane) to give the
title compound (2.4 g, 50%) as a colourless solid. 1H NMR
(360 MHz, CDCl3): d = 1.48–1.68 (2 H, m), 1.94–2.13 (2 H,
m), 2.17–2.38 (3 H, m), 2.56–2.65 (1 H, m), 2.83 (6 H, s),
2.88–2.94 (1 H, m), 3.73–3.80 (1 H, m), 5.54–5.72 (2 H, m).
13C NMR (90 MHz, CDCl3): d = 25.8, 29.8, 33.3, 34.9, 39.0,
42.4, 46.8, 125.8, 127.9. MS (ES+): m/z = 243 [MH+].
(10) (1¢R,2R,6¢S)-N,N-dimethyl-1H-spiro{aziridine-2,9¢-
bicyclo[4.2.1]non[3]ene}-1-sulfonamide (15). NaH (60%
disp., 600 mg, 15 mmol) was added portionwise to a stirred
solution of trimethylsulfoxonium iodide (3.3 g, 15 mmol) in
dry DMSO (25 mL) at r.t. under nitrogen. After 1 h, a
solution of imine 14 (2.4 g, 10 mmol) in dry DMSO (25 mL)
was added. After 1 h the reaction was quenched with H2O
(50 mL), then extracted with EtOAc (3 × 50 mL). The
combined extracts were washed with H2O (2 × 50 mL), brine
(50 mL) then dried (MgSO4), filtered and evaporated. The
residue was purified by chromatography (silica, 10%
EtOAc–isohexane) to give the title compound (2.2 g, 87%)
19f
20: R = PMB
21: R = H
c
Scheme 7 Reagents and conditions: a) RNH2, DMSO, 100 °C (19a:
87%; 19f: 64%); b) NaH, THF, n-PrBr, 96%; c) TFA, 99%.
In conclusion, we have developed a novel reaction of N,N-
dimethylsulfamoyl aziridines with primary amines to fur-
nish substituted 1,2,5-thiadiazolidines in a regioselective
manner. Furthermore, we have shown that the product
from reaction with 4-methoxybenzyl amine can be subse-
quently manipulated to give access to any desired nitrogen
substitution pattern in a controlled fashion.
Acknowledgment
The authors would like to thank Dr. I. J. Collins, Mr. M. P. Ridgill
and Miss L. Farnsworth for contributions to the work described in
Schemes 1 and 2, Miss M. Bettati for assistance with ee determina-
tion by chiral HPLC, and Mr. S. Thomas for accurate mass determi-
nations.
Synlett 2006, No. 6, 833–836 © Thieme Stuttgart · New York

836
J. Hannam et al.
LETTER
as a colourless solid. 1H NMR (400 MHz, CDCl3): d = 1.55–
1.61 (2 H, m), 1.93–1.97 (2 H, m), 2.09–2.18 (4 H, m), 2.39
(2 H, s), 2.65 (2 H, dd, J = 3.7, 13.2 Hz), 2.92 (6 H, s), 5.57
(2 H, br s). 13C NMR (90 MHz, CDCl3): d = 28.4, 34.1, 39.2,
41.3, 44.0, 58.4, 127.5. MS (ES+): m/z = 257 [MH+]. HRMS:
m/z calcd for C12H21N2O2S [MH+]: 257.1324; found:
257.1322.
hour, then partitioned between EtOAc (50 mL) and H2O (50
mL). The aqueous layer was extracted with EtOAc (50 mL).
The combined extracts were washed with brine (50 mL),
then dried (MgSO4), filtered and evaporated. The residue
was purified by chromatography (silica, 10% EtOAc–
isohexane) to give the cyclic sulfamide (718 mg, 96%) as a
colourless oil. 1H NMR (400 MHz, CDCl3): d = 0.95 (3 H, t,
J = 7.4 Hz), 1.69 (2 H, sext, J = 7.4 Hz), 2.71 (1 H, dd,
J = 9.1, 13.5 Hz), 2.78 (1 H, dd, J = 6.6, 9.3 Hz), 2.90 (1 H,
dt, J = 13.6, 7.7 Hz), 3.03–3.10 (2 H, m), 3.24 (1 H, dt,
J = 13.9, 7.0 Hz), 3.48–3.52 (1 H, m), 3.79 (3 H, s), 3.93 (1
H, d, J = 13.6 Hz), 4.19 (1 H, d, J = 13.6 Hz), 6.85 (2 H, d,
J = 8.6 Hz), 7.08 (2 H, d, J = 6.7 Hz), 7.21–7.28 (5 H, m).
13C NMR (90 MHz, CDCl3): d = 11.8, 22.0, 40.0, 49.8, 50.0,
50.5, 55.7, 58.9, 114.5, 127.3, 127.4, 129.2, 129.6, 130.4,
136.5, 159.9. HRMS: m/z calcd for C20H27N2O3S [MH+]:
375.1742; found: 375.1736.
(11) Typical Procedure for Aziridine Opening. A solution of
the aziridine (1 mmol) and the amine (5 mmol) in dry DMSO
(15 mL) was stirred and heated at 100 °C for 16 h under N2.
After cooling to r.t. the mixture was diluted with an equal
volume of H2O, then extracted with EtOAc (3 × 50 mL). The
combined extracts were washed with brine (50 mL) then
dried (MgSO4), filtered and evaporated. The residue was
purified by chromatography (silica, EtOAc–isohexane) to
give the cyclic sulfamide.
(12) Data for (4S)-4-Benzyl-2-propyl-1,2,5-thiadiazolidine-
1,1-dioxide (19a). 1H NMR (400 MHz, CDCl3): d = 0.96 (3
H, t, J = 7.4 Hz), 1.62 (2 H, sext, J = 7.3 Hz), 2.83–2.93 (2
H, m), 2.97–3.05 (2 H, m), 3.07 (1 H, dd, J = 9.2, 7.1 Hz),
3.42 (1 H, dd, J = 9.2, 6.8 Hz), 3.95 (1 H, sext., J = 7.0 Hz),
4.43 (1 H, br d, J = 6.2 Hz), 7.20 (2 H, d, J = 7.0 Hz), 7.26–
7.35 (3 H, m). 13C NMR (90 MHz, CDCl3): d = 11.8, 21.6,
41.1, 48.9, 53.8, 54.0, 127.7, 129.3, 129.5, 136.5. HRMS:
m/z calcd for C12H19N2O2S [MH+]: 255.1167; found:
255.1176. [a]D22 –35 (c 1, MeOH). The ee was determined
to be >99% by chiral HPLC (CHIRALPAK AD-H, 15%
EtOH–isohexane, 1 mL/min). The ee for the aziridine 12 was
also found to be >99% by chiral HPLC (CHIRALPAK
AS-H, 7% EtOH–isohexane, 1 mL/min).
(14) (3S)-3-Benzyl-2-propyl-1,2,5-thiadiazolidine-1,1-dioxide
(21). A solution of (3S)-3-benzyl-5-(4-methoxybenzyl)-2-
propyl-1,2,5-thiadiazolidine-1,1-dioxide (20, 562 mg, 1.5
mmol) in TFA (3 mL) was stirred at r.t. for 2 h. The mixture
was then concentrated in vacuo. The residue was taken up in
EtOAc (25 mL). The organic layer was washed with brine
(25 mL), then dried (MgSO4), filtered and evaporated. The
residue was purified by chromatography (silica, 10–20%
EtOAc–isohexane) to give the cyclic sulfamide (378 mg,
99%) as a colourless solid. 1H NMR (400 MHz, CDCl3):
d = 0.94 (3 H, t, J = 7.4 Hz), 1.69 (2 H, sext, J = 7.4 Hz), 2.79
(1 H, dd, J = 8.6, 13.6 Hz), 2.92 (1 H, dt, J = 7.8, 13.6 Hz),
3.06 (1 H, dd, J = 5.2, 13.6 Hz), 3.13–3.21 (2 H, m), 3.34 (1
H, dt, J = 7.1, 11.7 Hz), 3.61–3.68 (1 H, m), 4.54 (1 H, t,
J = 7.2 Hz), 7.19–7.34 (5 H, m). 13C NMR (100 MHz,
CDCl3): d = 11.1, 21.2, 39.0, 44.5, 47.8, 62.3, 126.8, 128.5,
128.9, 135.6. HRMS: m/z calcd for C12H19N2O2S [MH+]:
255.1167; found: 255.1154.
(13) (3S)-3-Benzyl-5-(4-methoxybenzyl)-2-propyl-1,2,5-
thiadiazolidine-1,1-dioxide (20). NaH (60% disp, 96 mg,
2.4 mmol) was added to a stirred solution of (4S)-4-benzyl-
2-(4-methoxybenzyl)-1,2,5-thiadiazolidine-1,1-dioxide
(19f, 665 mg, 2 mmol) in dry DMF (20 mL) at 0 °C under
N2. After 1 h, n-propyl bromide (220 mL, 2.4 mmol) was
added. The reaction was quenched with H2O after a further
(15) Still, W. C. Synthesis 1976, 453.
Synlett 2006, No. 6, 833–836 © Thieme Stuttgart · New York