1,2,4-Dithiazolidine-3,5-dione as an isocyanate equivalent in the Mitsunobu reaction

Article abstract of DOI:10.1039/b206793e

1,2,4-Dithiazolidine-3,5-dione 1 can be used as a nitrogen nucleophile in a modified Mitsunobu procedure to give N-alkylated products 2 which can be converted via isocyanates, into amine derivatives, under very mild conditions.

Full text of DOI:10.1039/b206793e

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1
,2,4-Dithiazolidine-3,5-dione as an isocyanate equivalent in the
Mitsunobu reaction
a
a
b
Mark E. Wood,* Daniel J. Cane-Honeysett and Michael D. Dowle
1
a
School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD.
E-mail: m.e.wood@exeter.ac.uk; Fax: ϩ(44) 1392 263434; Tel: ϩ(44) 1392 263450
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK SG1 2NY
b
Received (in Cambridge, UK) 11th July 2002, Accepted 8th August 2002
First published as an Advance Article on the web 19th August 2002
1
,2,4-Dithiazolidine-3,5-dione 1 can be used as a nitrogen
Table 1 Mitsunobu-type reaction of alcohols with 1
nucleophile in a modified Mitsunobu procedure to give
N-alkylated products 2 which can be converted via
isocyanates, into amine derivatives, under very mild
conditions.
Alcohol
Yield (%)
Ee (%)
5
6
7
8
9
51
51
78
80
51
54
42
38
52
37
38
—
71
a
The Mitsunobu procedure is now a well established method for
the preparation of amines from alcohols, using acidic imide
derivatives as the nitrogen nucleophile. Phthalimide is perhaps
the most common nucleophile that has been used in such reac-
tions, but the well known problems associated with the depro-
tection of phthalimides to amines have led to the development
—
70
1
b
1
0
c, d
11
12
13
14
c
92
2
71
of some alternative imides for this process.
c, e
1
5
The remarkably high acidity of 1,2,4-dithiazolidine-3,5-
3
a
b
dione 1 (pK = 2.85) suggested that it should be a synthetically
useful nucleophile in this procedure (Fig. 1). Most importantly,
Product enantiomers were inseparable by chiral HPLC. A trace of
c
a
the product resulting from allylic transposition was present. Racemic
d
alcohol used. 2 : 1 ratio of direct displacement : allylic transposition
products. 2 products obtained in a 3 : 1 ratio (tentatively assigned as
e
being from primary : secondary hydroxy group displacement).
1
(1–1.5 equiv.) and betaine 3 (1–1.5 equiv.) in dichloromethane
at room temperature (Scheme 1) gave the corresponding
N-alkylated 1,2,4-dithiazolidine-3,5-diones 2 (Table 1).†
Fig. 1
N-alkylated derivatives 2 can be readily transformed into either
4
3
amines or isocyanates (by very mild thiolysis or treatment
with triphenylphosphine under anhydrous conditions respect-
ively), whilst being stable towards commonly encountered
acidic, mildly basic and photolytic deprotection conditions. The
sensitivity of the heterocycle to phosphines does preclude the
use of traditional phosphine–azodicarboxylate Mitsunobu
conditions, but the observation that triphenylphosphine cyclic
sulfamide betaine 3 can be used to couple alcohols and nitrogen
Scheme 1 Reagents and conditions: 3 (1–1.5 equiv.), CH Cl , RT (see
2
2
Table 1).
Very good yields were obtained using more reactive alcohols
such as benzyl alcohol (alcohol 8, Table 1) whereas secondary
alcohols gave lower, but still reasonable, yields. As expected,
crotyl alcohol gave a trace of the product resulting from allylic
transposition (alcohol 10, Table 1) and racemic but-3-en-2-ol
produced a 2 : 1 ratio of products, in favour of that resulting
from direct displacement (alcohol 11, Table 1).
5
6
acids, including thiazolidine-2,4-dione 4, led us to examine the
compatibility of this reagent with 1.
A suitable range of alcohol substrates 5–15 (Fig. 2) was
Most importantly, the 52% yield obtained using (S)-methyl
lactate (alcohol 13, Table 1) correlates well with that achieved in
“
traditional” Mitsunobu reactions between phthalimide and
8
9
both racemic and (S)-ethyl lactate. The enantiomeric excess
for this reaction was found to be 92%.‡ In spite of the likeli-
hood of competing dehydration of (R)-ethyl 2-hydroxybutyrate
under the reaction conditions, an acceptable yield of 37% of
the corresponding N-alkylated 1,2,4-dithiazolidine-3,5-dione
with an enantiomeric excess of 71% was obtained (alcohol 14,
Table 1).
A number of N-alkylated derivatives 2 were converted
into urethanes 16 (Scheme 2) via the in situ trapping of the3
intermediate, triphenylphosphine generated isocyanates 17
with either benzyl or 4-nitrobenzyl alcohol. The results thus
obtained are summarised in Table 2.
Fig. 2 Alcohol substrates.
chosen in order to obtain results which could be compared with
known phthalimide Mitsunobu (and closely related ) reactions.
Treatment of these alcohols with 1,2,4-dithiazolidine-3,5-dione
7
2
046
J. Chem. Soc., Perkin Trans. 1, 2002, 2046–2047
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b206793e

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Table 2 Formation of urethanes via isocyanates
National Mass Spectrometry Service Centre (Swansea, UK) for
mass spectra.
R
RЈOH
Yield (%)
Ee (%)
Notes and references
(
(
(
(
(
(
S)-Et(Me)CH
4-NO C H CH OH
65
90
79
57
75
92
67
97
68
90
91
70
2
6
4
2
S)-C H (Me)CH
4-NO C H CH OH
6
13
2
6
4
2
†
0
3
0
In a typical procedure (alcohol 13, Table 1): betaine 3 (345 mg,
R)-Ph(Me)CH
4-NO C H CH OH
2 6 4 2
.87 mmol) was added to a stirred solution of 1,2,4-dithiazolidine-
R)-MeO C(Me)CH
C H CH OH
6 5 2
2
11
,5-dione 1 (110 mg, 0.81 mmol) and (S)-methyl lactate (75 µl,
R)-MeO C(Me)CH
4-NO C H CH OH
2
2 6 4 2
3
.79 mmol) in dichloromethane (1.5 cm ) under a nitrogen atmosphere
S)-EtO CCH (Me)CH
4-NO C H CH OH
2 6 4 2
2
2
at room temperature. After stirring for 16 h, the solvent was evaporated
in vacuo with adsorption of the crude product onto silica gel. Flash
chromatography on silica gel (eluting with 9 : 1 v/v light petroleum–
ethyl acetate) gave (R)-2-(3,5-dioxo-1,2,4-dithiazolidin-4-yl)propionic
acid methyl ester (91 mg, 52%, ee 92%) as an oil; R 0.7 (9 : 1 v/v light
f
2
1
Ϫ1
petroleum–ethyl acetate) [α]
1
D
; ϩ44 (c = 1, CHCl ); νmax/cm (CHCl3)
732 and 1716 (C᎐O); δH (300 MHz; CDCl ) 1.63 (3H, d, J 7, CH CH),
3
3
3
Scheme 2 Reagents and conditions: 2 (1.25 equiv.), PPh (1.25 equiv.),
3.76 (3H, s, CO
2
CH
3
) and 5.03 (1H, q, J 7, CH
3
CH); δ
CH
C
(75.5 MHz;
3
RЈOH (1 equiv.), PhMe, 110 ЊC (see Table 2).
CDCl
3
) 14.0 (CH
3
CH), 53.1, 54.3 (CH
3
CH and CO
2
3
) and 166.8,
ϩ
ϩ
1
2
‡
68.4 (C᎐O); m/z (EI) 221 (M , 38%) and 70 (100) [Found, MH (EI)
20.9823, C H NO S requires 220.9817].
6
7
4 2
Confirmation of the expected inversion of configuration
in the earlier Mitsunobu-type reactions was obtained by the
preparation of N-benzyloxycarbonyl--alanine methyl ester
Enantiomeric excesses were determined by chiral HPLC, using a
®
Chiralcel OD column, eluting with 9 : 1 v/v hexane–propan-2-ol.
Detection was carried out at a wavelength of 254 nm.
(
R = (R)-MeO C(Me)CH, RЈOH = C H CH OH, Table 2),
2
6
5
2
which in turn, originated from (S)-methyl lactate (alcohol 13,
Table 1). This protected amino acid was obtained with an
enantiomeric excess of 90%, with analytical data corresponding
to those of authentic samples. This result confirmed that within
experimental error, no appreciable racemisation had occurred
during the isocyanate generation process, a problem which can
accompany the deprotection of N-phthaloyl amino acids with
1 (a) O. Mitsunobu, Synthesis, 1981, 1; (b) D. L. Hughes, Org. React.
(N. Y.), 1992, 42, 335; (c) D. L. Hughes, Org. Prep. Proced. Int.,
1
996, 28, 127.
2
(a) For example, see: U. Ragnarsson and L. Grehn, Acc. Chem. Res.,
1991, 24, 285; (b) A. Klepacz and A. Zwierzak, Synth. Commun.,
001, 31, 1683.
2
3
4
D. J. Cane-Honeysett, M. D. Dowle and M. E. Wood, Synlett, 2000,
622.
G. Barany and R. B. Merrifield, J. Am. Chem. Soc., 1977, 99, 7363.
1
10
hydrazine.
In summary, we have demonstrated that 1,2,4-dithiazolidine-
,5-dione 1 can be used as an effective substitute for phthalim-
5 J. L. Castro and V. G. Matassa, J. Org. Chem., 1994, 59, 2289.
6 K. M. Brummond and J. Liu, J. Org. Chem., 1999, 64, 1723.
7 (a) A. G. M. Barrett, C. D. Braddock, R. A. James and
P. A. Procopiou, Chem. Commun., 1997, 433; (b) A. G. M. Barrett,
C. D. Braddock, R. A. James, N. Koike and P. A. Procopiou,
J. Org. Chem., 1998, 63, 6273.
3
ide in Mitsunobu-type amination reactions. Moreover, the
resulting alkylated derivatives 2 can be transformed, via iso-
cyanates, intousefulderivatives, underverymildconditions, with
no appreciable loss of stereochemical integrity. 1,2,4-Dithiazol-
idine-3,5-dione 1 can therefore be used as an isocyanate
equivalent in the Mitsunobu reaction.
8
O. Mitsunobu, M. Wada and T. Sano, J. Am. Chem. Soc., 1972, 94,
79.
(a) M. Wada, T. Sano and O. Mitsunobu, Bull. Chem. Soc. Jpn.,
973, 46, 2833; (b) L. D. Arnold, H. I. Assil and J. C. Vederas,
J. Am. Chem. Soc., 1989, 111, 3973.
6
9
1
Acknowledgements
10 R. C. Sheppard, in Comprehensive Organic Chemistry, eds. D. H. R.
Barton and W. D. Ollis, Pergamon Press, Oxford, 1979, vol. 5, p. 321.
11 L. Chen, T. R. Thompson, R. P. Hammer and G. Barany, J. Org.
Chem., 1996, 61, 6639.
The authors gratefully acknowledge GlaxoSmithKline for a
CASE-Quota studentship to D. J. C.-H. and the EPSRC
J. Chem. Soc., Perkin Trans. 1, 2002, 2046–2047
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