Aromatic or chiral heterocycle - Balance between 1,3-oxazoline-2-thione and 1,3-oxazolidine-2-thione

Article abstract of DOI:10.1055/s-2005-923583

1,3-Oxazoline-2-thiones (OXT) and bis-1,3-oxazol-idine-2-thiones (bis-OZT) were selectively prepared depending on the conditions and starting materials used, and then underwent some N- and S-selective reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-923583

LETTER
301
Aromatic or Chiral Heterocycle – Balance between 1,3-Oxazoline-2-thione and
1,3-Oxazolidine-2-thione
B
alance between 1
i
, 3-Oxa
c
zoline-2-th
o
ione and 1,3
l
as
one Leconte,a Sandrina Silva,a,b Arnaud Tatibouët,*a Amelia P. Rauter,b Patrick Rollina
a
ICOA - UMR 6005, Université d’Orléans, BP 6759, 45067 Orléans, France
E-mail: arnaud.tatibouet@univ-orleans.fr
b
Departamento de Química e Bioquímica, Facultade de Ciências, Universidade de Lisboa, 1749-016 Lisbon, Portugal
Received 30 August 2005
O
HSCN
HSCN
O
n
Abstract: 1,3-Oxazoline-2-thiones (OXT) and bis-1,3-oxazol-
idine-2-thiones (bis-OZT) were selectively prepared depending on
the conditions and starting materials used, and then underwent some
N- and S-selective reactions.
OH
OH
NH
NH
HO
HO
HO
HO
OH
n
S
S
O
aldoses
Key words: hydroxyketones, 1,3-oxazoline-2-thione, 1,3-oxazol-
idine-2-thione
HO
O
S
HO
HN
O
O
O
HO
OH
n
O
n
n
OH
The 1,3-oxazolidine-2-thione (OZT) system is gaining
further importance as a chiral auxiliary due to its broad
applicability in chiral induction, which mainly results
from its structural resemblance to Evans oxazolidinones.1
OZTs have also been applied in stereoselective sequences
due to their specific induction pattern but also for their
physico-chemical properties (UV-Vis sensitivity, lower
polarity, easier cleavage of acyl derivatives, etc.).2 Chiral
OZTs can readily be prepared via standard reaction of a b-
aminoalcohol with thiophosgene under basic conditions,
but some can also be produced through controlled myro-
sinase degradation of glucosinolate precursors.3 In glyco-
chemistry, OZTs have long been studied, their preparation
is either effected by reacting aminosugars with thiophos-
gene or by condensing thiocyanic acid with unprotected
carbohydrates.4 In that latter case, the OZT nitrogen occu-
pies an anomeric position on the sugar. Aldoses mainly
ketoses
Scheme 1 Major OZT structures obtained from carbohydrates.
produce fused furano-OZT structures, the 4-hydroxyl
group being generally implicated in the cyclisation pro-
cess. Applying the same protocol to ketohexoses leads to
much more complex mixtures of fused, spiro-, furano- and
pyrano-type molecules (Scheme 1).5 However 1,3-di-
hydroxyacetone, which can be regarded as the simplest
ketose, condenses with thiocyanic acid to produce an
amazingly simple chiral spiro-bis-OZT 1, with a C2 sym-
metric axis.6
Considering further the reaction mechanism, one might
wonder what would happen when only one a-hydroxyl is
present. Surprisingly, such reactions have scarcely been
explored, and only basic structures related to acetol have
S
S
HN
n
O
N
HO
– H2O
HSCN
R
R
OH
O
R
O
n
n
+ H2O
R = OH
γ or δ
R = H, alkyl
R = OH
α
S
S
HN
O
HN
S
O
O
H
HN
S
R
N
O
n
O
1,3-oxazoline-2-thione
bis-1,3-oxazolidine-2-thione
2
1
Scheme 2 Condensation of thiocyanic acid with a-hydroxyketones.
SYNLETT 2006, No. 2, pp 0301–0305
0
1.
0
2.
2
0
0
6
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923583; Art ID: D26105ST
© Georg Thieme Verlag Stuttgart · New York

302
N. Leconte et al.
LETTER
been converted into 1,3-oxazoline-2-thiones.7 This paper
describes our recent advances in controlling the condensa-
tion of a-hydroxyketones with thiocyanic acid towards
the formation of bis-1,3-oxazolidine-2-thiones (bis-OZT)
1 and 1,3-oxazoline-2-thiones (OXT) 2 (Scheme 2).
S
N-
O
NH+
O
S
S
H
S
O
S
HN
O
N
AcO
O
O
O
N
S
Ac2O, pyridine
N
O
L-Erythrulose 3, a member of the ketose family, appeared
to be a suitable starting material for condensation with
thiocyanic acid; the C4 carbon framework rules out the
formation of the furano or pyrano rings, which we had
previously observed and studied.5 Moreover, the intrinsic
chirality of the tetrulose would result in the production of
potentially separable stereoisomers.
O
HO
(S)-4
9
AcO
S
O
N
HN
O
O
S
AcO
Scheme 4 Plausible mechanism for the epimerization process.
Indeed L-erythrulose, underwent condensation, producing
4 as two diastereoisomers in an 85:15 ratio (Scheme 3).
Under standard conditions (KSCN and HCl in aqueous
medium) a white precipitate formed, which was revealed
to be the major stereoisomer. Simple filtration and recrys-
tallisation from water afforded crystals suitable for X-ray
crystallography; structural analysis revealed co-crystalli-
sation with one molecule of water and the new stereogenic
centre of this spiro[4,4]-bis OZT 4 to be S-configurated.8
hydroxymethyl bis-OZT (S)-4 was quantitatively O-silyl-
ated prior to S-alkylation to give 5,10 resulting in no ring-
opening and the expected compound 7 (Scheme 3) was
obtained in 79% yield.11 Actually, the mechanism of the
above-mentioned ring-opening does not seem to simply
rely on anion counter-attack of the OZT; standard nucleo-
philic salts KBr, NaI or KCN did not react with the S-ben-
zylated derivatives 6 or 7. In contrast, pure 6 underwent
ring-opening through a reaction with benzyl halides to
give the monocyclic derivative 8. This might possibly
suggest a reversible activation of the alkylthiooxazoline
through a benzylsulfonium intermediate, which sub-
sequently undergoes bromide attack. The ring-opened
intermediate is then hydrolysed to afford 8 (Scheme 5).
O
S
O
S
H
N
S
O
HSCN
HN
HO
OH
N
S
N
O
O
O
O
R
R
R = H 1
R = H, dihydroxyacetone
R = CH2OH, L-erythrulose 3
9
AcO
R = CH2OH (S)-4
S
SBn
O
H
SBn
O
SBn
S
S
SBn
N
BnS
HN
N
BnS
BnBr
HN
BnS
H
N
N
HN
HN
BnS
S
N
O
O
N
N
N
O
O
O
O
O
+
O
O
O
1
Br
6
Br
8
R
5
TBDMSO
R = H 6
R = CH2OTBDMS 7
8
Br–
H2O
Scheme 3
Ph
S+
Ph
Ph
Ph
S+
Evaluation of reactivities for both bis-OZT 1 and 4 was
considered, as their ambident character can allow S- or N-
functionalisation in different ways. Peracetylation of the
enantiopure bis-OZT (S)-4 under standard conditions
(Ac2O–pyridine) resulted in spontaneous epimerization at
the spiro carbon. This was also observed in a mixture en-
riched with the minor epimer (R)-4 leading to a 1:1
epimeric ratio of 9, which could result from stabilized
intermediate tautomers (Scheme 4). The sensitivity of
such N-acetylated structures might explain the degrada-
tion rate observed with a stronger electron-withdrawing
group when N-sulfonylation was realised.
N
N
O
O–
Br
Br–
N
N
O
SBn
SBn
O
Scheme 5 Plausible mechanism for the ring-opening.
Notwithstanding their simple structure, OXTs are a very
seldom studied heterocyclic family.7 Only a few papers
have addressed their preparation, their use as synthons
and the basic question of their thione–thiol tautomerism.12
We first considered the synthetic pathway to OXTs
(Table 1) using acetol as a model starting material, to try
and optimize the preparation conditions with a view to
further application to more complex – i.e. carbohydrate-
based – structures.
S-Alkylations were then performed on bis-OZTs. De-
pending on the reaction time, and the benzyl halide (Cl or
Br) used, bis-S-benzylation of 1 occurred in 85% yield
after three hours; a longer reaction time of 24 hours re-
sulted in a much reduced 40% yield of the bis-S-benzyl
derivative 6 along with a ring-opened structure 8, arising
from bromide ion counter-attack,9 in 35% yield. The
From the range of tests performed with acetol (Table 1,
entries 1–7), it was clear that under diverse acidic con-
ditions, both protic and aprotic solvents could be used
to prepare OXT 2a; the results show a reasonably good
Synlett 2006, No. 2, 301–305 © Thieme Stuttgart · New York

LETTER
Balance between 1,3-Oxazoline-2-thione and 1,3-Oxazolidine-2-thione
303
Table 1 Synthesis of OXTsa
OH
O
O
O
O
O
O
1) Bu2SnO, toluene
2) BnBr
MeOH
HO
OH
OH
Entry
R
Solvent
Acid
HCl
Temp. Yield
78 °C 74%
OH OH
OH OBn
1
2
CH3 (2a)
CH3 (2a)
CH3 (2a)
CH3 (2a)
CH3 (2a)
CH3 (2a)
CH3 (2a)
Ph (2b)
EtOH
H2O
10
11
PTSA 65 °C 70%
H2SO4 65 °C 17%
Scheme 6
3
H2O
4
H2O
HCl
HCl
65 °C 52%
65 °C 75%
Applying our procedure in water generated compound 2e
(Table 1, entry 16), although in a moderate 40% yield. Ex-
tension to a more complex substrate was then considered
(Scheme 7), aiming at an L-erythrulose-related OXT.
1,2:4,5-Di-O-isopropylidene-D-fructopyranose 12 was O-
benzylated, then the 4,5-O-isopropylidene acetal 13 was
selectively hydrolysed14 and the transient diol was sub-
mitted to oxidative cleavage followed by reduction to gen-
erate the diol precursor 14 in 70% overall yield.
Condensation of 14 with thiocyanic acid in water gave a
fair 60% yield of the L-erythrulose-related OXT 2f
(Table 1, entry 17).15
5
THF
THF
THF
EtOH
EtOH
H2O
6
H2SO4 65 °C 75%
PTSA 65 °C 37%
7
8
HCl
HCl
HCl
HCl
Reflux 83%
Reflux 95%
80 °C 41%
9
H (2c)
10
11
12
13
14
15
16
17
18
H (2c)
CH2OH (2d) EtOH
65 °C
5%
CH2OH (2d) EtOH–H2O (95:5) HCl
65 °C 16%
65 °C 21%
Reflux 91%
80 °C 62%
65 °C 40%
65 °C 60%
CH2OH (2d) H2O
HCl
HCl
HCl
HCl
HCl
HCl
O
O
H (2c)
H (2c)
EtOH
H2O
O
O
NaH, BnBr, DMF
O
O
OBn
13
OH
O
O
O
O
CH2OBn (2e) H2O
12
(2f)
H2O
H2O
a) AcOH–H2O
b) NaIO4
c) NaBH4
70%
(2g)
50 °C
2%
a KSCN (1.1 equiv).
S
KSCN, HCl, H2O
HN
O
O
O
reactivity depending on the choice of the solvent–acid
tandem. An extension to two other commercially avail-
able hydroxyketones – a-hydroxyacetophenone and gly-
colaldehyde dimer – was then considered. Standard
conditions (Table 1, entries 8 and 9) were applied to both
substrates delivering 2b and 2c in good yields, while the
use of water as the solvent (Table 1, entry 10) resulted in
a severe drop in yield. Attempts to obtain the OXT from
1,3-dihydroxyacetone proved more tricky, due to compet-
itive formation of the bis-OZT (Table 1, entries 11–13),
using water as the solvent (or co-solvent) seemed to
favour formation of OXT 2d albeit in low yield.
O
HO
60%
OBn
HO
HO
OBn
14
2f
Scheme 7
In a first approach to estimate comparative reactivity
features using OXT 2a, we first considered some simple
N- or S-selective reactions previously studied on OZTs in
our laboratory (Scheme 8).16
Standard S-alkylation proved efficient in generating
compounds 15 and 16 in reasonable to good yield. When
Only a limited range of a-hydroxyketones are easily ac-
cessible and most of those substrates pose stability prob-
lems. In contrast, acetal-protected ketones usually are
stable compounds which can readily be prepared and
stored. Such a protected ketone could thus be used to test
the direct formation of OXT; in the acidic reaction medi-
um, deprotection would regenerate a transient ketone,
able to condense with thiocyanic acid. With this in mind,
2,2-dimethoxyethanol was submitted to standard condi-
tions (Table 1, entry 14) to afford parent compound 2c in
91% yield; the condensation was less efficient (62%
yield) when performed in water (Table 1, entry 15). Fur-
thermore, in order to preclude competitive formation of
the bis-OZT, the dimethyl acetal 1013 was selectively O-
alkylated to produce the monoalcohol 11 in 40% overall
yield from 1,3-dihydroxyacetone (Scheme 6).
R
S
R-Br
N
O
15 R = Bn, 60%
16 R = CH2COPh, 83%
NaH, DMF
Et3N, DMF
S
HN
O
EWG
2a
S
S
EWG
N
O
R
N
O
EWG
R = H, EWG = CN
R = H, EWG = SO2Ph
R = EWG = SO2Ph
17 35%
19 62%
21 93%
18 28%
20 30%
not detected
Scheme 8
Synlett 2006, No. 2, 301–305 © Thieme Stuttgart · New York

304
N. Leconte et al.
LETTER
(4) (a) Zemplen, G.; Gerecs, A.; Rados, M. Ber. Dtsch. Chem.
Ges. B. 1936, 39, 748. (b) Bromund, W. H.; Herbst, R. M. J.
Org. Chem. 1945, 10, 267. (c) Garcia Fernandez, J. M.;
Ortiz Mellet, C. Sulfur Rep. 1996, 19, 61. (d) Diaz Perez, V.
M.; Garcia Moreno, M. I.; Ortiz Mellet, C.; Fuentes, J.; Diaz
Arribas, J. C.; Canada, F. J.; Garcia Fernandez, J. M. J. Org.
Chem. 2000, 65, 136. (e) Garcia Fernandez, J. M.; Ortiz
Mellet, C. Adv. Carbohydr. Chem. Biochem. 2000, 55, 35.
(5) Tatibouët, A.; Lawrence, S.; Rollin, P.; Holman, G. D.
Synlett 2004, 1945.
(6) Saul, R.; Kern, T.; Kopf, J.; Pinter, I.; Köll, P. Eur. J. Org.
Chem. 2000, 205.
(7) (a) Willems, J. F.; Vandenberghe, A. Bull. Soc. Chim. Belg.
1961, 70, 745. (b) Lacasse, G.; Muchowki, J. M. Can. J.
Chem. 1972, 50, 3082.
applying Michael-type N-alkylation conditions previous-
ly used with OZTs, a difference appeared in terms of
chemoselectivity; reacting 2a with either acrylonitrile or
phenyl vinyl sulfone unexpectedly afforded both N- and
S-alkylated derivatives (17–20). Complete N-selectivity
was attained when 1,2-bis-phenylsulfonylethylene
(BPSE), a much harder Michael acceptor, was used, to
furnish a high yield of vinylogous sulfonamide 21.17
We have developed controlled conditions for the conden-
sation of thiocyanic acid with hydroxyketones, targeting
construction of well-defined heterocyclic systems. De-
pending on the procedure used and the structure of the
starting molecule, a modular access to fused or spiro-
OZTs anchored on a carbohydrate template,5 to chiral bis-
OZTs (spiro[4.4]nonane) and to OXTs was devised.
OXTs were also shown to be accessible even when the
starting ketone is masked by a ketal function and more-
over, water was often shown to be a well-adapted solvent.
Tremendous efforts are needed to prepare OXT selective-
ly on a carbohydrate skeleton. Our recent studies on D-
fructose and thiocyanic acid condensation afforded a very
low yield of acyclic OXT 2g (Table 1, entry 18,
Scheme 9).
(8) Cioci, G.; Leconte, N.; Tatibouët, A.; Rollin, P.; Pérez, S.;
Imberty, A. Acta Crystallogr., Sect. E 2004, o2399.
(9) Nedolya, N. A.; Papsheva, N. P.; Afonin, A. V.; Trofimov,
B. A.; Kukhareva, V. A.; Kashik, T. V. Sulfur Lett. 1992, 14,
103.
(10) (4R,9S)-4-tert-Butyldimethylsilyloxymethyl-3,8-dioxa-
1,6-diazaspiro[4.4]nonane-2,7-dithione (5)
Bis-OZT (S)-4 (1.01 g, 4.59 mmol) was dissolved in DMF
(7 mL), TBDMSCl (1.99 g, 13 mmol) and imidazole (0.63 g,
9.3 mmol) were added and the reaction was stirred for 4 h at
r.t. When the reaction was complete, the mixture was
hydrolysed and extracted with EtOAc (2 × 50 mL). The
combined organic phases were washed with H2O, brine and
then dried over MgSO4. After flash chromatography on
silica gel (petroleum ether–EtOAc, 7:3), compound 5 (1.53
g) was obtained quantitatively as a solid; mp 154–157 °C;
[a]D25 +30 (c 1.0, MeOH). 1H NMR (CDCl3, 250 MHz):
d = 0.07 (s, 3 H, CH3), 0.09 (s, 3 H, CH3), 0.85 (s, 9 H, t-Bu),
3.89 (dd, 1 H, 2J = 10.8, 3J = 7.0 Hz, CHaHbOSi), 3.96 (dd, 1
H, 2J = 10.8, 3J = 6.5 Hz, CHaHbOSi), 4.60 (d, 1 H, 2J = 11.3
Hz, H9a), 4.64 (d, 1 H, 2J = 11.3 Hz, H9b), 4.87 (t, 1 H, 3J =
6.8 Hz, H4), 10.94 (s, 1 H, NH), 10.99 (s, 1 H, NH). 13C NMR
(CDCl3, 62.5 MHz): d = –5.7 (CH3), –5.6 (CH3), 17.7
[(CH3)3C], 25.6 [(CH3)3C], 59.3 (CH2OSi), 76.0 (C9), 81.3
(C5), 83.9 (C4), 186.6 (C2 or C7), 187.8 (C2 or C7). MS (IS+):
m/z = 335.3 (M + H)+. Anal. Calcd for C12H22N2O3S2Si: C,
43.08; H, 6.63; N, 8.37. Found: C, 42.85; H, 6.57; N, 8.31.
(11) (4R,9S)-2,7-Bisbenzylthio-4-tert-butyldimethylsilyloxy-
methyl-3,8-dioxa-1,6-diazaspiro[4.4]nonane-1,6-diene
(7); Typical Procedure
S
a) KSCN, HCl, H2O
b) acetone, H2SO4
O
HN
O
O
O
D-fructose
2%
2g
O
Scheme 9 Acyclic OXT from D-fructose.
Further studies are ongoing to devise new strategies to an-
chor the OXT heteroaromatic moiety to carbohydrate
backbones aiming at developing new saccharidic syn-
thons towards pseudo-nucleoside families.
Acknowledgment
Bis-OZT 5 (0.12g, 0.4 mmol) was dissolved in DMF (3 mL)
and the solution was cooled to 0 °C. NaH (60%, 36 mg, 0.9
mmol) and BnBr (108 mL, 0.9 mmol) were added
The authors would like to thank Gianluca Cioci, Serge Pérez and
Anne Imberty for the X-ray crystallography analysis, the CNRS and
the University of Orléans for their generous support and (i) the ARD
company for a generous gift of dihydroxyacetone (ii) the Schering-
Plough company for a generous gift of 2,2-dimethoxyethanol.
successively. After 3 h at r.t., the reaction mixture was
hydrolysed and extracted with EtOAc (2 ×). The collected
organic phases were washed with H2O, brine and dried over
MgSO4. After the solvent was removed, the crude was
purified on silica gel (petroleum ether–EtOAc; 95:5) to
afford compound 7 (0.145 g, 2.82 mmol, 79% yield).
[a]D25 +9 (c 1, CH2Cl2). 1H NMR (CDCl3, 250 MHz):
d = 0.07 (s, 3 H, CH3), 0.08 (s, 3 H, CH3), 0.89 (s, 9 H, t-Bu),
3.87 (dd, 1 H, 2J = 10.9, 3J = 6.2 Hz, CHaHbOSi), 3.96 (dd, 1
H, 2J = 10.9, 3J = 6.8 Hz, CHaHbOSi), 4.15 (d, 1 H, 2J = 9.1
Hz, H9a), 4.28 (s, 4 H, 2 × CH2Ph), 4.32 (t, 1 H, 3J = 6.6 Hz,
H4), 4.56 (d, 1 H, 2J = 9.0 Hz, H9b), 7.28 (m, 10 H, HAr).
13C NMR (CDCl3, 62.5 MHz): d = –5.3 (2 × CH3), 18.3
[(CH3)3C], 25.9 [(CH3)3C], 36.4 (2 × CH2Ph), 61.2
(CH2OSi), 78.5 (C9), 88.0 (C4), 98.0 (C5), 127.7–136.4 (CAr),
168.5 (C2 or C7), 168.9 (C7 or C2). MS (IS+): m/z = 515 (M
+ H)+. Anal. Calcd for C26H34N2O3S2S: C, 60.66; H, 6.66; N,
5.44. Found: C, 60.37; H, 6.62; N, 5.42.
References and Notes
(1) Velazquez, F.; Olivo, H. F. Curr. Org. Chem. 2002, 6, 1.
(2) (a) Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A.
L. J. Org. Chem. 2000, 65, 8499. (b) Crimmins, M. T.;
Zuercher, W. J. Org. Lett. 2000, 2, 1065. (c) Crimmins, M.
T.; Tabet, E. A. J. Org. Chem. 2001, 66, 4012.
(d) Chakraborty, T. K.; Jayaprakash, S.; Laxman, P.
Tetrahedron 2001, 57, 9461. (e) Crimmins, M. T.; Katz, J.
D.; Washburn, D. G.; Allwein, S. P.; McAtee, L. F. J. Am.
Chem. Soc. 2002, 124, 5661.
(3) (a) Gueyrard, D.; Grumel, V.; Leoni, O.; Palmieri, S.; Rollin,
P. Heterocycles 2000, 52, 827. (b) Leoni, O.; Bernardi, R.;
Gueyrard, D.; Rollin, P.; Palmieri, S. Tetrahedron:
Asymmetry 1999, 10, 4775.
Synlett 2006, No. 2, 301–305 © Thieme Stuttgart · New York

LETTER
Balance between 1,3-Oxazoline-2-thione and 1,3-Oxazolidine-2-thione
305
(12) (a) Bradscher, C. K.; Jones, W. J. J. Org. Chem. 1967, 32,
2079. (b) Guimon, C.; Pfister-Guillouzo, G.; Arbelot, M.;
Chanon, M. Tetrahedron 1974, 30, 3831. (c) Kapsomenos,
G. S.; Akrivos, P. D. Can. J. Chem. 1988, 66, 2835.
(d) Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1998, 63,
551.
(13) Casarotti, E.; Antognazza, P.; Pallavicini, M.; Villa, L. Helv.
Chim. Acta 1993, 76, 2344.
(14) OXT Formation; General Procedure
(15) (a) Lichtenthaler, F. W.; Doleschal, W.; Hahn, S. Liebigs
Ann. Chem. 1985, 2454. (b) Tatibouët, A.; Lefoix, M.;
Nadolny, J.; Martin, O. R.; Rollin, P.; Yang, J.; Holman, G.
D. Carbohydr. Res. 2001, 333, 327.
(16) (a) Girniene, J.; Gueyrard, D.; Tatibouët, A.; Sackus, A.;
Rollin, P. Tetrahedron Lett. 2001, 42, 2977. (b) Girniene,
J.; Tatibouët, A.; Sackus, A.; Yang, J.; Holman, G. D.;
Rollin, P. Carbohydr. Res. 2003, 338, 711. (c) Girniene, J.;
Tardy, S.; Tatibouët, A.; Sackus, A.; Rollin, P. Tetrahedron
Lett. 2004, 45, 6443.
Compound 14 (0.17 g, 0.54 mmol) and KSCN (1.5 equiv,
0.08 g) were dissolved in H2O. The solution was cooled to
–5 °C then HCl (1 equiv) was added. The solution obtained
was maintained at 60 °C for 24 h then extracted with EtOAc
(3 ×). The organic phases were further washed with H2O (3
×), brine and dried over MgSO4. The residue obtained after
solvent removal was purified by column chromatography
(petroleum ether–EtOAc, 7:3). OXT 2f was obtained in 60%
yield as a pale yellow oil; [a]D25 –60 (c 1, MeOH). 1H NMR
(250 MHz, CDCl3): d = 1.79 (br s, 1 H, OH), 3.77 (dd, 1 H,
(17) N-Alkylation; Typical Procedure
A solution of 4-methyl-13-oxazoline-2-thione (2a; 0.100 g,
0.869 mmol) in DMF (4 mL) was cooled to –5 °C (ice–salt
bath); Et3N (0.25 mL), E-BPSE (0.27 g) and Bu4NBr (cat.)
were then added. After stirring at r.t. for 24 h, the reaction
mixture was hydrolysed, then extracted with EtOAc (3 ×).
The combined organic phases were washed with H2O (3 ×),
brine and dried over MgSO4. The solvent was removed and
the residue was purified by column chromatography
(cyclohexane–acetone–CH2Cl2, 2:1:2). Compound 20 was
isolated in 93% yield; mp 102–104 °C. 1H NMR (250 MHz,
CDCl3): d = 2.24 (s, 3 H, Me), 7.08 (s, 1 H, H-5), 7.53–7.59
(m, 2 H, CHAr), 7.62–7.64 (m, 1 H, CHAr), 7.70 (d, 1 H,
J = 13.8 Hz, H-2¢), 7.91–7.94 (m, 2 H, CHAr), 8.38 (d, 1 H,
J = 13.8 Hz, H-1¢). 13C NMR (CDCl3, 62.5 MHz): d = 8.9
(CH3), 120.2 (C2¢), 126,4 (C4), 127.5, 129.5, 131.7 (CAr),
132.3 (C5), 133.7 (C1¢), 140.4 (CqAr), 177.1 (C2). Anal. Calcd
for C12H11NO3S2: C, 51.23; H, 3.94; N, 4.98. Found: C,
50.93; H, 3.92; N, 5.01.
J7b,7a = 11.8, J7b,6 = 3.8 Hz, H-7b), 3.95 (dd, 1 H, J7a,7b =
11.8, J7a,6 = 3.8 Hz, H-7a), 4.32 (t, 1 H, J6,7a = 3.8, J6,7b = 3.8
Hz, H-6), 4.37–4.63 (AB system, 2 H, = 11.7 Hz, H-8a, H-
8b), 7.26 (s, 1 H, H-5), 7.30–7.43 (m, 5 H, C-HAr), 10.72 (s,
1 H, N-H). 13C NMR (CDCl3, 62.5 MHz): d = 64.5 (C7), 70.3
(C6), 71.4 (C8), 128.1 (C4), 128.2, 128.5, 128.8 (CAr), 134.5
(C5), 136.5 (CqAr), 179.7 (C2). Anal. Calcd for C12H13NO3S:
C, 57.35; H, 5.21; N, 5.57. Found: C, 56.90; H, 5.17; N, 5.53.
Synlett 2006, No. 2, 301–305 © Thieme Stuttgart · New York