Bifunctional catalysts for catalytic asymmetric sulfur ylide epoxidation of carbonyl compounds

Article abstract of DOI:10.1039/a802362j

Carbonyl epoxidation using diazo compounds mediated by catalytic quantities of sulfide and metal catalyst has been investigated using sulfides linked to the metal catalyst. In this study a range of bisoxazolines with pendant sulfides were tested in the as

Full text of DOI:10.1039/a802362j

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Bifunctional catalysts for catalytic asymmetric sulfur ylide
epoxidation of carbonyl compounds
Varinder K. Aggarwal,* Louise Bell, Michael P. Coogan and Philippe Jubault
Department of Chemistry, University of Sheffield, Sheffield, UK S3 7HF
Carbonyl epoxidation using diazo compounds mediated by catalytic quantities of sulfide and metal
catalyst has been investigated using sulfides linked to the metal catalyst. In this study a range of bis-
oxazolines with pendant sulfides were tested in the asymmetric epoxidation process using Cu(I)Br (this
was the optimal metal catalyst). Although the enantioselectivity was poor (< 24% ee), it was possible
to use a much lower catalyst loading (5 mol%) than we had previously achieved (20 mol% was the lower
limit) without compromising the yield. This is believed to be because ylide formation is now an
intramolecular process and therefore fast compared to the reaction of the metal carbenoid with the
diazo compound (resulting in stilbene formation) which no longer competes significantly.
good metal for decomposition of diazo compounds for asym-
Introduction
metric cyclopropanation10–14) and can be easily manipulated to
incorporate sulfide functionality (Scheme 3). In this paper we
The catalytic asymmetric synthesis of epoxides is a high profile
reaction and this interest is largely driven by industrial needs for
the preparation of such intermediates in the synthesis of agro-
chemicals and pharmaceuticals. Considerable success has been
achieved in this area most notably by Sharpless,1 Katsuki,2,3
Jacobsen4 and Shi5 who have contributed excellent processes
for alkene oxidation. We have focused on carbonyl epoxidation
and have developed a catalytic,6 sulfur ylide mediated process
which, with thioacetal 1,7 gave good yields and excellent
diastereo- and enantio-control (Scheme 1).
O
O
O
O
R1
R1
R1
R1
PhCHN2
N
N
N
N
Cu
Cu
SMe
SMe
MeS
MeS
Ph
Cu(acac)2
O
Ph
+
+
PhCHN2
PhCHO
O
O
O
Ph
S
R1
R1
71%
N
N
O
1
93% ee
Ph
Cu
trans only
Ph
0.2 equiv.
SMe
MeS
Ph
Ph
Scheme 1
O
Substoichiometric amounts of sulfide can be used in this pro-
cess but there is a lower limit of 20 mol%; attempts to reduce
the number of equivalents of sulfide further (e.g. 10 mol%)
resulted in greatly reduced yields (~30%).7 The reduction in
yield is due to competing reactions of the metal carbenoid. The
metal carbenoid can either react with the sulfide to give the
sulfur ylide or react with another equivalent of diazocompound
to form stilbenes (Scheme 2). At low sulfide concentration the
Scheme 3
describe the synthesis and reactivity of oxazolines bearing
sulfide functionality for carbonyl epoxidation.
Ligand synthesis
The required oxazolines were prepared directly by one of two
methods. The unsubstituted (central carbon atom) bisoxazo-
lines were prepared from the reaction of diethyl malonimidate
with the appropriate amino alcohol (3,15 4,16 517) to produce the
corresponding bisoxazoline (Scheme 4, Table 1). Optimum
yields were obtained using freshly prepared malonimidate, as
reported by Lehn.18 The hydroxy-bearing bisoxazolines 8a were
smoothly converted into sulfenyl-bearing bisoxazolines 10a,
11a by standard methods. This class of ligands would give
neutral complexes with copper() salts.
R
R'
R
R'
Ph
N2
S
M
S
Ph
Ph
Ph
k1
k2
Ph
Scheme 2
former reaction is slowed and the latter reaction begins to
dominate.6
To achieve lower sulfide loading, the rate of reaction of the
metal carbenoid with the sulfide (k1) needs to be increased
relative to the rate of the reaction of the metal carbenoid with
diazo compound (k2). This could potentially be achieved if the
ylide formation was intramolecular i.e. the sulfide was attached
in some way to the metal carbenoid. Sulfides can be covalently
attached to ligands for metal complexes. Oxazoline and bis-
oxazoline ligands8,9 seemed ideal templates for this task as
they readily form complexes with copper (also known to be a
The substituted (non-enolisable) bisoxazolines were prepared
from the reaction of the amino alcohols 3–5 with malononitrile
12 and with 2-cyanopyridine 13 in the presence of Cd-
19,20
(OAc)2
to give, directly, bisoxazolines 6b–8b and oxazoline
14 (Scheme 5, Table 2). As before, 8b was converted into
sulfenyl-bearing bisoxazolines 10b and 11b by standard
methods. This class of ligands would give cationic complexes
with copper() salts.
J. Chem. Soc., Perkin Trans. 1, 1998
2037

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R1
O
CH2Cl2,
40 °C
O
NH2 NH2
OEt
R1
R1
N
N
+
R
OH
EtO
NH2
2Cl
R
R
2
6a R = CH2SMe, R1 = H
7a R = SMe, R1 = H
8a R = OH, R1 = Ph
9a R = OMs, R1 = Ph
10a R = SMe, R1 = Ph
11a R = SPh, R1 = Ph
3 R = CH2SMe, R1 = H
4 R = SMe, R1 = H
5 R = OH, R1 = Ph
(i)
(ii)
(iii)
Scheme 4 Reagents: (i) MsCl, Et3N, CH2Cl2 (ii) NaSMe, EtOH, 88% (iii) NaSPh, EtOH, 96%
Table 1 Yields for direct formation of bisoxazolines
R1
NC
CN
O
Entry
Ligand
R
R1
Yield/%
O
R1
R1
12
R
OH
N
N
1
2
3
6a
7a
8a
CH2SMe
SMe
OH
H
H
Ph
25
30
50
Cd(OAc)2•H2O
NH2
C6H5Cl
R
R
3 R = CH2SMe, R1 = H
4 R = SMe, R1 = H
5 R = OH, R1 = Ph
6b R = CH2SMe, R1 = H
7b R = SMe, R1 = H
8b R = OH, R1 = Ph
9b R = OMs, R1 = Ph
10b R = SMe, R1 = Ph
11b R = SPh, R1 = Ph
Table 2 Yields for direct formation of oxazolines
Entry
Nitrile
R
R1
Ligand
Yield/%
(i)
(iii)
(ii)
1
2
3
4
12
12
12
13
CH2SMe
SMe
OH
H
H
Ph
H
6b
7b
8b
41
42
50
73
CH2SMe
14
good and in all cases where low yields of epoxides were
obtained, aldehyde was recovered and phenyldiazomethane
dimerised to give stilbene.6
NC
N
O
N
MeS
13
OH
N
We next turned our attention to the cationic complexes
derived from oxazolines 6b, 7b, 10b, 11b and 14 (Table 4). As
with the neutral bisoxazoline-complexes, copper() triflate
gave poor yields (entry 1). Copper() salts gave consistently
good yields with the cationic complexes and better than those
from the neutral complexes. Copper() bromide proved to be
particularly efficient, giving excellent yields of epoxide (entries
4, 7, 8 and 10). High yields and good diastereocontrol were
observed but as before the enantiomeric excesses obtained were
very low.
We investigated whether lower catalyst loading was possible
and focused on bisoxazoline 7b with the two optimum copper
salts CuBr and Cu(MeCN)4ClO4. We also varied the concen-
tration of the reaction mixture as we had previously found that
low sulfide loading required higher concentrations to achieve
good yields6 and the results are shown in Table 5. It was found
that good yields were maintained at low catalyst loading
(entries 2 and 5) but that high concentrations were detrimental
(entries 3 and 6). In these cases, precipitation of the complexes
occurred and resulted in low yields of epoxides.
NH3Cl
Cd(OAc)2•H2O
14
C6H5Cl
73%
SMe
Scheme 5 Reagents: (i) MsCl, Et3N, CH2Cl2 (ii) NaSMe, EtOH, 89%
(iii) NaSPh, EtOH, 47%
Results of epoxidation
The neutral complexes formed between bisoxazolines 6a, 7a,
10a or 11a with copper salts were the first systems tested in the
catalytic cycle (Scheme 6, Table 3). The bisoxazoline complexes
'metal', 'Ligand'
DCM
O
4-Cl-C6H4CHO + PhCHN2
4-Cl-C6H4
Ph
Scheme 6
(10 mol%) were preformed in dichloromethane before adding
4-chlorobenzaldehyde followed by slow addition of phenyl-
diazomethane over three hours. The choice of copper as the
metal was based on the literature precedent for the use of this
metal for efficient diazo decomposition.10–14 Indeed, we have
found it to be superior to rhodium in decomposition of phenyl
diazomethane and subsequent reaction of the metal carbenoid
with sulfide to give a sulfur ylide.6 Copper() salts are known to
be reduced to copper() salts by diazo compounds21 which
meant that, in principle, it did not matter whether copper() or
copper() salts were used. Nevertheless, we decided to test a
range of both copper() and copper() salts in our chemistry.
Copper perchlorate–acetonitrile complex22 was chosen as a
copper salt because it is an air stable form of copper().
Conclusions
A range of bisoxazolines with pendant sulfide moieties have
been prepared and found to catalyse the epoxidation of 4-
chlorobenzaldehyde in excellent yield and with high diastereo-
selectivity. The optimum bis-oxazolines were ones that gave rise
to cationic complexes with copper() salts; neutral complexes
gave inferior yields. The optimum copper salt was Cu()Br.
This work represents an advance over existing technology as it
allows the use of one bifunctional catalyst where two independ-
ent catalysts were previously required. In addition, the copper
complexes allow lower catalyst loadings (5 mol%) than were
previously possible (20 mol%) as the carbene transfer to form
the ylide is now an intramolecular process.
However, highly variable yields were obtained with different
bisoxazolines and different metal salts. Copper() triflate gave
consistently poor results (entries 1, 4). In all cases only low
enantioselectivity was observed. Mass balance was generally
The enantiomeric excesses were very low, however, due to
poor stereocommunication between the chirality residing in the
2038
J. Chem. Soc., Perkin Trans. 1, 1998

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Table 3 Yields and enantioselectivities for epoxidation
Entry
Ligand (equiv.)a
Metalb
Yield/%c
trans:cisd
ee/%e
1
2
3
4
5
6
7
8
9
6a (1)
6a (2)
6a (1)
7a (1)
7a (2)
7a (1)
7a (1)
10a (2)
11a (2)
Cu(OTf)2
25
79
76
—
25
—
<10
30
—
100:0
94:6
92:8
—
100:0
—
—
100:0
—
2
3
0
—
14
—
—
—
—
Cu(OAc)2ؒH2O
Cu(MeCN)4ClO4
Cu(OTf)2
Cu(OAc)2ؒH2O
Cu(MeCN)4ClO4
CuBr
Cu(OAc)2ؒH2O
Cu(OAc)2ؒH2O
1
a Refers to the equivalents of ligand relative to the copper salt. b 10 Mol% metal catalyst used. c Isolated yield. d By H NMR. e Measured on a
Chiralcel OD column.
Table 4 Yields and enantioselectivities for epoxidation
Entry Ligand Metala Yield/%b trans:cisc ee/%d
extracted into dichloromethane (3 × 50 ml). The combined
organics were dried (MgSO4) and the solvent removed in vacuo
to yield an oil. The product was purified by column chrom-
atography (5% MeOH–CH2Cl2; Rf 0.24) to yield the title com-
pound as a white, low melting solid (0.163 g, 30%), [α]D25 Ϫ22 (c
0.45 in CHCl3) (Found: C, 48.0; H, 6.6; N, 10.0; S, 23.1 Calc. for
C11H18N2O2S2: C, 48.15; H, 6.6; N, 10.2; S, 23.4%); νmax(liquid
film)/cmϪ1 3415, 2966, 1660, 1585, 1249, 983; δH(250 MHz;
CDCl3) 2.14 (6 H, s, CH3), 2.53 (2 H, dd, J 8.0, 13.5, CH2S),
2.84 (2 H, dd, J 4.75, 13.5, CH2S), 3.35 (2 H, s, CH2), 4.10–4.24
(2 H, m, CH2O), 4.30–4.42 (4 H, m, CH2O ϩ CH); δC(63 MHz;
CDCl3) 15.9 (q), 28.3 (t), 39.9 (t), 65.9 (d), 72.4 (t), 162.6 (s); m/z
(EI) 274 (Mϩ, 45%), 228 (29), 213 (100), 182 (39), 167 (24)
and 61 (83) (Found: Mϩ, 274.0805. Calc. for C11H18N2O2S2: M,
274.0809).
1
2
3
4
5
6
7
8
9
7b
7b
Cu(OTf)2
Cu(MeCN)4ClO4
CuCl
CuBr
CuBr2
Cu(MeCN)4ClO4
CuBr
CuBr
CuBr
CuBr
8
84
72
82
46
73
90
100
43
93
100:0
95:5
95:5
12
5
6
7b
7b
96:4
6
7b
100:0
100:0
100:0
90:10
100:0
100:0
24
14
16
4
0
6
6b
6b
10b
11b
14
10
a 10 Mol% metal catalyst used. b Isolated yield. c By 1H NMR. d Meas-
ured on a Chiralcel OD column.
oxazoline and the incoming aldehyde. Attempts to synthesise
ligands which give increased enantioselectivity are progressing.
(؊)-(4S,4ЈS,5S,5ЈS)-4,4Ј,5,5Ј-Tetrahydro-4,4Ј-bis(hydroxy-
methyl)-5,5Ј-diphenyl-2,2Ј-methylenedioxazole 8a
(1S,2S)-(ϩ)-2-Amino-1-phenylpropane-1,3-diol (3.373 g, 20.2
mmol, 2 equiv.) and diethyl malonimidate (2.348 g, 10.1 mmol,
1 equiv.) were refluxed for 16 h in dry dichloromethane (25 ml)
under argon. Water (100 ml) was added and the product
extracted into dichloromethane (5 × 50 ml). The combined
organic extracts were dried over MgSO4 and the solvent
removed in vacuo to yield a yellow foam. The product was
purified by column chromatography (5% MeOH in CH2Cl2)
and the title compound was furnished as a white solid which
could be further purified by recrystallisation from ethyl acetate
if required18 (2.814 g, 79%), mp 112–113 ЊC (lit.,12,18 111 ЊC and
118–119 ЊC); [α]D21 Ϫ75 (c 1.04 in EtOH) (lit.,18 [α]D23 Ϫ77.3 (c 1.04
in EtOH); νmax(Nujol mull)/cmϪ1 2851, 1656; δH(250 MHz;
CDCl3) 3.47 (2 H, s, NCH2N), 3.56 (2 H, dd, J 3.3, 12.0,
CH2OH), 3.87 (2 H, dd, J 2.8, 12.0, CH2OH), 4.04 (2 H, m,
NCH), 5.45 (2 H, d, J 6.5, PhCH), 7.16–7.28 (10 H, m, ArH);
δC(63 MHz; CDCl3) 28.4 (t), 63.3 (t), 75.8 (d), 83.6 (d), 125.8
(d), 128.6 (d), 128.8 (d), 139.8 (s), 163.9 (s).
Experimental
(S)-Methioninol3,15 (S )-2-amino-3-(methylthio)propan-1-ol416
and dimethylmalonyl dinitrile 1319 were prepared as described
in the literature. J Values are given in Hz.
4,4Ј,5,5Ј-Tetrahydro-4,4Ј-bis(methylthioethyl)-2,2Ј-methylene-
dioxazole 6a
(S)-(Ϫ)-Methioninol (1.410 g, 10.4 mmol, 2 equiv.) and diethyl
malonimidate (1.201 g, 5.2 mmol, 1 equiv.) were refluxed in
dichloromethane for 24 h. The mixture was allowed to cool and
water (50 ml) was added. The aqueous washings were extracted
with copious amounts of dichloromethane. The combined
organics were dried over MgSO4 and the solvent removed in
vacuo to yield an oil. The product was purified by column
chromatography (5% MeOH–CH2Cl2, PdCl2 (aq.) stain; Rf
0.45) and the title material was furnished as a white solid after
Kugelrohr distillation (549 mg, 25%), mp 34–35 ЊC; bp 200–
220 ЊC/0.7 mmHg; [α]D21 Ϫ114 (c 1.0 in CHCl3) (Found: C, 51.5;
H, 7.35; N, 9.1; S, 21.15. Calc. for C13H22N2O2S2: C, 51.6; H,
7.3; N, 9.3; S, 21.2%); νmax(liquid film)/cmϪ1 3413, 2914, 1667,
1588; δH(250 MHz; CDCl3) 1.82 (4 H, m, CH2CH2S), 2.09 (6 H,
s, CH3), 2.57 (2 H, dd, J 2.3, 5.8, CH2S), 2.60 (2 H, dd, J 2.5,
6.6, CH2S), 3.32 (2 H, d br, J 0.9, CCH2C), 3.92 (2 H, t, J 8.0,
OCH2), 4.22 (2 H, m, NCH), 4.38 (2 H, dd, J 7.9, 9.8, OCH2);
δC(63 MHz; CDCl3) 15.5 (q), 28.3 (t), 30.5 (t), 35.1 (t), 65.3 (d),
72.8 (t), 161.9 (s); m/z (EI) 302 (Mϩ, 100%), 287 (45), 228 (23),
186 (68), 154 (49), 144 (54), 85 (75) and 61 (80) (Found: Mϩ,
302.1125. Calc. for C13H22N2O2S2: M, 302.1123).
(4R,4ЈR,5S,5ЈS)-4,4Ј,5,5Ј-Tetrahydro-4,4Ј-bis(methylthio-
methyl)-5,5Ј-diphenyl-2,2Ј-methylenedioxazole 10a
(Ϫ)-(4S,4ЈS,5S,5ЈS)-4,4Ј,5,5Ј-Tetrahydro-4,4Ј-bis(hydroxy-
methyl)-5,5Ј-diphenyl-2,2Ј-methylenedioxazole 8a (228 mg,
0.65 mmol, 1 equiv.) was dissolved in dichloromethane (20 ml)
under argon and cooled to 0 ЊC. Triethylamine (0.4 ml, 2.86
mmol, 4.4 equiv.) was added followed by methanesulfonyl
chloride (0.11 ml, 1.43 mmol, 2.2 equiv.). The reaction was
allowed to warm to room temperature and stirred for 2 h. An
aqueous work up was then performed, extracting into dichloro-
methane (3 × 50 ml). The combined organic extracts were dried
(MgSO4) and the solvent removed in vacuo. The resulting
mesylate (0.931 g, 1.78 mmol) was added neat to a solution of
sodium methyl thiolate (0.5 g, 7.1 mmol, 4 equiv.) in absolute
ethanol (20 ml) and heated briefly to dissolve the mesylate. The
mixture was then stirred for 16 h at ambient temperature and
the solvent was removed by distillation. Brine (20 ml) was
added and the aqueous phase extracted with dichloromethane
4,4Ј,5,5Ј-Tetrahydro-4,4Ј-bis(methylthiomethyl)-2,2Ј-methylene-
dioxazole 7a
Diethyl malonimidate (0.462 g, 2 mmol, 1 equiv.) and (ϩ)-(R)-
2-amino-3-(methylsulfanyl)propan-1-ol (0.497 g, 4 mmol, 2
equiv.) were refluxed in dry dichloromethane (5 ml) under
argon for 48 h. Water (20 ml) was added and the product
J. Chem. Soc., Perkin Trans. 1, 1998
2039

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Table 5 Yields for epoxidation of 4-ClC6H4CHO
Entry
Ligand
Metala
Total vol.b
Yield/%c
trans:cisd
1
2
3
4
5
6
7b (10 mol%)
7b (5 mol%)
7b (5 mol%)
7b (10 mol%)
7b (5 mol%)
7b (5 mol%)
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
CuBr
CuBr
CuBr
1 ml
1 ml
0.6 ml
1 ml
1 ml
84
60
4
82
78
56
95:5
100:0
100:0
96:4
100:0
100:0
0.6 ml
a 1:1 Ratio of ligand to metal. b Volume after addition of the diazo compound, reactions performed with 0.5 mmol of aldehyde. c Isolated yield.
d Determined by 1H NMR. All ees ~5%.
(3 × 50 ml). The combined organic extracts were dried (MgSO4)
and the solvent removed in vacuo. The product was purified by
column chromatography (5% MeOH–CH2Cl2; Rf 0.44) to yield
the title material as an oil (0.67 g, 88%), [α]D21 ϩ17 (c 0.59 in
CH2Cl2); νmax(Nujol mull)/cmϪ1 3054, 2831, 1664, 1605, 1551;
δH(250 MHz; CDCl3) 2.08 (6 H, s, SCH3), 2.65 (2 H, dd, J 7.5,
12.5, CH2S), 2.95 (2 H, dd, J 5.0, 12.5, CH2S), 3.59 (2 H, s,
NCH2N), 4.23 (2 H, q, J 5.0, CHCH2S), 5.37 (2 H, d, J 7.5,
CHPh), 7.33 (10 H, m, ArH); δC(63 MHz; CDCl3) 15.7 (q), 28.7
(t), 38.9 (t), 74.2 (d), 87.9 (d), 125.8 (d), 128.2 (d), 128.7 (d),
140.1 (s), 161.9 (s); m/z (EI) 426 (Mϩ, 6%), 365 (100), 317 (15),
117 (28) and 91 (39) (Found: Mϩ, 426.1429. Calc. for
C23H26N2O2S2: M, 426.1435).
(13 mg, 5 mol%). After cooling the crude material was purified
by column chromatography.
2,2-Bis[(4S)-4-methylthioethyl-5-phenyl-1,3-oxazolin-2-yl]-
propane 6b
The crude was purified by column chromatography (5% MeOH
in CH2Cl2) to yield the title compound as a clear oil (1.071 g,
74%), [α]D25 Ϫ156 (c 1.0 in CHCl3) (Found: C, 54.2; H, 7.9; N, 8.8;
S, 19.4. Calc. for C15H26N2O2S2: C, 54.6; H, 7.9; N, 8.5; S,
19.4%); νmax(liquid film)/cmϪ1 3414, 2916, 1659; δH(250 MHz;
CDCl3) 1.48 [6 H, s, C(CH3)2], 1.81 (4 H, m, CH2CH2S), 2.09
(6 H, s, SCH3), 2.54 (4 H, t, J 7.5, CH2S), 3.91 (2 H, dd, J 6.8,
7.8, OCH2), 4.21 (2 H, tdd, J 6.3, 6.3, 12.5, CH), 4.32 (2 H, dd,
J 7.8, 9.5, OCH2); δC(63 MHz; CDCl3) 15.5 (q), 24.3 (q), 30.2
(t), 35.1 (t), 38.5 (s), 65.0 (d), 72.5 (t), 169.1 (s); m/z (EI) 330
(Mϩ, 32%), 256 (16), 231 (15) and 187 (100) (Found: Mϩ,
330.1431. Calc. for C15H26N2O2S2: M, 330.1435).
(4R,4ЈR,5S,5ЈS)-4,4Ј,5,5Ј-Tetrahydro-4,4Ј-bis(phenylthio-
methyl)-5,5Ј-diphenyl-2,2Ј-methylenedioxazole 11a
(Ϫ)-(4S,4ЈS,5S,5ЈS)-4,4Ј,5,5Ј-Tetrahydro-4,4Ј-bis(hydroxy-
methyl)-5,5Ј-diphenyl-2,2Ј-methylenedioxazole 8a (0.298 g,
0.84 mmol, 1 equiv.) was dissolved in dichloromethane (20 ml)
and cooled to 0 ЊC. Triethylamine (1 ml, 7.4 mmol, 8.8 equiv.)
was added followed by methanesulfonyl chloride (287 µl, 3.7
mmol, 4.4 equiv.). The reaction was allowed to warm to room
temperature and stirred for an hour. A further equivalent of
both triethylamine and methanesulfonyl chloride were added
and the reaction stirred for another hour. The reaction was
judged to be complete by TLC and an aqueous work up was
performed, extracting into dichloromethane (3 × 50 ml). The
combined organic extracts were dried (MgSO4) and the solvent
removed in vacuo. A flask charged with sodium hydride (60% in
oil, 0.78 g, 19.5 mmol, 2.5 equiv.) was washed with light petrol-
eum (20 ml) the solvent decanted and the flask treated with 10
ml THF sealed under argon and cooled to Ϫ78 ЊC before drop-
wise treatment with benzenethiol (2 ml, 19.5 mmol, 2.5 equiv.).
After stirring for 30 min as the mixture attained ambient tem-
perature, the resultant thick paste was treated with the mesylate
prepared as above (4 g, 7.6 mmol) as a solution in THF (15 ml)
dropwise. The mixture was stirred for 16 h before treatment
with aqueous sodium hydroxide (2 , 20 ml) and extracted into
dichloromethane (3 × 20 ml). The combined organic extracts
were washed with brine (saturated, 20 ml) dried (Na2SO4) and
the solvent removed in vacuo. The product was purified by
column chromatography (2% MeOH–CH2Cl2; Rf 0.24) to yield
the title material as a white crystalline compound (4.010 g,
96%), mp 100–101 ЊC; [α]D21 Ϫ19 (c 0.36 in CH2Cl2); νmax(Nujol
mull)/cmϪ1 1663, 1221, 742; δH(250 MHz; CDCl3) 2.98 (2 H, dd,
J 9.0, 13.3, CH2S), 3.44 (2 H, dd, J 4.6, 13.3, CH2S), 3.55 (2 H,
s, NCH2N), 4.22 (2 H, m, CHCH2S), 5.38 (2 H, d, J 6.3,
CHPh), 7.18–7.29 (20 H, m, ArH); δC(63 MHz; CDCl3) 28.6 (t),
38.8 (t), 73.8 (d), 86.1 (d), 125.9 (d), 126.4 (d), 128.3 (d), 128.6
(d), 128.9 (d), 129.8 (d), 134.9 (s), 139.9 (s), 162.1 (s); m/z (FAB)
551 (Mϩ, 100%), 503 (9), 441 (14) and 427 (13) (Found: Mϩ,
551.1817. Calc. for C33H30N2O2S2: M, 551.1826).
2,2-Bis[(4S)-4-methylthiomethyl-1,3-oxazolin-2-yl]propane 7b
The crude was purified by column chromatography (5%
MeOH–CH2Cl2) to yield the title compound as a clear oil (0.066
g, 38%), [α]D21 Ϫ46 (c 0.48 in CH2Cl2) (Found: C, 51.1; H, 7.4; N,
9.3; S, 21.4. Calc. for C13H22N2O2S2: C, 51.6; H, 7.3; N, 9.3; S,
21.2%); νmax(liquid film)/cmϪ1 3381, 2918, 1651, 1519, 1257,
977; δH(250 MHz; CDCl3) 1.48 (6 H, s, CH3), 2.11 (6 H, s,
SCH3), 2.48 (2 H, dd, J 1.8, 7.0, CH2S), 2.80 (2 H, dd, J 4.8,
13.8, CH2S), 4.12 (2 H, d, J 1.5, OCH2), 4.33 (4 H, m,
OCH2, CH); δC(63 MHz; CDCl3) 16.1 (q), 24.3 (q), 38.7 (s),
39.3 (t), 65.7 (d), 72.4 (t), 170.1 (s); m/z (EI) 302 (Mϩ, 51%),
256 (38), 241 (68), 173 (78), 105 (43) and 61 (100) (Found:
Mϩ, 302.114. Calc. for C13H22N2O2S2: M, 302.1122).
(؊)-2,2-Bis[(4S,5S)-4-hydroxymethyl-5-phenyl-1,3-oxazolin-
2-yl]propane 8b
(1S,2S)-(ϩ)-2-Amino-1-phenylpropane-1,3-diol (6.221 g, 37.3
mmol, 2.5 equiv.), dimethylmalonyldinitrile (1.400 g, 14.9
mmol, 1 equiv.) and cadmium acetate hydrate (0.198 g, 5 mol%)
were refluxed in chlorobenzene (70 ml) for 16 h. The reaction
was judged to have proceeded to completion (by TLC) and the
reaction mixture was purified by column chromatography (5%
MeOH in CH2Cl2; Rf 0.22). The product was further purified
by recrystallisation from ethyl acetate and furnished white
crystals19.20 (2.506 g, 43%), mp 150–152 ЊC (lit.,19,20 157 ЊC);
δH(250 MHz; CDCl3) 1.70 (6 H, s, CH3), 3.67 (2 H, br d, J 10.0,
CH2OH), 3.84 (2 H, br s, OH), 3.96 (2 H, dd, J 2.5, 10.0,
CH2OH), 4.13 (2 H, m, CH), 5.52 (2 H, d, J 7.5, PhCH), 7.30
(10 H, m, Ph).
(؊)-2,2-Bis[(4R,5S)-4-methylthiomethyl-5-phenyl-1,3-oxazolin-
2-yl]propane 10b
The dihydroxybisoxazoline 8b (1.200 g, 3 mmol, 1 equiv.) was
dissolved in dichloromethane (60 ml) and cooled to 0 ЊC. Tri-
ethylamine (3.7 ml, 26.4 mmol, 8.8 equiv.) was added dropwise
followed by methanesulfonyl chloride (1.0 ml, 13.2 mmol, 4.4
equiv.). The reaction was allowed to warm to room temperature
and stirred for 4 h after which time the reaction was complete
(by TLC). Water (50 ml) was added and the product extracted
into dichloromethane (3 × 100 ml). The combined organic
General procedure for the formation of oxazolines using
cadmium acetate hydrate
The amino alcohol (2.5 mmol, 2.5 equiv.) and dimethyl-
malononitrile (1 mmol, 1 equiv.) were refluxed for 24 h in chloro-
benzene (3 ml) in the presence of cadmium acetate hydrate
2040
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
extracts were dried (MgSO4) and the solvent removed in vacuo
to furnish an oil. The oil was dissolved in absolute ethanol
(55 ml) and sodium methylthiolate (1.050 g, 15 mmol, 5 equiv.)
added. The mixture was refluxed for 16 h after which time the
reaction was complete (by TLC). Water (50 ml) was added and
the aqueous phase was extracted with copious amounts of
dichloromethane (5 × 100 ml). The combined organic extracts
were dried (MgSO4) and the solvent removed in vacuo. The
product was purified by column chromatography (5% MeOH–
CH2Cl2; Rf 0.5) and the title material was furnished as a pale
solid (1.218 g, 89%), mp 68 ЊC (pentane); [α]D21 ϩ25 (c 0.28 in
CH2Cl2) (Found: C, 65.8; H, 6.8; N, 6.0; S, 13.85. Calc. for
C25H30N2O2S2: C, 66.1; H, 6.6; N, 6.2; S, 14.1%); νmax(Nujol
mull)/cmϪ1 2921, 1655, 1147, 1119; δH(250 MHz; CDCl3) 1.62
(2 H, s, H2O), 1.70 (6 H, s, CH3), 2.64 (2 H, dd, J 8.5, 13.8,
CH2S), 2.94 (2 H, dd, J 4.3, 13.8, CH2S), 4.22 (2 H, ddd, J 4.3,
6.5, 8.5, CHCHCH2), 5.35 (2 H, d, J 6.5, CHCHCH2), 7.29 (10
H, m, Ph); δC(63 MHz; CDCl3) 15.8 (q), 24.7 (q), 39.1 (t), 74.2
(d), 85.8 (d), 125.9 (d), 128.1 (d), 128.7 (d), 140.6 (s), 169.4 (s);
m/z (EI) 454 (Mϩ, 24%), 393 (100), 186 (28) and 61 (50) (Found:
Mϩ, 454.1733. Calc. for C25H30N2O2S2: M, 454.1748).
7.93 (1 H, dt, J 7.5, 1.3, Ar), 8.62 (1 H, ‘dq’, J 4.8, 1.3, Ar);
δC(63 MHz; CDCl3) 15.1 (q), 30.3 (t), 34.9 (t), 65.6 (d), 72.5 (t),
123.5 (d), 125.2 (d), 136.2 (d), 146.2 (d), 149.3 (d), 162.4 (s); m/z
(EI) 222 (Mϩ, 29%), 175 (13), 161 (27), 148 (100), 123 (26) and
106 (38) (Found: Mϩ, 222.0837. Calc. for C11H14N2OS: M,
222.0827).
General procedure for epoxidation using bisoxazolines/oxazolines
and copper(II) triflate, copper(I) bromide, copper(II) bromide and
copper(II) chloride
The bisoxazoline or oxazoline (0.1 mmol, 1 equiv.) in dichloro-
methane (0.5 ml) was added to copper triflate (0.033 g, 0.1
mmol, 1 equiv.) under argon. An immediate darkening of the
solution was observed. The solution was stirred at ambient
temperature for 3 h before the addition of p-chlorobenz-
aldehyde (0.140 g, 1 mmol, 10 equiv.) in dichloromethane
(0.5 ml). Phenyldiazomethane (2 mmol, 20 equiv.) in dichloro-
methane (1 ml) was then added over 3 h and the reaction stirred
at room temperature overnight. The product was purified by
column chromatography (10% CH2Cl2–petrol).
General procedure for epoxidation using bisoxazolines and
copper acetate
(؊)-2,2-Bis[(4R,5S)-4-phenylthiomethyl-5-phenyl-1,3-oxazolin-
2-yl]propane 11b
The bisoxazoline (0.2 mmol, 2 equiv.) was dissolved in methanol
(1 ml) and copper() acetate (0.1 mmol, 1 equiv.) in methanol
(2 ml) was added. An immediate deep purple colour was
observed. The reaction was stirred at room temperature for an
hour before the solvent was removed. The residue was purified
by flushing through a short column of neutral alumina (MeOH
spiked CH2Cl2). The complex and p-chlorobenzaldehyde (0.140
g, 1 mmol, 10 equiv.) were dissolved in dichloromethane (1 ml)
under argon and phenyldiazomethane (2 mmol, 20 equiv.) in
dichloromethane (1 ml) added over 3 h. The reaction was
stirred at room temperature overnight before being purified by
column chromatography (10% CH2Cl2–petrol).
The dihydroxybisoxazoline 8b (1.000 g, 2.5 mmol, 1 equiv.) was
dissolved in dichloromethane (50 ml) and cooled to 0 ЊC. Tri-
ethylamine (3.1 ml, 22 mmol, 8.8 equiv.) was added dropwise
followed by methanesulfonyl chloride (0.85 ml, 11 mmol, 4.4
equiv.). The reaction was allowed to warm to room temperature
and stirred for 4 h after which time the reaction was complete
(by TLC). Water (50 ml) was added and the product extracted
into dichloromethane (3 × 100 ml). The combined organic
extracts were dried (MgSO4) and the solvent removed in vacuo
to furnish an oil. The oil was dissolved in absolute ethanol (55
ml) and sodium phenylthiolate (1.650 g, 12.5 mmol, 5 equiv.)
was added. The mixture was refluxed for 16 h after which time
the reaction was complete (by TLC). Water (50 ml) was added
and the aqueous phase was extracted with copious amounts of
dichloromethane (5 × 100 ml). The combined organic extracts
were dried (MgSO4) and the solvent removed in vacuo. The
product was purified by column chromatography (5% MeOH in
CH2Cl2; Rf 0.5) and the title material was furnished as a pale
solid (0.675 g, 47%), mp 78 ЊC (pentane); [α]D21 ϩ18 (c 0.22 in
CH2Cl2) (Found: C, 72.1; H, 6.0; N, 4.7; S, 11.2. Calc. for
C35H34N2O2S2ؒ1/4H2O: C, 72.1; H, 6.0; N, 4.8; S, 11.0%);
νmax(Nujol mull)/cmϪ1 2921, 1655, 1147, 1119; δH(250 MHz;
CDCl3) 1.65 (6 H, s, CH3), 2.97 (2 H, dd, J 9.0, 13.3,
CH2S), 3.45 (2 H, dd, J 3.7, 13.3, CH2S), 4.22 (2 H, m, NCH),
5.39 (2 H, d, J 6.5, PhCH), 7.21 (20 H, m, ArH); δC(63 MHz;
CDCl3) 24.5 (q), 38.9 (t), 39.0 (s), 73.7 (d), 85.9 (d), 126.1 (d),
126.3 (d), 128.2 (d), 128.5 (d), 128.8 (d), 129.8 (d), 135.1 (s),
140.2 (s), 169.5 (s); m/z (EI) (Mϩ Ϫ 1, 38%), 469 (85), 455
(43), 186 (21), 123 (100) (Found: Mϩ, 579.2121. Calc. for
C35H34N2O2S2: M, 579.2139).
General procedure for epoxidation using bisoxazolines and a
copper(I) perchlorate complex
The bisoxazoline (0.1 mmol, 1 equiv.) in dichloromethane (0.5
ml) was added to Cu(MeCN)4ClO4 (0.1 mmol, 1 equiv.) under
argon. The reaction was stirred at room temperature for 3 h
during which time the solid slowly dissolved to form a pale
solution. p-Chlorobenzaldehyde (140 mg, 1 mmol, 10 equiv.) in
dichloromethane (0.5 ml) was added, then phenyldiazomethane
(2 mmol, 20 equiv.) in dichloromethane (1 ml) was added over
3 h and the reaction stirred at room temperature overnight.
The product was purified by column chromatography (10%
CH2Cl2–petrol).
Acknowledgements
We thank EPSRC for support, and Gair Ford and Rachel
Stenson for help with the preparation of the manuscript and for
additional experiments.
(S)-2-(2-Pyridyl)-4,5-dihydro-4-(methylthioethyl)oxazole 14
(S)-Methioninol 3 (1.350 g, 10 mmol, 1.2 equiv.), 2-cyano-
pyridine (0.866 g, 8.3 mmol, 1 equiv.) and cadmium acetate
hydrate (0.133 g, 5 mol%) were refluxed in chlorobenzene
(10 ml) for 24 hours under argon. The reaction mixture was
then purified by column chromatography (5% MeOH in
CH2Cl2; Rf 0.30) and the title material obtained as a pale yellow
oil (1.207 g, 58%), [α]D25 Ϫ117 (c 0.35 in CH2Cl2) (Found: C,
59.15; H, 6.45; N, 12.58; S, 14.18. Calc. for C11H14N2OS: C,
59.43; H, 6.34; N, 12.60; S, 14.42%); νmax(liquid film)/cmϪ1 2919,
2253, 1646, 1470, 1365, 1264, 1098; δH(250 MHz; CDCl3) 1.74–
2.01 (2 H, m, CH2), 2.03 (3 H, s, CH3), 2.60 (1 H, dd, J 4.0, 7.0,
CH2S), 2.63 (1 H, dd, J 4.0, 6.5, CH2S), 4.04 (1 H, t, J 8.0,
CH2O), 4.40 (1 H, m, CH), 4.53 (1 H, dd, J 8.0, 9.8, CH2O),
7.30 (1 H, ddd, J 1.3, 4.8, 7.8, Ar), 7.69 (1 H, td, J 7.8, 2.0, Ar),
References
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a catalyst for this type of
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Paper 8/02362J
Received 26th March 1998
Accepted 12th May 1998
2042
J. Chem. Soc., Perkin Trans. 1, 1998