A novel class of conformationally constrained, masked cysteines: Synthesis of 2-alkyl- and 2-arylsulfanyl-1-aminocyclopropanecarboxylic acids

Article abstract of DOI:10.1021/jo9810011

A convenient synthesis of 4-sulfanylmethylene-5(4H)-oxazolones 3 was realized starting from 4-(chloromethylene)oxazolone 1 and mercaptans 2. Oxazolones 3 were used as starting materials for the preparation of unknown 2-sulfanyl-1-aminocyclopropanecarboxylic acid derivatives 5 and 7. Oxazolones 3 were cyclopropanated at the exocyclic double bond with diazomethane, giving a mixture of the two (Z)- and (E)-spirocyclopropane oxazolones 4 with good diastereoselectivity. These were then treated with ethanol and DMAP to produce the corresponding carboxylates 5. The trityl derivative 5d was converted into a mixture of diastereoisomeric disulfides 6 using iodine in ethanol solution. Disulfides 6 are convenient synthons for the preparation of 3-sulfanyl-substituted 2,3-methanoamino acids 7.

Full text of DOI:10.1021/jo9810011

726
J . Org. Chem. 1999, 64, 726-730
A Novel Cla ss of Con for m a tion a lly Con str a in ed , Ma sk ed
Cystein es: Syn th esis of 2-Alk yl- a n d
2-Ar ylsu lfa n yl-1-a m in ocyclop r op a n eca r boxylic Acid s
F. Clerici, M. L. Gelmi,* and D. Pocar
Istituto di Chimica Organica, Facolta` di Farmacia, Universita` di Milano, Via Venezian 21,
I-20133 Milano, Italy
Received May 26, 1998
A convenient synthesis of 4-sulfanylmethylene-5(4H)-oxazolones 3 was realized starting from
4-(chloromethylene)oxazolone 1 and mercaptans 2. Oxazolones 3 were used as starting materials
for the preparation of unknown 2-sulfanyl-1-aminocyclopropanecarboxylic acid derivatives 5 and
7. Oxazolones 3 were cyclopropanated at the exocyclic double bond with diazomethane, giving a
mixture of the two (Z)- and (E)-spirocyclopropane oxazolones 4 with good diastereoselectivity. These
were then treated with ethanol and DMAP to produce the corresponding carboxylates 5. The trityl
derivative 5d was converted into a mixture of diastereoisomeric disulfides 6 using iodine in ethanol
solution. Disulfides 6 are convenient synthons for the preparation of 3-sulfanyl-substituted 2,3-
methanoamino acids 7.
In tr od u ction
more, the unsaturated character of this molecular frag-
ment hinders rotation around the CR-Câ bond, giving,
for 2,3-methanoamino acids substituted at C-3, two
possible isomers (cis and trans). Their presence in the
peptide chain is expected to have marked effects on the
secondary structures, with consequent stabilization of the
peptide toward enzyme cleavage.8 Moreover, cycloprop-
aneamino acid derivatives possess, as single molecules,
a wide spectrum of biological actions.5b So, the interest
in the synthesis of these substrates is growing, but it is
worth noting that the known synthetic procedures are
lacking in the preparation of 2,3-methanoamino acids
substituted with a sulfur atom at C-3. To prepare a new
class of compounds with potential anticancer activity,9
we have synthesized 2-alkylsulfanyl- or 2-arylsulfanyl-
1-aminocyclopropanecarboxylic acid derivatives 5 and 7,
in which the cysteine skeleton exists.
In recent years significant attention has been focused
on the preparation of conformationally constrained amino
acids because their introduction into a peptide generates
important changes in the peptide conformation by modu-
lating its interaction with the active site of an enzyme
or bioreceptor.1 Different approaches making an amino
acid stiff have been used: introducing an element of
unsaturation in the chain (i.e. R,â-didehydroamino
acids),2 linking both the amino and carboxyl groups to a
ring (cyclohexyl-,3 cyclopentyl-,4 and cyclopropylamino
acids5), and synthesizing cyclic amino acids in which the
amino or carbonyl groups are inside the ring.6 In par-
ticular, the preparation of peptides containing meth-
anoamino acids is of great interest because the cyclopro-
pyl ring increases their rigidity as a result of the bond
stretching imposed by the methylene bridge.5,7 Further-
The use of 4-ylidene-5(4H)-oxazolones as starting
materials for the preparation of these compounds is
common, because diazomethane easily adds to the exo-
cyclic double bond of the oxazolone derivatives, making
the cyclopropane ring.5b,10 The compounds 4-alkylsulfa-
nyl- or 4-arylsulfanylmethylene-5(4H)-oxazolones 3 are
the key starting materials for the preparation of amino
acid derivatives 5 and 7 through the cyclopropanation
reaction of the exocyclic double bond.
(1) (a) Toniolo, C. J anssen Chim. Acta. 1993, 11, 10. (b) Kazmierski,
W. M.; Lipkowska, Z. U.; Hruby, V. J . J . Org. Chem. 1994, 59, 1789.
(c) Omstein, P. L.; Melikian, A.; Martinelli, M. J . Tetrahedron Lett.
1994, 35, 5759. (d) Colombo, L.; Di Giacomo, M.; Scolastico, C.;
Manzoni, L.; Belvisi, L.; Molteni, V. Tetrahedron Lett. 1995, 36, 625.
(e) Bisang, C.; Weber, C.; Inglis, J .; Schiffer, C. A.; van Gunsteren, W.
F.; J elesarov, I.; Bosshard, H. R.; Robinson, J . A. J . Am. Chem. Soc.
1995, 117, 7904. (f) Dubuisson, C.; Fukumoto, Y.; Hegedus, L. S. J .
Am. Chem. Soc. 1995, 117, 3697.
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Effenberger, F.; Ku¨hlwein, J .; Drauz, K. Liebigs Ann. Chem. 1993,
1295.
(3) (a) Vincent, M.; Remond, G.; Bure, J . Eur. Pat. Appl. 1, 193, 1979;
Chem. Abstr. 1980, 92, 163619. (b) Avenoza, A.; Busto, J . H.; Paris,
M.; Peregrina, J . M.; Cativiela, C. J . Heterocycl. Chem. 1997, 34, 1099
and references therein.
(4) Gaitanopulos, D. E.; Nash, J .; Dunn, D. L.; Skinner, C. G. J .
Med. Chem. 1976, 19, 342.
(8) (a) Mapelli, C.; Elrod, L. F.; Holt, E. M.; Switzer, F.; Stammer,
C. H.; Biopolymers 1989, 28, 123. (b) Malin, D. H.; Lake, J . R.; Ho,
K.-K.; Corriere, L. S.; Garber, T. M.; Waller, M.; Benson, T. M.; Smith,
D. A.; Luu, T. A.; Burgess, K. Peptides 1993, 14, 731.
(5) (a) Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett. 1994, 575.
(b) Stammer, C. H. Tetrahedron 1990, 46, 2231.
(6) (a) Leonard, N. J .; Ning, R. Y. J . Org. Chem. 1967, 32, 677. (b)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789.
(7) (a) Toniolo, C.; Crisma, M.; Valle, G.; Bonora, G. M.; Barone, B.;
Benedetti, E.; Blasio, B. D.; Pavone, V.; Pedone, C.; Santini, A.; Lelj,
F. Pept. Chem. 1987, 45. (b) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J .
Am. Chem. Soc. 1994, 116, 799. (c) Burgess, K.; Ho, K.-K.; Pettitt, B.
M. J . Am. Chem. Soc. 1995, 117, 54. (d) Burgess, K.; Ho, K.-K.; Pal, B.
J . Am. Chem. Soc. 1995, 117, 3808.
(9) The studies on the inhibition of cellular proliferation will be
described elsewhere.
(10) (a) King, S. W.; Riordan, J . M.; Holt, E. M.; Stammer, C. H. J .
Org. Chem. 1982, 47, 3270. (b) Arenal, I.; Bernabe´, M.; Alvarez, E. F.;
Izquierdo, M. L.; Penade´s, S. J . Heterocycl. Chem. 1983, 20, 607. (c)
Cativiela, C.; Diaz-de-Vilagaz, M. D.; Mayoral, J . A.; Mele´ndez, E. J .
Org. Chem. 1984, 49, 1436. (d) Bland, J . M.; Stammer, C. H.;
Varughese, K. I. J . Org. Chem. 1984, 49, 1634. (e) Lalitha, K.; Iyengar,
D. S.; Bhalerao, U. T. J . Org. Chem. 1989, 54, 1771. (f) Cativiela, C.;
Diaz-de-Vilagaz, M. D.; Garc´ıa, J . I.; J ime´nez, A. I. Tetrahedron 1997,
53, 4479 and references therein.
10.1021/jo9810011 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/09/1999

Conformationally Constrained Masked Cysteines
J . Org. Chem., Vol. 64, No. 3, 1999 727
Sch em e 1
Sch em e 2
Resu lts a n d Discu ssion
Oxazolones 3a -d were prepared by reacting 4-(chloro-
methylene)-2-phenyl-5(4H)-oxazolone 1 with sodium thio-
methoxide 2a or mercaptans 2b-d in the presence of
triethylamine as a base at room temperature and in
dichloromethane, in a method analogous to that described
for the synthesis of â-alkylthio-R,â-didehydroamino acids.2a
The reactions resulted in a mixture of two isomers, Z and
E, from which the thermodynamically more stable Z
isomer was isolated as the major product. Synthetically
useful procedures11 for the preparation of sulfanylmeth-
yleneoxazolones 3 have been reported, but to our knowl-
edge, chloroazlactone 1 was used as starting material
only for the preparation of aryl derivatives. In that case,
the presence of a Lewis acid (AlCl3) is mandatory.12 The
use of 1 as the starting material takes advantage of good
yields (70-90%) of oxazolones 3a -d and short reaction
times (30-60 min) (Scheme 1).
The IR spectra of compounds 3 show the typical
absorption of the unsaturated carbonyl group of oxazo-
lones (1740-1760 cm-1) and the configuration assigned
to compounds 3 was confirmed by 1H NMR data reported
in the literature for (Z)-3a ,c.11c
The spirooxazolone (Z)-4b was treated with 4-(di-
methylamino)pyridine (DMAP) in ethanol for 60 min at
room temperature. Pure ethyl 1-benzoylamino-2-phenyl-
sulfanylcyclopropanecarboxylate 5b was isolated in 75%
yield (Scheme 2). A useful synthetic improvement in the
preparation of isomeric carboxylates 5b was found with
the possibility of performing a “one pot” reaction starting
from oxazolone (Z)-3b and avoiding the isolation of the
mixture of two oxazolones 4b. In fact, reaction of (Z)-3b
with diazomethane, solvent elimination, and reaction of
the crude mixture with ethanol in the presence of DMAP
for 60 min gave isomers (Z)- and (E)-5b in good yield
(77%, 3:1). The same results were obtained starting from
oxazolones 3a ,c,d : 2-alkylsulfanyl-1-benzoylaminocyclo-
propanecarboxylates 5a ,c,d were isolated in good yields
(60-66%) as a mixture of two isomers (Scheme 2).
Structural assignments for compounds 4 and 5 have
In a typical procedure, pure isomers (Z)-3a -d were
made to react with an excess of diazomethane at room
temperature. The reactions were completed in 1-3 h, and
the 1H NMR analyses of the crude reaction mixtures
showed the formation of two isomeric spirooxazolones,
(Z)-4a -d and (E)-4a -d , in a variable ratio, but one in
which the Z isomer is always the major one (Z/ E: 3/1 to
5/1). The isomeric oxazolones 4 were obtained in satisfac-
tory yields (54-73%): the major isomers (Z)-4a -d were
isolated as pure compounds, whereas the (E)-4b-d
isomers were isolated as small samples of pure com-
pound. The isomeric ratio is in favor of the Z isomer,
which possesses the same geometry at the double bond
as the starting azlactone 3, and the loss of this geometry
in the cyclopropanation reaction is in agreement with the
literature data.10 This was confirmed by an independent
experiment: Starting from pure oxazolone (E)-3a the
reaction with diazomethane afforded the same isomeric
spirocyclopropane oxazolones (Z)- and (E)-4a but in a
reversed ratio (Scheme 2).
1
been made on the basis of IR, H NMR (Table 1), and
13C NMR spectral data as well as NOESY and COSY
experiments, and the results are in agreement with the
literature data.10 The IR spectra of spirocyclopropane
oxazolones 4 show a typical absorption at 1780-1800
cm-1 (lactone group), whereas the carbonyl ester group
stretching at 1720 cm-1 is present in the spectra of
compounds 5. The 1H NMR signals of protons on the
cyclopropyl ring, in both compounds 4 and 5, appear as
an ABX system: the signals of HX, as expected on the
basis of their proximity to the S substituent, are at lower
fields; the signals of geminal HA and HB could be assigned
by their vicinal coupling constants J AX and J BX since it
has been found that, for vicinal cyclopropyl ring protons,
(11) (a) Cornforth, J . W. In The Chemistry of Penicillins; Clarke, H.
T., J ohnson, J . R., Robinsons, R., Eds.; Princeton University Press:
Princeton, NJ , 1949; p 730.(b) Maquestiau, A.; Van Haverbeke, Y.;
Vanovervelt, J . C.; Postiaux, R. Bull. Soc. Chim. Belg. 1976, 85, 697.
(c) Thondorf, I.; Strube, M.; Augustin, M. Synthesis 1990, 1169. (d)
Homami, S. S.; Mukeryee, A. K. Indian J . Chem. Sect. B 1992, 31B,
411.
(12) Walter, R.; Zimmer, H.; Schwartz, I. L. J . Heterocycl. Chem.
1966, 3, 352.

728 J . Org. Chem., Vol. 64, No. 3, 1999
Ta ble 1. 1H NMR Da ta for Com p ou n d s 4-7
δ (CDCl3), (J / Hz)
Clerici et al.
compd
Ar
HX
HA
HB
J AB
J AX
J BX
(Z)-4a
(E)-4a
(Z)-4b
(E)-4b
(Z)-4c
(E)-4c
(Z)-4d
(E)-4d
(Z)-5a
(E)-5a
(Z)-5b
(E)-5b
(Z)-5c
(E)-5c
(Z)-5d a
6b
8.10-7.41
8.01-7.40
8.01-7.12
8.01-7.15
7.96-6.89
8.06-6.88
7.97-7.03
7.97-7.04
7.85-7.44
7.90-7.42
7.80-7.21
7.79-7.21
7.53-7.21
7.76-7.27
7.56-7.11
7.82-7.40
7.57-7.21
3.08
3.30
3.38
3.59
2.88
3.09
2.73
3.02
2.83
2.69
3.14
2.96
2.74
2.39
2.66
3.26
3.89
2.19
1.95
2.34
2.07
2.13
1.79
2.01
1.70
2.20
1.89
2.46
2.15
2.15
2.01
2.24
2.29
2.22
2.12
2.34
2.20
2.48
1.98
2.24
1.82
2.16
1.20
1.58
1.45
1.91
1.17
1.66
1.28
1.58
1.15
5.4
5.7
5.7
5.9
5.6
5.9
5.8
6.0
6.0
6.1
6.2
6.4
6.1
6.2
6.2
6.4
6.3
8.9
8.2
8.9
8.1
9.4
8.3
9.9
8.5
9.6
7.5
9.5
7.3
9.8
7.6
10.2
9.4
9.9
7.9
9.0
7.6
9.0
8.0
9.4
8.5
10.0
7.1
9.5
7.0
9.5
7.4
9.6
7.6
6.8
7.4
2.13 (SMe)
2.13 (SMe)
3.78 (SCH2)
3.74 (SCH2)
6.85 (NH, exch.), 4.19, 1.24 (OEt), 2.23 (SMe)
6.75 (NH, exch.), 4.23, 1.26 (OEt), 2.28 (SMe)
6.59 (NH, exch.), 4.31-4.13 1.27 (OEt)
6.82 (NH, exch.), 4.18, 1.19 (OEt)
5.71 (NH, exch.), 4.13, 1.20 (OEt), 3.75 (SCH2, J ) 13.7)
6.53 (NH, exch.) 4.19, 1.27 (OEt), 3.86 (SCH2, J ) 13.4)
5.32 (NH, exch.), 4.14-4.01 1.21 (OEt)
6.73 (NH, exch.), 4.15, 1.22 (OEt)
5.60 (NH, exch.), 5.0-4.0 (OH, exch.),
3.81 (SCH2, J ) 13.7)
6.79 (NH, exch.), 6.8-6.1 (OH, exch.), 6.02-5.83,
5.28-5.19 (m, CHdCH2) 3.27 (SCH2, J ) 7.7)
(Z)-7a
(Z)-7b
7.84-7.41
2.84
2.84
1.15
6.2
9.9
7.4
a
The 1H NMR spectrum of (E)-5d could be determined only on the diastereoisomeric mixture and shows characteristic signals at δ )
5.61 (s, NH), 2.61-2.53, 2.10-2.00, and 1.75-1.63 associated with HX, HA, and HB, respectively. Pure diastereoisomer. The 1H NMR
b
spectrum of the diastereoisomeric mixture of disulfides shows signals at δ ) 7.85-7.40 (m, Harom), 4.20-4.10, 1.26-1.18 (OEt), 3.36 (dd,
J AX ) 9.4, J BX ) 6.8, HX), 2.32-2.23 (m, HA), and 1.58-1.53 (m, HB).
Sch em e 3
13
J cis is larger than J trans
.
These results were also con-
direct alkylation of the sulfur atom because it allows for
the preparation of a series of cyclopropanecarboxylic acid
derivatives 7, while it avoids the steps involved in the
preparation and hydrolysis of compounds 5. This synthon
is particularly useful when the mercaptan derivatives are
not readily available or when a double bond is present
in the alkyl group because of its reactivity with diazo-
methane. In the alkylation reaction, disulfides 6 were
used as a diastereoisomeric mixture which is irrelevant
to the configuration of the final products. As shown in
Scheme 3, the alkylation of 6 was performed under phase-
transfer catalysis in THF using aqueous sodium hydrox-
ide (6%), CTACl as a catalyst, and the alkyl bromide
(benzyl bromide and allyl bromide). The use of amino-
iminomethanesulfinic acid14 in the reaction mixture led
to the reduction of disulfides 6 to the corresponding thiol,
which was not isolated, and instead was directly alky-
lated. The hydrolytic conditions produced the acids 7 in
satisfactory yields.
firmed by independent NOESY experiments for com-
pounds (Z)-4d , (Z)-5a ,c, and (E)-5c in which the close
spatial proximity of HX and HA in the Z isomers and HX
and HB in the E isomer has been demonstrated. NOESY
experiments confirmed the stereochemistry of compounds
5. In fact, a positive Overhauser effect was pointed out
between the HX and the hydrogen linked to nitrogen in
compound (E)-5c. As expected, this effect was absent for
Z isomers. The configuration of compounds 4 follows from
their transformation into the corresponding 5. When pure
compound (Z)-4b was treated with ethanol and DMAP,
1
pure ester (Z)-5b was found. The H NMR spectrum of
this compound is in agreement with H NMR spectra of
compounds (Z)-5a ,c,d (see Table 1).
1
The cyclopropanecarboxylate 5d is a synthetically
interesting substrate in which the trityl group linked to
the sulfur atom can be easily removed. As depicted in
Scheme 3, when compound (Z)-5d was treated with
iodine in ethanol for 2 h, a mixture of diastereoisomeric
disulfides 6 was obtained in good yield. The preparation
of disulfides, which, as shown later, are synthetic equiva-
lents of the corresponding thiol, is advantageous over the
In conclusion, the goal of our research was attained
by the preparation of new 3-sulfanyl substituted 2,3-
methanoamino acid derivatives 5 and 7, which cannot
be obtained by the apparently straightforward route of
nucleophilic substitution of a chloride atom in the known
(13) J ackman, L. M.; Sternhell, S. Applications of Nuclear Magnetic
Resonance Spectroscopy in Organic Chemistry; Pergamon Press: Ox-
ford, England, 1972; p 286.
(14) Comaseto, J . V.; Lang, E. S.; Ferreira, J . T. B.; Simonelli, F.;
Correira, V. R. J . Organomet. Chem. 1987, 334, 329.

Conformationally Constrained Masked Cysteines
Ta ble 2. Elem en ta l An a lyses
J . Org. Chem., Vol. 64, No. 3, 1999 729
calcd (%)
H
found (%)
compound
formula
mw
C
N
C
H
N
(E)-3a
(Z)-3b
(E)-3c
(Z)-3d
(Z)-4a
(Z)-4b
(E)-4b
(Z)-4c
(E)-4c
(Z)-4d
(E)-4d
(Z)-5a
(Z)-5b
(E)-5b
(Z)-5c
(E)-5c
(Z)-5d
6
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
11H9NO2S
16H11NO2S
17H13NO2S
29H21NO2S
12H11NO2S
17H13NO2S
17H13NO2S
18H15NO2S
18H15NO2S
30H23NO2S
30H23NO2S
14H17NO3S
19H19NO3S
19H19NO3S
20H21NO3S
20H21NO3S
32H29NO3S
26H28N2O6S2
18H17NO3S
14H15NO3S
219.26
281.33
295.36
447.55
233.28
295.36
295.36
309.38
309.38
461.58
461.58
279.35
341.42
341.42
355.45
355.45
507.65
528.64
327.40
277.34
60.26
68.31
69.13
77.83
61.78
69.13
69.13
69.88
69.88
78.06
78.06
60.19
66.84
66.84
67.58
67.58
57.71
59.07
66.04
60.63
4.14
3.94
4.44
4.73
4.75
4.44
4.44
4.89
4.89
5.02
5.02
6.13
5.61
5.61
5.95
5.95
5.76
5.34
5.23
5.45
6.39
4.98
4.74
3.13
6.00
4.74
4.74
4.53
4.53
3.03
3.03
5.01
4.10
4.10
3.94
3.94
2.76
5.30
4.28
5.05
60.11
68.05
69.03
77.67
61.50
69.25
69.00
70.01
69.70
78.18
77.92
60.30
66.99
66.68
67.42
67.63
57.55
59.00
65.89
60.50
4.10
4.09
4.24
4.78
4.85
4.32
4.57
4.99
4.95
5.10
5.14
6.25
5.70
5.73
5.88
6.04
5.88
5.29
5.33
5.61
6.30
4.78
4.68
3.02
5.91
4.84
4.61
4.42
4.44
3.15
2.98
5.23
4.23
4.01
3.83
3.82
2.69
5.25
4.13
4.98
(Z)-7a
(Z)-7b
νmax 1770 cm-1; 1H NMR δ 8.14-7.40 (m, 10 H), 7.62 (s, 1 H).
2-chloro-1-aminocyclopropanecarboxylic acid10d with mer-
captan derivatives, as has been demonstrated by the
literature data15 to be known and been verified by
ourselves. Our process has the advantage of showing a
good diastereoselectivity, the Z isomers being highly
prevalent over the E ones. These compounds are confor-
mationally constrained cysteine analogues, and for this
reason, can contribute to the study of their conforma-
tional effects in biologically interesting peptides.
1
(E)-3b: IR νmax 1770 cm-1; H NMR δ 8.14-7.40 (m, 10 H),
7.88 (s, 1 H).
4-(Ben zylsu lfa n ylm eth ylen e)-2-p h en yl-5(4H)-oxa zolo-
n e (3c): total yield 83% (Z/E: 5.5:1). (Z)-3c: mp 122 °C (122
°C);8c IR νmax 1780 cm-1; 1H NMR δ 8.08-7.30 (m, 11 H), 4.30
(s, 2 H). (E)-3c: mp 119 °C (CH2Cl2/Et2O); IR νmax 1780 cm-1
1H NMR δ 7.99-7.46 (m, 10 H), 7.61 (s, 1 H), 4.15 (s, 2 H).
;
2-P h en yl-4-(t r it ylsu lfa n ylm et h ylen e)-5(4H )-oxa zolo-
n e (3d ): total yield 84%. (Z)-3d : mp 185 °C; IR νmax 1780 cm-1
;
1H NMR δ 8.10-7.27 (m, 20 H), 7.15 (s, 1 H).
Gen er a l P r oced u r e for P r ep a r a tion of 1-Alk ylsu lfa n yl-
a n d 1-Ar ylsu lfa n yl-5-p h en yl-6-oxa -4-a za sp ir o[2.4]ep t-4-
en -7-on es 4. (Z)-Oxazolone 3 (1 mmol) was dissolved in CH2-
Cl2 and an ethereal solution of diazomethane (1.5 mmol, 6 mL,
0.25 M) was added to it. The mixture was allowed to stand at
room temperature until nitrogen evolution ceased (1-3 h).
After solvent evaporation and crystallization from CH2Cl2,
pure oxazolones (Z)-4a ,b were obtained. The mother liquor,
in the case of 4a ,b, and the crude reaction mixture, in the case
of 4c,d , were chromatographed [2-cm-width plate; silica-gel
Kieselgel 60 (Merck); 230-400-mesh ASTM; cyclohexane/
EtOAc (9:1) eluant; 6 mL/min flow rate] to give two fractions,
one containing pure Z isomer 4 and the other a mixture of Z
and E isomers. The pure E isomer was isolated in the case of
4b-d by recrystallization. The ratio of isomers is indicated
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. IR spectra ob-
tained by the Nujol method were measured using NaCl. 1H
and 13C NMR were recorded in CDCl3 at 200 and 50 MHz,
respectively, with CHCl3 as the internal standard. Ethanol-
free CH2Cl2 was used in all experiments. Oxazolone 1a 10d is a
known compound. Elemental analyses of all compounds appear
in Table 2.
Gen er a l P r oced u r e for th e P r ep a r a tion of 4-(Alk yl-
su lfa n ylm eth ylen e)- a n d 4-(P h en ylsu lfa n ylm eth ylen e)-
2-p h en yl-5(4H)-oxa zolon es 3. A solution of 4-(chlorometh-
ylene)-2-phenyl-5(4H)-oxazolone (1) (207 mg, 1 mmol) and
sodium thiomethoxide 2a (105 mg, 1.5 mmol) or mercaptans
2c-d (1 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature. Triethylamine (0.14 mL, 1 mmol) was added
dropwise (except for 3a ) over a few minutes, and stirring was
continued until the starting material 1 disappeared (30-60
min), after which the organic layer was washed with a solution
of HCl (10%, 10 mL), and H2O (10 mL) and dried over Na2-
SO4. After solvent elimination, the crude reaction mixture was
recrystallized from CH2Cl2/Et2O, and the pure isomer (Z)-3 was
isolated. Silica-gel (n-pentane/CH2Cl2, 1:0 to 0:1) column
chromathography of the mother liquor gave two fractions, one
containing the pure Z isomer and the other a mixture of E
and Z isomers. The pure E isomer was isolated only in the
case of 3a ,c after recrystallization of the mixture of isomers.
In the case of 3d only the Z isomer was obtained. The ratio of
isomers is indicated below.
1
below. H NMR data are given in Table 1.
1-Meth ylsu lfa n yl-5-p h en yl-6-oxa -4-a za sp ir o[2.4]ep t-4-
en -7-on e (4a ): total yield 70% (Z/E: 3:1). (Z)-4a : mp 137 °C
(CH2Cl2/Et2O); IR νmax 1780 cm-1
.
5-P h en yl-1-p h en ylsu lfa n yl-6-oxa -4-a za sp ir o[2.4]ep t-4-
en -7-on e (4b): total yield 73% (Z/E: 3:1). (Z)-4b: mp 165 °C
(CH2Cl2/Et2O); IR νmax 1795 cm-1 13C NMR δ 26.3 (C-2), 35.6
;
(C-1), 54.0 (C-3), 126.3-135.4 (Harom), 163.4 (C-5), 177.2 (C-
7). (E)-4b: mp 99 °C (CH2Cl2/Et2O); IR νmax 1795 cm-1
.
1-Ben zylsu lfa n yl-5-p h en yl-6-oxa -4-a za sp ir o[2.4]ep t-4-
en -7-on e (4c): total yield 54% (Z/E: 5:1). (Z)-4c: mp 131 °C
(CH2Cl2/i-Pr2O); IR νmax 1800 cm-1. (E)-4c: mp 88 °C (CH2-
Cl2/i-Pr2O); IR νmax 1800 cm-1
.
5-P h en yl-1-t r it ylsu lfa n yl-6-oxa -4-a za sp ir o[2.4]ep t -4-
en -7-on e (4d ): total yield: 67% (Z/E: 3:1). (Z)-4d : mp 75 °C
(CH2Cl2/i-PrOH); IR νmax 1795 cm-1. (E)-4d : mp 143-144 °C
4-(Meth ylsu lfa n ylm eth ylen e)-2-p h en yl-5(4H)-oxa zolo-
n e (3a ): total yield 85% (Z/E: 9:1). (Z)-3a : mp 143 °C (141
1
°C);8c IR νmax 1740 cm-1; H NMR δ 8.09-7.45 (m, 6 H), 2.70
(CH2Cl2/i-PrO2); IR νmax 1795 cm-1
.
(s, 3 H). (E)-3a : mp 139 °C; IR νmax 1740 cm-1
8.01-7.46 (m, 5 H), 7.63 (s, 1 H), 2.60 (s, 3 H).
;
1H NMR δ
Eth yl (Z)-1-Ben zoyla m in o-2-p h en ylsu lfa n ylcyclop r o-
p a n eca r boxyla te (5b). Compound (Z)-4b (40 mg, 0.12 mmol)
was dissolved in EtOH (1.5 mL) and stirred at room temper-
ature in the presence of DMAP (3.3 mg, 0.12 mmol) for 1 h.
The ethanol was removed in a vacuum, and the oil was
dissolved in CH2Cl2 (5 mL) and washed with 10% citric acid
(2 × 5 mL). The organic layer was dried over Na2SO4. After
2-P h en yl-4-(p h en ylsu lfa n ylm eth ylen e)-5(4H)-oxa zolo-
n e (3b): total yield 70% (Z/E: 2.3:1). (Z)-3b: mp 106 °C; IR
(15) Aksenov, V. S.; Terent’eva, G. A.; Savinykh, Y. V. Russ. Chem.
Rev. (Engl. Transl.) 1980, 49, 549.

730 J . Org. Chem., Vol. 64, No. 3, 1999
Clerici et al.
solvent evaporation, the oil was recrystallized from CH2Cl2/
Et2O, giving pure (Z)-5b (31 mg, 75%): mp 167 °C.
in EtOH (2 mL), and a solution of iodine in aqueous ethanol
(8 mL, 0.125 M, EtOH/H2O, 7:1) was added and stirring was
continued for 2 h. A solid was separated. After solvent
evaporation, the solid was taken up with CH2Cl2 (10 mL) and
washed with a solution of sodium thiosulfate and then with
H2O. After being dried over Na2SO4 and recrystallized from
CH2Cl2/i-Pr2O, a mixture of diastereoisomeric disulfides 6 (215
mg) was isolated. A further crop of 6 (40 mg) was obtained
from the mother liquor when it was chromatographed on silica-
gel (CH2Cl2/Et2O, 1:0 to 7:1): total yield: 97%. A pure amount
of one of the two diastereoisomers was isolated by a further
recrystallization: mp 214 °C (EtOH/H2O); IR νmax 3200, 1705,
Gen er a l P r oced u r e for P r ep a r a t ion of (Z)-E t h yl
2-Alk ylsu lfa n yl- a n d 2-Ar ylsu lfa n yl-1-ben zoyla m in ocy-
clop r op a n eca r boxyla tes 5. (Z)-Oxazolone 3 (1 mmol) was
reacted with diazomethane as indicated above. After solvent
evaporation, the oil was dissolved in EtOH (10 mL), and DMAP
(122 mg, 1 mmol) was added. The reaction was stirred at room
temperature for 1 h. The ethanol was removed in a vacuum,
and the residual oil was dissolved in CH2Cl2 (10 mL) and
washed with 10% citric acid (2 × 10 mL). The organic layer
was dried over Na2SO4. After solvent evaporation, the oil was
chromatographed on silica gel (CH2Cl2/Et2O, 1:0 to 20:1) to give
two fractions, one containing the pure Z isomer 5 and the other
containing a mixture of Z and E isomers 5. The pure E isomers
were isolated in the case of 5b,c by recrystallization. The ratio
of isomers is indicated below. 1H NMR data are given in Table
1.
1640 cm-1
.
Gen er a l P r oced u r e for th e P r ep a r a tion of (Z)-2-Alk yl-
su lfa n yl- 1-ben zoyla m in ocyclop r op a n e Ca r boxylic Acid s
7. To a solution of disulfides 6 (0.2 mmol), aminoiminosulfinic
acid (0.2 mmol), alkyl bromide (0.42 mmol), and CTACl (0.0032
mg, 0.01 mmol) in THF (2 mL) under nitrogen was added an
aqueous solution of NaOH (1.5 mL, 6%). The two-phase system
was vigorously stirred under reflux for 2 h. After solvent
evaporation, the mixture was taken up with CH2Cl2 (10 mL)
and washed with H2O (2 × 10 mL). The matched aqueous
layers were acidified with HCl (10%, Congo Red) and extracted
with CH2Cl2 (2 × 10 mL). After drying over Na2SO4, compound
7a was recrystallized from CH2Cl2, giving a pure product (47
mg). The mother liquor of 7a and the reaction mixture of 7b
were chromatographed on silica gel (CH2Cl2/Et2O, 1:0 to 2:1)
giving the corresponding pure compounds.
Eth yl 1-Ben zoyla m in o-2-m eth ylsu lfa n ylcyclop r op a n e-
ca r boxyla te (5a ): total yield 66% (Z/E: 3:1). (Z)-5a : mp 107
°C (CH2Cl2/Et2O); IR νmax 3300, 1720, 1640 cm-1
.
Eth yl 1-Ben zoyla m in o-2-p h en ylsu lfa n ylcyclop r op a n e-
ca r boxyla te (5b): total yield 77% (Z/E: 3:1). (Z)-5b: mp 167
°C (CH2Cl2/Et2O); IR νmax 3250, 1720, 1620 cm-1. (E)-5b: mp
117 °C (CH2Cl2/i-Pr2O); IR νmax 3250, 1720, 1620 cm-1
.
Eth yl 1-Ben zoyla m in o-2-ben zylsu lfa n ylcyclop r op a n e-
ca r boxyla te (5c): total yield 67% (Z/E: 5:1). (Z)-5c: mp 135
°C (CH2Cl2/Et2O); IR νmax 3300, 1720, 1640 cm-1 13C NMR δ
;
14.3 (Me), 23.2 (C-3), 31.7 (C-2), 38.2 (SCH2), 38.9 (C-1), 61.6
(OCH2), 127.2-139.1 (Harom), 168.4 (CONH), 170.8 (COOEt).
(E)-5c: mp 102 °C (CH2Cl2/i-Pr2O); IR νmax 3300, 1720, 1640
(Z)-1-Ben zoyla m in o-2-ben zylsu lfa n ylcyclopr op a n eca r -
boxylic Acid (7a ): total yield 74%; mp 173-174 °C (CH2-
Cl2); IR νmax 3300, 1685, 1620 cm-1
.
cm-1
.
(Z)-Be n zoyla m in o-2-a llylsu lfa n ylcyclop r op a n e ca r -
boxylic Acid (7b): total yield 67%; mp 166 °C (CH2Cl2/i-
Eth yl 1-Ben zoyla m in o-2-tr itylsu lfa n ylcyclop r op a n e-
Pr2O); IR νmax 3300, 1690, 1620 cm-1
.
ca r boxyla te (5d ): total yield 60% (Z/E: 5:1). (Z)-5d : mp 136
°C (CH2Cl2/i-Pr2O); IR νmax 3300, 1720, 1640 cm-1 13C NMR δ
;
14.3 (Me), 23.0 (C-3), 30.9 (C-2), 38.0 (C-1), 61.5 (OCH2),
127.2-134.1 (Harom), 168.2 (CONH), 170.4 (COOEt).
Bis(2-Ben zoyla m in o-2-et h oxyca r b on ylcyclop r op yl)-
d isu lfid e (6). The ester 5d (507 mg, 1 mmol) was dissolved
Ack n ow led gm en t. We thank MURST (40%) for
financial support.
J O9810011