Regioselective reduction of 5-substituted 2-alkylidene-4-oxothiazolidines by metal hydrides

Article abstract of DOI:10.1055/s-2004-820051

Thiazolidine β-enamino derivatives possessing a 5-substituted acetate substituent were chemoselectively reduced to corresponding alcohols, or new condensed 2-alkylidenethiazolidines. The method is based on the resistance of an enaminone fragment to reduction by metal hydrides.

Full text of DOI:10.1055/s-2004-820051

1034
LETTER
Regioselective Reduction of 5-Substituted 2-Alkylidene-4-Oxothiazolidines by
Metal Hydrides
b
Regioselective
a
R
a
d
5-Substitute
e
d
2-Alkylidene-4-
M
Oxothiazolidines arković,*a,b Marija Baranac,a,b Milovan Stojanović
Faculty of Chemistry, University of Belgrade, Studentski trg 16, P. O. Box 158, 11001 Belgrade, Serbia and Montenegro
b
Center for Chemistry ICTM, P. O. Box 473, 11000 Belgrade, Serbia and Montenegro
Fax +381(11)636061; E-mail: markovic@helix.chem.bg.ac.yu
Received 23 December 2003
enamines is based on the presence of the prochiral exocy-
clic double bond5 and an ester functionality.6 Lhommet et
al.7 described recently the synthesis of chiral pyrrolidine
b-amino esters by diastereoselective catalytic hydrogena-
tion of chiral pyrrolidine tetrasubstituted b-enamino es-
ters. Sodium triacetoxyborohydride in HOAc has been
employed for the chemoselective reduction of homochiral
b-enamino esters to biologically active b-amino esters.8
Reductions of acyclic and cyclic b-enamino ketones to
synthetically important g-aminoalcohols have also been
reported with various levels of diastereoselectivity.9
Palmieri et al.10 described the regioselective reduction of
cyclic and acyclic N-acylenamino ketones to the b-hy-
droxyenamides using NaBH4 in MeOH.
Abstract: Thiazolidine b-enamino derivatives possessing a 5-sub-
stituted acetate substituent were chemoselectively reduced to corre-
sponding alcohols, or new condensed 2-alkylidenethiazolidines.
The method is based on the resistance of an enaminone fragment to
reduction by metal hydrides.
Key words: thiazolidine, reductions, hydrides, regioselectivity,
ring closure
(Z)-4-Oxothiazolidines 1 (Scheme 1) bearing a trisubsti-
tuted exocyclic double bond at C(b) constitute a class of
typical exocyclic b-enaminocarbonyl compounds. They
are generally recognized as useful precursors in organic
synthesis.1 In particular, we have shown that the regiospe-
cific bromination of the enaminone-type heterocycles 1
leads to a-bromo-a,b-unsaturated compounds 2,2 which
are valuable a-acylvinyl anion equivalents.3
We present here results on the chemoselective reduction
of 4-oxothiazolidines 1 by metal hydrides. Initial reduc-
tions of enamino ketone 1a and N-methyl analogue 1f,
aimed at assessing the reactivity of enaminone moiety,
were carried out in EtOH by adding increasing amounts of
NaBH4 (1–5 mol equiv) at 0 ºC to room temperature. In
contrast to the literature results (vide ante) in the case of
1a, only starting material was recovered, even after 24 h.
However, reduction of 1a under more vigorous conditions
(a tenfold molar excess of NaBH4, EtOH, reflux, 2 h) pro-
ceeded cleanly, affording 5-(2-hydroxyethyl)thiazolidine
5a in 64% yield (Table 1, entry 1). Surprisingly, N-methyl
substituted lactam 1f was converted, via a reduction-ring
closure sequence at room temperature, employing 2 mol
equivalents of NaBH4, to a not easily accessible new fused
heterocycle, i.e. (Z)-(N-methyltetrahydrofuro[2,3-d]thiaz-
ol-2-ylidene)-1-phenylethanone (6f) (Table 1, entry 6). In
general, we found that the regioselective reduction of oth-
er thiazolidines 1b–e with excess NaBH4 proceeded
smoothly in refluxing EtOH giving rise to alcohols 5b–e
in moderate yields (49–64%).11 The key step responsible
for an inhibition of the enaminone moiety in 1 toward
chemical and catalytic reduction as well (Table 1, entry
CO2Et
O
S
β
α
O
R
N
H
H
(Z)-1a (R=Ph)
(Z)-1b (R=NHPh)
(Z)-1c (R=NHCH2CH2Ph)
(Z)-1d (R=OEt)
Lawesson's
reagent
α-bromination
CO2Et
S
S
S
O
S
EtO
N
R
O
R
N
H
O
Br
2a–d
3a–c
Scheme 1
More recently, we described a novel and highly efficient
4-oxothiazolidine-1,2-dithiole rearrangement induced by
Lawesson’s reagent (Scheme 1).4
CO2Et
S
CO2Et
S
The specific interest in exploring the reduction reactions
of (Z)-4-oxothiazolidines 1 and other functionalized b-
NaBH4(xs.)
EtOH
5a–e
(49-64%)
W
W
O
O
N
H
N
H
H
4a–e
1a–e
SYNLETT 2004, No. 6, pp 1034–1038
0
6.
0
5.
2
0
0
4
W = COPh, CONHPh, CONHCH2CH2Ph, CO2Et, CN
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820051; Art ID: G36203ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

LETTER
Regioselective Reduction of 5-Substituted 2-Alkylidene-4-Oxothiazolidines
1035
Table 1 Synthesis of (Z)-5-(2-Hydroxyethyl)-2-alkylidene-4-oxothiazolidines 5 and Condensed Thiazolidines 6
Entry Substrate
Reducing reagent (mol
equiv)–solvent
Product
Yield (%)a
64
Mp (°C)
1
NaBH4 (10)–EtOHb
NaBH4 (10)–EtOHb
NaBH4 (10)–EtOHb
NaBH4 (10)–EtOHb
NaBH4 (10)–EtOHb
NaBH4 (2)–EtOHc
LiBH4 (10)–THFc
158–159
223–224
156–158
110–111
119–120
121–122
Dec.
CH2OH
CO2Et
O
O
O
O
O
O
O
S
S
O
Ph
O
N
Ph
N
H
H
H
H
H
H
H
H
H
H
(Z)-5a
(Z)-1a
2
49
49
64
54
21
19
CO2Et
CH2OH
S
S
O
N
NHPh
O
NHPh
N
H
H
(Z)-1b
(Z)-5b
3
CO2Et
CH2OH
S
S
O
N
NHCH2CH2Ph
O
NHCH2CH2Ph
N
H
H
(Z)-1c
(Z)-5c
4
CH2OH
S
CO2Et
O
S
O
OEt
O
N
OEt
N
H
H
H
(Z)-5d
(Z)-1d
5
CO2Et
CH2OH
S
S
CN
CN
O
N
O
N
H
H
H
1e (Z/E mixture)
5e (Z/E mixture)
6
7
O
CO2Et
S
Ph
S
O
H
N
Me
O
O
Ph
N
(Z)-6f
Me
H
(Z)-1f
(Z)-1a
O
S
Ph
H
N
H
O
6a (Z/E mixture)
Synlett 2004, No. 6, 1034–1038 © Thieme Stuttgart · New York

1036
R. Markovič et al.
LETTER
Table 1 Synthesis of (Z)-5-(2-Hydroxyethyl)-2-alkylidene-4-oxothiazolidines 5 and Condensed Thiazolidines 6 (continued)
Entry Substrate
Reducing reagent (mol
equiv)–solvent
Product
Yield (%)a
83
Mp (°C)
134–135
8
(Z)-1d
NaBH4 (10)–MeOHb
CO2Me
O
S
O
OEt
N
H
H
(Z)-12d
9
1e (Z/E mixture)
NaBH4 (10)–MeOHb
76
146–148
CO2Me
S
CN
O
N
H
H
12e (Z/E mixture)
10
(Z)-1a
H2 (3 atm)–PtO2
NR
a Isolated yields following column chromatography on silica gel.
b Reflux.
c Room temperature.
10), is the formation of the highly stabilized anion 4 ester carbonyl is enhanced in the iminium ion 8, allowing
(Scheme 2).1d,6b,12,13
the reducing agent to become increasingly reactive even at
room temperature.
This is evidenced by the vigorous evolution of hydrogen
upon addition of the thiazolidine 1 to the reducing agent The reduction step affords alcohol 9, that subsequently
during the initial stage of the reaction (10–15 min, r.t.). In cyclizes to new bicyclic tetrahydrofurothiazolidine 6f,
the next step NaBH4 selectively reduces the side-chain ac- albeit in a small yield (21%). The detection of the hetero-
etate group,14 whereas the strongly deactivated W func- cyclic derivatives 10 and 11, which have been also isolat-
tion and C=C bond of the conjugated enaminone moiety ed and characterized, supports the proposed mechanism.16
remain unaffected.
Thus, an abstraction of the C(5)-hydrogen from the inter-
mediate 8 by an excess base affords 10 (18%), and addi-
tion of EtOH to the same transient species leads to the
traces of compound 11. As shown in entry 7 of Table 1,
the enaminone 1a undergoes the same reduction-cycliza-
tion transformation in the presence of the stronger reduc-
ing reagent, such as LiBH4 in THF. To the best of our
knowledge, the formation of condensed thiazolidines 617
The formation of the bicyclic product 6f is ascribed to the
presence of the methyl group at the nitrogen atom in the
starting thiazolidine 1f (Scheme 3). Based on the litera-
ture precedent15 that NaBH4 in pyridine can reduce prima-
ry and tertiary amides to the corresponding nitriles and
amines, respectively, we postulated the iminium ion 8 as
a key intermediate. Obviously, the electrophilicity of the
CO2Et
CO2Et
O
S
O
S
Ph
Ph
N
EtO
N
Me
Me
H
H
10
11
Base
EtOH
CO2Et
S
CO2Et
O
H
O
O
O
S
S
Ph
S
NaBH4 (2 eq.)
EtOH, r.t., 3 h
OH
O
Ph
Ph
Ph
N
Me
N
Me
N
N
Me
O
H
Me
H
H
H
1f
8
9
6f
Scheme 3
Synlett 2004, No. 6, 1034–1038 © Thieme Stuttgart · New York

LETTER
Regioselective Reduction of 5-Substituted 2-Alkylidene-4-Oxothiazolidines
1037
Table 2 Comparisons of the 13C NMR Chemical Shifts (ppm) of
Olefinic Carbon Atoms in Thiazolidine Derivatives 1 and 6
References
(1) (a) Xu, Z.-H.; Jie, Y.-F.; Wang, M.-X.; Huang, Z.-T.
Synthesis 2002, 523. (b) Brunerie, P.; Célérier, J. P.; Huché,
M.; Lhommet, G. Synthesis 1985, 735. (c) Nemes, P.;
Balázs, B.; Tóth, G.; Scheiber, P. Synlett 2000, 1327.
(d) Calvo, L.; Gonzáles-Ortega, A.; Sanudo, M. C. Synlett
2002, 2450. (e) Fustero, S.; G. de la Torre, M.; Jofré, V.;
Pérez-Carlón, R.; Navarro, A.; Simón-Fuentes, A. J. Org.
Chem. 1998, 63, 8825. (f) Fang, F. G.; Danishefsky, S. J.
Tetrahedron Lett. 1989, 30, 3621.
Entry
Compound
(Z)-1aa
(Z)-6aa
(E)-6aa
(Z)-1fa
C(b)
C(a)
DdC(b)C(a)
66.62
81.54
82.44
65.98
78.28
1
2
3
4
5
161.56
168.78
168.02
161.48
165.72
94.94
87.24
85.02
95.50
87.47
(2) (a) Marković, R.; Baranac, M. Synlett 2000, 607.
(b) Marković, R.; Dàmbaski, Z.; Baranac, M. Tetrahedron
2001, 57, 5833.
(3) Rezgui, F.; Amri, H.; El Gaïed, M. M. Tetrahedron 2003, 59,
1369.
(Z)-6fb
a DMSO-d6.
b CDCl3.
(4) (a) Marković, R.; Baranac, M.; Jovetić, S. Tetrahedron Lett.
2003, 44, 7087. (b) In the case of thionation of thiazolidines
1b and 1c initially formed 1,2-dithioles rearrange to 1,2,4-
dithiazole derivatives (ref.4a).
(5) (a) Kiddle, J.; Green, D. L. C.; Thompson, C. M.
Tetrahedron 1995, 51, 2851. (b) Howard, A. S.; Gerrans, G.
C.; Michael, J. P. J. Org. Chem. 1980, 45, 1713.
(6) (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277.
(b) Prugh, J.; Deana, A. A. Tetrahedron Lett. 1988, 29, 37.
(7) David, O.; Blot, J.; Bellec, C.; Fargeau-Bellassoued, M.-C.;
Haviari, G.; Célérier, J.-P.; Lhommet, G.; Gramain, J.-C.;
Gardette, D. J. Org. Chem. 1999, 64, 3122.
achieved through cyclization involving the 4- and 5-posi-
tions of thiazolidines 1 was not observed before.
The selected 13C NMR shift differences between the ole-
finic carbon atoms, i.e. DdC(b)C(a) values in compounds 1
and 6 are worth noting (Table 2), since they indicate an in-
crease of charge separation of C=C bond within the con-
densed thiazolidines 6, relative to the corresponding
precursors 1.18
Larger DdC(b)C(a) values (78–82 ppm) in the bicyclic deriv-
atives 6 (Table 2, entries 2,3 and 5) versus DdC(b)C(a) val-
ues (66–67 ppm) in thiazolidinones 1 (Table 2, entries 1
and 4) correlate with an increase of the push-pull effect in
the former.19 This is consistent with the reduction-cycliza-
tion process 1 →→ 6 (Scheme 3) occurring in the elec-
tron-donor portion of reactants 1 (an amide moiety),
which creates a more effective donor (i.e. an amine), so
fused thiazolidines 6 have larger DdC(b)C(a) values.
(8) Cimarelli, C.; Palmieri, G.; Bartoli, G. Tetrahedron:
Asymmetry 1994, 5, 1455.
(9) (a) Bartoli, G.; Cupone, G.; Dalpozzo, R.; De Nino, A.;
Maiuolo, L.; Procopio, A.; Tagarelli, A. Tetrahedron Lett.
2002, 43, 7441. (b) Bartoli, G.; Cimarelli, C.; Palmieri, G. J.
Chem. Soc., Perkin Trans. 1 1994, 537.
(10) Palmieri, G.; Cimarelli, C. Tetrahedron 1988, 54, 915.
(11) Typical Experimental Procedure: An appropriate 5-
substituted-4-oxothiazolidine 1 (100 mg) dissolved in
anhydrous EtOH (10 mL) was added dropwise at r.t. to the
tenfold molar excess of NaBH4 in EtOH (ca. 5 mL). When
the hydrogen evolution had ceased the reaction mixture was
heated under reflux with stirring for a period of time required
(2–3 h) to complete the reaction (TLC). The reaction mixture
was cooled, neutralized with NH4Cl and extracted with
EtOAc. The combined extracts, washed with brine and dried,
were evaporated in vacuo. The residue was purified by
column chromatography (SiO2, toluene–EtOAc, 10:0 →
8:2) to afford a pure product 5.
We wish to point out that the choice of solvent for the re-
duction of thiazolidinones 1a–e was found to be crucial.
By replacing EtOH with MeOH no reduced products
could be detected in the reaction mixture. Instead, as re-
sults reported in entries 8 and 9 of Table 1 indicate, the
change of solvent promotes nearly complete transesterifi-
cation of the acetate group at C(5). From the work of S.
Brown and H. Rapoport14a it is known that methyl esters
of heterocyclic, aromatic or acyclic acids can be reduced
by NaBH4 in MeOH. However, if they are resistant to re-
duction, then, the transesterification especially in MeOH
occurs due to the fast generation of the methoxy-substitut-
ed complex NaB(OMe)4.14c
Spectroscopic data for (Z)-[5-(2-Hydroxyethyl)-4-
oxothiazolidin-2-ylidene]-1-phenylethanone (5a): Colorless
solid; mp 158–159 °C. 1H NMR (200 MHz, DMSO-d6): d =
1.71–1.93 (m, 1 H, CHAHBCHX), 2.14–2.30 (m, 1 H,
CHAHBCHX); 3.58 (m, 2 H, CH2OH), 4.09 (dd, J1 = 9.5 Hz,
J2 = 4.2 Hz, 1 H, Hx), 4.82 (br s, 1 H, OH; signal disappears
upon D2O addition), 6.72 (s, 1 H, =CH), 7.47–7.62 (m, 3 H,
p-Ph and m-Ph), 7.83 (dd, 1 H, J1 = 7.6 Hz, J2 = 1.6 Hz, o-
Ph), 11.85 (br s, 1 H, NH; signal disappears upon D2O
addition). 13C NMR (50.3 MHz, DMSO-d6): d = 35.7
(CHAHB), 44.1 (CHX), 58.6 (CH2OH), 94.5 (=CH), 127.2
(m-Ph), 129.0 (o-Ph), 132.4 (p-Ph), 138.5 (C1-Ph), 161.2
(C=), 177.3 (COring), 187.3 (COexo). IR (KBr): 3453, 3194,
3068, 2924, 1685, 1631, 1577, 1517, 1468, 1364, 1295, 1198
cm–1. MS (EI): m/z (rel. intensity%) = 263 (100) [M+], 232
(86), 178 (8), 146 (20), 105 (80). UV (DMSO): lmax (e) =
335.0 (18000) nm. Anal. Calcd for C13H13NO3S: C, 59.30;
H, 4.98; N, 5.32; S, 12.18. Found: C, 59.03; H, 4.92; N, 5.33;
S, 12.24.
In conclusion, we have shown that in the case of 5-substi-
tuted push-pull thiazolidinones NaBH4 in EtOH is a suit-
able reagent for the regioslective reduction of the ester
functionality. Of particular interest is the synthesis of the
condensed 2-alkylidenethiazolidine derivatives by an in-
tramolecular annulation from the selected thiazolidinone
precursors.
Acknowledgment
Partial financial support by the Ministry of Science, Technology
and Development of the Republic of Serbia, grant no. 1709 (to R.
M.), is acknowledged.
(12) Greenhill, J. V.; Ramli, M.; Tomassini, T. J. Chem. Soc.,
Perkin Trans. 1 1975, 588.
Synlett 2004, No. 6, 1034–1038 © Thieme Stuttgart · New York

1038
R. Markovič et al.
LETTER
(17) (Z)-(N-Methyltetrahydrofuro[2,3-d]thiazol-2-ylidene)-1-
(13) Strong intramolecular 1,5-interactions of nonbonded S and
O within the SC=CC=O subunit with cis-configuration of
C=C bond additionally stabilize the enaminone structure.
(14) (a) Brown, S. M.; Rapoport, H. J. Org. Chem. 1963, 28,
3261. (b) Brown, H. C.; Narasimhan, S.; Choi, Y. M. J. Org.
Chem. 1982, 47, 4702. (c) Hajós, A. Complex Hydrides and
Related Reducing Agents in Organic Synthesis; Elsevier
Scientific Publishing Company: New York, 1979, Chap. 5.
(15) (a) Kikugawa, Y.; Ikegami, S.; Yamada, S. Chem. Pharm.
Bull. 1969, 17, 98. (b) For a reduction of lactams to amines
by NaBH4, see: Mandal, S. B.; G iri, V. S.; Sabeena, M. S.;
Pakrashi, S. C. J. Org. Chem. 1988, 53, 4236.
phenylethanone (6f): Colorless solid; mp 121–122 °C. 1H
NMR (200 MHz, CDCl3): d = 2.12–2.43 (m, 2 H,
CHAHBCHXS), 3.10 (s, 1 H, NCH3), 3.77–3.89 (m, 1 H,
OCHYCHXS), 4.02 (t, 1 H, J = 8.0 Hz, OCHQHZ), 4.12 (t, 1
H, J = 7 Hz, OCHQHZ), 5.67 (d, 1 H, JXY = 6.6 Hz,
OCHYCHXS), 6.08 (s, 1 H, =CH), 7.36–7.47 (m, 3 H, m-Ph,
p-Ph), 7.90–7.95 (m, 2 H, o-Ph). 13C NMR (50.3 MHz,
CDCl3): d = 33.7 (NCH3), 35.2 (CHAHB), 44.6 (CHX), 65.8
(CH2O), 87.5 (=CH), 99.1 (CHY), 127.2 (o-Ph), 128.2 (m-
Ph), 131.0 (p-Ph), 139.7 (C1Ph), 165.7 (C=), 186.9 (CO). IR
(KBr): 3530, 3412, 2974, 2939, 1602, 1571, 1525, 1433,
1355, 1264, 1213, 1028, 973, 727 cm–1. MS (EI, 70 eV):
m/z (rel. intensity) = 261 (57) [M+], 260 (100), 245 (34), 191
(20), 184 (42), 163 (32), 105 (97), 86 (39), 82 (58), 51 (26).
UV (DMSO): lmax (e) = 337.9 (19 700) nm. Anal. Calcd for
C14H15NO2S: C, 64.34; H, 5.79; N, 5.36; S, 12.27. Found: C,
64.24; H, 5.82; N, 5.30; S, 12.59.
(16) Methylation of (Z)-5a led to alcohol 13f, which, in a one-pot
sequence, comprising reduction followed by cyclization,
was transformed into the identical bicylic thiazolidine 6f in
moderate yield (Scheme 4).
O
S
(18) In all push-pull thiazolidines 1 and 6 high field 13C chemical
shifts (85–96 ppm) for the acceptor-substituted C(a) atoms,
and low field shifts (161–169 ppm) for the donor-substituted
C(b) atoms are typical.
HO
NaBH4 (2 equiv)
EtOH, r.t., 4 h
6f (55%)
O
Ph
N
Me
H
13f
(19) (a) Mueller, J. L.; Gibson, M. S.; Hartman, J. S. Can. J.
Chem. 1996, 74, 1329. (b) Kleinpeter, E.; Thomas, S.;
Uhlig, G.; Rudorf, W.-D. Magn. Reson. Chem. 1993, 31,
714.
Scheme 4
Synlett 2004, No. 6, 1034–1038 © Thieme Stuttgart · New York