Regiospecific reduction of 5-benzylidene-2,4-thiazolidinediones and 4- oxo-2-thiazolidinethiones using lithium borohydride in pyridine and tetrahydrofuran

Article abstract of DOI:10.1016/S0040-4020(00)00361-6

The novel regiospecific and general reduction of 5-benzylidene-2,4- thiazolidinediones and 5-benzylidene-4-oxo-2-thiazolidinethiones to the corresponding 5-benzyl derivatives has been accomplished using lithium borohydride in pyridine and tetrahydrofuran. Sodium borohydride and lithium chloride can also be used under these conditions, which represents a cheaper alternative to lithium borohydride. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00361-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4531±4537
Regiospeci®c Reduction of 5-Benzylidene-2,4-Thiazolidinediones
and 4-Oxo-2-thiazolidinethiones using Lithium Borohydride in
Pyridine and Tetrahydrofuran
*
Robert G. Giles, Norman J. Lewis, John K. Quick, Michael J. Sasse, Michael W. J. Urquhart
and Latifa Youssef
SmithKline Beecham Pharmaceuticals, Old Powder Mills, Nr Leigh, Tonbridge, Kent TN11 9AN, UK
Received 24 February 2000; revised 5 April 2000; accepted 20 April 2000
AbstractÐThe novel regiospeci®c and general reduction of 5-benzylidene-2,4-thiazolidinediones and 5-benzylidene-4-oxo-2-thiazo-
lidinethiones to the corresponding 5-benzyl derivatives has been accomplished using lithium borohydride in pyridine and tetrahydrofuran.
Sodium borohydride and lithium chloride can also be used under these conditions, which represents a cheaper alternative to lithium
borohydride. q 2000 Elsevier Science Ltd. All rights reserved.
The 5-benzylthiazolidine-2,4-dione moiety 2 has attracted
considerable pharmaceutical interest. The thiazolidinedione
2a is required in the production of the thiazolidinone
LY213829 which is being developed for the treatment of
in¯ammatory bowel disease.1 2a is prepared from the corre-
sponding benzylidene derivative 1a using Hantszch ester
methodology. The hypoglycemic agent 2b is formed from
a catalytic hydrogenation of the corresponding ole®n 1b,2
whilst cobalt hydride mediated reduction of 1c gives the
corresponding antidiabetic agent pioglitazone 2c.3 The
reduction methods described above are substrate speci®c
which highlights the lack of a general method available to
date.
can be effected cleanly by sodium borohydride in pyridine.
It has also been reported that this particular combination of
reagents can convert both primary and tertiary amides to the
corresponding nitriles and amines, respectively, but leave
secondary amides intact.6
It seemed likely therefore that these conditions could bring
about the conversion of 1d to 2d. Reaction of 1d with
2.25 equiv. of sodium borohydride in pyridine at re¯ux
led to a very slow conversion to 2d and required 24 h to
go to completion. Although the reaction was slow the selec-
tivity for 1,4- over 1,2-attack was excellent and simply
replacing NaBH4 by the more reactive lithium borohydride
gave a more rapid but still selective reaction. Hence 1d
reacted with 2.2 equiv. LiBH4 in THF/pyridine to give 2d
in 80% yield after 3 h at re¯ux and an aqueous work-up.
Reduction of a,b-unsaturated ketones with LiBH4 in
pyridine has been reported7 but generally leads to the corre-
sponding saturated alcohol. It is apparent that this reduction
method does not follow any literature precedent and it
represents the ®rst general chemoselective reduction of
5-alkenylthiazolidin-2,4-diones using a metal hydride
reagent.
Rosiglitazone 2d is being developed as its maleate salt for
the treatment of non-insulin dependent diabetes mellitus
(NIDDM). The key step in the synthesis of 2d is the chemo-
selective reduction of 1d. Use of catalytic hydrogenation to
reduce 1d is complex requiring high catalyst loading and
affords variable reaction times. A range of other reduction
conditions were investigated including Hantszch ester1 and
cobalt hydride3 methods, but gave mostly inef®cient or
unselective reductions where products derived from both
1,2- and 1,4-reduction were obtained (Scheme 1).
To explore the scope of this reduction method, a series of
5-benzylidenethiazolidin-2,4-diones and 5-benzylidene-4-
oxothiazolidin-2-thiones was prepared from the correspond-
ing carbonyl compound 3 and thiazolidine-2,3-dione 4a
(XˆO) or rhodanine 4b (XˆS). All condensations were
carried out using catalytic piperidine and acetic acid in
re¯uxing toluene with azeotropic removal of the water
formed, with the exception of 5f which was prepared by
reaction with sodium acetate in acetic acid.8
There are several reports in the literature that the conjugate
reduction of unsaturated ketones4 and bis-activated ketones5
Keywords: regiospeci®c; conjugate reduction; lithium borohydride;
benzylthiazolidinediones.
* Corresponding author. Tel.: 144-1732-372-314; fax: 144-1732-372-
100; e-mail: michael_w_urquhart@sbphrd.com
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00361-6

4532
R. G. Giles et al. / Tetrahedron 56 (2000) 4531±4537
Scheme 1.
In general, the reductions proceeded rapidly and with
complete regioselectivity (entries a to d). Substrates
containing functionality sensitive to catalytic hydrogenation
were selectively reduced (entries c, k). Tetrasubstituted
ole®ns (entries e, f) were also easily reduced, but the reac-
tion was slower for the 4-hydroxyphenyl derivatives (entries
g, h). The clean reduction of 5g to 6g was of particular
interest since this was reported as being impossible to effect
cleanly using hydride reagents.1 The rate of reduction of 5g
to 6g was improved from 8 days to 1 day by using the polar
co-solvent 1,3-dimethylimidazolidin-2-one. No reduction
was observed for 5i because the phenolate generated
under the reaction conditions was insoluble. Simply protect-
ing the phenol (TBDMS9 or benzyl) gave suitable substrates
Table 1. Preparation and reduction of 5-benzylidenethiazolidin-2,4-diones and 4-oxothiazolidin-2-thiones
Entry
R1
R2
R3
R4
X
Yield of 5 (%)
Time for reduction (h)
Yield of 6 (%)
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
tBu
tBu
H
H
F
Br
OMe
H
H
OH
OH
OH
H
H
H
H
Me
Me
H
H
H
O
O
O
O
O
S
O
S
O
O
O
O
93
83
89
97
51
38
69
84
88
70
95
82b
2
2.5
2
2
3
5
77
62
72
71
85
96
H
H
H
H
H
H
H
H
H
H
Me
181, 24a
4.5
156
2.3
4
5 (258C)
82, 89a
58
0
85
66
78
j
k
l
H
H
H
OTBDMS
OBn
H
H
H
H
a 1,3-Dimethylimidazolidin-2-one was added to dissolve the dilithium salt and increase the rate of reduction.
b N-Methyl imide was prepared from reaction of 5a with NaH and MeI in re¯uxing THF/DMF.

R. G. Giles et al. / Tetrahedron 56 (2000) 4531±4537
4533
5j and 5k for these reduction conditions. Reduction of the
N-methyl derivative (entry l) was achieved at room
temperature (Table 1).
ought to be more ef®cient for the metathesis of LiX and
NaBH4. This seems to be the case and 1d was reduced to
2d using NaBH4 and LiCl in comparable rates and yields to
those observed with the commercial LiBH4.
The exact mechanism for this reduction reaction is unclear.
The presence of pyridine is essential to modify the reactivity
of the LiBH4 and achieve the required selectivity. An
In conclusion, we have developed a general method for the
metal hydride regioselective reduction of 5-benzyl-
idenethiazolidin-2,4-diones 5 to the corresponding 5-benzyl
derivatives 6. This reduction method is also suitable for
substrates that would not be suitable for hydrogenation or
where hydrogenation has been reported to be dif®cult.
10
NMR experiment was conducted to ascertain whether the
pyridine was complexing/adding to the b-position of the
substrate. Compound 1d was dissolved in d8 tetrahydrofuran
and the 1H and 13C NMR spectra were run. A quantity of d5
pyridine was added in order that the solvent composition
was similar to that used in the reduction procedure and both
1
the H and 13C NMR spectra were taken. Comparing the
Experimental
spectra obtained before and after the pyridine addition
showed that the chemical shifts of 1d were unchanged (no
shift differences of .0.1 ppm or .1 ppm were observed in
General procedures
1
the H or 13C NMR spectra, respectively).
Reactions requiring anhydrous conditions were performed
using oven dried glassware and conducted under nitrogen.
Anhydrous solvents were purchased from Fisher Scienti®c
and were used without further puri®cation. Melting points
were determined on a Buchi 510 apparatus and are
uncorrected. IR spectra were recorded on a Nicolet 710
FT-IR spectrometer. NMR spectra were recorded on a
JEOL GSX400 instrument operating at 400 MHz for proton
and 100 MHz for carbon NMR and were performed in
DMSO-d6 solutions using tetramethylsilane as the internal
reference except where indicated otherwise. Mass spectra
were recorded on a Micromess Platform II, Sciex API III
and a VG Trio-2. High Resolution Mass spectra were
recorded on a 70-VSEQ instrument. Flash chromatography
was performed using Fisher Matrix silica gel (60, 40±
63 mm) according to the published procedure.18 TLC was
performed on glass backed plates pre-coated with silica
(0.2 mm, 60F254) and developed using standard visualising
agents: UV ¯uorescence (254 and 366 nm), potassium
permanganate and iodine.
Pyridine has been added to lithium aluminium hydride
reductions and it is known that an intermediate, lithium
tetrakis-(N-dihydropyridyl)aluminate 7a, is responsible for
the improved regioselectivity of reduction.11 It is feasible
that a similar intermediate 7b is involved in this chemistry
and is responsible for the remarkable regioselectivity
observed.
5-(2-[N-methylpyridin-2-yl]aminoethoxyphenylmethyl)-
2,4-thiazolidinedione 2d. A 2.0 M solution of lithium boro-
hydride in THF (110 cm3, 0.22 mol) was added dropwise to
a stirred solution of 1d (35.5 g, 0.1 mol) in pyridine
(61 cm3) and THF (67 cm3) over 10 min. The initial addition
was carried out carefully with vigorous stirring and both an
exothermic and effervescent reaction took place. After
approximately half of the LiBH4 had been added the effer-
vescence ceased and a yellow solution was formed. The
mixture was heated under re¯ux for 3 h during which time
the colour deepened to a wine red solution from which an
orange solid precipitated. The cooled mixture was added
dropwise to a stirred solution of hydrochloric acid
(48 cm3) in water (314 cm3) at 58C keeping the internal
temperature below 208C. The resulting orange±white
suspension was stirred below 158C for 15 min, and then
heated to re¯ux with stirring for 75 min during which the
colour of the mixture darkened to chocolate brown. The
mixture was ®ltered hot through Celite to remove a brown
residue and the stirred brown mother liquor was allowed to
cool to 258C with the precipitation of an off-white solid. The
mixture was cooled to 58C, stirred for 30 min and ®ltered
under vacuum. The residue was washed with water
(3£100 cm3), dried under suction and placed in an oven at
508C for 18 h to give crude 2d as an off-white solid (28.7 g,
The possibility of pyridine acting as a ligating agent for the
lithium cation12 and also as a scavenger for the borane4
produced within the reaction cannot be ruled out. Certainly
pyridine-borane does not reduce 1d even after prolonged
re¯ux. Non-coordinating cations such as tetrabutyl-
ammonium lead to preferential 1,4-attack with unsaturated
ketones13 but Bu4NBH4 does not reduce 1d. The fact that the
reduction of 1d to 2d is faster with LiBH4 than with NaBH4
indicates that a metastable ligate may be responsible for this
enhanced selectivity.
The process for reduction of benzylidenethiazolidinediones
1d and 5 using LiBH4 in pyridine/THF suffers one major
drawback which is the cost of the LiBH4. Although NaBH4
is markedly cheaper it is not as suitable a reagent for this
reduction reaction. There are numerous reports for the
preparation of LiBH4 from NaBH4 by metathesis using
various lithium salts in different solvent systems. These
include LiCl, LiBr or LiI in diethyl ether or THF,14 iso-
propylamine,15 liquid ammonia, ethanol16 and diglyme.17
Most of the available methods require extended reaction
times to prepare LiBH4 and it seemed likely that the reason
for this was the poor solubility of NaBH4 in the solvent. We
observed that pyridine is a good solvent for NaBH4 and

4534
R. G. Giles et al. / Tetrahedron 56 (2000) 4531±4537
80%). Recrystallisation from acetic acid and industrial
methylated spirit afforded a white solid which had identical
physical and spectroscopic properties to authentic
material.19
121.0, 77.1. HRMS, C11H9NO3S requires 235.0300:
Found, 235.0303.
(Z)-5-(1-Methyl-1-phenylmethylene)-2,4-thiazolidinedione
5e. Condensation of acetophenone 3e with 4a gave crude 5e.
Recrystallisation from ethyl acetate and hexane gave 5e as a
white solid (51%), mp 2188C; nmax (Nujol)/cm21 3155,
1735, and 1678; dH 2.66 (3H, s, CH3), 7.45 (5H, m, ArH),
12.29 (1H, bs, NH); dc 21.47, 121.86, 126.60, 128.89,
129.27, 142.03, 149.50, 166.48, 167.52; MS (EI, 70 eV),
m/z 220 [M1H], 149, 134, 115, 105, 91, 44. HRMS,
C11H9NO2S requires 219.0354: Found, 219.0358.
General method for the preparation of 5-benzylidene-
2,4-thiazolidinediones and 4-oxo-2-thiazolidinethione 5
(except 5f, 5j and 5l)
A mixture of the benzaldehyde 3 (47.0 mmol), thiazolidine-
dione or oxothiazolidinethione 4 (47.0 mmol), piperidine
(0.12 g, 1.41 mmol) and acetic acid (0.08 g, 1.41 mmol) in
toluene (50 cm3) was heated under re¯ux with azeotropic
removal of water for 16 h. The mixture was cooled to 58C,
®ltration gave crude 5 which was washed with cold toluene
(15 cm3) and dried.
(Z)-5-(3,5-Di-tert-butyl-4-hydroxyphenyl)methylene-2,4-
thiazolidinedione 5g. Condensation of 3,5-di-tert-butyl-4-
hydroxybenzaldehyde 3g with 4a gave orange crystals.
Recrystallisation from toluene gave 5g as pale yellow
needles (69%), mp 241±244.58C; nmax (Nujol)/cm21 3564,
3300, 1753, 1714 and 1699; dH 1.39 (18H, s, 2£tBu), 7.35
(2H, s, ArH), 7.74 (1H, s, vCHAr), 12.44 (1H, bs, NH); dc
29.95, 34.57, 119.04, 124.32, 127.43, 133.41, 139.37,
156.53, 167.33, 167.96; MS (EI, 70 eV), m/z 333.1 [M],
318.1 [M2Me], 262.1, 247.1, 57.0. HRMS, C18H23NO2S
requires 333.1398: Found, 333.1398.
The following compounds were prepared:
(Z)-5-Phenylmethylene-2,4-thiazolidinedione 5a. Conden-
sation of benzaldehyde 3a with 4a gave crude 5a as bright
yellow crystals. The solid was slurried in methanol (15 cm3)
and ®ltered under vacuum to give 5a as a pale yellow solid
(93%), mp 247±2498C; nmax (Nujol)/cm21 3142, 1693,
1609; dH 7.49 (3H, s, ArH), 7.57 (2H, m, ArH), 7.77 (1H,
s, vCHAr), 12.6 (1H, bs, NH); dc 123.60, 129.41, 130.08,
130.53, 131.92, 133.08, 167.40, 168.00; MS (EI, 70 eV),
m/z 204 [M2H], 133, 59, 42. HRMS, C10H7NO2S requires
205.0198: Found, 205.0214.
(Z)-5-(3,5-Di-tert-butyl-4-hydroxyphenyl)methylene-4-
oxo-2-thiazolidinethione 5h. Condensation of 3,5-di-tert-
butyl-4-hydroxybenzaldehyde 3g with 4b gave orange
crystals. The solid was slurried in methanol (30 cm3) for
30 min and ®ltered under vacuum to yield 5h as an
orange±yellow solid (84%), mp 249±2528C; nmax (Nujol)/
cm21 3615, 3125 and 1694; dH 1.40 (18H, s, 2£tBu), 7.34
(2H, s, ArH), 7.61 (1H, s, vCHAr), 13.70 (1H, bs, NH); dc
29.91, 34.56, 120.94, 124.30, 128.08, 133.58, 139.46,
157.04, 169.26, 195.35; MS (EI, 70 eV), m/z 349.1 [M],
334.1 [M2Me], 262.1, 247.1, 57.0. HRMS, C18H23NOS2
requires 349.1170: Found, 349.1181.
(Z)-5-(4-Fluorophenylmethylene)-2,4-thiazolidinedione
5b. Condensation of 4-¯uorobenzaldehyde 3b with 4a gave
crude 5b as orange crystals. The solid was slurried in metha-
nol (15 cm3) and ®ltered under vacuum to give 5b as orange
crystals (83%), mp 219.5 to 2208C; nmax (Nujol)/cm21 3119,
3039, 1754, 1733, 1726, 1699, 1689, 1594; dH 7.39 (2H, m,
ArH), 7.68 (2H, m, ArH), 7.82 (1H, s, vCHAr), 12.65 (1H,
bs, NH); dc 116.5, 123.1, 129.7, 130.7, 132.5, 162.9, 167.3,
167.8; MS (EI, 70 eV), m/z 223 (M11), 180, 152 (100%),
132, 107, HRMS, C10H6NO2FS requires 223.0103: Found,
223.0114.
(Z)-5-(4-Hydroxyphenylmethylene)-2,4-thiazolidinedione
5i. Condensation of 4-hydroxybenzaldehyde 3i with 4a gave
a yellow solid. The solid was slurried in methanol (30 cm3)
for 30 min and ®ltered under vacuum to yield 5i as a yellow
solid (88%), mp .3008C; nmax (Nujol)/cm21 3426, 3403,
3123, 1725, 1719, 1704 and 1680; dH 6.90 (2H, m, ArH),
7.43 (2H, m, ArH), 7.68 (1H, s, vCHAr), 10.28 (1H, s,
ArOH), 12.42 (1H, bs, NH); dc 116.32, 118.95, 123.92,
132.33, 132.38, 159.89, 167.46, 168.03; MS (EI, 70 eV),
m/z 221 [M], 149.9, 121. HRMS, C10H7NO3S requires
221.0140: Found, 221.0147.
(Z)-5-(4-Bromophenylmethylene)-2,4-thiazolidinedione
5c. Condensation of 4-bromobenzaldehyde 3c with 4a gave
a yellow solid. Recrystallisation from ethyl acetate and
hexane gave 5c as a pale yellow solid (89%), mp 242±
2448C; nmax (Nujol)/cm21 3148, 1719, and 1610; dH 7.53
(2H, m, ArH), 7.72 (2H, m, ArH), 7.76 (1H, s, vCHAr),
12.65 (1H, bs, NH); dc 123.88, 124.35, 130.54, 131.76,
132.24, 132.29, 167.05, 167.48; MS (EI, 70 eV), m/z 282
[M2H], 211, 179, 42. HRMS, C10H6BrNO3S requires
282.9303, 284.9282: Found, 282.9311, 284.9284.
(Z)-5-(4-Benzyloxyphenylmethylene)-2,4-thiazolidine-
dione 5k. Condensation of 4-benzyloxybenzaldehyde 3k
with 4a gave a fawn solid. The solid was slurried in
methanol (30 cm3) for 30 min and ®ltered in vacuo to
yield 5k as a cream solid (95%), mp 224 to 2268C; nmax
(Nujol)/cm21 3137, 2922, 2854, 1776, 1743, 1693 and
1599; dH 5.19 (2H, s, OCH2), 7.17 (2H, m, ArH), 7.27
(3H, m, ArH), 7.46 (2H, m, ArH), 7.55 (2H, m, ArH),
7.75 (1H, s, vCHAr), 12.50 (1H, bs, NH); dc 69.87,
116.05, 120.78, 126.05, 128.15, 128.36, 128.84, 132.13,
132.41, 136.85; MS (EI, 70 eV), m/z 311 [M], 167, 149,
121, 91, 84, 77, 65, 49. HRMS, C17H13NO3S requires
311.0616: Found, 311.0603.
(Z)-5-(4-Methoxyphenylmethylene)-2,4-thiazolidinedione
5d. Condensation of 4-methoxybenzaldehyde 3d with 4a
gave a yellow solid. Recrystallisation from ethyl acetate
and hexane gave 5d as a pale yellow solid (97%), mp
2188C; nmax (Nujol)/cm21 3221, 1730, and 1694; dH 3.82
(3H, s, OCH3), 7.09 (2H, m, ArH), 7.55 (2H, m, ArH), 7.74
(1H, s, vCHAr), 12.49 (1H, bs, NH); dc 55.50, 114.93,
120.25, 129.10, 131.87, 132.11, 160.99, 167.44, 167.98;
MS (EI, 70 eV), m/z 235 [M1H], 164.1 (100), 149.1,

R. G. Giles et al. / Tetrahedron 56 (2000) 4531±4537
4535
(Z)-5-(1-Phenylethylene)-4-oxothiazolidin-2-thione 5f. A
solution of rhodanine 4b (6.65 g, 50 mmol), acetophenone
3e (6.01 g, 50 mmol) and anhydrous sodium acetate (12.0 g,
0.146 mmol) in acetic acid (32 cm3) was heated under re¯ux
under nitrogen for 20 h. The cooled reaction mixture was
poured into water (200 cm3), neutralised with saturated
sodium hydrogen carbonate and extracted into ethyl acetate
(3£120 cm3). The organic extracts were washed with water
(3£200 cm3) and dried (Na2SO4). The organic extracts were
®ltered through silica and the residual silica was washed
with ethyl acetate (2£50 cm3). The combined ®ltrate and
washings were evaporated in vacuo and column chromato-
graphy (ethyl acetate±hexane, 1:4) of the residue gave 5f as
a yellow solid (3.77 g, 32%). Recrystallisation from ethyl
acetate and hexane gave 5f as orange±yellow needles, mp
166±1688C; nmax (nujol)/cm21 3145, 3057, 1692, 1673 and
1585; dH 2.66 (3H, s, CH3), 7.44 to 7.49 (5H, m, ArH),
13.53 (1H, bs, NH); dc 20.66, 124.56, 126.65, 128.96,
129.64, 141.79, 149.32, 167.61, 195.49; MS (EI, 70 eV),
m/z 235 [M], 148.1, 39.0. HRMS, C11H9NOS2 requires
235.0126: Found, 235.0116.
crystals (2.63 g, 82%), mp 130±1328C; nmax (Nujol)/cm21
3400, 2953, 1742, 1675 and 1605; dH 3.09 (3H, s, NCH3),
7.51 (3H, m, ArH), 7.61 (2H, m, ArH), 7.90 (1H, s,
vCHAr); dc 27.80, 121.53, 129.33, 130.06, 130.54,
132.52, 132.95, 165.77, 167.33; MS (EI, 70 eV), m/z 219
[M], 162, 133.9, 89.0. HRMS, C11H9NO2S requires
219.0354: Found, 219.0361.
General method for the preparation of 5-benzyl-2,4-
thiazolidinediones and 4-oxo-2-thiazolidinethione 6
A 2.0 M solution of lithium borohydride in THF (19.7 cm3,
39.47 mol) (2.2 equiv.) was added dropwise to a stirred
solution of 5 (17.94 mmol) in pyridine (14.6 cm3) and
THF (12 cm3) at 258C under nitrogen to give an orange
solution. Effervescence was controlled by the addition
rate. The mixture was heated to re¯ux and stirred until the
reduction was complete (typically 2±5 h). The cooled
mixture was carefully added to a stirred solution of hydro-
chloric acid (8.6 cm3) and deionised water (56 cm3) at 58C.
Extracted into ethyl acetate (3£70 cm3), the combined
organic extracts were washed with water (2£100 cm3),
dried (Na2SO4) and the solvent removed in vacuo to afford
crude 6.
(Z)-5-(4-tert-Butyldimethylsilyloxyphenylmethylene)-2,4-
thiazolidinedione 5j. A mixture of 5i (4.0 g, 16.72 mmol),
tert-butyldimethylsilyl chloride (2.77 g, 18.39 mmol),
imidazole (1.25 g, 18.39 mmol) in THF (60 cm3) and
DMF (30 cm3) was stirred at ambient under nitrogen for
17 h. The mixture was quenched into water (300 cm3),
extracted into ethyl acetate (3£100 cm3), the combined
organic extracts were washed with brine (2£100 cm3) and
dried (Na2SO4). The solvent was removed in vacuo and
column chromatography (ethyl acetate±hexane, 2:3) of the
residue gave 5j as a pale yellow solid (70%). Recrystallisa-
tion from ethyl acetate and hexane gave 5j as very pale
yellow needles, mp 142±1508C; nmax (Nujol)/cm21 3120,
2954, 1741, 1697 and 1591; dH 0.21 (6H, s, Si(CH3)2),
0.94 (9H, s, SitBu), 6.99 (2H, m, ArH), 7.51 (2H, m,
ArH), 7.73 (1H, s, vCHAr), 12.51 (1H, bs, NH); dc
24.59, 17.94, 25.44, 120.72, 126.32, 131.66, 132.11,
157.20, 167.32, 167.83; MS (EI, 70 eV), m/z 335 [M],
278, 207. HRMS, C16H21NO3SSi requires 335.1011:
Found, 335.1004.
The following compounds were prepared according to this
procedure:
(Z)-5-Phenylmethyl-2,4-thiazolidinedione 6a. Reduction
of 5a gave 6a as a white solid (77%) after column chromato-
graphy (ethyl acetate±hexane, 1:1). Recrystallisation from
ethyl acetate and hexane gave 6a as white crystals, mp
1038C; nmax (Nujol)/cm21 3145, 1743 and 3145, 1744,
1688, 1601; dH 3.11 (1H, dd, Jˆ9.3, 14.2 Hz, ArCH2CH),
3.36 (1H, dd, Jˆ4.5, 14.2 Hz, ArCH2CH), 4.91 (1H, dd,
Jˆ4.5, 9.3 Hz, C(5)H), 7.26 (3H, m, ArH), 7.30 (2H, m,
ArH), 12.02 (1H, bs, NH); dc 37.13, 52.62, 127.03,
128.41, 129.18, 136.82, 171.53, 175.60; MS (EI, 70 eV),
m/z 207 [M], 135, 91.0, 77.0, 65.0. HRMS, C10H9NO2S
requires 207.0354: Found, 207.0353.
(Z)-5-(4-Fluorophenylmethyl)-2,4-thiazolidinedione 6b.
Reduction 5b gave 6b as a white solid (62%) after column
chromatography (ethyl acetate-hexane, 1:1). Recrystallisa-
tion from ethyl acetate and hexane gave 6b as white crystals,
mp 101±1028C; nmax (Nujol)/cm21 3385, and 1685; dH 3.13
(1H, dd, Jˆ9.0, 14.2 Hz, ArCH2CH), 3.35 (1H, m,20
ArCH2CH), 4.91 (1H, dd, Jˆ4.6, 9.0 Hz, C(5)H), 7.13
(2H, m, ArH), 7.28 (2H, m, ArH), 12.02 (1H, bs, NH); dc
36.15, 52.58, 115.03, 115.24, 131.18, 131.26, 132.88,
132.92, 160.10, 162.51, 171.52, 175.59; MS (EI, 70 eV),
m/z 224.1 [M2H], 181.2, 152.8, 120.9, 42.1. HRMS,
C10H9NO2S requires 225.0260: Found, 225.0256.
(Z)-N-Methyl-5-phenylmethylene-2,4-thiazolidinedione
5l. A 60% dispersion of sodium hydride in mineral oil
(0.64 g, 16.10 mmol) under nitrogen was washed with
hexane (2£10 cm3) and the supernatant removed via a
pipette. The sodium hydride was suspended in THF
(50 cm3) and 5a (3.0 g, 14.63 mmol) was added in portions
to the stirred suspension. Vigorous effervescence was
observed with the precipitation of a white solid. The white
mixture was stirred at 258C for 15 min, treated with iodo-
methane (2.0 cm3, 32.13 mmol) in one portion and stirred
for an additional 15 min. The mixture was heated to re¯ux
but the sodium salt was still insoluble within the reaction
medium hence DMF (5.0 cm3) added and the mixture heated
under re¯ux (668C) for 50 min. The cooled reaction mixture
was ®ltered to remove precipitated sodium iodide and the
residue washed with toluene (3£10 cm3). The ®ltrate and
washings were evaporated in vacuo, azeotroped with
toluene (2£20 cm3), the resulting yellow solid was stirred
with water (50 cm3), ®ltered and dried. Recrystallisation
from ethyl acetate and hexane gave 5l as pale yellow
(Z)-5-(4-Bromophenylmethyl)-2,4-thiazolidinedione 6c.
Reduction of 5c gave 6c as a white solid (62%) after column
chromatography (ethyl acetate±hexane, 1:1). Recrystalli-
sation from ethyl acetate and hexane gave 6c as white
needles, mp 1268C; nmax (Nujol)/cm21 3150, 3034, 2953,
1746 and 1694; dH 3.13 (1H, dd, Jˆ8.9, 14.0 Hz,
ArCH2CH), 3.33 (1H, m,20 ArCH2CH), 4.91 (1H, dd,
Jˆ4.6, 8.9 Hz, C(5)H), 7.20 (2H, m, ArH), 7.50 (2H, m,
ArH), 12.03 (1H, bs, NH); dc 36.31, 52.16, 120.29,

4536
R. G. Giles et al. / Tetrahedron 56 (2000) 4531±4537
131.26, 131.53, 136.19, 171.40, 175.43; MS (EI, 70 eV),
m/z 286, 284 [M2H], 243, 241, 213, 79.0, 42. HRMS,
C10H9NO2S requires 284.9459, 286.9439: Found,
284.9457, 286.9459.
(Z)-5-(3,5-Di-tert-butyl-4-hydroxyphenyl)methyl-4-oxo-
2-thiazolidinethione 6h. Reduction of 5h with LiBH4
(3.26 equiv.) gave 6h as powder yellow crystals (58%)
after column chromatography (ethyl acetate±hexane, 1:1).
Recrystallisation from toluene gave 6h as a very pale yellow
powder, mp 178±1798C; nmax (Nujol)/cm21 3637, 3200,
(Z)-5-(4-Methoxyphenylmethyl)-2,4-thiazolidinedione 6d.
Reduction of 5d gave 6d as a white solid (71%) after
column chromatography (ethyl acetate±hexane, 1:1).
Recrystallisation from ethyl acetate and hexane gave 6d
as white crystals, mp 1158C; nmax (Nujol)/cm21 3168 and
1778; dH 3.06 (1H, dd, Jˆ9.1, 14.2 Hz, ArCH2CH), 3.29
(1H, m,20 ArCH2CH), 3.72 (3H, s, OCH3), 4.85 (1H, dd,
Jˆ4.4, 9.1 Hz, C(5)H), 6.86 (2H, m, ArH), 7.15 (2H, m,
ArH), 11.98 (1H, bs, NH); dc 36.23, 53.00, 54.97, 113.78,
128.50, 130.33, 130.39, 158.27, 171.61, 175.61; MS (EI,
70 eV), m/z 236 [M2H], 42. HRMS, C11H11NO3S requires
237.0460: Found, 237.0451.
t
3100, 1720, 1709; dH 1.35 (18H, s, 2£ Bu), 3.05 (1H, dd,
Jˆ9.1, 14.4 Hz, ArCH2CH), 3.24 (1H, dd, Jˆ4.3, 14.4 Hz,
ArCH2CH), 4.92 (1H, dd, Jˆ4.3, 9.1 Hz, C(5)H), 6.84 (1H,
s, ArOH), 6.94 (2H, s, ArH), 13.10 (1H, bs, NH); dc 30.35,
34.45, 36.73, 56.23, 125.11, 127.51, 139.22, 152.82, 178.16,
203.56; MS (EI, 70 eV), m/z 335 [M], 351.1, 219.1, 203.1,
91.0, 57.0. HRMS, C18H25NO2S2 requires 351.1327: Found,
351.1307.
(Z)-5-(4-tert-Butyldimethylsilyloxyphenylmethyl)-2,4-
thiazolidinedione 6j. Reduction of 5j gave 6j as white
crystals (85%) after column chromatography (ethyl
acetate±hexane, 2:3). Recrystallisation from toluene gave
6j as white crystals, mp 113±1158C; nmax (Nujol)/cm21
3145, 3052, 3025, 1769, 1760, 1680, 1661, 1612; dH 0.16
(6H, s, Si(CH3)2), 0.92 (9H, s, SitBu), 3.03 (1H, dd, Jˆ9.1,
14.2 Hz, ArCH2CH), 3.29 (1H, m,20 ArCH2CH), 4.85 (1H,
dd, Jˆ4.4, 9.1 Hz, C(5)H), 6.77 (2H, m, ArH), 7.11 (2H, m,
ArH), 11.98 (1H, bs, NH); dc 24.57, 17.89, 25.51, 36.36,
52.90, 119.66, 129.51, 130.43, 154.09, 171.54, 175.60; MS
(EI, 70 eV), m/z 337 [M], 280, 221, 205, 174, 91.0, 73.0.
HRMS, C16H23NO3SSi requires 337.1168: Found,
337.1171.
(Z)-5-(1-Phenylethyl)-2,4-thiazolidinedione 6e. Reduc-
tion of 5e gave 6e as a white solid (85%) after column
chromatography (ethyl acetate±hexane, 1:1). Recrystallisa-
tion from ethyl acetate and hexane gave 6e as a white solid,
mp 978C; nmax (Nujol)/cm21 3174, 3060, 1758, 1750, 1725,
and 1683; dH (1:1 mixture of diastereomers) 1.30 and 1.39
(3H, 2£d, Jˆ6.7, 7.1 Hz, CHCH3), 3.61 and 3.70 (1H, 2£m,
CHCH3), 4.93 and 4.95 (1H, 2£d, Jˆ5.8, 3.8 Hz, C(5)H),
7.30 (5H, m, ArH), 11.97 (1H, bs, NH); dc 13.81, 19.52,
40.88, 127.20, 128.06, 128.22, 128.54, 140.67, 141.96,
171.30, 171.56, 175.11, 175.15; MS (EI, 70 eV), m/z 221
[M], 60, 149.0, 134, 115, 105, 91, 77.0. HRMS,
C11H11NO2S requires 221.0505: Found, 221.0511.
(Z)-5-(4-Benzyloxyphenylmethyl)-2,4-thiazolidinedione
6k. Reduction of 5k gave crude 6k as off white crystals
(66%). Recrystallisation from toluene gave 6k as a white
powder, mp 121±1228C; nmax (Nujol)/cm21 3166, 2924,
2853, 1748, 1697, 1606, 1583; dH 3.08 (1H, m, ArCH2CH),
3.31 (1H, dd, Jˆ4.4, 14.2 Hz, ArCH2CH), 4.87 (1H, dd,
Jˆ4.4, 9.0 Hz, C(5)H), 6.96 (2H, m, ArH), 7.17 (2H, m,
ArH), 7.38 (3H, m, ArH), 7.45 (2H, m, ArH); dc 36.65,
53.35, 69.54, 115.01, 128.02, 128.15, 130.70, 157.79,
172.00, 176.05; MS (EI, 70 eV), m/z 313 [M], 197, 167,
149, 121, 107, 91, 84, 77, 65, 49. HRMS, C17H15NO3S
requires 313.0773: Found, 313.0777.
(Z)-5-(1-Phenylethyl)-4-oxothiazolidine-2-thione 6f. Reduc-
tion of 5f gave 6f as a pale yellow solid (96%) after column
chromatography (ethyl acetate±hexane, 1:4). Recrystallisa-
tion from ethyl acetate and light petroleum (bp 40±608C)
gave 6f as pale yellow crystals, mp 124±1258C; nmax
(Nujol)/cm21 3172 and 1711; dH (CDCl3) (1:1 mixture of
diastereomers) 1.43 and 1.50 (3H, 2£d, Jˆ7.1, 7.1 Hz,
CHCH3), 3.68 and 3.82 (1H, m, CHCH3), 4.60 and 4.70
(1H, 2£d, Jˆ5.8, 3.3 Hz, C(5)H), 7.30 (5H, m, ArH), 9.09
and 9.45 (1H, 2£bs, NH); dc 13.92, 19.59, 40.59, 42.00,
61.77, 62.85, 127.05, 127.73, 127.91, 128.12, 128.54,
129.00, 139.29, 141.26, 175.82, 176.08, 199.63, 200.38;
MS (EI, 70 eV), m/z 221 [M], 149.0, 134, 115, 105, 91,
77.0. HRMS, C11H11NO2S requires 237.0282: Found,
237.0283.
(Z)-N-methyl-5-phenylmethyl-2,4-thiazolidinedione 6l.
Reduction of 5l with LiBH4 (1.1 equiv.) gave 6l as a pale
yellow oil (78%) after column chromatography (ethyl
acetate±hexane, 1:1). Distilled at 1708C at 0.1 mbar as a
colourless oil which crystallised on standing, mp 57±
598C; nmax (Nujol)/cm21 3029, 2951, 1741, 1675, 1664;
dH 2.92 (3H, s, NCH3), 3.09 (1H, dd, Jˆ9.6, 14.1 Hz,
ArCH2CH), 3.45 (1H, dd, Jˆ4.4, 14.1 Hz, ArCH2CH),
4.91 (1H, dd, Jˆ4.4, 9.6 Hz, C(5)H), 7.28 (5H, m, ArH);
dc 27.49, 37.21, 50.81, 127.08, 128.42, 129.08, 136.69,
171.02, 173.90; MS (EI, 70 eV), m/z 335 [M], 221.0,
160.0, 135.0, 91.0, 65, 51.0. HRMS, C11H11NO2S requires
221.0511: Found, 221.0516.
(Z)-5-(3,5-Di-tert-butyl-4-hydroxyphenyl)methyl-2,4-thia-
zolidinedione 6g. Prolonged reduction (181 h) of 5g with
LiBH4 (3.26 equiv.) gave 6g as a pale yellow solid (82%)
after column chromatography (ethyl acetate±hexane, 1:1).
Recrystallisation from toluene and light petroleum (bp 60±
808C) gave 6g as white crystals, mp 169±1708C; nmax
(Nujol)/cm21 3564, 3300, 2956, 2924, 2854, 1753, 1714,
t
1699; dH 1.36 (18H, s, 2£ Bu), 2.99 (1H, dd, Jˆ9.4,
14.2 Hz, ArCH2CH), 3.30 (1H, dd, Jˆ4.2, 14.2 Hz,
ArCH2CH), 4.79 (1H, dd, Jˆ4.2, 9.4 Hz, C(5)H), 6.83
(1H, s, ArOH), 6.95 (2H, s, ArH), 11.98 (1H, bs, NH); dc
30.38, 34.46, 37.42, 53.32, 125.24, 127.73, 139.19, 152.81,
171.74, 175.84; MS (EI, 70 eV), m/z 335 [M], 320.1, 219.2,
203.1, 91.0, 57.0. HRMS, C18H25NO3S requires 335.1555:
Found, 335.1541.
(Z)-5-(3,5-Di-tert-butyl-4-hydroxyphenyl)methyl-2,4-
thiazolidinedione 6g. A 2.0 M solution of lithium boro-
hydride in THF (13.1 cm3, 26.20 mol) was added dropwise
to a stirred solution of 5g (2.81 g, 8.45 mmol) in pyridine
(6.5 cm3) and 1,3-dimethylimidazolidin-2-one (7.7 cm3) at
258C under nitrogen. Effervescence ensued during the

R. G. Giles et al. / Tetrahedron 56 (2000) 4531±4537
4537
2. Clark, D. A.; Goldstein, S. A.; Volkmann, R. A.; Eggler, J. F.;
Holland, G. F.; Hulin, B.; Stevenson, R. W.; Kreutter, D. K.; Gibbs,
E. M.; Krupp, M. N.; Merrigan, P.; Kelbaugh, P. L.; Andrews,
E. G.; Tickner, D. L.; Suleske, R. T.; Lamphere, C. H.; Rajeckas,
F. J.; Kappeler, W. H.; McDermott, R. E.; Hutson, N. J.; Johnson,
M. R. J. Med. Chem. 1991, 34, 319±325.
addition and a red solution was obtained. The mixture was
heated to re¯ux and stirred for 4.5 h. THF (5.0 cm3) was
added and the mixture was re¯uxed for an additional 15 h.
A gel had formed at this stage so a further quantity of THF
(4.0 cm3) and 1,3-dimethylimidazolidin-2-one (4.0 cm3)
was added and heating continued for an additional 4 h.
The cooled mixture was carefully added to a stirred solution
of hydrochloric acid (30 cm3) and water (200 cm3) at 58C.
Extracted into ethyl acetate (3£70 cm3), the combined
organic extracts were washed with brine (2£100 cm3),
dried (Na2SO4) and the solvent removed in vacuo to afford
crude 6g as an orange oil. Column chromatography (ethyl
acetate±hexane, 3:7) gave 6g as a yellow solid (2.5 g, 89%),
recrystallised from toluene and light petroleum (bp 60±
808C) as golden crystals. The spectroscopic and physical
characteristics of this material were identical to those
described above.
3. Huber, J. E. PCT Int. Appl. WO 92-US10329; CAN, 119,
24994.
4. Jackson, W. R.; Zurqiyah, A. J. Chem. Soc., C 1965, 5281±
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In-situ preparation of LiBH4 from LiCl and NaBH4 for
the preparation of 5-(2-[N-methylpyridin-2-yl]amino-
ethoxyphenylmethyl)-2,4-thiazolidinedione 2d
9. Trost, B. M.; Saulnier, M. G. Tetrahedron Lett. 1985, 26, 123±
126.
Pyridine (6 cm3) was added to stirred sodium borohydride
(0.24 g, 6.34 mmol) at 258C under nitrogen. The mixture
was stirred at 308C until all the solid had dissolved, heated
to 658C and treated dropwise with a solution of lithium
chloride (0.40 g, 9.44 mmol) in pyridine (5.0 m3) via cannu-
lar. The mixture was heated at 658C for 2 h, treated with
THF (12.0 cm3) and the mixture re¯uxed for an additional
30 min. 5-(2-[N-Methylpyridin-2-yl]aminoethoxyphenyl-
methylene)-2,4-thiazolidinedione 1d was added in portions
to the cooled solution (208C) with vigorous effervescence
and the formation of a clear yellow solution. The mixture
was heated to re¯ux for 2.5 h. The THF was removed from
the cooled reaction mixture by evaporation in vacuo, and the
resulting stirred mixture was acidi®ed to pH 6 using hydro-
chloric acid. The resulting suspension was stirred at 258C
for 16 h. Filtration under vacuum gave crude 2d as a white
solid which was washed with water (5 cm3) and dried
(0.86 g, 86%). This material had identical physical and
spectroscopic characteristics as those described above.
10. Reduction of 1d to 2d using either NaBH4 or LiBH4 in THF
alone led to indiscriminate reaction and the formation of a multi-
component mixture.
11. Lansbury, P. T.; Peterson, J. O. J. Am. Chem. Soc. 1963, 85,
2236±2242.
È
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