A Convenient Procedure for the Synthesis of Novel Modified 3-Substituted 1H-Quinoxaline-2-thiones via Side-Chain Lithiation of 3-Alkyl-1H-quinoxaline-2- thiones

Article abstract of DOI:10.1055/s-2003-42486

3-Methyl-1H-quinoxaline-2-thione (1) has been doubly lithiated, at nitrogen and at the 3-methyl group, with n-butyllithium at -78°C in THF. The resulting dilithium reagent obtained reacts with a variety of electrophiles (iodomethane, iodoethane, 1-bromobutane, D₂O, benzaldehyde, anisaldehyde, 2-hexanone, cyclohexanone, benzophenone, phenyl isothiocyanate) to give the corresponding modified 3-substituted 1H-quinoxaline-2-thiones 4-13 in high yields. Similarly, double lithiation of 3-ethyl- (4) and 3-propyl-1H-quinoxaline-2-thiones (5), followed by reaction with some electrophiles gave the corresponding modified 3-substituted derivatives 15-19 in high yields. Treatment of some of the products with trifluoroacetic acid in dichloromethane at room temperature led to formation of substituted 2,3-dihydrothieno[2,3-b]quinoxalines in good yields.

Full text of DOI:10.1055/s-2003-42486

PAPER
2799
A Convenient Procedure for the Synthesis of Novel Modified 3-Substituted
1H-Quinoxaline-2-thiones via Side-Chain Lithiation of 3-Alkyl-1H-quinoxa-
line-2-thiones
3-Substituted 1
H
-Q
a
uinoxaline
m
-2-thiones via
S
ide
a
L
ith
l
iation A. El-Hiti*1
Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
Fax +44(1792)295747; E-mail: g.a.el-hiti@swansea.ac.uk
Received 28 August 2003; revised 1 October 2003
3-Methyl-1H-quinoxaline-2-thione (1) was prepared ac-
Abstract: 3-Methyl-1H-quinoxaline-2-thione (1) has been doubly
lithiated, at nitrogen and at the 3-methyl group, with n-butyllithium
at –78 °C in THF. The resulting dilithium reagent obtained reacts
with a variety of electrophiles (iodomethane, iodoethane, 1-bro-
cording to the literature procedure.14 Double lithiation of
1 occurred smoothly with BuLi (2.2 equiv) at –78 °C in
anhydrous THF. Two mole equivalents of BuLi were
mobutane, D2O, benzaldehyde, anisaldehyde, 2-hexanone, cyclo- used, the first to remove the NH proton to give monolith-
hexanone, benzophenone, phenyl isothiocyanate) to give the
corresponding modified 3-substituted 1H-quinoxaline-2-thiones 4–
13 in high yields. Similarly, double lithiation of 3-ethyl- (4) and 3-
trophiles (iodomethane, iodoethane, 1-bromobutane,
propyl-1H-quinoxaline-2-thiones (5), followed by reaction with
some electrophiles gave the corresponding modified 3-substituted
derivatives 15–19 in high yields. Treatment of some of the products
with trifluoroacetic acid in dichloromethane at room temperature
led to formation of substituted 2,3-dihydrothieno[2,3-b]quinoxa-
lines in good yields.
ium reagent 2 and the other to form the dilithium reagent
3. Reactions of the dilithium reagent 3 with various elec-
D2O, benzaldehyde, anisaldehyde, 2-hexanone, cyclohex-
anone, benzophenone, phenyl isothiocyanate) gave the
corresponding modified 3-substituted 1H-quinoxaline-2-
thiones 4–13 (Scheme 1) in very good yields (Table 1).
Key words: quinoxalines, lithiation, electrophilic additions, cy-
clizations, heterocycles , sulfur
Directed ortho-lithiation of aromatic compounds has
proven to be an excellent synthetic tool for regioselective
functionalization.2 The use of directing groups to facilitate
lithiation followed by reaction of the organolithium re-
agents obtained with various electrophiles has found wide
application in a variety of synthetic transformations.2,3
Recently, lithiation of various heterocycles has been
achieved, and the lithiated reagents obtained in such lithi-
ation reactions are very useful intermediates for the syn-
thesis of more complex substituted heterocycles.4 We
have previously reported on the use of organolithiums in
organic synthesis.5 We have also shown that various 3H-
quinazolin-4-one derivatives undergo double lithiation
with lithium reagents at –78 °C.6 The organolithium re-
agents obtained in such lithiation reactions reacted with
various electrophiles to produce more complex substitut-
ed 3H-quinazolin-4-ones in good yields.6 However, there
are relatively few examples of the lithiation of quinoxa-
line derivatives.7–12 Compounds possessing the quinoxa-
line ring system have important pharmacological
activities.13 We now report on the successful synthesis of
more complex modified 3-substituted 1H-quinoxaline-2-
thiones via side-chain lithiation of 3-alkyl-1H-quinoxa-
line-2-thiones.
Scheme 1
As indicated in Table 1, the yields of isolated, purified
products were extremely good. The reaction with io-
domethane (1.2 equivalents) resulted in almost quantita-
tive yields of alkylated products, but as a mixture of 2-
ethyl-1H-quinoxaline-2-thione (4) and 3-ethyl-2-meth-
ylthio-1H-quinoxaline (14) in 89% and 4% yield, respec-
tively.
The spectral characteristics of compounds 4–14 were con-
sistent with the assigned structures (see experimental sec-
tion for details). The 1H NMR spectra of compounds 8–10
show diastereotopism for the two hydrogens of the CH2
group at position 3. The CH2 signals resonate as two sep-
arated double doublets (J = 14 and 4.5 Hz for one double
doublet, and 14 and 9 Hz for the other) in the case of com-
pounds 8 and 9, and two separated doublets (J = 14 Hz) in
the case of compound 10.
SYNTHESIS 2003, No. 18, pp 2799–2804
x
x.
x
x
.
2
0
0
3
Advanced online publication: 17.11.2003
DOI: 10.1055/s-2003-42486; Art ID: P07303SS
© Georg Thieme Verlag Stuttgart · New York

2800
G. A. El-Hiti
PAPER
Table 1 Yields of Products 4–13 According to Scheme 1
Table 2 Yields of Products 15–19 According to Scheme 2
Product
Electrophile
MeI
E
Yield (%)a
Product
R
Electrophile
D2O
E
Yield (%)a
90
4
5
Me
89b
90
87
92
86
15
Me
D
EtI
Et
16
Me
88
O
(OH)
6
BuBr
Bu
17
18
19
Me
Et
Ph2CO
PhCHO
Ph2CO
Ph2C(OH)
PhCH(OH)
Ph2C(OH)
91
89
92
7
D2O
D
8
PhCHO
4-MeOC6H4CHO
MeCOBu
PhCH(OH)
Et
9
4-MeOC6H4CH(OH) 83
a Yields of isolated, purified products.
10
MeC(OH)Bu
89
90
11
O
(OH)
12
13
Ph2CO
PhNCS
Ph2C(OH)
PhNHCS
91
81
a Yield of isolated, purified products.
b Compound 14 was obtained in 4% yield.
Scheme 3
Attention was next turned to the lithiation of 3-ethyl-1H-
quinoxaline-2-thione (4) and 3-propyl-1H-quinoxaline-2-
thione (5), which had been obtained by alkylation of the
dilithium reagent 3 according to Scheme 1. If successful,
this would suggest that the lithiation process was tolerant
of a variety of primary alkyl groups at position 3. It was
found that successful lithiation of 4 and 5 was achieved
using BuLi (2.2 equivalents) in anhydrous THF at –78 °C
under nitrogen for 2 hours. The dilithium reagents ob-
tained reacted with several electrophiles (D2O, cyclohex-
anone, benzophenone, benzaldehyde) (Scheme 2) to give
the corresponding modified derivatives 15–19 in very
good yields (Table 2).
1
The H NMR spectrum of compound 20 showed dia-
stereotopism for the two hydrogens of the CH2 group at
position 3. The CH2 signals resonate as two separated
double doublets (J = 17 and 8 Hz).
In conclusion, this work describes a simple and conve-
nient method for the side-chain substitution of 3-alkyl-
1H-quinoxaline-2-thiones to produce more complex 3-
substituted derivatives in very high yield. These deriva-
tives might have pharmacological activities and could be
difficult to prepare by other means.
Mps were determined on an electrothermal digital mp apparatus and
are reported uncorrected. 1H and 13C NMR spectra were recorded on
a Bruker AC-400 Fourier Transform spectrometer operating at 400
MHz for 1H and 100 MHz for 13C measurement. Chemical shifts are
reported in parts per million relative to tetramethylsilane. Low-res-
olution mass spectra were recorded on a VG 12-253 spectrometer,
electron impact (E1) at 70 eV and chemical ionization (CI) by use
of ammonia as ionizing gas. Accurate mass data were obtained on a
VG ZAB-E instrument. BuLi was obtained from Aldrich Chemical
Company and was estimated prior to use by the method of Watson
and Eastham.15 THF was distilled from sodium benzophenone
Scheme 2
The NMR spectra of compound 18 show the expected ketyl. Other chemicals were obtained from Aldrich Chemical Com-
pany and used without further purification.
presence of two racemic diastereoisomers in the ratio of
1:2.
Modified 3-Substituted 1H-Quinoxaline-2-thiones 4–19; Gener-
Some of the products obtained from Scheme 1 can be used
as starting materials for other transformations. As a dem-
onstration of this, compounds 9 and 12 were converted to
the corresponding 2,3-dihydrothieno[2,3-b]quioxalines
20 and 21 in 83% and 81% isolated yields, respectively,
on treatment with trifluoroacetic acid (TFA) in dichlo-
romethane (Scheme 3).
al Procedure
A solution of BuLi in hexane (1.8 mL, 2.5 M, 2.2 mmol) was added
in a dropwise manner to a cold (–78 °C), stirred solution of 3-alkyl-
1H-quinoxaline-2-thione (1, 4 or 5) (2.0 mmol) in anhyd THF (30
mL) under N2. The dilithium reagent of compound 1 was obtained
as reddish brown precipitate while the dilithium reagents of com-
pounds 4 and 5 were obtained as a deep red solution. The mixture
was stirred at –78 °C for 2 h to complete the formation of the dilith-
ium reagent. An electrophile (2.2 mmol), in anhyd THF (8 mL) if
solid, otherwise neat, was added. The reaction mixture was stirred
Synthesis 2003, No. 18, 2799–2804 © Thieme Stuttgart · New York

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3-Substituted 1H-Quinoxaline-2-thiones via Side-Chain Lithiation
2801
for 2 h at –78 °C, then removed from the cooling bath and allowed
to warm to r.t. The reaction mixture was diluted with EtOAc (20
mL) then quenched with sat. aq NH4Cl (20 mL). The organic layer
was separated, washed with H2O (2 × 20 mL), dried (MgSO4) and
evaporated under reduced pressure. The products obtained were re-
crystallized or subjected to column chromatography to give the ap-
propriate pure products 4–19.
EI-MS: m/z (%) = 177 (M+, 100), 144 (89), 134 (20), 102 (35), 90
(47), 76 (77), 50 (86), 43 (82).
CI-MS: m/z (%) = 178 (MH+, 100), 146 (62).
HRMS: m/z calcd for C9H8N2SD (MH+): 178.0544; found:
178.0546.
3-(2-Hydroxy-2-phenylethyl)-1H-quinoxaline-2-thione (8)
Recrystallized from MeOH; mp 182–183 °C.
3-Ethyl-1H-quinoxaline-2-thione (4)
Purified by column chromatography (silica gel; Et2O–hexane, 2:1);
mp 209–210 °C.
1H NMR (DMSO-d6): = 14.36 (s, exch., 1 H), 7.80 (d, J = 8 Hz, 1
H), 7.61–7.52 (m, 2 H), 7.42 (app. dt, J = 8, 1 Hz, 1 H), 3.08 (q,
J = 7 Hz, 2 H), 1.24 (t, J = 7 Hz, 3 H).
1H NMR (DMSO-d6): = 14.41 (s, exch., 1 H), 7.84 (d, J = 8 Hz, 1
H), 7.63–7.56 (m, 2 H), 7.46–7.43 (m, 3 H), 7.33 (t, J = 7.6 Hz, 2
H), 7.21 (app. dt, J = 8, 1 Hz, 1 H), 5.43 (m, 1 H), 5.28 (d, J = 4.5
Hz, exch., 1 H), 3.51 (dd, J = 14, 4.5 Hz, 1 H), 3.33 (dd, J = 14, 9
Hz, 1 H).
13C NMR (DMSO-d6): = 175.3 (s), 161.7 (s), 146.1 (s), 135.3 (s),
131.8 (s), 130.7 (d), 129.2 (d), 128.7 (d), 128.4 (d), 127.1 (d), 126.1
(d), 116.01 (d), 70.3 (d), 46.9 (t).
EI-MS: m/z (%) = 282 (M+, 19), 249 (11), 176 (61), 143 (34), 105
(72), 77 (100), 51 (50).
HRMS: m/z calcd for C16H14N2OS (M+): 282.0821; found:
282.0822.
13C NMR (DMSO-d6): = 175.1 (s), 164.9 (s), 135.2 (s), 131.6 (s),
130.5 (d), 128.6 (d), 126.0 (d), 116.0 (d), 29.6 (t), 11.5 (q).
EI-MS: m/z (%) = 191 (M+ + 1, 12), 190 (M+, 100), 189 (M+ – 1,
68), 157 (32), 145 (15), 134 (18), 129 (47), 102 (42), 90 (19), 76
(23).
CI-MS: m/z (%) = 191 (MH+, 91), 174 (5), 161 (19), 159 (100).
HRMS: m/z calcd for C10H11N2S (MH+): 191.0637; found:
191.0637.
3-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-1H-quinoxaline-2-
thione (9)
Recrystallized from MeOH; mp 159–160 °C.
3-Propyl-1H-quinoxaline-2-thione (5)
Recrystallized from aq MeOH; mp 198–199 °C (lit.16 198 °C).
1H NMR (DMSO-d6): = 14.41 (s, exch., 1 H), 7.84 (dd, J = 8, 1
Hz, 1 H), 7.62–7.54 (m, 2 H), 7.45 (app. dt, J = 8, 1 Hz, 1 H), 7.35
(d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.37 (m, 1 H), 5.17
(d, J = 4.5 Hz, exch., 1 H), 3.72 (s, 3 H), 3.49 (dd, J = 14, 4.5 Hz, 1
H), 3.33 (dd, J = 14, 9 Hz, 1 H).
13C NMR (DMSO-d6): = 175.3 (s), 161.8 (s), 158.5 (s), 138.1 (s),
135.3 (s), 131.7 (s), 130.7 (d), 128.7 (d), 127.3 (d), 126.0 (d), 116.0
(d), 113.7 (d), 69.9 (d), 55.3 (q), 46.8 (t).
1H NMR (DMSO-d6): = 14.11 (s, exch., 1 H), 7.64 (d, J = 8 Hz, 1
H), 7.51 (d, J = 8 Hz, 1 H), 7.42 (app. t, J = 8 Hz, 1 H), 7.30 (app.
t, J = 8 Hz, 1 H), 3.07 (q, J = 7 Hz, 2 H), 1.78 (sext, J = 7 Hz, 2 H),
0.96 (t, J = 7 Hz, 3 H).
13C NMR (DMSO-d6): = 175.4 (s), 164.2 (s), 135.4 (s), 131.6 (s),
129.7 (d), 128.3 (d), 125.3 (d), 115.8 (d), 38.3 (t), 20.3 (t), 14.1 (q).
EI-MS: m/z (%) = 204 (M+, 100), 189 (31), 176 (60), 155 (23), 143
(27), 129 (38), 102 (51), 90 (42), 76 (40), 51 (49).
CI-MS: m/z (%) = 205 (MH+, 79), 173 (100), 144 (20).
EI-MS: m/z (%) = 312 (M+, 10), 294 (12), 176 (82), 143 (69), 135
(100), 102 (23), 77 (48).
HRMS: m/z calcd for C11H13N2S (MH+): 205.0794; found:
CI-MS: m/z (%) = 313 (MH+, 11), 295 (62), 177 (60), 154 (100),
205.0791.
145 (51), 137 (81).
HRMS: m/z calcd for C17H17N2O2S (MH+): 313.1005; found:
313.1006.
3-Pentyl-1H-quinoxaline-2-thione (6)
Recrystallized from MeOH; mp 167–169 °C.
1H NMR (DMSO-d6): = 14.41 (s, exch., 1 H), 7.79 (d, J = 8 Hz, 1
H), 7.59–7.52 (m, 2 H), 7.42 (app. dt, J = 8, 1 Hz, 1 H), 3.06 (t,
J = 7.5 Hz, 2 H), 1.73 (pent, J = 7.5 Hz, 2 H), 1.38–1.27 (m, 4 H),
0.87 (t, J = 7.5 Hz, 3 H).
13C NMR (DMSO-d6): = 175.2 (s), 164.3 (s), 135.3 (s), 131.6 (s),
130.5 (d), 128.5 (d), 125.9 (d), 116.0 (d), 36.1 (t), 31.5 (t), 26.6 (t),
22.4 (t), 14.3 (q).
3-(2-Hydroxy-2-methylhexyl)-1H-quinoxaline-2-thione (10)
Recrystallized from MeOH; mp 102–103 °C.
1H NMR (DMSO-d6): = 14.44 (s, exch., 1 H), 7.81 (dd, J = 8, 1
Hz, 1 H), 7.62–7.54 (m, 2 H), 7.44 (app. dt, J = 8, 1 Hz, 1 H), 4.58
(s, exch., 1 H), 3.40, 3.35 (2 d, J = 14 Hz, 2 H), 1.51 (m, 2 H), 1.35
(m, 2 H), 1.25 (sext, J = 7 Hz, 2 H), 1.17 (s, 3 H), 0.85 (t, J = 7 Hz,
3 H).
EI-MS: m/z (%) = 232 (M+, 61), 203 (52), 199 (94), 189 (35), 176
(100), 155 (30), 143 (32), 129 (36), 102 (63), 90 (45), 76 (36), 41
(79).
13C NMR (DMSO-d6): = 176.2 (s), 162.5 (s), 134.8 (s), 131.5 (s),
130.9 (d), 128.6 (d), 126.2 (d), 116.0 (d), 72.9 (s), 45.0 (t), 42.0 (t),
27.4 (q), 25.12 (t), 23.2 (t), 14.4 (q).
CI-MS: m/z (%) = 233 (MH+, 100), 201 (87), 144 (13).
EI-MS: m/z (%) = 276 (M+, 10), 258 (9), 176 (100), 143 (61), 132
(22), 102 (23), 90 (18), 76 (17), 43 (75).
CI-MS: m/z (%) = 277 (MH+, 52), 245 (100), 227 (15), 177 (63),
HRMS: m/z calcd for C13H17N2S (MH+): 233.1107; found:
233.1106.
145 (65), 118 (33).
3-Deuteriomethyl-1H-quinoxaline-2-thione (7)
Recrystallized from MeOH; mp 250–251 °C.
1H NMR (DMSO-d6): = 14.33 (s, exch., 1 H), 7.75 (dd, J = 8, 1
Hz, 1 H), 7.55–7.49 (m, 2 H), 7.41 (app. dt, J = 8, 1 Hz, 1 H), 2.58
(1:1:1 t, J = 2 Hz, 2 H).
HRMS: m/z calcd for C15H21N2OS (MH+): 277.1369; found:
277.1375.
3-[(1-Hydroxycyclohexyl)methyl]-1H-quinoxaline-2-thione (11)
Recrystallized from MeOH; mp 187–188 °C.
13C NMR (DMSO-d6): = 175.2 (s), 161.7 (s), 135.1 (s), 131.7 (s),
130.5 (d), 128.3 (d), 126.0 (d), 115.8 (d), 24.8, 24.6, 24.4 (1:1:1 t).
1H NMR (DMSO-d6): = 14.45 (s, exch., 1 H), 7.83 (d, J = 8 Hz, 1
H), 7.62–7.53 (m, 2 H), 7.44 (app. dt, J = 8, 1 Hz, 1 H), 4.52 (s,
exch., 1 H), 3.37 (s, 2 H), 1.59–1.16 (m, 10 H).
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G. A. El-Hiti
PAPER
13C NMR (DMSO-d6): = 176.3 (s), 162.4 (s), 134.8 (s), 131.6 (s),
130.9 (d), 128.6 (d), 126.1 (d), 116.0 (d), 72.0 (s), 46.1 (t), 37.6 (t),
25.8 (t), 22.0 (t).
EI-MS: m/z (%) = 274 (M+, 11), 256 (18), 231 (8), 176 (100), 143
(42), 132 (22), 102 (25), 81 (30), 55 (68), 41 (77).
(app. dt, J = 8, 1 Hz, 1 H), 2.76 (q, J = 7.5 Hz, 1 H), 1.27 (d, J = 7.5
Hz, 3 H).
13C NMR (DMSO-d6): = 175.4 (s), 164.2 (s), 135.5 (s), 131.7 (s),
129.8 (d), 128.3 (d), 125.4 (d), 115.9 (d), 27.6, 27.3, 27.1 (1:1:1 d),
11.6 (q).
CI-MS: m/z (%) = 275 (MH+, 48), 243 (92), 255 (19), 177 (22), 145
EI-MS: m/z (%) = 191 (M+, 100), 158 (76), 129 (53), 102 (30), 76
(82), 116 (100).
(14).
HRMS: m/z calcd for C15H19N2OS (MH+): 275.1213; found:
CI-MS: m/z (%) = 192 (MH+, 77), 160 (100).
275.1213.
HRMS: m/z calcd for C10H10N2SD (MH+): 192.0700; found:
192.0703.
3-(2-Hydroxy-2,2-diphenylethyl)-1H-quinoxaline-2-thione (12)
Recrystallized from MeOH; mp 185–186 °C.
3-[1-(1-Hydroxycyclohexyl)ethyl]-1H-quinoxaline-2-thione (16)
Purified by column chromatography (silica gel; Et2O–hexane, 2:1);
mp 166–167 °C.
1H NMR (CDCl3) = 13.16 (s, exch., 1 H), 7.79 (dd, J = 8, 1 Hz, 1
H), 7.54–7.45 (m, 2 H), 7.40 (app. dt, J = 8, 1 Hz, 1 H), 5.00 (s,
exch., 1 H), 4.40 (q, J = 7 Hz, 1 H), 1.62–1.38 (m, 10 H), 1.28 (d,
J = 7 Hz, 3 H).
13C NMR (CDCl3): = 175.4 (s), 169.2 (s), 135.4 (s), 131.3 (d),
131.2 (s), 129.3 (d), 127.1 (d), 115.4 (d), 74.3 (s), 43.2 (d), 38.0 (t),
35.6 (t), 26.2 (t), 22.7 (t), 22.4 (t), 14.5 (q).
1H NMR (DMSO-d6): = 14.58 (s, exch., 1 H), 7.72 (d, J = 8 Hz, 1
H), 7.57 (app. dt, J = 8, 1 Hz, 1 H), 7.52–7.48 (m, 5 H), 7.36 (app.
dt, J = 8, 1 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 4 H), 7.14 (t, J = 7.5 Hz, 2
H), 6.77 (s, exch., 1 H), 4.18 (s, 2 H).
13C NMR (DMSO-d6): = 175.5 (s), 162.4 (s), 147.9 (s), 133.8 (s),
131.5 (s), 131.3 (d), 128.4 (d), 128.3 (d), 126.8 (d), 126.3 (d), 125.9
(d), 116.1 (d), 78.5 (s), 43.9 (t).
EI-MS: m/z (%) = 358 (M+, 22), 340 (87), 323 (76), 307 (51), 263
(100), 207 (79), 182 (33), 105 (90), 77 (78), 51 (35).
CI-MS: m/z (%) = 359 (MH+, 5), 341 (12), 200 (54), 183 (70), 145
EI-MS: m/z (%) = 288 (M+, 2), 270 (6), 239 (12), 190 (33), 158 (30),
(100), 105 (35).
129 (12), 98 (52), 84 (65), 55 (100), 42 (79).
HRMS: m/z calcd for C22H19N2OS (MH+): 359.1213; found:
CI-MS: m/z (%) = 289 (MH+, 32), 257 (100), 191 (5), 159 (11), 116
359.1226.
(24).
HRMS: m/z calcd for C16H21N2OS (MH+): 289.1369; found:
289.1371.
3-(Phenylaminothiocarbonylmethyl)-1H-quinoxaline-2-thione
(13)
Recrystallized from MeOH; mp >300 °C.
3-(2-Hydroxy-1-methyl-2,2-diphenylethyl)-1H-quinoxaline-2-
thione (17)
Recrystallized from EtOAc; mp 190–192 °C.
1H NMR (DMSO-d6): = 14.81 (s, exch., 1 H), 11.85 (s, exch., 1
H), 7.85 (d, J = 8 Hz, 1 H), 7.66–7.54 (m, 2 H), 7.47 (app. t, J = 8
Hz, 1 H), 7.40 (d, J = 7.5 Hz, 2 H), 7.37–7.11 (m, 3 H), 4.60 (s, 2
H).
13C NMR (DMSO-d6): = 187.2 (s), 180.8 (s), 160.5 (s), 144.8 (s),
139.7 (s), 128.3 (d), 126.7 (s), 126.6 (d), 126.0 (d), 124.1 (d), 123.5
(d), 116.1 (d), 115.6 (d), 53.5 (t).
1H NMR (DMSO-d6): = 14.62 (s, exch., 1 H), 7.81 (d, J = 8 Hz, 1
H), 7.56–7.49 (m, 5 H), 7.37 (d, J = 7.5 Hz, 4 H), 7.18 (app. t, J = 8
Hz, 1 H), 7.13 (t, J = 7.5 Hz, 2 H), 7.03 (app. t, J = 8 Hz, 1 H), 6.68
(s, exch., 1 H), 5.51 (q, J = 6.7 Hz, 1 H), 1.11 (d, J = 6.7 Hz, 3 H).
13C NMR (DMSO-d6): = 174.6 (s), 168.2 (s), 149.2 (s), 146.5 (s),
133.8 (s), 131.4 (d), 128.5 (d), 128.4 (d), 126.7 (d), 126.6 (d), 125.4
(d), 116.2 (d), 80.6 (s), 42.4 (d), 14.9 (q).
EI-MS: m/z (%) = 311 (M+, 18), 278 (5), 176 (91), 135 (53), 93
(100), 77 (89), 63 (49), 51 (47).
CI-MS: m/z (%) = 312 (MH+, 26), 157 (32), 113 (100).
EI-MS: m/z (%) = 372 (M+, 1), 346 (22), 313 (100), 265 (51), 190
(45), 157 (33), 129 (24), 105 (80), 77 (61), 51 (22).
CI-MS: m/z (%) = 373 (MH+, 6), 200 (71), 191 (100), 159 (32).
HRMS: m/z calcd for C16H14N3S2 (MH+): 312.0624; found:
312.0623.
HRMS: m/z calcd for C23H21N2OS (MH+): 373.1369; found:
373.1372.
3-Ethyl-2-methylthio-1H-quinoxaline (14)
Purified by column chromatography (silica gel; Et2O–hexane, 2:1);
mp 76–77 °C.
1H NMR (CDCl3): = 7.89 (dd, J = 8, 1 Hz, 1 H), 7.73 (dd, J = 8, 1
Hz, 1 H), 7.56–7.48 (m, 2 H), 2.91 (q, J = 7 Hz, 2 H), 2.60 (s, 3 H),
0.86 (t, J = 7 Hz, 3 H).
3-[1-(Hydroxyphenylmethyl)propyl]-1H-quinoxaline-2-thione
(18)
Purified by column chromatography (silica gel; Et2O–hexane, 2:1);
mp 127–129 °C; 18a/18b 1:2 (1H NMR).
13C NMR (CDCl3): = 156.6 (s), 156.5 (s), 141.7 (s), 139.7 (s),
129.2 (d), 129.0 (d), 128.1 (d), 127.8 (d), 28.5 (t), 13.2 (q), 11.9 (q).
EI-MS: m/z (%) = 310 (M+, 11), 275 (6), 204 (38), 189 (18), 122
(12), 105 (93), 91 (17), 77 (100), 51 (25).
EI-MS: m/z (%) = 204 (M+, 80), 189 (51), 156 (19), 145 (29), 129
HRMS: m/z calcd for C18H18N2OS (M+): 310.1134; found:
(71), 102 (100), 90 (43), 75 (73), 50 (69).
310.1129.
CI-MS: m/z (%) = 205 (MH+, 100), 159 (21).
HRMS: m/z calcd for C11H13N2S (MH+): 205.0794; found:
Compound 18a
1H NMR (CDCl3): = 12.95 (s, exch., 1 H), 7.79 (d, J = 8 Hz, 1 H),
7.49–7.25 (m, 8 H), 5.74 (m, 1 H), 5.31 (m, 1 H), 5.12 (d, J = 4 Hz,
exch., 1 H), 192–1.60 (m, 2 H), 0.80 (t, J = 7.5 Hz, 3 H).
205.0794.
3-(1-Deuterioethyl)-1H-quinoxaline-2-thione (15)
Recrystallized from aq MeOH; mp 209–210 °C.
1H NMR (DMSO-d6): = 14.13 (s, exch., 1 H), 7.70 (d, J = 8 Hz, 1
H), 7.49 (dd, J = 8, 1 Hz, 1 H), 7.41 (app. dt, J = 8, 1 Hz, 1 H), 7.25
13C NMR (CDCl3): = 173.4 (s), 161.0 (s), 141.0 (s), 140.6 (s),
132.6 (s), 129.8 (d), 128.9 (d), 127.4 (d), 127.1 (d), 126.3 (d), 125.2
(d), 114.1 (d), 73.1 (d), 50.7 (d), 22.9 (t) 11.2 (q).
Synthesis 2003, No. 18, 2799–2804 © Thieme Stuttgart · New York

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3-Substituted 1H-Quinoxaline-2-thiones via Side-Chain Lithiation
2803
Compound 18b
CI-MS: m/z (%) = 341 (MH+, 100), 308 (22), 230 (14), 181 (35),
131 (22), 78 (23), 60 (51).
HRMS: m/z calcd for C22H17N2S (MH+): 341.1107; found:
341.1106.
1H NMR (CDCl3): = 12.95 (s, exch., 1 H), 7.92 (d, J = 8 Hz, 1 H),
7.49–7.25 (m, 8 H), 5.12 (d, J = 4 Hz, exch., 1 H), 4.72 (m, 1 H),
4.55 (m, 1 H), 192–1.60 (m, 2 H), 0.63 (t, J = 7.5 Hz, 3 H).
13C NMR (CDCl3): = 174.5 (s), 165.3 (s), 141.5 (s), 139.6 (s),
134.3 (s), 129.9 (d), 128.6 (d), 127.6 (d), 126.6 (d), 126.0 (d), 125.1
(d), 114.3 (d), 73.4 (d), 48.6 (d), 22.0 (t), 11.0 (q).
Acknowledgment
I thank Professor K. Smith, Centre for Clean Chemistry, University
of Wales Swansea, UK for recording the NMR and mass spectra. I
also thank the Royal Society of Chemistry for an international au-
thor grant.
3-[1-(Hydroxydiphenylmethyl)propyl]-1H-quinoxaline-2-
thione (19)
Purified by column chromatography (silica gel; Et2O–hexane, 2:1);
mp 115–116 °C.
1H NMR (CDCl3): = 13.81 (s, exch., 1 H), 7.70 (d, J = 8 Hz, 1 H),
7.64 (t, J = 7.5 Hz, 4 H), 7.44 (app. dt, J = 8, 1 Hz, 1 H), 7.30 (d,
J = 7.5 Hz, 4 H), 7.16–6.98 (m, 3 H), 6.84 (app. t, J = 8 Hz, 1 H),
6.51 (s, exch., 1 H), 5.49 (2 d, J = 4 Hz, 1 H), 1.94–1.78 (m, 2 H),
0.77 (t, J = 8 Hz, 3 H).
13C NMR (CDCl3): = 176.5 (s), 168.6 (s), 149.0 (s), 146.6 (s),
135.1 (s), 131.5 (d), 128.7 (d), 128.4 (d), 127.1 (d), 126.8 (d), 125.8
(d), 115.4 (d), 81.8 (s), 49.2 (d), 26.0 (t), 12.8 (q).
References
(1) Current address: G. A. El-Hiti, Department of Chemistry,
University of Wales Swansea, Singleton Park, Swansea SA2
8PP, UK.
(2) See for example: (a) Anctil, E. J.-G.; Snieckus, V. J.
Organomet. Chem. 2002, 653, 150. (b) Turck, A.; Plé, N.;
Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4489.
(c) Monin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4059.
(d) El-Hiti, G. A. Heterocycles 2000, 53, 1839.
EI-MS: m/z (%) = 386 (M+, 4), 368 (39), 352 (100), 331 (61), 295
(59), 239 (67), 219 (54), 182 (32), 105 (52), 77 (81), 51 (56).
(e) Snieckus, V. Chem. Rev. 1990, 90, 879. (f) Beak, P.;
Zajdel, W. J.; Reitz, D. B. Chem. Rev. 1984, 84, 471.
(3) See for example: (a) Sato, N. Tetrahedron Lett. 2002, 43,
6403. (b) Rohonnstad, P.; Wensbo, D. Tetrahedron Lett.
2002, 43, 3137. (c) Geneste, H.; Schäfer, B. Synthesis 2001,
2259. (d) Turck, A.; Plé, N.; Quéguiner, G. Heterocycles
1994, 37, 2149. (e) Quéguiner, G.; Marsais, F.; Snieckus,
V.; Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52, 187.
(f) Narasimhan, N. S.; Mali, R. S. Synthesis 1983, 957.
(4) See for example: (a) Li, L.; Martins, A. Tetrahedron Lett.
2003, 44, 5987. (b) Lukás, G.; Porcs-Makkay, M.; Simig, G.
Tetrahedron Lett. 2003, 44, 3211. (c) Gros, P.; Choppin, S.;
Fort, Y. J. Org. Chem. 2003, 68, 2243. (d) Katritzky, A. R.;
Manju, K.; Steel, P. J. J. Org. Chem. 2003, 68, 407.
(e) Toudic, F.; Plé, N.; Turck, A.; Quéguiner, G.
CI-MS: m/z (%): 387 (MH+, 100), 369 (30), 355 (26), 242 (44), 200
(61).
HRMS: m/z calcd for C24H23N2OS (MH+): 387.1526; found:
387.1524.
Substituted 2,3-Dihydrothieno[2,3-b]quinoxalines 20 and 21;
General Procedure
To a stirred solution of 9 or 12 (0.15 mmol) in CH2Cl2 (10 mL),
TFA (0.2 mL) was added. The mixture was stirred at r.t. for 1 h then
sat. aq Na2CO3 (10 mL) was added and the mixture was then ex-
tracted with CH2Cl2 (10 mL). The organic layer was separated,
washed with H2O (2 × 10 mL), dried (MgSO4) and evaporated un-
der reduced pressure. The solid obtained was recrystallized from
EtOAc to give the pure products 20 and 21.
Tetrahedron 2002, 58, 283. (f) Mukherjee, C.; De, A..
Synlett 2002, 325. (g) Gros, P.; Louërat, F.; Fort, Y. Org.
Lett. 2002, 4, 1759. (h) Cuperly, D.; Gros, P.; Fort, Y. J.
Org. Chem. 2002, 67, 238. (i) Gros, P.; Fort, Y. Eur. J. Org.
Chem. 2002, 20, 3375. (j) Rebstock, A.-S.; Mongin, F.;
Trécourt, F.; Quéguiner, G. Tetrahedron Lett. 2002, 43, 767.
(5) (a) Smith, K.; El-Hiti, G. A.; Hawes, A. C. Synthesis 2003,
2047. (b) Smith, K.; El-Hiti, G. A.; Hawes, A. C. Synlett
1999, 945. (c) Smith, K.; El-Hiti, G. A.; Shukla, A. P. J.
Chem. Soc., Perkin Trans. 1 1999, 2305. (d) Smith, K.; El-
Hiti, G. A.; Pritchard, G. J.; Hamilton, A. J. Chem. Soc.,
Perkin Trans. 1 1999, 2299. (e) Smith, K.; El-Hiti, G. A.;
Hamilton, A. J. Chem. Soc., Perkin Trans. 1 1998, 4041.
(6) (a) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F. Russ. J.
Org. Chem. 2003, 39, 430. (b) Smith, K.; El-Hiti, G. A.;
Abdel-Megeed, M. F.; Abdo, M. A. Collect. Czech. Chem.
Commun. 1999, 64, 515. (c) Smith, K.; El-Hiti, G. A.;
Abdel-Megeed, M. F.; Abdo, M. A. J. Org. Chem. 1996, 61,
656. (d) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.;
Abdo, M. A. J. Org. Chem. 1996, 61, 647. (e) Smith, K.;
El-Hiti, G. A.; Abdo, M. A.; Abdel-Megeed, M. F. J. Chem.
Soc., Perkin Trans. 1 1995, 1029.
2-(4-Methoxyphenyl)-2,3-dihydrothieno[2,3-b]quinoxaline (20)
Recrystallized from EtOAc; mp 138–140 °C.
1H NMR (DMSO-d6): = 7.95 (dd, J = 8, 1 Hz, 1 H), 7.85 (dd,
J = 8, 1 Hz, 1 H), 7.73–7.64 (m, 2 H), 7.46 (d, J = 8.5 Hz, 2 H), 6.94
(d, J = 8.5 Hz, 2 H), 5.42 (t, J = 8 Hz, 1 H), 3.85 (dd, J = 17, 8 Hz,
1 H), 3.75 (s, 3 H), 3.66 (dd, J = 17, 8 Hz, 1 H).
13C NMR (DMSO-d6): = 161.5 (s), 159.4 (s), 158.4 (s), 141.4 (s),
139.4 (s), 132.5 (s), 129.8 (d), 129.0 (d), 128.8 (d), 128.6 (d), 127.6
(d), 114.6 (d), 55.5 (q), 48.0 (d), 42.0 (t).
EI-MS: m/z (%) = 294 (M+, 100), 279 (26), 218 (31), 187 (46), 151
(26), 134 (40), 119 (29), 102 (35), 91 (62), 65 (39).
CI-MS: m/z (%) = 295 (MH+, 100), 265 (31), 135 (22).
HRMS: m/z calcd for C17H15N2OS (MH+): 295.0900; found:
295.0901.
2,3-Diphenyl-2,3-dihydrothieno[2,3-b]quinoxaline (21)
Recrystallized from EtOAc; mp 149–150 °C.
1H NMR (DMSO-d6): = 7.95 (dd, J = 8, 1 Hz, 1 H), 7.86 (dd,
J = 8, 1 Hz, 1 H), 7.71–7.67 (m, 2 H), 7.52 (d, J = 7.8 Hz, 4 H), 7.35
(t, J = 7.8 Hz, 4 H), 7.26 (t, J = 7.8 Hz, 2 H), 4.35 (s, 2 H).
13C NMR (DMSO-d6): = 160.6 (s), 157.9 (s), 144.7 (s), 141.5 (s),
139.6 (s), 130.1 (d), 129.0 (d), 128.9 (d), 128.8 (d), 127.9 (d), 127.8
(d), 127.3 (d), 66.6 (s), 47.5 (t).
(7) Smith, K.; El-Hiti, G. A.; Mahgoub, S. A. Synthesis 2003,
2345.
(8) Parra, S.; Laurent, F.; Subra, G.; Deleuze-Masquefa, C.;
Benezch, V.; Fabreguettes, J.-R.; Vidal, J.-P.; Pocock, T.;
Elliott, K.; Small, R.; Escale, R.; Michel, A.; Chapat, J.-P.;
Bonnet, P.-A. Eur. J. Med. Chem. 2001, 36, 255.
EI-MS: m/z (%) = 340 (M+, 100), 305 (26), 263 (98), 191 (22), 178
(71), 165 (59), 152 (18), 102 (27), 77 (48), 51 (31).
Synthesis 2003, No. 18, 2799–2804 © Thieme Stuttgart · New York

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G. A. El-Hiti
PAPER
(9) Chapoulaud, V. G.; Salliot, I.; Plé, N.; Turck, A.; Quéguiner,
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(10) Turck, A.; Plé, N.; Tallon, V.; Quéguiner, G. J. Heterocycl.
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(11) Ward, J. S.; Merritt, L. J. Heterocycl. Chem. 1991, 28, 765.
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P. E.; Maguire, M. P. PCT Int. Appl. WO 3150, 2000; Chem.
Abstr. 2000, 133, 17478. (f) Spada, A. P.; He, W.; Myers,
M. R. PCT Int. Appl. WO 3149, 2000; Chem. Abstr. 2000,
133, 17477. (g) Nikam, S. S.; Cordon, J. J.; Ortwine, D. F.;
Heimbach, T. H.; Blackburn, A. C.; Vartanian, M. G.;
Nelson, C. B.; Schwarz, R. D.; Boxer, P. A.; Rafferty, M. F.
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(14) Badr, M. Z. A.; El-Naggar, G. M.; El-Sherief, H. A. H.;
Mahgoub, S. A. Bull. Chem. Soc. Jpn. 1984, 57, 1653.
(15) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9,
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(16) Asano, K. Yakugaku Zasshi 1958, 78, 729; Chem. Abstr.
1958, 52, 18428.
Synthesis 2003, No. 18, 2799–2804 © Thieme Stuttgart · New York