Large-scale synthesis of new cyclazines, 5-thia-1,8b-diazaacenaphthylene-3-carboxylic acid derivatives having the peripheral 12π-electron ring system

Article abstract of DOI:10.1016/S0040-4020(01)01171-1

The 5-thia-1,8b-diazaacenaphthylenes (2 and its ester, 8) are new cyclazines, in which a paramagnetic ring is present in the peripheral 12π-electron ring system. Three convenient methods of preparing 8 have been developed. One involved thioglycolation of a new compound, 5-fluoroimidazo[1,2-a]pyridine (6b), followed by the Duff reaction gave 8 in 64% yield without chromatographic purification.

Full text of DOI:10.1016/S0040-4020(01)01171-1

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 489±493
Large-scale synthesis of new cyclazines,
5-thia-1,8b-diazaacenaphthylene-3-carboxylic acid derivatives
having the peripheral 12p-electron ring system
a
a
a
Tomomi Ikemoto,a,p Tetsuji Kawamoto,b, Hiroki Wada, Toru Ishida, Tatsuya Ito,
Yasushi Isogami,a Yoshiko Miyano,a Yukio Mizuno,a Kiminori Tomimatsu,b
Kazumasa Hamamura,b Muneo Takatanib and Mitsuhiro Wakimasua
*
aChemical Development Laboratories, Takeda Chemical Industries, Ltd, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
bMedicinal Chemistry Research Laboratories, Takeda Chemical Industries, Ltd, 2-17-85 Jusohonmachi, Yodogawa-ku,
Osaka 532-8686, Japan
Received 17 October 2001; accepted 21 November 2001
AbstractÐThe 5-thia-1,8b-diazaacenaphthylenes (2 and its ester, 8) are new cyclazines, in which a paramagnetic ring is present in the
peripheral 12p-electron ring system. Three convenient methods of preparing 8 have been developed. One involved thioglycolation of a new
compound, 5-¯uoroimidazo[1,2-a]pyridine (6b), followed by the Duff reaction gave 8 in 64% yield without chromatographic puri®cation.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
evaluation. Compound 1 consists of 5-thia-1,8b-diaza-
acenaphthylene-4-carboxylic acid (2) and 4-amino-1-(3-
phenylpropan-1-yl)piperidine (3) as shown in Scheme 1.
In this paper, we describe the large-scale production of 2
as a segment of 1.
The 5-thia-1,8b-diazaacenaphthylenes (1,2 and 8) are new
cyclazines with fused tricyclic ring systems having an
internal nitrogen atom and 5, 6, and 6-members.1 These
heteroaromatic compounds were revealed to have a planar
1
structure by X-ray crystallographic analysis. The H NMR
data on these cyclazines showed unique properties between
those of stable `aromatic' and unstable `antiaromatic' ring
systems, and suggested the contribution of a paramagnetic
ring present in the peripheral 12p-electron ring system.2
Among these products, N-[1-(3-phenylpropan-1-yl)piper-
idin-4-yl]-5-thia-1,8b-diazaacenaphthylen-4-carboxamide
(1) reduced the amount of low and very low density lipo-
protein cholesterol and triglycerides in hamsters, and has
potential for preventing atherosclerosis.3 Hence, preparation
of 1 for large-scale was required to support toxicological
2. Results and discussion
2.1. Synthesis of 7b
Ethyl (imidazo[1,2-a]pyridin-5-ylthio)acetate (7b) as a
precursor of carboxylic acid (2) was synthesized, as
shown in Scheme 2. The sul®de (7b) was early prepared
by thiolation of 5-chloroimidazo[1,2-a]pyridine (6a) with
aqueous NaSH solution, followed by treatment with ethyl
bromoacetate.2,3 However, this reaction took more than 60 h
Scheme 1.
Keywords: 5-thia-1,8b-diazaacenaphthylene; cyclazine; 5-¯uoroimidazo[1,2-a]pyridine; Duff reaction; 12p-electron ring system.
Corresponding authors. Tel.: 181-6-6300-6840; fax: 181-6-6300-6251; e-mail: ikemoto_tomomi@takeda.co.jp; Tel.: 181-6-6300-5573; fax: 181-6-6300-
6306; e-mail: TetsujiKawamoto@takeda.co.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01171-1

490
T. Ikemoto et al. / Tetrahedron 58 (2002) 489±493
at 1008C to give 5-mercaptoimidazo[1,2-a]pyridine (9) and
the product contained a large quantity of sulfur as an
impurity. This approach was impractical for large-scale
production as tedious chromatographic puri®cation was
needed. To avoid contamination by sulfur, we conducted
the thioglycolation of 5-halogenoimidazo[1,2-a]pyridine
(6)4 and described the optimization of these reaction con-
ditions as shown in Table 1. The reaction of 5-chloro-
imidazo[1,2-a]pyridine (6a) and ethyl thioglycolate using
triethylamine in DMF gave 7b in 62% yield with 9 as by-
product. The replacement reaction of 6a at 708C in DMF
with pyridine or without a base gave 7b in 87% yield,
respectively (entry 2 and 3). These results showed that
the presence of a stronger base affected yield and the
decomposition of 7b providing 9. Moreover, the reaction
conditions requiring a higher temperature produced a tar-
product. The thioglycolation of a new compound, 5-¯uoro-
imidazo[1,2-a]pyridine (6b), was prepared by the condensa-
tion of chloroacetaldehyde and 2-amino-6-¯uoropyridine
(5b) from 2,6-di¯uoropyridine (4b)5, was also carried out.
The reaction of 6b hydrochloride salt (6b´HCl) with ethyl
thioglycolate and triethylamine in DMF at room tempera-
ture afforded 7b in 95% yield (entry 6).
Scheme 2.
Table 1. Reaction of 6 with HSCH2CO2Et (1.2 equiv.) in DMF
Entry
Substrate
Base (equiv.)
Conditions
Yield of 7b (%)a
1
2
3
6a (free)
6a (free)
6a (free)
6a´HCl
6a´HCl
6b´HCl
Et3N (1.0)
Pyridine (1.0)
±
Et3N (1.0)
Et3N (2.5)
Et3N (2.5)
708C, 2 h
708C, 5 h
708C, 7 h
708C, 7 h
808C, 4 h
Rt, 2 h
62
87
87
81
61
95
4
5b
6b
2.2. Synthesis of 8b using 7b
a
Assayed by HPLC.
Thioglycolate (1.5 equiv.) was used.
The new cyclazine 8b was synthesized by two independent
methods using 7b, as shown in Scheme 3. First, we
attempted to synthesize 8b by the formylation of 7b at the
a-position of the ester, followed by a electrophilic reaction
b
Scheme 3.
Table 2.
Entry
Substrate
Reagent (equiv.), solvent (v/w)
Conditions
Yield (%)a
1
2
3
4
5
7b (RˆEt)
7b (RˆEt)
7b (RˆEt)
7a (RˆMe)
7c (Rˆi-Pr)
POCl3 (5), DMF (5.5)
808C, 21h
908C, 8 h
1008C, 6 h
1008C, 5 h
1008C, 7 h
31 b
81b
79
59
81
(CH2)6N4 (2), AcOH (8.5)
(CH2)6N4 (1.7), AcOH (5)
(CH2)6N4 (1.7), AcOH (5)
(CH2)6N4 (1.7), AcOH (5)
a
Assayed by HPLC.
Isolated yield.
b

T. Ikemoto et al. / Tetrahedron 58 (2002) 489±493
491
3. Conclusion
We developed three independent pathways for the synthesis
of a new cyclazine, 5-thia-1,8b-diazaathenaphtalene (8b).
The reaction of 5-¯uoroimidazo[1,2-a]pyridine hydrochride
(6b´HCl) from 2,6-difuloropyridine (4b) and thioglycolate,
followed by treatment with HMTA, gave 8b in particularly
good yield. The hydrolysis of 8b quantitatively gave the
Scheme 4.
Table 3.
Entry
Reagents (equiv.)
Conditions
Yields (%)a
12
6a
1POCl
2
3 (12), DMF
Cl2CHOMe (1.5), SnCl4 (1.5),
CH2Cl2
90±1008C, 3 h
Rt, 2 h
3169
8
69
3
Cl2CHOMe (1.5), TiCl4 (4),
CH2Cl2
(CH2)6N4 (2), AcOH
Imidazole (1), Ac2O, then
NaOH
Rt, 3 h
2159
4
5
858C, 5 h
1258C, 1h
56 (18)b
±
Multi-spots
6
n-BuLi (1.5), DMF (1.5), THF
2608C, 1h, then rt, 2 h
Multi-spots
a
Assayed by HPLC.
Isolated yield.
b
at the 3-position of imidazo[1,2-a]pyridine (route A).
Compound 7b reacted with N,N-dimethyformamide
dimethyl acetal or NaH±ethyl formate to give a-formylester
derivatives 10. The treatment of 10 at 808C in acetic acid
successfully produced the desired 8b as a purple crystal.
Second, the preparation of 8b was carried out by the formyl-
ation of 7b at the 3-position of imidazo[1,2-a]pyridine
followed by intramolecular condensation (route B). The
treatment of 7b with phosphorous oxychloride (POCl3) in
DMF6 also gave 8b in 30±50% yield with 7b hydrochloride
salt (7b´HCl), without compound 11. It was thought that the
formation of 7b´HCl in the Vilsmeier reaction caused the
lack of electrophilicity at the 3-position. Therefore, we
conducted the formylation of 7b at the 3-position without
a strong acid to prevent the formation of 7b salt. As shown
in Table 2, the formylation of 7b with hexamethylenetetra-
mine (HMTA)7 at 1008C using acetic acid as solvent gave
8b in 81% isolated yield. Because of the stability of 7 to
heat, the yields of the Duff reaction7 were affected by the
substituted group of ester under the same conditions
(Me,Et,i-Pr). The hydrolysis of 8b with aqueous NaOH
solution quantitatively gave the desired compound 2.
desired compound 2. This process allows for large-scale
production without the need for a chromatographic
method.
4. Experimental
4.1. General
Melting points were recorded on a BuÈchi B-540 micro melt-
ing apparatus, and were uncorrected. IR spectra were
recorded on a Horiba FT-210 spectrophotometer. H NMR
1
spectra were recorded on a Bruker DPX-300 spectrometer
using tetramethylsilane as an internal standard. Column
chromatography was performed with a Wakogel C-200
(75±150 mm) system. HPLC was performed on a YMC-
Pack ODS-A302 column (6 i.d.£150 mm) with 0.05 M
aqueous KH2PO4 solution±MeCN (55:45) at 258C. Detec-
tion was effected with a Shimadzu SPD-10A spectrophoto-
metric detector at 254 nm. Elemental analyses and MS
spectra were carried out by Takeda Analytical Research
Laboratories, Ltd.
2.3. Synthesis of 8b using 12
4.1.1. 2-Amino-6-chloropyridine (5a). A solution of 2,6-
dichloropyridine (100.0 g, 675.7 mmol) and 25% aqueous
NH4OH solution (600 mL) was stirred for 5 h at 1258C
under a pressure of ca. 0.2 MPa. It was then cooled to
room temperature and stirred for 2 h. The resulting solid
was collected by ®ltration, washed with water (100 mL)
and dried at 408C in vacuo to give 5a (68.6 g, 79%) as a
white solid, mp 70±718C. Anal. calcd for C5H5ClN2: C,
46.71; H, 3.92; N, 21.79; Cl, 27.58. Found: C, 46.45; H,
3.81; N, 21.69; Cl, 27.53. 1H NMR (CDCl3): dˆ4.56±4.84
(2H, brs), 6.37 (1H, d, Jˆ8.1Hz), 6.63 (1H, d, Jˆ7.5 Hz),
7.35 (1H, dd, Jˆ8.1, 7.5 Hz). IR (KBr): nˆ1635, 1548,
Furthermore, an alternative synthetic method of synthesiz-
ing 8b was developed as shown in Scheme 4 (route C).8 We
synthesized 5-chloro-3-formylimidazo[1,2-a]pyridine (12)
and described the optimization of these reactions as
shown in Table 3. The Duff reaction of 6a gave 5-chloro-
3-formylimidazo[1,2-a]pyridine (12) in 56% yield, as
assayed by HPLC, although other reagents such as
POCl3±DMF and dichloromethylmethylether±titanium
tetrachloride gave lower yields. The treatment of 12 with
ethyl thioglycolate and sodium ethoxide resulted in thiola-
tion and successive intramolecular condensation to give 8b
in 65% yield.
1471, 1427, 1184, 781, 686 cm21
.

492
T. Ikemoto et al. / Tetrahedron 58 (2002) 489±493
4.1.2. 6-Chloroimidazo[1,2-a]pyridine hydrochloride
salt (6a´HCl). Crystal 5a (3600 g, 28.0 mol) was dissolved
in EtOH (28 L) at 608C. Aqueous chloroacetoaldehyde
solution (40%, 18.5 L, 112.2 mol) was added dropwise to
the resulting solution over 3 h at 50±608C, and the whole
was re¯uxed for 10 h, cooled to room temperature and
concentrated. A mixture of AcOEt and EtOH (1:1, 5.5 L)
was added to the resulting mixture, and the whole was
stirred for 2 h at 25±358C. The resulting solid was collected
by ®ltration and dried in vacuo to give 6a´HCl (4200 g,
79%) as a white solid. After the mother liquor was concen-
trated, a mixture of AcOEt and EtOH (1:1, 1.5 L) was added
to the resulting solution, and the whole was stirred for 2 h at
25±358C. The resulting solid was collected by ®ltration and
dried in vacuo to give 6a´HCl (488 g, 9%) as a white solid,
mp 1668C (decomposition). Anal. calcd for C7H6Cl2N2: C,
44.47; H, 3.20; N, 14.82; Cl, 37.51. Found: C, 44.21; H,
give 7b (95%, assayed by HPLC). An analytically pure
sample of 7b was obtained by chromatography on silica-
gel with AcOEt as a brown oil. MS (EI)ˆm/z 237 (M1,
calcd 237.3). 1H NMR (CDCl3): dˆ1.17 (3H, t,
Jˆ7.1Hz), 3.62 (2H, s), 4.12 (2H, q, Jˆ7.1Hz), 7.06
(1H, d, Jˆ7.1 Hz), 7.11 (1H, dd, Jˆ7.1, 8.8 Hz), 7.64
(1H, d, Jˆ8.8 Hz), 7.71(1H, s), 7.91(1H, s). IR (neat):
nˆ1731, 1488, 1294, 784 cm21
.
4.1.6.
Ethyl
5-thia-1,8b-diazaathenaphtalene-4-
carboxylate (8b using 7b via 10a, route A). A solution
of 7b (1.2 g, 5.0 mmol), N,N-dimethylformamide dimethyl
acetal (1.0 mL, 7.5 mmol) and DMF (12 mL) was stirred for
2 h at 808C, cooled to room temperature, and mixed with
water (10 mL). After extraction with AcOEt (24 mL), the
organic layer was washed with brine (12 mL£2), dried
(Na2SO4) and concentrated in vacuo. The residue was
puri®ed by chromatography on silica-gel with AcOEt to
give crude 10a (0.94 g, including AcOEt and DMF,
1
3.23; N, 14.65; Cl, 37.22. H NMR (D2O): dˆ7.51±7.54
(1H, m), 7.82±7.84 (2H, m), 7.93 (1H, d, Jˆ2.1Hz), 8.16
(1H, d, Jˆ2.1Hz). IR (KBr): nˆ1644, 1510, 1209,
1
1
analyzed by H NMR) as a brown oil. H NMR (CDCl3):
dˆ1.21 (3H, t, Jˆ7.1Hz), 3.27 (6H, s), 4.18 (2H, q,
Jˆ7.1Hz), 6.58 (1H, d, Jˆ7.1 Hz), 7.18 (1H, dd, Jˆ7.1,
8.8 Hz), 7.45 (1H, d, Jˆ9.0 Hz), 7.73 (1H, s), 7.79 (1H, s),
8.19 (1H, s). A solution of crude 10a (0.73 g) and AcOH
(7 mL) was stirred for 3 h at 808C, cooled to room tempera-
ture, and concentrated. Water (2.5 L) was added to the
resulting residue. After extraction with AcOEt (14 mL),
the organic layer was washed with water (12 mL£2).
Water (12 mL) was added to the organic solution, and the
mixture was adjusted to pH 9 with saturated NaHCO3 solu-
tion. The aqueous layer was separated, and the organic layer
was washed with brine (12 mL£2) and concentrated in
vacuo. The residue was puri®ed by chromatography on
silica-gel with AcOEt to give 8b (0.56 g, 35% from 7b) as
759 cm21
.
4.1.3. 2-Amino-6-¯uoropyridine (5b). A solution of 2,6-
di¯uoropyridine (75.0 g, 651.7 mmol) and 25% aqueous
NH4OH solution (375 mL) was stirred for 5 h at 1258C
under a pressure of ca. 1.4 MPa. It was then cooled to 08C
and stirred for 2 h at the same temperature. The resulting
solid was collected by ®ltration and dried at 408C in vacuo
to give 5b (67.2 g, 92%) as a white solid, mp 57±588C.
Anal. calcd for C5H5FN2: C, 53.57; H, 4.50; N, 24.97; F,
1
16.95. Found: C, 53.44; H, 4.45; N, 24.97; F, 17.25. H
NMR (CDCl3): dˆ4.33±4.74 (2H, brs), 6.16±6.19 (1H,
m), 6.28±6.30 (1H, m), 7.46 (1H, dd, Jˆ8.0, 8.0 Hz). IR
(KBr): nˆ1619, 1571, 1527, 1228, 781 cm21
.
a purple solid, mp 166±1678C. Anal. calcd for
C12H10N2O2S´0.1H2O: C, 58.10; H, 4.14; N, 11.29; S,
4.1.4. 6-Fluoroimidazo[1,2-a]pyridine hydrochloride salt
(6b´HCl). To a solution of 5b (40.0 g, 356.8 mmol) and
water (400 mL) was added dropwise 40% aqueous chloro-
acetoaldehyde solution (119 mL, 715.5 mmol) at 608C. The
mixture was stirred for 2 h at the same temperature and then
cooled to room temperature. AcOEt (200 mL£2) was added
to the reaction mixture and separated. The aqueous solution
was adjusted to pH 9 with saturated NaHCO3 solution. After
extraction with AcOEt (200 mL£3), the organic layer was
washed with water, dried (Na2SO4) and concentrated in
vacuo. The resulting residue was dissolved in THF
(120 mL) and 4.68N HCl±AcOEt (76 mL) was added drop-
wise to the solution in an ice-bath. The resulting solid was
collected by ®ltration, washed with AcOEt±THF and dried
in vacuo to give 6b´HCl (33.0 g, 54%) as a white solid, mp
1858C (decomposition). Anal. calcd for C7H6ClFN2: C,
48.72; H, 3.50; N, 16.23; Cl, 20.54; F, 11.01. Found: C,
1
12.91. Found: C, 57.81; H, 3.92; N, 11.14; S, 13.29. H
NMR (CDCl3): dˆ1.35 (3H, t, Jˆ7.1Hz), 4.28 (2H, q,
Jˆ7.1Hz), 5.72±5.75 (1H, m), 6.58±6.65 (2H, m), 6.86
(1H, s), 7.06 (1H, s). IR (KBr): nˆ1697, 1617, 1481,
1270, 1228, 1157, 1045 cm21
.
4.1.7. 8b using 7b (route B). A solution of 7b (288.4 g,
1.23 mol), HMTA (342.2 g, 2.44 mol) and AcOH (2.5 L)
was stirred for 8 h at 908C, cooled to room temperature
and concentrated. Water (2.5 L) was added to the resulting
residue. After extraction with AcOEt (2.5 L), the organic
layer was washed with water (2.5 L£2). Water (0.5 L) was
added to the organic solution, and the mixture was adjusted
to pH 9 with 30% NaOH solution at below 158C. The
aqueous layer was separated, and the organic layer was
washed with water (2 and 0.8 L) and concentrated in
vacuo. The residue was triturated with n-hexane (1L),
collected by ®ltration, and dried in vacuo to give 8b
(238.5 g, 79%) as a purple solid. Compound 8b (4.7 g,
2%) was recovered from the mother solution.
1
48.37; H, 3.51; N, 15.92; Cl, 20.41; F, 10.99. H NMR
(D2O): dˆ7.24 (1H, m), 7.78 (1H, d, Jˆ9.1Hz), 7.98±
8.10 (2H, m), 8.15 (1H, m). IR (KBr): nˆ1671, 1573,
1544, 1265, 755 cm21
.
4.1.5. Ethyl (imidazo[1,2-a]pyridin-5-ylthio)acetate (7b,
using 6b´HCl). Ethyl thioglycolate (2.8 mL, 26.1mmol)
was added to a suspension of 6b´HCl (3.0 g, 17.4 mmol),
triethylamine (6.1mL, 43.5 mmol), and DMF (30 mL) at
room temperature under an argon atmosphere, and the
mixture was stirred for 2 h under the same conditions to
4.1.8. 8b using 6b´HCl via 7b. Ethyl thioglycolate
(28.5 mL, 260.7 mmol) was added to a suspension of
6b´HCl (30.0 g, 173.8 mmol), triethylamine (60.5 mL,
434.5 mmol), and DMF (300 mL) at room temperature
under an argon atmosphere, and the whole was stirred for
2 h under the same conditions (88%, assayed by HPLC).

T. Ikemoto et al. / Tetrahedron 58 (2002) 489±493
493
AcOEt (900 mL) was added to the reaction mixture, and
extracted with 1N HCl (300 mL£2). The aqueous
solution was adjusted to pH 9 with saturated NaHCO3 solu-
tion, and extracted with AcOEt (300 mL£2). The organic
layer was washed with 5% aqueous NaCl solution
(90 mL£2), dried (Na2SO4) and concentrated in vacuo to
give crude 7b (31.8 g, 77%, assayed by HPLC) as a light-
brown oil.
4.1.11. 5-Thia-1,8b-diazaacenaphthylene-4-carboxylic
acid (2). 1N NaOH solution (120 mL) was added to a solu-
tion of 8b (15.0 g, 60.9 mmol), and the whole was stirred for
1 h at 35±408C. Water (60 mL) was added to the reaction
mixture and washed with AcOEt (96 mL). The aqueous
solution was added dropwise to 1N HCl solution (80 mL),
and stirred for 1h at room temperature. The resulting solid
was collected by ®ltration, and washed successively with
water and acetone to give 2 (12.7 g, 96%) as an orange
solid, mp 272±2738C. Anal. calcd for C10H6N2O2S´H2O:
C, 50.84; H, 3.41; N, 11.86; S, 13.57. Found: C, 50.84; H,
3.22; N, 12.09; S, 13.47. 1H NMR (DMSO-d6): dˆ5.99 (1H,
d, Jˆ7.0 Hz), 6.62 (1H, d, Jˆ9.2 Hz), 6.70 (1H, dd, Jˆ7.0,
9.2 Hz), 6.91 (1H, s), 7.15 (1H, s), CO2H was not found. IR
A solution of crude 7b (31.8 g, 134.2 mmol), HMTA
(32.9 g, 234.9 mmol) and AcOH (270 mL) was stirred for
4 h at 105±1108C, cooled to room temperature, and concen-
trated. AcOEt (500 mL) was then added to the resulting
residue. The organic layer was washed with water
(280 mL£3), concentrated in vacuo, and again water
(222 mL) was added to the resulting residue. The resulting
solid was collected by ®ltration, and dried in vacuo to give
8b (21.1 g, 64%) as a purple solid.
(KBr): nˆ3450, 1635, 1338, 781 cm21
.
Acknowledgements
The authors thank Dr Taiichi Okada for helpful discussions.
4.1.9. 5-Chloro-3-formylimidazo[1,2-a]pyridine (12). A
solution of 6a (17.2 g, 112.7 mmol), HMTA (31.6 g,
225.4 mmol) and AcOH (170 mL) was stirred for 5 h at
858C (56%, assayed by HPLC), cooled to room temperature,
and concentrated. Water (150 mL) and 2-butanone
(150 mL) were then added to the reaction mixture. The
mixture was adjusted to pH 9 with 30% NaOH solution,
the aqueous layer was separated, and the aqueous solution
was extracted with 2-butanone (150 mL). The combined
organic layer was washed with water, dried (Na2SO4) and
concentrated in vacuo. The residue was puri®ed by chroma-
tography on silica-gel with AcOEt to give 12 (3.6 g, 18%) as
a white solid, mp 157±1598C. Anal. calcd for C8H5ClN2O:
C, 53.21; H, 2.79; N, 15.51; Cl, 19.63. Found: C, 53.13; H,
2.85; N, 15.46; F, 19.49. 1H NMR (CDCl3): dˆ7.20 (1H, d,
Jˆ7.4 Hz), 7.44 (1H, dd, Jˆ7.4, 8.9 Hz), 7.76 (1H, d,
Jˆ8.9 Hz), 8.50 (1H, s), 10.71 (1H, s). IR (KBr):
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nˆ2952, 2921, 2854, 1648, 1502, 1459 cm21
.
4.1.10. 8b using 12 (route C). NaOEt (210 mg, 3.2 mmol)
was added to a solution of 12 (448 mg, 2.7 mmol), ethyl
thioglycolate (0.36 mL, 3.2 mmol), and EtOH (10 mL),
and the whole was re¯uxed for 3 h. After the mixture had
cooled to room temperature and been concentrated, AcOEt
(10 mL) was added to the resulting residue. The organic
solution was then extracted with 1N HCl solution
(5 mL£2), and the aqueous solution was adjusted to pH 9
with 1N NaOH solution in an ice-bath and extracted with
AcOEt (10 mL£2). The organic layer was washed with
water (10 mL£2), dried (Na2SO4) and concentrated in
vacuo. The residue was triturated with diisopropyl ether
(20 mL), and collected by ®ltration to give 8b (430 mg,
65%) as a white solid.
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