Characterization and Synthesis of a 6-Substituted Benzo[b]thiophene

Article abstract of DOI:10.1021/jo980537j

An impurity observed during the synthesis of zileuton (Zyflo) has been isolated and characterized as a benzo[o]thiophene derivative that has undergone electrophilic substitution in the 6 position (4). A nine-step synthesis confirms the structural assignment. Key steps in the synthesis include a regioselective Friedel-Crafts coupling between 2-hydroxythioanisole, 8, and 1-(benzo[6]thien-2-yl)ethanol, 1, and formation of a benzo[b]thiophene from an o-methylthiobenzaldehyde, 14, and chloroacetone. The synthesis provides a potentially general route to substituted benzo[6]thiophenes.

Full text of DOI:10.1021/jo980537j

J . Org. Chem. 1998, 63, 5903-5907
5903
Ch a r a cter iza tion a n d Syn th esis of a 6-Su bstitu ted
Ben zo[b]th iop h en e
Anthony R. Haight,*,† Gregory S. Wayne,† Gregory S. Lannoye,† Shyamal I. Parekh,†
Weijiang Zhang,† Richard R. Copp,† and L. Steven Hollis‡
Chemical Process Research, D54P, and Structural Chemistry, D-418, Abbott Laboratories, North Chicago,
Illinois 60064
Received March 23, 1998
An impurity observed during the synthesis of zileuton (Zyflo) has been isolated and characterized
as a benzo[b]thiophene derivative that has undergone electrophilic substitution in the 6 position
(4). A nine-step synthesis confirms the structural assignment. Key steps in the synthesis include
a regioselective Friedel-Crafts coupling between 2-hydroxythioanisole, 8, and 1-(benzo[b]thien-2-
yl)ethanol, 1, and formation of a benzo[b]thiophene from an o-methylthiobenzaldehyde, 14, and
chloroacetone. The synthesis provides a potentially general route to substituted benzo[b]thiophenes.
Inhibition of leukotriene synthesis has been an area
of intense pharmaceutical interest as a means of target-
ing inflammatory and vascular diseases.1 The 5-lipoxy-
genase enzyme catalyzes the formation of leukotriene-
A4 ultimately from arachidonic acid.2 Zileuton (Zyflo),
2, a 5-lipoxygenase inhibitor discovered at Abbott Labo-
ratories,3 is the first selective 5-lipoxygenase inhibitor
to receive approval by the FDA. The compound is
marketed as the racemate, with several racemic synthe-
ses having been reported to date.2,4 A synthetic route
currently being developed for the large scale manufacture
of zileuton produces impurities from di- and/or O-alky-
lation of hydroxyurea in the final crystallized product (eq
1). The only other impurity present with any regularity,
and had a mass of 396, suggesting zileuton had con-
densed again with 1 under the reaction conditions. 1H
NMR analysis of the impurity in CD3CN showed a
quartet at 5.63 ppm consistent with the hydroxyurea
having condensed on the benzylic carbon. However,
another quartet appeared at 4.53 ppm and suggested that
another benzylic center had coupled on a benzo[b]-
thiophene ring system.
In the downfield region of the spectrum, singlets at
7.80, 7.21, and 7.17 ppm and doublets at 7.75, 7.71, and
7.69 ppm all integrated to one proton each. This is in
agreement with the impurity having two benzo[b]-
thiophenes with one substituted at the 2 position and the
other at the 2 and either the 5 or 6 position (3 or 4).
(1)
in amounts greater than 0.1% by HPLC, was an unknown
compound varying from 0.0 to 0.6%. In order to do more
detailed toxological testing of this impurity, larger amounts
were required. Thus, an effort was undertaken to
characterize and synthesize the unknown impurity.
13C-NMR DEPT analysis of the impurity confirmed
that there were nine unsubstituted aryl carbons present,
and seven quaternary carbons, as would be expected in
either 3 or 4. Two of the methine carbon signals showed
splitting which was presumed to be the result of spectral
resolution of the diastereomers of the compound.
One-dimensional nuclear Overhauser effect (NOE)
difference spectral analysis showed a NOE on the doublet
at 7.69 ppm by irradiation at 7.21 ppm. Irradiation of
the singlet at 7.17 ppm showed a NOE on the doublet at
7.71 ppm, not the singlet at 7.80 ppm. This is in
agreement with structure 4 as the correct assignment.
Isola tion a n d Ch a r a cter iza tion
A 10 g sample of zileuton containing 0.6% of the
impurity was separated by a combination of C-18 func-
tionalized flash and prep-TLC plates. This yielded 18
mg of material that coeluted with the impurity by HPLC.
The isolated material was obtained as a pale yellow solid
† Chemical Process Research.
‡ Structural Chemistry.
(1) Brooks, C. D.; Summers, J . B. J . Med. Chem. 1996, 39, 2629.
(2) Brooks, D. W.; Carter, G. W. In The Search for Antiinflammatory
Drugs; Merluzzi, V. J ., Adams, J ., Eds.; Burkhauser: Boston, 1995;
Chapter 5.
(3) Summers, J . B.; Gunn, B. P.; Brooks, D. W. U.S. Patent 4,873,-
259, Oct 10, 1989.
(4) (a) Kolasa, T.; Brooks, D. W. Synth. Commun. 1993, 23, 743. (b)
Basha, A.; Ratajczyk, J . D.; Brooks, D. W. Tetrahedron Lett. 1991, 32,
3783.
Resu lts a n d Discu ssion
With the regiochemistry assigned, a synthetic route
capable of preparing gram quantities of 4 was required.
A mimetic approach was not considered feasible since
S0022-3263(98)00537-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/30/1998

5904 J . Org. Chem., Vol. 63, No. 17, 1998
Haight et al.
Sch em e 1
Sch em e 2
electrophilic substitution in the 6-position is not favored.5
We envisioned a 6-substituted benzo[b]thiophene as
arising from a 2-(alkylthio)benzaldehyde derivative, 5
(Scheme 1).6 This in turn was seen as coming from a
para-selective Friedel-Crafts coupling of the alcohol, 1,
with phenol 6.7 Treatment of 1 with 2 equiv of 6 in the
presence of 1 equiv of BF3Et2O afforded a 89:11 ratio of
HPLC products (eq 2).8 Purification gave the p-phenol,
7, in 56% overall yield. Unfortunately, attempts at
introducing a sulfur into 7 using (MeS)2/AlCl3,9 POCl3/
DMSO,10 or (MeS)2/SO2Cl2 gave incomplete or complex
11
reaction mixtures. A modification to this approach was
to carry out the alkylation with the alkylthio group
incorporated in the Friedel-Crafts substrate. Treatment
of a mixture of the alcohol, 1, with 2 equiv of 2-hydrox-
ythioanisole, 8, in the presence of BF3Et2O gave a 88:12
mixture favoring the desired alkylation product 9 over
the methylthio-directed alkylation product 10 (Scheme
2).8 None of the product where the condensation occurred
ortho to the hydroxy was observed. Careful chromato-
graphic separation of the two isomers gave 9 in 35% yield.
A cursory examination of Lewis acids in the condensation
demonstrated that the regioselectivity could be improved
using Et2AlCl (12:1, 9:10) or SnCl4 (42:1, 9:10). However,
the reaction profile using these acids was much more
complex, and the yield of isolated product was signifi-
cantly lower in the case of the SnCl4.
Phenol 9 was treated with triflic anhydride to afford
11 in 95% yield. Carbonylation of the triflate 11 was
accomplished with 2 equiv triethylamine in methanol
using Pd(dppf)Cl2-CH2Cl2 as the catalyst.13 Heating to
140 °C under 200 psi carbon monoxide gave the methyl
ester 12 in 43% yield. The major impurity was the
phenol 9. Reduction of the ester with 1 equiv of DIBAL
gave unselective reduction mixtures. Treatment of 12
with 2 equiv of DIBAL cleanly gave the primary alcohol
13. Following Swern oxidation,14 the aldehyde 14 was
obtained in 80% overall yield from the ester.
Assignment of the regiochemistry in the alkylation
1
products 9 and 10 was based on analysis of the H NMR.
The proton ortho to the hydroxy in 9 appears as a doublet
at 6.93 ppm with a coupling constant of 8.4 Hz consistent
3
with a J coupling. In 10 the proton ortho to the hydroxy
Treatment of aldehyde 14 with neat chloroacetone at
reflux for 36-80 h afforded the desired bis-benzo[b]-
thiophene 15 in 76% yield.6b The reaction was found to
be much cleaner in the presence of magnesium oxide as
a base. Presumably this reaction involves initial forma-
tion of a sulfonium salt, although no intermediates were
observed by HPLC during the reaction. Oximation with
aqueous hydroxylamine gave 16 as a 1:4 mixture of the
syn:anti isomers.15
in 10 appears as a doublet at 6.94 ppm with coupling
4
constant of 1.9 Hz, consistent with a J coupling.12
(5) Electrophilic substitution typically occurs at the 3-position on
2-substituted benzo[b]thiophenes: Scrowton, R. M. Adv. Heterocycl.
Chem. 1981, 29, 199.
(6) (a) Basha, A.; Brooks, D. W. J . Org. Chem. 1993, 58, 1293. (b)
Kagano, H.; Goda, H.; Yoshida, K.; Nakano, M. U.S. Pat. 5,298,630,
1994.
(7) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1984;
Vol. 3, p 310.
Reduction of the oxime mixture with BH3-pyridine in
(8) Ratios were determined by HPLC.
the presence of ethanolic HCl16 required 15 equiv of BH3-
(9) Votterro, C., Labat, Y., Poisier, J . M., U.S. Pat. 5113019, 1992.
(10) Stokker, G. E., Deana, A. A., deSolms, S. J ., Schultz, E. M.,
Smith, R. L., Cragoe, E. J ., Baer, J . E., Ludden, C. T., Russo, H. F.,
Scriabine, A., Sweet, C. S., Watson, L. S. J . Med. Chem. 1980, 23, 1414.
(11) Farah, B. S., Gilbert, E. E. J . Org. Chem. 1963, 28, 2807.
(12) Assignment of the regiochemistry of 9 and 10 was additionally
based on comparison of an authentic sample of 14 to an authentic
sample of the 5′-regioisomer of 14 prepared independently (A. R.
Haight, G. S. Wayne, G. S. Lannoye, W. Zhang, unpublished results).
(13) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 3931.
(14) Mancuso, A. J .; Brownfair, D. S.; Swern, D. J . Org. Chem. 1979,
44, 4148.
(15) The isomers were assigned based on the 13C shifts of the methyl
groups (Hawkes, G. E.; Herwig, K.; Roberts, J . D. J . Org. Chem. 1974,
39, 1017).

Synthesis of a 6-Substituted Benzo[b]thiophene
J . Org. Chem., Vol. 63, No. 17, 1998 5905
20 min, the solution was quenched with water (200 mL) and
extracted twice with ethyl acetate (200 mL). The organics
were combined, washed with water (100 mL), and concentrated
in-vacuo to a solid. The product was crystallized from heptane/
ethyl acetate (200 mL/15 mL) to give 21.7 g (87%) 1: Mp 60-
62 °C (lit.19 62-63 °C); 1H NMR (CDCl3) δ 7.90-7.70 (m, 2H),
7.40-7.20 (m, 2H), 7.20 (s, 1H), 5.25 (qd, 1H, J ) 6.3, 5.4 Hz),
2.15 (d, 1H, J ) 5.4 Hz), 1.70 (d, 3H, J ) 6.3 Hz).
pyridine and greater than 5 h to give the desired
N-hydroxylamine 17. Presumably a competition between
oxime reduction and BH3-pyridine decomposition under
the reaction conditions accounts for the large excess of
BH3-pyridine required. Careful analysis of the reaction
by HPLC revealed that syn-16 was being consumed faster
than anti-16, suggesting that the reduction rate is
dependent upon the stereochemistry of the oxime.17
To take advantage of this rate difference, the oxime
mixture was equilibrated with ethanolic HCl to a 5/1
(syn/ anti) mixture of oximes 16. Reduction of the syn
rich oxime mixture with only 4 equiv of BH3-pyridine
gave 72% conversion in only 1.5 h.18 Addition of 3 equiv
more of BH3-pyridine gave the hydroxylamine quanti-
tatively in 2 h.
Treatment of the unstable hydroxylamine immediately
with potassium cyanate gave the desired final material
4 in 91% yield from ketone 15. Comparison of the 1H
and 13C NMR confirmed that the product was identical
to the isolated impurity 4.
By exploiting the Friedel-Crafts alkylation of o-
hydroxylthioanisole and the condensation of chloroac-
etone with o-methylthiobenzaldehydes, a new tactic to
6-substituted benzo[b]thiophenes has been developed.
The regioselectivity of the Friedel-Crafts alkylation
appears to be tunable by the choice of the Lewis acid;
however, byproduct formation may be a limitation.
4-[1-(Ben zo[b]th ien -2-yl)eth yl]p h en ol (7). To a solution
of phenol, 6 (53 g, 0.56 mol), and 1 (50 g, 0.28 mol) in CH2Cl2
(3L), at -6 °C, was slowly added BF3-OEt2 (34.4 mL, 0.28
mol). The solution was stirred for 15 min at 0-5 °C before
quenching with saturated sodium bicarbonate (1 L). The
organics were separated and washed with water (500 mL).
Concentration in-vacuo gave 91 g of oil as a 89:11 ratio of
isomers.20 Column chromatography (C-18 functionalized silica
gel; MeOH/H2O, 50/50 to 70/30) gave, after crystallization from
methanol/water (v/v, 50/50), 40 g (56%) of phenol 7 as a white
crystalline solid: Mp 112-113 °C; IR 3431 (br), 1599, 1509,
1449, 1230 cm-1; 1H NMR (CDCl3) δ 7.62 (d, 1H, J ) 8.4 Hz),
7.54 (d, 1H, J ) 8.4 Hz), 7.20-7.10 (m, 2H), 7.10-7.02 (m, 2H),
6.90 (s, 1H), 6.70-6.65 (m, 2H), 4.62 (br s, 1H), 4.22 (q, 1H, J
) 7.3 Hz), 1.62 (d, 3H, J ) 7.3 Hz); 13C NMR (CDCl3) (DEPT)
δ 154.2, 152.0, 139.9, 139.5, 137.6, 128.6(+), 124.0(+), 123.6-
(+), 123.0(+), 122.1(+), 119.9(+), 115.3(+), 40.6(+), 22.9(+).
Anal. Calcd for
C16H14OS: C, 75.56; H, 5.55; S, 12.61.
Found: C, 75.50; H, 5.41; S, 12.58.
4-[1-(Ben zo[b]th ien -2-yl)eth yl]-2-(m eth ylth io)ph en ol (9).
To a solution of 2-hydroxythioanisole, 8 (15.8 g, 113 mmol), 1
(10.0 g, 56.0 mmol), and CH2Cl2 (200 mL) at ambient temper-
ature was added BF3-OEt2 (6.8 mL, 56.0 mmol). The reaction
was stirred 1 h and quenched with saturated sodium bicarbon-
ate (70 mL), and the layers were separated. The aqueous layer
was back-extracted with CH2Cl2 (100 mL), and the organics
were combined and concentrated in-vacuo. The biphasic
residue was diluted with CH2Cl2 (200 mL) and separated, and
the organics were dried over MgSO4. Concentration in-vacuo
gave a syrup containing the two regioisomers in a ratio of 88:
12 by HPLC. Flash chromatography (silica; ethyl acetate/
heptanes, 1/99) yielded 5.9 g (34.5%) of the major isomer 9.
1H NMR (CDCl3) δ 7.71 (d, 1H, J ) 7.8 Hz), 7.65 (d, 1H, J )
7.8 Hz), 7.41 (d, 1H, J ) 2.3 Hz), 7.31-7.19 (m, 2H), 7.16 (dd,
1H, J ) 8.4, 2.3 Hz), 7.00 (br s, 1H), 6.93 (d, 1H, J ) 8.4 Hz),
6.56 (s, 1H), 4.30 (q, 1H, J ) 7.1 Hz), 2.29 (s, 3H), 1.72 (d, 3H,
J ) 7.1 Hz); 13C NMR (CDCl3) (DEPT) δ 155.0, 151.5, 139.8,
139.4, 137.8, 133.4(+), 129.7(+), 124.1(+), 123.6(+), 123.0(+),
122.1(+), 120.8, 119.9(+), 114.8(+), 40.5(+), 22.8(+), 19.8(+);
IR (microscope) 3410 (br), 1483 cm-1; MS (CI) m/ z (rel
intensity 301 ([M + 1]+, 100)). Anal. Calcd for C17H16OS2 C,
67.96; H, 5.37; S, 21.35. Found: C, 67.85; H, 5.16; S, 20.97.
Minor isomer (0.2 g, 1%) 10. IR 3400 (br), 1567, 1489, 1433
Exp er im en ta l Section
Gen er a l Meth od s. All commercial reagents were used as
purchased without any further purification. 2-Hydroxythio-
anisole was obtained from Lancaster Synthesis. 2-Acetylben-
zothiophene was obtained from Sumitomo Seika. Melting
points were determined in open capillaries and are uncor-
rected. 1H and 13C NMR spectra were obtained at 300 and
75.5 MHz, respectively. Analytical thin-layer chromatography
(TLC) was performed on Merck silica 60F254 or C18-silica 60
plates. Flash chromatography was performed using Silica Gel
60 (230-400 mesh) or C-18 Silica Gel 60. HPLC analyses were
run on a Zorbax SB-C8 reverse-phase column using CH3CN:
0.1%H3PO4 (60:40) as the mobile phase (λ ) 254 nm).
Isola tion of 4. C-18 Functionalized silica (400 g) was
slurried in methanol and packed on a flash chromatography
column. The column was flushed with 1 L of methanol/water
(v/v, 80/20) to equilibrate. A solution of impure 2 (10 g) in
methanol (ca. 100 mL) was eluted with 14 L of methanol/water
(v/v, 80/20) followed by methanol (600 mL). The fractions
containing the impurity were collected and concentrated in-
vacuo to 200 mg. The residue was eluted on C18-silica 60 TLC
plates with methanol/water (v/v, 80/20), followed by extraction
with methanol to give 30 mg of a solid. The solid was dissolved
in ethyl acetate and filtered. The organics were concentrated
in-vacuo to a light yellow solid (18 mg). 1H NMR (CD3CN) δ
7.80 (s, 1H), 7.75 (d, 1H, J ) 8.0 Hz), 7.71 (d, 1H, J ) 7.5 Hz),
7.69 (d, 1H, 8.0 Hz), 7.33-7.23 (m, 2H), 7.21 (s, 1H), 7.17 (s,
1H), 7.07 (br s, 1H), 5.63 (q, 1H, J ) 7.0 Hz), 4.53 (q, 1H, 7.0
Hz), 1.78 (d, 3H, J ) 7.0 Hz), 1.57 (d, 3H, 6.5 Hz); 13C NMR
(CD3CN) δ 162.0, 153.0, 147.0, 143.0, 141.0, 140.9, 140.3, 139.4,
125.3(+), 125.3/125.2(+), 124.9(+), 124.5(+), 124.2(+), 123.2-
(+), 122.5(+), 121.6(+), 121.1(+), 54.0(+), 42.2(+), 23.0(+),
17.6(+); MS (CI) m/ z (rel intensity 397 ([M + 1]+, 100).
1-(Ben zo[b]t h ien -2-yl)et h a n ol (1). To a solution of
2-acetylbenzo[b]thiophene (25.0 g, 0.14 mol) in methanol (100
mL) cooled to 0 °C was added NaBH4 (6.4 g, 0.17 mol). After
1
cm-1; H NMR (CDCl3) 7.72 (d, 1H, J ) 8.2 Hz), 7.66 (d, 1H,
J ) 7.3 Hz), 7.42 (d, 1H, J ) 7.9 Hz), 7.32-7.20 (m, 2H), 7.05
(br s, 1H), 6.94 (d, 1H, 1.9 Hz), 6.82 (dd, 1H, J ) 8.0, 1.9 Hz),
6.62 (s, 1H), 4.33 (q, 1H, J ) 7.1 Hz), 2.29 (s, 3H), 1.73 (d, 3H,
J ) 7.1 Hz); 13C NMR (CDCl3) (DEPT) δ 156.3, 150.5, 148.5,
139.8, 139.4, 134.9(+), 124.1(+), 123.7(+), 123.0(+), 122.1(+),
120.2(+), 120.1(+), 119.0, 113.7(+), 41.2(+), 22.5(+), 19.9(+).
[4-[1-(Be n zo[b]t h ie n -2-yl)e t h yl]-2-(m e t h ylt h io)p h e -
n yl] Tr iflu or om eth a n esu lfon a te (11). To a solution of 9
(7.0 g, 23 mmol) in methylene chloride (125 mL) was added
triethylamine (7.0 g, 69 mmol). The solution was cooled to
-40 °C and maintained under a nitrogen atmosphere.
A
solution of trifluoroacetic anhydride (9.7 g, 35 mmol) was
added over a period of 15 min while maintaining the temper-
ature between -35 and -40 °C. The mixture was warmed to
ambient temperature for 1 h. The reaction was quenched with
saturated aqueous sodium bicarbonate (160 mL). The organic
(19) Hill, E. A.; Gross, M. L.; Stasiewicz, M.; Manion, M. J . Am.
Chem. Soc. 1969, 91, 7381.
(20) The minor isomer in the HPLC has tentatively been assigned
as the ortho condensation product based on analysis of the 1H NMR
spectrum of the crude reaction mixture. It was not possible to isolate
the minor isomer in a pure form.
(16) Herscheid, J . D. M.; Ottenheijm, H. C. J . Tetrahedron Lett.
1978, 5143.
(17) We are unaware of any examples where the rate of reduction
of an oxime is dependent upon the stereochemistry of the oxime.
(18) At 72% conversion, the syn/ anti ratio was 2/1 by HPLC.

5906 J . Org. Chem., Vol. 63, No. 17, 1998
Haight et al.
layer was separated, washed with saturated brine (160 mL),
dried over MgSO4, and passed through a plug of silica gel. The
silica was washed with methylene chloride (200 mL), and the
combined eluents were concentrated in-vacuo give 9.8 g of a
red liquid (97% yield) in >90% HPLC purity. This material
was used immediately without further purification. 1H NMR
(CDCl3) δ 7.75-7.72 (m, 1H), 7.70-7.66 (m, 1H), 7.34-7.20 (m,
3H), 7.17 (s, 1H), 7.13 (dd, 1H, J ) 2.1, 8.6 Hz), 7.04 (s, 1H),
4.40 (q, 1H, J ) 7.2 Hz), 2.45 (s, 3H), 1.75 (d, 3H, J ) 7.2 Hz);
13C NMR (CDCl3) (DEPT) δ 149.7, 146.0, 145.9, 139.6, 139.4,
132.9, 127.5(+), 125.6(+), 124.3(+), 124.0(+), 123.2(+), 122.2-
(+), 121.6(+), 120.5(+), 118.6 (J CF ) 319.8 Hz), 41.0(+), 22.7-
lytical sample: Mp 88.5-89.5 °C; 1H NMR (CHCl3) δ 10.21 (s,
1H), 7.75 (d, 1H, J ) 8.1 Hz), 7.75-7.66 (m, 2H), 7.34-7.22
(m, 3H), 7.20 (dd, 1H, J ) 1.5, 8.1 Hz), 7.06 (m, 1H), 4.45 (q,
1H, J ) 7.0 Hz), 2.47 (s, 3H), 1.79 (d, 3H, J ) 7.0 Hz); 13C
NMR (CHCl3) δ (DEPT) 190.8(+), 151.6, 149.4, 143.7, 139.6,
139.4, 133.7(+), 131.6, 124.6(+), 124.3(+), 124.0(+), 123.6(+),
123.2(+), 122.2(+), 120.6(+), 41.7(+), 22.4(+), 15.4(+); IR
(microscope) 1680 cm-1; MS (CI) m/ z (rel intensity 313 ([M +
H]+, 100). Anal. Calcd for C18H16OS2: C, 69.19; H, 5.16; S,
20.52. Found: C, 69.05; H, 5.13; S, 20.36.
1-{6-[1-(Ben zo[b]th ien -2-yl)eth yl]ben zo[b]th ien -2-yl}-
eth a n on e (15). A solution of 14 (2.0 g, 6.4 mmol) and MgO
(13 mg, 0.32 mmol) in chloroacetone (5.1 mL, 64 mmol) was
heated to reflux (115 °C). After 8 h the reaction was greater
than 90% complete (HPLC). Excess chloroacetone was re-
moved by vacuum distillation, leaving a dark brown oil.
Purification by chromatography (silica gel, CHCl3) gave a
yellow oil (1.75 g, 81%) which precipitated from tert-butyl
methyl ether (MTBE). Recrystallization from MTBE provided
an analytical sample: Mp 136-137 °C; 1H NMR (CHCl3) δ 7.89
(d, 1H, J ) 0.7 Hz), 7.81 (d, 1H, J ) 8.5 Hz), 7.80-7.78 (m,
1H), 7.74-7.66 (m, 2H), 7.36-7.22 (m, 3H), 7.09 (m, 1H), 4.51
(+), 15.7(+); IR (microscope) 1144, 1206, 1211, 1422 cm-1
.
Meth yl 4-[1-(Ben zo[b]th ien -2-yl)eth yl]-2-(m eth ylth io)-
ben zoa te (12). A solution of 11 (31.5 g, 72.9 mmol) in
methanol (100 mL) and DMF (200 mL) was charged to a high
pressure reactor. To this was added triethylamine (14.7 g, 145
mmol) and Pd(dppf)Cl2 (3.0 g, 3.7 mmol). The reactor was
heated to 140 °C and pressurized with carbon monoxide to 200
psi. After 16 h the mixture was filtered and the filtrate
concentrated in-vacuo to give a dark oil. This was dissolved
in toluene (500 mL) and washed twice with saturated aqueous
sodium bicarbonate. After washing with brine and subsequent
drying over MgSO4, the solution was concentrated to a dark
oil (32.1 g). This was purified by column chromatography (10%
ethyl acetate in heptane) to provide a yellow oil (11.2 g, 45%).
A small sample was purified again by column chromatography
(chloroform) to provide a pale yellow oil for use as an analytical
sample. 1H NMR (CDCl3) δ 7.95 (1H, d, J ) 8.1 Hz), 7.75-
7.39 (m, 2H), 7.34-7.22 (m, 2H), 7.20 (d, 1H, J ) 1.5 Hz), 7.09
(dd, 1H, J ) 1.8, 8.1 Hz), 7.04-7.02 (m, 1H), 4.43 (q, 1H, J )
(q, 1H, J ) 7.0 Hz), 2.63 (s, 3H), 1.82 (d, 3H, J ) 7.0 Hz); 13
C
NMR (CHCl3) δ (DEPT) 192.1, 150.5, 145.2, 143.9, 143.1, 139.7,
139.5, 137.9, 129.4(+), 126.0(+), 125.2(+), 124.2(+), 123.8(+),
123.1(+), 122.2(+), 121.3(+), 120.4(+), 41.6(+), 26.7(+), 22.7-
(+), IR (microscope) 1660 cm-1; MS (CI) m/ z (rel intensity 337
([M + H]+, 100). Anal. Calcd for C20H16OS2: C, 71.39; H, 4.79;
S, 19.06. Found: C, 71.01; H, 4.90; S, 18.73.
syn /a n ti-1-{6-[1-(Ben zo[b]th ien -2-yl)eth yl]ben zo[b]th ien -
2-yl}eth a n on e, Oxim es (16). To a homogeneous solution of
15 (1.2 g, 3.6 mmol) in isopropyl alcohol (30 mL) and ethyl
acetate (30 mL) were added 3 drops concd HCl and 50%
hydroxylamine (0.44 mL, 7.1 mmol). The mixture was heated
to reflux for 3 h followed by addition of more 50% hydroxy-
lamine (0.11 mL). After 30 min, the reaction was cooled to
room temperature and concentrated in-vacuo to give a solid.
The solid was dissolved in ethyl acetate (100 mL), washed with
water (50 mL), dried over MgSO4, and concentrated in-vacuo
to give a yellow solid (1.2 g, 94% yield). HPLC showed a 3.7:1
ratio of anti:syn isomers. This mixture was used without
further purification. MS (CI) m/ z (rel intensity 352 ([M + H]+,
7.1 Hz), 3.90 (s, 3H), 2.42 (s, 3H), 1.78 (d, 3H, J ) 7.1 Hz); 13
C
NMR (CDCl3) δ (DEPT) 166.6, 149.9, 149.8, 143.7, 139.7, 139.4,
131.7(+), 125.2, 124.2(+), 123.9(+), 123.4(+), 123.1(+), 122.6-
(+), 122.1(+), 120.5(+), 52.0(+), 41.6(+), 22.5(+), 15.6(+); IR
(CHCl3) 1710 cm-1; MS (CI) m/ z (rel intensity 343 ([M + 1]+,
100). Anal. Calcd for C19H18O2S2: C, 69.19; H, 5.16; S, 20.52.
Found: C, 69.05; H, 5.13; S, 20.36.
4-[1-(Ben zo[b]th ien -2-yl)eth yl]-2-(m eth ylth io)ben zen -
em eth a n ol (13). A solution of 12 (10.4 g, 30.4 mmol) in
methylene chloride (150 mL) was cooled to -75 °C. To this
was added, dropwise over 5 min, a solution of 1.0 M DIBAL
(61 mL, 61 mmol). The temperature was maintained below
-55 °C during the addition and then stirred at -75 °C for 30
min. The reaction was warmed to room temperature and
quenched with saturated aqueous NH4Cl (50 mL), followed by
5% aqueous HCl (100 mL). The organic layer was removed
and the aqueous back-extracted with methylene chloride (100
mL). The combined organics were washed with water (150
mL), dried over MgSO4, and concentrated in-vacuo to give a
yellow oil (8.06 g, 84%). 1H NMR (CHCl3) δ 7.74-7.64 (m, 2H),
7.33-7.20 (m, 4H), 7.11 (dd, 1H, J ) 1.8, 8.1 Hz), 7.03 (m,
1H), 4.72 (d, 2H, J ) 6.3 Hz), 4.38 (q, 1H, J ) 7.0 Hz), 2.45 (s,
3H), 1.75 (d, 3H, J ) 7.0 Hz); 13C NMR (CHCl3) δ (DEPT)
150.9, 145.5, 139.7, 139.4, 137.4, 136.8, 128.3(+), 125.8(+),
124.5(+), 124.1(+), 123.7(+), 123.0(+), 122.1(+), 120.2(+), 63.2-
(-), 41.2(+), 22.7(+), 16.2(+), IR (CHCl3) 3380 (br) cm-1; MS
(DCI/NH3) m/ z (rel intensity 332 ([M + NH4]+, 100). Anal.
Calcd for C18H18OS2: C, 68.75; H, 5.77; S, 20.39. Found: C,
68.48; H, 5.73; S, 20.15.
4-[1-(Ben zo[b]t h ien -2-yl)et h yl]-2-(m et h ylt h io)b en za l-
d eh yd e (14). Oxalyl chloride (3.1 mL, 36 mmol) in methylene
chloride (40 mL) was cooled to -78 °C. To this was added
DMSO (5.1 mL, 72 mmol) dropwise, and the reaction was
stirred at -78 °C for 15 min. A solution of 13 (7.5 g, 24 mmol)
in methylene chloride (25 mL) was added dropwise to the
reaction and stirred at -78 °C for 15 min. Triethylamine (7.2
g, 72 mmol) was added and the reaction allowed to warm to
room temperature. The reaction mixture was diluted with
methylene chloride (200 mL) and washed with water (200 mL).
After drying over MgSO4, the solution was concentrated in-
vacuo to a dark brown oil (7.2 g). Purification by column
chromatography (silica gel, CHCl3) afforded a yellow oil (6.67
g, 90%), which solidified on standing. A small amount was
recrystallized (isopropyl acetate/heptane) to provide an ana-
1
100). anti-16: H NMR (CDCl3) δ 7.79-7.62 (m, 4H), 7.42 (s,
1H), 7.35-7.20 (m, 3H), 7.06 (s, 1H), 4.49 (q, 1H, J ) 7.2 Hz),
2.36 (s, 3H), 1.81 (d, 3H, J ) 7.2 Hz); 13C NMR (CDCl3) δ 152.3,
151.1, 143.1, 140.2, 140.1, 139.8, 139.5, 138.2, 124.5, 124.1,
124.0, 123.7, 123.3, 123.1, 122.2, 120.7, 120.2, 41.4, 22.8, 11.9.
syn-16: 1H NMR (CDCl3) δ 7.79-7.62 (m, 4H), 7.41 (s, 1H),
7.35-7.20 (m, 3H), 7.06 (s, 1H), 4.50 (q, 1H, J ) 7.2 Hz), 2.42
(s, 3H), 1.85 (d, 3H, J ) 7.2 Hz); 13C NMR (CDCl3) δ 151.3,
147.7, 143.3, 142.5, 141.9, 140.8, 139.7, 136.2, 126.7, 125.6,
124.6, 124.1, 123.6, 123.3, 123.1, 122.4, 120.3, 41.6, 22.9, 20.2.
N-(1-{6-[1-(Ben zo[b ]t h ien -2-yl)et h yl]b en zo[b ]t h ien -2-
yl}eth yl)-N-h yd r oxyu r ea (4). To a solution of oximes 16 (1.1
g, 3.1 mmol) in methylene chloride (20 mL) was added a
solution of ethanolic HCl (1.6 g in 15 mL). This was stirred
at ambient temperature overnight. Analysis of the reaction
mixture by HPLC showed 83% syn oxime. The mixture was
concentrated in-vacuo to an oil and redissolved in ethanol (20
mL) and methylene chloride (20 mL). The solution was cooled
to 15 °C, and BH3-pyridine (1.16 g, 12.5 mmol) was slowly
added. A solution of HCl(g) in ethanol (840 mg in 10 mL) was
slowly added to the mixture over 10 min. The temperature
was maintained below 19 °C during the addition. After 1.5 h,
additional BH3-pyridine (1.0 g, 10.8 mmol) was added. The
reaction was shown by HPLC to be >90% complete after 3.5
h. The mixture was concentrated to a foam and dissolved into
ethyl acetate (50 mL) and water (25 mL). While stirring
rapidly and with the temperature below 10 °C, the pH was
raised to >10 by the addition of 50% NaOH solution. The
originate layer was separated and the aqueous extracted with
ethyl acetate. The ethyl acetate layers were combined and
carried on without isolation.
To the ethyl acetate solution was added 25 mL of aqueous
potassium cyanate (254 mg, 3.1 mmol), and the mixture was

Synthesis of a 6-Substituted Benzo[b]thiophene
J . Org. Chem., Vol. 63, No. 17, 1998 5907
cooled to 10-15 °C. While stirring rapidly, concd HCl was
added dropwise until the pH was <2. The reaction mixture
was allowed to warm to room temperature and stirred for 10
min. HPLC showed that the reaction was complete. The ethyl
acetate layer was separated and the aqueous extracted with
ethyl acetate (25 mL). The combined ethyl acetate layers were
dried over MgSO4 and concentrated in-vacuo to a tan-colored
solid (1.15 g, 95% overall). The crude product was recrystal-
lized from toluene (20 mL) to provide a creme-colored powder
(620 mg, 50%). Mp 125 °C (dec); 1H NMR (CD3CN) δ 7.80 (s,
1H), 7.75 (d, 1H, J ) 8.0 Hz), 7.71 (d, 1H, J ) 7.5 Hz), 7.69 (d,
1H, 8.0 Hz), 7.33-7.23 (m, 2H), 7.21 (s, 1H), 7.17 (s, 1H), 7.07
(br s, 1H), 5.63 (q, 1H, J ) 7.0 Hz), 4.53 (q, 1H, 7.0 Hz), 1.78
(d, 3H, J ) 7.0 Hz), 1.57 (d, 3H, 6.5 Hz); 13C NMR (CD3CN) δ
162.0, 153.0, 147.0, 143.0, 141.0, 140.9, 140.3, 139.4, 125.3-
(+), 125.3/125.2(+), 124.9(+), 124.5(+), 124.2(+), 123.2(+),
122.5(+), 121.6(+), 121.1(+), 54.0(+), 42.2(+), 23.0(+), 17.6-
(+); IR (KBr) 1620 cm-1; MS (CI) m/ z (rel intensity 337 ([M
+ H]+ 100). Anal. Calcd for C20H16N2O2S2: C, 63.61; H, 5.08;
N, 7.06; S, 16.17. Found: C, 63.32; H, 5.15; N, 7.04; S, 15.88.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra (29 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O980537J