Efficient method for synthesis of 2-acetylbenzo(b)thiophene and its derivatives, the key synthons for 5-lipoxygenase inhibitors

Article abstract of DOI:10.1080/00397910903162775

An efficient method was developed for synthesis of 2-acetylbenzo(b) thiophene (2a), the key intermediate for zileuton (1). Synthesis involves treatment of 2-chlorobenzaldehyde (5a) with tert-butylmercaptan (6) to form 2-(tert-butylthio)benzaldehyde (7a), which upon treatment with HBr in water gave the disulfide derivative 2,2'-disulfanediyldibenzaldehyde (8a) in 97% yield. Finally, the reaction of 8a with acetylacetone (9) and 1-chloroacetone (10) gave 2-acetylbenzo(b)thiophene (2a) in 94% yield. The methodology is general and suitable for the preparation of its derivatives, 2b-d. Copyright

Full text of DOI:10.1080/00397910903162775

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Efficient Method for Synthesis of 2-
Acetylbenzo(b)thiophene and Its
Derivatives, the Key Synthons for 5-
Lipoxygenase Inhibitors
Sanjay R. Chemburkar a , David G. Anderson a & Rajarathnam E.
Reddy a
a Abbott Laboratories, North Chicago, Illinois, USA
Published online: 08 Jun 2010.
To cite this article: Sanjay R. Chemburkar , David G. Anderson & Rajarathnam E. Reddy (2010):
Efficient Method for Synthesis of 2-Acetylbenzo(b)thiophene and Its Derivatives, the Key Synthons
for 5-Lipoxygenase Inhibitors, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:13, 1887-1894
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Synthetic Communications1, 40: 1887–1894, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903162775
EFFICIENT METHOD FOR SYNTHESIS OF
2-ACETYLBENZO(b)THIOPHENE AND ITS
DERIVATIVES, THE KEY SYNTHONS FOR
5-LIPOXYGENASE INHIBITORS
Sanjay R. Chemburkar, David G. Anderson, and
Rajarathnam E. Reddy
Abbott Laboratories, North Chicago, Illinois, USA
An efficient method was developed for synthesis of 2-acetylbenzo(b)thiophene (2a), the key
intermediate for zileuton (1). Synthesis involves treatment of 2-chlorobenzaldehyde (5a)
with tert-butylmercaptan (6) to form 2-(tert-butylthio)benzaldehyde (7a), which upon
treatment with HBr in water gave the disulfide derivative 2,20-disulfanediyldibenzaldehyde
(8a) in 97% yield. Finally, the reaction of 8a with acetylacetone (9) and 1-chloroacetone
(10) gave 2-acetylbenzo(b)thiophene (2a) in 94% yield. The methodology is general and
suitable for the preparation of its derivatives, 2b–d.
Keywords: 2-Acetylbenzo(b)thiophene; 5-lipoxygenease inhibitors; synthesis
INTRODUCTION
Inflammation of airways typically causes the hallmark clinical symptoms of
asthma, which affects about 10% of the population, and its prevalence and mortality
continue to increase.[1] Several factors contribute to the regulation of airflow in
patients suffering with asthma, which include mediators such as histamine, prosta-
glandins, thromboxane, and leukotrienes. All act as chemo-attractants for inflamma-
tory cells.[2] Leukotrienes (LTs) are potent inflammatory mediators, and they are
formed from arachidonic acid, which is catalyzed by a key enzyme, 5-lipoxygenease
(5-LOX).[3] The 5-LOX pathway, in addition to asthma, is also associated with a
variety of other diseases, such as atherosclerosis, rheumatoid arthritis, cancer, osteo-
porosis, and liver fibrosis.[4] Thus, inhibitors of 5-LOX may lead to the development
of novel therapeutic treatments, and the potential of this approach has been
extensively highlighted.[5] Zileuton [A-64077, (ꢀ)-N-benzo(b)then-2-ylethyl)-N-
hydroxyurea, 1] is a selective inhibitor of 5-LOX (Fig. 1), which is believed to form
a complex with the iron molecule in the active site of the enzyme and exhibits good
efficacy.[6] The core unit, N-aryethyl hydroxyurea, is identified as critical for its novel
Received April 13, 2009.
Address correspondence to Sanjay R. Chemburkar, API Chemistry (Dept. 04AR, Bldg. R13),
Manufacturing Science and Technology, Global Pharmaceutical Operations, Abbott Laboratories, 1401
Sheridan Road, North Chicago, IL 60064, USA. E-mail: sanjay.chemburkar@abbott.com
1887

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S. R. CHEMBURKAR, D. G. ANDERSON, AND R. E. REDDY
Figure 1. Zileuton (1) and its synthesis from 2-acetylbenzo(b)thiophene (2a).
activity, and research efforts continue to further understand and improve the
activity.[7] Several approaches have been developed for the synthesis of zileuton
(1).[8] Among these, the strategy based on conversion of 2-acetylbenzo(b)thiophene
(2a) to zileuton (1) in a three-step sequence (Fig. 1) is efficient, cost-effective, and
amenable for large-scale preparation.[8g,9] In this article, we describe an efficient
method for the synthesis of 2-acetylbenzo(b)thiophene (2a), the key intermediates
for preparation of zileuton (1) and its aryl substituted derivatives (2b–d).
RESULTS AND DISCUSSION
Several methods have been reported for the synthesis of 2-acetylbenzo(b)thio-
phene (2a) starting from 2-thiobenzoic acid,[10] 2-thiobenzaldehyde,[11] thiophe-
nol,[8g] or thiophene.[12] Among these methods, the synthesis involving
2-thiobenzoic acid (3)[10c] produces 2-acetyl-3-hydroxy-benzo(b)thiophene (5)
(Scheme 1) in good overall yield, which proceeds through a disulfide intermediate.
However, the use of concentrated sulfuric acid as a solvent in this transformation
and the need for removal of hydroxyl group at the 3-position of 4 make this method
practically unsuitable for the preparation of 2-acetylbenzo(b)thiophene (2a) or its
aryl substituted derivatives. We envisioned that a disulfide intermediate, such as
(8a) with an aldehyde group at the 2-position, which can be prepared from 2-tert-
butylthiobenzaldehyde (7a),[13] should yield the desired synthon, 2-acetylbenzo
(b)thiophene (2a).
Accordingly, the key intermediate, 2,20-disulfanediyldibenzaldehyde (8a),
was prepared from 2-chlorobenzaldehyde (5a) via 2-tert-butylthiobenzaldehyde
(7a) in two steps. Thus, reaction of 2-thiobenzaldehyde (5a) with 1.5 equiv. of
Scheme 1. Synthesis of 2-acetyl-3-hydroxybenzo(b)thiophene (4).

2-ACETYLBENZO(b)THIOPHENE AND ITS DERIVATIVES
1889
tert-butylmercaptan (6) and 1.1 equiv of potassium hydroxide in dimethylsulfoxide
(DMSO) at 110 ꢁC for 1 h gave 2-(tert-butylthio)benzaldehyde (7a) in almost quantitat-
ive yield. The next step in the synthesis was to convert 2-(tert-butylthio)benzaldehyde
(7a) into the desired disulfide intermediate, 2,20-disulfanediyldibenzaldehyde (8a), which
was achieved in 97% yield by treatment of (7) with 3.0 equiv of 48% HBr in acetic acid[13]
and DMSO. Our attempts to carry out this transformation of 7a to 8a using sulfuric
acid[10a] produced the desired 2-acetylbenzo(b)thiophene (2a), but significant decompo-
sition was also observed. In addition, the 2a produced by using sulfuric acid[10a] required
additional purification, including carbon treatment to remove unidentified colored
impurities. Finally, we found that the reaction of disulfide derivative (8a) with acetyl-
acetone (9) in the presence of anhydrous potassium carbonate in DMSO gave the
desired key synthon, 2-acetylbenzo(b)thiophene (2a), in about 45% yield along with
the by-product, sodium salt of mercaptobenzaldehyde (12a). Further, the by-product,
mercaptobenzaldehyde (12a), was also productively converted to the desired 2-acetyl-
benzo(b)thiophene (2a), as described in the next section.
As expected, the reaction of bisulfide (8a) with acetylacetone (9) produces both
1,10-(3-hydroxy-2,3-dihydrobenzo[b]thiophene-2,2-diyl)diethanone (11a) and the
sodium salt of mercaptobenzaldehyde (12a), as shown in Scheme 3. However, only
the intermediate 11a yields 2-acetylbenzo(b)thiophene (2a) with the loss of acetic
acid under reaction conditions, thus leaving theoretically 50% of mercaptobenzalde-
hyde (12a) as its sodium salt. We found that the addition of 1.1 equiv. of 1-chloroa-
cetone (10) to the reaction mixture to convert 12a to the desired 2a effectively
improved the yield of 2-acetylbenzo(b)thiophene (2a) to 94%. Thus, the overall yield
of 2-acetylbenzo(b)thiophene (2a), in a three-step sequence starting from 2-chloro-
benzaldehyde (5a), is 93%. The method is general and quite useful for the
preparation of aryl substituted 2-acetylbenzo(b)thiophene derivatives (Schemes 2
Scheme 2. Synthesis of 2-acetylbenzo(b)thiophene (2a–d).

1890
S. R. CHEMBURKAR, D. G. ANDERSON, AND R. E. REDDY
Scheme 3. Efficient conversion of 2,20-disulfanediyldibenzaldehyde (8a) to 2-acetylbenzo(b)thiophene (2a).
and 3), such as 2-acetyl-4-methylbenzo(b)thiophene (2b), 2-acetyl-4-chloroben-
zo(b)thiophene (2c), and 2-acetyl-5-(trifluoromethyl) benzo(b)thiophene (2d) in three
steps starting from the corresponding aryl aldehydes (5b–c), respectively.
In summary, a novel and highly efficient method was developed for the syn-
thesis of 2-acetylbenzo(b)thiophene (2a), the key intermediate for preparation of
zileuton (1). The three-step sequence produces 2-acetylbenzo(b)thiophene (2a) in
more than 93% overall yield. The methodology is suitable for preparation of
substituted 2-acetylbenzo(b)thiophene derivatives (2b–c), which may be useful in
the synthesis of improved 5-lipoxigenase inhibitors.
EXPERIMENTAL
General Methods and Materials
1H and 13C NMR spectra were recorded on a Varian Gemini spectrometer
(400 MHz), and the chemical shifts (d) were reported. Mass spectrometry was
performed on a ThermoFinnigan LCQ DECA XP quadrupole ion trap mass spec-
trometer utilizing positive-ion atmospheric pressure chemical ionization [APCI(þ)].
Sample introduction was accomplished by flow injection with a flow solvent con-
sisting of 1:1 acetonitrile=0.1M NH4OH at a flow rate of 0.3 mL=min. High-
resolution mass determinations were carried out on an Agilent LC=MSDTOF
instrument using negative-ion electrospray [ESI(–)] using internal mass references.
Helium is used as the collision gas for acquisition of data on LCQ DECA mass
spectrometer. Sample introduction was accomplished by flow injection with a flow
solvent consisting of 1:1 acetonitrile=0.1% HCOOH at a flow rate of 0.3 mL=min.
Thin-layer chromatography (TLC) was performed on precoated TLC silica-gel
60 F254 5- ꢂ 10-cm plates and visualized with shortwave ultraviolet (UV) light
(254 nm); solvent ratios are reported. Column chromatography was performed on
silica gel, Merck grade 60 (70–230 mesh). All solvents were HPLC grade, and the
reagents were purchased from Sigma-Aldrich (St. Louis, Missouri) and used without
purification. Analytical reversed phase (RP) HPLC was performed using Agilent
1200 series HPLC instrument equipped with an Agilent Eclipse XD8-C18 column
(4.6 ꢂ 150 mm, 5 mm).

2-ACETYLBENZO(b)THIOPHENE AND ITS DERIVATIVES
1891
Preparation of 2-Acetylbenzo(b)thiophene and Its Derivatives (2a–d)
Using Example of 2-Acetylbenzo(b)thiophene (2a)
In a 250-mL round-bottom flask equipped with a stir bar, DMSO (20.0 mL,
0.28 mol, 4 equiv.) and powdered postassium hydroxide (KOH; 4.7 g, 0.084 mol,
1.1 equiv.) were mixed under nitrogen stirred at room temperature. After 5 min,
2-methyl-2-propanethiol (6, 12.0 mL, 0.106 mol, 1.5 eq) was added, and the mixture
was stirred for 20 min. 2-Chlorobenzaldehyde (5a, 8.1 mL, 0.072 mol, 1.0 equiv.) was
added, and the reaction was heated to 110 ꢁC for 90 min. Reaction was monitored by
TLC, and after completion of the reaction, it was diluted with water (200 mL) and
extracted with ethyl acetate (2 ꢂ 200 mL). The combined organic layers were washed
with water (100 mL) and 3.5M aqueous NaCl solution (100 mL), dried (anhydrous
Na2SO4), and concentrated on a rotary evaporator to afford 2-(tert-butylthio)ben-
zaldehyde (7a), which was used in the next step with our purification. TLC: Rf
0.79 (20% ethyl acetate in hexanes; Rf 0.21 (20% dichloromethane in hexanes); ana-
lytical HPLC [gradient solvent, organic blend (19:1 acetonitrile=methanol): 20 mM;
pH 4.01; KH2PO4 buffer 55:45 for 25 min to 80:20 in 5 min and hold for 5 min;
0.8 mL=min at 265 nm]; and Rt: 15.31 min. Yield 83.4%.
In a 250-mL round-bottomed flask, the crude 2-(tert-butylthio)benzaldehyde (7a,
13.6g, 0.070 mol) was placed in an ice bath. Acetic acid (24.0 mL, 0.419 mol, 6.0 equiv.),
48% aqueous HBr (24.0 mL, 0.211 mol, 3.0 equiv.), and DMSO (5.0mL, 0.070 mol,
1.0 equiv.) were added to the resulting cooled mixture. The reaction was then allowed
to warm to room temperature and was stirred overnight. The reaction mixture, contain-
ing a solid precipitate, was diluted with cold water (50 mL), filtered, rinsed with hexanes,
and dried to afford 2,20-disulfanediyldibenzaldehyde (8a), which was used in the next
step without further purification. TLC (Rf): 0.23 in 20% ethyl acetate in hexanes.
DMSO (36.0 mL, 0.507 mol, 28 eqiv.), acetylacetone (9, 1.9 mL, 0.018 mol,
1.1 equiv.), and anhydrous K2CO3 (3.77 g, 0.027 mol, 1.5 equiv.) were added sequen-
tially under nitrogen to a single-necked, 250-mL, round-bottomed flask equipped with
a stir bar. The resulting slurry was stirred at room temperature for 20 min, and then
the crude 2,20-disulfanediyldibenzaldehyde (8a, 5.25 g, 0.019 mol, 1.0 equiv.) was
added. The reaction continued to be stirred for an additional 90 min at room tempera-
ture. Chloroacetone (1.65 mL, 0.021, 1.1 equiv.) was then added, and the mixture was
heated to 50 ꢁC for 90 min. Progress of the reaction was monitored by TLC. Upon
completion of reaction, the mixture was cooled to room temperature, poured into
ice, and filtered to afford 2-acetylbenzo(b)thiophene (2a) 6.62 g in 94% yield. TLC
(Rf): 0.31 in 3:1 hexanes=diethylether; analytical RP HPLC: gradient solvent, organic
blend (19:1 acetonitrile=methanol): 20 mM; pH 4.01; KH2PO4 buffer 55:45 for 25 min
to 80:20 in 5 min and hold for 5 min; 0.8 mL=min at 265 nm]; and Rt: 5.97 min. Yield
98.5%. 1H NMR (DMSO-d6): d 8.32 (s, 1H), 8.00 (m, 2H), 7.48 (m, 2H), 2.64 ( s, 3H);
13C NMR (DMSO-d6): d, 191.9, 143.0, 141.1, 138.7, 130.9, 127.3, 125.9, 124.9, 122.8,
26.8; ESI-LCMS (m=z): 177.0 (M þ H)þ. HRMS: calcd. m=z for C10H8OS, 177.0369
(M þ H)þ; observed m=z, 177.0363.
2-Acetyl-4-methylbenzo(b)thiophene (2b)[14]
Compound 2b was prepared from 6-methyl-2-chlorobenzaldehyde (5b) in three
steps by following the general procedure described for 2a. The crude compound was

1892
S. R. CHEMBURKAR, D. G. ANDERSON, AND R. E. REDDY
purified by silica-gel column chromatography (10–30% ethyl acetate in hexanes) to
afford 0.458 g in 39.1% yield. TLC (Rf): 0.44 in 20% ethyl acetate in hexanes; ana-
lytical RP HPLC: gradient solvent, organic blend (19:1 acetonitrile=methanol):
20 mM, pH 4.01, KH2PO4 buffer 55:45 for 25 min to 80:20 in 5 min and hold for
1
5 min; 0.8 mL=min at 265 nm, Rt: 8.42 min, 99.4%. H NMR (CDCl3): d, 8.00 (d,
1H, J ¼ 0.96 Hz), 7.69 (dd, 1H, J1 ¼ 8.16 Hz, J2 ¼ 0.62 Hz), 7.35 (m, 1H), 7.18 (dt,
1H, J1 ¼ 7.17 Hz, J2 ¼ 0.94 Hz), 2.68 (s, 3H), 2.65 (s, 3H); 13C NMR (CDCl3):
d 191.6, 142.8, 142.4, 138.5, 135.1, 127.5, 127.3, 125.1,120.3, 27.1, 19.8; ESI-LCMS
(m=z): 191.1 (M þ H)þ. HRMS: calcd. m=z for C11H10OS, 191.0525 (M þ H)þ;
observed m=z, 191.0531.
2-Acetyl-4-chlorobenzo(b)thiophene (2c)[15]
Compound 2c was prepared from 6-chloro-2-fluorobenzaldehyde (5c) in three
steps by following the general procedure described for 2a. The crude compound was
purified by column chromatography (10–20% tetrahydrofuran in hexanes) to afford
3.01 g in 43.4% yield. TLC (Rf): 0.62 in 20% tetrahydrofuran in hexanes; analytical
RP HPLC: gradient solvent, organic blend (19:1 acetonitrile=methanol): 20 mM,
pH 4.01, KH2PO4 buffer 55:45 for 25 min to 80:20 in 5 min and hold for 5 min;
1
0.8 mL=min at 265 nm; Rt: 10.24 min. Yield 86.5%. H NMR (CDCl3): d 8.06 (d,
1H, J ¼ 0.82 Hz), 7.75 (ddd, 1H, J1 ¼ 7.00 Hz, J2 ¼ 2.06 Hz, J3 ¼ 0.82 Hz), 7.39 (d,
1H, J ¼ 0.96 Hz), 7.38 (d, 1H, J ¼ 6.04 Hz), 2.70 (s, 3H); 13C NMR (CDCl3): d
191.4, 143.2, 137.5, 137.3, 130.4,127.7, 127.2, 124.6, 121.3, 27.0; ESI-LCMS (m=z):
211.1 (M þ H)þ. HRMS: calcd. m=z for C10H7ClOS, 210.9979 (M þ H)þ; observed
m=z, 210.9981.
2-Acetyl-5-(trifluoromethyl)benzo(b)thiophene (2d)
Compound 2d was prepared from 5-trifluoro-2-chlorobenzaldehyde (5d) in
three steps by following the general procedure described for 2a. The crude com-
pound was purified by column chromatography (5–20% ethyl acetate in hexanes)
to afford 0.550 g in 10.7% yield. TLC (Rf): 0.43 in 20% ethyl acetate in hexanes; ana-
lytical RP HPLC: gradient solvent, organic blend (19:1 acetonitrile=methanol):
20 mM; pH 4.01; KH2PO4 buffer 55:45 for 25 min to 80:20 in 5 min and hold for
5 min; 0.8 mL=min at 265 nm; Rt: 11.10 min. Yield 95.1%. 1H NMR (CDCl3):
d 8.16 (d, 1H, J ¼ 0.96 Hz), 7.99 (s, 1H), 7.98 (dd, 1H, J ¼ 0.69 Hz), 7.67 (dd, 1H,
J1 ¼ 8.58 Hz, J2 ¼ 1.3 Hz), 2.69 (s, 3H); 13C NMR (CDCl3): d 191.2, 145.7, 138.3,
128.9, 123.5, 123.21, 123.17, 122.79, 122.75, 122.70, 27.1. ESI-LCMS (m=z): 245.2
(M þ H)þ. HRMS: calcd. m=z for C11H7F3OS, 245.0243 (M þ H)þ; observed m=z,
245.0243.
ACKNOWLEDGMENTS
We thank Dr. Martin Babcock, director of API products, Abbott, for support
and Dr. Hua-Hai Gong, Abbott, for HRMS assistance.

2-ACETYLBENZO(b)THIOPHENE AND ITS DERIVATIVES
1893
REFERENCES
1. (a) Burney, P. G. J.; Chinn, S.; Rona, R. J. Has the prevalence of asthma increased in
children? Evidence from the national study of health and growth 1973–1986. BMJ
1990, 300, 1306–1310; (b) Jackson, R. J.; Sears, M. R.; Beaglehole, R.; Rey, H. H.
International trends in asthma mortality: 1970 to 1985. Chest 1988, 94, 914–918; (c) Weiss,
K. B.; Gergen, P. J.; Hodgson, T. A. Economic evaluation of asthma in the United States.
N. Engl. J. Med. 1992, 326, 1391–1396.
2. Barnes, P. J.; Chung, K. F.; Page, C. P. Inflammatory mediators and asthma. Pharmacol.
Rev. 1988, 40, 49–84; (b) Piacentini, G. L.; Kaliner, M. A. The potential roles of leuko-
trienes in bronchial asthma. Am. Rev. Respir. Dis. 1982, 126, 449–451.
3. (a) Samuelson, B. Leukotrienes: Mediators of immediate hypersensitivity reactions and
inflammation. Science 1983, 220, 568–575; (b) Henderson, W. R. The role of leukotrienes
in inflammation. Ann. Intern. Med. 1994, 121, 684–697.
4. (a) Werz, O.; Steinhilber, D. Therapeutic options for 5-lipoxygenase inhibitors. Pharma-
col. Ther. 2006, 112, 701–718; (b) Romano, M.; Claria, J. Cyclooxygenase-2 and 5-lipox-
ygenase converging functions on cell proliferation and tumor angiogenesis: Implications
for cancer therapy. FASEB J. 2003, 17, 1986–1995; (c) Spanbroek, R.; Habenicht, A. J.
The potential role of antileukotriene drugs in atherosclerosis. Drug News Perspect.
2003, 16, 485–489; (d) Werz, O.; Steinhilber, D. Development of 5-lipoxygenase inhibitors:
Lessons from cellular enzyme regulation. Biochem. Pharmacol. 2005, 70, 327–333; (e)
Awni, W. M.; Granneman, G. R.; Locke, C. S.; Brandwein, S. R.; Dube, L. M.
Population pharmacokinetics of zileution, a selective 5-lipoxygenase inhibitor, in patients
with rheumatoid arthritis. Eur. J. Clin. Pharmacol. 1995, 48, 155–160.
5. (a) Werz, O.; Steinhilber, D. Pharmacological intervention with 5-lipoxygenase: New
insights and novel compounds. Expert Opin. Ther. Patients 2005, 15, 505–519; (b) Funk,
C. D. Leukotriene modifiers as potential therapeutics for cardiovascular disease. Nat. Rev.
Drug Discovery 2005, 4, 664–672; (c) Yoshimura, R.; Matsuyama, M.; Kuratsukuri, K.;
Tsuchida, K.; Takemoto, Y.; Nakatani, T. Novel approach to anticancer therapies for
prostate cancer: Lipoxygenese as new target in the treatment of prostate cancer. Drugs
Future 2005, 30, 351–357.
6. (a) Carter, G. W.; Young, P. R.; Albert, D. H.; Bouska, J.; Dyer, R.; Bell, R. L.;
Summers, J. B.; Brooks, D. W. 5-Lipoxygenase inhibitory activity of zileuton. J. Pharma-
col. Exper. Ther. 1991, 256, 929–937; (b) Belle, R. L.; Young, P. R.; Albert, D.; Lanni, C.;
Summers, J. B.; Brooks, D. W.; Rubin, P.; Carter, G. W. The discovery and development
of zileuton: An orally active 5-lipoxygenase inhibitor. Int. J. Immunopharmac. 1992, 14,
505–510; (b) McGill, K. A.; Busse, W. W. Zileuton. Lancet 1996, 348, 519–524.
7. (a) Onuchina, O. A.; Zaitsev, S. A.; Levina, V. I.; Grigor’ev, N. B.; Chernyshev, V. V.;
Granik, V. G. Acyl migration during alkylation of acetoxyurea derivatives. Pharm. Chem.
J. 2007, 41, 160–165; (b) Stewart, A. O.; Bhatia, P. A.; Martin, J. G.; Summers, J. B.;
Rodriques, K. E.; Martin, M. B.; Holms, J. H.; Moore, J. L.; Craig, R. A.; Kolosa, T.;
Ratajczyk, J. D.; Mazdiyasni, H.; Kerdesky, F. A. J.; DeNinno, S. L.; Maki, R. G.;
Bouska, J. B.; Young, P. R.; Lanni, C.; Bell, R. L.; Carter, G. W.; Brooks, C. D. W.
Structure–activity relationship of N-hydroxyurea 5-lipoxygenase inhibitors. J. Med.
Chem. 1997, 40, 1955–1968.
8. For synthesis of zileuton (1), see (a) Guinchard, X.; Dennis, J.-N. Reactions of in situ gen-
erated N-Boc nitrones with aromatic and heteroaromatic Grignard reagents: Application
to the synthesis of zileuton. J. Org. Chem. 2008, 73, 2028–2031; (b) Ren-yun, W.; Zhen,
C.; Yu-ling, L. Synthesis of zileuton, an anti-asthmatic drug. Zhongguo Xinyao Zazhi
2004, 13, 1133–1134; (c) Copp, R. R.; Fohey, B. T.; Lannoye, G. Acid-catalyzed addition
of N-hydroxyurea to 1-aryl alcohol derivatives: A new synthesis of zileuton. Synth.

1894
S. R. CHEMBURKAR, D. G. ANDERSON, AND R. E. REDDY
Commun. 2001, 31, 3081–3086; (d) Ku, Y.-Y.; Patel, R.; Roden, B. A.; Sawick, D. P.
Synthesis of substituted heterocycles: Simple method for the introduction of the N-hydro-
xyurea functionality. Tetrahedron Lett. 1994, 35, 6017–6020; (e) Rohloff, J. C.; Alfredson,
T. V.; Schwartz, M. A. Enantioselective synthesis of 5-LO inhibitors using a gulofuranose
auxiliary. Tetrahedron Lett. 1994, 35, 1011–1014; (f) Basha, A.; Henry, R.; McLaughlin,
M. A.; Ratajczyk, J. D.; Wittenberger, S. J. Addition of organometallic reagents to
N-glycosyl nitrones. Enantioselective synthesis of (þ)-(R)- and (–)-(S)-Zileuton. J. Org.
Chem. 1994, 59, 6103–6106; (g) Basha, A.; Brooks, D. W. Synthesis of 5-lipoxygenase
inhibitor zileuton from thiophenol. J. Org. Chem. 1993, 58, 1293–1294; (h) Kolosa, T.;
Brooks, D. W. Practical synthesis of 2-acetylbenzo(b)thiophene. Synth. Commun. 1993,
23, 743–748; (i) Garigipati, R.; Sorenson, M.; Erhard, K.; Adams, J. Resolution of hydro-
xyureas. Tetrahedron Lett. 1993, 34, 5537–5540; (j) Hsiao, C.-N.; Kolasa, T. Synthesis of
chiral zileuton, a potent and selective inhibitor of 5-lipoxygenase. Tetrahedron Lett. 1992,
33, 2629–2632.
9. (a) Brooks, D. W.; Summers, J. B.; Rodriques, K. E.; Maki, R. G.; Dellaria, F.; Holms, J.
H.; Moore, J. L. Preparation of N-(benzo[b]thienylalkyl)-N-hydroxy amides and ureas
with polar substituents as 5-lipoxygenase inhibitors. U.S. Patent 4,873,259, 1991; (b)
Hengeveld, J.; Leese, E. H.; Moon, B. S.; Abad, D. M.; Allen, K. A.; Bauer, P. E.;
Murphey, D. B.; Fohey, B. T.; Copp Jr., R. R.; Lannoye, G. S.; Mittag, R. M. Synthesis
and isolation of N-(aryl or heteroaryl)-alkyl-N-hydroxyurea. U.S. Patent 6,080,874, 2000.
10. From 2-thiobenzoic acid, see (a) Smiles, S.; McClelland, E. W. Derivatives of
3-oxo(1)thionaphthalene. J. Chem. Soc. (London) 1921, 119, 1810–1816; (b) Hsiao, C.
N.; Bhagavatula, L.; Pariza, R. L. A practical synthesis of 2-carbonylbenzo(b)thiophenes.
Synth. Commun. 1990, 20, 1687–1695; (c) Learolini, R.; Pedulli, G. F.; Tundo, A.;
Zanardi, G. Reaction pathways for the cyclization of ortho-thioalkyl and ortho-thioaryl
substituted phenyl radicles with alkenes: Reaction of o-methylthioarenediazonium
tetrafluroborates with alkynes to give 2-substituted benzo(b)thiophenes. J. Chem. Soc.,
Chem. Commun. 1985, 1390–1391.
11. From 2-thiobenzaldehyde, see (a) Rahman, L. K. A.; Scrowston, R. M. 7-Substituted
benzo(bothiophenes and 1,2-benzisothiazoles, part 1: Hydroxy- or methoxy- derivatives. J.
Chem. Soc., Perkin Trans. 1 1983, 2973–2977; (b) Kasmai, H. S.; Machke, S. G. An
efficient and convenient synthesis of 2-mercaptobenzaldehyde. Synthesis 1989, 763–765.
12. Dickman, D. A.; Horrom, B. W.; Roden, B. A.; Chemburkar, S. R. Process for the
production of 2-acetylbenzo(b)thiophenes. U.S. Patent 5,169,961, 1992.
13. Dickman, D. A.; Chemburkar, S. R.; Konocapaki, D. B.; Elisseou, E. M. Oxidative cleav-
age of aryl or alkyl tert-butyl sulfides with dimethyl sulfoxide=hydrobromic acid to form
symmetrical aryl or alkyl disulfides. Synthesis 1993, 573–574.
14. Li, Z.; Yuequin, Z.; Liu, Z.; Si, S.; Yang, Z.; Shao, H.; Yang, J. Preparation of thiophene,
furan, and indole derivatives as regulators of bone morphogenetic protein for treatment of
osteoporosis. Faming Zhuanli Shenqing Gongkai Shuomingshu Chin. Patent 1,807,411,
2006.
15. Clark, P. D.; Clarke, K.; Scrowston, R. M.; Sutton, T. Substitution reactions of
benzo(b)thiophen derivatives, part VIII: Reactions of some substituted compounds and
of 4-chlorobenzo(b)thiophen and its 3-methyl derivatives. J. Chem. Res., Synop. 1978, 10.