Facile synthesis of trisubstituted thioindoles via a novel tricyclic thiolactone intermediate

Article abstract of DOI:10.1080/00397910802514993

Methodology to conveniently and systematically prepare biologically active indole 9 is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802514993

Synthetic Communications1, 39: 1175–1185, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802514993
Facile Synthesis of Trisubstituted Thioindoles via
a Novel Tricyclic Thiolactone Intermediate
Cangming Yang, Ronald M. Kim, Emma R. Parmee, and Qiang Tan
Department of Basic Chemistry, Merck Research Laboratories, Rahway,
New Jersey, USA
Abstract: Methodology to conveniently and systematically prepare biologically
active indole 9 is described.
Keywords: Alkylation, demethylation, substituted indole, thiolactone
INTRODUCTION
Substituted indoles exhibit wide-ranging biological activity and as a result
have been the focus of tremendous interest by the pharmaceutical indus-
try.[1] In particular, 3-thioindole analogs have been investigated for the
potential treatment of asthma,[2a] inflammation,[2b] obesity,[2c] cancer,[2d]
and heart disease.[2e] We have discovered that analogs of modified thio-
pyranoindole 1[3] and 3-t-butylthio-indole 2[4] showed interesting biological
activity in an ongoing drug discovery program. This prompted us to find a
Received September 15, 2008.
Address correspondence to Cangming Yang, Department of Basic Chemistry,
Merk Research Laboratories, P. O. Box 2000, Rahway, NJ 07065, USA. E-mail:
cangming_yang@merck.com
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C. Yang et al.
convenient method for the preparation of 6-alkoxy compounds 9. We
report here a facile synthesis of 9 via a novel thiolactone intermediate 7,
which allows for sequential modification of the thiol and phenol moieties.
Analogs of 3-thioindole compounds are generally prepared by Fisher
indole synthesis,[5] Gassman indole synthesis,[6a,6b] and various electro-
philic aromatic sulfenylations of indoles.[7a–h] To efficiently explore
structure–activity relationships (SAR) around structure 9, we envisioned
preparation of compound 5, alkylation of the indole nitrogen to afford 6,
then selective deprotection and modification of the orthogonally pro-
tected thiol and phenol moieties to allow for sequential modification of
these groups in either order.
RESULTS AND DISCUSSION
As depicted in Scheme 1, 3-t-butyl thiol indole 5 was prepared via Fischer
indole condensation of 3-methoxy phenyl hydrazine 3 and a tert-butyl
thioketone 4. Methylation of the indole nitrogen under conditions ii
(listed in Scheme 1) afforded 6.[8] Subsequent deprotection of the methyl
ether with 5 equivalents of BBr3 unexpectedly occurred with concomitant
formation of the thiolactone to form 7 in high yield, the structure of
which was confirmed by x-ray analysis (Fig. 1). Less BBr3 resulted in a
low-yielding reaction with a number of side products. One of the side
products was 7-methoxy-3,3,5-trimethyl-4,5-dihydrothiopyrano[3,2-
b]indol-2(3H)-one. Close examination of the reaction progress indicated
that thiolactone formation occurred prior to demethylation. We hypothe-
size that the thiolactone formed as shown at the bottom of Scheme 1,
involving nucleophilic addition of the sulfur atom in 6 to the BBr3
coordinated carbonyl group[9] and the resulting thiolactone sulfonium
intermediate eliminating isobutylene to give the thiolactone. Such isobu-
tylene elimination of t-butyl sulfonium cations to afford sulfides have
been reported previously.[10] Alternatively, conversion of 6 to 7 may pro-
ceed through BBr3 deprotection of the t-butyl thioether followed by ring
closure to the thiolactone.[11] We expected that alkylation of the thiolac-
tone 7 would occur on the phenol. To our surprise, however, alkylation
with a slight excess of alkylating reagent R2X with NaH under anhydrous
conditions, followed by base hydrolysis, proceeded preferentially on the
thiol to provide 8. No desired peak was observed based on LC-MS
analysis of the most of NaH-induced (anhydrous condition) alkylation
reactions. The obtained chromatograph shows a dimer and a number
of later-eluting peaks. Hydrolysis gives the product, indicating that ester
linkages could exist in the initial alkylation product. The same product
was obtained when aqueous NaOH was used instead of NaH in the first

Novel Tricyclic Thiolactone Intermediate
1177
Scheme 1. (i) t-Butanol, 95 ꢀC; (ii) CH3I, NaH, DMF, ꢁ10 ꢀC; to rt; (iii) BBr3,
DCM, ꢁ78 ꢀC to rt; (iv) R2X, NaH, DMF, rt or 70 ꢀC; 3 N NaOH, dioxane=
MeOH, 50 ꢀC; (v) R3X, NaH, DMF, rt or 70 ꢀC; 3 N NaOH, dioxane=MeOH,
50 ꢀC.
alkylation. It appears that NaOH hydrolyzes thiolactone, followed by
alkylation of thiolate, however, phenolate displacement cannot be ruled out.
Prior to saponification, liquid chromatographic–mass spectrographic
(LC-MS) analysis of the NaH alkylation reaction revealed ester dimer 10
(Fig. 2) and what appeared to be higher order structures, implicating phe-
nolate displacement of thiolactone, followed by alkylation of the resul-
tant thiolate, as the basis for the observed selectivity. The reaction
scope and mechanism is still not clear and is a subject of future investiga-
tion. Subsequent alkylation of 8 with excess alkylating reagent R3X and
base, followed by hydrolysis of the resultant ester, afforded 9 as the final
product.
The described alkylation sequence is illustrated by the synthesis of 9a
and 9b shown in Scheme 2. Reaction of 7 with 4-(chloromethyl)-1,
2-diphenylethane in NaH=dimethylformanide (DMF) followed by

1178
C. Yang et al.
Figure 1. X-ray structure of the tricyclic thiolactone 7.
reaction with MeI provided 9a. Reversal of the alkylation sequence
afforded 9b. The structural assignments of 9a and 9b were confirmed by
nuclear Overhauser effect (NOE).
In the case of first alkylation, where 4-(chloromethyl)-1,2-diphenyl-
ethane was used as alkylating reagent, the irradiation of the proton on
carbon next to the sulfur atom in 9a resulted in the enhancement of
the protons on the ortho-carbons of the phenyl group and methylene
and gem dimethyl groups in the carboxylic acid side chain. For the
second alkylation, where CH3I was employed as alkylating reagent, irra-
diation of the protons on the methoxy group resulted in enhancements of
protons on carbons adjacent to the methoxy group. Reversal of the alky-
lation sequence afforded compound 9b, in which irradiation of the pro-
tons on the thiol methyl group resulted in enhancement of the protons
on methylene and gem dimethyl groups in the carboxylic acid side chain.
Irradiation of the proton on the methylene next to the oxygen atom
resulted in enhancements of protons on the ortho-carbons of the phenyl
group and the indole.
Figure 2. Structure of dimer 10.

Novel Tricyclic Thiolactone Intermediate
1179
Scheme 2. (i) NaH=DMF, 70 ꢀC, 1 h; 3 N NaOH, dioxane=MeOH, 50 ꢀC, 1 h,
55%; (ii) NaH=DMF, rt, 1 h; 3 N NaOH, dioxane=MeOH, 50 ꢀC, 1 h, 57%.
In conclusion, we have described an efficient and practical route for
the direct synthesis of biologically active compounds 9 via a key thio-
lactone intermediate 7, which allows for sequential modification of –N,
–S, and –O groups.
EXPERIMENTAL
1H NMR spectra were recorded on
a 500-MHz or 600-MHz
spectrometer. LC-MS data were recorded by the RP-LC=MS system
[0.05% trifluoroacetic acid (TFA) or formic acid, acetonitrile=water,
10–100% gradient]. Flash chromatography was performed using Si 40
S=M cartridges.
Ethyl 5-(tert-Butylthio)-2,2-dimethyl-4-oxopentnaoate (4)
N,N-Diisopropylethylamine (DIEA) (0.96 mL, 5.5 mmol) was added
slowly to a solution of ethyl 5-bromo-2,2-dimethyl-4-oxopentanoate
(1.10 g, 4.4 mmol) and tert-butyl thiol (0.52 mL, 4.6 mmol) in dry

1180
C. Yang et al.
CH3CN (4 mL) at 0 ꢀC. The mixture was stirred at room temperature
for 3.5 h, quenched with H2O, and extracted with EtOAc=hexanes
(2=1). The organic layer was washed with 1 N HCl, H2O (2ꢂ), and
brine and dried with Na2SO4. Removal of the solvent in vacuo
afforded 1.13 g of crude product 4 as a colorless oil, which was used
without further purification in the next step.
Ethyl 3-[3-(tert-Butylthio)-6-methoxy-1H-indol-2-yl]-2,2-
dimethylpropanoate (5)
A mixture of 3 (1.34 g, 7.6 mmol), the crude ketone 4 (1.54 g, 5.9 mmol),
and tert-butanol (24 mL) in a sealed reaction vessel was stirred at 90 ꢀC
overnight. The solution was cooled, poured into saturated NaHCO3,
and extracted with DCM (2ꢂ). The combined organic layers were con-
centrated in vacuo. The crude residue was purified by silica-gel chroma-
tography, eluting with a gradient of 28% to 38% EtOAc=hexanes to
provide the compound 5 as yellow oil (1.42 g, 66%). LC-MS (ESI):
1
m=z ¼ 364.2 [M þ H]þ. H NMR (500 MHz, CD2Cl2): d 9.06 (s, 1H),
7.54 (d, J ¼ 9.0 Hz, 1H), 6.85 (d, J ¼ 2.0 Hz, 1H), 6.77 (dd, J ¼ 9.0 Hz,
2.0 Hz, 1H), 4.21 (quartet, J ¼ 7.5 Hz, 2H), 3.66 (s, 3H), 3.21 (s, 2H),
1.28 (t, J ¼ 7.5 Hz, 3H), 1.26 (s, 9 H), 1.21 (s, 6H).
Ethyl 3-[3-(tert-Butylthio)-6-methoxy-1-methyl-1H-indol-2-yl]-2,2-
dimethylpropanoate (6)
A solution of 5 (1.12 g, 3.08 mmol) in dry DMF (12 mL) was added
slowly at ꢁ10 ꢀC to a suspension of 95% NaH (84 mg, 3.38 mmol) in
dry DMF (4 mL) under N2 protection. After 20 min of stirring at room
temperature, a solution of CH3I (0.252 mL, 4.00 mmol) in dry DMF
(14 mL) was added. The mixture was stirred at ꢁ10 ꢀC for 1 h, and then
at room temperature overnight. The reaction was quenched with sat.
NH4Cl and extracted with EtOAc. The organic layer was washed with
water and brine and dried with Na2SO4. The solvent was evaporated.
The residue was purified by silica-gel chromatography, eluting with a
gradient of 20% to 35% EtOAc=hexanes to provide the compound 6
as yellow oil (1.1 g, 94%). LCMS (ESI): m=z ¼ 378.2 [M þ H]þ. 1H
NMR (500 MHz, CD2Cl2): d 7.59 (d, J ¼ 8.0 Hz, 1H), 6.81 (d,
J ¼ 8.0 Hz, 1H), 6.80 (s, 1H), 4.15 (quartet, J ¼ 7.0 Hz, 2H), 3.89 (s,
3H), 3.66 (s, 3H), 3.32 (s, 2H), 1.27 (t, J ¼ 7.0 Hz, 3H), 1.24 (s, 9H),
1.19 (s, 6H).

Novel Tricyclic Thiolactone Intermediate
1181
7-Hydroxy-3,3,5-trimethyl-4,5-dihydrothiopyrano[3,2-b]indol-
2(3H)-one (7)
Compound 6 (1.1 g, 2.91 mmol) was dissolved in dry DCM (15 mL). The
solution was cooled at ꢁ78 ꢀC under N2. BBr3 (14.5 mL) was added
slowly via a syringe. The reaction mixture was stirred at ꢁ78 ꢀC for
20 min and at room temperature for 45 min, quenched with saturated
NaHCO3, and extracted with EtOAc (3ꢂ). The combined organic layers
were washed with water and brine and dried with Na2SO4. The solvent
was evaporated. The crude solid was recrystallized from EtOAc=CH2Cl2
to provide the compound 7 as a solid (0.70 g, 92%). LC-MS (ESI):
1
m=z ¼ 262.15 [M þ H]þ. H NMR (500 MHz, CD2Cl2): d 7.23 (d, J ¼
8.5 Hz, 1H), 6.81 (d, J ¼ 2.0 Hz, 1H), 6.70 (dd, J ¼ 8.5 Hz, 2.0 Hz, 1H),
3.65 (s, 3H), 3.00 (s, 2H), 1.26 (s, 6H).
3-(6-Hydroxy-1-methyl-3-{[4-(2-phenylethyl)benzyl]thio}-
1H-indol-2-yl)-2,2-dimethylpropanoic Acid (8a)
To a stirred solution of 7 (26 mg, 0.1 mmol) in DMF (1 mL), 95% NaH
(3.8 mg, 0.15 mmol) and 4-(chloromethyl)-1,2-diphenylethane (25 mg,
0.11 mmol) were added. The reaction mixture was stirred at 70 ꢀC for
1 h, quenched with 1N HCl, and extracted with EtOAc (3ꢂ). The solvent
was evaporated. The residue was dissolved in a mixture of dioxane
(0.5 mL) and MeOH (0.5 mL) followed by addition of 3 N NaOH
(0.5 mL, 1.5 mmol). The reaction mixture was stirred at 50 ꢀC for 1 h,
cooled to room temperature, acidified with 3 N HCl, and extracted with
EtOA (3ꢂ). The combined organic layers were washed with brine, dried
with Na2SO4, and the solvent was evaporated. The crude product 8a
(LC-MS (ESI): m=z ¼ 474.54 [M þ 1]þ) was used in the next step without
further purification.
3-(6-Methoxy-1-methyl-3-{[4-(2-phenylethyl)benzyl]thio}-
1H-indol-2-yl)-2,2-dimethylpropanoic Acid (9a)
To the crude product 8a dissolved in DMF (1 mL), 95% NaH (10 mg,
0.4 mml) was added. The resultant mixture was stirred at room tempera-
ture for 10 min. Iodomethane (14 ml, 0.22 mmol) was added. The reaction
mixture was stirred at room temperature for 1 h, quenched with 1 N HCl
aqueous solution, and extracted with EtOAc (3ꢂ). The solvent was
evaporated. The residue was dissolved in a mixture of dioxane (0.5 mL)
and MeOH (0.5 mL) followed by addition of 3 N NaOH (0.5 mL,

1182
C. Yang et al.
1.5 mmol). The reaction mixture was stirred at 50 ꢀC for 1 h, cooled to
room temperature, acidified with 3 N HCl aqueous solution, and
extracted with EtOA (3ꢂ). The combined organic layers were concen-
trated in vacuo. The residue was purified by reverse-phase chromatogra-
phy (10–90% MeCN=H2O, both containing 0.05% TFA) to afford 9a as a
solid (26.8 mg, 55% in four steps). LC-MS (ESI): m=z ¼ 488.4 [M þ 1]þ.
1H NMR (500 MHz, CD3OD): d 7.45 (d, J ¼ 8.5 Hz, 2H), 7.25 (overlap-
ping t, d, 2H), 7.16 (overlapping d, d, 2H), 6.93 (d, J ¼ 8.0 Hz, 2H), 6.88
(s, 1H), 6.77 (dd, J ¼ 8.7 Hz, 2.0 Hz, 1H), 6.73 (d, J ¼ 8.0 Hz, 2H), 3.86 (s,
3H), 3.66 (s, 2H), 3.56 (s, 3H), 2.88–2.82 (m, 4 H), 2.69 (s, 2H), 1.10
(s, 6H).
3-[6-Hydroxy-1-methyl-3-(methylthio)-1H-indol-2-yl)-2,2-
dimethylpropanoic Acid (8b)
To a solution of 7 (26 mg, 0.1 mmol) in DMF (1 mL) 95% NaH (3.8 mg,
0.15 mmol) and CH3I (6.9 ml, 0.11 mmol) were added. The reaction mix-
ture was stirred at room temperature for 1 h, quenched with 1N HCl,
and extracted with EtOAc (3ꢂ). The solvent was evaporated. The residue
was dissolved in a mixture of dioxane (0.5 mL), and MeOH (0.5 mL),
followed by addition of 3 N NaOH (0.5 mL, 1.5 mmol). The reaction mix-
ture was stirred at 50 ꢀC for 1 h, cooled to room temperature, acidified
with 3N HCl, and extracted with EtOA (3ꢂ). The combined organic layers
were washed with brine and dried with Na2SO4, and the solvent was eva-
porated. The crude product 8b (LC-MS (ESI): m=z ¼ 294.21 [M þ 1]þ)
was used in the next step without further purification.
2,2-Dimethyl-3-(1-methyl-3-(methylthio)-6-{[4-(2-phenylethyl)-
benzyl]oxy}-1H-indol-2-yl) Propanoic Acid (9b)
The crude product 8b was dissolved in DMF (1 mL), followed by
addition of 95% NaH (10 mg, 0.4 mml), and stirred at room temperature
for 10 min. 4-(Chloromethyl)-1,2-diphenylethane (51 mg, 0.22 mmol) was
added. The reaction mixture was stirred at 70 ꢀC for 1 h, cooled to room
temperature, quenched with 1 N HCl, and extracted with EtOAc (3ꢂ).
The solvent was evaporated. The residue was dissolved in a mixture of
dioxane (0.5 mL) and MeOH (0.5 mL) followed by the addition of 3 N
NaOH (0.5 mL, 1.5 mmol). The reaction mixture was stirred at 50 ꢀC
for 1 h, cooled to room temperature, acidified with 3 N HCl, and
extracted with EtOAc (3ꢂ). The solvent was evaporated. The residue
was purified by reverse-phase chromatography (10–90% MeCN=H2O,

Novel Tricyclic Thiolactone Intermediate
1183
both containing 0.05% TFA) to afford the compound 9b as a solid
1
(28 mg, 57% in four steps). LC-MS (ESI): m=z ¼ 488.55 [M þ 1]þ. H
NMR (500 MHz, CD3OD): d 7.50 (d, J ¼ 6.75 Hz, 1H), 7.36 (d, J ¼
8.0 Hz, 2H), 7.23–7.12 (m, 7H), 6.96 (d, J ¼ 2 Hz, 1H), 6.86 (dd,
J ¼ 8.5 Hz, 2.5 Hz, 1H), 5.09 (s, 2H), 3.64 (s, 3H), 3.35 (s, 3H), 2.90 (s,
4H), 2.21 (s, 2H), 1.22 (s, 6H).
ACKNOWLEDGMENTS
C. Yang thanks Dr. Richard G. Ball and Nancy N. Tsou for x-ray
analysis, Dr. Hong Shen for editorial contributions, and Dr. Zhicai Wu
and Dr. Jason E. Imbriglio for helpful discussions during the preparation
of the manuscript.
REFERENCES
1. (a) Gribble, G. W. Recent developments in indole ring synthesis—Methodol-
ogy and applications. J. Chem. Soc., Perkin Trans. 1 2000, 1045; (b) Sund-
berg, R. J. Indoles; Academic Press: London, 1996; and references therein.
2. (a) Ko¨nig, W.; Scho¨nfeld, W.; Raulf, M.; Ko¨ller, M.; Knoller, J.; Scheffer, J.;
Brom, J. The neutrophil and leukotrienes—Role in health and disease.
Eicosanoids 1990, 3, 1–22; (b) Khandekar, S. S.; Gentry, D. R.; Van Aller,
G. S.; Doyle, M. L.; Chambers, P. A.; Konstantinidis, A. K.; Brandt, M.;
Daines, R. A.; Lonsdale, J. T. Identification, substrate specificity, and inhibi-
tion of the Streptococcus pneumoniae b-ketoacyl-acyl carrier protein synthase
III (FabH). J. Biol. Chem. 2001, 276, 30024; (c) Acton, J. L.; Meinke, P. T.;
Wood, H.; Black, R. M. Indoles having anti-diabetic activity. PCT Int. Appl.
WO 2004=019869 A2, 2004; (d) De Martino, G.; La Regina, G.; Coluccia, A.;
Edler, M. C.; Barbera, M. C.; Brancale, A.; Wilcox, E.; Hamel, E.; Artico, M.;
Silvestri, R. Arylthioindoles, potent inhibitors of tubulin polymerization. J.
Med. Chem. 2004, 47, 6120; (e) Funk, C. D. Leukotriene modifiers as potential
therapeutics for cardiovascular disease. Nat. Rev. Drug Discov. 2005, 4, 664.
3. Hutchinson, J. H.; Riendeau, D.; Brideau, C.; Chan, C.; Falgueyret, J.-P.;
´
Guay, J.; Jones, T. R; Lepine, C.; Macdonald, D.; McFarlane, C. S.;
Piechuta, H.; Scheigetz, J.; Tagari, P.; Therien, M.; Girard, Y.
´
Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: Synthesis, biological
profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyri-
din-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-
butanoic acid. J. Med. Chem. 1994, 37, 1153–1164.
´
´
4. Frenette, R.; Hutchinson, J. H.; Leger, S.; Therien, M.; Brideau, C.; Chan, C.
C.; Charleson, S.; Ethier, D.; Guay, J.; Jones, T. R.; McAuliffe, M. Substi-
tuted indoles as potent and orally active 5-lipoxygenase activating protein
(FLAP) inhibitors. J. Bioorg. Med. Chem. Lett. 1999, 9, 2391.

1184
C. Yang et al.
5. Hutchinson, J. H.; Riendeau, D.; Brideau, C.; Chan, C. C.; Delorme, D.;
Denis, D.; Falgueyret, J.-P.; Guay, J.; Hamel, P.; Jones, T. R.; Macdonald,
´
D.; McFarlane, C. S.; Piechuta, H.; Scheigetz, J.; Tagari, P.; Therien, M.;
Girard, Y. 3-Thioindole compounds were prepared by condensation of phe-
nyl hydrazines and alkyl (particularly t-butyl) thioketones. Substituted thio-
pyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of
5-lipoxygenase: Synthesis and biological evaluation of L-691,816. J. Med.
Chem. 1993, 36, 2771–2728.
6. One-pot reaction in which an aniline reacts sequentially with hypohalite, a b-
carbonyl sulfide derivative, and base to yield 3-thioindoles. (a) Gassman, P.
G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W. Jr. General method for
the synthesis of indoles. J. Am. Chem. Soc. 1974, 96, 5495; (b) Gassman, P.
G.; Gruetzmacher, G.; van Bergen, T. J. Generation of azasulfonium salts
from halogen-sulfide complexes and anilines: Synthesis of indoles, oxindoles,
and alkylated aromatic amines bearing cation stabilizing substituents. J. Am.
Chem. Soc. 1974, 96, 5512.
7. (a) Gilow, H. M.; Brown, C. S.; Copeland, J. N.; Kelly, K. E. Sulfenyla-
tion of some pyrroles and indoles. J. Heterocycl. Chem. 1991, 28, 1025;
(b) Matsugi, M.; Murata, K.; Gotanda, K.; Nambu, H.; Anikumar, G.;
Matsumoto, K.; Kita, Y. Facile and efficient sulfenylation method using
quinone mono-O,S-acetals under mild conditions. J. Org. Chem. 2001,
66, 2434; (c) Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed,
J. E.; Sexton, K. A highly efficient procedure for 3-sulfenylation of indole-
2-carboxylates. Org. Lett. 2004, 6, 819; (d) Maeda, Y.; Koyabu, M.;
Nishimura, T.; Uemura, S. Vanadium-catalyzed sulfenylation of indoles
and 2-naphthols with thiols under molecular oxygen. J. Org. Chem.
2004, 69, 7688; (e) Trost, B. M. a-Sulfenylated carbonyl compounds in
organic synthesis. Chem. Rev. 1978, 78, 363; (f) Kuehen, M. E. Reactions
of enamines with electrophilic sulfur compounds. J. Org. Chem. 1963, 28,
2124; (g) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.; Massa,
S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; La Colla, P. Novel
indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance
mutations: Synthesis and SAR studies. J. Med. Chem. 2003, 46, 2482;
(h) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G. R. Development
of a Novel, Highly efficient halide-catalyzed sulfenylation of indoles.
Org. Lett. 2006, 8, 565.
8. Mayer, S.; Merour, J.-Y.; Joseph, B.; Guillaumet, G. Synthesis and reactivity
of 1,4-oxazinoindole derivatives. Eur. J. Org. Chem. 2002, 1646–1653.
9. Jakubowski, H. Proofreading and the evolution of a methyl donor function:
Cyclization of methionine to S-methyl homocysteine thiolactone by Escheri-
chia coli methionyl-tRNA synthetase. J. Biol. Chem. 1993, 268, 6549.
10. (a) Hutchinson, J. H.; McEachern, E. J.; Scheigetz, J.; Macdonald, D.; Ther-
ien, M. Formation of a novel thiopyranoindole ring system. Tetrahedron
Lett., 1992, 33, 4713–4716; (b) Kamiya, T.; Teraji, T.; Sato, Y.; Hashimoto,
M.; Nakaguchi, O.; Oku, T. Studies on b-lactam antibiotics, I: A novel con-
version of penicillins into cephalosporins. Tetrahedron Lett. 1973, 32, 3001;

Novel Tricyclic Thiolactone Intermediate
1185
(c) Confalone, P. N.; Pizzolato, G.; Baggiolini, E. G.; Lollar, D.; Uskokovic,
M. R. Stereospecific total synthesis of d-biotin from L(þ)-cysteine. J. Am.
Chem. Soc. 1977, 99, 7020.
11. Hewawasam, P.; Fan, W.; Cook, D. A.; Newberry, K. S.; Boissard, C. G.;
Gribkoff, V. K.; Starrett, J.; Lodge, N. J. 4-Aryl-3-(mercapto)quinolin-2-
ones: Novel maxi-K channel opening relaxants of corporal smooth muscle.
Bioorg. Med. Chem. Lett. 2004, 14, 4479–4482.