New routes to 3-(arylthio)indoles: Application to the synthesis of the 3,3′-bis(indoyl) sulfone core of the marine alkaloid echinosulfone A

Article abstract of DOI:10.1055/s-2006-950427

A new approach to 3-(arylthio)indoles and related compounds has been developed, based on the reactions of aryl Grignard reagents or lithiated heteroaromatics with a phenylsulfonyl-protected 3,3′-bis(indolyl) disulfide. In addition, a rational approach to

Full text of DOI:10.1055/s-2006-950427

LETTER
2459
New Routes to 3-(Arylthio)indoles: Application to the Synthesis of the
3,3¢-Bis(indolyl) Sulfone Core of the Marine Alkaloid Echinosulfone A
New
R
outes to 3-(
a
A
rylthio)in
m
doles id Shirani,a Birgitta Stensland,b Jan Bergman,*a,c Tomasz Janosik*a
a
b
c
Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, 14157 Huddinge, Sweden
Preformulation and Biopharmaceutics, Solid State Analysis, AstraZeneca PAR & D / SBBG B341:3, 15185 Södertälje, Sweden
Södertörn University College, 14104 Huddinge, Sweden
Fax +46(8)6081501; E-mail: jabe@biosci.ki.se; E-mail: toja@biosci.ki.se
Received 15 May 2006
O
O
Abstract: A new approach to 3-(arylthio)indoles and related com-
pounds has been developed, based on the reactions of aryl Grignard
reagents or lithiated heteroaromatics with a phenylsulfonyl-protect-
ed 3,3¢-bis(indolyl) disulfide. In addition, a rational approach to the
3,3¢-bis(indolyl) sulfone core of the alkaloid echinosulfone A has
been accomplished, involving treatment of a 3-lithioindole with
bis(phenylsulfonyl) sulfide as the key step.
Cl
Br
O
O
S
Br
S
CONH2
N
N
N
H
H
HO2C
1
2
Figure 1
Key words: indoles, sulfides, sulfones, Grignard reagents, lithia-
tion
halides, followed by introduction of sulfuryl chloride6a or
sulfur.6b In our hands these methods gave only very low
yields of pure products after laborious work-up and sepa-
ration procedures, it was therefore desirable to develop
alternative, practical approaches to such systems. To
achieve this end, the readily available 3-bromo-1-(tert-
butyldimethylsilyl)indole (3)8 was subjected to halogen–
metal exchange using tert-butyllithium, followed by treat-
ment of the resulting 3-lithioindole derivative with 0.5
equivalents of bis(phenylsulfonyl) sulfide (Scheme 1).9
This gave 3,3¢-bis(indolyl) sulfide (4),10 the structure of
which was also supported by X-ray crystallography
(Figure 2).11 As anticipated, desilylation of 4 with TBAF
in THF gave the parent sulfide 5,12 which was subsequent-
ly oxidized using Oxone® in aqueous acetone to give the
target compound 3,3¢-bis(indolyl) sulfone (6).13 Interest-
ingly, the sulfide 5 has previously been encountered as a
side-product originating from the reaction of indolyl-
magnesium bromide with ethanesulfenyl chloride in
connection with early synthetic studies towards 3-alkyl-
thioindoles.6c
Several synthetic routes to 3-(alkylthio)- or 3-(arylthio)in-
doles are available,1 involving for example the use of di-
sulfides,1a quinone-O,S-acetals,1b thiols in the presence of
molecular oxygen,1c sulfenyl chlorides generated in situ,1d
or N-thioalkyl- and N-thioarylphthalimides1e as the
sulfenylating agents. Approaches utilizing sulfonyl
chlorides2a,b or chlorosulfonic acid in acetonitrile2c have
also been described. Although these procedures offer
access to a variety of products, there are still many limita-
tions, in particular concerning the accessibility and stabil-
ity of the reagents. Both 3-(arylthio)indoles and the
related sulfones have attracted considerable interest in
medicinal chemistry. For instance, the sulfone L-737,126
(Figure 1, 1) has been shown to exhibit potent anti-HIV
properties,3 triggering further efforts towards the design
and biological evaluation of numerous related deriva-
tives.4 It was also demonstrated that several 3-(aryl-
thio)indoles exhibited interesting activities as inhibitors
of tubulin polymerization and growth of MCF-7 human
breast cancer cells.5 Despite all these studies, only a lim-
ited number of structures featuring a pair of indole units
connected via a single sulfur atom bridge have been de-
scribed.6 A compound belonging to this class is the natural
product echinosulfone A (Figure 1, 2), which has been
isolated from a southern Australian marine sponge,
Echinodictyum.7
This background prompted us to initiate studies on the de-
velopment of viable routes to the heterocyclic core of
echinosulfone A (2). The only available approaches to
3,3¢-bis(indolyl) sulfone or the corresponding sulfide are
based on treatment of indole with alkylmagnesium
SYNLETT 2006, No. 15, pp 2459–2463
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950427; Art ID: G15206ST
© Georg Thieme Verlag Stuttgart · New York
Figure 2 The crystal structure of the 3,3¢-bis(indolyl) sulfide 4
determined at 200 K.

2460
H. Shirani et al.
LETTER
With useful amounts of the disulfide 8 available, experi-
ments involving lithiated heterocycles or aryl Grignard
reagents were undertaken. Treatment of the 3-lithioindole
(derived from 3) with the disulfide 8, gave the unsymmet-
rically protected 3,3¢-bis(indolyl) sulfide 9 (Table 1) in
moderate yield. Several other new 3-(heteroarylthio)- and
3-(arylthio)indoles (10–17) were prepared in a similar
manner, and the results are summarized in Table 1.
Br
S
a, b
c
N
N
N
TBS
TBS
O
TBS
3
4
O
S
S
NH
In a further extension, it was demonstrated that the N-
phenylsulfonyl group present in the resulting 3-thioindole
products may be readily cleaved using aqueous potassium
hydroxide in dioxane. This was illustrated by the conver-
sion of 2,3¢-bis(indolyl) sulfide (10) into the parent sulfide
18 (Scheme 3), which displayed spectral data fully consis-
tent with the assigned structure.22 This compound has
been previously claimed as a product obtained by heating
the indole with elemental sulfur at 115–125 °C for 48
hours.23 However, comparison of our data with those giv-
en in the literature clearly disprove the previous assign-
ment. In particular, a resonance (singlet) in the reported
1H NMR data (DMSO-d6) at d = 4.7723 is not consistent
with the spectrum obtained for 18. Further detailed studies
would be needed to provide full insight in this reaction.
The formation of 18 during the heating of indole with
sulfur is also contradicted by the fact that it is well estab-
lished that this operation, when performed either in DMF
or without solvent, gives predominantly a pentacyclic sys-
tem, namely 5H,10H-[1,2,3,4]tetrathiocino[5,6-b:8,7-
b′]diindole,24 the structure of which has also been later
corroborated by an independent synthesis, and finally
supported by X-ray crystallography.25
NH
d
N
H
N
H
5
6
Scheme 1 Reagents and conditions: (a) t-BuLi, THF, –78 °C,
0.5 h; (b) (PhSO2)2S, –78 °C to r.t., 16 h, 57%; (c) TBAF, THF,
0–5 °C, 1 h; then r.t., 20 min, 95%; (d) Oxone®, acetone, H2O, r.t.,
4 h, 70%.
Cleavage of disulfides with organolithium or organomag-
nesium reagents is a well established approach to unsym-
metrical sulfides. Hence, it was anticipated that treatment
of suitably protected 3,3¢-bis(indolyl) disulfides with C-
metallated aromatics or heteroaromatics would constitute
a route suitable for the preparation of a variety 3-(aryl-
thio)- or 3-(heteroarylthio)indoles, as well as unsymmet-
rical 3,3¢-bis(indolyl) sulfides. Consequently, the known
disulfide 7 was prepared employing a modification of a
literature procedure,14 and the reported yield of 23% could
be improved considerably to 60–80%, simply by passing
a stream of air through the reaction mixture for several
hours in order to facilitate the desired disulfide formation.
The crude product may thereafter be conveniently puri-
fied by trituration with diisopropyl ether. We were
pleased to note that the disulfide 7 proved to be remark-
ably stable under certain anhydrous basic conditions, as
N-protection with benzenesulfonyl chloride using stan-
dard phase-transfer conditions15 involving potassium
hydroxide, produced compound 816 in good yield, without
cleavage of the disulfide linkage (Scheme 2).
H
H
N
N
S
S
a
N
N
H
PhO2S
10
18
Scheme 3 Reagents and conditions: (a) 1 M KOH (aq)–dioxane
(1:1), 80 °C, 15 min, 77%.
S
S
a
In conclusion, new and convenient synthetic routes to var-
ious 3-thioindoles incorporating both heterocyclic and
carbocyclic moieties have been devised, involving reac-
tions of lithiated heterocycles or aryl Grignard reagents
with the 3,3¢-bis(indolyl) disulfide 8. These procedures
offer efficient access to 3-thioindoles which are not prac-
tically available by the existing approaches. Further stud-
ies probing additional synthetic applications of the
disulfide 8 and related compounds are in progress.
N
N
N
H
H
H
7
S
S
b
N
N
SO2Ph
PhO2S
8
Scheme 2 Reagents and conditions: (a) H2NCSNH2, I2, NaOH,
EtOH, H2O, air, r.t. 18–24 h, 60–80%; (b) PhSO2Cl, n-Bu4NHSO4,
KOH, CH2Cl2, 0 °C, 1 h, then r.t., 1.5 h, 72%.
Acknowledgment
Mr. John Ogden, Varian Inc., is gratefully acknowledged for
assistance with acquisition of the MS data.
Synlett 2006, No. 15, 2459–2463 © Thieme Stuttgart · New York

LETTER
New Routes to 3-(Arylthio)indoles
2461
Table 1 Reactions of Metallated Heterocycles and Aromatics with Disulfide 8
Entry
Substrate
Reagents and conditions
Product
Yield (%)a
Br
S
(i) t-BuLi, THF, –78 °C8
(ii) 8, –78 °C to r.t., 16 h
1
47
38
N
N
TBS
N
TBS
PhO2S
3
9
H
N
(i) BuLi, THF, –78 °C
(ii) CO2 (g)
S
2
(iii) t-BuLi, THF, –78 °C20
(iv) 8, –78 °C to r.t.
N
N
H
PhO2S
10
Z
S
(i) BuLi, THF, –78 °C
(ii) 8, –78 °C to r.t.
76 (11)17
79 (12)
3
4
5
N
Z
PhO2S
Z = S, O
11 Z = S
12 Z = O
S
S
(i) BuLi, THF, –78 °C
(ii) 8, –78 °C to r.t.
80
N
S
PhO2S
13
Ph
S
Br
(i) Mg, I2 (cat.), THF, reflux
(ii) 8, 0 °C to r.t.
7618
N
PhO2S
14
Br
S
(i) Mg, I2 (cat.), THF, reflux
6
7
62
77
(ii) 8, 0 °C to r.t.
N
PhO2S
15
S
Br
(i) Mg, I2 (cat.), THF, reflux
(ii) 8, 0 °C to r.t.
OMe
N
OMe
PhO2S
16
EtO2C
S
CO2Et
(i) i-PrMgCl, THF, –20 °C to 0 °C21
(ii) 8, –78 °C to r.t.
8
6919
N
I
PhO2S
17
a Yields of isolated products, based on disulfide 8.
Synlett 2006, No. 15, 2459–2463 © Thieme Stuttgart · New York

2462
H. Shirani et al.
LETTER
7.11 (m, 4 H); 13C NMR (75.5 MHz, DMSO-d6): d = 136.3,
130.1, 122.9, 122.8, 121.2, 118.7, 117.2, 112.6; ESI-MS:
m/z = 295 [M – H]¯ .
References and Notes
(1) For some examples, see: (a) Atkinson, J. G.; Hamel, P.;
Girard, Y. Synthesis 1988, 480. (b) Matsugi, M.; Murata,
K.; Gotanda, K.; Nambu, H.; Anilkumar, G.; Matsumoto,
K.; Kita, Y. J. Org. Chem. 2001, 66, 2434. (c) Maeda, Y.;
Koyabu, M.; Nishimura, T.; Uemura, S. J. Org. Chem. 2004,
69, 7688. (d) Schlosser, K. M.; Krassutsky, A. P.; Hamilton,
H. W.; Reed, J. E.; Sexton, K. Org. Lett. 2004, 6, 819.
(e) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G. R.
Org. Lett. 2006, 8, 565; and references cited therein.
(2) (a) Singh, D. U.; Singh, P. R.; Samant, S. D. Tetrahedron
Lett. 2004, 45, 9079. (b) Yadav, J. S.; Reddy, B. V. S.;
Krishna, A. D.; Swamy, T. Tetrahedron Lett. 2003, 44,
6055. (c) Janosik, T.; Shirani, H.; Wahlström, N.; Malky, I.;
Stensland, B.; Bergman, J. Tetrahedron 2006, 62, 1699.
(3) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;
Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.;
Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’Brien,
J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.;
Anderson, P. S. J. Med. Chem. 1993, 36, 1291.
(4) (a) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.;
Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.;
La Colla, P. J. Med. Chem. 2003, 46, 2482. (b) Silvestri, R.;
Artico, M.; De Martino, G.; La Regina, G.; Loddo, R.; La
Colla, M.; La Colla, P. J. Med. Chem. 2004, 47, 3892.
(5) (a) De Martino, G.; La Regina, G.; Coluccia, A.; Edler, M.
C.; Barbera, M. C.; Brancale, A.; Wilcox, E.; Hamel, E.;
Artico, M.; Silvestri, R. J. Med. Chem. 2004, 47, 6120.
(b) De Martino, G.; Edler, M. C.; La Regina, G.; Coluccia,
A.; Barbera, M. C.; Barrow, D.; Nicholson, R. I.; Chiosis,
G.; Brancale, A.; Hamel, E.; Artico, M.; Silvestri, R. J. Med.
Chem. 2006, 49, 947.
(6) (a) Oddo, B.; Mingoia, Q. Gazz. Chim. Ital. 1926, 56, 782.
(b) Madelung, W.; Tenzer, M. Chem. Ber. 1915, 48, 949.
(c) Jardine, R. V.; Brown, R. K. Can. J. Chem. 1964, 42,
2626.
(7) Ovenden, S. P. B.; Capon, R. J. J. Nat. Prod. 1999, 62, 1246.
(8) (a) Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J. J.
Org. Chem. 1994, 59, 10. (b) Amat, M.; Seffar, F.; Llor, N.;
Bosch, J. Synthesis 2001, 267.
(9) De Jong, F.; Janssen, M. J. J. Org. Chem. 1971, 36, 1645.
(10) Data for compound 4: Colorless crystals, mp 160.5–
161.5 °C; 1H NMR (300.1 MHz, CDCl3): d = 7.81–7.75 (m,
2 H), 7.48–7.42 (m, 2 H), 7.39 (s, 2 H), 7.17–7.08 (m, 4 H),
0.91 (s, 18 H), 0.59 (s, 12 H); 13C NMR (75.5 MHz, CDCl3):
d = 141.6, 134.9, 132.0, 122.0, 120.3, 119.7, 114.2, 109.1,
26.4, 19.6, –3.8; Anal. Calcd for C28H40N2SSi2: C, 68.23; H,
8.18; N, 5.68. Found: C, 68.25; H, 8.06; N, 5.59.
(14) Woodbridge, R. G.; Dougherty, G. J. Am. Chem. Soc. 1950,
72, 4320.
(15) (a) Illi, V. O. Synthesis 1979, 136. (b) Conway, S. C.;
Gribble, G. W. Heterocycles 1990, 30, 627.
(16) Preparation of disulfide 8: A stirred suspension of finely
powdered KOH (12.5 g, 0.22 mol) in CH2Cl2 (155 mL)
under N2 was cooled to 0 °C, followed by sequential addition
of the disulfide 7 (14.8 g, 50 mmol), and tetrabutylammo-
nium hydrogen sulfate (0.88 g, 2.6 mmol). To this mixture
was added a solution of benzenesulfonyl chloride (16.0 mL,
0. 125 mol) in CH2Cl2 (25 mL) at 0 °C over 1.25 h. The
resulting mixture was stirred at 0 °C for 1 h, and thereafter at
r.t. for 1.5 h, whereupon it was filtered, and the filter cake
was washed with several portions of CH2Cl2. Evaporation of
the combined filtrates and washings gave a solid residue,
which was recrystallized from MeCN (using activated
carbon), to give 8 (20.9 g, 72%) as pinkish crystals, mp 165–
166.5 °C; 1H NMR (300.1 MHz, CDCl3): d = 8.02–7.98 (m,
2 H), 7.91–7.88 (m, 4 H), 7.62–7.48 (m, 10 H), 7.42–7.36
(m, 2 H), 7.27–7.22 (m, 2 H); 13C NMR (75.5 MHz, CDCl3):
d = 137.8, 135.3, 134.5, 130.6, 130.4, 129.8, 127.1, 125.9,
124.1, 120.6, 115.8, 113.8; Anal. Calcd for C28H20N2O4S4:
C, 58.31; H, 3.50; N, 4.86. Found: C, 58.46; H, 3.58; N, 4.78.
(17) Compound 11 (Table 1, entry 3): To a solution of
benzo[b]thiophene (0.24 g, 2.0 mmol) in anhydrous THF (10
mL) was added BuLi (2.5 M in hexanes, 0.80 mL, 2.0 mmol)
over 10 min under N2 at –78 °C. The solution was stirred for
30 min at –78 °C, followed by addition of a solution of the
disulfide 8 (1.15 g, 2.0 mmol) in anhydrous THF (10 mL)
over ~15 min at –78 °C. The mixture was allowed to warm
to r.t. over 16 h, and was thereafter treated with sat. aq
NH4Cl (20 mL). The resulting mixture was extracted with
Et2O (2 × 30 mL). The combined organic layers were
washed with H2O (30 mL), brine (30 mL) and dried over
Na2SO4. Evaporation of the solvents gave a residue, which
was subjected to column chromatography on silica gel,
initially using n-heptane followed by EtOAc–n-heptane (1:9
Š 1:4), to provide 11 (0.64 g, 76%), as colorless crystals, mp
140–143 °C; 1H NMR (300.1 MHz, CDCl3): d = 8.02–7.99
(m, 1 H), 7.93–7.90 (m, 2 H), 7.86 (s, 1 H), 7.65–7.56 (m, 4
H), 7.50–7.45 (m, 2 H), 7.39–7.23 (m, 5 H); 13C NMR (75.5
MHz, CDCl3): d = 141.4, 139.9, 138.0, 136.9, 135.4, 134.4,
130.8, 130.1, 129.6, 127.1, 126.4, 125.8, 124.7, 124.6,
124.2, 123.2, 122.0, 120.4, 114.0, 113.7; Anal. Calcd for
C22H15NO2S3: C, 62.68; H, 3.59; N, 3.32. Found: C, 62.61;
H, 3.68; N, 3.25.
(11) Crystallographic data (excluding structure factors) for
compound 4 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 606016. Copies of the data can be obtained,
free of charge, on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: +44 (1223)336033 or email:
deposit@ccdc.cam.ac.uk].
(12) Data for compound 5: Colorless crystals, mp 227.5–229 °C
(Lit.6b 232 °C); IR (neat): 3409, 3393, 1452, 1405, 1335,
1236, 1085, 1002, 739 cm –1; 1H NMR (300.1 MHz, DMSO-
d6): d = 11.26 (s, 2 H), 7.74–7.70 (m, 2 H), 7.65 (d, J = 2.6
Hz, 2 H), 7.36–7.33 (m, 2 H), 7.10–7.00 (m, 2 H); 13C NMR
(75.5 MHz, DMSO-d6): d = 136.2, 129.7, 128.5, 121.5,
119.4, 118.6, 111.9, 105.3; ESI-MS: m/z = 263 [M – H]–.
The IR and 1H NMR data are in good agreement with those
discussed in reference 6c.
(18) Compound 14 (Table 1, entry 5): A solution of 2-bromo-
biphenyl (0.56 g, 2.4 mmol) in anhydrous THF (5 mL) was
added dropwise to a suspension of magnesium turnings (53
mg, 2.2 mmol) in anhydrous THF (5 mL) at r.t. under N2.
The mixture was heated at reflux for 1 h and was thereafter
cooled to 0 °C, whereupon a solution of the disulfide 8 (1.15
g, 2.0 mmol) in anhydrous THF (10 mL) was added drop-
wise during ~15 min at 0 °C. The mixture was allowed to
warm to r.t. over 16 h, followed by addition of 50% aq
NH4Cl (20 mL). Workup as for compound 11, followed by
column chromatography on silica gel, initially using n-
heptane, followed by Et2O–n-heptane (1:19 Š 15:85), gave
14 (0.67 g, 76%) as colorless crystals, mp 128–130 °C; 1H
NMR (300.1 MHz, CDCl3): d = 8.03–8.00 (m, 1 H), 7.90–
7.87 (m, 2 H), 7.69 (s, 1 H), 7.59–7.32 (m, 10 H), 7.26–7.15
(m, 3 H), 7.08–7.03 (m, 1 H), 6.84 (dd, J = 7.9, 0.9 Hz, 1 H);
13C NMR (75.5 MHz, CDCl3): d = 141.0, 140.4, 138.0,
135.6, 135.0, 134.3, 131.3, 131.1, 130.5, 129.6, 129.5,
(13) Data for compound 6: Colorless crystals, mp 304–306 °C;
1H NMR (300.1 MHz, DMSO-d6): d = 12.02 (s, 2 H), 8.22
(s, 2 H), 7.81–7.79 (m, 2 H), 7.44 (d, J = 7.4 Hz, 2 H), 7.21–
Synlett 2006, No. 15, 2459–2463 © Thieme Stuttgart · New York

LETTER
128.4, 128.1, 127.9, 127.5, 127.0, 125.9, 125.7, 124.1,
New Routes to 3-(Arylthio)indoles
2463
(21) (a) Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P.
Angew. Chem. Int. Ed. 1998, 37, 1701. (b) For a review on
generation and applications of functionalized organo-
magnesium reagents, see: Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.;
Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42,
4302.
(22) Data for compound 18: Off-white crystalline solid, mp 138–
140 °C; 1H NMR (300.1 MHz, DMSO-d6): d = 11.55 (s, 1
H), 11.17 (s, 1 H), 7.75 (d, J = 2.5 Hz, 1 H), 7.59 (d, J = 7.7
Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 7.7 Hz, 1 H),
7.23 (d, J = 8.1 Hz, 1 H), 7.16–7.11 (m, 1 H), 7.08–6.96 (m,
2 H), 6.93–6.88 (m, 1 H), 6.31 (d, J = 1.7 Hz, 1 H); 13C NMR
(75.5 MHz, DMSO-d6) d = 137.0, 136.3, 131.4, 131.1,
128.4, 128.0, 121.9, 121.0, 119.8, 119.1, 119.1, 118.4,
112.1, 110.8, 103.7, 100.8; ESI-MS: m/z = 265 [M + H]+;
Anal. Calcd for C16H12N2S: C, 72.70; H, 4.58; N, 10.60.
Found: C, 72.48; H, 4.65; N, 10.36.
120.7, 114.0, 112.6; Anal. Calcd for C26H17NO2S2: C, 70.72;
H, 4.34; N, 3.17. Found: C, 70.83; H, 4.39; N, 3.14.
(19) Compound 17 (Table 1, entry 8): A solution of i-PrMgCl
(2.0 M in Et2O, 1.2 mL, 2.4 mmol,) was added slowly (over
~10 min) to a solution of ethyl 2-iodobenzoate (0.55 g, 2.0
mmol) in anhydrous THF (10 mL) at –20 °C under N2.
The mixture was stirred at –20 °C for 30 min, and was
then allowed to warm to 0 °C over 30 min. After cooling to
–78 °C, a solution of the disulfide 8 (1.15 g, 2.0 mmol) in
THF (10 mL) was added over ~15 min. The resulting
mixture was allowed to warm to r.t. over 16 h, and was
subsequently treated with sat. aq NH4Cl (25 mL). Workup as
for compound 11, followed by column chromatography on
silica gel using n-heptane–EtOAc (8:1), afforded 17 (0.60 g,
69%) as a colorless viscous oil, which solidified upon
standing. 1H NMR (300.1 MHz, CDCl3): d = 8.08–8.02 (m,
2 H), 7.97–7.93 (m, 2 H), 7.90 (s, 1 H), 7.62–7.56 (m, 1 H),
7.51–7.46 (m, 2 H), 7.41–7.36 (m, 2 H), 7.25–7.19 (m, 1 H),
7.14–7.09 (m, 2 H), 6.69–6.66 (m, 1 H), 4.46 (q, J = 7.1 Hz,
2 H), 1.45 (t, J = 7.1 Hz, 3 H); 13C NMR (75.5 MHz, CDCl3):
d = 166.6, 141.6, 138.0, 135.8, 134.4, 132.5, 132.3, 131.4,
131.3, 129.6, 127.1, 126.8, 126.6, 125.8, 124.5, 124.2,
120.7, 114.0, 111.9, 61.5, 14.5.
(23) Hünig, S.; Steinmetzer, H.-C. Liebigs Ann. Chem. 1976,
1039.
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Synlett 2006, No. 15, 2459–2463 © Thieme Stuttgart · New York