1,3-Sulfanyl group migration: Formation of unexpected trifluoromethyl- containing bridged heterocycles

Article abstract of DOI:10.1055/s-2008-1042909

Concentrated sulfuric acid promoted the intramolecular dehydration and 1,3-sulfanyl migration of 1,1,1-trifluoro-4,4-bis(arylthio)butane-2,2-diol; this afforded, in addition to the expected unsaturated ketone, an unexpected trifluoromethyl-containing brid

Full text of DOI:10.1055/s-2008-1042909

LETTER
871
1,3-Sulfanyl Group Migration: Formation of Unexpected Trifluoromethyl-
Containing Bridged Heterocycles
1
, 3-Sulfanyl Group
u
Migration iling Jiang, Shizheng Zhu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhusz@mail.sioc.ac.cn
Received 14 November 2007
OH SR
Abstract: Concentrated sulfuric acid promoted the intramolecular
dehydration and 1,3-sulfanyl migration of 1,1,1-trifluoro-4,4-
bis(arylthio)butane-2,2-diol; this afforded, in addition to the expect-
ed unsaturated ketone, an unexpected trifluoromethyl-containing
bridged heterocycle.
HO
SR
F3C
2
O
neat
or
RSH
+
F3C
OEt
r.t., 3 d
Key words: 4-ethoxy-1,1,1-trifluorobut-3-en-2-one, thio nucleo-
philes, indium trichloride, Michael addition, dehydration
OH OEt
1
HO
SR
F3C
3
Bridged heterocycles have attracted much attention due to
their importance in the fields of natural products and me-
dicinal chemistry.1,2 These structural frameworks are
found in some alkaloids and they can also be elaborated
into more functionalized systems.3 Efforts have been di-
rected to the development of efficient methods to synthe-
size such bridged heterocycles. The classic methods for
preparing bridged heterocycles include the inter- and in-
tramolecular condensation of polyphenols such as cat-
echins,4 the Pd-catalyzed intramolecular coupling of vinyl
halides with ketone enolates,5 and three-component reac-
tion of salicylaldehyde, b-naphthol, and ethyl acetoacetate
under BF3·OEt2 catalysis.6 Recently, there have been an
increasing number of applications of ring-closing meta-
thesis (RCM) reactions to prepare bridged bicyclic oxy-
gen heterocycles.7 In the above approaches, expensive
transition-metal catalysts are usually used to activate un-
saturated bonds and promote the ring-closing process.
Herein, we wish to report a novel cyclization leading to
trifluoromethyl-containing bridged heterocycles by
H2SO4-promoted dehydration and 1,3-sulfanyl migration
Scheme 1 Reaction of compound 1 with thiols
part of our systematic study, we also attempted the reac-
tion of 1 with thio nucleophiles.
In general, thiols can react readily with unsaturated com-
pounds when catalyzed by metal salts13 under very mild
conditions, yielding the corresponding Michael addition
products. In consideration of environmentally friendly ef-
fects, we attempted the reaction of 1 with thiophenol in
the absence of catalyst. Interestingly, a double thio-
Michael addition reaction was observed and 2a was ob-
tained as the sole product, a yellow solid with a melting
point of 62–63 °C (Table 1, entry 1).14 The MS data (M+,
m/z = 360) for this product also confirmed that two equiv-
alents of thiophenol participated in the reaction. The yield
was increased to 72% by using more equivalents of
thiophenol. Subsequently, reaction of 4-methylthiophenol
or 4-methoxythiophenol with 1 afforded similar products
2b,c in 47–62% yields (Table 1, entries 2 and 3). Howev-
er, in the reaction of 1 with 4-chlorothiophenol, only one
single nucleophilic adduct 3 was obtained (Table 1, entry
4). Furthermore, the less nucleophilic 4-nitrothiophenol
of 1,1,1-trifluoro-4,4-bis(arylthio)butane-2,2-diol
2
(Scheme 1). The significant benefit of this cyclization
procedure, which does not need expensive transition-met-
al-complex participation, is that it provides a direct route
to constructing the bridged framework. The driving force
in this cyclization is the 1,3-sulfanyl migration.
Table 1 Reaction Results for Compound 1 with Thiols
Gerus and we have continuously studied the chemical
transformation of the 4-ethoxy-1,1,1-trifluorobut-3-en-2-
one (1) with various nucleophiles, such as Grignard re-
agents,8 terminal alkynes,9 alcohols,10 amines,11 and phos-
phorous nucleophiles,12 and a series of trifluoromethyl-
containing heterocycles, were synthesized. Naturally, as
Entry Thiol (RSH)
Time (d) Product 2 or 3 Yield (%)a
1
2
3
4
5
PhSH
3
4
4
2
6
2a
2b
2c
3
72
47
65
64
–
4-MeC6H4SH
4-MeOC6H4SH
4-ClC6H4SH
4-N2OC6H4SHb
n.r.
SYNLETT 2008, No. 6, pp 0871–0874
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042909; Art ID: W20107ST
© Georg Thieme Verlag Stuttgart · New York
a Isolated yields.
b PTSA (20 mg) was added to the reaction mixture as a catalyst.

872
H. Jiang, S. Zhu
LETTER
OH SR
OH OEt
RSH
HO
HO
SR
OEt
F3C
F3C
5
2
2d R = 4-ClC6H4 73%
2e R = 4-O2NC6H4 82%
Scheme 2 Reaction of 5 with thiols
OH SPh
H2SO4
0 °C
HO
SPh
S
S
F3C
CF3
Figure 1 Crystal structure of 4a
4a
2a
Table 2 Dehydration of 2a–e with Concentrated H2SO4
Scheme 3 Reaction of 5 with thiols
Entry 2 (R)
Time Yield of 4 Yield of 6
(h)
1.5
1
(%)a
(%, E/Z)a
could not react with 1, even after prolonged reaction time
in the presence of p-toluenesulfonic acid as the catalyst
(Table 1, entry 5).
1
2
3
4
5
2a (Ph)
4a (>99)
4b (83)
4c (26)
–
–
2b (4-MeC6H4)
2c (4-MeOC6H4)
2d (4-ClC6H4)
2e (4-O2NC6H4)
6b (trace)
6c (42, 3:2)
6d (78, 3:2)
6e (82, 3:2)
In order to prepare the similar bis(arylthio) products bear-
ing electron-withdrawing groups, 1 was converted into
4,4-diethoxy-1,1,1-trifluorobutane-2,2-diol (5) in the
presence of KOH.15 Subsequently, 5 was allowed to react
with excess 4-chlorothiophenol or 4-nitrothiophenol and
the expected bisarylthio products 2d,e were obtained in
73–82% yields (Scheme 2).
1
1
1
–
a Isolated yields.
Interestingly, subsequent treatment of 2a with concentrat-
ed sulfuric acid yielded a bridged cyclic product 4a, which
had a melting point of 169–171 °C (Scheme 3).16 The MS
data (M+, m/z = 324) for this product indicated that only
two molecules of H2O were removed. Its bridged cyclic
structure was further confirmed by single crystal X-ray
diffraction analysis (Figure 1).17
when compound 2d,e were treated under the same reac-
tion conditions (Table 2, entries 4 and 5).
The formation of two different products could be ex-
plained by the mechanism as shown in Scheme 5. Initial-
ly, 2 underwent dehydration in the presence of
concentrated sulfuric acid to form cationic intermediate
A, which could undergo either a 1,3-SPh shift or a subse-
quent proton-elimination reaction, depending on the elec-
tronic character of the substituent groups. When
compound 2 carried an electron-donating group or did not
have any substituents, such as in 2a, a 1,3-SPh shift oc-
curred to form an intermediate B, followed by intramolec-
ular nucleophilic attack to form cation C, which
subsequently lost a proton to form intermediate D. Then
another H2O was eliminated and intermediate E was cre-
ated, which underwent a second 1,3-SPh shift to form in-
termediate F, followed by a second intramolecular
nucleophilic attack and proton elimination. The final
bridged heterocycle 4a was then formed. On the other
When we treated other bisarylthio compounds 2b–e with
concentrated sulfuric acid in the same manner, we ob-
tained two different products (Scheme 4, Table 2). It was
clear that the electronic properties of the substituent
groups had an important influence on the reaction out-
come. When reactants carried electron-donating groups
such as methyl or methoxy substituents, bridged heterocy-
cles 4b,c were formed together with a small amount of
a,b-unsaturated product 6 (Table 2, entries 2 and 3). How-
ever, the corresponding a,b-unsaturated ketone was not
found in the case of compound 2a. In contrast, only a,b-
unsaturated compounds 6d,e were isolated in good yield
R
R
R
R
O
H2SO4
0 °C
OH
S
+
HO
F3C
S
S
S
S
F3C
R
CF3
2
4
6
Scheme 4 Dehydration of 2a–e with concd H2SO4
Synlett 2008, No. 6, 871–874 © Thieme Stuttgart · New York

LETTER
1,3-Sulfanyl Group Migration
873
H
O
HO
F3C
SC6H4NO2
– 4-O2NC6H4SH
F3C
SC6H4NO2
SC6H4NO2
– H+
6e
O
b (R = 4-O2NC6H4)
SC6H4NO2
SC6H4NO2
HO
F3C
SC6H4NO2
SC6H4NO2
– H+
F3C
OH
HO
F3C
SR
SR
SPh
SPh
H+
HO
F3C
OH
– H2O
+
+
S
3
A
F3C
S
S
a (R = Ph)
1,3-SPh shift
S
B
C
OH
F3C
1,3-SPh
shift
+
– H+
S
H+
– H2O
S
S
S
S
S
+
CF3
F3C
OH
F3C
F
D
E
+
H
– H+
S
S
S
S
CF3
CF3
4a
Scheme 5 Proposed mechanism for the formation of compounds 4a and 6e
(2) (a) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1.
(b) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49,
531. (c) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O.
Tetrahedron 1999, 55, 13521.
(3) (a) Isolation: Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanihi, T.;
Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M.
J. Antibiot. 1996, 49, 37. (b) Total synthesis: Snider, B. B.;
Lin, H. J. Am. Chem. Soc. 1999, 121, 7778. (c) Matzanke,
N.; Gregg, R. J.; Weinreb, S. M. J. Org. Chem. 1997, 62,
1920.
(4) (a) Banihashemi, A.; Rahmatpour, A. Tetrahedron 1999, 55,
7271. (b) Kazunari, K.; Masaaki, K.; Kiyoshi, F.; Takashi,
T.; Takashi, S.; Naoki, M.; Masatake, T. Tetrahedron Lett.
2000, 41, 485.
(5) Sole, D.; Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225.
(6) Mashraqui, S. H.; Patil, M. B.; Mistry, H. D.; Ghadigaonkar,
S.; Meetsma, A. Chem. Lett. 2004, 33, 1058.
(7) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(8) Gorbunova, M. G.; Gerus, I. I.; Kukhar, V. P. J. Fluorine
Chem. 1993, 65, 25.
hand, when compound 2 carried an electron-withdrawing
group, such as a nitro group which significantly reduced
the nucleophilicity of the carbon atom on the phenyl, it
was more favorable to eliminate H2O and thiol to afford
an unsaturated compound 6e than to undergo intramolec-
ular cyclization.
In summary, we have developed an intramolecular dehy-
dration and cyclization of 1,1,1-trifluoro-4,4-bis(aryl-
thio)butane-2,2-diol promoted by concentrated sulfuric
acid, which afforded trifluoromethyl-substituted bridged
heterocycles and unsaturated ketones. This methodology
affords a new entry into bridged cyclic systems. Utiliza-
tion of this synthetic methodology for the generation of
other bridged heterocycles is currently under way.
Acknowledgment
Financial support for this project was provided by The National Na-
tural Science Foundation of China (NNSFC) (Nos. 20472106 and
20532040).
(9) Zhu, S. Z.; Jin, G. F.; Jiang, H. L. Can. J. Chem. 2005, 83,
2127.
(10) Vdovenko, S. I.; Gerus, I. I.; Gorbunova, M. G. J. Fluorine
Chem. 1997, 82, 167.
(11) (a) Masaru, H.; Ryoichi, M.; Etsuji, O.; Syuhei, S.; Hitoshi,
N.; Katsushi, M. Tetrahedron Lett. 1989, 30, 6173.
(b) Gerus, I. I.; Gorbunova, M. G.; Vdovenko, S. I.;
Yagupol’skii, Y. u. L.; Kukhar’, V. P. J. Org. Chem. USSR
(Engl. Transl.) 1990, 26, 1623.
References and Notes
(1) Morehead, A.; Grubbs, R. Chem. Commun. 1998, 275.
Synlett 2008, No. 6, 871–874 © Thieme Stuttgart · New York

874
H. Jiang, S. Zhu
LETTER
(12) Zhu, S. Z.; Jiang, H. L.; Jin, G. F. J. Fluorine Chem. 2005,
126, 931.
(13) Garg, S. K.; Kumar, R.; Chakraborti, A. K. Synlett 2005,
1370.
(14) Typical Procedure and Spectroscopic Data of
Compounds 2 and 3
3JHH = 6.0 Hz, C6H4), 4.83 (1 H, t, 3JHH = 6.0 Hz, CH), 4.53
(2 H, s, OH), 2.31 (2 H, d, 3JHH = 8.0 Hz, CH2). 19F NMR
(298 MHz, CDCl3): d = –86.99 (s, CF3). MS: m/z (%) = 268
or 266 (27.12 or 97.86) [M+ – H2O – p-ClC6H4S+], 250 or
248 (25.14 or 58.83) [M+ – 2H2O – p-ClC6H4S+], 119 or 197
(28.55 or 58.47) [M+ – 2H2O – CF3 – p-ClC6H4S+], 146 or
144 (23.92 or 55.17) [p-ClC6H4SH], 108 or 106 (100) [M+ –
2H2O – 2p-ClC6H4S+], 69 (52.11) [CF3]. IR: n = 3823, 3753,
1477, 1168, 814 cm–1. Anal. Calcd for C16H13F3O2S2 (%): C,
44.77; H, 3.05. Found: C, 44.83; H, 3.01.
4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (1, 0.336 g, 2 mmol)
was added into a 10 mL flask containing thiol (4 mmol),
which was stirred at r.t.; TLC analysis was used to monitor
the reaction progress. After 2–4 d, the reaction was deemed
complete, and the reaction mixture was purified by column
chromatography on silica gel (hexane–EtOAc, 200:3) to
give the products 2 or 3.
1,1,1-Trifluoro-4,4-bis(phenylthio)butane-2,2-diol (2a)
Yellow solid, mp 62–63 °C; yield 72%. 1H NMR (300 MHz,
CDCl3): d = 7.54–7.28 (10 H, m, 2 C6H5), 4.92 (1 H, t,
3JHH = 7.0 Hz, CH), 4.68 (2 H, br, OH), 2.37 (2 H, d,
3JHH = 7.0 Hz, CH2). 13C NMR (75 MHz, CDCl3): d = 42.63
(CH2), 51.97 (CH), 115.17 (q, 1JCF = 233.3 Hz, CF3), 129.91
(Ph), 130.14 (q, 2JCF = 43.6 Hz, CF3C), 130.69 (Ph), 135.05
(Ph), 135.38 (Ph). 19F NMR (298 MHz, CDCl3): d = –87.38
(s, CF3). MS: m/z (%) = 360 (2.57) [M+], 342 (15.59) [M+ –
H2O], 251 (28.10) [M+ – SPh], 233 (100) [M+ – H2O – SPh],
109 (46.63) [SPh], 69 (5.42) [CF3]. IR: n = 3421, 3062, 1766,
1538, 1211, 1144, 1063 cm–1. Anal. Calcd for C16H15F3O2S2
(%): C, 41.32; H, 4.20. Found: C, 41.39; H, 4.20.
4-(4-Chlorophenylthio)-4-ethoxy-1,1,1-trifluorobutane-
2,2-diol (3)
(16) Typical Procedure and Spectroscopic Data for Bridged
Cyclic Compounds
Compound 2 was added to the cold concd H2SO4 (3 mL)
with efficient stirring. The temperature of the reaction during
the addition was kept below 10 °C and the reaction mixture
was stirred at 0 °C for 1 h. Then it was poured to the chipped
ice and set aside for 2 h in the refrigerator. The aqueous acid
solution was extracted with CH2Cl2 (3 × 10 mL). The
solvent was evaporated in vacuum to give the crude
products, which were purified by recrystallization (CH2Cl2–
hexane) to give the final product 4 and/or 6.
Compound 4a: white solid, mp 169–171 °C; yield >99%. 1H
NMR (300 MHz, CDCl3): d = 7.45–7.14 (8 H, m, 2 C6H4),
4.48 (1 H, s, CH), 2.61 (2 H, d, 3JHH = 4.0 Hz, CH2). 19
F
NMR (298 MHz, CDCl3): d = –73.73 (s, CF3). 13C NMR (75
MHz, CDCl3): d = 135.03 (C6H4), 130.33 (C6H4), 129.67
(C6H4), 127.56 (q, 1JCF = 286.0 Hz, CF3), 127.41 (C6H4),
126.62 (C6H4), 125.81 (C6H4), 39.40 (CF3C), 31.75 (CH),
29.71 (CH2). MS: m/z (%) = 324 (100) [M+], 255 (31.34)
[M+ – CF3], 215 (63.32) [M+ – Ph], 69 (7.29) [CF3]. IR: n =
1470, 1440, 1270, 1176, 1156, 760 cm–1. HRMS: m/z calcd
for C16H11F3S2: 324.030; found: 324.027.
Yellow solid; mp 106–107 °C; yield 64%. 1H NMR (300
MHz, CDCl3): d = 7.43–7.28 (4 H, m, C6H4Cl), 5.69 (1 H,
br, OH), 5.22 [1 H, dd, 3JHH = 3.0 Hz, 11 Hz, CH(OH)OEt],
4.21–4.16 (1 H, m, OCH2), 3.67–3.62 (1 H, m, OCH2), 3.38
(1 H, br, OH), 2.32–2.27 (1 H, m, CH2), 2.13–2.08 (1 H, m,
CH2), 1.32 (3 H, t, 3JHH = 7.0 Hz, CH3). 13C NMR (75 MHz,
CDCl3): d = 36.87 (CH3), 42.84 (CH2), 51.31 (OCH2), 51.90
(CH), 117.27 (q, 1JCF = 234.0 Hz, CF3), 128.78 (C6H4Cl),
129.26 (C6H4Cl), 132.95 (q, 2JCF = 82.0 Hz, CF3C), 133.34
(C6H4Cl), 133.64 (C6H4Cl). 19F NMR (298 MHz, CDCl3):
d = –87.15 (s, CF3). MS: m/z (%) = 330 (1.36) [M+], 312
(2.22) [M+ – H2O], 285 (0.53) [M+ – OEt], 267 (3.21) [M+ –
H2O – OEt], 187 (45.82) [M+ – SC6H4Cl], 169 (74.74)
[M+ – H2O – SPhCl], 141 (100) [M+ – SC6H4Cl – EtOH], 143
(44.78) [SC6H4Cl], 69 (34.39) [CF3]. IR: n = 3354, 1417,
1189, 1117, 1083, 1053 cm–1. Anal. Calcd for
X-ray Crystal Data: C16H11F3S2: FW = 324.37; 293 (K);
monoclinic, P2/c; l = 0.71 Å; a = 9.482(9) Å, b = 16.180(19)
Å, c = 9.482(9) Å, a = 90°, b = 109.203(10)°, g = 90°;
V = 1373.8(2) Å3; Z = 4, Dc = 1.568 mg/m3; absorption
coefficient 0.410 mm–1; F(000) = 664; size 0.501 × 0.290 ×
0.078 mm; 2.27 < q < 26.99; reflections collected 7979;
Absorption correction Empirical; transmission 1.00 mix-
0.741 min; goodness of fit on F2 0.98; final R indices
R1 = 0.0491, wR2 = 0.1190.
4-(4-Chlorophenylthio)-1,1,1-trifluorobut-3-en-2-one
(6d)
Yellow solid; mp 79–81 °C; yield 78%. 1H NMR (300 MHz,
CDCl3): d (E-isomer) = 8.22 (d, 3JHH = 15.0 Hz, =CH), 7.48–
7.40 (m, C6H4), 6.25 (d, 3JHH = 15.0 Hz, =CH). 19F NMR
(298 MHz, CDCl3): d (E-isomer) = –77.71 (s, CF3). 1H NMR
(300 MHz, CDCl3): d (for Z) = 7.80 (d, 3JHH = 10.0 Hz,
=CH), 7.48–7.40 (m, C6H4), 6.67 (d, 3JHH = 10.0 Hz, =CH).
19F NMR (298 MHz, CDCl3): d (for Z) = –78.10 (s, CF3).
MS: m/z (%) = 266 (36.22) [M+], 197 (100) [M+ – CF3], 143
(53.24) [M+ – +SC6H4Cl], 69 (28.63) [CF3]. IR: n = 1675,
1516, 1306, 1151, 1069, 898. Anal. Calcd for C10H6ClF3OS
(%): C, 45.04; H, 2.27. Found: C, 44.84; H, 2.24.
C12H14F3O3SCl (%): C, 43.58; H, 4.27. Found: C, 43.56; H,
4.26.
(15) Typical Procedure and Spectroscopic Data for Diols
4,4-Diethoxy-1,1,1-trifluorobutane-2,2-diol (5, 0.1 g, 0.5
mmol) was added into a 10 mL flask containing thiol (2
mmol), which was stirred at r.t.; TLC analysis was used to
monitor the process. After 3 d, the reaction finished, and the
reaction mixture was purified by column chromatography on
silica gel (hexane–EtOAc, 100:1) to give the products 2d or
2e.
4,4-Bis(4-chlorophenylthio)-1,1,1-trifluorobutane-2,2-
diol (2d)
(17) Single-crystal X-ray structural data for 4a have been
deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition number CCDC 644817.
Yellow solid, mp 66–67 °C; yield 73%. 1H NMR (300 MHz,
CDCl3): d = 7.41 (4 H, d, 3JHH = 6.0 Hz, C6H4), 7.34 (4 H, d,
Synlett 2008, No. 6, 871–874 © Thieme Stuttgart · New York