Synthesis of 2-aryl-3-fluoro-5-silylthiophenes via a cascade reactive sequence

Article abstract of DOI:10.1021/ol400141y

2-Aryl-3-fluoro-5-silylthiophenes were readily prepared only in two steps from 2-bromo-3,3,3-trifluoropropene in good yields. These transformations include the first successful S_N2′-type reaction of 2-bromo-3,3,3-trifluoropropene and benzylthio

Full text of DOI:10.1021/ol400141y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of 2‑Aryl-3-fluoro-5-
silylthiophenes via a Cascade
Reactive Sequence
Kensuke Hirotaki and Takeshi Hanamoto*
Department of Chemistry and Applied Chemistry, Saga University, Honjyo-machi 1,
Saga 840-8502, Japan
hanamoto@cc.saga-u.ac.jp
Received January 17, 2013
ABSTRACT
2-Aryl-3-fluoro-5-silylthiophenes were readily prepared only in two steps from 2-bromo-3,3,3-trifluoropropene in good yields. These
transformations include the first successful SN20-type reaction of 2-bromo-3,3,3-trifluoropropene and benzylthiols and [2,3]sigmatropic
rearrangement of 2-bromo-3,3-difluoroallyl benzyl sulfide.
The thiophene nucleus is a component of several classes
of bioactive natural compounds and functional materials.1
A facile preparation for multisubstituted thiophenes still
remains a challenging task in modern organic chemistry.
On the other hand, only a few procedures have been
reported for the preparation of fluorothiophenes despite
the fact that fluoro substituents are powerful modifiers of
chemical and biological properties of organic compounds
as reported in many pharmaceuticals and agrochemicals.2
From a synthetic viewpoint, most methods for the synthe-
sis of fluorothiophenes are based on an application of
the substitution reactions of fluorine on the thiophene
ring.3 In contrast to these traditional methods, cyclization
approaches to the regioselective synthesis are scarce.
To the best of our knowledge, only three groups have
reported this methodology for the synthesis of substituted
fluorothiophenes.4
Our group has been interested in the building block
strategy for the introduction of fluorine(s) into organic
molecules.5 To explore the utilization of 2-bromo-3,3,3-
trifluoropropene (1) as a starting material, we focused
on its SN20-type reaction. Although similar SN20-type
reactions have already been reported by several groups,6
there is only one example of using 2-bromo-3,3,3-
trifluoropropene.7 Herein, for the first time, we report
efficient SN20-type reactions of 1 with various thiolates,
providing highly selective 2-bromo-3,3-difluoroallyl sul-
fides (2). In this study we will report the stepwise synthesis
of 2-aryl-3-fluoro-5-silylthiophenes (10) in high yield.
(1) (a) Mishra, R.; Jha, K. K.; Kumar, S.; Tomer, I. Pharma Chem.
ꢀ
ꢀ
ꢀ
2011, 3, 38. (b) Puterova, Z.; Krutosikova, A.; Vegh, D. ARKIVOC
2010, (i), 209. (c) Bheeter, C. B.; Bera, J. K.; Doucet, H. J. Org. Chem.
2011, 76, 6407. (d) Heyde, C.; Zug, I.; Hartmann, H. Eur. J. Org. Chem.
2000, 3273.
(5) (a) Kasai, N.; Maeda, R.; Furuno, H.; Hanamoto, T. Synthesis
2012, 44, 3489. (b) Maeda, R.; Ishibashi, R.; Kamaishi, R.; Hirotaki, K.;
Furuno, H.; Hanamoto, T. Org. Lett. 2011, 13, 6240. (c) Hirotaki, K.;
Hanamoto, T. J. Org. Chem. 2011, 76, 8564. (d) Maeda, R.; Ooyama, K.;
Anno, R.; Shiosaki, M.; Azema, T.; Hanamoto, T. Org. Lett. 2010, 12,
2548. (e) Shiosaki, M.; Unno, M.; Hanamoto, T. J. Org. Chem. 2010, 75,
8326. (f) Hanamoto, T.; Yamada, K. J. Org. Chem. 2009, 74, 7559.
(g) Hanamoto, T.; Anno, R.; Yamada, K.; Ryu, K.; Maeda, R.; Aoi, K.;
Furuno, H. Tetrahedron 2009, 65, 2757.
(6) (a) Fuchibe, K.; Takahashi, M.; Ichikawa, J. Angew. Chem., Int.
Ed. 2012, 51, 12059. (b) Ichikawa, J.; Fukui, H.; Ishibashi, Y. J. Org.
Chem. 2003, 68, 7800. (c) D. Bonnet-Delpon, J. P.; Rock, M. H. J. Chem.
Soc., Perkin Trans. 1 1996, 1409. (d) Kitazume, T.; Ohnogi, T.; Miyauchi,
H.; Yamazaki, T. J. Org. Chem. 1989, 54, 5630. (e) Fuchikami, T.;
Shibata, Y.; Suzuki, Y. Tetrahedron Lett. 1986, 27, 3173.
(2) (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(d) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
(3) (a) Serdyuk, O. V.; Abaev, V. T.; Butin, A. V.; Nenajdenko, V. G.
Synthesis 2011, 2505. (b) Pomerantz, M.; Turkman, N. Synthesis
2008, 2333. (c) Dvornikova, E.; Bechcicka, M.; Kamienska-Trela, K.;
Krowczynski, A. J. Fluorine Chem. 2003, 124, 159.
€
(4) (a) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis
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2002, 1917. (b) Andres, D. F.; Laurent, E. G.; Marquet, B. S. Tetra-
hedron Lett. 1997, 38, 1049. (c) Burger, K.; Helmreich, B.; Jendrewski, O.
J. Fluorine Chem. 1994, 66, 13.
(7) Jiang, B.; Zhang, F.; Xiong, W. Chem. Commun. 2003, 536.
r
10.1021/ol400141y
XXXX American Chemical Society

Table 1. Reaction of 1 and Thiophenol under Various Conditions
Table 2. Substrate Scope of SN20-Type Reaction of 1a
time
[h]
yieldb
[%]
entry
R
2
2:3c
1
2,4-Me-C6H3
nC12H25
6
6
3
3
18
3
7
7
7
4
6
2b
2c
2d
2e
2f
84
82
75
86
82
88
78
73
75
79
77
94/6
2
>99/1
99/1
3
tBu
equiv
time
yielda
[%]
4
Ph3C
99/1
entry
1
solvent
THF
[min]
2a:3a:4ab
5
PhCH2CH2
PhCH2
99/1
6
2g
2h
2i
99/1
1
3.0
3.0
1.0
5.0
3.0
3.0
3.0
3.0
3.0
1.2
60
57
80/20/0
93/7/0
87/13/0
96/4/0
ꢀ
7
4-Me-C6H4CH2
4ꢀClꢀC6H4CH2
4-MeO-C6H4CH2
2ꢀClꢀC6H4CH2
2,4,6-Me-C6H4CH2
>99/1
99/1
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMF
360
360
360
10
73
8
3
66
9
2j
>99/1
99/1
4
69
10
11
2k
2l
5
tracec
tracec
tracec
NRd
NRd
94
>99/1
6
DMSO
10
ꢀ
7
MeCN
10
ꢀ
a The reaction of 1 (3.0 equiv) with RSH (1.0 equiv) was carried out in
the presence of NaH (1.3 equiv) in 1,4-dioxane at room temperature.
b Isolated yield. c The ratio was determined by 19F NMR spectroscopy.
8
ether
240
240
480
ꢀ
9
10e
toluene
EtOH
ꢀ
0/0/100
a Isolated combined yield. b The ratio was determined by 19F NMR
spectroscopy. c Major products were (E)- and (Z)-Phenyl
β-(trifluoromethyl)vinyl sulfides (4a). d No reaction. e KOH was used
instead of NaH. See ref 5a.
These findings suggest that one factor for the occurrence of
excessive SN20-type reaction of 2 might be associated with
the pKa value of thiols.
We then turned our attention to synthetic applications
of the above products 2. gem-Difluoroallenes have at-
tracted attention due to their potential as difluorinated
synthons; however the study on the facile preparation of
functionalized gem-difluoroallenes is rare.8 We therefore
examined the synthesis of gem-difluoroallenyl sulfide from
2-bromo-3,3-difluoroallyl sulfide using an elimination re-
action. The preliminary experiment involved the reaction
of 2a with a slight excess amount of LDA (1.2 equiv) in
THF at ꢀ78 °C. This reaction resulted in the decomposi-
tion of 2a along with recovery of the unreacted starting
material 2a, giving no desired gem-difluoroallenyl sulfide
5a. Instead of 2a, the use of 2d also lead to a similar result.
At this point, we were aware of the incomplete consump-
tion of 2a in spite of the excessive use of LDA. This result
led us to speculate that, prior to full deprotonation of 2a
by LDA, the produced product 5a might undergo the
next deprotonation process to generate the corresponding
allenyl anion which may easily decompose. On the basis
of this working hypothesis, we conducted the reaction of
2a with LDA (2.2 equiv) in the presence of an excess
amount of TMSCl (5.0 equiv) in order to trap the gener-
ated allenyl anion. The expecting reaction turned out to
be complicated, giving many productsby GC-MS analysis.
Initially, an SN20-type reaction of 1 and thiophenol was
examined under various reaction conditions (Table 1).
When the reaction of 1 (3.0 equiv) and thiophenol
(1.0 equiv) was conducted in THF in the presence of
NaH (1.3 equiv), the desired SN20-type product 2a was
obtained along with an unexpected structural isomer 3a,
with a ratio of 2a/3a = 80/20 in 57% combined yield.
Although this mixture could not be separated into its
components. The structures of 2a and 3a were assigned
1
on the basis of their H and 19F NMR (see Supporting
Information). The product 3a was probably formed via an
excessive SN20-type reaction of 2a with thiophenoxide.
When this reaction was carried out in 1,4-dioxane for
6 h, the selectivity was improved to give the products with
a ratio of 2a/3a = 93/7 in 73% combined yield. Modifica-
tions of the amount of 1 influenced the product selectivity
to some extent. Reducing the amount of 1 to 1.0 equiv
resulted in a slightly lower selectivity, whereas increasing
the amount of 1 to 5.0 equiv resulted in the slightly higher
selectivity. Interestingly, other tested solvents suppressed
the formation of the desired product 2a.
With the optimized reaction conditions in hand, the
substrate scope was explored using 3.0 equiv of 1 and
various thiols in the presence of NaH (1.3 equiv) at room
temperature. As shown in Table 2, the reaction smoothly
proceeded with a wide range of substrates, providing the
corresponding SN20-type product 2bꢀ2l in good to high
yields with high to excellent selectivities. It is note-
worthy that the alkylthiols gave the corresponding SN20-
type products exclusively, in sharp contrast to arylthiols.
(8) (a) Oh, K.; Fuchibe, K.; Ichikawa, J. Synthesis 2011, 881.
(b) Yokota, M.; Fuchibe, K.; Ueda, M.; Mayumi, Y.; Ichikawa, J.
Org. Lett. 2009, 11, 3994. (c) Mae, M.; Hong, J. A.; Xu, B.; Hammond,
G. B. Org. Lett. 2006, 8, 479. (d) Hammond, G. B. J. Fluorine Chem.
2006, 127, 476. (e) Shen, Q.; Chen, C.-H.; Hammond, G. B. J. Fluorine
Chem. 2002, 117, 131. (f) Shen, Q.; Hammond, G. B. Org. Lett. 2001, 3,
2213. (g) Wang, Z. G.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547.
(h) Shi, G.; Xu, Y. J. Fluorine Chem. 1989, 44, 161. (i) Xu, Y.-Y.; Jin,
F.-Q.; Huang, W-y J. Fluorine Chem. 1995, 70, 5.
B
Org. Lett., Vol. XX, No. XX, XXXX

1
Interestingly, when the reaction of 2d was carried out,
the generation of gem-difluorosilylallenyl sulfide 6d was
analyzed by GC-MS. The main GC-MS peak appeared at
m/z = 179 (MþꢀtBu) [MW = 236 (C10H18F2SSi)], which
would suggest the structure of 6d. After the usual workup
of the reaction, the residual oil was purified by distillation
to give 6d along with a small amount of inevitable con-
taminants. The structure of 6d was further confirmed by
19F and 13C NMR spectra. Both terminal fluorine signals
appeared at ꢀ103.48 ppm (s). The central sp-carbon was
observed at 165.3 ppm (t, J = 35.1 Hz), and two sp2-
carbons at two ends of the allenyl moiety appeared at
156.4 ppm (t, J = 259.3 Hz) and 134.4 ppm (t, J = 7.0 Hz)
(Scheme 1). Unfortunately, purification of the product
using silica gel column chromatography resulted in the
decomposition of 6d as observed by multiple peaks in
GC-MS analysis.
The structure of 8g was confirmed by H, 13C, and
19F NMR spectra and FT-IR. The methine proton signal
was observed at 4.4 ppm (ddd, J = 12.3, 8.2, 6.4 Hz). Two
sp-carbon signals appeared at 94.4 ppm (t, J = 4.7 Hz) and
96.1 ppm (t, J = 39.0 Hz). Two signals of the geminal
fluorines were observed at ꢀ85.0 ppm (dd, J = 267.0,
8.2 Hz) and ꢀ88.0 ppm (dd, J = 267.0, 12.2 Hz). The peak
at 2186 cmꢀ1 in the FT-IR spectrum was assigned to
CC triple bond stretching vibrations. However, this gem-
difluorohomopropargyl thiol 8g gradually turned yellow
at room temperature after solvent removal, giving several
peaks by GC-MS because of its unstable nature.
We also found further transformation of 8g to the
novel fluorinated thiophene 10ga via the corresponding
3,3-difluorodehydrothiophene 9g (Scheme 3).9
Scheme 3. Synthesis of 2-Phenyl-3-fluoro-5-triethylsilylthio-
phene (10ga)
Scheme 1. Reaction of 2a and 2d with LDA in the Presence of
Me3SiCl
These results prompted us to examine the overall trans-
formation reaction from 2g to 10ga. Selected reaction
conditions of this one-pot synthesis of 3-fluorothiophene
derivative 10 are shown in Table 3.
However, to our surprise, when we carried out the
reaction of 2g with LDA (2.2 equiv) in the presence of
TESCl (2.0 equiv) in THF at ꢀ78 °C for 10 min, we
observed one new peak in GC-MS analysis at m/z = 397
(MþꢀEt) [MW = 426 (C22H36F2SSi2)] which would
suggest the structure of 7g together with the unreacted
2g (ca. 40%). No consumption of the remaining 2g
occurred during stirring at room temperature for a pro-
longed reaction time. For the complete consumption of
2g we performed a similar reaction with excess LDA
(3.3 equiv) in the presence of excess TESCl (3.0 equiv).
The reaction cleanly proceeded to give the unexpected
gem-difluorohomopropargyl thiol 8g in 82% yield as a
desilylated product of 7g after silica gel column purifica-
tion (Scheme 2).
Table 3. Screening of One-Pot Reaction Conditions of 2g
yielda
entry
R3SiCl
workup
additive product
[%]
1
2
3
4
5
6
Et3SiCl
Et3SiCl
Et3SiCl
Me3SiCl
sat. NaHCO3
sat. NaCl
sat. NaCl
sat. NaCl
Et3N
none
Et3N
Et3N
Et3N
Et3N
10ga
10ga
10ga
10ga
10ga
10ga
82
79
83
79
PhMe2SiCl sat. NaCl
Ph2MeSiCl sat. NaCl
70b
45c
a Isolated yield. b 93% purity. c The corresponding desilylated
3-fluorothiophene derivative was isolated in 29% yield.
Scheme 2. Synthesis of gem-Difluorohomopropargyl Thiol (8g)
After an extensive screening of reaction parameters
(including chlorosilane, workup, and the additive), we
identified the following three factors for generating 2-phe-
nyl-3-fluoro-5-triethylsilylthiophene (10ga) in 83% chemi-
cal yield (entry 3): (1) Chlorotriethylsilane (Et3SiCl) was
1
(9) The structure of 9g waþs identified by H and 19F NMR spectra
and GC-MS [m/z = 312 (6, M )]. The methine proton signal appeared at
5.82 (s), and the vinylic proton signal, at 4.89 (dd, J = 20.8, 17.4 Hz),
respectively. Two gem-fluorine signals appeared at ꢀ85.0 (dd, J = 254.8,
20.8 Hz) and ꢀ86.1 (dd, J = 254.8, 17.4 Hz), respectively. This
4,4-difluoro-3,4-dihydrothiophene (9g) was easily transformed into
10ga during silica gel column chromatographic purification.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Plausible Mechanism for 3-Fluorothiophene
Formation
Figure 1. 2-Aryl-3-fluoro-5-triethylsilylthiophenes (10).
the optimal silylating agent. (2) Direct addition of aqueous
sodium chloride solution to the reaction mixture at ꢀ78 °C
was suitable for quenching the reaction. (3) The successive
cyclization reaction was accelerated in the presence of
triethylamine (see experimental details in Supporting
Information). It is noteworthy that this one-pot protocol
requires silica gel chromatographic purification only once.
Under the optimized reaction conditions, the scope of
this one-pot 3-fluorothiophene synthesis was demonstrated
with a series of 2-bromo-3,3-difluoroallyl sulfides 2fꢀ2l.
When we employed the sulfides 2hꢀ2k, the reaction simi-
larly proceeded to give the corresponding 3-fluorothiophene
derivative 10haꢀ10ka in high yields, respectively (Figure 1).
In contrast, treatment of 2f and 2l under identical conditions
did not give the desired 3-fluorothiophene derivatives but
the corresponding gem-difluoroallene derivatives 5f and 5l
(not shown).
With these experimental results, our plausible reaction
mechanism is postulated in Scheme 4. Initially, 2-bromo-
3,3-difluoroallyl benzyl sulfide (2g) undergoes deprotona-
tion at the benzylic instead of the allylic position, followed
by [2,3]sigmatropic rearrangement to form the corre-
sponding gem-difluorohomopropargyl thiolate B.10 After
the formation of the silylated product C, although such
intermediates have not been observed, the bromoethylene
moiety was transformed into the terminal acetylene
by LDA followed by silylation at the terminal carbon
to yield the product (7g). Desilylation of 7g proceeds,
giving the free gem-difluorohomopropargyl thiol (8g)
under basic aqueous conditions, which undergoes similar
intramolecular cyclization in a 5-endodig fashion, as re-
ported by Hammond.11 Finally, the resulting 4,4-difluoro-
3,4-dihydrothiophene (9g) easily undergoes aromatization
on the silica gel column chromatography yielding the
3-fluorothiophene 10ga.
In conclusion, we have developed the first successful
SN20-type reaction of 2-bromo-3,3,3-trifluoropropene (1)
and various thiols. The reaction provides the correspond-
ing 2-bromo-3,3-difluoroallyl sulfides (2) in good to high
yields with high to excellent selectivities. The resulting
2-bromo-3,3-difluoroallyl benzyl sulfides are then effi-
ciently transformed into the novel 2-aryl-3-fluoro-5-
triethylsilylthiophenes (10) in high yields. Studies on re-
lated synthetic transformations of 3-fluorothiophene
(10) and the alternative synthetic use of 2-bromo-3,3-
difluoroallyl sulfides (2) are in progress in our laboratory.
Acknowledgment. We greatly thank TOSOH FꢀTECH
Inc. for a gift of 2-bromo-3,3,3-trifluoropropene and also
thank Professor M. Jelokhani-Niaraki at Wilfrid Laurier
University for his crucial polishing of this manuscript.
Supporting Information Available. Experimental pro-
cedure and spectral data for new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(10) Biellmann, J.-F.; Ducep, J.-B. Org. React. 1982, 27, 1.
(11) (a) Arimitsu, S.; Jacobsen, J. M.; Hammond, G. B. J. Org. Chem.
2008, 73, 2886. (b) Sham, H. L.; Betebenner, D. A. Chem. Commun.
1991, 1134.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX