Silver-catalyzed vinylic C-F bond activation: Synthesis of 2-fluoroindoles from β,β-difluoro-o-sulfonamidostyrenes

Article abstract of DOI:10.1246/cl.160427

An electrophilic 5-endo-trig cyclization of β,β-difluoro-o-sulfonamidostyrenes was performed in 1,1,1,3,3,3-hexafluoropropan-2-ol using a Ag(I) catalyst and N,O-bis(trimethylsilyl)acetamide. In this process, vinylic C-F bond activation was achieved via silver-catalyzed β-fluorine elimination, accompanied by C-N bond formation, which led to the synthesis of 2-fluoroindoles.

Full text of DOI:10.1246/cl.160427

CL-160427
Received: April 27, 2016 | Accepted: May 13, 2016 | Web Released: May 20, 2016
Silver-catalyzed Vinylic C-F Bond Activation: Synthesis of
2-Fluoroindoles from β,β-Difluoro-o-sulfonamidostyrenes
Takeshi Fujita, Yota Watabe, Shigeyuki Yamashita, Hiroyuki Tanabe, Tomoya Nojima, and Junji Ichikawa*
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571
(E-mail: junji@chem.tsukuba.ac.jp)
An electrophilic 5-endo-trig cyclization of β,β-difluoro-o-
sulfonamidostyrenes was performed in 1,1,1,3,3,3-hexafluoropro-
pan-2-ol using a Ag(I) catalyst and N,O-bis(trimethylsilyl)acet-
amide. In this process, vinylic C-F bond activation was achieved
via silver-catalyzed β-fluorine elimination, accompanied by C-N
bond formation, which led to the synthesis of 2-fluoroindoles.
model substrate (Table 1). Heating 1a in 1,1,1,3,3,3-hexafluoro-
propan-2-ol (HFIP)10,11 yielded no cyclized product in the
presence of a catalytic amount of palladium complexes (Entries
2-4), although cationic Pd(II) complexes in HFIP, which are
effective for carbocycle construction from β,β-difluorostyrene
derivatives,6b,6c,6d were employed (Entries 3 and 4). While PtCl2
was ineffective (Entry 5), the use of 10 mol % of Cu(OTf)2 or
AuCl afforded 2-fluoroindole 2a, albeit in extremely low yield
(Entries 6 and 7). As a result of screening several Ag(I) complexes
(Entries 8-12), AgSbF6 was found to be a prospective catalyst
because the quantitative formation of 2a was observed on the basis
of the amount of AgSbF6 (10 mol %) used (Entry 12).12 Thus, with
the aim of effective fluoride elimination, silylating agents were
examined as fluoride captors with 10 mol % of AgSbF6 (Entries
13-15). Among them, 1.0 equiv of BSA13 drastically promoted
defluorinative 5-endo-trig cyclization to afford 2a in 52% yield
(Entry 15). This reaction definitively proceeded with a metal
Keywords: C–F bond activation
| Silver catalyst | Fluoroindole
Because 1,1-difluoro-1-alkenes are electron-deficient substan-
ces, they readily react with strong nucleophiles at the carbon α to
fluorine substituents. The nucleophilic addition, followed by β-
fluorine elimination, affords monofluoroalkenes.1 By applying the
above-mentioned reaction to intramolecular cyclization, we pre-
viously synthesized ring-fluorinated hetero- and carbocyclic com-
pounds.2 Particularly, we achieved 5-endo-trig cyclization, which
is disfavored in Baldwin’s rules,3 using β,β-difluoro-o-sulfonam-
idostyrenes 1 as substrates, leading to fluoroindole synthesis
(Scheme 1a).2
Addition-elimination reactions of 1,1-difluoro-1-alkenes with
weak nucleophiles require electrophilic alkene activation,4 recently
achieved by acids5 or transition-metal complexes.6 Electrophilic
addition-elimination of 1,1-difluoro-1-alkenes potentially exhibits
a wide substrate scope by excluding basic conditions. In some
cases, however, monofluoroalkene products were susceptible to
hydrolysis under such acidic conditions and converted to carbonyl
compounds.5c,5g,6a,6b We herein report a transition-metal catalysis
providing 2-fluoroindoles 2 via an electrophilic 5-endo-trig cy-
clization7 of difluorosulfonamidostyrenes 1 without hydrolysis
(Scheme 1b). The use of a Ag(I) catalyst and N,O-bis(trimethyl-
silyl)acetamide (BSA) as a fluoride captor is highly effective for
vinylic C-F bond activation8 via the β-elimination of AgF, an
unprecedented accomplishment.9
Table 1. Screening of conditions for electrophilic 5-endo-trig
cyclization of 1a
n-Bu
n-Bu
Catalyst (10 mol%)
Additive (1.0 equiv)
CF2
NHTs
1a
F
Solvent, reflux, 5 h
N
Ts
2a
Entry Catalyst
Additive
Solvent
2a/%a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19f
20h
®
Pd(OAc)2
[Pd(NCMe)4](BF4)2
PdCl2, AgOTf (1:2)
PtCl2
Cu(OTf)2
AuCl
AgF
®
®
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
N.D.b
N.D.b
N.D.b
N.D.b
N.D.b
<1
BF3¢OEt
BF3¢OEt
®
®
®
1
®
®
N.D.b
6
First, we sought suitable conditions for fluoroindole synthesis
using β,β-difluorostyrene 1a bearing a tosylamide group as a
AgOTf
AgNTf2
AgBF4
®
®
<1
7
10
N.D.b
31
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgF
®
(a) Previous Work
R'
TMSImdc
HMDSOd
BSAe
BSAe
BSAe
BSAe
BSAe
BSAe
NaH
CF2
NR''
52
Toluene
CH2Cl2
DMF
HFIP
HFIP
N.D.b
N.D.b
N.D.b
quant. (99)g
82 (82)g
R'
R'
Na
R
R
CF2
NHR''
F
N
R' Ag(I)
CF2
R
R''
R
cat. Ag(I)
BSA
1
2
aYield was determined by 19F NMR spectroscopy using PhCF3 as an
internal standard. bN.D.: not detected. cTMSImd: N-trimethylsilyl-
imidazole. dHMDSO: hexamethyldisiloxane. eBSA: N,O-bis(trimeth-
NHR''
NSiMe3
OSiMe3
BSA
(b) This Work
f
ylsilyl)acetamide. After a dropwise addition of BSA to the refluxed
solution over 2 h, the mixture was stirred for another 1 h. gIsolated
yield. hAfter a dropwise addition of BSA to the refluxed solution over
2 h, the mixture was stirred for another 3 h.
Scheme 1. Synthesis of 2-fluoroindoles 2 via 5-endo-trig cyclization
of β,β-difluoro-o-sulfonamidostyrenes 1.
964 | Chem. Lett. 2016, 45, 964–966 | doi:10.1246/cl.160427
© 2016 The Chemical Society of Japan

Table 2. Ag(I)-catalyzed synthesis of 2-fluoroindoles 2a
n-Bu
(a)
AgF
BSA*
(10 mol%)
(1.0 equiv)
R'
R'
AgSbF6 (10 mol%)
No Reaction
F
BSA (1.0 equiv)b
HFIP
reflux, 1 h
reflux, 5 h
n-Bu
N
CF2
Ts
F
HFIP, reflux
N
CF2
NHTs
1a
2a 81%
NHR''
R
R''
R
* Slow addition over 2 h
1
2
BSA
(1.0 equiv)
No Reaction
n-Bu
n-Bu
n-Bu
reflux, 5 h
F
F
F
F
(b)
(c)
N
N
N
n-Bu
BSA
(1.0 equiv)
1a
Ts
Ts
Ts
NSiMe3
(1.0 equiv)
Ag+
AgF
2a 99% (3 h)
n-Bu
2b 99% (4 h)
n-Bu
2c 98% (6 h)
n-Bu
F
HFIP
reflux, 20 min
O
reflux, 30 min
N
+
Ts
Me3SiF
92%
19F NMR yield)
2a 80%
MeO
EtO2C
Cl
F
F
F
(
N
N
N
Ts
2d 52% (6 h)
Ts
Ts
n-Bu
n-Bu
2e 87% (3 h)c
2f 79% (4 h)c
AgSbF6 (1.0 equiv)
HFIP, reflux, 5 h
CF2
NHTs
1a
F
N
sec-Bu
Bn
SiMe3
F
Ts
2a 25%
19F NMR yield)
F
(
N
N
N
Ts
Ts
Ts
2h 52% (5 h)c
Scheme 2. Mechanistic studies on Ag(I)-catalyzed cyclization of 1a.
2g 88% (3 h)
n-Bu
2i 82% (5 h)
n-Bu
n-Bu
AgSbF6
NSiMe3
F
F
F
N
N
N
R'
OSiMe3
Ms
Ns
SO2Mes
CF2
NHR''
2j 32% (6 h)
2k 66% (6 h)
2l 98% (3 h)
FSiMe3
NSiMe3
O
Ag+
aIsolated yield. bBSA was slowly added over 2 h. cAgF (20 mol %) was
used instead of AgSbF6.
R
1
NSiMe3
OSiMe3
R'
catalyst in HFIP because the formation of 2a was not observed in
the absence of the catalyst (Entry 1) or in other solvents (Entries
16-18). Eventually, the slow addition of BSA over 2 h was found
to be a significant operation, which led to an almost quantitative
formation of 2a (Entry 19). Notably, the combination of 10 mol %
of AgF and 1.0 equiv of BSA also successfully afforded 2a in 82%
isolated yield (Entry 20), although AgF caused no cyclization
without BSA (Entry 8).
Ag+
CF2
AgF
NSiMe3
–
NHR''
O
R
β-Fluorine
5-endo-trig
Addition
Elimination
R'
R'
Ag
F
F
N
F
R
R''
NHSiMe3
N
Using the above-mentioned optimal conditions, the scope of
the cyclization of amidodifluorostyrenes 1 was then investigated
(Table 2). β,β-Difluorostyrenes 1b and 1c bearing a methyl group
successfully underwent cyclization, leading to an almost quantita-
tive formation of the corresponding 2-fluoroindoles 2b and 2c,
respectively. Ether (MeO), ester (EtO2C), and halogen (Cl)
substituents in difluorostyrenes 1d-1f were tolerated in this
reaction, which afforded the corresponding fluoroindoles 2d-2f,
while AgF was more effective than AgSbF6 for the cyclization of 1e
and 1f. Secondary alkyl (sec-Bu), benzyl, and silyl (Me3Si) groups
were installed instead of a primary alkyl group at the 3-position of
the pyrrole rings of fluoroindoles 2g-2i. The substitution of mesyl,
nosyl, and mesitylenesulfonyl groups on a nitrogen atom was
achieved to afford diversely sulfonylated 2-fluoroindoles 2j-2l.
To gain information on the role of BSA, we performed
experiments shown in Scheme 2. In the presence of 10 mol % of
AgF, an HFIP solution of β,β-difluorostyrene 1a was refluxed, and
no reaction was observed (Scheme 2a; see also Entry 8, Table 1);
however, further addition of a stoichiometric amount of BSA
promoted 5-endo-trig cyclization to afford 2-fluoroindole 2a in
2
R''
R
O
Scheme 3. Proposed mechanism for Ag(I)-catalyzed 5-endo-trig
cyclization of 1a via C-F bond activation.
81% yield. Conversely, BSA alone did not cause cyclization
(Scheme 2a). When AgF was treated with BSA, trimethylsilyl
fluoride was obtained in 92% yield, indicating the formation of a
Ag(I) amidate complex (Scheme 2b). The addition of 1a to the
reaction mixture afforded 2a in 80% yield (Scheme 2b). Further-
more, on treatment with a stoichiometric amount of AgSbF6 in the
absence of BSA, 1a gave 2a in only 25% yield (Scheme 2c).
These results suggest that the active species is Ag(I) amidate and
not AgSbF6.
Based on all these observations, we propose a mechanism for
the Ag(I)-catalyzed 5-endo-trig cyclization of β,β-difluorostyrenes
1 (Scheme 3). The reaction starts with the generation of the Ag(I)
amidate complex from AgSbF6 and BSA. The coordination of 1
to the Ag(I) amidate complex induces 5-endo-trig addition of the
Chem. Lett. 2016, 45, 964–966 | doi:10.1246/cl.160427
© 2016 The Chemical Society of Japan | 965

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In summary, we developed a synthetic method for the
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fluorine substituent at the 2-position. The obtained fluoroindoles
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This work was financially supported by JSPS KAKENHI
Grant Number JP16H01002 (J.I.) in Precisely Designed Catalysts
with Customized Scaffolding and JSPS KAKENHI Grant Number
JP16K20939 (T.F.) in Grant-in-Aid for Young Scientists (B). We
acknowledge the generous gifts of (CF3)2CHOH (HFIP, Central
Glass Co., Ltd.), CF3CH2OH, and CF3CH2I (Tosoh F-Tech, Inc.).
Supporting Information is available on http://dx.doi.org/
10.1246/cl.160427.
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966 | Chem. Lett. 2016, 45, 964–966 | doi:10.1246/cl.160427
© 2016 The Chemical Society of Japan