Silver-catalyzed Vinylic C­F 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)
The silver(I)-catalyzed vinylic C­F bond activation was achieved via 5-endo-trig addition/β-ﬂuorine elimination sequence of
diﬂuorosulfonamidostyrenes by using N,O-bis(trimethylsilyl)acetamide (BSA) to aﬀord 2-ﬂuoroindoles.
R' Ag(I)

R'
CF2
R

NH
R''

F

cat. Ag(I)
Si X
R

F
NH
R''

5-endo-trig
AdditionR'

β-Fluorine
Elimination

N
R''

F
R

REPRINTED FROM

Vol.45 No.8

2016 p.964–966
CMLTAG
August 5, 2016

The Chemical Society of Japan

CL-160427

Received: April 27, 2016 | Accepted: May 13, 2016 | Web Released: May 20, 2016

Silver-catalyzed Vinylic C­F 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-osulfonamidostyrenes 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 C­F bond activation was achieved
via silver-catalyzed β-ﬂuorine elimination, accompanied by C­Nbond formation, which led to the synthesis of 2-ﬂuoroindoles.
Keywords: C–F bond activation | Silver catalyst | Fluoroindole

Because 1,1-diﬂuoro-1-alkenes are electron-deﬁcient substances, they readily react with strong nucleophiles at the carbon α toﬂuorine substituents. The nucleophilic addition, followed by βﬂuorine elimination, aﬀords monoﬂuoroalkenes.1 By applying theabove-mentioned reaction to intramolecular cyclization, we previously synthesized ring-ﬂuorinated hetero- and carbocyclic compounds.2 Particularly, we achieved 5-endo-trig cyclization, which
is disfavored in Baldwin’s rules,3 using β,β-diﬂuoro-o-sulfonamidostyrenes 1 as substrates, leading to ﬂuoroindole synthesis(Scheme 1a).2
Addition­elimination reactions of 1,1-diﬂuoro-1-alkenes withweak nucleophiles require electrophilic alkene activation,4 recently
achieved by acids5 or transition-metal complexes.6 Electrophilic
addition­elimination of 1,1-diﬂuoro-1-alkenes potentially exhibitsa wide substrate scope by excluding basic conditions. In somecases, however, monoﬂuoroalkene products were susceptible tohydrolysis under such acidic conditions and converted to carbonylcompounds.5c,5g,6a,6b We herein report a transition-metal catalysis
providing 2-ﬂuoroindoles 2 via an electrophilic 5-endo-trig cyclization7 of diﬂuorosulfonamidostyrenes 1 without hydrolysis(Scheme 1b). The use of a Ag(I) catalyst and N,O-bis(trimethylsilyl)acetamide (BSA) as a ﬂuoride captor is highly eﬀective forvinylic C­F bond activation8 via the β-elimination of AgF, an
unprecedented accomplishment.9
First, we sought suitable conditions for ﬂuoroindole synthesis
using β,β-diﬂuorostyrene 1a bearing a tosylamide group as amodel substrate (Table 1). Heating 1a in 1,1,1,3,3,3-hexaﬂuoropropan-2-ol (HFIP)10,11 yielded no cyclized product in thepresence of a catalytic amount of palladium complexes (Entries
2­4), although cationic Pd(II) complexes in HFIP, which areeﬀective 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 8­12), AgSbF6 was found to be a prospective catalyst
because the quantitative formation of 2a was observed on the basisof the amount of AgSbF6 (10 mol %) used (Entry 12).12 Thus, withthe aim of eﬀective ﬂuoride elimination, silylating agents were
examined as ﬂuoride captors with 10 mol % of AgSbF6 (Entries
13­15). 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
Table 1. Screening of conditions for electrophilic 5-endo-trig
cyclization of 1a
n-Bu
CF2
NHTs

R

R

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
AgOTf
AgNTf2AgBF4AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6AgF®
®
BF3¢OEt
BF3¢OEt
®
®
®
®
®
®
®
®
TMSImdc
HMDSOd
BSAe
BSAe
BSAe
BSAe
BSAe
BSAe

HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
Toluene
CH2Cl2
DMF
HFIP
HFIP

N.D.b
N.D.b
N.D.b
N.D.b
N.D.b
<1
1
N.D.b
6
<1
7
10
N.D.b
31
52
N.D.b
N.D.b
N.D.b
quant. (99)g
82 (82)gF

1

R' Ag(I)cat. Ag(I)

N
R''

R

CF2

F

Additive

R'

CF2
NHR''

N
Ts
2a

1a

CF2
NR'' Na

Solvent, reflux, 5 hCatalyst

R'

R'

n-Bu

Entry

(a) Previous Work
NaH

Catalyst (10 mol%)
Additive (1.0 equiv)

2

Yield was determined by 19F NMR spectroscopy using PhCF3 as aninternal standard. bN.D.: not detected. cTMSImd: N-trimethylsilylimidazole. dHMDSO: hexamethyldisiloxane. eBSA: N,O-bis(trimethylsilyl)acetamide. fAfter 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.
a

BSA
R

NHR''

(b) This Work

NSiMe3OSiMe3
BSA

Scheme 1. Synthesis of 2-ﬂuoroindoles 2 via 5-endo-trig cyclizationof 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 2aR'
CF2

AgSbF6 (10 mol%)
BSA (1.0 equiv)b

HFIP
reflux, 1 h

F

n-Bu
F

No Reaction
F

(b)

n-Bu

BSA
(1.0 equiv)
HFIP
reflux, 20 min

n-Bu
Cl

F

F

F

N
Ts

N
Ts

N
Ts

2d 52% (6 h)2e 87% (3 h)c

2f 79% (4 h)c

(c)

Bn
F

N
Ts

SiMe3
F

N
Ts

2g 88% (3 h)
n-Bu

O

n-Bu

2i 82% (5 h)n-Bureflux, 30 min

NTs
2a 80%

F+
Me3SiF
92%(19F NMR yield)

AgSbF6 (1.0 equiv)
HFIP, reflux, 5 hNTs2h 52% (5 h)c1a(1.0 equiv)

n-Bu

NHTs
1a

F

Ag+

n-Bu
CF2

sec-BuNSiMe3AgF

2c 98% (6 h)

EtO2C

F

reflux, 5 hNTs

2b 99% (4 h)

n-Bu

N
Ts
2a 81%

BSA(1.0 equiv)

n-Bu

N
Ts

2a 99% (3 h)reflux, 5 h* Slow addition over 2 h

NHTs
1a

F

N
Ts

n-Bu

CF2

2

n-Bu

BSA*
(1.0 equiv)
No Reaction

N
R''

R

1

MeO

AgF
(10 mol%)n-Bu

HFIP, reflux

NHR''

R

(a)

R'

F
N
Ts
2a 25%(19F NMR yield)

Scheme 2. Mechanistic studies on Ag(I)-catalyzed cyclization of 1a.

n-Bu

AgSbF6FN
Ms
2j 32% (6 h)FNNs
2k 66% (6 h)NSiMe3F
N
SO2MesR'

OSiMe32l 98% (3 h)CF2FSiMe3aIsolated yield. bBSA was slowly added over 2 h. cAgF (20 mol %) wasused instead of AgSbF6.

NSiMe3Ag+

R

O

NSiMe3NHR''
1

OSiMe3

catalyst in HFIP because the formation of 2a was not observed in
the absence of the catalyst (Entry 1) or in other solvents (Entries
16­18). Eventually, the slow addition of BSA over 2 h was foundto 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).
Using the above-mentioned optimal conditions, the scope ofthe cyclization of amidodiﬂuorostyrenes 1 was then investigated(Table 2). β,β-Diﬂuorostyrenes 1b and 1c bearing a methyl groupsuccessfully underwent cyclization, leading to an almost quantitative formation of the corresponding 2-ﬂuoroindoles 2b and 2c,
respectively. Ether (MeO), ester (EtO2C), and halogen (Cl)substituents in diﬂuorostyrenes 1d­1f were tolerated in thisreaction, which aﬀorded the corresponding ﬂuoroindoles 2d­2f,
while AgF was more eﬀective than AgSbF6 for the cyclization of 1eand 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 2g­2i. The substitution of mesyl,
nosyl, and mesitylenesulfonyl groups on a nitrogen atom wasachieved to aﬀord diversely sulfonylated 2-ﬂuoroindoles 2j­2l.
To gain information on the role of BSA, we performedexperiments shown in Scheme 2. In the presence of 10 mol % of
AgF, an HFIP solution of β,β-diﬂuorostyrene 1a was reﬂuxed, andno 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

Chem. Lett. 2016, 45, 964–966 | doi:10.1246/cl.160427

R' Ag+AgF

CF2

NSiMe3–

NHR'' OR

β-Fluorine
Elimination

R'

5-endo-trig
Addition
R'

F
N
R''

R
2

R

Ag
F
N F
R''

NHSiMe3O

Scheme 3. Proposed mechanism for Ag(I)-catalyzed 5-endo-trig
cyclization of 1a via C­F 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 aAg(I) amidate complex (Scheme 2b). The addition of 1a to thereaction mixture aﬀorded 2a in 80% yield (Scheme 2b). Furthermore, on treatment with a stoichiometric amount of AgSbF6 in theabsence of BSA, 1a gave 2a in only 25% yield (Scheme 2c).
These results suggest that the active species is Ag(I) amidate andnot 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© 2016 The Chemical Society of Japan | 965

sulfonamido group. Unprecedented β-elimination of AgF causesC­F bond cleavage to aﬀord 2-ﬂuoroindoles 2. The reaction of
AgF with BSA then regenerates Ag(I) amidate to complete thecatalytic cycle.
In summary, we developed a synthetic method for theformation of 2-ﬂuoroindoles via Ag-catalyzed vinylic C­F bondactivation achieved by a 5-endo-trig addition/β-ﬂuorine elimination sequence. The current method enables the simultaneous
construction of an indole framework and the installation of a
ﬂuorine substituent at the 2-position. The obtained ﬂuoroindoles
are expected to constitute a new class of bioactive compounds
because the indole ring and ﬂuorine substituent are common
components in pharmaceuticals.14
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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© 2016 The Chemical Society of Japan