Highly enantioselective monofluoromethylation of C2-arylindoles using FBSM under chiral phase-transfer catalysis

Article abstract of DOI:10.1021/ol4013102

The highly enantioselective addition of 1-fluoro-1,1-bis(phenylsulfonyl) methane (FBSM) to vinylogous imines generated in situ from 2-aryl-3-(1- arylsulfonylmethyl)indoles was achieved using chiral ammonium salts derived from cinchona alkaloids. One-pot c

Full text of DOI:10.1021/ol4013102

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Enantioselective
Monofluoromethylation of C2-Arylindoles
Using FBSM under Chiral Phase-Transfer
Catalysis
Kohei Matsuzaki,† Tatsuya Furukawa,† Etsuko Tokunaga,† Takashi Matsumoto,‡
Motoo Shiro,‡ and Norio Shibata*,†
Department of Frontier Materials, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya, 466-8555, Japan, and Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima,
Tokyo 196-8666, Japan
nozshiba@nitech.ac.jp
Received May 11, 2013
ABSTRACT
The highly enantioselective addition of 1-fluoro-1,1-bis(phenylsulfonyl)methane (FBSM) to vinylogous imines generated in situ from 2-aryl-3-(1-
arylsulfonylmethyl)indoles was achieved using chiral ammonium salts derived from cinchona alkaloids. One-pot conversion from 2-arylindoles
with FBSM was also adaptable under the same reaction conditions. The key for this transformation is the effective use of the arylsulfonyl group.
Fluorine has become a fundamental tool for drug dis-
covery and material science because of its exceptionally
unique properties such as high electron negativity and
small size, despite its extremely rare natural occurrence.1
Nearly 30% of pharmaceuticals and agrochemicals on the
market are said to contain at least one fluorine atom
somewhere intheir structures.2 Due tothe sizeresemblance
of fluorine and hydrogen, fluorine is often used as an
isosteric substitution of hydrogen.3 From the viewpoint
of electronegativity, however, fluorine substitution can be
recognized as an isosteric substitution of hydroxy group.3
Therefore, a monofluoromethyl group (CH2F) is an at-
tractive impersonator of both the corresponding methyl
(CH3) and hydroxymethyl (CH2OH) groups, which are
often encountered in biologically active materials.4 There-
fore, the development of a new strategy to synthesize
CH2F-containing organic compounds has attracted much
attention. In particular, the asymmetric introduction of
a CH2F function into target molecules is important due to
a recent requirement from the chiral drug industry. In
2006, our group5 and Hu’s group6 independently devel-
oped 1-fluoro-1,1-bis(phenylsulfonyl)methane (FBSM) as
a synthetic equivalent of a monofluoromethyl anion spe-
cies for the direct construction of a CÀCH2F bond. FBSM
(4) (a) Grunewald, G. L.; Seim, M. R.; Regier, R. C.; Martin, J. L.;
Gee, L.; Drinkwater, N.; Criscione, K. R. J. Med. Chem. 2006, 49, 5424.
(b) Kollonitsch, J.; Patchett, A. A.; Marburg, S.; Maycock, A. L;
Perkins, L. M.; Doldouras, G. A.; Duggan, D. E.; Aster, S. D. Nature
1978, 274, 906.
† Nagoya Institute of Technology.
‡ Rigaku Corporation.
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S.; Toru, T. Angew. Chem., Int. Ed. 2006, 45, 4973. (b) Liu, W. B.; Zheng,
S. C.; He, H.; Zhao, X. M.; Dai, L. X.; You, S. L. Chem. Commun. 2009,
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r
10.1021/ol4013102
XXXX American Chemical Society

is now commercially available, and the FBSM method
has clear advantages over other methods for the synthesis
of chiral C*ÀCH2F compounds such as dehydroxy-
fluorination of C*ÀCH2OH compounds by DAST, since
asymmetric synthesis of chiral C*ÀCH2OH compounds
followed by racemization-free dehydroxyfluorination
should be required. A number of nucleophilic monofluor-
omethylation reactions using FBSM have emerged,7,8 and
the Mannich-type reaction via in situ generated imines is
effective for the asymmetric synthesis of R-monofluoro-
methylated amines (Scheme 1a).9 As an extension of this
work, herein we disclose an enantioselective monofluor-
omethylation reaction of C2-arylindoles 1 via vinylogous
imines generated in situ with FBSM to provide mono-
fluoromethylated indole derivatives 2 (Scheme 1b). The
key for these transformations is the effective use of the
arylsulfonyl group for the activation of both the substrates
and reagent, FBSM.10
Indole and its derivatives are important and common
structural motifs in pharmaceuticals and agrochemicals.11
In particular, C2-arylindoles are ubiquitous substructures
indoles.12 With these background facts, we were interested
in the asymmetric synthesis of C2-arylindoles having a
CH2F group on the chiral center. The idea for the genera-
tion of vinylogous imines of indoles using an arylsulfonyl
group as a leaving group was initially reported by Petrini
group. Broad scopes of C3-substituted indoles can be
obtained via this method.13
Scheme 1. Strategies for Enantioselective Monofluoromethyla-
tion via in Situ Generated Imines (a) and Vinylogous Imines (b)
Using FBSM
Although some work on enantioselective nucleophilic
additions to vinylogous imine intermediates generated
from arylsulfonyl indoles 1 under organo or Lewis acid
catalysis has been reported,14 these conditions are not
applicable for the monofluoromethylation of 1 by FBSM,
since the activation of the CH group of FBSM requires a
stronger basic condition. We first tested the monofluor-
omethylation reaction of arylsulfonyl indoles 1a with
FBSM under the best conditions for our reported asym-
metric Mannich-type fluoromethylation reaction using
benzylquinidium chloride 3a as a phase-transfer catalyst
in the presence of K2CO3 in CH2Cl2 at room temperature.
However, the initial attempt was quite disappointing, and
a racemic product 2a was afforded in 56% yield (Table 1,
entry 1). Similar results were obtained when the reaction
was performed in the presence of catalysts QN-3b or
CD-3d, respectively (entries 2 and 4). The enantioselec-
tivity increased slightly to 16% when benzylcinchoninium
chloride CN-3c was attempted (entry 3). Then we tried to
tune the steric hindrance of the catalyst based on CN-3c
(entries 5À7). In the presence of benzylcinchoninium
bromide CN-3f, which bears a sterically demanding benzyl
substituent, high yield with an acceptable enantioselectiv-
ity (70%) was afforded (entry 6). After screening various
basesand solvents(Table1, entries8À10),15 a combination
of CN-3f and Cs2CO3 in toluene gave (R)-2a with high
enantioselectivity, up to 74% ee (entry 10). Further opti-
mization of reaction temperature and concentration was
studied, and high enantioselectivity (90% ee) was found in
toluene (0.040 M) at À10 °C (entry 12). It should be noted
that OH-protected derivative CN-3h led to high yield but
low enantioselectivity (entry 14). The result indicated
that the free hydroxy group of the cinchona alkaloid is
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(15) Among the solvents tested, toluene was optimal. Reactions
conducted in more polar solvents showed increased background reac-
tivity and decrease in enantiocontrol.
B
Org. Lett., Vol. XX, No. XX, XXXX

indispensable for achieving high enantiocontrol, presum-
ably by hydrogen bonding.
thereactionand the eevaluewasexcellent (entry 11). When
we attempted to react the substrates having an alkyl group
at the R position with FBSM, the yields and ee values
remained good (entries 12À14). It should be noted that the
C2-aryl group of indole derivatives is often crucial for their
biological activities;11,12 it also plays an important role for
asymmetric induction in the present reaction. The reac-
tions of substrates possessing either methyl or hydrogen at
the C2 position afforded an almost racemic mixture of 2
with high yields (entries 14 and 15). Since it was reported
that E/Z configurations of imino intermediates play an
important role on enantioselectivities,14bÀe we assumed
that the phenyl group at the C2 position was the ideal
intermediate for this reaction. The absolute stereochemis-
try of (R)-2a was determined by X-ray crystallographic
analysis (CCDC 937472, see the Supporting Information),
and all of the other products are tentatively assigned by
analogy to 2a.
Table 1. Optimization of the Reaction Conditionsa
Table 2. Enantioselective Monofluoromethylation of C3-Substi-
tuted Indoles with FBSM Catalyzed by Phase-Transfer Catalysta
entry
catalyst
base
K2CO3
yieldb (%)
eec (%)
1
QD-3a
QN-3b
CN-3c
CD-3d
CN-3e
CN-3f
CN-3g
CN-3f
CN-3f
CN-3f
CN-3f
CN-3f
CN-3f
CN-3h
56
56
53
51
34
52
11
58
92
99
99
94
93
94
1 (S)
6 (S)
2
K2CO3
3
K2CO3
16 (R)
10 (S)
58 (R)
70 (R)
9 (S)
entry
1
Ar, R
Ph, Ph
2
yieldb (%)
eec (%)
4
K2CO3
5
K2CO3
1
1a
1a
1b
1c
1d
1e
1f
(R)-2a
(S)-2a
(R)-2b
(R)-2c
(R)-2d
(R)-2e
(R)-2f
(R)-2g
(R)-2h
(R)-2i
(R)-2j
(R)-2k
(R)-2l
(R)-2m
(R)-2n
94
98
78
77
91
99
83
80
74
78
92
54
74
93
94
90
86
80
87
85
88
88
86
84
83
97
53
57
17
1
2d
3
Ph, Ph
6
K2CO3
7
K2CO3
Ph, 4-ClC6H4
Ph, 3-ClC6H4
Ph, 4-FC6H4
Ph, 3-FC6H4
Ph, 3-BrC6H4
Ph, 4-MeOC6H4
Ph, 4-MeC6H4
Ph, 4-iBuC6H4
4-MeC6H4, Ph
Ph, Et
8
KF/alumina
K3PO4
67 (R)
70 (R)
74 (R)
84 (R)
90 (R)
76 (R)
7 (R)
4
9
5
10d
11e
12e,f
13e,g
14e,f
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
6
7
8
1g
1h
1i
9
10
11e
12
13
14
15
1j
a Reactions were carried out using 2a, FBSM (1.1 equiv), catalyst
(10 mol %), and base (1.2 equiv) in toluene (0.20 M) at rt for 3À4 d unless
otherwise noted. b Isolated yield by silica gel column chromatography.
c The ee value was determined by HPLC analysis. d Reaction time was
1 d. e Reaction was carried out at À10 °C. f Reaction was carried out in
toluene (0.040 M). g Reaction was carried out in toluene (0.40 M).
1k
1l
Ph, C6H11
1m
1n
Me, Ph
H, Ph
a Reactions were carried out using 1, FBSM (1.1 equiv), CN-3f
(10 mol %), and Cs2CO3 (1.2 equiv) in toluene (0.040 M) at À10 °C
for 3À5 d. b Isolated yield by silica gel column chromatography. c The ee
value was determined by HPLC analysis. d CD-3i was used instead of
CN-3f. e Reaction was carried out using solvent (0.20 M).
With optimal conditions in hand, the scope of substrate
1 for enantioselective monofluoromethylation with FBSM
was investigated (Table 2). By using a catalytic amount of
CN-3f (10 mol %), all substrates functionalized at R and
the Ar position with the aryl group afforded products in
moderate to excellent yield and high enantioselectivity
(entries 1À11). Notably, using the analogous ammonium
bromide derived from cinchonidine (CD-3i), a similar ee
value was obtained for 2a, albeit with the opposite (S)
stereochemistry (entry 2). Bothelectron-withdrawingand -
donating groups at the para or meta position of the phenyl
ring were tolerated (entries 3À11). In the case of substrate
1j, a smaller amount of toluene was required to complete
The conjugate addition adduct 2a could be directly
converted into the corresponding monofluoromethylated
derivative 4a. A simple one-step reduction of the two
phenylsulfonyl groups was realized under conventional
Mg/MeOH conditions to furnish the product in 61%
without major loss of enantiopurity of 2a (Scheme 2).
To further expand the application of this reaction, we
were interested in a one-pot process from simple indoles to
the asymmetric conjugate addition of FBSM using indium
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Reductive Desulfonylation of (R)-2a
Scheme 3. One-Pot Reaction from 5 to 2a
a Reactions were carried out using indoles 5 (1.1 equiv), R-amidosul-
fones 6, InBr3 (10 mol %), CN-3f (10 mol %), Cs2CO3 (2.0 equiv), and
FBSM (1.1 equiv) in toluene (0.040 M) at rt to À10 °C for 6 d.
salt as a Lewis acid promoter (Scheme 3). In the first step,
InBr3 was used tocatalyzethe FriedelÀCraftsalkylationof
indoles 5 with R-amido sulfones 6,16 which are readily
available from a commercial source.17 As the result, fol-
lowing the in situ formation of arylsulfonyl indoles, the
addition of FBSM, CN-3f, and Cs2CO3 furnished enan-
tioenriched products 2 in moderate to high yields with high
enantioselectivities. Compared with the results shown in
Table 2, the ee’s (%) of desired products 2 were slightly
lower owing to the potential interaction of FBSM with
indium salts.7a Thus, it is noteworthy that the addition of
all reagents in one pot would lead to the formation of a
Mannich-type adducts9 that resulted from R-amidosul-
fones 6 and FBSM.
In conclusion, the PTC-catalyzed asymmetric mono-
fluoromethylation of indole derivatives with FBSM via
in situ generated vinylogous imino intermediates was
achieved in high yields with high enantioselectivities for
the first time. Both enantiomers of the products (R)-2a
and (S)-2a with promised ee values can be accessible based
on the alterability of the catalysts, CN-3f or CD-3i. The
conjugate addition adducts would be useful building
blocks for the synthesis of chiral monofluoromethylated
2-arylindoles. The method developed herein can also be
extended into an asymmetric one-pot reaction. Further
investigations of this reaction and applications to the
synthesis of biologically interesting targets are underway
in our laboratory.
Acknowledgment. This study was financially supported
in part by the Platform for Drug Discovery, Informatics,
and Structural Life Science from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, by
Grants-in-Aid for Scientific Research from MEXT
(Ministry of Education, Culture, Sports, Science and
Technology) (24105513, Project No. 2304: Advanced Mo-
lecular Transformation by Organocatalysts), and JST
(ACT-C: Creation of Advanced Catalytic Transformation
for the Sustainable Manufacturing at Low Energy, Low
Environmental Load).
Supporting Information Available. Experimental de-
tails, X-ray crystal structure, analytical data (HRMS,
1
HPLC), and copies of H, 13C, and 19F NMR spectra
are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Thirupathi, P.; Kim, S. S. J. Org. Chem. 2009, 74, 7755.
(17) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX