Cinchona alkaloid-catalyzed enantioselective monofluoromethylation reaction based on fluorobis(phenylsulfonyl)methane chemistry combined with a Mannich-type reaction

Article abstract of DOI:10.1021/ja071509y

A catalytic protocol for the unprecedented enantioselective monofluoromethylation of in situ generated prochiral imines using 1-fluorobis(phenylsulfonyl)methane (FBSM, 1) in the presence of a chiral PTC based on the Mannich-type reaction followed by reduc

Full text of DOI:10.1021/ja071509y

Published on Web 04/27/2007
Cinchona Alkaloid-Catalyzed Enantioselective Monofluoromethylation
Reaction Based on Fluorobis(phenylsulfonyl)methane Chemistry Combined
with a Mannich-type Reaction
Satoshi Mizuta, Norio Shibata,* Yosuke Goto, Tatsuya Furukawa, Shuichi Nakamura, and
Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso,
Showa-ku, Nagoya 466-8555, Japan
Received March 3, 2007; E-mail: nozshiba@nitech.ac.jp; toru@nitech.ac.jp
Enantiocontrolled synthesis of fluorine-containing organic mol-
ecules is extremely important in the field of medicinal chemistry
and material science. Enantioselective fluorination and fluorom-
Table 1. Optimization of Bases, Quaternary Ammonium
Salts, and Solvents in the Reaction of R-Amido Sulfone 2a with
FBSM (1)a
1
ethylation reactions are especially attractive for this purpose because
nonfluorinated prochiral substrates can be directly transformed to
chiral fluoroorganic compounds with controlled absolute configu-
2
ration by these methods. Significant progress has been made in
the development of asymmetric fluorination reactions in recent
2
years; however, direct enantioselective fluoromethylation remains
a challenge.2
b-d,3,4
There are several reports on the stereocontrolled
nucleophilic additions of fluoromethyl groups to imines, and the
2b,4
majority of them have been accomplished using chiral auxiliaries.
Prakash et al. showed the fluoride anion catalyzed diastereoselective
temp
C)
yield
(%)
ee
run
catalyst
base
solvent
(
°
(%)
nucleophilic trifluoromethylation of optically active N-tert-(bu-
in 2001.4 Hu and co-workers
a-c
+
-
-
-
-
-
tanesulfinyl) imines using TMSCF
3
1
2
3
4
5
6
7
8
9
QD Cl
K2CO3
K2CO3(aq)
Cs2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
toluene
CH2Cl2
CH2Cl2
-40
-40
-40
-40
-40
-40
-40
-40
-80
-80
-80
trace
trace
trace
72
40
91
22
83
trace
72
79
+
QD Cl
successively demonstrated the diastereoselective difluoromethylation
+
QD Cl
as well as the monofluoromethylation reactions of the N-tert-
+
QD Cl
CsOH‚H2O
CsOH‚H2O
CsOH‚H2O
CsOH‚H2O
CsOH‚H2O
CsOH‚H2O
CsOH‚H2O
CsOH‚H2O
92
0
0
13
90
4d,e
(
butanesulfinyl) imines using LiCF
2
SO
2
Ph or LiCFHSO
2
Ph.
+
QN Cl
+
-
-
-
These nucleophilic additions of fluoromethyl groups to the chiral
CD Cl
+
CN Cl
imines offer chiral, nonracemic R-fluoromethyl amines of biological
+
QD Cl
5
interest; however, the corresponding enantioselective reactions have
+
-
-
-
QD Cl
been elusive until now in our knowledge. We recently found
+
10
QD Cl
97
97
b
+
1
-fluorobis(phenylsulfonyl)methane (FBSM, 1) to be a synthetic
11
QD Cl
equivalent of a fluoromethide species under the Tsuji-Trost allylic
alkylation conditions, which provided the palladium-catalyzed
asymmetric allylic monofluoromethylation reaction with high
a
All of the reaction was performed on 0.086 mmol scale of 2a. The
absolute stereochemistry of 3a was determined to be S after chemical
derivatization (see Supporting Information). b 5 mol % of catalyst was used.
6a
enantiocontrol. In connection with our studies on the development
of new methodology for asymmetric synthesis,2
f,g,6
herein we
corresponding R-amido sulfones8g via desulfonylation would be
disclose an unprecedented catalytic enantioselective monofluorom-
ethylation reaction of in situ generated prochiral imines with 1 in
the presence of a chiral phase transfer catalyst (PTC). The
methodology consists of two consecutive steps, the Mannich-type
reaction and reductive desulfonylation. The quaternary ammonium
salts derived from cinchona alkaloids are found to be effective for
chiral induction to the process. The key feature of our strategy is
the effective use of phenylsulfonyl groups throughout the sequence
of transformations that provide efficient access to enantiomerically
enriched R-monofluoromethylated amines.
suitable for the reaction with an unstable anion of 1. FBSM (1)
2 3
was added to a mixture of 2a and 1.2 equiv of K CO in toluene
in the presence of a catalytic amount of N-benzylquinidinium
+
-
chloride (QD Cl ) at -40 °C. However, even after 2 days of
stirring, a large amount of the starting material was detected by
TLC analysis, with a trace of addition product (Table 1, run 1).
The reaction was then attempted using aqueous K
as base, but the results were not improved (runs 2 and 3). To our
delight, the use of CsOH‚H O afforded the desired addition product
a in 72% with 92% ee (run 4). A considerable difference in
2 3 2 3
CO or Cs CO
2
3
asymmetric induction was noticed between ammonium salts derived
from quinine, quinidine, cinchonine, and cinchonidine, and quini-
dine was the most effective (runs 4-7). Better enantioselectivity
2 2
was observed in CH Cl (run 8), and the optimal enantiocontrol
was observed by lowering the temperature to -80 °C (run 10).
The amount of catalyst can be reduced to 5 mol % without any
loss of enantioselectivity (run 11).
Initially, we studied the nucleophilic addition of FBSM (1) to
N-Boc R-amido sulfone 2 by applying the conditions developed
With these optimized conditions established, the scope of the
reaction in terms of substrates was investigated (Table 2). We find
7
8
by Ricci et al. for the Mannich reaction of malonates with R-amido
sulfones7 since the in situ generation of N-Boc imines from the
,8
that QD Cl is an extremely general catalyst for the asymmetric
+
-
6394
9
J. AM. CHEM. SOC. 2007, 129, 6394-6395
10.1021/ja071509y CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Enantioselective Monofluoromethylationa
presumably due to the steric bulk of the tert-butyl group (entry
11). The substituents on the aryl groups, furanyl, and alkyl chains
were well tolerated, and the enantiomeric excesses of the starting
R-fluorobisphenylsulfonyl amines 3a-k were nearly maintained
during the desulfonylation reaction. The desulfonylation of 3 was
2 4
also possible using Na(Hg)/Na HPO in MeOH to give 4 (entry 12).
yield
(%)
ee
entry
2
R
3
(%)
In conclusion, we have described the first catalytic enantiose-
lective fluorobisphenylsulfonylmethylation of in situ generated
imines from R-amido sulfones under the combination of Mannich-
1
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
98
94
88
96
81
85
95
80
93
70
96
b
c
m-Cl-C6H4
p-Cl-C6H4
p-MeO-C6H4
2-naphthyl
2-furyl
PhCH2CH2
Me(CH2)6
c-C6H11
97
87
95
90
93
90
95
98
99
96
c
c
c
d
d
d
d
d
d
9
3
4
5
6
7
8
type conditions with FBSM chemistry. The R-fluorobisphenylsul-
fonylmethylated amines were converted to R-monofluoromethyl
amines by reductive desulfonylation. Application to the synthesis
of biologically important molecules is currently under investigation
via the FBSM/Mannich strategy.
e
9
1
1
0
1
2j
2k
i-Pr
t-Bu
3j
3k
Acknowledgment. Support was provided by JSPS KAKENHI
(19390029, 17590087) and by Japan Science & Technology (JST).
e
a
All of the reaction was performed on 0.35 mmol scale of 2. b 10 mol
Supporting Information Available: Experimental procedures and
spectral data for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
c
%
of catalyst was used. The absolute stereochemistry was tentatively
determined by comparing the optical rotation with that of 3a. The
stereochemistry was not determined. The reaction was carried out at
d
e
-
40 °C.
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(%)
ee
entry
3 (ee)
reagent
4
(%)
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3c (87)
3d (95)
3e (90)
3f (93)
3g (90)
3h (95)
3i (98)
3j (99)
3k (96)
3a (92)
Mg
Mg
Mg
Mg
Mg
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Mg
Mg
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4b
4c
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4e
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4g
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80
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b
b
b
c
c
c
c
c
c
a
83
93
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92
90
96
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96
92
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b
derivatization (see Supporting Information). The absolute stereochemistry
was tentatively determined by comparing the optical rotation with that of
a. The absolute stereochemistry was not determined. Based on the
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(
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With a range of enantiomerically enriched N-Boc R-fluoro-
bisphenylsulfonyl amines 3 in hand, we were now in a position to
investigate the reductive desulfonylation of 3 to complete the
sequence of enantioselective monofluoromethylation. A simple one-
step removal of the two phenylsulfonyl groups from 3a-k was
affected under Mg/MeOH conditions to afford the corresponding
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2
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(9) The reaction of 2a using 1-fluoro(phenylsulfonyl)methane (CH
2 2
FSO Ph)
in place of FBSM (1) under the same condition did not give the
corresponding product. More basic conditions might be needed.
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