Trifluoromethanesulfinic acid derivatives as nucleophilic trifluoromethylating reagents

Article abstract of DOI:10.1055/s-2003-36788

Secondary trifluoromethanesulfinamides and alkyl trifluoromethanesulfinates can be used as nucleophilic trifluoromethylating reagents towards various electrophiles by action of potassium tert-butoxide.

Full text of DOI:10.1055/s-2003-36788

LETTER
233
Trifluoromethanesulfinic Acid Derivatives as Nucleophilic Trifluoro-
methylating Reagents
T
rifluoromethanes
a
ulfinic
A
cid
v
D
erivatives
i
as
N
uc
d
leophilic Trifluoro
I
methyla
n
ting
R
eagent
s
s
chauspe, Jean-Baptiste Sortais, Thierry Billard,* Bernard R. Langlois*
Laboratoire SERCOF (UMR CNRS 5622), Université Claude Bernard - Lyon 1, Bât. E. Chevreul, 43 Bd du 11 novembre 1918, 69622
Villeurbanne, France
Fax +33(4)72431323; E-mail: billard@univ-lyon1.fr
Received 26 November 2002
CF3 moiety, we could expect that these reagents should be
Abstract: Secondary trifluoromethanesulfinamides and alkyl tri-
more reactive than aldehydes towards t-BuOK.
fluoromethanesulfinates can be used as nucleophilic trifluorometh-
ylating reagents towards various electrophiles by action of
potassium tert-butoxide.
In order to test the ability of such compounds to perform
nucleophilic trifluoromethylation, we studied their reac-
Key words: trifluoromethylation, trifluorosulfinamide, fluorinated tivity towards benzophenone and benzaldehyde (Table 1).
compounds, trifluoromethylcarbinols, tetrahedral intermediate
From these results, it appears that, once again, the N-benz-
ylpiperazine derivative was the most efficient reagent.
The hypothesis about the high electrophilicity of the sul-
The growing interest of fluorinated compounds,1 and es-
fur(IV) atom was verified since aldehydes could be tri-
pecially trifluoromethylated products, requires new meth-
fluoromethylated under these conditions. We can also
ods to introduce directly the CF3 moiety. Among all the
notice the necessity to work at 0 °C to get optimal results
presently available strategies,2 the nucleophilic one is
certainly because of the higher instability of the tetrahe-
probably the most popular.3
dral intermediate around sulfur compared to the carbon
analogue (Scheme 2). At lower temperature, the rate of re-
action becomes too slow.
We have recently described the use of trifluoroacetalde-
hyde hemiaminals as powerful reagents for the nucleo-
philic trifluoromethylation of various electrophiles.4 As
fluoral is usually prepared from trifluoroacetic acid, we
also focused our interest on the design of a new tri-
fluoromethylating system from derivatives of CF3CO2H.
In a previous paper, we described a new process to tri-
fluoromethylate carbonyl compounds with trifluoroacet-
amides or trifluoroacetates in presence of t-BuOK
(Scheme 1).5
O
S
O
F3C
N
NBn
F3C
N
NBn
OtBu
OtBu
Less stable
More stable
CF3
Scheme 2
O
O
This trifluoromethylation technique has been extended to
other electrophiles (Table 2).
OH
O
tBuOK
R1
R2
R1
R2
F3C
Y
F3C
Y = OR
Y
As shown in Table 2, non-enolizable ketones and alde-
hydes provided moderate to excellent yields even in the
heterocyclic series. Of course, enolizable compounds
could not be trifluoromethylated because of the use of a
strong base (t-BuOK) which gave rise to aldolisation. We
can also notice that disulfides could undergo trifluorome-
thylation to yield trifluoromethyl sulfides.
OtBu
CF3
NRR'
Scheme 1
Nevertheless, with such reagents, aldehydes don't under-
go trifluoromethylation but a Cannizaro-like reaction with
t-BuOK.
In conclusion, we have shown that trifluoromethane-sulfi-
nates and trifluoromethane-sulfinamides can be used as
efficient reagents for nucleophilic trifluoromethylation.
To improve this new methodology, we were looking for
more electrophilic trifluoromethylated compounds able
to add t-BuOK and expel a trifluoromethyl anion. We
thus focused our interest on trifluoromethane-sulfinates
and -sulfinamides, which can be easily prepared from tri-
fluoromethanesulfinate salts.6 Indeed, because of the high
electrophilic character of the sulfur atom, enhanced by the
–
Such reagents, easily available from CF3SO2 , arising
from trifluoroacetic acid, constitute interesting substi-
tutes, on a economic and ecological point of view, to
many other reagents.
Acknowledgment
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2003,0,02,0233,0235,ftx,en;D24202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
We thank the CNRS and the French Ministry of Research for finan-
cial support and Rhodia for a generous gift of triflinate.

234
D. Inschauspe et al.
LETTER
Table 1 Trifluoromethylation with Trifluoromethane-sulfinates
Table 2 Reaction of 2a with Various Electrophiles7
and -sulfinamides
THF
t
2a + BuOK + E +
F3C
E
O
S
O
0 °C → r.t.
(1equiv)
OH
3 or 4
(after hydrolysis)
(1equiv)
(1 equiv)
THF
1h
+ tBuOK +
(1 equiv)
R
R'
F3C
X
R
R'
CF3
3 or 4(%)a
1 (X=OR)
2 (X=NR2)
(1 equiv)
(1equiv)
RC(O)R′
3
(after hydrolysis)
HO CF3
O
Ph
Ph
Ph
Ph
Ph
N°
1
CF3S(O)X
RC(O)R′
Temp 3 (%)a
(°C)
3a: 75 (85)
PhC(O)Ph
r.t.
3a: 29
O
HO CF3
O
O
Ph
N
O
F3C
O
O
N
3b: 80 (91)
O
S
HO CF3
Ph
O
1a
O
Ph
Ph
Ph
Ph
2
3
4
1a
1a
PhC(O)Ph
PhC(O)H
PhC(O)Ph
0
3a: 73
3d: 19
3a: 69
3c: 53 (55)
0
O
HO CF3
r.t.
O
Ph
H
H
3d: 80 (95)
O
O
CHO
HO CF3
H
O
CF3
S
O
O
MeO
O
MeO
1b
3e: 91 (95)
5
6
7
1b
1b
PhC(O)Ph
PhC(O)H
PhC(O)Ph
0
0
0
3a: 72
3d: 28
3a: 63
HO CF3
H
O
H
O
N
S
N
F3C
OBu
3f: 40 (55)
1c
HO
F3C
8
PhC(O)Ph
r.t.
3a: 70
CHO
N
O
S
F3C
H
N
NBn
2a
N
9
10
11
2a
2a
PhC(O)Ph
PhC(O)H
PhC(O)Ph
0
0
0
3a: 85
3d: 95
3a: 42
3g: 30 (35)
OH
H
O
O
F3C
2b
Bu
Bu
N
N
S
N
CF3
Me
Me
H
3h: 75 (86)
2b
12
13
PhC(O)H
PhC(O)Ph
0
0
3d: 39
3a: 77
SCF3
SS
O
S
F3C
Me
Ph
4a: 50 (67)
N
2c
Cl
SCF3
Cl
S
14
2c
PhC(O)H
0
3d: 21
2
4b: (20)
a Crude yield determined by 19F NMR with internal standard
(PhOCF3).
C8H17 S CF3
C8H17–SS–C8H17
4c: 30 (44)
a Isolated yield. In parentheses: crude yield determined by 19F NMR
with internal standard (PhOCF3).
Synlett 2003, No. 2, 233–235 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Trifluoromethanesulfinic Acid Derivatives as Nucleophilic Trifluoromethylating Reagents
and extracted with diethyl ether. The organic phase was
235
References
dried over Na2SO4 and the solvent was evaporated in vacuo.
The crude products were purified by chromatography over
silica gel.
(1) Schofield, H. J. Fluorine Chem. 1999, 100, 7.
(2) Mc Clinton, M. A.; Mc Clinton, D. A. Tetrahedron 1992, 48,
6555.
Spectral Data: Compound 3c: 1H NMR (300MHz, CDCl3):
δ = 7.64 (s, 1 H), 7.22–7.43 (m, 8 H), 6.88 (d, 1 H, J = 16
Hz), 6.71 (d, 1 H, J = 16 Hz), 2.79 (s, 1 H). 13C NMR (75
MHz, CDCl3): δ = 137.6, 135.7, 133.7, 129.0, 128.9, 128.8,
128.5, 127.1, 127.0 (q, J = 1.2 Hz), 126.6, 125.2 (q, J = 286
Hz), 80.3 (q, J = 28.5 Hz). 19F NMR (282MHz, CDCl3): δ =
–78.97. Compound 3e: 1H NMR (300MHz, CDCl3): δ = 7.84
(s, 1 H), 7.75 (t, 2 H, J = 8.2 Hz), 7.53 (d, 1 H, J = 8.5 Hz),
7.18 (m, 2 H), 5.16 (q, 1 H, J = 6.7 Hz), 3.93 (s, 3 H), 3.23
(s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 158.7, 135.4,
130.2, 129.6 (q, J = 1.2 Hz), 128.8, 127.7, 127.6, 124.3,
124.9 (q, J = 282.0 Hz), 119.8, 106.1, 73.4 (q, J = 32.0 Hz),
55.8. 19F NMR (282MHz, CDCl3): δ= –78.17 (d, J = 6.7
Hz). Compound 3f: 1H NMR (300MHz, CDCl3): δ = 9.08 (d,
1 H, J = 1.5 Hz), 8.53 (d, 1 H, J = 1.5 Hz), 8.11 (dd, 1 H,
J = 8.4 Hz, J = 1.2 Hz), 8.05 (dd, 1 H, J = 8.2 Hz, J = 1.3
Hz), 7.82 (ddd, 1 H, J = 8.4 Hz, J = 6.8 Hz, J = 1.6 Hz), 7.66
(ddd, 1 H, J = 8.2 Hz, J = 6.8 Hz, J = 1.2 Hz), 6.49 (s, 1 H),
5.62 (q, 1 H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): δ =
150.0 (q, J = 1.5 Hz), 148.7, 135.5, 130.4, 129.5, 129.3 (q,
J = 1.5 Hz), 128.7, 127.5, 125.4 (q, J = 281.9 Hz), 123.6,
70.4 (q, J = 31.7 Hz). 19F NMR (282MHz, CDCl3): δ =
–78.73 (d, 3JF-H = 7.1 Hz).
(3) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757. (b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56,
7613. (c) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem.
2001, 112, 123. (d) Folleas, B.; Mareck, I.; Normant, J. F.;
Saint-Jalmes, L. Tetrahedron Lett. 1998, 39, 2973.
(e) Folleas, B.; Mareck, I.; Normant, J. F.; Saint-Jalmes, L.
Tetrahedron 2000, 56, 275. (f) Large, S.; Roques, N.;
Langlois, B. R. J. Org. Chem. 2000, 65, 8848.
(g) Motherwell, W. B.; Storey, L. J. Synlett 2002, 646.
(4) (a) Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett. 2000, 2,
2101. (b) Billard, T.; Langlois, B. R.; Blond, G. Tetrahedron
Lett. 2000, 41, 8777. (c) Billard, T.; Langlois, B. R.; Blond,
G. Eur. J. Org. Chem. 2001, 1467. (d) Blond, G.; Billard,
T.; Langlois, B. R. Tetrahedron Lett. 2001, 42, 2473.
(5) Jablonski, L.; Joubert, J.; Billard, T.; Langlois, B. R. Synlett
2003, 230.
(6) Billard, T.; Greiner, A.; Langlois, B. R. Tetrahedron 1999,
55, 7243.
(7) Typical Procedure: To a solution of 2a (1 mmol) and the
electrophile (1 mmol) in THF (1 mL), cooled at 0 °C, was
dropped a 1 M solution of t-BuOK in THF (1 mL). The
temperature is allowed to rise to r.t. over 1 h.. Then, the
crude mixture was hydrolyzed by 1 M HCl (1 mL) overnight
Synlett 2003, No. 2, 233–235 ISSN 0936-5214 © Thieme Stuttgart · New York