Single electron transfer approaches to the practical synthesis of aromatic and heterocyclic-CF2H derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00873-5

Single electron transfer (SET) approaches with organic reductants such as sodium hydroxymethanesulfinate (Rongalite), sodium dithionite (regarded as precursors of sulfoxylate radical anion) and tetrakis(dimethylamino)ethylene (TDAE) were employed for the reductive dehalogenation of a series of halogeno-difluoromethylated aromatics and heterocycles, and for the practical synthesis of the corresponding difluoromethylated derivatives.

Full text of DOI:10.1016/S0040-4039(01)00873-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4811–4814
Single electron transfer approaches to the practical synthesis of
aromatic and heterocyclic-CF H derivatives
2
a
b,
b
William R. Dolbier, Jr., Maurice M e´ debielle * and Samia Ait-Mohand
a
University of Florida, Department of Chemistry, PO Box 117200, Gainesville, FL 32611-7200, USA
b
Universit e´ Denis Diderot-Paris 7, Laboratoire d’Electrochimie Mol e´ culaire, UMR CNRS 7591, 2 Place Jussieu,
F-75251 Paris Cedex 05, France
Received 23 February 2001; revised 15 March 2001; accepted 22 May 2001
Abstract—Single electron transfer (SET) approaches with organic reductants such as sodium hydroxymethanesulfinate (Ron-
®
galite ), sodium dithionite (regarded as precursors of sulfoxylate radical anion) and tetrakis(dimethylamino)ethylene (TDAE)
were employed for the reductive dehalogenation of a series of halogeno-difluoromethylated aromatics and heterocycles, and for
the practical synthesis of the corresponding difluoromethylated derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
There continues to be an interest in the synthesis of new
fluorinated aromatics, heterocycles as well as fluori-
nated ketones because of their potential and biological
As part of our ongoing efforts in the search of new
methodologies for the synthesis of fluorinated com-
pounds with potential biological and synthetic applica-
tions, we wish to report a mild and practical synthesis
of aromatic and heterocyclic difluoromethylated deriva-
1
3
properties. The a,a-difluoroketones are of special
interest as they have the capability to form hydrates
1
and hemiketals. It is believed that this property allows
tives 12–22 using halodifluoromethylated compounds
4
some fluorinated ketones to mimic the transition states1
involved in the hydrolytic action of many enzymes.
Fluorinated-substituted aromatics and heterocycles
have found broad applications such as in agrochemi-
1–11, as valuable starting materials (Scheme 1). As it
was anticipated that the carbonꢀhalogen bond should
be quite reactive in single electron transfer (SET) reac-
tions both chemically and electrochemically, three dif-
ferent systems were employed and compared: sodium
2
cals, anticancer and antiviral agents.
NMe2
NMe2
N
O
Ph
N
O
COCF2Y
CF X
2
CF X
2
N
X= Br: 1
X= H: 12
X= Br: 2
X= H: 13
COCF X
COCF X
2
2
X= Cl: 3
X= H: 14
X= Y= Cl: 4
X= Y= H: 15
N
PhCOCF X
2
X= Cl, R= H: 6; X= H, R= H; 17
R
X= Cl: 5
X= H: 16
X= Cl; R= p-CH3C6H4: 7; X= H; R= p-CH3C6H4: 18
X= Cl; R= p-ClC H : 8; X= H; R= p-ClC H : 19
N
6
4
6 4
COCF Cl
2
X= Cl; R= p-BrC H : 9; X= H; R= p-BrC H : 20
6
4
6 4
X= Cl; R= p-C H : 10; X= H; R= pC H : 21
6
5
6 5
X= Cl; R= m-NO : 11; X= H; R= m-NO : 22
2
2
Scheme 1.
*
Corresponding author. Present address: Universit e´ Claude Bernard-Lyon 1. Domaine Scientifique de la Doua, Laboratoire SERCOF (UMR
CNRS 5622), B aˆ timent E. Chevreul, 43, Bd du 11 Novembre 1918, F-69622 Villeurbanne Cedex, France. Fax: +33 (0) 4 72 43 13 23; e-mail:
medebiel@univ-lyon1.fr
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00873-5

4
812
W. R. Dolbier, Jr. et al. / Tetrahedron Letters 42 (2001) 4811–4814
®
hydroxymethanesulfinate (Rongalite ), sodium dithion-
ite, (regarded as precursors of sulfoxylate radical anion)
and tetrakis(dimethylamino)ethylene (TDAE). Sodium
ther reduced and protonated to give the final product
(Scheme 2).
®
hydroxymethanesulfinate (Rongalite ) as well as
sodium dithionite (Na S O ) are cheap and readily
available materials. Reductive dechlorination reactions
of various a-halo-
genated ketones have been previously reported but
Dehalogenation reactions with TDAE involves the for-
mation, at low temperature, of a deep-red charge trans-
fer complex that dissociates readily after a stepwise
electron transfer to the corresponding difluoromethyl
−
2
2
4
®
5a
5b
4
with Rongalite
and Na S O
2
2
2
+
anion with the formation of the insoluble TDAE , 2X
surprisingly only one example of their application to
salt demonstrating that TDAE has been clearly oxi-
dized (Scheme 3).
6
the synthesis of R-CF H derivatives is known. Most
2
frequently these reagents have been successfully used in
free-radical addition and cyclization reactions with
perfluoroalkyl halides as starting materials. Tetra-
None of the yields have been optimized (Table 1) and
room for improvement certainly exists. In addition the
simplicity of the experimental procedures including
purification of the products, cheapness and readily
availability of the reagents makes these approaches
quite attractive for organic chemists. Obviously other
systems would have possibly worked for the dehalo-
genation reactions presented here:
7
kis(dimethylamino)ethylene is also readily available and
we have found that this organic reductant was useful
for the in-situ generation of difluoromethyl and a,a-
difluoroacetyl anions which participated in reactions of
8
considerable synthetic utility.
®
Among the different approaches tested, Rongalite was
ꢀ
found to be the best system in terms of yields and
experimental procedure. Indeed with this reducing
agent, solvent such as ethanol (reflux for 2–5 h as
monitored by TLC) could be used with only 1.5 equiv.
of the sulfoxylate radical anion precursor (3 equiv. were
used to yield 15); purification of the products was
simple as only evaporation of the solvent and filtration
Zn/HOAc: acetic acid is used as solvent, and there-
fore, acid-catalyzed hydrolysis of the benzoxazole
and oxadiazole rings (compounds 1, 2, 12 and 13)
into the corresponding amides may have occurred.
ꢀ
SmI /THF/HMPA: the cost of SmI and the use of
2
2
HMPA (toxic) as a co-solvent limits its practical use
in industry.
9
ꢀ
through a short pad of silica gel was needed. With
n-Bu
bromodifluoromethylated heterocycles 1 and 2 (not
with the RCOCF Cl substrates 3–11) but trouble in
removing tin impurities is a major drawback.
3
SnH/AIBN: this system only works with the
sodium dithionite (1.2 equiv.), DMF/H O (4/1, v/v) was
2
used as solvent at 65°C for 2 h. NaHCO (1.2 equiv.)
2
3
was also necessary to keep the reaction mixture slightly
basic and to prevent decomposition of Na S O . Under
2
2
4
Therefore, our approaches are, in our mind, safer and
more practical for the chemical industry and pharma-
ceutical companies, interesting in developing new
strategies to the synthesis of fluorinated compounds.
Work is under progress to use these derivatives in
synthetic reactions.
these conditions, and with the chlorodifluoromethylated
ketones as substrates, fluorine NMR of the crude
product revealed formation of RCHOHCF H, as by-
2
products, in 5–10% yields characterized by an ABXX%
1
0
system. The TDAE approach (−20°C for 1 h and then
room temperature for 2 h) also gives good yields of
desired products after silica-gel chromatography;
among the different solvents tested (acetonitrile, THF,
toluene) DMF was the solvent of choice to get the
Acknowledgements
1
1
higher yields. For the sulfoxylate radical anion pre-
cursors, it is believed that an electron transfer between
’
−
−
the starting material R-CF X and SO
(or HSO )
We thank Marie-Noelle Rager (ENSCP, Paris) for the
2
2
2
occurs generating a difluoromethyl radical that is fur-
fluorine and proton NMR spectra and David Clain-
with Na S O (sodium dithionite)
with NaO2SCH2OH
2
2
4
(Rongalite: sodium hydroxymethanesulfinate)
2
-
HOCH SO2
HCHO + HSO2
S O
2SO2
RCF + SO + X
2
2
4
RCF X + SO2
RCF2X + HSO2
RCF2 + HSO2 + X
2
2
2
RCF + SO2
RCF2 + SO2
RCF2 + SO + H+
2
RCF + HSO2
2
2
Scheme 2.
Scheme 3.
-
20°C
RCF X + TDAE
RCF X-------TDAE
CTC (deep-red)
RCF + X + TDAE
2
2
2
2+
RCF + TDAE
RCF + TDAE
2
2

W. R. Dolbier, Jr. et al. / Tetrahedron Letters 42 (2001) 4811–4814
4813
a
Table 1. Reductive dehalogenation syntheses of the R-CF H derivatives
2
Substrates
System
Products (%)b
Spectral datag
See Ref. 10
c
1
Na S O
4
12, 62
12, 68
12, 71
13, 72
13, 65
13, 75
14, 72
14, 68
14, 71
15, 72
2
2
d
d
d
Rongalite
TDAEe
c
+
+
2
3
4
Na S O
lF=−121. 2 (2F, d, J=57.4 Hz); GC/MS: M =196, M −CF H=145
2
2
4
2
Rongalite
TDAEe
c
Na S O
4
See Ref. 9
2
2
Rongalite
TDAEe
c,f
+
+
Na S O
4
lF=−119. 3 (2F, d, J=57 Hz), −123.2 (2F, d, J=52 Hz); GC/MS: M =327, M
2
2
−
CF H=276
2
d,f
Rongalite
15, 68
15, 71
16, 71
16, 63
16, 51
17, 68
17, 65
17, 71
18, 72
18, 71
18, 66
19, 65
19, 62
19, 58
20, 71
20, 68
20, 70
21, 65
21, 62
21, 71
22, 68
22, 72
22, 62
e,f
TDAE
c
+
+
5
6
7
8
9
Na S O
lF=−119. 2 (2F, d, J=57.2 Hz); GC/MS: M =156, M −CF H=105
2
2
2
4
d
Rongalite
TDAEe
c
lF −126.3 (2F, d, 2JF-H=55 Hz). GC/MS: M =196, M −CF H=145.
+
+
Na S O
2
2
4
2
d
Rongalite
TDAEe
c
Na S O
4
See Ref. 11
2
2
d
Rongalite
TDAEe
c
lF −124.6 (2F, d, 2JF-H=52.7 Hz). GC/MS: M =306, M −CF H=255.
+
+
Na S O
2
2
4
2
d
Rongalite
TDAEe
c
lF −124.5 (2F, d, 2JF-H=52.7 Hz). GC/MS: M =350, M −CF H=299.
+
+
Na S O
2
2
4
2
d
Rongalite
TDAEe
c
lF −124.7 (2F, d, 2JF-H=52.7 Hz). GC/MS: M =348, M −CF H=297.
+
+
1
1
0
1
Na S O
2
2
4
2
d
Rongalite
TDAEe
c
lF −124.0 (2F, d, 2JF-H=52.7 Hz). GC/MS: M =317, M −CF H=266.
+
+
Na S O
2
2
4
2
d
Rongalite
TDAEe
a
b
c
d
e
f
All reactions were run under nitrogen with 1.76 mmol of starting material and 2.12 mmol of reductant.
Isolated yields.
DMF/H O (20 ml, 4/1 by volume) was used as solvent at 65°C for 2 h.
2
Absolute EtOH (25 ml) was used as solvent under reflux (2 h for substrates 1–5 and 5 h for substrates 6–11).
Anhydrous DMF (5 ml) was used as solvent; −20°C for 1 h and room temperature for 2 h.
5
.28 mmol of reductant was used.
g
Fluorine NMR was taken in CDCl3 (CCl F as internal reference).
3
quart (Universit e´ Denis Diderot-Paris 7) for the mass
spectra. This work was partly supported by a research
grant from the Universit e´ Denis Diderot-Paris 7 (Appel
d’offres SIDA 1999).
M e´ debielle, M.; Pinson, J.; Sav e´ ant, J.-M. Electrochim.
Acta 1997, 42, 2049; (f) Xu, Y.; Dolbier, Jr., W. R. J.
Org. Chem. 1997, 62, 6503; (g) M e´ debielle, M.; Oturan,
M. A.; Pinson, J.; Sav e´ ant, J.-M. J. Org. Chem. 1996, 61,
131.
4
. For the synthesis of the bromodifluoromethylated hetero-
cycles: (a) Burkholder, C.; Dolbier, Jr., W. R.; M e´ debielle,
M. J. Fluor. Chem. 1999, 95, 127. For the synthesis of the
naphthalene-derived chlorodifluoromethylated ketones:
(b) Hapiot, P.; M e´ debielle, M. J. Fluor. Chem. 2001, 107,
285. For the synthesis of the imidazo[1,2-a]pyridine-
References
1
2
. Tozer, M. J.; Herpin, T. Tetrahedron 1996, 52, 8619.
. Bergstrom, D. E.; Swartling, D. J. In Fluorine-Containing
Molecules, Structure, Reactivity, Synthesis and Applica-
tions; Liebman, J. F.; Greenberg, A.; Dolbier, Jr., W. R.,
Eds. Fluorine substituted analogues of nucleic acid com-
ponents; VCH: New York, 1988; pp. 259–308.
derived
chlorodifluoromethylated
ketones:
(c)
Burkholder, C.; Dolbier, Jr., W. R.; Ait-Mohand, S.;
M e´ debielle, M. Tetrahedron Lett. 2001, 42, 3077.
5. (a) Harris, A. R. Synth. Commun. 1987, 17, 1587; (b)
Chung, S.-K.; Hu, Q.-Y. Synth. Commun. 1982, 12, 261.
6. Kumar, V.; McCloskey, P.; Bell, M. R. Tetrahedron Lett.
1994, 35, 833.
3
. (a) Burkholder, C.; Dolbier, Jr., W. R.; M e´ debielle, M.
J. Fluor. Chem. 2000, 102, 369; (b) Fujii, S.; Kato, K.;
M e´ debielle, M. Tetrahedron 2000, 56, 2655; (c) Xu, Y.;
Dolbier, Jr., W. R. J. Org. Chem. 2000, 65, 2134; (d) Xu,
Y.; Dolbier, Jr., W. R. Tetrahedron 1998, 54, 6319; (e)
7. Selected examples. (a) Zur, C.; Mietchen, R. Eur. J. Org.
Chem. 1998, 531–539; (b) Wang, Z.; Lu, X. Tetrahedron

4
814
W. R. Dolbier, Jr. et al. / Tetrahedron Letters 42 (2001) 4811–4814
995, 51, 2639–2658; (c) Guan, H.-P.; Tang, X.-Q.; Luo,
1
ml) and dried over MgSO . Evaporation of the solvent
4
B.-H.; Hu, C.-M. Synthesis 1997, 1489; (d) Bergeron, S.;
Brigaud, T.; Foulard, G.; Plantier-Royon, R.; Portella, C.
Tetrahedron Lett. 1994, 35, 1985–1988; (e) Tordeux, M.;
Langlois, B.; Wakselman, C. J. Chem. Soc., Perkin Trans.
left a yellowish viscous oil as crude product which was
filtered through a short pad of silica gel eluting with
hexane/EtOAc (80:20) to give 0.18 g (1.09 mmol, 62%)
of 12 as
a
pale yellowish viscous liquid. 2-
1
1
1990, 2293–2299.
(Difluoromethyl)benzoxazole: H NMR (DMSO-d ): l
6
H
2
8
. (a) Burkholder, C.; Dolbier, Jr., W. R.; M e´ debielle, M.;
Ndedi, A. Tetrahedron Lett. 1998, 39, 8853; (b)
Burkholder, C.; Dolbier, Jr., W. R.; M e´ debielle, M. J.
Org. Chem. 1998, 63, 53854.
7.22–7.64 (1H, t, J =52 Hz, -CF H), 7.43–7.86 (4H,
H–F 2
19
m, H-arom). F NMR (DMSO-d /CFCl ): l −119.8
6
3
F
2
+
F–H 2
+
(
2F, d, J =52.1 Hz). GC/MS: M =169, M −CF H=
1
8
18. Anal. calcd for C H F NO: C, 56.81; H, 2.98; N,
8 5 2
.28. Found C, 56.74; H, 3.03; N, 8.15.
9
. A typical procedure for the reaction between 3 and
®
Rongalite is as follows: Into a three-necked flask
1
1. A typical procedure for the reaction between 7 and
TDAE is as follows: Into a two-necked flask equipped
with a silica-gel drying tube and a nitrogen inlet was
added, under nitrogen at −20°C, 5 ml of anhydrous DMF
and then 7 (0.56 g, 1.76 mmol). The solution was stirred
and maintained at this temperature for 30 min and then
was added dropwise (via a syringe) the TDAE (0.42 g,
equipped with a reflux condenser (with a silica-gel drying
tube) and a nitrogen inlet, were added under nitrogen, 25
ml of absolute EtOH followed by 3 (0.50 g, 1.76 mmol).
The solution was stirred until complete dissolution and
®
then Rongalite (0.32 g, 2.12 mmol) was added. The
whole mixture was then heated at reflux until complete
consumption of starting material (2 h, TLC). The solu-
tion was filtered, and evaporated to dryness. The crude
product was filtered through a short pad of silica-gel
eluting with hexane/EtOAc (70:30) and recrystallized
from hexane to give 0.31 g (1.19 mmol, 68%) of 14.
2.12 mmol). A red color immediately developed with the
formation of a white fine precipitate. The solution was
vigorously stirred at −20°C for 1 h and then warmed up
to room temperature for 2 h. After this time TLC analy-
sis (EtOAc–hexane, 90–10) clearly showed that 7 was
totally consumed. The orange–red turbid solution was
filtered (to remove the octamethyloxamidinium dichlo-
4
7
-Dimethylamino-naphthalen-1-yl-1-difluoroacetyl: Mp=
1
0–72°C (yellow needles). H NMR (CDCl ): l 3.07
3
H
2
(
(
6H, s, -NMe ), 6.44 (1H, t, -CF H, JH–F=57 Hz), 6.92
1H, d, H-2, J=8.36 Hz), 7.50–7.68 (2H, m, H-6 and
2
2
ride) and hydrolyzed with 30 ml of H O. The aqueous
2
solution was extracted with CHCl (3×30 ml), the com-
3
H-7), 8.13–8.20 (2H, m, H-3 and H-8), 9.2 (1H, d, H-5,
1
9
bined organic solutions washed with brine (3×30 ml),
H O (3×30 ml) and dried over MgSO . Evaporation of
J=8.38 Hz). F NMR (CDCl /CFCl ): l −119.31 (2F,
3
+
3
F
+
2
2
4
d, JF–H=54 Hz). GC/MS: M =249, M −CF H=198.
2
the solvent left a yellowish viscous liquid as crude
product. Purification by silica-gel chromatography
Anal. calcd for C H F NO: C, 67.46; H, 5.22; N, 5.62.
14
13 2
Found C, 67.68; H, 5.43; N, 5.87.
(
6
EtOAc–hexane, 90–10 as eluent) gave 0.33 g (1.16 mmol,
6%) of 18 as pale–yellowish crystals: 2,2-Difluoro-1-(2-p-
1
0. A typical procedure for the reaction between 1 and
Na S O is as follows: Into a three-necked flask equipped
2
2
4
1
tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone.
(
H
NMR
with a reflux condenser (with a silica-gel drying tube) and
a nitrogen inlet, were added under nitrogen, 20 ml of
2
CDCl ): lH 2.45 (3H, s, CH ), 5.80–6.07 (1H, t, JH–F=
3
3
5
2.7 Hz, -CF H), 7.21–7.23 (1H, m, H-6), 7.33–7.35 (2H,
DMF/H O (4/1, v/v) followed by 1 (0.44 g, 1.76 mmol).
2
2
AA%BB%, H-arom), 7.49–7.51 (2H, AA%BB%, H-arom),
7.65–7.67 (1H, m, H-7), 7.81–7.83 (1H, d, J=8.85 Hz,
The solution was stirred until complete dissolution and
then Na S O (0.37 g, 2.12 mmol) followed by NaHCO
3
2
2
4
19
(0.18 g, 2.12 mmol) were added. The whole mixture was
H-8), 9.75–9.76 (1H, d, J=6.94 Hz, H-5). F NMR
2
then heated at 65°C until complete consumption of start-
ing material (2 h, TLC). The solution was hydrolyzed
(CDCl
MS: M =286, M −CF
C H F N O: C, 67.13; H, 4.23; N, 9.79. Found C,
3 3 F
+
/CFCl ): l −124.8 (2F, d, JF–H=52.7 Hz). GC/
+
H=235. Anal. calcd for
2
with H O (25 ml) and extracted with EtOAc (3×25 ml),
2
16 12
2
2
the combined organic extracts washed with brine (3×25
67.34; H, 4.03; N, 9.83.
.