Synthesis of 1,1-difluoroalkanes via phase transfer catalysed reaction of 1,1-bis-Triflates with KF in the presence of cocatalyst - Ph3SnF

Article abstract of DOI:10.1055/s-2002-32959

1,1-bis-Triflates treated with KF in the presence of triphenyltin fluoride and tetrabutylammonium hydrogen sulfate give 1,1-difluoroalkanes.

Full text of DOI:10.1055/s-2002-32959

LETTER
1285
Synthesis of 1,1-Difluoroalkanes via Phase Transfer Catalysed Reaction of 1,1-
bis-Triflates with KF in the Presence of Cocatalyst – Ph3SnF
S
ynthesis of 1,1-
o
ifluoroalka
b
nes ert Bujok, Mieczys aw M kosza*
Institute of Organic Chemistry, Polish Academy of Sciences ul., Kasprzaka 44, 01-224 Warszawa 42, POB 58, Poland
Fax +48(22)6326681; E-mail: icho-s@icho.edu.pl
Received 26 April 2002
nucleofugal group in an aliphatic compound with fluorine,
Abstract: 1,1-bis-Triflates treated with KF in the presence of tri-
phenyltin fluoride and tetrabutylammonium hydrogen sulfate give
1,1-difluoroalkanes
the reaction can be performed in a cocatalytic liquid-solid
phase-transfer catalysis (PTC) system, in which the PT
catalyst is assisted by Ph3SnF and analogous compounds.
The system operates thanks to the possibility of continu-
Key words: phase transfer catalysis, tin compound, fluorination
–
ous formation of the Ph3SnF2 anion in the reaction of
Ph3SnF with solid KF and is efficient for the synthesis
of fluoroalkanes, including secondary derivatives
(Scheme 2).
Fluoro substituents modify biological activity of organic
molecules hence numerous drugs and plant protection
agents contain fluorine.1 Introduction of fluorine into or-
ganic molecules, is a rather difficult task for which typical
methods of synthesis of other halo derivatives usually are
not applicable, thus there is a continuous interest in meth-
ods of fluorination of organic compounds.
1,1-Difluoroalkanes are usually prepared from aldehydes
Scheme 2
2
via direct reaction with SF4 or DAST3,4 or in two-step
processes: conversion of the aldehydes into hydrazones
followed by reaction of the latter with IF5 or conversion
into gem-bis-trifluoromethanesulfonates (triflates), which
Application of this system to the synthesis of 1,1-difluo-
roalkanes from 1,1-bis-triflates was not obvious. Earlier
attempts to prepare 1,1-difluoroalkanes via the reaction
with tetrabutylammonium fluoride or F– anions in solid-
liquis PTC system: CsF/18-crown-6 failed – the bis-tri-
flates underwent decomposition to produce aldehydes and
unidentified products.6
are subsequently treated with Bu4N+Ph3SnF2
–6
(Scheme 1).
On the other hand when a solution of the gem-bis-triflates
obtained from various aldehydes was treated with solid
–
anhydrous KF in the presence of 10% molar Bu4N+HSO4
and Ph3SnF the replacement of the triflic groups with flu-
orine proceeded smoothly giving the expected 1,1-difluo-
roalkanes usually in good yields (Scheme 3, Table).
Scheme 1
All these methods are inconvenient due to high cost, dif-
ficulties in handling and availability of the required re-
agents. In particular, the reaction of the gem-bis-triflates
–
with Bu4N+Ph3SnF2 , a commercially available and stable
Scheme 3
compound, is prohibitive for practical synthesis, because
of its high cost and high molecular weight. Since for com-
plete conversion of the bis-triflates into 1,1-difluoroal-
kanes at least three equivalents of the salt is necessary, in
order to prepare 1 g of difluoroalkane, more than 12 g of
the reagent has to be used. In our previous
communication7 we have reported that instead of using
this salt as a stoichiometric reagent for replacement of a
Yield determined by GLC are usually good – somewhat
lower when there is a secondary carbon in vicinity of the
reaction center. In the latter case the reaction is slower and
accompanied with -elimination process giving vinyl tri-
flates.
All the reactions presented in the Table were carried out
under identical standard conditions, without optimiza-
tion.8 As usually in the case of volatile products prepared
in small scale experiments, isolated yields were substan-
tially lower than those determined by GLC analyses due
to losses during isolation and purification.
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1285,1286,ftx,en;G11502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1286
R. Bujok, M. M kosza
LETTER
mixture was diluted with ether (25 mL), the solid was
Table 1 Yields of 1,1-Difluoroalkanes in the Reaction of bis-Tri-
filtered off, washed with diethyl ether (3 8 mL). The ether
extracts were combined and the solvent was distilled using a
20 cm Vigreux column. The products were purified by
chromatography (silica gel, n-pentane or n-pentane/
CH2Cl2).
flates with KF in Cocatalytic PTC System
Entry
Product
Time [h] Yield [%]a
1
2
3
4
5
6
1,1-Difluorooctane
30
30
30
30
48
48
68 (50)
72 (57)
65
1,1-Difluorooctane: 1H NMR (200 MHz, CDCl3): 0.89 (t, J
[1H-1H] = 6.5 Hz, 3 H CH3), 1.25–1.50 (m, 10 H), 1.65–1.95
(m, 2 H), 5.79 (tt, 2J [19F–1H] = 57 Hz; J [1H–1H] = 4.5 Hz,
1 H, CHF2). 19F NMR (178 MHz, CDCl3): –116.2 (dt, 2J
[19F–1H] = 57 Hz; 3J [19F–1H] = 17.5 Hz), MS (EI, 70 eV):
150 (M+, <1), 130 (M–HF, 1); 84(20), 81(17), 73(15),
71(21), 69(14), 68(12), 59(12), 57(60), 56(36), 55(37),
43(100), 42(23), 41(65).
1,1-Difluorodecane
1,1-Difluoro-2-phenyl-ethane
1,1-Difluoro-3-phenyl-propane
2-Ethyl-1,1-difluorohexane
Difluoromethylcyclohexane
70
48
58
1,1-Difluorodecane: 1H NMR (200 MHz, CDCl3): 0.88 (t, J
[1H–1H] = 6.5 Hz, 3 H CH3), 1,23–1,50 (m, 14 H), 1.65–1.95
(m, 2 H), 5.79 (tt, 2J [19F–1H] = 57 Hz; J [1H–1H] = 4.5 Hz,
1 H, CHF2). 19F NMR (178 MHz, CDCl3): –116.2 (dt; 2J
[19F–1H] = 57 Hz, 3J [19F–1H] = 17.5 Hz). MS (EI, 70 eV):
178 (M+, 3), 107(13), 85(31), 84(16), 83(11), 82(15), 81(10),
73(16), 71(34), 70(21), 69(17), 57(80), 56(24), 55(34),
43(100), 42(15), 41(43).
a Determined by GLC using biphenyl as internal standard; isolated
yields are given in parentheses.
Acknowledgement
1,1-Difluoro-2-phenyl-ethane: 1H NMR (200 MHz,
CDCl3): 3.07 (td, 3J [19F–1H] = 17.3 Hz, J [1H–1H] = 4.6 Hz,
2 H; Ph-CH2-CHF2), 5.85 (tt, 2J [19F–1H] = 56 Hz, J [1H–
1H] = 4.6 Hz, 1 H, CHF2), 7.15–7,32 (m, 5 H, Ph). 19F NMR
(178 MHz, CDCl3): –115,5 (dt, 2J [19F–1H] = 56.6 Hz, 3J
[19F–1H] = 17.3 Hz). MS (EI, 70 eV): 142 (M+, 33), 91(100),
65(14).
This work was generously supported by Bayer Pharma, Wuppertal,
Germany. We thank the Foundation for Polish Science for Pro-
fesorial Subsydium.
References
1,1-Difluoro-3-phenyl-propane: 1H NMR (200 MHz,
CDCl3): 2.01– 2.29 (m, 2 H, CH2-CHF2), 2.78 (t, J [1H–
1H] = 7.9 Hz, 2 H, Ph-CH2), 5.80 (tt, 2J [19F–1H] = 56.7 Hz,
(1) (a) Fluorine-containing Molecules. Structure, Reactivity,
Synthesis and Applications; Liebman, J. F.; Greenberg, A.;
Dolbier, W. R. Jr., Eds.; VCH: New York, 1988. (b) Filler,
R. Organofluorine Compounds in Medicinal Chemistry and
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(2) Hasek, W. R.; Smith, W. C.; Engelhardt, V. J. Am. Chem.
Soc. 1960, 82, 543.
(3) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
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Rüchardt, C. Liebigs Ann. Chem. 1997, 1333.
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(6) García Martínez, A.; Osío Barcina, J.; Rys, A. Z.;
Subramanian, L. R. Tetrahedron Lett. 1992, 33, 7787.
(7) M kosza, M.; Bujok, R. Tetrahedron Lett. 2002, 43, 2761.
(8) Typical Procedure: Dried powdered KF (3.094 g, 53.3
mmol), Ph3SnF (98 mg, 0.27 mmol) Bu4N+HSO4– (91 mg,
0.27 mmol) and a freshly prepared solution of RCH(OTf)2 in
CH2Cl2 (2.7 mmol in 4.5 mL) were vigorously stirred at r.t.
till the reaction was completed (16–48 h). The reaction
J [1H–1H] = 4.5 Hz, 1 H, CHF2), 7.16–7.36 (m, 5 H, Ph). 19
F
NMR (178 MHz, CDCl3): –117.7 (dt, 2J [19F–1H] = 56.8 Hz,
3J [19F–1H] = 17.1 Hz). MS (EI, 70 eV): 156 (M+, 28),
92(11), 91(100), 65(11).
2-Ethyl-1,1-difluorohexane: 1H NMR (200 MHz, CDCl3):
0.85–1.03 (m, 6 H), 1.25–1.55 (m, 8 H), 1.90–2.10 (1 H,
CHCHF2), 5.71 (td, 2J [19F–1H] = 58.0 Hz, J [1H–1H] = 4.0
Hz, 1 H, CHF2). 19F NMR (178 MHz, CDCl3): –123.43 (dd,
2J [19F–1H] = 57.0 Hz, 3J [19F–1H] = 15.7 Hz). MS (EI, 70
eV): 130 (M+ – HF, 1), 57(100), 56(11), 55(16), 43(49),
42(22), 41(48), 39(13).
Difluoromethylcyclohexane: 1H NMR (200 MHz, CDCl3):
1.01–1.38 (m, 6 H), 1.61–1.84 (m, 5 H), 5.52 (td, 2J [19F–
1H] = 56.7 Hz, J [1H–1H] = 4.2 Hz, 1 H, CHF2). 19F NMR
(178 MHz, CDCl3): –123.82 (dd, 2J [19F–1H] = 56.8 Hz, 3J
[19F–1H] = 14.1 Hz).
Synlett 2002, No. 8, 1285–1286 ISSN 0936-5214 © Thieme Stuttgart · New York