Preparation of masked 2,2-difluoro-1,3-diols and 2,2-difluoro-1,3,4-butanetriol via photochemical and thermal addition of oxygenated radicals to 2,2-difluorovinyl carbamate

Article abstract of DOI:10.1055/s-2001-16809

Photoreaction of difluorovinyl carbamate in some alcohols except for methanol gave radical addition products as masked forms of 2,2-difluoro-1,3-diols. 1,3-Dioxolane also gave a radical product in thermal radical reaction initiated bynzoyl peroxide. Radical product of 2,2-Dimethyl-1,3-dioxolane was converted into masked 2,2-difluoro-1,3-propanediol.

Full text of DOI:10.1055/s-2001-16809

LETTER
1449
Preparation of Masked 2,2-Difluoro-1,3-diols and 2,2-Difluoro-1,3,4-
butanetriol via Photochemical and Thermal Addition of Oxygenated Radicals
to 2,2-Difluorovinyl Carbamate
Takashi Okano,* Akira Nakajima, Shoji Eguchi
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Fax +81-52-789-3199; E-mail: okano@apchem.nagoya-u.ac.jp
Received 14 June 2001
in 86% yield as a mixture (3: 4a = 83: 17). The reaction
Abstract: Photoreaction of difluorovinyl carbamate in some alco-
time depends on the stability of the generated oxygenated
radicals. The reaction in 2-propanol, in which a stable ter-
tiary hydroxyisopropyl radical is involved, took 4 h for
hols except for methanol gave radical addition products as masked
forms of 2,2-difluoro-1,3-diols. 1,3-Dioxolane also gave a radical
product in thermal radical reaction initiated bynzoyl peroxide. Rad-
ical product of 2,2-Dimethyl-1,3-dioxolane was converted into 1.0 mmol of 1 to disappear from the reaction mixture. 1,3-
masked 2,2-difluoro-1,3-propanediol.
Dioxolan-2-yl radical is also stable and photoreaction of
1.0 mmol of 1 in 1,3-dioxolane took 7 h.
Key words: acetals, fluorine, free radicals, diols, photochemistry
Table Photoreaction1) of Difluorovinyl Carbamate 1 in Alcohols
Difluoromethylene compounds are attracting increasing
interests in the view of potential biological activities.1
However, the synthetic methods for the difluoromethyl-
ene building blocks2 are still limited except for the usually
employed moderately reactive Reformatsky reagent de-
rived from BrCF2CO2Et and the modified reagents.3 Our
synthetic strategy for the difluoromethylene compounds
is trapping of alkyl radicals with the suitably substituted
gem-difluoro olefins.4 Steric effect and destabilizing ef-
fect of fluoroolefins caused by n repulsive interaction
between the fluorine atom and the C C double bond con-
trol the regiochemistry of the addition of alkyl radicals.
We report here radical addition of -hydroxy or alkoxy
radicals to 2,2-difluorovinyl carbamate to yield masked
2,2-difluoro-1,3-diols and 2,2-difluoro-1,3,4-butanetriol.
1)A 100-W high-pressure mercury lamp and a quartz filter were used.
2)Reaction time for 100% conversion of 5.00 mmol of 1. 3)Slow me-
thanolysis of 1 was observed.
2,2-Difluorovinyl N,N-diethylcarbamate (1) was prepared
according to the procedure reported by Percy et al.5 UV ir-
radiation of 1 by a 100-W high-pressure mercury lamp
with a quartz filter in ethanol for 32 h at 5.0 mmol scale
gave 2,2-difluoro-3-hydroxybutyl carbamate (2a) in 82%
yield.6 The photochemically generated -hydroxyethyl
radical7 reacted with 1 at the fluorinated carbon as expect-
ed. The regiochemistry was confirmed by the 19F NMR
spectrum, in which two diastereotopic fluorine peaks cou-
pled each other (JF−F = 262 Hz) showed also coupling with
three vicinal protons. In a similar manner, both 1-propanol
and 2-propanol gave the corresponding difluoro-1,3-diol
monocarbamates 2b,c in 81% and 88% yields, respective-
ly (Table). However, photochemical generation of hy-
droxymethyl radical is unlikely to occur, and no addition
product was obtained in the reaction of 1 in methanol.
Prolonged reaction caused replacement of fluorine by
methoxide followed by hydrolysis to dimethoxyacetate
probably via dark ionic reaction. Addition of an alterna-
tive C1-block radical was performed by the photoreaction
of 1 in 1,3-dioxolane to give ethylene acetal of , -diflu-
oroaldehyde 3 accompanied with an isomeric product 4a
For a preparative scale of the synthesis of 3, photoreaction
takes long time, so that we tried thermal radical reaction
using radical initiators. While azobisisobutyronitrile was
not effective because of low energy of the generated radi-
cal, reaction of carbamate 1 in 1,3-dioxolane at 80 °C ini-
tiated by benzoyl peroxide gave a mixture of 3 and 4a (73:
27) in 75% yield with small amounts of some unidentified
products. Although neither photochemical nor thermal re-
action conditions gave radical adduct in ethylene glycol,
thermal radical addition of 2,2-dimethyl-1,3-dioxolane to
1 initiated with benzoyl peroxide gave the addition prod-
uct 4b in 63% yield without regiochemical problem8,9
(Scheme 1).
Acetals 3 and 4 would be the versatile precursors as the
masked forms of multifunctional difluoromethylene com-
pounds. Thus, deacetalization of 3 was attempted using
typical acidic conditions. However, the acetal structure of
3 is surprisingly stable to acid even at such strong condi-
Synlett 2001, No. 9, 1449–1451 ISSN 0936-5214 © Thieme Stuttgart · New York

1450
T. Okano et al.
LETTER
References and Notes
(1) Recent examples: Esler, W. P.; Kimberly, W. T; Ostaszewski,
B. L.; Diehl, T. S.; Moore, C. L.; Tsai, J.-Y.; Rahmati, T.; Xia,
W.; Selkoe, D. J.; Wolfe, M. S. Nat. Cell Biol. 2000, 2, 428.
Shiozaki, M.; Arai, M.; Macindoe, W. M.; Mochizuki, T.;
Wakabayashi, T.; Kurakata, S.; Tatsuta, T.; Maeda, H.;
Nishijima, M. Bull. Chem. Soc. Jpn. 1997, 70, 1149.
(2) For reviews of preparation of difluoromethylene compounds,
see: (a) Burton, D. J., Drakesmith, F. G.; Hutchinson, J.;
Kitazume, T.; Lu, L.; Percy, J. M.; Sanford, G.; Yamazaki, T.
In Organofluorine Chemistry, Techniques and Synthesis;
Chambers R. D., Ed.; Springer: Berlin, 1997. (b) Tozer, M. J.;
Herpin, T. F. Tetrahedron 1996, 52, 8619.
(3) Fried, J.; Hallinan, E. A.; Szwedo, Jr., M. F. J. Am. Chem. Soc.
1984, 106, 3871. Hallinan, E. A.; Fried, J. Teterhedron Lett.
1984, 25, 2301. Kitagawa, O.; Taguchi, T.; Kobayashi, Y.
Tetrahedron Lett. 1988, 29, 1803. Lang, R. W.; Schaub, B.
Tetrahedron Lett. 1988, 29, 2943. Kitagawa, O.; Murata, A.;
Kobayashi, Y.; Taguchi, T. Chem. Lett. 1990, 1011.
Kitagawa, O.; Hashimoto, A.; Kobayashi, Y.; Taguchi, T.
Chem. Lett. 1990, 1307.
(4) Okano, T.; Takakura, N.; Nakano, Y.; Okajima, A.; and
Eguchi, S. Tetrahedron 1995, 51, 1903. Okano, T.; Ishihara,
H.; Takakura, N.; Tsuge, H.; Eguchi, S.; Kimoto, H. J. Org.
Chem. 1997, 62, 7192.
Scheme 1 Reagents and conditions: i) h ; ii) (C6H5COO)2, 80 °C;
iii) HCl/CH3OH rt; iv) NaIO4, rt; v) NaBH4/CH3OH, rt.
tions as refluxing in conc. HCl (12 M) because of the car-
bocation-destabilizing inductive effect of the difluoro
substitution at the -carbon. On the contrary, isopropy-
lidene acetal 4b was readily deacetalized with conc. HCl
in CH3OH (1:10) at room temperature to hydroxy carbam-
ate 5 in 76% yield. Oxidative cleavage of diol 5 with so-
dium periodate followed by NaBH4 reduction of the
resulting mixture of the corresponding aldehyde and alde-
hyde hydrate gave the desired masked 2,2-difluoro-1,3-
propanediol derivative 6 in 71% yield from 5 (Scheme 1).
(5) Benett, A. J.; Percy, J. M.; Rock, M. H. Synlett 1992, 483. Lee,
J.; Tsukazaki, M.; Sniekus, V. Tetrahedron Lett. 1993, 34,
415.
(6) Experimental procedure for the photoreaction of difluoro
olefin 1 in ethanol: A stirred mixture of 1 (895 mg, 5.0 mmol)
in EtOH (70 mL) at room temperature was irradiated by a 100-
W high-pressure-mercury lamp with a quartz filter under Ar
atmosphere for 32 h until no 1 was detected by GLC. The
solvent was removed under reduced pressure. The residue was
purified by distillation with a Kugel-Rohr distillation
apparatus to give pure alcohol 2a as colorless oil: 917 mg
(82%); bp 150 200 °C/ 3 mmHg; 1H NMR (CDCl3, 300
MHz) 1.150 (6 H, t, J = 7.5 Hz), 1.309 (3 H, d, J = 6.6 Hz),
3.31 (4 H, m), 3.857 (1 H, dqd, J = 19.8, 6.6, 3.6 Hz), 4.151 (1
H, td, J = 12.6, 6.9 Hz), 4.731 (1 H, ddd, J = 23.4, 12.6, 6.0
Hz): 19F NMR [CDCl3, 282 MHz, internal standard:
Monoalcohol 6 was utilized for the synthesis of a poten-
tially ferroelectric material 7, which has two major (CF2)
and four minor ( O ) parallel dipoles perpendicular to
the long molecular axis.10 Bis-ether formation to 8 was
achieved with m-bisbromomethylbenzene and NaH in
THF followed by transesterification with KOH in reflux-
ing 2-propanol to give diol 9 in 56% yield from 6. Bis-
benzylation of diol 9 with benzyl bromide and NaH in
THF led tetrafluorinated linear ether 7 in 56% yield
(Scheme 2).
CF3COOC2H5 ( 75.75 from CFCl3)]
115.6 (ddd, 1 F,
J = 262, 24, 12 Hz), 126.5 (ddt, 1 F, J = 262, 19, 6 Hz).
(7) Elad, D. Organic Photochemistry, Vol. 2; Chapman, O., Ed.;
Marcel Dekker: New York, 1969; p 168.
(8) Experimental procedure for the radical reaction of
difluoroolefin 1 in 2,2-dimethyl-1,3-dioxolane: To a stirred
solution of 1 (1.00 g, 5.6 mmol) in 2,2-dimethyl-1,3-dioxolane
(10 mL) at 80 °C, benzoyl peroxide (200 mg, 0.83 mmol) was
periodically (every 20 min) added in portions. After
In summary, alcohols 2a-c, 5 and 6 were prepared by the
radical reaction initiated by irradiation or benzoyl perox-
ide. These polyol derivatives are expected to be employed
as the starting materials for the synthesis of biologically
active compounds and functional materials including po-
tentially ferroelectric 7.
Scheme 2 Reagents and conditions: i) m-(BrCH2)2C6H4, NaH/THF, rt.; ii) KOH/(CH3)2CHOH, reflux; iii) HCl; iv) C6H5CH2Br, NaH/
THF, rt.
Synlett 2001, No. 9, 1449–1451 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Preparation of Masked 2,2-Difluoro-1,3-diols and 2,2-Difluoro-1,3,4-butanetriol
1451
disappearance of olefin 1 in the gas chromatogram, excess
dioxolane with some perfluoroolefins have been reported
while the reported method can not provide 1,3-diol
derivatives: Církva, V.; Paleta, O. J. Fluorine Chem. 1999, 94,
141.
dioxolane was removed by distillation (bp 93 °C). The residue
was chromatographed on a silica gel column (hexane
EtOAc, 2: 1) to afford 4b as colorless oil: 983 mg, 63%. 1H
NMR (CDCl3, 500 MHz) 1.144 (t, 6 H, J = 7.2 Hz), 1.371 (s,
3 H), 1.454 (s, 3 H), 3.30 (m, 4 H), 4.134 (dd, 1 H, J = 9, 8Hz),
4.213 (dd, 1 H, J = 9, 5 Hz), 4.52 4.25 (m, 3 H): 19F NMR
(10) T. Furukawa, Phase Transitions 1989, 18, 143.
(CDCl3, 282 MHz)
115.8 (dtd, 1 F, J = 261, 17, 5 Hz),
Article Identifier:
123.4 (dddd, 1 F, J = 261, 21, 12, 5 Hz).
1437-2096,E;2001,0,09,1449,1451,ftx,en;Y21501ST.pdf
(9) During the course of this research, photochemical and thermal
radical reactions of 1,3-dioxolane and 2,2-dimethyl-1,3-
Synlett 2001, No. 9, 1449–1451 ISSN 0936-5214 © Thieme Stuttgart · New York