Addition of CFCl3 to aromatic aldehydes under ultrasonic irradiation

Article abstract of DOI:10.1055/s-2006-926367

Reductive addition of CFCl₃ to aromatic aldehydes under the influence of activated aluminum powder and ultrasonic irradiation produced chlorofluoro carbinols in reasonable to excellent yields. Georg Thieme Verlag Sttugart.

Full text of DOI:10.1055/s-2006-926367

PAPER
959
Addition of CFCl3 to Aromatic Aldehydes under Ultrasonic Irradiation
A
a
toAroma
l
tic
A
ld
a
ehyde
s
und
k
er
U
ltrasonic
a
Irradiation Barkakaty, Yutaka Takaguchi, Sadao Tsuboi*
Department of Material and Energy Science, The Graduate School of Environmental Science, Okayama University, Tsushima,
Okayama 700-8530, Japan
Fax +81(86)2518898; E-mail: stsuboi6@cc.okayama-u.ac.jp
Received 24 August 2005; revised 8 November 2005
with less electrophilic ketones to give dichlorofluorome-
thyl carbinols.8 However, it was found that these reactions
were extremely sensitive to the temperature as they pro-
ceeded smoothly only at –20 °C to –15 °C to give the de-
sired products with moderate yields (45–62%), while even
at 0 °C, the reaction turned vigorous yielding pinacol as
the main product. Herein, we wish to report a facile and
simple method for the reductive addition of CFCl3 to aro-
matic aldehydes in the presence of activated aluminum
under ultrasonic irradiation.
Abstract: Reductive addition of CFCl3 to aromatic aldehydes un-
der the influence of activated aluminum powder and ultrasonic irra-
diation produced chlorofluoro carbinols in reasonable to excellent
yields.
Key words: chlorofluoro alcohols, aluminum, ultrasonic effects
Compounds bearing fluorine are often found to exhibit
important biological properties.1 Therefore, novel, effi-
cient and convenient methodologies towards the prepara-
tion of new fluoro compounds, which can serve as useful
synthons for other valuable target molecules, are gaining
immense importance in research. Moreover, the strict
control on chlorofluorocarbons (CFCs) like trichlorofluo-
rocarbon (CFCl3) has led to an ever-increasing demand
for newer and environmentally benign applications of
such compounds in both academics and industry.2,3 In any
kind of synthetic chemistry, carbinols are always consid-
ered as an important class of precursors. Therefore, novel
methods towards the synthesis of fluorinated carbinols
would assist in the design and synthesis of more useful
and complex fluorinated structures by using them as vital
precursors.
In this method, we have employed stannous chloride in
N,N-dimethylformamide for the activation of powdered
aluminum. The role of stannous chloride in this particular
method is noteworthy. We have used 1.25 equivalents of
stannous chloride (with respect to the aldehyde) for the re-
quired conversion (Scheme 1); a lower amount resulted in
much lower yields, and no product at all was obtained in
its absence.
OH
R
H
CFCl3
CFCl2
O
Al, SnCl2, DMF
ultrasonic irradiation
R
H
Scheme 1
A number of reported methods already exist for the syn-
thesis of perfluorinated compounds,4 however the facile
introduction of perfluoro groups into the desired site of an
organic molecule using unconventional technique like ul-
trasonic irradiation draws special attention.5 It has already
been reported that polyhalomethanes like carbon tetra-
chloride, carbon tetrabromide or bromotrichloromethane
add reductively to aldehydes under the influence of acti-
vated aluminum to produce polyhalocarbinols.6 Also, the
addition of CFCl3 to carbonyl compounds under similar
conditions has been accomplished mainly in the case of
compounds where the carbonyl group has been activated
by additional electron-withdrawing substituents such as
trifluoromethyl and fluorine-substituted aromatic
compounds7 or with perfluoro carboxylic acid esters.3 It is
worth mentioning here that even after activation with tri-
fluoromethyl or fluoro aromatic substituents, the yields of
the products obtained is only satisfactory (58–79%) while
in the case of unactivated benzaldehyde, only 39% of the
desired product was obtained.7 Hu et al. described the use
of Mg/LiCl systems as initiators for the reaction of CFCl3
Though similar reactions in the case of other polyhalom-
ethanes or with other activated carbonyl compounds re-
quire much reduced amounts of catalysts,3,6 the
requirement of almost stoichiometric ratios in this case is,
however, not well understood. This method is applicable
to aromatic aldehydes only (Table 1) because with ali-
phatic aldehydes, condensation reaction predominates by
the abstraction of a-protons thereby indicating an anionic
pathway. The mechanism of this reaction is supposed to
be similar to that proposed for analogous reactions with
other polyhalomethanes undergoing reductive couplings
with aldehydes in the presence of aluminum activated by
lead salts.6
We suppose that CFCl3, being a highly volatile compound
(bp 23.7 °C), can easily enter into the cavitation bubbles
formed under ultrasonic irradiation. The chemical envi-
ronment inside the bubbles and the extreme mechanical
effects produced in its surroundings when the bubble col-
lapses is responsible for providing the high activation en-
ergy for the reaction which is not attainable under usual
conditions.9 To investigate further the effects of ultrasonic
irradiation during the course of the reaction, the reaction
was carried out in two different ways: 1) At first, a solu-
SYNTHESIS 2006, No. 6, pp 0959–0962
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.02.2006
DOI: 10.1055/s-2006-926367; Art ID: F14205SS
© Georg Thieme Verlag Stuttgart · New York

960
B. Barkakaty et al.
PAPER
Table 1 Addition of CFCl3 to Aromatic Aldehydes
seem to be the major driving forces for these reactions.
Although initial activation of the metal by ultrasound also
triggers the reaction, a constant source of activation and
the constant hammering effect of the cavitating liquid by
sonication are important for completion of the reaction
and a better yield of the products. However, we cannot
fully justify that cavitation is the only important phenom-
enon in this process. The interaction of ultrasound with a
heterogeneous system produces many interesting changes
which requires thorough research.10 Nevertheless, the fea-
sibility of reductive addition of polyhalomethanes (except
CFCl3) to aldehydes6 and that of CFCl3 to activated carbo-
nyl compounds5,7 under normal conditions as well as the
low product yields obtained from the reductive addition of
benzaldehyde to CFCl3 under high temperature under-
scores the importance of activation produced as a result of
sonochemical cavitation.
OH
R
H
O
CFCl2
R
H
1
2
Entry
Substrate 1a
Time (h)
8
Yield of 2 (%)b
a
85
CHO
b
c
8
6
78
91
CHO
Cl
CHO
d
e
f
6
8
9
87
70
42
Br
CHO
MeO
CHO
CHO
Thus, to conclude, the formidable coupling of aromatic al-
dehydes with CFCl3 under usual conditions has been
achieved by carrying out the reaction under ultrasonic ex-
posure. This method is simple and efficient in attaining
the required conversions in reasonable to excellent yields.
g
7
78
CHO
O
All reactions were carried out with an ultrasonic laboratory cleaner
(Yamato 5510, 42 KHz, 135 W). 1H NMR, 13C NMR (internal stan-
dard: tetramethylsilane) and 19F NMR (internal standard: C6F6)
spectra were recorded on a JEOL JNM-AL300 spectrometer. IR
spectra were recorded on a Thermo Nicolet Avatar 360T2 infrared
spectrophotometer. Elemental analyses were performed on a Per-
kin–Elmer 2400 series II CHNS/O analyzer. For TLC, aluminum
sheets, Merck silica gel coated 60 F254 plates were used and the
plates were visualized with UV light and phosphomolybdic acid
(5% in EtOH). Merck silica gel 60 N (spherical, neutral) (40–50
mm) was used for the flash chromatography.
a Carried out with aldehydes 1 (1.0 equiv), Al (3.0 equiv), SnCl2 (1.25
equiv) and CFCl3 (3.0 equiv) in DMF under ultrasonic irradiation.
b Isolated yields based on starting material (aldehydes 1) consumed.
tion of aluminum, N,N-dimethylformamide and CFCl3 in
DMF was ultrasonically irradiated for five minutes below
20 °C till cavitation bubbles were observed to be formed
vigorously. The ultrasonic irradiation was then stopped
and benzaldehyde was added to the reaction vessel. The
reaction mixture was then allowed to stir at room temper-
ature without ultrasonic application. 2) In this case, a so-
lution of aluminum, stannous chloride and CFCl3 in DMF
was stirred below 20 °C for five minutes, then after the ad-
dition of benzaldehyde, the reaction mixture was irradiat-
ed with ultrasound for eight hours. It was found that in the
former case only 20% of the desired product was isolated
while most of the starting materials remained unreacted
even after stirring for 24 hours. In the case of the second
procedure, 80% of the desired carbinol was isolated with
only 5% recovery of the starting material. The effect of
varying temperature on the reaction without ultrasound
was also studied. At 35–40 °C, benzaldehyde gave 35% of
the desired chlorofluoro carbinol. This result was similar
to that reported by Zeifman and co-workers,7 but on in-
creasing the temperature to 100 °C, 50% of the chloroflu-
oro carbinol was obtained. However, the reactions at such
higher temperatures were not easy as CFCl3 being a high-
ly volatile compound reacted violently and generated a lot
of heat and pressure which demanded great care and cau-
tion.
Trichlorofluoromethane was obtained from commercial source and
was stored over 4 Å molecular sieves. Unless otherwise noted, ma-
terials were obtained from commercial suppliers and were used
without further purification. Stannous chloride was purchased from
Aldrich and reagent grade aluminum powder was used. Anhydrous
DMF was obtained by distillation from calcium hydride and was
stored over 4 Å molecular sieves.
Reductive Addition of CFCl3 to Aromatic Aldehydes under
Ultrasonic Irradiation; Typical Procedure
A two-necked flask equipped with a reflux condenser was charged
with SnCl2 (2.23 g, 11.8 mmol) and Al powder (763 mg, 28.3
mmol) in DMF (25 mL) and then benzaldehyde (0.99 g, 9.4 mmol,
0.96 mL) followed by CFCl3 (3.85 g, 28.3 mmol) were added to the
reaction vessel. Then the reaction mixture was irradiated in the wa-
ter-bath of an ultrasonic laboratory cleaner for 8 h. It must be noted
that: (1) The flask was immersed in the water-bath of the ultrasonic
cleaner positioned in a manner that the level of water in the bath was
adjusted ca. 0.5 cm above the level of solvent inside the flask. (2)
The temperature of the water-bath was maintained below 20 °C to
minimize the loss of CFCl3, which is important for a better output
of the product. The reaction was quenched with 5% HCl acid, and
the mixture was extracted with EtOAc (5 × 30 mL). The combined
extracts were washed with aq NaHCO3 (30 mL) and brine (4 × 30
mL), dried over MgSO4 and concentrated. The crude product was
purified by column chromatography (hexane–EtOAc, 3:1) to give
2,2-dichloro-2-fluoro-1-phenylethanol (1.65g; 85% yield). Other
compounds were also obtained by this method.
Thus, the above results enforce the importance of ultra-
sonic activation in the reaction. The extremely high tem-
perature and pressure generated under ultrasonic exposure
Synthesis 2006, No. 6, 959–962 © Thieme Stuttgart · New York

PAPER
Addition of CFCl3 to Aromatic Aldehydes under Ultrasonic Irradiation
961
2,2-Dichloro-2-fluoro-1-phenylethanol (2a)
1,1-Dichloro-1-fluoro-4-phenylbut-3-en-2-ol (2f)
IR (neat): 3449, 3074, 2914, 1490, 1462, 1387, 1190, 1099, 1013,
IR (neat): 3391, 3078, 2930, 1651, 1577, 1449, 1392, 1305, 1219,
955, 927, 869, 787, 754, 700 cm–1.
1104, 1017, 873, 816, 746, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53 (m, 2 H), 7.41 (m, 3 H), 5.16
(d, J = 8.4 Hz, 1 H), 2.97 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 134.63, 129.43, 128.36, 128.15,
124.72, 120.72, 81.40.
1H NMR (300 MHz, CDCl3): d = 7.34 (m, 5 H), 6.89 (d, J = 1.2 Hz,
1 H), 6.27 (dd, J = 6.3, 15.9 Hz, 1 H), 4.72 (dd, J = 5.7, 6.3 Hz, 1
H), 3.40 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 137.24, 135.54, 128.91, 128.40,
127.58, 126.68, 125.80, 124.58, 121.14, 81.14.
19F NMR (CDCl3): d = 158.12, 155.01.
19F NMR (CDCl3): d = 158.29, 155.72.
Anal Calcd for C8H7Cl2FO: C, 45.96; H, 3.38. Found: C, 46.06; H,
3.43.
Anal. Calcd for C10H9Cl2FO: C, 51.09; H, 3.86. Found: C, 50.96; H,
3.90.
2,2-Dichloro-2-fluoro-1-(2-methylphenyl)ethanol (2b)
IR (neat): 3445, 3058, 2939, 1601, 1499, 1383, 1301, 1124, 1071,
1009, 951, 881, 869, 824, 754, 737, 680 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.66 (d, J = 6.9 Hz, 1 H), 7.25 (m,
3 H), 5.43 (d, J = 9.3 Hz, 1 H), 3.05 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 137.04, 133.39, 130.54, 129.25,
127.58, 125.93, 123.19, 79.78, 19.88.
2,2-Dichloro-2-fluoro-1-(2-furyl)ethanol (2g)
IR (neat): 3420, 3132, 1507, 1392, 1248, 1161, 1062, 1017, 976,
931, 857, 787, 742 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.48 (s, 1 H), 6.57 (d, J = 3.0 Hz,
1 H), 6.44 (s, 1 H), 5.18 (d, J = 8.4 Hz, 1 H), 3.11 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 158.90, 143.69, 123.53, 111.15,
110.94, 94.00.
19F NMR (CDCl3): d = 155.05.
19F NMR (CDCl3): d = 158.84, 155.49.
Anal. Calcd for C9H9Cl2FO: C, 48.46; H, 4.07. Found: C, 48.90; H,
4.04.
Anal. Calcd for C6H5Cl2FO: C, 36.21; H, 2.53. Found: C, 36.0; H,
2.48.
2,2-Dichloro-2-fluoro-1-(2-chlorophenyl)ethanol (2c)
IR (neat): 3412, 3074, 1593, 1445, 1387, 1272, 1190, 1087, 1017,
955, 886, 799, 754, 725, 696 cm–1.
References
1H NMR (300 MHz, CDCl3): d = 7.75 (m, 1 H), 7.36 (m, 3 H), 5.77
(d, J = 9.3 Hz, 1 H), 3.17 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 134.45, 132.77, 130.56, 129.61,
126.87, 124.41, 120.38, 80.78.
(1) (a) Seiler, N.; Jung, M. J.; Koch-Weser, J. Enzyme-Activated
Irreversible Inhibitors; Elsevier/North-Holland Biomedical
Press: Amsterdam, 1978. (b) Rando, R. R. Pharmacol. Rev.
1984, 36, 111. (c) Banks, R. E. Organofluorine Chemicals
and their Industrial Applications, Vol. 123; Royal Society of
Chemistry: London, 1979, 154. (d) Banks, R. E.
19F NMR (CDCl3): d = 154.64.
Organofluorine Chemicals and their Industrial
Anal. Calcd for C8H6Cl3FO: C, 39.46; H, 2.48. Found: C, 39.28; H,
2.41.
Applications, Vol. 123; Royal Society of Chemistry:
London, 1979, 169. (e) Fuller, R.; Kobayashi, Y.
Biomedical Aspects of Fluorine Chemistry; Kodansha/
Elsevier: New York, 1982.
2,2-Dichloro-2-fluoro-1-(4-bromophenyl)ethanol (2d)
IR (neat): 3457, 3083, 2910, 1585, 1486, 1412, 1239, 1079, 1009,
951, 881, 824, 795, 766, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53 (m, 2 H), 7.40 (d, J = 8.1 Hz,
2 H), 5.11 (d, J = 7.5 Hz, 1 H), 3.24 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 133.51, 131.34, 130.01, 129.99,
124.37, 123.73, 120.38, 80.66.
(2) (a) Shimakoshi, H.; Maeyema, Y.; Kaieda, T.; Matsuo, T.;
Matsui, E.; Naruta, Y.; Hisaeda, Y. Bull. Chem. Soc. Jpn.
2005, 78, 859. (b) Krahl, T.; Kemintz, E. Angew. Chem. Int.
Ed. 2004, 43, 6653. (c) Nenajdenko, V. G.; Shastin, A. V.;
Korotchenko, V. N.; Varseev, G. N.; Balenkova, E. S. Eur.
J. Org. Chem. 2003, 302. (d) Saikia, A. K.; Tsuboi, S. J.
Org. Chem. 2001, 66, 643.
19F NMR (CDCl3): d = 154.87.
(3) Zeifman, Y. V.; Postovoi, S. A. J. Fluorine Chem. 2004,
Anal. Calcd for C8H6BrCl2FO: C, 33.37; H, 2.10. Found: C, 33.43;
H, 2.07.
125, 1815.
(4) (a) Boswell, G. A. Jr.; Ripka, W. C. Org. React. (N.Y.) 1974,
21, 1. (b) Sheppard, W. A.; Sharts, C. M. In Organic
Fluorine Chemistry; Benjamin, Inc.: New York, 1969, 185.
(c) Haszeldine, R. N. J. Chem. Soc. 1950, 3037.
2,2-Dichloro-2-fluoro-1-(4-methoxyphenyl)ethanol (2e)
IR (neat): 3449, 3004, 2902, 1618, 1519, 1462, 1248, 1174, 1087,
1030, 955, 886, 816, 787, 754, 725, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.45 (d, J = 8.4 Hz, 2 H), 6.92 (d,
J = 8.4 Hz, 2 H), 5.10 (d, J = 8.7 Hz, 1 H), 3.82 (s, 3 H), 2.97 (br s,
1 H, OH).
13C NMR (75 MHz, CDCl3): d = 141.18, 135.15, 133.93, 128.49,
124.98, 115.62, 114.63, 82.37, 56.82.
19F NMR (CDCl3): d = 155.07.
(d) Leedham, K.; Haszeldine, R. N. J. Chem. Soc. 1954,
1634. (e) Culler, W. R.; Waldmen, M. C. Can. J. Chem.
1969, 47, 3039. (f) Coe, P. L.; Milner, N. E. J. Organomet.
Chem. 1974, 70, 147. (g) Cantacuzene, D.; Wakselman, C.;
Dorme, R. J. Chem. Soc., Perkin Trans. 1 1977, 1365.
(h) Umemoto, T.; Kuriu, Y.; Nakayama, S.; Miyano, O.
Tetrahedron Lett. 1982, 23, 1471. (i) McLoughlin, V. C. R.;
Throwers, J. Tetrahedron 1969, 25, 5921. (j) Kobayashi,
Y.; Kumadaki, I. Tetrahedron Lett. 1969, 4095.
(k) Ishikawa, N.; Ochiai, M. Nippon Kagaku Kaishi 1973,
2351. (l) Umemoto, T.; Kuriu, Y.; Nakayama, S.
Tetrahedron Lett. 1982, 23, 1169. (m) Umemoto, T.; Kuriu,
Y.; Miyano, O. Tetrahedron Lett. 1982, 23, 3579.
Anal. Calcd for C9H9Cl2O2F: C, 45.22; H, 3.79. Found: C, 45.10; H,
3.85.
Synthesis 2006, No. 6, 959–962 © Thieme Stuttgart · New York

962
B. Barkakaty et al.
PAPER
(7) Postovoi, S. A.; Kagramanova, E. M.; Mysov, E. I.;
Zeifman, Y. V. Russ. Chem. Bull. 1996, 45, 1425.
(8) Hu, C.-M.; Tu, M.-H. J. Fluorine Chem. 1994, 67, 9.
(9) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443.
(10) De Souza-Barboza, J. C.; Petrier, C.; Luche, J.-L. J. Org.
Chem. 1988, 53, 1212.
(5) (a) Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107,
5186. (b) Kitazume, T.; Ishikawa, N. Chem. Lett. 1981,
1679. (c) Kitazume, T.; Ishikawa, N. Chem. Lett. 1982, 137,
1453. (d) Kitazume, T.; Ishikawa, N. Nippon Kagaku Kaishi
1984, 1725. (e) Ishikawa, N.; Takahashi, M.; Sato, T.;
Kitazume, T. J. Fluorine Chem. 1983, 22, 585.
(6) Tanaka, H.; Yamashita, S.; Yamanoue, M.; Torii, S. J. Org.
Chem. 1989, 54, 444.
Synthesis 2006, No. 6, 959–962 © Thieme Stuttgart · New York