Facile substitution of N,N-dimethylanilines and phenols with trifluoroacetaldehyde ethyl hemiacetal

Article abstract of DOI:10.1055/s-1999-2867

2,2,2-Trifluoro-1-(N,N-dimethylaminophenyl)ethanols were easily formed in excellent yields by electrophilic substitution between N,N- dimethylanilines 1a, b and trifluoroacetaldehyde ethyl hemiacetal (TFAE). The corresponding substitution of phenols 2a-e

Full text of DOI:10.1055/s-1999-2867

LETTER
1403
Facile Substitution of N,N-Dimethylanilines and Phenols with
Trifluoroacetaldehyde Ethyl Hemiacetal
Yuefa Gong, Katsuya Kato, Hiroshi Kimoto
National Industrial Research Institute of Nagoya, Hirate-cho, Kita-ku, Nagoya 462-8510, Japan
Fax: +81 (52)911 2428
Received 16 June 1999
The reaction was carried out by heating equivalent
Abstract: 2,2,2-Trifluoro-1-(N,N-dimethylaminophenyl)ethanols
were easily formed in excellent yields by electrophilic substitution
between N,N-dimethylanilines 1a, b and trifluoroacetaldehyde eth-
amounts of N,N-dimethylanilines 1a, b and TFAE at
8
1
20 °C (Scheme 2). 2,2,2-Trifluoro-1-[4-(dimethylami-
9
yl hemiacetal (TFAE). The corresponding substitution of phenols no)phenyl]ethanol 3a was the main product in the reac-
2
a-e to prepare 2,2,2-trifluoro-1-(hydroxyphenyl)ethanols, howev- tion of N,N-dimethylaniline 1a, only a trace amount of the
er, occurred only in the presence of catalytic amounts of anhydrous o-substituted isomer being detected by GC. When the para
potassium carbonate.
site was blocked by a methyl group, i.e. 1b, the o-substi-
Key words: a-trifluoromethylbenzylic alcohol, N,N-dimethyla- tuted product 2,2,2-Trifluoro-1-[2-(dimethylamino)-5-
niline, phenol, trifluoroacetaldehyde ethyl hemiacetal, aromatic
substitution
methylphenyl] ethanol 5b was the only product.
NMe2
NMe2
NMe2
Trifluoromethylated compounds have attracted much at-
tention because of their unique properties, and the devel-
CH(OH)CF3
1
CF3CH(OH)OEt
opment of new preparation methods is still an important
area of research. α-Trifluoromethylbenzylic alcohols, es-
2
CH(OH)CF3 Me
R
1
1
a: R = H
b: R = Me
pecially the optically active ones, are of great interest be-
cause of their potential use as ferroelectric liquid crystals.3
For practical applications, p-substitutents such as hydrox-
yl or amino groups, are introduced into their benzene
3a
5b
Scheme 2
4
rings. Compound 4a is one of the most important inter-
mediates used for this. It is usually prepared by Grignard On the other hand, no reaction occurred between 2a-e and
reaction of p-anisylmagnesium bromide and trifluoroace- TFAE under the same conditions. In the presence of cata-
tic acid, followed by demethylation and reduction lytic amounts of anhydrous potassium carbonate, howev-
5
(
Scheme 1).
er, these reactions proceeded smoothly and gave rise to
the formation of the substituted products, 10 2,2,2-trifluo-
ro-1-(hydroxyphenyl)ethanols (Scheme 3). Details of
these reactions are given in Table 1. Both the p- and o-
substituted products, 4aand 6a, were formed in the reac-
tion of phenol 2a, the ratio of 4a/6a being higher at a low-
er temperature. When the reaction was performed at
OMe
OMe
OH
OH
1
1
CF3COOH
BBr3-CH2Cl2
NaBH4
MgBr
COCF3
COCF3
CH(OH)CF3
1
20 °C, a certain amount of di-substituted product 4a’ was
4a
also formed. In the case of 2,6-dimethylphenol 2c, howev-
12
er, only the p-substituted product 4c was generated even
if the reaction occurred at 120 °C. Moreover, only the o-
substituted products were formed in the reactions of 4-me-
thylphenol 2b and 4-phenylphenol 2e, though mono-sub-
stituted product 6b was the predominant product for 2b,
but both mono- and di-substituted products 6e and 6e’
were formed for 2e.
Scheme 1
Trifluoroacetaldehyde, a potentially very useful precursor
to trifluoromethyl carbinols, is rarely used directly be-
cause of the volatility and the commercial unavailability.
For this reason trifluoroacetaldehyde ethyl hemiacetal
In conclusion, the substitution of N,N-dimethylanilines or
phenols with trifluoroacetaldehyde ethyl hemiacetal is an
appropriate pathway to prepare α-trifluoromethylbenzylic
alcohols. Further applications of this substitution are be-
ing investigated.
(
TFAE) is usually used as an important synthetic equiva-
6
lent. Its substitution reaction with electron-rich het-
eroarenes, such as indoles and imidazoles, readily occurs
under mild conditions. In our continuing investigations,
substitutions of TFAE with electron-rich benzene deriva-
tives have been carried out to prepare useful α-trifluoro-
methylbenzylic alcohols. We here report its reactions with
N,N-dimethylanilines and with phenols.
7
Synlett 1999, No. 9, 1403–1404 ISSN 0936-5214 © Thieme Stuttgart · New York

1
404
Y. Gong et al.
LETTER
OH
OH
OH
1997, 86, 81.
R
1
R
2
R1
R2
R
1
CH(OH)CF
3
Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J. M. J.
Org. Chem. 1999, 64, 2579.
(3) Nohira, H. J. Synth. Org. Chem. Jpn. 1991, 49, 467. Walba, D.
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(5) Creary, X. J. Org. Chem. 1987, 52, 5027. Fujisawa, T.;
Ichikawa, K.; Shimizu, M. Tetrahedron: Asymmetry 1993, 4,
CF
3
CH(OH)OEt
CO
K
2
3
R
3
CH(OH)CF3
=R =H;
R
3
2
a: R
b: R
c: R
d: R
e: R
1
=R
=R
=R
=MeO,R
=R
2
=R
=H, R
=Me, R
3
=H;
4a: R
4a': R
6a: R
6b: R
6d: R
1
=R
1
3
=H;
=H, R
=MeO, R
=Ph
=CH(OH)CF
=Ph
1
2
(
2
2
2
2
1
2
3
=Me;
1
=H,
3
=Me;
=H
1
2
3
=H;
R
=CH(OH)CF
=R =Me;
=MeO, R
=MeO,
=CH(OH)CF
1
3
2
1
3
1
2
=R
3
3
=H;
4
4
4
c: R
d: R
d': R
6e: R
=H 6e': R
1
=H, R
3
2
1
2
=H, R
=Ph
1
2
1
R
3
3
1
1237. Fujisawa, T.; Onogawa, Y.; Sato, A.; Mitsuya, T.;
R
2
3
Shimizu, M. Tetrahedron 1998, 54, 4267.
(
6) Loh, T. P.; Li, X. R. J. Chem. Soc., Chem. Commun. 1996,
1
929. Kubota, T.; Iijima, M.; Tanaka, T. Tetrahedron Lett.
Scheme 3
1992, 33, 1351. Sakumo, K.; Kuki, N.; Kuno, T.; Takagi, T.;
Koyama, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 1999,
3, 165. Olah, G. A.; Wang, Q.; Li, X.-Y.; Parakash, G. K. S.
9
Synlett 1993, 1, 32. Mikami, K.; Takasaki, T.; Matsukawa, S.;
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(
(
7) Fujii, S.; Maki, Y.; Kimoto, H. J. Fluorine Chem. 1986, 30,
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Fluorine Chem. 1988, 39, 47.
8) Typical procedure: A mixture of 3.63 g (30 mmol) of N,N-
dimethylaniline and 4.32 g (30 mmol) of
trifluoroacetaldehyde ethyl hemiacetal was heated with
stirring at 120 °C for 6 h. After being cooled, the mixture
became a solid cake. The crude product was then
recrystallized in CH Cl to give the pure compound 3a.
2
2
1
(
9) 3a: white solid; m.p. 98-99 °C; H NMR (CDCl , TMS) δ 2.55
3
(
1 H, br, s), 2.94 (6 H, s), 4.85 (1 H, q, J = 6.5 Hz), 6.70 (2 H,
1
9
d, J = 8.7 Hz), 7.29 (2 H, d, J = 8.7 Hz). F NMR (CDCl ,
C F ), δ 85.81 (d, J = 6.5 Hz). MS m/z 219 (M , 94), 150 (100).
3
+
6
6
Anal. calcd. for C H NOF C% 54.77; H% 5.52, N% 6.39.
1
0
12
3
Found C% 54.56, H% 5.46, N% 6.55.
10) Typical procedure: A mixture of 2.82 g (30 mmol) of phenol,
.32 g (30 mmol) of trifluoroacetaldehyde ethyl hemiacetal
and 0.21 g (1.5 mmol) of anhyd K CO was heated with
(
4
2
3
stirring at 60 °C for 12 h. After being cooled, the mixture was
dissolved in Et O, washed with water, and dried over Na SO .
2
2
4
The solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(
6
9:1 to 5:1 hexane: EtOAc), 6a (0.58g, 10%) and 4a (3.74g,
5%) being collected.
1
(
11) 4a: white solid; mp 123.5-125 °C. H NMR (acetone-d , TMS)
6
δ 5.30 (2 H, br, s), 5.06 (1 H, q, J = 7.4 Hz), 6.86 (2 H, d, J =
1
9
8
.5 Hz), 7.36 (2 H, d, J = 8.5 Hz). F NMR (acetone-d , C F ),
6 6 6
+
δ 85.73 (d, J = 7.4 Hz). MS m/z 192 (M , 38), 123 (100).
HRMS. Calculated: 192.0398. Found: 192.0398. 6a: white
References and Notes
1
needle; m.p. 118 – 118.5 °C. H NMR (acetone-d , TMS) δ
6
2
.87 (2 H, br, s), 5.57 (1 H, q, J = 7.4 Hz), 6.91 (2 H, m), 7.17
(
1) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Organofluorine
Compounds in Medicinal Chemistry and Biomedical
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Yamazaki, T. Tetrahedron: Asymmetry 1991, 2, 235. Banks,
R. E. Ed. Preparation, Properties and Industrial Applications
of Organofluorine Compounds, Ellis Horwood, Chichest,
1
9
(
1 H, dd, J = 7.0 Hz and 2.0 Hz), 7.50 (1 H, d, J = 7.0 Hz). F
NMR (acetone-d , C F ), δ 85.94 (d, J = 7.4 Hz). MS m/z 192
6
6 6
+
(
M , 55), 174 (18), 146 (40), 123 (95), 77 (100). HRMS.
Calculated: 192.0398. Found: 192.0378.
1
(
12) 4c: white solid; mp 136-138 °C. H NMR (CDCl , TMS) δ
3
2.25 (6 H, s), 4.88 (1 H, q, J = 7.2 Hz), 5.12 (2 H, br, s), 7.07
1
9
(
2 H, s). F NMR (CDCl , C F ), δ 85.91 (d, J = 7.2 Hz). MS
3 6 6
1982.
+
m/z 220 (M , 60), 151 (100). HRMS. Calculated: 220.0711.
Found: 220.0711.
(
2) Xu, Y.; Dolbier, Jr. W. R. Tetrahedron Lett. 1998, 39, 9151.
Prakash, G. K.; Yudin, K. A. Chem. Rev. 1997, 97, 757. Loh,
T. P.; Li, X. R. Tetrahedron Lett. 1997, 38, 869. Bravo, P.;
Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661.
Article Identifier:
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McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,
1
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Synlett 1999, No. 9, 1403–1404 ISSN 0936-5214 © Thieme Stuttgart · New York