TiCl4-catalyzed friedel-crafts reaction of trifluoroacetaldehyde ethyl hemiacetal (TFAE)

Article abstract of DOI:10.1080/00397911.2010.516860

The TiCl₄-catalyzed Friedel-Crafts reaction with trifluoroacetaldehyde ethyl hemiacetal is shown to serve as an efficient route for the synthesis of CF3-substitituted compounds of biological and synthetic importance, producing 2,2,2-trifluoroet

Full text of DOI:10.1080/00397911.2010.516860

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TiCl4-Catalyzed Friedel–Crafts Reaction
of Trifluoroacetaldehyde Ethyl
Hemiacetal (TFAE)
Jing Zhang a , Yong-Jun Chen b & Liang Zhang a
a Institute of Materia Medica, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, China
b Institute of Chemistry, Chinese Academy of Sciences, Beijing,
China
Available online: 11 Jul 2011
To cite this article: Jing Zhang, Yong-Jun Chen & Liang Zhang (2011): TiCl4-Catalyzed Friedel–Crafts
Reaction of Trifluoroacetaldehyde Ethyl Hemiacetal (TFAE), Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:20, 3045-3052
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Synthetic Communications1, 41: 3045–3052, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.516860
TiCl4-CATALYZED FRIEDEL–CRAFTS REACTION OF
TRIFLUOROACETALDEHYDE ETHYL HEMIACETAL
(TFAE)
Jing Zhang,1 Yong-Jun Chen,2 and Liang Zhang1
1Institute of Materia Medica, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing, China
2Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
GRAPHICAL ABSTRACT
Abstract The TiCl4-catalyzed Friedel–Crafts reaction with trifluoroacetaldehyde ethyl
hemiacetal is shown to serve as an efficient route for the synthesis of CF3-substitituted
compounds of biological and synthetic importance, producing 2,2,2-trifluoroethyl phenols
in good yields under mild conditions.
Keywords Friedel–Crafts reaction; phenol; TiCl4; trifluoroacetaldehyde ethyl hemiacetal
(TFAE)
INTRODUCTION
The unique behavior of fluorinated compounds makes them suitable for numer-
ous applications. Organofluorine compounds play an important role in several scien-
tific disciplines, and the synthesis of compounds containing fluorine is an important
field of chemistry.[1] One of the important fluorine-containing groups is the trifluor-
omethyl group, which has been found to have unique physical and biological proper-
ties.[2] In particular, the lipophilicity attached to the trifluoromethyl moiety makes
trifluoromethylated molecules of great interest, especially for biological purposes.
However, their preparation by direct introduction of a nucleophilic CF3 moiety on
organic substrates, which is the most promising general route, still suffers from a lim-
ited number of efficient reagents that are able to stabilize the very unstable –CF3
anion.[3] Trifluoromethylated compounds continue to be of great industrial interest,[4]
Received April 23, 2010.
Address correspondence to Jing Zhang, Insititute of Materia Medica, Chinese Academy of
Medical Sciences and Peking Union Medical College, 2 Nanwei Road, Beijing 100050, China. E-mail:
jingzhang.2009@yahoo.com.cn
3045

3046
J. ZHANG, Y.-J. CHEN, AND L. ZHANG
and therefore the development of new methods to incorporate the trifluoromethyl
group into organic compounds remains an important area of research.[5]
The Friedel–Crafts alkylation of aromatic and heteroaromatic compounds is
one of the most fundamental carbon–carbon bond-forming reactions in organic
synthesis.[6–8] We have reported the Friedel–Crafts reactions of N,N- and N,O-
acetals with phenols promoted by TiCl4.[9] To continue progress in Friedel–Crafts
alkylation, we reasoned that if trifluoroacetaldehyde ethyl hemiacetal (TFAE) is
used in a similar reaction, we might be able to prepare ortho- or para-(2,2,2-
trifluoro-1-hydroxyethyl)phenol in one step.
Trifluoroacetaldehyde has always been recognized as a potentially very useful pre-
cursor to trifluoromethyl compounds.[10] However, because of its volatility, high reactivity,
and commercial unavailability, trifluoroacetaldehyde is almost never used directly; we
chose its hydrate hemiacetal as an electrophilic agent. Because of our continuing interest
in organofluorine chemistry, we studied the reaction and herein report our results.
RESULTS AND DISCUSSION
Trifluoroacetaldehyde was chosen as an electrophile in the Friedel–Crafts
reaction of phenols. In attempts to determine the most advantageous conditions,
optimization experiments were carried out using 4-tert-butyl phenol (1a) as the
substrate. The reaction of 4-tert-butyl phenol with trifluoroacetaldehyde ethyl hemi-
acetal (3) was studied for different catalysts under the same reaction conditions
(Scheme 1); the different conversion yields obtained in the presence of various Lewis
acids are given in Table 1.
No detectable substitution product was found by thin-layer chorromatography
(TLC) using Zn(OTf)3 or La(OTf)3 as the Lewis acid. Although Lewis acids such as
Zn(OTf)3 and La(OTf)3 were not effective, use of either Sc(OTf)3 or AlCl3 afforded
an adduct (2a) in good yield. TiCl4 exhibited the greatest activity and afforded 2a in
79% yield. Meanwhile, we found that the yields were notably improved by the addition
˚
˚
of molecular sieves 4 A (4 A MS) when TiCl4 was employed as the Lewis acid. The tem-
perature also affected the reaction. Lowering the reaction temperature (below room
temperature) was not successful because the amount of adduct (2a) was diminished
when the reaction was carried out at ꢀ20ꢁC. The yield of the adduct (2a) was improved
to 93% when the reaction was carried out at a slightly elevated temperature (40ꢁC).
Once we had established the optimal conditions for the reaction, various
phenols (1a–o) were investigated in the presence of TiCl4 in dichloromethane
(DCM) (Scheme 1, Table 2).
Scheme 1. Friedel–Crafts reaction of 4-tert-butyl phenol and trifluoroacetaldehyde ethyl hemiacetal.

TiCl4-CATALYZED FRIEDEL–CRAFTS REACTION
3047
Table 1. Screening Lewis acids by reaction of trifluoroacetaldehyde ethyl hemiacetal (3) with 1a
Entry
Lewis acida
Substrate
Temp. (ꢁC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
Sc(OTf)3
AlCl3
BF3
1a
1a
25
25
25
25
40
25
25
25
25
8
8
68
75
1a
1a
8
25
79
TiCl4
TiCl4
8
1a (4A MS)
8
93
Y(OTf)3
Zn(OTf)3
La(OTf)3
None
1a
1a
1a
1a
24
24
24
24
Trace
None
None
None
aLewis acids were added as equimolar amounts of phenol and TFAE.
bConversion yields were determined after isolation by flash chromatography on silica gel.
The TiCl4-promoted Friedel–Crafts reactions all afforded the desired products
(2a–h) in moderate to good yields (50.7–93%). Some observations are worthy of
specific comments. The products showed that the Friedel–Crafts alkylation of
phenols has excellent ortho regioselectivity. Substituents on the phenols such as halo-
gen, OMe, and alkyl, and aryl, have no significant effect on the regioselectivity of the
Friedel–Crafts reaction (entries 1–18). The Friedel–Crafts reaction occurs exclusively
at the a-position (2c, entry 3), for b-naphthol (1c) and at the b-position (2h, entry 9).
for a-naphthol (1h). For 1,10-binaphthol (BINOL, 1g), the mono-Friedel–Crafts
product (2g) at the 3-position was obtained in 50.7% yield when triple-fold of TFAE
and TiCl4 were used (entry 8). The indole compounds do not have an available lone
pair of electrons, because of their delocalization into the aromatic ring, so coordi-
nation to the titanium is not a strong interaction. In addition, the indole compounds
were unstable when TiCl4 was added in a blank reaction, TLC and 1H NMR clearly
showing that very complicated adducts were produced.
Second, to further demonstrate the utility of the hydroxyl-directed C-ortho
Friedel–Crafts reaction, the reaction of phenol 1e (1 eq.) with 1 eq. of TFAE in
the presence of TiCl4 (1.5 eq.) was carried out. The reaction afforded ortho-2,2,2-
trifluoro-1-hydroxyethyl (2e) products in 86.2% yield (entry 6). Product analysis
by 1H NMR and 13C NMR showed that the ortho-substituted compound was
predominantly formed, and no detectable amount of 4-substituted compound was
1
observed by H or 13C NMR, even after the reaction was carried out at reflux
temperature (40 ꢁC). However, the 2,6-dimethyl phenol (1d) can be treated with 1
eq. of TFAE in the presence of TiCl4 (1 eq.) at reflux temperature to give the
4-(2,2,2-trifluoro-1-hydroxyethyl) product (2d, entry 4) in 56.2% yield. It was shown
that the reaction can still occur when the a-position of the phenol was taken up;
meanwhile, the regiochemistry of the reaction was controlled by the hydroxyl group.
Although the explanation for this regiochemical result is not very clear, it could be
due to multiple coordination with the hydroxyl group. According to the same
procedure, the Friedel–Crafts reaction of 1n (entry 15) with TFAE carried out in
stepwise mode gave a yield of 34.2%.
Furthermore, we found that the reaction of 4-fluorophenol and TFAE readily
took place in the presence of TiCl4, preferentially forming the ortho-substituted
product, whereas we did not obtain any product in the reaction of N,O-hemiacetals

3048
J. ZHANG, Y.-J. CHEN, AND L. ZHANG
Table 2. Friedel–Crafts alkylation of phenols (1a–n) with TFAE (3)
Entry
Substrate
Molar ratioa
Product
Yieldb (%)
1
1:1.1
89.0
2
3
1:1.1
1:1.0
81.2
78.1
4
1:1.5
56.2
5
6
1:1.1
1:3.0
86.2
68.1
7
1:1.0
50.7
(Continued )

TiCl4-CATALYZED FRIEDEL–CRAFTS REACTION
3049
Table 2. Continued
Entry
Substrate
Molar ratioa
Product
Yieldb (%)
8
1:1.1
70.8
9
1:1.1
54.2
10
1:2.0
62.8
11
1:1.5
71.2
12
1:1.1
79.6
13
14
1:1.1
1:1.1
34.2
73.2
aPhenol=TFAE.
bIsolated yield by flash chromatography on silica gel.
c1g: racemic BINOL.

3050
J. ZHANG, Y.-J. CHEN, AND L. ZHANG
as electrophilic agents, even when a large amount of TiCl4 was used. The obtained
results are summarized in Table 2.
CONCLUSION
In summary, we have demonstrated a novel hydroxyl-directed Friedel–Crafts
reaction of various phenols with TFAE that provides direct access to C-ortho,
2,2,2-trifluoro-1-hydroxyethyl phenols. This method leads to a simple synthetic
procedure for the introduction of the –CF3 anion. TFAE has been found to be a
good electrophilic agent for use in a direct Lewis acid–catalyzed Friedel–Crafts reac-
tion with phenol to form various 2,2,2-trifluoro-1-hydroxyethyl phenols of a general
structure. The potential of this new Friedel–Crafts reaction is evident in Table 2,
which contains highly valuable products that are employed in the synthesis of the
analogs of natural products, and pharmaceutically interesting compounds can be
easily obtained in good yields. Further studies on the scope and mechanism of the
asymmetric reactions of TFAE are under active investigation.
EXPERIMENTAL
Typical Experimental Procedure
˚
TiCl4 (1.0 eq.) was added dropwise to a solution of phenol 1a (1.0 eq.) and 4 A
molecular sieves (9 mg) in anhydrous dichloromethane at room temperature under
nitrogen. After the mixture was stirred for 30 min, TFAE (1.1 eq.) was added. The
reaction was completed within 8 h at room temperature (monitored by TLC).
The usual workup furnished a residue that was separated and purified by flash chro-
matography on silica gel to give the pure product.
Data
4-t-Butyl-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2a). 1H NMR (CDCl3):
d 1.28 (s, 9H), 4.36 (s, 1H), 5.18 (m, 1H), 6.82 (d, J ¼ 8.5 Hz, 1H), 7.17 (s, 1H),
7.29 (d, J ¼ 8.5 Hz, 1H); 13C NMR (CDCl3): d 73.8, 77.4,109.8, 120.1, 122.6,
123.8, 125.8, 126.0, 126.1, 127.7, 127.8, 135.2, 153.2. HRMS (FAB) calcd. for
C12H15O2F3: 248.2425. Found: 248.2416.
1
4-Methoxy-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2b). H NMR (CDCl3):
d 3.78 (s, 3H), 5.15 (q, 1H), 6.73 (s, 1H), 6.80 (m, 2H); 13C NMR (CDCl3): d 56.2,
72.8, 77.4,114.9, 116.7, 118.4, 123.6, 125.9, 149.3, 153.8; MS-EI m=z (%): 176 (56.1),
204 (100), 223 (Mþ, 31.2).
1-(2,2,2-Trifluoro-1-hydroxyethyl)-2-naphthol (2c). 1H NMR (CDCl3): d
5.32 (q, 1H), 7.09 (d, J ¼ 8.49 Hz, 1H), 7.37 (d, J ¼ 8.50 Hz, 1H), 7.51 (m, 2H),
7.77 (m, 1H), 8.12 (s, 1H), 8.27 (m, 1H); 13C NMR (CDCl3): d 74.9, 77.4, 109.7,
120.1, 122.6, 123.8, 125.8, 126.1, 126.2, 127.8, 135.2, 153.2; MS-EI m=z (%): 196
(59.4), 224 (100), 243 (Mþ, 15.7).
2,6-Dimethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2d). 1H NMR
(CDCl3): d 2.22 (s, 6H), 4.74 (q, J ¼ 7.2 Hz, 1H), 4.89 (s, 1H), 7.08 (s, 2H); 13C NMR

TiCl4-CATALYZED FRIEDEL–CRAFTS REACTION
3051
(CDCl3): d 16.3, 73.2, 77.4,123.6, 125.8, 126.1, 128.1, 129.7, 130.2, 152.2; HRMS (FAB)
calcd. for C10H11O2F3: 220.0711. Found: 220.0709.
2-(2,2,2-Trifluoro-1-hydroxyethyl)phenol (2e). 1H NMR (CDCl3): d 5.23
(q, J ¼ 5.2 Hz, 1H), 6.92 (m, 2H), 7.17 (d, 1H), 7.29 (d, 1H); 13C NMR (CDCl3): d
73.3, 77.4,117.7, 121.0, 123.7, 125.9, 130.0, 131.3, 155.7. HRMS (FAB) calcd. for
C8H7O2F3: 192.0431. Found: 192.0420.
4-Fluoro-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2f). 1H NMR (CDCl3):
d 3.5 (s, 1H), 5.21 (q, J ¼ 5.2 Hz, 1H), 6.53 (s, 1H), 6.84 (m, 1H), 7.0 (m, 2H);
13C NMR (CDCl3): d 72.3, 77.4, 117.7, 121, 123.7, 126.0, 130.0, 131.3, 155.7. MS-EI
m=z (%): 180 (100), 198 (41.2), 211 (Mþ, 21.5).
3-(2,2,2-Trifluoro-1-hydroxyethyl)-1,1’-binaphthol (2g). 1H NMR (CDCl3):
d 2.03 (s, 1H), 5.56 (q, 1H), 7.09–7.17 (m, 2H), 7.27–7.45 (m, 5H), 7.89–8.0 (m, 3H),
8.17 (s, 1H); 13C NMR (CDCl3): d 70.4, 77.4,110.4, 112.7, 118.3, 122.5, 123.8, 124.3,
124.6, 124.7, 125.2, 126.1, 128.1, 128.8, 128.9, 129.3, 129.9, 131.6, 132.2, 133.6, 133.9,
150.8, 153.2. MS-EI m=z (%): 366 (100), 385 (Mþ, 39.8)
2-(2,2,2-Trifluoro-1-hydroxyethyl)-1-naphthol (2h). 1H NMR (CDCl3): d
5.35 (m, 1H), 7.12 (d, J ¼ 8.39 Hz, 1H), 7.39 (d, J ¼ 8.39 Hz, 1H), 7.53 (m, 2H),
7.80 (m, 1H), 8.1 (s, 1H), 8.28 (m, 1H); 13C NMR (CDCl3): d 75.1, 77.4, 109.8,
120.1, 122.6, 123.8, 125.8, 126.0, 126.1, 127.7, 127.8, 135.2, 153.2. HRMS (FAB)
calcd. for C12H9O2F3: 242.1951. Found: 242.1943.
4-Chloro-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2i). 1H NMR (CDCl3):
d 5.18 (m, 1H), 6.81 (d, J ¼ 8.59 Hz, 1H), 6.86 (s, 1H), 7.29 (s, 1H), 7.52 (d,
J ¼ 8.59 Hz, 1H); 13C NMR (CDCl3): d 72.8, 77.4, 112.9, 118.5, 121.1, 125.6,
128.8, 133.4, 134.1. MS-EI m=z (%): 196 (100), 214 (28.1), 227 (Mþ, 15.3).
1
4-Bromo-2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2j). H NMR (CDCl3):
d 5.20 (m, 1H), 6.80 (d, J ¼ 8.69 Hz, 1H), 6.91 (s, 1H), 7.39 (s, 1H), 7.42 (d,
J ¼ 8.69 Hz, 1H); 13C NMR (CDCl3): d 72.4, 77.4, 112.8, 119.5, 121.1, 125.6,
127.8, 132.4, 134.1, 154.9. MS-EI m=z (%): 241 (100), 259 (36.5), 271 (Mþ, 19.6).
2-Hydroxy-4-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2k). 1H
NMR (CDCl3): d 2.28 (s, 3H), 3.73 (s, 1H), 5.17 (s, 1H), 5.56 (s, 1H), 6.61 (d,
J ¼ 7.93 Hz, 1H), 6.72 (d, J ¼ 7.93 Hz, 1H); 13C NMR (CDCl3): d 15.9, 73.9, 77.4,
115.1, 120.0, 122.4, 123.6, 125.9, 128.1, 143.4. HRMS (FAB) calcd. for C9H9O3F3:
222.1611. Found: 222.1609.
4-Indo-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2l). 1H NMR (CDCl3): d
3.6 (s, 1H), 5.16 (q, J ¼ 5.2 Hz, 1H), 6.68 (d, J ¼ 8.63 Hz, 1H), 6.91 (s, 1H), 7.54
(s, 1H), 7.57 (d, J ¼ 8.63 Hz, 1H); 13C NMR (CDCl3): d 75.4, 77.4, 82.3, 119.9,
123.3, 125.6, 138.3, 140.0, 155.8. HRMS (FAB) calcd. for C9H9O3F3: 318.1536.
Found: 318.1601.
2,3,6-Trimethyl-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2m). 1H NMR
(CDCl3): d 2.20 (m, 9H), 4.67 (s, 1H), 4.80 (s, 1H), 5.32 (q, 1H), 7.01 (s, 1H). MS-EI
m=z (%): 216 (100), 235 (Mþ, 30.7)

3052
J. ZHANG, Y.-J. CHEN, AND L. ZHANG
1
2-Methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)phenol (2n). H NMR (CDCl3):
d 2.27 (s, 3H), 3.5 (s, 1H), 5.21 (q, 1H), 6.84 (t, 1H), 6.98 (d, J ¼ 7.36 Hz, 1H), 7.20 (d,
J ¼ 5.9 Hz, 1H); 13C NMR (CDCl3): d 16.1, 73.2, 120.4, 123.7, 125.9, 126.2, 127.6,
132.5, 154.2. HRMS (FAB) calcd. for C9H9O2F3: 206.2157. Found: 206.2169.
ACKNOWLEDGMENT
This work was partially supported by the National High Technology Research
and Development Program of China (Program 863, Grant 2002AA2Z343B).
REFERENCES
1. Robert, I.; Higuchi, K.-L.; Arienti, F.-J. Novel series of potent, nonsteroidal, selective
androgen receptor modulators based on 7H-[1,4]oxazine[3,2-g]quinolin-7-ones. J. Med.
Chem. 2007, 50, 2486–2496; (b) Filler, R.; Kobayashi, Y.; Yagulpolskii, Y.-L. Organofluorine
compounds in medicinal chemistry and biomedical applications; Elsevier: Amsterdam, 1993.
2. Lin, P.; Jiang, J. Synthesis of monotrifluoromethyl-subsituted saturated cycles. Tetra-
hedron 2000, 56, 3635–3671.
3. Surya, G. K. P.; Andrei, K.-Y. Perfluoroalklation with organosilicon reagents. Chem. Rev.
1997, 97, 757–786.
4. Jun, T.; Hirotaka, K.; Takahiko, A. Mannich-type reaction with trifluoromethylated
N,O-himiacetal: Facile preparation of b-amino-b-trifluoromethyl carbonyl compounds.
Org. Lett. 2000, 11, 1577–1597.
5. Katsuya, K.; Gong, Y. F.; Roxana, I. Resolution of 4-(1-hydroxy-2,2,2-trifluoroethyl)-
phenol and its derivatives by lipase-catalyzed enantioselective alcoholysis. Biotechnol.
Lett. 2002, 24, 1623–1630.
6. Fernandez, I.; Hermatschweiler, R.; Breher, F.; Pregosin, P.; Verios, L. High-yield
ruthenium-catalyzed Friedel–Crafts-type allylation reactions using dicationic RuIV
catalysts. Angew. Chem., Int. Ed. 2006, 45, 6386–6391.
7. (a) Chen, Y.-J.; Lei, F.; Liu, L.; Wang, D. Highly diastereoselective synthesis of arylgly-
cine derivatives via TFA-promoted Friedel–Crafts reactions of phenols with cyclic
glyoxylate imines. Tetrahedro. 2003, 59(38), 7609–7614; (b) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Lewis acid–catalyzed asymmetric Friedel–Crafts alkylation. Angew.
Chem., Int. Ed. 2004, 43, 550.
8. (a) Ishii, A.; Soloshonok, V.; Mikami, K. Asymmetric catalysis of the Friedel–Crafts
reaction with fluoral by chiral binaphthol-derived titanium catalysts through asymmetric
activation. J. Org. Chem. 2000, 65, 1597; (b) Bertolini, F.; Dibussolo, V.; Crotti, P.;
Pineschi, M. Mild and stereoselective Friedel–Crafts alkylation of phenol derivatives with
vinyloxiranes: A new access to cycloalkeno benzofurans. Synlett 2007, 19, 3011–3015.
9. Ge, C. S.; Zhang, J.; Chen, Y. J.; Wang, D. Friedel–Crafts reactions of N,N– and
N,O-acetals with phenols promoted by TiCl4. Acta Chim. Sin. 2001, 10, 1835–1840.
10. (a) Funabiki, K.; Matsunaga, M.; Shibata, K. Efficient generation of trifluoroacetalde-
hyde and successive reaction with imines affording b-hydroxy-b-trifluoro methyl
ketones. Synlett 1999, 1477; (b) Funabiki, K.; Nojiri, M.; Matsui, M.; Shibata, K.
Enamine-assisted facile generation of trifluoroacetaldehyde from trifluoroacetaldehyde
ethyl hemiacetal and its carbon-carbon bond forming reaction leading to b-hydroxy-
b-trifluoromethyl ketones. Chem.Commun. 1998, 2051; (c) Gong, Y.; Kato, K.
Convenient synthesis of a-trifluoromethyl amines via aminofluoroalkylation of arenes
with N-trimethylsilyl a-trifluoroacetaldehyde hemiaminal. J Fluorine Chem. 2002, 103.