Condensations of aryl trifluoromethyl ketones with arenes in acidic media

Article abstract of DOI:10.1016/j.tetlet.2010.07.067

The chemistry of trifluoromethyl ketones has been studied. The work examines the condensation reactions of trifluoromethyl ketones with arenes in the superacid, including both synthetic and mechanistic aspects.

Full text of DOI:10.1016/j.tetlet.2010.07.067

Tetrahedron Letters 51 (2010) 4984–4987
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Tetrahedron Letters
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Condensations of aryl trifluoromethyl ketones with arenes in acidic media
Matthew J. O’Connor, Kenneth N. Boblak, Ashley D. Spitzer, Peter A. Gucciardo, Andrew M. Baumann,
*
Joshua W. Peter, Connie Y. Chen, Ronald Peter, Adam A. Mitton, Douglas A. Klumpp
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemistry of trifluoromethyl ketones has been studied. The work examines the condensation reac-
Received 17 May 2010
Revised 9 July 2010
Accepted 13 July 2010
Available online 16 July 2010
tions of trifluoromethyl ketones with arenes in the superacid, including both synthetic and mechanistic
aspects.
Ó 2010 Elsevier Ltd. All rights reserved.
The hydroxyalkylation reaction involves the acid-catalyzed con-
densations of aldehydes and ketones with arenes.1 Although the
reaction is often limited to activated, electron-rich arenes, it has
been shown in many instances that aldehydes and ketones bearing
electron-withdrawing groups may react with benzene and even
deactivated arenes.2 For example, acetophenone will not react with
benzene in CF3SO3H (triflic or trifluoromethanesulfonic acid), de-
spite being protonated in the superacid.3 As shown by Kray and
Rosser,2a 2,2,2-trifluoroacetophenone (1) does however react in
high yield with benzene to give the condensation product (3, Eq.
1). The inductive effects of the
The condensation chemistry of a variety of trifluoromethyl ke-
tones was studied, including acetophenones, biaryl, and heterocy-
clic systems (Table 1).6 In condensation reactions with substituted
acetophenones (6–12), generally good conversions were observed
from benzene and CF3SO3H. The 4-(trifluoroacetyl)benzoic acid
(10) reacts cleanly to form the benzoyl-substituted product (17),
indicating that Friedel–Crafts chemistry occurs at both the ketone
and acid functional groups. In the case of 2,2,2-trifluoro-4-methyl-
acetophenone (8), the condensation does take place, however the
reaction is complicated by formation of major impurities from
transmethylation (the intermolecular exchange of methyl groups)
at 25 °C. If the reaction is done at low temperature (ꢀ10 °C), the ex-
pected product 15 is formed in good yield and is relatively pure.
The reaction of 2,2,2,40-tetrafluoroacetophenone (9) forms the ex-
pected condensation product (16) however, it is accompanied by
the formation of ca. 5% of an impurity identified as 1,1,1-tri-
fluoro-2,2,2-triphenylethane (3). When the 2-(trifluoroace-
tyl)biphenyl (11) is reacted with CF3SO3H and C6H6, the
condensation involves intra- and intermolecular reaction steps to
produce a fluorene ring system (18). A similar transformation is
seen with the quinoline derivative 12.
Previous results have shown that the condensation reactions of
trifluoromethyl ketones will occur with activated, electron-rich
arenes and with benzene.2a,4a As such, ketone 7 condenses in good
yield with the activated arene, benzo-18-crown-6 (Scheme 1).
With reaction of precisely 2.0 equiv of arene to 1.0 equiv of 7, the
crown-derivative (20) is prepared cleanly. We have also found that
this electrophile will react with somewhat deactivated arenes.
When compound 7 is reacted with o-dichlorobenzene, the conden-
sation product (21) is formed in reasonable yield.
O
OH
CF3
Ph
C6H6
CF3SO3H
C6H6
Ph
Ph
CF3
ð1Þ
CF3
1
2
3
trifluoromethyl group activate the carboxonium ion intermediate
(2) and this leads to enhanced electrophilic reactivity. The hydrox-
yalkylation reaction has had an important role in polymer chemis-
try, as it is the reaction used to make bis-phenol-A and many
condensation polymers with phenols. Recently, this chemistry has
been applied in the synthesis of several novel condensation poly-
mers (4 and 5) through the reactions of compound 1
O
Ph CF3
Ph
CF3
n
n
O
O
4
5
with biaryl substrates.4 The step-growth polymerizations of elec-
tron-deficient ketones continue to be an active area of research in
polymer synthesis.5 As such, there is renewed interest in the
hydroxyalkylation reaction of ketones and aldehydes. In the follow-
ing Letter, we describe our studies of superacid-promoted hydrox-
yalkylation chemistry.
Although the reaction conditions have not been fully optimized,
we have found that the reaction is best done with an excess of
CF3SO3H and that weaker acids do not promote the condensation.
Using the condensation of 2,2,2-trifluoroacetophenone (1) with
benzene as a test reaction, the quantity of CF3SO3H was varied
(25 °C and 24 h reaction). While the reaction proceeds with 1 equiv
of acid, product 3 was isolated in just 58% yield. Using 5 equiv of
* Corresponding author. Tel.: +1 815 753 1959; fax: +1 815 753 4802..
E-mail address: dklumpp@niu.edu (D.A. Klumpp).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.067

M. J. O’Connor et al. / Tetrahedron Letters 51 (2010) 4984–4987
4985
Table 1
studies were done with the 2,2,2-trifluoroacetophenone deriva-
tives in CF3SO3H solution (Table 2). It has been known for some
time that 13C NMR chemical shift values are extremely sensitive
to electron density and charge formation. With closely related
structures, 13C NMR chemical shift values are useful in characteriz-
ing the nature of carbocationic intermediates.7 By comparing the
13C NMR spectra from CDCl3 and CF3SO3H solutions, we sought
to gain insight regarding the structures of protonated ketones in
CF3SO3H. When 2,2,2-trifluoroacetophenone (1) is examined in
the two solutions, it is remarkable to note the large downfield
shifts of the carbonyl carbon (d 180.6?187.7) and ortho, para car-
bons (d 130.2, 135.5?132.9, 140.5). Similar results are seen for ke-
tone 8. These data suggest a fairly high equilibrium concentration
of the carboxonium ions (i.e., 2). Formation of the protonated ke-
tone is favorable due to the good electron-donating abilities of
the phenyl and 4-methylphenyl groups. With ketone 7, the car-
boxonium group 13C resonances are shifted downfield, although
to a less extent than with compounds 1 and 8. This is likely due
to lower equilibrium concentration of the carboxonium ion (23).
The 4-(N,N-dimethylammonium) phenyl group is
Products and yields from the reactions of ketones 6–13 with C6H6 in CF3SO3H
Substrate
Product
Yielda (%)
O
Ph
Ph
96c
CF3
CF3
13
Cl
6
Cl
O
Ph
Ph
CF3
CF3
89c
H3C
N
H3C
N
14
7
CH3
CH3
O
Ph
Ph
CF3
15
Ph
CF3
90b
86c
CF3
H3C
8
H3C
O
Ph
CF3
16
9
F
F
O
Ph
Ph
CF3
CF3
73c
99c
71d
Ph
HO
17
10
OH
CF3
O
O
O
O
H
Ph
CF3
F3C
H
H
CF3
N
N
H3C
H3C
CH3
CH3
Ph
11
22
23
18
Ph
O
expected to destabilize the carboxoniun ions due to inductive and
electrostatic effects. Despite an apparently lower equilibrium con-
centration of the carboxonium ion 23, the condensation product
with benzene (14) is formed in good yield. This suggests relatively
high electrophilic reactivity for carboxonium ion (23), a feature that
is confirmed by its reaction with o-dichlorobenzene. While strong
electron-withdrawing aryl groups may tend to further activate car-
boxonium electrophiles, it should be noted however that the basi-
city of the carbonyl group could drop-off and the formation of the
carboxonium ion may not be possible. This may be similar to the
experimental observation that 1,1,1-trifluoroacetone readily forms
condensation polymers with biaryl substrates, but hexafluoroace-
tone does not form polymers.4a,5a
Besides the role of the carboxonium ion, there are other mech-
anistic considerations with this hydroxyalkylation chemistry. In
the reactions of ketones 8 and 9, by-products were observed. For
example, reaction of 9 produces the major product 16, but com-
pound 3 is also produced in small amounts (5%). The formation
of by-product 3 can be explained by an aryl-group exchange
involving ipso-protonation of the fluorophenyl group (Eq. 2). The
very
CF3
CF3
N
Ph
12
N
19
a
b
c
Isolated yield.
Reaction done at ꢀ10 °C.
Reaction done at 25 °C.
Reaction done at 50 °C.
d
Cl
Cl
Cl
O
Cl
CF3SO3H
CF3
H3C
N
C6H6
39%
CF3
H3C
7
CH3
N
21
CH3
O
O
O
O
O
O
O
O
O
O
O
CF3SO3H
O
Ph
H
CF3
Benzo-18-C-6
67%
Ph
H
Ph
Ph
-C6H5F
H3C
N
CF3
CF3
16
20
CH3
ð2Þ
24
F
C6H6
Scheme 1.
3
CF3SO3H, the reaction quantitatively produces compound 3. Reac-
tions were also done with large excesses of H2SO4 and CF3CO2H
(20 equiv), but no condensation product was detected. These re-
sults are consistent with the need for very strong acids, or superac-
ids, to effectively promote the condensations of trifluoromethyl
ketones.
The mechanism of the hydroxyalkylation reaction is generally
thought to proceed through a carboxonium ion intermediate, or
protonated carbonyl group. In order to further examine the car-
boxonium ions involved in the condensation reactions, 13C NMR
high acidity of CF3SO3H facilitates this chemistry.8 The undesired
by-product (3) tends to form in greater quantities under conditions
of excess acid and elevated temperature. In the case of 2,2,2-tri-
fluoro-4-methylacetophenone (8), transmethylation is observed,
but another side-reaction also occurs. When compound 8 was re-
acted with toluene at 70 °C in CF3SO3H (5 equiv), three types of
products were detected by GC–MS and NMR analysis (Scheme 2).
As reported previously by Kray and Rosser,2a the condensation
product 25 is formed as a major product. However, the diarylethane
(26) is also formed as a major product (ratio of 25/26 is 4:1).

4986
M. J. O’Connor et al. / Tetrahedron Letters 51 (2010) 4984–4987
Table 2
13C NMR spectral data from trifluoromethyl ketones in CDCl3 and CF3SO3H (q, quartet)
Solvent (temp)
13C NMR signals, d
O
CDCl3 (25 °C)
CF3SO3H (ꢀ20 °C)
116.8 (q), 129.2, 130.1, 130.2, 135.5, 180.6 (q)
116.5 (q), 127.3, 129.9, 132.9, 140.5, 187.7 (q)
CF3
1
O
CDCl3 (25 °C)
21.9, 116.8 (q), 127.5, 129.8, 130.2, 147.0, 180.1 (q)
22.4, 118.3 (q), 123.0, 132.1, 136.4, 162.2, 187.5 (q)
CF3SO3H (ꢀ20 °C)
CF3
O
H3C
H3C
8
CDCl3 (25 °C)
CF3SO3H (ꢀ20 °C)
40.0, 110.9, 117.4, 117.5 (q), 132.7, 154.7, 177.9 (q)
47.7, 116.2 (q), 122.1, 131.0, 134.0, 147.6, 183.9 (q)
CF3
N
7
CH3
CH3
Sheets, M. A.; Li, A.; Bower, E. A.; Weigel, A. R.; Abbott, M. P.; Gallo, R. M.;
Mitton, A. A.; Klumpp, D. A. J. Org. Chem. 2009, 73, 2502.
CH3
H3C
H
3. Ohwada, T.; Yamagata, N.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 1364.
4. (a) Diaz, A. M.; Zolotukhin, M.; Fromine, S.; Salcedo, S.; Manero, O.; Cedillo, G.;
Velasco, V. M.; Guzman, M. T.; Fritsch, D.; Khalizov, A. F. Macromol. Rapid
Commun. 2007, 28, 183; (b) Zolotukhin, M.; Fromine, S.; Salcedo, S.; Khalilov, L.
Chem. Commun. 2004, 1030; (c) Guzman-Gutierrez, M. T.; Zolotukhin, M. G.;
Fritsch, D.; Ruiz-Trevino, F. A.; Cedillo, G.; Fregoso-Israel, E.; Ortiz-Estrada, C.;
Chavez, J.; Kudla, C. J. Membr. Sci. 2008, 323, 379.
CF3SO3H
F3C
8
toluene
70°C
CH3
CF3
H3C
25
26
27
CH3
5. (a) Rusanov, A. L.; Chebotarev, V. P.; Lovkov, S. S. Russ. Chem. Rev. 2008, 77, 547;
(b) Fu, Y.; Van Oosterwijck, C.; Vandendriessche, A.; Kowalczuk-Bleja, A.;
Zhang, X.; Dworak, A.; Dehaen, W.; Smet, M. Macromolecules 2008, 41, 2388.
6. Typical procedure: the trifluoromethyl ketone (1 mmol) is dissolved in 2 mL of
C6H6, and CF3SO3H (2 mL, 23 mmol) is added with stirring. After 4 h, the
mixture is poured onto ice. If the substrate contains a strong base site (amino
group or N-heterocycle), then the solution is neutralized with 10 M NaOH. The
aqueous solution is then extracted twice with CHCl3 (2 ꢁ 30 mL) and the
organic phase is washed with water and twice with brine. The solution is then
dried over MgSO4 and isolated by column chromatography or recrystallization.
In the case of compound 20, 2 mmol of benzo-18-crown-6 is reacted with
1 mmol of compound 7.
OH
CF3
OH
H
H3C
H2C
CF3
H3C
H3C
Scheme 2.
Formation of this product can be explained by the involvement of a
hydride transfer step.
7. Olah, G. A.; Berrier, A.; Prakash, G. K. S. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 1998.
8. Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J. Superacid Chemistry, 2nd
ed.; Wiley & Sons: New York, 2009.
This proposed mechanism is supported by the observation of
diarylmethane by-product (27).9 These data suggest that good hy-
dride donors may be unsuitable as substrates in hydroxyalkyla-
tions that utilize trifluoromethyl ketones. These undesirable side
reactions may however be suppressed by using lower reaction
temperatures (vide supra).
In conclusion, we have found that substituted trifluoroacetoph-
enones condense with benzene and substituted arenes in superac-
idic CF3SO3H.10 While the strength of this acid facilitates rapid
condensations of the ketones with arenes, it can also lead to unde-
sirable side reactions, such as aryl-group exchange and side reac-
tions in alkyl-substituted arenes. Depending on the structure of
the trifluoromethyl ketone, intramolecular reactions may compete
with intermolecular reactions.
9. Alternatively, hydride transfer might occur after arylation and formation of the
carbocation intermediate. Products 25–27 could not be separated; their
identities and relative yields were established by GC–MS, GC-FID, and 1H
NMR analysis of the crude product mixture.
10. Characterization of data of new compounds. Compound 13: 1H NMR, d, CDCl3:
7.12 (d, J = 9 Hz, 2H), 7.16–7.17 (m, 3H), 7.33 (d, J = 9 Hz, 2H), 7.34–7.38 (m,
7H). 13C NMR, d, CDCl3: 64.9 (q, JC–F = 24 Hz), 127.8 (q, JC–F = 285 Hz), 127.9,
128.2, 128.3, 129.9, 131.4, 133.9, 138.7, 139.7. LR MS: 348/346 (M+), 279/277,
201/199, 165. HRMS,
C20H14F3Cl calcd 346.07361, found 346.07434.
Compound 14: 1H NMR, d, CDCl3: 3.03 (s, 6H), 6.73 (d, J = 8.3 Hz, 2H), 7.06
(d, J = 8.6 Hz, 2H), 7.27–7.28 (m, 4H), 7.37–7.39 (m, 6H). 13C NMR, d, CDCl3:
40.3, 64.5 (q, JC–F = 23 Hz), 111.6, 127.5, 128.0, 128.4, (q, JC–F = 285 Hz), 130.1,
130.8, 140.9, 149.5. LR MS: 355 (M+), 286, 165. HRMS,
C22H20NF3 calcd
355.15478, found 355.15586. Compound 15: 1H NMR, d, CDCl3: 2.47 (s, 3H),
7.16 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.30–7.37 (4H), 7.40–7.48 (m,
6H). 13C NMR, d, CDCl3: 21.0, 65.0 (q, JC–F = 94 Hz), 127.7, 128.1, 128.2 (q,
JC–F = 284 Hz), 128.9, 130.0, 130.0, 137.4, 137.6, 140.4. LR MS: 326 (M+), 257,
165. HRMS, C21H17F3 calcd 326.12824, found 326.12735. Compound 16: 1H
NMR, d, CDCl3: 7.04–7.08 (m, 2H), 7.18–7.22 (m, 6H), 7.37–7.42 (m, 6H). 13C
NMR, d, CDCl3: 64.8 (q, JC–F = 94 Hz), 115.0 (d, JC–F = 21 Hz), 127.8, 128.0 (q,
JC–F = 285 Hz), 128.2, 129.9, 131.8 (d, JC–F = 30 Hz), 136.0, 140.1, 162.1 (d,
JC–F = 247 Hz). LR MS: 330 (M+), 261, 183, 165. HRMS, C20H14F4 calcd
330.10316, found 330.10356. Compound 17: 1H NMR, d, CDCl3: 7.19–7.23
(m, 2H), 7.35–7.40 (m, 2H), 7.51–7.54 (m, 1H), 7.62–7.65 (m, 8H), 7.82 (d,
J = 8.3 Hz, 2H), 7.89 (d, J = 7.4 Hz, 2H). 13C NMR, d, CDCl3: 65.3 (q, JC–F = 24 Hz),
127.8 (q, JC–F = 284 Hz), 128.0, 129.9, 129.9, 129.9, 132.7, 136.8, 137.3, 139.4,
139.5, 143.6, 144.7, 146.2, 196.2. LR MS: 416 (M+), 347, 165, 105. HRMS,
Acknowledgments
This work was done in large part by the CHEM 339 labora-
tory class at Northern Illinois University. Financial support by
the National Science Foundation (CHE-0749907) is greatly
appreciated.
C
27H19OF3 calcd 416.13881, found 416.13955. Compound 18: 1H NMR, d,
References and notes
CDCl3: 7.28–7.32 (m, 3H), 7.35–7.38 (m, 4H), 7.50–7.53 (m, 2H), 7.58 (d,
J = 12 Hz, 2H), 7.84 (d, J = 8 Hz, 2H). 13C NMR, d, CDCl3: 63.8 (q, JC–F = 26 Hz),
120.3, 126.3, 126.8 (q, JC–F = 281 Hz), 126.3, 127.3, 127.3, 127.7, 128.1, 128.7,
129.2, 137.5, 141.4, 144.3. LR MS: 310 (M+), 241, 183, 119. HRMS, C20H13F3
calcd 310.09694, found 310.09619. Compound 19: 1H NMR, d, CDCl3: 7.31–7.34
(m, 3H), 7.39–7.41 (m, 2H), 7.55–7.58 (m, 2H), 7.62–7.67 (m, 2H), 7.78–7.84
(m, 2H), 8.22–8.28 (m, 2H), 8.36–8.40 (m, 1H). 13C NMR, d, CDCl3: 61.4 (q,
JC–F = 281 Hz), 122.4, 126.5, 126.5, 126.6 (q, JC–F = 26 Hz), 127.4, 127.5, 128.0,
128.5, 128.9, 129.3, 129.9, 130.2, 131.1, 133.4, 136.4, 137.2, 140.4, 145.7, 149.1,
160.5. LR MS: 361 (M+), 292, 234, 145. HRMS, C23H14NF3 calcd 361.10783,
found 361.10910. Compound 20: 1H NMR, d, CDCl3: 2.94 (s, 6H), 3.65–3.78 (m,
1. (a) Hofmann, J. E.; Schriesheim, A.. In Friedel–Crafts and Related Reaction; Olah,
G. A., Ed.; Wiley: New York, NY, 1964; Vol. 2, pp 597–640; (b) March, J.
Advanced Organic Chemistry, 4th ed.; Wiley: New York, NY, 1992. pp 548–549.
2. (a) Kray, W. D.; Rosser, R. W. J. Org. Chem. 1977, 42, 1186; (b) Khodakovskly, P.
V.; Mykhailiuk, P. K.; Volochnyuk, D. M. Synthesis 2010, 967; (c) Prakash, G. K.
S.; Panja, C.; Shakhmin, A.; Shah, E.; Mathew, T.; Olah, G. A. J. Org. Chem. 2009,
74, 8659; (d) Prakash, G. K. S.; Paknia, F.; Chacko, S.; Mathew, T.; Olah, G. A.
Heterocycles 2008, 76, 783; (e) O’Connor, M.; Boblak, K.; Topinka, M.; Briski, J.;
Kindelin, P.; Zheng, C.; Klumpp, D. K. J. Am. Chem. Soc. 2010, 113, 3266; (f)

M. J. O’Connor et al. / Tetrahedron Letters 51 (2010) 4984–4987
4987
20H), 3.84–3.86 (m, 4H), 3.91–3.93 (m, 4H), 3.99–4.02 (m, 4H), 4.14–4.16 (m,
4H), 4.20–4.21 (m, 4H), 6.60–6.65 (m, 4H), 6.75–6.82 (m, 3H), 6.95–6.98 (m,
3H). 13C NMR, d, CDCl3: 40.4, 63.5 (q, JC–F = 19 Hz), 64.3, 64.4, 67.1, 68.9, 69.2,
69.6, 69.6, 70.7, 70.8, 70.9, 111.7, 112.7, 116.5, 119.8, 121.3, 128.3 (q,
JC–F = 278 Hz), 130.6, 133.7, 142.8, 148.0, 148.3. LR MS: 823 (M+), 754, 647,
578. HRMS, C42H56O12NF3 calcd 823.37548, found 823.37399. Compound 21:
1H NMR, d, CDCl3: 3.01 (s, 6H), 6.68 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H),
7.04 (dd, J = 8.4, 2.4 Hz, 2H), 7.28 (d, J = 2.4 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H). 13
NMR, d, CDCl3: 40.1, 63.5 (q, JC–F = 24 Hz), 111.8, 124.8, 127.1 (q, JC–F = 284 Hz),
C
129.2, 130.1, 130.3, 131.8, 132.5, 132.7, 140.7, 150.4. LR MS: 495/493/491
(M+), 426/424/422, 175. HRMS,
490.99808.
C22H16NCl4F3 calcd 490.99888, found