A perfect double role of CF3 groups in activating substrates and stabilizing adducts: The chiral Bronsted acid-catalyzed direct arylation of trifluoromethyl ketones

Article abstract of DOI:10.1039/b900474b

A direct and efficient Bronsted acid-promoted arylation of tri- and difluoromethyl ketones, as well perfluoroalkyl ketones, has been developed; good to excellent enantioselectivities (up to 99% ee) were achieved. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b900474b

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A perfect double role of CF3 groups in activating substrates
and stabilizing adducts: the chiral Brønsted acid-catalyzed direct
arylation of trifluoromethyl ketonesw
Jing Nie,a Guang-Wu Zhang,a Lian Wang,a Aiping Fu,b Yan Zhenga and Jun-An Ma*ac
Received (in Cambridge, UK) 9th January 2009, Accepted 16th February 2009
First published as an Advance Article on the web 9th March 2009
DOI: 10.1039/b900474b
A direct and efficient Brønsted acid-promoted arylation of
tri- and difluoromethyl ketones, as well perfluoroalkyl ketones,
has been developed; good to excellent enantioselectivities
(up to 99% ee) were achieved.
(generated in situ) with high enantioselectivities.5 Although
chiral Brønsted acids have not been used to activate simple
ketones in direct arylation reactions, this previous success led
us to believe that phosphoric acids may promote the direct
enantioselective arylation of trifluoromethyl ketones with
electron-rich aromatic compounds to give optically active
trifluoromethyl-substituted tertiary alcohols, which are
valuable pharmaceutical intermediates and chiral building
blocks.6,7 On the other hand, we envisioned that simple aryl
and alkyl trifluoromethyl ketones could be the best choice for
this direct arylation reaction, in accordance with the following
terms: (1) The CF3 group, with its potent electron-withdrawing
ability, could improve the reactivity of substrates. (2) According
to DFT calculations (at the B3LYP/6-31G* level), comparing
the structures of organofluorine adduct A and its non-
fluorinated analogue B shows that an apparent shortening of
the C1–O bond is computed, and significant changes in charge
at O (ꢀ0.74 e), C1 (0.19 e), C2 (1.12 e), C3 (ꢀ0.14 e) and C4
(ꢀ0.07 e) are found in the case of A (Fig. 1). Presumably,
Brønsted acid-catalyzed O–H activation would be difficult
and re-arylation of the trifluoromethyl-substituted tertiary
alcohols might be suppressed.
Asymmetric organocatalysis has emerged as a powerful
synthetic tool that is complementary to established metal
complex and enzyme-catalyzed transformations. Since 2000,
numerous chiral organocatalysts have been designed, and a
variety of new asymmetric reactions have been developed in
organic synthesis.1 In this scenario, BINOL-derived chiral
phosphoric acids (independently reported by Akiyama
et al.,2a and Uraguchi and Terada2b in 2004) have become
some of the most successful catalysts, and various asymmetric
transformations of imines and enamides have been carried out
with high enantioselectivities.2 Subsequently, Antilla’s group
demonstrated that not only imines but also meso-aziridines
can be activated effectively by a VAPOL-derived chiral
phosphoric acid.3 Recently, the more highly reactive and
acidic N-triflyl phosphoramides have been explored as
Brønsted acid catalysts that enable the activation of carbonyl
groups and further extend the type of asymmetric reactions
achievable.4 Despite this impressive progress with Brønsted
acids, the direct catalytic asymmetric arylation of simple
ketones for the synthesis of chiral tertiary alcohols has not
been reported, and thus remains an important challenge. This
is not surprising, since simple ketones seem to have too low a
reactivity to be directly arylated in the presence of chiral
phosphoric acids. Another significant issue arises from the
fact that with the more acidic N-triflyl phosphoramides, the
diarylation of ketones can take place smoothly (see ESIw).
In this Communication, we report the first example of a
Brønsted acid-catalyzed enantioselective direct arylation of
trifluoromethyl ketones to give trifluoromethyl-substituted
tertiary alcohols with good to excellent enantioselectivities
(up to 99% ee).
To validate our hypothesis, we initially investigated the
reaction of indole (2a) with 2,2,2-trifluoroacetophenone (3a)
in the presence of readily available BINOL-derived phosphoric
acids (10 mol %) in toluene. To our delight, the reaction
proceeded well to afford the desired adduct, 4a, in quantitative
yield. Moreover, diarylation of the ketone was not observed. A
preliminary screening of catalysts (see ESIw) showed that
phosphoric acid 1, with bulky 2,4,6-triisopropylphenyl groups
at the 3,30-positions of the binaphthyl scaffold, gave the highest
enantioselectivity (76% ee). Subsequently, an optimization of
Recently, we have demonstrated that chiral phosphoric
acids can catalyze the arylation reactions of trifluoroacetaldimines
a Department of Chemistry, Tianjin University, Tianjin 300072, China.
E-mail: majun_an68@tju.edu.cn; Fax: +86 22 27403475;
Tel: +86 22 27402903
b Institute for Computational Science and Engineering, Qingdao
University, Qingdao 266071, Shandong, China
c State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 713022. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b900474b
Fig. 1 The 3D structures of fluorinated A and un-fluorinated B
adducts. The bond lengths are given in A.
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Table 1 Optimization of the reaction conditions
Table 2 Scope of the enantioselective Brønsted acid-catalyzed aryla-
tion reaction of trifluoromethyl ketones
Yield ee
t/h (%)a (%)b
Catalyst
(mol%)
Yield
(%)a
ee
Entry
2
R1
Entry
Solvent
t/h
48
48
48
48
48
48
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22c
Indole
Ph
Ph
Ph
Ph
Ph
72 99
48 99
48 99
48 99
96 52
48 93
48 96
48 99
48 99
48 99
36 99
96 81
48 99
48 99
92
92
92
90
92
90
92
95
98
87
91
86
85
90
90
85
89
99
87
86
76
65
1
2
3
4
5
10
10
10
10
10
10
10
10
5
Toluene
CHCl3
ClCH2CH2Cl
CH2Cl2
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
99
99
99
99
20
36
99
68
99
40
76
83
90
92
83
85
92
94
92
92
5-MeO-indole
5-F-indole
5-Cl-indole
5-Br-indole
5-MeO2C-indole Ph
6
6-Cl-indole
7-Me-indole
7-Et-indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
2-Et-pyrrole
Ph
Ph
Ph
7c
8d
9
120
120
72
4-MeOC6H4
4-MeC6H4
2-MeC6H4
3,5-Me2C6H3
Biphenyl
10
1
120
a
b
Isolated yield. The ee was determined by chiral HPLC analysis.
c
d
Reaction temperature: 0 1C. Reaction temperature: ꢀ20 1C.
3,5-(CF3)2C6H3 36 99
3,4,5-F3C6H2
4-FC6H4
4-ClC6H4
4-BrC6H4
2-Thiophene
PhCH2
36 91
36 99
36 99
36 99
72 84
72 86
10 99
the reaction conditions was undertaken (Table 1). The solvent
was found to have an important effect on the stereoselectivity.
The reaction provided quantitative conversion and good to
high enantioselectivities in toluene and chlorinated alkanes
(Table 1, entries 1–4). Additionally, coordinating solvents,
such as THF and CH3CN, gave low yields (Table 1, entries
5 and 6). Among the solvents tested, CH2Cl2 was found to be
the best with respect to catalytic activity and asymmetric
induction. Substantial changes in reaction temperature and
the amount of catalyst did not have any significant effect on
the enantioselectivity; however, reduced yields were observed,
even with prolonged reaction times (Table 1, entries 8 and 10).
With the optimal conditions established, the scope of the
reaction was then probed. As highlighted in Table 2, a wide
range of functional groups, including electron-withdrawing,
-donating and neutral groups, can be readily tolerated on the
aromatic rings of both substrates (Table 2, entries 1–20). In
most cases, respectable yields (81–99%) and high ee values
(85–99%) were obtained. Only one example provided a
moderate yield while maintaining a high ee (Table 2, entry 5).
One of the trifluoromethyl-substituted tertiary alcohols was
crystallized from CH2Cl2–hexane, and its structure, including
its absolute configuration, was determined by Rontgen
diffraction studies (Fig. 2).z It is noteworthy that the relatively
unreactive trifluoromethyl alkyl ketone also gave the desired
product in 86% yield with 76% ee (Table 2, entry 21).
Furthermore, the reaction worked well with 2-ethylpyrrole
under our current reaction conditions to afford the regioselective
product (at the 5-position of 2-ethylpyrrole) in quantitative
yield with good enantioselectivity (Table 2, entry 22).
Ph
a
b
Isolated yield. The ee was determined by chiral HPLC analysis.
Substrate is 2-ethylpyrrole.
c
Fig. 2 The X-ray structure of one of the products (ORTEP).
Scheme 1 The enantionselective Brønsted acid-catalyzed arylation of
difluoromethyl and pentafluoroethyl ketones
2-fluoroacetophenone and acetophenone. As a result, only the
diarylated products were observed (see ESIw).
Our methodology can also be extended to CHF2-
and C2F5-ketones to demonstrate the scope of this direct
arylation reaction. While a somewhat prolonged reaction
time was required with 1 mol% of catalyst 1, the desired
products, 5a and 5b, were isolated in high yields and with
excellent enantioselectivities (Scheme 1). We also investigated
In conclusion, we have developed a direct and efficient
Brønsted acid-promoted arylation reaction of simple trifluoro-
methyl ketones. This protocol offers several advantages,
including operational simplicity, mild reaction conditions,
low catalyst loading, and high yields and enantioselectivities,
which make it a useful and attractive strategy for the synthesis
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of chiral trifluoromethyl-substituted tertiary alcohols.
Furthermore, excellent enantioselectivities were also achieved
with difluoromethyl and perfluoroalkyl ketones. Further
investigations to understand the mechanism and the exact role
of the Rf groups are under way.
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This work was supported financially by NSFC (20772091)
and Tianjin MSTC (07JCDJC04700).
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Notes and references
z Crystal data were collected on a Bruker Nonius Kappa CCD with an
Mo rotating anode generator; standard procedures were followed.
Crystal data: C16H11ClF3NO, Mr
= 325.71, T = 293(2) K,
monoclinic, space group P212121, a = 7.4634(15) A, b = 13.393(3) A,
c = 15.347(3) A, a = 901, b = 90(5)1, g = 901, V = 1534.0(5) A3,
calculated density = 1.410 Mg mꢀ3, Z = 4, reflections collected
16 222, independent reflections 3510 (Rint = 0.0752), final R indices
[I 4 2s(I)]: R1 = 0.0644, wR2 = 0.0911, R indices (all data):
R1 = 0.1184, wR2 = 0.1036.w
5 G.-W. Zhang, L. Wang, J. Nie and J.-A. Ma, Adv. Synth. Catal.,
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2358 | Chem. Commun., 2009, 2356–2358