Titanium-mediated direct carbon-carbon double bond formation to α-trifluoromethyl acids: A new contribution to the knoevenagel reaction and a high-yielding and stereoselective synthesis of α- trifluoromethylacrylic acids

Article abstract of DOI:10.1002/adsc.201100339

An efficient strategy for a high-yielding and stereoselective synthesis of α-trifluoromethyl unsaturated carboxylic acids directly from the reactions of 3,3,3-trifluoropropanoic acid (CF₃CH₂COOH) with various aryl aldehydes in the pr

Full text of DOI:10.1002/adsc.201100339

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DOI: 10.1002/adsc.201100339
Titanium-Mediated Direct Carbon-Carbon Double Bond
Formation to a-Trifluoromethyl Acids: A New Contribution
to the Knoevenagel Reaction and a High-Yielding and
Stereoselective Synthesis of a-Trifluoromethylacrylic Acids
Yanmei Liu,a Hua Lai,a Bo Rong,c Tie Zhou,c Jia Hong,a Chao Yuan,a
Shujing Zhao,a Xiaolong Zhao,b Biao Jiang,b and Qiang Fanga,*
a
Key Laboratory of Organofluorine Chemistry and Laboratory for Polymer Materials, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-5492-5327; phone: (+86)-21-5492-5337; e-mail: qiangfang@mail.sioc.ac.cn
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
The Museum of the Terra-cotta Warriors and Horses of QIN SHIHUANG, Lintong 710600, Shaanxi Province, Peopleꢀs
c
Republic of China
Received: May 2, 2011; Revised: July 27, 2011; Published online: November 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100339.
Abstract: An efficient strategy for a high-yielding
and stereoselective synthesis of a-trifluoromethyl
unsaturated carboxylic acids directly from the
standard route (e.g., for preparing aryl substituted cy-
anoacrylic acids)[4] for the preparation of most of the
organic dyes in dye-sensitized solar cells (DSSCs),
one of new generation energy resources. However,
the base-catalysed Knoevenagel reactions face a cru-
cial challenge when CF3-containing substrates are
used, because there is a tendency for the a-trifluoro-
methyl carbanions formed under alkaline conditions
to produce1,1-difluoroolefins through b-elimination,[5]
as shown in Scheme 1.
Accordingly, in many cases, the researchers have
preferred to choose more complicated procedures[6]
rather than use the Knoevenagel reaction via a
merely one-step route. Such a situation has hindered
the development of these carbanions for use in organ-
ic synthesis.[7]
reactions
of
3,3,3-trifluoropropanoic
acid
(CF3CH2COOH) with various aryl aldehydes in the
presence of titanium tetrachloride (TiCl4) is report-
ed here for the first time, which is a valuable expan-
sion for the classical Knoevenagel reaction. Because
these compounds may have potential applications
in organic electronics and can be easily converted
to the corresponding fluorinated alcohols and
amino acids with excellent bioactivity, this route
should be a good choice for the preparation of a-
trifluoromethyl-containing derivatives.
Keywords: catalysis; Knoevenagel reaction; stereo-
selectivity; titanium tetrachloride; a-trifluorometh-
yl-a,b-unsaturated carboxylic acids
It is well known that trifluoromethylated molecules
play a significant role in the fields of pharmaceuti-
cal,[6b,8] agricultural,[9] and material sciences,[4,10] and
that introduction of a CF3 group with strong electron-
The Knoevenagel reaction between aldehydes and
acids (or esters) with active methylene groups un-
doubtedly is one of the most straightforward ways for
the synthesis of a,b-unsaturated carboxylic acids (or
esters).[1] Therefore, it has been well investigated and
widely used in cosmetic, pharmaceutical and material
industry[1c,2,3] during the past more than 100 years. In
recent years, the ever-increasing attention to new
Scheme 1. The b-elimination reaction of CF3-containing
energy resource has aided this reaction to become a compounds under alkaline conditions.[5]
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Yanmei Liu et al.
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have potential applications in optoelectronic fields.
Nevertheless, no examples of the synthesis of
AFUCA directly from readily available starting re-
agents have been reported previously,[13] to the best of
our knowledge. Herein, we report our discovery of a
high-yielding and stereoselective synthesis of these
compounds directly from a-CF3 acid by using TiCl4 as
a catalyst. Although there have been some reports on
À
forming C C bonds to a-CF3 ketone and esters via a
soft enolization strategy,[5a,14] no investigation on
direct C=C bond formation to a-CF3-acids has been
done. This is the first example involving the Knoeve-
nagel-type reaction of a-CF3 acids, and would be a
valuable expansion for the classical Knoevenagel re-
Figure 1. The chemical structures of aryl-substituted a-tri-
fluoromethyl-a,b-unsaturated carboxylic acids (AFUCA)
and their transformation products.[4,6,8,11,12]
withdrawing ability into molecules can result in big action.
changes of their properties.[11] Accordingly, the explo-
Our initial approaches were performed with the re-
ration and development of convenient routes for the action between CF3CH2COOH (1) and 4-bromoben-
preparation of such molecules are very desirable. zaldehyde (2) in the presence of TiCl4/N-methylmor-
Among the CF3-containing compounds, aryl-substitut- pholine using a molar ratio of 1:1 between 1 and the
ed a-trifluoromethyl-a,b-unsaturated carboxylic acids base. No target acid 2a was detected by 19F NMR
(AFUCA, see Figure 1) would be one of the most val- spectroscopy (Table 1, entry 1). Guessing that the
uable building blocks for the synthesis of CF3-contain- base may be neutralized by the acid, we then in-
ing molecules on the basis of the ease of their trans- creased the amount of N-methylmorpholine. The
formations into the corresponding CF3-substituted al- yield of 2a was dramatically enhanced from 2% to
cohols and amino acids with good bioactivity,[6,8,11] as 69% with the increase of the molar ratio between the
well as into p-conjugated molecular materials[4,12] that base and 1 (entries 2–4). Further optimization of the
Table 1. Optimization of reaction conditions.[a]
Entry
1/2/TiCl4/base[b] (equiv.)
Solvent
T [8C]
Yield[c] [%]
Z/E[d]
1
2
3
4
5
6
7
8
1.0/1.5/2.0/MM (1.0)
1.0/1.5/2.0/MM (2.0)
1.0/1.5/2.0/MM (3.0)
1.0/1.5/2.0/MM (4.0)
1.0/1.5/2.5/MM (4.0)
1.0/1.5/3.0/MM (4.0)
1.0/1.5/4.0/MM (4.0)
1.0/1.5/1.5/MM (4.0)
1.0/1.0/2.0/MM (4.0)
1.5/1.0/3.0/MM (6.0)
2.0/1.0/4.0/MM (8.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CHCl3
toluene
THF
THF
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
0
0
2
–
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
87:13
79:21
72:28
68:32
>99:1
>99:1
>99:1
>99:1
>99:1
32
69
67
64
53
81
44
53
64
54
89
67
62
89
90
9
10
11
12
13
14
15
16
17
3.0/1.0/6.0/MMACHTUNTRGNEUNG(12.0)
1.0/1.5/1.5/Et3N (4.0)
1.0/1.5/1.5/Et3N (4.0)
1.0/1.5/1.5/Et3N (4.0)
1.0/1.5/1.5/Et3N (4.0)
1.0/1.5/1.5/Et3N (4.0)
r.t.
[a]
Reaction conditions: 1, 2, TiCl4, solvent, T, 0.5 h, then base, room temperature, 40 h.
MM=N-methylmorpholine.
[b]
[c]
Yields calculated based on 1 as determined from 19F NMR spectroscopy using C6H5SCF3 as an internal standard. The
yields of entries 1–9 and 13–17 were based on compound 1, and the yields of entries 10–12 were referred to compound 2,
respectively.
[d]
Z/E ratios determined by 19F NMR spectroscopy.
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Titanium-Mediated Direct Carbon-Carbon Double Bond Formation to a-Trifluoromethyl Acids
Table 2. Scope of the reaction of a-CF3 acid and aryl aldehydes.[a]
Entry
Ar
Product
Yield[b] [%]
Z/E[c]
1
2
3
4
5
phenyl (3)
3a
4a
5a
6a
7a
91
86
83
83
95
>99:1
>99:1
>99:1
92:8
4-tert-butylphenyl (4)
4-methoxyphenyl (5)
4-nitrophenyl (6)
5-bromothiophene (7)
96:4
[a]
Reaction conditions: 1 (0.4 mmol), aldehyde (0.6 mmol), TiCl4 (0.6 mmol), THF (2 mL), room temperature, 0.5 h, then
Et3N (1.6 mmol), room temperature, 40 h.
[b]
[c]
Isolated yields based on 1.
Z/E ratios determined by 19F NMR spectroscopy.
reaction conditions was done by changing the molar CF3CH2COOH was dehydrated by TiCl4 to form the
ratio of 1 to 2 or TiCl4, or N-methylmorpholine (en- anhydride, followed by reaction with aldehydes in the
tries 5–12). The better results were obtained when the presence of a base. However, such a mechanism is not
molar ratio of 1/2/TiCl4/N-methylmorpholine was supported by the following facts: (i) if the anhydride
1.0:1.5:1.5:4.0 (entry 8). We then chose Et3N as a base existed, an example for the optimization reaction con-
for examination of the reaction. The target product ditions (entry1, Table 1) would give the target prod-
was prepared in good yield (entry 13), suggesting that uct; (ii) no defluorinated by-products were detected
Et3N would fit into this reaction. After completion of in any of our experiments, this indicated that there
the above mentioned examinations, we turned our at- was no the anhydride in the reaction system, because
tention to the influence of a variety of solvents on the the base-catalyzed Perkin reaction usually formed at
reaction (entries 14 and 15). The results showed that first a carbanion, which was sure to lead to the b-
THF was favourable. With an eye to the practicability elimination of CF3 species; (iii) we tried to prepare an
of this method, we subsequently ran the reaction at
08C and room temperature, respectively. Product 2a
was obtained both in a high yield and good stereose-
lectivity, implying that this procedure has high opera-
bility (entries 16 and 17).
By using the above optimized TiCl4/Et3N-catalyzed
system, we further investigated the generality of the
substrates (Table 2, entries 1–4). The replacement of 2
by a series of aryl aldehydes gave the products with
isolated yields of more than 83%, exhibiting that the
activity of aldehydes is not crucial in this procedure
and, in other words, this route is suitable for a wide-
range of the substrates. In addition, the successful
construction of the heterocyclic substituted a-CF3 un-
saturated acid with good yield and stereoselectivity
(Table 2, entry 5) implies that this route could provide
an efficient tool for the facile investigation on the
properties of the fluorine-containing p-conjugated
materials.[4]
To further confirm the geometric configuration of
the obtained products, the single crystal X-ray diffrac-
tion studies of 2a and 5a were carried out and the re-
sults shown in Figure 2. Such X-ray structures corro-
borated the results from 19F NMR analyses.
We then became interested in the reaction mecha-
nism. At first, we considered that the reaction may
Figure 2. Single-crystal X-ray diffraction structure of 2a
proceed through a Perkin-type process, in which (top) and 5a (bottom).[6e]
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Yanmei Liu et al.
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Scheme 2. Proposed mechanism for the reaction described in this work.
anhydride from pentadecafluorooctanoic acid in the the first example involving the Knoevenagel-type re-
presence of TiCl4 at room temperature, whereby no action of an a-CF3 acid, and is a valuable expansion
target product was detected by GC-MS, suggesting for the classical Knoevenagel reaction. The wide
that using a general route cannot be used to prepare range and ready availability of the substrates, high
the anhydrides from the fluorine-containing acids yields, no defluorinated by-products, excellent stereo-
with strong acidity. We also examined the reaction of selectivity and the convenient synthetic procedure
CF3CH2COOCH3 with 2, and the obtained product suggest that our approach could be a good choice for
showed a yield of 90% and a Z/E ratio of 96:1, fur- the preparation of the precursors of CF3-containing
ther excluding the Perkin reaction mechanism. Hence, derivatives.
we would incline to such a reaction process,[14] as de-
picted in Scheme 2, in which TiCl4 reacted at first
with both CF3CH2COOH and the aldehydes to form Experimental Section
a six-membered chair-like ring complex. Then the
base attacked the H near the CF3 group to form a C= General Procedure (see Table 1, entry 17)
C bond, accompanying the leaving of the Ti species.
This proposed mechanism can well explain the results
To a stirred solution of 4-bromobenzaldehydede 2 (111 mg,
0.6 mmol), 1 (35 mL, 0.4 mmol) and dry THF (2 mL) was
listed in Table 1. For example, entry 1 showed no
product when the molar ratio of the base to 1 was 1:1,
which was attributed to a quantitative complex forma-
tion between the acid and the amine (see Scheme 1),
resulting in a lack of base for inducing the leaving of
of Ti species. To prove the existence of a three-com-
ponent complex derived from TiCl4, the aldehydes
and a-CF3 acid, we changed the feed order. For exam-
added TiCl4 (1M in CH2Cl2, 0.8 mL, 0.8 mmol) at room tem-
perature. The mixture was vigorously stirred for 0.5 h, fol-
lowed by adding dropwise Et3N (1.6 mmol). After being
kept for an additional 40 h, the reaction was quenced by
adding water (3 mL), and the obtained mixture was extract-
ed with CH2Cl2. The organic layer was dried over anhydrous
Na2SO4, followed by concentration under reduced pressure.
The obtained residue was purified by flash chromatograph
using a mixture of CH2Cl2 and methanol (v/v, 15:1) as the
eluent to give the target product 2a as a white solid; yield,
90%, Z/E>99:1
CCDC 836798 and CCDC 836799 contain the supplemen-
tary crystallographic data for compounds 2a and 5a, respec-
tively. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
ple, adding an aldehyde
2
to
a
mixture of
CF3CH2COOH, TiCl4 and Et3N gave the product with
lower yield (less than 20%). Such a result means that
solely the acid or the aldehyde cannot well react with
TiCl4, indirectly indicating the formation of a three-
component complex when the acid, TiCl4 and the al-
dehydes were put in at one time in one reaction
system. Because the mechanism of the Knoevenagel
reaction is more complicated, and there may be an in-
teraction between titanium and CF3,[14e] in our case, a
detailed investigation on the mechanism will be car-
ried out in our future work.
Acknowledgements
In conclusion, we have successfully realized the syn-
thesis of aryl-substituted a-trifluoromethyl-a,b-unsa-
turated carboxylic acids (AFUCA) via a direct reac-
Financial support from National Natural Science Foundation
of China (NSFC) (No. 20872171) and Ministry of Science
and Technology of China (2010BAK67B12) is gratefully ac-
tion of a-CF3 acids and various aryl aldehydes. This is knowledged.
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Titanium-Mediated Direct Carbon-Carbon Double Bond Formation to a-Trifluoromethyl Acids
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