Phosphine-mediated synthesis of trifluoromethyl substituted pyrroles using TFAA as the CF3 source

Article abstract of DOI:10.1016/j.tetlet.2014.05.127

A phosphine-mediated synthesis of trifluoromethyl substituted pyrrole derivatives was achieved. The method described here is very fast, operationally simple, and easily amenable to scale-up, and commercially available trifluoroacetic anhydride (TFAA) is used as the only trifluoromethyl source. A wide range of products were obtained with good yields under mild condition using this method.

Full text of DOI:10.1016/j.tetlet.2014.05.127

Accepted Manuscript
Phosphine-Mediated Synthesis of Trifluoromethyl Substituted Pyrroles Using
TFAA as the CF3 Source
Dan-Dan Tang, Yao Wang, Jun-Ru Wang, Peng-Fei Xu
PII:
S0040-4039(14)00960-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.127
TETL 44718
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
8 April 2014
24 May 2014
30 May 2014
Please cite this article as: Tang, D-D., Wang, Y., Wang, J-R., Xu, P-F., Phosphine-Mediated Synthesis of
Trifluoromethyl Substituted Pyrroles Using TFAA as the CF3 Source, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.05.127
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Phosphine-Mediated Synthesis of
Trifluoromethyl Substituted Pyrroles Using
TFAA as the CF3 Source
Leave this area blank for abstract info.
Dan-Dan Tanga,b, Yao Wangb, Jun-Ru Wang*a and Peng-Fei Xu*b
a College of Sciences, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Phosphine-Mediated Synthesis of Trifluoromethyl Substituted Pyrroles Using TFAA
as the CF3 Source
Dan-Dan Tanga,b, Yao Wangb, Jun-Ru Wang*a and Peng-Fei Xu*b
a College of Sciences, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China,
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A phosphine-mediated synthesis of trifluoromethyl substituted pyrrole derivatives was achieved.
The method described here is very fast, operationally simple and easily amenable to scale-up,
and commercially available trifluoroacetic anhydride (TFAA) is used as the only trifluoromethyl
source. A wide range of products were obtained with good yields under mild condition using
this method.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
phosphine
trifluoromethyl
pyrrole
wittig
trifluoroacetic anhydride
The incorporation of trifluoromethyl group often leads to
significant changes in the physical and chemical properties of
molecules such as solubility, metabolic stability, and
bioavailability, etc.1 Organic compounds bearing trifluoromethyl
group have so far been widely applied in the fields of functional
materials, agrochemicals and pharmaceutical due to their special
properties.2 Therefore, the development of new methodologies
for the synthesis of trifluoromethyl-substituted compounds is
undoubtedly one of the most exciting and dynamic areas in
contemporary organic synthesis, especially the development of
reliable and powerful methods using simple and readily available
trifluoromethyl sources.3 Among these useful compounds,
trifluoromethyl-substituted pyrrole is an important subclass due
to the prevalence of such motif in pharmaceutical compounds
and natural products.4-5 These bioactive compounds have been
shown to exhibit significant insecticidal and medical activities,
such as the insecticide Chlorfenapyr,6 general anesthesia
inducer,7 antitumor compound,8 and numerous others (Figure 1).
Although a few elegant approaches have been developed for the
construction of trifluoromethyl-substituted pyrroles,9 the
synthesis of such compounds is still a significantly challenging
task due to some major problems such as the use of costly
transition metals, high time-consumption, high temperature and
low efficiency.10 Therefore, the development of an efficient
method is highly desired. Our group has been focusing on the
time,11 and has reported a highly efficient method for the
synthesis trifluoromethylated furans.12 We found that other than
many reported special-tailored trifluoromethyl sources,
trifluoroacetic anhydride (TFAA), one of the most common
reagents, can be used as a powerful CF3 transfer reagent.
Encouraged by this promising finding, we envisioned that
Figure 1. Examples of biologically important pyrrole derivatives
development of various trifluoromethylation methods for some
———
* Corresponding author. Tel.: +86-029-87092829; fax: +86-029-87092829; e-mail: wangjunru@nwsuaf.edu.cn
* Corresponding author. Tel.: +86-931-8912281; fax: +86-931-8915557; e-mail: xupf@lzu.edu.cn

2
Tetrahedron Letters
trifluoromethylated pyrroles might be efficiently synthesized by
have no obvious influence on the reaction behavior (Table 2,
employing TFAA as well.
entries 6–7, 9–11).
Table 1. Screening for Optimal Conditions for the
Table 2. Substrate Scopea
Trifluoromethylated Pyrrolea
Entry
1
1
R
Products
2a
Yield (%)b
Entry
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH3CN
THF
TFAA (equiv)
PPh3 (equiv)
Yield (%)b
1a
1b
1c
1d
1e
1f
Ph
99
87
95
94
97
95
96
90
90
97
95
91
92
1
1.3
1.3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.5
0.5
1.0
1.5
1.0
1.0
1.0
1.0
1.0
93
91
48
99
94
97
96
89
91
23
2
2-Naphthyl
3-NO2C6H4
4-CF3C6H4
2-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-OMeC6H4
2b
2c
2
3
3
4
2d
2e
4
5
5
6
2f
6
7
1g
1h
1i
2g
7
8
2h
2i
8
9
9
xylene
MeOH
10
11
12
13
1j
2j
10
1k
1l
2k
2l
a Unless otherwise noted, the reaction was performed with 1a (0.20 mmol),
TFAA (0.30 mmol), and PPh3 (0.20 mmol) in solvent (1.0 mL) at room
temperature within 1 min. b Yield of isolated product. equiv = equivalent.
1m
3,4-(OCH2O)
C6H3
2m
Compound 1a with TFAA in the presence of PPh3 were
chosen for initial optimization of the reaction parameters at room
temperature (Table 1, entry 1). Indeed, the desired reaction was
found to take place and afforded the product in 93% yield.
Further optimizing conditions by adjusting the amount of PPh3
and TFAA revealed that the result of the 99% yield (Table 1,
entry 4) was achieved using 1.0 equiv of PPh3 and 1.5 equiv of
TFAA. Results of experiments in various solvents (Table 1,
entries 6–10) showed that the reaction has a wide adaptability for
different solvents except for MeOH, the yield with which is
merely 23%. The structure of the product was unequivocally
established by the X-ray crystallography of 2h.13
14
15
1n
1o
2-furyl
2n
2o
68
65
2-thienyl
a Unless otherwise noted, the reaction was performed with 1 (0.2 mmol),
TFAA (0.3 mmol), and PPh3 (0.2 mmol) in CH2Cl2 (1.0 mL) at room
temperature within 1 min. b Yield of isolated product.
Scheme 1. One-pot Synthesis of 2aa and 2kk and Scalable
Synthesis of 2k
MeO2C
F3C
CO2Me
N
Ts
Br
2h
Figure 2: The X-ray structure of compound 2h.
To further investigate the scope and limitation of this reaction,
various types of substrates were tested in the cascade process
under the optimal reaction condition (Table 2). Results show that
almost all the substrates were well tolerated with satisfying yields
(Table 2, 65%–99%), including both of the electron-withdrawing
and -donating groups substituted substrates. However, the yields
with the heterocyclic substituted substrates were not as high as
expected, i.e. 65% to 68% as listed in entry 14 and 15 of Table 2.
As also can be seen from the results, the substitution positions
To further investigate the synthetic value of the products from
the present transformation, one-pot removal of Ts group of the
product was conducted. It was found that the Ts group could be
smoothly removed with treatment of 2a with NaOH in the same
vessel in THF, delivering N-free trifluoromethylated pyrrole 2aa
in 68% yield from 1a (Scheme 1a). Furthermore, a one-pot
sequential pyrrole formation/reduction was also successful in
affording the desired products with good yield (2kk, 72%)
(Scheme 1b). Additionally, when the present reaction was

3
Ed. 2013, 52, 8214; (h) Khangarot, R. K.; Kaliappan, K. P. Eur.
performed on a 10 mmol scale (1k, 4.154 g), the reaction
remained fast and efficient with 95% yield (Scheme 1c). Thus we
can conclude that the reaction proposed in this paper is fast,
efficient and adaptable to gram-scale synthesis.
J. Org. Chem. 2013, 2692; (i) Nagib, D. A.; MacMillan, D. W. C.
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Scheme 2. Possible Reaction Pathways
3.
4.
(a) Bovy, P. R.; Reitz, D. B.; Collins, J. T.; Chamberlain, T. S.;
Olins, G. M.; Corpus, V. M.; McMahon, E. G.; Palomo, M. A.;
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5.
6.
For a recent review of trifluoromethylated pyrroles, see:
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On the basis of our experimental results, a plausible approach
is outlined in scheme 2. Nucleophilic addition of Lewis basic
PPh3 to 1 generates a highly reactive zwitterionic intermediate A
in the presence of TFAA, which then undergoes the
intramolecular Wittig reaction on the assistance of conjugate base
of TFA, affording the corresponding trifluoromethylated pyrrole
2.
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In conclusion, we have developed a phosphine-mediated
cascade transformation for the synthesis of trifluoromethyl
pyrroles using readily available trifluoroacetic anhydride as a CF3
source. The reaction is operationally simple with wide substrate
generality and amenable to scale-up, furnishing trifluoromethyl
substituted pyrroles in high yields under mild conditions.
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Acknowledgments
We are grateful for the NSFC (21372105, 21032005,
21172097), PCSIRT (IRT1138), the International S&T
Cooperation Program of China (2013DFR70580), the National
Basic Research Program of China (No. 2010CB833203), and the
“111” program from MOE of P.R. China.
Supplementary data
13. Crystallographic data for compound 2h in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC-972951. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.Uk).
Supplementary data (compound characterization data)
associated with this article can be found, in the online version, at
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