A powerful cascade approach for expeditious synthesis of trifluoromethylated furans

Article abstract of DOI:10.1021/ol2022092

A powerful approach to synthesize trifluoromethylated furans has been developed. The method is operationally simple, broad in substrate scope, and amenable to scale-up using trifluoroacetic anhydride. Meanwhile, the strategy not only provided a versatile

Full text of DOI:10.1021/ol2022092

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5346–5349
A Powerful Cascade Approach
for Expeditious Synthesis of
Trifluoromethylated Furans
Yao Wang, Yong-Chun Luo, Xiu-Qin Hu, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China
xupf@lzu.edu.cn
Received August 15, 2011
ABSTRACT
A powerful approach to synthesize trifluoromethylated furans has been developed. The method is operationally simple, broad in substrate scope,
and amenable to scale-up using trifluoroacetic anhydride. Meanwhile, the strategy not only provided a versatile approach to synthesize
trifluoromethylated furans but also provides a new method for exploring the new reactivity of trifluoroacetic anhydride.
Trifluoromethylated compounds have found broad
applications in medicinal,1 agrochemical,2 and material
science.3 Trifluoromethyl-substituted furan derivatives,
with thousands of them patented as drug molecules, are
a highly valuable class of heterocyclic compounds with
remarkable biological activities. More specifically, a large
number of reported pharmacologically active compounds
have been shown to contain a subunit of either type A or B
(Figure 1),4 and these bioactivecompounds havebeen used
for treatment of various diseases4 such as cancers,4g,f
HIV,4b obesity,4j diabetes,4j,n gastrointestinal4i/sleep4e
disorders, neurodegenerative4c/hyperproliferative4d/ auto-
immune4h diseases, inflammations,4m and numerous others.
Needless to say, this kind of compound has been proven to
be an excellent drug candidate and hence has generated
great interest in the pharmaceutical sector (for example,
(1) (a) Purser, S.; More, P. R.; Swallow, S.; Gouverneuer, V. Chem.
Soc. Rev. 2008, 37, 320. (b) Filler, R.; Kobayashi, Y.; Yagupolski, L. M.
Organofluorine Compounds in Medicinal Chemistry & Biomedical Appli-
cations; Elsevier: Amsterdam, 1993.
(2) (a) Banks, R. E.; Smart, B. E.; Tatlow, C. J. Organofluorine
Figure 1. Examples of biologically active furan derivatives.
Chemistry, Principles and Comercial Applications; Springer: New York,
1994. (b) Jeschke, P. ChemBioChem 2004, 5, 570.
(3) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Re-
activity, Applications; Wiley-VCH: Weinheim, 2004. (b) Yamamoto, H.;
Roche,4e,j Merck,4d Takeda,4f,n Abbott,4h Astrazeneca,4i Basf,4k
Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimzu, M. Organo-
Bayer,4l Aventis,4m etc.). Even though such compounds are
fluorine Compounds: Chemistry and Application; Springer: Berlin, 2000.
r
10.1021/ol2022092
Published on Web 09/08/2011
2011 American Chemical Society

present in some agricultural products,4k,l it is not practical
to obtain them in large amounts for downstream usage.
Consequently, the exploitation of simple methods for the
synthesis of this kind of compound and its derivatives are
becoming extremely important.
our whole society makes every effort to save energy and
reduce emission.
Clearly, a mild, straightforward, and broadly applicable
method for the formation of trifluoromethylated furans is
highly desired. There are several significant issues that
must be addressed to develop a useful method for this
purpose. These issues include the following: (1) the ex-
ploration of time and energy economy for the process; (2)
the development of efficient and step-economical7 methods
withhighyields, preferably metal-free cascade approaches;
(3) the use of low-cost, reliable, and simple CF3 sources; (4)
the development of a facile method with a broad substrate
scope which can be easily adapted to scale-up; (5) the
addition of one more functional group onto the furan ring
to provide novel opportunities for drug design and dis-
covery. Herein, we report our preliminary findings toward
solving these challenging problems.
However, despite the pharmaceutical importance of
trifluoromethylated furans, only very few methods have
been reported for the synthesis of this kind of compound
due to the difficulty in constructing these molecules,5 and
these limited methods heavily involvedthe use of transition
metals and required energy-consuming high temperatures.
Furthermore, the synthesis of functionalized trifluoro-
methylated furans mainly requires multiple steps and
specially tailored building blocks. Thus, these synthesis
methods, to the best of our knowledge, still suffer from
several disadvantages, such as high temperatures, very low
product yields, time-consuming multiple synthesis steps,
and use of toxic transition metals and special reagents.5
Notably, a much more practical problem is that almost all
ofthese reported approaches have been limited insubstrate
selection.6 Particularly, time and energy economy are
important aspects of streamlining a synthesis route since
Table 1. Optimization of Reaction Conditionsa
(4) Selected examples from the extensive recent patent literature: (a)
Inoue, T.; Watanabe, S.; Yamagishi, T.; Arano, Y.; Morita, M.;
Shimada, K. WO 2010137351, 2010. (b) Yoakim, C.; Bailey, M. D.;
Bilodeau, F.; Carson, R. J.; Fader, L.; Kawai, S.; Laplante, S.; Simoneau, B.;
Surprenant, S.; Thibeault, C.; Tsantrizos, Y. S. WO 2010130034, 2010. (c)
Griffioen, G.; Van Dooren, T.; Rojas de la Parra, V.; Marchand, A.; Allasia, S.;
Kilonda, A.; Chaltin, P. WO 2010142801, 2010. (d) Sutton, A. E.; Richardson,
T. E.; Huck, B. R.; Karra, S. R.; Chen, X.; Xiao, Y. ; Goutopoulos, A.; Lan, R.;
Perrey, D.; Vandeveer, H. G.; Liu-Bujalski, L.; Stieber, F.; Hodous, B. L.; Qiu,
H.; Jones, R. C.; Heasley, B. WO 2010093419, 2010. (e) Knust, H.;
Nettekoven, M.; Pinard, E.; Roche, O.; Rogers-Evans, M. US 20090163485,
2009. (f) Sakai, N.; Imamura, S.; Miyamoto, N.; Hirayama, T. WO
2008016192, 2008. (g) Gould, A. E.; Greenspan, P. D.; Vos, T. J. WO
2008030448, 2008. (h) George, D. M.; Dixon, R. W.; Friedman, M.; Hobson,
A.; Li, B.; Wang, L.; Wu, X.; Wishart, N. WO 2008060621, 2008; (i) Bauer,
U.; Brailsford, W.; Gustafsson, L; Svensson, T. WO 2007073300, 2007. (j)
Bolin, D. R.; Cheung, A. W.-H.; Firooznia, F.; Hamilton, M. M.; Li, S.;
McDermott, L. A.; Qian, Y.; Yun, W. WO 2007060140, 2007. (k) Witschel,
M.; Zagar, C.; Hupe, E.; Kuehn, T.; Moberg, W. K.; Parra Rapado, L.; Stelzer,
F.; Vescovi, A.; Rack, M.; Reinhard, R.; Sievernich, B.; Grossmann, K.;
Ehrhardt, T. WO 2006125687, 2006. (l) Mansfield, D.; Rieck, H.; Coqueron,
P.-Y.; Desbordes, P.; Villier, A.; Grosjean-Cournoyer, M.-C.; Genix, P. WO
2006108791, 2006. (m) Borcherding, D. R.; Gross, A.; Shum, P. W.-K.;
Willard, N.; Freed, B. S. WO 2004100946, 2004. (n) Hamamura, K.; Sasaki,
S.; Amano, Y.; Sakamoto, J.; Fukatsu, K. WO 2004022551, 2004.
entry
solvent
x mol (%)
time
yield (%)b
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
10
5
<1 min
<1 min
<1 min
<1 min
<1 min
<1 min
<1 min
<1 min
<1 min
95
91
93
95
89
91
94
93
99
2
3
1
4
0
5
0
6
0
7c
8d
9e
0
0
0
a Unless otherwise noted, the reactions were performed with 1a (0.20
mmol), TFAA (0.26 mmol), PPh3 (0.24 mmol), and DMAP (x mol %) in
solvent (1.0 mL) at room temperature within 1 min. b Yield of isolated
product. c 1.5 equiv of PPh3 was used. d 1.0 equiv of PPh3 was used. e 1.0 equiv
of PPh3 and 1.5 equiv of TFAA were used. equiv = equivalent, TFAA =
trifluoroacetic anhydride, DMAP = 4-dimethylaminopyridine.
(5) For an excellent review: (a) Petrov, V. A. Fluorinated Heterocyclic
Compounds: Synthesis, Chemistry, and Applications; Wiley: Hoboken, NJ,
2009 and references cited therein; for selected examples: (b) Kino, T.;
Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.;
Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (c) Pang, W.; Zhu, S.;
Xin, Y.; Jiang, H.; Zhu, S. Tetrahedron 2010, 66, 1261. (d) Zhang, D.;
Yuan, C. Eur. J. Org. Chem. 2007, 3916. (e) Bouillon, J.-P.; Kikelj, V.;
Tinant, B.; Harakat, D.; Portella, C. Synthesis 2006, 1050. (f) Aristov,
S. A.; Vasil’ev, A. V.; Rudenko, A. P. Russ. J. Org. Chem. 2006, 42, 66.
Initially, we considered a practical question of whether
or not the direct and synthetically efficient transfer of a
CF3 group from trifluoroacetic anhydride (TFAA), one of
the most common reagents, would be possible, since
TFAA were previously employed in the construction of
special building blocks and yet had not been used directly
in the process of synthesis of trifluoromethylated aromatic
compounds. Then we examined the reaction of easily
available compound 1a8 with TFAA in the presence of
PPh3 and a catalytic amount of DMAP in CH2Cl2 at room
temperature (Table 1, entry 1). To our delight, the reaction
ꢀ
(g) Bouillon, J.-P.; Henin, B.; Huot, J.-F.; Portella, C. Eur. J. Org. Chem.
2002, 1556. (h) Linderman, R. J.; Jamois, E. A.; Tennyson, S. D. J. Org.
Chem. 1994, 59, 957. (i) Begue, J.-P.; Bonnet-Delpon, D.; Dogbeavou,
R.; Ourevitch, M. J. Chem. Soc., Perkin Trans. 1 1993, 2787. (j) Bucci,
R.; Laguzzi, G.; Pompili, M. L.; Speranzia, M. J. Am. Chem. Soc. 1991,
113, 4544. (k) Sawada, H.; Nakayama, M. J. Fluorine Chem. 1990, 46,
423. (l) Neumann, D.; Kischkewitz, J. J. Fluorine Chem. 1990, 46, 265.
(m) Jullien, J.; Pechine, J. M.; Perez, F.; Piade, J. J. Tetrahedron 1982, 38,
1413. (n) Bambury, R. E.; Yaktin, H. K.; Wyckoff, K. K. J. Heterocycl.
Chem. 1968, 5, 95.
(6) To the best of our knowledge, there are only two methods
reported thus far that investigated more than five different substrates
(see ref 5c and 5d) and many cases only employed one or two substrates
(see ref 5).
(7) (a) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197. (b) Wender,
P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008,
41, 40.
(8) (a) Nair, V.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.; Devi,
B. R.; Menon, R. S.; Rath, N. P.; Srinivasc, R. Synthesis 2003, 1895. (b)
Li, C.-Q.; Shi, M. Org. Lett. 2003, 5, 4273.
Org. Lett., Vol. 13, No. 19, 2011
5347

proceeded efficiently and afforded the desired product in
95% yield. Most remarkably, the reaction occurred im-
mediately and was completed in seconds. We next reduced
the catalyst loading to 5 and 1 mol %, respectively, and the
reactions proceeded similarly (Table 1, entries 2 and 3).
The following study revealed that catalyst DMAP was not
necessary for this reaction (Table 1, entry 4). Solvent
screening showed that CH2Cl2 was an optimal selection
(Table 1, entries 4À6). Further tests by adjusting the
amount of PPh3 and TFAA disclosed that the best result
was obtained (99% yield) by using 1.0 equiv of PPh3 and
1.5 equiv of TFAA (Table 1, entry 9). The structure of the
product was clearly established by single crystal X-ray
diffraction of 2h.9
with excellent yields. More importantly, this cascade pro-
tocol is also amenable to scale-up. When the reaction was
carried out on a 5 mmol (1c, 1.375 g) scale, it also was
completed in seconds and afforded the product in 96%
yield. We then further conducted the reaction on a 40
mmol (1c, 10.920 g) scale and found the reaction was as
efficient as the smaller scale reaction, completing in sec-
onds with the same excellent yield (scheme 1). Therefore,
this method is fast, easy to handle, and adaptable to large-
scale synthesis.
Scheme 1. Example of Scalable Synthesis
Table 2. Substrate Scopea
We next focused on the synthesis of biologically attrac-
tivefuran derivatives oftypeA and B. Under the optimized
reaction conditions, the cascade process was efficient for
either type A or B synthesis. Both aromatic and alkyl
substrates could be successfully employed in this cascade
process (Scheme 2). The expected product 4a was obtained
with excellent yield (94%) by the use of substrate 3a. A
one-pot cascade formation of furan and ester hydrolysis
were also successful in affording the desired products
with good yield (4b, 76%; 4c, 72%). Since furans 4b, 4c
and their derivatives4 are known intermediates extensively
used in the synthesis of a large number of drug molecules4
(for example, see figure 1), it is of crucial importance for
them to be efficiently synthesized.
entry
1
R
products
yield (%)b
1
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
99
97
99
97
93
99
99
99
92
91
87
97
95
2
3-NO2C6H4
4-CNC6H4
4-CF3C6H4
2-ClC6H4
3
4
5
6
3-ClC6H4
7
1g
1h
1i
4-FC6H4
2g
2h
2i
8
4-BrC6H4
9c
10c
11
12
13
2-OMeC6H4
2-MeC6H4
4-CH3C6H4
4-OMeC6H4
2-furylC6H4
1j
2j
1k
1l
2k
2l
1m
2m
a Unless otherwise noted, all the reactions were performed with 1 (0.2
mmol), TFAA (0.3 mmol), and PPh3 (0.2 mmol) in CH2Cl2 (1.0 mL) at
room temperature. b Yield of isolated product. c The reaction was
allowed to proceed for 5 min.
Scheme 2. Synthesis of A- and B-Type Compounds
Under the optimal reaction conditions, the scope of the
cascade reaction was then investigated by using a variety of
substrates to establish the generality of the process (Table
2). The cascade process was found to be broad in scope,
with very good to excellent yields obtained for all products
(2; 87À99%). The reaction allowed incorporation of a
wide range of functional groups in the furan products. The
aromatic groups bearing electron-withdrawing or -donating
groups were both well tolerated, as were ortho-, meta-, and
para-substituted aromatic rings. Sterically demanding
substrates (Table 2, entries 9 and 10) and heteroaromatic
groups, such as furan (Table 2, entry 13), were also
successfully converted into the corresponding products
A series of control experiments were carried out to
determine the triggering step (see Supporting Information
for details). The reactions were performed in the absence of
TFAA, PPh3, and 1a, respectively (Scheme 3). Omission of
TFAAonlygavea trace amount of conversion withrespect
(9) CCDC 830674 (2h) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
5348
Org. Lett., Vol. 13, No. 19, 2011

Scheme 3. Control Experiments
Scheme 4. Possible Reaction Pathways
to 1a even when the reaction was conducted for 1 h
(path 1). Then we questioned whether or not the trace
amount of TFA decomposed from TFAA in the reaction
system triggered the reaction in the initial step as a
Brønsted acid catalyst. In fact, when we added 10 mol %
TFA to the reaction mixture of PPh3 and 1a, an improved
conversion of 19% compared to path 1 was observed (path
2). However, the major products of the two paths were
different as detected by 1H NMR analysis (see Supporting
Information). To further justify the role of TFA, TFAA
was added to an alkaline reaction mixture of 3.0 equiv of
Et3N, PPh3, and 1a (path 3). The reaction was as efficient
as in the previous study (Table 1), and this observation
indicates that a Brønsted acid catalyst is not needed for the
success of this cascade reaction. As expected, omission of
PPh3 afforded no conversion of 1a even after 1 h (path 4).
In the absence of 1a, the reaction was conducted for 1 min
and gave 20% conversion of PPh3 to a new product (path 5).
Further analysis showed that triphenylphosphine oxide,
which is associated with new CF3-containing fragments or
compounds generated during the reaction as observed by
19F NMR analysis (see Supporting Information for
details), was formed as a major product in this reaction.
During a prolonged reaction time, a much more complex
mixture of trifluoromethylated/fluorinated fragments/com-
pounds was detected by 19F NMR analysis. Taking all the
evidence together, it is likely that TFAA and PPh3 reacted
rapidly to generate a highly reactive intermediate that
triggered and participated in this complicated transforma-
tion reaction (Scheme 4, path A). However, the reaction
pathway in which PPh3 and 1a reacted slowly initially and
then TFAA participated and promoted the following steps
for expeditious synthesis of trifluoromethylated furan is
still a possible approach (Scheme 4, path B).
In summary, we have developed a time and energy
economical method for the synthesis of drug-related tri-
fluoromethylated furans. This cascade approach is extre-
mely efficient since the reaction was completed just in
seconds and afforded the desired products with very good
to excellent yields. Furthermore, this method is operation-
ally simple with wide substrate generality and amenable to
scale-up. Notably, the simpleand commonly available CF3
source TFAA was employed in trifluoromethylated het-
erocyclic compound synthesis.
Therefore, this strategy provides a new general
approach for activation and application of TFAA.
We expect this novel method to be of broad utility
in the synthesis of biologically active medicinal agents.
We are continuing to explore the mechanism of
this reaction with various anhydrides and study the
bioactivities of these furan derivatives. The results of
these investigations will be reported elsewhere.
Acknowledgment. We are grateful for the NSFC
(21032005, 20972058), the National Basic Research Program
of China (Nos. 2009CB626604, 2010CB833203),the “111”
program from MOE of P. R. China, the Fundamental
Research Funds for the Central Universities (lzujbky-2009-
159), and a Syngenta fellowship to Y. Wang.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5349