Highly efficient construction of trifluoromethylated heterocycles; [3+2] annulation of N,N′-cyclic or C,N-cyclic azomethine imines with trifluoromethyl-containing electron-deficient olefins

Article abstract of DOI:10.1002/ejoc.201201244

A highly regio-and stereoselective synthesis of pyrazolidine analogues by the use of N,N′-cyclic or C,N-cyclic azomethine imines with two different trifluoromethyl-containing olefins has been developed. The method affords highly functionalized trifluorome

Full text of DOI:10.1002/ejoc.201201244

FULL PAPER
DOI: 10.1002/ejoc.201201244
Highly Efficient Construction of Trifluoromethylated Heterocycles;
[3+2] Annulation of N,NЈ-Cyclic or C,N-Cyclic Azomethine Imines with
Trifluoromethyl-Containing Electron-Deficient Olefins
De Wang,[a] Hong-Ping Deng,[b] Yin Wei,[b] Qin Xu,*[a] and Min Shi*[a,b]
Keywords: Synthetic methods / Nitrogen heterocycles / Fluorine / Diastereoselectivity / Annulation
A highly regio- and stereoselective synthesis of pyrazolidine
analogues by the use of N,NЈ-cyclic or C,N-cyclic azometh-
tionalized trifluoromethyl-containing pyrazolidine analogues
in excellent yields with high diastereoselectivities under mild
ine imines with two different trifluoromethyl-containing ole- conditions.
fins has been developed. The method affords highly func-
Pyrazolidine is an important structural motif that exists
in a broad range of biologically and pharmaceutically rel-
evant compounds.[1] For example, bicyclic pyrazolidinones
(LY) have potential use as antibiotics[2a,2b,2c] and their iso-
quinoline derivatives show antimicrobial activities (Fig-
ure 1).[2d] Synthetic methods to access these molecules in-
clude [3+2] cycloaddition reactions of azomethine imines,
diazoalkanes, and nitrile imines with activated alkenes.[3]
Among those, azomethine imines, as a class of 1,3-dipoles,
have been widely used in [3+2] annulations with alkenes or
alkynes,[4] and some effective asymmetric variants by using
different chiral catalysts have been also reported.[5]
Recently, significant research efforts have focused on the
strategic introduction of trifluoromethyl groups into drug-
like molecules in medicinal and agricultural chemistry due
to the unique physical properties of this group.[6] There are
Figure 1. Examples of biologically active pyrazolidine and pyraz-
two general methods to achieve trifluoromethyl-containing oline derivatives.
compounds: one is direct introduction of the trifluorome-
thyl group through nucleophilic, electrophilic, or radical re-
actants; the second uses a building-block strategy involving
struct stereogenic tertiary carbon centers bearing a tri-
the assembly of readily accessible trifluoromethyl-contain-
ing organic compounds as starting materials.[7–9] Both ap-
proaches have their own particular advantages; whereas the
latter approach is well-suited for the valorization of readily
available trifluoromethyl-containing building blocks, 2,2,2-
trifluoroethylidene malonates are good substrates to con-
fluoromethyl group. In this research field, Lu and co-
workers applied 2,2,2-trifluoroethylidene malonates to
asymmetric Michael addition and Friedel–Crafts alkylation
to give the desired products in good yields.[10] Fang and co-
workers have synthesized aryl-substituted α-trifluoro-
methyl-α,β-unsaturated carboxylic acids (AFUCA), which
are one of the most valuable building blocks for the synthe-
sis of CF3-containing molecules.[11]
The annulation of azomethine imines with trifluoro-
methyl-containing olefins is fascinating because it not only
provides a method with which to construct five-membered
heterocycles, but also leads to the generation of products
containing the trifluoromethyl group. Great efforts have fo-
cused on [3+2] cycloaddition of azomethine imines with dif-
ferent olefins,[4,5] however, the reactivities of azomethine
[a] Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, School of Chemistry & Molecular Engineering, East
China University of Science and Technology,
130 Mei Long Road, Shanghai 200237, China
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201244.
Eur. J. Org. Chem. 2013, 401–406
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
401

D. Wang, H.-P. Deng, Y. Wei, Q. Xu, M. Shi
FULL PAPER
imines with trifluoromethyl-containing olefins has rarely (Table 1, entry 9). The relative configuration of 3a was as-
been reported. Only Shibata’s group reported one example signed on the basis of X-ray diffraction studies. The OR-
of [3+2] annulation using N,NЈ-cyclic azomethine imines TEP drawing is shown in Figure 2 and the CIF data are
with α-trifluoromethyl acrylate (MAF-TBE),[12a] giving the summarized in the Supporting Information.
products in 79–97% yields along with between 59:41 and
75:25 diastereoselectivities.[12b]
In this paper, we wish to report a highly regio- and
stereoselective synthesis of trifluoromethyl-containing pyr-
azolidine analogues by the use of N,NЈ-cyclic or C,N-cyclic
azomethine imines with two different trifluoromethyl-con-
taining olefins under mild conditions.[13]
Initial examination was carried out using N,NЈ-cyclic
azomethine imine 1a (0.2 mmol) and trifluoroethylidene
malonate 2a (0.24 mmol) as the substrates in tetra-
hydrofuran (THF) at room temperature for 24 h (Table 1,
entry 1). We found that the desired cycloadduct 3a was ob-
tained in 55% yield and more than 99:1 diastereoselectivity.
Subsequently, we attempted to optimize the reaction condi-
tions by screening several solvents; the results are summa-
rized in Table 1 (entries 2–6). As can be seen, in acetonitrile
(CH3CN), the desired product 3a could be obtained in 65%
yield with 99:1 diastereoselectivity, and in toluene or ethyl
acetate (EtOAc), 3a was formed in 60 and 80% yields,
respectively, with excellent diastereoselectivities (Table 1,
entries 3 and 4). Using 1,2-dichloroethane (DCE) or dichlo-
Figure 2. ORTEP drawing of product 3a.
With the identification of the optimal reaction condi-
romethane (CH2Cl2) as solvent, the yield of 3a increased tions, the generality of this catalyst-free [3+2] cycloaddition
to 92 and more than 99%, respectively, also with excellent was examined by using a variety of azomethine imines 1
diastereoselectivities (Table 1, entries 5 and 6). Thus, and trifluoroethylidene malonates 2; the results are summa-
CH2Cl2 was found to be the most suitable solvent for this rized in Table 2. All reactions proceeded smoothly to give
reaction. Lowering the reaction temperature to 0 °C or the corresponding products 3 in good yields and moderate
–20 °C in CH2Cl2 led to a significant decrease in the yield to excellent diastereoselectivities under the optimal condi-
of 3a to 30% or barely no product, respectively, even upon tions (Table 2). Excellent yields and diastereoselectivities
prolonging the reaction time to 48 h (Table 1, entries 7 and were obtained when utilizing diethyl 2-(2,2,2-trifluoroethyl-
8). Upon reducing the reaction time to 2 h, the reaction idene)malonate (2b) or dimethyl 2-(2,2,3,3,3-pentafluoro-
also proceeded smoothly to give 3a in more than 99% yield propylidene)malonate (2c) instead of 2-(2,2,2-trifluoroethyl-
idene)malonate (2a; Table 2, entries 2 and 3). Regardless of
whether R1 was an electron-rich or -deficient aromatic ring,
the reactions proceeded smoothly to give the corresponding
bicyclic pyrazolidinone products 3d–g in good yields and
good dr values (Table 2, entries 4–7). Only in the case of p-
Table 1. Optimization of the reaction conditions for [3+2] annu-
lation.
BrC6H4 azomethine imine 1b, was the corresponding ad-
duct 3d obtained in a slightly lower yield (87%), but still
with more than 99:1 dr; in this case the reaction time was
lengthened to 24 h because 1b is not very soluble in CH2Cl2
(Table 2, entry 4). Multisubstituted azomethine imine 1f
was also investigated in this reaction, affording the corre-
sponding product 3h in more than 99:1 dr and 89% yield
(Table 2, entry 8). When R1 was a heteroaromatic group (R1
= 2-furan) or a sterically more bulky 2-naphthalene moiety,
the reactions also proceeded efficiently to afford the corre-
sponding products 3i–j in 77 and 82% yields with high dr
values, respectively (Table 2, entries 9 and 10). Changing
the aromatic group to an aliphatic group provided the cor-
responding product 3k in 94% yield with Ͼ99:1 dr (Table 2,
entry 11). When R2 was a methyl group, the desired bicyclic
product 3l was obtained in 88% yield with 2:1 dr (Table 2,
entry 12). When R3 was a methyl group, almost no reaction
occurred (Table 2, entry 13).
Entry[a]
Solvent
T (°C)
t [h]
dr[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
24
24
24
24
24
24
48
48
2
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
–
55
65
60
80
92
Ͼ99
30
trace
Ͼ99
CH3CN
toluene
EtOAc
DCE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–20
r.t.
Ͼ99:1
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), solvent
(1.0 mL). [b] Determined by 1H and 19F NMR spectroscopic analy-
sis. [c] Isolated yield.
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Trifluoromethylated Heterocycles
Table 2. Substrate scope of [3+2] annulation of azomethine imine 1 with trifluoroethylidene malonate 2.
Entry[a]
1
2
dr[b]
Product Yield [%][c]
R1
R2
R3
R4
R3
1
2
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
Me
Et
Et
CF3
CF3
Ͼ99:1
Ͼ99:1
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ͼ99
96
90
87
98
Ͼ99
92
89
77
82
3
CF2CF3 Ͼ99:1
4[d]
5
4-BrC6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
3,4,5-(CH3O)3C6H4
2-furyl
2-naphthyl
n-Octyl
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
2:1
6
7
8
9[d]
10
11
12
13
3j
3k
3l
–
94
88
trace
Ph
CH3
–
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), CH2Cl2 (2.0 mL), r.t., 2 h. [b] Determined by 19F NMR spectroscopic analysis.
[c] Isolated yield. [d] The reaction was carried out for 24 h and monitored by TLC.
Encouraged by the [3+2] annulation of N,NЈ-cyclic azo- was assigned on the basis of X-ray diffraction studies. The
methine imine with trifluoroethylidene malonate, we next ORTEP drawing of 5a is shown in Figure 3 and the CIF
attempted to use C,N-cyclic azomethine imine 4 instead of data are summarized in the Supporting Information.
N,NЈ-cyclic azomethine imine 1 to examine the reaction
outcome. We found that the reactions also proceeded
smoothly to give the annulation products in high yields and
high diastereoselectivities; the results are summarized in
Table 3. The reaction was tolerant of either electron-de-
ficient or -rich aromatic rings on the azomethine imines 4a–
c (R5 = H, Br, or Me) with various trifluoroethylidene ma-
lonates 2a–c, providing a series of the corresponding prod-
ucts 5a–g in 81–99% yields with excellent diastereoselectivi-
ties (Table 3, entries 1–7). The relative configuration of 5a
Table 3. Substrate scope of [3+2] annulation of azomethine imine
4 with trifluoroethylidene malonate 2.
Entry[a]
4
R5
2
R4 Rf
dr[b]
Product
Yield [%][c]
1
2
3
4a
4a
4a
4b Br
4b Br
4b Br
H
H
H
2a Me CF3
2b Et CF3
2c Me CF2CF3 Ͼ99:1
2a Me CF3
2b Et CF3
2c Me CF2CF3 Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
5a
5b
5c
5d
5e
5f
91
82
96
94
81
Figure 3. ORTEP drawing of product 5a.
To extend this synthetic methodology to other trifluoro-
methyl-containing olefins or other 1,3-dipoles, we next at-
tempted the reactions of 1a with 6 or 7 under the standard
conditions. However, none of the desired cycloadducts were
formed [Scheme 1, Equations (1) and (2)]. Using compound
8 instead of 1a to react with 2a, no reaction occurred, prob-
ably because 8 is a relatively unreactive 1,3-dipole; see
Scheme 1, Equation (3).
4[d]
5[d]
6[d]
7
Ͼ99:1
Ͼ99:1
Ͼ99
Ͼ99
4c CH3 2a Me CF3
5g
[a] Reaction conditions: 4 (0.2 mmol), 2 (0.24 mmol), CH2Cl2
(2.0 mL), r.t., 2 h. [b] Determined by 19F NMR spectroscopic
analysis. [c] Isolated yield. [d] The reaction was carried out in 4–8 h
and monitored by TLC.
Eur. J. Org. Chem. 2013, 401–406
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403

D. Wang, H.-P. Deng, Y. Wei, Q. Xu, M. Shi
FULL PAPER
Because aryl-substituted α-trifluoromethyl α,β-unsatu-
rated carboxylic acids (AFUCA)[11] are one of the most
valuable building blocks for the synthesis of CF3-containing
molecules, we also prepared AFUCA esters 6a–c and ap-
plied them to this [3+2] annulation reaction; the results are
summarized in Scheme 2. Regardless of whether R1 or R6
were electron-rich or electron-deficient aromatic rings, the
reactions proceeded smoothly to give the [3+2] annulation
products in 58–99% yields along with 17:1–20:1 dr values
(Scheme 2). Switching to azomethine imine 4a, the desired
annulation product 10 could also be obtained in 66% yield
along with high diastereoselectivity. The relative configura-
tions of 9c and 10 were assigned on the basis of X-ray dif-
fraction analysis. The ORTEP drawing of 9c and 10 are
shown in Figure 4 and the CIF data are summarized in the
Supporting Information. Increasing the scale of the reac-
tion (0.5 mmol) afforded 3a in 98% yield and Ͼ99:1 dr un-
der the standard conditions (Scheme 3).
Scheme 1. Attempted reactions using other 1,3-dipoles and CF3-
containing olefins.
Scheme 2. Substrate scope of [3+2] annulation of azomethine imine 1 or 4 with 6.
404
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Trifluoromethylated Heterocycles
Figure 4. ORTEP drawing of products 9c and 10.
chromatography on silica gel (petroleum ether/EtOAc, 6:1Ǟ4:1) to
provide the desired product.
Dimethyl 5-Oxo-1-phenyl-3-(trifluoromethyl)tetrahydropyrazolo[1,2-
a]pyrazole-2,2(1H)-dicarboxylate (3a): Yield 78 mg (Ͼ99%); color-
1
less solid; m.p. 172–173 °C. H NMR (400 MHz, CDCl3, TMS): δ
= 7.37–7.34 (m, 3 H), 7.18–7.15 (m, 2 H), 5.51 (q, J = 7.2 Hz, 1
H), 4.86 (s, 1 H), 3.81 (s, 3 H), 3.40–3.32 (m, 4 H), 3.17–3.11 (m,
1 H), 2.37 (ddd, J1 = 2.4, J2 = 10.0, J3 = 17.2 Hz, 1 H), 1.96 (dt,
J1 = 10.0, J2 = 17.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 172.6, 166.5, 166.0, 132.4, 129.3, 129.0, 128.9, 122.9 (q, J =
280.4 Hz), 72.0, 69.4, 59.2 (q, J = 33.8 Hz), 53.6, 53.1, 44.3,
32.6 ppm. 19F NMR (376 MHz, CFCl3): δ = –69.6 (d, J =
Scheme 3. The [3+2] annulation of 1a and 2a performed on a larger
scale.
An asymmetric variant of these cyclizations has also
been investigated by using a variety of chiral catalysts, but
the cyclization products were obtained with low ee values
(see the Supporting Information for details).
7.5 Hz) ppm. IR (neat): ν = 2952, 2362, 1740, 1716, 1401, 1270,
˜
1178, 1142, 933, 704 cm–1. MS (ESI): m/z (%) = 387.1 (100) [M +
H+]. HRMS: Calcd. for C17H18F3N2O5+ [M + H+] 387.1168; found
387.1162.
In conclusion, we have developed a novel [3+2] annu-
lation of N,NЈ-cyclic or C,N-cyclic azomethine imines with
CF3-containing olefins, affording the corresponding trifluo-
romethyl-containing pyrazolidine analogues in excellent
yields (up to Ͼ99%) with high diastereoselectivities (up to
99:1) under mild conditions. Current efforts focusing on de-
veloping an asymmetric version of this reaction and apply-
ing this methodology to synthesize biologically active prod-
ucts are in progress.
CCDC-866876 (for 3a), -875407 (for 5a), -876533 (for 9c), and
-895560 (for 10) contain 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.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data of the compounds shown in Tables 1, 2,
and 3, and Schemes 1 and 3, detailed descriptions of experimental
procedures and the crystal structure data of 3a, 5a, 9c, and 10.
Acknowledgments
Experimental Section
General Procedure: Under an argon atmosphere, CF3-containing
olefin (0.25 mmol) was added to a solution of azomethine imine 1
or 4 (0.20 mmol) in CH2Cl2 (2.0 mL) and the resulting reaction
mixture was stirred at room temperature for 2–48 h. The solvent
was removed under reduced pressure and residue was purified by
We thank the Shanghai Municipal Committee of Science and Tech-
nology (grant number 11JC1402600), the National Basic Research
Program of China, (973)-2009CB825300, the Fundamental Re-
search Funds for the Central Universities, and the National Natu-
ral Science Foundation of China (NSFC) for financial support
Eur. J. Org. Chem. 2013, 401–406
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
405

D. Wang, H.-P. Deng, Y. Wei, Q. Xu, M. Shi
FULL PAPER
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Received: September 18, 2012
Published Online: November 9, 2012
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