Expeditious synthesis of trifluoromethylated heterocycles: Noncatalytic 1,3-dipolar cyclization of azomethine imines with (α-trifluoromethyl) acrylates

Article abstract of DOI:10.1055/s-0030-1258189

A convenient, simple, and expeditious procedure for the preparation of novel trifluoromethylated bicyclic pyrazolidinone systems by noncatalytic 1,3-dipolar cyclization of azomethine imines with tert-butyl 2-(trifluoromethyl)prop-2-enoate is presented. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258189

3274
PAPER
Expeditious Synthesis of Trifluoromethylated Heterocycles: Noncatalytic 1,3-
Dipolar Cyclization of Azomethine Imines with (a-Trifluoromethyl)acrylates
C
yclization of
h
A
zomethine
i
Imines
n
w
ith (
a
-Trif
i
luorom
c
ethyl)acryl
h
ates i Ogawa, Takayuki Nishimine, Etsuko Tokunaga, Norio Shibata*
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, Japan
Fax +81(52)7357543; E-mail: nozshiba@nitech.ac.jp
Received 7 May 2010
acrylates for the synthesis of trifluoromethylated biologi-
Abstract: A convenient, simple, and expeditious procedure for the
preparation of novel trifluoromethylated bicyclic pyrazolidinone
systems by noncatalytic 1,3-dipolar cyclization of azomethine
imines with tert-butyl 2-(trifluoromethyl)prop-2-enoate is presented.
cally interesting molecules.10 tert-Butyl 2-(trifluorometh-
yl)prop-2-enoate (MAF-TBE®) is particularly attractive
as a substrate because of its commercial availability on a
bulk scale, its chemical stability resulting from the steri-
cally demanding tert-butyl group, and the ease with which
the tert-butyl ester moiety can be removed by acids. Here,
we report a rapid synthesis of trifluoromethylated hetero-
cycles by a noncatalytic 1,3-dipolar cyclization of azo-
methine imines with MAF-TBE.
Key words: bicyclic compounds, fluorine, cycloadditions, hetero-
cycles, imines, drugs
Heterocycles are an important group of structural units
that are frequently encountered in biologically active nat-
ural products as well as in pharmaceuticals and agrochem-
icals.1 Indeed, many heterocycles carrying a variety of
substituents have been synthesized for a wide variety of
medicinal applications during the last hundred years or
so.1 Partially fluorinated compounds, on the other hand,
have only recently emerged as promising biologically ac-
tive moieties for drug design.2 These facts led us to ex-
plore efficient and simple routes for constructing fluorine-
containing heterocycles to provide attractive surrogates
for drug-like molecules.3 Our group has been engaged in
developing efficient and selective syntheses of fluorine-
containing organic compounds.4 Two principal strategies
are generally considered when planning syntheses of
fluorine-containing compounds: the direct introduction of
fluorine atoms or fluorine-containing substituents into tar-
get molecules, or a building-block strategy involving the
assembly of readily accessible fluorine-containing organ-
ic compounds as starting materials.5 Although both ap-
proaches have their own particular advantages for
syntheses of fluorinated molecules, the latter approach is
especially attractive when the fluorinated building blocks
are inexpensive and commercially available.6 Among the
group of easily accessible fluorine-containing building
blocks, trifluoropyruvates have emerged as one of the
most popular for the construction of fluorinated organic
materials and they can provide valuable synthetic inter-
mediates that can be converted into a variety of useful tri-
fluoromethylated heterocycles.7 On the other hand,
despite their widespread use in polymer science, a-tri-
fluoromethyl acrylates have not been actively studied for
this purpose even though they are commercial available
on a bulk scale.8,9 We have therefore started a research
program aimed at the effective use of a-trifluoromethyl
The cycloaddition of 1,3-dipoles with olefins is one of the
most powerful methods for the preparation of five-mem-
bered heterocycles.11 In particular, the cycloaddition of
azomethine imines with olefins12 is of considerable inter-
est because it permits the direct formation of biologically
important bicyclic pyrazolidinone systems, potentially
useful as antibiotics (Figure 1).12f,j,13 Indeed, azomethine
imines have been widely used as 1,3-dipoles in [3+2]-cy-
cloaddition reactions; however, to the best of our knowl-
edge, no example of the use of an a-trifluoromethyl
acrylate as a cycloaddition partner has been reported. Fur-
thermore, the reaction permits medicinally attractive tri-
fluoromethylated bicyclic pyrazolidinone systems to be
accessed in one step.
MeO
N
O
HN
N
H2N
COOH
LY 186826 (R = COMe)
LY 193239 (R = SO2Me))
LY 255262 (R = CN)
N
O
S
N
R
Figure 1 Examples of biologically active pyrazolidinone systems
We first examined the [3+2]-cycloaddition reaction of
MAF-TBE with the azomethine imine 1a, derived from
benzaldehyde. We were surprised to find that the reaction
proceeded without the help of a catalyst or additive when
the reactants were stirred together in dichloromethane at
room temperature for 20 hours to give the desired trifluo-
romethylated bicyclic pyrazolidinone 2a in 96% yield as
a 62:38 mixture of diastereoisomers (Table 1, entry 1).
The solvent had little effect on the conversion (entries 2–
4), although a longer reaction time was required in polar
solvents such as N,N-dimethylformamide or methanol
(entries 5 and 6). To understand the high reactivity in-
volved in this transformation, we next attempted the reac-
tion of 1a with nonfluorinated methyl methacrylate under
SYNTHESIS 2010, No. 19, pp 3274–3281
x
x.
x
x
.
2
0
1
0
Advanced online publication: 09.08.2010
DOI: 10.1055/s-0030-1258189; Art ID: C03710SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cyclization of Azomethine Imines with (a-Trifluoromethyl)acrylates
3275
the same reaction conditions. In this case, only 23% of the likely to play an important role in this noncatalytic cy-
corresponding product was obtained, even after 80 hours cloaddition reaction, so we examined the generality of this
(Scheme 1).
cycloaddition by using a series of azomethine imines. The
reactions of the azomethine imines 1b–o with MAF-TBE
proceeded well to give the corresponding 1,3-dipolar cy-
clization products 2b–o in high yields that were almost in-
dependent of the functional groups present, including
alkyl, halo, methoxy, or sterically demanding naphthyl
moieties, or of their positions on the aromatic ring (entries
7–17). We also obtained the bicyclic products 2m–n in
high yields from the corresponding aromatic analogues
bearing hetaryl groups, although a slightly higher reaction
temperature was required in these cases (entries 18 and
19). The cinnamyl-substituted azomethine imine 1o is
We realized that the inherent properties of the fluorine at-
om, such as its powerful electron-withdrawing nature, are
O
O
N–
CH2Cl2
N
+
80 h, 40 °C
N
N
COOMe
H
COOMe
3a 23% (dr = 71:29)
Ph
Ph
1a
Scheme 1 Reaction of 1a with methyl methacrylate
Table 1 Reactions of Azomethine Imines 1 with MAF-TBE
O
O
CF3
solvent
N–
N
+
N
time, r.t.
N
COOt-Bu
CF3
H
COOt-Bu
R
R
1a–o
MAF-TBE
2a–o
Entrya
1
Reactant
1a
R
Solvent
CH2Cl2
CHCl3
THF
Time (h)
20
24
11
43
192
144
21
9
Product
2a
2a
2a
2a
2a
2a
2b
2c
Yield (%)
96
drb
Ph
62:38
62:38
60:40
62:38
60:40
66:34
64:36
63:37
64:36
65:35
58:42
62:38
59:41
61:39
52:48
69:31
63:37
63:37
64:36
75:25
2
1a
Ph
86
3
1a
Ph
88
4
1a
Ph
MeCN
DMF
96
5
1a
Ph
88
6
1a
Ph
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
82
7
1b
1c
4-MeC6H4
4-i-PrC6H4
3,4-Me2C6H3
4-MeOC6H4
2-MeOC6H4
3-MeOC6H4
4-BrC6H4
4-ClC6H4
3,5-Br2C6H3
1-naphthyl
2-naphthyl
2-furyl
95
8
79
9
1d
1e
5
2d
2e
91
10
11
12
13c
14
15c
16d
17d
18c,d
19c,d
20
9
97
1f
70
10
14
22
14
5
2f
89
1g
2g
2h
2i
94
1h
1i
86
87
1j
2j
84
1k
1l
2k
2l
92
48
48
90
25
85
1m
1n
1o
2m
2n
2o
92
2-thienyl
96
(E)-PhCH=CHCH2
97
a Reaction conditions: 1 (0.1 mmol), MAF-TBE (0.2 mmol), solvent (1 mL), r.t. (unless otherwise stated).
b Determined by 19F NMR analysis after purification.
c The reaction was carried out at 40 °C.
d CH2Cl2 (2.0 mL) was used.
Synthesis 2010, No. 19, 3274–3281 © Thieme Stuttgart · New York

3276
S. Ogawa et al.
PAPER
Table 2 Reactions of Polysubstituted Azomethine Imines 4 with 2-(Trifluoromethyl)prop-2-enoate Esters
O
O
BzHN
Ph
BzHN
Ph
CF3
–
CH2Cl2
N
N
+
time, 40 °C
COOR2
N
N
CF3
COOR2
H
R2 = t-Bu, Bn
R1
4a–e
R1
5a e
– : R2 = t-Bu
6c: R2 = Bn
Entrya
Reactantb
R1
R2
Time (h)
Product
5a
Yield (%)
drc
1
2
3
4
5
6
4a
4b
4c
4c
4d
4e
Ph
t-Bu
t-Bu
t-Bu
Bn
71
58
26
28
49
65
94
90
80
90
38
71
70:20:8:2
72:20:6:2
69:22:6:3
38:37:18:7
67:19:10:4
60:23:11:6
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
4-O2NC6H4
5b
5c
6c
t-Bu
t-Bu
5d
5e
a Reaction conditions: 1 (0.1 mmol), MAF-TBE (0.2 mmol) CH2Cl2 (1 mL), r.t.
b Racemic 4 was used.
c Determined by 19F NMR analysis after purification.
1
1
spherical neutral, size 63–210 mm. The H NMR (600 MHz), H
also suitable as a substrate for the noncatalytic cycloaddi-
tion, giving the cycloadduct 2o in 97% yield (entry 20).
NMR (300 MHz), 1H NMR (200 MHz), 19F NMR (282 MHz), 19
F
NMR (188 MHz), 13C NMR (151 MHz), 13C NMR (75.5 MHz), and
13C NMR (50.2 MHz) spectra for solns in CDCl3 were recorded on
Buruker Avance 600, Varian Oxford 300, and Varian Mercury 200
spectrometers. Chemical shifts (d) are expressed in ppm downfield
from TMS or CHCl3 as internal standards. Mass spectra were re-
corded on a Shimadzu GCMS-QP5050A or Shimadzu LCMS-
2010EV spectrometers. IR spectra were recorded on a JASCO FT/
IR-200 spectrophotometer.
Encouraged by the success of the noncatalytic [3+2]-
cycloaddition reaction of MAF-TBE with a series of azo-
methine imines, we next turned our attention to the 1,3-
cycloaddition reactions of MAF-TBE with the polysubsti-
tuted pyrazolidinone azomethine imines 4a–e to give
polysubstituted 1H,5H-pyrazolo[1,2-a]pyrazol-1-ones,
which could be useful as valuable scaffolds for the synthe-
sis of conformationally constrained peptidomimetics.13
Under reaction conditions similar to those used for the
azomethine imine 1, the polysubstituted benzoylamino
pyrazolidinone azomethine imine 4 also gave the [3+2]-
cycloaddition product 5 in a high yield regardless of the
electronic nature of the substituents on the aromatic ring
(Table 2, entries 1–6). When benzyl 2-(trifluorometh-
yl)prop-2-enoate was used instead of MAF-TBE in the re-
action with azomethine imine 4c, the corresponding
benzyl ester 6c was obtained in 90% yield (entry 4).
tert-Butyl 5-Oxo-1-phenyl-2-(trifluoromethyl)tetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2a); Typical
Procedure
MAF-TBE (35.8 mL, 0.20 mmol) was added slowly to a stirred soln
of azomethine imine 1a (17.4 mg, 0.10 mmol) in CH2Cl2 (1.0 mL)
at r.t. under N2, and the mixture was stirred for 20 h. The solvent
was then removed under vacuum, and the crude product was puri-
fied by column chromatography [silica gel, hexane–EtOAc (6:4)] to
give a white solid; yield: 35.7 mg (96%); dr = 62:38; mp 92.8–
93.9 °C.
IR (KBr): 2985, 1726, 1457, 1370, 1335, 1301, 1261, 1171, 1137,
842, 743, 729, 700 cm–1.
In summary, we have established a convenient, simple,
expeditious, and inexpensive procedure for the prepara-
tion of novel trifluoromethylated bicyclic pyrazolidinone
systems by the noncatalytic 1,3-dipolar cyclization of
azomethine imines with MAF-TBE or related com-
pounds. Further work is proceeding to develop asymmet-
ric variants of the reaction, and efforts to incorporate this
method into syntheses of peptidomimetics are underway.
1H NMR (200 MHz, CDCl3): d = 7.47–7.32 (m, total 5 H, Ar-H),
4.48 (d, J = 12.8 Hz, 62/100 × 1 H, CH2), 4.29 (d, J = 12.4 Hz, 38/
100 × 1 H, CH2), 4.21 (s, 62/100 × 1 H, Ar-CH), 4.08 (d, J = 12.4
Hz, 38/100 × 1 H, CH2), 3.97 (s, 38/100 × 1 H, Ar-CH), 3.66–3.49
(m, total 1 H + 62/100 × 1 H, CH2), 3.06–2.92 (m, total 1 H, CH2),
2.85–2.61 (m, total 2 H, CH2), 1.52 (s, 62/100 × 9 H, t-Bu), 1.02 (s,
38/100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –66.1 (s, 62/100 × 3 F), –69.5 (s,
38/100 × 3 F).
13C NMR (50.3 MHz, CDCl3): d = 174.7, 174.2, 166.0, 163.4,
133.4, 132.1, 129.0, 128.8, 128.7, 128.6, 128.3, 128.1, 124.0 (q,
J = 282 Hz), 119.7 (q, J = 280 Hz), 84.7, 83.8, 73.1, 72.1, 66.5 (q,
J = 24.6 Hz), 65.9 (q, J = 24.3 Hz), 47.1, 46.4, 45.4, 45.2, 30.0,
29.9, 27.9, 27.3.
All reactions were performed in oven-dried glassware under a pos-
itive pressure of N2. Solvents were transferred by syringe and were
introduced into the reaction vessels though rubber septa. All reac-
tions were monitored by TLC on 0.25 mm Merck silica gel (60-
F254). The TLC plates were visualized with UV light and 7% phos-
phomolybdic acid or aq KMnO4 with heating. Column chromatog-
raphy was carried out on a column packed with silica gel (60N
MS (EI): m/z = 370 [M]+.
Synthesis 2010, No. 19, 3274–3281 © Thieme Stuttgart · New York

PAPER
Cyclization of Azomethine Imines with (a-Trifluoromethyl)acrylates
3277
HRMS (EI): m/z calcd for C18H21F3N2O3: 370.1504; found:
370.1519.
(s, total 6 H, CH3 × 2), 1.52 (s, 64/100 × 9 H, t-Bu), 1.02 (s, 36/
100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –66.1 (s, 64/100 × 3 F), –69.5 (s,
tert-Butyl 1-(4-Methylphenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2b)
White solid; yield: 95%; dr = 64:36; mp 91.0–92.3 °C.
36/100 × 3 F).
13C NMR (151 MHz, CDCl3): d = 174.8, 174.4, 166.4, 163.8, 137.5,
137.2, 136.6, 136.4, 130.9, 130.8, 130.1, 129.6, 129.6, 129.5, 126.8,
125.5 (q, J = 282 Hz), 126.3, 123.8 (q, J = 284 Hz), 84.6, 83.6, 73.4,
72.2, 66.5 (q, J = 24.1 Hz), 65.9 (q, J = 23.7 Hz), 46.9, 46.2, 45.4,
45.2, 30.0, 29.8, 27.7, 27.1, 19.7, 19.6, 19.5, 19.4.
IR (KBr): 2978, 1715, 1516, 1456, 1370, 1259, 1182, 1076, 1054,
834, 762, 609 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.30 (m, total 2 H, Ar-H),
7.16–7.14 (m, total 2 H, Ar-H), 4.47 (d, J = 12.6 Hz, 64/100 × 1 H,
CH2), 4.27 (d, J = 12.3 Hz, 36/100 × 1 H, CH2), 4.16 (s, 64/100 × 1
H, Ar-CH), 4.07 (d, J = 12.3 Hz, 36/100 × 1 H, CH2), 3.94 (s, 36/
100 × 1 H, Ar-CH), 3.63–3.50 (m, total 1 H + 64/100 × 1 H, CH2),
3.02–2.92 (m, total 1 H, CH2), 2.78–2.60 (m, total 2 H, CH2), 2.35
(s, total 3 H, CH3), 1.51 (s, 64/100 × 9 H, t-Bu), 1.03 (s, 36/100 × 9
H, t-Bu).
19F NMR (282 MHz, CDCl3): d = –66.3 (s, 64/100 × 3 F), –69.6 (s,
36/100 × 3 F).
13C NMR (75.5 MHz, CDCl3): d = 174.7, 174.3, 166.2, 163.7,
138.8, 138.5, 130.4, 129.0, 128.9, 128.7, 125.4 (q, J = 281 Hz),
124.2 (q, J = 283 Hz), 84.7, 83.8, 73.1, 72.0, 65.8 (q, J = 24.2 Hz),
47.0, 46.4, 45.4, 45.2, 30.1, 29.9, 27.8, 27.2, 21.3, 21.2 (one carbon
atom resonance was not detected).
MS (EI): m/z = 398 [M]+.
HRMS (EI): m/z calcd for C20H25F3N2O3: 398.1817; found:
398.1822.
tert-Butyl 1-(4-Methoxyphenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2e)
Pale yellow oil; yield: 97%; dr = 65:35.
IR (neat): 2979, 2937, 1731, 1515, 1461, 1395, 1371, 1304, 1218,
1081, 838 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.41–7.34 (m, total 2 H, Ar-H),
6.89–6.86 (m, total 2 H, Ar-H), 4.47 (d, J = 12.6 Hz, 65/100 × 1 H,
CH2), 4.26 (d, J = 12.3 Hz, 35/100 × 1 H, CH2), 4.14 (s, 65/100 × 1
H, Ar-CH), 4.06 (d, J = 12.9 Hz, 35/100 × 1 H, CH2), 3.93 (s, 35/
100 × 1 H, Ar-CH), 3.81 (s, 35/100 × 3 H,OCH3), 3.80 (s, 65/
100 × 3 H, OCH3), 3.63–3.49 (m, total 1 H + 65/100 × 1 H, CH2),
3.02–2.92 (m, total 1 H, CH2), 2.78–2.60 (m, total 2 H, CH2), 1.51
(s, 65/100 × 9 H, t-Bu), 1.06 (s, 35/100 × 9 H, t-Bu).
MS (EI): m/z = 384 [M]+.
HRMS (EI): m/z calcd for C19H23F3N2O3: 384.1661; found:
384.1674.
19F NMR (282 MHz, CDCl3): d = –66.3 (s, 65/100 × 3 F), –69.6 (s,
tert-Butyl 1-(4-Isopropylphenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2c)
Pale yellow oil; yield: 79%; dr = 63:37.
35/100 × 3 F).
13C NMR (75.5 MHz, CDCl3): d = 174.7, 174.3, 166.2, 163.7,
160.0, 159.7, 130.3, 130.0, 125.4 (q, J = 281 Hz), 125.3, 124.2 (q,
J = 283 Hz), 123.9, 113.8, 113.6, 84.6, 83.7, 72.9, 71.8, 66.4 (q,
J = 24.5 Hz), 65.6 (q, J = 23.9 Hz), 55.4, 55.2, 46.8, 46.4, 45.3,
45.1, 30.2, 29.8, 27.8, 27.3.
IR (neat): 2963, 1731, 1461, 1370, 1304, 1257, 1170, 1080, 839,
610 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.34 (m, total 2 H, Ar-H),
7.21–7.18 (m, total 2 H, Ar-H), 4.46 (d, J = 12.3 Hz, 63/100 × 1 H,
CH2), 4.27 (d, J = 12.3 Hz, 37/100 × 1 H, CH2), 4.18 (s, 63/100 × 1
H, Ar-CHN), 4.07 (d, J = 12.3 Hz, 37/100 × 1 H, CH2), 3.96 (s, 37/
100 × 1 H, Ar-CH), 3.64–3.51 (m, total 1 H + 63/100 × 1 H, CH2),
3.05–2.86 [m, total 2 H, CH2, (CH3)2CH], 2.78–2.61 (m, total 2 H,
CH2), 1.52 (s, 63/100 × 9 H, t-Bu), 1.25 (d, J = 10.2 Hz, 63/100 × 6
H, CH3 × 2), 1.24 (d, J = 10.5 Hz, 37/100 × 6 H, CH3 × 2), 1.01 (s,
37/100 × 9 H, t-Bu).
MS (EI): m/z = 400 [M]+.
HRMS (EI): m/z calcd for C19H23F3N2O4: 400.1610; found:
400.1611.
tert-Butyl 1-(2-Methoxyphenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2f)
Colorless oil; yield: 89%; dr = 58:42.
19F NMR (282 MHz, CDCl3): d = –66.3 (s, 63/100 × 3 F), –69.6 (s,
37/100 × 3 F).
IR (neat): 2978, 1731, 1602, 1590, 1494, 1463, 1369, 1305, 1254,
1189, 1078, 1049, 1027, 759 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.60–7.30 (m, total 2 H, Ar-H),
7.02–6.83 (m, total 2 H, Ar-H), 4.59–4.56 (m, total 1 H, CH2, Ar-
H), 4.34 (d, J = 12.6 Hz, 58/100 × 1 H, CH2), 4.24 (s, 42/100 × 1 H,
Ar-CH), 4.13 (d, 42/100 × 1 H, J = 12.4 Hz, CH2), 3.81 (s, 42/
100 × 3 H, OCH3), 3.74 (s, 58/100 × 3 H, OCH3), 3.69–3.40 (m, to-
tal 1 H + 58/100 × 1 H, CH2), 3.15–2.93 (m, total 1 H, CH2), 2.79–
2.49 (m, total 2 H, CH2), 1.55 (s, 58/100 × 9 H, t-Bu), 1.06 (s, 42/
100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –68.4 (s, 58/100 × 3 F), –69.3 (s,
42/100 × 3 F).
13C NMR (150.9 MHz, CDCl3): d = 177.3, 167.1, 167.1, 164.0,
158.5, 158.2, 129.9, 129.8, 129.5, 128.3, 124.3 (q, J = 283 Hz),
125.5 (q, J = 280 Hz), 122.6, 121.9, 120.7, 120.6, 110.4, 110.0,
83.7, 83.5, 67.8, 66.4 (q, J = 24.5 Hz), 64.1 (q, J = 23.4 Hz), 55.3,
55.1, 48.9, 48.9, 46.4, 45.4, 44.7, 43.9, 30.2, 29.1, 27.7, 27.2.
13C NMR (75.5 MHz, CDCl3): d = 174.8, 174.4, 166.2, 163.6,
149.7, 149.3, 131.0, 129.8, 129.0, 128.7, 126.4, 126.2, 125.4 (q,
J = 280 Hz), 124.1 (q, J = 283 Hz), 84.6, 83.7, 73.1, 72.0, 66.4 (q,
J = 24.8 Hz), 65.7 (q, J = 24.2 Hz), 47.0, 46.3, 45.4, 45.2, 34.0,
33.9, 30.0, 29.9, 27.8, 27.2, 24.1, 24.0, 24.0, 23.9.
MS (EI): m/z = 412 [M]+.
HRMS (EI): m/z calcd for C21H27F3N2O3: 412.1974; found:
412.1971.
tert-Butyl 1-(3,4-Dimethylphenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2d)
Pale yellow oil; yield: 91%; dr = 64:36.
IR (neat): 2979, 2937, 1731, 1714, 1504, 1456, 1395, 1370, 1352,
1301, 1217, 1144, 1083, 840 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.21–7.08 (m, total 3 H, Ar-H),
4.47 (d, J = 12.6 Hz, 64/100 × 1 H, CH2), 4.26 (d, J = 12.6 Hz, 36/
100 × 1 H, CH2), 4.12–4.03 (m, total 1 H, Ar-CH, CH2), 3.91 (s, 36/
100 × 1 H, Ar-CH), 3.64–3.48 (m, total 1 H + 64/100 × 1 H, CH2),
3.05–2.91 (m, total 1 H, CH2), 2.84–2.57 (m, total 2 H, CH2), 2.26
MS (EI): m/z = 400 [M]+.
HRMS (EI): m/z calcd for C19H23F3N2O4: 400.1610; found:
400.1613.
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tert-Butyl 1-(3-Methoxyphenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2g)
Colorless oil; yield: 94%; dr = 62:38.
13C NMR (151 MHz, CDCl3): d = 174.9, 174.5, 166.2, 163.6, 135.1,
134.7, 132.4, 131.1, 130.6, 130.4, 128.7, 128.6, 124.2 (q, J = 284
Hz), 124.1 (q, J = 288 Hz), 85.0, 84.2, 72.2, 71.5, 66.6 (q, J = 24.9
Hz), 66.0 (q, J = 24.4 Hz), 46.8, 46.4, 45.4, 45.1, 29.8, 29.6, 27.7,
27.2.
IR (neat): 2979, 1731, 1602, 1586, 1491, 1457, 1370, 1301, 1155,
1080, 1051, 840, 698 cm–1.
MS (EI): m/z = 404 [M]+.
1H NMR (200 MHz, CDCl3): d = 7.30–7.21 (m, total 1 H, Ar-H),
7.07–7.02 (m, total 2 H, Ar-H), 6.90–6.86 (m, total 1 H, Ar-H), 4.46
(d, J = 12.6 Hz, 62/100 × 1 H, CH2), 4.28 (d, J = 12.4 Hz, 38/
100 × 1 H, CH2), 4.19 (s, 62/100 × 1 H, Ar-CH), 4.09 (d, J = 12.6
Hz, 38/100 × 1 H, CH2), 3.94 (s, 38/100 × 1 H, Ar-CH), 3.80 (s, to-
tal 3 H, OCH3), 3.68–3.44 (m, total 1 H + 62/100 × 1 H, CH2), 3.08–
2.95 (m, total 1 H, CH2), 2.85–2.52 (m, total 2 H, CH2), 1.52 (s, 62/
100 × 9 H, t-Bu), 1.05 (s, 38/100 × 9 H, t-Bu).
1F NMR (188 MHz, CDCl3): d = –66.1 (s, 62/100 × 3 F), –69.5 (s,
38/100 × 3 F).
13C NMR (151 MHz, CDCl3): d = 175.0, 174.5, 166.3, 163.7, 159.8,
159.6, 135.2, 133.9, 129.5, 129.2, 125.5 (q, J = 282 Hz), 124.3 (q,
J = 285 Hz), 121.7, 121.4, 121.4, 115.0, 114.5, 114.3, 84.7, 83.8,
73.1, 72.1, 66.5 (q, J = 24.1 Hz), 64.0 (q, J = 24.1 Hz), 55.3, 55.2,
47.0, 46.3, 45.4, 45.2, 29.8, 29.8, 27.7, 27.2.
HRMS (EI): m/z calcd for C18H20ClF3N2O3: 404.1115; found:
404.1128.
tert-Butyl 1-(3,5-Dibromophenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2j)
Pale yellow oil: yield 84%; dr = 52:48.
IR (neat): 2980, 1731, 1714, 1585, 1557, 1426, 1371, 1349, 1299,
1256, 1173, 1084, 837, 742 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.67–7.50 (m, total 3 H, Ar-H),
4.50 (d, J = 12.8 Hz, 52/100 × 1 H, CH2), 4.29 (d, J = 12.4 Hz, 48/
100 × 1 H, CH2), 3.69–3.53 (m, total 1 H, Ar-CH, CH2) 3.88 (s, 48/
100 × 1 H, Ar-CH), 3.69–3.53 (m, total 1 H + 52/100 × 1 H, CH2),
3.03–2.89 (m, total 1 H, CH2), 2.78–2.56 (m, total 2 H, CH2), 1.53
(s, 52/100 × 9 H, t-Bu), 1.12 (s, 48/100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –66.0 (s, 52/100 × 3 F), –69.6 (s,
48/100 × 3 F).
13C NMR (151 MHz, CDCl3): d = 174.7, 174.5, 165.9, 163.1, 138.2,
136.7, 134.5, 131.0, 125.3 (q, J = 281 Hz), 125.3, 124.0 (q, J = 286
Hz), 123.2, 122.8, 122.8, 85.5, 84.6, 71.4, 70.7, 66.7 (q, J = 25.0
Hz), 66.4 (q, J = 24.9 Hz), 46.7, 46.4, 45.6, 45.3, 29.7, 29.5, 27.7,
27.3.
MS (EI): m/z = 400 [M]+.
HRMS (EI): m/z calcd for C19H23F3N2O4: 400.1610; found:
400.1620.
tert-Butyl 1-(4-Bromophenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2h)
White solid; yield: 86%; dr = 59:41; mp 107.8–109.1 °C.
IR (KBr): 2979, 1737, 1490, 1368, 1304, 1256, 1170, 1146, 1077,
1012, 838 cm–1.
MS (ESI): m/z = 526 [M + H]+.
HRMS (EI): m/z [M + H]+ calcd for C18H19Br2F3N2O3: 525.9715;
1H NMR (200 MHz, CDCl3): d = 7.52–7.32 (m, total 4 H, Ar-H),
4.4 (d, J = 12.8 Hz, 59/100 × 1 H, CH2), 4.28 (d, J = 12.2 Hz, 41/
100 × 1 H, CH2), 4.16 (s, 59/100 × 1 H, Ar-CH), 4.05 (d, J = 12.4
Hz, 41/100 × 1 H, CH2), 3.93 (s, 41/100 × 1 H, Ar-CH), 3.66–3.49
(m, total 1 H + 59/100 × 1 H, CH2), 3.02–2.84 (m, total 1 H, CH2),
2.78–2.61 (m, total 2 H, CH2), 1.51 (s, 59/100 × 9 H, t-Bu), 1.06 (s,
41/100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –66.2 (s, 59/100 × 3 F), –69.6 (s,
41/100 × 3 F).
13C NMR (151 MHz, CDCl3): d = 174.8, 174.4, 166.2, 163.5, 132.9,
131.7, 131.6, 131.5, 130.9, 130.7, 125.4 (q, J = 281 Hz), 124.2 (q,
J = 284 Hz), 123.2, 122.9, 85.0, 84.2, 72.3, 71.5, 66.6 (q, J = 24.7
Hz), 66.0 (q, J = 24.4 Hz), 46.8, 46.4, 45.4, 45.1, 29.8, 29.6, 27.7,
27.2.
found: 525.9726.
tert-Butyl 1-(1-Naphthyl)-5-oxo-2-(trifluoromethyl)tetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2k)
Pale yellow oil; yield: 92%; dr = 69:31.
IR (neat): 2979, 1732, 1596, 1458, 1371, 1301, 1260, 1188, 1077,
838, 786 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.06–7.40 (m, total 7 H, Ar-H),
5.06 (s, 69/100 × 1 H, Ar-CH), 4.86 (s, 31/100 × 1 H, Ar-CH),
4.51–3.45 (m, total 3 H, CH2), 3.09–1.58 (m, total 3 H, CH2), 1.58
(s, 69/100 × 9 H, t-Bu), 0.75 (s, 31/100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –66.8 (s, 69/100 × 3 F), –68.4 (s,
31/100 × 3 F).
13C NMR (151 MHz, CDCl3): d = 176.8, 173.6, 167.6, 163.4, 133.7,
133.6, 132.6, 132.4, 130.6, 129.5, 129.3, 129.2, 128.9, 128.9, 127.7,
127.3, 126.6, 126.4, 125.8, 125.6, 125.5, 125.4, 125.3 (q, J = 281
Hz), 124.2 (q, J = 283 Hz), 122.5, 122.4, 85.0, 83.7, 69.7, 67.1 (q,
J = 25.0 Hz), 65.4 (q, J = 24.4 Hz), 49.1, 46.1, 46.1, 45.0, 30.4,
29.2, 27.6, 26.9.
MS (EI): m/z = 448 [M]+.
HRMS (EI): m/z calcd for C18H20BrF3N2O3: 448.0609; found:
448.0613.
tert-Butyl 1-(4-Chlorophenyl)-5-oxo-2-(trifluoromethyl)tet-
rahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2i)
White solid; yield: 87%; dr = 61:39; mp 108.3–110.0 °C.
MS (EI): m/z = 420 [M]+.
HRMS (EI): m/z calcd for C22H23F3N2O3: 420.1661; found:
420.1677.
IR (KBr): 2979, 1739, 1710, 1493, 1367, 1304, 1257, 1170, 1146,
1078, 838 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.48–7.25 (m, total 4 H, Ar-H),
4.47 (d, J = 12.6 Hz, 61/100 × 1 H, CH2), 4.28 (d, J = 12.4 Hz, 39/
100 × 1 H, CH2), 4.18 (s, 61/100 × 1 H, Ar-CH), 4.06 (d, J = 12.4
Hz, 39/100 × 1 H, CH2), 3.94 (s, 39/100 × 1 H, Ar-CH), 3.64–3.49
(m, total 1 H + 61/100 × 1 H, CH2), 3.02–2.89 (m, total 1 H, CH2),
2.85–2.61 (m, total 2 H, CH2), 1.51 (s, 61/100 × 9 H, t-Bu), 1.06 (s,
39/100 × 9 H, t-Bu).
tert-Butyl 1-(2-Naphthyl)-5-oxo-2-(trifluoromethyl)tetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2l)
Pale yellow oil; yield: 85%; dr = 63:37.
IR (neat): 2979, 1731, 1714, 1457, 1371, 1345, 1301, 1257, 1218,
1171, 1084, 838, 737 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.99–7.80 (m, total 4 H, Ar-H),
7.59–7.47 (m, total 3 H, Ar-H), 4.53 (d, J = 12.8 Hz, 63/100 × 1 H,
CH2), 4.37–4.30 (m, total 1 H, CH2, Ar-CH), 4.18–4.09 (m, 37/
19F NMR (188 MHz, CDCl3): d = –66.1 (s, 61/100 × 3 F), –69.5 (s,
39/100 × 3 F).
Synthesis 2010, No. 19, 3274–3281 © Thieme Stuttgart · New York

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Cyclization of Azomethine Imines with (a-Trifluoromethyl)acrylates
3279
100 × 2 H, CH2, Ar-H), 3.71–3.53 (m, total 1 H + 63/100 × 1 H,
CH2), 1.54 (s, 63/100 × 9 H, t-Bu), 0.83 (s, 37/100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –66.0 (s, 63/100 × 3 F), –69.4 (s,
37/100 × 3 F).
13C NMR (151 MHz, CDCl3): d = 175.0, 174.5, 166.4, 163.7, 133.6,
133.5, 133.1, 133.1, 131.1, 129.9, 128.6, 128.1, 128.1, 128.1, 127.9,
127.7, 127.6, 126.7, 126.5, 126.3, 124.3 (q, J = 283 Hz), 84.8, 83.9,
73.3, 72.4, 66.8 (q, J = 26.3 Hz), 66.2 (q, J = 26.3 Hz), 47.0, 46.4,
45.5, 45.3, 29.9, 29.7, 27.8, 27.0 (one carbon atom resonance was
not detected).
tert-Butyl 5-Oxo-1-styryl-2-(trifluoromethyl)tetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2o)
Pale yellow solid; yield: 97%; dr = 75:25; mp 82.4–84.1 °C.
IR (KBr): 2983, 1740, 1709, 1456, 1368, 1263, 1231, 1173, 1084,
841, 744, 693 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.30 (m, total 5 H, Ar-H),
6.76 (d, J = 15.9, total 1 H, Ar-CH), 6.74 (d, J = 15.9, total 1 H, Ar-
CH), 6.19–6.00 (m, total 1 H, ArCH=CH), 4.42 (d, J = 12.9 Hz, 75/
100 × 1 H, CH2), 4.22 (d, J = 12.3, 25/100 × 2 H, CH2), 3.99 (d,
J = 12.3, 25/100 × 2 H, CH2), 3.68 (d, J = 8.1 Hz, 75/100 × 1 H,
ArCH=CHCH), 3.63–3.50 (m, total 2 H, CH2, ArCH=CHCH),
3.22–3.13 (m, total 1 H, CH2), 2.80–2.58 (m, total 2 H, CH2), 1.49
(s, 75/100 × 9 H, t-Bu), 1.37 (s, 25/100 × 9 H, t-Bu).
19F NMR (282 MHz, CDCl3): d = –66.1 (s, 75/100 × 3 F), –69.8 (s,
25/100 × 3 F).
13C NMR (75.5 MHz, CDCl3): d = 174.8, 174.6, 165.8, 164.3,
137.3, 136.4, 135.8, 135.4, 128.8, 128.7, 128.7, 128.5, 126.8, 126.6,
125.2 (q, J = 281 Hz), 124.5 (q, J = 284 Hz), 121.4, 120.7, 84.7,
84.5, 72.7, 70.9, 65.4 (q, J = 25.4 Hz), 64.9 (q, J = 24.4 Hz), 46.2,
44.8, 30.0, 29.7, 27.8, 27.7.
MS (EI): m/z = 420 [M]+.
HRMS (EI): m/z calcd for C22H23F3N2O3: 420.1661; found:
420.1656.
tert-Butyl 1-(2-Furyl)-5-oxo-2-(trifluoromethyl)tetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2m)
White solid; yield: 92%; dr = 63:37; mp 93.3–95.2 °C.
IR (KBr): 2981, 1740, 1459, 1350, 1288, 1144, 1089, 1039, 768,
755, 719 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.43 (m, total 1 H, Ar-H),
6.48–6.39 (m, total 2 H, Ar-H), 4.44 (d, J = 12.4 Hz, 63/100 × 1 H,
CH2), 4.35 (s, 63/100 × 1 H, Ar-CH), 4.20–4.15 (m, 37/100 × 3 H,
Ar-CH, CH2), 3.68 (d, J = 12.4 Hz, 63/100 × 1 H, CH2), 3.54–3.44
(m, total 1 H, CH2), 3.21–3.08 (m, total 1 H, CH2), 2.80–2.57 (m,
total 2 H, CH2), 1.51 (s, 63/100 × 9 H, t-Bu), 1.24 (s, 37/100 × 9 H,
t-Bu).
MS (EI): m/z = 396 [M]+.
HRMS (EI): m/z calcd for C20H23F3N2O3: 396.1661; found:
396.1678.
Methyl 2-Methyl-5-oxo-1-phenyltetrahydro-1H,5H-pyrazo-
lo[1,2-a]pyrazole-2-carboxylate (3a)
Colorless oil; yield: 23%; dr = 71:29.
19F NMR (282 MHz, CDCl3): d = –67.9 (s, 63/100 × 3 F), –69.9 (s,
37/100 × 3 F).
IR (neat): 3473, 2987, 2951, 2842, 1739, 1415, 1285, 1234, 1126,
1081, 986, 776, 750, 703 cm–1.
13C NMR (75.5 MHz, CDCl3): d = 174.5, 174.3, 165.4, 163.2,
146.9, 145.8, 143.2, 124.9 (q, J = 282 Hz), 123.8 (q, J = 282 Hz),
110.9, 110.7, 110.6, 84.8, 84.1, 66.9, 65.5, 65.0 (q, J = 24.8 Hz),
46.4, 45.7, 45.2, 44.8, 30.2, 30.0, 27.7, 27.4 (one carbon atom reso-
nance was not detected).
1H NMR (300 MHz, CDCl3): d = 7.37–7.28 (m, total 5 H, Ar-H),
3.84 (s, 29/100 × 3 H, OCH3), 3.82 (s, 71/100 × 3 H, OCH3), 3.66–
3.36 (m, total 2 H, CH2, ArCH), 3.07–2.89 (m, total 1 H, CH2),
2.82–2.55 (m, total 4 H, CH2), 1.90 (s, 71/100 × 3 H, CH3), 1.73 (s,
29/100 × 3 H, CH3).
13C NMR (151 MHz, CDCl3): d = 172.4, 171.9, 164.6, 163.6, 136.6,
136.3, 128.7, 128.4, 128.3, 127.2, 127.1, 69.2, 69.2, 60.8, 60.7,
53.1, 53.0, 52.6, 51.9, 51.8, 51.1, 36.7, 36.1, 22.3, 22.1 (one carbon
atom resonance was not detected).
MS (EI): m/z = 360 [M]+.
HRMS (EI): m/z calcd for C16H19F3N2O4 : 360.1297; found:
360.1311.
tert-Butyl 5-Oxo-1-(2-thienyl)-2-(trifluoromethyl)tetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (2n)
White solid; yield: 96%; dr = 64:36; mp 93.8–95.1 °C.
MS (EI): m/z = 274 [M]+.
HRMS (EI): m/z calcd for C15H18N2O3: 274.1317; found: 274.1313.
IR (KBr): 2979, 1728, 1459, 1372, 1348, 1297, 1251, 1219, 1147,
1085, 837, 786, 731, 709 cm–1.
tert-Butyl 6-(Benzoylamino)-5-oxo-1,7-diphenyl-2-(trifluoro-
methyl)tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxy-
late (5a)
1H NMR (200 MHz, CDCl3): d = 7.35–7.00 (m, total 3 H, Ar-H),
4.51–4.45 (m, CH2, 64/100 × 2 H, Ar-H), 4.31–4.25 (m, 36/100 × 2
H, CH2, Ar-H), 4.14 (d, J = 12.4 Hz, 36/100 × 1 H, CH2), 3.72–3.56
(m, total 1 H + 64/100 × H, CH2), 3.17–2.61 (m, total 1 H, CH2),
2.75–2.61 (m, total 2 H, CH2), 1.52 (s, 64/100 × 9 H, t-Bu), 1.14 (s,
36/100 × 9 H, t-Bu).
19F NMR (188 MHz, CDCl3): d = –66.6 (s, 64/100 × 3 F), –69.7 (s,
36/100 × 3 F).
13C NMR (151 MHz, CDCl3): d = 174.5, 174.4, 166.0, 163.5, 136.1,
134.2, 128.1, 128.1, 127.1, 126.8, 126.5, 126.5, 125.3 (q, J = 281
Hz), 124.1 (q, J = 284 Hz), 85.0, 84.1, 69.2, 68.1, 66.5 (q, J = 24.9
Hz), 65.6 (q, J = 23.4 Hz), 46.5, 46.3, 45.7, 45.4, 29.8, 29.6, 27.7,
27.2.
White solid; yield: 94%; dr = 70:20:8:2; mp 120.5–123.2 °C.
IR (KBr): 3381, 2977, 1739, 1699, 1666, 1538, 1458, 1371, 1305,
1262, 1193, 1087, 699 cm–1.
1H NMR (300 MHz, CDCl3): 7.71–6.92 (m, total 15 H, Ar-H),
5.23–5.14 (m, total 1 H, COCH), 4.78–4.52 (m, total 2 H, ArCHN,
PhCHN), 4.19–3.95 (m, total 2 H, CH2), 1.59 (s, 28/100 × 9 H, t-
Bu), 1.58 (s, 28/100 × 9 H, t-Bu), 1.02 (s, 72/100 × 9 H, t-Bu), 0.98
(s, 72/100 × 9 H, t-Bu).
19F NMR (282 MHz, CDCl3): d = –64.8 (s, 20/100 × 3 F), –65.7 (s,
8/100 × 3 F), –69.3 (s, 2/100 × 3 F), –69.8 (s, 70/100 × 3 F).
MS (EI): m/z = 565 [M]+.
MS (EI): m/z = 376 [M]+.
HRMS (EI): m/z calcd for C31H30F3N3O4: 565.2188; found:
HRMS (EI): m/z calcd for C16H19F3N2O3S: 376.1068; found:
565.2208.
376.1065.
The 13C NMR spectrum of this compound is provided in the
Supporting Information.
Synthesis 2010, No. 19, 3274–3281 © Thieme Stuttgart · New York

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tert-Butyl 6-(Benzoylamino)-1-(4-methylphenyl)-5-oxo-7-phe-
nyl-2-(trifluoromethyl)tetrahydro-1H,5H-pyrazolo[1,2-a]pyra-
zole-2-carboxylate (5b)
tert-Butyl 6-(Benzoylamino)-1-(4-nitrophenyl)-5-oxo-7-phenyl-
2-(trifluoromethyl)tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-
2-carboxylate (5e)
White solid; yield: 90%; dr = 72:20:6:2; mp 117.0–119.4 °C.
Yellow solid; yield: 71%; dr = 60:23:11:6; mp 190.7–194.5 °C.
IR (KBr): 3322, 2981, 1740, 1716, 1653, 1541, 1457, 1302, 1251,
1153, 841, 697 cm–1.
IR (KBr): 3447, 3065, 2981, 1735, 1716, 1524, 1349, 1301, 1251,
1151, 833, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70–7.59 (m, total 2 H, Ar-H),
7.48–7.14 (m, total 10 H, Ar-H), 6.94–6.65 (m, total 2 H, Ar-H),
5.18–5.11 (m, total 1 H, COCH), 4.91–4.30 (m, total 2 H, ArCHN,
PhCHN), 4.10–3.78 (m, total 2 H, CH2), 2.37 (s, total 3 H, CH3),
2.32 (s, total 3 H, CH3), 2.20 (s, total 3 H, CH3), 1.80 (s, total 1 H,
NH), 1.57 (s, 26/100 × 9 H, t-Bu), 1.54 (s, 26/100 × 9 H, t-Bu), 1.04
(s, 74/100 × 9 H, t-Bu), 1.00 (s, 74/100 × 9 H, t-Bu).
19F NMR (282 MHz, CDCl3): d = –65.3 (s, 20/100 × 3 F), –66.3 (s,
6/100 × 3 F), –69.9 (s, 2/100 × 3 F), –70.4 (s, 72/100 × 3 F).
MS (EI): m/z = 579 [M]+.
1H NMR (300 MHz, CDCl3): d = 8.38–7.74 (m, total 4 H, Ar-H),
7.45–7.06 (m, total 10 H, Ar-H), 5.31–4.98 (m, total 1 H, COCH),
4.87–4.47 (m, total 2 H, ArCHN, PhCHN), 4.27–3.83 (m, total 2 H,
CH2), 3.75 (s, total 1 H, NH), 3.36 (s, total 1 H, NH), 1.64 (s, 34/
100 × 9 H, t-Bu), 1.59 (s, 34/100 × 9 H, t-Bu), 1.05 (s, 66/100 × 9
H, t-Bu), 0.99 (s, 66/100 × 9 H, t-Bu).
19F NMR (282 MHz, CDCl3): d = –64.8 (s, 23/100 × 3 F), –66.0 (s,
11/100 × 3 F), –69.4 (s, 6/100 × 3 F), –70.1 (s, 60/100 × 3 F).
MS (EI): m/z = 610 [M]+.
HRMS (EI): m/z calcd for C31H29F3N4O6: 610.2039; found:
HRMS (EI): m/z calcd for C32H32F3N3O4: 579.2345; found:
610.2028.
579.2368.
The 13C NMR spectrum of this compound is provided in the
Supporting Information.
The 13C NMR spectrum of this compound is provided in the
Supporting Information.
Benzyl 6-(Benzoylamino)-1-(4-methoxyphenyl)-5-oxo-7-phe-
nyl-2-(trifluoromethyl)tetrahydro-1H,5H-pyrazolo[1,2-a]pyra-
zole-2-carboxylate (6c)
tert-Butyl 6-(Benzoylamino)-1-(4-methoxyphenyl)-5-oxo-7-phe-
nyl-2-(trifluoromethyl)tetrahydro-1H,5H-pyrazolo[1,2-a]pyra-
zole-2-carboxylate (5c)
White solid; yield: 90%; dr = 37:7:38:18; mp 89.8–93.8 °C.
White solid; yield: 80%; dr = 69:22:6:3; mp 119.3–122.4 °C.
IR (KBr): 3324, 3033, 2958, 1745, 1654, 1515, 1456, 1253, 1179,
1073, 1031, 749, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.86–6.44 (m, total 19 H, Ar-H),
5.46–5.31 (m, total 1 H, COCH), 5.28–3.99 (m, total 6 H, ArCHN,
PhCHN, NCH2, PhCH2), 3.83 (s, total 3 H, OCH3), 3.75 (s, total 3
H, OCH3), 3.67 (s, total 3 H, OCH3), 3.67 (s, total 3 H, OCH3).
IR (KBr): 3322, 3064, 2979, 1739, 1714, 1669, 1515, 1457, 1302,
1253, 837, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.60 (m, total 2 H, Ar-H),
7.43–7.17 (m, total 8 H, Ar-H), 6.97–6.57 (m, total 4 H, Ar-H),
5.16–5.09 (m, total 1 H, COCH), 4.86–4.52 (m, total 2 H, ArCHN,
PhCHN), 4.12–3.93 (m, total 2 H, CH2), 3.83 (s, total 3 H, MeO),
3.78 (s, total 3 H, MeO), 3.68 (s, total 1 H, NH), 1.81 (s, 28/100 × 9
H, t-Bu), 1.07 (s, 72/100 × 9 H, t-Bu), 1.03 (s, 72/100 × 9 H, t-Bu).
19F NMR (282 MHz, CDCl3): d = –65.2 (s, 7/100 × 3 F), –66.3 (s,
38/100 × 3 F), –69.4 (s, 18/100 × 3 F), –70.0 (s, 37/100 × 3 F).
MS (EI): m/z = 629 [M]+.
19F NMR (282 MHz, CDCl3): d = –64.9 (s, 22/100 × 3 F), –66.0 (s,
HRMS (EI): m/z calcd for C35H30F3N3O5: 629.2138; found:
629.2141.
The 13C NMR spectrum of this compound is provided in the
Supporting Information.
6/100 × 3 F), –69.5 (s, 3/100 × 3 F), –70.0 (s, 69/100 × 3 F).
MS (EI): m/z = 595 [M]+.
HRMS (EI): m/z calcd for C32H32F3N3O5: 595.2294; found:
595.2299.
The 13C NMR spectrum of this compound is provided in the
Supporting Information.
Supporting Information for this article (13C NMR spectra of
compounds 5a–e and 6c) is available online at http://www.thieme-
connect.com/ejournals/toc/synthesis.
tert-Butyl 6-(Benzoylamino)-1-(4-bromophenyl)-5-oxo-7-phe-
nyl-2-(trifluoromethyl)tetrahydro-1H,5H-pyrazolo[1,2-a]pyra-
zole-2-carboxylate (5d)
Acknowledgment
White solid; yield: 38%; dr = 67:19:10:4; mp 194.8–198.3 °C.
This study was financially supported in part by Kakenhi (21390030,
22106515). We also thank TOSOH F-TECH Inc. for their gift of
MAF-TBE.
IR (KBr): 3382, 2979, 1737, 1706, 1665, 1540, 1457, 1305, 1251,
837, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69–7.63 (m, total 2 H, Ar-H),
7.46–7.11 (m, total 12 H, Ar-H), 5.16–5.10 (m, total 1 H, COCH),
4.71–4.44 (m, total 2 H, ArCHN, PhCHN), 4.24–4.09 (m, total 2 H,
CH2), 1.64 (s, 28/100 × 9 H, t-Bu), 1.59 (s, 28/100 × 9 H, t-Bu),
1.07 (s, 72/100 × 9 H, t-Bu), 1.02 (s, 72/100 × 9 H, t-Bu).
References
(1) (a) Bioactive Heterocycles I; Eguchi, S., Ed.; Springer:
Heidelberg, 2006. (b) Joule, J. A.; Mills, K. Heterocyclic
Chemistry at a Glance; Blackwell: Oxford, 2007.
(c) Georgii, G. F. In Advances in Heterocyclic Chemistry,
Vol. 86; Katritzky, A. R., Ed.; Elsevier: Amsterdam, 2004,
129.
(2) (a) Kirk, K. J. Fluorine Chem. 2006, 127, 1013. (b) Ismail,
F. M. D. J. Fluorine Chem. 2002, 118, 27. (c) Fluorine in
Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.;
Blackwell: Oxford, 2009. (d) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
19F NMR (282 MHz, CDCl3): d = –65.3 (s, 19/100 × 3 F), –66.4 (s,
10/100 × 3 F), –69.9 (s, 4/100 × 3 F), –70.3 (s, 67/100 × 3 F).
MS (EI): m/z = 643 [M]+.
HRMS (EI): m/z calcd for C31H29BrF3N3O4: 643.1294; found:
643.1323.
The 13C NMR spectrum of this compound is provided in the Sup-
porting Information.
Synthesis 2010, No. 19, 3274–3281 © Thieme Stuttgart · New York

PAPER
Cyclization of Azomethine Imines with (a-Trifluoromethyl)acrylates
3281
320. (e) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006,
127, 303. (f) Bégué, J.-P.; Bonnet-D, D. J. Fluorine Chem.
Asymmetry 1990, 1, 215. (i) Hanzawa, Y.; Suzuki, M.;
Kobayashi, Y. Tetrahedron Lett. 1989, 30, 571.
2006, 127, 992.
(j) Kitazume, T.; Murata, K.; Kokusho, Y.; Iwasaki, S.
J. Fluorine Chem. 1988, 39, 75. (k) Fuchikami, T.; Shibata,
Y.; Suzuki, Y. Tetrahedron Lett. 1986, 27, 3173.
(l) Yamazaki, T.; Hiraoka, S.; Kitazume, T. J. Org. Chem.
1994, 59, 5100.
(3) (a) Andrei, A. G.; Kirk, L. K. Fluorinated Heterocycles, In
Fluorinated Heterocycles, ACS Symposium Series 1003;
Andrei, A. G.; Kirk, L. K., Eds.; American Chemical
Society: Washington DC, 2009, Chap. 1, 3–20. (b) Harper,
D. B.; O’Hagan, D. Nat. Prod. Rep. 1994, 11, 123.
(c) O’Hagan, D.; Harper, D. B. J. Fluorine Chem. 1999, 100,
127. (d) Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A.
V.; Balenkova, E. S.; Haufe, G. Synthesis 2009, 2249.
(4) (a) Shibata, N.; Furukawa, T.; Reddy, D. S. Chim. Oggi
2009, 27, 38. (b) Shibata, N.; Mizuta, S.; Kawai, H.
Tetrahedron: Asymmetry 2008, 19, 2633. (c) Shibata, N.;
Ishimaru, T.; Nakamura, S.; Toru, T. J. Fluorine Chem.
2007, 128, 469. (d) Shibata, N. J. Synth. Org. Chem. Jpn.
2006, 64, 14.
(5) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004. (b) Organofluorine Compounds in
Medicinal Chemistry and Biomedical Applications; Filler,
R.; Kobayashi, Y.; Yagupolskii, L. M., Eds.; Elsevier:
Amsterdam, 1993.
(6) (a) Percy, J. M. Top. Curr. Chem. 1997, 193, 131.
(b) Konev, A. S.; Khlebnikov, A. F. Collect. Czech. Chem.
Commun. 2008, 73, 1553.
(7) (a) Skarpos, H.; Röschenthaler, G.-V. Chim. Oggi 2008, 76,
7. (b) Shibata, N.; Fujimoto, H.; Mizuta, S.; Ogawa, S.;
Ishiuchi, Y.; Nakamura, S.; Toru, T. Synlett 2006, 3484.
(8) Eguchi, H.; Nishiyama, S.; Ishikawa, S. TOSOH Res.
Technol. Rev. 2003, 47, 85; Chem. Abstr. 2004, 141, 227160.
(9) (a) Avenoza, A.; Busto, J. H.; Jimènez-Osés, G.; Peregrina,
J. M. J. Org. Chem. 2005, 70, 5721. (b) Salaheldin, A. M.;
Yi, Z.; Kitazume, T. J. Fluorine Chem. 2004, 125, 1105.
(c) Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P.
A. Org. Lett. 2004, 6, 197. (d) Matteis, V. D.; Delft, F. L.
V.; Gelder, R. D.; Tiebes, J.; Rutjes, F. P. J. T. Tetrahedron
Lett. 2004, 45, 959. (e) Iseki, K.; Kuroki, Y.; Nagai, T.;
Kobayashi, Y. Chem. Pharm. Bull. 1996, 44, 477. (f) Iseki,
K.; Kuroki, Y.; Nagai, T.; Kobayashi, Y. J. Fluorine Chem.
1994, 69, 5. (g) Hanzawa, Y.; Suzuki, M.; Kobayashi, Y.;
Taguchi, T.; Iitaka, Y. J. Org. Chem. 1991, 56, 1718.
(h) Yamazaki, T.; Ohnogi, T.; Kitazume, T. Tetrahedron:
(10) Ogawa, S.; Yasui, H.; Tokunaga, E.; Nakamura, S.; Shibata,
N. Chem. Lett. 2009, 38, 1006.
(11) (a) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products;
Padwa, A.; Pearson, W. H., Eds.; Wiley: New York, 2003.
(b) 1,3-Dipolar Cycloaddition Chemistry, Vols.1-2; Padwa,
A., Ed.; Wiley: New York, 1984. (c) Carmen, N.; Jose, M.
S. Top. Heterocycl. Chem. 2008, 12, 117.
(12) (a) Huisgen, R.; Weinberger, R. Tetrahedron Lett. 1985, 26,
5119. (b) Dorn, H. Tetrahedron Lett. 1985, 26, 5123.
(c) Dorn, H.; Kreher, T. Heterocycles 1994, 38, 2171.
(d) Svete, J.; Preseren, A.; Stanovnik, B.; Golic, L.; Golic-
Grdadolnik, S. J. Heterocycl. Chem. 1997, 34, 1323.
(e) Chuang, T.-H.; Sharpless, K. B. Helv. Chim. Acta. 2000,
83, 1734. (f) Pezdirc, L.; Jovanovski, V.; Bevk, D.; Jakše,
R.; Pirc, S.; Meden, A.; Stanovnik, B.; Svete, J. Tetrahedron
2005, 61, 3977. (g) Chen, W.; Yuan, X.-H.; Li, R.; Du, W.;
Wu, Y.; Ding, L.-S.; Chen, Y.-C. Adv. Synth. Catal. 2006,
348, 1818. (h) Pezdirc, L.; Cerkovnik, J.; Pirc, S.;
Stanovnik, B.; Svete, J. Tetrahedron 2007, 63, 991.
(i) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett. 2007, 9, 97.
(j) Pezdirc, L.; Bevk, D.; Grošelj, U.; Meden, A.; Stanovnik,
B.; Svete, J. J. Comb. Chem. 2007, 9, 717. (k) Chen, W.;
Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.; Chen, Y.-C.
Angew. Chem. Int. Ed. 2007, 46, 7667. (l) Kato, T.;
Fujinami, S.; Ukaji, Y.; Inomata, K. Chem. Lett. 2008, 37,
342. (m) Sibi, M. P.; Rane, D.; Stanley, L. M.; Soeta, T. Org.
Lett. 2008, 10, 2971. (n) Pezdirc, L.; Stanovnik, B.; Svete, J.
Collect. Czech. Chem. Commun. 2009, 74, 835.
(o) Yamashita, Y.; Kobayashi, S. Chem. Lett. 2009, 38, 678.
(13) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789; and references
cited therein.
Synthesis 2010, No. 19, 3274–3281 © Thieme Stuttgart · New York