Study on the reactions of ethyl 4,4,4-trifluoro-3-oxobutanoate with arylidenemalononitriles

Article abstract of DOI:10.1016/j.tet.2005.12.039

In the presence of a catalytic amount of NEt₃, ethyl 4,4,4-trifluoro-3-oxobutanoate 1 reacted readily with arylidenemalononitriles 2 in ethanol at room temperature. It gave two products 2-trifluoromethyl-3,4- dihydro-2H-pyran derivatives 3 and

Full text of DOI:10.1016/j.tet.2005.12.039

Tetrahedron 62 (2006) 2255–2263
Study on the reactions of ethyl 4,4,4-trifluoro-3-oxobutanoate
with arylidenemalononitriles
b
b
b,
Xianfu Li,a Liping Song,a,b, Chunhui Xing, Jingwei Zhao and Shizheng Zhu
*
*
aDepartment of Chemistry, School of Science, Shanghai University, No. 99, Shangda Road, Shanghai 200444, China
bShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 7 October 2005; revised 30 November 2005; accepted 5 December 2005
Abstract—In the presence of a catalytic amount of NEt3, ethyl 4,4,4-trifluoro-3-oxobutanoate 1 reacted readily with arylidenemalononitriles
2 in ethanol at room temperature. It gave two products 2-trifluoromethyl-3,4-dihydro-2H-pyran derivatives 3 and 2-(trifluoromethyl)piper-
idine derivatives 4, the ratio of 3 and 4 was depended on the substrates 2 and reaction solvents. Reflux of the ethanol solution of 4 with a
catalytic amount of NEt3 afforded 2-trifluoromethyl-1,4,5,6-tetrahydropyridine derivatives 5 in moderate to good yields. The structures of
new compounds 3, 4 and 5 were determined by spectral methods, microanalysis and X-ray diffraction analysis. A possible reaction
mechanism for the formation of 3, 4 and 5 was presented.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of ethyl 4,4,4-trifluoro-3-oxobutanoate 1 with arylidenema-
lononitriles 2.
It is well known that 1,3-dicarbonyl compounds reacted
with the a,b-unsaturated carbonyl compounds or acryloni-
trile derivatives through Michael addition reaction,1 some
adducts could further proceed intramolecular condensation
to give cyclic compounds.2 Furthermore, the selective
incorporation of a fluorine atom or fluoroalkyl group
into aromatic or heterocyclic system frequently confers
biological or physical properties to such molecules.3 The
reactions of fluorinated-1,3-dicarbonyl compounds as
fluorine-containing building blocks have been studied
extensively.4,5 For example, our group have reported the
reaction of trifluoromethyl-1,3-diketone with per(poly)-
fluorophenylhydrazines.5
2. Results and discussion
2.1. Reaction of 4,4,4-trifluoro-3-oxobutanoate 1 with
arylidenemalononitriles 2
Firstly, the reaction of ethyl 4,4,4-trifluoro-3-oxobutanoate
1 with benzylidenemalononitrile 2a was investigated as a
model reaction. To a solution of 2a (3 mmol) in ethanol
(10 ml, AR, 99.7%) was added an equimolecular amount
of ethyl 4,4,4-trifluoro-3-oxobutanoate 1 and a catalytic
Arf
Arf
Arf
HO
F3C
R
O
O
N
N
N
P2O5
EtOH
F3C
+
N
+ ArfNHNH2
N
N
rt or reflux
R
F3C
R
CF3
R
amount of NEt3 (0.5 mmol). After stirring of the mixture for
6 h at room temperature, the TLC analysis showed that the
starting materials disappeared and two new compounds
formed. After removal of the solvent under reduced
pressure, the residue was separated and purified by column
chromatography on silica gel using petroleum ether–ethyl
acetate (4/1, v/v) as the eluent, compound 3a was first
isolated as a white solid in 59% yield and the more polar
product 4a was obtained later in 32% yield (scheme 1).
However, to the best of our knowledge, the reactions of
trifluoromethyl-containing 1,3-dicarbonyl compounds with
arylidenemalononitriles have not been reported. In this
paper, we wish to describe our recent study on the reactions
Keywords: Ethyl 4,4,4-trifluoro-3-oxobutanoate; Arylidenemalononitriles;
Heterocycles; X-ray diffraction analysis.
*
Corresponding authors. Fax: C86 21 64166128;
e-mail: zhusz@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.039

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X. Li et al. / Tetrahedron 62 (2006) 2255–2263
O
Ar
O
Ar
O
O
CN
Ar
CN
CN
CN
O
NEt3, 15%
EtOH rt
EtO
F3C
EtO
EtO
+
+
F3C
OEt
2a
F3C
HO
O
NH2
N
H
1
2
3
4
Ar=
Ph
2f p-FC6H4
2b p-MeOC6H4
2c p-HOC6H4
2d p-MeC6H4
2e p-ClC6H4
2g p-O2NC6H4
2h Furan-2-yl
2i α-Naphthyl
Scheme 1.
The structures of 3a and 4a were determined by spectral
methods and elemental analysis. The 1H NMR spectrum of
3a in CDCl3 consisted of eight peaks; they were at d 0.99 (t,
JZ7.2 Hz, 3H), 3.88 (q, JZ7.2 Hz, 2H), 1.32 (t, JZ7.2 Hz,
3H), 3.95 (q, JZ7.2 Hz, 2H), 2.94 (d, JZ11.7 Hz, 1H), 4.13
(d, JZ11.7 Hz, 1H), 4.66 (br, s, 2H), and 7.25–7.34 (m,
5H), corresponding to two ethoxyl groups(CH3CH2O), two
six-membered ring protons, CONH2 and five aromatic
protons. The coupling constant of the vicinal six-membered
ring protons in 3a was 11.7 Hz, which indicated a trans
confirmation of the vicinal hydrogen atoms.6 In its 19F NMR
spectrum, the chemical shift of CF3 group of 3a was a
singlet peak at d K77.33, which indicated it was bonded to
the sp3 saturated carbon atom. The MS spectrum of 3a had a
strong molecular ion peak at m/z 384 (MC, 39.7%), and the
base peak was at m/z 171 (MCKEtO–CO2Et–CF3–CN,
100%). Meanwhile, the typical and strong absorptions at
3422 and 2203 cmK1 in IR spectrum confirmed the
existence of NH2 and CN groups in 3a. The compound 4a
had eight peaks in its 1H NMR spectrum, they were at d 0.78
(t, JZ7.2 Hz, 3H), 3.28 (dd, JZ9, 3 Hz, 1H), 3.86 (q, JZ
7.2 Hz, 2H), 3.86 (d, JZ9 Hz, 1H), 3.87 (d, JZ3 Hz, 1H),
6.0 (br, s, 1H), 6.59 (br, s, 1H) and 7.26–7.44 (m, 5H). The
19F NMR spectrum of 4a was a singlet peak at d K84.39.
Compound 4a had a weak molecular ion peak at m/z 356
(MC, 3.68%) and the base peak was at m/z 239 (MCK
H2O–CO2Et–CN, 100%). The strong absorptions at 3257,
2273, 1735 and 1690 cmK1 in IR were corresponding to OH,
NH, CN, CO2Et and CONH2 groups, respectively. Under the
same reaction condition, other arylidenemalononitriles such
as 2b–i reacted with ethyl 4,4,4-trifluoro-3-oxobutanoate 1 to
afford the similar reaction products. All the reaction results
were summarized in Table 1.
The steric structures of 3d and 4d were further determined
by the single crystal X-ray crystallographic study. It was
Figure 1. The ORTEP view of 3d.
Table 1. Reaction of CF3COCH2CO2Et 1 and arylidenemalononitriles 2a
Entry
Ar in 2
Time
(h)
Yields (%)b
Product 3 and 4
1
2
3
4
5
6
7
8
9
2a C6H5
2b p-MeOC6H4 48
6
3a
3b
3c
3d
3e
3f
3g
3h
3i
59
4a
4b
4c
4d
4e
4f
4g
4h
4i
32
62
35
71
16
27
20
51
80
20
70
80
2c p-HOC6H4
2d p-MeC6H4
2e p-ClC6H4
2f p-FC6H4
72
24
6
32
Tracec
60
6
2g p-NO2C6H4
2h Furan-2-yl-
2i a-Naphthyl-
6
50
50
Tracec
Tracec
a Reaction conditions: 1 (3 mmol), 2 (3 mmol), NEt3 (0.5 mmol), ethanol
(10 ml, AR 99.7%), room temperature.
b Isolated yields.
c Not isolated.
Figure 2. The ORTEP view of 4d.

X. Li et al. / Tetrahedron 62 (2006) 2255–2263
2257
˚
Table 2. Selected bond lengths (A), bond angles (8) of 3d, 4d and 5d
3d
4d
5d
Bond lengths
O(1)–C(1)
O(1)–C(5)
O(2)–C(5)
N(1)–C(1)
N(2)–C(7)
C(1)–C(2)
C(2)–C(3)
C(2)–C(7)
C(3)–C(4)
C(4)–C(5)
1.361(4)
1.422(3)
1.361(4)
1.324(4)
1.146(4)
1.347(4)
1.509(4)
1.404(4)
1.541(4)
1.535(4)
O(1)–C(1)
O(2)–C(5)
N(1)–C(1)
N(1)–C(5)
N(2)–C(7)
C(1)–C(2)
C(2)–C(3)
C(2)–C(7)
C(3)–C(4)
C(4)–C(5)
1.202.(2)
O(1)–C(1)
O(2)–C(7)
O(3)–C(8)
N(1)–C(1)
N(1)–C(5)
C(1)–C(2)
C(2)–C(3)
C(2)–C(7)
C(3)–C(4)
C(4)–C(5)
1.220(2)
1.207(3)
1.193(3)
1.356(3)
1.403(3)
1.513(3)
1.533(3)
1.541(3)
1.508(3)
1.335(3)
1.405(2)
1.350(2)
1.428(2)
1.131(2)
1.522(3)
1.528(3)
1.459(3)
1.538(3)
1.529(3)
Bond angles
N(1)–C(1)–C(2)
N(1)–C(1)–O(1)
C(2)–C(1)–O(1)
C(1)–C(2)–C(7)
C(1)–C(2)–C(3)
C(7)– C(2)–C(3)
O(1)–C(5)–C(4)
C(1)–O(1)–C(5)
N(2)–C(7)–C(2)
127.2(3)
110.2(3)
122.6(3)
117.9(3)
122.0(3)
120.2(3)
110.8(3)
118.7(2)
178.9(3)
O(1)–C(1)–N(1)
O(1)–C(1)–C(2)
N(1)–C(1)–C(2)
C(7)–C(2)–C(1)
C(7)–C(2)–C(3)
C(1)–C(2)–C(3)
C(2)–C(3)–C(4)
C(1)–N(1)–C(5)
N(2)–C(7)–C(2)
122.45(18)
121.44(17)
116.00(17)
108.40(16)
111.64(16)
114.88(15)
107.78(15)
125.40(16)
179.0(3)
O(1)–C(1)–N(1)
O(1)–C(1)–C(2)
N(1)–C(1)–C(2)
C(5)–C(4)–C(8)
C(5)–C(4)–C(3)
C(8)–C(4)–C(3)
C(4)–C(5)–N(1)
C(4)–C(5)–C(6)
N(1)–C(5)–C(6)
122.0(2)
122.5(2)
115.4(2)
125.9(2)
120.1(2)
113.93(19)
121.3(2)
126.3(2)
112.42(19)
unambiguous to observe the trans relationship between the
vicinal six-membered ring protons in compound 3d and 4d
(Figs. 1 and 2). The selected bond lengths and bond angles
of 3d and 4d were listed in Table 2. The bond lengths
of O(1)–C(1), C(1)–C(2), C(2)–C(7), and N(2)–C(7) in
Table 3. Reaction of CF3COCH2CO2Et 1 and 2a in different solventsa
Entry
Solvent
Time (h)
Product yields (%)b
3a
4a
1
2
3
4
5
6
7
8
9
10
EtOHc
6
7
3
48
6
4
6
4
7
8
59
85
10
0
32
0
80
90
˚
3d was 1.361(4), 1.347(4), 1.404(4), and 1.146(4) A,
EtOHd
respectively, indicating that compounds 3 consisted of a
conjugated system in O(1)–C(1)–C(2)–C(7)–N(2) as shown
in Scheme 2.
EtOH–H2O(2/1)
H2O
CH3CNd
CH3CNc
No reaction
0
No reaction
No reaction
60
No reaction
55
10
0
d
CH2Cl2
CH2Cl2
O
Ar
c
O
Ar
0
N
N
CH3OHc
CH3OHd
80(3a0)e
85
C
C
EtO
F3C
EtO
F3C
a Reaction conditions: 1 (3 mmol), 2 (3 mmol), NEt3 (0.5 mmol), room
temperature.
O
NH2
O
NH2
EtO
EtO
b Isolated yields.
3d
3d'
c AR and without purification.
d Absolute solvent.
e Structure of 3a0.
Scheme 2.
2.2. Solvent effect on the reaction of 1 with 2
O
According to the structures of 3 and 4, it was clear that the
solvent EtOH and H2O participated in the reaction. To
investigate the solvent effects, this reaction was carried out
in several different solvent systems; all the results were
summarized in Table 3.
CN
EtO
F3C
H3CO
O
NH2
3a'
In absolute ethanol (entry 2, Table 3), the reaction of 1 with
2a completed within 7 h and gave 3a exclusively in 85%
yield. Using methanol (AR, 99.5%) as the solvent, the
similar product 3a0 was obtained in a yield of 80%
accompanying with a small amount of 4a (10%) (entry 9,
Table 3). In aqueous ethanol (C2H5OH/H2OZ2:1), the
reaction of 1 with 2a completed within 3 h and gave 4a as a
major product (80%) accompanying with a 10% yield of 3a
(entry 3, Table 3). Meanwhile, when the reaction of 1 with
2a was carried out in water, it required 48 h to finish the
reaction, because of the poor solubility of the starting
materials in water, and it afforded 4a (90%) as the exclusive
product. In unpurified solvent of CH3CN (AR) or CH2Cl2
(AR), the product 4a was isolated in 60 and 55%,
respectively, without formation of 3a. However, in absolute
Table 4. Reaction of CF3COCH2CO2Et 1 with 2 in EtOH–H2O (2/1, v/v)a
Entry
Ar in 2
Time (h)
Yields (%)b
3
4
1
2
3
4
5
6
7
8
2a C6H5–
3
5
4.5
3
4
3
5
6
3a 10
3b 5
3d 5
3e 7
4a 80
4b 78
4d 63
4e 69
4f 75
4g 75
2b p-MeOC4H5–
2d p-MeC4H5–
2e p-ClC4H5–
2f p-FC4H5–
2g p-NO2C4H5–
2h 2-Furanyl–
2i a-Naphthyl–
3f 8
3g 5
Trace
Trace
c
—
c
—
a Reaction conditions: 1 (3 mmol), 2 (3 mmol), NEt3 (0.5 mmol), room
temperature.
b Isolated yields.
c Decomposed on the workup.

2258
X. Li et al. / Tetrahedron 62 (2006) 2255–2263
Cl
Cl
Cl
O
O
O
O
O
O
CN
CN
NEt3, 15%
CN
EtO
F3C
EtO
EtO
NH2
+
F3C
OEt
EtOH, reflux
+
O
NH2
F3C
N
H
1
2e
3e
5e
Scheme 3.
O
Ar
O
NEt3, 15%
EtO
F C
NH
2
O
Ar
5a,b,d–g
EtOH, reflux
CN
O
N
O
3
EtO
F C
H
3
N
HO
H
EtOH, refluxX
4a,b,d–g
Scheme 4.
CH3CN or CH2Cl2, no reaction occurred (entries 5 and 7,
Table 3).
reaction of 1 (3 mmol) and an equimolecular amount of 2-
(4-chlorobenzylidene)malononitrile 2e with a catalytic
amount of Et3N (0.5 mmol) was refluxed in ethanol
(10 ml, AR 99.7%). After stirring for 6 h, TLC analysis
showed the reaction was completed and a new compound
formed in addition to the expected product 3e, but no 4e
was detected by TLC. A new compound ethyl 5-carbamoyl-
4-(4-chlorophenyl)-6-oxo-2-(trifluoromethyl)-1,4,5,6-tetra-
hydropyridine-3-carboxylate 5e was isolated in 20% yield
along with 3e in 50% isolated yield (Scheme 3). It could be
speculated that under the reflux condition, compound 4e
could be transformed into compound 5e.
When the reaction was carried out in aqueous ethanol
(C2H5OH/H2OZ2:1), the reaction time was dramatically
reduced comparing to that required in ethanol (Table 1).
Under this condition, compounds 4a–b,d–g were isolated as
the major products. Unfortunately, the 4h and 4i were
not isolated because the products decomposed and gave a
complex mixture during the work-up. All the results were
listed in Table 4.
It should be noted that the primary Michael addition products
could not be obtained under the investigated reaction
conditions, because they readily undergo the consecutive
and irreversible reaction. This phenomenon should be
attributed to the strong electronic withdrawing nature of
CF3, leading to the carbonyl group was much more easily to
be attacked by the nucleophiles such as ethanol or water.
Thus, a series of transformation of 4 to 5 was investigated.
As expected, reflux of the solution of 4a (2 mmol) in 8 ml
ethanol (AR 99.7%) with NEt3 (0.3 mmol) afforded 5a in
69% yield. In the absence of a catalytic amount of NEt3, no
reaction occurred. Under the same reaction conditions, a
series of new compounds 5b,d–g was also obtained
(Scheme 4). The reaction results were listed in Table 5.
As shown in Table 1, it was found that reactions of
arylidenemalononitriles 2b–d (entries 2–4, Table 1), which
have an electronic donating group on the para position of the
phenyl group with ethyl 4,4,4-trifluoro-3-oxobutanoate 1
required longer reaction time comparing to other arylide-
nemalononitriles such as 2a and 2e,f,g (entries 5–7,
Table 1), which bear an electronic withdrawing group on
the para position of phenyl group. This result was similar to
the kinetic studies on the Michael reaction of arylidenema-
lononitriles.7 The reaction of 1 with 2f, 2h and 2i (entries 6,
8, and 9, Table 1) afforded 3f, 3h, and 3i in 80, 70, and 80%
yields, respectively, but the corresponding 4f, 4h, and 4i
were not isolated. The electronic effect of substituted group
(in Table 1) affecting the ratio of products 3 and 4 could not
be explained at this stage.
a
Table 5. Transformation of 4 to 5 in EtOH in the presence of NEt3
Entry
4
Time (h)
Product 5
Yield (%)b
1
2
3
4
5
6
4a
4b
4d
4e
4f
4
4
4
4
4
4
5a
5b
5d
5e
5f
69
53
66
80
65
50
4g
5g
a Reaction condition: 4 (2 mmol), NEt3 (0.3 mmol), refluxed in ethanol
(8 ml AR, 99.7%).
b Isolated yields.
All the new compounds 5 were fully characterized. For
example, the H NMR spectrum of 5a in CDCl3 showed
1
eight peaks: they were at d 1.19 (t, JZ7.2 Hz, 3H), 3.61 (d,
JZ3 Hz, 1H), 4.17 (q, JZ7.2 Hz, 2H), 4.91 (s, 1H), 5.49
(br, s, 1H), 6.19 (br, s, 1H), 7.2–7.37 (m, 5H,), 7.52 (br, s,
1H). It was noteworthy that the signals of two protons
attached to nitrogen atom of amide group showed two
2.3. Transformation of 4 to 5
The above results prompted us to further study the
temperature effect on this reaction. A mixture of the

X. Li et al. / Tetrahedron 62 (2006) 2255–2263
2259
different chemical shifts at d 5.49 and 6.19, respectively. In
2.4. Mechanism
its 19F NMR spectrum, the chemical shift of CF3 group in 5a
was a singlet peak at d K64.27, indicating that it was
bonded to the unsaturated sp2 carbon atom. The MS
spectrum of 5a showed its weak molecular ion peak at m/z
356 (MC, 1.98%) and the base peak at 312 (MCKCONH2,
100%). Meanwhile, in the IR spectrum of 5a, no absorption
peaks in the range of 2000–2400 cmK1, indicating that there
was no cyano group in 5a. Furthermore, the steric structure
of 5d was further confirmed by single crystal X-ray
diffraction analysis (Fig. 3). The selected bond lengths
and bond angles of 5d were also listed in Table 2. The
crystal data and structure refinement parameters of 3d, 4d
and 5d were listed in Table 6.
According to the structure of 3, which has the ethoxyl group
at the 2-position of the ring, while 4 had a lactam unit, it was
clear that the ethanol and water participated in the reaction
processes, respectively. To determine how the cyano group
hydrolyzed during the reaction, a solution of 2a in ethanol
with a catalytic amount of NEt3 was carried out. After
stirring for 2 days at room temperature, TLC analysis
showed that no reaction occurred and the starting material
2a remained (Scheme 5), which indicated that the cyano
group hydrolyzed after the formation of intermediate A.
Moreover, to this reaction, a catalytic amount of Et3N was
necessary, otherwise the reaction did not occur even with
prolonged reaction time.
Ph
CN
CN
NEt3
No reaction
EtOH rt 2 day
2a
Scheme 5.
Based on these results above, a possible mechanism for the
formation of 3, 4 and 5 was illustrated in Scheme 6. Firstly,
the Michael adduct intermediate A was formed by Michael
addition reaction, and then the solvent ethanol attacked
trifluoroacetyl group of the intermediate A, followed by
the intramolecular attack to the enimine to form the six-
membered ring product 3. Alternatively, the intermediate A
could be hydrolyzed by water to form B, then through
intramolecular condensation yielding the cyclic product 4.
At refluxed temperature, 4 could be transformed into 5 by
losing a water molecule, and followed by the hydrolysis of
the cyano group. However, it should be noted that in the
absence of a catalytic amount of NEt3, 5 could not be
Figure 3. The ORTEP view of 5d.
Table 6. The crystal data of 3d, 4d and 5d
3d
4d
5d
CCDC
28,4791
C19H21F3N2O4
398.38
28,4792
28,4793
C17H17F3N2O4
370.33
Empirial formula
Fw
Temp (K)
Wavelength (A)
Cryst syst
C17H17F3N2O4
370.33
293(2)
0.71073
Monoclinic
P2(1)/c
293(2)
293(2)
˚
0.71073
Triclinic
PK1
0.71073
Monoclinic
C2/c
Space group
Unit cell dimens
˚
a (A)
8.3233(10)
9.5566(12)
13.1239(16)
76.801(2)
80.048(2)
88.410(2)
1001.0(2)
2
8.3300(9)
10.4557(11)
20.118(2)
90
91.672(2)
90
1751.4(3)
4
1.404
20.197(2)
11.6217(14)
15.4193(18)
90
94.328(2)
90
3609.0(7)
8
1.363
˚
b (A)
˚
c (A)
a (8)
b (8)
g (8)
Volume (A )
Z
3
˚
Calcd density
(Mg/m3)
1.322
Absorp coeff (mmK1
F(000)
Cryst size (mm)
)
0.111
416
0.516!0.427!0.368
1.62–26.00
1.055
R1Z0.0793
wR2Z0.2410
R1Z0.0982
wR2Z0.2601
0.748 and K0.451
0.121
768
0.506!0.427!0.218
2.03–27.00
1.002
R1Z0.0519
wR2Z0.1396
R1Z0.0796
wR2Z0.1532
0.285 and K0.250
0.117
1536
0.505!0.332!0.070
2.02–27.00
0.839
R1Z0.0523
wR2Z0.1151
R1Z0.1083
wR2Z0.1321
0.222 and K0.182
q Range for data collection (8)
Goodness-of-fit on F2
Final R indices
[IO2s (I)]
R indices (all data)
K3
˚
Largest diff peak and hole (e A
)

2260
X. Li et al. / Tetrahedron 62 (2006) 2255–2263
OH
O
O
O
F3C
OEt
F3C
OEt
CN
CN
Ar
CF3
CF3
CN
O
O
Ar
O
O
CN
O
NEt3
OEt
EtO
F3C
EtOH
k1
O
OEt
H2O
k2
Unchanged
H2N
Reflux
Ar
NH2
Ar
HN
EtO
O
CN
3
B
A
O
Ar
O
Ar
O
O
O
Ar
H
H
NH
CN
C
O
NEt3
Reflux
EtO
F3C
EtO
F3C
NH2
EtO
F3C
H2O
N
H
O
N
H
N
H
HO
HNEt3
5
4
C
Scheme 6.
obtained under the refluxed condition. This should be partly
attributed to the active proton of the vicinal cyano group in
compound 4, which could assist the hydrolysis by the
intermediate C as depicted in scheme 6. In contrast, the
cyano group in compound 3 was much more stable than that
in compound 4, it resisted to hydrolysis and remained
unchanged under the refluxed condition, this was partly
because there existed a conjugated system in compound 3 as
mentioned above, partly because there was no active proton
at the vicinal position of cyano group in compound 3.
Furthermore, in the aqueous EtOH, the reaction could
complete within a shorter time (Table 4), which manifested
that the rate constant k2 for the formation of 4 from
intermediate A should be larger than the rate constant k1 for
the formation of 3.
CDCl3 (unless mentioned in text) Bruker AM-300 instru-
ments with Me4Si and CFCl3 (with upfield negative) as the
internal and external standards, respectively. IR spectra
were obtained with a Nicolet AV-360 spectrophotometer.
Lower resolution mass spectrum were obtained on Finnigan
GC–MS 4021 using the electron impact ionization
technique (70 ev). High-resolution mass spectra (HRMS)
were obtained on Ionspec 4.7 T FTMS using MALDI/DHB.
Elemental analyses were performed by this Institute. X-ray
diffraction crystal structure analysis was obtained on Bruker
P4 instrument.
4.1. General procedure for the reaction of ethyl 4,4,4-
trifluoro-3-oxobutanoate 1 with arylidenemalononitriles
2a in ethanol
To a 50 ml round bottle flask containing 2a (462 mg,
3 mmol) was added 10 ml ethanol, and then ethyl 4,4,
4-trifluoro-3-oxobutanoate 1 (552 mg, 3 mmol) and NEt3
(0.5 mmol) were added under stirring at room temperature.
The mixture was continuously stirred at room temperature.
After 6 h, the TLC analysis showed the reaction was
finished. The solvent was evaporated and the residue was
chromatographed on a silica column using petroleum ether–
ethyl acetate (4/1, v/v) as eluent to afford the 3a (512 mg,
59%) and 4a (299 mg, 32%), respectively. The two solid
products were recrystallized from petroleum ether/ethyl
acetate to give the pure compounds.
3. Conclusions
In summary, the reaction of CF3COCH2CO2Et 1 with
arylidenemalononitriles 2 under NEt3 catalysis was studied
in detail. Different reaction conditions gave different results.
In ethanol (AR, 99.7%) the reaction gave two products
2-trifluoromethyl-3,4-dihydro-2H-pyrans derivatives 3 and
2-(trifluoromethyl)piperidine derivatives 4. When it was
carried out in aqueous ethanol (C2H5OH/H2OZ2:1), 4
became the major product. In absolute ethanol, 3 was the
exclusive product. In CH3CN or CH2Cl2 (AR) the reaction
only afforded 4, whereas in absolute CH3CN or CH2Cl2, no
reaction occurred. Reflux of 4 with the catalysis of NEt3
in ethanol afforded 2-trifluoromethyl-1,4,5,6-tetrahydro-
pyridines derivatives 5. Further chemical transformation
of above compounds now is under investigation.
4.1.1. Ethyl 6-amino-5-cyano-2-ethoxy-4-phenyl-2-tri-
fluoromethyl-3,4-dihydro-2H-pyran-3-carboxylate 3a.
1
White solid; mp 154–156 8C; H NMR (CDCl3, 300 MHz)
d 0.99 (t, JZ7.2 Hz, 3H), 1.32 (t, JZ7.2 Hz, 3H), 2.94
(d, JZ11.7 Hz, 1H), 3.88 (q, JZ7.2 Hz, 2H), 3.95 (q, JZ
7.2 Hz, 2H), 4.13 (d, JZ11.7 Hz, 1H), 4.66 (br, s, 2H),
7.25–7.36 (m, 5H); 19F NMR (CDCl3, 282 MHz) d K77.33
(s, 3F); IR (KBr) ymax 3422, 3330, 3285, 2992, 2203,
1735, 1670, 1615 cmK1; MS (70 eV, EI) m/z (%) 385
(MHC, 8.02), 384 (MC, 39.70), 355 (MCKEt, 5.74), 338
4. Experimental
Melting points were measured in Melt-Temp apparatus and
were uncorrected. 1H and 19F NMR spectra were recorded in

X. Li et al. / Tetrahedron 62 (2006) 2255–2263
2261
(MCKEtOH, 8.24), 309 (MCKEt–EtOH, 6.88), 265
(MCKCO2Et–EtOH, 65.83), 292 (MCK2EtOH, 10.33),
223 (MCK2EtOH–CF3, 4.95), 171 (MCKEtO–CO2Et–
CF3–CN, 100), 69 (CF3C, 14.65). Anal. Calcd for
C18H19F3N2O4: C, 56.25%; H, 4.95%; N, 7.29%. Found:
C, 56.14%; H, 5.16%; N, 7.23%.
4.1.6. Ethyl 6-amino-5-cyano-2-ethoxy-4-(4-hydroxyphe-
nyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyran-3-car-
boxylate 3c. White solid; mp 188–191 8C; 1H NMR
(CDCl3, 300 MHz) d 1.03 (t, JZ7.2 Hz, 3H), 1.30 (t, JZ
7.2 Hz, 3H), 2.92 (d, JZ11.7 Hz, 1H), 3.88 (q, JZ6.9 Hz,
2H), 3.97 (q, JZ7.2 Hz, 2H), 4.07 (d, JZ11.7 Hz, 1H), 4.66
(br, s, 2H), 5.88 (s, 1H), 6.72 (d, JABZ8.4 Hz, 2H), 7.09 (d,
JABZ8.7 Hz, 2H); 19F NMR (282 MHz, CDCl3) d K77.36
(s, 3F); IR (KBr) ymax 3421, 3333, 3290, 2203, 1730, 1665,
1600 cmK1; MS (m/z, %): 401 (MHC, 3.64), 400 (MC,
16.08), 371 (MCKEt, 2.14), 354 (MCKEtOH, 4.50), 281
(MCK CO2Et–EtOH, 46.23), 188 (MCC1KEtO–CO2Et–
CF3–CN, 100), 69 (CF3C, 5.91). Anal. Calcd for
C18H19F3N2O5: C, 54.00%; H, 4.75%; N, 7.00%. Found:
C, 53.96%; H, 4.85%; N, 7.06%.
4.1.2. Ethyl 5-cyano-2-hydroxy-6-oxo-4-phenyl-2-
(trifluoromethyl)piperidine-3-carboxylate 4a. White
1
solid; mp 163–166 8C; H NMR (CDCl3, 300 MHz) d 0.78
(t, JZ7.2 Hz, 3H), 3.28 (dd, JZ9, 3 Hz, 1H), 3.86 (q, JZ
7.2 Hz, 2H), 3.86 (d, JZ9 Hz, 1H), 3.87 (d, JZ3 Hz, 1H),
6.0 (br, s, 1H), 6.59 (br, s, 1H), 7.26–7.44 (m, 5H); 19F NMR
(CDCl3, 282 MHz) d K84.39 (s, 3F); IR (KBr) ymax 3257,
3138, 2989, 2273, 1735, 1690 cmK1; MS (70 eV, EI) m/z
(%): 356 (MC, 3.68), 265 (MCKH2O–CO2Et, 67.70), 239
(MCKH2O–CO2Et–CN, 100), 69 (CFC3 , 11.70). Anal.
Calcd for C16H15F3N2O4: C, 53.93%; H, 4.21%; N,
7.87%. Found: C, 53.98%; H, 4.22%; N, 7.84%.
4.1.7. Ethyl 5-cyano-2-hydroxy-4-(4-hydroxyphenyl)-6-
oxo-2-(trifluoromethyl)-piperidine-3-carboxylate 4c.
White solid; mp 215–217 8C; 1H NMR (CD3COCD3,
300 MHz) d 0.87 (t, JZ7.2 Hz, 3H), 3.64 (d, JZ12.3 Hz,
1H), 3.83–3.95 (m, 3H), 4.48 (d, JZ12.3 Hz, 1H), 6.56 (br,
s, 1H), 6.83–6.88 (m, 2H), 7.32–7.36 (m, 2H), 8.42 (br, s,
1H), 8.56 (br, s, 1H); 19F NMR (CD3COCD3, 282 MHz) d
K83.63 (s, 3F); IR (KBr) ymax 3563, 3531, 3481, 3298,
2976, 2258, 1732, 1703, 1615, 1599, 1520 cmK1; MS
(70 eV, EI) m/z (%): 372 (MC, 9.54), 327 (MCKEtO,
7.53), 281 (MCKH2O–CO2Et, 100), 255 (MCK
H2O–CO2Et–CN, 45.43), 69 (CFC3 , 20.31). Anal. Calcd
for C16H15F3N2O5: C, 51.61%; H, 4.03%; N, 7.53%, Found:
C, 51.67%; H, 4.02%; N, 7.52%.
4.1.3. Ethyl 6-amino-5-cyano-2-methoxy-4-phenyl-2-
trifluoromethyl-3,4-dihydro-2H-pyran-3-carboxylate 3a0
(reaction in methanol). White solid; mp 153–155 8C; H
1
NMR (CDCl3, 300 MHz) d 0.98 (t, JZ7.2 Hz, 3H), 2.95 (d,
JZ11.4 Hz, 1H), 3.60 (s, 3H), 3.95 (q, JZ7.2 Hz, 2H), 4.10
(d, JZ11.4 Hz, 1H), 4.72 (br, s, 2H), 7.23–7.35 (m, 5H); 19F
NMR (CDCl3, 282 MHz) d K76.99 (s, 3F); IR (KBr) ymax
3439, 3336, 2963, 2199, 1732, 1673, 1605, 1465 cmK1; MS
(70 eV, EI) m/z (%) 370 (MC, 28.40), 338 (MCKCH3OH,
2.85), 265 (MCKCO2Et–CH3OH, 78.11), 171 (MCK
CH3O–CO2Et–CF3–CN, 100), 69 (CFC3 , 6.52). Anal.
Calcd for C17H17F3N2O4: C, 55.14%; H, 4.59%; N,
7.57%. Found: C, 54.90%; H, 4.64%; N, 7.52%.
4.1.8. Ethyl 6-amino-5-cyano-2-ethoxy-4-p-tolyl-2-(tri-
fluoromethyl)-3,4-dihydro-2H-pyran-3-carboxylate 3d.
White solid; mp 179–181 8C; H NMR (CDCl3, 300 MHz)
1
d 1.02 (t, JZ7.2 Hz, 3H), 1.30 (t, JZ7.2 Hz, 3H), 2.32 (s,
3H), 2.92 (d, JZ11.7 Hz, 1H), 3.87 (q, JZ7.2 Hz, 2H), 3.96
(q, JZ7.2 Hz, 2H), 4.09 (d, JZ11.7 Hz, 1H), 4.64 (br, s,
2H), 7.13 (m, 4H); 19F NMR (CDCl3, 282 MHz) d K77.34
(s, 3F); IR (KBr) ymax 3449, 3273, 3222, 3182, 2987, 2197,
1740, 1647, 1599, 1518 cmK1; MS (70 eV, EI) m/z (%) 399
(MHC, 4.86), 398 (MC, 21.07), 369 (MCKEt, 2.55), 352
(MCKEtOH, 4.15), 323 (MCKEt–EtOH, 3.77), 306
(MCK2EtOH, 8.88), 279 (MCKCO2Et–EtOH, 60.60),
185 (MCKEtO–CO2Et–CF3–CN, 100), 69 (CFC3 , 6.63).
Anal. Calcd for C19H21F3N2O4: C, 57.29%; H, 5.28%; N,
7.04%. Found: C, 57.46%; H, 5.53%, N, 7.01%.
4.1.4. Ethyl 6-amino-5-cyano-2-ethoxy-4-(4-methoxy-
phenyl)-2-trifluoromethyl-3,4-dihydro-2H-pyran-3-
1
carboxylate 3b. White solid; mp 168–169 8C; H NMR
(CDCl3, 300 MHz) d 1.01 (t, JZ7.2 Hz, 3H), 1.29 (t, JZ
7.2 Hz, 3H), 2.89 (d, JZ11.7 Hz, 1H), 3.77 (s, 3H), 3.86 (q,
JZ7.2 Hz, 2H), 3.95 (q, JZ7.2 Hz, 2H), 4.07 (d, JZ
11.7 Hz, 1H), 4.68 (br, s, 2H), 6.84 (d, JABZ8.7 Hz, 2H),
7.16 (d, JABZ8.7 Hz, 2H); 19F NMR (CDCl3, 282 MHz) d
K77.37 (s, 3F); IR (KBr) ymax 3438, 3348, 3186, 2992,
2193, 1736, 1647, 1601, 1517 cmK1; MS (70 eV, EI) m/z
(%) 415 (MHC, 3.03), 414 (MC, 13.24); 385 (MCKEt,
1.42), 368 (MCKEtOH, 2.82), 295 (MCK CO2Et–EtOH,
31.00), 202 (MCC1–EtO–CO2Et–CF3–CN, 100), 69 (CFC3 ,
2.81). Anal. Calcd for C19H21F3N2O5: C, 55.07%; H,
5.07%; N, 6.76%. Found: C, 55.07%; H, 5.20%; N, 6.72%.
4.1.9. Ethyl 5-cyano-2-hydroxy-6-oxo-4-p-tolyl-2-(tri-
fluoromethyl)-piperidine-3-carboxylate 4d. White solid;
1
mp 147–149 8C; H NMR (CDCl3, 300 MHz) d 0.8 (t, JZ
7.2 Hz, 3H), 2.35 (s, 3H), 3.27 (d, JZ10.8 Hz, 1H), 3.85 (q,
JZ7.2 Hz, 2H), 3.78–3.91 (m, 2H), 6.03 (br, s, 1H), 6.87
(br, s, 1H), 7.15–7.26 (m, 4H); 19F NMR (CDCl3, 282 MHz)
d K84.30 (s, 3F); IR (KBr) ymax 3273, 3187, 2900, 2257,
1728, 1516, 1477 cmK1; MS (70 eV, EI) m/z (%): 370 (MC,
2.30), 279 (MCKH2O–CO2Et, 41.34), 253 (MCK
H2O–CO2Et–CN, 50.00), 69 (CFC3 , 34.60). Anal. Calcd
for C17H17F3N2O4: C, 55.14%; H, 4.59%; N, 7.57%. Found:
C, 55.24%; H, 4.81%; N, 7.60%.
4.1.5. Ethyl 5-cyano-2-hydroxy-4-(4-methoxyphenyl)-6-
oxo-2-(trifluoromethyl)-piperidine-3-carboxylate 4b.
White solid; mp 162–164 8C; H NMR (CDCl3, 300 MHz)
1
d 0.85 (t, JZ7.2 Hz, 3H), 3.24 (dd, JZ7.2, 4.8 Hz, 1H),
3.82 (s, 3H), 3.80 (JZ4.8 Hz, 1H), 3.81 (JZ7.2 Hz, 1H),
3.90 (q, JZ7.2 Hz, 2H) 5.98 (br, s, 1H), 6.71 (br, s, 1H),
6.92 (d, JABZ8.4 Hz, 2H), 7.20 (d, JABZ8.4 Hz, 2H);
19F NMR d (CDCl3, 282 MHz) K84.36 (s, 3F); IR (KBr)
ymax 3554, 3459, 3325, 3071, 2261, 1733, 1689, 1613,
1518 cmK1; MS (70 eV, EI) m/z (%): 386 (MC, 17.58), 359
(MCKHCN, 8.93), 295 (MCKH2O–CO2Et, 100), 269
(MCKH2O–CO2Et–CN, 48.92), 69 (CF3C, 5.75); HRMS
for C17H17F3N2O5NaC1 Calcd: 409.0982. Found: 409.0999.
4.1.10. Ethyl 6-amino-4-(4-chlorophenyl)-5-cyano-
2-ethoxy-2-(trifluoromethyl)-3,4-dihydro-2H-pyran-3-
carboxylate 3e. White solid; mp 138–140 8C; 1H

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X. Li et al. / Tetrahedron 62 (2006) 2255–2263
NMR (CDCl3, 300 MHz) d 1.03 (t, JZ7.2 Hz, 3H), 1.30 (t,
JZ7.2 Hz, 3H), 2.88 (d, JZ11.7 Hz, 1H), 4.12 (d, JZ
11.7 Hz, 1H), 3.87 (q, JZ7.2 Hz, 2H), 3.96 (q, JZ7.2 Hz,
2H), 4.66 (br, s, 2H), 7.18–7.32 (m, 4H); 19F NMR (CDCl3,
282 MHz) d K77.20 ppm; IR (KBr) ymax 3421, 3329, 2988,
2189, 1749, 1655, 1598, 1492 cmK1; MS (70 eV, EI) m/z (%)
420/418 (MC, 8.97/25.14), 374/372 (MCKEtOH, 5.20/10.31),
345/343 (MCKEt–EtOH, 3.44/5.93), 328/326 (MCK
2EtOH, 6.53/7.30), 301/299 (MCKCO2Et–EtOH, 34.92/
76.23), 207/205 (MCKEtO–CO2Et–CF3–CN, 100/84.31),
69 (CFC3 , 14.84); HRMS for C18H18ClF3N2O4NaC1 Calcd:
441.0799. Found: 441.0819.
2987, 2199, 1741, 1654, 1524, 1350 cmK1; MS (70 eV, EI)
m/z (%) 431 (MCC2, 4.50), 400 (MCKEt, 3.11), 383
(MCKEtOH, 6.59), 310 (MCKCO2Et–EtOH, 29.34), 69
(CFC3 , 16.49). Anal. Calcd for C18H18F3N3O6: C, 50.35%; H,
4.20%; N, 9.79%. Found: C, 50.46%; H, 4.14%; N, 9.85%.
4.1.15. Ethyl 5-cyano-2-hydroxy-4-(4-nitrophenyl)-6-
oxo-2-(trifluoromethyl)-piperidine-3-carboxylate 4g.
White solid; mp 174–175 8C; H NMR (CDCl3, 300 MHz)
1
d 0.87 (t, JZ7.2 Hz, 3H), 3.36 (d, JZ12 Hz, 1H), 3.84–4.07
(m, 4H), 5.78 (br, s, 1H), 6.62 (br, s, 1H), 7.53 (d, JAB
Z
8.4 Hz, 2H), 8.31 (d, JABZ8.4 Hz, 2H); 19F NMR (CDCl3,
282 MHz) d K84.41 (s, 3F); IR (KBr) ymax 3545, 3484,
3291, 2270, 1729, 1702, 1640, 1609, 1523 cmK1; MS
(70 eV, EI) m/z (%): 310 (MCKH2O–CO2Et, 25.47), 284
(MCKH2O–CO2Et–CN, 100), 69 (CFC3 , 6.89); HRMS for
C16H14F3N3O6NaC1 Calcd: 424.0727. Found: 424.0743.
4.1.11. Ethyl 4-(4-chlorophenyl)-5-cyano-2-hydroxy-6-
oxo-2-(trifluoromethyl)-piperidine-3-carboxylate 4e.
White solid; mp 146–148 8C; H NMR (CDCl3, 300 MHz)
1
d 0.87 (t, JZ7.2 Hz, 3H), 3.25 (d, JZ10.8 Hz, 1H), 3.82–3.86
(m, 2H), 3.90 (q, JZ7.2 Hz, 2H), 5.91 (br, s, 1H), 6.52 (br, s,
1H), 7.23–7.43 (m, 4H); 19F NMR (CDCl3, 282 MHz) d
K84.36 (s, 3F); IR (KBr) ymax 3268 (br), 3182, 2900, 2258,
1708, 1590, 1492 cmK1; MS (70 eV, EI) m/z (%): 392/390
(MC, 2.15/6.20), 301/299 (MCKH2O–CO2Et, 30.72/80.20),
275/273 (MCKH2O–CO2Et–CN, 40.17/100), 69 (CFC3 ,
11.13). Anal. Calcd for C16H14ClF3N2O4: C, 49.17%; H,
3.59%; N, 7.17%. Found: C, 49.15%; H, 3.59%; N, 7.27%.
4.1.16. Ethyl 6-amino-5-cyano-2-ethoxy-4-(furan-2-
yl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyran-3-car-
boxylate 3h. White solid; mp 178–179 8C; 1H NMR
(CDCl3, 300 MHz) d 1.11 (t, JZ7.2 Hz, 3H), 1.28 (t, JZ
7.2 Hz, 3H), 3.18 (d, JZ11.7 Hz, 1H), 3.85 (q, JZ7.2 Hz,
2H), 4.06 (q, JZ7.2 Hz, 2H), 4.30 (d, JZ11.7 Hz, 1H), 4.59
(br, s, 2H), 6.28–6.31 (m, 1H), 7.24–7.27 (m, 1H), 7.35–
7.37 (m, 1H); 19F NMR (CDCl3, 282 MHz) d K77.32 (s,
3F); IR (KBr) ymax 3415, 3333, 2198, 1736, 1663, 1616,
1376 cmK1; MS (70 eV, EI) m/z (%) 374 (MC, 100), 345
(MCKEt, 12.28), 328 (MCKEtOH, 67.46), 255 (MCK
CO2Et–EtOH, 95.93), 69 (CFC3 , 22.10). Anal. Calcd for
C16H17F3N2O5: C, 51.34%; H, 4.55%; N, 7.49%. Found: C,
51.53%; H, 4.86%; N, 7.48%.
4.1.12. Ethyl 6-amino-5-cyano-2-ethoxy-4-(4-fluorophe-
nyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyran-3-car-
boxylate 3f. White solid; mp 123–128 8C; 1H NMR (CDCl3,
300 MHz) d 1.01 (t, JZ7.2 Hz, 3H), 1.29 (t, JZ6.9 Hz,
3H), 2.87 (d, JZ12.0 Hz, 1H), 3.89 (q, JZ6.9 Hz, 2H), 3.96
(q, JZ7.2 Hz, 2H), 4.12 (d, JZ12.0 Hz, 1H), 4.78 (br, s,
2H), 6.98–7.04 (m, 2H, Ar–H), 7.21–7.26 (m, 2H, Ar–H);
19F NMR (CDCl3, 282 MHz) d K77.29 (s, 3F), K114.4 (m,
1F); IR (KBr) ymax 3489, 3332, 2195, 1748, 1738, 4660,
1608, 1596, 1346 cmK1; MS (70 eV, EI) m/z (%) 403
(MHC, 6.92), 402 (MC, 24.19), 373 (MCKEt, 4.59), 356
(MCKEtOH, 10.15), 283 (MCK CO2Et–EtOH, 76.42),
189 (MCKEtO–CO2Et–CF3–CN, 100), 69 (CFC3 , 8.78).
Anal. Calcd for C18H18F4N2O4: C, 53.73%; H, 4.48%; N,
6.97%. Found: C, 53.75%; H, 4.56%; N, 6.93%.
4.1.17. Ethyl 6-amino-5-cyano-2-ethoxy-4-(naphthalen-
1-yl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyran-3-car-
boxylate 3i. White solid; mp 198–199 8C; 1H NMR (CDCl3,
300 MHz) d 0.73 (t, JZ7.2 Hz, 3H), 1.39 (t, JZ7.1 Hz,
3H), 3.20 (d, JZ11.7 Hz, 1H), 3.69 (q, JZ7.2 Hz, 2H), 3.95
(q, JZ7.2 Hz, 2H), 4.64 (br, s, 2H), 5.16 (d, JZ11.7 Hz),
7.33–7.58 (m, 4H), 7.77–8.00 (m, 2H), 8.26 (d, JZ8.4 Hz);
19F NMR (CDCl3, 282 MHz) d K76.9 (s, 3F); IR
(KBr) ymax 3419, 3321, 3194, 2203, 1741, 1655, 1606,
1375 cmK1; MS (70 eV, EI) m/z (%): 435 (MCC1, 74.52),
434 (MC, 3.16), 405 (MCKEt, 4.56), 315 (MCK CO2Et–
EtOH, 76.83), 233 (MCKEtO–CO2Et–CF3–CN, 29.41), 69
(CFC3 , 21.88). Anal. Calcd for C22H21F3N2O4: C, 60.83%; H,
4.84%; N, 6.45%. Found: C, 61.05%; H, 4.85%; N, 6.27%.
4.1.13. Ethyl 5-cyano-4-(4-fluorophenyl)-2-hydroxy-6-
oxo-2-(trifluoromethyl)-piperidine-3-carboxylate 4f.
White solid; mp 147–150 8C; H NMR (CDCl3, 300 MHz)
1
d 0.86 (t, JZ7.2 Hz, 3H), 3.25 (d, JZ10.8 Hz, 1H), 3.78–
3.95 (m, 4H), 5.92 (br, s, 1H), 6.50 (br, s, 1H), 7.11–7.32 (m,
4H); 19F NMR (CDCl3, 282 MHz) d K84.56 (s, 3F),
K111.4 (m, 1F); IR (KBr) ymax 3309, 3292, 3243, 1734,
1689, 1516, 1379 cmK1; MS (70 eV, EI) m/z (%): 374 (MC,
3.15), 283 (MCKH2O–CO2Et, 77.32), 257 (MCK
H2O–CO2Et–CN, 100), 69 (CFC3 , 18.23). Anal. Calcd for
C16H14F4N2O4: C, 51.34%; H, 3.74%; N, 7.49%. Found: C,
50.95%; H, 3.93%; N, 7.47%.
4.2. General procedures for the transformation of 4 to 5
To the solution of 4a (2 mmol in 8 ml ethanol) was added
NEt3 (0.3 mmol) under stirring, and then the mixture was
heated to reflux. After 6 h, the TLC analysis showed the
reaction was completed. After removal of the solvent under
reduced pressure the residue was purified by column
chromatography on silica gel using petroleum and ethyl
acetate (6/4, v/v) as eluent. Recrystallization from pet-
roleum and ethyl acetate gave the pure 5a.
4.1.14. Ethyl 6-amino-5-cyano-2-ethoxy-4-(4-nitrophe-
nyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyran-3-car-
1
boxylate 3g. White solid; mp 72–74 8C; H NMR (CDCl3,
300 MHz) d 1.04 (t, JZ7.2 Hz, 3H), 1.32 (t, JZ7.2 Hz, 3H),
2.92 (d, JZ11.7 Hz), 3.89 (q, JZ7.2 Hz, 2H), 3.96 (q, JZ
7.2 Hz, 2H), 4.40 (d, JZ11.7 Hz, 1H), 4.74 (br, s, 2H), 7.46–
7.51 (m, 2H), 8.20–8.23 (m, 2H); 19F NMR (CDCl3,
282 MHz) d K77.17 (s, 3F), IR (KBr) ymax 3453, 3329,
4.2.1. Ethyl 5-carbamoyl-6-oxo-4-phenyl-2-(trifluoro-
methyl)-1,4,5,6-tetrahydropyridine-3-carboxylate 5a.
White solid; mp 160–163 8C; H NMR (CDCl3) d 1.19 (t,
1
JZ7.2 Hz, 3H), 3.61 (d, JZ3 Hz, 1H), 4.17 (q, JZ7.2 Hz,

X. Li et al. / Tetrahedron 62 (2006) 2255–2263
2263
2H), 4.91 (s, 1H), 5.49 (br, s, 1H), 6.19 (br, s, 1H), 7.2–7.37
(m, 5H), 7.52 (br, s, 1H); 19F NMR d K64.27 (s, 3F);
IR (KBr) nmax 3444, 3232, 3169, 1701, 1680, 1305,
1159 cmK1; MS (70 eV, EI) m/z (%): 356 (MC, 1.98),
312 (MCKCONH2, 100), 69 (CF3, 7.23), 44 (CONHC2 ,
53.82). Anal. Calcd for C16H15F3N2O4: C, 53.93%; H,
4.21%; N, 7.87%. Found: C, 53.87%; H, 4.38%; N, 7.85%.
7.41–7.43 (m, 2H), 7.48 (br, s, 1H), 8.21–8.24 (m, 2H); 19F
NMR d K64.22 (s, 3F), IR (KBr) nmax 3408, 3217, 3119,
1716, 1678, 1624, 1599, 1519, 1353, 1305 cmK1; MS
(70 eV, EI) m/z (%): 401 (MC, 0.59), 357 (MCK44, 100),
69 (CF3, 4.28), 44 (CONHC2 , 13.25). Anal. Calcd for
C16H14F3N3O6: C, 47.88%; H, 3.49%; N, 10.47%. Found:
47.92%; H, 3.43%; N, 10.58%.
4.2.2. Ethyl 5-carbamoyl-4-(4-methoxyphenyl)-6-oxo-2-
(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-car-
boxylate 5b. White solid; mp 151–153 8C; 1H NMR
(CDCl3) d 1.20 (t, JZ7.2 Hz, 3H), 3.58 (d, JZ3.6 Hz,
1H), 3.78 (s, 3H) 4.16 (q, JZ7.2 Hz, 3H), 4.83 (s, 1H), 5.51
(br, s, 1H), 6.18 (br, s, 1H), 6.85 (d, JABZ8.4 Hz, 2H), 7.27
(d, JABZ8.4 Hz, 2H), 7.54 (br, s, 1H); 19F NMR d K62.95
(s, 3F); IR (KBr) nmax 3403, 3170, 2943, 1682, 1611, 1512,
1307, 1180 cmK1; MS (70 eV, EI) m/z (%): 386 (MC, 2.21),
342 (MCKCONH2, 100), 69 (CF3, 7.46), 44 (CONHC2 ,
44.48). Anal. Calcd for C17H17F3N2O5: C, 52.85%; H,
4.40%; N, 7.25%. Found: C, 52.95%; H, 4.49%; N, 7.34%.
4.3. X-ray crystal structure data of compounds 3d, 4d
and 5d
Intensity data were collected at 293(2) K on Bruker P4
diffractometer with graphite monochromator and Mo Ka
˚
radiation (lZ0.71073 A). The structure was solved by
direct methods and expanded using Fourier techniques. The
non-hydrogen atoms were refined anisotropically, hydrogen
atoms were included but not refined. The final cycle of full
matrix least-squares refinement was based on F2, respect-
ively. All calculations were performed using SHELXS-97
and SHELXL-97 programs. X-ray data for compounds 3d,
4d and 5d are listed in Table 6.
4.2.3. Ethyl 5-carbamoyl-6-oxo-4-p-tolyl-2-(trifluoro-
methyl)-1,4,5,6-tetrahydropyridine-3-carboxylate 5d.
Crystallographic data have been deposited to the Cambridge
Crystallographic Data Center, CCDC 284791 for 3d,
284792 for 4d and 284793 for 5d. Copies of the information
may be obtained free of charge from the Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: C44 1223 336
033; e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.
ac.uk), upon request.
1
White solid; mp 155–158 8C; H NMR (CDCl3) d 1.19 (t,
JZ7.2 Hz, 3H), 2.31 (s, 3H), 3.58 (d, JZ2.7 Hz, 1H), 4.15 (q,
JZ7.2 Hz, 2H), 4.83 (s, H), 5.76 (br, s, 1H), 6.22 (br, s, 1H),
7.07–7.14 (m, 4H), 7.98 (br, s, 1H); 19F NMR d K64.32 (s,
3F); IR (KBr) nmax 3446, 3048, 3232, 3146, 1701, 1637, 1607,
1307, 1165 cmK1; MS (70 eV, EI) m/z (%): 370 (MC, 0.52),
326 (MCKCONH2, 100), 69 (CF3, 1.55), 44 (CONHC2 ,
4.32). Anal. Calcd for C17H17F3N2O4: C, 55.14%; H, 4.59%;
N, 7.57%. Found: 55.08%; H, 4.56%; N, 7.70%.
Acknowledgements
This work is supported by the National Science Foundation
of China (Nos. 20472106 and 20532040).
4.2.4. Ethyl 5-carbamoyl-4-(4-chlorophenyl)-6-oxo-2-
(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-car-
boxylate 5e. White solid; mp 176–178 8C; 1H NMR
(CDCl3) d 1.21 (t, JZ7.2 Hz, 3H), 3.56 (d, JZ3 Hz, 1H),
4.17 (q, JZ7.2 Hz, 2H), 4.89 (s, 1H), 5.52 (br, 1H), 6.19 (br,
s, 1H), 7.14–7.17 (m, 2H), 7.27–7.51 (m, 2H), 7.75 (br, s,
1H); 19F NMR d K64.30 (s, 3F); IR (KBr) nmax 3446, 3228,
3139, 2952, 1701, 1603, 1493, 1372, 1303, 1165 cmK1; MS
(70 eV, EI) m/z (%): 390 (MC, 0.71), 348/346 (MCK
CONH2, 37.11/100), 69 (CF3, 4.88), 44 (CONHC2 , 10.35).
Anal. Calcd for C16H14ClF3N2O4: C, 49.17%; H, 3.59%; N,
7.17%. Found: 49.10%; H, 3.74%; N, 7.17%.
References and notes
1. Bergmann, E. D.; Ginsburg, D.; Pappo, R.; The Michael Reaction.
Organic Reactions; Wiley: New York, 1959; Vol. 10, p 416.
2. (a) Bloxham, J.; Dell, C. P.; Smith, C. W. Heterocycles 1994,
38, 399–408. (b) Maggi, R.; Ballini, R.; Sartori, G.; Sartorio, R.
Tetrahedron Lett. 2004, 45, 2297–2299.
3. (a) Organofluorine Compounds. Chemistry and Applications;
Hiyama, T., Ed.; Springer: New York, 2000. (b) Organofluorine
Chemistry: Principles and Commercial Applications; Banks,
R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New York,
1994. (c) Fluorine in Bioorganic Chemistry; Welch, J. T.,
Eshwarakrishman, S., Eds.; Wiley: New York, 1991. (d)
Fluorine-Containing Molecules. Structure, Reactivity, Syn-
thesis, and Applications; Liebman, J. F., Greenberg, A.,
Dolbier, W. A., Jr., Eds.; VCH: New York, 1988.
4.2.5. Ethyl 5-carbamoyl-4-(4-fluorophenyl)-6-oxo-2-
(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-car-
boxylate. 5f. White solid; mp 137–139 8C; 1H NMR
(CDCl3) d 1.20 (t, JZ7.2 Hz, 3H), 3.57 (d, JZ3.3 Hz,
1H), 4.16 (q, JZ7.2 Hz, 2H), 4.90 (s, 1H), 5.55 (br, s, 1H),
6.20 (br, s, 1H), 6.96–7.07 (m, 2H), 7.18–7.28 (m, 2H), 7.51
(br, s, 1H); 19F NMR d K64.36 (s, 3F), K114.23 (m, 1F); IR
4. (a) Wang, Y. L.; Zhu, S. Z. Org. Lett. 2003, 5, 745–748. (b)
Marull, M.; Schlosser, M. Eur. J. Org. Chem. 2003, 1576–1588.
(c) Be’gue’, J.-P.; Bonnet-Delpon, D.; Dogbeavou, R.;
(KBr) nmax 3444, 1697 (br), 1606, 1373, 1305, 1163 cmK1
;
MS (70 eV, EI) m/z (%): 374 (MC, 0.50), 330 (MCK
CONH2, 100), 69 (CF3, 2.85), 44 (CONHC2 , 5.85); HRMS
for C16H14F4N2O4NaC1 Calcd: 397.0781. Found: 397.0794.
Oure’vitch, M. J. Chem. Soc., Perkin Trans.
1 1993,
2787–2791. (d) Volochnyuk, D. M.; Pushechnikov, A. O.;
Krotko, D. G.; Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev,
A. A. Synthesis 2003, 1531–1540.
4.2.6. Ethyl 5-carbamoyl-4-(4-nitrophenyl)-6-oxo-2-(tri-
fluoromethyl)-1,4,5,6-tetrahydropyridine-3-carboxylate
5g. White solid; mp 190–195 8C; H NMR (CDCl3) d 1.21
5. Song, L. P.; Zhu, S. Z. J. Fluorine Chem. 2001, 111, 201–205.
6. Venkati, M.; David Krupadanam, G. L. Indian J. Chem., Sect. B
2005, 618–621.
1
(t, JZ7.2 Hz, 3H), 3.59 (d, JZ3 Hz, 1H), 4.18 (q, JZ
7.2 Hz, 2H), 5.05 (s, 1H), 5.50 (br, 1H), 6.24 (br, s, 1H),
7. Lemek, T.; Mayr, H. J. Org. Chem. 2003, 68, 6880–6886.