2778
D. A. Sibgatulin et al. / Tetrahedron Letters 48 (2007) 2775–2779
1
3
Yellow oil (1.84 g, 88%) H NMR (300 MHz, C
6
D
6
): 0.84
), 1.08 (3H, t, JHH = 7.2, CH ),
.59–2.82 (4H, m, NCH ), 2.93 and 3.11 (2H, AB-syst.,
(3H, s, CH
3
), 3.22 (4H, t, JHH = 4.5, NCH
2
), 3.86 (4H, t,
), 4.36 (2H, q, JHH = 7.2, CH ), 6.85
(1H, s, CH), 6.97 (1H, s, CH). C NMR (125 MHz,
CDCl ): 13.9, 20.0, 48.3, 61.6, 66.5, 110.1 (CCCF
3
3
3
3
(
3H, t, JHH = 7.2, CH
3
3
JHH = 4.5, OCH
2
2
1
3
2
J
2
2
3
HH = 16.2, CH
2
), 3.29 (5H, m), 3.77 (2H, q, JHH = 7.2,
3
3
,
3
3
1
CH
1H, s, CH), 6.42 (1H, br s, OH). C NMR (100 MHz,
C D ): 13.4, 14.3, 28.9, 35.3, 45.5, 59.1, 60.9, 65.9, 75.3
2
), 4.07 (2H, q, JHH = 7.2, CH
2
), 4.34 (1H, br m), 4.89
J
CF = 3.8), 119.1, 122.7, 123.7 (CF
3
,
JCF = 265.4),
1
3
2
(
128.7 (CCF
3
, JCF = 31.4), 137.9, 151.4, 168.0. MS (EI,
70 eV): m/z (%) = 318 (17) [M +1], 317 (100) [M ], 272
(52), 259 (55), 214 (37). Anal. Calcd for C15 NO : C,
+
+
6
6
2
1
(
CCF
3
,
J
CF = 27.6), 93.1, 125.4 (CF
3
,
JCF = 284.4),
H
18
F
3
3
1
58.3, 169.1, 172.3. MS (EI, 70 eV): m/z (%) = 383 (10)
56.78; H, 5.72; N, 4.41. Found C, 56.80; H, 5.74; N, 4.39.
13. Ethyl 5-(pyrrolidin-1-yl)-3-(trifluoromethyl)-[1,1‘-biphen-
yl]-2-carboxylate (9a).
+
[
M ], 338 (37), 199 (77), 198 (100), 170 (23), 126 (93), 69
36). Anal. Calcd for C16 NO : C, 50.13; H, 6.31; N,
.65. Found C, 50.09; H, 6.33; N, 3.66.
2. General procedure for the preparation of compounds 7 and
a:
(
3
H
24
F
3
6
A mixture of enamine 4a (1 g, 4.65 mmol) and 4,4,4-
trifluoroacetoacetate 1 (0.86 g, 4.65 mmol) in 15 mL of
acetic acid was refluxed for 2 h. The solvent was evapo-
rated in vacuo, water (10 mL) was added and the pH of
the reaction mixture was adjusted to ꢀ7 with sodium
bicarbonate. The aqueous layer was extracted with
dichloromethane (2 · 10 mL). The combined organic layer
was dried over sodium sulfate, evaporated and the crude
product was purified by column chromatography using
1
8
Method A. To a solution of enamine 3 (5.46 mmol) in
benzene (15 mL) was added 4,4,4-trifluoroacetoacetate 1
(
5
1.0 g, 5.46 mmol). The reaction mixture was refluxed for
h. The solvent was evaporated in vacuo and the residue
was subjected to flash column chromatography using
EtOAc as eluent. After evaporation of the eluent, the
resulting crude mixture of products was dissolved in n-
hexane (10 mL). The solution was left for 1 h at 4 ꢁC
during which time 8a precipitated as a white solid (953 mg,
EtOAc–n-hexane = 2:1 as eluent (R = 0.8) to give com-
f
pound 9a as a pale yellow solid (0.96 g, 57%). Mp = 53 ꢁC.
1
3
H NMR (300 MHz, CDCl
3
): 0.97 (3H, t,
J
HH = 7.2,
),
4.02 (2H, q, J = 7.2, CH ), 6.57 (1H, d, J = 2.4,
3
36%). Evaporation of the mother liquor afforded 7a as
CH ), 2.04 (4H, m, CH ), 3.34 (4H, t, JHH = 4.3, NCH
3
2
2
3
4
colorless oil (640 mg, 40%). Method B. A mixture of
enamine 3 (5.46 mmol) and 4,4,4-trifluoroacetoacetate 1
HH
3
HH
4
13
CH), 6.77 (1H, d, JHH = 2.4, CH), 7.37 (5H, m, Ph).
NMR (125 MHz, CDCl ): 13.6, 25.6, 47.8, 62.3, 108.2
CF = 6.5), 119.8, 120.2, 123.5 (CF
JCF = 271), 123.8, 125.3, 128.7, 129.4 (CCF3,
C
(
1.11 g, 6 mmol) was refluxed in AcOH (15 mL) for 3 h.
3
3
The solvent was evaporated in vacuo, water (10 mL) was
added and the pH of the reaction mixture was adjusted to
(CCCF
3
,
J
3
,
1
2
ꢀ
8 with aqueous ammonia. The aqueous layer was
JCF = 31.5), 131.9, 137.9, 150.2, 162.9. MS (EI, 70 eV):
+ +
extracted with ether (2 · 10 mL). The combined organic
layer was dried over sodium sulfate, evaporated and the
crude product was purified by column chromatography
m/z (%) = 364 (23) [M +1], 363 (100) [M ], 334 (13), 318
(44). Anal. Calcd for C H F NO : C, 66.11; H, 5.55; N,
2
0
20
3
2
3.85. Found C, 66.14; H, 5.54; N, 3.87.
14. General procedure for the preparation of compounds 13 and
14a:
f
using EtOAc as eluent (R = 0.85) to give compound 7 as
an orange oil.
Ethyl 2-methyl-4-pyrrolidin-1-yl-6-(trifluoromethyl)benzo-
Enamine 3a (1 g, 6.54 mmol) and 1,1,1-trifluoroacetyl-
acetone 12b (1.06 g, 6.54 mmol) were mixed without
solvent in a pressure tube and heated for 4 h. The resulting
ate (7a):
1
3
H NMR (300 MHz, CDCl
3
): 1.35 (3H, t,
HH
J =
3
7
.2, CH
3
), 2.03 (4H, t,
J
HH = 6.9, CH ), 2.34 (3H, s,
2
oil was separated by column chromatography on SiO
using EtOAc–cyclohexane = 1:9 as eluent giving targeted
compounds 13 (R = 0.62) and 14a (R = 0.38).
2
3
CH ), 3.30 (4H, t, JHH = 6.9, NCH ), 4.34 (2H, t,
3
2
3
J
HH = 7.2, CH
2
), 6.46 (1H, s, CH), 6.61 (1H, s,
f
f
13
CH). C NMR (125 MHz, CDCl
3
): 13.9, 20.2, 25.4,
1-[3-Methyl-5-(trifluoromethyl)phenyl]pyrrolidine (13):
1
1
4
1
7
7.5, 61.3, 106.5, 115.4, 118.5, 123.4 (CF
3
, JCF = 272.5),
Brown oil (0.67 g, 45%). H NMR (300 MHz, CDCl
3
):
2
28.8 (CCF , J = 31.2), 137.9, 147.8, 168.6. MS (EI,
2.04 (4H, m, CH ), 2.38 (3H, s, CH ), 3.32 (4H, m,
3
CF
2
3
+
+
0 eV): m/z (%) = 301 (100) [M ], 300 (48) [M À1], 272
NCH ), 6.54 (1H, s, CH), 6.61, (1H, s, CH), 6.75 (1H, s,
2
13
(
22), 256 (61), 228 (19). Anal. Calcd for C15
H
18
F
3
NO : C,
2
CH). C NMR (125 MHz, CDCl
3
): 21.7, 25.5, 47.7,
1
5
4
9.79; H, 6.02; N, 4.65. Found C, 59.81; H, 6.03; N,
.63.
105.3, 112.6, 115.2, 124.7 (CF , JCF = 271.6), 131.2
3
2
(CCF3, JCF = 31.4), 139.5, 147.9. Anal. Calcd for
Ethyl
2-[4-ethoxy-2-hydroxy-4-oxo-2-(trifluoromethyl)-
12 14 3
C H F N: C, 62.87; H, 6.16; N, 6.11. Found C, 62.85;
butyl]-4-pyrrolidin-1-yl- 6-(trifluoromethyl)benzoate (8a):
H, 6.15; N, 6.13.
1-[2-Methyl-6-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]eth-
3
Mp = 49 ꢁC. 1.26 (3H, t, J = 7.2, CH ), 1.36 (3H, t,
HH
3
3
3
J
HH = 7.2, CH
3
), 2.05 (4H, t, JHH = 6.3, CH
2
), 2.49 and
anone (14a):
2
1
2
.71 (2H, AB-syst., JHH = 15.3, CH
2
), 3.09 and 3.16 (2H,
Orange oil (0.73 g, 41%). H NMR (300 MHz, CDCl
3
):
),
2
3
AB-syst.,
JHH = 14.1, CH
2
), 3.33 (4H, t,
JHH = 6.3,
1.94 (4H, m, CH ), 2.25 (3H, s, CH ), 2.46 (3H, s, CH
2 3
3
3
13
NCH ), 4.15 (2H, t, JHH = 7.2, CH ), 4.34 (2H, t,
), 6.16 (1H, s, OH), 6.73 (1H, d,
HH = 2.1, CH), 6.97 (1H, d,
3.23 (4H, m, NCH ), 6.87 (2H, s, CH). C NMR
2
2
2
3
4
J
J
HH = 7.2, CH
2
(125 MHz, CDCl
3
): 19.8, 25.5, 31.7, 51.4, 108.9 (CCCF
3
,
,
4
13
3
3
J
HH = 2.1, CH).
C
JCF = 3.77), 116.7 (CCCF
3
, 2 JCF = 3.77), 124.1 (CF
3
1
NMR (125 MHz, CDCl ): 13.7, 13.8, 25.4, 35.7, 36.3,
JCF = 272.9), 131.2 (CCF3, JCF = 32.7), 133.1, 147.0,
206.7. Anal. Calcd for C H F NO: C, 61.99; H, 5.94; N,
3
2
4
1
2
1
7.6, 61.3, 62.2, 74.6 (CCF , JCF = 26.4), 108.5, 117.6,
3
1 1
14 16 3
18.7, 123.7 (CF
59.1), 129.8 (CCF
71.4. MS (EI, 70 eV): m/z (%) = 486 (20) [M +1], 485
3
,
J
CF = 246.5), 126.1 (CF
3
,
J
CF
=
5.16. Found C, 62.01; H, 5.95; N, 5.17.
2
3
,
J
CF = 30.2), 134.8, 148.0, 169.5,
15. [2-Methyl-6-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]-
(phenyl)methanone (14b).
+
+
(
100) [M ], 440 (16), 352 (12), 301 (15), 252 (13), 228 (11).
Enamine 4a (1 g, 4.65 mmol) and 1,1,1-trifluoroacetyl-
acetone 12b (0.72 g, 4.65 mmol) were mixed without
solvent in a pressure tube and heated for 4 h. The resulting
oil was purified by column chromatography using EtOAc–
Anal. Calcd for C20 NO : C, 50.96; H, 4.92; N, 2.97.
H
23
F
6
5
Found C, 50.93; H, 4.95; N, 3.01.
Ethyl 2-methyl-4-(4-morpholinyl)-6-(trifluoromethyl)ben-
zoate (7b):
n-hexane = 1:2 as eluent (R = 0.7) to give compound 14b
f
1
1
Method B was applied. Brown oil (1.35 g, 72%). H NMR
as a yellow oil (0.65 g, 42%). H NMR (300 MHz, CDCl
3
):
3
(
300 MHz, CDCl ): 1.37 (3H, t, JHH = 7.2, CH ), 2.34
1.79 (4H, m, CH ), 2.08 (3H, s, CH ), 3.18 (4H, br s,
3
3
2
3