Synthesis and some transformations of γ-(p-fluorophenyl)-γ-(2- furyl)propylamine

Article abstract of DOI:10.1007/s10593-006-0108-0

Ethyl α-cyano-β-(p-fluorophenyl)-β-(2-furyl)propionate was obtained by the condensation of ethyl α-cyano-β-(2-furyl)acrylate with p-fluorophenylmagnesium bromide. Its deethoxycarbonylation led to β-(p-fluorophenyl)-β-(2-furyl)propionitrile. Reduction of t

Full text of DOI:10.1007/s10593-006-0108-0

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
SYNTHESIS AND SOME TRANSFORMATIONS
OF γ-(p-FLUOROPHENYL)-γ-(2-FURYL)PROPYLAMINE
N. S. Arutyunyan1, L. A. Akopyan1, G. M. Snkhchyan1, O. A. Papoyan1, G. A. Panosyan2,
and G. A. Gevorgyan1
Ethyl α-cyano-β-(p-fluorophenyl)-β-(2-furyl)propionate was obtained by the condensation of ethyl
α-cyano-β-(2-furyl)acrylate with p-fluorophenylmagnesium bromide. Its deethoxycarbonylation led to β-
(p-fluorophenyl)-β-(2-furyl)propionitrile. Reduction of the nitrile with lithium aluminum hydride gave γ-
(p-fluorophenyl)-γ-(2-furyl)propylamine. Some transformations of the latter were studied.
Keywords: γ-(p-fluorophenyl)-γ-(2-furyl)propylamine, ethyl furfurylidenecyanoacetate, ethyl
β-(p-fluorophenyl)-β-(2-furyl)propionate, reduction, deethoxycarbonylation.
Earlier we reported the synthesis and some transformations of γ-(2-furyl)-γ-phenylpropylamine [1]. In
order to investigate the relation between the biological activity and structure in the present work we synthesized
analogous derivatives containing a fluorine atom at the p-position of the benzene ring. Thus, in the reaction of
p-fluorophenylmagnesium bromide with ethyl α-cyano-β-(2-furyl)acrylate (1) [2] we obtained ethyl α-cyano-
β-(p-fluorophenyl)-β-(2-furyl)propionate (2), the deethoxycarbonylation of which led to the corresponding
nitrile 3. Reduction of the latter with lithium aluminum hydride gave the amine 4. Reaction of the amine with
substituted aromatic aldehydes or ketones 5a-h led to the corresponding azomethines 6a-h, which were reduced
by sodium borohydride without isolation to the amines 7a-h and transformed by treatment with various acid
chlorides into the amides 8a-f. From the amine 4 by reaction with succinic or phthalic anhydrides we obtained
the N-substituted succinimide 9 and phthalimide 10 respectively (Scheme 1).
The compositions and structures of the synthesized compounds were confirmed by elemental analysis
(Table 1) and 1H NMR spectra (Table 2).
EXPERIMENTAL
1
The IR spectra were recorded in vaseline oil on a UR-20 spectrometer. The H NMR spectra were
recorded on a Varian Mercury-300 instrument (300 MHz) with TMS as internal standard.
Ethyl furfurylidenecyanoacetate 1 was obtained by the familiar procedure [2].
__________________________________________________________________________________________
1 A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Republic
of Armenia, Erevan 375014; e-mail: gagevorgyan@yahoo.com. 2 Molecule Structure Research Center, National
Academy of Sciences of the Republic of Armenia, Erevan 375014. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 503-509, April, 2006. Original article submitted October 22, 2002.
Revision submitted January 21, 2005.
440
0009-3122/06/4204-0440©2006 Springer Science+Business Media, Inc.

Scheme 1
CN
p-FC6H4MgBr
COOEt
CN
KOH
Het
Het
COOEt
HOCH2CH2OH
Ar
2
1
R
O=C
Ar1
CN
Het
NH2
Het
LiAlH4
5a–h
Ar
Ar
4
3
R
Het
N
O
Ar
O
Ar1
O
6a–h
O
O
H
R
Het
O
N
Ar
O
Ar1
7a–h
N
Het
R1COCl
7a–f
O
Ar
O
9
Ar1
N
Het
R1
Het
N
O
Ar
10
O
Ar
8a–f
Het = 2-furyl, Ar = p-fluorophenyl; 5a-f – 7a-f R = H, a Ar1 = Ph, b Ar1 = p-Me2NC6H4;
c Ar1 = p-i-C3H7OC6H4, d Ar1 = p-MeOC6H4, e Ar1 = m,p-(MeO)2C6H3, f Ar1 = o-FC6H4, 5g-h – 7g-h R = Me,
g Ar1 = p -ClC6H4, h Ar1 = Ph; 8 a-b R1 = Me, a Ar1 = Ph, b Ar1 = p-MeOC6H4,
c-f R1 = Et, c Ar1 = Ph, d Ar1 = p-MeOC6H4, e Ar1 = m,p-(MeO)2C6H3, f Ar1 = p-FC6H4
TABLE 1. The Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
bp, °C (mm Hg)
Yield, %
C
3
H
4
N
5
1
2
2
6
7
C16H14FNO3
C13H10FNO
C13H14FNO
66.83
66.89
72.60
72.55
71.27
71.21
4.85
4.91
4.62
4.68
6.48
6.43
4.91
4.87
6.45
6.50
6.32
6.38
160-162 (1)
138-141 (1)
118 (2)
81
54
87
3
4
441

TABLE 1 (continued)
1
2
3
4
5
6
7
7a
C20H20FNO
C22H25FN2O
C23H26FNO2
C21H22FNO2
C22H24FNO3
C20H19F2NO
C21H21ClFNO
C21H22FNO
C22H22FNO2
C23H24FNO3
C23H24FNO2
C24H26FNO3
C25H28FNO4
C23H23F2NO2
C17H16FNO3
C21H16FNO3
77.68
77.64
75.02
74.97
75.15
75.17
75.15
75.19
71.55
71.52
73.33
73.37
70.52
70.48
77.95
77.99
75.24
75.19
72.40
72.42
75.63
75.59
72.72
72.70
70.60
70.56
75.76
72.04
67.80
67.76
72.33
72.19
6.48
6.51
7.17
7.14
7.11
7.15
6.50
6.53
6.50
6.54
5.88
5.84
6.00
5.97
6.81
6.85
6.33
6.30
6.30
6.34
6.66
6.61
6.62
6.60
6.60
6.63
6.32
6.04
5.39
5.35
4.56
4.61
4.50
4.52
8.00
7.94
3.80
3.81
4.16
4.12
3.82
3.79
4.23
4.27
3.86
3.91
4.30
4.33
4.02
3.98
3.63
3.67
3.80
3.83
3.52
3.53
3.25
3.29
3.80
3.65
4.60
4.64
4.05
4.00
182-184 (2)
220-221 (1)
226-229 (1)
195-198 (1)
220-224 (1)
189-191 (2.5)
215-217 (2)
200-201 (2)
210-213 (1.5)
245-248 (2)
225-228 (1.5)
240-244 (1)
253-256 (2)
215-219 (1)
190-193 (1)
210-214 (1)
90
78
90
93
86
87
76
74
69
71
66
67
64
70
68
72
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
8e
8f
9
10
TABLE 2. The 1H NMR Spectra of Compounds 2-4, 7-10
Com-
pound*
Chemical shifts, δ, ppm (SSCC, J, Hz)*2
1
2
2
1.18 (1.5H, t, J = 7.1) and 1.20 (1.5H, t, J = 7.1, CH3); 4.15 (1H, q, J = 7.1) and 4.15 (1H,
q, J = 7.1, CH2); 4.61 (0.5H, d, J = 7.4) and 4.71 (0.5H, d, J = 7.4, CHCN); 4.77 (0.5H, d,
J = 7.4) and 4.82 (0.5H, d, J = 7.4, CHAr); 6.27 (0.5H, d, J = 3.4, HHet-3);
6.34-6.42 (1.5H, m, HHet-3,4); 7.06 (1H, t, J = 8.5) and 7.09 (1H, t, J = 8.5, HAr-3,5);
7.36-7.46 (3H, m, HAr-2,6, HHet-5)
3
4
3.05 (1H, dd, J1 = 16.9, J2 = 7.4) and 3.11 (1H, dd, J1 = 16.9, J2 = 7.4, CHCH2);
4.45 (1H, t, J = 7.4, CH); 6.24 (1H, d, J = 3.2, HHet-3); 6.34 (1H, dd, J1 = 3.2, J2 = 2.0,
HHet-4); 7.05 (2H, t, J = 8.7, HAr-3,5); 7.31 (2H, dd, J1 = 8.7, J2 = 5.4, HAr-2,6);
7.42 (1H, d, J = 2.0, HHet-5)
1.92 (1H, m) and 2.13 (1H, dq, J1 = 13.5, J2 = 7.0, CHCH2); 1.97 (2H, br, NH2);
2.53 (2H, m, NCH2); 4.14 (1H, t, J = 7.7, CH); 6.06 (1H, d, J = 3.2, HHet-3);
6.26 (1H, dd, J1 = 3.2, J2 = 1.8, HHet-4); 6.98 (2H, t, J = 8.7, HAr-3,5);
7.22 (2H, dd, J1 = 8.7, J2 = 5.4, HAr-2,6); 7.32 (1H, d, J = 1.8, HHet-5)
7a
1.75 (1H, br, NH); 1.89 (1H, dtd, J = 13.7, J = 8.2 and J = 6.5) and 2.22 (1H, dq,
J1 = 13.7, J2 = 7.1, CHCH2); 2.47 (1H, dt, J1 = 11.5, J2 = 6.8) and 2.51 (1H, dt,
J1 = 11.5, J2 = 6.8, NCH2); 3.66 (1H, d, J = 13.4) and 3.69 (1H, d, J = 13.4, CH2C6H5);
4.17 (1H, dd, J1 = 8.2, J2 = 7.1, CH); 6.04 (1H, d, J = 3.3, HHet-3); 6.25 (1H, dd, J1 = 3.3,
J2 = 1.8, HHet-4); 6.96 (2H, t, J = 8.7, HAr-3,5); 7.14-7.27 (7H, m, HAr-2,6 and C6H5);
7.31 (1H, d, J = 1.8, HHet-5)
442

TABLE 2 (continued)
1
2
7b
1.90 (1H, br, NH); 1.99 (1H, dtd, J1 = 13.5, J2 = 8.3, J3 = 6.6) and 2.24 (1H, dq,
J1 = 13.5, J2 = 7.0, CHCH2); 2.49 (1H, dt, J1 = 11.6, J2 = 6.6) and 2.53 (1H, dt,
J1 = 11.6, J2 = 6.6, NCH2); 2.93 (6H, s, N(CH3)2); 3.57 (1H, d, J = 12.8) and 3.61 (1H, d,
J = 12.8, CH2Ar1); 4.18 (1H, dd, J1 = 8.3, J2 = 7.0, CH); 6.08 (1H, d, J = 3.2, HHet-3);
6.28 (1H, dd, J1 = 3.2, J2 = 1.9, HHet-4); 6.64 (2H, d, J = 8.7, HAr1-3,5); 6.98 (2H, t, J = 8.7,
HAr-3,5); 7.11 (2H, d, J = 8.7, HAr1-2,6); 7.22 (2H, dd, J1 = 8.7, J2 = 5.4, HAr-2,6);
7.34 (1H, d, J = 1.9, HHet-5)
7c
1.33 (6 H, d, J = 6.0, (CH3)2); 1.91 (1H, br, NH); 1.98 (1H, dtd, J1 = 13.5, J2 = 8.2,
J3 = 6.4) and 2.23 (1H, dq, J1 = 13.5, J2 = 7.0, CHCH2); 2.47 (1H, dt, J1 = 11.6, J2 = 6.7)
and 2.51 (1H, dt, J1 = 11.6, J2 = 6.7, NCH2); 3.59 (1H, d, J = 13.0) and 3.62 (1H, d,
J = 13.0, CH2Ar1); 4.17 (1H, dd, J1 = 8.2, J2 = 7.0, CH); 4.52 (1H, с. п, J = 6.0, OCH);
6.05 (1H, d, J = 3.2, HHet-3); 6.27 (1H, dd, J1 = 3.2, J2 = 1.8, HHet-4); 6.76 (2H, d, J = 8.6, HAr13,5);
6.97 (2H, t, J = 8.6, HAr1-3,5); 7.15 (2H, d, J = 8.6, HAr12,6); 7.21 (2H, dd, J1 = 8.6, J2 = 5.5,
HAr1-2,6); 7.32 (1H, d, J = 1.8, HHet-5)
7d
7e
1.47 (1H, br, NH); 1.97 (1H, dtd, J1 = 13.6, J2 = 8.4, J3 = 6.8) and 2.21 (1H, dq,
J1 = 13.6, J2 = 6.8, CHCH2); 2.40-2.54 (2H, m, NCH2); 3.58 (1H, d, J = 13.1) and 3.62
(1H, d, J = 13.1, CH2Ar1); 3.76 (3H, s, OCH3); 4.16 (1H, dd, J1 = 8.4, J2 = 6.8, CH);
6.04 (1H, d, J = 3.2, HHet-3); 6.26 (1H, dd, J1 = 3.2, J2 = 1.8, HHet-4); 6.78 (2H, d, J = 8.7,
HAr1-3,5); 6.96 (2H, t, J = 8.7, HAr-3,5); 7.16 (2H, d, J = 8.7, HAr1-2,6); 7.20 (2H, dd,
J1 = 8.7, J2 = 5.6, HAr-2,6); 7.31 (1H, d, J = 1.8, HHet-5)
1.54 (1H, br, NH); 1.97 (1H, dtd, J1 = 13.5, J2 = 8.2, J3 = 6.4) and 2.22 (1H, dq,
J1 = 13.5, J2 = 7.0, CHCH2); 2.45 (1H, dt, J1 = 11.8, J2 = 6.7) and 2.49 (1H, dt,
J1 = 11.8, J2 = 6.7, NCH2); 3.58 (1H, d, J = 13.2) and 3.60 (1H, d, J = 13.2, CH2Ar1);
3.78 (3H, s, OCH3); 3.80 (3H, s, OCH3); 4.15 (1H, dd, J1 = 8.2, J2 = 7.0, CH); 6.05 (1H, d,
J = 3.2, HHet-3); 6.26 (1H, dd, J1 = 3.2, J2 = 1.9, HHet-4); 6.73 (2H, br.. s, HAr1-5,6);
6.84 (1H, br.. s, HAr1-2); 6.96 (2H, t, J = 8.7, HAr-3,5); 7.20 (2H, dd, J1 = 8.7, J2 = 5.5,
HAr-2,6); 7.31 (1H, d, J = 1.9, HHet-5)
7f
1.78 (1H, br, NH); 2.02 (1H, dtd, J1 = 13.6, J2 = 8.2, J3 = 6.4) and 2.26 (1H, dq,
J1 = 13.6, J2 = 6.9, CHCH2); 2.51 (1H, dt, J1 = 11.5, J2 = 6.7) and 2.55 (1H, dt,
J1 = 11.5, J2 = 6.7, NCH2); 3.76 (2H, CH2Ar1); 4.21 (1H, dd, J1 = 8.2, J2 = 6.9, CH);
6.08 (1H, d, J = 3.3, HHet-3); 6.28 (1H, dd, J1 = 3.3, J2 = 1.8, HHet-4); 6.99 (2H, t, J = 8.7,
HAr-3,5); 7.03 (1H, m); 7.09 (1H, t, J = 7.5); 7.21 (1H, m) and 7.38 (1H, td, J1 = 7.5, J2 = 1.7,
HAr1-3,4,5,6); 7.23 (2H, dd, J1 = 8.7, J2 = 5.5, HAr-2,6); 7.33 (1H, d, J = 1.8, HHet-5)
7g
1.25 (1.5H, d, J = 6.6) and 1.26 (1.5H, d, J = 6.6, CH3); 1.74 (1H, br, NH);
1.86–2.03 (1H, m) and 2.09-2.25 (1H, m, CHCH2); 2.23–2.41 (2H, m, NCH2);
3.63 (0.5H, q, J = 6.6) and 3.64 (0.5H, q, J = 6.6, CHAr1); 4.10 (0.5H, dd, J1 = 8.6,
J2 = 6.0) and 4.15 (0.5H, t, J = 7.7, CH); 6.01 (0.5H, d, J = 3.1) and 6.02 (0.5H, d, J = 3.1,
HHet-3); 6.24 (1H, br, HHet-4); 6.94 (1H, t, J = 8.6) and 6.97 (1H, t, J = 8.6, HAr-3,5);
7.14 (1H, dd, J1 = 8.6, J2 = 5.4) and 7.20 (1H, dd, J1 = 8.6, J2 = 5.4, HAr-2,6); 7.22 (2H, s)
and 7.23 (2H, s, HAr1-2,3,5,6); 7.30 (1H, br, HHet-5)
7h
1.28 (1.5H, d, J = 6.6) and 1.29 (1.5H, d, J = 6.6, CH3); 1.52 (1H, br, NH);
1.87-2.00 (1H, m) and 2.11-2.24 (1H, m, CHCH2); 2.24-2.44 (2H, m, NCH2);
3.64 (0.5H, q, J = 6.6) and 3.65 (0.5H, q, J = 6.6, CHAr1); 4.12 (0.5H, dd, J1 = 8.9,
J2 = 6.3) and 4.16 (0.5H, t, J = 7.7, CH); 6.00 (0.5H, d, J = 3.2) and 6.02 (0.5H, d, J = 3.2,
HHet-3); 6.23 (0.5H, dd, J1 = 3.2, J2 = 1.9) and 6.25 (0.5H, dd, J1 = 3.2, J2 = 1.9, HHet-4);
6.92 (1H, t, J = 8.7) and 6.97 (1H, t, J = 8.7, HAr-3,5); 7.14 (1H, dd, J1 = 8.7, J2 = 5.4) and 7.18
(1H, dd, J1 = 8.7, J2 = 5.4, HAr-2,6); 7.17-7.25 (5H, m, C6H5); 7.29 (0.5H, d, J = 1.9) and 7.30
(0.5H, d, J = 1.9, HHet-5)
8a
8b
1.93 (1.5H, s) and 2.00 (1.5H, s, Ac); 2.02-2.14 (1H, m) and 2.20-2.36 (1H,
m, CHCH2); 3.03-3.22 (1.5H, m) and 3.31 (0.5H, ddd, J1 = 13.3, J2 = 9.7, J3 = 5.7,
NCH2); 3.93 (0.5H, t, J = 7.6) and 3.94 (0.5H, t, J = 7.6, CH); 4.45 (1H, s) and 4.45 (0.5H,
d, J = 14.8) and 4.49 (0.5H, d, J = 14.8, CH2Ar1); 6.06 (0.5H, d, J = 3.2) and 6.08 (0.5H,
d, J = 3.2, HHet-3); 6.25 (0.5H, dd, J1 = 3.2, J2 = 2.0) and 6.28 (0.5H, dd, J1 = 3.2, J2 = 2.0,
HHet-4); 6.96 (1H, t, J = 8.7) and 6.98 (1H, t, J = 8.7, HAr-3,5); 7.09-7.33 (7H, m, HAr-2,6,
C6H5); 7.30 (0.5H, d, J = 2.0) and 7.34 (0.5H, d, J = 2.0, HHet-5)
1.91 (1.5H, s) and 2.02 (1.5H, s, Ac); 2.00-2.14 (1H, m) and 2.19-2.36 (1H, m, CHCH2);
3.00-3.20 (1.5H, m) and 3.28 (0.5H, ddd, J1 = 13.5, J2 = 9.5, J3 = 5.7, NCH2);
3.76 (1.5H, s) and 3.77 (1.5H, s, OCH3); 3.93 (1H, t, J = 7.7, CH); 4.37 (1H, s) and 4.38
(0.5H, d, J = 14.5) and 4.43 (0.5H, d, J = 14.5, CH2Ar1); 6.07 (0.5H, d, J = 3.1) and 6.09
(0.5H, d, J = 3.1, HHet-3); 6.26 (0.5H, dd, J1 = 3.1, J2 = 1.9) and 6.29 (0.5H, dd, J1 = 3.1,
J2 = 1.9, HHet-4); 6.77 (1H, d, J = 8.6) and 6.82 (1H, d, J = 8.6, HAr1-3,5); 6.97 (2H, t,
J = 8.6, HAr-3,5); 7.01 (1H, d, J = 8.6) and 7.05 (1H, d, J = 8.6, HAr1-2,6); 7.20 (2H, dd,
J1 = 8.6, J2 = 5.4, HAr-2,6); 7.31 (0.5H, d, J = 1.9) and 7.35 (0.5H, d, J = 1.9, HHet-5)
443

TABLE 2 (continued)
1
2
8c
8d
8e
1.06 (1.5H, t, J = 7.2) and 1.07 (1.5H, t, J = 7.2, CH3); 2.01–2.14 (1H, m)
and 2.22-2.36 (1H, m, CHCH2); 2.19 (1H, q, J = 7.2) and 2.27 (1H, q, J = 7.2, CH2CH3);
3.03-3.23 (1.5H, m) and 3.34 (0.5H, ddd, J1 = 13.4, J2 = 9.6, J3 = 5.6, NCH2);
3.93 (0.5H, t, J = 7.7) and 3.95 (0.5H, t, J = 7.7, CH); 4.47 (1H, s) and 4.48 (0.5H, d,
J = 14.7) and 4.53 (0.5H, d, J = 14.7, CH2C6H5); 6.06 (0.5H, d, J = 3.2) and 6.11 (0.5H,
d, J = 3.2, HHet-3); 6.26 (0.5H, dd, J1 = 3.2, J2 = 1.9) and 6.28 (0.5H, dd, J1 = 3.2, J2 = 1.9,
HHet-4); 6.97 (1H, t, J = 8.7) and 6.99 (1H, t, J = 8.7, HAr-3,5); 7.11-7.35 (8H, m,
HAr-2,6, C6H5, HHet-5)
1.04 (3H, t, J = 7.3, CH2CH3); 1.97-2.11 (1H, m) and 2.19-2.31 (1H, m, CHCH2); 2.14 (1H, q,
J = 7.3) and 2.27 (1H, q, J = 7.3, CH2CH3); 2.96-3.18 (1.5H, m) and 3.28 (0.5H, ddd, J1 = 13.4,
J2 = 9.6, J3 = 5.5, NCH2); 3.76 (3H, s, OCH3); 3.91 (1H, br. t, J = 7.7, CH); 4.37 (1H, s) and 4.37
(0.5H, d, J = 14.5) and 4.42 (0.5H, d, J = 14.5, CH2Ar1); 6.05 (0.5H, d, J = 3.2) and 6.08 (0.5H, d,
J = 3.2, HHet-3); 6.25 (0.5H, dd, J1 = 3.2, J2 = 1.9) and 6.27 (0.5H, dd, J1 = 3.2, J2 = 1.9, HHet-4);
6.75 (1H, d, J = 8.6) and 6.80 (1H, d, J = 8.6, HAr1-3,5); 6.93-7.03 (4H, m, HAr-3,5, HAr1-2,6);
7.19 (2H, dd, J1 = 8.7, J2 = 5.4, HAr-2,6); 7.30 (0.5H, d, J = 1.9) and 7.34 (0.5H, d, J = 1.9,
HHet-5)
1.05 (3H, t, J = 7.3, CH2CH3); 1.99-2.12 (1H, m) and 2.19-2.36 (1H, m, CHCH2);
2.16 (1H, q, J = 7.3) and 2.28 (1H, q, J = 7.3, CH2CH3); 3.00-3.19 (1.5H, m) and 3.30
(0.5H, ddd, J1 = 13.5, J2 = 9.7, J3 = 5.5, NCH2); 3.74 (1.5H, s) and 3.76 (1.5H, s, OCH3);
3.77 (3H, s, OCH3); 3.93 (1H, br. t, J = 7.7, CH); 4.37 (1H, s) and 4.37 (0.5H, d,
J = 14.5) and 4.41 (0.5H, d, J = 14.5, CH2Ar1); 6.07 (0.5H, d, J = 3.2) and 6.10 (0.5H, d,
J = 3.2, HHet-3); 6.26 (0.5H, dd, J1 = 3.2, J2 = 1.8) and 6.28 (0.5H, dd, J1 = 3.2, J2 = 1.8,
HHet-4); 6.55–6.61 (1H, m, HAr1-6); 6.62-6.70 (1H, m, HAr1-2); 6.72 (0.5H, d, J = 8.1,
HAr1-5); 6.97 (1H, t, J = 8.7) and 6.99 (1H, t, J = 8.7, HAr-3,5); 7.20 (2H, dd, J1 = 8.7,
J2 = 5.5, HAr-2,6); 7.31 (0.5H, d, J = 1.8) and 7.35 (0.5H, d, J = 1.8, HHet-5)
8f
1.05 (3H, t, J = 7.3, CH2CH3); 1.98-2.13 (1H, m) and 2.21-2.38 (1H, m, CHCH2);
2.18 (1H, q, J = 7.3) and 2.28 (1H, q, J = 7.3, CH2CH3); 3.07-3.23 (1.5H, m) and 3.32
(0.5H, ddd, J1 = 13.5, J2 = 9.7, J3 = 5.6, NCH2); 3.95 (1H, t, J = 7.7, CH); 4.50 (1H, s)
and 4.56 (1H, s, CH2Ar1); 6.07 (0.5H, d, J = 3.2) and 6.10 (0.5H, d, J = 3.2, HHet-3);
6.26 (0.5H, dd, J1 = 3.2, J2 = 1.9) and 6.27 (0.5H, dd, J1 = 3.2, J2 =1.9, HHet-4);
6.94-7.29 (6H, m, HAr-3,5, HAr1-3,4,5,6); 7.20 (2H, dd, J1 = 8.7, J2 = 5.4, HAr-2,6);
7.31 (0.5H, d, J = 1.9) and 7.34 (0.5H, d, J = 1.9, HHet-5)
9
2.10 (1H, dtd, J1 = 13.8, J2 = 7.9, J = 6.3) and 2.30 (1H, dtd, J1 = 13.8, J2 = 7.7, J = 6.7,
CHCH2); 2.53 (4H, s, C(O)CH2); 3.37 (1H, ddd, J1 = 13.3, J2 = 7.9, J3 = 6.3)
and 3.42 (1H, ddd, J1 = 13.3, J2 = 7.9, J3 = 6.3, NCH2); 4.01 (1H, br. t, J = 7.6, CH);
6.10 (1H, d, J = 3.2, HHet-3); 6.27 (1H, dd, J1 = 3.2, J2 = 1.9, HHet-4); 7.00 (2H, t, J = 8.7,
HAr-3,5); 7.24 (2H, dd, J1 = 8.7, J2 = 5.4, HAr-2,6); 7.34 (1H, d, J = 1.9, HHet-5)
10
2.23 (1H, dtd, J1 = 13.6, J2 = 8.1, J = 6.5) and 2.41 (1H, dq, J1 = 13.6, J2 = 6.8, CHCH2);
3.60 (1H, ddd, J1 = 13.7, J2 = 7.8, J3 = 6.4) and 3.63 (1H, ddd, J1 = 13.7, J2 = 7.8,
J3 = 6.4, NCH2); 4.06 (1H, br. t, J = 7.6, CH); 6.10 (1H, d, J = 3.2, HHet-3); 6.23 (1H, dd,
J1 = 3.2, J2 = 1.9, HHet-4); 6.96 (2H, t, J = 8.7, HAr-3,5); 7.25 (2H, dd, J1 = 8.7, J2 = 5.4,
HAr-2,6); 7.30 (1H, d, J = 1.9, HHet-5); 7.73-7.81 (4H, m, Ar1)
_______
*Compounds 2, 7g,h, and 8a-f were in the form of mixtures of two
diastereoisomers in approximately equal amounts.
1
*2 The H NMR spectra were recorded in a 1:3 mixture of DMSO-d6 and
carbon tetrachloride.
Ethyl α-Cyano-β-(p-fluorophenyl)-β-(2-furyl)propionate (2). To an ether solution of the Grignard
reagent prepared from magnesium (8.4 g, 0.33 mol) in absolute ether (50 ml) and p-fluorobromobenzene (59.5 g,
0.34 mol) in ether (200 ml) we added with gentle boiling and stirring a solution of the ester 1 (53.5 g, 0.27 mol)
in benzene (50 ml). The reaction mixture was stirred at 42-44°C for 1.5 h, kept at room temperature for 16-20 h,
acidified with 10% hydrochloric acid, and extracted with ether. The extract was washed with water and dried.
The residue after distillation of the solvents was distilled under vacuum. We obtained 65.0 g (81.2%) of the ester
2. IR spectrum, ν, cm-1: 1590, 1610 (C=C arom.), 1720 (C=O), 2225 (CN).
444

β-(p-Fluorophenyl)-β-(2-furyl)propionitrile (3). Potassium hydroxide (25.2 g, 0.45 mol) was dissolved
by heating in ethylene glycol (135 ml). The obtained solution was added to the ester 2 (65 g, 0.22 mol). The
mixture was boiled with a reflux condenser for 3 h and was then cooled, water (135 ml) was added, and the
product was extracted with ether. The extract was washed with water and dried, and the residue after distillation
of the ether was distilled under vacuum. We obtained 48.7 g of the nitrile 3. IR spectrum, ν, cm-1: 1585, 1615
(C=C arom.), 2225 (CN).
γ-(p-Fluorophenyl)-γ-(2-furyl)propylamine (4). To a cooled solution of lithium aluminum hydride
(10.6 g, 0.28 mol) in dry ether (200 ml) we added dropwise an ether solution of the nitrile 3 (30 g, 0.14 mol)
while keeping the temperature of the reaction mass in the range of 0±2°C. Stirring was continued for a further
1 h at the same temperature, the mixture was cooled to -10°C (in a bath of ice and salt), and water (10 ml), 15%
sodium hydroxide solution (10 ml), and water (31 ml) were added dropwise in succession. The reaction mass
was filtered, the inorganic precipitate was washed with ether, and the ether was then combined with the organic
layer of the filtrate. The ether solution was dried, and the residue after removal of the ether was distilled under
vacuum. We obtained 26.5 g of the amine 4. IR spectrum, ν, cm-1: 1590, 1610 (C=C arom.), 3300 (NH2).
Ar1(R)-Methyl[γ-(p-fluorophenyl)-γ-(2-furyl)propyl]amines (7a-h). A mixture of equimolar amounts
of the amine 4 and the aromatic aldehyde 5a-f or ketone 5g,h in benzene or xylene (in the case of 5g,h) was
boiled for 4 h with a Dean–Stark tube until the water had completely separated. The solvent was then distilled,
the residue was dissolved in methanol, and an equimolar amount of NaBH4 was added to the obtained solution in
portions with stirring and cooling in water so that the temperature of the mixture did not exceed 20°C. The
reaction mass was stirred for a further 1 h at room temperature, and the methanol was then distilled. The residue
was made alkaline with 20% sodium hydroxide solution and extracted with ether. The extract was dried, the
ether was distilled from the residue, and the amines 7a-h were isolated by distillation.
N-(R1CO)[Ar1(R)-Methyl][γ-(p-fluorophenyl)-γ-(2-furyl)propyl]amines (8a-f). To a solution of the
amine 7a-f (0.03 mol) and triethylamine (3 g, 0.032 mol) in absolute benzene (30 ml) we added an equimolar
amount of acetyl chloride (in the case of 7a,b) or propionyl chloride (7c-f). The mixture was boiled with a reflux
condenser for 4 h, cooled, washed with water, and extracted with benzene. The extract was dried, and the amides
8a-f were isolated from the residue after distillation of the benzene.
N-[γ-(p-Fluorophenyl)-γ-(2-furyl)propyl]maleimide (9). A mixture of the amine 4 (7 g, 0.032 mol) and
succinic anhydride (3.2 g, 0.02 mol) in benzene (50 ml) was boiled for 10 h with a Dean–Stark tube until the
water had been completely separated. The benzene was then evaporated, and 6.3 g of the product 9 was isolated
from the residue by vacuum distillation. IR spectrum, ν, cm-1: 1590, 1610 (C=C arom.), 1690 (C=O).
N-[γ-(p-Fluorophenyl)-γ-(2-furyl)]propylphthalimide (10). From the amine 4 (7 g, 0.032 mol) and
phthalic anhydride (4.8 g, 0.032 mol) by the procedure described above for the product 9 we obtained 6.6 g of
the phthalimide 10. IR spectrum, ν, cm-1: 1590, 1610 (C=C arom.), 1690 (C=O).
REFERENCES
1.
2.
N. S. Arutyunyan, L. A. Akopyan, G. A. Gevorgyan, G. M. Snkhchyan, and G. A. Panosyan, Khim.
Geterotsikl. Soedin., 517 (2005).
J. S. Sandhu, S. Mahan, and P. S. Sethi, J. Indian Chem. Soc., 48, 693 (1971).
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