Synthesis and some transformations of 2-(3-amino-1-phenylpropyl)furan

Article abstract of DOI:10.1007/s10593-005-0166-8

A preparative method was developed for the synthesis of ethyl furfurylidenecyanoacetate. Its condensation with phenylmagnesium bromide gave ethyl α-cyano-β-(2-furyl)hydrocinnamate, the decarboxylation of which led to β-(2-furyl)hydrocinnamonitrile. Reduct

Full text of DOI:10.1007/s10593-005-0166-8

Chemistry of Heterocyclic Compounds, Vol. 41, No. 4, 2005
SYNTHESIS AND SOME TRANSFORMATIONS
OF 2-(3-AMINO-1-PHENYLPROPYL)FURAN
N. S. Arutyunyan1, L. A. Akopyan1, G. A. Gevorgyan1, G. M. Snkhchyan1, and G. A. Panosyan2
A preparative method was developed for the synthesis of ethyl furfurylidenecyanoacetate. Its
condensation with phenylmagnesium bromide gave ethyl α-cyano-β-(2-furyl)hydrocinnamate, the
decarboxylation of which led to β-(2-furyl)hydrocinnamonitrile. Reduction of this nitrile with lithium
aluminum hydride gave 2-(3-amino-1-phenylpropyl)furan. Some of its transformations were studied.
Keywords: 2-(3-amino-1-phenylpropyl)furan, ethyl furfurylidenecyanoacetate, ethyl α-cyano-β-(2-
furyl)hydrocinnamate, reduction, decarbethoxylation.
In a continuation of our research [1, 2] by the reaction of ethyl furfurylidenecyanoacetate (1) with
phenylmagnesium bromide we obtained ethyl α-cyano-β-(2-furyl)hydrocinnamate (2), in the molecule of which
there are simultaneously phenyl and furyl radicals at the asymmetric carbon atom. Its decarbethoxylation led to
β-(2-furyl)hydrocinnamonitrile (3), while reduction of the latter with lithium aluminum hydride in ether or
tetrahydrofuran gave 2-(3-amino-1-phenylpropyl)furan (4). Condensation of the amine 4 with various aromatic
aldehydes and ketones gave the corresponding azomethines, which were reduced by sodium borohydride without
isolation to the secondary amines 5-13. With the chlorides of various acids the amides 14-16 were obtained, and
with succinic and phthalic anhydrides substituted succinimide 17 and phthalimide 18 were obtained.
EXPERIMENTAL
The IR spectra were recorded in vaseline oil on a Varian Mercury-300 instrument (300 MHz) in
deuterochloroform and DMSO-d6 with TMS as internal standard (Table 2). The characteristics of compounds
2-18 are given in Table 1.
Ethyl Furfurylidenecyanoacetate (1). A mixture of furfural (42 g, 0.43 mol), ethyl cyanoacetate (50 g,
0.44 mol), and ammonium acetate (3 g) was boiled in benzene (300 ml) until completely dehydrated (about
10 h). The next day the obtained crystals were filtered off, washed with water and then with benzene, dried at
room temperature, and recrystallized from benzene or distilled. Yield 79.8 g (95%). The IR spectrum and
bp (138-141°C/2 mm Hg) of the obtained compound were identical with published data [3].
Ethyl α-Cyano-β-(2-furyl)hydrocinnamate (2). A benzene solution of compound 1 (33.6 g, 0.18 mol)
was added to an ether solution of the Grignard reagent obtained from magnesium (5.3 g, 0.22 mol) and
bromobenzene (38 g, 0.22 mol) with gentle boiling and stirring. The reaction mixture was stirred at 42-44°C for
__________________________________________________________________________________________
1 A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Republic
2
of Armenia, Erevan; e-mail: gagevorgyan@yahoo.com.
Molecular Structure Research Center, National
Academy of Sciences of the Republic of Armenia, Erevan 375014. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 517-521, April, 2005. Original article submitted May 21, 2002.
Revision submitted January 25, 2005.
0009-3122/05/4104-0437©2005 Springer Science+Business Media, Inc.
437

CN
O
NCCH2COOEt
PhMgBr
OEt
CN
O
O
O
1
H
CN
OEt
LiAlH4
O
O
KOH
O
3
2
H
NH2
N
O
O
R'
R'Cl
4
14–16
RR"C=O
N
O
R
O
N
O
R''
O
A
18
O
O
H
N
R
O
N
O
R''
17
5–13
5–11 R'' = H; 5 R = MeOC6H4-p; 6 R = i-PrOC6H4-p; 7 R = 3,4-(CH3O)2C6H3; 8 R = o-FC6H4;
9 R = Ph; 10 R = p-Me2NC6H4; 11 R = 2-furyl; 12 R = Ph, R'' = Me; 13 R = p-ClC6H4, R'' = Me;
14 R' = COCH2CHMe2; 15 R' = COCH2Cl; 16 R' = p-SO2C6H4Me
1.5 h. After cooling it was acidified with 10% hydrochloric acid, extracted with ether, washed with water, and
dried, and after removal of the solvents it was distilled. We obtained 41 g (87%) of the product; bp 170°C/2 mm
Hg. IR spectrum, ν, cm-1: 1590, 1610 (C=C arom.), 1720 (CO), 2230 (CN).
β-(2-Furyl)hydrocinnamonitrile (3). Potassium hydroxide (14.6 g, 0.26 mol) was dissolved by heating
in ethylene glycol (80 ml). The solution was added to the cyano ester 2 (35 g, 0.13 mol). The mixture was boiled
with a reflux condenser for 3 h. The mixture was cooled, water (80 ml) was added, and product was extracted
with ether, washed with water, and dried. After removal of the ether the product was distilled at reduced
pressure. Yield 13.3 g (52%); bp 127°C/1 mm Hg. IR spectrum, ν, cm-1: 1585, 1615 (C=C arom.), 2225 (CN).
2-(3-Amino-1-phenylpropyl)furan (4). To a cooled solution of lithium aluminum hydride (5.8 g,
0.15 mol) in dry ether (100 ml) we added dropwise an ether solution of the nitrile 3 (15 g, 0.076 mol), while
keeping the temperature of the reaction mixture in the range of 0±2°C. The stirring was continued for a further
438

TABLE 1. The Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
bp, °С/mm
Yield, %
C
H
N
5
C21H23NO2
78.53
78.47
79.79
79.73
75.07
75.01
77.60
77.64
82.48
82.43
79.53
79.48
76.90
76.84
82.63
82.58
74.27
74.21
75.81
75.75
64.80
64.86
67.51
67.58
70.10
70.02
76.06
76.11
7.16
7.21
7.02
6.98
7.50
7.44
6.45
6.51
7.20
7.26
7.33
7.27
6.74
6.80
7.53
7.59
6.46
6.52
8.18
8.12
5.74
5.80
6.03
5.95
6.06
6.00
5.11
5.17
4.40
4.35
4.09
4.04
4.00
3.97
4.56
4.51
4.74
4.80
8.36
8.42
5.03
4.97
4.54
4.58
4.16
4.12
5.00
4.90
5.10
5.04
4.02
3.94
5.02
4.94
4.28
4.22
210/2
206-208
208-210
185/1
92
90
87
93
90
83
94
76
78
87
79
88
63
67
6
C23H24NO2
C22H26NO3
C20H20FNO
C20H21NO
7
8
9
180/1
10
11
12
13
14
15
16
17
18
C22H24N2O
C18H19NO2
C21H23NO
205-208/1
170/2
178/1
C21H22ClNO
C18H23NO2
C15H16ClNO2
C20H21NSO3
C17H17NO3
C21H17NO3
186-189/1
185-187/1
184-186/2
110-112
195-197/1
215-218/1
1
TABLE 2. The H NMR Spectra for Compounds 2-4 (CDCl3) and 5-18
(DMSO-d6/CCl4 1/3)
Com-
pound
Chemical shifts, δ, ppm (SSCC, J, Hz)
1
2
2*
1.17 (3H, t, J = 7.1, CH3); 4.16 (2H, q, J = 7.1, CH2); 4.11 (0.5H, d, J = 7.5) and
4.33 (0.5H, d, J = 7.5, CHCN); 4.77 (0.5H, d, J = 7.5) and 4.82 (0.5H, d, J = 7.5, CHAr);
6.20 (0.5H, d, J = 3.3) and 6.34 (0.5H, dd, J1 = 3.3, J2 = 1.9, Hfur-4);
6.36 (1H, br. s, Hfur-3,4); 7.29-7.42 (5H, m, C6H5); 7.44 (0.5H, d, J = 1.9)
and 7.46 (0.5H, d, J = 1.9, Hfur-5)
3
4
5
2.99 (1H, dd, J1 = 14.6, J2 = 7.7) and 3.13 (1H, dd, J1 = 14.6, J2 = 8.0, CH2); 4.52 (1H, dd,
J1 = 7.7, J2 = 8.0, CH); 6.11 (1H, d, J = 3.2, Hfur-3); 6.33 (1H, dd, J1 = 3.3, J2 = 1.8,
Hfur-4); 7.26-7.40 (6H, m, Hfur-5, C6H5)
1.49 (2H, br. s, NH2); 2.04 (1H, m) and 2.26 (1H, dq, J1 = 13.3, J2 = 7.2, CH2);
2.67 (2H, m, NCH2); 4.08 (1H, t, J = 7.7, CH); 6.08 (1H, d, J = 3.2, Hfur-3);
6.29 (1H, dd, J1 = 3.2, J2 = 1.8, Hfur-4); 7.19-7.34 (6H, m, Hfur-5, C6H5)
2.02 (1H, m) and 2.25 (1H, m, CH2); 2.10 (1H, br, NH); 2.51 (2H, t, J = 6.6, NCH2);
3.62 (2H, s, CH2Ar); 3.77 (3H, s, OCH3); 4.15 (1H, dd, J1 = 8.1, J2 = 7.7, CH);
6.06 (1H, d, J = 3.2, Hfur-3); 6.27 (1H, dd, J1 = 3.2, J2 = 2.0, Hfur-4);
6.79 (2H, m, HAr-3,5); 7.14-7.29 (7H, m, HAr-2,6, C6H5); 7.32 (1H, d, J = 2.0, Hfur-5)
6
7
1.31 (6H, d, J = 6.0, CH3); 2.25 (1H, m) and 2.42 (1H, m, CH2); 2.77 (2H, m, NCH2);
3.99 (2H, s, CH2Ar); 4.10 (1H, t, J = 7.7, CH); 4.57 (1H, q, J = 6.0, CH);
6.14 (1H, d, J = 3.2, Hfur-3); 6.28 (1H, dd, J1 = 3.2, J2 = 2.0, Hfur-4); 6.82 (2H, m, HAr-3,5);
7.15-7.37 (8H, m, HAr-2,6, C6H5, Hfur-5)
2.25 (1H, m) and 2.42 (1H, m, CH2); 2.77 (2H, m, NCH2); 3.77 (3H, s, OCH3);
3.78 (3H, s, OCH3); 3.96 (2H, s, CH2Ar); 4.10 (1H, t, J = 7.7, CH); 6.14 (1H, d, J = 3.2,
Hfur-3); 6.28 (1H, dd, J1 = 3.2, J2 = 2.0, Hfur-4); 6.81 (1H, d, J = 8.1, HAr-5); 6.89 (1H, dd,
J1 = 8.1, J2 = 2.0, HAr-6); 7.12 (1H, d, J = 8.0, HAr-2); 7.15-7.29 (5H, m, C6H5)
439

TABLE 2 (continued)
1
2
8
9
1.77 (1H, br, NH); 2.05 (1H, m) and 2.28 (1H, dq, J1 = 13.8, J2 = 6.9, CH2);
2.54 (2H, m, NCH2); 3.76 (2H, s, CH2Ar); 4.18 (1H, t, J = 7.7, CH); 6.08 (1H, d, J = 3.2,
Hfur-3); 6.28 (1H, dd, J1 = 3.2, J2 = 1.9, Hfur-4); 6.98-7.41 (10H, m, Hfur-5, C6H5, C6H4)
1.81 (1H, br, NH); 2.09 (1H, m) and 2.31 (1H, dq, J1 = 13.8, J2 = 6.9, CH2);
2.58 (2H, m, NCH2); 3.74 (2H, s, CH2Ar); 4.21 (1H, t, J = 7.7, CH); 6.10 (1H, d, J = 3.2,
Hfur-3); 6.31 (1H, dd, J1 = 3.2, J2 = 1.9, Hfur-4); 7.18-7.34 (10H, m, C6H5);
7.36 (1H, d, J = 1.9, Hfur-5)
10
1.68 (1H, br, NH); 2.03 (1H, m) and 2.26 (1H, dq, J1 = 13.5, J2 = 7.0, CH2); 2.53 (2H, m,
NCH2); 2.93 (6H, s, N(CH3)2); 3.58 (1H, d, J = 13.0) and 3.60 (1H, d, J = 13.0, CH2Ar);
4.16 (1H, t, J = 7.7, CH); 6.07 (1H, d, J = 3.2, Hfur-3); 6.28 (1H, dd, J1 = 3.2, J2 = 1.9,
Hfur-4); 6.64 (2H, m, HAr-3,5); 7.10 (2H, m, HAr-2,6); 7.15-7.30 (5H, m, C6H5);
7.34 (1H, d, J = 1.9, Hfur-5)
11
1.70 (1H, br, NH); 2.01 (1H, dtd, J1 = 13.5, J2 = 8.3, J3 = 6.6) and 2.24 (1H, dq,
J1 = 13.5, J2 = 7.1, CH2); 2.52 (2H, m, NCH2); 3.68 (2H, s, CH2Ar); 4.15 (1H, dd,
J1 = 8.3, J2 = 7.1, CH); 6.07 (1H, d, J = 3.2, Hfur-3); 6.10 (1H, d, J = 3.2, Hfur-3); 6.28 (2H,
dd, J1 = 3.2, J2 = 1.9, two Hfur-4); 7.15-7.30 (5H, m, C6H5); 7.33 (1H, d, J = 1.9, Hfur-5);
7.35 (1H, d, J = 1.9, Hfur-5)
12*
1.28 (3H, d, J = 6.6, CH3); 1.47 (1H, br, NH); 1.91-2.44 (4H, m, CH2, NCH2); 3.64 (0.5H,
q, J = 6.6) and 3.65 (0.5H, q, J = 6.6, NCH); 4.10 (0.5H, dd, J1 = 8.6, J2 = 6.7) and 4.14
(0.5H, t, J = 7.6, CH); 6.01 (0.5H, d, J = 3.3) and 6.03 (0.5H, d, J = 3.3, Hfur-3);
6.24 (0.5H, dd, J1 = 3.2, J2 = 2.0); 6.25 (0.5H, dd, J1 = 3.2, J2 = 2.0, Hfur-4);
7.14-7.26 (10H, m, two C6H5); 7.30 (0.5H, d, J = 2.0) and 7.31 (0.5H, d, J = 2.0, Hfur-5)
13*
14
1.25 (3H, d, J = 6.6, CH3); 1.80 (1H, br, NH); 1.90-2.42 (4H, m, CH2, NCH2); 3.63 (0.5H,
q, J = 6.6) and 3.64 (0.5H, q, J = 6.6, NCH); 4.08 (0.5H, dd, J1 = 8.6, J2 = 5.9) and 4.12
(0.5H, t, J = 7.6, CH); 6.01 (1H, d, J = 3.3, Hfur-3); 6.24 (1H, br. s, Hfur-4);
7.13-7.30 (10H, m, C6H4, C6H5, Hfur-5)
0.92 (6H, d, J = 6.5, CH3); 1.92 (2H, d, J = 6.8, C(O)CH2); 1.95-2.07 (4H, m, CH2,
NCH2); 2.22 (1H, m, CH); 3.01 (2H, m, NCH2); 4.01 (1H, t, J = 7.6, CH), 6.11 (1H, d,
J = 3.2, Hfur-3); 6.27 (1H, dd, J1 = 3.2, J2 = 1.9, Hfur-4); 7.14-7.29 (5H, m, C6H5);
7.33 (1H, d, J = 1.9, Hfur-5); 7.47 (1H, br. t, J = 5.7, NH)
15
2.06 (1H, dq, J1 = 13.6, J2 = 7.0) and 2.28 (1H, dq, J1 = 13.6, J2 = 7.2, CH2); 3.11 (2H,
m, NCH2); 3.90 (2H, s, CH2Cl); 4.03 (1H, t, J = 7.6, CH); 6.13 (1H, d, J = 3.3, Hfur-3);
6.28 (1H, dd, J1 = 3.3, J2 = 2.0, Hfur-4); 7.15-7.30 (5H, m, C6H5); 7.34 (1H, d, J = 2.0,
Hfur-5); 7.95 (1H, br. t, J = 5.5, NH)
16
1.94 (1H, dtd, J1 = 13.6, J2 = 7.7, J3 = 6.5) and 2.18 (1H, dtd, J1 = 13.6, J2 = 7.7, J3 = 6.5,
CH2); 2.42 (3H, s, CH3); 2.67 (2H, td, J1 = 6.5, J2 = 5.8, NCH2); 4.04 (1H, t, J = 7.7, CH);
6.02 (1H, d, J = 3.2, Hfur-3); 6.24 (1H, dd, J1 = 3.2, J2 = 1.9, Hfur-4); 7.12-7.28 (7H, m,
C6H5, HAr-3,5); 7.30 (1H, d, J = 1.9, Hfur-5); 7.41 (1H, br. t, J = 5.8, NH);
7.62 (2H, m, HAr-2,6)
17
18
2.19 (1H, dtd, J1 = 13.9, J2 = 7.6, J3 = 6.5) and 2.34 (1H, dtd, J1 = 13.6, J2 = 7.6, J3 = 6.5,
CH2); 2.49 (4H, s, (CH2)2); 3.46 (2H, m, NCH2); 4.02 (1H, t, J = 7.6, CH); 6.12 (1H, d,
J = 3.1, Hfur-3); 6.30 (1H, dd, J1 = 3.1, J2 = 1.9, Hfur-4); 7.18-7.33 (5H, m, C6H5);
7.36 (1H, d, J = 1.9, Hfur-5)
2.26 (1H, dtd, J1 = 14.3, J2 = 8.1, J3 = 6.6) and 2.42 (1H, dtd, J1 = 14.3, J2 = 7.5, J3 = 6.6,
CH2); 3.62 (2H, m, NCH2); 4.05 (1H, dd, J1 = 8.1, J2 = 7.5, CH); 6.10 (1H, d, J = 3.2,
Hfur-3); 6.23 (1H, dd, J1 = 3.2, J2 = 1.9, Hfur-4); 7.13 (1H, m) and 7.22-7.25 (4H, m, C6H5);
7.30 (1H, d, J = 1.9, Hfur-5); 7.72-7.80 (4H, m, C6H4)
_______
* A mixture of two diastereomers (~1:1).
hour at this temperature, the mixture was cooled to -10°C in a bath of ice and salt, and water (6 ml), 15% sodium
hydroxide solution (6 ml), and water (17 ml) were added successively drop by drop. The inorganic precipitate
was filtered off and washed with ether, combined organic extracts dried and after evaporation of the solvent the
residue was distilled. We obtained 13 g (85%) of the amine 4; bp 108°C/1 mm Hg. IR spectrum, ν, cm-1: 1600,
1610 (C=C arom.), 3300 (NH2).
440

Synthesis of Compounds 5-13. A mixture of equimolar amounts of one of the aromatic aldehydes (or
ketones, in the case of aromatic ketones xylene was used as solvent) and the amine 4 in benzene was heated for 4
h with a Dean–Stark tube until completely dehydrated. The benzene was removed, the remaining mass was
dissolved in methanol (0.1 mol of the azomethine and 40 ml of methanol), and an equimolar amount of sodium
borohydride was added in portions with stirring and cooling with water so that the temperature of the reaction
mixture did not exceed 20°C. The reaction mixture was then stirred for a further 1 h at room temperature. After
distillation of the methanol the mixture was made alkaline with a 20% sodium hydroxide solution and extracted
with ether. The extract was dried, the ether was distilled, and the remaining mass was distilled. The yields and
constants of the obtained amines 5-13 are given in Table 1.
Synthesis of Amides 14-16. To a solution of the amine 4 (6 g, 0.03 mol) in absolute benzene (30 ml)
and triethylamine (3 g, 0.032 mol) we added an equimolar amount of the respective acid chloride. The mixture
was boiled with a reflux condenser for 4 h. After cooling the product was washed with water, extracted with
benzene, and dried, and after distillation of the benzene the residue was distilled. Compounds 14-16 were
obtained (Table 1).
N-[γ-Phenyl-γ-(2-furyl)propyl]succinimide (17) and the Phthalimide 18. A mixture of equimolar
amounts of succinic (phthalic) anhydride and the amine 4 in benzene was heated for 10 h with a Dean–Stark tube
until completely dehydrated. The benzene was distilled, and the remaining mass was distilled under vacuum
(Table 1).
REFERENCES
1.
2.
3.
N. S. Arutyunyan, L. A. Akopyan, N. A. Apoyan, A. E. Tumadzhyan, and S. A. Vartanyan, Khim.-
Farm. Zh., 23, No. 2, 182 (1989).
N. S. Arutyunyan, L. A. Akopyan, R. G. Paronikyan, and N. E. Akopyan, Khim.-Farm. Zh., 24, No. 5,
29 (1990).
J. S. Sandhu, S. Mahan, and P. S. Sethi, J. Indian Chem. Soc., 48, 693 (1971).
441