Yellow oil. Rf = 0.15 (Hexane/EtOAc 9/1). 1H NMR
(300 MHz, CDCl3): d 0.73 (1H, d ¥ d, J = 7.0, 5.3 Hz,
CH(HCH)CNtrans); 0.91 and 1.06 (2 ¥ 1H, 2 ¥ d ¥ d, J = 8.7, 6.7, 5.6
HzCHCH2CNcis); 1.24–1.37 (1H, m, CHcis); 1.44 (1H, d ¥ d, J =
9.4, 5.3 Hz, CH(HCH)CNtrans); 1.74–1.84 (1H, m, CHtrans); 2.33
(3H, s, CH3); 2.47 (1H, d ¥ d, J = 13.5, 6.6 Hz, N(HCH)CHtrans);
Synthesis of cis- and trans-2-{[N-benzyl-N-(3-methoxybenzyl)-
amino]methyl}-1-benzylcyclopropanecarboxamide 16b
To a solution of 1-benzyl-2-{[N-benzyl-N-(3-methoxybenzyl)-
amino]methyl}cyclopropanecarbonitrile 15c (2 mmol) in
ethanol/water (3/1, 20 mL), potassium hydroxide (10 mmol,
5 equiv) was added at room temperature, and the resulting mixture
was heated under reflux for 3 days. The reaction mixture was
poured into water (30 mL) and extracted with EtOAc (3 ¥ 50 mL).
Drying (MgSO4), filtration of the drying agent and evaporation of
the solvent afforded 2-{N-benzyl-N-(3-methoxybenzyl)amino]-
methyl}-1-benzylcyclopropanecarboxamide 16b, which was
purified by means of column chromatography on silica gel
(Hexane/EtOAc 9/1).
Alternative procedure: To a solution of 1-benzyl-2-{[N-benzyl-
N -(3-methoxybenzyl)amino]methyl}cyclopropanecarbonitrile
15c (2 mmol) in ethanol/water (3/1, 20 mL), potassium hydroxide
(8 mmol, 4 equiv) was added at room temperature, and the
resulting mixture was heated for 30 min at 185 ◦C under microwave
conditions (200 Watt). The reaction mixture was poured into water
(30 mL) and extracted with EtOAc (3 ¥ 50 mL). Drying (MgSO4),
filtration of the drying agent and evaporation of the solvent affor-
ded 2-{N-benzyl-N-(3-methoxybenzyl)amino]methyl}-1-benzyl-
cyclopropanecarboxamide 16b, which was purified by means of
column chromatography on silica gel (Hexane/EtOAc 9/1).
2.31 and 2.80 (2H, 2 ¥ d, J = 15.1 Hz, (Cquat(HCH)Carom,quat
)
,
,
trans
(Cquat(HCH)Carom,quat
)trans); 2.61–2.90 (5 ¥ 1H, m, N(HCH)CHtrans
(Cquat(HCH)Carom,quat)cis, (Cquat(HCH)Carom,quat
)
and NCH2CHcis);
cis
3.48–3.69 (8H, m, 2¥(NCH2Carom
)
cis and 2¥(NCH2Carom
)trans); 7.03–
7.40 (2 ¥ 14H, m, (CHarom cis and (CHarom
)
)
trans).13C NMR (75 MHz,
ref = CDCl3): d 15.06, 17.34, 19.31, 19.51, 21.35, 23.95, 24.13,
35.03, 40.85, 51.62, 55.10, 58.32, 58.43, 58.62, 121.76, 123.91,
127.13, 127.18, 127.39, 127.42, 128.43, 128.55, 128.81, 128.90,
129.09, 129.15, 129.25, 136.03, 136.43, 136.67, 136.93, 137.64,
139.30, IR (ATR, cm-1): nCN= 2231. MS (70 eV): m/z (%): 381
(M++1, 100). Anal. Calcd for C27H28N2: C 85.22; H 7.42; N 7.36.
Found: C 85.44; H 7.67; N 7.22.
Synthesis of 2-{[N-benzyl-N-(4-chlorobenzyl)amino]methyl}-1-
benzylcyclopropanecarboxamide 16a
To an ice-cooled solution of 1-benzyl-2-{[N-benzyl-N-(4-
chlorobenzyl)amino]methyl}cyclopropanecarbonitrile
15b
(2.2 mmol) in dry CH2Cl2 (10 mL), concentrated sulfuric
acid (4.2 mL, 26 equiv) was added, and the resulting solution
was stirred for 21 hours at 10 ◦C. The reaction mixture was
poured into ice water (30 mL), followed by extraction using a
saturated solution of aqueous ammonium hydroxide and EtOAc
(3 ¥ 50 mL). Drying (MgSO4), filtration of the drying agent
and evaporation of the solvent afforded 2-{[N-benzyl-N-(4-
chlorobenzyl)amino]methyl}-1-benzylcyclopropanecarboxamide
16a, which was purified by means of column chromatography on
silica gel (hexane/EtOAc 9/1).
cis- and trans-2-{N-benzyl-N-(3-methoxybenzyl)amino]methyl}-
1-benzylcyclopropanecarboxamide 16b
Spectral data derived from the mixture of diastereomers.
Orange oil. Rf = 0.15 (Hexane/EtOAc 9/1). 1H NMR
(300 MHz, CDCl3): d 0.67 (1H, d ¥ d, J = 6.9, 4.1 Hz,
CH(HCH)CNtrans); 0.91–0.98 (2H, m, CHCH2CNcis); 1.25–
1.41 (1H, m, CHcis); 1.68–1.72 (1H, m, CH(HCH)CNtrans);
1.82–1.92 (1H, m, CHtrans); 2.43–2.56 (2H, m, NCH2CHtrans);
2.52 (1H, d ¥ d, J = 13.2, 8.8 Hz, N(HCH)CHcis); 2.58
(1H, d,
(1H, m, (Cquat(HCH)Carom,quat
13.2, 5.5 Hz, N(HCH)CHcis); 2.95 (1H, d, J = 17.6 Hz,
(Cquat(HCH)Carom,quat trans); 3.14 (1H, d, 14.6 Hz,
J
=
14.6 Hz, (Cquat(HCH)Carom,quat)cis); 2.65–2.74
cis- and trans-2-{[N-benzyl-N-(4-chlorobenzyl)amino]methyl}-
)
trans); 2.71 (1H, d ¥ d, J =
1-benzylcyclopropanecarboxamide 16a
Spectral data derived from the mixture of diastereomers.
)
J
=
Yellow oil. Rf = 0.15 (Hexane/EtOAc 9/1). 1H NMR
(300 MHz, CDCl3): d 0.64 (1H, d ¥ d, J = 6.6, 4.0 Hz,
CH(HCH)CNtrans); 0.92–1.02 (2H, m, CHCH2CNcis); 1.25–1.39
(1H, m, CHcis); 1.66 (1H, d ¥ d, J = 9.1, 4.0 Hz, CH(HCH)CNtrans);
1.79–1.90 (1H, m, CHtrans); 2.41 (1H, d ¥ d, J = 13.2,
(Cquat(HCH)Carom,quat)cis); 3.24 and 3.26 (2H, 2 ¥ d, J = 13.2 Hz,
(NCH2Carom,quat)cis); 3.54 and 3.56 (2H, 2 ¥ d, J = 13.5 Hz,
(NCH2Carom,quat
and (NCH2Carom,quat
5.13 and 5.34 (4 ¥ 1H, 4 ¥ s, 2 ¥ NH2cis and 2 ¥ NH2trans);
)trans); 3.66–3.81 (2 ¥ 2H, m, (NCH2Carom,quat)
cis
)
trans); 3.77 (OCH3,cis); 3.79 (OCH3,trans); 4.90,
7.2 Hz, N(HCH)CHtrans); 2.50–2.73 (5H, m, N(HCH)CHtrans
,
6.71–6.79, 6.91–6.96 and 7.12–7.38 (2 ¥ 14H, m, (CHarom
)
and
cis
(CHarom
)
trans).13C NMR (75 MHz, ref = CDCl3): d 18.19, 21.28,
(Cquat(HCH)Carom,quat)cis, (Cquat(HCH)Carom,quat
)
)
trans and NCH2CHcis);
trans); 3.09 (1H, d, J =
2.89 (1H, d, J = 18.2 Hz, (Cquat(HCH)Carom,quat
22.93, 24.04, 26.87, 31.93, 34.21, 42.62, 52.62, 54.41, 55.25, 58.12,
58.21, 58.29, 58.32, 112.37, 114.50, 115.04, 126.66, 126.77, 127.09,
127.30, 128.12, 128.37, 128.64, 128.99, 129.04, 129.35, 138.52,
138.77, 139.53, 140.25, 141.33, 159.64, 159.71, 174.72, 177.15. IR
(ATR, cm-1): nC=O= 1663. MS (70 eV): m/z (%): 415 (M++1, 100).
Anal. Calcd for C27H30N2O2: C 74.54; H 6.50; N 6.69. Found:
C 74.48; H 6.65; N 6.74.
14.9 Hz, (Cquat(HCH)Carom,quat)cis); 3.26, 3.27, 3.51, 3.55, 3.65 and
3.69 (6 ¥ 1H, 3¥(2 ¥ d), J = 13.2 Hz, 3¥(NCH2Carom); 3.49–3.82
(2H, m, NCH2Carom); 5.18, 5.46, 5.59 and 5.66 (4 ¥ 1H, 4 ¥ s,
2 ¥ NH2,cis and 2 ¥ NH2,trans); 7.05–7.35 (2 ¥ 14H, m, (CHarom
)
cis
and (CHarom
)
trans).13C NMR (75 MHz, ref = CDCl3): d 18.4, 21.5,
23.1, 23.9, 26.7, 31.8, 34.2, 42.7, 52.6, 57.4, 57.4, 58.2, 57.5, 58.3,
126.7, 126.9, 127.2, 127.4, 128.1, 128.4, 128.5, 128.7, 128.8, 128.9,
129.0, 129.3, 130.3, 130.6, 132.7, 138.2, 138.5, 139.3, 132.9, 137.3,
Acknowledgements
138.3, 138.8, 174.5, 176.9. IR (ATR, cm-1): nC=O= 1630, nNH2
=
3386. MS (70 eV): m/z (%): 419/21 (M++1, 100). Anal. Calcd for
C26H27ClN2O: C 74.54; H 6.50; N 6.69. Found: C 74.81; H 6.76;
N 6.45.
The authors are indebted to the “Institute for the Promotion of
Innovation through Science and Technology – Flanders” (IWT-
Vlaanderen), to the “Fund for Scientific Research – Flanders”
3278 | Org. Biomol. Chem., 2009, 7, 3271–3279
This journal is
The Royal Society of Chemistry 2009
©