~
J. MAGALHAES ET AL.
34
product was extracted with ethyl acetate (3 ꢄ 20 ml) and the com- N-(3-Dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride
bined organic layers were separated, washed with brine, dried (2 equiv) were added in one portion. The reaction mixture was
over anhydrous Na2SO4, and concentrated under reduced pressure stirred at room temperature for 30 min and then the proper amine
to yield a residue that is purified by flash chromatography on sil- (2 equiv) was added. Afterwards, reaction mixture was heated at
ica gel. Yields, purification methods and other analytical data are 50 ꢁC overnight. Volatiles were evaporated and the residue was
reported below.
solubilised in acetonitrile (1 ml), filtered and purified by HPLC.
Yields and other analytical data are reported below.
Ethyl 1-(4-methylbenzyl)-2-(4-nitrophenyl)cyclopropane-1-
carboxylate (6). The product was obtained as a yellow oil in 9%
(1R,2S)-1-N-methyl-1-(4-methylbenzyl)-2-phenyl-N-(tetrahy-
yield after purification by flash column chromatography using dro-2H-pyran-4-yl)cyclopropane-1-carboxamide (16). Colourless
ethyl acetate/petroleum ether (1:99) as eluent. 1H NMR (300 MHz, oil in 45% yield.1H NMR (400 MHz, CDCl3) d 7.41 ꢀ 7.32 (m, 2H),
CDCl3) d 8.18 (d, J ¼ 8.8 Hz, 2H), 7.39 (d, J ¼ 8.4 Hz, 2H), 7.00 (q, 7.31 ꢀ 7.25 (m, 3H), 7.02 ꢀ 6.94 (m, 2H), 6.87 (s, 2H), 4.50
J ¼ 8.1 Hz, 4H), 4.15 (tt, J ¼ 7.1, 3.5 Hz, 2H), 3.12 (d, J ¼ 15.6 Hz, 1H), (s, 1H), 3.99 (d, J ¼ 8.8 Hz, 2H), 3.44 (t, J ¼ 12.3 Hz, 2H), 2.77 (s, 4H),
2.99 ꢀ 2.82 (m, 1H), 2.29 (s, 3H), 2.08 ꢀ 1.88 (m, 2H), 1.47 (dd, 2.51 ꢀ 2.43 (m, 1H), 2.38 (d, J ¼ 14.3 Hz, 1H), 2.26 (s, 3H),
J ¼ 7.2, 5.3 Hz, 1H), 1.21 (t, J ¼ 7.1 Hz, 3H).
1.77 ꢀ 1.58 (m, 3H), 1.36 (dd, J ¼ 6.6, 5.9 Hz, 1H), 0.83 (dd, J ¼ 6.5,
3.3 Hz, 2H).13C NMR (101 MHz, CDCl3) d 179.7, 147.7, 136.6, 135.7,
Ethyl 2-(4-(chloromethyl)phenyl)-1-(4-methylbenzyl)cyclo-
propane-1-carboxylate (7). Purification by flash column chroma- 131.7, 128.6, 128.5, 128.2, 126.4, 67.1, 59.8, 36.9, 29.5, 27.8, 25.4,
tography on silica gel using ethyl acetate/petroleum ether (1:9
22.5, 20.8, 13.9. HRMS (ESI): calculated for C24H30O2N [M þ H]
1
9 ! 3:97) afforded the product as a colourless oil in 30% yield. H
364.22711 found 364.22717.
NMR (400 MHz, CDCl3) d 7.39 (d, J ¼ 7.5 Hz, 2H), 7.27 (d, J ¼ 7.9 Hz,
(1R,2S)-1-N-((1-ethylpyrrolidin-2-yl)methyl)-1-(4-methylben-
2H), 7.06 (s, 4H), 4.62 (s, 2H), 4.25 ꢀ 4.09 (m, 2H), 3.20 (d, zyl)-2-phenylcyclopropane-1-carboxamide (17). White oil in
1
J ¼ 15.4 Hz, 1H), 2.86 (t, J ¼ 7.9 Hz, 1H), 2.32 (s, 3H), 1.98 (d, 34% yield. H NMR (400 MHz, CDCl3) d 8.55 (s, 1H), 7.35 ꢀ 7.20 (m,
J ¼ 15.6 Hz, 2H), 1.49 ꢀ 1.38 (m, 1H), 1.24 (t, J ¼ 7.1 Hz, 3H).
4H), 7.16 ꢀ 6.95 (m, 5H), 3.54 ꢀ 3.35 (m, 3H), 3.21 ꢀ 3.07 (m, 1H),
2.70 ꢀ 2.52 (m, 3H), 2.31 ꢀ 2.17 (m, 4H), 2.10 ꢀ 1.44 (m, 6H),
(1R,2S)-1-Ethyl 1-(4-methylbenzyl)-2-phenylcyclopropane-1-
carboxylate (14). Flash chromatography on silica gel using ethyl 1.44 ꢀ 1.30 (m, 1H), 1.23 ꢀ 1.11 (m, 2H), 1.07 ꢀ 0.91 (m, 2H). 13 C
acetate/petroleum ether (1:99) afforded the product as yellow oil
NMR (101 MHz, CDCl3) d 168.8, 136.9, 136.1, 135.1, 129.0, 128.7,
128.6, 128.1, 126.5, 53.2, 52.8, 40.7, 33.8, 33.2, 31.1, 30.4, 28.1, 23.0,
in 65% yield. 1H NMR (300 MHz, CDCl3) d 7.30 (dddd, J ¼ 13.4,
11.6, 7.5, 3.7 Hz, 5H), 7.03 (s, J ¼ 7.9 Hz, 4H), 4.21 ꢀ 4.08 (m, 2H), 20.7, 17.1, 10.4. HRMS (ESI): calculated for C25H32ON2 [M þ H]
3.22 ꢀ 3.06 (m, 1H), 2.86 ꢀ 2.77 (m, 1H), 2.29 (s, 3H), 1.91 ꢀ 1.83
377.25874 found 377.25821.
(m, 2H), 1.40 (dd, J ¼ 7.2, 5.0 Hz, 1H), 1.21 (t, J ¼ 7.1 Hz, 3H).
(1R,2S)-1-N-benzyl-1-(4-methylbenzyl)-2-phenylcyclopro-
pane-1-carboxamide (18). Pearl powder in 55% yield. 1H NMR
Ethyl 2-(4-((isopropylamino)methyl)phenyl)-1-(4-methylben-
zyl)cyclopropane-1-carboxylate (9). Isopropylamine (26 mL, (400 MHz, CDCl3) d 7.42 ꢀ 7.17 (m, 8H), 7.05 (dd, J ¼ 18.9, 8.1 Hz,
0.292 mmol) was added dropwise to compound
7 (50 mg,
4H), 6.92 ꢀ 6.77 (m, 2H), 5.84 (s, 1H), 4.43 (dd, J ¼ 15.0, 5.8 Hz, 1H),
4.28 (dd, J ¼ 15.0, 4.9 Hz, 1H), 3.04 ꢀ 2.90 (m, 1H), 2.83 (d,
0.15 mmol) in neat at 0 ꢁC, and the mixture was allowed to stir at
room temperature for 24 h. The reaction was quenched with the J ¼ 17.5 Hz, 1H), 2.38 ꢀ 2.20 (m, 4H), 1.99 (dd, J ¼ 8.6, 4.1 Hz, 1H),
1.44 (dd, J ¼ 7.0, 4.7 Hz, 1H). 13 C NMR (101 MHz, CDCl3) d 173.8,
addition of 4 M NaOH aq. solution, extracted with dichlorome-
thane (3 ꢄ 5 ml), and the combined organic layers were separated,
138.4, 137.7, 136.6, 135.9, 129.8, 129.6, 128.8, 128.7, 128.3, 127.6,
washed with brine, dried over anhydrous Na2SO4, and concen- 127.5, 127.1, 44.3, 34.6, 31.0, 30.8, 21.4, 18.9. HRMS (ESI): calculated
trated under reduced pressure. The residue obtained was purified
by flash chromatography on silica gel using methanol/dichlorome-
for C25H28ON [M þ H] 356.20089 found 356.20071.
(1R,2S)-1-(4-methylbenzyl)-2-phenyl-N-(thiophen-2-ylme-
thane (2:98) to obtain the title compound as a colourless oil in thyl)cyclopropane-1-carboxamide (19). Pearl powder in 56%
1
60% yield. H NMR (300 MHz, CDCl3) d 7.31 (t, J ¼ 7.9 Hz, 2H), 7.22 yield. 1H NMR (400 MHz, CDCl3) d 7.37 ꢀ 7.21 (m, 5H), 7.15 (d,
(d, J ¼ 8.0 Hz, 2H), 7.05 (s, 4H), 4.27 ꢀ 4.06 (m, 2H), 3.81 (s, 2H), J ¼ 5.1 Hz, 1H), 7.03 (q, J ¼ 8.2 Hz, 4H), 6.92 ꢀ 6.81 (m, 1H), 6.65 (d,
3.19 (d, J ¼ 15.6 Hz, 1H), 2.87 (ddd, J ¼ 16.3, 13.4, 7.1 Hz, 2H), 2.31 J ¼ 3.1 Hz, 1H), 5.89 (s, 1H), 4.52 (d, J ¼ 4.4 Hz, 2H), 2.94 (t,
(s, 3H), 1.93 ꢀ 1.79 (m, 2H), 1.40 (dd, J ¼ 7.2, 5.0 Hz, 1H), 1.22 (t, J ¼ 8.1 Hz, 1H), 2.83 (d, J ¼ 17.3 Hz, 1H), 2.32 ꢀ 2.23 (m, 4H), 1.96
J ¼ 7.1 Hz, 3H), 1.14 (d, J ¼ 6.3 Hz, 6H).
(dd, J ¼ 9.1, 4.7 Hz, 1H), 1.47 ꢀ 1.36 (m, 1H). 13 C NMR (101 MHz,
CDCl3) d 173.8, 141.4, 137.7, 136.6, 135.7, 129.8, 129.6, 128.7,
Ethyl 2-(4-aminophenyl)-1-(4-methylbenzyl)cyclopropane-1-
carboxylate (11). Pd/C (18 mg) and triethylsilane (73 mL, 128.4, 127.2, 127.1, 125.8, 125.2, 39.2, 34.5, 31.3, 30.8, 21.4, 18.8.
0.46 mmol) were added portion-wise to a solution of compound 6
HRMS (ESI): calculated for C23H24ONS [M þ H] 362.15731
(44 mg, 0.13 mmol) in dry methanol (6 ml), and the reaction mix-
ture was stirred at room temperature under argon until complete
found 362.15735.
(1R,2S)-1-N-((1-methyl-1H-imidazol-2-yl)methyl)-1-(4-methyl-
consumption of the starting material. After filtration through a benzyl)-2-phenylcyclopropane-1-carboxamide (20). Yellow oil in
plug of celite, the organic layers were washed with brine, dried 52% yield.1H NMR (400 MHz, CDCl3) d 8.33 (s, 1H), 7.28 (tdd,
over anhydrous sodium sulphate, and concentrated under J ¼ 7.7, 4.9, 3.7 Hz, 5H), 7.03 ꢀ 6.88 (m, 5H), 6.77 (d, J ¼ 1.4 Hz, 1H),
reduced pressure to afford the target compound as a yellow oil in 4.47 (dd, J ¼ 5.7, 1.9 Hz, 2H), 3.55 (d, J ¼ 16.5 Hz, 3H), 2.96 (d,
1
quantitative yield. H NMR (400 MHz, MeOD) d 7.05 ꢀ 6.97 (m, 6H), J ¼ 16.8 Hz, 1H), 2.79 ꢀ 2.67 (m, 1H), 2.26 (s, J ¼ 8.6 Hz, 3H), 2.18 (d,
6.72 (d, J ¼ 8.5 Hz, 2H), 4.75 (s, 2H), 4.10 (dq, J ¼ 11.0, 3.5 Hz, 2H), J ¼ 16.8 Hz, 1H), 1.94 (ddd, J ¼ 9.1, 5.0, 1.3 Hz, 1H), 1.38 (dd, J ¼ 7.0,
3.06 (d, J ¼ 15.5 Hz, 1H), 2.68 (dd, J ¼ 9.2, 7.3 Hz, 1H), 2.27 (s, 3H), 5.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3) d 173.8, 167.0, 144.9, 137.1,
1.98 (d, J ¼ 15.5 Hz, 1H), 1.74 (ddd, J ¼ 9.2, 4.9, 1.3 Hz, 1H), 1.38 135.8, 129.3, 129.1, 128.4, 128.1, 126.8, 125.3, 121.3, 34.7, 34.1,
(dd, J ¼ 7.2, 4.9 Hz, 1H), 1.19 (t, J ¼ 7.1 Hz, 3H).
33.2, 31.2, 30.8, 21.0, 17.4. HRMS (ESI): calculated for C23H26N3O
[M þ H] 360.20704 found 360.20645.
General procedure for the synthesis amides 16–22. To a
solution of 1-(4-methylbenzyl)-2-phenylcyclopropanecarboxylic
(1R,2S)-1-(4-methylbenzyl)-2-phenyl-N-(prop-2-yn-1-yl)cyclo-
acid (1 equiv) in dry DMF (20 ml/mmol), N-ethyldiisopropylamine propane-1-carboxamide (21). Pearl powder in 57% yield. 1H
(5 equiv), 1-hydroxybenzotriazole hydrate (1.5 equiv) and NMR (400 MHz, CDCl3) d 7.34 ꢀ 7.28 (m, 2H), 7.26 ꢀ 7.20 (m, 2H),