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Organic & Biomolecular Chemistry
the solvent gave compound ( )-4c (235 mg, 98%), which was CHH), 1.33–1.17 (4 H, m + t, CHH and CH3 (t centered to
recrystallized from mixture of CH2Cl2–hexane. Mp 1.22 ppm, J = 7.1 Hz); δC (75.5 MHz, CDCl3) 172.8 (CvO),
a
117–118 °C. IR (KBr) ν (cm−1) 3401, 3347, 3304, 3202, 1734, 170.0 (CvO), 137.9 (C), 128.5 (CH), 127.8 (CH), 127.4 (CH),
1658, 1617; δH (300.13 MHz, CDCl3) 7.44–7.30 (5 H, m, Ph), 60.9 (CH2), 43.8 (CH2), 24.0 (CH), 21.3 (CH), 14.7 (CH2), 14.0
5.72 and 5.51 (2 H, two overlapped broad singlets, NH2), AB (CH3). HRMS (ESI+) Calcd for C14H18NO3: ((M + H)+): 248.1281.
system centered to 5.13 ppm (2 H, | JA,B| = 15.0 Hz, CH2–Ph), Found: 248.1283.
Ethyl
( )-trans-2-(N-allylcarbamoyl)cyclopropanecarboxylate
2.24 (1 H, ddd, J1 = 8.6 Hz, J2 = 5.7 Hz, J3 = 3.8 Hz, CH), 2.02
(1 H, ddd, J1 = 8.6 Hz, J2 = 5.7 Hz, J3 = 3.7 Hz, CH), 1.49 (1 H,
ddd, J1 = 8.7 Hz, J2 = 5.8 Hz, J3 = 3.8 Hz, CHH), 1.40 (1 H, ddd,
J1 = 8.6 Hz, J2 = 5.8 Hz, J3 = 3.8 Hz, CHH); δC (75.5 MHz,
CDCl3) 172.4 (CvO), 172.3 (CvO), 135.5 (C), 128.5
(CH), 128.3 (CH), 128.1 (CH), 66.8 (CH2), 23.5 (CH), 21.8
(CH), 15.1 (CH2); MS (ESI+) m/z: 242 (M + Na)+. HRMS (ESI+)
(( )-9b). White solid (0.288 g, 73%); mp 75–76 °C; IR (KBr)
ν (cm−1) 3298, 3087, 2985, 1724, 1642, 1550; δH (300.13 MHz,
CDCl3) 5.90 (1 H, broad s, NH), 5.84 (1 H, ddt, Jtrans = 17.2 Hz
(d), Jcis = 10.2 Hz (d), J = 5.7 Hz (t), CHvCH2), 5.24–5.12 (2 H,
m, CHvCH2), 4.14 (2 H, q, J = 7.1 Hz, OCH2), 3.89 (2 H, tt, J1 =
5.8 Hz, J2 = 1.5 Hz, NCH2), 2.17 (1 H, ddd, J1 = 8.8 Hz, J2
=
Calcd for C12H13NNaO3 ((M
242.0773.
+
Na)+): 242.0788. Found:
5.7 Hz, J3 = 3.8 Hz, CH), 1.93 (1 H, ddd, J1 = 8.8 Hz, J2 = 5.9 Hz,
J3 = 3.8 Hz, CH), 1.46 (1 H, ddd, J1 = 8.8 Hz, J2 = 5.9 Hz, J3 =
3.8 Hz, CHH), 1.37–1.18 (4 H, ddd and t partially overlapped,
CHH and CH3 (t centered at 1.26 ppm, J = 7.1 Hz)); δC
(75.5 MHz, CDCl3) 172.7 (CvO), 170.0 (CvO), 133.9 (CH),
116.6 (CH2), 60.9 (CH2), 42.2 (CH2), 24.1 (CH), 21.4 (CH), 14.7
(CH2), 14.1 (CH3). HRMS (ESI+) Calcd for C10H16NO3
((M + H)+): 198.1125. Found: 198.1130.
( )-trans-2-(Ethoxycarbonyl)cyclopropanecarboxylic
acid
(( )-6a). A slight modification of the method described by
Wiberg et al.15 was followed: a solution of ( )-3a (1.25 g,
6.72 mmol) in ethanol (2.7 mL) was heated at reflux. Aqueous
14 M NaOH (0.480 mL, 6.72 mmol) was added over a period of
2 min. The reflux was maintained for 5 min. After this time,
the reaction mixture was cooled and water (30 mL) was added.
The aqueous solution was manually extracted with CH2Cl2 (2 ×
20 mL). From the combined organic phases, the unreacted
starting material was recovered (19%). The aqueous layer was
acidified with aq. 3 M HCl until pH 0.7, and continuously
extracted with CH2Cl2 for 8 h. The new organic phase was
dried (Na2SO4) and the solvent was removed to yield ( )-6a
(0.786 g, 74%) as a white solid; mp 54–56 °C (lit.15 mp
58–60 °C; lit.20 mp 52–54 °C). Spectroscopy data matched with
that reported by Csuk and von Scholz.20
Ethyl
( )-trans-2-(N-allyl-N-methylcarbamoyl)cyclopropane-
carboxylate (( )-9c). Colorless oil (0.338 g, 80%); IR (neat)
ν (cm−1) 3079, 2986, 2933, 1725, 1644; δH (300.13 MHz, CDCl3)
corresponding to a 47 : 53 mixture of rotamers: 5.88–5.64 (1 H,
m, CHvCH2), 5.27–5.10 (2 H, m, CHvCH2), 4.20–4.10 (2 H,
two overlapped q corresponding to both rotamers, J = 7.1 Hz,
OCH2), 4.07–3.92 (2 H, m, NCH2), 3.10 (3 H for minor rotamer,
s, NCH3), 2.95 (3 H for major rotamer, s, NCH3), 2.40–2.10
(2 H, m, 2 × CH), 1.55–1.10 (5 H, m, CH2 and CH3); δC
(75.5 MHz, CDCl3) corresponding to a mixture of rotamers:
172.9, 172.8, 170.4, 170.0, 132.7, 132.4, 117.4, 116.7, 60.9, 60.8,
52.2, 50.4, 34.7, 34.2, 21.9, 21.8, 21.1, 21.0, 15.4, 15.2, 14.1.
HRMS (ESI+) Calcd for C11H17NNaO3 ((M + Na)+): 234.1101.
Found: 234.1091.
Ethyl ( )-trans-2-(N-alkyl- or N,N-dialkylcarbamoyl)cyclopro-
panecarboxylate (( )-9a–c). Typical procedure. To a solution of
( )-6a (0.316 g, 2.00 mmol) in anhydrous THF (3.5 mL), DMF
(one drop) was added. The solution was cooled at 0 °C and
oxalyl chloride (0.34 mL, 4.0 mmol) was slowly added. After
( )-trans-N-Alkyl(or N,N-dialkyl)cyclopropane-1,2-dicarboxa-
12 h at room temperature, both the solvent and excess oxalyl mides (( )-10a–c). General procedure. The corresponding ami-
chloride were removed under reduced pressure to give the doester ( )-9a–c (1.0 mmol) was dissolved in 5.0 mL of a
corresponding acid chloride which was used in the next step methanolic solution of ammonia (obtained by bubbling of
without purification. This crude acid chloride was dissolved in ammonia through methanol at 0 °C) in a sealed flask, and the
anhydrous THF (5.0 mL) and the corresponding amine mixture was stirred at room temperature until the disappear-
(4.0 mmol) was added at 0 °C, under a nitrogen atmosphere. ance of the starting material (TLC control, hexane–ethyl
The mixture was stirred at room temperature for 12 h. CH2Cl2 acetate 1 : 1). Evaporation of the solvents yielded the corres-
and water were added to the mixture, the phases were separ- ponding diamide ( )-10a–c, which was purified as indicated
ated, and the aqueous layer was newly extracted with CH2Cl2. below.
( )-trans-N-Benzylcyclopropane-1,2-dicarboxamide
(( )-10a).
The organic phases were combined, and washed successively
with aq. 1 M HCl, aq. saturated NaHCO3, and brine. Evapor-
ation of solvents yielded a residue, which was submitted to
flash chromatography using n-hexane–ethyl acetate 2 : 1 (for
( )-9a) or 3 : 1 (for ( )-9b,c) as an eluent.
The crude material was washed with dichloromethane to give
pure ( )-10a as a white solid (0.183 g, 84%). Mp 232–233 °C; IR
(KBr) ν (cm−1) 3392, 3248, 3195, 3081, 1659, 1631, 1564; δH
(300.13 MHz, CD3OD) 7.40–7.18 (5 H, m, Ph), AB system cen-
Ethyl ( )-trans-2-(N-benzylcarbamoyl)cyclopropanecarboxylate tered to 4.37 ppm (2 H, |JA,B| = 15.3 Hz, CH2-Ph), 2.18–1.97
(( )-9a). White solid (0.425g, 86%); mp 88–89 °C; IR (KBr)
ν (cm−1) 3305, 2979, 2930, 1723, 1636, 1550; δH (300.13 MHz,
CDCl3) 7.38–7.20 (5 H, m, Ph), 6.61 (1 H, br s, NH), 4.39 (2 H,
d, J = 5.5 Hz, CH2Ph), 4.03 (2 H, q, J = 7.1 Hz, OCH2), 2.20–2.11
(1 H, m, CH), 2.03–1.92 (1 H, m, CH), 1.49–1.38 (1 H, m,
(2 H, m, 2 × CH), 1.37–1.16 (2 H, m, CH2); δC (75.5 MHz,
DMSO-d6) 172.7 (CvO), 170.7 (CvO), 139.5 (C), 128.4 (CH),
127.4 (CH), 126.9 (CH), 42.4 (CH2), 22.0 (CH), 21.8 (CH), 12.6
(CH2); HRMS (ESI+) Calcd for C12H14N2NaO2 ((M + Na)+):
241.0947. Found: 241.0962.
620 | Org. Biomol. Chem., 2014, 12, 615–623
This journal is © The Royal Society of Chemistry 2014