The Journal of Organic Chemistry
Note
using TMS as internal standard. High-resolution mass spectra (ESI/
HRMS) were recorded on a mass spectrometer. Melting points were
uncorrected. All reactions were monitored by TLC with GF254 silica
gel-coated plates. Chromatography was carried out on flash silica gel
(300−400 mesh). The synthesis of PhI(OPiv)2,22 PhI(OH)(OTs),23
and 1-acetyl N-aryl cyclopropane-/cyclopentanecarboxamides 119,24
followed the literature methods.
General Procedure for Synthesis of 2 (2a as an example).
Compound 1a (0.3 mmol, 71 mg) and PhI(OPiv)2 (0.9 mmol, 366
mg) were dissolved in MeNO2 (1.80 mL), and then propanoic acid
(4.5 mmol, 0.34 mL) was added to the mixture and stirred at 110 °C
until the reaction was completed (monitored by TLC). After the
mixture was cooled, it was concentrated under reduced pressure. The
crude product was purified by silica gel chromatography (petroleum
ether/acetic ether = 15/1, v/v) to give 2a as a white solid (60 mg,
85%).
Hz 1H), 7.74 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
19.4, 22.4, 33.2, 56.5, 117.8, 120.2, 131.1, 132.6, 134.7, 137.1, 171.3,
+
204.4; HRMS (ESI-TOF) calcd for C13H13ClNO2 ([M + H]+)
250.0629, found 250.0633.
5-Phenyl-5-azaspiro[2.4]heptane-4,7-dione (2i). white solid (44
1
mg, 73%); mp 209−212 °C; H NMR (500 MHz, CDCl3) δ 1.75−
1.77 (m, 2H), 1.83−1.86 (m, 2H), 4.39 (s, 2H), 7.20 (t, J = 7.5 Hz,
1H), 7.42 (t, J = 8.0 Hz, 2H), 7.69 (t, J = 7.5 Hz 2H); 13C NMR (125
MHz, CDCl3) δ 22.3, 33.3, 56.6, 119.8, 125.0, 129.2, 138.4, 171.3,
+
204.9; HRMS (ESI-TOF) calcd for C12H12NO2 ([M + H]+)
202.0863, found 202.0862.
5-(m-Tolyl)-5-azaspiro[2.4]heptane-4,7-dione (2j). white solid (44
mg, 68%); mp 183−185 °C; 1H NMR (500 MHz, CDCl3) δ 1.76 (dd,
J1 = 4.5 Hz, J2 = 3.0 Hz, 2H), 1.84 (dd, J1 = 4.5 Hz, J2 = 3.0 Hz, 2H),
2.39 (s, 3H), 4.38 (s, 2H), 7.02 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz,
1H), 7.43 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 21.6, 22.3, 33.3, 56.8, 116.9, 120.7, 125.9, 128.9, 138.3,
5-(4-Chlorophenyl)-5-azaspiro[2.4]heptane-4,7-dione (2a). white
solid (60 mg, 85%); mp 204−206 °C; 1H NMR (500 MHz, CDCl3) δ
1.76−1.78 (m, 2H), 1.83−1.85 (m, 2H), 4.35 (s, 2H), 7.37−7.39 (m,
2H), 7.64−7.66 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 22.5, 33.2,
56.5, 120.9, 129.2, 130.1, 137.0, 171.4, 204.2; HRMS (ESI-TOF) calcd
+
139.2, 171.3, 205.2; HRMS (ESI-TOF) calcd for C13H14NO2 ([M +
H]+) 216.1019, found 216.1017.
5-(3-Methoxyphenyl)-5-azaspiro[2.4]heptane-4,7-dione (2k).
1
white solid (43 mg, 62%); mp 169−172 °C; H NMR (500 MHz,
+
for C12H11ClNO2 ([M + H]+) 236.0473, found 236.0481.
CDCl3) δ 1.75−1.79 (m, 2H), 1.83−1.85 (m, 2H), 3.83 (s, 3H), 4.37
(s, 2H), 6.75 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.14 (dd, J1 = 8.5 Hz,
5-(4-Fluorophenyl)-5-azaspiro[2.4]heptane-4,7-dione (2b). white
solid (53 mg, 80%); mp 171−172 °C; 1H NMR (500 MHz, CDCl3) δ
1.75−1.77 (m, 2H), 1.83−1.85 (m, 2H), 4.36 (s, 2H), 7.11 (t, J = 9.0
Hz, 2H), 7.64−7.66 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 22.3,
33.1, 56.8, 115.9 (d, J = 22.5 Hz), 121.7 (d, J = 8.0 Hz), 134.5, 159.7
(d, J = 244.1 Hz), 171.3, 204.6; HRMS (ESI-TOF) calcd for
J2 = 1.5 Hz, 1H), 7.31 (t, J = 8.5 Hz, 1H), 7.47 (t, J = 2.5 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 22.4, 33.4, 55.3, 56.7, 105.9, 110.7, 111.6,
129.9, 139.6, 160.2, 171.4, 204.9; HRMS (ESI-TOF) calcd for
+
C13H14NO3 ([M + H]+) 232.0968, found 232.0968.
5-(4-Methyl-2-(prop-1-en-2-ylperoxy)phenyl)-5-azaspiro[2.4]-
heptane-4,7-dione (2l). red solid (66 mg, 76%); mp 163−166 °C; 1H
NMR (500 MHz, acetone-d6) δ 1.17 (t, J = 7.5 Hz, 3H), 1.53−1.58
(m, 4H), 2.08 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 4.43 (s, 2H), 7.24 (d, J
= 8.5 Hz, 1H), 7.45 (q, J = 8.5 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H); 13C
NMR (125 MHz, acetone-d6) δ 8.8, 15.0, 20.8, 27.1, 32.7, 56.6, 113.8,
116.6, 126.2, 131.0, 138.4, 149.9, 171.5, 172.1, 204.6; HRMS (ESI-
+
C12H11FNO2 ([M + H]+) 220.0768, found 220.0777.
5-(4-Bromophenyl)-5-azaspiro[2.4]heptane-4,7-dione (2c). white
solid (74 mg, 88%); mp 214−216 °C; 1H NMR (500 MHz, CDCl3) δ
1.76−1.79 (m, 2H), 1.84−1.86 (m, 2H), 4.35 (s, 2H), 7.52−7.54 (m,
2H), 7.58−7.61 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 22.5, 33.2,
56.4, 117.8, 121.1, 132.2, 137.5, 171.4, 204.2; HRMS (ESI-TOF) calcd
+
for C12H11BrNO2 ([M + H]+) 279.9968, found 279.9979.
+
TOF) calcd for C16H18NO4 ([M + H]+) 288.1230, found 288.1237.
5-(2-Fluorophenyl)-5-azaspiro[2.4]heptane-4,7-dione (2d). white
solid (48 mg, 73%); mp 163−165 °C; 1H NMR (500 MHz, CDCl3) δ
1.76−1.81 (m, 2H), 1.81−1.86 (m, 2H), 4.40 (s, 2H), 7.17−7.23 (m,
2H), 7.29−7.34 (m, 1H), 7.51−7.54 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 22.2, 31.9, 58.1 (d, J = 4.3 Hz), 116.8 (d, J = 19.6 Hz), 124.7
(d, J = 3.4 Hz), 124.8 (d, J = 11.5 Hz), 128.1, 129.0 (d, J = 8.1 Hz),
157.0 (d, J = 249.0 Hz), 171.8, 205.5; HRMS (ESI-TOF) calcd for
5-(4-Chlorophenyl)-6-methyl-5-azaspiro[2.4]heptane-4,7-dione
1
(2o). white solid (54 mg, 72%); mp 180−182 °C; H NMR (500
MHz, CDCl3) δ 1.41 (d, J = 7.0 Hz, 3H), 1.73−1.76 (m, 2H), 1.78−
1.87 (m, 2H), 4.60 (q, J = 7.0 Hz, 1H), 7.39−7.41 (m, 2H), 7.43−7.45
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 15.8, 21.8, 22.3, 31.5, 62.3,
124.3, 129.3, 131.3, 134.9, 170.9, 208.3; HRMS (ESI-TOF) calcd for
+
C13H13ClNO2 ([M + H]+) 250.0629, found 250.0629.
+
C12H11FNO2 ([M + H]+) 220.0768, found 220.0773.
5-(4-Chlorophenyl)-6-isopropyl-5-azaspiro[2.4]heptane-4,7-
5-(2-Chlorophenyl)-5-azaspiro[2.4]heptane-4,7-dione (2e). white
solid (36 mg, 51%); mp 181−183 °C; 1H NMR (500 MHz, CDCl3) δ
1.74−1.79 (m, 2H), 1.82−1.84 (m, 2H), 4.34 (s, 2H), 7.31−7.37 (m,
2H), 7.39−7.40 (m, 1H), 7.50−7.51 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 21.7, 31.7, 57.9, 127.9, 129.5, 129.6, 130.6, 132.1, 134.7,
171.8, 205.4; HRMS (ESI-TOF) calcd for C12H11ClNO2+ ([M + H]+)
236.0473, found 236.0474.
5-(2-Bromophenyl)-5-azaspiro[2.4]heptane-4,7-dione (2f). white
solid (39 mg, 47%); mp 177−179 °C; 1H NMR (500 MHz, CDCl3) δ
1.75−1.77 (m, 2H), 1.83−1.86 (m, 2H), 4.35 (s, 2H), 7.26−7.29 (m,
1H), 7.37−7.43 (m, 2H), 7.68−7.70 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 21.8, 31.9, 58.1, 122.3, 128.7, 129.8, 130.1, 133.8, 136.4,
171.8, 205.6; HRMS (ESI-TOF) calcd for C12H11BrNO2+ ([M + H]+)
279.9968, found 279.9965.
1
dione (2p). white solid (35 mg, 41%); mp 109−110 °C; H NMR
(500 MHz, CDCl3) δ 0.81 (d, J = 7.0 Hz, 3H), 1.13 (d, J = 7.0 Hz,
3H), 1.61−1.64 (m, 1H), 1.74−1.80 (m, 3H), 2.14−2.18 (m, 1H),
4.48 (d, J = 3.5 Hz, 1H), 7.38−7.41 (m, 2H), 7.41−7.44 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 16.3, 17.9, 21.1, 22.6, 32.9, 71.1, 124.9,
129.4, 131.5, 135.2, 171.5, 207.6; HRMS (ESI-TOF) calcd for
+
C15H17ClNO2 ([M + H]+) 278.0942, found 278.0956.
2-Phenyl-2-azaspiro[4.4]nonane-1,4-dione (2s). white solid (45
1
mg, 65%); mp 124−127 °C; H NMR (500 MHz, CDCl3) δ 1.87−
1.92 (m, 2H), 1.94−2.01 (m, 4H), 2.08−2.13 (m, 2H), 4.29 (s, 2H),
7.20 (t, J = 7.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.69 (d, J = 7.5 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 27.1, 35.9, 55.7, 58.4, 120.1,
125.1, 129.1, 138.2, 175.4, 210.0; HRMS (ESI-TOF) calcd for
+
C14H16NO2 ([M + H]+) 230.1176, found 230.1180.
5-(3-Fluoro-4-methylphenyl)-5-azaspiro[2.4]heptane-4,7-dione
1
2-(4-Chlorophenyl)-2-azaspiro[4.4]nonane-1,4-dione (2t). white
solid (66 mg, 83%); mp 149−151 °C; 1H NMR (500 MHz, CDCl3) δ
1.88−1.92 (m, 2H), 1.94−2.01 (m, 4H), 2.07−2.11 (m, 2H), 4.26 (s,
2H), 7.37 (dd, J1 = 6.5 Hz, J2 = 1.5 Hz 2H), 7.65 (dd, J = 7.0 Hz, J2 =
2.0 Hz 2H); 13C NMR (125 MHz, CDCl3) δ 27.0, 35.9, 55.5, 58.3,
121.2, 129.1, 130.3, 136.8, 175.5, 209.3; HRMS (ESI-TOF) calcd for
(2g). white solid (45 mg, 64%); mp 179−180 °C; H NMR (500
MHz, CDCl3) δ 1.76−1.78 (m, 2H), 1.84−1.86 (m, 2H), 2.27 (d, J =
1.5 Hz, 3H), 4.35 (s, 2H), 7.21 (t, J = 8.5 Hz, 1H), 7.24−7.25 (m,
1H), 7.56−7.59 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 14.0 (d, J =
3.4 Hz), 22.4, 33.3, 56.5, 107.1 (d, J = 27.6 Hz), 114.4 (d, J = 3.3 Hz),
121.3 (d, J = 17.6 Hz), 131.5 (d, J = 6.3 Hz), 137.4 (d, J = 10.5 Hz),
161.1 (d, J = 243.1 Hz), 171.3, 204.5; HRMS (ESI-TOF) calcd for
+
C14H15ClNO2 ([M + H]+) 264.0786, found 264.0787.
+
C13H13FNO2 ([M + H]+) 234.0925, found 234.0925.
2-(4-Bromophenyl)-2-azaspiro[4.4]nonane-1,4-dione (2u). white
solid (80 mg, 87%); mp 157−159 °C; 1H NMR (500 MHz, CDCl3) δ
1.87−1.91 (m, 2H), 1.92−1.96 (m, 2H), 1.97−2.01 (m, 2H), 2.07−
2.12 (m, 2H), 4.26 (s, 2H), 7.52 (t, J = 9.0 Hz, 2H), 7.60 (d, J = 9.0
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 27.1, 35.9, 55.5, 58.4, 117.9,
5-(3-Chloro-4-methylphenyl)-5-azaspiro[2.4]heptane-4,7-dione
1
(2h). white solid (52 mg, 70%); mp 179−181 °C; H NMR (500
MHz, CDCl3) δ 1.75−1.78 (m, 2H), 1.83−1.85 (m, 2H), 2.37 (s, 3H),
4.34 (s, 2H), 7.25 (d, J = 9.0 Hz, 1H), 7.48 (dd, J1 = 8.5 Hz, J2 = 2.5
736
dx.doi.org/10.1021/jo302144w | J. Org. Chem. 2013, 78, 733−737