The Formal [3ϩ2ϩ1] Cyclisation of Cyclopropylamines with Carboxylic Anhydrides
FULL PAPER
brown oil (2.2 g). Purification by flash column chromatography
(ethyl acetate/heptane, gradient from 50 to 100%) yielded pure 17
(1.5 g, 5.9 mmol, 63%). White solid. C16H20N2O (256.3): calcd. C
74.87, H 7.86; found C 74.66, N 7.95. M.p. 101.0Ϫ101.9 °C. MS
(CI, NH3): m/z ϭ 177, 191, 199, 257 [MHϩ]. IR (mixture of two
Vinylogous Amide 21: n-Butyric anhydride (16 equiv., 9.2 mmol,
1.5 mL) was added to a solution of the cyclopropylamine 2 (1.0
equiv., 0.58 mmol, 0.10 g) in chlorobenzene (10 mL). The mixture
was heated at reflux for 3.5 h, then washed with 1 sodium hydrox-
ide aqueous solution (2 ϫ 20 mL). The organic layer was dried
rotamers): ν˜ ϭ 3176, 2925, 1614, 1487, 1455, 1368, 1232, 1210 with sodium sulfate, filtered and concentrated to afford a yellow
1
cmϪ1. H NMR (mixture of two rotamers): δ ϭ 1.91 and 2.12 (2
oil (0.63 g). Flash column chromatography (ethyl acetate/heptane,
ϫ s, 3 H), 2.26 and 2.34 (2 ϫ q, J ϭ 7 Hz, 2 H), 2.99 and 3.03 (2 gradient from 0 to 20%) of the crude product gave pure 21 (71 mg,
ϫ t, J ϭ 7 Hz, 2 H), 3.23 and 3.46 (2 ϫ t, J ϭ 7 Hz, 2 H), 3.53 0.29 mmol, 50%) and 22 (36 mg, 0.11 mmol, 20%). A 36:64 mixture
and 3.63 (2 ϫ t, J ϭ 7 Hz, 2 H), 4.99Ϫ5.12 (m, 2 H), 5.65Ϫ5.85 of both compounds was also isolated (16 mg, 20 and 35 µmol, 3
(m, 1 H), 6.94 and 6.97 (2 ϫ d, J ϭ 2 Hz, 1 H), 7.07Ϫ7.23 (m, 2
H), 7.33 and 7.37 (2 ϫ d, J ϭ 7 Hz, 1 H), 7.55 and 7.66 (2 ϫ d, ν˜ ϭ 2960, 2871, 1646, 1599, 1584, 1544, 1493, 1459, 1409, 1295,
and 6%).Yellow oil. MS (EI): m/z ϭ 172, 184, 200, 243 [Mϩ·]. IR
1
J ϭ 7 Hz, 1 H), 8.09 and 8.18 (2 ϫ br. s, 1 H) ppm. 13C NMR
(mixture of two rotamers): δ ϭ 21.4 and 21.8 ppm, 23.6 and 24.7,
32.3 and 33.3, 45.3 and 47.1, 48.9 and 49.6, 111.3 and 111.6, 111.8
and 113.0, 116.7 and 117.7, 118.1, 118.7, 119.2, 119.4, 121.8, 122.1,
122.2, 122.5, 127.1 and 127.5, 134.3 and 135.5, 136.4 and 136.4,
170.5 and 170.8 ppm.
1136, 1056 cmϪ1. H NMR: δ ϭ 0.87 (t, J ϭ 7 Hz, 3 H), 1.28 (d,
J ϭ 7 Hz, 3 H), 1.55 (sext, J ϭ 7 Hz, 2 H), 1.77 (ddd, J ϭ 12, 6,
1 Hz, 1 H), 2.11Ϫ2.35 (m, 3 H), 3.62 (ddd, J ϭ 10, 9, 1 Hz, 1 H),
3.88 (ddd, J ϭ 11, 10, 6 Hz, 1 H), 4.19 (quint, J ϭ 7 Hz, 1 H), 5.27
(s, 1 H), 7.21Ϫ7.30 (m, 3 H), 7.39Ϫ7.47 (m, 2 H) ppm. 13C NMR:
δ ϭ 14.1, 18.2, 19.1, 29.6, 38.2, 45.9, 52.7, 91.2, 125.1, 126.4, 129.5,
141.4, 168.9, 197.5 ppm.
Cyclopropylamine 18: A similar procedure as for the preparation
of 2, starting from 17 (2.6 mmol, 0.67 g), yielded pure 18 (0.58 g,
2.4 mmol, 93%). Colourless crystals. C16H20N2 (240.3): calcd. C
79.96, H 8.39; found C 79.67, N 8.61. M.p. 112.0Ϫ112.9 °C (etha-
nol). MS (CI, NH3): m/z ϭ 241 [MHϩ]. IR ν˜ ϭ 3412, 3257, 3058,
2925, 2852, 1619, 1456 cmϪ1. 1H NMR: δ ϭ 0.10 (dd, J ϭ 8, 5 Hz,
1 H), 0.80 (t, J ϭ 5 Hz, 1 H), 1.19 (dt, J ϭ 8, 5 Hz, 1 H), 1.40 (s,
3 H), 1.74Ϫ1.88 (m, 1 H), 1.90Ϫ2.16 (m, 2 H), 2.41 (ddd, J ϭ 11,
9, 7 Hz, 1 H), 3.00 (t, J ϭ 8 Hz, 2 H), 3.22 (ddd, J ϭ 11, 9, 8 Hz,
1 H), 3.22Ϫ3.33 (m, 1 H), 7.00 (d, J ϭ 2 Hz, 1 H), 7.12Ϫ7.24 (m,
2 H), 7.30 (d, J ϭ 8 Hz, 1 H), 7.60 (d, J ϭ 8 Hz, 1 H), 8.16 (br. s,
1 H) ppm. 13C NMR: δ ϭ 7.9, 19.7, 22.5, 24.9, 26.2, 46.3, 49.9,
52.7, 111.1, 114.8, 118.8, 119.1, 121.3, 121.9, 127.5, 136.3 ppm.
Vinylogous Amide 22: When the conditions described above were
applied to cyclopropylamine 2 (1.1 mmol, 0.19 g) with 24 h of heat-
ing at reflux, the diketone 22 was the major product. Flash column
chromatography (ethyl acetate/heptane, gradient from 0 to 30%) of
the crude product (yellow oil, 1.5 g) gave pure 21 (42 mg,
0.17 mmol, 16%) and 22 (0.17 g, 0.54 mmol, 49%). Yellow oil. MS
(EI): m/z ϭ 172, 173, 198, 199, 200, 242, 243, 270, 313 [Mϩ·]. IR
ν˜ ϭ 2960, 2872, 1709, 1642, 1536, 1493, 1461, 1409, 1297, 1175,
1148, 1126, 1060 cmϪ1 1H NMR: δ ϭ 0.82 (t, J ϭ 7 Hz, 3 H),
.
0.94 (t, J ϭ 7 Hz, 3 H), 1.50 (sext, J ϭ 7 Hz, 2 H), 1.54 (s, 3 H),
1.67 (sext, J ϭ 7 Hz, 2 H), 1.89 (ddd, J ϭ 12, 7, 2 Hz, 1 H), 2.12
(t, J ϭ 7 Hz, 2 H), 2.21 (dt, J ϭ 12, 10 Hz, 1 H), 2.49 (dt, J ϭ 17,
7 Hz, 1 H), 2.69 (dt, J ϭ 17, 7 Hz, 1 H), 3.71 (td, J ϭ 10, 2 Hz, 1
H), 3.88 (td, J ϭ 10, 7 Hz, 1 H), 5.32 (s, 1 H), 7.26Ϫ7.34 (m, 3 H),
7.44Ϫ7.50 (m, 2 H) ppm. 13C NMR: δ ϭ 13.9, 14.0, 17.2, 19.0,
19.2, 34.9, 39.3, 45.3, 52.3, 59.7, 91.9, 125.0, 126.9, 129.7, 141.2,
166.5, 196.3, 206.6 ppm.
Diketone 19: A similar procedure as for the synthesis of 4 and 5
was applied to cyclopropylamine 18 (0.42 mmol, 0.10 g), with 2 h
of heating at reflux to give pure compound 19 (69 mg, 2.1 mmol,
51%). Colourless crystals. C20H24N2O2 (324.4): calcd. C 74.04, H
7.46; found C 73.82, N 7.47. M.p. 185.0Ϫ187.2 °C (toluene). MS
(CI, NH3): m/z ϭ 283, 325 [MHϩ]. IR ν˜ ϭ 3225, 3055, 2927, 1705,
1622, 1537, 1481, 1458, 1355, 1300, 1201 cmϪ1. 1H NMR: δ ϭ 1.40
(s, 3 H), 1.68 (dd, J ϭ 12, 7 Hz, 1 H), 1.92Ϫ2.03 (m, 1 H), 1.99 (s,
3 H), 2.20 (s, 3 H), 3.10 (t, J ϭ 7 Hz, 2 H), 3.22 (td, J ϭ 10, 2 Hz,
1 H), 3.34 (td, J ϭ 10, 7 Hz, 1 H), 3.61 (m, 2 H), 5.09 (s, 1 H),
7.03 (d, J ϭ 2 Hz, 1 H), 7.10Ϫ7.22 (m, 2 H), 7.40 (d, J ϭ 8 Hz, 1
H), 7.63 (d, J ϭ 8 Hz, 1 H), 8.23 (br. s, 1 H) ppm. 13C NMR: δ ϭ
19.6, 22.0, 25.6, 30.2, 34.4, 47.4, 50.8, 60.4, 88.8, 111.7, 111.8,
118.2, 119.4, 122.1, 122.7, 127.2, 136.6, 167.3, 192.3, 205.3 ppm.
Alcohol 23 and Tetrahydroindolone 24: These compounds were ob-
tained when the procedure leading to alcohol 6 was applied to dike-
tone 22 (0.54 mmol, 0.17 g) with 25 h of heating at reflux. Purifi-
cation by flash column chromatography (ethyl acetate/heptane,
gradient from 0 to 50%) yielded pure 23 (76 mg, 0.24 mmol, 45%)
as a single diastereoisomer and an 81:19 mixture of starting mate-
rial 22/dehydrated product 24 (61 mg). The estimated yields of
these compounds are thus 51 mg for 22 (0.16 mmol, 30%) and
10 mg for 24 (34 µmol, 6%). Pure 24 could be obtained by further
flash column chromatography. 23: Colourless crystals. C20H27NO2
Alcohol 20: This alcohol was prepared in the same way as 6, start-
ing from diketone 19 (0.15 mmol, 50 mg), with 77 h of heating at (313.4): calcd. C 76.64, H 8.68; found C 76.84, N 8.77. M.p.
reflux. Purification by flash column chromatography (ethyl acetate/
heptane, gradient from 50 to 100%) yielded pure 20 (44 mg,
0.14 mmol, 88%) as a single diastereoisomer. Colourless crystals.
188.3Ϫ189.1 °C (ethyl acetate). MS (EI): m/z ϭ 184, 198, 199, 242,
261, 313 [Mϩ·]. IR ν˜ ϭ 3389, 2958, 2872, 1603, 1572, 1495, 1414,
1209 cmϪ1 1H NMR: δ ϭ 0.84 (t, J ϭ 7 Hz, 3 H), 1.20 (t, J ϭ
.
C20H24N2O2 (324.4): calcd. C 74.68, H 7.44; found C 74.55, N 7.62. 7 Hz, 3 H), 1.18Ϫ1.29 (m, 2 H), 1.47 (s, 3 H), 1.53Ϫ1.75 (m, 4 H),
M.p. 201.5Ϫ202.7 °C (ethyl acetate). MS (EI): m/z ϭ 130, 136, 143, 1.83Ϫ1.98 (m, 1 H), 1.84 (dd, J ϭ 12, 6 Hz, 1 H), 2.28 (dt, J ϭ 12,
144, 177, 194, 195, 324 (Mϩ·). IR ν˜ ϭ 3250, 3052, 2975, 2923, 2875, 10 Hz, 1 H), 2.51 (dd, J ϭ 8, 3 Hz, 1 H), 3.89 (t, J ϭ 10 Hz, 1 H),
1606, 1552, 1457, 1435, 1361, 1293, 1254, 1215, 1141, 1117, 1086
3.96 (td, J ϭ 10, 6 Hz, 1 H), 5.29 (s, 1 H), 7.18Ϫ7.26 (m, 3 H),
1
cmϪ1. H NMR: δ ϭ 1.22 (s, 3 H), 1.25 (s, 3 H), 1.57 (dd, J ϭ 11,
7.38 (m, 2 H) ppm. 13C NMR: δ ϭ 15.2, 16.2, 18.1, 19.3, 20.7,
6 Hz, 1 H), 2.02 (br. s, 1 H), 2.05 (q, J ϭ 11 Hz, 1 H), 2.57 (AB 29.5, 38.3, 52.5, 52.6, 54.3, 78.4, 95.6, 123.6, 126.1, 129.5, 140.8,
system, δA ϭ 2.29, δB ϭ 2.86, JAB ϭ 17 Hz, 2 H), 2.98Ϫ3.09 (m,
169.0, 197.5 ppm. 24: Orange oil. HRMS (ESϩ): calcd. for
2 H), 3.30 (m, 1 H), 3.44 (td, J ϭ 11, 6 Hz, 1 H), 3.48Ϫ3.60 (m, 2 C20H26NO [MHϩ] 296.2014; found 296.2005. IR ν˜ ϭ 2961, 2871,
H), 4, 99 (s, 1 H), 6.99 (s, 1 H), 7.10Ϫ7.21 (m, 2 H), 7.37 (d, J ϭ 1697, 1642, 1587, 1497, 1457, 1405, 1371, 1308, 1254, 1176 cmϪ1
8 Hz, 1 H), 7.57 (d, J ϭ 8 Hz, 1 H), 8.5 (br. s, 1 H) ppm. 13C 1H NMR: δ ϭ 1.04 (t, J ϭ 7 Hz, 6 H), 1.42 (s, 3 H), 1.51Ϫ1.65
NMR: δ ϭ 19.5, 22.4, 24.9, 28.9, 46.9, 49.2, 51.8, 52.6, 73.4, 90.2, (m, 2 H), 2.07Ϫ2.28 (m, 3 H), 2.29Ϫ2.50 (m, 3 H), 3.85 (td, J ϭ
111.2, 111.9, 118.3, 119.5, 122.2, 127.1, 136.3, 173.4, 194.5 ppm. 10, 6 Hz, 1 H), 3.98 (td, J ϭ 10, 1 Hz, 1 H), 5.68 (s, 1 H), 7.14 (m,
.
Eur. J. Org. Chem. 2004, 3517Ϫ3525
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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