Reactions of benzodiazepines with activated alkynes Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
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diluted with water (60 mL), and extracted with diethyl ether
(3×40 mL). The extract was dried with magnesium sulfate. The
solvent was evaporated in vacuo to obtain benzylꢀsubstituted diꢀ
azepines 2 and 9, a yellow oil solidifying on standing.
N, 17.27. IR, /cm–1: 3303 (NH). 1H NMR (400 MHz,
DMSOꢀd6), : 2.41 (s, 3 H, Me); 2.88 (m, 2 H, CH2); 3.15
(m, 2 H, CH2); 3.72 (s, 2 H, CH2); 3.88 (br.s, 1 H, NH); 6.74
(m, 1 H, Ar); 6.85 (m, 1 H, Ar); 7.11 (m, 2 H, Ar). MS, m/z
(Irel (%)): 162 [M]+ (61), 147 (36), 130 (32), 118 (100), 91 (97),
77 (34), 65 (51), 44 (44).
Diazepine 2. The yield was 74%, Rf 0.42 (sorbfil, ethyl aceꢀ
tate). Found (%): C, 70.28; H, 6.11; N, 8.55. C19H20N2O3. Calꢀ
culated (%): C, 70.35; H, 6.21; N, 8.64. IR, /cm–1: 1721, 1674
(CO). 1H NMR (400 MHz, CDCl3), : 2.50 (s, 3 H, NMe); 3.17
(s, 2 H, C(5)H2); 3.42 (s, 2 H, C(3)H2); 3.91 (s, 3 H, CO2Me);
5.12 (s, 2 H, CH2Ph); 7.20—7.24 (m, 5 H, Ph); 7.31 (d, 1 H,
C(6)H, J = 7.8 Hz); 7.84 (dd, 1 H, C(7)H, J = 1.5 Hz, J = 7.8 Hz);
7.95 (d, 1 H, C(9)H, J = 1.5 Hz). MS (ESI+), m/z: 325 [M + H]+.
Diazepine 9. The yield was 79%, Rf 0.52 (sorbfil, ethyl acetꢀ
ate). Found (%): C, 72.06; H, 6.39; N, 8,05. C21H22N2O3. Calꢀ
culated (%): C, 71.98; H, 6.33; N, 7.99. IR, /cm–1: 1724, 1663
(CO). 1H NMR (400 MHz, CDCl3), : 1.84—1.92 (m, 1 H,
C(1)H2); 2.05—2.14 (m, 1 H, C(1)H2); 2.44—2.56 (m, 2 H,
C(2)H2); 3.06—3.11 (m, 1 H, C(3)H2); 3.19 (d, 1 H, C(5)H2,
J = 10.9 Hz); 3.61 (dd, 1 H, C(3)H2, J = 2.1 Hz, J = 7.7 Hz); 3.74
(d, 1 H, C(5)H2, J = 10.9 Hz); 3.91—3.92 (s, 1 H, C(11a)H);
3.93 (s, 3 H, CO2Me); 4.81 (d, 1 H, CH2Ph, J = 14.7 Hz); 5.42
(d, 1 H, CH2Ph, J = 14.7 Hz); 7.21—7.25 (m, 5 H, Ph); 7.36
(d, 1 H, C(6)H, J = 7.8 Hz); 7.84 (dd, 1 H, C(7)H, J = 1.6 Hz,
J = 7.8 Hz); 7.96 (d, 1 H, C(9)H, J = 1.6 Hz). MS (ESI+), m/z:
351 [M + H]+.
4ꢀMethylꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ1,4ꢀbenzodiazepine (10)
and 7ꢀfluoroꢀ4ꢀmethylꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ1,4ꢀbenzodiꢀ
azepine (11). A mixture of 2Hꢀ3,1ꢀbenzoxazineꢀ2,4(1H)ꢀdione
(11.66 g, 61.30 mmol) or 6ꢀfluoroꢀ2Hꢀ3,1ꢀbenzoxazineꢀ2,4(1H)ꢀ
dione (12.76 g, 61.30 mmol) with sarcosine (5.46 g, 61.30 mmol)
in pyridine (22 mL) was refluxed for 7 h, cooled to 5 C. Precipꢀ
itates of benzodiazepinediones were filtered off and recrystalꢀ
lized from ethanol to obtain 4ꢀmethylꢀ3,4ꢀdihydroꢀ1Hꢀ1,4ꢀdiꢀ
benzodiazepineꢀ2,5ꢀdione. The yield was 70%, m.p. 246—247 C.
Found (%): C, 63.18; H, 5.32; N, 14.82. C10H10N2O2. Calculatꢀ
ed (%): C, 63.15; H, 5.30; N, 14.73. IR, /cm–1: 1632 (CO);
1698 (CO); 3212 (NH). 1H NMR (400 MHz, DMSOꢀd6), : 3.12
(s, 3 H, NMe); 3.84 (s, 2 H, CH2); 7.10 (d, 1 H, Ar, J = 8.0 Hz);
7.21—7.24 (m, 1 H, Ar); 7.14 (d, 1 H, Ar, J = 8.0 Hz); 7.50 (m, 1 H,
Ar); 10.46 (s, 1 H, NH). MS, m/z (Irel (%)): 190 [M]+ (100), 161
(69), 146 (13), 119 (69), 92 (50), 64 (13), 44 (46). In addition,
7ꢀfluoroꢀ4ꢀmethylꢀ3,4ꢀdihydroꢀ1Hꢀ1,4ꢀdibenzodiazepineꢀ2,5ꢀ
dione was isolated. The yield was 76%, m.p. 213—215 C.
Found (%): C, 57.78; H, 4.21; N, 13.52. C10H9FN2O2. Calcuꢀ
lated (%): C, 57.69; H, 4.36; N, 13.46. IR, /cm–1: 1636 (CO);
1703 (CO); 3248 (NH). 1H NMR (400 MHz, DMSOꢀd6),
: 3.11 (s, 3 H, NMe); 3.86 (s, 2 H, CH2); 7.13 (m, 1 H, Ar); 7.45
(m, 2 H, Ar); 10.49 (s, 1 H, NH). MS, m/z (Irel (%)): 208 [M]+
(4), 179 (13), 137 (24), 109 (25), 82 (31), 42 (100).
Benzodiazepine 11. The yield was 62%, m.p. 48—50 C (from
a mixture of hexane—ethyl acetate). Found (%): C, 66.91;
H, 7.14; N, 15.25. C10H13FN2. Calculated (%): C, 66.64;
H, 7.27; N, 15.54. IR, /cm–1: 3263 (NH). 1H NMR (400 MHz,
DMSOꢀd6), : 2.39 (s, 3 H, Me); 2.86 (m, 2 H, C(2)H2); 3.09
(m, 2 H, C(3)H2); 3.67 (s, 2 H, C(5)H2); 3.80 (br.s, 1 H, NH);
6.68 (dd, 1 H, C(9)H, J = 4.9 Hz, J = 8.6 Hz); 6.78 (ddd, 1 H,
C(8)H, J = 2.9 Hz, J = 8.6 Hz, J = 9.3 Hz); 6.85 (dd, 1 H,
C(6)H, J = 2.9 Hz, J = 9.1 Hz). MS, m/z (Irel (%)): 180 [M]+
(81), 165 (24), 148 (16), 138 (77), 109 (95), 83 (51), 44 (100).
Reaction of benzodiazepines 10 and 11 with alkynes (general
procedure). Methyl propiolate or methyl acetylenedicarboxilate
(2.78 mmol) was added to a solution of benzodiazepine 10 or 11
(1.85 mmol) in methanol (15 mL) at 20 C. After 1 h (TLC
monitoring), the solvent was evaporated in vacuo, the residue
was subjected to chromatography on silica gel, using chloroꢀ
form—methanol (20 : 1) as an eluent to obtain 5ꢀmethylꢀ1ꢀvinylꢀ
benzodiazepines 12—14.
Methyl (2E)ꢀ3ꢀ(4ꢀmethylꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ1,4ꢀbenzoꢀ
diazepinꢀ1ꢀyl)acrylate (12). The yield was 88%, yellow oil.
Found (%): C, 68.35; H, 7.21; N, 11.30. C14H18N2O2. Calculatꢀ
ed (%): C, 68.27; H, 7.37; N, 11.37. IR, /cm–1: 1687 (CO).
1H NMR (400 MHz, CDCl3), : 2.38 (s, 3 H, NMe); 2.89
(m, 2 H, C(2)H2); 3.56 (m, 2 H, C(3)H2); 3.69 (s, 3 H, CO2Me);
3.71 (s, 2 H, C(5)H2); 4.84 (br.s, 1 H, =CH); 7.20 (m, 3 H, Ar);
7.21 (m, 1 H, Ar); 7.72 (d, 1 H, =CH, J = 13.3 Hz). 13C NMR
(100 MHz, CDCl3), : 43.4 (Me); 49.2 (CH2); 50.5 (Me); 55.8
(CH2); 59.8 (CH2); 88.2 (CH=); 124.8 (CH); 126.6 (CH); 128.8
(CH); 130.7 (C); 133.4 (C); 145.1 (C); 149.9 (=CH); 169.9 (CO).
MS, m/z (Irel (%)): 246 [M]+ (57), 231 (67), 215 (38), 203 (85),
188 (22), 170 (44), 144 (88), 130 (100), 117 (51), 91 (62), 77 (42),
65 (31).
Methyl (2E)ꢀ3ꢀ(7ꢀfluoroꢀ4ꢀmethylꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ
1,4ꢀbenzodiazepinꢀ1ꢀyl)acrylate (13). The yield was 72%, yellow
oil. Found (%): C, 63.58; H, 6.55; N, 10.62. C14H17FN2O2.
Calculated (%): C, 63.62; H, 6.50; N, 10.58. IR, /cm–1: 1616
(CO). 1H NMR (400 MHz, CDCl3), : 2.38 (s, 3 H, NMe); 2.91
(m, 2 H, C(2)H2); 3.55 (m, 2 H, C(3)H2); 3.68 (br.s, 5 H,
CO2Me, C(5)H2); 4.79 (br.s, 1 H, =CH); 6.97 (m, 2 H, Ar); 7.16
(m, 1 H, Ar); 7.64 (d, 1 H, =CH, J = 13.3 Hz). 13C NMR (100
MHz, CDCl3), : 43.2 (Me); 48.2 (CH2); 50.7 (Me); 55.4 (CH2);
59.4 (CH2); 88.0 (=CH); 115.2 (d, CH, J = 22 Hz); 117.4
(d, CH, J = 22 Hz); 126.6 (C); 136.4 (C); 140.9 (C); 149.9 (=CH);
160.6 (d, C—F, J = 248 Hz); 169.6 (CO). MS, m/z (Irel (%)): 264
[M]+ (49); 249 (29), 233 (19), 221 (100), 206 (19), 188 (20), 162
(92), 148 (85), 135 (38), 109 (19), 83 (14), 42 (18).
Dimethyl 2ꢀ(7ꢀfluoroꢀ4ꢀmethylꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ1,4ꢀ
benzodiazepinꢀ1ꢀyl)butꢀ2ꢀenedioate (14). The yield was 78%,
colorless crystals, m.p. 106—107 C (from a mixture of ethyl
acetate—hexane). Found (%): C, 59.78; H, 6.10; N, 8.51.
C16H19FN2O4. Calculated (%): C, 59.62; H, 5.94; N, 8.69. IR,
/cm–1: 1693, 1737 (CO). 1H NMR (400 MHz, CDCl3), : 2.34
(s, 3 H, NMe); 2.80—3.90 (m, 12 H, C(2)H2, C(3)H2, C(5)H2,
2 CO2Me); 4.69 (br.s, 1 H, =CH); 6.98 (m, 2 H, Ar); 7.19 (m, 1 H,
Ar). MS, m/z (Irel (%)): 322 [M]+ (48); 307 (38), 290 (28), 263
The thus obtained benzodiazepinediones (54.76 mmol) were
added in portions to a suspension of lithium aluminum hydride
(10.3 g, 0.27 mmol) in anhydrous dioxane (200 mL) at 0—5 C
under argon. The reaction mixture was refluxed for 4 h cooled to
~20 C, quenched with aq. dioxane and 15% aq. NaOH. The
organic layer was decanted. The solvent was evaporated in vacuo.
The residue was subjected to chromatography on silica gel,
using chloroform as an eluent. Benzodiazepines 10 or 11 were
obtained as colorless crystals.
Benzodiazepine 10. The yield was 64%, m.p. 42—44 C (from
a mixture of hexane—ethyl acetate). Found (%): C, 73.92;
H, 8.80; N, 17.30. C10H14N2. Calculated (%): C, 74.03; H, 8.70;