ACCEPTED MANUSCRIPT
CH2); 1.72-1.80 (m, 2H, CH2); 2.36-2.44 (m, 4H, 2CH2); 3.41 (s, 3H, NCH3); 3.78 (d, J = 11.4 Hz,
1H, CHH); 4.86 (d, J = 11.4 Hz, 1H, CHH); 7.29 (d, J = 8.8 Hz, 1H, arom.); 7.33 (d, J = 2.0 Hz, 1H,
arom.); 7.42-7.46 (m, 2H, arom.); 7.50-7.53 (m, 1H, arom.); 7.59 (dd, J = 8.8 Hz, 2.0 Hz, 1H,
arom.); 7.63-7.67 (m, 2H, arom.) ppm.
3.1.2. 5-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-7-yl)pent-4-ynoic acid
16
Following the same procedure used for 15, 13 (0.48 g, 1.28 mmol) was treated with 6-pentynoic
acid ethyl ester [15] (0.25 g, 1.95 mmol), CuI (0.03 g, 0.15 mmol), Pd(PPh3)4 (0.06 g, 0.05 mmol)
and anhydrous Et3N (9 mL) at 55 °C for 2 h under nitrogen. Purification with flash chromatography
(CH2Cl2/MeOH 99:01) gave ethyl 5-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-
7-yl)pent-4-ynoate 18 in 88% yield. Yellow waxy solid. [1H]-NMR (CDCl3) δ: 1.23 (t, J = 7.2 Hz,
3H, CH2CH3); 2.57 (t, J = 7.0 Hz, 2H, CH2CH2); 2.68 (t, J = 7.0 Hz, 2H, CH2CH2); 3.40 (s, 3H,
NCH3); 3.77 (d, J = 11.0 Hz, 1H, CHH); 4.14 (q, J = 7.2 Hz, 2H, CH2CH3); 4.84 (d, J = 11.0 Hz,
1H, CHH); 7.28 (d, J = 8.4 Hz, 1H, arom.); 7.32 (d, J = 2.0 Hz, 1H, arom.); 7.41-7.45 (m, 2H,
arom.); 7.48-7.52 (m, 1H, arom.); 7.56 (dd, J = 8.8 Hz, 2.0 Hz, 1H, arom.); 7.63-7.65 (m, 2H,
arom.) ppm. When the reaction was performed with 6-pentynoic acid, 17 was obtained; this
compound was not further purified, nor the stereochemistry on the double bond was investigated.
MS (ESI) 347 (M+1). [1H]-NMR (CDCl3) δ: 2.57-2.75 (m, 2H, CH2CO); 2.97-3.02 (m, 2H,
CH2C=C); 3.40 (s, 3H, NCH3); 3.79 (d, J = 11.0 Hz, 1H, CHH); 4.82 (d, J = 11.0 Hz, 1H, CHH);
6.23 (t, J = 2.2 Hz, 1H, C=CH); 7.12 (d, J = 2.0 Hz, 1H, arom.); 7.33 (d, J = 8.4 Hz, 1H, arom.);
7.38-7.49 (m, 4H, arom.); 7.62-7.66 (m, 2H, arom.) ppm.
A solution of 18 (0.42 g, 1.12 mmol), NaOH (0.07 g, 1.70 mmol) in 2 mL of MeOH, 2 mL of THF
and 2 mL of H2O were stirred at RT for 2 hr, then it was treated with sat. aqueous NH4Cl and
extracted with ethyl acetate. Drying (Na2SO4) and removal of the solvent gave the title compound in
93% yield. Rose solid, m.p. 50-51 °C. [1H]-NMR (CDCl3) δ: 2.60-2.70 (m, 4H, CH2CH2); 3.41 (s,
3H, NCH3); 3.78 (d, J = 11.6 Hz, 1H, CHH); 4.90 (d, J = 11.6 Hz, 1H, CHH); 7.31-7.34 (m, 2H,
arom.); 7.15-7.49 (m, 2H, arom.); 7.54-7.58 (m, 1H, arom.); 7.63 (dd, J = 8.8 Hz, 2.0 Hz, 1H,
arom.); 7.69-7.71 (m, 2H, arom.) ppm.
3.1.3. (2E)-5-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-7-yl)pent-2-en-4-
ynoic acid 20
Ethyl pent-4-yn-2-enoate [16] (0.30 g, 2.44 mmol), prepared according to Wei [17] as 4.3:1 E/Z
mixture, was reacted with 13 (0.61 g, 1.62 mmol) CuI (0.04 g, 0.19 mmol), Pd(PPh3)4 (0.07 g, 0.06
mmol) and anhydrous Et3N (10 mL) at 55 °C for 2 h and 30’ under nitrogen, following the same
procedure used for 15. Purification with flash chromatography (cyclohexane/ethyl acetate 7:3) gave
ethyl (2E)-5-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-7-yl)pent-2-en-4-ynoate
19 (0.34 g), the 2-Z isomer 19a (0.06 g) and a mixed fraction (19/19a 2:1, 0.10 g). 19: yellow waxy
solid. [1H]-NMR (CDCl3) δ: 1.30 (t, J = 7.0 Hz, 3H, CH2CH3); 3.43 (s, 3H, NCH3); 3.79 (d, J =
11.2 Hz, 1H, CHH); 4.22 (q, J = 7.0 Hz, 2H, CH2CH3); 4.88 (d, J = 11.2 Hz, 1H, CHH); 6.28 (d, J =
16.0 Hz, 1H, CH=CH); 6.91 (d, J = 16.0 Hz, 1H, CH=CH); 7.35 (d, J = 8.8 Hz, 1H, arom.); 7.41-
7.47 (m, 3H, arom.); 7.50-7.54 (m, 1H, arom.); 7.64-7.68 (m, 3H, arom.) ppm. 19a: Yellow waxy
solid. [1H]-NMR (CDCl3) δ: 1.24 (t, J = 7.2 Hz, 3H, CH2CH3); 3.40 (s, 3H, NCH3); 3.77 (d, J =
8