[Synthesis]
General procedure for the synthesis of 4-(2-(dimethylamino)vinyl)-3-nitrobenzonitrile from 4-(2-(dimethylamino)vinyl)-3-nitrobenzonitrile: Sodium periodate (65.0 g, 304 mmol) was added to a mixture of tetrahydrofuran and water (350 mL of each) of Intermediate 66 (21.0 g, 96.7 mmol). The reaction mixture was stirred for 2.5 hours, then filtered, extracted with ethyl acetate and concentrated by evaporation. The suspension of the residue in chloroform was filtered through a silica plug and subsequently recrystallized from toluene with activated carbon to give the yellow crystal product 4-cyano-2-nitrobenzaldehyde (13.1 g, 77% yield): melting point 109-111 °C; 1H NMR (δ, ppm) 10.27 (s, 1H), 8.75 (d, J = 1.5 Hz, 1H), 8.40 (dd , J = 8.0 and 1.5 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H). Elemental analysis (C8H4N2O3) C, H, and N were consistent with theoretical values. Reagents and conditions:(a) H2, 10% Pd/C, ethanol; (b) NaNO2, aqueous sulfuric acid; (c) CH3, NaH, DMF; (d) NBS, benzoyl peroxide, carbon tetrachloride; (e) AgNO3, aqueous ethanol; (f) DMFDMA, DMF; (g) NaIO4, aqueous THF; (h) diethylphosphite, (i-) Pr)2NEt, THF; (i) 2-nitropropane, NaOEt, ethanol; (j) NaNO2, aqueous hydrochloric acid, followed by the addition of CuCN, KCN; (k) methanol, H2SO4; (l) DCC, DMAP, methanol, methylene chloride; (m) Red-Al, potassium tert-butyl alcohol, pyrrolidine, methyl tert-butyl ether; (n) NH2OH-HCl water/ethanol or pyridine/ethanol; (o) NCS, DMF.The synthesis of benzaldehyde chloroxime synthesizers 52 is described in Scheme 4. Of the eight aldehydes 44e-f and 74a-f, only 44e and 74d are commercially available. The preparation of aldehyde 44f begins with the known three-step conversion of 4-methyl-3-nitrobenzyl cyanide 63 to the methoxy compound 64. see Reiner, J.E. et al, Bioorg. Med. Chem. Lett. 12, 1203-1208 (2002). The α-bromination reaction using 1 equiv. of N-bromosuccinimide was less selective between mono- and dibromo adducts, but a similar reaction using 2.5 equiv. gave almost complete dibromide 65. silver nitrate oxidation of dibromide 65 gave the aldehyde 44f. see Hill, R.A. et al, J. Chem. Soc., Perkin Trans. 2215 (1987). The reaction of o-nitrotoluene 63 with N,N-dimethylformamide dimethyl acetal in DMF afforded enamine 66, which was oxidatively cleaved using sodium periodate in THF, cf. Riesgo, E.C. et al. J. Org. Chem., 61, 3017-3022 (1996), and aldehyde 74a was obtained by a simpler method of preparation than previously reported. cf. Dann, O. et al, Liebigs Ann. Chem., 3, 409-425 (1984). The preparation of aldehyde 74b has been reported. See Schultz, E.M. et al, J. Med. Chem., 19(6), 783-787 (1976). A more favorable method of preparing 74b begins with chlorotoluene 67 undergoing α-bromination to 68, see Gilbert, A.M. et al, J. Med. Chem., 43, 1203-1214 (2000), by a modification of the original procedure. See Liu, P. et al, Synthesis, 14, 2078-2080 (2001). Reaction of 68 with 2-nitropropane and sodium ethoxide in ethanol gave 74b. see Mallory, F.M. et al, Tetrahedron, 57, 3715-3724 (2001). For commercially available aldehydes 69 and 71, see Hino, K. et al, Chem. Pharm. Bull., 36(6), 3462-3467 (1988), which are prepared by the Sandmeyer reaction of commercially available 70 and converted to methyl esters 72 and 73, respectively. the esters were converted to aldehydes using Red-Al (sodium bis(2-methoxyethoxy)hydroaluminum), respectively 74c and 74e. see Abe, T. et al, Tetrahedron, 57, 2701-2710 (2001). Cyanal 74f was prepared by debromocyanation of 44d. cf. Laali, K.K. et al. J. Org. Chem., 58, 1385-1392 (1993). Conversion of aldehydes 44e-44f and 74a-74f to oxime derivatives 75a-h (where 75a,e were previously known), see Quan, M.L. et al, J. Med. Chem., 42(15), 2752-2759 (1999), using hydroxylamine hydrochloride in water/ethanol or pyridine/ethanol. Treatment of the oxime with N-chlorosuccinimide in DMF according to the method reported for 52e gave chloroxime 52a-h. See Liu, K.-C. et al, J. Org. Chem., 45, 3916-3918 (1980). Chloroxime 52 reacts with acetylene 51 without further purification. |