4-Chloro-3-iodobenzonitrile

914106-25-5

914106-26-6

As an example of the synthesis of 4-chloro-3-iodobenzonitrile (60f), the aldoxime 59 (5.65 g, 20.0 mmol) was dissolved in acetic anhydride (10 mL) and the reaction was carried out at reflux for 4 hours. After completion of the reaction, the mixture was poured into ice water and stirred for 1 hour. The product was collected by filtration to give a light yellow solid 4-chloro-3-iodobenzonitrile (4.79 g, 91% yield) with a melting point of 91-93 °C. The product was characterized by 1H NMR (δ 8.49, d, J = 2.2 Hz, 1H; 7.90, dd, J = 8.2 and 2.2 Hz, 1H; 7.79, d, J = 8.2 Hz, 1H) and HPLC (Method B, tR = 6.24 min, % area at 254 nm 91.75%). The results of elemental analysis (C7H3ClIN) were in accordance with theoretical values. Reagents and conditions are summarized as (a) fuming HNO3, H2SO4; (b) Fe, AcOH, EtOH; (c) NaNO2, aq. HCl, followed by CuCl; (d) NaIO4, I2, AcOH, Ac2O, H2SO4; (e) NH2OH-HCl, Py, EtOH; (f) Ac2O; (g) TMSA. Pd2Cl2(PPh3)2, CuI, Et3N; (h) TMSA, PPh3, Pd(PPh3)4, CuI, piperidine; (j) 2-methyl-3-butyn-2-ol, Pd2Cl2(PPh3)2, CuI, Et3N; (k) 2-methyl-3-butyn-2-ol, 10% Pd/C, PPh3, CuI, aq. K2CO3/DME; (l) Cs2CO3, aq. CH3CN or MeOH; (m) NaH, toluene. The second general method, as described in Scheme 2, involves the cycloaddition reaction of cyclic cyano-phenylacetylene 51 with benzaldehyde chloroxime 52 in the presence of bis(tributyltin) oxide (Moriya, O. et al., J. Chem. Soc., Perkin Trans. 1, 413-417, 1994; Moriya, O. et al. Soc., Chem. Commun., 17-18, 1991), or in the presence of triethylamine (Thomsen, I. et al., Acta Chem. Scand. B, 319-313, 1988), isoxazole dicarbonitrile 53a-h, k-s and bromonitrile 53i were prepared in nonpolar solvents. the latter was treated with copper(I) cyanide to give dinitrile 53j (Friedman, L. et al., J. Org. Chem., 26, 2522-2524, 1961). This method also provides an alternative route to the dinitriles 50a, b, g, k prepared by the first method in Scheme 1. Phenylacetylene synthesizers 51a-g were prepared as shown in Scheme 3. The starting materials 60a, e, g are commercially available. 60a was subjected to nitration to give 60b (Borsche, W. et al., Chem. Ber., 49, 2222-2243, 1916), which was subsequently reduced to aniline 56 (Blanksma, J.J. et al., Recl. Trav. Chim. Pays-Bas, 66, 365-373, 1947). 365-373, 1947), followed by diazotization and treatment with copper(I) chloride to give chlorobenzene 60c. 4-Bromo-3-hydroxybenzonitrile was treated with trifluoromethanesulfonic anhydride to prepare trifluoromethanesulfonate 60d. Synthesis of aryl iodine 60f began with the conversion of a known aldehyde 57 to the iodine derivative 58 (Lulinski, P. et al., Bull. Chem. Soc. Jpn., 73(4), 951-956, 2000), 58 was treated with hydroxylamine hydrochloride to give aldoxime 59, which was then dehydrated with acetic anhydride to give nitrile 60f. Aryl halides or trifluoromethanesulfonates 60a-g react with (trimethylmethylsilyl)acetylene (Roesch, K.R. et al., J. Org. Chem., 66, 412-420, 2001) or 2-methyl-3-butyn-2-ol (Bleicher, L.S. et al., J. Org. Chem., 63, 1109- 1118, 1998) to give intermediates 61a-f or 62a-f, respectively, of which 61a, d and 62a have been reported (Dekker, S.M. et al., Tetrahedron, 59(3), 287-293, 2003; Bleicher, L.S. et al. 1109-1118, 1998). Acetylene 51 (of which 51a, e is known) is obtained by treatment of intermediates 61 or 62 with cesium carbonate or sodium hydride in acetonitrile or toluene (Blackburn, B.K. et al., J. Med. Chem., 40(5), 717-729, 1997; Dulog, L. et al., Liebigs Ann. Chem. 1663-1671, 1995). Notably, attempts to deprotect compound 61b with cesium carbonate in acetonitrile after treatment with potassium carbonate in methanol failed to yield product 51b (Blackburn, B.K. et al., J. Med. Chem., 40(5), 717-729, 1997). The route using 2-methyl-3-butyn-2-ol provides a more economical preparation for all phenylethynes 51 except the nitro analog 51b.