Synthesis of Important Pharmaceutical Building Blocks
FULL PAPERS
N-p-Tolyl Benzophenone Hydrazone[18b]
References
In a 16-L glass reactor equipped with a condenser, a mechani-
cal stirrer and linked by an optic fiber to a Raman spectrome-
ter, were charged under a nitrogen atmosphere 4-chloroto-
luene (1.605 kg, 12.675 mol) and ground sodium hydroxide
(709.8 g, 17.745 mol) in 8 L of freshly degassed tert-amyl alco-
hol. The mixture was heated at reflux. The complex catalyst
was pre-formed under argon by mixing Pd(OAc)2 (1.42 g,
6.3 mmol) and MePhos (4.61 g, 12.7 mmol) for 20 minutes at
room temperature in 100 mL of tert-amyl alcohol and then add-
ed into the glass vessel. Benzophenone hydrazone (2.487 kg,
12.675 mol) was added in 13 portions every 10 minutes. The re-
action was followed by Raman spectroscopy. When the reac-
tion had reached completion, the mixture was cooled to
room temperature and insoluble salts were quenched with wa-
ter (2 L). Layers were separated and the arylhydrazone crystal-
lized at about 58C in the organic phase. The solid was filtered,
washed with 2.5 L of tert-amyl alcohol and dried at 408C
(10 mbar). The arylhydrazone was obtained as a pale yellow
solid (93%). 1H and 13C NMR are in accordance with the liter-
ature data.[24]
[1] a) T. L. Gilchrist, J. Chem. Soc. Perkin Trans. 1 1999,
2849; b) N. Mꢁller, in: Methods of Organic Chemistry
(Houben-Weyl), 4th edn., Vol. E16a/Teil 1, (Ed.: D. Kla-
mann), Thieme, Stuttgart, 1990, pp. 588–678; c) B. Rob-
inson, Chem. Rev. 1963, 63, 373; d) H. Ishii, Acc. Chem.
Res. 1981, 14, 233; e) D. L. Hughes, Org. Prep. Proced.
Int. 1993, 25, 607.
[2] a) M. Negwer, Organic-chemical Drugs and their Syno-
nyms: (an international survey), 7th edn, Akademie Ver-
lag GmbH, Berlin, 1994; b) J. H. Montgomery, Agro-
chemicals Desk Reference: Environmental Data, Lewis
Publishers: Chelsea, MI, 1993; c) R. O. Loutfy, C. K.
Hsiao, P. M. Kazmaier, Photograph. Sci. Eng. 1983, 27,
5; d) G. DꢂAprano, M. Leclerc, G. Zotti, G. Schiavon,
Chem. Mater. 1995, 7, 33; e) A. W. Czarnik, Acc. Chem.
Res. 1996, 29, 112.
[3] a) B. Robinson, The Fischer Indole Synthesis, Wiley, Chi-
chester, 1982; b) B. Robinson, Chem. Rev. 1969, 69, 227.
[4] R. Huisgen, R. Lux, Chem. Ber. 1960, 93, 540.
[5] a) L. A. Lasky, Science 1992, 258, 964; b) J. P. Wolfe, S.
Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118,
7215; c) J-F Marcoux, S. Wagaw, S. L. Buchwald, J.
Org. Chem, 1997, 62, 1568; d) J. P. Wolfe, S. L. Buchwald,
J. Org. Chem. 1997, 62, 6066; e) M. S. Driver, F. Hartwig,
J. Am. Chem. Soc. 1996, 118, 7217; f) F. Hartwig, Synlett
1997, 329.
[6] B. H. Yang, S. L. Buchwald, J. Organomet. Chem. 1999,
576, 125.
[7] a) D. Baranano, G. Mann, J. F. Hartwig, Curr. Org.
Chem. 1997, 1, 287; b) J. F. Hartwig, Angew. Chem. Int.
Ed. 1998, 37, 2046.
[8] S. Wagaw, B. H. Yang, S. L. Buchwald J. Am. Chem. Soc.
1998, 120, 6621.
[9] S. L. Buchwald has proven the high efficiency of MePhos
towards the carbon-nitrogen coupling reaction, see: H.
Tomori, J. M. Fox, S. L. Buchwald, J. Org. Chem. 2000,
65, 5334.
N-p-Trifluoromethylphenyl Benzophenone Hydrazone
In a 500-mL glass reactor equipped with a condenser and a me-
chanical stirrer, were charged under a nitrogen atmosphere 4-
chlorotrifluoromethylbenzene(0.2 mol), benzophenone hy-
drazone (39.25 g, 0.2 mol) and ground potassium phosphate
(59.4 g, 0.28 mol) in freshly degassed anisole (120 mL). The
mixture was heated at 1458C. The complex catalyst was pre-
formed under argon by mixing Pd(OAc)2 (44.8 mg;
0.2 mmol) and XPhos (47.7 mg; 0.4 mmol) in degassed xylene
(15 mL) for 20 minutes at room temperature and then added
into the glass vessel. The reaction was followed by GC analysis.
When completion was reached, the reaction mixture was
cooled to room temperature and unsoluble salts were
quenched with water. Layers were separated and the organic
layer was concentrated under vacuum. tert-Amyl alcohol
(100 mL) was added to the solid residue and the arylhydrazone
crystallized at about 58C. Upon filtration, two washes with tert-
amyl alcohol, and drying at 408C (10 mbar), the N-p-trifluoro-
methylphenyl benzophenone hydrazone was isolated as a pale
yellow solid in a good yield (85%).
[10] R. F. Heck, Palladium Reagents in Organic Syntheses,
Academic Press, New York, 1985, p. 179.
[11] a) H. Tomori, J. M. Fox, S. L. Buchwald, J. Org. Chem.
2000, 65, 5334; b) S. L. Buchwald, Adv. Synth. Catal.
2001, 343, 789.
[12] a) H. H. Szmant, Angew. Chem. Int. Ed. Engl. 1968, 7,
120; b) D. F. Taber, S. J. Stachel, Tetrahedron Lett. 1992,
33, 903.
[13] S. Wagan, B. H. Yang, S. L. Buchwald, J. Am. Chem. Soc.
1999, 121, 44, 10251.
N-p-Tolylhydrazine Salt
[14] Handbook of Chemistry and Physics, 1985–1986, 66th
edn., CRC Press, Boca Raton, D-146.
In a 16-L Bꢁchi glass reactor equipped with a condensor, a me-
chanical stirrer and under argon was placed N-p-tolyl benzo-
phenone hydrazone (2.477 kg, 8.65 mol) in 9.9 L of hydrochlor-
ic acid (aqueous solution at 37% wt). 990 mL of ethanol were
then added. The mixture was allowed to stirr for 24 hours at
room temperature. Conversion was followed by GC analysis.
On conversion, the solid formed was filtered, washed three
times with 4 L of dichloromethane and dried at 408C
(10mbar). The hydrazine salt was obtained as a white solid;
yield: 1.477 kg (>95%).
[15] a) D. Baranano, G. Mann, J. F. Hartwig, Curr. Org.
Chem. 1997, 1, 287; b) J. F. Hartwig, Angew. Chem. Int.
Ed. 1998, 37, 2046; c) S. Wagaw, B. H. Yang, S. L. Buch-
wald J. Am. Chem. Soc. 1998, 120, 6621.
[16] T. Rosner, A. Pfaltz, D. G. Blackmond, J. Am. Chem.
Soc. 2001, 123, 4621.
[17] C. Amatore, A. Jutand Acc. Chem. Res. 2000, 33, 314.
Adv. Synth. Catal. 2005, 347, 773–782
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