Synthesis of Schaefferals A and B, Unusual Phenylhydrazine Derivatives from Mushrooms of the Genus Agaricus

Abstract

Schaefferals were identified as chromogens responsible for the development of an orange to red color after treating the caps of certain Agaricus species with aniline and nitric acid (Schaeffer’s cross reaction). The structures of schaefferals A and B were confirmed by total synthesis. The color reaction can be explained by reaction of their aldehyde group with aniline and protonation of the azomethine thus formed, yielding a red delocalized cation.

Key words

schaefferals - 4-hydrazinobenzaldehyde derivatives - Agaricus - Schaeffer reaction

References

• 1a Schäffer J. Schweiz. Z. Pilzk.  1933,  11:  137 
• 1b Schäffer J. Dtsch. Blätter Pilzk.  1943,  5:  1 
• 1c Schäffer J. Möller P. Ann. Myc.  1938,  36:  64 
• 2a Hilbig S. Ph.D. Thesis   University of Bonn; Germany: 1986. 
• 2b Kileci-Ksoll R. Ph.D. Thesis   University of Bonn; Germany: 1989. details of the isolation procedure and the structural elucidation of schaefferals A and B will be given in a separate publication
• 3 Ohta S. Okamoto M. Synthesis  1982,  756 
• 4 The obvious synthesis of 1 from 4-(hydroxymethyl)phenyl-hydrazine and aromatic aldehydes and subsequent oxidation of the resulting (hydroxymethyl)-phenylhydrazones is less effective and afforded schaefferals A and B only in 15% and 3.5% yield, respectively (Kilecy-Ksoll, R.; Steglich, W. unpublished). The approach is hampered by difficulties in the conversion of the hydroxymethyl group into the aldehyde group in presence of the hydrazone moiety. Most of the common reagents for this transformation, e.g. MnO₂, Ni₂O₃, and PDC or PCC, were either ineffective or led to partial cleavage of the hydrazone function. The problem could finally be solved by the use of nicotinium dichromate, cf.: López C. González A. Cossio FP. Palomo C. Synth. Commun.  1985,  15:  1197 
• 5 Frank found that nitric acid is not mandatory for the Schaeffer reaction and that it can also be performed with other acids such as HCl and H₂SO₄, or even AcOH; see: Frank HM. Z. Mykol.  1988,  54:  103 ; his suggestion that the red color may be due to azo dye formation via coupling of a diazonium ion is invalidated by our results
• See, for example, agaritine:
• 6a Levenberg B. J. Am. Chem. Soc.  1961,  83:  503 
• 6b Baumgartner D. Hoesch L. Rast D. M. Phytochemistry  1998,  49:  465 ; and references cited therein
• Agaritinal:
• 6c Chulia AJ. Bernillon J. Favre-Bonvin J. Kaouadji M. Arpin N. Phytochemistry  1988,  27:  929 
• 4-(Hydroxymethyl)phenylhydrazine:
• 6d Toth B. Nagel D. Patil K. Erickson J. Antonson K. Cancer Res.  1978,  38:  177 
• Xanthodermin:
• 6e Hilbig S. Andries T. Steglich W. Anke T. Angew. Chem., Int. Ed. Engl.  1985,  24:  1063 ; Angew. Chem. 1985, 97, 1063

7

The biosynthesis of the schaefferals 1 from 4-(hydroxy­-methyl)phenylhydrazine and aromatic aldehydes appears plausible. It is supported by the fact that these likely precursors occur in certain Agaricus species.