II. CHEMISTRY AND INDUSTRIAL PREPARATION 35 



line nature and biological activity of the vitamin A acid, sexeral investiga- 

 tors, in addition to those already mentioned, studied its preparation. '-''^^ 



The use of the Grignard of the ethoxyacetylene to prepare LI and, from 

 it, the Ci5-aldehyde, LIII, was also studied by several investigators. ^"-129 

 A similar condensation was repeated with the Ci8-ketone to give LVII, 

 from which the vitamin A aldehyde, LIX, was prepared as outlined in Fig. 

 G. In these reactions some of the intermediates formed contain hydroxyl 

 groups in direct allylic relationship to the double bond in the ring and are 

 therefore subject to the limitations mentioned above. 



(2) Synthesis via Cu- Aldehyde. The synthesis of vitamin A via Cu-alde- 

 hyde (Fig. 7) is not subject to the limitations imposed on the syntheses 

 described in the previous section, and for this reason it is the preferred 

 synthesis. Cu-Aldehyde was first synthesized by Ishikawa and Matsuura^'" 

 by the application of the Darzens reaction tojS-ionone. The application of 

 this aldehj'-de to the synthesis of vitamin A was first recognized by 

 Milas^^i'' and later by Heilbron et al}^- and by Isler et alP^^ Since the Cu- 

 aldehyde may exist in more than one form, its structure has been the sub- 

 ject of several investigations. ^^^-'^^ If the aldehyde is purified by chroma- 

 tography with activated alumina, the product obtained is the same irrespec- 



1" I. Heilbron, E. R. H. Jones, and D. G. O'Sullivan, ./. Chem. Soc. 1946, 866. 



1" P. Karrer, E. Jucker, and E. Schick, Helv. Chim. Ada 29, 704 (1946). 



"s H. H. Inhoffen, F. Bohlmann, and M. Bohlmann, Aim. 568, 47 (1950). 



»26 H. O. Huisman, Rec. trav. chim. 69, 851 (1950). 



*" J. F. Arens, D. A. van Dorp, G. van Dijk, and B. J. Brandt, Rec. trav. chim. 67, 



973 (1948). 

 " N. A. Preobrazhenskil and I. A. Rubstov, /. Gen. Chem. {U. S. S. R.) 18, 1719 



(1948). 

 '•'^ I. Heilbron, E. R. H. Jones, and B. C. L. Weedon, /. Chem. Soc. 1949, 1823. 

 "0 S. Ishikawa and T. Matsuura, Sci. Repts. Tokyo Bunrika Daigaka 3A, 173 (1937). 

 »" (a) N. A. Milas, U. S. Pat. 2,369,156 (filed Aug. 22, 1940; issued Feb. 13, 1945, and 



several additional patents issued in 1945; see ref. 103). 



(b) Science 103, 581 (1946). 

 "2 I. Heilbron, A. W. Johnson, E. R. H. Jones, and A. Spinks, J . Chem. Soc. 1942, 



727. 

 »" (a) O. Isler, M. Koefier, W. Ilubcr, and A. Ronco, Experienlia 2, 31 (1946). 



(b) Helv. Chim. Ada 30, 1911 (1947). 

 134 J. Cymerman, I. Heilbron, E. R. H. Jones, and R. N. Lacey, ./. Chem. Soc. 1946, 



500. 

 '" N. A. Milas, S. W. Lee, E. Sakal, H. C. Wohlers, N.'S. MacDonald, F. X. Grossi, 



and H. F. Wright, J. Am. Chem. Soc. 70, 1584 (1948). 

 '«« G. W. H. Cheeseman, I. Heilbron, E. R. H. Jones, F. Sondheimer, and B. C. L. 



Weedon, J. Chem. Soc. 1949, 1516. 

 '" H. H. Inhoffen, F. Bohlmann, and G. Linhoff, Ann. 670, 73 (1950). 

 "* Y-R. Naves, H. Barbier, and P. Ardizio, Bull. soc. chim. France 1950, 1188. 

 "' N. A. Milas, P. Davis, and M. T. Burgess, Unpublished results. 



