Arens-van Dorp synthesis

Finally, the synthesis is completed by using the Meyer-Schuster rearrangement of the Aren-van Dorp synthesis on enone acetal 152. Treatment of 152 with lithium etoxyacetilide in THF gives an unstable tertiary allylic-propargylic alcohol that, when dissolved in methanol with a catalytic quantity of sulphuric acid produces 63 and its epimer 98 in a proportion of 7 3, respectively, in 42% yield. 

The original Arens-van Dorp Synthesis (see below) used ethoxyacetylene, which is difficult to make, as the starting material. The advantage of the Isler Modification is the use of (5-chlorovinyI ether which will generate lithium ethoxyacetylene in situ. 

Arens-van Dorp synthesis. The preparation of alkoxyethynyl alcohols from ketones and ethox-yacetylene. In the Isler modification, (i-ch loro vinyl ether is reacted with lithium amide to give lithium ethoxyacetylene which is then condensed with the ketone. This avoids the tedious preparation of ethoxyacetylene. 

The original Arens-van Dorp Synthesis (see below) us eAox cetylene is difficult to... 

Modified Arens-van Dorp synthesis s. 12, 849 y-Ketocarboxylic acids... 

ARENS VAN DORP Cinnamaldehyde Synthesis Synthesis ol cinnamaldehydes from aryl ketones... 

Synthetic uses. Arens,° in reviewing the many reactions of ethynyl ethers and thioethers, states that the first use of ethoxyacetylene for the synthesis of a,/3-unsaturated aldehydes was described in a paper published in Russia in 1945, but that the paper was abstracted incorrectly and remained unknown in the western world, van Dorp and Arens" rediscovered the method and in 1947 described its use in the synthesis of vitamin A aldehyde. Ethoxyacetylene is treated with ethyl-magnesium bromide to form the Orignard reagent, and this is added to the carbonyl group of the "C lii-kelone" to produce the acetylenic cnrbinol (I). Semlhydrogenation... 

The synthesis of Arens and van Dorp is shown in Figure 3.7. This synthesis, completed in 1948, may not look much cleaner nor more effective than that of Barbier, Bouveault and Tiemann, but it is an important development since it laid the intellectual basis of the most efficient modern syntheses of citral, as will be seen in Chapter 9. The key feature of this synthesis is its use of acetylenic chemistry. 

Arens and van Dorp used acetone and acetylene as the starting point for their synthesis. Sodamide was generated in situ from sodium metal and liquid ammonia and used to remove the acidic proton of acetylene. The acetylene anion was then added to acetone to give methylbutynol... 

The synthesis of Arens and van Dorp also has a poor atom efficiency, though not quite as bad as that of Barbier, Bouveault and Tiemann. The use of sodium in liquid ammonia would require refrigeration and the ability to distil and recover ammonia and this would lead to high... 

The discovery of the Carroll reaction in 1940 allowed significant improvements to be made to Arens and van Dorp s synthesis. The Carroll reaction involves heating the acetoacetate ester of an allyl alcohol. The ester can be formed in situ from the alcohol and ethyl acetoacetate. The reaction is an electrocyclic one which results in the elimination of carbon dioxide and the addition of an acetone fragment to the terminal carbon of the double bond of the alcohol. The mechanism is shown in Figure 9.8. 

This reaction was first reported by Arens et at. in 1947. It is the synthesis of a,p-unsaturated aidehyde from the reaction of ethoxyethynemagnesium bromide and ketone or aidehyde and is known as the Arens and van Dorp reaction. Because the preparation of ethoxyacetyiene is tedious, this reaction has been modified to generate lithium ethoxy-acetylene by treatment of /3-chlorovinyl ether with lithium amide, which then reacts with a ketone or aldehyde to form a,/3-unsaturated aldehyde. This new protocol is referred to as the Isler modification. 

In 1937 Holmes and Corbet (1937) were able to crystallize pure retinol from fish liver. A decade later, Arens and Van Dorp (1946) and Isler and his associates (Isler et aL, 1947) succeeded in achieving the chemical synthesis of pure retinoic acid and retinol. Shortly thereafter, the total synthesis of -carotene was also reported (Karrer and Eugster, 1950). 

The successful synthesis of (all- )-retinoic acid (3) was reported by Arens and van Dorp (van Dorp and Arens, 1946) in 1946, but almost 10 years passed before Robeson et aL (1955a) were able to prepare 13-cw-retinoic acid (17). Between 1946 and 1956, a large number of papers were published on successful syntheses of the natural C20 retinoids retinol (1), retinaldehyde (2), and retinoic acid (3), and nine industrial processes for the synthesis of vitamin A were developed during this period (Isler, 1979). 

Since the first synthesis of (all- )-retinoic acid (3) by van Dorp and Arens (1946), a large number of processes for the preparation of (3) or of esters of (all- )-retinoic acid (3) have been published, the majority of these processes having the reduction of the resulting product to retinol (1) as a final stage. The most important of these processes have been summarized in review articles (Pommer, 1960 Eiter et aL, 1960 Isler, 1971, 1979) and are discussed in Section V,A of this chapter, and hence are not listed again at this point. 

Arens, J. F. and Van Dorp, D. A. (1946). Synthesis of some compounds possessing vitamin A activity. Nature (London), 157,190... 

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