Arndt—Eistert homologation

One carbon homologation of carboxylic acids using diazomethane. 

Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200. Fritz Arndt (1885—1969) was bom in Hamburg, Germany. He discovered the Arndt—Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its reactions with aldehydes, ketones, and acid chlorides. Fritz Arndt s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bernd Eistert (1902-1978), bom in Ohlau, Silesia, was Arndt s Ph.D. student. Eistert later joined I. G. Earbenindustrie, which became BASE after the Allies broke the conglomerate up after WWII. 

Matthews, J. L. Braun, C. Guibourdenche, C. Overhand, M. Seebach, D. in Enanti-oselective Synthesis of /3-Amino Acids Juaristi, E. ed. Wiley-VCH, New York, N. Y. 1997, pp 105-126. (Review). 

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Overall yields from Boc-a-amino acids are between 40 and 70% depending on the method and the R side-chain [200, 225], Although feasible, the double Arndt-Eistert homologation of Boc-protected a-amino acids proved unsatisfactory with only low yields of y-amino acids 124 (<20% over five steps) [200] (for previous studies with Z- and phfhalyl- protected a-amino acids, see [226, 227]). 

Saaby S, Knudsen KR, Ladlow M, Ley SV (2005) The Use of a Continuous Flow-Reactor Employing a Mixed Flydrogen-Liquid Flow Stream for the Efficient Reduction of Imines to Amines. Chem Commun 23 2909-2911 Seebach D, Overhand M, Kilhnle FNM, Martinoni D, Oberer L, Hommel U, Widmer H (1996) Beta-Peptides Synthesis by Arndt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-ray Crystallography. Helical Secondary Structure of a Beta-Hexapeptide in Solution and its Stability Towards Pepsin. Helv Chim Acta 79 913-941... 

The assignment of (/ )-2,3-dihydro-2-phenylfuran rests on Jones oxidation which furnished (ft)-dihydro-5-phenyl-2(3//)-furanone [(/ )-24]80. The configuration of the corresponding S-enantiomer (obtained by yeast reduction of 4-oxo-4-phenylbutanoic acid) was established by correlation with ethyl (S)-3-hydroxy-3-phenylpropanoate (of known configuration, obtained itself by a baker s yeast reduction) by a sequence featuring an Arndt -Eistert homologization as the key step (see also p 403)19. 

Aminomethyl)biphenyl-2-carboxylic acid (70) and -acetic acid (69) have been prepared from dibenzo-substituted oxepin-2-one 66 by potassium phthalimide ring opening. Further Arndt-Eistert homologation of 67 provided 68.[104]... 

The Wolff rearrangement and the Arndt-Eistert homologation sequence are very useful in organic synthesis. One of the most popular applications involves amino acids. An interesting example has been described as a key reaction in the synthesis of a 14C-labeled amino acid used for deciphering the biosynthesis of penicillin N from glutamic acid (Scheme 3.2).9 This rearrangement proceeds without racemization and can thus be applied in peptide synthesis. 

Fig. 8.13. Arndt-Eistert homologation of carboxylic acids—addition of H20 to a ketene in part 2 of the third reaction of this three-step reaction sequence.

The Wolff rearrangement is the third step of the Arndt-Eistert homologation of carboxylic acids. Figure 11.25 picks up an example that was discussed in Section 7.2, that is, the homologation of trifluoroacetic acid to trifluoropropionic acid. The first step of the Arndt-Eistert synthesis consists of the activation of the carboxylic acid via the acid chloride. The Q elongation to an a-diazoketone occurs in the second step. 

In summary, the method described here provides an efficient and convenient route to a variety of a-diazo ketones including unsaturated derivatives that were not previously available by diazo transfer. a-Diazo ketones serve as key intermediates in a number of important synthetic methods including the Arndt-Eistert homologation, the photo-Woltf ring contraction strategy, and the carbenoid-mediated cyclopropanation reaction. We anticipate that improved access to a-diazo ketones will serve to enhance the utility of these valuable synthetic strategies. 

ARNDT - EISTERT Homologation 7 ATHERTON - TODD Phosphorarmdale synthesis 8... 

In the first step of the reaction sequence a methyl ester is formed via a Wolff rearrangement. The Wolff rearrangem ent provides acids, esters or amides from a-diazo ketones and is often used in a ring contractive way to form strained ring systems, which are not accessible by other sequences.It also occurs as the key step in the Arndt-Eistert homologation of carboxylic acids. ... 

The well-known Arndt-Eistert homologation" of an acyl halide to a carboxylic acid also involves the migration of an R group (with its electron pair) to an electron-deficient acyl carbene (presumably through a hypercarbon species) [Eq. (6.132)]. This rearrangement is also known as the Wolff rearrangement. 

The reaction of esters of methylenedioxyphthalic acid (387) with the imine (388) affords the ester-lactam (389) and hydrolysis of this to the lactam-acid followed by Arndt-Eistert homologation and cyclisation yields the ketone (390, R R =0). Reduction of this to the secondary alcohol (390, R =H, R =0H), followed by dehydration and aerial oxidation affords oxosangui-narine (391), from which sanguinarine can be prepared (Shamma and H. Tomlinson, J.org.Chem., 1978, 2852). A similar... 

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