Synthesis acidic conditions

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an Ai-aryUiydra2one is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3] sigmatropic rearrangement of an enehydra2one tautomer of the hydra2one. 

Combes Synthesis. When aniline reacts with a 1,3-diketone under acidic conditions a 2,4-disubstituted quinoline results, eg,... 

Pomeranz-Fntsch Synthesis, Isoquinolines aie available fiom the cycUzation of benzalamiaoacetals undei acidic conditions (165). The cyclization is preceded by the formation of the Schiff base (33). Although the yields ate modest, polyphosphoric acid produces product in all cases, and is especially useful for 8-substituted isoquinolines (166). 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

Flavin mononucleotide was first isolated from the yellow en2yme in yeast by Warburg and Christian in 1932 (4). The yellow en2yme was spHt into the protein and the yellow prosthetic group (coen2yme) by dialysis under acidic conditions. Flavin mononucleotide was isolated as its crystalline calcium salt and shown to be riboflavin-5Lphosphate its stmeture was confirmed by chemical synthesis by Kuhn and Rudy (94). It is commercially available as the monosodium salt dihydrate [6184-17 /, with a water solubiUty of more than 200 times that of riboflavin. It has wide appHcation in multivitamin and B-complex solutions, where it does not require the solubili2ers needed for riboflavin. 

The Piloty-Robinson pyrrole synthesis (74JOC2575,18JCS639) may be viewed as a monocyclic equivalent of the Fischer indole synthesis. The conversion of ketazines into pyrroles under strongly acidic conditions apparently proceeds through a [3,3] sigmatropic rearrange-... 

In Sarett s total synthesis of cortisone, mild acid conditions were developed for the hydration of an ethoxyacetylenic carbinol to the ester without complete dehydration of the tertiary hydroxyl group. An acid-sensitive ketal group in another part of the molecule was also maintained. 

Developed as a carboxyl protective group for peptide synthesis because of its stability to hydrogenolysis and acidic conditions, the acetol (hydroxy acetone) ester is prepared by DCC coupling (68-92% yield) of the acid with acetol. It is cleaved with TBAF in THF. ... 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Cacchi and Palmier (83T3373) investigated a new entry into the quinoline skeleton by palladium-catalyzed Michael-type reactions. They found that phenyl mercurial 134 was a useful intermediate for the synthesis of quinoline derivatives, and that by selecting the reaction conditions the oxidation level of the heterocyclic ring in the quinoline skeleton can be varied. On such example is shown in Scheme 16. PdCla-catalyzed coupling between organomercurial reagent 134 and enone 135 delivered adduct 136 which was subsequently cyclized to quinoline 137 under acidic conditions. 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

Stork s elegant use of a protected cyanohydrin function in the synthesis of PGF2a (2) is also noteworthy. The electron-withdrawing cyano substituent in intermediate 21 (Scheme 7) confers nucleophilic potential to C-9 and permits the construction of the saturated cyclopentane nucleus of PGF2a (2) through intramolecular alkylation. In addition, the C-9 cyanohydrin function contained within 40 is stable under the acidic conditions used to accomplish the conversion of 39 to 40 (see Scheme 7), and it thus provides suitable protection for an otherwise labile /J-hydroxy ketone. 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

You will note that the oxygen atoms attached to carbons 5 and 12 in 43 reside in proximity to the C-9 ketone carbonyl. Under sufficiently acidic conditions, it is conceivable that removal of the triethylsilyl protecting groups would be attended by a thermodynamically controlled spiroketalization reaction.30 Indeed, after hydro-genolysis of the C-26 benzyl ether in 43, subjection of the organic residue to the action of para-toluenesulfonic acid in a mixture of methylene chloride, ether, and water accomplishes the desired processes outlined above and provides monensin methyl ester. Finally, saponification of the methyl ester with aqueous sodium hydroxide in methanol furnishes the sodium salt of (+)-monensin [(+)-1], Still s elegant synthesis of monensin is now complete.13... 

The completion of the synthesis of key intermediate 86 only requires some straightforward manipulations. Differential protection of the two hydroxyl groups in 123 can be easily achieved. Selective silylation of the primary hydroxyl with ieri-butyldiphenylsilyl chloride provides, after /ert-butyldimethylsilylation of the remaining secondary hydroxyl, compound 124 (95% overall yield). Acet-onide protecting groups can usually be removed under acidic conditions, and the one present in 124 is no exception. Treatment of a solution of 124 in CFhC MeOH (1 1) at 0°C with CSA... 

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