Ketones, hydroxymethyl synthesis

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

Alkylfurans are usually obtained by ring synthesis, decarboxylation of alkylfurancarboxy-lic acids, Wolff-Kishner reduction of aldehydes or ketones, or by reduction of halomethyl groups with zinc and acetic acid or LAH (79JOC3420) alkylation is of limited value. The chemistry of these compounds is conventional but oxidation to furancarboxylic acids cannot usually be carried out due to the lability of the ring. NBS bromination (Section 3.11.2.2.5) is a useful route to side-chain substituted compounds but reduction of esters to hydroxymethyl groups and subsequent transformation is often preferable. The haloalkyl compounds are extremely sensitive to resinification but if adequate precautions are taken they are... 

Isoflavanones.1 A synthesis of these products from a poly hydroxy desoxy-benzoin such as 2 involves conversion of the nonhydrogen-bonded hydroxyl group to the protected ether by reaction with 1 and K2C03 in acetone at 25°. Further reaction with 1 at 60-70° gives an a-hydroxymethyl ketone 3 in 85-95% yield. This product cyclizes to the isoflavanone 4 in the presence of Na2C03. The final step involves deprotection of the ethoxymethyl group to give 5 (92-94% yield). 

The key step in the synthesis was bromination of ketone 59, followed by hydrogenation to liberate the free guanidine, which underwent an intramolecular Sn2 reaction to form the tetrahydropyrimidine ring B. Further hydrogenation reduced the ketone to yield 42% of 63 containing the fully functionalized tricyclic system and protected hydroxymethyl-uracil side chain of cylindrospermopsin. Hydrolysis of the pyrimidine of 63 in concentrated hydrochloric acid at reflux and selective monosulfation completed the synthesis of cylindrospermopsin. 

In a synthesis of the natural insecticide ajugarin-IV (4),4 the butenolide portion was prepared from the acid chloride 3 in two steps. Reaction with tris(lrimethylsilyloxy)ethylene (8, 523 9, 512)5 led to a hydroxymethyl ketone, which on reaction with 1 was converted into the butenolide 4. In this series, 1 was vastly Kupcrior to the alternative Wittig-Horner reagent 2. 

Hydroxymethylation of ketone (155) was followed by protection of the aliphatic hydroxy group (2-methoxypropyl ether) and addition of an a-benzyloxymethylene group at C-4. Acidic workup at the last stage of the reaction sequence produced (156). Its transformation to aldehyde (157) was carried out by successive treatment with methoxypropyl ether, acetic anhydride and pyridine, hydrochloric acid and methanol, and finally chromic acid, pyridine and hydrochloric acid. Dehydration of (157) led to the formation of (158) in 20% yield. Reagents other than the mentioned produced appreciable quantities of the cis A/B isomer. The butenolide (159) was finally synthesized by oxidation and hydrogenolysis. In order to complete the synthesis of triptolide it was necessary to introduce the... 

The combined action of lithium in liquid ammonia and carbon dioxide upon androst-4-en-3-one led to a synthesis of the /3-keto-ester (189), after esterification of the intermediate acid the reaction is one of reductive methoxycarbonyla-tion.82 Alkylation of the keto-ester (189) afforded a separable mixture of the 4/3-methyl steroid (190) as the major product (55%) and the corresponding 4a-methyl epimer. Reduction of the steroid (190) led to 4a-hydroxymethyl-4/3-methyl-5a-androstan-3/3-ol. Finally in this section, it has been noted that vinyl-magnesium bromide effects 1,4-addition to the a(3-unsaturated ketone 17/3-hydroxy-5a-androst-l-en-3-one to yield la-vinyl-5a-androstan-3-on-17/3-ol, which could be further reduced to the la-ethyl-3-ketone.83... 

Spiroketalization. The synthesis of talaron ycin B (3) with four chiral centers by cyclization of an acyclic precursor presents stcrcot hcmical problems. A solution involves cyclization of a protected (3-hydroxy ketone witii only one chiral center. Because of thermodynamic considerations (i.e.. all substituents being equatorial and the anomcric effect), cyclization of 1 with HgCl, in CH,CN lollowcd by acetonation results in the desired product (2, 65% yield) with a stereoselectivity of —10 1. Final steps involve conversion of the hydroxymethyl group to ethyl by tosylation and displacement with lithium dimethylcupratc (80% yield) and hydrolysis of the acetonidc group. 

Reduction of CO and ketones Hydro formylation Fischer-Tropsch synthesis Synthesis of methanol from CO Hydrogenation of amides Alkyne cyclization Hydroxymethylation... 

Song / t/. have designed a series of structurally and electronically well-defined (72-symmetric chiral ketones 84-86 for use in the epoxidation of unfunctionalized olefins (max. 59% ee for /ra r-stilbene oxide) <1997TA2921>. Adam reported the synthesis and application of chiral (72-symmetric ketones 87 and 88, derived from mannitol and TADDOL, respectively, in the epoxidation of prochiral olefins (ee s up to 80.5%) (TADDOL = (-)-/ra r-4,5-bis(diphenyl-hydroxymethyl)-2,2-dimethyl-l,3-dioxolane) <1997TA3995>. 

Hydroxyketones are versatile intermediates in the synthesis of pharmaceutical intermediates and heterocyclic molecules. a-Aryl hydroxyketones have been prepared by reaction of aryl aldehydes with 1,4-dioxane followed by reduction with lithium aluminum hydride (LAH) and by the selective LAH reduction of a-silyloxy a,P-unsaturated esters." WissneC has shown that treatment of acid chlorides with tris(trimethylsilyloxy)ethylene affords alkyl and aryl hydroxymethyl ketones. 1-Hydroxy-3-phenyl-2-propanone (3) has been generated by the osmium-catalyzed oxidation of phenylpropene and by the palladium-catalyzed rearrangement of phenyl epoxy alcohoP both in 62% yield. 

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