Hydroxy-, C-methylation

In the first example of Figure 5.35, base-catalyzed reaction of two equivalents of aqueous H CHO with diethyl malonate furnished diethyl bis(hydroxy[ C]methyl)malonate 108. Concurrent bis-bromodehydroxylation, ester hydrolysis and decarboxylation of 108, followed by re-esterification and dehydrobromination provided ethyl 2-bromo[ C]-meth[3- C]acrylate 109, a key intermediate in the Reformatsky reaction with ketones, which give a-[ " C]methylene y- - C]butyrolactones 110. ... 

The reaction of H"CH0 with Al-acyl protected dialkyl aminomalonates and a-amino-ketones stops at the hydroxymethylation step. This behavior could be exploited for the synthesis of (R,S)-, (R)- and (5)-[3-"C]serine, (/f,5)-[3- C]cysteine and e.p. [1-"C]-chloramphenicol, as illustrated in Figure 5.38. In the [3-"C]serine preparations, saponification and decarboxylation converted the hydroxy["C]methyl derivatives 121 (R = acetyl orp-nitrobenzoyl), generated from H"CH0 and diethyl iV-acylaminomalonate, to racemic Af-acyl[3-"C]serine (122). Optical resolution of 122 with quinine and brucine followed by acid-catalyzed cleavage of the A -acyl groups afforded the enantiomerically pure... 

Hydroxy[ C]methylation of W(p-nitrophenacyl)acetamide (124). a Wacetyl protected a-aminoketone, provided [ C]hydroxymethyl derivative 125. which was converted to [l- C]chloramphenicol (126) by means of straightforward transformations, e.g. Meerwein-Ponndorf-Verley reduction, hydrolytic cleavage of the Wacetyl group, optical resolution with (-)-dibenzoyltartaric acid and re-acylation of the amino group with methyl dichloroacetate ... 

Fluorodesilylation is a valuable alternate method for the in situ generation of carbanions, which can be trapped as hydroxy[ C]methyl derivatives through treatment with H CHO. This sequence, applied to diethyl difluoro(trimethylsilyl)methylphospho-nate (127), afforded the 0-silylated intermediate 128. which served as a precursor for the preparation of 2,2-difluoro[l- C]ethylene. This was conveniently accomplished through thermolysis of 128 in the presence of catalytic amounts of CsF °. 

Under acid catalysis [ " C]formaldehyde reacts with benzene, alkyl, alkoxy, and haloben-zenes to give aryl[ " C]methanols. Depending on the reactivity of the arene and the nature of the acid catalyst, the initially formed hydroxy[ C]methyl intermediates may further react to give either the corresponding diaryl[ C]methylene species or aryl[ C]methyl halides (Blanc chloromethylation). These outcomes are illustrated in Figure 5.41. 

The reaction of desmethyl-a-tocopherol 130 and para[ C]formaldehyde, for example, gave the hydroxy[ C]methyl derivative 131. Hydrogenolytic cleavage of the alcoholic hydroxyl group followed by acylation of the phenolic hydroxyl provided a-[5-methyl- C]-tocopherol (132) in an overall radiochemical yield of 48%. Chloro[ C]methylations are illustrated by the conversion of substrates 133 to 134 with H CHO under the influence of concentrated HCl. Subsequent transformation to [ CJmethyl 135 " and to aminoxy[ C]-methyl 136. the latter obtained through reaction with A-hydroxyphthalimide and... 

H " CHO also undergoes acid-catalyzed addition to olefinic substrates (Prins reaction). Treatment of the tetrahydropyridine derivative 138 with H " CHO in half-concentrated HCl provided racemic 3-hydroxy[ C]methyl product 139. a key intermediate in the synthesis of e.p. [7- C]paroxetine . Similarly, Prins-hydroxy[ C]methylation of acyl-... 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

Deuteration of C-methyl protons in simple methylpyrimidines and their amino and hydroxy derivatives has been studied under acidic and basic conditions. The exchange is acid/base catalyzed with, for example, a minimal rate at pH 4 for 1,4,6-trimethylpyrimidin-2(lH)-imine (67JCS(B)171). 

H-Carbazole, 3-hydroxy-2-methyl- C NMR, 4, 174 <79ZN(B)650) 9H-Carbazole, 6-methoxy- 1,4-dimethyl- C NMR, 4, 174 <78T2385)... 

H-Cyclopenta[7,8]naphtho[2,3-6]furan-7-yl glyoxylate, 2,3,6,10-tetrahydro-6-hydroxy-6-methyl-3,10-dioxo-, methyl ester H NMR. 4, 560 (66JCS(C)743) Cyclopenta[6]quinoline, 6,7,8,9-tetrahydro- C NMR, 2, 122 (77JOC300, 77JOC2742)... 

Pyrazolin-2-one, 5-hydroxy-3-methyl-1-phenyl- C NMR, 5, 194 (77JCS(P2)1024) 2-Pyrazolin-5-one, 3-methyl-1 -phenyl- C NMR, 5, 194 (77JCS(P2)1024)... 

Thiazolo[3,2-a]pyridinium, 3-(4-bromophenyl)-X-ray, 6, 669 (80AX(B)1229) Thiazolo[3,2-a]pyridinium, 3-carboxy-2,3-dihydro-8 hydroxy-5-methyl- C NMR, 6, 678 (82UP42900) Thiazolo[3,2-a]pyridinium, 2,3-dihydro- C NMR, 6, 678 (82UP42900) Thiazolo[3,2-a]pyridinium, 2,3-dihydro-2,5-dimethyl-... 

UV, 6, 679 (69JCS(C)707, 71BSF1491) Thiazolo[3,4-a]pyridinium, 7-bromo-8-hydroxy-3-methyl-... 

Thiazolo[3,2-c]pyrimidinium, anhydro-2,3-dihydro-8 hydroxy-5-methyl- H NMR, 6. 676 (69ACS2437)... 

Cyclopent-2-en-l-one, 2-hydroxy-3-methyl-synthesis, 3, 693 Cyclopentenone, 4-methoxy-formation, 1, 423 Cyclopenthiazide as diuretic, 1, 174 Cyclopent[2,3-d]isoxazol-4-one structure, 6, 975 Cyclophane conformation, 2, 115 photoelectron spectroscopy, 2, 140 [2,2]Cyclophane conformation, 2, 115 Cyclophanes nomenclature, 1, 27 Cyclophosphamide as pharmaceutical, 1, 157 reviews, 1, 496 Cyclopiloselloidin synthesis, 3, 743 Cyclopolymerization heterocycle-forming, 1, 292-293 6H-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine pyrazoles from, 5, 285 Cydopropabenzopyran synthesis, 3, 700 Cyclopropachromenes synthesis, 3, 671 Cyclopropa[c]dnnolines synthesis, 7, 597 Cyclopropanation by carbenes... 

Piperidine, l-(2-hydroxythiobenzoyI)-neutron diffraction, 2, 116 Piperidine, 4-hydroxy-2,2,6-trimethyI-as local anaesthetic, 1, 179 Piperidine, JV-methoxycarbonyl-electrolytic oxidation, 2, 374 Piperidine, 2-methyl-synthesis, 2, 524 Piperidine, 3-methyI-mass spectrometry, 2, 130 Piperidine, C-methyl-NMR, 2, 160 Piperidine, JV-methyl- C chemical shifts, 2, 15 catalyst... 

Syn 3-(EthyltHloniethyl)-4-hydroxy-6-pt)enyl-2-hexanone (4) and anti (5) To ethanethiol (10 0 mg 0 17 mmol) in THF (2 mL) was added 1 54 M n butyltittnum m hexane (0 11 mL) at 0 C under Ar Stannous triflate (69 0 mg 017 nvnol) was added and alter 20 mm the mocture was cooled to 4S°C Methyl vinyl Ketone 1 (118 mg 1 98 mmol) m THF (1 5 mL) was added followed by 3 phenyiptopanal 3 350 mg 2 61 mmol) m THF (1 S mL) Alter 12 h aq cilnc acid was added and the organic material extracted with OHjClj The resxlue after evaporation was dissolved in MeOH and treated with citric acxt After 30 min stimng, the mixture was quenched with pH 7 phosphate buffer extracted with CH2CI2, the solvent evaporated and the residue chromatographed to afford 336 mg ot 4 (75%), syn anti (90 10)... 

A -Benzyl-A -methylephedrinium bromide [benzyl(2-hydroxy-l-methyl-2-phenethyl) dimethylammonium bromide] [58648-09-2] M 350.3, m 209-211 , 212-214 , [al -3.8 (c... 

Alkylquinazolines are catalytically reduced to the corresponding 3,4-dihydro derivatives/ The only example of a 4-substituted quin-azoline which was reduced to its 3,4-dihydro derivative is 2-chloro-4-phenylquinazoline which gave 4-phenyl-3,4-dihydroquinazoline/ 4-Methylquinazolines are susceptible to oxidation, as is shown by the attempted nitration of 2,4-diraethylquinazoline which causes the removal of the methyl group with formation of 4-hydroxy-2-methyl-6-nitroquinazoline/ When the 4-substituent is —C(Et) (C02Et)2 recrystallization of the picrate from ethanol is sufficient to convert it to 4-hydroxyquinazoline/ Similar hydrolyses occur in acid solution and the mechanism undoubtedly involves a hydrated intermediate/... 

The ratio, at equilibrium, of the hydrated to anhydrous forms (for both neutral species and anions) has been measured for the following 2-hydroxjrpteridine and its 4-, 6-, and 7-methyl and 6,7-dimethyl derivatives 6-hydroxypteridine and its 2-, 4-, and 7-methyl derivatives 2,6-dihydroxypteridine and 2-amino-4,6-dihydroxypteridine. The following showed no evidence of hydration 4- and 7-hydroxy-pteridine 2,4-, 2,7-, 4,7-, and 6,7-dihydroxypteridine and 2-amino-4-hydroxypteridine. The kinetics of the reversible hydration of 2-hydroxypteridine and its C-methyl derivatives (also 2-mercapto-pteridine) have been measured in the pH region 4-12, and all these reactions were found to be acid-base cataljrzed. The amount of the hydrated form in the anions is always smaller than in the neutral species, but it is not always negligible. Thus, the percentages in 2-hydroxy-, 2-hydroxy-6-methyl-, 2-mercapto-, and 2,6-dihydroxypteridine are 12, 9, 19, and 36%, respectively (see also Table VI in ref. 10). 

Reaction of 2-aminopyridine with dimethyl 2-methylmalonate in the presence of some drops of cone. HCl at 150°C for 1 h (96EUP733633), and with diethyl 2-(l-decyl)malonate at 120°C for 5 min (94JCR(S)206) gave 2-hydroxy-3-methyl- and 2-hydroxy-3-(l-decyl)-4//-pyrido[l, 2-n]pyrimidin-4-ones in 2.2% and 7.5% yields, respectively. Reaction of 3-benzyl-2-aminopyridine and diethylmalonate at 190-200 °C for 4 h yielded 9-benzyl-2-hydroxy-4//-pyrido[l, 2-n]pyrimidin-4-one (01MIP9). Cyclocondensation... 

Hydroxy-2-methyl-4//-pyrido[l,2-n]pyrimidin-4-one was prepared in the reaction of 2-amino-3-benzyloxypyridine and ethyl acetoacetate at 60 °C, then at 100 °C for 3 h in 22% yield (96MIP1). Reaction of 2-amino-3-hydroxypyridine and ethyl 2-methylacetoacetate in a 1 2 mixture of... 

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