Situ ketalization

Methylenetetrahydropyrans could also be obtained by [CpRu(CH3CN)3]PF6-catalyzed coupling of allylethylether with optically active 1-trimethylsilyl-l-alkyn-3-ols followed by in situ ketalization. Fiuther Fewis acid-induced cyclization afforded enantiomerically pure 1,5-oxygen-bridged carbocycles [62]. 

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

Dichloroquinoxalme (191) and isopropyl 2-lithio-2-methoxy-2-( 1-methoxy-l-methylethoxy)acetate (192) (prepared in situ) gave the mixed ketal intermediate (194) that underwent gentle acid hydrolysis to afford 2-chloro-3-propoxyoxaloquinoxaline (193) [THF-(Me2NO)3PO, —78°C 20°C then 2M HCl, 25°C, 20 min 90%]. ... 

The reagent of choice for the reduction of ketals to ethers is alone prepared in situ from lithium aluminum hydride and aluminum chloride in ether. At room temperature ethers are obtained in 61-92% yields [792, 934]. Cyclic ketals prepared from ketones and 1,2- or 1,3-diols afford on hydrogenolysis by alanes alkyl P- or y-hydroxyalkyl ethers in 83-92% yields [792]. 

Stable five-membered ring adducts of Cgg can be synthesized by ]3+2] cycloadditions of trimethylenemethanes (TMM) [13, 195], The TMM intermediates are prepared in situ by thermolysis of 7-alkylidene-2,3-diazabicycloheptene (non-polar TMM) or methylenecyclopropanone ketals (polar TMM). With the mefhylenecyclopropanone ketal addition (Scheme 4.31), 185 and 186 were isolated after chromatography on silica gel. 

A more convergent synthesis of frovatriptan using the methylamino-substituted cyclohexanone equivalent 75 is shown in Scheme 25.° The mono-ketal of 1,4-cyclohexanedione (74) was treated with methylamine in ethanol and then hydrogenated to give 75 as an oil, which was converted to the hydrochlonde salt. The hydrazine of 76, formed in situ by treatment with sodium nitrite followed by reduction of the diazonium salt with sodium dithionite, was reacted with 75 and additional concentrated HCl at 70 °C to deliver racemic frovatriptan (rac-6). 

Methyl a-arylalkanoates. Treatment of methyl ketals of a-halogenoalkyl aryl ketones, prepared in situ, with a number of silver salts, particularly silver tetrafluoroborate or hexafluoroantimonate, in methanol induces a rearrangement to methyl a-arylalkanoates in yields generally around 98%. The rate is influenced by substituents on the aryl group, the oxygens of the ketal group greatly facilitate this reaction (equation I).1... 

Martin periodinane to deliver the desired key intermediate, ketone 208. The total synthesis of 181 was finalized in two more steps (49% overall yield) by removal of the acetal and the MEM protective group with simultaneous formation of the desired intramolecular ketal 216, followed by cleavage of the Cl 1 TBDMS ether and in situ oxidation with IBX. The highly complex secondary metabolite 181 was thus accessed in 16 linear steps starting from 210 with an impressive 14% overall yield (Fig. 36). 

The bicyclic ketal 61 is converted cleanly into the pyridine 62 in the presence of an alkylnitrile and TMSOMe (Equation 195) <1997JHC325>. The active reagent, boron difluoromethanesulfonate, is generated in situ. 

The tellurium-lithium exchange reaction of functionalized alkyl tellurides is described. A / -(butyltelluro)-ketal is prepared in situ and then reacted with -butyllithium to give the corresponding functionalized alkyllithium 157, which is captured with electrophiles (Scheme 92).250... 

Ozonolysis of (i )-carvone and in situ trapping with primary alcohols produced hydroperoxy ketals 286, as a 1 1 mixture of diastereomers. Cyclization of these latter with catalytic amount of NaOMe in MeOH gave the corresponding bridged dioxocins 287 in 24-38% yields (Scheme 58) <1998TL6065>. 

Titanium trichloride fimctions as an excellent reductive Nef alternative reagent. This aqueous reagent is very acidic, so that acid sensitive groups such as ketals and esters do not survive unless an acetate buffer is used. Systems prcme to acid-catalyzed rearrangements may then successfully undeigo the reaction (equation 10).Some veiy sensitive multifunctional compounds have been obtained using this modified Nef procedure (equation 11). A related process is the formation of 1,4-diketones via in situ generation of a nitronatc anion by the Lewis acid catalyzed addition of an enol silyl ether to a nitroalkene (equation 12). ... 

Hydrostannation of carbonyl compounds with tributyltin hydride is promoted by radical initiation and Lewis or protic acid catalysis.The activation of the carbonyl group by the acidic species allows the weakly nucleophilic tin hydride to react via a polar mechanism. Silica gel was a suitable catalyst allowing chemoselective reduction of carbonyl groups under conditions that left many functional groups unchanged. Tributyltin triflate generated in situ from the tin hydride and triflic acid was a particularly efficient catalyst for the reduction of aldehydes and ketones with tributyltin hydride in benzene or 1,2-di-chloromethane at room temperature. Esters and ketals were not affected under these conditions and certain aldehydes were reduced selectively in preference to ketones. 

The first cyclopropenone, diphenylcyclopropenone (28), was reported in 1959. This, the most common of the cyclopropenones, was prepared by the reaction of phenylketene dimethylacetal with benzal chloride and potassium r-butoxide. The chlorocyclopro-penone ketal (29) which is produced from these reagents via phenyl (chloro)carbene addition to the ketal undergoes )8-elimination yielding 30 which can be hydrolyzed, in situ, to give the cyclopropenone (equation 25). A series of arylphenylcyclopropenones were prepared using this method. ... 

The dithiane-derived anion can be generated by the action of Bu°U in THF at -78 C or with complex bases NaNH2-RONa at room temperature. Lithiated dithiane can also be prepared in situ by sonica-tion of n-butyl chloride with lithium in the presence of dithiane. Dithioacetals or ketals are resistant to acidic or basic hydrolysis. Regeneration of the carbonyl group from the dithioketal sometimes presents difficulties but can be carried out by hydrolysis in polar solvents (acetone, alcohols, acetonitrile) in the presence of metallic ions such as Hg , Cu, Ag, 71 177 qj j m ise Alternatively, alkylative hy lysis... 

A method has been developed to use formation of 16a, 17a-ketals and acetals in. situ-on papergrams for the early recognition of the 16a,17a-diol feature of triamcinolone and related 16a-hydroxylated steroids. 

Enol ethers represented by the general structure (81 Scheme 6) and their vinylogs react with salt (1) to give iminium salts (82). Enol ethers (81) are often prepared in situ by treating acetals or ketals (83) with salt (1). Acetals (83) react with an excess of chloromethyleniminium salt (1) to provide iminium salts (82 R = H, = alkyl or phenyl) that are hydrolyzed under basic conditions to afford 3-dimethyl-aminoacrolein derivatives (84 48-89%). Synthetically useful vinylamidinium salts (85 R = H) can be prepared by 0-methylation of compounds (84) followed by treatment with dimethylamine. Ketals (83 R = Et) similarly yield iminium salts (82 R = Et, R = alkyl or phenyl, R = alkyl) from which either p-ethoxyacrolein derivatives (86 R = Et 59-92%) are isolated after basic hydrolysis or vinylamidinium... 

The synthesis of tropine and of its esters has been made practical because succinic dialdehyde has become easily available. Furane, now available commercially, gives on anodic oxidation in methanol with ammonium bromide as electrolyte good yields of 2,5-dimethoxy-2,5-2H-furane (37a). This mixed ketal of maleic dialdehyde could be hydrogenated readily and quantitatively over Raney nickel to 2,5-dimethoxy-4H-furane (37b). The latter as a mixed ketal of succinic dialdehyde undergoes acid hydrolysis easily. Optimum conditions for the condensation of this dialdehyde formed in situ to tropinone have been recorded (38) with yield up to 93% and at a higher rate than described earlier (18). 

The kinetics of the copolymerization of norbornenes and maleic anhydride has been analyzed in situ by IR spectroscopy [254]. Gas phase FT-IR has been combined with TGA to investigate outgassing from the ketal-based KRS-XE e-beam resist [222]. A flow cell which allows exposure and heating of a resist-coated wafer was attached to the IR spectrometer to study exposure- and temperature-dependent outgassing. Real time deprotection of the KRS resist has been also monitored by infrared reflectance-absorbance spectroscopy [222,494]. 

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