Methylation under phase-transfer condition

Chiral a-methoxy aldehydes.2 The anion of 1 undergoes 1,2-addition to bcnzaldehyde in quantitative yield. The adduct can be methylated under phase-transfer conditions and then reduced3 to give the dithioacetal 2, from which the aldehyde 3 is liberated by reaction with I2 and NaIlC03.4 The optical yield of 3 is >70%. 

Loughhead (90JOC2445) coupled 5-amino-2,2-dimethyl-7-methoxy-chromene 244 with 2-bromobenzoic acid, and the resultant product 245 was cyclized with TFAA. The de-A-methylacronycine 210 was then converted to acronycine 208 by methylation under phase-transfer conditions (Scheme 40). The same approach has been used by Elomri et al. to prepare 6-demethoxyacronycine 246 which was found to be more potent than acronycine 208 in some biological assays (92H799). 

Excellent yields of the former product are also obtained with quinoline N-oxide. Improved yields of Reissert compounds are found under phase-transfer conditions (29). The regiochemistry of the method changes dramatically with /V-alkyl quin olinium salts, eg, /V-methy1quino1inium iodide [3947-76-0] (12), which form 4-cyanoquinoline [23395-72-4] (13) (30), through the intermediary in this example of A[-methyl-4-cyano-l,4-dihydroquinoline... 

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

Methylation of indeno[l,2-r/]azepin-4(3//)-one (22) with iodomethane under phase transfer conditions produces the A-methyl derivative, whereas ethylation with Meerwein s reagent yields purple crystals of the indeno[l, 2-r/Jazepine 23, a 147r-aromatic system.57 1 l-Bromo-4-ethoxyin-deno[l,2-r/]azepine (69% mp 143-144°C) can be prepared similarly. 

Af-Methylation of the thienodiazepinedione 1 is achieved by treatment with dimethyl sulfate under phase-transfer conditions (PTC).307... 

In 1988, Linstrumelle and Huynh used an all-palladium route to construct PAM 4 [21]. Reaction of 1,2-dibromobenzene with 2-methyl-3-butyn-2-ol in triethylamine at 60 °C afforded the monosubstituted product in 63 % yield along with 3% of the disubstituted material (Scheme 6). Alcohol 15 was then treated with aqueous sodium hydroxide and tetrakis(triphenylphosphine)palladium-copper(I) iodide catalysts under phase-transfer conditions, generating the terminal phenylacetylene in situ, which cyclotrimerized in 36% yield. Although there was no mention of the formation of higher cyclooligomers, it is likely that this reaction did produce these larger species, as is typically seen in Stephens-Castro coupling reactions [22]. 

More recently, Maruoka and co-workers have reported several new phase-transfer catalysts one of which incorporates a morpholine ring as part of an azoniaspirocyclic core 161 <2007TL4675>. These were employed in the catalytic enantioselective conjugate addition of a-benzylcyanoacetate to acetylenic methyl ketone under phase transfer conditions. 

Equation 11.8 Arylation of methyl acrylate under phase-transfer conditions. (TBAB = tetrabutyl ammonium bromide)... 

The difference in reactivity between isoprenol and isoprenyloxide, methal-lyl methyl ether and methallyloxide were investigated in the reaction with (phenylthio)carbene generated under phase-transfer conditions. With isoprenol, (phenylthio)methyl ether (41%) was the major product, whereas with methyl ether cyclopropanation (36%) was the sole reaction.1519 With alkoxides, in contrast, the major product was the C-H insertion product (45%) and (phenyl-... 

Propargyl halides [56] and propargyl acetates [57] have also been employed for Pd-catalyzed carbonylation (Scheme 3.22). From the latter substrates, allenylcarboxylic acids were obtained under phase-transfer conditions (with nBu4NBr in aqueous NaOH and 4-methyl-2-pentanone) [56],... 

In 1981 we reported (2, 3) the first examples of free radical polymerizations under phase transfer conditions. Utilizing potassium persulfate and a phase transfer catalyst (e.g. a crown ether or quaternary ammonium salt), we found the solution polymerization of acrylic monomers to be much more facile than when common organic-soluble initiators were used. Somewhat earlier, Voronkov and coworkers had reported (4) that the 1 2 potassium persulfate/18-crown-6 complex could be used to polymerize styrene and methyl methacrylate in methanol. These relatively inefficient polymerizations were apparently conducted under homogeneous conditions, although exact details were somewhat unclear. We subsequently described (5) the... 

Reaction of the a-hydroxyketone (+)-1402 with hydroxylamine hydrochloride gave the oxime (—)-1407 in 95% yield. A bis-methylation of (—)-1407 under phase transfer conditions afforded the corresponding dimethyl derivative (—)-1408. Stereoselective hydrogenation of (—)-1408 using H2/Pt02 led to the amine... 

The Sonogashira reaction of 2-iodothiophene with 2-methyl-3-butyne-2-ol or trimethylsilylacetylene under phase transfer conditions using sodium hydroxide as base led to the formation of the expected products, which released their end group spontaneously under the applied conditions giving rise to the intermediate formation of 2-ethynylthiophene. This terminal acetylene, in turn, reacted with another molecule of aryl halide, yielding either non symmetrical or symmetrical diarylethynes. When 2-methyl-3-butyn-2-ol was used as acetylene equivalent68 it was possible to introduce a benzothiophene moiety in the second step, while the reaction of 2-iodothiophene and trimethylsilylacetylene led to the formation of l,2-bis(2 -thienyl)acetylene (6.47.),69... 

The indanone substrate was methylated in 94% enantiomeric excess, by the use of a chiral catalyst, N-(/>-(trifluoromethyl)benzyl)cinchoninium bromide, under phase transfer conditions.1468 In another method enantioselective alkylation can be achieved by using a chiral base to form the enolate.1469... 

Ethyl N-alkylcarbamates via hydroboratitm. The reaction of trialkylboranes with carboethoxynitrene is best conducted under phase-transfer conditions (equation I). Either benzyltriethylammonium chloride or methyl trioclylammonium chloride is a satisfactory catalyst.2... 

Willner and Halpern185 have described quantitative O-methylation of ac-ridone (119) under phase transfer conditions. But a more detailed study on alkylation of acridone under biphasic conditions by Galy et al.1 6 arrives at another conclusion the reaction gives a mixture of N- and O-alkylation products, with the N-alkyl derivative (120) predominating (65-100%). The yield of isolated N-alkyl derivative is 41-66%. 

Methyl carhoxylates.2 The reagent (1) is alkylated by alkyl halides under phase-transfer conditions with NaOH as base. The product is converted to a methyl ester by oxidation followed by a Pummerer-type rearrangement (equation I). 

Michael additions of C-nudeophiles such as the indanone 1 have been the subject of numerous further studies For example, the reaction between the indanone 1 and methyl vinyl ketone was effected by a solid-phase-bound quinine derivative in 85% yield and with remarkable 87% ee by d Angelo, Cave et al. [5], Co-polymers of cinchona alkaloids with acrylonitrile effected the same transformation Kobaya-shi and Iwai [6a] achieved 92% yield and 42% ee and Oda et al. [6b] achieved almost quantitative yield and up to 65% ee. Similarly, partially resolved 2-(hydroxy-methyl)quinudidine was found to catalyze the reaction between 1 and acrolein and a-isopropyl acrolein with induction of asymmetry, but no enantiomeric excesses were determined [7]. As shown in Scheme 4.4, the indanone 7 could be added to MVK with up to 80% ee under phase-transfer conditions, by use of the Cinchona-derived PT-catalysts 9a and 9b, affording the Michael-product 8 or enf-8, respectively [8]. The adducts 8 or ent-8 were intermediates in the stereoselective Robinson anellation of a cydohexenone ring to the indanone 7 [8],... 

Belokon and co-workers designed a glycine-derived nickel complex 60 and examined its asymmetric addition to methyl acrylate under phase-transfer conditions. The screening of various NOBIN and iso-NOBIN derivatives in combination with NaH as a base revealed that N-pivaloyl-iso-NOBIN (62b) proved to be highly efficient catalyst, affording the product 61 in 80% yield with 96% ee, as illustrated in Scheme 4.20 [59]. 

In the presence of alkyl halides and base, alkyltetracarbonylcobalt complexes are formed with Co2(CO)8 these species [RCo(CO)4] carbonylate a wide range of aryl halides or heterocyclic halides to various products, which depend upon the specific conditions. In the presence of alcohols, carboxylic esters are formed. Under phase transfer conditions and with iodomethane, mixtures of methyl ketone and carboxylic acid formation are realized (equation 207). In the presence of sodium sulfide or NaBH4 in water-Ca(OH)2 (equation 208) good amounts of double carbonylation are realized under very mild conditions412-414. 

Carbonylation with iron carbonyls parallels that of cobalt carbonyls. Benzylic chlorides and bromides are carbonylated with Fe(CO)5 in the presence of base. Esters are realized when carbonylation is performed in alcohols under 1 atm of CO with catalytic amounts of iron pentacarbonyl415. Under phase transfer conditions, two predominant routes are available. With catalytic amounts of iron under a CO atmosphere and strongly basic conditions, the carboxylic acids are realized in reasonable yields415,416, whereas mild bases [Ca(OH)2l, stoichiometric amounts of iron carbonyl and the omission of CO give dibenzyl ketones417. In at least a few cases, it is possible to prepare unsymmetrical methyl benzyl ketones418, des Abbayes and coworkers have observed the formation of acyltetracarbonyl anion (52) under the reaction conditions, and have proposed the catalytic cycle in Scheme 8 for the ketone formation418. 

The m-nitrobenzyl chloride analogue 2-(chloromethyl)-l-methyl-4-nitroimidazole reacts with the 2-nitropropane anions by the S l mechanism under phase-transfer conditions. A base-promoted nitrous acid elimination from the C-alkylated product gives alkenylimidazole derivatives84. 

The anionic form of 5-chloropyrimidin-2( 1 H)-one, particularly under phase-transfer conditions, was selectively methylated and benzylated at... 

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