Methylation, general methods

Doebner-von Miller reaction Condensation of an aromatic amine with an aldehyde or ketone in the presence of hydrochloric acid to form a quinoline derivative. A general method, thus aniline and ethanal give 2-methyl-quinoline (quinaldine) and p-phenetidine. 

The Teoc derivative can be prepared by cleavage of an N-Bn bond with Teoc-Cl in THE. This is a general method for removal of benzyl groups from nitrogen. Methyl and ethyl groups are also cleaved, but more slowly (24 h vs. 4 h) and in lower yield ... 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

The present procedure was developed from those of Wallach and Freylon, based upon the general method discovered by Leuckart. a-Phenylethylamine also can be prepared satisfactorily by the reduction of acetophenone oxime with sodium and absolute alcohol or sodium amalgam, but the reagents are more expensive and the processes less convenient. The amine has been obtained by reducing acetophenone oxime electro-lytically, by reducing acetophenone phenylhydrazone with sodium amalgam and acetic acid, from a-phenylethyl bromide and hexamethylenetetramine, and by the action of methyl-magnesium iodide upon hydrobenzamide, as well as by other methods of no preparative value. 

A variety of substituted corticoids has been prepared by this general method, e.g., 6- and 9-hydroxy, 6-methyl, 2-, 12-, °... 

The synthesis of 3,4-dihydroisoquinolines via intramolecular reactions of phenethyl amides was first reported by August Bischler and Bernard Napieralski in 1893. The authors described the conversion of A-acyl phenethylamide (1, R = Me) and A-benzoyl phenethylamide (1, R = Ph) to 1-methyl-3,4-dihydroisoquinoline (2, R = Me) and 1-phenyl-3,4-dihydroisoquinoline (2, R = Ph), respectively, in the presence of P2O5. This reaction has subsequently proven to be one of the most general methods ever developed for the synthesis of dihydroisoquinolines. 

The Favorsky reaction should be considered a general method for producing pyrazolyl-Q -acetylenic alcohols because even the less reactive 4-ethynyl-l,3,5-trimethylpyrazole, additionally deactivated by three donor methyl groups, reacts with acetone (Scheme 61). 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

The synthesis of 2-chloro-2,3,3-trifluorocyclobutyl acetate illustrates a general method of preparing cyclobutanes by heating chlorotrifluoroethylene, tetrafluoroethylene, and other highly fluorinated ethylenes with alkenes. The reaction has recently been reviewed.11 Chlorotrifluoroethylene has been shown to form cyclobutanes in this way with acrylonitrile,6 vinylidene chloride,3 phenylacetylene,7 and methyl propiolate.3 A far greater number of cyclobutanes have been prepared from tetrafluoroethylene and alkenes 4,11 when tetrafluoroethylene is used, care must be exercised because of the danger of explosion. The fluorinated cyclobutanes can be converted to a variety of cyclobutanes, cyclobutenes, and butadienes. 

The synthesis of chlorotrifluorobutadiene illustrates a general method that has been used to make tetrafluorobutadiene and substituted fluorodienes.3- 9 The same procedure can be used to transform fluorocyclobutenes and chlorofluorocyclobutenes to the isomeric dienes 2-methyl-1,1,4,4-tetrafluorobutadiene, 2-chloro-l,l,4,4-tetrafluorobutadiene, and l-chloro-l,4,4-trifluoro-2-phenylbutadiene have been made thus.3... 

Diels-Alder reactions provide one of the few general methods of forming two carbon-carbon bonds simultaneously. The main features of these reactions are described in Box 1.3. The reaction finds widespread industrial use for example hardeners for epoxy resins are made by reaction of maleic anhydride with dienes such as 2-methyl-1,4-butadiene. 

The Michael addition to nitroalkenes followed by cyclization provides a general method for the synthesis of various pyrroles. The reaction of nitroalkenes with acetoacetate followed by reduction with Zn in acetic acid provides another route to 2-methyl-3-pyrrolecarboxylates (Eq. 10.8).10... 

The synthesis of triquinane acids, initiated by the preparation of isocomenic acid [22], thus provided a general method for control of the stereochemistry of secondary methyl groups in these terpenes. The [4+1] annulation based on the dienes of type 23 then laid the groundwork for the first-generation design and a model study for the approach to retigeranic acid [23]. 

This sequence illustrates a very general method for the synthesis of methyl y-oxoalkanoates which are valuable intermediates in organic synthesis.3 6 The scope of the cyclopropanation reaction is very broad only functional groups interacting with the carbenoid generated from melhyl diazoacetate are not compatible. Use of Rh2(OAc)4 instead of Cu(acac)2 as catalyst did not afford better yields.3 The cyclopropanation reaction has been performed with similar efficiency on scales from 4 mmol up to 500 mmol. 

The electrochemical oxidation is often more sensitive to the reaction conditions than to the substituents. Platinum electrodes are recommended for methoxylation and the equivalent acetoxylation procedures.290 In acetonitrile buffered by hydrogen carbonate ion, 3,4-diethylfuran affords the 2,5-dihydroxy-2,5-dihydro derivative (84%) and Jones oxidation readily leads to diethylmaleic anhydride in what is claimed to be the best general method for such conversions.291 In unbuffered methanol and under current density control, the oxidation of 2-methylfuran appears to eliminate the methyl group since the product is the acetal-ester 111 also obtained from methyl 2-furoate.292 If sodium acetate buffer is used, however, the methyl group is retained but oxidized in part to the aldehyde diacetate 112 in a... 

An improved synthesis of li/-2,l-benzothiazine 4(3i/)-one 2,2-dioxide 33 that results in a relatively high overall yield was developed by Lombardino s group <710PP33 72JHC315>. This general method offered an easier entry into the 2,1-benzothiazine 2,2-dioxide heterocyclic system <67JHC403>. Treatment of methyl A-benzyl-A-methylsulfonylanthranilate 35 with sodium hydride led to 1-benzyl-4-oxo-l//-2,l-benzothiazine-4(3/7)-one 2,2-dioxide 36 in 68% yield. Reduction of 36 gave 4-oxo-17/-2,1 -... 

Reaction of 3-Lithiomethyl-2-methyl-l-phenylpyrazolin-5-one with 6 A New General Method for the Synthesis of 1,2-Disubstituted Indazolones and Their Condensed Analogs (Type III, 3a Model)... 

The C-H insertion a to nitrogen can be extended to acyclic systems. The reaction with jY-benzyl-iV-methylamine is an excellent example of the interplay between steric and electronic effects. The benzylic position would be electronically the most activated, but due to the steric crowding, the C-H insertion occurred exclusively at the iV-methyl site (Equation (27)).86 This is a general method for generating a-aryl-/5-amino acid derivatives. The N,N-dimethylamino group undergoes a very favorable C-H insertion by the donor/acceptor-substituted carbenoids. Indeed, the reaction is so favorable that double C-H insertion was readily achieved to form the elaborated -symmetric amine 10 (Equation (28)).87... 

Hydrozirconation of alkynes with the Schwartz reagent, Cp2Zr(H)Cl (6), and subsequent methylation is also a general method (Eq. 2.5) [16]. 

This is a general method for making N-alkylallenimines, and the following ones have been made in this way N-methyl-,6 N-propyl-,6 N-isopropyl-,4 N-butyl-,4 N-hexyl-,e and N-(3,5,5-tri-methylhexyl)-.4 N-Z-Butylallenimine6 and l-(l-allenimino)-2-hydroxy-3-butene 7 have also been prepared by this method, but with sodium amide/2-bromoallylamine mole ratios of 1.75 and 2.1, respectively. This method has been used for the preparation of pure N-alkylpropargylamines from 2-chloroallylaminesA7 The optimum sodium amide/2-chloroallylamine ratio for the preparation of N-alkylpropargylamines is 2.1. 

This procedure illustrates a general method of carboxylating saturated hydrocarbons that have a tertiary hydrogen.7 It has been used to convert isopentane to 2,2-dimethylbutanoic acid, 2,3-dimethylbutane to 2,2,3-trimethylbutanoic acid, and methyl-cyclohexane to 1-methylcydohexanecarboxylic add. 

This preparation illustrates a general method for the synthesis of N-methylalkylamines. The submitters have used it to prepare N-methylbutylamine (Note 4) and N-methylallylamine, and the checkers have used it to prepare N-methylisopropylamine (80%), N-methylisobutylamine (67%), N-methyl-fert-butylamine (52%), and N-methyl-2-methoxyethylamine (55%). Secondary amines are useful as starting materials for the synthesis of 1,1-disubsti-tuted hydrazines and asymmetric amine imides. 

Methyl orange buffered at pH 3.5 binds to albumin with greater affinity than to other proteins and the resulting complex shows reduced absorbance at 550 nm. The method is unsuitable as a general method for protein determination because of considerable variation in the binding of the dye with different proteins. 

A GENERAL METHOD FOR THE PREPARATION OF a-BRANCHED AMINO ACIDS (L-Proline, 2 methyl-)... 

A. K. Beck, S. Blank, K. Job, 0. Seebach, and Th. Sommerfeld 62 SYNTHESIS OF (S)-2-METHYL-PROLINE A GENERAL METHOD FOR THE PREPARATION OF o-BRANCHED AMINO ACIDS... 

This procedure illustrates a general method for the selective splitting of a carbomethoxy group in the presence of easily hydrolyzed esters of other alcohols, such as the easily hydrolyzed equatorial acetoxy group. The specificity of the reaction is not affected by steric hindrance, and a highly hindered methyl ester can be split in the presence of other less hindered esters of secondary alcohols. Normal alkaline saponification goes in exactly the opposite way. 

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