Hydroxy halides, alkylation amination

Aromatic nitro groups Aromatic rings N-oxides Alkyl hydrazines Alkyl aldehydes N-methyl derivatives Monoalkenes p-Haloethyl mustards N-Chloroamines Alkyl N-nitrosoamines Alkyl esters of either phosphoric or sulfonic adds Aromatic mono- and dialkylamino groups Aromatic azo groups (because of possible reduction to aromatic amines) Aromatic and aliphatic aziridinyl derivatives Aromatic and aliphatic substituted primary alkyl halides Aromatic amines (including their N-hydroxy derivatives and the derived esters Propriolactones and propriosultones Derivatives of urethane (carbamates) Aliphatic and aromatic epoxides... 

Oxidation of Halides and Amines. N-Trifluoromethylsulphonylaniline (3) oxidizes secondary bromides, activated by a carbonyl group, to 1,2-diketones, whereas the more reactive p-hydroxy analogue (4) will oxidize unactivated alkyl halides to aldehydes (Scheme 2). ... 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Reductive amination of dihydropyran (which may be regarded as the dehydration product of the cyclic acetal of 5-hydroxy-pentanal) in the presence of isopropylamine and a trace of acid affords the aminoalcohol, 96. Treatment of this compound with thionyl chloride affords the haloamine, 97. Alkylation of the quinoline, 92, with this halide yields pentaquine (98). ... 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

Alkylation with organic halides carrying a second functional group affords a good synthesis of some difficultly obtained difunctional compounds including diamines, " amino halides, hydroxy amines, amino ketones, amino acids, " amino cyanides, and... 

Ladlow and coworkers have reported the use of fluorous-tagged aldehydes as a protecting group in the synthesis of a library of sulfonamides. The F-aldehyde was prepared via a simple alkylation of 4-hydroxy-2-meoxybanzaldehyde with a perfluo-roalkyl halide. The authors have protected various primary amines with the F-aldehyde followed by reduction, sulfonylation and Suzuki coupling and acid-mediated deprotection. Filtration via a fluorous SPE (solid phase extraction) was... 

The classical Hofmann elimination reaction (which dates back to 1851) has been adapted to the solid phase in combination with the Michael addition. The REM resin, called this way because the resin tinker is REgenerated after product cleavage and functionalized by means of a Michael addition, has been developed to prepare arrays of tertiary amines. The procedure involves acylation of hydroxy-methylpolystyrene with acrylic chloride to furnish the acrylate on resin. Then, a secondary amine, whose substituents offer two potential sites of diversity, is bound by Michael addition. Quaternization of the amine with an alkyl halide (or reductive animation) introduces another site of diversity and activates the tinker to release the amine by a Hofmann elimination with DIEA (Figure 15.14) [127-129]. Additionally, the use of a second basic resin has been described as a source reagent to promote the elimination [130, 131]. 

It is important to note that strong basic conditions, such as sodium hydride or potassium t-butoxide, favor the reaction between the hydroxy group and an alkyl halide or tosylate over alkylation by the amine (Bradshaw et al., 1989). Weak bases, such as sodium or potassium carbonate, favor the alkylation of amines over ether formation. Thus, a compound containing both alcohol and amine functions can undergo amine alkylation to give a product with a free substituent alcohol. 

Carbamates are formed by trapping the condensation products of amines and CO2 with alkyl halides. The initial step is promoted by electrogenerated superoxide ion. Heating amines and oxetanes at 40 atm leads to 3-hydroxy alkyl carbamates. ... 

In general, aldehydes, ketones, acids, esters, and acid chlorides are all reduced to the corresponding alcohols hy this reagent. Alkyl halides are unreactive towards DIBAL. Amides are reduced to amines, while nitriles afford aldehydes upon hydrolysis of an intermediate imine. Isocyanates are also reduced to the corresponding imines. Nitro compounds are reduced to hydroxy-lamines. Disulfides are reduced to thiols, while sulfides, suhbnes, and sulfonic acids are unreactive in toluene at 0°C. Tosylates are converted quantitatively to the corresponding alkanes. Cyclic imides can be reduced to carbinol lactams. 

The Inifer process developed by Kennedy can be used to functionalize vinyl monomers via a cationic route by initiating a polymerization with an alkyl halide-boron trichloride mixture R BCl. The termination by transfer to an alkyl halide leaves a halide-terminated polymer. This can be transformed to a hydroxyl terminal unit via the sequence (1) dehydrohalogenation, (2) hydroboration, and (3) oxidation and hydrolysis (Equation 5.24). These co-functional blocks may be coupled to form diblock copolymers using standard reaction techniques, e.g., diisocyanate will couple cohydroxy and co-amine blocks together. Direct reactions can also occur, and co-acid chlorides combine readily with co-hydroxy units. 

Fragmentations of heterocycles have played an important role in the preparation of amide derivatives. Moderate to good yields of a-hydroxy-amides were obtained on reaction of a-hydroxy-acid aceto-nides with primary amines.N-Alkyl-2-methyl-2-oxazolinium salts (obtained by mixing alkyl halides and 2-methyl-2-oxazoline in dichloromethane) were found to react with sodium benzeneselenolate to yield -(2-phenylselenoethyl)-t -alkylacetamides, which after oxidation to ] -vinyl analogues with sodium metaperiodate in methanol, gave secondary amides on sequential treatment with mercuric acetate in aqueous tetrahydrofuran and sodium borohydride/3M... 

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