Aldehydes, reductive alkylation with alcohols

Additional reactions which need to be highlighted are the reductive alkylation of alcohols and amines with aldehydes leading to the green synthesis of ethers and amines. These reactions are generally catalyzed by palladium [35]. This reaction can replace the classical Williamson s synthesis of ethers which requires an alcohol and an alkyl halide together with a base, and always results in the concomitant production of salt. The choice of Pd/C as catalyst is due to the low efficiency of this metal for the competitive carbonyl reduction. Analysis of the... 

Alkylations, A stepwise synthesis of amines via I-aminomethylbenzotriazoles involves reductive alkylation with Zn in DME. Stereoselective synthesis of 1,2-amino alcohols is attained by Zn-mediated allylation of a-amino aldehydes. Change of regioselectivity is observed in the reactions of fluorinated prenylzinc species with aldehydes (aliphatic vs. aromatic)."... 

Scheme 19 The palladium catalyzed reductive alkylation of alcohols with an aldehyde.

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-... 

Treatment of the alcohol 211 with f-butyklimethylsilyl triflate and 2,6-lutidine affords disiloxyester 212 with high yield. Reduction of the ester function of 212 with DIBAL followed by Swern oxidation gives the corresponding aldehyde 213, and subsequent alkylation with MeMgBr and Swern oxidation produce methyl ketone 214 (Scheme 7-70). 

After epoxidation of the terminal olefin in syn-89 the pyrrolidine 91 was formed by reductive cleavage of the Cbz-protection and concomitant Sn2 cyclization of the free amine to epoxide 90. In five additional steps (+)-preus-sin (2) was synthesized with an overall yield of 19%. After AT-methoxycar-bonylation and oxidation of the alcohol to an aldehyde the alkyl side chain was introduced by a Wittig reaction. 

Similar reductions were effected by heating of triethylaluminum (triethyl-alane) in ether with aldehydes and ketones. The alcohols are formed by hydrogen transfer from the alkyl groups which are transformed to alkenes. 

The competition between insertion and hydrogen transfer is also crucial to the selectivity of the reaction of aluminium alkyls with carbonyl compounds. Aluminium alkyls, like organolithium compounds and Grignard reagents, can add to aldehydes and ketones to form secondary or tertiary alcohols, respectively. If the aluminium alkyl has a j -hydrogen, however, reduction of the carbonyl compound is a common side reaction, and can even become the main reaction [16]. Most authors seem to accept that reduction involves direct j5-hydrogen transfer to ketone. 

Raney Ni and copper-chromium oxide can be used satisfactorily for these reductive alkylations at elevated temperatures and pressures in ethanol solution or without a solvent (eq. 6.11). 2-pnm-Alkylaminoethanols were prepared in a similar manner in 60-90% yields by hydrogenating mixtures of aldehydes with ethanolamine. In these cases the alcohol solution of ethanolamine was cooled in ice while the aldehyde (15% molar excess) was added slowly in order to avoid polymerization. 

Tertiary arylamines were prepared in good yields by hydrogenation of an alcoholic solution of a nitro compound and an aldehyde over Raney Ni in the presence of triethy-lamine hydrochloride or, better, over platinum oxide in the presence of acetic acid (eq. 6.22).48 Base metal and platinum metal sulfides are also effective to the reductive alkylation of nitro compounds with ketones36,37 as in an example shown in eq. 6.23. 

Selective reduction of aldehydes. In the absence of radical initiators, tributyltin hydride does not ordinarily reduce carbonyl groups. However, when slurried in cyclohexane with dried silica gel (activated by heating at 220° under reduced pressure), this hydride reduces aldehydes and ketones to alcohols in high yield. The rate of reduction is aldehydes > dialkyl ketones > aryl alkyl ketones > diaryl ketones. Thus it is possible to reduce aldehydes selectively. The function of Si02 apparently is that of a mild acid catalyst. 

The system consisting of gaseous BFs/EtsSiH has been reported "- to reduce aldehydes and ketones thus benzaldehyde was reduced to toluene in 52% yield. In alkyl carbonyl compounds, aldehydes afford the corresponding alcohol products, whereas ketones, such as undecan-2-one and cyclohexanone, are readily converted to the hydrocarbons in high yields. On reduction with limited amounts of both reagents these alkyl ketones were reduced to the alcohols, indicating the intermediacy of the corresponding borate ester. In the case of aromatic compounds, aryl aldehydes and diaryl and alkyl aryl ketones are reduced to... 

As a rather special case, alkyl aldehydes are reduced with titanocen dichloride to the hydrocarbons through a titanium-bonded alkenic intermediate as shown by a deuterium-labeling experiment. Thus, dodecanal was converted to dodecane in 71% yield, along with dodecan-I-ol in 15-20% yield alkyl ketones such as adamantan-2-one and dodecan-6-one afforded alcohols as the major products. No reduction occurred in the case of aryl aldehydes where alkene formation is impossible. ... 

---