Chloroformates, alkyl, reduction

Extraction with chloroform, volume reduction, alkylation or silylation... 

Contaminants and by-products which are usually present in 2- and 4-aminophenol made by catalytic reduction can be reduced or even removed completely by a variety of procedures. These include treatment with 2-propanol (74), with aUphatic, cycloaUphatic, or aromatic ketones (75), with aromatic amines (76), with toluene or low mass alkyl acetates (77), or with phosphoric acid, hydroxyacetic acid, hydroxypropionic acid, or citric acid (78). In addition, purity may be enhanced by extraction with methylene chloride, chloroform (79), or nitrobenzene (80). 

Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modem equivalent (reaction with alkyl chloroformate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16]. 

Alkanes are formed when the radical intermediate abstracts hydrogen from solvent faster than it is oxidized to the carbocation. This reductive step is promoted by good hydrogen donor solvents. It is also more prevalent for primary alkyl radicals because of the higher activation energy associated with formation of primary carbocations. The most favorable conditions for alkane formation involve photochemical decomposition of the carboxylic acid in chloroform, which is a relatively good hydrogen donor. 

In coals alkylated in this manner, the number of acidic sites is substantially reduced, and acid-base associations are virtually precluded. Extracts from alkylated coals should, therefore, be amenable to GPC fractionation. Such fractionation, conducted on Bio Beads S-Xl and S-X2, results in separation by molecular weight and indicates that both benzene and chloroform extracts contain substantial amounts of high ( 6000) and fairly low (560-640) molecular weight fractions (Figure 2). While the extract yields from non-reductively ethylated vitrinite increase in the order benzene extr. chloroform extr. - pyrid. extr > the molecular weights determined by VPO in pyridine, decrease in this order. 

Sulphoxides and sulphoximines are reduced to thioethers by similar reaction sequences [3, 4], In most cases, the yields of the thioethers are higher (>70%) from the diaryl compounds, than from dialkyl or aryl alkyl derivatives but, when the reductions are conducted in an excess of chloroform, the yields of the thioethers are diminished [3], This observation suggests that the thioethers are reacting with dichlorocarbene and that the dialkyl and aryl alkyl compounds are more susceptible than the diaryl derivatives (Table 11.20). 

The key intermediates 692 required for the thermal cyclization were prepared from the readily available indole-2,3-diones 693. The condensation of 693 with 3-methyl-4-phenylbut-3-en-2-one (694) afforded the 3-hydroxy derivatives 695. The dehydration of 695, followed by selective reduction of the 3,1 -double bond of compounds 696, provided the 3-alkyl derivative 697. Finally, the compounds 697 were transformed to the 3-(l,3-butadienyl)indoles 692 by reaction with an excess of ethyl chloroformate (Scheme 5.62). 

Several syntheses of muraghtazar (3) have appeared in patents (Cheng et al.) and journals (Devasthale et al., 2005) (Scheme 8.3). Alkylation of 4-hydroxybenzaldehyde with the phenyloxazolemesylate 23, prepared readily from commercially available alcohol 22, yielded aldehyde 24, which was treated with glycine methyl ester under reductive amination conditions to provide secondary amine 25 in excellent yield. Reaction of amine 25 with 4-methoxyphenyl chloroformate followed by hydrolysis of the methyl ester afforded 3 in 94% yield. 

Cyclization of the product (27-2) under Friedel-Crafts conditions gives the desired indolinone (27-3). Reaction of the carbanion obtained on treatment of that with 3-chloropropyldimethylamine then gives the alkylation product (27-4). It should be noted that, in spite of this extra step, the scheme is greatly simplified by starting with the very readily available tertiary amine. The superfluous methyl group is then removed by reaction of (27-4) with ethyl chloroformate in the current version of the Von Braun reaction. There is thus obtained amedalin (27-5). Reduction of the amine by any of several methods, for example diborane, leads to the antidepressant daledalin (27-6) [28]. 

For the preparation of MBM, the starting phenol was alkylated to 2-(n)-butoxy-1,4-dimethoxybenzene in methanolic KOH with n-butyl bromide. The benzaldehyde melted at 79.5-81 °C from methanol, and formed a malononitrile derivative that had a melting point of 134.5-135 C. The nitrostyrene from the aldehyde and nitroethane in acetic acid crystallized from methanol with a mp of 71 -72 °C. Lithium aluminum hydride reduction in ether gave the ether-insoluble chloroform-soluble product 4-(n)-butoxy-2,5-dimethoxyamphetamine hydro-... 

Kempter and co-workers prepared benzodiazocines 134 (R = R1 = H R2 = H, Me) from 135 (R = H, Me) by reduction and subsequent cyclo-condensation with the appropriate carbonyl compound (75MI7 87ZC36). For example, these workers condensed 3-(o-aminophenyl)propylamine with either phosgene or alkyl chloroformate to obtain 134 (R = R1 = R2 = H, X = O). Reaction of the same diamine (77MI5 87ZC36) and substituted derivatives (77MI5) with carbon disulfide afforded thio-... 

Methods for the conversion of derivatives of morphine into their N-nor-com-pounds, using vinyl chloroformate,149 trichloroethyl chloroformate,150 and phenyl chloroformate,151 have been patented. Norneopine has been prepared from neopine and diethyl azodicarboxylate and by the hydrolysis of 7V-nitrosonor-neopine.152 The conversion of N-nor-bases into N-alkyl-compounds by the reduction of amides has been covered by a further patent.153... 

In Schemes 8.204 and 8,205 above we showed that tritylamines can be generated by reductive amination and N-alkylation of trityiamine. However, N-alkyla-tion of amines by triphenylmethyl chloride (mp 110-112 °C) or triphenylmethyl bromide (mp 152-154 °C) in an aprotic solvent such as chloroform or chloro-form-DMF mixtures together with a base such as triethylamine is the most common method for introduting the trityl group [Scheme 8,212]434 4,4 -Dimethoxy-trityl tetrafluoroborate and 4i4, 4"-trimethoxytrityl tetrafluoroborate are also... 

---