2.2.2- Trichloroacetamides

Speziale and his co-workers have carried out comprehensive studies of the reactions of phosphorus compounds. It has been shown 108) that the reaction of N,N-dialkyl-a-trichloroacetamides (127) with phosphites and phosphines gives trichlorovinylamines (128). In general the trialkyl-phosphines gave somewhat higher yields (60 to 83%) and purer products... 

In a later paper Speziale and Smith 109) investigated the reaction of trivalent phosphorus compounds with N-monosubstituted a-trichloro-acetamides and a-trichloroacetamide. The products were imidoyl chlorides (129) and dichloroacetonitrile (130), respectively. The intermediacy of enamines (131) was assumed. For the monosubstituted amides the enamine... 

Diethyl succinate, reaction with 3 hy droxycinchomnic acid to yield 3-hydroxyquinoline, 40, 56 N,N-Diethyl-2,2,2-trichloroacetamide, 41, 21... 

C 3H,sCl2Ni02 41936-93-0) see Clenbuterol 7V-(4-amino-3,5-dichlorophenyl)trichloroacetamide (C (H5Cl5N20 S686/-4/-S) see Apraclonidine... 

O-Allyl imidate esters undergo [3,3]-sigmatropic rearrangements to /V-allyl amides. Trichloromethyl imidates can be made easily from allylic alcohols by reaction with trichloroacetonitrile. The rearrangement then provides trichloroacetamides of IV-allylamines.260... 

The isolation of 73 was then fully optimized. Upon completion of the etherification reaction, the insoluble trichloroacetamide 68 was filtered, leaving a 17 1 mixture of 18 and 19 as a DCE/heptane solution, together with starting material 10. The solvent was switched to MeOH and the esters were saponified with KOH. The carboxylic acid was isolated after neutralization and the addition of NEt3 which gave the highly crystalline triethylamine solvate 73 as a 40 1 mixture of diastere-omers. Recrystallization from MTBE/heptane gave a 109 1 diastereomeric mixture of 73 in 54% overall yield from 10. This final process was successfully implemented in the pilot plant without incident. 

Alkylation of trifluoro- and trichloroacetamides with a-bromoacetic esters has been utilized for the synthesis of a wide range of a-aminoacetic acids [11-13] (Table 5.13). Hydrolysis of the intermediate a-trihaloacetamidoacetic esters with methanolic potassium hydroxide converts the methyl and ethyl esters directly into the amino carboxylic acids. /-Butyl a-aminoacetates are more stable, but they are hydrolysed under phase-transfer catalytic conditions (see Chapter 9.2). Reaction of the trihaloacetamides with 1,4-dibromobutane and 1,5-dibromopentane and subsequent hydrolysis provides a simple route to pyrrolidine-2-carboxylic acid (75%) and piperidine-2-carboxylic acid (58%) [11, 12],... 

The reduction of the trichloroacetamide derivative 56 with (TMS)3SiH afforded 57 in a 60% yield (Reaction 7.58) [68]. The final product is the result of cyclization and further removal of two chlorine atoms. In fact, 3.5equiv of silane and 1.1 equiv of AIBN are used. 

Stereoselective transformation of allylic alcohol to allylic trichloroacetamide via trichloroacetimidate intermediate. 

Amides can also be removed by partial reduction. If the reduction proceeds only to the carbinolamine stage, hydrolysis can liberate the deprotected amine. Trichloroacetamides are readily cleaved by sodium borohydride in alcohols by this mechanism.84 Benzamides, and probably other simple amides, can be removed by careful partial reduction with diisobutylaluminum hydride.85... 

Epoxytrichloroacetimidates 153 also undergo oxazoline ring formation in the presence of a catalytic amount of Lewis acids.Diethylaluminum chloride was found to be superior to boron trifluoride, which tends to further hydrolyze the oxazoline 154 to the trichloroacetamide. Generally, formation of the six-membered ring oxazine 155 is not favored, but it can be a serious side reaction if the epoxide contains substituents that stabilize the incipient cation generated prior to ring closure. Examples from this study are summarized in Table 8 19 (Fig 8 8 Scheme 8.45). 

Reaction of 7V,A-diethyl-2,2,2-trichloroacetamide with trialkyl phosphites or triphenylphosphine to give N, N-diethyl-1,2,2-trichlorovinylamine [152-154],... 

A. N,N-Diethyl-2,2,2-trichloroacetamide. A 1-1. three-necked flask equipped with a stirrer and dropping funnel is charged with 73 g. (1.00 mole) of diethylamine, 500 ml. of ether, and a solution of 40 g. (1.00 mole) of sodium hydroxide in 160 ml. of water. The mixture is stirred and maintained at a temperature of —10° to — 15° by a bath of Dry Ice and acetone while 200 g. (1.10 moles) of trichloroacetyl chloride is added in the course of 1 hour. The cooling bath is removed, the temperature is allowed to rise to 10°, and the organic layer is separated. The aqueous layer is extracted with two 50-ml. portions of ether. The ether extracts are combined, washed with 50 ml. of 5% hydrochloric acid, two 50-ml. portions of 5% sodium bicarbonate solution, and 50 ml. of water, and dried over magnesium sulfate. The ether is removed by distillation at atmospheric pressure. The residue is distilled through a short indented Claisen still head at reduced pressure. N,N-Diethyl-2,2,2-trichloroacetamide is collected at 77-79°/1.5 mm. 1.4902-1.4912 weight 183-200 g. (84-92%). 

N,N-Diethyl-l,2,2-trichlorovinylamine has been prepared by the action of trimethyl, triethyl, or triisopropyl phosphite or triphenylphosphine on N,N-diethyl-2,2,2-trichloroacetamide., These methods require a reaction temperature of 150-160° and several distillations in order to obtain a pure product. Consequently, the yields of the vinylamine are lower than by the present procedure.3... 

The procedure has also been applied to the synthesis of N,N-dimethyl-l,2,2-trichlorovinylamine from trichloroacetamide (60% yield),3 and it probably is a general means of preparing N,N-dialkyl-l,2,2-trichlorovinylamines. The reaction is an unusual one involving reduction of the amide and halogen migration and is of theoretical interest. 

Alcohol Trichloroacetamide Product Overall Isolated Yield (%)... 

Trichloroacetamide [594-65-0] M 162.4, m 139-141°, b 238-240°. Its xylene soln was dried. witKj P2O5, then fractionally distd. Nyl... 

A-f(2E)-4-Benzyl-5-(tetrahydro-2/f-pyran-2-yloxy)pent-2-enyl]-2,2,2-trichloroacetamide (128) [29)... 

Amides with electron-withdrawing substituents can be sufficiently labile towards nucleophilic attack to enable their use as protective groups. This is the case, for example, with trifluoro- [102,290] and trichloroacetamides [163], which are readily hydrolyzed under mild conditions (Figure 10.13). Suitable nucleophiles are hydrazine [291], aliphatic amines, and hydroxide, but if a hydrophobic support has been chosen, it must be borne in mind that the reactivity of alkali metal hydroxides will be reduced because of poor diffusion into the support. Amides of electron-poor amines (e.g. anilides) can also be readily cleaved by nucleophiles [292],... 

Protection of hydroxyl groups Benzyl or allyl ethers of carbohydrates are obtained in satisfactory yield by reaction with 1 or 2 in cyclohexane in the presence of triflic add (20°). Trichloroacetamide precipitates and the desired ethers are obtained from the filtrate after neutralization. 

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