Alkyl trichloroacetimidates

Electron-deficient nitriles, such as for instance trichloroacetonitrile and trifluoroacetonitrile (A=B A = N B = CCC13, CCF3), are known to undergo direct and reversible, base-catalyzed addition of alcohols providing O-alkyl trichloroacetimidates (1,50). This imidate synthesis has the advantage that the free imidates can be isolated as stable adducts, which are less sensitive to hydrolysis than their corresponding salts. 

H. P. Weasel, T. Iversen, and D. R. Bundle, Acid-catalysed benzylation and allylation by alkyl trichloroacetimidates, J. Chem. Soc. Perkin Trans. 7 2247 (198S). 

Acid-catalysed alkylation of an alcohol with O-alkyl trichloroacetimidate prepared from allyl alcohol and trichloroacetonitrile is readily accomplished Scheme 4.233]440 as previously discussed for the preparation of benzyl and tert-butyl ethers.311 However, these conditions are not compatible with many of the protecting groups employed in oligosaccharide synthesis. For such cases, two methods for 0-allylation under essentially neutral conditions have been devised. The first method takes advantage of the mild conditions and regioselectivity of stannylene alkylations (see section 4.3.3). The method is illustrated by the selective O-allylation of o-lactal, which began with stannylene formation on an 0.8 mole scale [Scheme 4.234].441... 

Protonation of the alkyl trichloroacetimidate (at nitrogen) activates the electrophile towards nucleophilic attack by the hydroxyl group of the sugar to generate the alkyl ether and liberate trichloroacetamide. 

Procedure, The alkyl trichloroacetimidate can be prepared as follows. To a stirred suspension of sodium hydride (0.50 g, 21.0 mmol) in anhydrous diethyl ether (20 ml) add dropwise via cannula a solution of para-methoxybenzyl alcohol (29.0 g, 210 mmol) in diethyl ether (30 ml). After the solids have dissolved, cool the reaction vessel in an ice-salt bath and add trichloroacetonitrile (20.0 ml, 200 mmol) over a period of 15 min, then allow the reaction mixture to warm to room temperature. After 1 h concentrate the solution in vacuo to afford a syrup, then add pentane (20 ml) containing anhydrous methanol (0.8 ml) and stir vigorously. Filter off the precipitate and wash with pentane (2 X 20 ml) concentrate the filtrate and washings in vacuo to yield the alkyl trichloroacetimidate. 

Alkylation by means of reductive condensation of amines with aldehydes Alkylation with alkyl trichloroacetimidates CONCLUSIONS REFERENCES... 

Alkyl trichloroacetimidates 2.18 Alkylations, under neutral conditions, of substances bearing acid- or alkali-labile substituents [136, 137] Solubility of the substance to be alkylated in a non-polar solvent is of advantage... 

Alkylation using Trichloroacetimidates. Under mildly acidic conditions, alkyl trichloroacetimidates act as reasonable alkylating agents toward heteroatom nucleophiles, most notably alcohols (eq 6). Alkyl groups which have been... 

In the synthesis of analogues of calicheamicin 71 and esperamicin Ajb, Moutel and Prandi employed the glycosyla-tion of a nitrone with a trichloroacetimidate as a key step - /3-N-O glycosidic bond formation. Preparation of the nitrone begins with the alkylation of the known alcohol 69 <1992CC1494> with 1,4-dibromobutane in the presence of sodium hydride. Subsequent aminoalkylation, amine protection with 9-fluorenylmethoxycarbonyl (Fmoc), and reduction with NaBHsCN were followed by nitrone 70 formation with 4-methoxybenzaldehyde (Scheme 8) <2001J(P1)305>. 

Trichloroacetimidates are the only type of imino ethers to have found some application in solid-phase synthesis. Trichloroacetimidates can readily be prepared from support-bound alcohols by treatment with trichloroacetonitrile and a base (Entry 6, Table 13.18). Because trichloroacetimidates are good alkylating agents, this reaction offers a convenient alternative for converting support-bound aliphatic alcohols into alkylating agents. Trichloroacetimidates prepared from Wang resin or from hydroxymethyl polystyrene are quite stable and can be stored for several months without decomposition [253],... 

Perhaps the most versatile of the recent additions to the repertoire of methods for appending rm-butyl ethers involves alkylation of alcohols with 0-/m-butyl trichloroacetimidate (mp 21 CT bp 65 01.5 kPa) in the presence of a catalytic amount of trifluoroborane at room temperature for 16-21 h in cyclohexane -dichloromethane [Scheme 4.127].227 O-fm-Butyi trichloroacetimidate is commercially available but it can be had more cheaply by synthesis from trichloroa-cetonitrile and potassium fm-butoxide (70% yield). 

Benzyl 2,2,2-trichloroacetimidate (bp 106-114 °C/0.07 kPa) alkylates alcohols in the presence of trifluoromethanesulfomc acid.311 Esters, imides, isopropylidene and benzylidene acetals are unaffected. This method allows the formation of benzyl ethers in molecules that are base-sensitive. In the example [Scheme 4,167],312 benzylation of the P-hydroxy ester 167.1.1 under the usual basic conditions would lead to retro-aldol reactions and/or elimination. A synthesis of the cellular messenger L-a-phosphatidyl-D-myo-inositol 3,4-bisphosphate exemplifies the use of trityl cation-promoted benzylation of two adjacent hydroxyls [Scheme 4.168].313314... 

Pyruvated glycosyl donors (halides and trichloroacetimidates) are conveniently prepared from the corresponding alkyl or aryl 0- and S-glycosides or from 1-0 unprotected glycoses using standard methods [39d,41]. In addition, 1-thio-glycosides can be used directly as pyruvated glycosyl donors when adequate thiophilic activations are applied [39b, d]. 

Carboxylic acids can be converted to tert-butyl esters by treatment with tert-butyl 2,2,2-trichloroacetimidate (see 10-10) and BF3<)Et2." Carboxylic esters can be formed from the carboxylate anion and a suitable alkylating agent (10-26). 

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