Tritylamines

Meisenbach M, Voelter W (1997) New methoxy-substituted tritylamine linkers for the solid phase synthesis of protected peptide amides. Chem Lett 1265— 1266... 

Reductive animation of aromatic aldehydes to give benzylamines is accomplished by heating the aldehyde and tritylamine with molecular sieves, followed by the addition of sodium cyanoborohydride. Catalytic hydrogenolysis of the products with palladium on charcoal yields the benzylamines (equation 56)167. 

A mixture of tritylamine (13 g, 0.050 mol) and a freshly distilled aldehyde (0.055 mol) in benzene (50 mL) was heated to reflux in a Dean-Stark distillation device with a calibrated receiver. When the calculated amount of H20 (0.9 mL) had separated, the mixture was concentrated to give the product, which was recrystallized. For acetaldehyde imine 1 (R =Trt R2=Me) yield 100% mp 144-147°C (dec). 

Tritylamine linkers have not been extensively used for the attachment of amides, probably because A -tritylamides are difficult to prepare. This is not the case for strongly acidic amides and cyclic imides, which are readily N-tritylated with trityl chlo-... 

Table 3.11. Acidolytic cleavage of resin-bound (diarylmethyl)amine and tritylamine derivatives.

Aliphatic primary and secondary amines can be linked to insoluble supports as ben-zylamines by reductive alkylation with support-bound benzaldehydes or by N-alkyla-tion with support-bound benzyl halides or sulfonates (Figure 3.25 see also Section 10.1). Benzhydrylamines and tritylamines are usually prepared by N-alkylation with the corresponding halides. 

Tritylamines can serve as both linkers and protective groups for aliphatic amines because, unlike benzhydrylamines, they do not usually undergo acylation when treated with activated acid derivatives. Tritylation of aliphatic amines is readily accomplished by adding excess amine to a support-bound trityl chloride. Illustrative cleavage reactions are listed in Table 3.21. 

Table 3.21. Benzhydrylamine and tritylamine linkers for aliphatic amines.

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-phcnyl-l -aza-2-cyanobuta-l, 3-dicnc reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Dihydro-4//-1,2-oxazines have been shown to be useftd as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-1,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(t-butyldimcthylsilyloxy)-l-azabuta-l, 3-diene (107) reacts with halobenzo-quinones, naphthoquinones, and /V-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with /V-(cinnarnylidcnc)tritylamine produces the 3,4-adduct whereas with /V-(ci nnamyI i dcnc)bcnzyI idi nc the 1,2-adduct is produced.190... 

Sterically demanding amines have a high tendency to induce -elimination when treated with alkyl halides. Their alkylation is, however, feasible with reactive alkylating agents, and even 2,2,6,6-tetramethylpiperidines have been N-alkylated (Scheme 6.5). Secondary tritylamines, however, cannot usually be alkylated or acy-lated intermolecularly (last reaction, Scheme 6.4), but examples of intramolecular alkylations have been reported [27]. 

The rearrangement of tritylamine to an imine occurs with n-buly I lithium (Scheme 59).94... 

In the second example [Scheme 8.205], a tritylamine group was introduced by reductive amination whereupon the N-trityl group and a benzyl ester were removed simultaneously by hydrogenolysis,417... 

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... 

Li, naphthalene, THE, 0 C, 80-92% yield. These conditions cleave a trityl ether in the presence of a tritylamine. 

Detritylation. YbfOTflj catalyzes cleavage of trityl ethers and V-tritylamines in THF (containing one equiv of water) at room temperature. 

In the cases of tritylamines, ketones, phosphonates, and cyanides, for example, (4-methoxyphenyl)diphenylacetonitrile and tris(4-methoxyphenyl)acetonitrile, the di-7t-methane reaction occurred in competition with homolysis of the C-X bond. The homolysis had a quantum efficiency of 0.06 in the case of the two mentioned acetonitriles in methanol [172]. Similar behavior was reported in the photolysis of vinyl halides in methanol [173]. 

Just [50] described a survey of the amine component of the cycloaddition in a search for reagents that would allow deprotection of the resulting azetidin-ones. Azidoacetyl chloride was the ketene source, with acetaldehyde or cinnam-aldehyde employed for imine formation. Hydroxylamine and 0-benzylhydrox-ylamine formed oximes which did not undergo the cycloaddition. Tritylamine and tertbutyldimethylsilylamine would not form imines. Trimethylsilylethyl-amine and allylamine reacted well with cinnamaldehyde, but the p-lactams could not be deprotected. L-phenylethylamine, benzhydrylamine, and p,p -... 

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