Benzhydrylamines

This group was developed for the protection of primary amides of amino acids. It is introduced by amide bond formation with the benzhydrylamine. It is cleaved with 1 MSiCl4/anisole/TFA/0° or 1 MTMSOTf/thioanisole/TFA, 0°. Cleavage occurs by initial sulfoxide reduction followed by acidolysis. ... 

Functionalized supports with amino groups such as benzhydrylamine (BHA) 26 [32] and 4-methylbenzhydrylamine (MBHA) 3 [3] provided C-terminal amides upon HF cleavage (Fig. 2). Polyalkoxyaminobenzyl and alkoxydiphenylamino resins such as PAL (5-(4-aminomethyl-3,5-dime-... 

Benzhydrylamine Derivatives Attachment of piperazine nitrogen directly to a benzhydryl carbon leads to a pair of compounds which show vasodilator activity, and which should be useful in disease states marked by impaired blood circulation. Reaction of piperonyl chloride (18) with a mixture of piperazine and piperazine dihydrochloride leads to the monoalkylation product (19). (It may be supposed that the mixture of free base and salt equilibrates to the monobasic salt, thus making the second amine less nucleophilic.) Alkylation of 19 by means of benzhydryl chloride then... 

Benzenediol, h86 Benzenemethanol, b78 1,2,3-Benzenetriol, t317 Benzenethiol, tl 56 Benzhydrazide, b71 Benzhydrol, d760 Benzhydrylamine, d761... 

BENZHYDRYLAMINE RESIN FOR SYNTHESIS OF PEPTIDE AMIDES USING BOC/BZL CHEMISTRY... 

FIGURE 5.16 Production of amides by cleavage of benzhydryl amides. Recognition that removal by acidolysis of benzhydryl protectors from carboxamides gave the amides (B) led to development of benzhydrylamine (BHA) resin (C).33 Treatment with HF of a peptide amide that has been assembled on a BHA resin using Boc/Bzl chemistry gives the peptide amide (D). Peptide amide is also obtainable by ammonolysis of the resin-bound benzyl ester (A), a reaction that is more efficient if gaseous NH3 is employed (see Section 8.3). 

PG Pietta, PF Cavallo, K Takahashi, GR Marshall. Preparation and use of benzhydrylamine polymers in peptide synthesis. II. Syntheses of thyrotropin releasing hormone, thyrocalcitonin 26-32, and eledoisin. J Org Chem 39, 44, 1974. 

For the synthesis of primary allylic amines, an allyl acetate, e.g. 175, is treated with the benzhydrylamine 176 (Ar = d-MeOCgFLt) in the presence of a catalytic amount of (Ph3P)4Pd and the product 177 is cleaved to the amine 178 with 88% formic acid186. 

The preparation of vicinal diallyldiamines is illustrated by the following sequence condensation of glyoxal with benzhydrylamine yields the diimine 189, which is converted into 190 by the action of allylmagnesium chloride. The diphenylmethyl groups are then removed reductively by treatment with triethylsilane196. 

Bio-beads consists of (1% cross-linked polystyrene with 1.25 mmol chloromethyl substitution per gram of dry resin respectively benzhydrylamine polymer (1% cross-linked polystyrene with 0.24 mmol NH2 per gram of dry resin, Bio-Rad Laboratories (Richmond, CA, USA). 

For the hydrolysis of peptides linked to resins, the release of the C-terminal amino acid is strongly dependent upon the type of resin and amino acid residue. For this purpose the use of propanoic acid/12M HC1 (1 1 )[6 is recommended. More studies, however, indicate hydrolysis with TFA/12M HC1 (1 3) at 160°C is more appropriate since quantitative release of the most stable Phe residue from benzhydrylamine- (BHA-), 4-methylbenzhydrylamine-(pMeBHA-), and 4-(hydroxymethyl)phenylacetamidomethyl-resins occurs in 20, 6, and 5 h, respectively, compared to the 30,18, and 18h required with propanoic acid/12M HC1 (1 1)) ... 

Unsubstituted azetidine is synthesized on the kilogram scale by the condensation of 1-bromo-3-chloropropane with benzhydrylamine to give 1-benzhydrylazetidine followed by hydrogenolysis and basic workup (Scheme 18) (88SC205). 

Azetidine-2-carboxylic acid (2) is commercially available. It is readily prepared as the racemate by refluxing 2,4-dibromobutyric acid ester with benzhydrylamine in acetonitrile. If benzyl 2,4-dibromobutyrate is treated with benzhydrylamine, the resulting benzyl TV-benz-hydryl-D,L-azetidine-2-carboxylate is hydrogenolytically processed to D,L-azetidine-2-car-boxylic acid in a one-step reaction. 101,107 Resolution of the racemate can be performed by the method of Vogler 108 via fractional crystallization of the Z-D,L-Aze-OH-H-Tyr-N2H3 salt thereby the salt of the D-imino acid precipitates first from methanol. 96 A stereoselective synthesis of A-tosyl-L-azetidine-2-carboxylic acid can be achieved by a two-step reaction from N-tosyl-L-homoserine lactone. 94 ... 

A better, higher yielding approach for the preparation of templates attached to different peptides employs a combination of solid-phase and solution-phase couplings (Scheme ll).121 A peptide chain is synthesized on a low-loading benzhydrylamine resin and reacted with a bifunctional electrophile such as the bis(pentafluorophenyl) ester 4 (R1 = Pfp) (low resin... 

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. 

Benzhydrylamines are better suited than benzylamines as acid-labile linkers for amines. The MBHA linker ( methylbenzhydrylamine ), which is usually used to prepare peptide amides (see Section 3.3), can also be used as a linker for amines (Entry 1, Table 3.21). Hydrogen fluoride is, however, required as the cleavage reagent. Easier to cleave are alkoxy-substituted benzhydrylamines (Entries 2-5, Table 3.21), which can be prepared from the corresponding benzhydryl chlorides [263] or by reductive alkylation [410] or solvolysis [411] of the Rink amide linker. In the case of benzhydrylamines linked to polystyrene as benzyl ethers, treatment with TFA can lead to the release of the linker into solution (acidolysis of the benzylic C-O bond, see Figure 3.18). 

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.

Table 3.25. Benzylamine and benzhydrylamine linkers for aromatic amines.

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