Tert-amino effect

An ingenious method for the construction of the pyridine ring based on the tert-amino effect was used (1990RTC481) in the synthesis of a series of [3,2-Z>]-annu-lated thienoazines. Prolonged refluxing of diene aminodinitriles 166 in butanol affords thieno[3,2-Z>]indolizines and thieno[2,3-e]quinolizines of general formula 167. 

Thermolysis of 3-(2,2-dicyanovinyl)-4-(l-piperidyl)pyridine (15, X = CH2) in DMSO produces the naphthyridine (16, X = CH2) by means of the "tert-amino effect" proposed by Meth-Cohn and Suschitzky <95SL622>. Where, however, X is a N, O or S an alternative cyclisation takes place, when the pyridoazepines (17) are formed. This new variant of the "rert-amino effect" is postulated to arise by the intermediate formation of (18). 

Significant improvements in the synthesis of pyrido-fused heterocycles were achieved when the reaction was performed under solvent-free conditions and applying the tert-amino effect as the key ring-closure method [183]. It was shown, as depicted in Eq. (91), that MW can improve the reaction yield under similar sets of conditions compared with A heating. When extending the reaction time, as often quoted, nearly quantitative yields were obtained, irrespective of the mode of activation. The specific MW effect observed here is consistent with the proposed polar mechanism for the cyclization [184],... 

The development of a cost-effective microwave-assisted procedure for synthesis of pyrido fused-ring systems, by applying the tert-amino effect, has been described by Van der Eycken and coworkers (Scheme 10.62) [126]. 

C(sp )-H Bond Adjacent to TV/t-Amino Moieties as Hydride Donor (tert-Amino Effect)... 

Scheme 27 Synthesis of 7,8,9-trisubstituted dihydropurine derivatives via tert-amino effect...

The ten membered N-heterocycles have also attracted a lot of interest due to their structural appearance with various biologically interesting molecules like the alkaloid Dysazecine (Aladesanmi et al., 1983), Protopine (Xiao et al., 2008) (a potent antimalarial lead compound) as well as the nanomolar dopamine receptor antagonist LE300 (Mohr et al., 2006). Dunkel et al. (2010) reported a straight forward, microwave-assisted synthesis of tribenzo[b,d,f]- and pyridazino[d]dibenzo[b,f] azecines, employing the tert-amino effect. The desired compounds were furnished via an open-vessel microwave-assisted cyclization of corresponding triphenyl intermediates at 100-200 °C for 2-150 min. 

Figure 3. Effect of solvent on the reduced viscosity-concentration plots for a,cu -quaternary ammonium chloride-PMS at 25 C ( ) toluene, (A) THF, ( ) DMF and ( ) non-quaternized a,w -di tert-amino PMS in DMF.

Unfortunately, as none of these catalysts induced useful levels of selectivity in the KR of secondary aryl alkyl alcohols. Miller et al. set out to identify specific peptide-catalysts for specific applications using automated peptide synthesis and high-throughput fluorescent screening. This allowed them to unveil some particularly effective catalysts for various transformations such as the KR of an intermediate in the synthesis of aziridomitosane [22h, k], the KR of a series of tertiary alcohols [22i], the regioselective acylation of carbohydrates [22k], and the KR of N-acylated tert-amino alcohols [22ij. 

Trichloromethyl chloroformate has proven effective in the preparation of N-carboxy-a-amino acid anhydrides from amino acids, and various compounds having isocyanate, acid chloride, and chloroformate groups.For example, trichloromethyl chloroformate may be used instead of phosgene in the preparation of 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile. The use of this reagent is illustrated here by the synthesis of 3-isocyanato-propanoyl chloride from 3-aminopropanoic acid hydrochloride. 

Racemic cw-l-amino-2-phenylcyclohexanecarboxylic acid 693 can be prepared by Diels-Alder reaction of (Z)-4-benzyhdene-2-phenyl-5(47/)-oxazolone 621 and butadiene in an analogous manner. Coupling A-tert-butyloxycarbonyl-L-proline with 693 yielded diastereomeric dipeptides that were separated chromatographi-cally. The behavior of the individual dipeptides was studied as a means to effect p-tum modulation by such cyclohexane analogues of phenylalanine. ... 

The authors proposed a chelating transition state model to explain these results (Fig. 8.14). The thermodynamically more stable intermediate resulting from initial lithium amide addition should have the amino group on the face opposite to the bulky tert-butyl group. Due to the same steric effect, the HMPA ligand should also occupy a position on the p face. The electrophile approaches the enolate from the ot face and gives the trans product. For bulky amines, either the aza enolate does not form due to severe steric hindrance or the aza enolate is inactive for the same reason. 

In order to demonstrate the effect, it was felt that cleaner kinetic data was needed. This was secured by modification of the participants in the cycloaddition. A tertiary butyl group was introduced onto the amino nitrogen of each substrate (Fig. 7, R = t-Bu). This renders the reaction noncatalytic in the strict sense. Because the tert-hutyl substituents are too large to pass through the cavity of cucurbituril, the resulting product of cycloaddition is a stable rotaxane, i.e. the triazole cannot dissociate. However, this is desirable in that the chemically meaningful presteady-state phase becomes delineated in a way that could only be incompletely realized in the previous kinetics. As a bonus the undesirable substrate inhibition by propargylammonium ion, which also obscured earlier kinetic measurements, could be avoided as well. 

Reduction of acid halides with lithium tri-tert-butoxyaluminum hydride is an effective method for synthesis of amino aldehydes. Nonfunctionalized amino aldehydes 22 are readily prepared from respective reduction of the N-terminal Fmoc, Boc, or Z acid chlorides or fluorides 21 (Scheme 8, Table 9). This method afforded these aldehydes in about 60% yield with small differences in optical rotation as compared to literature values 11,33 48 54 55 ... 

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