Non-hydrolytic conditions

The methods described in this section are of great significance because of the essentially neutral non-hydrolytic conditions employed. 

Attempts to prepare tricyclic homologues of the naphthyridines have been partially successful. 4-Amino-1,5-naphthyridine (109) reacts under Skraup conditions to give 4,5,9-triazaphenanthrene (110), and 1,8,9-triazaanthracene derivatives (111) can be isolated from the mixtures of products obtained by treatment of 2-amino-l,8-naphthyridin-7-one and its derivatives with ethyl ethoxymethylenemalonate, acetylacetone and alkyl /3-oxoglutarates (72JHC801) (see also earlier papers in that series). However, 2-amino-1,8-naphthyridine (112 R = H) reacts under Skraup conditions to give the 2-oxo derivative (113 R = H) instead of a 1,8,9-triazaanthracene, and 2-amino-1,6-naphthyridine behaves similarly (75MI21103). Under non-hydrolytic conditions, naphthyridines (112 R = Aik, Ar, H) cyclize... 

Wynberg et al. have synthesized the interesting spiro[adamantane-2,l -cyclo-butane-2, 3 -dione] (8) from methyl 2(2-methoxycarbonyladamantyl)acetate (6) by acyloin condensation in the presence of trimethylchlorosilane to give the bis(trimethylsiloxy)cyclobutene derivative (7) in 75% yield. The key step, conversion of (7) into (8), was accomplished under non-hydrolytic conditions by addition of bromine to a solution of (7) in carbon tetrachloride.5... 

The 9-fluorenylmethoxycarbonyl group provides a mode of protection to amines which is stable to acids and catalytic reduction cleavage (Scheme 124) is readily achieved under mild basic, non-hydrolytic conditions, a... 

Non-hydrolytic Protic Reactions. The categorization of non-hydrolytic sol-gel methods may be made difficult by the occurrence of complex mechanisms involving both hydrolytic and non-hydrolytic reactions. Thus the strict definition of non-hydrolytic conditions would preclude reactions in which water may be produced in situ. However, the addition of carboxylic acids to a tetraalkoxysilane is referred to as a non-hydrolytic method, even though it probably involves water formation by esterification (Eq. 26-1) besides non-hydrolytic hydroxylation (Eq. 26-2) and aprotic condensation (Eq. 26-3). 

Non-hydrolytic Aprotic Reactions. Actually, rigorously non-hydrolytic conditions are more surely preserved by the use of aprotic condensation reactions (excluding hydroxyl groups), which involve the elimination of ester, alkyl halide or ether. 

Some tellurium anionic reagents offer a great contribution to these deblocking reactions owing to the use of mild experimental conditions and a non-hydrolytic medium. 

Meyers, with the tricyclic (117) as a starting point, used the reactivity of the quinoline a-methylene to make a dihydropyridone intermediate (118) (Scheme 28). The main difficulties in the synthesis were concerned with the selective release of one protected aldehyde from intermediates such as (119), and unwanted cyclizations such as that [—> (120)] which resulted from treatment of (119) with non-selective hydrolytic conditions. 

The Fmoc group is a lineal descendent of the p-nitroethyl acetates whose base-catalysed elimination by an Elcb mechanism (see section 1.2.6), first propounded by Chattaway in 1936, laid the foundation for the numerous progeny which have been tailored to amino and carboxyl protection. Fmoc groups undergo rapid non-hydrolytic cleavage on treatment with simple bases (ammonia, piperidine, morpholine), usually in polar solvents such as dimethylforma-mide or acetonitrile, to liberate the yV-terminus of a peptide in the free base form. The conditions are mild enough to preclude -elimination in the sensitive O-glycosylserine derivatives [Scheme 8.84].2 Other bases include DBU and TBAF.2 ... 

Decarbalkoxylation with triethylenediamine, l,5-diazabicyclo[4.3.0]non-5-ene (s. Synth. Meth. 29, 963), or 3-quinuclidinol in o-xylene is advantageous in cases where the usual hydrolytic conditions are precluded because of the presence of sensitive moieties, as well as for compds. not soluble in aq. solvents. E., also monodecarbalkoxylation of hindered gem. diesters by triethylenediamine, s. D. H. Miles and B.-S. Huang, J. Org. Chem. 41, 208 (1976) s. a. Synth. Commun. 5, 341 (1975). 

Scheme 12.9 once again shows the details of the reaction conditions and workup. The work-up requires protection of all the remaining amino groups by acetylation, and removal of the TBS group by a non-hydrolytic agent in THF. 

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