Exocyclic

Figure 10.3-40. The rating for the disconnection strategy carbon-heteroatom bonds is illustrated, Please focus on the nitrogen atom of the tertiary amino group. It is surrounded by three strategic bonds with different values. The low value of 9 for one ofthese bonds arises because this bond leads to a chiral center. Since its formation requires a stereospecific reaction the strategic weight of this bond has been devalued. In contrast to that, the value of the bond connecting the exocyclic rest has been increased to 85, which may be compared with its basic value as an amine bond.

Thompson points out that there is no evidence that adducts give other than acetates on thermolysis. The exocyclic methylene intermediate (iv) postulated by Robinson could arise by proton abstraction from a Wheland intermediate analogous to (vll) above, rather than from the adduct (in). Similarly its decomposition does not necessarily require the intermediacy of the adduct (v). The fact that i -methyl-4-nitromethylnaphthalene is the product even when the nitrating medium is nitric acid and nitromethane would then require no separate explanation. 

The N-basicity of the commonly used amines (pyrrolidine > piperidine > morpholine) drops by 2-3 orders of magnitude as a consequence of electron pair delocalization in the corresponding enamines. This effect is most pronounced in morpholino enamines (see table below). Furthermore there is a tendency of the five-membered ring to form an energetically favorable exocyclic double bond. This causes a much higher reactivity of pyrroUdino enamines as compared to the piperidino analogues towards electrophiles (G.A. Cook, 1969). 

Palladium catalyzed cycloisomerizations of 6-cn-l-ynes lead most readily to five-membered rings. Palladium binds exclusively to terminal C = C triple bonds in the presence of internal ones and induces cyclizations with high chemoselectivity. Synthetically useful bis-exocyclic 1,3-dienes have been obtained in high yields, which can, for example, be applied in Diels-Alder reactions (B.M. Trost, 1989). 

The exocyclic 1,3-dioxolane ring is much more vulnerable to acid hydrolysis than the ring connected with the acetal group. Partial deprotection of the side-chain is easily achieved by treatment with sulfurie acid. 

Various terminal allylic compounds are converted into l-alkenes at room temperature[362]. Regioselective hydrogenolysis with formate is used for the formation of an exo-methylene group from cyclic allylic compounds by the formal anti thermodynamic isomerization of internal double bonds to the exocyclic position[380]. Selective conversion of myrtenyl formate (579) into /9-pinene is an example. The allylic sulfone 580 and the allylic nitro compound... 

J lie decarboxylation is frequently the most troublesome step in this sequence. Attempts at simple thermal decarboxylation frequently lead to recycliz-ation to the lactam. The original investigators carried out decarboxylation by acidic hydrolysis and noted that rings with ER substituents were most easily decarboxylated[2]. It appears that ring protonation is involved in the decarboxylation under hydrolytic conditions. Quinoline-copper decarboxylation has been used successfully after protecting the exocyclic nitrogen with a phthaloyl, acetyl or benzoyl group[3]. 

H transfer from the methyl to the exocyclic nitrogen of the acetamido group. 

With the more acidic 2-acetamido-4-R-thiazoles. using the weaker base NaOH as condensation agent, a mixture of ring (45) and exocyclic N-alkylation (46) may be observed (Scheme 33) (121). Reaction of 2-acetamido-4-methylthiazole in alcoholic sodium ethoxide solution with a variety of alkylating agents has been reported (40-44). 

Use of aprotic solvents increases the quantity of exocyclic N-alkylation the potassium salt of A -(2-thiazolyDcaTbamate heated in DMF with 2-phthalimidoethyl bromide gives predominantly exocyclic N-alkylation (70% 47a, 30% 47b) (Scheme 34) (131). 

The nature of the substituent on the exocyclic nitrogen also influences the ambident activity of anion 48 in DMF (Scheme 35) when R is an heterocyclic ring, nitrogen alkylation predominates (189) when R is a methylamino group, a mixture of the two isomers is reported (190) when... 

Nitraminothiazoles are sufficiently acidic to be alkylated by diazomethane the methyl substituent is introduced on the exocyclic nitrogen (194). When sulfathiazole is methylated with diazomethane in ether, a mixture of ring-methylated and amino-methylated products is obtained, the ratio being 30 70 (85). With anion 31 (R = p-NO CsH4SO -) the ratio becomes 15 85 (195). 

Reactions of the 2-amino-4,5-substituted thiazole (52) in acetic acid with ethylene oxide has been reported to give the N-exocyclic disubstitution product (S3) (201) in a 40% yield (Scheme 38). The reactive species in this reaction is probably the carbocation generated in acetic acid by ethvlene oxide. 

All the examples of reactivity in acidic medium (Scheme 40) involve a reagent with a sp C hybridized electrophilic center, but the actual reactive species generated bears a sp C electrophilic center. In this case, exocyclic N-alkylation is not surprising (see Section III.2). 

If the medium is sufficiently basic to generate the arabident anion 31. mixtures of products resulting from N-nng and N-exocyclic reactivity are observed. Here again steric effects can preferentially orient the whole reaction toward one of the two nitrogens. A general study clearly delineating the rules of behavior for 31 accordine to the nature of R. the... 

The exocyclic nitrogen atom is involved when 2-aminothiazoles and aromatic aldehydes react under mild conditions yielding 61 (Scheme 42)... 

Both carbonyl groups of terephthaldehyde are reported to react with the exocyclic nitrogen of 2-aminothiazole yielding 1.4-phenylene bis(2-methyleneamino)thiazole. The same report describes the reactions of 2-amino-4-phenylthiazole with terephth aldehyde and salicylaldehyde as yielding 64 and 65, respectively (Scheme 45) (215), whose structures are based on ultraviolet and infrared spectra. 

The metabolite of 2-amino-4-phenylthiazole (used as an anaesthetic for fish) was identified (223) as 2-amino-4-phenylthiazole 2-N, -d-glucopyranosiduronic acid (71) (Scheme 50). The formation of this compound probably involves the reaction of the exocyclic nitrogen on the Open-chain form of the acid. The isolation of this metabolite is part of a very Systematic study by Japanese researchers related to the anaesthetic... 

Small amounts of salt-like addition products (85) formed by reaction on the ring nitrogen may be present in the medium. (Scheme 60) but. as the equilibrium is shifted by further reaction on the exocyclic nitrogen, the only observed products are exocyclic acylation products (87) (130. 243. 244). Challis (245) reviewed the general features of acylation reactions these are intervention of tetrahedral intermediates, general base catalysis, nucleophilic catalysis. Each of these features should operate in aminothiazoles reactivity. 

Benzoyl chloride and derivatives acylate 2-amino-4-aryithiazoles in dioxane in yields of 80 to 90% (249, 250). The location of the acyl group on the exocyclic N has been demonstrated by the fact that the benzoyla-tion product is identical to the benzamidothiazole synthesized from benzamide and 2-bromothiazole (251). 3-Indolyl acetic acid chloride (89) acylates 2-aminothiazole in pyridine (Scheme 62) (81). 

Zugravescu et al. (263) showed that ethyl chloroformate reacts on the exocyclic nitrogen of 2-amino-4-methylthiazole to yield the carbamate (101) (Scheme 70) (see also Refs. 264 and 265). With an excess of chloroformate (2 moles for one of the thiazole) under Schotten-Bauman conditions the jV.A -dicarbamate of 2-imino-4-methylthiazoline (102) is obtained (263),... 

The exocyclic nitrogen is reactive even when already substituted 2-anilinothiazole (110) is acetylated by acetic anhydride (120). other examples of this reactivity are given in the tables (Section VII). 

Acetylation of 2-phenyl-4-amino-5-benzoylthiazole takes place on the exocyclic nitrogen (49). This exocyclic nitrogen remains the reactive center even with 2-imino-3-aryl-4-amino-5-carboxamido-4-thiazoline (111). Its acetylation with acetic anhydride gives the 4-acetamido derivative (112), which reacts further on heating to yield 2-(acetylimino)-(3H)-3-aryl-5-methylthiazolo[4,5-d]pvrimidin-7-(6H)-one (113) (Scheme 76) (276). 

Vollmann found that the reaction between l-imino-3-amino isoin dolenine (124) and 2-amino-4-methylthiazole is catalyzed by ammonium chloride and involves the exocyclic nitrogen (285). This reaction (Scheme 82) was later used to prepare dyes (286). 

Picryl halides react with 2-amino-4-methylthiazole. Again, the exocyclic nitrogen is the reactive center (288). and the product formed (128) is... 

The high reactivity of the exocyclic 4-NH- group is again illustrated by the reaction of 2-imino-3-phenyl-4-amino-5-(ethoxycarbonyl)-4-thiazoline with EtOjCCH SCN, which yields 134 (296), and by the intramolecular preparation of the dihydrothiazolo[4,5-h]pyridine derivative 136 (297) (Scheme 89). 

Scheme 91). Yamamoto et al. have shown unambiguously that the reaction takes place on the N-exocyclic atom (303). 

Treatment of 2-imino-3-phenyl-4-amino-(5-amido)-4-thiazoline with isocyanates or isothiocyanates yields the expected product (139) resulting from attack of the exocyclic nitrogen on the electrophilic center (276). Since 139 may be acetylated to thiazolo[4,5-d]pyrimidine-7-ones or 7-thiones (140). this reaction provides a route to condensed he erocycles (Scheme 92). 

The exocyclic nitrogen is more reactive toward the sp-C (.A) than toward the sp C. but selectivity is lower than in the case of the ring nitrogen. 

The exocyclic nitrogen is slightly more reactive toward the electrophilic center A than is its ring counterpart. 

Butler recently reviewed the diazotization of heterocyclic amines (317). Reactions with nitrous acid yield in most cases N-exocyclic compounds. Since tertiary amines are usually regarded as inen to nitrosation, this... 

The reasons for this apparent polywalent activity toward nitrosation (N ring reaction, N exocyclic reaction, nitrosation on the 5-position) are not... 

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