Amide cyclisation

Amides cyclise directly to ketones such as 80 the carbamates on the other hand pass through a cyclic transition state which collapses to an amide 82 (an anionic ortho-Fries rearrangement - section 2.3.2.1.4) which lactonises to 83. 

Epoxides will also capture organolithiums formed by deprotonation, notably cyclopropyllithiums and ortholithiated tertiary amides. Ortholithiated amides cyclise regioselectively in a valuable route to benzofurans such as 142 and 143 and (less efficiently) benzopyrans 144.70... 

Attempted catalytic asymmetric amide cyclisations analogous to those of Lee and Hartwig [193] proved the high activity of these palladium catalysts, but the chiral resolution was again low (9% ee) [192]. 

A synthesis of 5-(aioylamino)-2-aryloxazoles 39 is outlined in Scheme 9. Heating the glycol 37 (Bt = benzotriazol-l-yl), prepared from glyoxal and benzotriazole, with an amide in the presence of an ion exchange resin yields the acylated diamine 38, which cyclises by the action of sodium hydiide in DMF <95JHC1651>. 

Tin and HCl reduce out the ben/.ylic OH from (43) in high yield.The Mannich base (45) decomposes to (41) simply on heating. Cyanide addition gives (46) which can be hydrolysed to (40), but a short cut is to hydrolyse to amide (47) and reduce out the carbonyl group by the Clemmensen method (Table T 24.1). Under these conditions the amide is hydrolysed to the acid. Cyclisation to (38) occurs with strong acid, acid anhydrides, or by AlClg-catalysed reaction of the acid chloride. 

The analgesic and anti-inflammatory Indoprofene (42) can be made by several routes, two of which involve cyclisations. Treatment of phthalic anhydride with amino acid (43) gives imide (45) in one step - the cyclisatlon of (44) must be faster than the inter-molecular reaction by which it is formed. Reduction of (45) give.s Indoprofene as the reactive imide is easily reduced as far as the unreactive amide. 

In 2003, Livinghouse et al. also reported that chelating bis(thiophosphonic amidates) complexes of lanthanide metals, such as yttrium or neodymium, were able to catalyse intramolecular alkene hydroaminations. These complexes were prepared by attachment of the appropriate ligands to the metals by direct metalation with Ln[N(TMS)2]3- When applied to the cyclisation of 2-amino-5-hexene, these catalysts led to the formation of the corresponding pyrrolidine as a mixture of two diastereomers in almost quantitative yields and diastereos-electivities of up to 88% de (Scheme 10.81). 

In general for the C20 series, maximal activity is achieved with amides of arachidonic acid (1) [81], mead acid (199) [149], and dihomo-y-linoleic acid (200) [150] (see Table 6.18). Decreasing the unsaturation (201), (202), or abolishment of the n-pentyl chain (203) [150] led to less active or inactive compounds. Variable results were seen with longer chains. The C22 4 n-6 analogue (204) is as active as AEA (1) whereas the C22 6 n-3 analogue (205) is less active than the C20 5 n-3 analogue (203) [150]. Replacement of the double bonds with triple bonds (206) resulted in loss of activity [150] (see Table 6.18). Forcing the fatty acid chain into a hairpin conformation by cyclisation (207) also resulted in inactive compounds [151]. 

Five approaches to the synthesis of 5-amino-4-unsubstituted imidazoles (96) have been described and are summarized in Scheme 9. These are (a) reduction of 5-nitroimidazoles (97), (b) hydrolysis of carbamates and amides (98), (c) decarboxylation of imidazole carboxylic acids (99), (,d) ring transformations of 5-aminothiazoles (100), and (e) cyclisation of nitrile derivatives (101). 

Cyclisation of an NH amide toward a cyclic thionium ion was described for the synthesis of a tetrahydropyrrolo-[l,2-tf]pyrimidine-2,6(l//,7//)-dione 351. Compound 349 was transformed to 351 in two steps. The first one is the formation of a transient alkylthio-substituted lactam 350 from amidothioacetal 349 in the presence of dimethyl-(methylthio)sulfonium tetrafluoborate (DMTSF) followed by intramolecular cyclization <2000JOC235>. 

Alkyl oxazoline-5-carboxylates 71, precursors of P-amino-a-hydroxycarboxylic acids, have been produced by iodocyclisation of alkyl 3-benzamidocatboxylates 70. The oxazolines can be resolved enzymatically <99SL1727>. The amides 72 are cyclised to N-aryloxazolium salts 73 by fluoroboric acid <99EJ0297>. 

Titanium chloride catalysed cyclisation of the methoxylated amide 17 is highly dependent upon the nature of the substituent R <99TL7939>. If R = Me cyclisation to the 6,6 system 18 occurs, but the merest hint of an electron withdrawing character results in a different path for the reaction ending in the formation of the 7,6 system 9 (Scheme 3). 

The amide [Sm(45a) N(SiMe3)2 ] was a catalyst for an aUene-based hydroamination/ cyclisation. As an illustration, one such product upon hydrogenation yielded a naturally occurring alkaloid. Scheme 4.8. " " The same samarium(lll) amide was also active for the intramolecular hydrophosphination/cyclisation of phosphino-alkenes or -alkynes e.g., H2P(CH2)3C=CPh was transformed into 76. " ... 

VIII. Asymmetric cyclisation with chiral lithium amides 79... 

I managed to convince chemists at Merck Sharp and Dohme in Harlow that this new reaction was worth investigating further, and in collaboration with them I appointed my second PhD student, Anjum Ahmed, to work on this project. We quickly established that the cyclisation is a general reaction of /V-benzyl amides,29,30 along with some allyl-substituted amides.31 Naphthamides29 such as 11 were easier to... 

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