Schiff bases, cyclization

The number of methods available for the synthesis of bicyclic systems containing two fused five-membered rings with one bridgehead nitrogen can be summarized in a few general reactions dehydrative ring closure, oxidative Schiff base cyclization, and base-induced closure (Scheme 3). One-pot reactions involving precursor synthesis followed by cyclization are also known. 

The reduction of a nitroketone with H2 and Raney nickel in EtOH directly provided the bridged myosmine (42) (76%), presumably via an intermediate amino ketone which undergoes an intramolecular Schiff base cyclization (Equation (17)) <83JOC492>. 

Pd-cataly2ed reactions of butadiene are different from those catalyzed by other transition metal complexes. Unlike Ni(0) catalysts, neither the well known cyclodimerization nor cyclotrimerization to form COD or CDT[1,2] takes place with Pd(0) catalysts. Pd(0) complexes catalyze two important reactions of conjugated dienes[3,4]. The first type is linear dimerization. The most characteristic and useful reaction of butadiene catalyzed by Pd(0) is dimerization with incorporation of nucleophiles. The bis-rr-allylpalladium complex 3 is believed to be an intermediate of 1,3,7-octatriene (7j and telomers 5 and 6[5,6]. The complex 3 is the resonance form of 2,5-divinylpalladacyclopentane (1) and pallada-3,7-cyclononadiene (2) formed by the oxidative cyclization of butadiene. The second reaction characteristic of Pd is the co-cyclization of butadiene with C = 0 bonds of aldehydes[7-9] and CO jlO] and C = N bonds of Schiff bases[ll] and isocyanate[12] to form the six-membered heterocyclic compounds 9 with two vinyl groups. The cyclization is explained by the insertion of these unsaturated bonds into the complex 1 to generate 8 and its reductive elimination to give 9. 

Pomeranz-Fntsch Synthesis, Isoquinolines aie available fiom the cycUzation of benzalamiaoacetals undei acidic conditions (165). The cyclization is preceded by the formation of the Schiff base (33). Although the yields ate modest, polyphosphoric acid produces product in all cases, and is especially useful for 8-substituted isoquinolines (166). 

A variation involves the reaction of benzylamines with glyoxal hemiacetal (168). Cyclization of the intermediate (35) with sulfuric acid produces the same isoquinoline as that obtained from the Schiff base derived from an aromatic aldehyde and aminoacetal. This method has proved especially useful for the synthesis of 1-substituted isoquinolines. 

Aldehydes. Alkyleneamines react exothermically with ahphatic aldehydes. The products depend on stoichiometry, reaction conditions, and stmcture of the alkyleneamine. Reactions of aldehydes with ethyleneamines like EDA or DETA give mono- and disubstituted imidazohdines via cyclization of the intermediate Schiff base (20). 

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

Cyclization of the 3-(2-aminoethyl)-l,2,4-triazoles 60 with aromatic aldehydes gave a mixture of the corresponding Schiff bases 61 and the 5,6,7,8-tetrahydro-l,2,4-triazolo[l,5-c]pyrimidines 62. Cyclization of 60 with car-bonyl-1,1 -diimidazole (CDI) afforded the 5-oxo analogs 63 (92JPR630) (Scheme 22). 

The 8-hydroxy-7-aminoquinoline-5-sulfonic acid was used to clarify the role of intramolecular hydrogen bonding on the cyclization rate of hydroxy Schiff bases in the preparation of 2-aryloxazolo[4,5-/i]quinoline-5-sulfonic acids 13. Irradiation... 

Phthalide enolates 4 add to Schiff bases to produce intermediate adducts 5 which cyclize to mixtures of cis- and Rcws-isoquinolones 6 and 724. The er.y-product predominates consistently by — 2 1 over a series of nonenolizable arylintines. 

The Ru-Schiff base complex (95) with the cis-[3 structure serves as a good catalyst for the cyclization of E- and tri-substituted allyl diazoacetates (Scheme 83).262... 

The excellent reducing properties of potassium tetracarbonylhydrido-ferrate have been used to good effect in providing an efficient general piperidine synthesis from alkyl and aryl amines and glutaraldehyde210 (Scheme 138). The reaction probably proceeds via reduction of intermediate Schiff bases and cyclization via the iminium salt. 

Likewise, Schiff bases of type 379 react with triafulvenes again (see p. 75) via the tautomeric vinylamine form to give products of C—C-insertion 253. In the presence of a COOR group at triafulvene C4, the cross-conjugated system 536 undergoes facile cyclization to 2-pyridones 537 by loss of alcohol. 

Other template cyclizations. In another Schiff-base template reaction, 1,3-diaminopropane monohydrochloride was reacted with biacetyl in methanol in the presence of Ni(n) to yield the nickel complex of the corresponding cyclic tetraimine - see [2.16] (Jackels et al., 1972). The success of the procedure illustrated is quite dependent on the reaction conditions employed. Attempts to isolate the metal-free macrocycle were unsuccessful - this once again emphasizes the stabilizing role of the metal... 

Cyclization of histidine -pyridoxal Schiff base Reverse micelles affect relative rates of the first and second steps of cyclization Sunamoto et al., 1983b... 

The Schiff base derivatives 73 of the 3-hetaryl-substituted 4-amino-3-thiol-l,2,4-triazoles, on treatment with acetic anhydride, undergo cyclization to give the corresponding 3-substituted-5-acetyl-5,6-dihydro-6-phenyl[l,2,4]triazolo[3,4-7][l,3,4]thiadiazoles 76 (Equation 16) <1990IJB135>. Similar treatment of 4-(A-bcnzoylamino)-4,5-dihydro-l-methyl-3-mcthylthio-1 //-[ 1,2,4 triazolc-5-thione 77 leads to the [l,2,4]triazolo[3,4-4][l,3,4]thiadiazolium trifluoromethanesulfonate 78 (Equation 17) <1986LA1540>. 

The most common cyclization reactions in drug metabolism proceed with elimination of a H20 molecule. These reactions produce lactams, lactones, cyclic Schiff bases, and even more-complex metabolites. 

The pyrimidine 46 was obtained from methyl /3-alaninate after cyclization with an isourea derivative (90T7803) and when the ester was transformed into the amide and Schiff base was cyclized with benzoic anhydride, the result was a racemic substituted perhydropyrimidin-4-one (91JOC2553). 

The cyclizations of cis- and lrans-2-hydroxymethyl-l-cyclohexylamine and cis- and lram-2-aminomethyl-l-cyclohexanol with 4-nitrobenzaldehyde have been studied by means of H NMR spectroscopy in CDCI3 solution (90ACSA364 91T2229). The time-dependent spectra confirmed that the reactions of all these amino alcohols proceeded via Schiff bases. With the exception of cis-2-hydroxymethyl-l-cyclohexylamine, the thermodynamically more stable perhydrobenzoxazine epimer is also the kinetically favored product. In the former case, from amino alcohol 21 (R = H), the Schiff base 37 with N-outside predominant conformation is formed first due to kinetic control, the less stable epimeric ring form 38 is obtained with N-outside predominant conformation. The thermodynamically controlled product 33 is formed subsequently, via the less stable open-chain form 37, in a slow equilibration process (90ACSA364). 

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