C oxidative cyclizations

Arcyria pigments (bisindolylmaleimides and in-dolo[2,3-a]carbazoles). The tiny fruit bodies of the slime molds Arcyria denudata, A. nutans, and related myxomycetes contain indole pigments of the bisindol-ylmaleinimide type. Parent compounds are the red ar-cyriarubins A, B, and C. Oxidative cyclization in the 2,2 -position furnishes the pale yellow and poorly soluble arcyriaflavins A, B, and C (table I). Indolocarba-zoles of this type are also known as active principles from streptomycetes ( rebeccamycin). 

Benzo[2,l ]thiazolo[2,3-c][l,2,4]triazines [CsNS-CsNs-C ].—Oxidative cyclization of 3-(o-amino-aryl)-2-imino-4-phenyl-AMhiazolines (117) with A -bromo-succinimide gives the corresponding 9/f-benzo[2,l-c]thiazolo[2,3-c][l,2,4]-triazine. ... 

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. 

Retrosynthetic path e in Scheme 2.2 requires a regioselective oxidation of an o-nitrostyrene to the corresponding phenylacetaldehyde. This transformation has been accomplished hy Wacker oxidation carried out in such a way as to ensure the desired regioselectivity. The required o-nitrostyrenes can be prepared by Heck vinylation. One procedure for oxidation uses 1,3-propaiiediol to trap the product as a l,3-dioxane[15]. These can then be hydrogenated over Rh/C and cyclized by treatment with dilute HCl,... 

The bromo substituent in l-bromo-19-meLhyl-l,l9-dideoxybiladienes- c is not essential for porphyrin formation. When 1-methylbiladiene-ac dihydrobromide or the 1,19-dimethyl-biladienc-ac are heated in refluxing methanol or dimethylformamide in the presence of cop-per(II) salts, the porphyrin copper complexes 13 are formed by oxidative cyclization. The free porphyrins can then be obtained by removal of the copper with acid. A wide range of porphyrins 13 can be prepared by this method. However, a restriction is the accessibility of the starting material with special substitution patterns. 

Iodination of 4 with molecular iodine in the presence of mercuric oxide formed the 3-iodo derivative (52JA4951 66CJC2283). Iodine in tetrahydro-furan oxidatively cyclized /3-(3-benzo[b]thienyl)-a-mercaptoacrylic acids rather than iodinating the thiophene ring [70JCS(C)2431]. 

This approach offers unique opportunities for the generation of multi-functionalized cyclic 2-azadiene systems. A wide variation of the substitution pattern at the positions N-1 and C-6 can be determined by an appropriate choice of the aldehyde and amine. Various substituents can easily be introduced at the C-3 position via addition/elimination reactions on the sensitive imidoyl chloride moiety [24]. Upon reaction with bi-functional reagent, an adequately AT-protected 2(lH)-pyrazinone was elaborated into C-nucleoside analogues (Scheme 8). The desired skeleton and functionalities were obtained by oxidation-cyclization reaction followed by photochemical removal of the protective o-nitrobenzyl group [25]. 

Synthesis of thiopheno[3,4-c]isoxazoline is shown in Eq. 4.4, in which the Michael addition of allyl thiol to 3-nitro enones and subsequent nitrile oxide cyclization are involved.7... 

Tao, J., Hu, S., Pacholec, M. and Walsh, C.T. (2003) Synthesis of proposed oxidation-cyclization-methylation intermediates of the coumarin antibiotic biosynthetic pathway. Organic Letters, 5, 3233-3236. 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

Oxidative cyclization of acylhydrazones 110a, derived from aldehydes or ketones, with the use of lead tetraacetate (LTA) has been developed into a useful route to several disubstituted and tetrasubstituted oxadiazole derivatives 122, being a convenient source of relatively stable carbenes, like N(0)C , S(0)C , 0(0)C , or S(S)C <2000J(P1)2161 >. Some representative recent examples of the syntheses are collected in Table 2. 

Type C syntheses are typified by the oxidative cyclization of amidinothiono groups, and this has become the basis of a versatile synthesis of 1,2,4-thiadiazoles. This type of reaction is known for its speed and absence of side reactions. The synthesis of unsymmetrical 3,5-disubstituted-l,2,4-thiadiazoles of unambiguous structure in high yields is possible by this method. 

A plausible mechanism for the cyclotrimerization includes initial oxidative cyclization between the less-hindered alkyne terminus and the ketone carbonyl group to form an oxaruthenacyclopentene intermediate. The insertion of the second alkyne terminus into the C-Ru bond, followed by reductive elimination, affords the 277-pyran compounds. 

A new convergent total synthesis of reserpine (109) has been developed by Martin and co-workers (399). In the first phase of the synthesis they constructed the trisubstituted cis-decahydroisoquinoline 549 as the key intermediate by utilizing a number of stereoselective reaction steps as shown in Scheme C. N-Alkyla-tion with 6-methoxytryptophyl bromide and subsequent oxidative cyclization of 547 resulted in reserpine (109) and 3-epireserpine (514). 

In a series of papers, Itahara established the utility of Pd(OAc)2 in the oxidative cyclization of C- and A-benzoylindoles, and two examples are shown [61-63], Itahara also found that the cyclization of 3-benzoyl-1,2-dimethylindole proceeds to the C-4 position (31% yield) [61]. Under similar conditions, both 1-acetylindole and l-acetyl-3-methylindole are surprisingly intermolecularly arylated at the C-2 position by benzene and xylene (22-48% yield) [64,65],... 

Hill described the Pd(OAc)2-oxidative cyclization of bisindolylmaleimides (e.g., 49) to indolo[2,3-a]pyrrolo[3,4-c]carbazoles (e.g., 50) [69], which is the core ring system in numerous natural products, many of which have potent protein kinase activity [70]. Other workers employed this Pd-induced reaction to prepare additional examples of this ring system [71, 72]. Ohkubo found that PdClj/DMF was necessary to prevent acid-induced decomposition of benzene-ring substituted benzyloxy analogues of 49, and the yields of cyclized products under these conditions are 85-100% [71]. 

An oxidative cyclization leads to the C-N bond formation and furnishes the carbazole nucleus. The three modes of the iron-mediated carbazole synthesis differ in the procedures which are used for the oxidative cyclization [77,78]. 

The total synthesis of the carbazomycins emphasizes the utility of the iron-mediated synthesis for the construction of highly substituted carbazole derivatives. The reaction of the complex salts 6a and 6b with the arylamine 20 leads to the iron complexes 21, which prior to oxidative cyclization have to be protected by chemoselective 0-acetylation to 22 (Scheme 13). Oxidation with very active manganese dioxide followed by ester cleavage provides carbazomycin B 23a [93] and carbazomycin C 23b [94]. The regioselectivity of the cyclization of complex 22b to a 6-methoxycarbazole is rationalized by previous results from deuterium labeling studies [87] and the regiodirecting effect of the 2-methoxy substituent of the intermediate tricarbonyliron-coordinated cyclo-hexadienylium ion [79c, 79d]. Starting from the appropriate arylamine, the same sequence of reactions has been applied to the total synthesis of carbazomycin E (carbazomycinal) [95]. 

Despite many applications of the iron-mediated carbazole synthesis, the access to 2-oxygenated tricyclic carbazole alkaloids using this method is limited due to the moderate yields for the oxidative cyclization [88,90]. In this respect, the molybdenum-mediated oxidative coupling of an arylamine and cyclohexene 2a represents a complementary method. The construction of the carbazole framework is achieved by consecutive molybdenum-mediated C-C and C-N bond formation. The cationic molybdenum complex, required for the electrophilic aromatic substitution, is easily prepared (Scheme 23). 

Ether cleavage of 4-heptyl-3-methylveratrole 121 using boron tribromide affords 4-heptyl-3-methylcatechol 122 (Scheme 38). Oxidation of the catechol 122 with o-chloranil to 4-heptyl-3-methyl-l,2-benzoquinone 123 and subsequent immediate addition of aniline leads to 5-anilino-4-heptyl-3-methyl-l,2-benzo-quinone 124. Unlike the very labile disubstituted ort/zo-quinone 123, compound 124 is stable and can be isolated. Palladium(II)-mediated oxidative cyclization of the anilino-l,2-benzoquinone 124 provides carbazoquinocin C 51. 

The experimental mechanistic study of the anodic cyclization reactions requires values for the variation of the peak potential (Ep) in LSV with the sweep rate (v), the concentration of substrate (C) and the concentration of added base (B). The plots of dEp/dlogv, dEp/dlogC, and dEp/dlogB provide an effective tool for qualitative mechanistic analysis. The diagnostic criteria developed for discrimination between the various possible mechanisms [5] and adopted for oxidative cyclizations are presented in Table 1. 

Our final conclusion was therefore that the mechanism of intramolecular oxidative cyclization of 1,3,5-triphenylformazan to 2,3,5-triphenyltetrazolium perchlorate involves cyclization of the initial radical cation and deprotonation as the rate-determining step, following the mechanistic scheme e-c-P-e. 

Application of the reaction sequence periodate oxidation - cyclization with nitromethane hydrogenation to rt6o-nucleosides provides a general synthetic entry to 3-aminohexosyl p5nimidines i7-20) and purines 21-as) which otherwise are not readily accessible. That this sequence can be extended to nitroethane to give 3 -C-methyl branched aminosugar nucleosides, has been demonstrated, starting from uridine 4.10,26)... 

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