Oxidative cyclization transformation

The initially proposed mechanism [14], and one that continues to be considered as the likely pathway for most variants, involves the oxidative cyclization of a Ni(0) complex of an aldehyde and alkyne to a metallacycle (Scheme 18). Metallacycle formation could proceed independently of the reducing agent via metallacycle 19, or alternatively, metallacycle 20a or 20b could be formed via promotion of the oxidative cyclization transformation by the reducing agent. Cleavage of the nickel-oxygen bond in a o-bond metathesis process generates an alkenyl nickel intermediate 21. In the variants involv-... 

Syntheses of this type have been reported only recently (78H(9)1367, 79JOC3524). Unsaturated 1,4-dioximes are transformed by oxidative cyclization into pyridazine 1,2-dioxides... 

The [4+ 4]-homolog of the [4 + 2]-Alder-ene reaction (Equation (48)) is thermally forbidden. However, in the presence of iron(m) 2,4-pentanedioate (Fe(acac)3) and 2,2 -bipyridine (bipy) ligand, Takacs57 found that triene 77 cyclizes to form cyclopentane 78 (Equation (49)), constituting an unprecedented formal [4 + 4]-ene cycloisomerization. The proposed mechanism for this transformation involves oxidative cyclization followed by /3-hydride elimination and reductive elimination to yield the cyclized product (Scheme 18). 

An efficient synthesis of ( )-yohimbine has been published by Stork and Guthikonda (222). Reaction of the pyrrolidine enamine of A-methylpiperidone with methyl 3-oxo-4-pentenoate gave 411 in good yield. Reduction of 411 with lithium in liquid ammonia furnished trans-TV-methyldecahydroisoquinolone 412. This building block was transformed in simple reaction steps to secoyohimbane 413 from which ( )-yohimbine could be obtained by oxidative cyclization with... 

A new multistep synthesis of ( )-reserpine (109) has been published by Wender et al. (258). The key building block of the synthesis is cw-hexahydroiso-quinoline derivative 510, prepared by the extension of the previously elaborated (259) Diels-Alder addition-Cope rearrangement sequence. Further manipulation of 510 gave 2,3-secoreserpinediol derivative 512, which already possesses the required stereochemistry in ring E. Oxidative cyclization of 512 yielded 3-isoreserpinediol (513), which was transformed by the use of simple reaction... 

Pyrrole rings frequently serve as precursors to indole rings [37] and PdCl2 induces the oxidative cyclization of pyrrole 37 to a mixture of 38 and 39 [38]. Since the oxidation of tetrahydroindoles to indoles, such as 38 to 39, is usually straightforward, this transformation can be viewed as a novel and efficient indole ring synthesis. 

The same authors reported in a later study <2000H(3)69> that pyrazinone 340 is also a suitable starting material for a such transformation. The reaction proceeds in two steps the starting pyrazinone 340 when treated with benzonitrile oxide yields an addition product 341 which undergoes oxidative cyclization in the presence of iodine-potassium iodide to the ring-closed [l,2,4]oxadiazolo[4,5-tf]pyrazines 342. 

A novel Ni(cod)2-catalyzed allene/alkene cyclization has been utilized in the synthesis of (-)-a-kainic acid (Scheme 16.88) [96], A stereocontrolled metallacycle would be generated via coordination of Ni(0) species to both an alkene of the enone and a proximal allenyl double bond followed by oxidative cyclization of the Ni(0) complex. The metallacycle would be transformed into the product through transmetallation of Me2Zn and ensuing reductive elimination. 

A two-step transformation of conjugated dienes into non-conjugated ones was proposed for the synthesis of the difficult to-obtain lapachol (355) (a member of a class of antimalarial agents having an activity against the Walker carcinosarcoma 256) from the more available isolapachol 352183. This method consists in an oxidative cyclization of isolapachol 352 by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to form a mixture of the products 353 and 354 (equation 127). Treatment of this mixture with dilute acid in... 

The molybdenum-mediated arylamine cyclization was also applied to the total synthesis of pyrano[3,2-a]carbazole alkaloids (Scheme 26). Reaction of the 5-aminochromene 71 with the complex salt 62 affords the complex 72, which on oxidative cyclization provides girinimbine 73, a key compound for the transformation into further pyrano[3,2-a] carbazole alkaloids. Oxidation of 73 with DDQ leads to murrayacine 74, while epoxidation of 73 using meta-chloro-perbenzoic acid (MCPBA) followed by hydrolysis provides dihydroxygirinim-bine75 [113]. 

The oxidative cyclization of Ar,Ar-diarylamines to carbazoles has been achieved by thermal or photolytic induction [7, 75]. However, the yields for this transformation are mostly moderate. Better results are obtained by the palladium(II)-mediated oxidative cyclization of Ar,Ar-diarylamines (Scheme 27). Oxidative cyclization by heating of the Ar,Ar-diarylamines 76 in the presence of a stoichiometric amount of palladium(II) acetate in acetic acid under reflux provides the corresponding 3-substituted carbazoles 77 in 70-80% yield [118]. The cou-... 

Scheme 29 describes a plausible mechanism for the formation of the products which fit the observed coulometric (n 0.45 F/mol) and preparative results. The intramolecular cyclization process involves a dimerization between a radical cation 52a and the ketene imine 52 to form the intermediate radical cation 52b which then cyclizes to the radical 52c which can abstract a hydrogen atom leading to 54 or can be further oxidized and transformed through a cyclization and deprotonation reaction to 53 which involves 1 F/mol. However, it seems that the [2 -1- 3]-cycloaddition between the parent compound 52 and the cation 52d giving rise to 55 is the fastest reaction as compared with the intramolecular cyclization of 52d to 53. This can also explain the low consumption of electricity. 

Pyrroles can also be obtained from aminocrotonates by oxidation. The transformation is actually a dimerization resulting from a two-electron oxidation of the enamine (Scheme 12) (83T793). 1,4-Addition of nitrometh-ane to the vinilogous ester of A A in presence of l,8-diazabicyclo[5.4.0]un-dec-7-ene (DBU) gave a 1 1 diastereomeric mixture of adducts which, upon reduction, spontaneously cyclized into a mixture of pyrrolidinones, formed in a ratio of 8 2 (Scheme 13) (93TL7529). 

Starting from acylated 2-azidomethylbenzimidazoles (145), an additional imidazole ring can be condensed by transformation of the azido group with tri-n-butylphosphane into the appropriate iminophosphorane intermediate 146. After extrusion of phosphane oxide, cyclization occurs to the 1-substituted 4//-imidazo[l,5-a]benzimidazole 147 (Scheme 58) (89T1823 94S1197). 

Tricarbonyliron-coordinated cyclohexadienylium ions 569 were shown to be useful electrophiles for the electrophilic aromatic substitution of functionally diverse electron-rich arylamines 570. This reaction combined with the oxidative cyclization of the arylamine-substituted tricarbonyl(ri -cyclohexadiene)iron complexes 571, leads to a convergent total synthesis of a broad range of carbazole alkaloids. The overall transformation involves consecutive iron-mediated C-C and C-N bond formation followed by aromatization (8,10) (Schemes 5.24 and 5.25). 

Over the past 15 years, we developed three procedures for the iron-mediated carbazole synthesis, which differ in the mode of oxidative cyclization arylamine cyclization, quinone imine cyclization, and oxidative cyclization by air (8,10,557,558). The one-pot transformation of the arylamine-substituted tricarbonyl(ri -cyclohexadiene) iron complexes 571 to the 9H-carbazoles 573 proceeds via a sequence of cyclization, aromatization, and demetalation. This iron-mediated arylamine cyclization has been widely applied to the total synthesis of a broad range of 1-oxygenated, 3-oxygenated, and 3,4-dioxygenated carbazole alkaloids (Scheme 5.24). 

An attempt to directly convert hyellazole (245) to 6-chlorohyellazole (246) by reaction with N-chlorosuccinimide in the presence of a catalytic amount of hydrochloric acid led exclusively to 4-chlorohyellazole. On the other hand, bromination of 245 using NBS and a catalytic amount of hydrobromic acid gave only the expected 6-bromohyellazole (733). Alternatively, a direct one-pot transformation of the iron complex 725 to 6-bromohyellazole (733) was achieved by reaction with an excess of NBS and switching from oxidative cyclization conditions (basic reaction medium) to electrophilic substitution conditions (acidic reaction medium). Finally, a halogen exchange reaction with 4 equivalents of cuprous chloride in N,N-dimethylformamide (DMF) at reflux, transformed 6-bromohyellazole (733) into 6-chlorohyellazole (246) (602) (Scheme 5.73). 

Using a one-pot process of oxidative cyclization in air, the arylamine 780a was transformed to the tricarbonyl(ri -4b,8a-dihydro-9H-carbazole)iron complex 792. Finally, demetalation of 792 and subsequent aromatization gave carbazomycin A (260). This synthesis provided carbazomycin A (260) in three steps and 65% overall yield based on 602 (previous route four steps and 35% yield based on 602) (610) (Scheme 5.88). 

The total synthesis of carbazomycin D (263) was completed using the quinone imine cyclization route as described for the total synthesis of carbazomycin A (261) (see Scheme 5.86). Electrophilic substitution of the arylamine 780a by reaction with the complex salt 779 provided the iron complex 800. Using different grades of manganese dioxide, the oxidative cyclization of complex 800 was achieved in a two-step sequence to afford the tricarbonyliron complexes 801 (38%) and 802 (4%). By a subsequent proton-catalyzed isomerization, the 8-methoxy isomer 802 could be quantitatively transformed to the 6-methoxy isomer 801 due to the regio-directing effect of the 2-methoxy substituent of the intermediate cyclohexadienyl cation. Demetalation of complex 801 with trimethylamine N-oxide, followed by O-methylation of the intermediate 3-hydroxycarbazole derivative, provided carbazomycin D (263) (five steps and 23% overall yield based on 779) (611) (Scheme 5.91). 

The intramolecular oxidative cyclization of the anilinobenzoquinone 940 with a catalytic amount of palladium(II) acetate in the presence of copper(II) acetate in air afforded the carbazole-l,4-quinone 941 in almost quantitative yield. The regioselective introduction of the heptyl side chain at C-1 of the carbazole-l,4-quinone 941 was achieved by a 1,2-addition of the corresponding Grignard reagent to give the carbazole-l,4-quinol 942 in 55% yield. However, 1,4-addition at C-3 and 1,2-addition at C-4 led to the regioisomeric products 943 and 944 as well. Finally, under acidic reaction conditions, the carbazole-l,4-quinol 942 was smoothly transformed to... 

Following a synthetic pathway similar to the one reported for carbazoquinocin C (274) (see Scheme 5.127), the veratrole ( + )-818 was transformed to the arylamino-1,2-benzoquinone (+ )-954. By palladium(II)-mediated oxidative cyclization, compound... 

One of the carbazole-l,4-quinones, 3-methoxy-2-methylcarbazole-l,4-quinone (941), required for the total synthesis of carbazomycin G (269), was already used as a key intermediate for the total synthesis of carbazoquinocin C, and was obtained by the addition of aniline (839) to 2-methoxy-3-methyl-l,4-benzoquinone (939), followed by oxidative cyclization with catalytic amounts of palladium(II) acetate (545,645) (see Schemes 5.124 and 5.125). Similarly, in a two-pot operation, 4-meth-oxyaniline (984) was transformed to 3,6-dimethoxy-2-methylcarbazole-l,4-quinone... 

According to the reaction types these syntheses may be classified as cyclocondensations, cycloadditions, or oxidative cyclizations (80PAC1611). To some extent TPs are prepared by other transformations of the five- and/or six-membered ring. 

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