Reductive cyclisation

A general synthesis of pyrrolo[3,4-mediated reductive cyclisation of the pyrrolidinones 16 with amidines. The suggested mechanism is that shown in Scheme 2 < 95JOC7687 >. 

Macrolactones 77 and/or 78 can be prepared from the reductive cyclisation of ynals 76 in the presence of NHC-nickel complexes (Scheme 5.21) [21], This maaolactonisation occnrs with different selectivity depending on the ligands attached to the nickel. If carbenes snch as IMes or IPr are nsed, the exocyclic olefin 77 is preferentially obtained, however when phosphine ligands are nsed, the endocyclic adducts 78 are preferentially obtained. 

Scheme 5.21 Macrolactones prepared from the reductive cyclisation of ynals in the presence of NHC-nickel complexes...

The radical reductive cyclisation of diesters to acyloins (see also Section 5.9.1, p. 628) is an important method of synthesis for ring sizes from four-membered upwards. The example selected here is 2-hydroxy-3-methylcyclopent-2-enone ( corylone ) (29) (Expt 7.10), which is an important perfumery and flavouring material.53 In the first step (i), methyl acrylate is converted into its dimer with tris(cyclohexyl)phosphine in pyridine solution.5b Step (ii) is the protection of the double bond by conversion into the dimethylamino adduct. The acyloin reaction is step (iii), and the product is trapped as its bis(trimethylsilyl)ether. Finally, in step (iv), the protecting dimethylamino and trimethylsilyl groups are removed by passage down a column of silica gel. 

Reaction of the l-aryl-2-phenacylcyclopropanes with chlorosulphonyl isocyanate and subsequent removal of the chlorosulphonyl group with benzenethiol in pyridine affords the 4,5-dihydro-1,3-oxazepines (91) <95SCI939> and in a reaction sequence in which an aziridine is the source of nitrogen, methyl l-benzyloxycarbonylaziridine-2-carboxylate reacts with 2-(N-benzyl-A -/t /7-butoxycarbonyl)aminoethanol to give the derivative (92) which, after removal of the Boc group, is subject to a reductive cyclisation to yield the hexahydro-l,4-oxazepine (93) <95CPBI 137>. 

Stannous chloride-mediated reductive cyclisation-rearrangement of the nitro-ketone 269 (obtained from the nitro-acid, 268) gave the dibenzothiazepine derivative 270 in good overall yield mechanistically it was proposed that a hydroxylamine intermediate leads to the rearrangement after intramolecular nucleophilic addition to the ketone [02JOC8662]. 

Although many early synthetic studies employed HMPA as a cosolvent, its mechanistic role remained unclear. Its role was later clarified by Molander, who studied the influence of HMPA concentration on the product distributions from the Sml2-mediated reductive cyclisations of unactivated olefinic ketones.16 The addition of HMPA was required to promote efficient ketyl-alkene cyclisation, and correlations between the concentration of HMPA, product ratios and diastereoselectivities were apparent (Scheme 2.6). In the absence of HMPA, attempted cyclisations led to the recovery of starting material 1, reduced side-product 3 and desired cyclisation product 2. Addition of 2 equiv of HMPA provided 2 and only a small fraction of 3. Further addition of HMPA (3-8 equiv) provided 2 exclusively (Scheme 2.6). 

With the non-C2-symmetrical dialdehyde 11, reductive cyclisation on treatment with Sml2 led to the preferential formation of the cyclic cz s-diol 12. The intervention of the transition state structure 13 was invoked to rationalise the uratz-selectivity observed with the bulky silyl ether-protected hydroxyl group. 

Fang used similar reductive cyclisations of l,l -dicinnamoylferrocenes such as 161 to prepare 3-ferrocenophane diols 162.164 In this case, the aldol cyclisation is followed by ketone reduction in a highly diastereoselective, sequential operation (Scheme 5.105). 

Animals. In rats, the major metabolic routes for pendimethalin involve hydroxylation of the 4-methyl and AM-ethyl groups, oxidation of these alkyl groups to carboxylic acids, nitro-reduction, cyclisation and conjugation (J. Zulian, J. Agric. Food Chem., 1990, 38, 1743)... 

The polyHIPE supported thiol is a good catalyst for radical reduction of alkyl halides and reductive cyclisations of e-bromoalkenes by triethylsilane. 

Acylation of the homoallylic alcohol 11 derived from a stannane and 3-phenylpropanal and a subsequent SmI2-promoted reductive cyclisation provides high yields of cA-2,6-disubstituted 2-methoxy-4-methylidenetetrahydropyrans. The methodology has been utilised to synthesise a... 

Denmark reported a protocol for the formation of 3-substituted azepines 4 from nitro acylsilanes 3, which were formed by the conjugate addition of an acylsilane-derived dienol-ether 2 to nitroalkenes 1 <07JOC7050>. The reaction of the nitro acylsilane with aluminium-amalgam gave a mixture of azepines and lactams, however, this was overcome by conversion of the acylsilane to an aldehyde prior to the reductive cyclisation. 

A related reductive cyclisation has been developed by Schafer et al. in which the cathodic cyclisation of A-(oxoalkyl)pyridinium salts led to indolizidine and quinolizidine derivatives <95AG(E)2007, 03EJO2919>. Electrolyses of the pyridinium salts were carried out in a divided beaker-t5q)e cell at a mercury pool cathode under constant current, using 1 M aqueous sulfuric acid as the electrolyte. In this way, cyclisation of cyclopentanone 129 to the isomeric quinolizidines 130 and 131 was achieved in high yield and with excellent diastereoselectivity (Scheme 38). The stereochemical course of the reaction with cyclohexanone 133 was not as well defined, with three of the four possible diastereoisomers being given in a ratio of 10 21 26 (for 134,135 and 136 respectively). 

On principle, both the hydroxamic acid and the hemiacetal are partially oxidised structures. Thus, the hydroxamic acid should be accessible both fi-om a nitro precursor by reductive cyclisation and from a lactam by N-oxidation (Fig. (7)). Similarly, access to the hemiacetal should e.g. be possible by oxidation of a 2-methylene group as well as by reduction of a 2-carbonyl group, and also by hydrolysis of a 2-haIogen function. The influence of substituents at the aromatic ring on the synthesis of the 1,4-benzoxazinone ring is hardly foreseeable. However, another circumstance has a very rational basis. Due to the fact that the structural instability arises from the cyclohemiacetal (see Fig. (4)) this tmit is prepared at the very end of most syntheses. 

The first synthesis (left pathway) affording DIBOA started from a protected 2-nitrophenoI [109], The need to handle a free donor-substituted arylhydroxylamine reduces the yield distinctly and is a serious disadvantage. The second synthesis (middle left pathway), subject of a patent issued in 1975 to Hoffman-La Roche, is also starting from an appropriate ortho-suhstituted nitrobenzene [110]. In both syntheses the hydroxamic acid is generated by reductive cyclisation and the hemiacetal by hydrolysis of a chloride precursor. However, only the second procedure is applicable to the synthesis of the 7-methoxy compound DIMBOA. Therefore, this principle has later been developed further. The strategy of the third synthesis (middle right pathway) is different [111]. After alkaline cyclisation of the dichloroacetamide precursor to the hemiacetal unit the hydroxamic acid is obtained by oxidation of the... 

Appropriate 5-substituted 2-nitrophenols have been transformed by acylation with chloroformylformate into (substituted) ethyl 2-nitrophenyl oxalates as extremely reactive building blocks for the synthesis of the 2,3-dioxo-l,4-benzoxazine skeleton [115]. Due to their extreme sensitivity towards hydrolysis water has to be excluded on reductive cyclisation of these nitrophenyl esters. 

Reductive cyclisations of methyl 2-methoxy-2-(2-nitrophenyl-thio)acetate by means of a catalytic transfer hydrogenation or of methyl 2-(2-nitrophenylthio)acetate by electrochemical reduction have been used as key steps in the synthesis of DIBTA and the corresponding lactam [125]. The hemiacetal function results in all pathways by hydrolysis from halogen precursor. 

Scheme 4.8 Radical chain reduction/cyclisation of 3-(2-bromoethoxy)prop-l-ene using the (TMS)3SiH-thiol (RSH) reducing system.

A trczns-octahydrobenzo [g] quinoline is also formed by the reductive cyclisation of 3-(2-cyanoethyl)-2-tetralone (J.G. Cannon et al., J. heterocyclic Chem., 1980, H, 1633. 

The epoxide is opened regioselectively with the anion of the nitrobenzene thiol 66 and the rest of the synthesis is essentially as described earlier (reduction, cyclisation, addition of substituents to O and N). 

The second synthetic sequence involves bisoxindoles of the type (17). Compound (17) in both racemic and weso-forms can be obtained by the action of sodium hydride and iodine on 3-(j -ethoxycarbamidoethyl)oxindole. Reductive cyclisation of racemic (17) with lithium aluminium hydride gives racemic (7) and racemic (1) in low yield the corresponding meso-compound (meso-17) gives (8). ... 

The oxidation of indolines with sodium tungstate/hydrogen peroxide both aromatises and also oxidises the nitrogen, resulting in 1-hydroxy-indoles. 1-Hydroxy-indoles can also be obtained via ring synthesis involving lead-promoted reductive cyclisation of ortfto-nitrobenzyl-ketones (or -aldehydes)." ... 

Phthalocyanine can be produced by the reductive cyclisation of 2-cyanobenzamide or, in a route which makes its relationship to isoindole more obvious, by the combination of four molecules of 1,3-diiminoisoindoline with the elimination of ammonia. ... 

Nitrogen Heterocycles. The [3,2-6]-l-pyrroline (231) formed by reductive cyclisation of the nitro-ketone (230) afforded the as-fused [3,2-b]pyrrolidine (232) on partial reduction with NaBH4. With AC2O at room temperature the pyrroline (231) suffered rearrangement to the acid sensitive 0,A -heterocycle (233). 

NENITZESCU Indole Synthesis Synthesis of indoles by reductive cyclisation of o, co-dinitrostyrenes. 

It is strongly adsorbed by soil colloids and is not leached into deeper soil layers. In the soil dinitramine is degraded in 90-120 days by microorganisms (Smith, 1973 Lanio et al.. 1973). At the soil surface and in water it is rapidly degraded by photolysis, with the reductive cyclisation of one of the nitro groups and the adjacent N-diethyl group (Newson and Woods, 1973) ... 

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