A free radical cyclization approach to indolo-benzodiazocine derivatives

Bremner, John B.; Sengpracha, Waya

doi:10.1016/j.tet.2004.11.007

Cited by 26 publications

(5 citation statements)

References 14 publications

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“…Rates of rapid radical cyclization reactions can exceed those of amide bond rotations, so the starting rotamer ratio of an amide radical precursor can have a significant effect on downstream radical reactions. Along these lines, Ishibashi and co-workers postulated that chloride 1a might have a ground-state preference for E -amide rotamer 1a E (Figure ), and thus its derived radical 11 E would be prone to cyclization .…”

Section: Resultsmentioning

confidence: 99%

How Do Analogous α-Chloroenamides and α-Iodoenamides Give Different Product Distributions in 5-EndoRadical Cyclizations?

2008

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5-Endo cyclizations of N-alkenyl carbamoylmethyl radicals provide gamma-lactam radicals, which in turn evolve to reduced or non-reduced (alkene) products depending on reagents and reaction conditions. Several groups have made surprising observations that chlorides are better radical precursors than iodides in such cyclizations. Here is described a detailed study of tin and silicon hydride-mediated radical cyclizations of N-benzyl-2-halo-N-cyclohex-1-enylacetamides. The ratios of directly reduced, cyclized/reduced, and cyclized/non-reduced products depend not only on the reaction conditions and reducing reagent but also on the precursor. Prior explanations for the precursor-dependent product ratios based on amide rotamer effects are ruled out. The precursor-dependent behavior is further dissected into two different effects: (1) the ratio of cyclized/reduced products to cyclized/non-reduced products depends on the ability of the radical precursor to react with the product gamma-lactam radical in competition with tin hydride (iodides can compete, chlorides cannot), and (2) the occurrence of large amounts of directly reduced (noncyclized) products in the case of iodides is attributed to a competing ionic chain reaction by which the precursor is reductively deiodinated with HI. This side reaction is not available to chlorides, thereby explaining why the chlorides are better precursors in such reactions. The ability of the iodides to provide cyclized products can be largely restored by adding base. The chlorides and iodides then become complementary precursors, with chlorides giving largely cyclized/reduced products and iodides giving largely cyclized/non-reduced products.

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Section: Resultsmentioning

confidence: 99%

How Do Analogous α-Chloroenamides and α-Iodoenamides Give Different Product Distributions in 5-EndoRadical Cyclizations?

2008

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“…However, when an electron-withdrawing group is present at 3-C, normal aromatic homolytic substitution is largely favoured. [95][96][97][98][99] Other cyclisations of alkyl radicals have been reported, e.g. pyrroles, 36,90 1,3,4-triazoles 100 and 2-and 4-quinolones.…”

Section: Cyclisation Onto Heteroarenesmentioning

confidence: 99%

Synthesis using aromatic homolytic substitution—recent advances

2007

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This critical review aims at presenting recent developments in intramolecular aromatic homolytic substitution which has become one of the common methodologies in modern synthesis. The application of Bu3SnH-mediated cyclisations have proved especially useful. The critical review illustrates the mechanistic considerations required for planning synthetic applications and a wide range of synthetic protocols and natural product syntheses are shown. The latest evidence for the mechanisms involved in aromatic homolytic substitution are presented. (152 references).

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“…22,29, 30 However, the lower aromaticity in the pyrrole ring of indole, facilitates both reductive and oxidative cyclisation depending on the conditions. 11,12, 31 The radical intermediate 10, whether a p-radical or not, is still a strongly stabilised anilyl radical and therefore the rate of reduction by Bu 3 SnH to yield 12 is probably too low to be competitive with loss of hydrogen to yield the 'oxidised' product. The reactions could also be regarded as exo-cyclisations onto imines which are well known.…”

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confidence: 99%

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

et al. 2007

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Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone 2, mackinazolinone 3, tryptanthrin 4, luotonin A 5 and rutaecarpine 8 were synthesised by radical cyclisation onto 3H-quinazolin-4-one.The 3H-quinazolin-4-one ring system is important to the biological activity of both naturally occurring alkaloids, biosynthesised from anthranilic acid, and pharmaceuticals. The alkaloids include vasicinone 1 and deoxyvasicinone 2, 1 mackinazolinone 3, 2 tryptanthrin 4, 3 luotonins A 5, B 6 and E 7 4 and rutaecarpine 8. 5 3H-Quinazolin-4-one alkaloids have been recently reviewed. 6 All the 3H-quinazolin-4-one natural products have interesting biological activity and have therefore been extensively investigated for useful pharmaceutical activity. The 3H-quinazolin-4-one ring is regarded as a 'privileged structure' in combinatorial synthesis. 7 These are structures which represent molecules that are capable of binding at multiple sites with high affinity and facilitate more rapid discovery of useful medicinally active compounds. 7Our study involved the development of protocols involving radical cyclisation for the synthesis of polycyclic 3H-quinazolin-3-ones (Scheme 1). The protocols have also been used for the synthesis of novel polycyclic quinazolinones including the natural Department of Chemistry, Loughborough University, Loughborough, Leics, UK LE11 3TU. E-mail: g.w.weaver@lboro.ac.uk; Fax: 44(0) 1509 223925; Tel: 44(0) All of the above cyclisations are 'oxidative' i.e. the intermediate p-radicals are not reduced by triorganometal hydrides [e.g. tributyltin hydyride (Bu 3 SnH)] as normally observed for these reagents. The cyclisations proceed by aromatic homolytic substitution with abstraction of hydrogen in a rearomatisation process. Aromatic homolytic substitution has been recently reviewed 27 and the mechanism of Bu 3 SnH mediated 'oxidative' cyclisation elaborated. 28 The pyrimidin-4-one ring of the quinazolin-4-ones has some aromaticity and therefore aromatic homolytic substitution could be predicted, and was observed in our studies, as shown in Scheme 1 (9 to 11 via the p-radical 10). However, the lower aromaticity could favour reductive cyclisation in which the intermediate p-radical 10 is intercepted by reagents such as Bu 3 SnH. Our prediction that radical cyclisation onto the quinazolin-4-one ring would be 'oxidative' was supported by the 'oxidative' radical cyclisation onto related ring systems, e.g. pyrimidine-2,4-diones, 23,24This journal is

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A free radical cyclization approach to indolo-benzodiazocine derivatives

Cited by 26 publications

References 14 publications

How Do Analogous α-Chloroenamides and α-Iodoenamides Give Different Product Distributions in 5-EndoRadical Cyclizations?

How Do Analogous α-Chloroenamides and α-Iodoenamides Give Different Product Distributions in 5-EndoRadical Cyclizations?

Synthesis using aromatic homolytic substitution—recent advances

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

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