Radical reactions annulation

In another approach, the annulated [5.6.5] ring system 3-259 was obtained from 3-258 in a radical reaction in 61 % yield (Scheme 3.67) [106]. This motif is found as the central core in several important natural products. 

Finally, a rather early (but from a mechanistic viewpoint a very interesting) sequence of radical reactions has been described by Pattenden and coworkers, in which an acetylenic oxime ether 3-312 was converted into the bicyclic oxime 3-319 in 70% yield (Scheme 3.78) [126]. Hydrolysis of 3-319 led to the bicyclic enone 3-320, which in fact can also more easily be synthesized by a Robinson annulation. 

After two years working as a postdoctoral fellow under Dr. H.-P. Husson (Institut de Chimie de Substance Naturelles, CNRS, Gif-sur-Yvette, France) (CNRS methods in asymmetric synthesis) (1984-85), he worked as an associate researcher under Professor Wolfgang Oppolzer (Departement de Chimie Organique, Geneve, Suisse) (aldol reaction) (1986) and was a visiting professor at the Department of Chemistry, Duke University, NC, working with Professor Fraser-Reid (free radical chemistry annulated furanoses formal total synthesis of phyllathocin). 

In the present chapter, however, because the problem is considered from a retrosynthetic point of view, we will distinguish only between heterolytic and homolytic disconnections -to which we will refer to as "retro-annulations"- and concerted or "pericyclic (or cheletropic) cycloreversions". In the same way that Woodward-Hoffmann rules [2] apply to pericyclic reactions, the Baldwin rules [3] may be said to apply to heterolytic as well as to homolytic "monotopic" annulations (see Table 6.1). Although in the preceding Chapter (see 5.5) we have already described some radical "monotopic" annulations, later on in this Chapter (see 6.1.3) and mainly in Chapter 7 we will refer to some new methods, syntheses and strategies which have been developed recently. 

Free-radical reaction of vinyl iodides having dienoate function in the presence of (TMS)3SiH and AIBN in refluxing benzene caused a tandem cyclization reaction to produce (4 - -1) and (4 - - 2) annulated compounds [94]. Reaction (7.83) shows the transformation resulted from a tandem 5-exo, 6-endo cyclization to give the isoindole skeleton where the stereogenic centres were highly controlled, whereas Reaction (7.84) proceeded via a tandem 6-exo, 5-exo cyclization to furnish a (4 -b 1) cycloadduct. 

Indoles, which are especially electron-rich and thus unsuitable for ordinary Diels-Alder reactions, have performed successfully in the cation-radical reaction as dienophiles (Scheme 44)107 and as dienes (Scheme 45)126. Interestingly, the site of annulation (across the C—C or the C—N bond) in vinylindole cation radicals (functioning as dienes for eneamine dienophiles) may be manipulated by varying the substituent on the enamine and thereby altering its push-pull nature (Scheme 45). 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

The reaction is not carried out in the dark. Irradiation with a 275 W GE sunlamp is performed. It is a radical domino annulation. 

Smith, M.B. Organic Synthesis, 2nd ed., McGraw-Hill, NY 2001, pp. 1172-1181. Fora review of radical-mediated annulation reactions, see Rheault, T.R. Sibi, M.P. Synthesis 2003, 803. 

On the other hand, carbonylation via a one-electron reduction system by reducing metals can also lead to useful transformations [Scheme 4-33]. The first example in Scheme 4-34 shows that a zinc reduction system of pent-4-enyl iodide undergoes dual annulations, a [4-f1] radical annulation with CO and a [3-f2] anion annulation with alkenes, to give a bicyclo[3.3.0]octanol, in which four C-C bonds are produced [59]. An extension of the present strategy to the construction of bicyclo[3.2.1]octanol skeletons has also been successful with a system in which 6-endo cyclization is favored over 5-exo cyclization. In these two reactions three C-C bonds were created by radical reactions and one by anionic reaction. 

Interestingly, the 3 chloro 1 iodopropane addition (Table 2.6, entry 9) led exclusively to pyrrolidine 37 (Scheme 2.4) none ofthe acyclic adducts was found [31]. Presumably, radical addition was followed by in situ Sn2 type cyclization. The same type ofcyclization, giving the epimeric pyrrolidine (epi 37), occurs upon ethyl addition to the 3 chlorobu tyraldehyde hydrazone (Table 2.6, entry 18). These reactions are hybrid radical ionic annulations of the C=N bond, a new class of radical polar crossover reactions [32]. 

The stereochemical requirements for the synthesis were fulfilled starting from enantiomerically pure alkynes 16, whereas the regiocontrol was achieved, when necessary (the [4-1-1] annulation can afford mixtures of quinoline derivatives, see Scheme 6), using ort/ o-(trimethylsilyl)-substituted arylisonitriles 15 (Scheme 7). In conclusion, the authors set up an asymmetric, regioselective, and widely applicable protocol that allowed the synthesis of more than fifty different compounds, proving once more the broad scope and functional-group tolerance of radical reactions. 

Benati L, Calestani G, Leardini R, Minozzi M, Naimi D, Spagnolo P, Strazzari S, Zanardi G (2003) Cascade radical reactions via a-(arylsulfanyl)imidoyl radicals competitive [4-1-2] and [4+1] radical annulations of alkynyl isothiocyanates with aryl radicals. J Org Chem 68 3454-3464... 

In a total synthesis of )-camptothecin 1579, which shows high potential in terms of anti-tumor and anti-retroviral activity, a new [4+1] radical annulation has been established, facilitated by the use of phenyl isocyanide 1574. With 1575, 1574 effects a cascade of free radical reactions via 1576-1578 forming two new ring systems, a quinoline and a pyrrolidine, in a one-pot-synthesis [1191, 1192]. An improved synthesis of camptothecin analogues, in which the alkyne moiety is protected by a TMS group, has been filed for a patent application [1193]. 

The alcohol adducts from Q -(trimethylsilyl)vinyllithium and aldehydes have found many uses in organic synthesis. The ketones obtained by oxidation (eq 4) are especially good Michael acceptors and have been used in a modified Robinson annulation reaction for the construction of cyclohexenones. Cyclopropana-tion leads to cyclopropylsilane adducts, which can be converted into a variety of cyclopentenes (eq 5). Halogenation followed by stannylation gives synthons (eq 6) useful for making substituted vinylsilanes through radical reactions. ... 

Amino acids, sulphoxide, radiolysis of 909 a-Amino acids, reactions of 776, 777 a-Aminosulphones, synthesis of 176 Aminosulphonyl radicals 1093 Aminosulphoxides rearrangement of 740 synthesis of 336 Andersen synthesis 60 / -Anilinosulphoxides, synthesis of 334, 335 Anion radicals 1048-1050 ESR spectra of 1050-1054 formation of during electrolysis 963 during radiolysis 892-897, 899, 903 Annulation 778, 781, 801, 802 Antibiotics, synthesis of 310 Arenesulphenamides 740 Arenesulphenates 623 reactions of 282 rearrangement of 719 Arenesulphinates 824, 959 chiral 618... 

Extension to carbocyclization of butadiene telomerization using nitromethane as a trapping reagent is reported (Eq. 5.48).72 Palladium-catalyzed carbo-annulation of 1,3-dienes by aryl halides is also reported (Eq. 5.49).73 The nitro group is removed by radical denitration (see Section 7.2), or the nitroalkyl group is transformed into the carbonyl group via the Nef reaction (see Section 6.1). 

Smith and co-workers have recently expanded the scope of the [4+1] radical annulation reaction between isonitriles and 1-iodoalkynes to include vinylisonitriles <00JCS(P1)641>. Thus, vinylisonitrile 17 and iodide 18 afford annulated pyridine 19. 

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