Regioselectivity radical cyclization

Table 12.3. Regioselectivity of Radical Cyclization as a Function of Ring Size "...

Radical cyclization of perhydro-l,3-benzoxazines 64, promoted by Bu4SuH in the presence of AIBN gave a mixture of perhydropyrido[2,l-6][1,3]benzoxazin-9-ones 65 and 66 and seven membered tricyclic derivatives 67 and 68, formed in a 6-exo and 7-endo cyclization process, respectively (99TL2421). Cyclization of parent acrylamide 64 (R = R = H) occured with moderate regioselectivity (6-exo/7-endo ratio 65 35) and poor stereoselectivity (65/66 ratio 42 43). The presence of a /3-methyl group in... 

Sequential radical cyclizations are also featured in an efficient and clever synthesis of the cedrane framework 83 (see Scheme 15).30 Compound 81, the product of a regioselective Diels-Alder reaction between isoprene (79) and nitroethylene (80), participates in a nitroaldol reaction (Henry reaction) with 5-methyl-4-hexenal in the presence of a basic resin to give 82. Because the nitro group in... 

Cyclic ethers were also obtained by cyclization of alkoxyl radicals, generated in a radical chain reaction by reacting the thione 42 with (TMSfsSiH under photochemical conditions at 20 °C (Reaction 46). Regioselectivities of cyclization have been investigated and a progressive increase of the 6-endo-trig selectivity along the series R2 = H[Pg.140]

Alkyl Co oxime complexes have been used as chain transfer catalysts in free radical polymerizations.866,867 Regioselective hydronitrosation of styrene (with NO in DMF) to PhCMe=NOH is catalyzed by Co(dmg)2(py)Cl in 83% yield.868,869 Catalytic amounts of the trivalent Co(dmg2tn)I2 (192) (X = I) generate alkyl radicals from their corresponding bromides under mild reaction conditions, allowing the selective preparation of either saturated or unsaturated radical cyclization products.870... 

Radical cyclization of perhydro-l,3-benzoxazines 518, promoted by Bu vSnI I in the presence of 2,2 -azobis(2-methylpro-pionitrile) (AIBN) gave a mixture of perhydropyrido[2,T ][l,3]benzoxazin-9-ones 519 and 520 and the seven-membered tricyclic derivatives 521 and 522, formed by a 6-exo- and a 7-rwr/o-cyclization process, respectively (Scheme 54) < 1999TL2421 >. Cyclization of parent acrylamide 518 (R = R1 = H) occurred with moderate regioselectivity (()-exo/7-endo ratio = 65 35) and poor stereoselectivity (519/520 ratio = 42 43). The presence of a [1-methyl group in crotylamide 518 (R = Me, R1 = H) disfavored the 7-/w/ -cyclization process, but did not influence the stereoselectivity of the cyclization (519/520 ratio = 66 34). The presence of an a-methyl group in methylacrylamide 518 (R=H, R1 Me) caused a retardation of the 6-oeo-attack, favoring the 7-/w/ -cyclization with a higher stereoselectivity (521/522 ratio = 75 12). 

J(P1)427>. The regioselectivity of the second radical cyclization depends on the electronic nature of the homoallylic double bond pyrrolizinones 240 which result from a final 5-o -cyclization mode are preferred in the case of electron-poor carbon-carbon double bonds, such as enones or enoates electron-rich double bonds lead to indolizinones via a final 6-f db-cyclization. The best yields of pyrrolizinones were observed with iodide precursors. The cir-isomers of 240 predominate in this 5-f rf6i-5-f3co-cyclization. 

Partially saturated derivatives can also be prepared through aryl radical cyclization of A-2-halobenzoyl cyclic ketene-iVA-acetals <2005TL3801>. In this event, treatment of ketene-acetal 418 with Bu3SnH afforded good yield of cyclized products 419 and 420, as a mixture of two diastereoisomers, but with a total regioselectivity (Scheme 108). 

In summary, intramolecular radical cyclization reactions onto aromatic rings can provide quick access of otherwise not so easily assembled Ca0. -C.ryi bonds, although the yields are generally low and the process suffers from a lack of regioselectivity. Noticeably, Crich found that a catalytic amount of benzeneselenol, which can also be generated in situ reduction of diphenylselenide with stannane [57]. This method should find synthetic utility in intramolecular radical addition to arenes. 

As described in section 3.1, when a radical cyclization reaction involves the 5-hexenyl radical intermediate, the 6-endo-trig radical cyclization will prevail when the usually favoTed 5-exo-trig regioselectivity is suppressed by substitution at the 5-position. Such a tactic was... 

Intramolecular cyclizations of alkenylaminyl radicals produced from tetrazenes have been reported. The regioselectivity of cyclizations of aminyl radicals derived from N-3-butenyltetrazene (1), A-4-pentenyl tetrazene (2), and JV-5-hexenyl tetrazene (3) have been studied (78MI1). The position of the alkene moiety is important because other reaction pathways can compete with cyclization. 

Intramolecular radical cyclization of an aryl bromide and an alkyne can be used to produce dihydroquinolines (Equation 57) <1998TL2965>. An analogous reaction setup utilizes a Lewis acid-catalyzed novel one-pot domino pathway using silver catalysis in high regioselectivity (Scheme 26) <2005OL2675>. Three mole equivalents of the alkyne are used with the final cyclization step arising from alkynic addition. 

Thiopyrans are produced in high yield by the microwave-induced one-pot reaction between a,/ -unsaturated ketones, dienophilic alkynes, and Lawesson s reagent. The equivalent thermal reaction is unsuccessful <2006TL4925>. Calculations at the G3MP2B3 level show that the introduction of a 5-methyl substituent into n -sul I cnyl-. a-sulfinyl-, and ct-sulfonyl- hex-5-enyl radicals shifts the regioselectivity of cyclization to the 6-endo products, tetrahydrothiopyran derivatives <2006JOC9595>. 

Hasegawa et al. [85] have explored the electron transfer-promoted regioselective ring opening of cyclopropyl silyl ethers 183 for the generation of cyclopropoxy radical 185 which, upon intramolecular radical cyclization, leads to the formation of spirocydic compound 184 in moderate yields (Scheme 8.51). 

The intramolecular C—C bond formation (or cyclization) mediated by (TMS)3SiH has been the subject of numerous publications in the last few years. For example, radical cyclization of bromides 73 was found to be totally regioselective following 5-exo mode ring closure and afforded tetrahydrofuran derivatives (equation 37)89. Furthermore, the chiral auxiliary together with the configuration of the double bond allow for complete diastereocontrol. 

There exists also a synthesis of cyclopentadecanone (VII/81) and ( )-mus-cone, based on a three-carbon annulation of cyclic ketones followed by the regioselective radical cleavage of the zero bridge of the so formed bicyclic system [44], The synthesis of cyclopentadecanone is summarized in Scheme VII/16. The cyclization of VII/78 to the bicyclic alcohol VII/79 proceeds best (94 % yield) with samarium diiodide in the presence of hexamethylphosphoric acid triamide and tetrahydrofuran [45], The oxidative cleavage of VII/79 to the ring expanded product VII/80, was performed by treatment with mercury(II)-oxide and iodine in benzene, followed by irradiation with a 100 Watt high pressure mercury arc. Tributyltinhydride made the de-iodination possible. 

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