Nitrogen-centered radicals cyclizations

The 5-dig-mode of cyclization has been applied in the synthesis of N-heterocycles. For example, treatment of the /i-allenyl dithiosemicarbazide 37 with Bu3SnH and AIBN in hot benzene furnishes the substituted 3H-pyrrole 38 in 41% yield and the isomeric heterocycle 39 in 30% yield (Scheme 11.13) [68], Iminyl radical 40 is formed via Bu3Sn addition to the thiocarbonyl group of the radical precursor 37 and fragmentation of the adduct (not shown). Nitrogen-centered radical 40 adds 5-dig-selectively to provide substituted allyl radical 41. The latter intermediate is trapped by Bu3SnH to furnish preferentially product 38 with an endocydic double bond. 

To facilitate the cyclizations of nitrogen-centered radicals, one need only increase the electronegativity at nitrogen. This makes the radical more electrophilic (which accelerates the cyclization), and strengthens the forming bonds (which shifts the equilibrium to the cyclic product). Amminium radical cations are more well-behaved in cyclizations than aminyl radicals, and these radical cations can either be formed directly from ammonium salts, or by protonation of aminyl radicals (which are relatively weak bases and require strong acids for protonation). Metal-complexed aminyl radicals are highly reactive, and amidyl radicals are also useful.178... 

The electronic nature of a nitrogen centered radical, dictated by reaction conditions and/or the radical precursor employed, is crucial to the mode of reaction, to the ability to undergo efficient intramolecular cyclizations or intermolecular additions, and to the products isolated from the radical reaction. The types of radicals discussed in this review include neutral aminyl radicals, protonated aminyl radicals (aminium cation radicals), metal complexed aminyl radicals, and amidyl radicals. Sulfonamidyl and urethanyl radicals are known (71S1 78T3241), but they are not within the scope of this chapter. 

Azides are highly valuable radical acceptors that form nitrogen-centered radicals after addition onto them, as in the case of the transformation of 31 into 32. This reaction opens new possibilities for making pyrrolidines. Murphy, for instance, disclosed the synthesis of ( )-horsfihne and ( )-coerulescine by tandem cyclization of iodoaryl alkenyl azides such as 29 [42]. By the same strategy and using precursor 33, formal syntheses of ( )-vindohne [43] and ( )-aspidospermidine [44] have been rendered possible (Scheme 10). 

The ease of preparation of the precursors and the mild conditions under which nitrogen-centered radicals are produced offer advantages Over other routes to these radicals. However, the diastereoselectivity of the cyclization is relatively low, and is only slightly improved by lowering the temperature (Table 1). 

Other groups have reported free-radical approaches to lycoranoids less richly decorated than 66. For example, Rigby has reported a short synthesis of ot-lycorane (67) via an aryl radical-enamide cyclization that constructs the C 2a-Ci2b bond [42]. Padwa focused on the same bond construction via an aryl radical-dihydroindole cyclization in his synthesis of anhydrolycorin-7-one (68) [43]. Both Zard [44] and Cossy [45] have reported syntheses of y-lycorane (69) that involve initial construction of the N-Ci2a bond via cyclization of nitrogen-centered radicals. Both ap-... 

This chapter has attempted to present a thorough overview of alkaloid syntheses in which free-radical cyclizations have played a pivotal role. It is not meant to be a comprehensive review, but focusses on syntheses in which nitrogen plays a clear role in the cyclization process, either as an attenuator of radical reactivity (Sections 4,1.2 and 4.1.3), a tether (Section 4.1.4), or a radical acceptor (Section 4.1.5). Several other notable alkaloids syntheses have been reported in which carbocyclizations play the pivotal role and introduction of nitrogen is secondary, for example Sha s syntheses of (-)-dendrobine [76] and (-t-)-paniculatine [77], and Clive s synthesis of (+)-fredericamycin [78]. Syntheses in which nitrogen-centered radicals play a critical role are also known, such as the Zard synthesis of (—)-dendrobine [79]. My apologies to these authors for not elaborating on their fine contributions, to authors who have nicely used intermolecular radical addition reactions in alkaloid synthesis, and to others whose contributions may have escaped my attention. 

In stark contrast to azoalkanes, azoxy compounds rarely form radicals on heating or irradiation. Furthermore, they are unreactive to alkyl radical attack unless the reaction is intramolecular. For example, P-carbon centered radicals cyclize to azoxy nitrogen or oxygen and produce short-lived aminyl nitroxides that reopen or hydrazyl radicals that undergo fragmentation. The azoxy group is a powerful stabilizer of an adjacent radical center but the chemistry of a-azoxy radicals (hydrazonyloxides) and their dimers is not fully understood. 

Useful synthetic methodologies are based on the cyclization or rearrangement of the nitrogen-centered radicals generated in the reaction of the appropriate amides with (diacetoxyiodo)benzene in the presence of iodine [652-655]. Specific examples are illustrated by the synthesis of bicyclic spirolactams 622 from amides 621 [653] and preparation of the oxa-azabicyclic systems (e.g., 624) by the intramolecular hydrogen atom transfer reaction promoted by carbamoyl and phosphoramidyl radicals generated from the appropriately substituted carbohydrates 623 (Scheme 3.244) [654],... 

To solve the first challenge, the structure of the carbamate was tuned to optimal reactivity of the nitrogen-centered radical. Ultimately, a trifluoroethyl carbamate 7 proved to affect the desired intra-molecular C—H functionalization most productively. Investigations into the second challenge established that silver carbonate ensured the carbamate cyclized through the carbonyl oxygen atom, rather than the carbamate nitrogen atom. 

Several functional groups containing carbon-nitrogen double bonds can participate in radical cyclizations. Among these are oxime ethers, imines, and hydrazones.337 Hydrazones and oximes are somewhat more reactive than imines, evidently because the adjacent substituents can stabilize the radical center at nitrogen.338 Cyclization at these functional groups leads to amino- substituted products. 

A radical cascade reaction has been accompHshed by StaHnski and coworkers which converts dipeptide derivatives to nitrogen-containing heterocycles (Scheme 6) [9]. In this work, N-bromobenzyl-hf-propargyl-substituted dipeptides such as 10 were subjected to Stork s catalytic procedure with tributyltin hydride [10]. An aryl radical is formed followed by a 1,5-hydrogen shift, generating the a-centered carbon radical 11. 5-Fxo-dig radical cyclization... 

Other uses of cobalt(I) catalysts include the reductive intramolecular cyclization of bromocyclohexenones to form bicyclic ketones [391] and the radical cyclization of bro-moacetals [392,393]. Krautler and coworkers [394] found that 1,4-dibromobutane interacts with electrogenerated cob(I)alamin to afford a tetramethylene-l,4-di = Co -cobalamin species. In a recent study of the reactions of cobalt(I) tetraphenyl porphyrin with benzyl chloride or 1-chlorobutane, Zheng and coworkers [395] reported that alkyl radicals are transferred from the cobalt center to a nitrogen of a pyrrole ring, leading to formation of an A-alkyl cobalt porphyrin complex. 

The first step in the mechanism is the homolysis of the 0-N bond to form an oxygen-centered radical and a nitrogen-centered free radical. Next, the highly reactive alkoxyl radical abstracts a hydrogen atom from the 5-position (5-position) via a quasi chair-like six-atom transition state to generate a new carbon-centered radical that is captured by the initially formed NO free radical. If a competing radical source such as iodine is present, the reaction leads to an iodohydrin, which can cyclize to form a tetrahydrofuran derivative. Occasionally, tetrahydropyran derivatives are obtained in low yields. 

Synthesis of (—)-Sibirine. Various types of alkaloids have been prepared by conjugate addition of carbon-centered radicals to unsaturated sulfones. This approach is used in the stereoselective synthesis of the Nitraria spirocyclic alkaloid (—)-sibirine, where a 6-exo-trig radical cyclization to an a,(3-unsaturated sulfone leads to the spirocyclic skeleton of the natural product (Eq. 153).263 The y-nitrogen-functionalized sulfone so obtained is then desulfonylated under dissolving-metal conditions. 

Bertrand and coworkers have reported that quaternization of the nitrogen center upon coordination with BH3, provides a significant increase in the selectivity of the 5-exo radical cyclization of 3-aza-5-hexenyl radicals derived from substrates equipped with a terminal double bond (Equation 28) [30]. Coordination of BH3 to the nitrogen of the parent amine creates strong steric interactions, which disfavor the trans product. 

In this case, the information was taken from the study of the n-BusSnH-media-ted cyclization of substituted A -(phenylthio)amides 8, detailed in Scheme 39.6. The reaction is a radical process in which the nitrogen-eentered radical 11 formed in the first instance, cyclizes onto the C=C double bond to give carbon-centered radical species 13 which, after quenching, yields cyclized compound 9. The cyclization step follows the exo-mode in agreement with the Baldwin rules (5-exo-trig). 

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