Radical oxime ethers

The (TMS)3Si radical addition to terminal alkenes or alkynes, followed by radical cyclization to oxime ethers, were also studied (Reaction 50). The radical reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized pyrrolidines via a carbon-carbon bond-forming process. Yields of 79 and 63% are obtained for oxime ethers connected with an olefin or propargyl group, respectively. 

The radical alkylation of ketones is achieved by their conversion into the desired N-silyloxy enamines 81 (Scheme 13). The reaction of 81 with diethyl bromomalonate in the presence of EtsB (0.5 equiv) in benzene was performed in open air and stirred at room temperature for 3h. With nitro compounds it is achieved by their conversion into the desired ]V-bis(silyloxy)enamines (82) (Scheme 13). When the reaction is carried out with 82 and alkyl iodides with an electron-withdrawing substituent at the a-position, using V-70 as radical initiator (2,2 -azobis(4-methoxy-2,4-dimethylvaleronitrile)), it underwent a clean radical alkylation reaction to yield an oxime ether. Successful radical alkylation of... 

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. 

The reactivity of oxime ethers as radical acceptors is enhanced by Lewis acids, BF3 being the most effective.343... 

Entries 20 to 23 involve additions to C=N double bonds in oxime ethers and hydrazones. These reactions result in installation of a nitrogen substituent on the newly formed rings. Entry 20 involves the addition of the triphenylstannyl radical to the terminal alkyne followed by cyclization of the resulting vinyl radical. The product can be proto-destannylated in good yield. The ring closure generates an anti relationship for the amino substituent, which is consistent with the TS shown below. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

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. 

Scheme 3.78. Domino radical double ring expansion/cyclization process with oxime ethers.

Scheme 10.14. Domino radical addition-cyclization process of oxime ethers.

Domino radical transformations on solid support can also be used, as shown by Naito and coworkers [18]. Thus, immobilized oxime ether 10-55 (Wang resin) afforded the tetrahydrofuranones 10-57 after removal of the resin, when it was exposed to BEt3 in the presence of different alkyl iodides 10-56 (Scheme 10.14). 

The ZnEt2-initiated radical additions to glyoxylic384 and other374 oxime ethers, including those anchored to a polymer (e.g., 272), yielded valuable precursors for a-amino acids (Scheme 143). 

Radical reaction of oxime ethers. A report1 that an oxime ether, unlike the... 

The other study3 of oxime ethers focused on radical cyclizations to alkoxyami-nocyclopentanes and -cyclohexanes (equations III and IV). Yields decrease as chain length of the precursors is increased, mainly because of reduction. The cyclizations... 

Tandem processes mediated by triethylborane involving conjugate addition to enones followed by aldol reaction are reported (Scheme 52, Eq. 52a). More recently, a tandem process involving addition of an isopropyl radical to an o ,/3-unsaturated oxime ether afforded an azaenolate intermediate that reacts with benzaldehyde in the presence of trimethylaluminum. The aldol product cyclizes to afford an isopropyl substituted y-bulyroloaclonc in 61% overall yield (Scheme 52) [116]. In these reactions, triethylborane is acting as a chain transfer reagent that delivers a boron enolate or azaenolate necessary for the aldolization process. 

In qualitative terms, the rearrangement reaction is considerably more efficient for the oxime acetate 107b than for the oxime ether 107a. As a result, the photochemical reactivity of the oxime acetates 109 and 110 was probed. Irradiation of 109 for 3 hr, under the same conditions used for 107, affords the cyclopropane 111 (25%) as a 1 2 mixture of Z.E isomers. Likewise, DCA-sensitized irradiation of 110 for 1 hr yields the cyclopropane derivative 112 (16%) and the dihydroisoxazole 113 (18%). It is unclear at this point how 113 arises in the SET-sensitized reaction of 110. However, this cyclization process is similar to that observed in our studies of the DCA-sensitized reaction of the 7,8-unsaturated oximes 114, which affords the 5,6-dihydro-4//-l,2-oxazines 115 [68]. A possible mechanism to justify the formation of 113 could involve intramolecular electrophilic addition to the alkene unit in 116 of the oxygen from the oxime localized radical-cation, followed by transfer of an acyl cation to any of the radical-anions present in the reaction medium. 

B. Free Radical Additions to Oximes, Oxime Ethers and Nitrones. 142... 

Free radical addition to oximes and oxime ethers emerged as a useful alternative to addition of organometallic reagents, particularly for intramolecular reactions. The most important advantage of free radical V5. organometallic addition is its tolerance for almost any functional group (with the exception of thiocarbonyl and iodoalkyl functions). 

Free radicals generated by zinc and alkyl iodides easily add to oxime ethers (e.g. 106, equation 75), providing good yield of corresponding hydroxylamines 107. This reaction has also been performed in solid-phase bound oxime ethers. ... 

More recently, Kim and coworkers have developed a novel radical alkylation reaction of organic nitro derivatives 16a-d via bis(silyloxy)enamines 17a-d (Scheme 16). This method enables not only P -alkylation to the nitro gronp, bnt also the conversion of the nitro group (16a-d) into an oxime ether fnnctionahty (18a-d). The irradiation of a solntion of 16a-d with iodomethyl phenyl snlfone (or ethyl iodoacetate) and hexamethylditin in benzene at 300 nm give the oxime ethers 18a-d in good yields. 

Tin-based reagents are not always snitable owing to the toxicity of organotin derivatives and the difficulties often encountered in removing tin residues from the final product. Therefore, the same authors have carried out additional experiments with 17d and several different alkyl halides under tin-free conditions. The treatment of 16d with tert-butyldiphenylsilyl chloride (TBDPSCl) and triethylamine in the presence of silver triflate in CH2CI2 affords the bis(silyloxy)enamine 17d in 92% yield (Scheme 17). When the radical reaction was carried out with ethyl iodoacetate in the presence of 2,2 -azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) as the initiator in CH2CI2, the oxime ether 19 was obtained in 83% yield (Scheme 17). 

Recently, Kim and colleagues have described a new efficient method for the preparation of a-keto esters 48 via a free-radical acylation approach using (phenylsulfonyl) methoxycarbonyl oxime ether 46 as carbonyl equivalent radical acceptor (Scheme 28). The oxime 46 was conveniently prepared from readily available methylphenylsulfonyl acetate 44 by a two-step sequence (via oxime 45) as shown in Scheme 28. Nitrosation of 44 with isoamyl nitrite in the presence of sodium methoxide gave oxime 47 in 78% yield. 

Recent advances in radical reactions have greatly benefited from the efficiency of organotin reagents as mediators. Radical reaction of alkyl iodides with trifluoromethyl phenylsulfonyl oxime ether 69 and hexamethylditin at 300 nm in benzene afforded the corresponding trifluoromethyl oxime ethers 70 in high yields (Scheme 37) . 

Radical cyclization of oxime ethers having allylic substiffients to five-membered rings including furan and pyrrole derivatives was described in reviews A thiophenol-promoted radical cyclization of oxime ethers into tetrahydrofurans was recently described. For example, oxime derivative 36 in the presence of thiophenol and azobisisobuty-ronitrile (AIBN) afforded substimted tetrahydrofurans 37 and 38 in a ratio 1.2-3 1 (equation 17) . Radical cyclization of oxime ethers 39 to tetrahydrofurans 40 was successfully realized in the presence of alkyl iodides and EtsB in refluxing toluene (equation 18) . ... 

Cobaloxime-mediated intramolecular radical cychzation of oxime ethers 41 to furan derivatives 42 occurred during electrolysis in yields up to 76% (equation 19) . ... 

Radical cyclization of oximes or oxime ethers having allylic substituents or an aldehyde group to tetrahydropyrrole derivatives was described Thus, Sm -induced 5-exo-trig radical cyclization of oxime ethers containing a formyl group was found to be particularly effective for the preparation of cyclic trans-wimo alcohols. For example, oxime 96 in the system SmE/THF/f-BuOH at 25 °C or —78°C afforded pyrrolidin-3-ols 97 and 98 in a ratio 3 2 or 9 1 (equation 41) . Cyclization of oxime ether 99 in the... 

Total synthesis of (-l-)-lycoricidine, (—)-lycoricidine and (-l-)-narciclasine via 6-exo cyclization of substituted vinyl radicals with oxime ethers has been reported . Thus, interaction of oxime ether 321 with thiophenol and then with Sml2 and TFA afforded (-l-)-lycoricidine 322 in good overall yield (equation 139). 

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

On the other hand, since oxime ethers were electrochemically more inert than ketones under the electroreduction conditions, the electroreductive intra- and inter-molecular coupling of ketones with oxime ethers proceeded via anion radicals in good yields (equations 5 and 6) °4i. Moreover, cobaloxime-mediated intramolecular radical addition onto oxime functions in the electrolysis media proceeded to afford the cyclized aminoethers (equation 7). ... 

Other approaches to synthesize highly substituted cyclopentanes, including amino and hydroxy groups, from y- and lactones, has been radical and anionic Michael cyclizations of the a-iodo-y- and -<5-lactones [94]. Likewise, methods using radical cyclization to oxime ethers have been reported to give amino substituted cyclopentanes [95,103,104]. It should be noted that although only one isomer is often obtained [103], such cyclizations generating a secondary radical may not be stereospecific [95,100,101]. 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Although persistent radicals can be thermodynamically favored with respect to their dimers, they often react rapidly with other molecules and radicals. For example, TEMPO couples with alkyl radicals with rate constants that are nearly as large as diffusional rate constants to give oxime ethers that are stable... 

An alkyl group (primary, secondary, or tertiary) can be added to the oxime ether CHr=NOCH2Ph by treatment with the appropriate alkyl halide and an equimolar amount of bis(trimethylstannyl)benzopicolinate.483 This reaction, which is a free radical addition, is another way to extend a chain by one carbon. 

The phenylthionocarbonate procedure was also used for the cyclization of a 5-oxime-ether radical (Scheme 6) [17]. The stereochemical outcome of this reaction is almost identical with that observed for a closely related 6-methoxyhex-5-enyl radical cyclization [12,14]. A related glucosamine-derived radical cyclization has been employed for the synthesis of allosamizoline 13 [18]. Other examples in this area include the cyclization of... 

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