Oxime ethers, radical addition reactions

Jang and co-workers reported on the development of an enantioselective radical addition reaction to glyoxylate oxime ether for the preparation of a-amino acids under mild reaction conditions with chiral quaternary ammonium salts of hypophosphorous acid in aqueous media.26 The newly prepared chiral quaternary ammonium hypophosphites are inexpensive, less toxic than metal-containing compounds and the reaction conditions and workup are mild and simple (Table 7.2). It is also important to note that chiral quaternary hypo-phosphites are recyclable without altering their performance. The... 

Table 7.2 Radical addition reactions to glyoxylic oxime ether under various reaction conditions.

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. 

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... 

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. 

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). 

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). 

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. 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

Miyabe et al. developed a tandem addition/cycUzation reaction featuring an unprecedented addition of alkoxycarbonyl-stabihzed radicals on oxime ethers [117], and leading to the diastereoselective formation of /1-amino-y-lactone derivatives [118,119]. The reaction proceeds smoothly in the absence of toxic tin hydride and heavy metals via a route involving a triethylborane-mediated iodine atom-transfer process (Scheme 37). Decisive points for the success of this reaction are (1) the differentiation of the two electrophilic radical acceptors (the acrylate and the aldoxime ether moieties) towards the nucleophilic alkyl radical and (2) the high reactivity of triethylborane as a trapping reagent toward a key intermediate aminyl radical 125. The presence of the bulky substituent R proved to be important not only for the... 

The use of simple imines in intermolecular radical additions has been rarely exploited, in part, because of modest reactivity of the C=N bond toward nucleophilic radicals such acceptors may benefit from the presence of electron withdrawing groups at the imine carbon. Thus, Bertrand found these reactions to be particularly successful with a iminoesters 2 (Figure 2.2a) [6]. More reactive oxime ethers have been extensively exploited for radical addition, mainly through the longstanding efforts of Naito [7]. Stereocontrol has been imparted through the substituent on the imino carbon, as exemplified by camphorsultam 4 (Figure 2.2b). Attempts to use chiral O substituents on oximes for stereocontrol have been ineffective, presumably due to poor rotamer control [8, 9]. 

The radical carbonylation of an alkyl iodide in the presence of Kim s sulfonyl oxime ethers [58, 59, 60] provides a new type of multicomponent coupling reaction where plural radical Cl synthons are consecutively combined [61]. In the transformation, allyltin was used to serve as a trap of benzenesulfonyl radical which converts sulfonyl radical to a tin radical, thus creating a chain. Scheme 14 illustrates such an example, where the product was easily dehydroxylated to give the corresponding tricarbonyl compound on treatment with zinc/AcOH. The radical acylation reaction by Kim s sulfonyl oxime ethers can be conducted under irradiation with the addition of hexamethylditin. This is an alternative path for achieving a similar transformation without the use of photolysis equipment. Scheme 15 illustrates several examples where carbon monoxide and Kim s sulfonyl oxime ethers are successfully combined to create new tandem radical reaction sequences [61],... 

The Naito group has also prepared pyrrolidines [23] on solid phase by a combination of intermolecular radical addition to alkene 43 (Scheme 10) followed by intramolecular oxime ether cyclization to yield 44. These reactions proceeded sluggishly with triethylborane at room temperature, while the analogous solution-phase process was kinetically much faster. Radical additions to the phenylsulfonyl oxime ether 45 were reported by Jeon et al. [24]. Yields were better with primary and secondary alkyl iodides, and the tandem cyclization sequence with iodide 46 to afford bicyclic 47 was also accomplished, albeit in modest yield. 

Addition of aryl radical to oximes was explored by Jenkins and coworkers [53]. Reaction of the oxime ethers 221 with Bu3SnH and AIBN using slow addition techniques furnished the tricyclic alkoxyamines 222 via 1-exo trig radical cyclization along with the uncyclized reduction product 223. 

Naito and coworkers [65] have reported the synthesis of hexahydroazepine part of balanol employing a radical addition of an aldehyde to an oxime ether. Treatment of the aldehyde 260 with Bu3SnH and AIBN furnished a 1 2 mixture of cis and trans amino alcohols 261 via a 1-exo trig radical cyclization reaction. The effi-... 

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