Hydrazones radical addition

Hexafluoroacetone azine accepts nucleophiles (ROH, RSH, R NH) in positions 1 and 2 to yield hydrazones [27] Phosphites give open-chain products via a skeletal rearrangement [22] Radical addition reactions are also reported [22] Treatment of tnfluoropyruvates with tosylhydrazine and phosphorus oxychlo-ride-pyndme yields tnfluoromethyl-substituted diazo compounds [24] (equation 3)... 

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... 

Intramolecular addition of trialkylboranes to imines and related compounds have been reported and the main results are part of review articles [94, 95]. Addition of ethyl radicals generated from Et3B to aldimines affords the desired addition product in fair to good yield but low diaster control (Scheme 40, Eq. 40a) [96]. Similar reactions with aldoxime ethers [97], aldehyde hydrazones [97], and N-sulfonylaldimines [98] are reported. Radical addition to ketimines has been recently reported (Eq. 40b) [99]. Addition of triethylborane to 2H-azirine-3-carboxylate derivatives is reported [100]. Very recently, Somfai has extended this reaction to the addition of different alkyl radicals generated from trialkylboranes to a chiral ester of 2ff-azirine-3-carboxylate under Lewis acid activation with CuCl (Eq. 40c) [101]. 

Enantioselective radical addition to AT-acyl hydrazone using triethylborane as chain transfer reagent has been reported by Friestad. Enantiomeric excesses up to 95% were obtained in the presence of copper(II)-bisoxazolines Lewis acid (Scheme 51) [115]. 

Scheme 31 Enantioselective radical additions onto hydrazones...

Friestad and co-workers recently demonstrated that N-acyl hydrazones were excellent radical acceptors in the presence of a chiral Lewis acid [84], Valerolactam-derived hydrazone 117 proved to be the optimal substrate for enantioselective radical additions. Upon further optimization it was found that Cu(OTf )i and f-bulyl bisoxazoline ligand 96 gave the best yields and ee s (Scheme 31). Interestingly, a mixed solvent system (benzene dichloromethane in a 2 1 ratio, respectively) in the presence of molecular sieves (4 A) were necessary to achieve high yields and selectivities. 

Radical Additions to Chiral Hydrazones Stereoselectivity and Functional Group Compatibility... 

Based on all these considerations, we chose to develop a new type of chiral hydrazone, tailored for use in free radical addition reactions, which would incorporate Lewis acid activation [35-37] and restriction of rotamer populations as key design elements [1-7] (Fig. 2). 

An early transition state is commonly assumed for exothermic radical addition reactions, and this enables approximation of the transition state geometry based on the ground-state structure. From this assumption, we hypothesized that a substituent above or below the plane of the C=N bond in the ground state hydrazone structure... 

The first test of the chiral /V-acylhydrazones was in tin-mediated radical addition [47,48]. Addition of isopropyl iodide to propionaldehyde hydrazone 3a was chosen for initial screening (Scheme 2). Using the tin hydride method with triethylborane initiation [51, 52] (Bu3SnH, Et3B/02), with InCl3 and ZnCU as Lewis acid additives, desired adduct 13a was obtained with high diastereoselectivity. In contrast, 13a was produced with poor selectivity (diastereomer ratio, dr 2 1) in the absence of Lewis acid. 

Variations to the radical acceptor component were also examined with a series of aldehyde hydrazones (Table 3, entries 7-15) [48]. Branching at a saturated a-carbon diminished the yields (entries 7-10), but the aromatic hydrazone 7 allowed successful radical addition (entries 11-14). The reactions were generally quite clean with the exception of 8a, which decomposed under these conditions (entry 15). It should be noted that low yields were accompanied by unreacted hydrazones 80-90% mass balance was generally observed. 

Diastereoselectivity in radical additions to hydrazones 3 and 7 proved to be quite promising, with diastereomer ratios ranging from 93 7 to 99 1 (Table 3) [47]. In search of optimal stereocontrol, substituents on the oxazolidinone moiety were varied. Thus, isopropyl radical additions to several /V-acylhydrazones 3a-3e were compared for stereoselectivity (Scheme 3). High diastereoselectivities were observed in all adducts 13a-13e, although a rigorous measurement was not obtained on 13c. All of the auxiliaries impart stereocontrol suitable for practical synthetic application [48],... 

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. 

Because disconnection of a-alkoxy-y-amino acid 28 calls for (3-alkoxyhydra-zone 30, the potential for (3-elimination of the alkoxy group from the hydrazone precursor 30 (Scheme 7) makes non-basic conditions critical. In fact, treatment of 30 with TBAF in THF led to just such a (3-elimination (Marie, University of Iowa, unpublished). However, the manganese-mediated radical addition of isopropyl iodide proceeded in 77% yield, without any evidence of (3-elimination, to afford 31 as a single diastereomer. Reductive removal of the chiral auxiliary and oxidation to the carboxylic acid gave 28 in good overall yield [103]. 

In combination with the range of standard transformations of alcohols, alkenes, and vinylsulfides, these silicon-tethered additions of functionalized radicals offer a versatile and stereoselective approach to amino alcohol synthesis. Whereas vinyl and 2-oxoethyl radicals have not yet been demonstrated as competent participants in the various intermolecular additions reported in the literature, the temporary tether approach allows such functionalized fragments to be installed in an efficient and stereoselective manner. Synthesis of the aminosugar daunosamine from achiral precursors shows how this concept, employing hydrazone radical acceptors, can be merged with asymmetric catalysis to achieve practical synthetic advances. 

Furthermore, we also performed kinetic studies for alkyl radical additions onto different types of C=N bonds such as imines and oxime ethers. The kinetic data are summarized in Figure S. Kinetic analysis of the intramolecular addition of alkyl radicals to C=N bonds provides several experimentally important results. First, alkyl radical additions to C=N bonds are much faster than the corresponding additions to C=C bonds, indicating that C=N bonds are much better radical acceptors than C=C bonds. Furthermore, 5-exo cyclization is faster than 6-exo cyclization. Second, the intramolecular additions of alkyl radicals to C=N bonds are essentially irreversible. Third, alkyl radical additions to oxime ethers and hydrazones are faster than alkyl radical additions to imines, suggesting the possibility of a dependence of the cyclization rate on the electron density at the carbon atom of the radical acceptor. 

---