Hydrazones alkyl halides

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... 

Hydrazinothiatriazole (133) reacts rapidly with ketones and aldehydes to give thermally relatively stable hydrazones (134) in good yields ( 80%) <85ZC136, 87JPR409). Compounds (134) are alkylated with alkyl halides exclusively at the hydrazino functionality (rather than at N(4)) to give (135) (Scheme 27). 

The metalated hydrazones are alkylated by alkyl halides, dialkyl sulfates or alkyl sulfonates at low temperatures in tetrahydrofuran (—95°C) or diethyl ether (— 110°C) to form the a-sub-stituted hydrazones in nearly quantitative yields. The ambident azaenolates react exclusively at the C-terminus side products resulting from N-, di-, or polyalkylation are not observed. The crude alkylated hydrazones can be purified by distillation or silica gel chromatography (diethyl ether/pentane) without epimerization. However, in most cases, they are pure enough to be directly cleaved to the desired alkylated carbonyl compound. 

A solution of 1 equiv of (S)- or (/ )-2-methoxymetliyl-1-[(2,2-dimethyl-l,3-dioxan-5-ylidene)amino]pyrro-lidine in THF (4 mL/mmol) is cooled to — 78 °C. 1.1 Equiv of tert-butyllithium in hexane (1.7 M) are added dropwise and the mixture is stirred for 2 h at — 78 °C. The solution of the metalated hydrazone is cooled to — 100 CC, 1.2 equiv of the alkyl halide (neat or as a solution in anhyd THF) are added dropwise, and the mixture is stirred for 1 h at —100 °C and then warmed slowly to r.t. (about 15 h). Finally, diethyl ether (30 mL/mmol) is added and the mixture is washed with pH 7 buffer (3 mL/mmol) and two 3-mL portions of brine, dried over MgSO and evaporated under reduced pressure. The Crude product is heated to 50 C for a short time if necessary (about 15 min for isomerization from the Z- to the L-isotiler monitored by TLC) and purified by silica gel column chromatography (diethyl ether/ pentane, 1 1 -2 5 Rf - > RfZ-iso-mer) to give a colorless or pale yellow product. See Table 2 for physical data. 

The oxidation of phenylhydrazine and 1,2-disubstituted hydrazines to hydrazones and diazenes by CI2C proceeds via formation of unstable azomethine imines.95 The conversion of alcohols into alkyl halides is achieved by reaction with CCI4 (or CBr4) in DMF under electrochemical reduction.96 The reaction of dihalocarbene X2C with DMF to form a Vilsmaier reagent (93) is proposed as the key process. The reaction of simple isocyanates (RNCO) with dimethoxycarbene normally gives hydantoin-type products. In the reaction with vinyhsocyanates such as (94), however, hydroindoles (95) are formed in good yields.97... 

However for the formation of optically active a-alkyl aldehydes, the imine or hydrazone routes have proved of considerable value.122 In the preparative example123 the aldehydes propanal and octanal are converted with (S)-( — )-2-amino-l-methoxy-3-phenylpropane (14) into the imines (15) and (16) respectively. Treatment with lithium diisopropylamide then yields the corresponding lithioenamines [only the (fs)-isomers are formulated, since the (Z)-isomers would be less stable]. These intermediates have a topography which determines the subsequent direction of attack by the alkyl halide (see also Section 5.11.7, p. 688). In the formulation below, this stereoselection is from above the plane of the paper and leads to the (/ )- and (S)-2-methyloctanals respectively. 

Reaction of cyanide ion with an alkyl halide is often the most convenient route to a nitrile, but in those cases where the corresponding aldehyde or ketone is more readily available than the alkyl halide, the following procedure is very convenient. The carbonyl compound is first converted into its 2,4,6-triisopropyl-benzenesulphonyl hydrazone (1) (Expt 6.42 gives the method for the preparation of the reagent, TBSH), which without isolation is then reacted with potassium cyanide under gentle reflux.169... 

Both sides of acetone have been alkylated with different alkyl groups, in one operation, by treatment of the A, A -dimethylhydrazone of acetone with n-BuLi, followed by a primary alkyl, benzylic, or allylic bromide or iodide then another mole of n-BuLi, a second halide, and finally hydrolysis of the hydrazone. " Alkylation of an unsymmetrical ketone at the more substituted position was reported using an alkyl bromide, NaOH, and a calix[n]arene catalyst (see p. 122 for calixarenes). ... 

The deprotonation of the SAMP/RAMP hydrazone derivatives leads to the formation of azaenolates that can be trapped by the alkyl halide. In theory, four isomeric azaenolates can form in the deprotonation step, but it was shown that around the C-C double bond stereochemistry is dominant, while around the C-N bond Z stereochemistry EccZcn is dominant for cyclic- and acyclic ketones. This observation was confirmed by trapping experiments,... 

The group of Tietze has described syntheses of variously substituted pyrazolones 20 starting from solid-phase-bound p-keto esters. Single or iterative alkylation of the dianion of immobilized acetoacetate with allyl-, benzyl- or alkyl halides produced a set of y-substituted ketoesters 18 that could be transformed to the phenyl-hydrazones 19. Treatment of these intermediates in toluene at 100 °C produced 1-phenylpyrazolone derivatives 20 in 40-75% yield (Scheme 6) [14]. 

The same group reported an approach to trisubstituted pyrazolones beginning with a solution-phase acylation of Meldrum s acid 21 and resin-capturing of the intermediates 22 with the add-stable resin 27. The products 23 were a-alky-lated using tetrabutylammonium fluoride (TBAF) and primary alkyl halides under strict exclusion of moisture, as otherwise the yields dropped dramatically. Treatment of the products 24 with phenyUiydrazines produced the corresponding hydrazones 25, which were cleaved from the solid phase by cyclization using 2% TFA in acetonitrile at room temperature to form pyrazolones 26 [15[ (Scheme 7). 

The Mn mediated radical additions offer an inherently flexible carbon carbon bond construction approach to amine synthesis. Because of the broad functional group compatibility in both the radical precursor and the aldehyde hydrazone acceptor, the roles of these precursors can be switched to result in the construction of either of two C C bonds at the chiral amine (Scheme 2.10) with excellent stereocontrol. The epimeric configuration can be selected by either (a) employing the enantiomeric auxiliary or (b) interchanging the roles of R and in the alkyl halide and aldehyde precursors [47]. By combining these two tactics, the optimal roles of R and with respect to yield and selectivity can be chosen. Such strategic flexibility contributes to the synthetic potential of these radical addition reactions. 

Until about 30 years ago, hydrazones derived from carbonyl compounds were not used in organic synthesis. They were used only for analytical purposes , and as protecting groups of aldehydes and ketones ". Corey investigated dimethylhydrazones of ketones and aldehydes with a-hydrogens, and found that they undergo deprotonation with LDA or BuLi in THF at the a-carbons to the hydrazonic moiety in 90-100% yield. The formed lithium compounds, used as enolate anion equivalents, create new carbon-carbon bonds in their reaction with different electrophiles such as alkyl halides or oxiranes, ketones and aldehydes (equation 21). 

The a-diketones, e.g. (37), made by oxidation of benzoin or acyloin products, can be converted into acetylenes either by removing both oxygens with P(OR)j or via the 6is-hydrazone (38) and oxidation with Hg(ll). This method is useful for acetylenes such as (39) which cannot be made by displacement on alkyl halides by acetylide ion (Chapter 16). In this case, the starting material (37) is made from benzoin (Chapter 23) by nitric add oxidation. 

Other activated systems, specifically activated alkynes and hydrazones, have been employed as radical acceptors for alkyl radicals generated from alkyl halides and Sml2 [11]. Radical addition reactions to activated alkynes appear to be more capricious than the reactions with activated alkenes, and thus are perhaps more limited in scope. Additionally, mixtures of diastereomers inevitably result from such systems (Eq. 11) [12]. Diphenylhydrazones were shown to react approximately 200 times faster than the analogous alkenes in 5-exo additions as determined in a series of studies by Fallis and Sturino [13]. Reasonable diastereoselectivities were exhibited in these processes (Eq. 12). 

Conversion of alkyl halides to hydrazones. Primary and activated secondary alkyl halides react with this triflyl hydrazine and K2 CO3 (2 eq.) in acetonitrile to form acyl hydrazones of aldehydes and ketones, respectively. The reaction involves alkylation followed by elimination of HSO2CF3. Yields are high (80-90%) in the case of aldehyde derivatives, but they are lower in the case of ketone derivatives. 

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