Hydrazones alkylation

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 1.05 equiv of lithium diisopropylamide in diethyl ether (4-7 mL/mmol) is prepared as above. 1 Equiv of the a-alkylated hydrazone is added and the mixture is stirred for 5 h at 20°C. The solution of the metalated hydrazone is cooled to — 110 °C, 1.1 equiv of the electrophile are added dropwise, and the mixture is stirred for an additional 3 h at this temperature. After the mixture has warmed up slowly (15 h) to 20 "C, diethyl ether (40 mL/mmol) is added and the mixture is worked up as above. 

Starting Hydrazoneb Reaction Conditions Alkylated Hydrazone Cleavage Methodf Con fig. of Stcrcogenic Center Formed eed s (%) Yield (%) Over- all [a]D (c, solvent)6 Ref... 

Starting Hydrazoneh Reaction Conditions Alkylated Hydrazone Cleav- Config. of eef Yield Over- [ Id Ref... 

One equiv of the alkylated hydrazone is dissolved in 5 equiv of iodomethane and the solution is heated to 60 cC in a reflux condenser. After 20 -48 h the reaction is complete (monitored by TLC) and excess iodomethane is removed in vacuo. The remaining methoiodide (viscous brown oil) is dissolved in 3 4N hydrochloric acid (50 mL/10 mmol) and stirred for 5 min at 20 C. Pentane (200 mL/10 mmol) is then added and the two-phase system is vigorously stirred for 30 min. The organic layer is separated, washed with a few mL of a sodium hydrogen sulfite soln and a pH 7 buffer soln, and dried over Na2S04. The solvent is removed in vacuo and the remaining crude product is purified by short path or Kugelrohr distillation. 

Since the above cleavage methods proceed without racemization, the enantiomeric excess of the alkylated carbonyl compounds obtained can be safely determined by measuring the diastereomer-ic ratio of the alkylated hydrazones (see Section I.I.I.4.2.3.). The diastereomeric excess of SAMP-hydrazones derived from aldehydes was further determined by gas chromatography41. 

In addition, alkylated aldehydes can be transformed to (—)-(5)-l-amino-2-(tcr/-butyldi-methylsilyloxymethyl)pyrrolidine (SASP)-hydrazones without racemization. The diastereomeric ratio of these hydrazones can be determined directly using HPLC. Furthermore, this method allows determination of the absolute configuration of the alkylated hydrazones, since SASP-hy-drazones of (S, -configuration always elute first11 25. 

Having the electrophile 95 to hand, the synthesis proceeded by metallation of the SAMP hydrazone 96 followed by alkylation with the iodide affording the a-alkylated hydrazone 97 with diastereomeric excess de = 9S% (Scheme 1.2.21). The removal of the auxiliary proceeded smoothly with oxalic acid, leading to 98 in good yield (80%, two steps) and no epimerization without deprotection of the amino group. 

Aryl and alkyl hydrazones of propanal and of alkanones are transformed into 1-chloroalkylazo compounds by reaction with -butyl hypochlorite (equation ll)24. This... 

In carrying out such a dehydrogenative cyclization on alkyl hydrazones 280 derived from 6-hydrazinotetrazolo[l, 5-/ ]pyridazine (279) using lead... 

Alkylations of hydrazone anions derived from aldehydes and ketones are closely related to imine anion alkylations. Lithiated hydrazones are particularly powerful nucleophiles for alkylation reactions. The alkylated hydrazones may be cleaved with periodate, as shown below.The choice of solvent and base is critical to the success of hydrazone alkylations hexane-free medium is essential for complete metalation. °... 

Asymmetric synthesis via chiral, nonracemic hydrazones have gained wide acceptance in the community of synthetic organic chemists. Some examples of asymmetric alkylations of acyclic, satu-rated and unsaturated cyclic ketones - and aldehydes, which are applicable in the natural products field, are shown in Scheme 55. Various methods of cleavage of the alkylated hydrazones are also illustrated in Scheme 55. 

Two points should be mentioned for TV-alkylated amidrazone ligands (Type 6). Firstly, the reaction of TV-alkylated hydrazones (R1R2C=N—NH2) with corresponding imidates (R3C(=NH)OMe) may also be a practical synthetic method. Secondly, an earlier literature reference (Case, 1965150) suggested that such compounds are triazoline species as shown below. 

Auch (l-Phenyl-alkyl)-hydrazone, die am besten aus den entsprechenden Ketazinen mit Phenyl-magnesiumbromid hergestellt werden, lassen sich iiber Platin (I V)-oxid in Athanol zu 1,2-Dialkyl-hydrazinen hydrieren11 ... 

Asymmetric synthesis of a-alkylated ketones and aldehydes Chiral hydra-zones of ketones prepared from 1 on metalation (LDA) and alkylation are converted into ot-alkyl hydrazones of the ketones. The a-alkyl ketones are obtained on ozonolysis or hydrolysis. Optical yields in this conversion are 30-85% and depend on the structures of the ketone and alkylating agents. a-Chiral aldehydes can be obtained in the same way and with similar optical yields. 

This set of ARl values illustrates that the simplest alkyl hydrazones (methyl, ethyl, dimethyl, etc.) have appropriate GC retention parameters and theoretically can be recommended as the derivatives of carbonyl compounds. But in real... 

The asymmetric hydrogenation of imine derivatives that contain a second ligating functionality to create two-point binding of the substrate have been investigated. Reactions of two types of such substrates are shown in Equations 15.85 and 15.86. In the first example, an aroyl hydrazone undergoes selective hydrogenation to form the enantioenriched N-alkyl hydrazone. Oxidative cleavage of the N-N bond then leads to the primary amine. 

A novel method related to the insertion of carbenes into N-H bonds has been reported. It involves the reductive coupling of A-tosylhydrazones under mild basic conditions to afford the corresponding A-alkylated hydrazones in moderate to good yields The procedure benefits from the well-known ability of A-tosylhydrazones to generate carbenes in situ, the so-formed carbene finally undergoing insertion into the N-H bond of the second equivalent of A-tosylhydrazones. 

Reaction with Aldehydes and Ketones. Classical preparations of aryl and alkyl hydrazones with hydrazine lead to mixtures of hydrazones and azines (eq 2). 

This problem can be surmounted by the use of BTBSH, which affords the (V-silyl hydrazones cleanly and in high yield (eq 3). Thus, iV-silylated aryl and alkyl hydrazones are prepared hy reaction of l,2-bis(t-butyldimethylsilyl)hydrazine with an aldehyde or ketone in the presence of a catalytic amount of Sc(OTf)3 in dichloromethane (eq 3). A number of Lewis acid catalysts were explored, with Sc(OTf)3 being the most effective, giving the hydrazones in yields of up to 95% as mixtures of the syn- and anti-isomers. In the absence of Lewis acid catalysis, the reaction does not proceed. Unlike the simple hydrazine-derived hydrazones, the resulting iV-silyl hydrazones are stable, isolable, and capable of being stored for extended periods of time. 

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