2,2-Dialkylated hydrazone

Of note, the above methodology has also been extended to the synthesis of a chiral non-racemic 2,2-disubstituted oxetane-3-one, with the generation of a quaternary center firom an a-CH2 unit, by simply exploiting a one-pot double alkylation protocol. Starting firom oxetane-3-one 45, 2,2-dialkylated hydrazone 49 was first obtained with an overall yield of... 

Fluorocylatwn of enarnines and enamides has been intensively studied by different groups [78, 79, 80 SI] The effectiveness of this particular electrophilic substitution reaction becomes obvious when the nitrogen atom of the enamine moiety is engaged in an aromatic system [82 S3] or when the olefinic system is part of an aromatic nucleus [84] (equations 37 and 38) A further extension of this reaction is demonstrated by the tnfluoracetylation of aldehyde dialkyl hydrazones [S5 86] (equation 39)... 

Thiamine-catalyzed transformations are reversible, thus TV,/V-dialkyl hydrazones were selected as alternative acyl anion equivalents that were reported to react with electrophiles without acidic activation.41 One especially reactive example, formaldehyde hydrazone resin 13, was constructed from polymer-supported hydrazines and was employed in the first polymer-supported, uncatalyzed acyl anion additions (Fig. 8).38 As test substrates, nitroalkenes (as Michael acceptors) and activated aldehydes were selected. Reactivity of these acyl anion equivalents depended critically not only on the nature of the starting hydrazine, but also on the protocol for hydrazine formation. 

In DMF, benzalazine (VII) shows two, one-electron steps in CV. Preparative reduction of VII in the presence of an alkylating agent yields alkylated bis-hydrazines (VIII) or the dialkylated hydrazone (IX) [51], as in Eq. (14). An assignment of the stereochemistry of the bis-hydrazones, obtained by reduction of VII followed by protonation, could be achieved by cyclization with aldehydes to imidazolidines. 

Mit guten Ausbeutenlassen sich auch Dialkyl-hydrazone mit Palladium/Kohle bzw. Platin(IV)-oxid zu Trialkyl-hydrazinen hydrierenvgL 1 so erhalt man z. B. aus Formalde-hyd- bzw. Acetaldehyd-dimethylhydrazon iiber Pd/Kohle (25—3871 bar) 73% d.Th. Trimethyl-hydrazin bzw. 77% d.Th. 2,2-Dimethyl-l -athyl-hydrazin2. 

Latterly a superior method for producing the (trifluoromethyl)-l,3,4-oxadiazines (199) rapidly (6 h), and in high yields (72-97%), has been found which involves treating the a-(trifluoro-acetyl)hydrazones (197) with trifluoroacetic acid at room temperature <90S493>. The reaction is successful with a range of A-mono- (197 R = Bu , R = Me) and A,A-dialkylated hydrazones, with the exception of the A-/-butyl-hydrazone which suffers de-/-butylation. However, cyclization of the /-butyl derivative is possible in warm (50 °C) acetic acid higher temperatures have to be avoided in order to prevent imidazole formation. 

Staudinger reactions have been used to obtain P-lactams as substituents on quinones (e.g. 55) <01TL1503> and as spiro compounds (e.g. 56) <001JC(B)304>. The MA -dialkyl-hydrazone 57 was used to obtain 58, which was A -deprotected in high yield with magnesium monoperoxyphthalate in methanol to give the 1,4-unsubstituted P-lactam <00AG(E)2893>. 

Hojo reported a selective synthesis of 4-(trifluoromethyl)imidazoles (Scheme 35) [49], The diketones, prepared from aldehyde dialkyl hydrazones via the hydrolysis of 3-(dialkylhydrazino)-l,l,l-trifluoro-2-aIkanone intermediates, were treated with 1,1-dimethylhydrazine to afford the adduct. These adducts were generally unstable even at room temperature and, thus, were immediately dehydrated using POCI3-pyridine to afford 3-aryl-l,l,l-trifluoropropane-2-,3-dione-2-dimethylhydrazone. Intramolecular cyclization of these hydrazones in refluxing toluene afforded the desired 4-(trifluoromethyl)imidazoles. 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

SCHEME 7.13. (A) Regioselectivity of bisalkylation of dialkyl hydrazones and imines and (B) regioselectivity of bisalkylation of ACC hydrazones. 

N-Acyl-hydrazone werden durch Lithiumalanat zu 1,2-Dialkyl-hydrazinen und Acyl-hydrazinen reduziert3 ... 

An adaptation of the Arbuzov reaction (Scheme 14) using the hydrazones of 1-chloroalkyl ketones provides a route to dialkyl (2-oxoalkyl)phosphonates (79 R =Me, C1CH2, Ph, EtOOCCH2, or (Et0)2P(0)CH2 R2=H, generally R3=MeO, EtO).73... 

Hydrazinobenzimidazole derivative 336 was treated with oxocarboxylic acids to give a hydrazone 337 which underwent ring closure to the fused triazinone 338 <2000JME96, 2001JME316>. Reaction with dialkyl oxalate allowed the synthesis of the triazinedione derivative 339 <2001JME4359>. 

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. 

Hydrazines may be nucleophiles such as when they interact with aldehyde and keto groups to form hydrazones. This is the basis for the inhibition of enzymes such as transaminases, which rely on pyridoxal phosphate as a coenzyme. Mono-substituted hydrazines can be formed as metabolites when azo groups are reduced, dialkylated hydrazines are dealkylated or hydrazides are hydrolysed. 

The known disuhstituted ketencs include dialkyl-ketcnes, diary lkctcncs. and ihe ester analogs. Rimcthylkelene may be made from u-bromoisobuiy-ryl bromide by reaction with zinc in boiling ether, Diphenylketene may be made similarly, but the usual way lo prepare it is to oxidize benzil hydrazone with yellow mercuric oxide to benzoylphenyldiuzomethnne which, on healing in benzene solution, decomposes inio Ihe ketene. 

In addition to the methyleneindolines, 4-methylene derivatives of 1,3-dialkyl-pyrimidin-2-one have also been used to prepare hydrazone dyes (e.g., 12) [26,32], A dye of this series is C.I. Basic Yellow49. ... 

The introduction of a phosphorus-containing group into the side chain of the hydrazone fragment of isatin was reported in [97]. The results of a study of the kinetic relationships and mechanism of the addition of dialkyl phosphites to substituted benzylideneamines, which were related to the basicity of the initial amines, were published as abstracts in [98]. 

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