A-Acyl hydrazone

Reductions of hydrazones with LAH may, as expected, proceed further if carbonyls or other susceptible groups are present. Thus, A -acyl hydrazones (e.g. 30) give A -alkylhydrazines along with the A -acyl derivative (equation 7), while the phenylosazone (31) gave further rearrangements of the intermediate dihydrazine to afford (32 equation... 

In the course of our work, we became interested in the development of an NHC-catalyzed synthesis of y-lactams from a formal [3+2] cycloaddition reaction between enals and imines. While this reaction had been first reported by Bode [143], its enantioselective version remained elusive at the onset of our studies. We identified aminoindanol-derived azolium salt 10 as an efficient precatalyst to afford y-lactams with excellent enantioselectivity level when cinnamaldehyde reacts with A -acyl hydrazones derived from ethyl glyoxylate (Scheme 21) [144], Unfortunately, this reaction proved to be sluggish, affording a low yield of the target product after 24 h of reaction time. 

Rhodium diphosphine catalysts can be easily prepared from [Rh(nbd)Cl]2 and a chiral diphosphine, and are suitable for the hydrogenation of imines and N-acyl hydrazones. However, with most imine substrates they exhibit lower activities than the analogous Ir catalysts. The most selective diphosphine ligand is bdppsuif, which is not easily available. Rh-duphos is very selective for the hydrogenation of N-acyl hydrazones and with TOFs up to 1000 h-1 would be active enough for a technical application. Rh-josiphos complexes are the catalysts of choice for the hydrogenation of phosphinyl imines. Recently developed (penta-methylcyclopentyl) Rh-tosylated diamine or amino alcohol complexes are active for the transfer hydrogenation for a variety of C = N functions, and can be an attractive alternative for specific applications. 

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. 

Reaction of thionyl chloride with the A -acylated or tosyl hydrazone derivatives to provide the 1,2,3-thiadiazole in one step. 

As proof of principle, Lehn and coworkers individually synthesized all acyl hydrazone combinations from the 13 DCL building blocks and measured their inhibition of acetylthiocholine hydrolysis by ACE in a standard assay. They then established a dynamic deconvolution approach whereby the pre-equilibrated DCL containing all members is prepared, frozen, and assayed. Thirteen sublibraries were then prepared containing all components minus one hydrazide or aldehyde component, and assayed. Active components in the DCL were quickly identified by an increase in ACE activity, observed in sublibraries missing either hydrazide 7 or dialdehyde i, pointing to the bis-acyl hydrazone 7-i-7 as the most likely active constituent. This was in line with the individual assay data recorded earlier resynthesis of this compound characterized it as a low nanomolar inhibitor of the enzyme. 

In 2008, the same group employed chiral dicarboxylic acid (R)-5 (5 mol%, R = 4- Bu-2,6-Me2-CgHj) as the catalyst in the asymmetric addition of aldehyde N,N-dialkylhydrazones 81 to aromatic iV-Boc-imines 11 in the presence of 4 A molecular sieves to provide a-amino hydrazones 176, valuable precursors of a-amino ketones, in good yields with excellent enantioselectivities (35-89%, 84-99% ee) (Scheme 74) [93], Aldehyde hydrazones are known as a class of acyl anion equivalents due to their aza-enamine structure. Their application in the field of asymmetric catalysis has been limited to the use of formaldehyde hydrazones (Scheme 30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to formaldehyde hydrazone 81a (R = H) but also allowed for the use of various aryl-aldehyde hydrazones 81b (R = Ar) under shghtly modified conditions. Prior to this... 

A new synthesis of the pyrazolo[4,3-r ]pyridine core based on an unusual one-step tandem ring closure and rearrangement of bisacetylenic N-acylated hydrazones using aqueous ammonia has been reported (Equation 81 Table 34) <2004T933>. 

Uber eine Relais-Synthese lassen sich aus 4-(a-Amino-benzy]idenamino)-4H-l,2,4-triazolcn mit Carbonsaureanhydriden oder Carbonsaure-chloriden in Dimethylformamid 2-substi-tuierte 1,3,4-Oxadiazole im Eintopfverfahren herstellen552,553. Diese Reaktion verlauft iiber Acyl-hydrazone von 1-Formyl-3-phenyl-l,2,4-triazol, dessen Pyrolyse ebenfalls gute Aus-beuten liefert552. Mit dieser Methode konnten einige 1,3,4-Oxadiazole in besseren Ausbeuten und groBerer Reinheit als nach anderen Verfahren synthetisiert werden. 

Appropriate functionalization of C=N bonds can greatly assist their asymmetic reduction. In particular, the reduction of N-acyl hydrazones with a rhodium complex of the ligand DuPHOS (P13) represents an outstanding example. In this process (Scheme 62) a product of up to 97% e.e. is obtained in high yield. After the reduction, samarium-iodide cleavage of the N—N bond gives the product amine273,274. 

The cis and trans isomers of 18 behave somewhat differently in this reaction the trans isomer reacts faster at the stage of the aziridine cycle nucleophilic attack, whereas for another isomer this stage is inhibited by an adjacent cis substituent (Scheme 1.14). Such inhibition of the cyclization stage results in the formation of acyl hydrazone 56 as a by-product as well as the formation of pyrazole 55 from the intermediate aminopyrazoline by a rapid trans elimination. In the case of tnms-aziridinyl ketone 18, the slowest step is the cis elimination of RNH2, isolating 4-alkylaminopyrazines 54 in most cases. 

A large number of derivatives of the triazolo[l,2-6]triazoles (178) have been prepared either by self-condensation of aroyl- or acyl-hydrazones (177 -> 178) or by condensation of dihydrazones with dicarbonyl derivatives (179 -> 178) (57CB2411,63CB1827,67GEP1245386, 71GEP1620103). 

Having learned this, Dupont workers [52] have added a temporary auxiliary donor atom to an unsaturated substrate in order to be able to steer adduct formation, and so the enantioselectivity of the hydrogenation. For example, asymmetric hydrogenation of imines or ketones was a reaction that yielded rather low enantiomeric excesses. However, by converting these first into acyl hydrazones the hydrazide oxygen can function as the secondary complexation function and now extremely high enantiomeric excesses can be obtained (Fig. 6.23). 

The small-molecule-based machine conceived by von Delius, Geertsema, and Leigh [45] is a linear (for reviews, see [46], [100]) motor based on dynamic covalent chemistry [19-24] (forming, breaking, and reforming of dynamic covalent bonds with relatively fast equilibration in response to stimuli), namely on acyl-hydrazone and disulfide exchanges. The motor consists of a track that has four functional groups disposed alternately aldehyde-thiol-aldehyde-thiol which are the positions 1,2, 3, and 4 of the track, a walker NH2-NH-CO-(CH2)5-SH which has the feet A (hydrazide or acyl-hydrazine) and B (thiol), and a placeholder with a foot C of type thiol (Fig. 10). 

In a similar way, other pyridazines [306], such as 3-phenyl-6-methoxypyridazine and 3-methyl-6-chloropyridazine, are reduced, but the dihydropyridazines are in these cases rather unstable and may lose methanol or hydrogen chloride, forming the corresponding 4,5-dihydropyridazinone, which being an acylated hydrazone is cleaved with ring opening and reduction or hydrolysis of the ketimine (Chapter 11). 

Many thiadiazoles are polarographically reducible [148, 351] not many of them have been investigated by controlled potential electrolysis. The wave height of 2,5-diphenyl-1,3,4-thiadiazole (LX) corresponds in acid solution to a two-electron reduction to a dihydro derivative, which is probably hydrolyzed to benzaldehyde thiobenzoylhydrazone. This compound is reducible at the reduction potential of LX and will thus be reduced further similarly to other acylated hydrazones (Chapter 11). 

A reduction route similar to that of phenylhydrazones [229] seems to be rather general for azomethine derivatives of hydrazine [229] as it s followed by cyclic and acylic phenylhydrazones, semicarbazones, azines, cyclic hydrazones, and acylated cyclic and acyclic hydrazones [231] under pro tic conditions in DMF, acylated hydrazones of aromatic aldehydes are reduced with saturation of the C=N bond and cleavage of the N-N bond at a more negative potential [232]. The suggestion that the cleavage of the N-N bond precedes the saturation of the azomethine bond is also an essential part of the interpretation of many of the ring contractions of heterocyclic compounds (Chapter 18). 

Substituted 1,3,4-oxadiazoles have been synthesized by traditional methods according to several approaches, two of the more popular being the cyclization of diacyl hydrazides and the oxidation of acyl hydrazones. SoHd-phase syntheses involving cyclodehydration of a diacyl hydrazide intermediate have also been reported [100]. 

Figure 2.1 The C C bond disconnection approach to asymmetric amine synthesis and a generalized structure of N acyl hydrazones (1).

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