Acyl hydrazones

In general, the reaction can be performed between 0-60°C with the majority of the reactions being run at room temperature. The reactivity of the hydrazones with either the acyl or tosyl leaving group with thionyl chloride depends on the substrate. However, the acylated hydrazones generally provide gaseous by-products where as the tosyl chloride reaction products have to be separated from the reaction mixture. 

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

Cyclische N-Acyl-hydrazone mit einer cnr/o-Hydrazinocarbonyl-Gruppe ergeben ahnlich den entsprechenden Carbonsaure-hydraziden keine einheitlichen Reduktions-produkte. Im Gegensatz zu den acyclischen Acyl-hydrazonen werden hauptsachlich cyclische Hydrazone gebildet. 5-Oxo-3,4,4-trimethyl-l-phenyl-4,5-dihydro-pyrazol er-gibt z. B. 50% d.Th. 3,4,4-Trimethyl-l-phenyl-4,5-dihydro-pyrazol und 20% d.Th. 5-Hydroxy-3,4,4-trimethyl-1 -phenyl-4,5-dihydro-pyrazoV ... 

Phenyl- und Acyl-hydrazone werden im sauren Milieu in der Regel unter N-N-Spaltung zu Aminen reduziert z. B. ... 

Acyl-hydrazone vom Typ der 3-Oxo-2-methyl-2,3-dihydro-l,2,4-triazine werden im sauren Medium unter Reduktion einer C=N-Doppelbindung im alkalischen unter 1,4-Addition angegriffen2 ... 

Scheme 4.1 The Pd(II) complexes containing acyl-hydrazone ligands, Pd(PNO)X.

Less-common types of C=N derivatives can also be reduced enantioselectively. An interesting example is the hydrogenation of the aromatic N-acyl hydrazones 13 with the Rh-duphos catalyst (Table 34.6 entry 6.1). This reaction was devel-... 

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. 

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]. 

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. 

One can in principle combine different exchange reactions in the same system in order to further increase the structural diversity accessed by the library. However, as this compounds the problem of selectivity (i.e., one now has two or more reactions that must exclusively involve one pair of functional groups), there are very few examples thus far of the practical implementation of this concept. An early, highly intriguing example was described by Lehn and coworkers in 2001 [68]. In this system, imine exchange (acyl hydrazone formation) and reversible metal coordination were employed in library generation. 

Figure 2.3 Hydrazide and aldehyde components for acyl hydrazone DCL.

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. 

Figure 2.4 Key acyl hydrazone DCL components for kinase inhibition.

Carbonic anhydrase [17] Acyl hydrazone exchange <300 ESI-FTICR-MS... 

The yields of pyridines are generally low, but precursors for equation (10) are easily prepared by condensation of cinnamaldehydes with acetophenones. Sulfonyl- and acyl-hydrazones of o-ethynylbenzaldehyde can be cyclized by base to give isoquinolinium ylides (equation 12) (80JCS(P1)1331>. 

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). 

Chaur MN et al (2011) Configurational and constitutional information storage multiple dynamics in systems based on pyridyl and acyl hydrazones. Chem Eur J 17 248-258... 

---