Hydrazone precursors

Because disconnection of a-alkoxy-y-amino acid 28 calls for (3-alkoxyhydra-zone 30, the potential for (3-elimination of the alkoxy group from the hydrazone precursor 30 (Scheme 7) makes non-basic conditions critical. In fact, treatment of 30 with TBAF in THF led to just such a (3-elimination (Marie, University of Iowa, unpublished). However, the manganese-mediated radical addition of isopropyl iodide proceeded in 77% yield, without any evidence of (3-elimination, to afford 31 as a single diastereomer. Reductive removal of the chiral auxiliary and oxidation to the carboxylic acid gave 28 in good overall yield [103]. 

Hydrazone A in Figure 14.31 (the procedure in Figure 10.31 shows one possibility for the preparation) undergoes oxidation just like an amine, and amine A-oxidc B is formed. Immediately, B undergoes a /1-elimination via a cyclic transition state, and nitrile C and a hydroxylamine are formed. Since the hydrazone precursor is accessible as a pure enantiomer, the nitrile also can be generated as a pure enantiomer. 

Since the isolation of reaction intermediate (32 equation 30) by Hurd and Mori there has been no further work to illustrate the mechanism for its formation, nor has there been any further work to unravel the mechanism for its conversion to product under the reaction conditions. Only recently for hydrazone precursor (33), where R = Me and R1 = alkyl or aryl groups, it has been reported that cyclization predominates at the more reactive methylene site rather than the methyl site (81CB2938). Other workers have shown that when sulfur dichloride (SC12) is substituted for thionyl chloride, 1,2,3-thiadiazoles are still formed from a-methylene hydrazones. In several instances sulfur dichloride afforded products in higher yield than did thionyl chloride (81G289). 

A variety of aldehyde hydrazones were screened [24b]. Branching at a saturated a carbon was detrimental in the tin mediated radical additions, but an aromatic benzaldehyde hydrazone 12 offered some success, with yields ranging from 30 to 83% (Table 2.3, entries 5 8). With the exception of 8a, which decomposed under the reaction conditions, the reactions were quite dean. Even in the examples with lower yields, the mass balance after recovery of the hydrazone precursor was generally 80 90%, demonstrating the excellent chemoselectivity of the reactions of radicals with N acylhydrazones. We were delighted to find that the radical additions had occurred with excellent stereocontrol in all secondary and tertiary radical additions to hydrazones 8 and 12 (Table 2.3), with diastereomer ratios ranging from 93 7 to 99 1 [24]. 

Ajaikumar S, Pandurangan A (2009) Efficient S5mthesis of quinoxaline derivatives over Z1O2/ MxOy (M = Al, Ga, In and La) mixed metal oxides supported on MCM-41 mesoporous molecular sieves. Appl Catal A 357(2) 184—192. doi 10.1016/j.apcata.2009.01.021 Ajani OO, Nwinyi OC (2009) Synthesis and evaluation of antimicrobial activity of phenyl and furan-2-yl[l,2,4]triazolo[4,3-a]quinoxalin-4(5i7)-one and their hydrazone precursors. Can J Puie Appl Chem 3(3) 983-992... 

PhI(OTf)2 is an effective oxidant for the direct formation of bicyclic diazenium salts from a variety of linear hydrazone precursors. This oxidative cyclization is postulated to occur by the iodine(III)-mediated formation of an l-aza-2-azoniaallene salt intermediate. A direct intermolecular allylic amination has been achieved with up to 99% yields using metal-free conditions. The reaction employs a hypervalent iodine(lll) reagent as an oxidant and bistosylimide as a nitrogen source. Mechanistic studies including isotope labelling and Hammett correlation indicated that depending... 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

Pyrimido[4,5- f]pyrimidines may be used as pyrimidine precursors. Thus, the dihydro derivative (736) undergoes alkaline hydrolysis to the amide (737 R = PrCO) which may be deacylated in ethanolic hydrogen chloride to give 5-aminomethyl-2-propylpyrimidin-4-amine (737 R = H) (64CPB393) rather similarly, the pyrimidopyrimidinedione (738) reacts with amines to give, for example, 6-amino-5-benzyliminomethyl-l,3-dimethylpyrimidine-2,4(lFf,3Ff)-dione (739 R = CH2Ph) or the hydrazone (739 R = NH2) (74JCS(Pl)1812). 

Some advantages of this reaction are high yield if the tosylate is in a sterically accessible position excellent isotopic purity of the product (usually higher than-95%) and perhaps most important, access to stereospecifically labeled methylene derivatives. For example, deuteride displacement of 3j -tosylates (183) yields the corresponding Sa-d derivative (185) in 96-98% isotopic purity. Application of this method to the labeled sulfonate (184), obtained. by lithium aluminum deuteride reduction of a 3-ketone precursor (see section HI-A) followed by tosylation, provides an excellent synthesis of 3,3-d2 labeled steroids (186) without isotopic scrambling at the adjacent positions. The only other method which provides products of comparable isotopic purity at this position is the reduction of the tosyl-hydrazone derivative of 3-keto steroids (section IV-B). 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

Cyclization of hydrazone 38 with mercuric oxide and EDTA gave dihy-drotriazine 39 (87AP198). On the other hand, methyl hydrazone 38, under 4-electron withdrawal and neighboring group participation reacts with the same reagent to give lactam 40, a useful precursor for the synthesis of the pyrrolo[2,l-c]triazinium salt 41 by cyclization with perchloric acid (87AP258) (Scheme 12). 

Hydrazine 746 could be a precursor for this ring system through the formation of its respective hydrazones and oxidation with ferric chloride to give 748 (93BCJ00) and not the isomeric [1,2,4]triazolo[4,3-6][l,2,4] triazine ring. 

Benzophenone hydrazone is a particularly active substrate for palladium-catalyzed reactions, as summarized in (Equation (24)), 99 and these products can serve as precursors to A-aryl hydra-... 

For oxalate detection, authors proposed a similar detection approach for recognition of oxalate via an immobilized oxalate oxidase/peroxidase couple and dye precursors MBTH (3-methyl-2-benzothiazolinone hydrazone) and DMAB (3-dimethylaminobenzoic acid). The peroxide generated by oxidation of oxalate to CO2 reacted with the dye precursors in a peroxidase-catalyzed reaction to yield an indamine dye with absorption maximum at 590 nm. The concentration of oxalate was correlated with increased absoiption from dye. 

The hydrazine-aldehyde reaction has been used intracellularly to deliver non-toxic drug components, which when linked to form a hydrazone bond in situ, become cytotoxic (Rideout, 1986, 1994 Rideout et al., 1990). This same approach has been used to generate enzyme inhibitors in vivo, wherein the hydrazine and aldehyde precursors are not active, but when coupled together within cells to form a hydrazone linkage, become active site binders (Rotenberg etal, 1991). 

Hydralazine 219 is a good precursor for that ring system. Its reactions with pyruvic acid (75JOC2901), arylidene pyruvic acids (81AP1030), and 4-aryl-2-oxo-butanoic acids (87JHC63) gave the respective hydrazones... 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

Precursors for this task were obtained by addition of /-butylmagnesium bromide to the central bond of [1.1.1 ]propellane 40a followed by conversion of the 3-f-butylbicyclo[ 1.1.1 Jpentyl-1 -y 1-magnesium bromide (88) into the ketones 89 by standard methods.27 Reaction of ketones 89 with tosyl hydrazide afforded the hydrazones 90, which gave the corresponding lithium salts 91 by reaction with MeLi in ether. These salts were dried under high vacuum and then pyrolized at 4 x 10 5 torr in the temperature range of 100-130°C and the volatile products condensed in a liquid nitrogen-cooled trap. 

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... 

L-Ascorbic acid and its analogs are excellent precursors for this type of acyclonucleoside. Thus, reaction of their oxidation products with arylhy-drazines gave the bis-hydrazones 1032, whose rearrangement with alkali... 

Other approaches to alkylidenecycloproparenes have been attempted without success. Aromatization of appropriate alkylidenecyclopropanes or their precursors could not be realized, and flash vacuum pyrolysis of methylene phthalide and 3-methylene-2-coumaranone afforded rearrangement products rather than alkylidenecycloproparenes via extrusion of 002. The photochemical or thermal decomposition of the sodium salt of benzocyclobutenone p-toluenesulfonyl hydrazone led to products derived from dimerization of the intermediate benzocy-clobutenylidene, or from its reaction with the solvent, but no ring-contracted products were observed. When the adduct of methylene-l,6-methano[10]annulene to dicyanoacetylene (249) was subjected to Alder-Rickert cleavage, phenylacety-lene (250) was formed, which derives reasonably from the parent 234. ... 

The carbonyl ylide precursor can be generated by lead tetraacetate oxidation of the hydrazone 58. Thermolysis of 59 in the presence of perdeuterated acetone led to a variety of products, some of which are shown above. An internal quench of the ylide via a 1,4-proton migration led to enol ether 61, while cycloaddition with perdeuterated acetone formed the dioxolane 62 and its regioisomer. Interestingly, the presence of products such as acetone and propene-t/s are proposed to indicate a reversible fragmentation of the ylide to a carbonyl derivative and a carbene. 

---