Hydrazones stereochemistry

Hydroboration of imines of cyclohex-2-enones has also been investigated. Regiospecificity in olefin formation from toluene-p-sulphonylhydrazones and methyl-lithium is clearly seen. Thus the anti-hydrazone (44) gave the diene (45a) whereas the syn-hydrazone gave a mixture of (45a) and (45b). Several solvent systems were investigated but results showed that the hydrazone stereochemistry had a consistent effect, and that syn anti isomerism was not in operation. 

The reduction of 2-methyl-1,2,3,4-tetrahydro-y-carboline (92) with zinc and hydrochloric acid in the presence of mercuric chloride gives the indolenine derivative, 2-methyl-l,2,3,4,4a,9b-hexahydro-y-carbo-line (93). A related compound, 4,9b-diethyl-2-methyl-l,2,3,4,4a,9b-hexahydro-y-carboline (96), was obtained by catalytic hydrogenation of 95, which was prepared by Fischer ring closure of the phenyl-hydrazone 94. The stereochemistry of the B/C ring junction in these... 

This regiospecificity has been shown to depend on the stereochemistry of the C=N bond in the starting hydrazone. There is evidently a strong preference for abstracting the proton syn to the arenesulfonyl group, probably because this permits chelation with the lithium ion. 

Ketone p-toluenesulphonyl hydrazones can be converted to alkenes on treatment with strong bases such as alkyl lithium or lithium dialkylamides. This reaction is known as the Shapiro reaction68. When w./i-LinsaUi rated ketones are the substrates, the products are dienes. This reaction is generally applied to the generation of dienes in cyclic systems where stereochemistry of the double bond is fixed. A few examples where dienes have been generated by the Shapiro reaction have been gathered in Table 669. 

Hydrazones can also be deprotonated to give lithium salts which are reactive toward alkylation at the j> carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.79 The / A Alimcthy I hydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent of the stereochemistry of the hydrazone.80 Two successive alkylations of the A A -dimethylby-drazone of acetone can provide unsymmetrical ketones. 

Scheme 12 Stereochemistry of the reaction between methoxyketene (38) and (E)-hydrazone (50)...

The stereochemistry and conformational behavior of a series of 20 2-methyl-2-alkyl(aryl)-4-fV-methyl-1,2,3,4-tetra-hydro-57/-l,3,4-benzotriazepin-5-ones 19-38 and their open-chain hydrazone isomers 39-58 (Scheme 3) in various solvents were studied by 1-D and 2-D NMR techniques in the temperature range from 193 to 410 K <1997JOC5080>. The authors wanted to establish the species present in solution and to study the effect of the different substituents in the ring/open-chain equilibrium. 

The mechanisms of the reaction involving oc,(3-unsaturated ketones and hydrazines were studied in several publications [30, 66, 67, 68, 69, 70, 71, 72, 73, 74]. The first stage of the reaction is the addition of hydrazine to the carbonyl group of the ketone (compound 61, Scheme 2.15). Subsequent cycliza-tion by addition of the second nucleophilic center to the ethylene bond under acidic conditions is the rate-determining stage—its rate significantly depends on the stereochemistry and electronic structure of the intermediate hydrazone 62 (Scheme 2.15). 

From the viewpoint of stereochemistry the most interesting metal complexes are the octahedrally coordinated 1 2 chromium and cobalt complex dyes, which are medially metallized azo and azomethine compounds with functional groups in the o- and o -positions. Three types of isomerism can be discriminated geometrical, N-a, 3, and that arising from azo-hydrazone tautomerism. 

The concurrent formation of two rings by chromium catalysis is demonstrate in Scheme 6 <95TL3027>. Conversion of the hydrazone (48) into the complex (49) and subsequent reaction with hex-6-yn-l-ol affords the annulated complex (50) which is decomplexed by irradiation in benzene. The stereochemistry of the intermediate complex (50) was determined by recomplexation of the final product (51), which gave a separable mixture of the two possible diastereoisomers. 

Geometrical stereoselectivity can often be achieved in the condensation of unsymmetrical ketones 8 with tosylhydrazine l,2 and this feature means Shapiro reactions direct from an unsymmetrical ketone 8 via E-9 lead to the less substituted vinyllithium 11. On the other hand, a sequential alkylation-Shapiro sequence from a starting symmetrical hydrazone 12 will reliably form the more substituted vinyllithium 14 via Z-9 Retention of Z stereochemistry in Z-9 is dependent on its re-use almost immediately on standing, for example, Z-9 (R = vinyl) equilibrates to an 85 15 ratio E Z-9J ... 

The product is still a hydrazone, and it needs hydrolysing to the ketone with 1 M HC1. These conditions cause immediate hydrolysis of the THP protecting groups and then cyclization to the spiroacetal, which forms with complete control over stereochemistry— a single diastereoisomer is formed in which both alkyl groups go equatorial and both oxygens axial. 

Enders and coworicers have shown that deprotonation of chiral SAMP/RAMP hydrazones (or their substituted analogs) derived from ketones or aldehydes, followed by reaction with Davis oxaziridine reagent provides the a-hydroxy hydrazones in moderate yield but with high diastereoselectivity. Direct unmasking or protection followed by unmasking provides the corresponding a-hydroxy ketones or aldehydes respectively (Scheme 24). Both antipodes of the hydroxylated compounds are available by appropriate choice of (5)- or (R)-proline-deiived auxiliaries. The direction of induction is predictable, if not wholly uniform (R substitution alters the a-stereochemistry for aldehyde hydrazones). The process clearly provides a valuable approach to both systems. 

Similarly, for alkenes derived from saturated methyl ketones the regioselectivity is determined by starting hydrazone ( ) (Z) ratios in some solvents but not in others. Thus 2-octanone trisylhydrazone, which is an inseparable 85 15 mixture of ( )- and (Z)-isomers, gives an 85 15 ratio of l-octene 2-octene if vinyllithium formation is carried out in THF, but a 98 2 ratio of the same products when 10% TMEDA-hexane is the solvent. The implication of this observation is that in THF the regioselectivity is determined by azomethine stereochemistry but that in TMEDA-hexane it is not. Note, however, that in this case a iyn-directing effect does not occur in TMEDA, whereas in the previous example it does. Thus more than 10 years after it was asserted that a detailed explanation of the observed solvent dependencies...await further studies owing to the complexities of the reaction system. , little headway has been made. 

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. 

The deprotonation of the SAMP/RAMP hydrazone derivatives leads to the formation of azaenolates that can be trapped by the alkyl halide. In theory, four isomeric azaenolates can form in the deprotonation step, but it was shown that around the C-C double bond stereochemistry is dominant, while around the C-N bond Z stereochemistry EccZcn is dominant for cyclic- and acyclic ketones. This observation was confirmed by trapping experiments,... 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

The total synthesis of (-)-denticulatin A, a polypropionate metabolite, was accomplished in the laboratory of F.E. Ziegler. To establish the absolute stereochemistry at C12, they utilized the Enders SAMP/RAMP hydrazone alkylation. To this end, the RAMP hydrazone of 3-pentanone was successfully alkylated with 1-bromo-2-methyl-2( )-pentene. Hydrolysis of the hydrazone under standard acidic conditions led to loss of the enantiomeric purity. This problem was avoided by using cupric acetate for the cleavage. 

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