Hydrazones Michael addition

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

The Michael addition of formaldehyde hydrazone of (S)-1 -amino-2-(methoxymethyl)pyr-rolidine to nitroalkenes gives P-nitrohydrazones in good chemical yield and stereoselectivity (Eq. 4.70).89... 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

Scheme 6.12 Product range of the 9-catalyzed Michael addition between nucleophilic hydrazones and various nitroalkenes.

A new derivative of adriamycin, namely (6-maleimidocaproyl)hydrazone of adriamycin was synthesized and conjugated to mAbs via a Michael addition... 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

As shown in Scheme 1.2.12, the aldehyde or ketone SAMP hydrazones 50 were metallated using LDA to generate the desired azaenolate, and then TMEDA was added. Subsequent Michael addition with methyl-2-cyclopentenone carboxylate (51) resulted in a clean 1,4-addition leading to the desired adducts 52 in good yields. 

The methyl group was introduced by a two-step procedure. Thus, the hydrazone Michael adducts 52 were converted into the enol pivaloates 53 in excellent yields and diastereomeric excesses de > 96%) by treatment with pivaloyl chloride and triethylamine. After treatment with lithium dimethylcuprate the chiral auxiliary was removed by addition of 6n HCl in order to obtain the 5-substituted 2-methylcyclopentene carboxylate 54 in good yields and with excellent stereoselectivity (de, ee > 96%). Finally, the asymmetric synthesis of dehydroiridodiol (55, R = Me, = H) and its analogues was accomplished by reduction of 54 with lithium aluminum hydride or L-selectride leading to the desired products in excellent yields, diastereo- and enantiomeric excesses (de, ee > 96%). 

J.-M. Lassaletta and R. FemSndez, Michael addition of formaldehyde dimethyl-hydrazone to nitroolefins. A new formyl anion equivalent, Tetrahedron Lett. 33 3691 (1992). 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

Beyond the scope discussed so far, Michael additions also include additions of stoichio-metrically generated enolates of ketones, SAMP or RAMP hydrazones, or esters to the C=C double bond of ,/Tun saturated ketones and a,/Tunsaturated esters. These Michael additions convert one kind of enolate into another. The driving force stems from the C—C bond formation, not from differential stabilities of the enolates. It is important that the addition of the preformed enolate to the Michael acceptor is faster than the addition of the resulting enolate to another molecule of the Michael acceptor. If that reactivity order were not true, an anionic polymerization of the Michael acceptor would occur. In many Michael additions, however, the enolate created is more hindered sterically than the enolate employed as the starting material, and in these cases Michael additions are possible without polymerization. 

Heating of 1-methyl-l-(3-pyridazinyl)hydrazines (15) or their hydrazones at 240-250°C gives exclusively a pyridazino[3,4-t]pyridazine derivative (16). This reaction probably proceeds via a pyridazinone intermediate (17) which undergoes an intramolecular Michael addition leading to the pyridazino[3,4-c]pyridazine (16) (Scheme 3) <89T1793>. 

A stereoselective synthesis of substituted pyrrolidines has been achieved by a sequential domino Michael addition and intramolecular carbozincation. The intermediate zinc-copper reagent obtained after cyclization can be trapped with an electrophile such as allyl bromide (Scheme 18).180 Addition of zincated hydrazones 52 on alkenyl boronates, followed by a trapping with an electrophile, provides adduct of type 53 with good yield and high diastereoselectivity (Scheme 19).181 By this addition/trapping sequence, several contiguous stereogenic centers are created in one step. 

Asymmetric Michael additions The anions of hydrazones (2), obtained from 1 and methyl ketones, undergo conjugate addition to a,p-unsaturated esters with virtually complete 1,6-asymmetric induction to give the adducts (S,R)-3. Ozonolysis converts these products into P-substituted 8-keto esters, (R)-4, obtained in optical yields of 96-l(X)%, with recovery of the chiral auxiliary as the nitrosamine (S)-5. The overall chemical yields of 4 are 45-62%. 

Michael addition of trialkylstannyllithium to cyclohexenone SAMP- or RAMP-hydrazone gives 3-stannyl derivatives with de values of 42-44%, while subsequent alkylation of the enolate formed affords trans-products with de values >96%. The hydrazones obtained are subjected to ozonolysis to give 3-stannylcyclohexanones trans-1 with ee values up to 96%17. 

Azodicarboxylates undergo Michael addition to the electron-rich 5-position. The intermediate hydrazino ester is converted with bases to fervenu-lones or converted with Vilsmeier reagent (POCl3-DMF) to fervenulins, which are available by oxidation of the corresponding hydrazone using lead tetraacetate [75JOC2321 76JCS(P 1)2398] (Scheme 82). 

The utility of the SAMP/RAMP hydrazone method in diastereo- and enantioselective Michael additions was demonstrated in the synthesis of 5-oxo esters " (eq 9), -lactones (eq 10), 0x0 diesters and dinitriles, heterocyclic compounds (eq 11), MIRC (Michael initiated ring closure) reactions, and 2-substituted 4-oxo sulfones. ... 

Enders, D., Bettray, W., Schankat, J., Wiedemann, J. Diastereo- and enantioselective synthesis of P-amino acids via SAMP hydrazones and hetero Michael addition using TMS-SAMP as a chiral equivalent of ammonia. Enantioselective Synthesis of/T-Amino Acids 1997,187-210. 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

Michael addition of diethyl cyanomethylphosphonate to a-nitroalkenes in the presence of LDA (1 eq) followed by treatment with Mc,SiOI provides a one-pot synthesis of 2-isoxazoline derivatives. The reaction proceeds through a 1,3-dipolar cycloaddition of trimethylsilyl nitronate with an a-cyanovinylphosphonate. Similarly, the 1,4-addition of the sodium diethyl cyanomethylphosphonate to the azo-ene system of conjugated alkenes results in the formation of l,2-diamino-3-(dietlioxyphosphinyl)pyrroles in moderate to good yields via a hydrazonic intermediate. - In a route to phosphonylated pyrones, the sodium diethyl cyanomethylphosphonate reacts with 3-anilinometliylene derivatives of 4-hydroxycouinaiins in DMF with displacement of aniline. ... 

The asymmetric Michael addition of metaUated SAMP hydrazones to a variety of diethyl 1-alkenylphosphonates followed by oxidative cleavage of the 1,4-adducts produces 2,3-disubstituted 4-oxoalkylphosphonates with good yields (58-80%), but low to moderate de s (6-74%) and excellent ee s (> 93%). ... 

Enders, D., Wahl, H., and Papadopoulos, K., Asymmetric Michael additions via SAMP/RAMP hydrazones. Enantioselective synthesis of 2-substituted 4-oxophosphonates, Liebigs Ann. Org. Bioorg. Chem., 1177, 1995. 

Due to the presence of two functional groups, there is a wide range of possible postmodifications. One possibility is the conversion of the double bond, as in the Michael addition of amines leading to 1,3-amino-alcohols [19], by epoxidation or a Michael addition of a P-ketoester to form pyrazolones [23] after the conversion into hydrazones, followed by an intramolecular cyclization. 

Enders has used these asymmetric Michael additions as the key steps in the enantioselective synthesis of various esters and alcohols (69-73) which are chiral volatile ant pheromones. In these syntheses, asymmetric Michael additions of the lithio salt of the SAMP hydrazone of propanal to methyl 2-but-enoate and methyl 2-pentenoate were used to establish the chiral centers. Subsequent hydrolysis and reduction of the aldehyde or carboxylic acid ester by conventional procedures afforded the pheromones. ... 

By coupling the asymmetric Michael additions of a SAMP or RAMP acetaldehyde hydrazone like those shown in equation (30) with hydrolysis and reduction of the chiral (3-substituted 8-oxopentanoates, Enders was able to prepare chiral 8-lactones with control of stereochemistry at C-3 of the lactone ring. As would be expected based on the results shown above, the enantioselectivity in this overall process was high (90-96%) and good chemical yields were obtained. 

---