Hydrazone Carbanions

In Section 9.4.A, it was noted that there were problems with aldol-type reactions, especially with the directed aldol condensation. In particular, aldehydes with an a-hydrogen have great difficulty adding to ketones due to their propensity for self-condensation. The ability to use kinetic control conditions in enolate reactions of ketones and aldehydes often solves this problem. There are also several alternative approaches that involve the use of carbanions derived from imines and hydrazones and these can be very useful. l 

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F.ii. Hydrazone Carbanions. Corey and Endersl introduced an alternative to Wittig s imine-carbanion methodology discussed in Section 9.4.F.i. Changing the imine to a hydrazone unit led to a more controllable and useful reaction. A,A-Dimethylhydrazone 313 was formed by reaction of 2-methylcyclo-hexanone and dime thy Ihydrazine. Subsequent reaction with LDA was followed by addition of methyl... 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

The mechanism of the reaction may involve the formation of an anion by the base B, followed by the shift of hydrogen on the hydrazone anion with simultaneous loss of nitrogen to yield a carbanion ... 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Mechanism. The aqueous base deprotonates the hydrazone, and the anion produced is resonance stabilized. The carbanion picks up a proton from water, and another deprotonation by the aqueous base generates an intermediate, which is set up to eliminate a molecule of nitrogen (N2), and produce a new carbanion. This carbanion is quickly protonated by water, giving the final reduced product as alkane. 

In several related transformations, guanidines and hydrazones were employed as nucleophiles instead of carbanions that then leads to annulation of the 1,2,4-triazine ring. For example, 2-nitronaphthalene with guanidine, in the presence of an excess... 

The use of potassium f-butoxide as the base directly produced a low yield of 1-azirine contaminated with propiophenone. However, Nair has reported that azirine (37) can be prepared from hydrazone (34) in 63% yield by using the dimethylsulfinyl carbanion as the base.18... 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

The mechanism for formation of the hydrazone is the same as the mechanism for imine formation (Key Mechanism 18-5 in Section 18-15). The actual reduction step involves two tautomeric proton transfers from nitrogen to carbon (Mechanism 18-7). In this strongly basic solution, we expect a proton transfer from N to C to occur by loss of a proton from nitrogen, followed by reprotonation on carbon. A second deprotonation sets up the intermediate for loss of nitrogen to form a carbanion. This carbanion is quickly reprotonated to give the product. 

Carbanions derived from organometallic reagents react with aryldiazoalkanes diazoketones and diazoesters to yield hydrazones after hydrolysis (7). 

Mechanism The reaction involves converting a ketone to the corresponding hydrazone A, which undergoes a base-catalyzed double bond migration (tautomerization) of the initially formed hydrazone to an azo-isomer B, and the loss of N2 then follows to give carbanion C. Finally, an alkane derivative is formed by protonation of carbanion C (Scheme 6.30). 

A recent modification [la] uses potassium tert-butoxide in anhydrous dimethyl sulphoxide, when reaction is rapid even at room temperature. The enhanced rate is attributed to the high reactivity of anions in this solvent (c/. p. 45). The reaction is usually formulated as a prototropic rearrangement of the hydrazone to give a diimide (i), followed by fragmentation of the diimide anion (2) to give a nitrogen molecule and the carbanion (3) [2], Rapid protonation then affords the reduced product. A recent study [3] oi solvent effects on the reduction... 

Epoxides will fragment if carbanions are formed adjacent to the epoxide ring. Decomposition of the hydrazone of an epoxy ketone in the presence of base may lead to an allylic alcohol (Scheme 2.24). Since the epoxy ketone may be prepared from an unsaturated ketone, this can form part of a sequence for the 1- 3 transposition of an oxygen function. 

In summary, notable advances have been made in controlling stereoselectivity resulting ffom the addition of nonstabilized carbanions to chiral imine/imine derivatives. Unfortunately our level of mechanistic understanding in these additions is unsatisfactory. While additions involving chiral nitrones, hydrazones and some cyclic imines have been evaluated in reasonable detail, few systematic studies of other al-dimine/aldimine derivatives are available. 

The reaction of alkyllithium reagents with acyclic and cyclic tosylhydrazones can lead to mixtures of elimination (route A) and addition (route B) products (Scheme 22). The predominant formation of the less-substituted alkene product in the former reaction (Shapiro Reaction) is a result of the strong preference for deprotonation syn to the N-tosyl group. Nucleophilic addition to the carbon-nitrogen tosyl-hydrazone double bond competes effectively wiA a-deprotonation (and alkene formation) if abstraction of the a-hydrogens is slow and excess organolithium reagent is employed. Nucleophilic substitution is consistent with an Su2 addition of alkyllithium followed by electrophilic capture of the resultant carbanion. 

The proposed mechanism for the formation of the vinyl carbanion intermediate involves removal of the acidic N-H proton from the hydrazone by the strong base to form the mono-anion A. In the presence of a second equivalent of base, the a-proton... 

Carbanions (c/. Chapter 2, Chapter 3.4) derived from ketones, hydrazones or phosphonates react with 0-alkyl chlorothioformates or thiocarbonates, resulting in 0-alkyl P-oxo- (59), p-hydrazono- (60) or a,P-unsaturated-carbothioates (equation 56). ... 

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