Reactions with Nucleophilic Carbon Compounds

Investigations of the conformational analysis of 5-alkyl-5-nitro-tetrahydro-l,3-oxazines by dipole moments1 have been extended to derivatives with various substituents in positions 3 and 5.281-282 They 

When hydrogen was in position 5, an equilibrium between axial NOa-axial V-methyl and equatorial NOg-equatorial W-methyl was suggested on the basis of dipole moment measurement [Eq. (86)]. 

These findings have been confirmed by NMR analysis.284-286 Allingham and Crabb et a/.287 agreed with these conclusions on the basis of NMR examination, but they did not rule out a certain amount of form 119 existing in equilibrium with 117 due to nitrogen inversion. 

Eliel et a/.268 seem to confirm the observation that the nitro group in this type of heterocyclic system is preferred in the axial position. Katritzky et a/.269-271 have found on the basis of dipole moment measurements that tetrahydro-l,3-oxazines without a 5-nitro group have V-alkyl in the preferred equatorial position, although the axial N-CH3 and -C2H5 are important minor contributors (42 and 32%, respectively). 

Since the advent of NMR as a tool for conformational analysis, a number of papers have been dedicated to conformation of tetrahydro-1,3-oxazine in addition to those mentioned above. Nevertheless, conclusions based on coupling constant measurements are valid only for closely related compounds.289 

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The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The analogy between this type of C-C disconnection and 1,2-diX disconnections was explained at the start of this chapter with compounds 5, 6 and 7. The epoxide route works particularly well if the epoxide is mono-substituted as the reaction with nucleophilic carbon should then be regioselective. Alcohol 53 is used in perfumery and can be disconnected 53a at the next-but-one bond to the alcohol group with the idea of using the epoxide 54 made from the but-l-ene. 

TT-Aliylpalladium chloride reacts with a soft carbon nucleophile such as mal-onate and acetoacetate in DMSO as a coordinating solvent, and facile carbon-carbon bond formation takes place[l2,265], This reaction constitutes the basis of both stoichiometric and catalytic 7r-allylpalladium chemistry. Depending on the way in which 7r-allylpalladium complexes are prepared, the reaction becomes stoichiometric or catalytic. Preparation of the 7r-allylpalladium complexes 298 by the oxidative addition of Pd(0) to various allylic compounds (esters, carbonates etc.), and their reactions with nucleophiles, are catalytic, because Pd(0) is regenerated after the reaction with the nucleophile, and reacts again with allylic compounds. These catalytic reactions are treated in Chapter 4, Section 2. On the other hand, the preparation of the 7r-allyl complexes 299 from alkenes requires Pd(II) salts. The subsequent reaction with the nucleophile forms Pd(0). The whole process consumes Pd(ll), and ends as a stoichiometric process, because the in situ reoxidation of Pd(0) is hardly attainable. These stoichiometric reactions are treated in this section. 

The reaction of A-acyliminium ions with nucleophilic carbon atoms (also called cationic x-amidoalkylation) is a highly useful method for the synthesis of both nitrogen heterocycles and open-chain nitrogen compounds. A variety of carbon nucleophiles can be used, such as aromatic compounds, alkcncs, alkyncs, carbcnoids, and carbanions derived from active methylene compounds and organometallics. 

Iodomethyltrialkyltin compounds, R3SnCH2I (from R3SnCl and ICH2ZnI), provide an entry to other functionally substituted organotin compounds. Reaction with nucleophiles such as R10, R1S, R 2N, or R 3P gives further a-substituted derivatives, and carbon nucleophiles can be used to locate the functional groups at more distant positions on the alkyl chain. Some examples are shown in Scheme 3. 

The carbon alpha to the carbonyl of aldehydes and ketones can act as a nucleophile in reactions with other electrophilic compounds or intermolecu-larly with itself. The nucleophilic character is imparted via the keto-enol tau-tomerism. A classic example of this reactivity is seen in the aldol condensation (41), as shown in Figure 23. Note that the aldol condensation is potentially reversible (retro-aldol), and compounds containing a carbonyl with a hydroxyl at the (3-position will often undergo the retro-aldol reaction. The aldol condensation reaction is catalyzed by both acids and bases. Aldol products undergo a reversible dehydration reaction (Fig. 23) that is acid or base catalyzed. The dehydration proceeds through an enol intermediate to form the a,(3-unsaturated carbonyl containing compound. 

The diols 4 and 6-10 are particularly suited for the preparation of small molecules, like insect pheromones, that contain relatively few chiral carbon atoms in their framework and whose chirality is due to oxygen substitution.From related isopropyli-dene structures it is possible to synthesize the chiral C, C and Cg carbonyl compounds (11)-(14) by ozonolysis, that are convertible into the a-epimers (15)-(18) by base treatment. Furthermore, the number of synthons that are potentially available is increased by the adducts accessible from (11)-(18) by reaction with suitable carbon nucleophiles under conditions allowing control of the stereochemistry by the two oxygen functions. 

To show how these general principles of nucleophilic substitution and addition apply to carbonyl compounds, we are going to discuss oxidation and reduction reactions, and reactions with organometallic reagents—compounds that contain carbon-metal bonds. We begin with reduction to build on what you learned previously in Chapter 12. 

Up to now, the discussion of carbonyl compounds has centered on their reactions with nucleophiles at the electrophilic carbonyl carbon. Two general reactions are observed, depending on the structure of the carbonyl starting material. 

Chapter 24 concentrates on the second general reaction of enolates—reaction with other carbonyl compounds. In these reactions, one carbonyl component serves as the nucleophile and one serves as the electrophile, and a new carbon-carbon bond is formed. 

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