Acids, conjugated, addition ammonia

Lengthening the side chain produces the antidepressant maprotiline (73), which has a topological relationship to the clinically useful tricyclic antidepressants. The requisite acid is constructed by conjugate addition of the carbanion of anthrone (64) to acrylonitrile, followed by hydrolysis to give 70. Reduction of the carbonyl group with zinc and ammonia gives anthracene 71 by dehydration of the intermediate... 

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]. 

Ammonia itself, the simplest amine, is very volatile (it is a gas at room temperature, but a very water-soluble one, and bottles of ammonia are actually a concentrated aqueous solution of ammonia), and the high temperatures required for conjugate addition to this unsaturated carboxylic acid can only be achieved in a sealed reaction vessel. 

J-Mercurio nitro compounds have been used to prepare nitroalkenes, which undergo conjugate addition with various nucleophiles. For example, the addition of ammonia or sodium azide/hy-drazoic acid mixture to 1-nitrocyclohexene allows the multistep preparation of either cis- or trans-1,2-cyclohexanediamine14 ... 

Piperidazine takes part in conjugate addition to esters of tranj-cinnamic acid to give a saturated pyrazolo[l,2-a]pyridazine, but with chiral esters there was only marginal asymmetric induction reduction of the adducts with sodium in ammonia (Scheme 48) cleaves the N—N bond to form a 1,5-diazacyclononanone <87H(26)85>. 

Alternative preparations of 2-allyl-3-methylcyclohexanone include a) lithium-ammonia reduction of 2-allyl-3 methylcyclohex-2-enone (see Note 13), which can be prepared by alkylation of 3-methjdcyclohex-2-enone or by alkjdation of 4-carboethoxy-3-methylcyclohex-2-enone [Hagemann s ester 2-Cyclohexene-l-carboxylic acid, 2-inethyl-4-oxo-, ethyl ester], followed bj hydrolysis and decarboxylation and b) conjugate addition of lithium dimethylcupratc [Cuprate (1-), dimethyl-, lithium] to 2-cyolohexen-l-one followed by trapping of the enolate with allyl iodide or allyl bromidein an appropriate solvent. 

So far we have shown you conjugate additions mainly of a,P-unsaturated aldehydes and unsaturated a,P-ketones. You won t be at all surprised to learn, however, that unsaturated acids, esters, amides, and nitriles—in fact all carboxylic acid derivatives—can also take part in conjugate addition reactions. Two examples, an amide and an ester, are shown on the right below. But notice how the selectivity of these reactions depends on the structure of the unsaturated compound compare the way butyllithium adds to this a,P-unsaturated aldehyde and a,P-unsaturated amide. Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives from direct... 

Ammonia is sufficiently nucleophilic that addition to the double bond of a conjugated ester is possible, even in the presence of the acyl carbon. Similarly, amines undergo conjugate addition. In both cases, the product is a 3-aminopropan-oic acid derivative (a P-amino acid derivative). Both ammonia and amine nucleophiles will be discussed in this section. 

The most common method for producing substituted P-amino acids is via conjugate addition to a,p-unsaturated acids or esters. Amines and ammonia add to... 

As seen above, acrylic acid derivatives readily add ammonia or amines to give the 3-aminopropanoic acid derivative. When the terminal carbon of the alkene is substituted, the reaction is slower and the yields of conjugate addition product are... 

The usual conjugate addition reactions of ammonia or amines to a,P-unsaturated esters can produce the amino acids discussed in this section. Just as amides were seen to undergo addition to conjugated esters in section 3.1.B (see 3.42 and 3.43), amine stabilized radicals add in a conjugate manner to a, )-unsaturated esters. The product of this reaction is an amino acid derivative. An example is the reaction of... 

There are a handful of examples where amino acids with ring sizes of seven members and larger have been prepared using the carboxyl refunctionalization reaction just shown. Reaction of anhydride 7.29H with ammonia, for example, gave amide-acid 7.30. Hofmann rearrangementl of the amide led to cfs-2-aminocyclo-heptane-1-carboxylic acid, 731. An alternative synthesis conjugate addition of ammonia to cycloheptenecarboxylic acid, 7.32. This reaction gave rra/is-2-amino-cycloheptane-1-carboxylic acid, 7.33. 

Birch reductions of alkyl benzoates are not normally feasible due to the preference for Bouveault-Blanc-type reduction of the ester group. However, it has now been found that if one to two equivalents of water are added to the ammonia before addition of the metal, then good yields of cyclohexadiene-esters [e.g. (191) from ethyl benzoate] can be realised. It is known that Birch reductions of benzoic acids can be used to generate dianonic species (192). These have been found to undergo conjugate additions to methyl acrylate and... 

Aminopropanoic acid, sometimes called P-alanine, is a nonsteroidal anti-inflammatory agent used in veterinary medicine. It is prepared by a conjugate addition reaction using ammonia and acrylonitrile (CHj=CH—CN). The resulting nitrile is then hydrolyzed to give the product. Why is conjugated addition favored ... 

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 introduction of conjugate acid-base pairs completes our inventory of acids and bases, hi addition to strong bases, ammonia, and amines, the anions of weak acids act as bases. 

As noted in Chapter 1, this is one of the best methods for generating a specific enolate of a ketone. The enolate generated by conjugate reduction can undergo the characteristic alkylation and addition reactions that are discussed in Chapters 1 and 2. When this is the objective of the reduction, it is important to use only one equivalent of the proton donor. Ammonia, being a weaker acid than an aliphatic ketone, does... 

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