Nucleophiles reaction with carbonyl

Most main group organometallic compounds undergo nucleophilic reactions with carbonyl groups, whereas 1,4-conjugate addition to enones... 

Analogous to its reaction with carbonyl compounds (see 6.3.4), benzyltrimethyl-silane undergoes a fluoride-induced nucleophilic substitution reaction on pyridine-1-oxides and quinoline-l-oxide to form 2-benzylpyridines (>70%) and 2-benzyl-quinoline (65%), respectively [57], Allyltrimethylsilane reacts with pyridine-l-oxide to produce 2-propenylpyridine (56%). 

Cyclodditions to Carbonyl Derivatives. Electrophilic transient carbenes are known to react with carbonyl derivatives through the oxygen lone pair to give carbonyl ylides 26.43 These 1,3-dipolar species are usually characterized by [3 + 2]-cycloaddition reactions or can even be isolated44 a small amount of the corresponding oxiranes is sometimes obtained.433,45 To date, no reaction of transient nucleophilic carbenes with carbonyl derivatives has been reported. 

The reactions of 2-iodopyrazine, 2-methylsulfanyl-4-iodopyrimidine and 3-iodo-6-phenylpyridazine with lithium tributylmagnesate resulted in very efficient iodine-magnesium exchange to yield the corresponding heteroarylmagnesium species (equations 35-37)" °. The reactions with carbonyl compounds and diphenyl disulfide proceeded with good yields. The reactions proceeded smoothly, and neither the starting iodide nor any butylated compounds derived from nucleophilic addition to the heteroaromatic nuclei were observed. 

A discussion of nucleophilic reactions in carbonyl systems, and in particular in derivatives of carboxylic acids, is included in the present text because of the importance of these reactions and their analogy with well-known processes in solution. While the actual mechanism of these reactions is more adequately described in many cases as an addition-elimination, we shall restrict our comments to systems which formally behave as displacement reactions. 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

Bis(dialkylamino)cyclopropenylium magnesium halides, like their lithium counterparts, react as nucleophiles in various reactions, but their use is much less extensive. Like typical Grignard reagents they undergo hydrolysis, alkylation and reactions with carbonyl compounds at the carbenoid carbon (equation 292)357. 

The Tebbe reagent functions as a nucleophilic carbenoid in its reactions with carbonyl groups. The carbenoid is activated in the presence of a Lewis base which presumably complexes with the aluminum atom. Tetrahydrofuran is the Lewis base in the reactions described above. If the reaction is performed in the absence of added tetrahydrofuran, the carbonyl oxygen atom can function as a weak Lewis base, although the methylenation process is considerably slower. 

Reactions of carbocations with water as a base removing a [3-proton to form an alkene or aromatic product have been less studied than nucleophilic reactions with water. Nevertheless, the correlations included in Fig. 1 (p. 43) represent a considerable range of measurements and these can be further extended to include loss of a proton a to a carbonyl group.116 Indeed, if one places these reactions in the wider context of proton transfers, it can be claimed that they constitute the largest of all groups of reactions for which correlations of rate and equilibrium constants have been studied.116,244,245... 

Isocyanides, formal divalent carbon functionalities, are ideal candidates for the development of MCRs. Their reaction with carbonyls and imines, through an a-addition process, generates a zwitterionic intermediate, which is then trapped by a nucleophile. The resulting double a-addition adduct is unstable and rapidly undergoes the Mumm rearrangement to afford the final product (Scheme 12.32). The venerable three-component Passerini reaction is the first MCR based on this type of reaction process [116]. It addresses the formation of a-acyloxycarboxamides, which constitute a class of very versatile synthons in organic chemistry. In the present context, this reaction was utilized by Schmidt and collaborators for the elaboration of intermediate 234 [117], a key fragment for the synthesis of the prolyl endopeptidase inhibitor Eurystatin A 231 (Scheme 12.33) [118]. 

The synthetic method may be seen to be complementary to direct nucleophilic displacement. Whereas amines often react relatively sluggishly in metal-mediated nucleophilic displacements, they usually undergo facile reaction with carbonyls to form imines. The reduction of the imines (free or co-ordinated) may then be achieved by reduction with Na[BH4] or (less conveniently) by direct hydrogenation. This provides a very convenient method for the preparation of cyclic amines (Fig. 6-14). 

More general solutions come from the replacement of alkylations by reactions with carbonyl compounds. These generally occur once only and in many cases cannot occur twice as the products—amides 12 or imines 15 for example—are much less nucleophilic than the starting amine. The products are reduced to the target amines. The amide route is restricted to amines with a CH2 group next to nitrogen 13 but the imine route is very general and is known as reductive animation.1 It is the most important way to make amines and a recent survey showed that the majority of amines made in the pharmaceutical industry are made this way. 

Trapping the carbonyl compound 1 in Scheme 3.3 with various nucleophiles provides various catalytic oxidative transformations of alcohols. When a primary or secondary amine is employed as a nucleophile, intermediate 13 undergoes nucleophilic reaction with amine to give iminium ion complex 14 along with water. Intramolecular hydride transfer of 14 gives the corresponding N-alkylated amine 15 with regen-... 

While this approach has been applied primarily to nucleophilic reactions of carbonyl compounds, it can also be used to determine the primary direction of hydrogenation since adsorption on a catalyst surface is preferred from the less hindered side of the carbonyl group. The synthesis of dl ephedrine (20) was accomplished by the hydrogenation of the amino ketone, 19, one enantiomer of which is depicted in Eqn. 14.17.5 xhe hydrogen bond to the carbonyl oxygen helps fix the conformation with hydrogenation taking place from the side of the... 

Reactions with carbonyl compounds as both nucleophile and electrophile... 

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