Addition of Nitrogen Nucleophiles

It is interesting to note that an alkene can be prepared by two different Wittig pathways, depending on which of the doubly bonded carbons was originally the carbon of the carbonyl group and which was the carbon of the ylide. Thus, the synthesis of 13-carotene has also been accomplished by using the reaction of a diylide with two equivalents of an aldehyde, as illustrated in the following equations  

Amines add to the carbonyl groups of aldehydes or ketones to produce compounds containing CN double bonds and water. These nitrogen analogs of aldehydes and ketones are called imines. 

O The addition step occurs according to the basic conditions mechanism. If the solution is too acidic, the amine is protonated and is no longer nucleophilic. The rate of this first step then becomes very slow. 

The intermediate is called a carbinol-amine. (Most of the other addition reactions presented so far stop at this stage where the nucleophile has added to the carbonyl carbon and a proton has added to the oxygen.) 

0 To proceed onward to the imine, the oxygen must be protonated so that water can act as a leaving group. 

Due to the important role of nitrogen functional groups, the addition reactions of an electrophilic selenium reagent and a nitrogen nucleophile to a carbon-carbon double bond represent a synthetically relevant process with potential practical applications. Among the reactions of this type which have been described already, perhaps the most important contribution is represented by the Ritter-type amide synthesis described by Toshimitsu and Uemura [48a, 48b]. The addition of a phenylselenyl and of an acylamino group to a mono or a 1,2-disubstituted olefin was accomplished by treating the olefin with PhSeCl in acetonitrile and water in the presence of trifluoromethanesulfonic acid. 

Other amidoselenenylation reactions have been described. Salazar [50] reported that the carbamatoselenenylation of alkenes can be effected using hT-(phenylseleno)phthalimide, in the presence of tetrafluoboric acid, and ethyl carbamate as the nucleophile. The reaction is a stereospecific anti addition and works well with monosubstituted and 1,2-disubstituted alkenes. In the case of monosubstituted alkenes mixtures of regioisomers were obtained. 

Quite recently Tiecco reported that the electrophilic azidoselenenylation of alkenes can be effected with PhSeOTf and sodium azide in acetonitrile [571. This reaction is a stereospecific anti addition in every case the regiochemistry is instead determined by the structure of the starting alkene. Products 70 derived from phenyl substituted alkenes 69 were formed with complete regio- and stereoselectivity. Terminal alkenes gave, in contrast, a mixture of the two regio-isomers thus, for instance, 1-octene 71 afforded a 2 1 mixture of 72 and 73. 

A number of important chemical and biochemical processes are initiated by addition of a nitrogen nucleophile to a carbonyl group.86 These processes have been the subject of extensive study, and we shall not attempt to do more than outline the main features. 

Addition of primary amines to carbonyl groups follows the pattern we have established for other nucleophiles with formation of a carbinolamine (Equation 8.49). These compounds are sufficiendy stable to be isolated in some cases,87 

Reprinted with permission from W. P. Jencks, J. Amer. Chem. Soc., 81, 475 (1959). Copyright by the American Chemical Society. 

Another possible reaction of the carbinolamine, observed in the addtion of amide or urea nitrogen, is substitution of the hydroxyl by a second molecule of the nucleophile (Equation 8.51). Addition of secondary amines leads to carbinol- 

a process similar to that which occurs in aldol-type condensations (see Table 8.8). The vinyl amines (20) are referred to as enamines they find applica- 

Ammonia, amines, and certain related compounds have an unshared electron pair on the nitrogen atom and act as nitrogen nucleophiles toward the carbonyl carbon atom. For example, primary amines react as follows  

The tetrahedral addition product that is formed first is similar to a hemiacetal, but with an NH group in place of one of the oxygens. These addition products are normally not stable. They eliminate water to form a product with a carbon-nitrogen double bond. With primary amines, the products are called imines. Imines are like carbonyl compounds, except that the O is replaced by NR. They are important intermediates in some biochemical reactions, particularly in binding carbonyl compounds to the free amino groups that are present in most enzymes. 

Imines are compounds containing a carbon-nitrogen doubie bond. 

For example, retinal (see A Word About... The Chemistry of Vision in Chapter 3) binds to the protein opsin in this way to form rhodopsin. 

PROBLEM 9.18 Write an equation for the reaction of benzaldehyde with aniline (the formula of which is C H5NH2). 

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Certain proteases, for example alkaline protease from Bacillus suhtilis, have also proven to be good catalysts for the Michael addition of nitrogen nucleophiles to a,/3-efhylenic compounds [118, 119]. 

Figure 15.7. Palladium catalysed addition of nitrogen nucleophiles to alkenes...

As synthetic steps, the Michael additions of nitrogen nucleophiles were followed by nucleophilic substitutions of the chlorine atom with a primary amine and, finally, alkylations of the then secondary amino group with various alkyl bromides were performed just as previously developed for the chloro ester 1-Me in solution (see, e.g. Schemes 25,27,36 etc.). With differently substituted pyra-zoles as Michael addends, different primary amines and alkyl bromides, combinatorial libraries consisting of 8, 24 and 84 compounds were thus successfully prepared in ca. 60% yield and proved by the LC-MS technique to contain all the individual compounds in about equal amounts (Scheme 80) [127]. 

Addition of Nitrogen Nucleophiles to Carbonyl Compounds in Combination with Subsequent El Eliminations of the Primary Product Condensation Reactions... 

The intermolecular addition of nitrogen nucleophiles has been shown to lead to interesting products, with remarkable control based on the reaction conditions (Scheme 10). Carbonylation of the organo-Pd intermediate can also be efficient, leading to /3-amino esters. Unfortunately, these processes require stoichiometric Pd no reoxidation scheme has been developed. 

The cyclization of 4,5-hexadienamines and -amides, catalyzed by palladium salts in the presence of copper(II) chloride under a carbon monoxide atmosphere, afforded 2-(2-pyrrolidinyl)acrylates. A different mechanism is operating here, which does not involve the intramolecular addition of nitrogen nucleophile to a rt-complex, but, instead, the addition of PdX2 to a double bond, followed by SN2 or S 2 displacement in the cyclization step28. 

Table 19. Additions of nitrogen nucleophiles to alkynes, RC CR, to form acyclic adducts ... 

Dondoni, A, Fantin, G, Fogagnolo, M, Merino, P, Regio- and stereoselective conjugate addition of nitrogen nucleophiles to 2-alkenyl iV-methylthiazolium iodides. Synthesis of 3-epi-daunosamine and some lincosamine analogues. Tetrahedron, 46, 6167-6184, 1990 see also Ref. [97b]. 

An interesting methodology to highly oxygenated p)razolidines and indolizidines from 2,3-unsaturated sugar lactones was presented by Chmielewski [84]. The synthesis was initiated by a 1,4-addition of nitrogen nucleophiles to unsaturated lactones 93, which resulted in formation of appropriate heterocyclic derivative 94 (O Scheme 38). 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

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