N-Nucleophiles

When we first learned about acetal formation, we said that the mechanism would serve as a foundation for other reactions in this chapter. Now, we will see the power of mechanisms in helping us understand the similarities between reactions. 

The products are not similar. When ROH is used as the nucleophile, an acetal is obtained. When a primary amine is used as the nucleophile, an imine is obtained. When a secondary amine is used as the nucleophile, an enamine is obtained. The products of these reactions look very different, but when we analyze the mechanisms, we will see that they are aU very similar up until the very end of the mechanism. It is the last step of each mechanism that makes them different from each other. Let s take a closer look. We U start with primary amines. 

When a ketone is treated with a primary amine under acid-catalyzed conditions, the mechanism begins just like the mechanism of acetal formation. Shown below is an incomplete mechanism (only the first two-thirds of the mechanism) showing what happens when ROH attacks a ketone. And directly below it, you will see an incomplete mechanism of RNH2 attacking a ketone. Compare both mechanisms, step-by-step  

Noto There is experimental evidence that the first two steps of this mechanism (protonation and nucleophilic attack) more likel/ occur either simultaneously or In the reverse order of what is shown above. Most nitrogen nucleophiles are sufficiently nucleophilic to attack a carbonyl group directly, before protonation occurs. Nevertheless, the first two steps of the mechanism above have been drawn in the order shown (which only rarely occurs), because this sequence enables a more effective comparison of all acid-catalyzed mechanisms in this chapter. Be sure to look In your lecture notes to seethe order of events that your instructor used for the first two steps of the mechanism. 

In the first process above, the identity of HA+ (the proton source) is most likely a protonated alcohol, which received its proton from the acid catalyst. Similarly, in the second process above, the identity of HA is most likely a protonated amine (called an ammonium ion), which received its proton from the acid catalyst Other than that small difference (and the difference described in the note beneath the second process), both mechanisms are the same. Both involve a proton transfer and a nucleophilic attack, followed hy more proton transfer steps, and then loss of water. But the conclusions of these meehanisms truly depart fiom one another. Let s try to understand why. 

Inter- and Intramolecular Reactions with Aliphatic Amines and Ammonia as Nucleophiles 

Catalyst activation became a necessity when reactions with bulky aliphatic amines and arylamines (cf Section 9.4.2) as nucleophiles were probed. It was also required for intramolecular aminations [8,18]. Thus, with Ph2CHNH2, an ammonia equivalent, conversion was only 11% upon application of procedure (a) (Table 9.2, entry 11), while the reaction promoted by the activated catalyst proceeded with high selectivity and yield. Catalyst activation is faster with ligand L2 than LI, and accordingly in situ activation occurs more readily for the former (cf entries 10 and 12). Examples presented in entries 16-20 further demonstrate the advantages of catalyst activation [53] (note that excellent results can be achieved with the simpH-fied ligand L5a). 

Procedure (d) (cf Section 9.2.4.2), which is useful for alkylations, was not appH-cable to aminations because of coordination of Cu to the amine. Further screening of the salts of soft cations revealed that the addition of Pb salts in conjunction with base activation of the precatalyst led to significantly faster reaction rates. The reaction could be accompHshed with catalyst loading as low as 0.4mol% (compare entries 14 and 15). 

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Even when deactivated by nitro substitution on C-5, the 2-aminothiazoles still undergo diazotization (35, 338-340). As with carbonyl derivatives (Section III.2.B), competition may occur between N nucleophilic reactivity and nitrosation of the 5-position when it is unsubstituted (341-344). 

Te-Methyl-2-phenylbenzotelluroniumazole perchlorate 20 behaves as a strong methylating agent in reactions with O- and N-nucleophiles (92MI1). 

Synthesis of natural compounds by intramolecular attack of N-nucleophile on electrophilic center 99CSR61. 

The nucleophilic substitution of the nitro group in nitro-arene complexes works almost as well as that of Cl" and such substitutions were achieved by Chowdhurry et al. with O, S, and N nucleophiles and with stabilized carbanions [97,98] Eq. (28) and Table 8. 

Subsequently, the scope of the reaction was extended to N-nucleophiles 82. Because the inherent basicity of the substitution products 83 imposed some problems concerning catalyst decomposition, the addition of catalytic amoimts of piperidine hydrochloride (pip-HCl) proved to be necessary. Under optimized reaction conditions different aromatic amines 82 were allylated with almost exclusive regioselectivites in favor of the ipso substitution products 83 (eq. 1 in Scheme 20) [64]. 

Kovacs, G., Ujaque, G. and Lledos, A. (2008) The Reaction Mechanism of the Hydroamination of Alkenes Catalyzed by Gold(I)-Phosphine The Role of the Counterion and the N-Nucleophile Substituents in the Proton-Transfer Step. Journal of the American Chemical Society, 130, 853-864. 

Using the chiral a-amino acetal 1-120 ion and two different N-nucleophiles 1-122 and 1-123, the pyrrolidines 1-124 and 1-125, respectively, are obtained in good di-... 

A similar approach was used by the Alcaide group [183] in the synthesis of tricyclic (3-lactams 6/1-391 from 6/1-390 (Scheme 6/1.99). In this domino process the primarily obtained it-allyl-Pd-complex reacts with the N-nucleophile of the urethane moiety to form a C-N-bond and a vinyl halide. The final step is then an intramolecular Heck-type reaction of the vinyl halide with the alkyne moiety and re-... 

A rather complex reactivity towards the cyclopropenone system is exhibited by N-nucleophiles. Thus, ammonia reacts with diphenyl cyclopropenone to yield either the enamino aldehyde 323222> or a mixture of the cis and trans isomeric diphenyl azetidinones 522223 depending on the reaction conditions these products result from primary addition of the nucleophile at C,(2 ... 

Amongst other N-nucleophilic species, hydroxylamine exhibits some abnormal behavior besides oxime formation (p. 25). Thus it reacts with diphenyl cyclopropenone42 probably by 1,4-addition and subsequent oxidation and/or decarboxylation giving rise to 3,4-diphenyl isoxazolone (328) and desoxybenzoin oxime. With pentyl cyclopropenone48 hydroxylamine undergoes addition followed by normal oxima-tfon after ring fission yielding 2,3-dioximino octane (329). 

The same direction of nucleophilic attack was found for quinocyclopropene 116 on reaction with Na-ethanolate and Na-acetonitrile, which gave the salts 485/486%7 . As systematic investigations88 show, the primary attack of N-nucleophiles like ammonia and amines exclusively occurs at C1(2 of the triafulvene system. Further transformation strongly depends on N-substitution and triafulvene type. 

Very often, a nucleophilic attack on the ring carbon atom leads to ring cleavage with the formation of acyclic intermediates that frequently recyclize into triazoles <2001ARK101, 20050L1039>, particularly in the case of N-nucleophiles, as shown in Scheme 10 and Equation (4) <2000EJM267>. 

In the case of 2-amino-1,3,4-oxadiazoles, an external N-nucleophile is not necessary for their conversion into the corresponding triazole derivatives the reaction occurred in ethanol in the presence of potassium hydroxide (Equation 5) <2003BML769>. 

Nitrile oxides add to various N-nucleophiles, bearing N-H bonds to give amidoximes. These nucleophiles comprise primary and secondary amines, amides, N-heterocycles and so on. Thus, N-unsubstituted pyrazole, imidazole, 1,2,3- and... 

Interesting examples of the addition of N-nucleophiles to nitrile oxides are syntheses of chelated Z-amidoxime, N-[2-(dimethylaminomethyl)phenyl]mesitylene-carboamidoxime (118), and pyranosyl amidoximes (119) from the respective nitrile oxides and amines. Aromatic aldoximes undergo unusual reactions with chloramine-T (4 equiv, in refluxing MeOH). N-(p-toly 1 )-N-(p-tosy 1 )benzamides are formed via addition of 2 equiv of chloramine-T to the intermediate nitrile oxide followed by elimination of sulfur dioxide (120). 

To prepare the desired D-mY/no-isomer D-30b, benzyl urethane 32 is prepared via the p-nitrophenylcarbonate 31 in a one pot reaction. Treating this N-nucleophile 32 with 5 equivalents of NaN(SiMe3)2 leads to the desired oxa-zolidine 33. Li/NH3 cleavage affords D-mY/no-sphingosine, which may also be characterized as its triacetate d-30 (Scheme 4-14). 

Ring opening induced by nucleophilic attack with P- and N-nucleophiles 235... 

C-nucleophile (X = active H-borate, boronate) N-nucleophile (amine, NaN3, tosyl amide, amide, lactam, imine, carbamate, urea) O-nucleophile (alcohol, acid, carbonate) S-nucleophile (PhS02Na)... 

Hydroformylation of unsaturated amines offer a convenient synthetic access to cyclic AT.O-hemiacetals. If performed in the presence of alcohols or orthoesters AT,O-acetals are formed. With additional N-nucleophiles N,N-acetals are obtained. These compounds are synthetically attractive building blocks and were therefore used as a key step in the synthesis of various natural products [27,35]. Thus the synthesis of (+)-prosopinine starting from enantiopure (T)-scrinc leads to a cyclic N,O-acetal functionality with the required functionality for the attachment of the side chain (Scheme 6) [36]. 

Fio. 13. Occupation of energy levels in Wheland structures II for (E) electrophilic, (N) nucleophilic, and (R) radical reactions. 

New rearrangements of 2-imino-2//-l-benzopyran-3-carboxamides under the action of anthranilic acid as an N-nucleophile have been revealed. Depending on the conditions 2-(2-oxo-2//-l-benzopyran-2-yl)-3//-quinazolin-4-ones or 2-oxo-2//-l-benzo-pyran-3-((V-2-carboxyphenyl)carboxamides were found to be the products. 

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