Weak nucleophilic amines

Dmitrofluorobenzene also serves as an arylation agent for a wide vanety of biologically useful amines including aromatic amines [5b], ammo acids [57], and ammocarbohydrates [55,59] Weak nucleophilic amines such as benzimidazole [60] and fluoroamines [61] can also be arylated (equation 30)... 

The intramolecular variant, reported by Hegedus in 1976, expanded the scope to weakly nucleophilic amines. ort/io-Allylaniline 1 delivered 2-methyl indole in 84% yield using a stoichiometric amount of (CH3CN)2PdCl2 and triethylamine in THF via the intermediacy of 5. 

Weakly nucleophilic amines such as 2,4-dinitroaniline are acylated in excellent yields by the mixed anhydride 301, prepared from the trimethylsilyl esters 299 (R = Me, i-Pr, t-Bu, PhCH2CH2, 2-MeCgH4 etc.) and 4-trifluoromethylbenzoic anhydride (300) under titanium(IV) catalysis 340... 

Allylammonium ylides can undergo 2,3-sigmatropic rearrangement [1234]. With weakly nucleophilic amines, C-H bond insertion or hydride abstraction can compete efficiently with ammonium ylide formation. 

The reaction was also performed with various types of amines using different kinds of 1-chloroalkyl carbonates (Ref. 64) and was proved to be quite general except with weakly nucleophilic amines. Some examples of carbamates obtained by the reaction of 1-chloroethyl carbonates with primary and secondary amines are given in table 3-27. 

N-Acylation, The polymer-supported base 1 adequately serves for use in the acylation of weakly nucleophilic amines. 

N-Arylsulfonamides are an important class of therapeutic agents in medicinal chemistry. Traditional preparation involves reaction of sulfonyl chlorides with amines, but the sulfonation of weakly nucleophilic amines is difficult. Pd catalysis proved to be effective for N-Arylation of sulfonamides with 4-chloroquinoline (Scheme 10.32) [71]. 

A 2004 report by Izdebski detailed the preparation of ort/to-halogenated N-Cbz S-methylisothioureas (04S37).The presence of the halogen atom is claimed to obviate the need for toxic mercuric chloride, which is required for weakly nucleophilic amines. 

B. Imine formation with weakly nucleophilic amines. These amines require acid catalysis in both the nucleophilic addition and the dehydration. 

Hong (entries 4 and 5), ° and Williams (entries 2 and 8). Whereas many catalysts effectively liberate H2, some require a hydrogen acceptor, such as a ketone or olefin (entries 2, 8, and 9), for effective amide formation. Most of the catalysts mentioned above efficiently couple primary amines and primary alcohols to deliver secondary amides. Difficulties arise when weakly nucleophilic amines (anilines) or more hindered secondary amines are utilised (see Table 12.1 for more detail). 

There are amines such as A-methylnitroamine, that are too weakly nucleophilic to be able to form covalent adducts with arenediazonium ions. The products of the latter appear to be those of salts ArNJ N(N02)CH3, as found by Baranchik et al. (1957). Amides also appear not to be sufficiently nucleophilic, but thioamides are, as is shown by the reaction of A-phenylthiourea in the presence of NaOH (Scheme 13-12 Nesynov et al., 1970). First a (probably homolytic) phenylation-de-diazoniation takes place, followed by A-coupling. Selenourea also reacts a mixture of products is formed, which indicates a reaction of the same type as with thiourea (Nesynov and Aldokhina, 1976). 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58... 

Electron-rich carbyne complexes can react at the carbyne carbon atom with electrophiles to yield carbene complexes. Numerous examples of such reactions, mostly protonations, have been reported [519]. Depending on the nucleophilicity of the carbyne complex, such reactions will occur more or less readily. The protonation of weakly nucleophilic carbyne complexes requires the use of strong acids, such as triflic [533], tetrafluoroboric [534] or hydrochloric acid [535,536]. More electron-rich carbyne complexes can, however, even react with phenols [537,538], water [393,539], amines [418,540,541], alkyl halides, or intramolecularly with arenes (cyclometallation, [542]) to yield the corresponding carbene complexes. A selection of illustrative examples is shown in Figure 3.25. 

As shown in Figure 4.1, the initial step of the conversion of an ylide into a carbene complex is an electrophilic attack at the ylide. Reactions of this type will, therefore, occur more readily with increasing nucleophilicity of the ylide and increasing electrophilicity of the metal complex L M. Complexes which efficiently catalyze the decomposition of even weakly nucleophilic ylides can easily react with other nucleophiles also, such as amines or thiols. This has to be taken into account if reactions with substrates containing such strongly nucleophilic functional groups are to be performed. 

However, the hemiaminal 17 is unstable as a free base and readily undergoes exchange reactions. Since the hydroxy moiety of 17 is more easily displaced than the amine moiety, a highly reactive cyclopropyliminium salt 18 is formed, which then reacts with weak nucleophiles such as ethanol, to give e. g., 19. Otherwise in water solution 17 can also probably eliminate ammonia to form the highly reactive cyclopropanone 20, which is in equilibrium with its hydrate 21 and hemi-acetal 22, Eq. (8) [20]. It has been reported that hydrate 21 is also a potent inhibitor of ALDH [20,21]. 

Surprisingly though, the rather weakly nucleophilic (diphenylmethylene) amine (DPMA-H) and its cyclopropyl analog (cyclopropylphenylmethylene) amine (CPMA-H) 93 [8, 9, 10 c, 21b, 22b, 58-601 which can also serve as ammonia equivalents, add to 1-R and 2-R cleanly and in most cases quantitatively in a 1,4-fashion (Scheme 29). 

It is to be noted that there are essentially no principal differences between the catalytic reaction, when the ring is activated by a hydroxyl-containing component, and the noncatalytic one when amine acts as an electrophilic reagent (proton donor). It should be emphasized that for epoxy ring opening by such weakly nucleophilic reagents as amines, an electrophilic assistance is essential. This idea will be confirmed below several times because it is the key idea for understanding the kinetic mechanism of the reaction of epoxy compounds with amines. 

The limit is reached with 1,3,5-triazine. This reacts very easily even with weak nucleophiles, and ring cleavage nearly always follows. Thus, it behaves as a formylating agent toward amines and other active hydrogen compounds. 

The Paal-Knorr method can be applied to the synthesis of a variety of 1-substituted pyrroles using commercially available 2,5-dialkoxytetrahydrofurans as a butane-1,4-dial equivalent. When an appropriate tetrahydrofuran derivative is available, the reaction can be used for more highly substituted pyrroles. Aliphatic and aromatic amines react readily and even weakly nucleophilic sulfonamides undergo cyclization (equation 66) (73SC303). 

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