Alkyl halides with nitrogen, reaction

Scheme 2.4 Reactions of alkyl halides with nitrogen nucleophiles...

Non-deprotonated amides are weak nucleophiles and are only alkylated by trialkyl -oxonium salts or dimethyl sulfate at oxygen or by some carbocations at nitrogen [16, 83]. Alkylation with primary or secondary alkyl halides under basic reaction conditions is usually rather difficult, because of the low nucleophilicity and high basicity of deprotonated amides. Non-cyclic amides are extremely difficult to N-alkylate, and few examples of such reactions (mainly methylations, benzylations, or allyla-tions) have been reported (Scheme 6.21). 4-Halobutyramides, on the other hand, can often be cyclized to pyrrolidinones in high yield by treatment with bases (see Scheme 1.8) [84—86]. 

So the only remaining question is when thioamides combine with a-haloketones, which atom (N or S) attacks the ketone, and which atom (N or S) attacks the alkyl halide Carbonyl groups are hard electrophiles—their reactions are mainly under charge control and so they react best with basic nucleophiles (Chapter 12). Alkyl halides are soft electrophiles—their reactions are mainly under frontier orbital control and they react best with large uncharged nucleophiles from the lower rows of the periodic table. The ketone reacts with nitrogen and the alkyl halide with sulfur. 

The relative inertness of divalent sulfur and trivalent phosphorus compounds toward proton and their avidity in reaction with soft alkyl halides are well documented. Competition for alkyl halides among nitrogen and phos-... 

Our laboratory at Osaka University began studies on catalysis for direct reactions of alkyl halides with tinfoil in 1959. The studies revealed that alcohols and amines show high catalytic activity in these reactions. This catalytic activity is considered to be caused by the coordination of lone electron pair of hetero atoms such as oxygen and nitrogen to a tin atom. That is, metal activation of the tin atom is cansed by these compounds. Two or more reaction products, R SnX4 (R alkyl, X halogen atom n=0, 1, 2, 3, or 4), are always obtained. 

Amines react as nucleophiles with alkyl halides in Sn2 reactions, as seen in Section 11.2.1 for the conversion of 21 to 23. This example is repeated, but the isolated product is tertiary amine 38 rather than ammonium salt 23. Displacement of bromide ion by the nucleophilic nitrogen in dimethylamine (22) leads to formation of N,iV-dimethylammonium-l-aminopropane, 23, as described previously. However, this salt is a weak acid, and it is formed in the presence of amine 22, which is a base (Chapter 6, Section 6.4.1) as well as a nucleophile. A simple acid-base reaction occurs between 23 and 22 to generate the neutral amine (N,iV-dimethylaminopropane, 38) along with dim-ethylammonium bromide. This reaction may not be quite as simple as shown, however. 

Sonogashira coupling reactions of primary alkyl halides have been reported. " The key to this was the use of an NHC ligand with bulky alkyl groups on the two nitrogen atoms (Scheme 2.121) lAd 1.51 and ItBu 1.55. This reaction is an alternative to the classical alkylation of acetylides ions with alkyl halides, with the advantage that base-sensitive functionality is tolerated. 

In the alkylation of l-phenylpyrazole-3,5-diones both carbon and oxygen compete successfully with nitrogen (B-76MI40402). Phenylbutazone (Section 4.04.4.1.1) can be prepared by reaction of l,2-diphenylpyrazole-3,5-dione with -butyl halides and alkali, even if the industrial procedure uses -butyl malonic diesters and hydrazobenzene (Section 4.04.3.1.2(h)). 

Enby 6 is an example of a stereospecific elimination reaction of an alkyl halide in which the transition state requires die proton and bromide ion that are lost to be in an anti orientation with respect to each odier. The diastereomeric threo- and e/ytAra-l-bromo-1,2-diphenyl-propanes undergo )3-elimination to produce stereoisomeric products. Enby 7 is an example of a pyrolytic elimination requiring a syn orientation of die proton that is removed and the nitrogen atom of the amine oxide group. The elimination proceeds through a cyclic transition state in which the proton is transferred to die oxygen of die amine oxide group. 

The problem of nitrogen alkylation of enamines, which one encounters with alkyl halides, is of no consequence in alkylations with positively activated olefins, since the generation of amonium salts can be expected to be reversible in these cases. Thus such enamine alkylations are obviously attractive to the synthetic chemist. Their particular importance, however, arises from avoidance of the serious obstacles often found with parallel enolate anion reactions. 

The 4,5-dihydro compounds (34) might be expected to show different properties. Here, as with the pyrazolines discussed in Section IV, A, lone pairs of electrons should be available on both nitrogen atoms for reaction to give salts of type 35 and/or 36. No salts of type 35 have been reported. Indeed, the reaction between the alkyl halide... 

With alkali cyanides, a reaction via a SN2-mechanism takes place the alkyl halide is attacked by cyanide with the more nucleophilic carbon center rather than the nitrogen center, and the alkylnitrile is formed. In contrast, with silver cyanide the reaction proceeds by a SnI-mechanism, and an isonitrile is formed, since the carbenium intermediate reacts preferentially with the more electronegative center of the cyanide—i.e. the nitrogen (Kornblum s rule, HSAB concept). ... 

One consequence of tetrahedral geometry is that an amine with three different substituents on nitrogen is chiral, as we saw in Section 9.12. Unlike chiral carbon compounds, however, chiral amines can t usually be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion, much as an alkyl halide inverts in an Sfg2 reaction. Pyramidal inversion occurs by a momentary rehybridization of the nitrogen atom to planar, sp2 geometry, followed by rehybridization of the planar intermediate to tetrahedral, 5p3 geometry... 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

B. Reactions.—(/) Nucleophilic Attack at Phosphorus. A reinvestigation of the reaction between phosphorus trichloride and t-butylbenzene in the presence of aluminium chloride has shown that the product after hydrolysis is the substituted phosphinic acid (11), and not the expected phosphonic acid (12). Bis(A-alkylamino)phosphines have been reported to attack chlorodiphenyl phosphine with nitrogen, in the presence of a base, to give bis-(A-alkyl-A-diphenylphosphinoamino)phenylphosphines (13). In (13), the terminal phosphorus atoms are more reactive than the central one towards sulphur and towards alkyl halides. 

Secondary amides can be alkylated on nitrogen by using sodium hydride for deprotonation, followed by reaction with an alkyl halide.62... 

Normally the reaction Is useful for the conversion of alkyl halides to primary amines without concomitant formation of secondary amines.29 Treatment of polymer 17 with hexamethylenetetramine in a mixture of ethanol/THF afforded an insoluble resin. Using diazabicyclooctane (DABCO), we demonstrated that the reaction could be limited to attack by a single nitrogen in a multifunctional amine, so we did not anticipate crosslinking via bis-quat salt formation. Hydrolysis of 2 with anhydrous HC1 in ethanol generated free amino groups as evidenced by a positive ninhydrin test, but quantitative hydrolysis could not be achieved and the product remained insoluble. One would have expected a simple bis-quat to hydrolyse and open the crosslinked structure. 

The nitrogen atom in quinolizidine derivatives behaves as a tertiary amine and hence it can undergo quaternization by reaction with alkyl halides. For instance, berberine derivative 101 was transformed into 102 by treatment with 3-iodopropanol followed by anion exchange. Compound 102 was then transformed into intermediate 103, which was employed as a precursor for the the preparation of bis-ammonium salt 104 (Scheme 10). This compound showed ultrashort curare-like activity in rhesus monkeys <2001JOC3495>. 

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