Alkylation on Nitrogen

See also page 779, Section 4 page 831, Section 9 and page 835, Section 10. 

For alkylation or arylation by alkyl / aryl halides or sulfonates, see page 779, Section 4. 

Organic Synthesis with Palladium Compounds, Springer Verlag, Berlin (1980) R. F. Heck, Palladium Reagents in Organic Synthesis, Academic Press, London (1985) 

Organic Synthesis with Palladium Compounds, Springer Verlag, Berlin (1980) 

Palladium Reagents in Organic Synthesis, Academic Press, London (1985) 

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Chemical Properties. The presence of both a carbocycHc and a heterocycHc ring faciUtates a broad range of chemical reactions for (1) and (2). Quaternary alkylation on nitrogen takes place readily, but unlike pyridine both quinoline and isoquinoline show addition by subsequent reaction with nucleophiles. Nucleophilic substitution is promoted by the heterocycHc nitrogen. ElectrophiHc substitution takes place much more easily than in pyridine, and the substituents are generally located in the carbocycHc ring. 

Enamines derived from aldehydes disubstituted on the jS carbon such as those derived from isobutyraldehyde (16) are alkylated on nitrogen by alkyl... 

Even 5,5-dimethyl-3-cyclohexylaminocyclohex-2-en-l-one (52), the mono-Schiff s base derived from the 1,3-diketone which is stable in the enamino ketone form (7) and theoretically could alkylate on nitrogen, gave the O-alkylated product (53) (23). 

The synthesis of a benzamide with a somewhat more complex side chain starts by condensation of acid 144 with racemic cis-aminopiperidine 152. Removal of the benzyl group of 153 by hydrogenolysis gives the secondary amine 154. Alkylation on nitrogen with the halide 155 gives finally the dopamine antagonist, cisapride (156) [38,39]. 

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

In 1984, Corey and co-workers reported that A -hydroxyarachidonamides (111) were potent reversible inhibitors of cRBL (0.03-0.2 juM) [284]. Alkylation on nitrogen increased the inhibitory potency significantly, and truncation to (112) still gave activity (1.9 juM). An alternative approach at Abbott placed the hydroxamic acid moiety in the 5-position, giving analogues of 5-HPETE such as (113) which also inhibited cRBL [285]. 

The double bond in indole and its homologs and derivatives is reduced easily and selectively by catalytic hydrogenation over platinum oxide in ethanol and fluoroboric acid [456], by sodium borohydride [457], by sodium cyanoborohydride [457], by borane [458,459], by sodium in ammonia [460], by lithium [461] and by zinc [462]. Reduction with sodium borohydride in acetic acid can result in alkylation on nitrogen giving JV-ethylindoline [457]. 

The hydroxyquinoline (39-2) provides the starting material for a quinolone that incorporates a hydrazine function. Reaction of (39-2) with 2,4-dintrophenyl O-hydroxylamine ether (41-1) in the presence of potassium carbonate leads to a scission of the weak N-O hydroxylamine bond by the transient anion from the quinolone the excellent leaving character of 2,4-dinitrophenoxide adds the driving force for the overall reaction, resulting in alkylation on nitrogen to form the hydrazine (41-2). The primary amine is then converted to the formamide (41-3) by reaction with the mixed acetic-formic anhydride. Alkylation of that intermediate with methyl iodide followed by removal of the formamide affords the monomethylated derivative (41-4). Chlorine at the 7 position is then displaced by A-methylpiperazine and the product saponified. There is thus obtained amifloxacin (41-6) [48]. 

Relatively electron-deficient indoles such as (39) can be alkylated on nitrogen using Mitsunobu reaction conditions (Equation 1) (94TL1847). 

Imidothioesters offer a number of other possibilities. Thus, it was orted that N-phenyl thioimidoesters can be metallated at low perature by LDA or n-butyllithum. Although the resulting enaminates wn in the scheme) were alkylated on nitrogen when R1 was an alkyl up, more interesting alkylation occurred regioselectively at carbon when 1 was a vinyl or aryl group [152] and also with R =H or Me3Si [380]. 

We need a formaldehyde equivalent that is less electrophilic than formaldehyde itself and will therefore add only once to enol(ate)s. The solution is the Mannich reaction.7 Formaldehyde is combined with a secondary amine to give an iminium salt that adds 47 to the enol of the aldehyde or ketone in slightly acidic conditions to give the amino ketone (or Mannich base ) 48. If the product of the aldol reaction 50 is wanted, alkylation on nitrogen provides a good leaving group and ElcB elimination does the trick. 

A-Aminopyridinium iodide may also be alkylated on nitrogen with A-benzoylthioureas in the presence of base and thiophiles such as bismuth nitrate and mercury chloride to give pyridinium A-benzoylguanidines in moderate to good yields <2005T10536>. 

Triazoles and tetrazoles can be alkylated on nitrogen under basic conditions, as in the synthesis of the clinically-used antifungal drug 8.35 in which 11,2,4-triazole is alkylated by a chloromethyl ketone and an epoxide, both good alkylating agents. What is the mechanism of formation of epoxide 8.34 Of compounds 8.34 and 8.35, which is achiral and which is racemic ... 

Thiamine pyrophosphate looks quite like a nucleotide. It has two heterocyclic rings, a pyrimidine similar to those found in DNA and a thiazolium salt. This ring has been alkylated on nitrogen by the pyrimidine part of the molecule. Finally, there is a pyrophosphate attached to the thiazolium salt by an ethyl side chain. 

Relatively acidic indoles such as 44 can be alkylated on nitrogen using an alcohol and diethyl azodicarboxylate (DEAD), i.e. Mitsunobu reaction conditions (Scheme 11). 

Despite this tendency, examples of alkylation, acylation, sulfonylation, halogenation, silylation, and phosphorylation of aziridines at nitrogen abound. Aziridinium salts can be prepared by further alkylation of the aziridine nitrogen. Aziridines can also be alkylated on nitrogen with epoxides producing -hydroxyamines. 

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