Abstract
2.2. Present Work
2.2.3. Substrate scope
After identifying the optimized conditions, the scope of the N-alkylation reaction was first studied. I investigated a wide range of substrate scope to demonstrate the generality of the reaction. At the outset, differently substituted aniline and alcohols were tested. Substrates having the electron-donating or electron-withdrawing group in the aryl of aniline or benzyl alcohols were reacted smoothly under the optimized condition to afford N-monoalkylated product in high yields. Even the sterically hindered aniline such as 2-(ethylthio)aniline and 2,4,6-trimethylaniline underwent N-alkylation smoothly, affording the corresponding N-monoalkylated product in good yields (Table 2.2).
Alcohols possessing heteroaromatic moieties or naphthyl moieties also worked well.
Furthermore, the N-alkylation of diaminobenzene was investigated. There is a possibility of formation of dialkylated (N-alkyalation of both the NH2 and mono-alkylated (N- alkylation of one of the NH2) product. Indeed, when, 1,3-diamino benzene and benzyl
alcohol were taken in 1:2.4 ratio, mixture of mono- and dialkylated- product was formed (29%) and increasing the ratio to 1:3, the dialkylated product was isolated 85% yield. In the case of 1,2-diaminobenzene, only 46% desired dialkylated product was obtained due to the formation of 1,2-disubstituted benzimidazole as side product. Pure aliphatic amine like cyclohexyl amine reacted smoothly under the reaction condition.
Table 2.2: Scope of N-alkylation reaction of aniline derivatives with benzyl alcohol derivativesa,b
a Reaction conditions: Cat 2.12a (5 mol %), amine (1 mmol), alcohol (1.2 mmol), tBuOK (1.2 mmol.) 140
°C (oil bath temperature), 24 h, toluene (2 mL), b isolated yield, c diaminobenzene (0.5 mmol), alcohol (1.5 mmol), 36 h, d 18 h.
Table 2.3:Scope of N-alkylation reaction of secondary amines with benzyl alcohol derivativesa,b
a Reaction conditions: Cat 2.12a (5 mol %), amine (1 mmol), alcohol (1.2 mmol), tBuOK (1.2 mmol.) 140
°C (oil bath temperature), 24 h, toluene (2 mL), b isolated yield.
To demonstrate the usefulness of the present protocol, the N-alkylation of secondary amine to synthesize unsymmetrically substituted tertiary amine (Table 2.3) were explored. The challenging substrates like N-methylaniline22b and less basic N- methylbenzylamine reacted well with different benzylic and heteroaryl alcohols, which to the best of my knowledge are not yet reported with any manganese catalyst.
To illustrate the synthetic utility, the scope of N-alkylation reaction with regard to different heterocyclic amines was investigated further. 2-(N-alkylamino)benzothiazoles are structurally important units in many bioactive compounds,25 and have a broad range of physiological and pharmacological activities.26 Thus, initially, the N-alkylation of 2- aminobenzothiazole with different alcohols were studied; gratifyingly N-exosubstituted 2-(N-alkylamino)benzothiazoles were obtained in high yield (Table 2.4). The reaction catalyzed by Mn-complex is completely regioselective towards N-exosubstituted 2-(N- alkylamino)benzothiazoles whereas N-alkylation of 2-aminobenzothiazoles with alkyl halides give N-endosubstituted 3-alkyl-2-iminobenzothiazolines.27
Next, I interested to investigate the N-alkylation of aminopyridines as the selective N-alkylation of the amino-pyridine is a challenging as amides can be formed as byproducts.28 Delightfully, the N-alkylation of aminopyridines proceeds well to afford the desired N-alkylated product in good yield (Table 2.4). Next, I am interested in
Table 2.4: Scope of N-alkylation reaction of heterocyclic amines with benzyl alcohol derivativesa,b
a Reaction conditions: Cat 2.12a (5 mol %), amine (1 mmol), alcohol (1.2 mmol), tBuOK (1.2 mmol.) 140
°C (oil bath temperature), 24 h, toluene (2 mL), b isolated yield, c diaminobenzene (0.5 mmol), alcohol (1.5 mmol), 36 h, d melamine (0.5 mmol), alcohol (2.25 mmol), cat 2.12a (0.08 mmol) ), tBuOK (1.6 mmol), 52 h.
the tri N-alkylation of melamine as substituted s-triazine derivatives are known to have different biological activities.29 Thus, the reaction of melamine with different benzyl alcohols was studied. Upon refluxing melamine (0.5 mmol) with 4-chlorobenzyl alcohol (2.25 mmol) in toluene led to the formation of corresponding trialkyalted product in 58%
yield after 36 h, which was further improved to 95% just by increasing the reaction time (52 h).
Next, I have applied this protocol for the chemoselective N-alkylation 4- aminostilbene with different alcohols to afford Resveratrol derivatives (Table 2.5) in good isolated yield, as resveratrol-derived amines are known for their activity towards the treatment of Alzheimer’s disease.30
Table 2.5: Scope of the reaction to synthesize resveratrol derivatives from (E)-4-styrylaniline and benzyl alcohol derivativesa,b
a Reaction conditions: Cat 2.12a (5 mol %), 4-aminostilbene (1 mmol), alcohol (1.2 mmol), tBuOK (1.2 mmol) 140 °C (oil bath temperature), 24 h, toluene (2 mL), b isolated yield.
Then, I am interested to synthesize imine directly from the alcohol and amines using these Mn-complexes just by tuning the reaction condition. From the optimization Table, it was found that the nature and amount of the base are very important to get the desired selectivity towards imine (Table 2.1, entry 18, 19). Thus, when a toluene solution having aniline (1.0 mmol) and 4-methoxybenzyl alcohol (1.2 mmol) was refluxed in presence of KOH (0.5 mmol) and 5 mol% cat 2.12a under argon flow, the desired imine was obtained in 75% yield which was further improved to 88% when 0.3 mmol KOH has been used. The substrate scope of the reaction is summarized in the Table 2.6.
Table 2.6: Scope of the reaction to synthesize imines derivatives from primary amine and primary alcohol derivativesa,b
a Reaction conditions: Cat 2.12a (5 mol %), amine (1.0 mmol), alcohol (1.2 mmol), KOH (0.3 mmol), 140
°C (oil bath temperature), 24 h, toluene (2 mL). b the NMR yield (the yield in the parenthesis is the isolated yield).
Encouraged by the versatility of this current catalytic system, I tried to apply this protocol to synthesize 2,3-dihydro-1H-perimidines as they are important class of compounds having useful biological activity.31 Thus, when 1.0 mmol of 1,8- diaminonaphthalene is reacted with 1.2 mmol of primary alcohol in presence of 5 mol%
of cat 2.12a and 0.3 mmol of KOH, corresponding 2,3-dihydro-1H-perimidines
electron-withdrawing, electron donating as well as heterocyclic alcohol undergo this reaction to produce good to excellent yield (Table 2.7). Octanol gave only 30% yield of the desired product after 72 h.
Table 2.7:Scope of the reaction to synthesize 2,3-dihydro-1H-perimidine derivatives from naphthalene- 1,8-diamine and primary alcohol derivativesa,b
a Reaction conditions: Cat 2.12a (5 mol %), 1,8-diaminonaphthalene (1.0 mmol), alcohol ( 1.2 mmol), KOH (0.3 mmol), 140 °C, 24 h, toluene (2 mL). b isolated yield. c alcohol (2.0 mmol), KOH (0.5 mmol), 72 h.