CERTIFICATE
Scheme 2.21: Schematic diagram of N-methylation of amine via various methodologies
N-methylated amines have important uses in the pharmaceutical industry (Figure 2.1). Among the various methods that are available for methylations of amines, most of the cases lead to an
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Kanu Das, Ph.D Thesis, IIT Guwahati 63 equivalent amount of waste products (Scheme 2.21). The use of methanol as a methylating agent21, 28, 31, 59, 64, 72, 83-84, 106-110 presents an attractive strategy to generate valuable N-methylated amines.
Scheme 2.22: Copper catalyzed coupling reaction that lead to methylation of amines.108 Methodologies involving the palladium-catalyzed111 and copper-catalyzed112 coupling reactions have been explored for the C−N bond formation. The formation of mono/di methylated products usually requires the controlled addition of reagents. So, copper-mediated C−N bond formation via the cross-coupling of amine with aryl boronic acids have been a powerful method in this respect. A plethora of boronic acids have been used in the presence of an excess nitrogenous base and a stoichiometric amount of copper salt (Scheme 2.22).
Gonzalez an co-workers have studied the monomethylation of various aniline derivatives including heterocycle amines in a single step with good to excellent yield.108
Scheme 2.23: Ruthenium catalyzed methylation of amine with carbon dioxide.109
In general, classical methods for mono/di methylation have been well explored (Scheme 2.21).
However, using CO2 as a C1 source remains a highly attractive route. Using a renewable source of thermodynamically stable CO2 for the application of methylation with high selectivity requires a different strategy. In a representative process, Beller used the ruthenium-complexes in the presence of phosphine ligand to obtain good chemoselectivity and good productivity towards N-methylation (Scheme 2.23). Interestingly, Beller demonstrated that the ruthenium complex initially hydrogenates CO2 to methanol and formic acid in the presence of H2. From the mechanistic pathway, it is understood that formamide was formed during the reaction,
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Scheme 2.24: Iron catalyzed methylation of amines using DMC as a C1 source.72
Another alternative methodology for the methylation of primary/secondary amines that have attracted attention is the use of dimethyl carbonate (DMC) or diethyl carbonate (DEC) as a C1
source while using silane or hydrogen as reducing agents. Notably, due to the electrophilic nature of DMC, it can easily be attacked by a nucleophile (e.g. alcohols, amines) at high temperature at the methyl carbon, which leads to the formation of CO2 and methanol. The advantages of using DMC are its non-toxicity, biodegradable in nature, and easy handling.
Using iron carbene complex Darcel and co-workers reported the methylation of secondary amines under mild reaction conditions (Scheme 2.24).
Scheme 2.25: One-pot methylation of nitro compounds through hydrogen-borrowing approach.113
Yang and co-workers reported ruthenium-catalyzed one-pot methylation of nitroarenes using methanol as a methylating agent (Scheme 2.25). Using this method, without involving amines they successfully demonstrated the desired methylation of the corresponding nitroarenes by combining dichloro(p-cymene)ruthenium(II) dimer with pincer ligand in-situ. This process initially reduced the nitro group to amine, which further participates in the N-methylation reaction.
The versatile and environmentally benign N-methylation starting from methanol is the most accepted route. Following the pioneering work of Grigg et al., many groups developed their methodologies using iridium,114-115 ruthenium31, 116-117 and other transition metals.22, 118-119
Though the hydrogen-borrowing method provides alternative greener approaches for
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Kanu Das, Ph.D Thesis, IIT Guwahati 65 methylation, there are some restrictions in the substrate scope due to lack of selectivity.
However, Chen and co-workers reported iridium catalyzed methylation reaction with a broad substrate scope, high selectivity and lower catalyst loading (Scheme 2.26).
Scheme 2.26: Iridium catalyzed methylation of amines.59
Scheme 2.27: N-methylation of amines with methanol catalyzed by a pincer-manganese complex.21, 99
The direct transformation of N-methylated amines using methanol with amines are highly advantageous.120 There are few examples of methylated amines reported using methanol as a source of alkylating agents, such as Ru,28, 31, 37, 46, 117 Ir,59 and Mn.21 Beller and co-workers demonstrated the first example of non-noble metal catalyzed N−methylations of various amines with methanol under mild conditions (Scheme 2.27) using a pincer-manganese complex 2.35.21,
99
Scheme 2.28: N-methylation of amines with methanol catalyzed by pincer-ruthenium complex.46
Similarly, Kundu and co-workers demonstrated NNN pincer-ruthenium 2.38 catalyzed selective mono N-methylation of amines using methanol as an alkylating precursor with a greener synthetic route (Scheme 2.28).46 Considering these facts, the imine-based ruthenium
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Kanu Das, Ph.D Thesis, IIT Guwahati 66 pincer catalytic system is still relevant in the methylation of amine using methanol as an alkylating agent.
2.3.5 N-methylation catalyzed by pincer-ruthenium complex (tBu2NNN)RuCl2(PPh3) (2.48d)
As the optimized conditions given in Table 2.3 (entry 6) gave poor yield of methylated aniline (2.51a, Table 2.4) the reaction parameters were further optimized for the use of methanol as the alkylating agent (Table 2.5). While high turnovers (ca. 1750, entries 5 and 6, Table 2.5) were observed for a combination of aniline and methanol in the ratio of 1:4.8 using 0.02 mol
% (tBu2NNN)RuCl2(PPh3) (2.48d), the yields could be further improved (81%, entry 9, Table 2.5) upon increasing the catalyst loading. The optimized condition (entry 6, Table 2.5) that provided the best turnover was employed for the (tBu2NNN)RuCl2(PPh3) (2.48d) catalyzed N- methylation of various amines (Table 2.6).
Table 2.5. Optimization of N-methylation of aniline catalyzed by 2.48d.
Entry Sodium (x equiv.)a (2.48d) (mol %) (2.49): MeOH Yield (%)b TON
1 0.75 0.02 1.0:1.0 12 600
2 1.00 0.02 1.0:1.0 3 150
3 0.75 0.02 1.0:2.5 18 900
4c 1.00 0.02 1.0:4.8 22±2 1100±80
5 1.00 0.02 1.0:4.8 30 1500
6d 1.00 0.02 1.0:4.8 35 1750
7d 1.00 0.05 1.0:4.8 52 1040
8d 1.00 0.10 1.0:4.8 66 660
9d,e 1.00 0.20 1.0:4.8 81±2.6 405±12
Reaction conditions: Methanol (0.5 mL, 12.35 mmol), Na (x equiv.), aniline (0.23 mL, 2.4 mmol) and 2.48d (0.02 mol %) at 120 C. aEquivalent calculated with respect to aniline. bYield was determined from 1H NMR spectroscopy by using toluene as an internal standard. cReported as an average of NMR spectra and GC yield.
dReaction was performed at 140 C. eReported as an average of NMR spectra and isolated yield.
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Kanu Das, Ph.D Thesis, IIT Guwahati 67 2.3.6. Scope of the pincer-ruthenium catalyzed N-methylation reaction
The TON obtained in the 2.48d (0.02 mol %) catalyzed N-methylation of amines with electron- withdrawing groups were comparable to those obtained with aniline (compare TON of product 2.51a with 2.51b and with 2.51d, Table 2.6). The N-methylation reactions of amines with electron-donating groups, proceeded with higher TON (compare TON of product 2.51a with 2.51e and with 2.51f, Table 2.6). Furthermore, the turnovers obtained in the N-methylation of p-anisidine could be improved (12000 TON of product 2.51e, Table 2.6) by operating at very low loading (0.002 mol %) of 2.48d. While the N-methylated products 2.51g and 2.51h (Table 2.6) did not form, moderate TON were obtained in the 2.48d (0.02 mol %) catalyzed N- alkylation of aniline with ethanol and 2-propanol (products 2.51i-l, Table 2.6). Upon lowering the loading of 2.48d (0.002 mol %), excellent turnovers were observed for the catalytic N- alkylation of aniline with n-butanol and n-hexanol (products 2.51k and 2.51l, Table 2.6).
Table 2.6: Scope of N-Methylation and N-alkylation of aniline catalyzed by (2.48d)a
Reaction conditions: Methanol (0.5 mL, 12.35 mmol), Na (1 equiv.), aniline (0.23 mL, 2.4 mmol) and 2.48d (0.02 mol %) at 140 C. aYield was determined from 1H NMR spectroscopy by using toluene as an internal standard.
bReported as an average of NMR spectroscopy and isolated yield. cReaction was performed 48h with 0.002 mol
% 2.48d. dAverage of NMR spectra and isolated yield of two runs. *Side product was obtained.
However, when methylation of 4-(trifluoromethyl) aniline was attempted, instead of the expected product 2.51c, 1700 turnovers of methyl-4-(dimethylamino) benzoate (2.51cc) were obtained along with trace amounts of 2.51ca and 2.51cb. Accordingly, one could anticipate the involvement of hydrolysis and subsequent esterification reactions leading to the formation of
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Kanu Das, Ph.D Thesis, IIT Guwahati 68 2.51ca (Scheme 2.29). Subsequent methylation of 2.51ca could lead to product 2.51cc via 2.51cb. Grinter121 and Jones122 have independently demonstrated the hydrolysis of hydroxy- substituted and amino-substituted benzotrifluorides to the corresponding benzoic acids.