CERTIFICATE
Scheme 2.4: Hydrogen-borrowing strategy for N-Alkylation
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Kanu Das, Ph.D Thesis, IIT Guwahati 48 Scheme 2.5: Transition metal catalyzed N-alkylation of amines with alcohols.16-23
The concept of “hydrogen borrowing” for catalytic alkylation of amine was first implemented independently by Grigg24 and Watanabe25 in 1981. Subsequently, over the years, catalytic N- alkylation has been reported with complexes based on precious metals such as Pd,26-27 Ru,25, 28-
48 Rh,24 and Ir.49-66 However, in recent years, the studies on the development of the catalytic systems have led to the replacement of expensive noble-metal based complexes by inexpensive metal based complexes such as PNNNP pincer-Mn,19-23, 67-70 and PNCNP/NNN pincer-Co16-18 along with complexes based on Fe,9, 71-79 Ni80-81 and Cu27, 82 (Scheme 2.5). Notably, several heterogeneous catalytic systems derived from Pd,26, 83 Ag,84-85 W,86 Cu82 and Ni87-88 have also enjoyed great success in catalytic N-alkylation.
Scheme 2.6: Alkylation of nitroarene catalyzed by ruthenium trichloride.89
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Kanu Das, Ph.D Thesis, IIT Guwahati 49 N-alkylated amines could be synthesized using nitrenes as an amine precursor with alcohols as alkylating agents (Scheme 2.6).89 In many cases, a large excess of alcohol was used not only as alkylating agents but also as a hydrogen source to reduce the nitrenes.90-91 Usually, an excess amount of alcohol is required in a ratio of 6:1 to 8:1 with respect to nitrenes.90-91 Shi and co- workers reported a clean synthetic pathway with feedstock glycerol as a hydrogen source. In this way, they demonstrated a one-pot ruthenium catalyzed N-alkylation without using a large amount of alcohol, which gave very high productivity (up to 40 TON).
Scheme 2.7: Alkylation of amines catalyzed by an iridium half-sandwich complex.61
Efficient N-alkylation was demonstrated by Limbach using the iridium half-sandwich complex (Scheme 2.7).61 Notably, this condition shows high reactivity not only under base-free condition but also at lower temperature (95 C). The reaction occurred both in organic medium as well as in water with high activity.
Scheme 2.8: Iron catalyzed N-alkylation of amines.71
A large number of transition metal complexes, particularly iridium and ruthenium have been studied for catalytic C−N bond formation.71 A better alternate for ruthenium was reported by the Barta group, who investigated an inexpensive and sustainable iron complex for the direct alkylation of amines with alcohol via “hydrogen-borrowing” strategy (Scheme 2.8).71
Beller and co-workers demonstrated that the scope of N-alkylation was not limited to simple amines,71 but also could be extended to alkylation of amides and sulfonamides with alcohols.92 A hydrogen-borrowing strategy was employed in these copper catalyzed alkylation of
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Kanu Das, Ph.D Thesis, IIT Guwahati 50 sulfonamides with primary alcohols in the presence of K2CO3 and air (Scheme 2.9).92 Excellent yields (up to 99 TON) are obtained in this reaction where active species appears to be a bissulfonylated amidine intermediate with the Cu(OAc)2/K2CO3/air system.
Scheme 2.9: N-alkylation of sulfonamides with alcohol using a copper catalyst.92
Chiral amines, which have great value in the pharmaceutical industry can be conveniently obtained via asymmetric hydrogenation of ketimines,93-94 which in turn can be easily synthesized by the above discussed atom economical ‘hydrogen borrowing’ methodology.62 Zhao group was the first to report the synthesis of chiral amines via the N-alkylation of amines with alcohols (Scheme 2.10). The chiral iridium catalyst (S,S-2.26) in the presence of chiral phosphoric acid 2.25 catalyzed the synthesis of a large number of chiral enantioselective amines with good to excellent yields.
Scheme 2.10: Synthesis of chiral amines using hydrogen-borrowing strategy.62
It is notable that N-alkylation reactions have also been catalyzed by ruthenium-based complexes. Watanabe and co-workers reported several ruthenium based complexes such as [RuX2(PPh3)3] (X = Cl,25, 30 Br48), [RuH2(PPh3)4],25 [RuHCl(PPh3)3]48 for the N-alkylation of amines using alcohols. The N-alkylation of amines with alcohols have also been successfully demonstrated by using a variety of other ruthenium-phosphine containing complexes.32, 38, 48, 95-96 The use of ruthenium precursors in the presence of amino/amide ligands resulted in one- pot N-alkylation of primary and secondary amines with alcohols along with a vast substrate
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Kanu Das, Ph.D Thesis, IIT Guwahati 51 scope.34, 43 The N-heterocyclic carbene (NHC) ligand 2.30 based ruthenium system catalyzed N-alkylation of amines with alcohols exhibiting high activity and selectivity under low catalyst loading (Scheme 2.11).97
Scheme 2.11: N-alkylation of amines with alcohols catalyzed by Ru(COD)Cl2 in the presence of NHC ligand 2.30.97
Scheme 2.12: Pincer-ruthenium catalyzed N-alkylation of amines with alcohols.35
In their pioneering work, van-Koten and co-workers reported N-(cyclo)alkylation reactions of amines with diols by well-defined dicationic pincer-ruthenium(II) complex 2.33 (Scheme 2.12).35 The Me2NNN pincer-ruthenium complex system gave up to 33 % yield of N- phenylpiperidine derivative.
Scheme 2.13: Pincer-cobalt catalyzed N-alkylation reaction of amines with alcohols.50, 98 Kempe and co-workers reported the first PNP pincer-cobalt 2.34 catalyzed N-alkylation of amines with alcohols under relatively mild conditions.50, 98 They also demonstrated the selective synthesis of unsymmetrically substituted diamines (Scheme 2.13).
Beller and co-workers reported highly stable pincer-manganese 2.35 catalyzed inter- and intramolecular N-alkylation of amines with alcohols. The catalytic system under mild
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Kanu Das, Ph.D Thesis, IIT Guwahati 52 conditions provided excellent chemoselectivity and tolerates various functional groups (Scheme 2.14).21, 99
Scheme 2.14: Pincer-manganese catalyzed N-alkylation of amines with alcohols.21, 99
Milstein group has demonstrated higher order amine synthesis following the similar procedure when amines were reacted with alcohols in the presence of pincer catalyst 2.36. Similarly, reacting ammonia with alcohols provided access to direct synthesis of secondary amines (via N-alkylation reaction catalyzed by PNN pincer-ruthenium complex 2.36 (Scheme 2.15).100-101
Scheme 2.15: Pincer-ruthenium catalyzed N-alkylation of alcohols with ammonia.101
Scheme 2.16: Pincer-ruthenium catalyzed N-alkylation of amines with alcohols.46
Kundu and co-workers demonstrated the excellent catalytic activity of bifunctional 2- hydroxypyridine based NNN pincer-ruthenium(II) complex 2.38 towards N-alkylation reaction. Notably, they also studied the mono N-methylation of amines under the same catalytic conditions. In addition, a wide substrate scope with various functional groups are tolerated for N-alkylation to achieve remarkably high turnovers (42840 TON, Scheme 2.16).46 Including
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Kanu Das, Ph.D Thesis, IIT Guwahati 53 these examples many other groups have demonstrated a significant progress on pincer-metal catalyzed N-alkylation reaction.102
Thus, among the various complexes tested for N-alkylation, pincer complexes based on a variety of metals (Ru in particular have enjoyed) great success. Generally, either for N- alkylation or for dehydrogenative coupling, stoichiometric amounts of base such as KOtBu43,
50 or NaOtBu19, 81 are required as water scavengers. This results in the generation of equivalent amount of metal hydroxide and t-butanol. While the use of molecular seives62 would be more atom economical for this reaction, it would be advantageous even if one avoids the formation of one of the possible by-products.
Scheme 2.17: Transfer hydrogenation by bis(ketimino) pincer-ruthenium complexes.103-104 A comprehensive literature survey reveals that pincer complexes are more effective than others in catalyzing N-alkylation reactions and that there are no reports on N-alkylation that are catalyzed by pincer based on bis(imino) pyridine ligands. However, there are only two reports on transfer hydrogenation reaction by imine-based pincer-Ru complexes. Çetinkaya group demonstrated a ketimine-based pincer-ruthenium complex 2.39 for transfer hydrogenation of acetophenone (Scheme 2.17). In the presence of 1 mol % of KOH, ruthenium-ketimine catalyst 2.39 (0.1 mol%) gave 990 TON of 1-phenylethanol upon transfer hydrogenation (Scheme 2.17).104 Karabuga and co-workers explored bis(ketimino) pyridine-based pincer-ruthenium complex 2.40 catalyzed transfer hydrogenation of secondary alcohols using isopropanol as a hydrogen source and obtained a maximum of 198 TON (Scheme 2.17).103-104
2.2 Objectives
Considering the vast literature that is available on the Ru-catalyzed N-alkylation and the fact that the studies with environmentally benign ‘nitrogen’ based ligand systems are very sparse, the studies on the chemistry of ruthenium catalyzed N-alkylation is still relevant. Furthermore,
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Kanu Das, Ph.D Thesis, IIT Guwahati 54 while use of molecular sieves would be the best way to make the N-alkylation reaction atom economical, it would be a win-win situation even if one accomplishes the reaction with the minimal by-products. These formed the basis of the current chapter that attempts to address the following questions.
• Can one utilize pincer-Ru complexes based on air stable NNN bis(imino) pyridine ligands for N-alkylation?
• Could Na be used effectively to generate the required base in-situ for the pincer- ruthenium catalyzed N-alkylation reaction (Scheme 2.18)?
• What is the operative mechanism in these NNN-Ru catalyzed N-alkylation?