CERTIFICATE
Scheme 2.18: Transition metal catalyzed N-alkylation using hydrogen-borrowing strategy
2.3 Result and Discussions
2.3.1 Synthesis of pincer bis(imino) ligands and their complexes
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?
Kanu Das, Ph.D Thesis, IIT Guwahati 55 diimine based NNN ligands (2.47a; R = Cy, 2.47b; R = Ph, 2.47c; R = iPr and 2.47d; R = tBu) were synthesized by condensation reaction between pyridine-2,6-dicarbaldehyde (2.46) with the corresponding amines. While in the 1H NMR spectroscopy, the imine protons of all the considered pincer ligands (2.47a-d) resonate in the range of = 8.69-8.42 ppm, the corresponding aza-carbonyl carbons appears at = 160.29-156.39 ppm in the 13C NMR spectroscopy.
Scheme 2.19: General synthetic route to pincer-ruthenium complexes (R2NNN)RuCl2(PPh3) (2.48a; R = Cy, 2.48b; R = Ph, 2.48c; R = iPr and 2.48d; R = tBu).
The corresponding pincer-ruthenium complexes (2.48a; R = Cy, 2.48b; R = Ph, 2.48c; R = iPr and 2.48d; R = tBu) were obtained in good yields by heating to reflux a solution of the NNN ligands (2.47a; R = Cy, 2.47b; R = Ph, 2.47c; R = iPr and 2.47d; R = tBu) and RuCl2(PPh3)3 in THF. The newly synthesized complex (2.48b) showed high thermal stability (up to 334 C) (Appendix I, Figure 2.104). The pincer-Ru complexes (2.48a; R = Cy, 2.48b; R = Ph, 2.48c; R
= iPr and 2.48d; R = tBu) were fully characterized by NMR spectroscopy, HRMS spectroscopy and single crystal X-ray analysis. The crystals were obtained by slow diffusion of pentane (1 mL) into dichloromethane (1 mL) solution of the ruthenium complexes (10 mg). The structure with ORTEP drawn at 50% probability is provided in Figure 2.2. The Ph groups on P, all the hydrogen atoms and the solvent molecules are omitted for the sake of clarity.
The crystallographic data is provided in Table 2.10. Selected bond distances and bond angles are given in Table 2.1. In all the complexes, the Ru center adopted a distorted octahedral geometry with the ligand (2.47) coordinated in a meridional fashion. The other three coordination sites are satisfied by two chlorides and one PPh3 moiety. Notably, the PPh3 moiety
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Kanu Das, Ph.D Thesis, IIT Guwahati 56 is trans to one of the chlorides and both the coordinated chlorides are cis to each other. In the solid-state, all the complexes are stabilized mainly by C−H∙∙∙Cl−Ru interactions either with the solvent molecules or the ligand itself. The complex (2.48a) crystallizes in the triclinic crystal system having P-1 space group with two symmetry non-equivalent molecules being present in the asymmetric unit.
Figure 2.2: ORTEP diagram of (a) (Cy2NNN)RuCl2(PPh3) (2.48a); (b) (Ph2NNN)RuCl2(PPh3) (2.48b); (c) (iPr2NNN)RuCl2(PPh3) (2.48c) and (d) (tBu2NNN)RuCl2(PPh3) (2.48d) with the ellipsoids drawn at the 50% probability level. The Ph groups on P, all the H atoms and the solvent molecules were omitted for the sake of clarity.
The complex 2.48a also has of one molecule of dichloromethane in the crystal lattice. In one of the non-equivalent units of complex 2.48a, the chloride trans to pyridyl−N exhibits C−H∙∙∙Cl−Ru interactions with C−H of both the cyclohexyl groups (2.942 Å & 3.040 Å) and with C−H of the phenyl groups in PPh3 (2.665 Å & 2.628 Å) respectively. Similarly, the chloride that is trans to PPh3 exhibits C−H∙∙∙Cl−Ru interactions with C−H cyclohexyl group (2.996 Å & 3.015 Å). The second non-equivalent unit of 2.48a also shows similar type of C−H∙∙∙Cl−Ru interactions. Additionally, the chloride trans to pyridyl−N in one of the non- equivalent unit of 2.48a, shows C−H∙∙∙Cl−Ru interaction with the imine C−H (2.657 Å),
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Kanu Das, Ph.D Thesis, IIT Guwahati 57 cyclohexyl C−H (3.260 Å) and pyridyl C−H (3.014 Å) of the other non-equivalent unit in 2.48a. Surprisingly, the solvent molecules do not show any kind of interaction with both the units in 2.48a and is likely to act as a space-filler.105
Table 2.1: Selected crystallographic bond distances (Å) and bond angles () of complexes 2.48a-d
2.48a 2.48b 2.48c 2.48d
Ru−N(imine)
2.103 (4) (unit I) 2.081 (4) (unit I) 2.079 (4) (unit II) 2.095 (4) (unit II)
2.128 (3) 2.111 (3)
2.103 (3) 2.071 (3)
2.151 (9) 2.154 (10)
Ru−N(pyridine) 1.943 (3) (unit I)
1.938 (3) (unit II) 1.939 (3) 1.936 (3) 1.930 (8)
Ru−Cl
2.4419 (12) (unit I) 2.4480 (11) (unit I) 2.4513 (12) (unit II) 2.4298 (11) (unit II)
2.449 (13) 2.461 (12)
2.461 (11) 2.453 (12)
2.463 (3) 2.455 (3)
Ru−P 2.3093 (12) (unit I)
2.3157 (12) (unit II) 2.322 (13) 2.315 (11) 2.366 (3)
C=N(imine)
1.295 (5) (unit I) 1.293 (5) (unit I) 1.287 (5) (unit II) 1.297 (5) (unit II)
1.296 (5) 1.287 (5)
1.293 (6) 1.283 (6)
1.297 (14) 1.293 (13)
(imine)N−Ru−N(imine) 156.44 (14) (unit I)
157.58 (13) (unit II) 155.64 (14) 156.54 (14) 155.6 (4) Both the complexes 2.48b and 2.48c crystallizes in a monoclinic crystal system (P21/n and P21/c space group respectively). The complex 2.48b contains one molecule each of dichloromethane and water but complex 2.48c contains only one molecule of dichloromethane in the crystal lattice. The chloride which is trans to the pyridyl N of complex 2.48b exhibits C−H∙∙∙Cl−Ru interaction with phenyl C−H of the imine group (2.667 Å & 2.898 Å) and with C−H of phenyl group in PPh3 molecule (2.668 Å & 2.685 Å) respectively. On the other hand, the chloride which is trans to the PPh3 group exhibits C−H∙∙∙Cl−Ru interaction only with the phenyl C−H of the imine group (3.145 Å & 3.482 Å). Similarly, while the chloride (trans to pyridyl N) in complex 2.48c shows C−H∙∙∙Cl−Ru interaction with isopropyl C−H of the imine group (2.900 Å, 3.226 Å and 3.528 Å) and with C−H of phenyl group in PPh3 (2.615 Å & 2.739 Å) respectively, the chloride which is trans to PPh3 shows C−H∙∙∙Cl−Ru interactions with isopropyl C−H of the imine group (3.024 Å & 3.193 Å).105
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Kanu Das, Ph.D Thesis, IIT Guwahati 58 Interestingly, the solvent molecules in the crystal shows strong Ru−Cl∙∙∙H−C interaction in both the complexes 2.48b and 2.48c. In complex 2.48b, the dichloromethane interacts with the chloride atom that is trans to PPh3 (2.606 Å) and with the chloride atom which is trans to pyridyl−N (3.091 Å). Similarly, in 2.48c, dichloromethane demonstrates Ru−Cl∙∙∙H−C interaction with the chloride atom (trans to pyridyl N, ca. 2.654 Å) and a C−H∙∙∙Cl−C interactions with the isopropyl of the imine group (3.109 Å & 3.504 Å). The complex 2.48d crystallizes in orthorhombic crystal system. In the resulting Pbca space group of 2.48d two molecules of dichloromethane are present in the crystal lattice. The chloride, which is trans to pyridyl−N exhibit interactions with C−H of the phenyl group in PPh3 (2.549 Å) and C−H of both the tert-butyl groups (2.734 Å, 2.761 Å, 2.733 Å and 2.705 Å). Similarly, the chloride (trans to PPh3) shows C−H∙∙∙Cl−Ru interactions with C−H of the tert-butyl groups (3.055 Å, 3.077 Å, 3.117 Å and 2.940 Å). Both the dichloromethane molecules present in the crystal lattice shows C−H∙∙∙Cl−Ru interaction with chloride atom that is trans to PPh3 group (2.303 Å
& 2.612 Å).105
2.3.2 N-alkylation catalyzed by the pincer-ruthenium complexes of the type (R2NNN)RuCl2(PPh3) (2.48a; R = Cy, 2.48b; R = Ph, 2.48c; R = iPr and 2.48d; R = tBu ) To arrive at the optimal reaction conditions (Scheme 2.20), the 2.48d (0.02 mol %) catalyzed reactions were carried out at 120 °C in a sealed vessel using benzyl alcohol (2.29) and aniline (2.49) as model substrates in the presence of varying amounts of KOtBu (entries 1-4, Table 2.2) for 20 h. For this variation, the best results (26% yield, 1300 TON) (TON = [Product]/[Catalyst]) were obtained with use of 0.75 equivalent KOtBu (entry 3, Table 2.2).
Operating at a catalyst loading of 0.05 mol % resulted in a higher yield albeit with lower turnover (entry 5, Table 2.2). Further increment in catalyst loading hardly improved the yields (entries 6 and 7, Table 2.2).
Scheme 2.20: N-alkylation reaction catalyzed by the pincer-ruthenium complexes of the type (R2NNN)RuCl2(PPh3) (2.48a; R = Cy, 2.48b; R = Ph, 2.48c; R = iPr and 2.48d; R = tBu ).
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Kanu Das, Ph.D Thesis, IIT Guwahati 59 Table 2.2: N-Alkylation of aniline with benzyl alcohol under varying loading of the base and catalyst 2.48d
Entry Additive (x equiv.) 2.48d (mol %) Yield (%)a TON
1 KOtBu (0.25) 0.02 7 350
2 KOtBu (0.50) 0.02 15 750
3 KOtBu (0.75) 0.02 26 1300
4 KOtBu (1.00) 0.02 16 800
5 KOtBu (0.75) 0.05 46±1b 920
6b KOtBu (0.75) 0.10 45 450
7 KOtBu (0.75) 0.20 52 260
8 Et3N (0.75) 0.02 0 0
9 KOH (0.75) 0.02 9 450
10 K2CO3 (0.75) 0.02 0 0
11 Na (0.75) 0.02 53 2650
12 NaOtBu (0.75) 0.02 53 2650
13 NaOH (0.75) 0.02 12 (6)c 600
Reaction conditions: benzyl alcohol (0.53 mL, 5.1 mmol), additive (x equiv.), aniline (0.47 mL, 5.14 mmol) and 2.48d (0.02 mol %) at 120 C. aYield determined from 1H NMR spectroscopy using toluene as an internal standard.
bReported as an average of NMR spectroscopy and isolated yield. cYield of the corresponding imine is given in parenthesis.
Use of 0.75 equivalents of either K2CO3 or Et3N as the base in the (tBu2NNN)RuCl2(PPh3) (2.48d) (0.02 mol %) catalyzed reactions did not yield any products (entries 8 and 10, Table 2.2). On the other hand, presence of 0.75 equivalents of KOH resulted in very poor yield (entry 9, Table 2.2). To test the hypothesis of generating the base in-situ (vide-supra), 0.75 equivalents of sodium was treated with benzyl alcohol 2.29 at 120 °C. To the resulting slurry (likely to be 2.29 and sodium benzyloxide in the ratio 0.25:0.75) at room temperature, equivalent amounts of aniline (2.49) containing 0.02 mol % of 2.48d was added and stirred at 120 °C in a sealed vessel. This reaction resulted in 53% yields and better turnovers (2650) (entry 11, Table 2.2).
Notably, under these conditions, the use of an additional base such as KOtBu is completely mitigated. In addition, there is no possibility of the formation of one of the by-products (Path B, Scheme 2.18). These features make the current reaction (entry 11, Table 2.2) more atom- economical in comparison with other reactions (entries 1-10, Table 2.2) and earlier reports.19,
75 Interestingly, the water formed in the reaction promotes the conversion of sodium benzyloxide back to 2.29, thus maintaining its continuous supply in the catalytic cycle (Path A, Scheme 2.18).
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Kanu Das, Ph.D Thesis, IIT Guwahati 60 Under these optimized conditions, the introduction of solvent gave reduced yields (entries 2-5, Table 2.3) of N-alkylated product. Under solvent-free conditions, the yield of 2.48d catalyzed N-alkylation could be improved (ca. 73%) at higher catalyst loading (entry 9, Table 2.3) however at the cost of TON. The catalytic activity of other complexes 2.48a, 2.48b and 2.48c were not on par when compared to that of 2.48d (compare entries 10, 11 and 12 with entry 1, Table 2.3).
Table 2.3: N-Alkylation catalyzed by (2.48a-d) in different solvents.
Entry Na (x equiv.) (2.48d) (mol %) Solvent Yield (%)a TON
1 0.75 0.02 -- 53 2650
2 0.75 0.02 Benzene 17 (8)c 850
3 0.75 0.02 Dioxane 28 (7)c 1400
4 0.75 0.02 THF 26 (2)c 1300
5b 0.75 0.02 Toluene 21±1 (10)c 1050
6d 0.75 0.02 -- 57 2850
7e 0.75 0.02 -- 16 800
8 1.00 0.10 -- 47 470
9 0.75 0.10 -- 73 730
10 0.75 (2.48a) 0.02 -- 44 2200
11 0.75 (2.48b) 0.02 -- 37 1850
12 0.75 (2.48c) 0.02 -- 44 2200
Reaction conditions: benzyl alcohol (0.53 mL, 5.1 mmol), Na (x equiv.), aniline (0.47 mL, 5.14 mmol) and 2.48 (0.02 mol %) at 120 C. aYield determined from 1H NMR by using toluene as an internal standard. bReported as an average of NMR spectra and GC yield. cYield of the corresponding imine given in parenthesis. dReaction was performed at 140 C. eReaction was performed at 100 C.