Cyclometalated Iridium Complexes as Highly Active Catalysts for the Hydrogenation of Imines

Abstract

A robust cyclometalated iridium catalyst has been developed for highly effective hydrogenation of imines. With very low catalyst loading (down to 0.005%), good to excellent yields have been achieved for a range of substrates in a short reaction time under mild conditions, providing an easy, efficient protocol for making amines.

Key words

cyclometalated complexes - hydrogenation - imines - iridium - iridicycles

Amines are important building blocks for the synthesis of numerous pharmaceutical and agrochemical substances.[1] Among the various methods of synthesising amines, including stoichiometric boron hydride and organocatalytic reduction of C=N double bonds, transition-metal-catalysed hydrogenation of imines is one of the most convenient and efficient.[2] [3] Although significant progress has been achieved in this area, highly efficient reduction of C=N double bonds is still challenging. Recently, our group[4] and other groups[5,6] have explored a series of cyclometalated iridium compounds, some of which have been successfully applied to transfer hydrogenation of imines and reductive amination of ketones. More recently, we have found that these iridicycles allow for efficient hydrogenation of imines[4f] as well as N-heterocycles.[4g] Herein, we report a tailor-made, more robust iridicycle, which ­catalyses the hydrogenation of imines with hydrogen gas under low catalyst loading.

Scheme 1 Synthesis of the cyclometalated iridium complexes C1 and C2

We started with preparation of the cyclometalated iridium complexes. Using procedures reported previously,[4] [5] [6] two new cyclometalated iridium complexes were synthesised readily from tetralone and its derivative in two steps (Scheme [1]). With the imino carbon being embedded in a ring, the resulting iridicycles C1 and C2 were expected to be more robust in comparison with those reported before.[4]

Table 1 Screening of Conditions for the Hydrogenation of Imine 1a ^a

Entry	Cat.	S/C ratio	Solvent	Temp (°C)	Yield (%)b
1	C1 or C2	5000	CH2Cl2	40	NO
2	C1 or C2	5000	THF	40	NO
3	C1 or C2	5000	toluene	40	NO
4	C1 or C2	5000	EtOH	40	<2
5	C1 or C2	5000	Et2O	40	NO
6	C1	5000	TFE	40	20
7	C2	5000	TFE	40	10
8c	C1	5000	toluene	40	19
9	C1	5000	TFE	85	93
10c	C1	5000	toluene	85	93
11d	C1	10000	TFE	85	90
12e	C1	20000	TFE	85	86

^a The reaction was carried out with 1a (0.15 mmol), C1 or C2 (0.02–0.005 mol%), solvent (0.7 mL), in reaction time of 1 h, at initial H₂ pressure of 20 bar.

^b The yield was determined by ¹H NMR with an internal standard (1,3,5-trimethoxybenzene); NO = no reaction observed.

^c NaBARF (2 equiv) was added.

^d Amount of 1a used was 0.3 mmol.

^e Amount of 1a used was 0.6 mmol, and the reaction time was 2 h.

Having obtained these precatalysts, the hydrogenation of ketoimine 1a was then examined. The reduction was carried out at a high substrate to catalyst (S/C) ratio of 5000 with 20 bar initial hydrogen pressure at 40 °C. As shown in Table [1], little reaction was observed with both of the catalysts in either polar or nonpolar common organic solvents, such as CH₂Cl₂, THF, toluene, EtOH, and Et₂O (Table [1], entries 1–5). However, to our satisfaction, some conversion was obtained for the reduction by using trifluoroethanol (TFE) as solvent (Table [1], entries 6 and 7). This is probably due to the dissociation and/or solvation of the chloride ion of the catalyst by the strongly ionising TFE.[7] This significant solvent effect has been noted in our previous studies.[4f] [g] Indeed, promoting the dissociation of chloride with NaBARF makes the reaction work in the nonpolar toluene (Table [1], entry 8). Full conversion was obtained with C1 at a high temperature of 85 °C (Table [1], entries 9 and 10). The hydrogenation reaction proceeded well at even a higher S/C ratio of 20000 in TFE (Table [1], entries 11 and 12). The screening indicates that C1 is more active than C2 (Table [1], entries 6 and 7).

With the optimal reaction conditions in hand, the scope of substrates was explored subsequently with C1 and the results are listed in Table [2]. In general, most of the imines were fully hydrogenated at a high S/C ratio of 10000, affording good to excellent isolated yields. However, a significant electronic effect arising from the substituents on the aryl rings of the substrates was observed, with electron-donating groups favouring hydrogenation. Thus excellent yields were obtained for imines with methyl and methoxy groups on the aryl rings (Table [2], entries 1–7). However, for substrates with electron-withdrawing substituents on the aryl rings, good yields could only be obtained at a higher catalyst loading (Table [2], entries 10–12). For weakly electron-withdrawing substituents (e.g., Cl on one aryl ring), a good yield was afforded under the standard conditions (Table [2], entries 8 and 9). It is worth noting that the hydrogenation can be readily scaled up. Thus, 1a was fully converted on a two-gram scale into the desired amine product in two hours under the optimised conditions, affording 93% isolated yield.

In summary, we have synthesised a new type of robust cyclometalated iridium catalysts, and the catalyst has been shown to be effective for the hydrogenation of imines at high S/C ratios under mild conditions.[8] The high activity, air-stability and ease of preparation make the catalyst ­attractive for imine hydrogenation and possibly for other reactions as well.

Table 2 Hydrogenation of Imines with C1 ^a

Entry	Substrate	Product	Yield (%)b
1	1a		90
2	1b		90
3	1c		90
4	1d		85
5	1e		93
6	1f		89
7	1g		91
8	1h		89
9	1i		91
10	1j		53
11	1k		45 (91)c
12	1l		11 (91)c

^a The reaction was carried out with imine (0.3 mmol), C1 (0.01 mol%), solvent (0.7 mL), in reaction time of 1 h, at initial H₂ pressure of 20 bar.

^b Isolated yield.

^c Amount of C1 used was 0.1 mol%.

Acknowledgment

We thank EPSRC for a postdoctoral fellowship (W.J.T.) and the University of Liverpool for funding (X.F.W.). Thanks also go to the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass analysis.

• References and Notes


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• 8 General Procedure for the Synthesis of the Cyclometalated Iridium Complexes: An oven-dried Schlenk tube containing a magnetic stirrer bar was charged with [Cp*IrCl₂]₂ (1 equiv), imine ligand⁵ (2 equiv) and NaOAc (10 equiv). Following degassing with N₂ (3 ×), freshly distilled CH₂Cl₂ was injected. The resulting mixture was stirred at r.t. overnight. The reaction mixture was then filtered through Celite^®, washed with CH₂Cl₂ and the combined organic solvents were concentrated in vacuo. The resulting solid was washed with Et₂O–hexane and recrystallised from CH₂Cl₂–hexane. C1: orange powder (90.5 mg, 98%). ¹H NMR (400 MHz, CDCl₃; 258 K): δ = 7.79 (br, 1 H), 7.62–7.64 (d, J = 7.6 Hz, 1 H), 7.12–7.16 (m, 1 H), 6.92–6.99 (m, 3 H), 6.76–6.78 (d, J = 7.2 Hz, 1 H), 3.85 (s, 3 H), 2.63–2.97 (m, 4 H), 1.87–1.88 (m, 2 H), 1.43 (s, 15 H). ¹³C NMR (100 MHz, CDCl₃; 258 K): δ = 182.9, 168.4, 157.4, 144.6, 143.4, 143.0, 132.7, 132.4, 125.2, 123.3, 121.2, 115.0, 112.3, 88.9, 55.7, 30.4, 29.2, 23.8, 15.5, 8.9. Anal. Calcd for C₂₇H₃₁ClIrNO: C, 52.88; H, 5.10; N, 2.61. Found: C, 52.69; H, 5.12; N, 2.09. C2: pale orange powder (31.7 mg, 98%). ¹H NMR (400 MHz, CDCl₃; 258 K): δ = 7.76–7.79 (m, 1 H), 7.15–7.16 (d, J = 1.6 Hz, 1 H), 6.82–6.93 (m, 3 H), 6.33 (s, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 2.56–2.93 (m, 4 H), 1.84–1.85 (m, 2 H), 1.42 (s, 15 H). ¹³C NMR (100 MHz, CDCl₃): δ = 181.4, 170.7, 162.3, 157.5, 144.7, 143.5, 138.4, 124.8, 117.6, 114.2, 113.8, 113.5, 106.9, 88.7, 55.6, 55.0, 30.2, 29.5, 23.9, 8.7. Anal. Calcd for C₂₈H₃₃ClIrNO₂: C, 52.28; H, 5.17; N, 2.18. Found: C, 52.43; H, 5.48; N, 1.94. Procedure for the Hydrogenation of Imines with Cyclometalated Iridium Complex C1: A glass liner containing a stirrer bar was charged with the requisite imine (0.3 mmol) and TFE (0.75 mL). The mixture was stirred until the imine was dissolved and catalyst C1 was then added (10 μL stock solution, made by dissolving C1 in TFE: 0.03 mmol C1 in 10 mL TFE). The glass liner was then placed into an autoclave followed by degassing with H₂ (3 ×). The hydrogenation was carried out at 20 bar H₂ with stirring at 85 °C for 1 h. After the reaction was finished, the autoclave was allowed to cool to r.t. The hydrogen gas was then carefully released in the fume hood, the solution transferred to a flask and concentrated in vacuo to afford the crude product. Flash chromatographic purification with a column of silica gel eluted with petroleum ether–EtOAc (20:1 → 5:1) yielded the desired amine product.