Benzimidazol-2-ylidene ruthenium complexes for C–N bond formation through alcohol dehydrogenation

Abstract

A low temperature hydrogen borrowing approach to generate secondary amines using benzimidazole-based N-heterocyclic carbene (BNHC) ruthenium complexes is reported. A series of the piano-stool complexes of the type [(η⁶-p-cymene)(BNHC)RuCl₂] (1a–g) were synthesized via one-pot reaction of the NHC salt precursor, Ag₂O, and [RuCl₂(p-cymene)]₂ and characterized using conventional spectroscopic techniques. The geometry of two precursors, [(η⁶-p-cymene)(^Me4BnMe₂BNHC^CH2OxMe)RuCl₂] (1f) and [(η⁶-p-cymene)(^Me5BnMe₂BNHC^CH2OxMe)RuCl₂] (1g), was studied by single crystal X-ray diffraction. These catalysts were found to dehydrogenate alcohols efficiently at temperatures as low as 50 °C to allow Schiff-base condensation and subsequent imine hydrogenation to afford secondary amines. Notably, this ruthenium-based procedure enables the N-alkylation of aromatic and heteroaromatic primary amines with a wide range of primary alcohols in excellent yields of up to 98%. The present methodology is green and water is liberated as the sole byproduct.

1. Introduction

Amines, organic derivatives of ammonia, are extensively found in bioactive molecules and medicines [1]. Amines are the key precursor in the manufacture of a number of relevant therapeutics medicines [2–4]. Conventionally, the most common methods for producing alkylated amines involve alkyl halides [5] or stoichiometric reducing agents, which are used for reduction of imines formed between carbonyls and amines [6,7]. The toxicity of the alkylating and reducing reagents and the generation of huge volumes of undesired byproducts are all significant disadvantages of these reactions. To address these difficulties, catalytic techniques have been devised including Buchwald–Hartwig amination [8], hydroamination [9,10], and hydroaminomethylation [11] as well as hydrogen borrowing or hydrogen autotransfer (HB/HA) methodologies [12].

In the HB/HA procedure, first dehydrogenation of the alcohol produces the equivalent aldehyde, which then undergoes reductive amination to produce the required amine. Because the alcohol functions as the hydrogen donor, an additional hydrogen source is not required in this approach. Furthermore, because a variety of alcohol derivatives are easily available from renewable feedstocks, this technology is particularly well suited for the valorization of biomass or biomass-derived building blocks. The HB/HA technique is the most attractive methodology for their synthesis [13–15]. These reactions are notable for being not only ecologically friendly, but also atom efficient, with only water as a byproduct. Grigg [16] and Watanabe [17] independently described the first examples of amine alkylation with alcohols via hydrogen borrowing while employing the homogeneous ruthenium catalysts [(PPh₃)₄RhH] and [(PPh₃)₃RuCl₂]. Since that time, several noble metal-based Ru [18–21], Pd [22–24], Ir [25–27], and Pt [28] complexes and nonnoble metal-based Mn [29] Co [30] Ni [31], and Fe [32] complexes have been used. Heterogeneous catalysts [33], biocatalysts [34,35], and chiral catalysts [36,37] have also been used. Importantly, many of the catalysts that have previously been described for this reaction require relatively high temperatures of 100 °C or greater and high catalytic loading [38–43], but some other complexes have comparative working conditions for this reaction [18,44].

N-Heterocyclic carbene (NHC) ligands have become a common alternative to phosphine ligands in homogeneous catalysis over the last 30 years [45–48], especially in combination with ruthenium salts [44,49–52]. We recently described the synthesis of benzimidazolium salts (the precursors to benzimidazole-based NHC (BNHC) ligands) and their silver(I) complexes, which were determined to be active catalysts for carboxylation of epoxides to generate carbonates [53] and aldehyde–amine–alkyne coupling. The preparation and identification of new ruthenium(II) complexes having the general formula [(η⁶-p-cymene)(BNHC)RuCl₂] (1a-g) are described in the present paper (Scheme 1). The hydrogen borrowing approach was used to test these complexes as catalysts for the N-alkylation of anilines and amine-substituted heterocycles with a variety of alcohols.

Scheme 1.

Synthesis of ruthenium p-cymene BNHC complexes.

2. Experimental section

2.1. Materials and methods

All metal complex preparation methods and catalytic reactions were performed using normal Schlenk procedures. Reagents were bought from commercial sources and were not purified prior to use. The melting point of the produced compounds was determined using open capillary tubes in an Electrothermal 9200 melting point device. A PerkinElmer Spectrum 100 spectrometer with a range of 4000–400 cm⁻¹ was utilized for FT-IR analysis. NMR spectra were obtained using a Bruker Ascend 400 Avance III HD, which operated at 400 MHz (¹H) and 100 MHz (¹³C) using tetramethyl silane as an internal reference. NMR experiments were conducted in high-quality 5-mm Young NMR tubes. Chemical shifts (δ) and coupling constants (J) are expressed in parts per million (ppm) and hertz (Hz). ¹³C chemical shifts are given relative to deuterated solvents (=77.16 ppm for CDCl₃). ¹H NMR spectra are referenced to residual protonated solvents (=7.26 ppm for CDCl₃).

2.2. General synthetic methodologies used for the synthesis of benzimidazol-2-ylidene ruthenium complexes, 1a-g

Complexes [(η⁶-p-cymene)(BNHC)RuCl₂] were synthesized in a one-step process through transmetalation. Dimeric complex of ruthenium [RuCl₂(p-cymene)]₂ (0.19 mmol) was added to Ag(I)–BNHC complexes (0.383 mmol) in situ without isolation and the mixture was stirred at 25 °C in dichloromethane (DCM) for 48 h. Orange–brown complexes 1a, 1b, 1c, 1d, 1e, 1f, and 1g of ruthenium carbene were isolated in good yields of 42.5%–80%. Data regarding the ¹H and ¹³C NMR spectra are given in Tables 1 and 2.

Table 1.

Selected ¹H NMR data for 1.

Comp.	4	5	6	8	9	10	11	12	13	14	15	16
1a	-	7.09 (t) 7.18 (td), 7.24– 7.40 (m)	4.50 (s)	4.74–5.05 (m)	1.98 (s)	1.15 (s)	1.25 (d)	2.93 (hept)	5.86–5.72 (m)	5.41 and 5.27 (s)	2.21 (s)	6.98 (d), 6.80 (d) 6.39(d)
1b	-	7.19 (dd), 7.04 (d) 7.01–6.93 (m)	5.13 (s)	4.73 and 4.39 (d)	1.88 (s)	1.22 (s)	1.32 (d)	3.03 (hept)	6.68 (s), 6.57 (d), 5.72 (d), 5.43–5.31 (m)	5.52 (d)	2.49(s), 2.25(s) 1.80 and 1.71 (s)	6.57 (s) 6.68 (s)
1c	-	7.16 (t) 7.02 (d) 6.97 (s) 6.91 (t)	5.17 (d)	4.75 and 4.39 (d)	1.79 (s)	1.21 (s)	1.32 (d)	3.02 (hept)	6.36 and 5.53 (d) 5.71 (s)	5.44 and 5.53 (s)	2.34, 2.06, and 1.71 (s)	7.22 (s)
1d		7.21–7.07 (m) 6.99 (d), 6.94–6.83 (m)	5.18 (d)	4.76 and 4.40 (d)	1.95 (s)	1.19 (s)	1.32 (d)	3.02 (hept)	6.35 (d), 5.70 (s) 5.44 (s), 4.44 (s)	5.53 (d)	2.47–1.77 (m)	–
1e		7.32–7.23 (m), 7.22–7.15 (m), 7.06 (d)	5.03 (d)	4.79 and 4.44 (d)	1.91 (s)	1.15 (s)	1.28 (d)	3.02 (hept)	6.26 (d), 5.78 (m), 4.54 (d)	5.43 (d)	3.80 and 3.70 (s)	6.43 (s)
1f	2.28 and 2.02 (s)	7.16 and 6.98 (s)	5.13 (d)	4.74 and 4.37 (d)	1.90 (s)	1.21 (s)	1.31 (d)	3.02 (hept)	6.05, 5.63 (s), 5.36 (d)	5.51 (d)	2.45–2.21 (m), 1.16–1.81(m)	6.77 (s)
1g	2.27 and 2.28 (s)	7.22–6.92 (m), 6.74 (s)	5.14 (d)	4.75 and 4.38 (d)	2.00 (s)	1.19 (s)	1.31 (d)	3.01 (hept)	6.01, 5.63 (s), 5.46–5.31 (m)	5.51 (d)	2.44–2.29 (m) 2.16–2.01 (m) 1.92 (s)	–

Table 2.

Selected ¹³C NMR data for 1.

Comp.	2	4	5,13,16	6	7	8	9	10	11	12	14	15
1a	190.3	-	138.7, 137.2, 135.6, 135.5, 128.8, 128.3, 126.7, 122.9, 112.0, 109.3	52.7	40.3	98.9	21.5	18.5	21.7	30.7	55.5	20.6
1b	187.7	-	137.4, 135.9, 135.4, 128.5, 111.5, 109.9, 109.6	50.0	40.8	98.6	21.3	18.5	21.6	30.7	54.2	20.9
1c	187.5	-	135.9, 135.4, 131.9, 131.5, 122.9, 122.8, 111.8, 109.7, 109.5	50.8	40.8	98.5	21.2	18.6	23.2	30.7	54.2	20.9, 20.5, 16.2
1d	187.5	-	135.9, 135.5, 135.2, 128.9, 122.9, 122.6, 112.0, 109.6, 109.5	51.4	40.8	98.5	21.1	18.6	21.1	30.8	54.4	17.2
1e	189.7	-	153.4, 137.3, 135.7, 135.4, 132.4, 123.4, 112.0, 110.4, 109.9, 104.0	53.3	40.7	98.6	20.7	18.6	21.3	30.7	54.6	60.9, 56.1
1f	184.9	20.4, 20.3	134.6, 134.1, 131.8, 131.7, 109.8, 109.6, 98.6	50.6	40.9	98.6	21.3	18.5	21.2	30.6	53.9	20.4, 20.3
1g	184.9	20.4, 20.3	135.1, 134.6, 134.2, 131.6, 131.6, 129.0, 112.5, 109.8, 109.5	51.1	40.8	98.6	21.2	18.5	21.3	30.7	54.1	20.4, 20.3, 17.2

• 1a. Yield: 63%; orange–brown solid: mp 172–174 °C.

• 1b. Yield: 55%; orange–brown solid: mp 172–174 °C.

• 1c. Yield: 67%; orange–brown solid: mp 180–182 °C.

• 1d. Yield: 78%; orange–brown solid: mp 180–182 °C.

• 1e. Yield: 48%; orange–brown solid: mp 298.5–298.7 °C.

• 1f. Yield: 80%; light brown solid: mp 145–148 °C.

• 1g. Yield: 42.5%; dark brown solid: mp 242–243 °C.

2.2.1. X-ray crystallography

X-ray measurements were performed with a STOE IPDS II diffractometer at room temperature using graphite-monochromated MoKα radiation by applying the w-scan method. Data collection and cell refinement were carried out using X-AREA, while data reduction was applied using X-RED32. The structure was solved by direct methods with SIR2019 [54] and refined by means of the full-matrix least-squares calculations on F² using SHELXL-2018 [55]. All H atoms were located in difference maps and then treated as riding atoms, fixing the bond lengths at 0.98, 0.93, 0.97, and 0.96 Å for methine CH, aromatic CH, CH₂, and CH₃ atoms, respectively. The displacement parameters of the H atoms were fixed at U_iso(H) = 1.2 U_eq (1.5 U_eq for CH₃). Crystal data, data collection, and structure refinement details are given in Table 3. The molecular graphic was generated using OLEX2 [56].

Table 3.

Crystal data and structure refinement parameters for 1f and 1g.

Parameters	1f	1g
CCDC depository	2085163	2173756
Color/shape	Dark red/prism	Light brown/prism
Chemical formula	[RuCl2(C10H14)(C25H32N2O)]	[RuCl2(C10H14)(C26H34N2O)]
Formula weight	682.71	696.73
Temperature (K)	296(2)	296(2)
Wavelength (Å)	0.71073 Mo Kα	0.71073 Mo Kα
Crystal system	Triclinic	Orthorhombic
Space group	P–1 (No. 2)	Pbca (No. 61)
Unit cell parameters
a, b, c (Å)	7.1553(5), 15.4318(12), 15.5762(12)	7.2829(2), 21.3438(5), 43.0193(13)
α, β, γ (°)	86.525(6), 85.527(6), 77.055(6)	90, 90, 90
Volume (Å3)	1669.4(2)	6687.1(3)
Z	2	8
Dcalc. (g/cm3)	1.358	1.384
μ (mm−1)	0.659	0.659
Absorption correction	Integration	Integration
Tmin., Tmax.	0.7919, 0.9579	0.8533, 0.9667
F 000	712	2912
Crystal size (mm3)	0.48 × 0.23 × 0.09	0.40 × 0.09 × 0.05
Diffractometer/measurement method	STOE IPDS II/ω scan	STOE IPDS II/ω scan
Index ranges	−9 ≤ h ≤ 9, −20 ≤ k ≤ 20, −20 ≤ l ≤ 20	−8 ≤ h ≤ 8, −25 ≤ k ≤ 25, −52 ≤ l ≤ 52
θ range for data collection (°)	1.928 ≤ θ ≤ 27.676	1.894 ≤ θ ≤ 25.646
Reflections collected	26,948	48,873
Independent/observed reflections	7728/6314	6304/3620
R int.	0.0768	0.0927
Refinement method	Full-matrix least-squares on F2	Full-matrix least-squares on F2
Data/restraints/parameters	7728/0/380	6304/0/385
Goodness-of-fit on F2	0.999	0.906
Final R indices [I > 2σ(I)]	R1 = 0.0362, wR2 = 0.0727	R1 = 0.0417, wR2 = 0.0708
R indices (all data)	R1 = 0.0519, wR2 = 0.0768	R1 = 0.1006, wR2 = 0.0833
Δρmax., Δρmin. (e/Å3)	0.56, −0.34	0.37, −0.40

2.3. A general approach: N-alkylation of amines with alcohols

At room temperature, compound 1e (1 mol %), KO^tBu (75 mol %), alcohols (1 mmol), and amine (1 mmol) were added to a 15-mL reaction tube in a glove box. The tube was then closed and taken out of the glove box. The reaction mixture was then heated at 120 °C for 12 h with degassed toluene (3 mL). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, filtered, and vacuum dried. The product was purified using a suitable mixture of petroleum ether and ethyl acetate in column chromatography over silica gel (300–400 mesh) (80:1).

2.4. A general approach: aniline N-methylation with methanol

In a glove box, amine (1 mmol), MeOH (2 mL), 1e (1 mol %), and KO^tBu were introduced into a 15-mL sealing tube (75 mol %). The tube was then removed from the glove box and sealed with a screw cap. At 110 °C, the reaction mixture was agitated for 12 h. The liquid was diluted with ethyl acetate and filtered through a short pad of silica after cooling to room temperature (2 cm in a Pasteur pipette). Ethyl acetate was used to wash the silica. The crude residue was refined by column chromatography (SiO₂, petroleum ether:ethyl acetate = 80:1) after the filtrate had evaporated.

3. Results and discussion

3.1. Preparation of ruthenium(II) complexes

Starting with previously described benzimidazolium salts [53,57], the addition of Ag₂O followed by [(p-cymene)RuCl₂]₂ in dry dichloromethane resulted in the formation of the corresponding [(η⁶-p-cymene)(^RBNHC^CH2OxMe)RuCl₂] (1a–g) compounds after 48 h at ambient temperature (Scheme 1). A large band was observed in the FT-IR spectra of the free ligands in the 1572–1556 cm⁻¹ range, which corresponds to the vibration of the C=N bonds in ligands. In the ruthenium complex, these bands shifted to the 1461–1486 cm⁻¹ range, which clearly indicated the shifting of double bond (C=N) character to single bond character υ_(NCN). The ¹H NMR spectra of these complexes revealed that the characteristic downfield NCHN signal of the salts had disappeared. The methine proton of the p-cymene group was located as a septet between 2.97 and 3.02 ppm for the respective complexes, while the methyl protons of the p-cymene appeared at 1.15–1.21 ppm. In the ¹³C NMR spectra of complexes 1a–g, the carbene carbon attached to ruthenium gave characteristic signals in the range of 184.9–190.3 ppm (see Tables 1 and 2 and Sup Inf).

3.2. Structural analysis

The molecular structures of 1f and 1g with complete atom numbering are displayed in the Figure, while important bond distances and angles are listed in Tables 3 and 4. Both structures consist of a BNHC ligand coordinated to a ruthenium center, which also features a p-cymene and two chloride ligands in the coordination sphere. Compound 1f crystallizes in triclinic space group P–1 with two molecules in the unit cell, while 1g crystallizes in orthorhombic space group Pbca with eight molecules in the unit cell.

Figure.

Molecular structures of 1f (a) and 1g (b) drawn at the 30% probability level. H atoms have been omitted for clarity.

Table 4.

Selected geometric parameters for 1f and 1g.

Parameters	1f	1g	Parameters	1f	1g
Bond lengths (Å)			Bond angles (°)
Ru1–Cg	1.7098(11)	1.7058(17)	Cl1–Ru1–Cl2	84.35(3)	84.05(4)
Ru1–Cl1	2.4122(7)	2.4193(11)	Cl1–Ru1–C1	95.53(7)	95.76(10)
Ru1–Cl2	2.4288(7)	2.4307(11)	Cl1–Ru1–Cg	124.38(4)	122.90(7)
Ru1–C1	2.074(2)	2.096(4)	Cl1–Ru1–Carene	88.20(7)–158.11(7)	85.23(11)–159.05(10)
Ru1–Carene	2.161(2)–2.249(2)	2.194(4)–2.240(4)	Cl2–Ru1–C1	90.89(7)	91.24(10)
N1–C1	1.361(3)	1.364(5)	Cl2–Ru1–Cg	127.60(4)	126.94(7)
N2–C1	1.370(3)	1.366(4)	Cl2–Ru1–Carene	91.24(7)–156.33(6)	89.88(11)–157.66(11)
			C1–Ru1–Cg	123.23(7)	124.93(12)
			C1–Ru1–Carene	86.78(9)–153.24(10)	87.70(14)–157.11(15)
			N1–C1–N2	105.29(18)	104.7(3)

Note: Cg represents the centroid of the arene ring.

In the structures, the BNHC ligand is coordinated to Ru(II) in a monodentate manner via a neutral carbenic carbon, while the arene ring of p-cymene is coordinated to the metal ion in an η⁶-fashion. The complexes can be identified as characteristic three-legged piano stool complexes with a pseudooctahedral geometry that is common for ruthenium half-sandwich arene complexes. Furthermore, the geometry around the metal atoms may be regarded as a tetrahedron with considerable trigonal distortion, if bonding to the p-cymene centroid is considered.

Defining Cg as the centroid of the arene ring, the Ru–Cg distance is 1.7098(11) Å in 1f and 1.7058(17) Å in 1g, while the Cl1–Ru1–Cg, Cl2–Ru1–Cg and C1–Ru1–Cg angles are 124.38(4), 127.60(4), and 123.23(7)° in 1f, and 122.90(7), 126.94(7), and 124.93(12)° in 1g, respectively. The Cl1–Ru1–Cl2, Cl1–Ru1–C1 and Cl2–Ru1–C1 angles are smaller than the ideal tetrahedral angle (109.47°), which is compensated for by extension of the Cg–Ru–L (L is Cl1, Cl2, or C1) angles. The ruthenium atom is bound to the arene ring with a mean Ru–C bond distance of 2.21 Å in both complexes. The Ru1–C1 bond distance is 2.074(2) Å in 1f and 2.096(4) Å in 1g, while the Ru–Cl bonds range from 2.4122(7) to 2.4307(11) Å. The structural data of the complexes are consistent with those of previously reported NHC-Ru(II)(p-cymene)Cl₂ complexes [51,58–63].

3.3. Optimization of amine alkylation with alcohols

The ability of synthesized (BNHC)Ru complexes that might promote amine alkylation was then evaluated, as shown in Table 5. In the presence of potassium tert-butoxide, 1.0 mol % of ruthenium complex 1e, which features meta and para methoxy substitution, was fully benzylated 4-methoxy aniline (>99% conversion, entry) after 12 h at 120 °C to generate secondary amine product A. KO^tBu was an efficient base for obtaining high yields. However, conversion was not possible when substituting weaker bases for KO^tBu, such as K₂CO₃ and Na₂CO₃. KO^tBu was required at 75 mol % to achieve satisfactory conversion. Surprisingly, the reaction still reached 98% conversion at a lower temperature of 70 °C (Table 5, entry 2). However, this trial did lead to the observation of imine product B (92:8 A:B ratio).

Table 5.

The use of benzyl alcohol to optimize the N-alkylation of 4-methoxyaniline.

Entry	Cat (mol %)	Base (75 mol %)	Temp (°C)	Time (h)	Conversion (%)	A/B
1	1e (1.0)	KOtBu	120	12	> 99	>99/0
2	1e (1.0)	KOtBu	70	12	98	92/8
3	1e (1.0)	KOtBu	50	12	96	88/12
4	1e (0.5)	KOtBu	70	12	96	65/35
5	1e (1.0)	KOtBu	70	5	98	87/13
6	1f (1.0)	KOtBu	70	12	94	85/15
7	1g (1.0)	KOtBu	70	12	92	78/22
8a	1e (1.0)	KOtBu	70	12	26	-b
9c	1e (1.0)	KOtBu	70	12	5	-b

Reaction conditions: All reactions were conducted in 2 mL of toluene and conversion is based on ¹H NMR spectroscopy.

^aAn open-air environment.

^bMixture of products.

^cReaction was conducted in water.

Lowering the temperature even further to 50 °C still allowed 96% conversion with lower selectivity for product A (88:12, Table 5, entry 3). A more pronounced loss of selectivity was observed when the catalyst loading was lowered to 0.5 mol % (65:35, Table 5, entry 4). Similarly, stopping a 70 °C reaction after 5 h revealed 98% conversion, but incomplete imine hydrogenation. Compounds 1f and 1g, featuring significant methyl substitution, were slightly less effective for this reaction (Table 5, entries 6 and 7). When the reaction was carried out in an open-air environment or in water, conversion was significantly reduced (Table 5, entries 8 and 9).

Table 6.

Aniline alkylation using a variety of primary alcohols.

Table 7.

The use of benzyl alcohol to alkylate a variety of primary amines.

Table 8.

Methylation of aromatic amines.

Table 9.

Comparison of Ru–NHC catalyst (1e) with reported NHC systems.

S/NO	Cat (mol %)	Substrate 1 Alcohol	Substrate 2 Primary amine	Temp (°C)	Time (h)	Yield (%)	Reference
1	1	aniline	Substituted alcohol	70	12	92	This work
2	2.5	-	-	120	24	97	[38]
3a	1.0	Substituted aniline	MeOH	150	24	84	[67]
4	0.5	-	-	130	24	85	[68]
5	1.0	-	-	135	36	95	[69]

^aFor the same reaction we use 1e (1 mol %) at 110 °C for 12 h and we get 97% selective yield.

3.4. N-Alkylation on aniline with substituted primary alcohols

Encouraged by these findings, the scope of aniline N-alkylation under mild conditions (70 °C, 12 h) using 1e was explored. Table 6 illustrates that both electron-rich and electron-deficient benzylic alcohols worked well, yielding alkylated aniline derivatives 2a–j in 55%–94% isolated yield. Catalysis was compatible with several functional groups, including methoxy groups (2c and 2f), halides (2a and 2d), and trifluoromethyl groups (2i). Debromination was observed in the case of para-bromobenzyl alcohol, but the brominated product was extracted in a reasonable yield (Table 6, 55%). At 90 °C, the sterically hindered ortho-methyl benzylic alcohol and ortho-methoxy benzylic alcohol still allow monoalkylated amine products 2e and 2f in 90% and 87% yield, respectively. Products 2g and 2h were obtained in 65% and 71% yield when heterocyclic alcohols such as 2-furylmethanol and 2-thiophenemethanol were utilized as substrates. Using the aliphatic alcohol heptanol afforded aniline derivative 2j in 75% isolated yield (Table 6). The N-alkylation of anilines with secondary alcohols like 1-phenethyl alcohol, cyclohexanol, and isopropyl alcohol, on the other hand, was ineffective, generating only trace amounts of products. This observation is consistent with a mechanism that involves alcohol dehydrogenation to generate an aldehyde intermediate.

3.5. N-Alkylation of substituted anilines and heterocyclic amines with benzyl alcohol

The scope of amines that could undergo alkylation was then explored (Table 7). The N-alkylated products 3a–i were obtained in good yield (81%–92%) from substrates containing either electron-donating or electron-withdrawing substituents. For example, 1,3-benzodioxan-5-amine was treated with benzyl alcohol to produce 3h in high yield (Table 7, 87%). Heteroaromatic amines like 2-aminopyridine, 3-aminopyridine, and 2-aminopyrimidine were successfully converted into products 3d–f in good yield (Table 7, 81%–86%). The secondary amine morpholine (3i), on the other hand, was not tolerated. The N-alkylation of p-nitroaniline with benzyl alcohol and the N-alkylation of aniline with 4-nitrobenzyl alcohol were also not successful, even with a greater catalyst loading (2 mol %) when conducted at 110 °C. These observations indicate that nitro groups are not tolerated by 1e.

3.6. N-Methylation of anilines

N-Methylamines are commonly employed as intermediates and building blocks in the production of bulk and fine chemicals, as well as materials [64,65]. Due to the higher activation barrier (21 kcal mol⁻¹) of methanol dehydrogenation compared to that of higher alcohols, such as ethanol (16 kcal mol⁻¹), methanol can be a problematic substrate for the N-alkylation of amines [66]. Therefore, the N-methylation of amines with methanol was examined to further broaden the scope of 1e promoted C–N bond formation. To our delight, we were able to successfully N-methylate anilines with methanol in the presence of 1.0 mol % of 1e at 110 °C (Table 8). As indicated in Table 8, the majority of the catalytic reactions were efficient, yielding at least 81% of the desired product (Table 8, 4a–g in 46%–97% yield). When 2-iodoaniline was used, the reaction produced 5g in moderate isolated yields (46%) and was also dehalogenated. Biologically important motifs like pyridine-2-amine and 3-trifluoromethylaniline were also successfully methylated (Table 8, 4d and 4e). Despite the use of copious MeOH and high temperatures, we did not observe dialkylation products in any case. Attempts to obtain N-methylate aliphatic amines like benzylamine and n-hexylamine, on the other hand, were ineffective, giving just traces of methylated product.

A comparison of the most active catalyst (1e) with other reported catalysts is shown in Table 9. It is the best Ru–NHC-based catalyst in terms of low catalyst loading (1 mol %) and low temperature (70 °C). Furthermore, most of the literature reports that the hydrogen transfer reaction is used to convert the alcohol into ketone or aldehyde using Ru–NHC complexes. Very few reports of such secondary amine products through the coupling of primary amine and alcohols have been reported using ruthenium–NHC complexes. These Ru–NHC complexes are also applicable for the conversion of highly complicated products like methanol and convert them into secondary amines.

3.7. Proposed mechanism

Given that catalysis requires the presence of KO^tBu (75 mol % relative to 1.0 mol % of 1e), it is reasonable to propose that a salt metathesis reaction occurs to form the corresponding bis(tert-butoxide) complex, which can undergo σ-bond metathesis with incoming benzyl alcohol to generate intermediate A (Scheme 2).

Scheme 2.

A plausible mechanism for C–N bond formation catalyzed by 1e.

Alternatively, intermediate A may be generated directly from 1e if any KOBn is generated in solution. This intermediate can undergo subsequent β-hydride elimination steps to generate B and ultimately dihydride complex C. As has been observed for other hydrogen borrowing C–N bond forming reactions, the in situ generation of aldehyde results in Schiff base condensation with any primary amine that is present to generate the corresponding aldimine (this is also the reason why secondary amines do not become alkylated again to yield tertiary amines). This aldimine can insert into dihydride C to generate intermediate E. At this point, the desired secondary amine product can be liberated in one of two ways. Reductive elimination from E can occur to generate intermediate D (as shown in Scheme 2) or E can undergo σ-bond metathesis with the next equivalent of benzyl alcohol to generate intermediate B. If Ru(0) intermediate D is formed during the reaction, it quickly reacts with any alcohol or hydrogen that is present to generate the corresponding hydride complex.

4. Conclusion

We have described the synthesis and characterization of a series of ruthenium complexes with BNHC proligands that feature a variety of benzyl group substitution patterns. Through a HB/HA mechanism, these compounds were discovered to be highly effective catalysts for the selective monoalkylation of aromatic primary amines. Complex 1e was the most active of the catalysts tested, and it is one of the most active ruthenium catalysts ever reported for amine alkylation given that it operates efficiently at temperatures as low as 50 °C at low catalyst loadings (1.0 mol %). A wide range of (hetero)aromatic amines and primary alcohols were successfully converted into secondary amines in good to exceptional isolated yields, including physiologically relevant examples. The methylation of primary amines was also achieved using methanol, a transformation that is particularly difficult to demonstrate.

Supporting Information

Characterizing data of ruthenium–BNHC complex 1a

Dichloro-[1-((3-methyloxetan-3-yl)methyl)-3-(3-methylbenzyl)benzimidazole-2-ylidene](p-cymene) ruthenium(II) (1a)

Figure S1

¹H NMR spectrum of ruthenium–BNHC complex 1a (in CDCl₃, 25 °C, TMS, 400 MHz).

Figure S2

¹³C NMR spectrum of ruthenium–BNHC complex 1a (in CDCl₃, 25 °C, TMS, 101 MHz).

Figure S3

FT-IR spectrum of ruthenium–BNHC complex 1a.

Characterizing data of ruthenium–BNHC complex 1b

Dichloro-[1-((3-methyloxetan-3-yl)methyl)-3-(2,4,6-trimethylbenzyl)benzimidazole-2-ylidene](p-cymene) ruthenium(II) (1b)

Figure S4

¹H NMR spectrum of ruthenium–BNHC complex 1b (in CDCl₃, 25 °C, TMS, 400 MHz).

Figure S5

¹³C NMR spectrum of ruthenium–BNHC complex 1b (in CDCl₃, 25 °C, TMS, 101 MHz).

Figure S6

FT-IR spectrum of ruthenium–BNHC complex 1b.

Characterizing data of ruthenium–BNHC complex 1c

Dichloro-[1-((3-methyloxetan-3-yl)methyl)-3-(2,3,5,6-tetramethylbenzyl)benzimidazole-2-ylidene](p-cymene) ruthenium(II) (1c)

Figure S7

¹H NMR spectrum of ruthenium–BNHC complex 1c (in CDCl₃, 25 °C, TMS, 400 MHz).

Figure S8

¹³C NMR spectrum of ruthenium–BNHC complex 1c (in CDCl₃, 25 °C, TMS, 101 MHz).

Figure S9

FT-IR spectrum of ruthenium–BNHC complex 1c.

Characterizing data of ruthenium–BNHC complex 1d

Dichloro-[1-((3-methyloxetan-3-yl)methyl)-3-(2,3,4,5,6-pentamethylbenzyl)benzimidazole-2-ylidene](p-cymene) ruthenium(II) (1d)

Figure S10

¹H NMR spectrum of ruthenium–BNHC complex 1d (in CDCl₃, 25 °C, TMS, 400 MHz).

Figure S11

¹³C NMR spectrum of ruthenium–BNHC complex 1d (in CDCl₃, 25 °C, TMS, 101 MHz).

Figure S12

FT-IR spectrum of ruthenium–BNHC complex 1d.

Characterizing data of ruthenium–BNHC complex 1e

Dichloro-[1-((3-methyloxetan-3-yl)methyl)-3-(3,4,5-trimethoxybenzyl)benzimidazole-2-ylidene](p-cymene) ruthenium(II) (1e)

Figure S13

¹H NMR spectrum of ruthenium–BNHC complex 1e (in CDCl₃, 25 °C, TMS, 400 MHz).

Figure S14

¹³C NMR spectrum of ruthenium–BNHC complex 1e (in CDCl₃, 25 °C, TMS, 101 MHz).

Figure S15

FT-IR spectrum of ruthenium–BNHC complex 1e.

Characterizing data of ruthenium–BNHC complex 1f

Dichloro-[(5,6-dimethyl-1-((3-methyloxetan-3-yl)methyl)-3-(2,3,5,6-tetramethylbenzyl)benzimidazole-2-ylidene](p-cymene) ruthenium(II) (1f)

Figure S16

¹H NMR spectrum of ruthenium–BNHC complex 1f (in CDCl₃, 25 °C, TMS, 400 MHz).

Figure S17

¹³C NMR spectrum of ruthenium–BNHC complex 1f (in CDCl₃, 25 °C, TMS, 101 MHz).

Figure S18

FT-IR spectrum of ruthenium–BNHC complex 1f.

Characterizing data of ruthenium–BNHC complex 1g

Dichloro-[(5,6-dimethyl-1-((3-methyloxetan-3-yl)methyl)-3-(2,3,4,5,6-pentamethylbenzyl)benzimidazole-2-ylidene](p-cymene) ruthenium(II) (1g)

Figure S19

¹H NMR spectrum of ruthenium–BNHC complex 1g (in CDCl₃, 25 °C, TMS, 400 MHz).

Figure S20

¹³C NMR spectrum of ruthenium–BNHC complex 1g (in CDCl₃, 25 °C, TMS, 101 MHz).

Figure S21

FT-IR spectrum of ruthenium–BNHC complex 1g.

Characterizing data of the tested (2a–h) substituted benzyl alcohol with aniline by the complex 1e

N-(4-chlorobenzyl)aniline (2a)

¹H NMR (400 MHz, CDCl₃) δ 7.32 (s, 4H), 7.20 (dd, J = 8.4, 7.5 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.66–6.57 (m, 2H), 4.32 (s, 2H), 4.05 (s, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 147.9, 138.0, 132.9, 129.3, 128.7, 117.8, 112.9, 47.6.

Figure S22

¹H NMR and ¹³C NMR spectrum of 2a (in CDCl₃, 25 °C, TMS, 400 MHz).

N-(4-methylbenzyl)aniline (2b)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 11.1 Hz, 4H), 7.21 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 4.77 (s, 2H), 4.31 (s, 1H), 2.85 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 148.7, 137.3, 136.8, 129.7, 128.0, 117.9, 113.3, 48.5, 21.6.

Figure S23

¹H NMR and ¹³C NMR spectrum of 2b (in CDCl₃, 25 °C, TMS, 400 MHz).

N-(4-methoxybenzyl)aniline (2c)

¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.6 Hz, 2H), 7.26–7.17 (m, 2H), 6.93 (dd, J = 9.2, 2.4 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 7.7 Hz, 2H), 4.28 (s, 2H), 3.98 (s, 1H), 3.83 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 158.9, 148.3, 131.5, 129.3, 128.8, 117.5, 114.1, 112.9, 55.3, 47.8.

Figure S24

¹H NMR and ¹³C NMR spectrum of 2c (in CDCl₃, 25 °C, TMS, 400 MHz).

N-(4-bromobenzyl)aniline (2d)

¹H NMR (400 MHz, CDCl₃) δ 7.43 (dd, J = 6.8, 1.5 Hz, 2H), 7.21 (d, J = 7.3 Hz, 2H), 7.15 (tt, J = 7.2, 1.7 Hz, 2H), 6.74–6.68 (m, 1H), 6.62–6.53 (m, 2H), 4.25 (s, 2H), 3.92 (s, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 145.9, 136.0, 130.9, 127.3, 126.7, 115.8, 110.9, 45.6.

Figure S25

¹H NMR and ¹³C NMR spectrum of 2d (in CDCl₃, 25 °C, TMS, 400 MHz).

N-(2-methylbenzyl)aniline (2e)

¹H NMR (400 MHz, CDCl₃) δ 7.25 (dt, J = 14.9, 7.9 Hz, 5H), 7.13 (d, J = 7.3 Hz, 1H), 6.76 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 7.8 Hz, 2H), 4.32 (s, 2H), 4.02 (s, 1H), 2.39 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 148.3, 139.4, 138.3, 129.3, 128.6, 128.3, 128.0, 124.6, 117.5, 112.9, 48.4, 21.5.

Figure S26

¹H NMR and ¹³C NMR spectrum of 2e (in CDCl₃, 25 °C, TMS, 400 MHz).

N-(2-methoxybenzyl)aniline (2f)

¹H NMR (400 MHz, CDCl₃) δ 7.26 (ddd, J = 14.8, 11.4, 4.3 Hz, 3H), 7.00 (d, J = 13.3 Hz, 2H), 6.87 (d, J = 8.1 Hz, 1H), 6.77 (dd, J = 10.4, 4.2 Hz, 1H), 6.68 (d, J = 7.5 Hz, 2H), 4.34 (s, 2H), 3.98 (s, 1H), 3.83 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.0, 148.2, 141.3, 129.7, 129.3, 119.8, 117.6, 113.0, 112.7, 55.2, 48.3.

Figure S27

¹H NMR and ¹³C NMR spectrum of 2f (in CDCl₃, 25 °C, TMS, 400 MHz).

N-(furan-2-ylmethyl)aniline (2g)

¹H NMR (400 MHz, CDCl₃) δ 7.40–7.33 (m, 1H), 7.22–7.15 (m, 2H), 6.77–6.72 (m, 1H), 6.68 (ddd, J = 4.6, 2.1, 1.1 Hz, 2H), 6.36–6.29 (m, 1H), 6.23 (dd, J = 3.2, 0.8 Hz, 1H), 4.32 (s, 2H), 3.95 (s, 1H). ¹³C NMR (101 MHz, CDC₃) δ 152.7, 147.6, 141.9, 129.2, 118.0, 113.1, 110.3, 106.9, 41.4.

Figure S28

¹H NMR and ¹³C NMR spectrum of 2g (in CDCl₃, 25 °C, TMS, 400 MHz).

N-(3,5-bis(trifluoromethyl)benzyl)aniline (2h)

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 2H), 7.79 (s, 1H), 7.18 (td, J = 7.8, 0.7 Hz, 2H), 6.77 (td, J = 7.4, 0.8 Hz, 1H), 6.60 (dd, J = 7.7, 0.8 Hz, 2H), 4.47 (s, 2H), 4.18 (s, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 147.2, 142.5, 129.4, 118.5, 113.0, 47.7.

Figure S29

¹H NMR and ¹³C NMR spectrum of 2h (in CDCl₃, 25 °C, TMS, 400 MHz).

Characterizing data of the tested (3a–h) substituted aniline with benzyl alcohol by the complex 1e

N-benzyl-4-chloroaniline (3a)

¹H NMR (400 MHz, CDCl₃) δ 7.34–7.30 (m, 4H), 7.26 (dd, J = 8.8, 4.6 Hz, 1H), 7.10–7.03 (m, 2H), 4.26 (d, J = 5.5 Hz, 2H), 4.02 (s, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 147.9, 138.0, 132.9, 129.3, 128.7, 117.8, 112.9, 47.6.

Figure S30

¹H NMR and ¹³C NMR spectrum of 3a (in CDCl₃, 25 °C, TMS, 400 MHz).

N-benzyl-4-methylaniline (3b)

¹H NMR (400 MHz, CDCl₃) δ 7.41–7.19 (m, 5H), 6.96 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H), 4.27 (s, 2H), 3.86 (s, 1H), 2.22 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 146.0, 139.7, 129.8, 128.6, 127.5, 127.2, 113.0, 48.7, 20.4.

Figure S31

¹H NMR and ¹³C NMR spectrum of 3b (in CDCl₃, 25 °C, TMS, 400 MHz).

N-benzyl-4-methoxyaniline (3c)

¹H NMR (400 MHz, CDCl₃) δ 7.37 (dt, J = 20.8, 10.2 Hz, 4H), 7.31–7.24 (m, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 4.30 (s, 2H), 3.76 (s, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 152.2, 142.4, 139.7, 128.6, 127.6, 114.9, 114.2, 55.8, 49.3.

Figure S32

¹H NMR and ¹³C NMR spectrum of 3c (in CDCl₃, 25 °C, TMS, 400 MHz).

N-benzylpyridin-2-amine (3d)

¹H NMR (400 MHz, CDCl₃) δ 8.10–8.00 (m, 1H), 7.46–7.28 (m, 5H), 7.27–7.21 (m, 1H), 6.55 (ddd, J = 7.1, 5.0, 0.9 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.16 (s, 1H), 4.47 (d, J = 5.8 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 158.7, 148.2, 139.2, 128.6, 127.3, 113.1, 106.7, 46.3.

Figure S33

¹H NMR and ¹³C NMR spectrum of 3d (in CDCl₃, 25 °C, TMS, 400 MHz).

N-benzylpyridin-3-amine (3e)

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 2.9 Hz, 1H), 7.94 (dd, J = 4.7, 1.2 Hz, 1H), 7.34 (d, J = 4.4 Hz, 4H), 7.30–7.24 (m, 1H), 7.04 (dd, J = 8.3, 4.7 Hz, 1H), 6.85 (ddd, J = 8.3, 2.8, 1.2 Hz, 1H), 4.32 (s, 2H), 4.25 (s, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 144.0, 138.8, 138.5, 136.1, 128.7, 127.4, 123.7, 118.5, 47.8.

Figure S34

¹H NMR and ¹³C NMR spectrum of 3e (in CDCl₃, 25 °C, TMS, 400 MHz).

N-benzylpyrimidin-2-amine (3f)

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J = 3.3 Hz, 2H), 7.33 (q, J = 7.9 Hz, 4H), 7.28–7.23 (m, 1H), 6.50 (t, J = 4.8 Hz, 1H), 5.96 (s, 1H), 4.62 (d, J = 5.9 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 158.0, 139.1, 128.6, 127.5, 127.2, 110.7, 45.4.

Figure S35

¹H NMR and ¹³C NMR spectrum of 3f (in CDCl₃, 25 °C, TMS, 400 MHz).

N-benzylbenzo[1,3]dioxol-5-amine (3g)

¹H NMR (400 MHz, CDCl₃) δ 7.40–7.33 (m, 4H), 7.30–7.25 (m, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.27 (d, J = 2.3 Hz, 1H), 6.07 (dd, J = 8.3, 2.3 Hz, 1H), 5.84 (d, J = 0.5 Hz, 2H), 4.26 (s, 2H), 3.67 (s, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 148.3, 143.9, 139.7, 139.4, 128.6, 127.5, 127.2, 108.6, 104.4, 100.6, 96.0, 49.2.

Figure S36

¹H NMR and ¹³C NMR spectrum of 3g (in CDCl₃, 25 °C, TMS, 400 MHz).

N-benzyl-3,5-bis(trifluoromethyl)aniline (3h)

¹H NMR (400 MHz, CDCl₃) δ 7.43–7.31 (m, 5H), 7.17 (s, 1H), 6.97 (s, 2H), 4.45 (s, 1H), 4.36 (d, J = 5.4 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 148.6, 137.6, 128.9, 127.8, 127.5, 111.9, 111.0, 48.0.

Figure S37

¹H NMR and ¹³C NMR spectrum of 3h (in CDCl₃, 25 °C, TMS, 400 MHz).

Characterizing data of the tested (4a–e) substituted aniline with methanol by the complex 1e

N-methylaniline (4a)

¹H NMR (400 MHz, CDCl₃) δ 6.72 (t, J = 7.8 Hz, 2H), 6.24 (t, J = 7.3 Hz, 1H), 6.15 (d, J = 7.8 Hz, 2H), 3.21 (s, 1H), 2.36 (s, 3H).

Figure S38

¹H NMR and ¹³C NMR spectrum of 4a (in CDCl₃, 25 °C, TMS, 400 MHz).

N,4-dimethylaniline (4b)

¹H NMR (400 MHz, CDCl₃) δ 7.02 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 8.3 Hz, 2H), 3.44 (s, 1H), 2.82 (s, 3H), 2.26 (s, 3H).

Figure S39

¹H NMR spectrum of 4b (in CDCl₃, 25 °C, TMS, 400 MHz).

4-Methoxy-N-methylaniline (4c)

¹H NMR (400 MHz, CDCl₃) δ 6.82–6.74 (m, 2H), 6.63–6.55 (m, 2H), 3.74 (s, 3H), 2.79 (s, 3H), 0.82 (s, 1H).

Figure S40

¹H NMR spectrum of 4c (in CDCl₃, 25 °C, TMS, 400 MHz).

Chloro-N-methylaniline (4d)

¹H NMR (400 MHz, CDCl₃) δ 6.11 (dd, J = 4.5, 3.8 Hz, 2H), 5.50 (d, J = 8.1 Hz, 2H), 2.62 (s, 1H), 1.78 (s, 3H).

Figure S41

¹H NMR spectrum of 4d (in CDCl₃, 25 °C, TMS, 400 MHz).

N-methylpyridin-2-amine (4e)

¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J = 2.8 Hz, 1H), 7.91 (dd, J = 4.7, 1.1 Hz, 1H), 7.05 (dd, J = 8.3, 4.7 Hz, 1H), 6.82 (ddd, J = 8.3, 2.8, 1.3 Hz, 1H), 3.80 (dd, J = 14.9, 10.1 Hz, 1H), 2.80 (s, 3H).

Figure S42

¹H NMR spectrum of 4e (in CDCl₃, 25 °C, TMS, 400 MHz).

N-methyl-3,5-bis(trifluoromethyl)aniline (4f)

¹H NMR (400 MHz, CDCl₃) δ 7.13 (s, 1H), 6.91 (s, 2H), 4.16 (s, 1H), 2.89 (d, J = 5.0 Hz, 3H).

Figure S43

¹H NMR spectrum of 4f (in CDCl₃, 25 °C, TMS, 400 MHz).

Appendix A. Supplementary data

CCDC 2085163 and 2173756 contain the supplementary crystallographic data for the compounds reported in this article. These data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.

Funding Statement

Z.N. gratefully acknowledges the Higher Education Commission of Pakistan (HEC) for research funding as an IRSIP fellow at Arizona State University (USA).