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Synlett 2025; 36(01): 75-81
DOI: 10.1055/a-2294-1643
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Microwave-Assisted Transfer Hydrogenation of Carbonyl and ­Nitro Compounds Using Bimetallic Ru(II) Cymene Complexes

Gopal Deshmukh
,
Ramaswamy Murugavel  ∗

This work was supported by the Science and Engineering Research Board (SERB), New Delhi through a J. C. Bose Fellowship grant to R.M. (SB/S2/JCB-85/2014). G.D. thanks the Council of Scientific and Industrial Research/University Grants Commission (CSIR/UGC), New Delhi and the Indian Institute of Technology Bombay (IIT Bombay) for a research fellowship.
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Dedicated to Professor P. Selvam on the occasion of 65th Birthday.

Abstract

We report an investigation of the microwave-assisted catalytic transfer hydrogenation (TH) of carbonyl and nitro compounds by employing Ru(II) complexes: bimetallic [(p-cymene)2(RuCl)2L1]2X (X = BF4 (Cat2); X = PF6 (Cat3)) and mononuclear [(p-cymene)(RuCl)L2]BF4 (Cat4) (where L1 = N,N′-(3,3′,5,5′-tetraisopropyl-[1,1′-biphenyl]-4,4′-diyl)bis(1-(pyridin-2-yl)methanimine) and L2 = N-(2,6-diisopropylphenyl)-1-(pyridin-2-yl)methanimine). At a low catalyst loading of 0.01 mol% (Cat2/Cat3), a broad range of substrates, comprising aromatic as well as aliphatic ketones and aldehydes, undergo the TH reaction in a short reaction time of just 10 minutes. Additionally, chemoselective hydrogenation of nitroaromatic compounds is achieved under microwave irradiation in the presence of Cat2 within 5 minutes. Control experiments demonstrate that microwave heating conditions outperform conventional heating in terms of improved catalytic activity and reaction efficiency. The bimetallic catalyst Cat2 is used at a very low loading of 0.001 mol% to achieve high TONs and TOFs of 7.7 × 104 and 2.3 × 105 h–1, respectively, for the TH reaction. Spectrometry experiments involving trapping of intermediates are used to propose a mechanism for the TH of the carbonyl compounds.


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Key words

bimetallic - microwave - transfer hydrogenation - ruthenium - mechanism

Catalytic transfer hydrogenation (TH) has become a powerful synthetic tool during recent times for the production of alcohols from carbonyl compounds, starting from inexpensive sources of hydrogen.[1] [2] Among various first-row transition-metal catalysts used in TH, Ru(II) complexes are a well-investigated class of such catalysts.[3–9] Despite the development of various types of Ru(II) complexes for efficient TH, highly active catalytic systems are still sought after for extending the substrate scope and enhancing reaction efficiency. The electronic and steric effects of the ligands used to prepare these Ru(II) complexes often dictate both the activity and selectivity of the catalyst.[8,10] We have previously revealed that a series of pseudo-C 2-symmetric ligands can potentially play an important role in the catalytic activity of the complexes formed from them.[11] Besides, organometallic complexes that incorporate more than one metal center have been shown to exhibit unusual reactivity and enhanced catalytic activity due to the cooperative effects emanating from multidentate ligands and ML n fragments.

In recent times, bimetallic complexes have gained attention as effective catalysts for the reasons described above.[11] [12] For example, various organic transformations have been catalyzed effectively using bimetallic catalysts compared to their monometallic counterparts.[8] , [13–18] In 2015, Uyeda and Steiman reported a bimetallic nickel complex containing a direct Ni–Ni bond that promoted the hydrosilylation of olefins with a broad substrate scope.[19] Similarly, a Rh(I) NHC/phosphine bimetallic complex, reported by Pernik and co-workers in 2023, effectively catalyzes intermolecular hydrosilylation of alkynes with high selectivity, displaying significant superiority over mono-rhodium catalysts with NHC-pyrazole donors.[20] Additionally, binuclear indium catalysts were found to exhibit high catalytic activity for the ring-opening polymerization of lactide to form poly(lactic acid) at room temperature.[21] Both bimetallic cobalt and ruthenium N-heterocyclic carbene complexes have been reported to promote the oxidation of water.[22] [23] Meanwhile, Yu and co-workers have demonstrated the TH of ketones by employing various phosphine-based bimetallic or multimetallic Ru(II)-pincer complexes.[24–26]

Bimetallic and trimetallic complexes demonstrate high catalytic activity in hydrogen-borrowing reactions when compared to the corresponding monometallic catalysts.[2] [27] [28] Our previous work has shown the pseudo-C 2-symmetric Ru(II) cymene neutral complex Cat1 to be a highly effective catalyst for chemoselective reductive amination reactions of aldehydes in water (Figure [1]).[29] We have also developed analogous cationic bimetallic Ru(II) cymene complexes Cat2 and Cat3 for synthesizing quinolines and alpha-alkylated ketones.[30] To date, only a few examples of bimetallic catalysts that contain moisture-sensitive phosphine ligands are known for TH using conventional heating conditions,[31] [32] whereas under microwave heating examples are unexplored. Microwave heating can improve the overall reaction efficiency and can be beneficial for green catalysis.[33] [34] [35] [36] [37] [38]

Zoom Image
Figure 1 Bimetallic and monometallic Ru(II) catalysts

Although bimetallic catalysts exhibit remarkable performance for various organic transformations, the TH of carbonyl and nitro compounds has not been investigated by employing such catalysts to improve the catalytic efficiency. In the present work, we report the first microwave-assisted hydrogenation of carbonyl and nitro compounds catalyzed by the bimetallic ruthenium complexes Cat2–Cat4, which were recently synthesized by us.[30]

The efficiency of Cat2 in transfer hydrogenation was probed by using acetophenone as a model substrate under conventional heating (see Table S1 in the Supporting Information).[39] Initially, the reaction was conducted by employing 1 mol% of Cat2 at 90 °C along with HCOOH/HCOONa buffer (pH 3.5) in water, and the expected product, 1-phenyl ethanol (2a), was formed in 21% yield (Table S1, entry 1). The use of solvents such as water, methanol and ethanol, in conjunction with KOH or HCOONa as the base, resulted in low yields of 2a (Table S1, entries 2–4). However, when the reaction was carried out in isopropanol using 0.01 mol% of Cat2, the desired alcohol 2a was produced in 92% yield, revealing isopropanol as the ideal solvent for this TH (Table S1, entry 10). An investigation into the effect of the base (required to carry out alcohol deprotonation) with a Cat2 loading of 0.01 mol% showed that KOH was superior when compared to NaOH, Cs2CO3 and K2CO3 (Table S1, entries 5–7). Further lowering of the catalyst loading from 0.01 mol% to 0.005 mol% reduced the yield of 2a (Table S1, entry 9). To optimize the temperature, the reaction was conducted at temperatures ranging from 40 °C to 90 °C, with the best result being obtained at 80 °C. The reaction failed to proceed in the absence of a base or catalyst (Table S1, entries 13 and 14). To screen the most effective catalyst, the reaction of 1a in isopropanol using KOH as the base was conducted with Cat3 (0.01 mol%) and Cat4 (0.02 mol%, since it is monometallic) at 80 °C for 1 hour. This resulted in the formation of 2a in yields of 89% and 63%, respectively, suggesting that the bimetallic complexes Cat2 and Cat3 exhibit higher catalytic activity compared to the monometallic analogue Cat4 (Table S1, entries 15 and 16).

Bimetallic complexes offer a distinct advantage over their monometallic counterparts due to their unique ability to facilitate electronic interactions between the two metal centers. This interaction plays a crucial role in influencing the reactivity of the catalyst and stabilizing the active intermediates formed during the catalytic cycle, as shown in our recent study on the reductive amination of aldehydes.[29] From both experimental data and computational studies, a catalyst model was developed in which one Ru center was reactive while the second remained inactive. This revealed that the simultaneous engagement of both Ru centers expedited the formation of intermediate species, thereby enhancing product formation through structural and electronic cooperativity. In contrast, employing a monometallic catalyst, which lacks this cooperative interaction between metal centers, would likely result in the slower formation of intermediates and consequently, slower product formation. Based on these results, the optimum reaction conditions for the conventional heating method involve 0.01 mol% of the Cat2 complex in isopropanol, with KOH as the base at 80 °C for 1 hour.

Due to the fact that microwave-mediated reactions are often faster than their counterparts conducted under conventional heating, we have investigated the catalytic activity of Cat2 under microwave irradiation for the system described above. The reaction was carried out by keeping a constant microwave power of 70 W, a pressure of 100 psi, and utilizing KOH as the base in isopropanol. Other parameters such as the time (10–30 min), the temperature (40–80 °C), and the catalyst loading (0.001–1 mol%) were optimized (see Table S2 in the Supporting Information). The reaction conducted by employing a minimal catalyst loading of 0.001 mol% of Cat2 at 80 °C produced a 77% yield of product 2a in 20 minutes (Table S2, entry 1). When the catalyst loading was increased to 0.01 mol%, the yield was improved to 97% (Table S2, entry 3). Variation of the temperature showed that lowering it to 60 °C had no impact on the yield of 2a, but any further decrease led to lower yields. Thus, the optimal conditions for the microwave-assisted method involve a catalyst loading of 0.01 mol% of Cat2, in isopropanol in the presence of KOH, under microwave irradiation at 70 W for 10 minutes at 60 °C (Table S2, entry 3).

Driven by these optimization results, we next focused on the hydrogenation of various carbonyl substrates under microwave irradiation using Cat2.[40] Thus, different carbonyl compounds were hydrogenated in the presence of Cat2, at 60 °C in isopropanol in a microwave reactor within 10 minutes, to afford the corresponding alcohols in high yields (Table [1]). Ketones having an electron-donating group on the aryl ring produced the expected alcohol products in yields of 95% and 98% (Table [1], entries 2 and 3) within 10 minutes. Halo-substituted alcohols were also obtained chemoselectively in excellent yields (91–96%), and no competing formation of dehalogenated products was observed (Table [1], entries 4–9). 3-Hydroxyacetophenone and benzophenone were also reduced effectively to produce the desired alcohols in good yields (Table [1], entries 10 and 12). Various benzaldehyde derivatives reacted very efficiently under the optimized conditions to afford the corresponding alcohols (Table [1], entries 13–19). Interestingly, disubstituted benzaldehydes underwent rapid hydrogenation to produce the corresponding carbonyl products in high yields (Table [1], entries 18 and 19). Furthermore, a nitrile group was tolerated under the reaction conditions to produce the corresponding alcohol in 99% yield (Table [1], entry 14). When aliphatic cyclic and acyclic carbonyl compounds were subjected to hydrogenation under optimal conditions, the desired alcohols were obtained in yields of 87–96% yield (Table [1], entries 20–28). Significantly, tetralone derivatives were hydrogenated in yields of 96% and 93% (Table [1], entries 20 and 21). Easily reducible functional groups such as the alkene in citronellal and the dioxolane in piperonal remained intact during the course of the reaction, affording the desired products in yields of 95% and 98%, respectively (Table [1], entries 27 and 28).

Table 1 Substrate Scope of Carbonyl Compounds in TH Reactions under Microwave-Assisted and Conventional Heating Methodsa

Entry

Product

Yield (%)b

Entry

Product

Yield (%)b

A

B

A

B

1

97

92

15

97

90

2

95

89

16

99

92

3

98

87

17

97

93

4

91

82

18

99

95

5

94

86

19

99

98

6

96

89

20

96

89

7

93

88

21

93

87

8

92

88

22

94

89

9

94

91

23

91

82

10

89

79

24

90

81

11

97

92

25

87

79

12

98

93

26

94

87

13

97

95

27

95

81

14

99

97

28

98

89

a Reaction conditions: carbonyl compound (2 mmol), isopropanol (1 mL), KOH (0.5 mmol), Cat2 (0.01 mol%), 60 °C, 10 min.

b Isolated yields.

The substrate scope for the hydrogenation under conventional heating conditions was also investigated and compared with the results of the microwave-assisted heating in terms of the product yield and the reaction conditions (Table [1]). Thus, reduction of the carbonyl compounds (carbonyl, aryl-alkyl, and aliphatic cyclic carbonyls) was accomplished in 1 hour. The hydrogenation of 4-methylacetophenone, 4-methoxyacetophenone, and 3,4-dimethoxyacetophenone gave the corresponding alcohols in yields of 89%, 87% and 92%, respectively (Table [1], entries 2, 3 and 11). 4-Halo-substituted acetophenones, 2-bromoacetophenone and 3-hydroxyacetophenone were converted into the desired products in yields of 79–89% (Table [1], entries 4–8 and 10). Transfer hydrogenation of aliphatic ketones was also accomplished, achieving good yields (79–89%) within 60 min. (Table [1], entries 20–25). A benzaldehyde substrate bearing both electron-donating and electron-withdrawing substituents on the aryl ring was selectively hydrogenated within 30 minutes (Table [1], entries 13–19). In addition, aliphatic aldehyde derivatives were hydrogenated to give the corresponding alcohols in high yields within 40 minutes (Table [1], entries 26–28). Overall, the above results highlight the better efficiency of the microwave heating method for the described TH process, especially in terms of the shorter reaction times and lower temperature (Table [S2], entry 3).

Table 2 Substrate Scope for the Reduction of Nitro Compounds Using Microwave-Assisted and Conventional Heating Methodsa

Entry

Product

Yield (%)

Microwave

Conventional

1

98

95

2

95

89

3

98

87

4

84:16

63:37

5

96

86

6

92

83

a Reaction conditions: nitro compound (2 mmol), isopropanol (1 mL), KOH (0.5 mmol), Cat2 (0.01 mol%), 60 °C, 5 min.

b Isolated yields.

Notably, when 4-nitroacetophenone was subjected to the microwave-assisted hydrogenation, 4-aminoacetophenone was selectively produced in 98% yield in less than 10 minutes, whilst leaving the carbonyl group intact (Table [2], entry 1). In order to further demonstrate the scope of the microwave-assisted hydrogenation approach with the Cat2 catalyst, we turned our attention to other aromatic nitro compounds. Nitrobenzenes containing acid and cyano functionalities were also tolerated and produced the desired amino products in yields of 95% and 98%, respectively, within 5 minutes (Table [2], entries 2 and 3). When the reaction 2-nitrobenzophenone was conducted, a mixture of 2-aminobenzophenone (16%) and 2-methyl-4-phenylquinoline (84%) was obtained in 5 minutes (due to the coupling of in situ formed acetone with 2-aminobenzophenone) (Table [2], entry 4). On running the same reaction for a longer period (45 min), the quinoline was obtained as the major product. On the other hand, the ratio of these products changed when the reaction was performed under conventional heating (Table [2], entry 4; 63%/37%). A nitroarene having a bromo substituent gave the desired aniline derivative in 96% yield (Table [2], entry 5). When the same reaction was carried out under conventional heating at 80 °C, the yield of the desired aniline was reduced significantly along with an increase in the reaction time (1 h). These results provide evidence for the importance of the microwave-assisted reaction for the sustainability and efficiency of the catalytic system.

The efficiency of catalyst Cat2 in microwave-assisted TH was revealed in terms of TONs and TOFs for the model reaction. The highest TON and TOF of 7.7 × 104 and 2.3 × 105 h–1, respectively, were observed when the catalyst loading was 0.001 mol%, although alcohol formation occurred in low yield. A comparison of the reaction parameters of the present system with earlier reported catalysts is presented in Table S3 (see the Supporting Information). It is important to highlight that the existing system can be used in scale-up reactions, as demonstrated by the success of the synthesis of 1-phenylethanol in scale-up reactions with Cat2. The scale-up reaction of acetophenone (10 mmol) with isopropanol (10 mL) under the optimized reaction conditions using 0.01 mol% of the catalyst produced the desired alcohol in an excellent yield of 91% (1.09 g) (see Scheme S1 in the Supporting Information).

The nature of the catalytic process was determined through a mercury-drop experiment. The addition of mercury had no impact on the reaction yield, thereby confirming the homogeneous nature of the catalyst (see Scheme S2 in the Supporting Information).

We have proposed the following mechanism based on our experimental evidence and previous literature reports (Scheme [1]).[41] [42] [43] [44] To start with, the chlorides in the ligand in Cat2 (I) were displaced by alkoxide species, which were generated in situ from isopropanol and KOH, giving rise to Ru-alkoxide species II. The formation of II was confirmed through examination of the reaction mixture by mass spectrometry (m/z 1119.42) (Figure [2a] and Figure S1 in the Supporting Information). This species undergoes β-hydride elimination, leading to the formation of a ketone intermediate and Ru-H species (III), which was also supported by mass spectrometry (m/z 1151.42) (Figure [2b]). Subsequent coordination of the carbonyl group of the acetophenone to the metal center, followed by insertion of the Ru–H bond into the carbonyl group results in formation of Ru–alkoxide species V. Finally, species V undergoes alcohol metathesis to furnish the desired product and regenerates the Ru-alkoxide species II.

Zoom Image
Scheme 1 Plausible catalytic cycles for the transfer hydrogenation of carbonyl and nitro compounds using Cat2
Zoom Image
Figure 2 ESI-MS spectra showing the experimental and simulated patterns of (a) Ru-alkoxide intermediate II at m/z 1119.42 corresponding to [M – H]+, and (b) Ru-hydride intermediate III at m/z 1151.42 corresponding to [M + BF4 + Na + K – H]+.

For the TH of nitro compounds using isopropanol or NaBH4 as the hydride source, both the Gupta and Beller groups have proposed a mechanism involving a series of hydride transfers from the in situ generated Ru-H intermediate to nitrobenzene.[45] [46] The reaction begins with the insertion of nitrobenzene into the Ru-hydride species III, leading to formation of the Ru-ONO intermediate (A). Subsequently, in the presence of isopropanol, water is eliminated, resulting in the generation of the Ru-alkoxide species II, accompanied by the release of nitrosobenzene. Following this, hydrogenation of nitrosobenzene occurs, finally producing aniline. This direct route involves the reduction of nitrosobenzene to hydroxylamine, followed by hydrogenation to yield the aniline.

In summary, we have successfully employed a bimetallic Ru catalyst, Cat2, in microwave-assisted transfer hydrogenation reactions of carbonyl compounds. A broad substrate scope for aromatic and aliphatic ketones or aldehydes has been demonstrated to produce excellent yields of the desired products, often in less than 10 minutes. Furthermore, Cat2 demonstrates chemoselectivity in the reduction of nitroaromatic compounds under microwave heating (at 60 °C) within 5 minutes. This investigation also highlights the significance of microwave-assisted reactions over conventional heating for better sustainability and efficiency of catalytic systems. Significantly, Cat2 achieves highest TONs and TOFs of 7.7 × 104 and 2.3 × 105 h–1, respectively, for the microwave-assisted transfer hydrogenation, even with a minimum catalyst loading of 0.001 mol%. To gain a better understanding of the mechanism, we used mass spectrometry to identify intermediates involved in the reactions.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

The authors thank the IoE-funded central facilities and the Sophisticated Analytical Instrument Facility (SAIF), Indian Institute of Technology Bombay (IIT Bombay) for help with various spectral measurements.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2294-1643.
  • Supporting Information

Corresponding Author

Ramaswamy Murugavel
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400076
India   

Publication History

Received: 27 January 2024

Accepted after revision: 25 March 2024

Accepted Manuscript online:
25 March 2024

Article published online:
19 April 2024

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Zoom Image
Figure 1 Bimetallic and monometallic Ru(II) catalysts
Zoom Image
Scheme 1 Plausible catalytic cycles for the transfer hydrogenation of carbonyl and nitro compounds using Cat2
Zoom Image
Figure 2 ESI-MS spectra showing the experimental and simulated patterns of (a) Ru-alkoxide intermediate II at m/z 1119.42 corresponding to [M – H]+, and (b) Ru-hydride intermediate III at m/z 1151.42 corresponding to [M + BF4 + Na + K – H]+.