Cobalt-Catalyzed Reduction of Aldehydes to Alcohols via the Hydroboration Reaction

: A method for the reduction of aldehydes with pinacolborane catalyzed by pincer cobalt complexes based on a triazine backbone is developed in this paper. The presented methodology allows for the transformation of several aldehydes bearing a wide range of electron-withdrawing and electron-donating groups under mild conditions. The presented procedure allows for the direct one-step hydrolysis of the obtained intermediates to the corresponding primary alcohols. A plausible reaction mechanism is proposed.


Introduction
Alcohols represent one of the major groups of organic chemistry compounds and receive constant attention from both academia and industry.Due to their properties, they are crucial reagents used in chemistry, with applications from solvents to highly specialized drugs or materials [1][2][3][4][5][6].Each year sees numerous articles devoted to methods for the synthesis and functionalization of alcohols being published [7][8][9][10][11][12].
One of the most important methods for obtaining alcohols is the reduction of carbonyl compounds (aldehydes, ketones) [13].The most commonly used for this purpose are highly reactive and dangerous hydrides [14] or hydrogen gas [15][16][17][18], which exhibit low selectivity and require much attention being paid to storage and handling (Figure 1a).With this in mind, several alternative reduction methods based on transfer hydrogenation [19,20] (Figure 1b) or hydroelementation [21][22][23] reactions of carbonyl compounds have been developed, employing much safer reagents (formic acid, isopropanol, silanes, and pinacolborane).In the case of hydroelementation, this reaction leads to intermediate silyl ethers or borate esters, which, upon hydrolysis, yield the corresponding alcohol.In this context, methods based on pinacolborane hydroboration reactions appear to be of particular interest, which, unlike hydrosilylation reactions, most often do not require the use of expensive precious metal catalysts [24].
Although the hydroboration of aldehydes and their subsequent hydrolysis to primary alcohols are known to occur without a catalyst, this process has some limitations [25].In particular, it requires elevated temperatures or long reaction times and the elimination of the solvents, which leads to low conversion for most solid substrates.For this reason, in the scientific literature, there are many examples utilizing catalysts based on main-or transition-group elements [21,23,26].
Regarding cobalt catalysts, recent comprehensive research concerning the use of SNS cobalt complexes in the hydroboration reaction of aldehydes has been published [43].However, to maintain the selectivity of the reactions toward the formyl group, they must be carried out in deuterated benzene; otherwise, the authors observed a partial reduction of the acyl group.There are also reports on the use of Co(IMes) 2 Cl [44] and Co(acac) 3 [45] complexes, but both of these systems also catalyze the reduction reaction of ketones, preventing the selective reduction of the formyl group for multifunctional compounds.
catalysis based on Ti [37], Mn [38], Fe [39], Ni [40], Cu [41], and Zn [42] (Figure 1d).Regarding cobalt catalysts, recent comprehensive research concerning the use of SNS cobalt complexes in the hydroboration reaction of aldehydes has been published [43].However, to maintain the selectivity of the reactions toward the formyl group, they must be carried out in deuterated benzene; otherwise, the authors observed a partial reduction of the acyl group.There are also reports on the use of Co(IMes)2Cl [44] and Co(acac)3 [45] complexes, but both of these systems also catalyze the reduction reaction of ketones, preventing the selective reduction of the formyl group for multifunctional compounds.With this in mind, and encouraged by our previous research on the use of pincer cobalt complexes in catalysis [46][47][48][49][50], we decided to investigate the possibility of using them in aldehyde reduction reactions.The decision to choose pincer complexes was dictated by their high air and thermal stability as well as their catalytic activity in many chemical transformations [51,52].We have demonstrated their high catalytic activity in the hydroboration reactions of silylacetylenes [53], alkenes [54], and allenes [55], as well as in the reduction reaction of ketones with diphenylsilane [56].Moreover, a great advantage of the discussed triazine backbone-based ligands is their straightforward synthesis from readily available precursors.Herein, we present a method that allows for the reduction of aldehydes with pinacolborane under mild conditions and showing high tolerance to substrate functional groups (Figure 1e).

Results and Discussion
First, according to the synthetic protocol developed by the Kempe group [57,58], we synthesized a series of pincer cobalt complexes based on a triazine backbone (Figure 2), which we then tested in a model reduction reaction of 4-methylbenzaldehyde with pinacolborane.With this in mind, and encouraged by our previous research on the use of pincer cobalt complexes in catalysis [46][47][48][49][50], we decided to investigate the possibility of using them in aldehyde reduction reactions.The decision to choose pincer complexes was dictated by their high air and thermal stability as well as their catalytic activity in many chemical transformations [51,52].We have demonstrated their high catalytic activity in the hydroboration reactions of silylacetylenes [53], alkenes [54], and allenes [55], as well as in the reduction reaction of ketones with diphenylsilane [56].Moreover, a great advantage of the discussed triazine backbone-based ligands is their straightforward synthesis from readily available precursors.Herein, we present a method that allows for the reduction of aldehydes with pinacolborane under mild conditions and showing high tolerance to substrate functional groups (Figure 1e).

Results and Discussion
First, according to the synthetic protocol developed by the Kempe group [57,58], we synthesized a series of pincer cobalt complexes based on a triazine backbone (Figure 2), which we then tested in a model reduction reaction of 4-methylbenzaldehyde with pinacolborane.
The initial results show the catalytic activity of the obtained precatalysts in the aldehyde hydroboration reaction (Table 1).Among the tested complexes, the highest activity was shown by precatalyst D, which led to full conversion in the reaction carried out at 35 • C for 60 min.Control experiments without a catalyst, with cobalt (II) chloride, or with ligands showed minor conversions, confirming that the obtained complexes are fully responsible for the catalytic activity.The initial results show the catalytic activity of the obtained precatalysts in the aldehyde hydroboration reaction (Table 1).Among the tested complexes, the highest activity was shown by precatalyst D, which led to full conversion in the reaction carried out at 35 °C for 60 min.Control experiments without a catalyst, with cobalt (II) chloride, or with ligands showed minor conversions, confirming that the obtained complexes are fully responsible for the catalytic activity.With optimal conditions, we decided to apply them in the reduction of various aldehydes, omitting the isolation of borate esters by performing hydrolysis to the corresponding alcohols using SiO2 (Figure 3).The reaction with benzaldehyde (1a) proceeded smoothly, resulting in benzyl alcohol in a quantitative yield.In the case of reactions with aromatic aldehydes with electron-donating groups (1b-1d) at both para and meta positions, we observed high catalytic activity of the designed system.In the case of halogen-substituted aromatic aldehydes (1e-1h), we observed very good conversions, although for 2-fluorobenzaldehyde and 4-bromobenzaldehyde, we had to increase the amount of catalyst to 2 mol%.Interestingly, for the strongly deactivating nitro group in the para or meta position (1i,1j), we observed smooth conversions to the corresponding alcohols.However, for some of the more challenging aldehydes with electronwithdrawing groups (1k, 1m, 1o), as well as for 4-vinylbenzaldehyde (1l) or thiophene-2carboxaldehyde (1n), we had to increase the amount of catalyst to 5 mol%.In the reaction with cinnamaldehyde (1p), this system allowed its conversion to cinnamyl alcohol.The initial results show the catalytic activity of the obtained precatalysts aldehyde hydroboration reaction (Table 1).Among the tested complexes, the h activity was shown by precatalyst D, which led to full conversion in the reaction c out at 35 °C for 60 min.Control experiments without a catalyst, with cobalt (II) ch or with ligands showed minor conversions, confirming that the obtained complex fully responsible for the catalytic activity.With optimal conditions, we decided to apply them in the reduction of v aldehydes, omitting the isolation of borate esters by performing hydrolysis corresponding alcohols using SiO2 (Figure 3).The reaction with benzaldehyd proceeded smoothly, resulting in benzyl alcohol in a quantitative yield.In the c reactions with aromatic aldehydes with electron-donating groups (1b-1d) at bot and meta positions, we observed high catalytic activity of the designed system.In th of halogen-substituted aromatic aldehydes (1e-1h), we observed very good conve although for 2-fluorobenzaldehyde and 4-bromobenzaldehyde, we had to increa amount of catalyst to 2 mol%.Interestingly, for the strongly deactivating nitro gr the para or meta position (1i,1j), we observed smooth conversions to the correspo alcohols.However, for some of the more challenging aldehydes with ele withdrawing groups (1k, 1m, 1o), as well as for 4-vinylbenzaldehyde (1l) or thioph carboxaldehyde (1n), we had to increase the amount of catalyst to 5 mol%.In the re with cinnamaldehyde (1p), this system allowed its conversion to cinnamyl a  With optimal conditions, we decided to apply them in the reduction of various aldehydes, omitting the isolation of borate esters by performing hydrolysis to the corresponding alcohols using SiO 2 (Figure 3).The reaction with benzaldehyde (1a) proceeded smoothly, resulting in benzyl alcohol in a quantitative yield.In the case of reactions with aromatic aldehydes with electron-donating groups (1b-1d) at both para and meta positions, we observed high catalytic activity of the designed system.In the case of halogen-substituted aromatic aldehydes (1e-1h), we observed very good conversions, although for 2-fluorobenzaldehyde and 4-bromobenzaldehyde, we had to increase the amount of catalyst to 2 mol%.Interestingly, for the strongly deactivating nitro group in the para or meta position (1i,1j), we observed smooth conversions to the corresponding alcohols.However, for some of the more challenging aldehydes with electron-withdrawing groups (1k, 1m, 1o), as well as for 4-vinylbenzaldehyde (1l) or thiophene-2-carboxaldehyde (1n), we had to increase the amount of catalyst to 5 mol%.In the reaction with cinnamaldehyde (1p), this system allowed its conversion to cinnamyl alcohol.Similarly, the reaction of (E)-oct-2-enal (1s) yielded a selective reduction with retention of the conjugated double bond.In the case of reactions with aliphatic aldehydes (1r, 1t), the reduction proceeded smoothly, producing products with high yields.Importantly, the presented examples demonstrate the high functional group tolerance of the developed method, permitting the selective reduction of the formyl group in the presence of other reactive functional groups (nitro, nitrile, vinyl) without any side reactions.Moreover, the developed method allows for the precise reduction of the formyl group in substituted esters and ketones while preserving their carbonyl group.This selectivity allows the developed procedure to be used as a powerful tool for reducing the formyl group in complex molecules, increasing its application potential.
Similarly, the reaction of (E)-oct-2-enal (1s) yielded a selective reduction with retention of the conjugated double bond.In the case of reactions with aliphatic aldehydes (1r, 1t), the reduction proceeded smoothly, producing products with high yields.Importantly, the presented examples demonstrate the high functional group tolerance of the developed method, permitting the selective reduction of the formyl group in the presence of other reactive functional groups (nitro, nitrile, vinyl) without any side reactions.Moreover, the developed method allows for the precise reduction of the formyl group in substituted esters and ketones while preserving their carbonyl group.This selectivity allows the developed procedure to be used as a powerful tool for reducing the formyl group in complex molecules, increasing its application potential.To confirm the utility of the presented method for the reduction of aldehydes, we performed comparative tests under the developed conditions with and without a catalyst (Table 2).In each of the carried-out reactions, the addition of a catalyst proved to be crucial for achieving high conversion rates.This indicates the applicability of the developed To confirm the utility of the presented method for the reduction of aldehydes, we performed comparative tests under the developed conditions with and without a catalyst (Table 2).In each of the carried-out reactions, the addition of a catalyst proved to be crucial for achieving high conversion rates.This indicates the applicability of the developed method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.

11% 99%
method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.

2% 95%
Int. J. Mol.Sci.2024, 25, x FOR PEER REVIEW 5 of 10 method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.

10% 99%
method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.

<1%
93% 3 method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.

6% 97%
Int. J. Mol.Sci.2024, 25, x FOR PEER REVIEW 5 of 10 method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.

2% 98%
Int. J. Mol.Sci.2024, 25, x FOR PEER REVIEW 5 of 10 method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.method, particularly for substrates that are sensitive to high temperatures or which require the use of a solvent.The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.

8%
97% 4 The presented system complements our previously developed method for the reduction of ketones with diphenylsilane (Figure 4) [56].Interestingly, in the case of the hydrosilylation-based reduction presented there, the developed system only allowed the reduction of ketones and showed no catalytic activity in the reduction of the formyl group.By contrast, we observed the opposite reactivity in the case of the hydroboration-based reaction presented here, in which it is the ketones that are not reduced.
Based on our previous studies and literature reports [47,48,[53][54][55][56]59,60], we assume that the reaction follows a Co(I)/Co(III) mechanism (Figure 5).In the first step, the cobalt precatalyst is activated by pinacolborane, resulting in the active form of the Co(I) catalyst.It then undergoes oxidative addition, resulting in a Co(III) molecule, into which the aldehyde is inserted.In the next step, the product is released by means of reductive elimination with simultaneous Co(I) regeneration.Alternatively, reductive elimination can be replaced by transmetallation with a pinacolborane molecule, resulting in the formation of the product and the regeneration of Co(III).Based on our previous studies and literature reports [47,48,[53][54][55][56]59,60], we assume that the reaction follows a Co(I)/Co(III) mechanism (Figure 5).In the first step, the cobalt precatalyst is activated by pinacolborane, resulting in the active form of the Co(I) catalyst.It then undergoes oxidative addition, resulting in a Co(III) molecule, into which the aldehyde is inserted.In the next step, the product is released by means of reductive elimination with simultaneous Co(I) regeneration.Alternatively, reductive elimination can be replaced by transmetallation with a pinacolborane molecule, resulting in the formation of the product and the regeneration of Co(III).Based on our previous studies and literature reports [47,48,[53][54][55][56]59,60], we assume that the reaction follows a Co(I)/Co(III) mechanism (Figure 5).In the first step, the cobalt precatalyst is activated by pinacolborane, resulting in the active form of the Co(I) catalyst.It then undergoes oxidative addition, resulting in a Co(III) molecule, into which the aldehyde is inserted.In the next step, the product is released by means of reductive elimination with simultaneous Co(I) regeneration.Alternatively, reductive elimination can be replaced by transmetallation with a pinacolborane molecule, resulting in the formation of the product and the regeneration of Co(III).

Materials and Methods
Air-and moisture-sensitive reactions were carried out under an argon atmosphere using standard Schlenk techniques or a glove box.Solvents used for all experiments were purchased from Honeywell (Charlotte, NC, USA) or Sigma Aldrich (St. Louis, MO, USA) (Merck, Rahway, NJ, USA), dried over calcium hydride (CaH 2 ), and purified by means of distillation.Toluene was additionally dried over sodium.Ligands and Co complexes were prepared in accordance with previously reported methods [61] using reagents purchased from Sigma Aldrich (Merck) or ABCR GmBH (Karlsruhe, Germany).Pinacolborane and aldehydes were purchased from Sigma-Aldrich, dried over calcium hydride, and purified by means of distillation.The progress of reactions (conversion of aldehyde) was monitored via GC chromatography using Agilent 8860 GC and Agilent 5977B GC/MSD with the Agilent 8860 GC System (Agilent, Santa Clara, CA, USA).The structures of products were determined by means of NMR spectroscopy and mass spectrometry.The 1 H NMR (400 MHz), 13 C NMR (101 MHz), and 31 P NMR (162 MHz) spectra were recorded on a Bruker Avance III HD NanoBay spectrometer (Bruker, Billerica, MA, USA), using chloroform-d1 (CDCl 3 ) as a solvent.Deuterated solvents were purchased from Deutero GmbH (Kastellaun, Germany) (CDCl 3 99.6 atom% D) or Sigma Aldrich (Merck) (CDCl 3 99.8 atom% D) and were used as received.

General Procedure for the Synthesis of Compounds (1a-1t)
To a 12 mL vial equipped with a magnetic stirring bar, precatalyst E (0.01 eq. for 1a-1e, 1h-1j, 1r, 1t or 0.02 eq. for 1f, 1g, 1s or 0.05 eq. for 1k-1p), toluene (170 µL), the corresponding aldehyde (0.3 mmol, 1.0 eq.), and pinacolborane (0.45 mmol, 1.4 eq.) were added under an inert gas atmosphere (glove box).A reference sample was taken.Subsequently, the reaction mixture was stirred at 35 • C for 60 min, and the progress of the reaction was monitored by GC or GC/MS.After the reaction was completed, the volatiles were evaporated under reduced pressure.The residue mixture was subjected to column chromatography using silica gel and hexane/ethyl acetate (1:1, v/v) as an eluent, which was then evaporated under reduced pressure giving the desired product.The products were identified by means of 1 H and 13 C spectroscopies and mass spectrometry.

Conclusions
In summary, we have developed a catalytic method for the reduction of aldehydes to the corresponding alcohols under mild conditions utilizing cobalt pincer complexes based on a triazine backbone.Aldehydes possessing a wide range of electron-withdrawing and electron-donating groups were reduced.The presented protocol demonstrates high tolerance to the functional groups of the substrates, allowing for the selective reduction of the formyl group in the presence of other reactive functional groups.Moreover, the simple work-up of the reaction is a significant advantage of the presented method, with one-pot hydrolysis of the intermediate to the corresponding alcohols.Based on our earlier studies, we also present a possible reaction mechanism.
Informed Consent Statement: Not applicable.

2 Figure 1 .
Figure 1.Various methods for the aldehyde reduction.

Figure 1 .
Figure 1.Various methods for the aldehyde reduction.

10 Figure 2 .
Figure 2. Procedure for the synthesis of pincer cobalt complexes.

Figure 2 .
Figure 2. Procedure for the synthesis of pincer cobalt complexes.

Figure 2 .
Figure 2. Procedure for the synthesis of pincer cobalt complexes.

Figure 3 .
Figure 3. Reduction of aldehydes.a Conversion of aldehyde determined by GC with n-dodecane as the internal standard-the isolated yields are in parentheses; b 2 mol% cat.D; c 5 mol% cat.D.

Figure 3 .
Figure 3. Reduction of aldehydes.a Conversion of aldehyde determined by GC with n-dodecane as the internal standard-the isolated yields are in parentheses; b 2 mol% cat.D; c 5 mol% cat.D.

Figure 4 .
Figure 4. Comparison of cobalt PNP traizine-based methods for the reduction of cabonyl compounds using hydroelementation reactions.

Figure 4 .
Figure 4. Comparison of cobalt PNP traizine-based methods for the reduction of cabonyl compounds using hydroelementation reactions.

Figure 4 .
Figure 4. Comparison of cobalt PNP traizine-based methods for the reduction of cabonyl compounds using hydroelementation reactions.

Table 1 .
Optimization for the cobalt-catalyzed reduction of aldehydes.
1Conversion of aldehyde determined by GC with n-dodecane as the internal standard.

Table 1 .
Optimization for the cobalt-catalyzed reduction of aldehydes.

Table 1 .
Optimization for the cobalt-catalyzed reduction of aldehydes.
1Conversion of aldehyde determined by GC with n-dodecane as the internal standard.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.

Table 2 .
Comparison of aldehyde reduction under catalytic and catalyst-free conditions.