DOI: 10.1039/C7SC03025H (Edge Article) Chem. Sci., 2017, 8, 8362-8372
Rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids with nitroalkenes: reaction mechanism and development of homogeneous and heterogeneous catalysts†
Received 10th July 2017 , Accepted 10th October 2017
First published on 11th October 2017
Asymmetric 1,4-addition reactions with nitroalkenes are valuable because the resulting chiral nitro compounds can be converted into various useful species often used as chiral building blocks in drug and natural product synthesis. In the present work, asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes catalyzed by a rhodium complex with a chiral diene bearing a tertiary butyl amide moiety were developed. Just 0.1 mol% of the chiral rhodium complex could catalyze the reactions and give the desired products in high yields with excellent enantioselectivities. The homogeneous catalyst thus developed could be converted to a reusable heterogeneous metal nanoparticle system using the same chiral ligand as a modifier, which was immobilized using a polystyrene-derived polymer with cross-linking moieties, maintaining the same level of enantioselectivity. To our knowledge, this is the first example of asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes in a heterogeneous system. Wide substrate generality and high catalytic turnover were achieved in the presence of sufficient water without any additives such as KOH or KHF2 in both homogeneous and heterogeneous systems. Various insights relating to a rate-limiting step in the catalytic cycle, the importance of water, role of the secondary amide moiety in the ligand, and active species in the heterogeneous system were obtained through mechanistic studies.
IntroductionAsymmetric synthesis is crucial in fine chemical production, such as the synthesis of drugs, biologically active compounds, and natural products. In particular, asymmetric carbon–carbon bond formation is useful because both chiral centers and carbon-based skeletons of target molecules are constructed simultaneously. Asymmetric 1,4-addition reactions with nitroalkenes are valuable because the resulting chiral nitro compounds can be converted into various useful species often used as chiral building blocks in drug and natural product synthesis. The first rhodium-catalyzed asymmetric 1,4-addition reaction of aryl boronic acids with nitroalkenes was reported by Hayashi et al. and several homogeneous systems for this transformation have been developed using chiral rhodium and palladium complexes.1–12 In the rhodium-catalyzed 1,4-addition reaction of aryl boronic acids with nitroalkenes, it was suggested that the catalyst regeneration step is relatively slow because of the strong coordination ability of the generated nitronate to the rhodium complex. This slow catalytic regeneration often caused low catalytic turnover and by-product formation, and then, in most previously reported rhodium-catalyzed reactions, stoichiometric to substoichiometric additives, such as KOH or KHF2, were required to achieve an efficient catalytic turnover.2–6,9–11
In contrast, to our knowledge heterogeneous catalyst systems for this asymmetric reaction have never been developed hitherto, probably because the strong coordination ability of the nitro group can induce serious metal leaching and poisoning of the catalytically active center, which might be generally less robust compared with that of corresponding homogeneous complexes. Heterogeneous catalysts have attracted great attention because of their facile separation from products, reusability, and application to industrial processes.13–17 As general strategies to develop heterogeneous metal catalysts for asymmetric transformations, immobilized chiral ligands to form immobilized chiral metal complexes have been widely explored.18–21 However, these strategies suffer from complicated preparation of immobilized ligands, metal leaching during asymmetric reaction, and often instability of immobilized ligands. In addition, immobilized metal catalysts for organic transformations are generally less active than the corresponding homogeneous catalysts, and they often suffer from serious leaching of metals during reactions and decreased activity during recovery and reuse. As a strategy to convert homogeneous catalysis to heterogeneous catalysis, the use of heterogeneous metal nanoparticle catalysts is of great interest because of their reusability, robustness and high reactivity.22–25 Recently, several organic transformations originally catalyzed by homogeneous catalysts have been successfully converted to heterogeneous metal nanoparticle catalysis.26,27 Asymmetric organic synthesis with heterogeneous metal nanoparticle systems using chiral ligands as “chiral modifiers” have been investigated, especially in asymmetric hydrogenation reactions pioneered by Orito et al.28,29 Several mechanistic studies, even including theoretical calculations, have been conducted for Orito-type reactions.30–35 In contrast, asymmetric C–C bond formation reactions using heterogeneous metal nanoparticle systems is a very limited and developing field, and their reaction mechanisms are obscure in contrast to matured asymmetric hydrogenation reactions.27,36–43
In this context, we have developed chirally modified rhodium and bimetallic nanoparticle systems based on a polymer-incarcerated (PI) strategy, in which polystyrene derivatives with cross-linking moieties (Fig. 1a) are used to immobilize metal nanoparticles.44–48 The metal nanoparticles are encapsulated and stabilized with weak, but multiple interactions of benzene rings in the polymer and physical entrapment by cross-linked polymer cage.49 The chirally modified rhodium-based metal nanoparticle systems thus developed can be applied to asymmetric 1,4-addition reactions of aryl boronic acids with α,β-unsaturated carbonyl compounds, such as ketones, esters and amides. In addition, we have newly developed a chiral diene ligand, including a secondary amide moiety with bifunctionality, interacting with a metal nanoparticle through a diene moiety and activating a substrate through hydrogen bonding (ligand 4c in Fig. 1b).45,50 In the course of these studies, we obtained insight into the reaction mechanism of chirally modified metal nanoparticle systems, in which active species in heterogeneous systems are different from those in corresponding homogeneous systems, and a direct interaction between the chiral ligand and metal nanoparticle surface was proven.45,51
|Fig. 1 Copolymer for immobilization and chiral dienes.|
In the present article, we report the development of asymmetric 1,4-addition reactions of aryl boronic acids with nitroalkenes with a high catalytic turnover and excellent enantioselectivity using both homogeneous metal complex and heterogeneous metal nanoparticle systems of chiral diene ligand 4c without any additives, such as KOH and KHF2. This is the first heterogeneous system for this asymmetric transformation, and we have also found various insights into the reaction mechanism, especially that are different from asymmetric 1,4-addition reactions with α,β-unsaturated carbonyl compounds.
Results and discussion
Development of homogeneous reaction systemsA family of chiral dienes with bicyclo[2,2,2]hexadiene structure were developed independently by Hayashi et al. and Carreira et al. They have been widely used for transition metal-catalyzed asymmetric reactions, particularly Rh-catalyzed asymmetric 1,4-addition-type reactions.52–55 We previously designed and developed chiral diene ligands containing secondary amide functionality as highly efficient and selective bifunctional ligands for asymmetric 1,4-additions of α,β-unsaturated carbonyl compounds in both homogeneous and heterogeneous systems.45 In this context, we initiated an investigation of the asymmetric 1,4-addition reaction of 3-methoxy phenyl boronic acid (2a) with nitrostyrene (1a) using homogeneous systems of 0.05 mol% of [Rh(C2H4)2Cl]2 (0.1 mol% of Rh) and different types of chiral diene ligands at 100 °C in a 2:1 ratio of toluene and water solvents (Table 1). Chiral diene ligands with bulky ester moieties (4a and 4b) gave the desired product 3aa in high yields with good enantioselectivities (entries 1 and 2). The diene ligand with secondary bulky amide 4c gave 3aa with excellent enantioselectivity, even in moderate yield (entry 3). In contrast, the enantioselectivity was dramatically reduced with chiral diene ligand 4d containing a tertiary amide moiety, although an excellent yield was observed (entry 4). We determined ligand 4c to be the best in terms of enantioselectivity. Next, we investigated the solvent system using phenyl boronic acid (2b) as the substrate (Table 2). Phenyl boronic acid (2b) gave a higher yield under the same reaction conditions of Table 1, entry 3, obtaining an excellent yield (entry 1). When a 1:1 ratio of toluene and water maintaining the same concentration was employed, the yield was improved slightly (entry 2). Finally, an almost quantitative yield was obtained under twice-diluted conditions in a 1:1 ratio of toluene and water solvents even in the presence of 0.1 mol% of the rhodium source under almost neutral conditions (entry 3). Remarkably, additives such as bases were not required in this catalytic system, while previously developed metal complex systems for asymmetric 1,4-addition reactions of aryl boronic acids with nitroalkenes required either basic conditions or higher metal loadings of more than 3 mol%.2–6,9–12 The rhodium complex of ligand 4c would provide an ideal chiral reaction environment for this enantioselective transformation.
Table 1Effect of chiral dienes
Table 2Optimization of solvent ratio in a homogeneous system
Various combinations of nitroalkenes and arylboronic acids were examined under the optimal conditions. In almost all cases, the products were obtained in more than 90% yield with high enantioselectivities. Electron-rich and -deficient arylboronic acids could be used (Table 3, entries 1–7). ortho-Substituted arylboronic acids afforded 1,4-adducts with excellent enantioselectivities (entries 6 and 7). Alternatively, electron-rich and -deficient nitroalkenes could be used to give the desired products in high yields with high enantioselectivities (entries 8–15). In these nitroalkenes, a bromo-substituted nitroalkene could be used to afford the 1,4-adducts in 98% yield with 90% ee with tolerance of a bromine atom (entries 13 and 14). Twice the amount of chiral rhodium complex could afford the products in high yields with high enantioselectivities using heteroaromatic moieties including nitroalkenes (entries 17–20). When aliphatic nitroalkenes were examined, the reactions proceeded smoothly to afford the products in high yields with high enantioselectivities (entries 21–24). In the case of n-butyl-substituted nitroalkene, both the yield and enantioselectivity were slightly reduced. However, moderate yields of the desired products were observed and then ee values were high (entries 25 and 26). We note that no additives were required for any of these substrates.
Table 3Substrate scope in the homogeneous systema
Discussion of proposed reaction mechanismThe assumed catalytic cycle of the asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes is shown in Fig. 2.2
|Fig. 2 The assumed catalytic cycle.|
The induction of chirality occurs during the step where the aryl group is added to the β position of the nitroalkene (III → IV) from the viewpoint of the formation of the chirality in the product. However, some of the enantioselectivity is determined in the previous step (II → III); that is, the approach direction of nitroalkenes to the rhodium aryl complex II and the stability of the intermediate III are critical for stereocontrol of the desired product. A comparison of the yields and the enantioselectivities using ligands 4b, 4c and 4d in homogeneous systems is shown in Table 1. For comparison, the results of the asymmetric 1,4-addition reaction of an arylboronic acid with an α,β-unsaturated ester in homogeneous systems depending on chiral dienes are shown in Table 4.45
Table 4Comparison of chiral dienes in asymmetric 1,4-addition to an estera
In the case of the asymmetric 1,4-addition reaction of a nitroalkene, good to high yields of the desired product were obtained, while the enantioselectivities of the desired product were extremely diverse (Table 1). In the case of chiral diene 4b bearing a tertiary butyl ester, the desired product was obtained with 81% ee (Table 1, entry 2), and the enantioselectivity was 90% ee when chiral diene 4c bearing a tertiary butyl amide was used (entry 3). When a ligand lacking a proton on the nitrogen atom of the amide moiety, chiral diene 4d, was used, the enantioselectivity was dramatically reduced (entry 4). These results suggest the importance of the presence of an amide proton for the enantioselectivities.
In contrast, in the case of the asymmetric 1,4-addition reaction of an α,β-unsaturated ester (Table 4), the presence of the proton on the secondary amide notably affects both the yields and the enantioselectivities (entry 2). It was suggested that the amide proton of 4c not only participated in the stabilization of the ester substrate on the rhodium center through hydrogen bonding, but also accelerated the 1,4-addition step (or both) through its Brønsted acidity.45 Following our development, a similar bifunctional role of diene ligands containing a secondary amide moiety in asymmetric 1,4-addition reactions was discussed.9 Similarly, the amide proton in ligand 4c might participate in the rigid fixation of a nitroalkene to realize high stereoselectivity, stabilizing key intermediate III more than in the case without hydrogen bonding. Several assumed transition state models of both desired and undesired intermediates III with three different ligands are shown in Fig. 3.
|Fig. 3 Assumed stereoselective models for intermediate III.|
In asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes, the major enantiomer formed via the desired intermediate IIIb is shown in Fig. 3. During the approach of nitroalkenes to the rhodium aryl complex (II → III), because there is a large steric repulsion between the nitro group and the bulky part of the chiral diene (represented by a gray ball), the formation of the undesired intermediate (II → IIIa) is slower than the formation of the desired intermediate (II → IIIb). In addition, the stability of the intermediate IIIa may be lower than that of the intermediates IIIb because of the steric repulsion. The stereocontrol of the desired products derives from both the kinetics of the process (II → III) and thermodynamic stability of intermediate IIIb. Next, the structures of intermediates IIIb with different chiral dienes are compared. In the case of chiral diene 4c bearing a secondary amide moiety, the nitroalkene would be fixed as shown by IIIb-4c in Fig. 3via hydrogen bonding between the oxygen atoms of the nitro group and the proton of the amide. However, in the case where chiral diene 4b bears a tertiary butyl ester moiety, there is no stabilization through hydrogen bonding. Therefore, the stability of IIIb-4b could be lower than that of IIIb-4c, thus resulting in the difference in enantioselectivity. In the case of chiral diene 4d, bearing tertiary amide moiety, there is also no stabilization through hydrogen bonding. In addition, there appears to be steric repulsion between the nitro group and the methyl group on the amide nitrogen (IIIb-4d). Because of these factors, the dramatic drop in the enantioselectivity with chiral diene 4d might be rationalized. That is, in the series of stereoselective pathways (II → III and stability of III), the amide proton of chiral diene 4c plays an important role in achieving excellent enantioselectivities.
In contrast, improvement of the yield was not observed through the introduction of a secondary amide moiety in the ligand, unlike in the case of 1,4-addition to an α,β-unsaturated ester. In the case of 1,4-addition to an α,β-unsaturated ester, either the approach of the ester to a rhodium aryl complex or the 1,4-addition step is the rate-determining step and the secondary amide moiety in the ligand 4c might accelerate these steps.45 This difference suggests that there is a variation in kinetic behavior (for example, a rate-determining step) between the case of a nitroalkene and the case of an α,β-unsaturated ester.
In a previous report, it was postulated that the hydrolysis of Rh nitronate would be relatively slow.2 To investigate whether or not this is true in our present catalytic system, reactions in nondeuterated water and deuterated water were compared to examine whether the protonation step (IV → I) was the rate-determining step (Table 5). If protonation is the rate-determining step, the initial rate of the reaction in deuterated water should be slower than that in nondeuterated water because of the kinetic isotope effect. The reactions were conducted for 2 h in both cases and the yields and ee values of the desired product were examined. There was a clear kinetic isotope effect, that is, the yield in nondeuterated water (Table 5, entry 1) was much higher than that in deuterated water (entry 2), and this suggested protonation (IV → I) as the rate-determining step. In contrast, in the case of the asymmetric 1,4-addition of an arylboronic acid to an α,β-unsaturated ester, no difference in the yields between nondeuterated water and deuterated water was observed (Scheme 1). From these results, we concluded that the rate-determining step of the 1,4-addition to a nitroalkene was different from that of the 1,4-addition to an α,β-unsaturated ester.
Table 5Reactions in nondeuterated and deuterated water
|Scheme 1 Reactions in nondeuterated and deuterated water in the case of esters.|
Under conditions with a smaller proportion of water, that is, a 2:1 ratio of toluene:water, the reaction was much slower than that in a 1:1 ratio of toluene:water (Table 5, entry 1 [2 h; 74% yield] vs.Table 6, entry 3 [16 h; 62% yield]), probably because of slower protonation as a result of the lower availability of water. When we screened additives to enhance the reaction, we found that adding 0.5 mol% dimethylurea notably accelerated the reaction under these conditions. The chiral dienes bearing ester moiety 4b, bearing secondary amide moiety 4c, and bearing tertiary amide moiety 4d were used as ligands and the effect of dimethylurea is summarized in Table 6. When the reactions were conducted without dimethylurea (Table 6, entries 1, 3 and 5, as in Table 1, entries 2–4), the yield was lower (1a remained) using chiral diene 4c than using chiral dienes 4b and 4d. When we focus on the rate-determining step (IV → I), these results may be understood as a stabilizing effect of the rhodium nitronate intermediate IV through the amide proton of chiral diene 4c, which makes the catalytic regenerations slow. The yields of the desired product were improved around 20% in the presence of dimethylurea, when either chiral diene 4b or 4c was used (entries 1 vs. 2 and entries 3 vs. 4). The enantioselectivities of the desired product were not associated with the presence of dimethylurea, and they depend on the structure of chiral dienes in these cases. These results suggest that dimethylurea affects only the rate-determining catalytic regeneration step (IV → I), which is separated from the chiral-inducing step. Based on these findings, we propose the possible transition states of the protonation, in which the amide proton of ligand 4c stabilizes the rhodium nitronate intermediate (Fig. 4a) and dimethylurea accelerates the protonation of this intermediate (Fig. 4b and c). The role of dimethylurea in accelerating the regeneration of the catalyst is expected to attract a water molecule through hydrogen-bonding networks near the intermediate (Fig. 4b). Another possible role of dimethylurea is to be in perturbing the stabilizing effect of the amide proton through steric repulsion between the ligand and dimethylurea interacting with the nitro group (Fig. 4c). In both cases, newly formed hydrogen bonding between the nitro group and dimethylurea might weaken the existing hydrogen bonding to the secondary amide proton in ligand 4c and the regeneration of the catalyst might be facilitated. We note that no acceleration of the reaction with the addition of dimethylurea was observed under the optimized conditions (in which toluene:water = 1:1), probably because the protonation was so fast that the effect of dimethylurea became undetectable in the presence of sufficient water (see ESI†). In other words, our catalytic system involving diene ligand 4c with the secondary amide moiety possesses sufficiently high performance to achieve high catalytic turnover up to 1000 in the presence of sufficient water, even without any additives, while previously reported rhodium-catalyzed 1,4-addition reaction of aryl boronic acid with nitroalkenes required such additives to realize efficient catalytic turnover.2–6,9–11
Table 6Effect of dimethylureaa
|Fig. 4 Assumed role of dimethylurea in the protonation step (IV → I).|
In contrast, when ligand 4d with its tertiary amide moiety was used, very high yield was obtained regardless of the addition of dimethylurea, while enantioselectivities were extremely poor (Table 6, entries 5 vs. 6). In these cases, an intermediate before catalyst regeneration step IV might already be destabilized through the steric effect of the bulky tertiary amide moiety, and thus the protonation step (IV → I in Fig. 2) would be sufficiently fast.
Development of heterogeneous metal nanoparticle systemsWe next investigated heterogeneous chiral metal nanoparticle systems for the asymmetric 1,4-addition of aryl boronic acids to nitroalkenes. We initiated the study using PI metal nanoparticle catalysts containing rhodium and silver bimetallic nanoparticles with different ratios, PI/CB Rh/Ag (Table 7).44–49 The role of silver in the bimetallic nanoparticles was found to be in producing small nanoparticles with good dispersibility in the polymer support.44 We used 1 mol% of Rh in the heterogeneous catalysts with 0.1 mol% of ligand 4c, because the Rh atoms that make up the core of the nanoparticles would not participate in catalysis. When the Rh nanoparticle catalyst was used under the optimized reaction conditions for homogeneous catalyst systems, a high yield and excellent enantioselectivity were observed (entry 1). When the ratio of silver was increased from 2:1 to 1:1, the yields were slightly improved maintaining excellent enantioselectivity (entries 2 and 3). Further increasing the proportion of silver in the heterogeneous catalysts resulted in decreased activity (entries 4 and 5). We considered the heterogeneous catalyst containing a 1:1 ratio of rhodium and silver as optimized. However, in all cases, a small amount of rhodium leaching was observed, probably because of the strong coordination ability of the nitro moiety in the substrate and the product.
To suppress rhodium leaching and improve the yield, we investigated solvent systems (Table 8). When concentrated conditions were employed, the yield decreased and the amount of leaching increased (entries 2 vs. 3). When the proportion of toluene was reduced to 1:2, the yield of the product was low, and a significant amount of rhodium leached out (entry 1). These results indicate that the heterogeneous catalyst system is very sensitive to the organic solvent concentration. We continued careful investigations and decreased the proportion of water (entry 4), and it was found that diluted conditions both improved the activity and suppressed leaching (entries 4 and 5). Further decreasing of the proportion of water while maintaining the concentration of toluene (5:1 = toluene:water) resulted in an excellent yield without rhodium leaching, while maintaining excellent enantioselectivity as optimized conditions (entry 6). The amphiphilic nature of the polymer support might help the protonation of rhodium nitronate, for example, providing a hydrogen-bonding network with water molecules through ether and alcoholic moieties in polymer side chains, and resulting in smooth catalyst regeneration even with a smaller proportion of water compared with the homogeneous system.
Table 8Effect of the proportion of toluene
Under optimized conditions, various combinations of arylboronic acids and nitroalkenes were examined. The results are shown in Table 9. Electron-rich and -deficient arylboronic acids were examined (Table 9, entries 1–7). Under the optimized conditions, the desired product 3aa was obtained in 90% yield with 92% ee (entry 1); however, other arylboronic acids afforded the desired products in around 60% yields. A prolonged reaction time (48 h) afforded the desired products in moderate-to-high yields while maintaining high enantioselectivities (entries 2–5). In the cases of ortho-substituted arylboronic acids, the desired products were obtained with excellent enantioselectivities as observed in the homogeneous system (entries 6 and 7). In the case of o-methoxyphenylboronic acid, 5 mol% of the catalyst and 0.5 mol% of the chiral diene 4c gave only a 36% yield of the desired product (entry 6). Steric hindrance of the methoxy group at the ortho-position might make the reaction slower. Electron-rich and -deficient nitroalkenes were then examined (entries 8–15). When phenylboronic acid was used, the desired products were obtained in moderate yields. The reactions were conducted for prolonged times and the desired products could be obtained in high yields with high enantioselectivities (entries 8, 9, 12 and 14). In the case of 3-methoxyphenylboronic acids, the optimal conditions gave the desired products in high yields with high enantioselectivities (entries 10, 11, 13 and 15). Nitroalkenes bearing heteroaromatic moieties also gave the 1,4-adducts in moderate-to-high yields with high enantioselectivities through increasing the loading of the catalyst and chiral diene 4c (entries 16 and 17). While a sulfur atom can usually coordinate to metal nanoparticles and might poison the catalyst, the reaction could be applied to a thienyl-substituted nitroalkene (entry 17). Next, aliphatic nitroalkenes were examined. When a cyclohexyl-substituted nitroalkene was used, the desired product was obtained in 71% yield with 91% ee under the optimal conditions (entry 18). In the case of an isopropyl-substituted nitroalkene, 2 mol% of the catalyst and 0.2 mol% of chiral diene 4c afforded the desired product in 70% yield with 90% ee (entry 19). However, in the case of n-butyl-substituted nitroalkene, the desired product was obtained in only 25% yield. To improve the yield, we tried prolonging the reaction time and increasing the catalyst loading; however, these trials showed no improvement of the yield.
Table 9Substrate scope in a heterogeneous systema
|Entry||Diene||Yield (%)||eea (%)|
|Entry||R||Ar||Product||Yield (%)||ee (%)|
|Entry||Diene||Yield (%)||eeb (%)|
|Entry||Water||Yield (%)||ee (%)|
|Entry||Chiral diene||X (mol%)||Yield (%)||ee (%)|
|Entry||R||Ar||Product||Yield (%)||ee (%)|
Not to be confused with borinic acid.
A boronic acid is a compound related to boric acid in which one of the three hydroxyl groups is replaced by an alkyl or aryl group. As a compound containing a carbon–boron bond, members of this class thus belong to the larger class of organoboranes. Boronic acids act as Lewis acids. Their unique feature is that they are capable of forming reversible covalent complexes with sugars, amino acids, hydroxamic acids, etc. (molecules with vicinal, (1,2) or occasionally (1,3) substituted Lewis base donors (alcohol, amine, carboxylate)). The pKa of a boronic acid is ~9, but they can form tetrahedral boronate complexes with pKa ~7. They are occasionally used in the area of molecular recognition to bind to saccharides for fluorescent detection or selective transport of saccharides across membranes.
Boronic acids are used extensively in organic chemistry as chemical building blocks and intermediates predominantly in the Suzuki coupling. A key concept in its chemistry is transmetallation of its organic residue to a transition metal.
The compound bortezomib with a boronic acid group is a drug used in chemotherapy. The boron atom in this molecule is a key substructure because through it certain proteasomes are blocked that would otherwise degrade proteins. Boronic acids are known to bind to active site serines and are part of inhibitors for porcine pancreatic lipase,subtilisin and the protease Kex2. Furthermore, boronic acid derivatives constitute a class of inhibitors for human acyl-protein thioesterase 1 and 2, which are cancer drug targets within the Ras cycle.
Structure and synthesis
In 1860, Edward Frankland was the first to report the preparation and isolation of a boronic acid. Ethylboronic acid was synthesized by a two-stage process. First, diethylzinc and triethyl borate reacted to produce triethylborane. This compound then oxidized in air to form ethylboronic acid. Several synthetic routes are now in common use, and many air-stable boronic acids are commercially available.
Boronic acids typically have high melting points. They are prone to forming anhydrides by loss of water molecules, typically to give cyclic trimers.
Boronic acids can be obtained via several methods. The most common way is reaction of organometallic compounds based on lithium or magnesium (Grignards) with borate esters. For example, phenylboronic acid is produced from phenylmagnesium bromide and trimethyl borate followed by hydrolysis
- PhMgBr + B(OMe)3 → PhB(OMe)2 + MeOMgBr
- PhB(OMe)2 + H2O → PhB(OH)2 + MeOH
Another method is reaction of an arylsilane (RSiR3) with boron tribromide (BBr3) in a transmetallation to RBBr2 followed by acidic hydrolysis.
A third method is by palladium catalysed reaction of aryl halides and triflates with diboronyl esters in a coupling reaction. An alternative to esters in this method is the use of diboronic acid or tetrahydroxydiboron ([B(OH2)]2).
Boronic esters (also named boronate esters)
Boronic esters are esters formed between a boronic acid and an alcohol.
|Compound||General formula||General structure|
The compounds can be obtained from borate esters by condensation with alcohols and diols. Phenylboronic acid can be selfcondensed to the cyclic trimer called triphenyl anhydride or triphenylboroxin.
Compounds with 5-membered cyclic structures containing the C–O–B–O–C linkage are called dioxaborolanes and those with 6-membered rings dioxaborinanes.
Organic chemistry applications
Suzuki coupling reaction
Boronic acids are used in organic chemistry in the Suzuki reaction. In this reaction the boron atom exchanges its aryl group with an alkoxy group from palladium.
In the Chan–Lam coupling the alkyl, alkenyl or aryl boronic acid reacts with a N–H or O–H containing compound with Cu(II) such as copper(II) acetate and oxygen and a base such as pyridine forming a new carbon–nitrogen bond or carbon–oxygen bond for example in this reaction of 2-pyridone with trans-1-hexenylboronic acid:
The reaction mechanism sequence is deprotonation of the amine, coordination of the amine to the copper(II), transmetallation (transferring the alkyl boron group to copper and the copper acetate group to boron), oxidation of Cu(II) to Cu(III) by oxygen and finally reductive elimination of Cu(III) to Cu(I) with formation of the product. Direct reductive elimination of Cu(II) to Cu(0) also takes place but is very slow. In catalytic systems oxygen also regenerates the Cu(II) catalyst.
In the Liebeskind–Srogl coupling a thiol ester is coupled with a boronic acid to produce a ketone.
The boronic acid organic residue is a nucleophile in conjugate addition also in conjunction with a metal. In one study the pinacol ester of allylboronic acid is reacted with dibenzylidene acetone in such a conjugate addition:
- The catalyst system in this reaction is tris(dibenzylideneacetone)dipalladium(0) / tricyclohexylphosphine.
Another conjugate addition is that of gramine with phenylboronic acid catalyzed by cyclooctadiene rhodium chloride dimer:
Boronic esters are oxidized to the corresponding alcohols with base and hydrogen peroxide (for an example see: carbenoid)
Boronic ester homologization
In this reaction dichloromethyllithium converts the boronic ester into a boronate. A Lewis acid then induces a rearrangement of the alkyl group with displacement of the chlorine group. Finally an organometallic reagent such as a Grignard reagent displaces the second chlorine atom effectively leading to insertion of an RCH2 group into the C-B bond. Another reaction featuring a boronate alkyl migration is the Petasis reaction.
Electrophilic allyl shifts
Allyl boronic esters engage in electrophilic allyl shifts very much like silicon pendant in the Sakurai reaction. In one study a diallylation reagent combines both[note 1]:
Hydrolysis of boronic esters back to the boronic acid and the alcohol can be accomplished in certain systems with thionyl chloride and pyridine. Aryl boronic acids or esters may be hydrolyzed to the corresponding phenols by reaction with hydroxylamine at room temperature.
C–H coupling reactions
The diboron compound bis(pinacolato)diboron reacts with aromatic heterocycles or simple arenes to an arylboronate ester with iridium catalyst [IrCl(COD)]2 (a modification of Crabtree's catalyst) and base 4,4′-di-tert-butyl-2,2′-bipyridine in a C-H coupling reaction for example with benzene:
In one modification the arene reacts using only a stoichiometric equivalent rather than a large excess using the cheaper pinacolborane:
Unlike in ordinary electrophilic aromatic substitution (EAS) where electronic effects dominate, the regioselectivity in this reaction type is solely determined by the steric bulk of the iridium complex. This is exploited in a meta-bromination of m-xylene which by standard AES would give the ortho product:[note 2]
Protodeboronation is a chemical reaction involving the protonolysis of a boronic acid (or other organoborane compound) in which a carbon-boron bond is broken and replaced with a carbon-hydrogen bond. Protodeboronation is a well-known undesired side reaction, and frequently associated with metal-catalysed coupling reactions that utilise boronic acids (see Suzuki reaction). For a given boronic acid, the propensity to undergo protodeboronation is highly variable and dependent on various factors, such as the reaction conditions employed and the organic substituent of the boronic acid:
The covalent pair-wise interaction between boronic acids and hydroxy groups as found in alcohols and acids is rapid and reversible in aqueous solutions. The equilibrium established between boronic acids and the hydroxyl groups present on saccharides has been successfully employed to develop a range of sensors for saccharides. One of the key advantages with this dynamic covalent strategy lies in the ability of boronic acids to overcome the challenge of binding neutral species in aqueous media. If arranged correctly, the introduction of a tertiary amine within these supramolecular systems will permit binding to occur at physiological pH and allow signalling mechanisms such as photoinduced electron transfer mediated fluorescence emission to report the binding event.
Potential applications for this research include blood glucose monitoring systems to help manage diabetes mellitus. As the sensors employ an optical response, monitoring could be achieved using minimally invasive methods, one such example is the investigation of a contact lens that contains a boronic acid based sensor molecule to detect glucose levels within ocular fluids.
- ^IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "Boronic Acids".
- ^Garner, C. W. (1980-06-10). "Boronic acid inhibitors of porcine pancreatic lipase". The Journal of Biological Chemistry. 255 (11): 5064–5068. ISSN 0021-9258. PMID 7372625.
- ^Lindquist, R. N.; Terry, C. (January 1974). "Inhibition of subtilisin by boronic acids, potential analogs of tetrahedral reaction intermediates". Archives of Biochemistry and Biophysics. 160 (1): 135–144. doi:10.1016/s0003-9861(74)80018-4. ISSN 0003-9861. PMID 4364061.
- ^Holyoak, Todd; Wilson, Mark A.; Fenn, Timothy D.; Kettner, Charles A.; Petsko, Gregory A.; Fuller, Robert S.; Ringe, Dagmar (2003-06-10). "2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor". Biochemistry. 42 (22): 6709–6718. doi:10.1021/bi034434t. ISSN 0006-2960. PMID 12779325.
- ^Zimmermann, Tobias J.; Bürger, Marco; Tashiro, Etsu; Kondoh, Yasumitsu; Martinez, Nancy E.; Görmer, Kristina; Rosin-Steiner, Sigrid; Shimizu, Takeshi; Ozaki, Shoichiro (2013-01-02). "Boron-based inhibitors of acyl protein thioesterases 1 and 2". Chembiochem: A European Journal of Chemical Biology. 14 (1): 115–122. doi:10.1002/cbic.201200571. ISSN 1439-7633. PMID 23239555.
- ^Frankland, E.; Duppa, B. F. (1860). "Vorläufige Notiz über Boräthyl". Justus Liebigs Ann. Chem.115 (3): 319. doi:10.1002/jlac.18601150324.
- ^Frankland, E.; Duppa, B. (1860). "On Boric Ethide". Proceedings of the Royal Society. 10: 568. doi:10.1098/rspl.1859.0112.
- ^Frankland, E. (1862). "On a new series of organic compounds containing boron". J. Chem. Soc.15: 363. doi:10.1039/JS8621500363.
- ^Dennis G. Hall, ed. (2005). Boronic Acids. Wiley. ISBN 3-527-30991-8.
- ^Example: Kristensen, Jesper Langgaard; Lysén, Morten; Vedsø, Per; Begtrup, Mikael (2005). "Synthesis of Ortho Substituted Arylboronic Esters by in situ Traping of Unstable Lithio Intermediates: 2-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)benzoic acid ethyl ester". Organic Syntheses. 81: 134. ; Collective Volume, 11, pp. 1015 prep= v81p0134
- ^Example: Li, Wenjie; Nelson, Dorian P.; Jensen, Mark S.; Scott Hoerrner, R.; Cai, Dongwei; Larsen, Robert D. (2005). "Synthesis of 3-Pyridylboronic Acid and its Pinacol Ester. Application of 3-Pyridylboronic acid in Suzuki Coupling to Prepare 3-Pyridin-3-ylquinoline". Organic Syntheses. 81: 89. ; Collective Volume, 11, p. 393
- ^Charette, André B.; Lebel, Hélène (1999). "(2S,3S)-(+)-(3-Phenylcyclopropyl)methanol". Organic Syntheses. 76: 86. ; Collective Volume, 10, p. 613
- ^Washburn, Robert M.; Levens, Ernest; Albright, Charles F.; Billig, Franklin A. (1959). "Benzeneboronic anhydride". Organic Syntheses. 39: 3. ; Collective Volume, 4, p. 68
- ^Pilarski, Lukasz T.; Szabó, Kálmán J. (2011). "Palladium-Catalyzed Direct Synthesis of Organoboronic Acids". Angewandte Chemie International Edition. 50: 8230–8232. doi:10.1002/anie.201102384.
- ^Molander, Gary A.; Trice, Sarah L. J.; Dreher, Spencer D. (2010). "Palladium-Catalyzed, Direct Boronic Acid Synthesis from Aryl Chlorides: A Simplified Route to Diverse Boronate Ester Derivatives". Journal of the American Chemical Society. 132 (50): 17701–17703. doi:10.1021/ja1089759.
- ^Kidwell, R. L.; Murphy, M.; Darling, S. D. (1969). "Phenols: 6-Methoxy-2-Naphthol". Organic Syntheses. 49: 90. ; Collective Volume, 5, p. 918
- ^Washburn, Robert M.; Levens, Ernest; Albright, Charles F.; Billig, Franklin A. (1959). "Benzeneboronic anhydride". Organic Syntheses. 39: 3. ; Collective Volume, 4, p. 68
- ^Chan, Dominic M.T. (2003). "Copper promoted C–N and C–O bond cross-coupling with phenyl and pyridylboronates". Tetrahedron Letters. 44: 3863–3865. doi:10.1016/S0040-4039(03)00739-1.
- ^Lam, Patrick Y.S (2003). "Copper-promoted/catalyzed C–N and C–O bond cross-coupling with vinylboronic acid and its utilities". Tetrahedron Letters. 44: 4927–4931. doi:10.1016/S0040-4039(03)01037-2.
- ^Sieber, Joshua D. (2007). "Catalytic Conjugate Addition of Allyl Groups to Styryl-Activated Enones". Journal of the American Chemical Society. 129: 2214–2215. doi:10.1021/ja067878w.
- ^Gabriela (2007). "Benzylic Substitution of Gramines with Boronic Acids and Rhodium or Iridium Catalysts †". Organic Letters. 9: 961–964. doi:10.1021/ol063042m.
- ^Matteson, Donald S. (1986). "99% Chirally selective synthesis via pinanediol boronic esters: insect pheromones, diols, and an amino alcohol". Journal of the American Chemical Society. 108: 810–819. doi:10.1021/ja00264a039.
- ^Peng, Feng (2007). "Simple, Stable, and Versatile Double-Allylation Reagents for the Stereoselective Preparation of Skeletally Diverse Compounds". Journal of the American Chemical Society. 129: 3070–3071. doi:10.1021/ja068985t.
- ^Matteson, Donald S. (2003). "New asymmetric syntheses with boronic esters and fluoroboranes"(PDF). Pure Appl. Chem. 75 (9): 1249–1253. doi:10.1351/pac200375091249.
- ^Kianmehr, Ebrahim; Yahyaee, Maryam; Tabatabai, Katayoun (2007). "A mild conversion of arylboronic acids and their pinacolyl boronate esters into phenols using hydroxylamine". Tetrahedron Letters. 48: 2713–2715. doi:10.1016/j.tetlet.2007.02.069.
- ^Ishiyama, Tatsuo; Murata, Miki; Ahiko, Taka-aki; Miyaura, Norio (2000). "Bis(pinacolato)diboron". Organic Syntheses. 77: 176. ; Collective Volume, 10, p. 115
- ^Takagi, Jun (2002). "Iridium-catalyzed C–H coupling reaction of heteroaromatic compounds with bis(pinacolato)diboron: regioselective synthesis of heteroarylboronates". Tetrahedron Letters. 43: 5649–5651. doi:10.1016/S0040-4039(02)01135-8.
- ^Ishiyama, Tatsuo (2002). "Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate". Journal of the American Chemical Society. 124: 390–391. doi:10.1021/ja0173019.
- ^Ishiyama, Tatsuo (2003). "Room temperature borylation of arenes and heteroarenes using stoichiometric amounts of pinacolborane catalyzed by iridium complexes in an inert solvent". Chemical Communications (23): 2924. doi:10.1039/b311103b.
- ^Murphy, Jaclyn M. (2007). "Meta Halogenation of 1,3-Disubstituted Arenes via Iridium-Catalyzed Arene Borylation". Journal of the American Chemical Society. 129: 15434–15435. doi:10.1021/ja076498n.
- ^Zhao, Jianzhang; Davidson, Matthew G.; Mahon, Mary F.; Kociok-Köhn, Gabriele; James, Tony D. (2004). "An Enantioselective Fluorescent Sensor for Sugar Acids". J. Am. Chem. Soc. 126 (49): 16179–16186. doi:10.1021/ja046289s.
- ^"Boronic Acids in Saccharide Recognition". 2006. doi:10.1039/9781847557612.
- ^Rowan, Stuart J.; Cantrill, Stuart J.; Cousins, Graham R. L.; Sanders, Jeremy K. M.; Stoddart, J. Fraser (2002). "Dynamic Covalent Chemistry". Angewandte Chemie International Edition. 41 (6): 898–952. doi:10.1002/1521-3773(20020315)41:6<898::AID-ANIE898>3.0.CO;2-E. PMID 12491278.
- ^US 6850786, Wayne Front March, "Ocular analyte sensor", issued 2005-02-01