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Synlett 2025; 36(01): 1-7
DOI: 10.1055/a-2275-3719
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Nickel-Catalyzed Asymmetric Borylative Coupling of 1,3-Dienes with Aldehydes

Jin-Tao Ma
,
Li-Jun Xiao∗

We thank the National Key R&D Program of China (2022YFA1503200), the National Natural Science Foundation of China (No. 22188101, 22201140), the Fundamental Research Funds for the Central Universities, and the Haihe Laboratory of Sustainable Chemical Transformations for financial support.
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Abstract

The nickel-catalyzed borylative coupling of aldehydes and 1,3-dienes with diboron reagents offers an efficient method for synthesizing valuable homoallylic alcohols from easily accessible starting materials. However, achieving enantioselectivity in this reaction has been a significant challenge. We discuss our recent report on the first example of a nickel-catalyzed enantioselective borylative coupling of aldehydes with 1,3-dienes, employing a chiral spiro-phosphine–oxazoline ligand. Notably, by utilizing (E)-1,3-dienes or (Z)-1,3-dienes, we can reverse the diastereoselectivity, yielding either anti- or syn-products, respectively.


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Key words

borylative coupling - homoallylic alcohols - nickel catalysis - spiro compound - enantioselectivity - diastereoselectivity

1,3-Dienes serve as readily accessible building blocks for organic synthesis, with bulk chemicals such as butadiene,[1] isoprene,[2] and myrcene[3] being particularly prevalent. Chemists, recognizing the potential of these simple feedstocks, have sought methods to transform them into more-intricate and more-valuable molecules. Of particular interest are transition-metal-catalyzed processes in fine-chemical synthesis, notably the enantioselective homoallylation or allylation of aldehydes with 1,3-dienes to produce synthetically useful chiral alcohols (Scheme 1).[4] In the 1990s, the groups of Mori and Tamaru pioneered the nickel-catalyzed reductive coupling of 1,3-dienes with aldehydes with 2,1-selectivity and 1,4-selectivity in the adducts (Scheme 1A).[5–9] This method typically employs reducing agents such as silanes,[5] BEt3,[6a–c] or ZnEt2 [6d] for the homoallylation reactions. More recently, significant advances in enantioselective control in these nickel-catalyzed couplings have been made through the use of chiral phosphoramidite ligands.[10–14] In the 2010s, Krische and co-workers spearheaded the development of ruthenium-catalyzed enantioselective reductive 1,3-diene–carbonyl couplings that proceed through hydrogenation or transfer hydrogenation, resulting in 1,2-selectivity in the adducts.[15] Subsequently, Buchwald and co-workers have developed chiral CuH catalysts that substantially enhance the enantioselectivity of the reductive coupling of 1,3-dienes with aldehydes and ketones while maintaining a consistent regioselectivity.[16] Despite significant advances in reductive coupling, little attention has been given to replacing typical reducing agents with diboron (B–B) reagents for borylative coupling (Scheme 1B).[17]

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Jin-Tao Ma(left) received his B.Sc. degree from Hunan Normal University in 2017, and obtained his M.Sc. in chemistry from Beijing Normal University in 2021. He is currently pursuing his Ph.D. degree at Nankai University under the supervision of Professor Li-Jun Xiao. Li-Jun Xiao is currently a tenure-track professor at the State Key Laboratory and Institute of Elemento-Organic Chemistry at Nankai University. He earned his B.Sc. degree from China Pharmaceutical University in 2012, and subsequently pursued postgraduate studies at Nankai University, where he obtained his Ph.D. degree in 2017 under the supervision of Professor Qi-Lin Zhou. From 2018 to 2021, he served as a postdoctoral fellow at Scripps Research Institute with Professor Jin-Quan Yu. His research interests focus on developing new synthetic methodologies by studying the formation, transformation, and selectivity control of metallacycles generated from alkenes, carbonyls, and transition metals.
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Scheme 1 Transition-metal-catalyzed reductive and borylative coupling of 1,3-dienes with aldehydes

Copper catalysis has emerged as a highly effective strategy for the introduction of boron into π-unsaturated systems.[18] Notably, the Oestreich group[19] and the Chen group[20] have independently reported enantioselective borylative couplings of 1,3-dienes with ketones and aldehydes by using this technique (Scheme 2A).[21] Typically, these copper-catalyzed borylative couplings commence with the generation of a CuB species and proceed through migratory insertion into the alkene, yielding 1,2-adducts selectively. In a distinct approach, nickel-catalyzed coupling of 1,3-dienes with aldehydes often proceeds via nickelacycle intermediates arising from oxidative cyclization of zero-valent nickel complexes with dienes and aldehydes.[5–14],[22] In 2008, the Morken group reported a nickel(0)/PCy3-catalyzed borylative coupling of aldehydes with 1,3-dienes (Scheme 2B).[23] This method offers an efficient strategy for the synthesis of highly valuable homoallylic alcohols from easily available starting materials with excellent diastereoselectivity and E-selectivity.[24] It is conceivable that an enantioselective variant of this reaction might be accomplished by incorporating a chiral ligand onto the nickel catalyst. However, due to the scarcity of efficient chiral phosphines,[23,24] achieving enantioselective borylative coupling reactions has remained challenging. Inspired by our finding regarding the impact of phosphine ligands on nickel catalysis,[25] we hypothesized that the development of novel ligands might provide a more comprehensive solution. Here, we discuss our recent report on the first example of nickel-catalyzed enantioselective borylative coupling of aldehydes with 1,3-dienes with a chiral spiro-phosphine–oxazoline as a ligand (Scheme 2C).[26] This reaction provides an efficient method to access chiral (E)-2-methylpent-3-ene-1,5-diols in excellent diastereoselectivities and enantioselectivities. Importantly, the product diastereoselectivity can be reversed by the use of (E)-1,3-dienes or (Z)-1,3-dienes to give anti- or syn-products, respectively, with invariably outstanding diastereoselectivity and excellent enantioselectivity for a range of alkyl and aryl aldehydes.

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Scheme 2 Transition-metal-catalyzed borylative coupling of 1,3-dienes with carbonyls. B2(pin)2 = bis(pinacolato)diboron. B2(neop)2 = bis(neopentylglycolato)diboron.

Enantiopure (E)-2-methylpent-3-ene-1,5-diols are important structural components in many bioactive natural products (Figure 1).[27] However, the current methods for obtaining these compounds often involve multiple steps and suffer from limited efficiency. Despite the elegant enantioselective approaches developed by Morken[28] and Chen[29] for (E)-2-methylpent-3-ene-1,5-diol synthesis, several manipulations are still necessary. We suggest that our nickel-catalyzed enantioselective borylative coupling of 1,3-dienes with aldehydes might provide a direct and complementary approach.

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Figure 1 Natural products containing (E)-2-methylpent-3-ene-1,5-diols or their reduced or oxidized forms

We began our study by evaluating various chiral phosphine ligands (10 mol%) with Ni(COD)2 (10 mol%) in the presence of benzaldehyde (1.0 equiv), (3E)-penta-1,3-diene (1.5 equiv), and bis(pinacolato)diboron [B2(pin)2] (2.0 equiv) in DMF at room temperature (Scheme 3). We were pleased to find that the borylative coupling in the presence of the spiro-phosphine ligand L1 gave the desired products in 77% yield and 42% ee. However, our attempts to enhance the enantioselectivity by using the other monodentate phosphine ligands L2–4 were unsuccessful. Previous mechanistic studies indicated that monodentate phosphine ligands are required for the oxidative cyclization step, leading to key oxo-nickelacycle intermediates from aldehydes, 1,3-dienes, and nickel(0) complexes.[7] However, monodentate phosphine ligands often exhibit weak chiral induction due to P–Ni bond rotation. Consequently, we explored spiro-phosphine ligands with an additional hemilabile coordination site to alter the coordination pattern of the catalyst, with the aim of improving the enantioselectivity by restricting P–Ni bond rotation. As expected, spiro-phosphine ligands with weak coordination sites, such as methoxy (L5), ester (L6), or oxazoline (L7)[30] groups enhanced the enantioselectivity from 42% to 80% ee. Further investigation revealed that substituents on the oxazoline moiety of L7 influenced the enantioselectivity, with a phenyl substituent [(S,S)-L10] yielding the best result of 84% ee. To optimize the reaction, we subsequently employed the bis(neopentylglycolato)diboron [B2(neop)2] as the reagent at 0 °C for 48 hours, which resulted in a 77% NMR yield and 90% ee. However, the use of the diastereomer (R,S)-L13 led to a decreased enantioselectivity of –70% ee for product 3a. Notably, phosphine–oxazoline ligands with various scaffolds (L14 and L15) and the phosphine–amine ligand L16 exhibited low activities and enantioselectivities, probably due to their stronger binding with the nickel catalyst hindering the formation of oxo-nickelacycle intermediates. In the case of the spiro-phosphine-oxazoline ligand, we hypothesized that the rigidity of the spiro skeleton reduced the coordination ability of the oxazoline moiety, resulting in weak coordination with the catalyst.

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Scheme 3 Optimization of the reaction conditions. Reaction conditions: Ni(COD)2 (10 mol%), ligand (10 mol%), 1a (0.1 mmol), 2a (0.15 mmol), DMF (0.5 mL). The yield, diastereoselectivity (dr), and E-selectivity of 3a were determined by 1H NMR analysis using dibromomethane as an internal standard. The isolated yield is given in parentheses. The enantioselectivity (ee) was determined by chiral HPLC analysis. a Using B2(neop)2 instead of B2(pin)2. b Performed at 0 °C for 48 h.

After establishing the optimal reaction conditions, we investigated the substrate scope of the borylative coupling between various aldehydes and dienes (Scheme 4). Initially, we examined the reaction of several aromatic aldehydes with (3E)-penta-1,3-diene (3a–i). We found that aromatic aldehydes with various substituents underwent this reaction smoothly, yielding 1,5-diols 3a–g in moderate to high yields and excellent enantioselectivities. The absolute configuration of (R,R)-3c was determined by single-crystal X-ray diffraction analysis of acylated 3c. A steric effect of ortho-substituents in aromatic aldehydes, such as 2-methylbenzaldehyde, led to a lower yield of 3g (46% yield), but the enantioselectivity remained excellent. The heteroaromatic aldehydes 6-methoxynicotinaldehyde and 5-methylthiophene-2-carbaldehyde reacted with (3E)-penta-1,3-diene to produce the desired products 3h and 3i with 90% ee and 94% ee, respectively. Subsequently, we assessed a series of aliphatic aldehydes and found that they were compatible with the catalytic reaction, yielding products 3j–o in satisfactory yields (59–80%) and with high enantioselectivity (86–92% ee). Notably, the coupling product 3k, previously synthesized in nine steps from methyl (R)-lactate,[31] can now be synthesized in a single step from isobutyraldehyde. Furthermore, chiral citronellal underwent the coupling smoothly, yielding 3o in a 73% yield with excellent diastereoselectivity. We then investigated the generality of the reaction by using a diverse set of alkyl-substituted dienes with 4-methoxybenzaldehyde (Scheme 4). These substrates coupled smoothly to provide the corresponding 1,5-diols 3p–u in good yields and with excellent enantioselectivities. Even the simplest 1,3-diene, buta-1,3-diene, was capable of generating the 1,5-diol 3v in a good yield, albeit with a slightly reduced enantioselectivity (82% ee). However, a phenyl-substituted diene showed a lower enantioselectivity, giving 3w in 72% ee. Regarding limitations of this method, a few substrates, such as methyl 4-formylbenzoate, and cinnamaldehyde, showed no reaction, although the specific reasons for this remain unclear.

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Scheme 4 Substrate scope of aldehydes and (E)-1,3-dienes. Reaction conditions: Ni(COD)2 (10 mol%), L10 (10 mol%), aldehyde 1 (0.2 mmol), diene 2 (0.3 mmol), 0 °C, 48 h, DMF (0.5 mL). The diastereoselectivity (dr) and E-selectivity were determined by 1H NMR analysis. The enantioselectivity (ee) was determined by chiral HPLC analysis. Isolated yields are reported. a Performed at 20 °C.

Surprisingly, when we used a (Z)-diene in the borylative coupling, we made a remarkable discovery: the resulting product displayed a diastereoselective reversal, with a syn-configuration. Initially, treatment of (3Z)-penta-1,3-diene with 4-methoxybenzaldehyde in the presence of ligand L10 produced compound 5a in 81% yield and 82% ee. However, with ligand L7, the enantioselectivity improved to 90% ee (see Scheme 5 for details).

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Scheme 5 Evaluation of ligands for (Z)-dienes in the borylative coupling. Reaction conditions: 1c (0.1 mmol), 4a (0.15 mmol), B2(neop)2 (0.2 mmol), Ni(COD)2 (10 mol%), ligand (10 mol%), 0 °C, DMF (0.25 mL). The yield, diastereoselectivity (dr), and E-selectivity of 5a were determined by 1H NMR analysis using dibromomethane as an internal standard. The enantioselectivity (ee) was determined by chiral HPLC analysis.

This progress, facilitated by the chiral nickel complex, enabled us to explore various aldehydes with (Z)-1,3-dienes, leading to the successful synthesis of coupling products with a syn-configuration (Scheme 6). Aliphatic aldehydes with various alkyl substituents, including three to six-membered rings, gave the corresponding 1,5-diols 5b–h with high diastereo- and enantioselectivities (80–92% ee). Notably, even a (Z)-diene with a long-chain alkyl group proved suitable for the reaction, providing compound 5i with 80% yield and 90% ee. Finally, we tested enantiopure aldehydes such as citronellal and an amino aldehyde, and we found that additional stereocenters in the aldehyde substrate had no effect on the diastereoselectivity (5j and 5k). Overall, all aldehydes examined in our reaction exhibited excellent diastereoselectivities (dr > 20:1) when reacting with (Z)-1,3-dienes.

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Scheme 6 Substrate scope of aldehydes and (Z)-1,3-dienes. Reaction conditions: Ni(COD)2 (10 mol%), L7 (10 mol%), diene (0.3 mmol), aldehyde (0.2 mmol), 0 °C, 48 h, DMF (0.5 mL). The diastereoselectivity (dr) and E-selectivity were determined by 1H NMR analysis. The enantioselectivity (ee) was determined by chiral HPLC analysis. Isolated yields are reported. a B2(pin)2 instead of B2(neop)2. b Performed at 40 °C.

To expand the practical applications of the reaction, we pursued additional transformations of the allylboronate intermediates formed from the borylative coupling (Scheme 7A). Specifically, we initiated the borylative coupling of 4-methoxybenzaldehyde and (3E)-penta-1,3-diene, followed by a Suzuki–Miyaura coupling with bromobenzene.[32] This process produced the allylbenzene derivative 6 in 52% yield and 93% ee. Furthermore, treating the intermediate allylboronate with benzaldehyde led to a highly enantioselective formation of the homoallylic alcohol 7 (94% ee).[33] Notably, when we scaled up the borylative coupling reaction to a 1.0 mmol scale with a catalyst loading as low as 5 mol%, we observed no significant decrease in the yield or ee (Scheme 7B).

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Scheme 7 Transformation of allylboronate and low-catalyst-loading experiment. (A) Transformation of allylboronate beyond oxidation. (B) Catalyst loading 5 mol% on a 1.0 mmol scale.

Based on Morken’s borylative coupling mechanism,[23,24] an enantioselective variation of this reaction has been proposed. This reaction begins with a nickel-induced oxidative cyclization of the aldehyde with either the (E)-1,3-diene or (Z)-1,3-diene to give the oxo-nickelacycle 8 or 9, respectively (Scheme 8). The disposition of the substituents on the oxo-nickelacycle is regulated by the bulky spiro backbone of ligand L10 or L7, effectively mitigating steric clashes between the bulky ligand and the methyl substituent on the diene. The oxazoline moiety of the ligand operates in a steric capacity, orienting the phenyl group of the aldehyde downward. The diastereoselectivity depends upon the configuration of the oxo-nickelacycle intermediates. Notably, the trans-orientation between the phenyl group of the aldehyde and the methyl substituent of the (E)-diene averts unfavorable 1,2-interactions across the metallacycle ring. Similarly, the cis-orientation between the phenyl group of the aldehyde and the methyl substituent of the (Z)-diene prevents interactions between the allylic group and the oxazoline moiety of the ligand. After these steps, the diboron reagent undergoes a σ-bond metathesis reaction, leading to the generation of the allylboronate product. The resulting allylboronate then undergoes further oxidation, ultimately yielding the 1,5-diol during the oxidative workup.

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Scheme 8 Proposed mechanism and steric enantioinduction model. (A) Borylative coupling of benzaldehyde with (E)-diene to access the anti-product. (B) Borylative coupling of benzaldehyde with (Z)-diene to access the syn-product.

In summary, we have developed an efficient method for accessing chiral 2-alkylpent-3-ene-1,5-diols. This method involves a nickel-catalyzed enantioselective borylative coupling of 1,3-dienes with aldehydes using chiral spiro-phosphine–oxazoline ligands. The method permits the construction of multiple bonds and two stereogenic centers and it displays a high enantioselectivity and diastereoselectivity. Importantly, the method permits the selective synthesis of either the anti or syn diastereomer of the product. The resulting enantiomerically enriched 1,5-diols and allylboronate intermediates offer potential as building blocks for the synthesis of valuable derivatives and natural products.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Professor Zhenbo Mo from Nankai University for his assistance with the X-ray diffraction analysis. We also thank Professor Ming Chen of Auburn University and Professor Bo Su of Nankai University for their insightful discussions.


Corresponding Author

Li-Jun Xiao
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University
Tianjin 300071
P. R. of China   

Publication History

Received: 30 November 2023

Accepted after revision: 23 February 2024

Accepted Manuscript online:
23 February 2024

Article published online:
13 March 2024

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Zoom Image
Jin-Tao Ma(left) received his B.Sc. degree from Hunan Normal University in 2017, and obtained his M.Sc. in chemistry from Beijing Normal University in 2021. He is currently pursuing his Ph.D. degree at Nankai University under the supervision of Professor Li-Jun Xiao. Li-Jun Xiao is currently a tenure-track professor at the State Key Laboratory and Institute of Elemento-Organic Chemistry at Nankai University. He earned his B.Sc. degree from China Pharmaceutical University in 2012, and subsequently pursued postgraduate studies at Nankai University, where he obtained his Ph.D. degree in 2017 under the supervision of Professor Qi-Lin Zhou. From 2018 to 2021, he served as a postdoctoral fellow at Scripps Research Institute with Professor Jin-Quan Yu. His research interests focus on developing new synthetic methodologies by studying the formation, transformation, and selectivity control of metallacycles generated from alkenes, carbonyls, and transition metals.
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Scheme 1 Transition-metal-catalyzed reductive and borylative coupling of 1,3-dienes with aldehydes
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Scheme 2 Transition-metal-catalyzed borylative coupling of 1,3-dienes with carbonyls. B2(pin)2 = bis(pinacolato)diboron. B2(neop)2 = bis(neopentylglycolato)diboron.
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Figure 1 Natural products containing (E)-2-methylpent-3-ene-1,5-diols or their reduced or oxidized forms
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Scheme 3 Optimization of the reaction conditions. Reaction conditions: Ni(COD)2 (10 mol%), ligand (10 mol%), 1a (0.1 mmol), 2a (0.15 mmol), DMF (0.5 mL). The yield, diastereoselectivity (dr), and E-selectivity of 3a were determined by 1H NMR analysis using dibromomethane as an internal standard. The isolated yield is given in parentheses. The enantioselectivity (ee) was determined by chiral HPLC analysis. a Using B2(neop)2 instead of B2(pin)2. b Performed at 0 °C for 48 h.
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Scheme 4 Substrate scope of aldehydes and (E)-1,3-dienes. Reaction conditions: Ni(COD)2 (10 mol%), L10 (10 mol%), aldehyde 1 (0.2 mmol), diene 2 (0.3 mmol), 0 °C, 48 h, DMF (0.5 mL). The diastereoselectivity (dr) and E-selectivity were determined by 1H NMR analysis. The enantioselectivity (ee) was determined by chiral HPLC analysis. Isolated yields are reported. a Performed at 20 °C.
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Scheme 5 Evaluation of ligands for (Z)-dienes in the borylative coupling. Reaction conditions: 1c (0.1 mmol), 4a (0.15 mmol), B2(neop)2 (0.2 mmol), Ni(COD)2 (10 mol%), ligand (10 mol%), 0 °C, DMF (0.25 mL). The yield, diastereoselectivity (dr), and E-selectivity of 5a were determined by 1H NMR analysis using dibromomethane as an internal standard. The enantioselectivity (ee) was determined by chiral HPLC analysis.
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Scheme 6 Substrate scope of aldehydes and (Z)-1,3-dienes. Reaction conditions: Ni(COD)2 (10 mol%), L7 (10 mol%), diene (0.3 mmol), aldehyde (0.2 mmol), 0 °C, 48 h, DMF (0.5 mL). The diastereoselectivity (dr) and E-selectivity were determined by 1H NMR analysis. The enantioselectivity (ee) was determined by chiral HPLC analysis. Isolated yields are reported. a B2(pin)2 instead of B2(neop)2. b Performed at 40 °C.
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Scheme 7 Transformation of allylboronate and low-catalyst-loading experiment. (A) Transformation of allylboronate beyond oxidation. (B) Catalyst loading 5 mol% on a 1.0 mmol scale.
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Scheme 8 Proposed mechanism and steric enantioinduction model. (A) Borylative coupling of benzaldehyde with (E)-diene to access the anti-product. (B) Borylative coupling of benzaldehyde with (Z)-diene to access the syn-product.