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. 2026 Jul 4;4(9):1366–1374. doi: 10.1021/prechem.6c00059

Intermolecular Selective 1,2-Aminohydroxylation of 1,3-Dienes Enabled by Palladium/Copper/Oxygen Cooperation

Xuan Yang †,‡, Yanbo Wang ‡,§, Yunyi Li ‡, Ke Wen ‡, Huikang Liu ‡,§, Jiatong Zhang ‡,§, Zhengxing Wu ‡,§,*, Zehua Yang †,*, Wanbin Zhang ‡,§,*
PMCID: PMC13625911  PMID: 42820055

Abstract

β-Amino alcohols are important structural motifs that are widely present in pharmaceutical molecules and natural products with significant biological activities, making the development of synthetic methodologies for their preparation a long-standing research focus. Among current synthetic approaches, 1,2-aminohydroxylation of alkenes offers a direct route to β-amino alcohols. In particular, metal-catalyzed 1,2-aminohydroxylation of alkenes represents an efficient methodology. However, existing methods are restricted to intramolecular reactions or rely on either directing groups or active reagents (preoxidized nitrogen sources or special oxidants). Therefore, the development of a more general catalytic system that does not require intramolecular reactions, directing groups, or active reagents has remained highly desirable. Herein, we report an intermolecular selective 1,2-aminohydroxylation of 2,3-disubstituted 1,3-dienes enabled by palladium/copper/oxygen cooperation, using a simple nitrogen source. Notably, for 2,3-dialkyl-1,3-dienes bearing different alkyl groups, this aminohydroxylation enables alkyl recognition, favoring the less-hindered double bond with moderate to good chemoselectivity. This methodology provides a direct and powerful route to the synthesis of β-amino alcohols.

Keywords: palladium; copper; oxygen; 1,3-diene; aminohydroxylation

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graphic file with name pc6c00059_0007.webp

β-Amino alcohols, an important class of structural motifs, are widely found in pharmaceutical molecules and natural products exhibiting significant biological activities. − Consequently, the development of synthetic methodologies for these motifs has long been a focal point of research. − Current synthetic approaches to β-amino alcohols and derivatives mainly include aminohydroxylation of alkenes, − C–H functionalization, , ring-opening reactions of epoxides, − reduction of α-aminoketones, and derivatization of amino acids (Figure A). 1,2-aminohydroxylation of alkenes, − as an important class of alkene difunctionalization, − offers a powerful and direct route to β-amino alcohols from readily available starting materials by simultaneously introducing amino and oxygen moieties. Among them, metal-catalyzed 1,2-aminohydroxylation of alkenes is an efficient methodology. − Over the past decade, several significant examples of metal-catalyzed 1,2-aminohydroxylation of alkenes have been reported (Figure B), including: (a) regioselective intramolecular 1,2-aminohydroxylation of unactivated alkenes; − (b) 1,2-aminohydroxylation of monoalkenes or conjugated dienes using active reagents (preoxidized nitrogen sources − ,− or special oxidants − , ); (c) intermolecular 1,2-aminohydroxylation of alkenes employing 8-aminoquinoline (AQ) as a directing group.

1.

1

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Aminohydroxylation of alkenes. (A) Synthetic methods for β-amino alcohols. (B) Progress in metal-catalyzed 1,2-aminohydroxylation of alkenes. (C) Challenge: reaction activity and selectivity. (D) Our work.

However, despite significant progress, these methods generally rely on intramolecular reactions, active reagents (preoxidized nitrogen sources or special oxidants), or directing groups to overcome challenges associated with reactivity and selectivity. Therefore, intermolecular aminohydroxylation of alkenes without using active reagents or directing groups remains challenging because of low reaction activity and complex selectivity issues (Figure C). Based on our previous studies on the difunctionalization of 1,3-dienes, − we envisioned that this intermolecular transformation could be achieved via an allylpalladium intermediate through palladium/copper/oxygen cooperation. Herein, we report an intermolecular selective 1,2-aminohydroxylation of 2,3-disubstituted 1,3-dienes enabled by palladium/copper/oxygen cooperation using a simple nitrogen source, providing a direct synthetic method for β-amino alcohols (Figure D). Notably, for 2,3-dialkyl-substituted 1,3-dienes bearing different alkyl groups, this difunctionalization exhibits alkyl-group recognition, resulting in preferential aminohydroxylation at the less sterically hindered double bond with moderate to good chemoselectivity. We speculate that this aminohydroxylation of dienes proceeds through a rarely reported mechanism, namely through the hydroxylation of the formed π-allyl palladium intermediate.

Using p-toluenesulfonamide 1a as the nitrogen source and 2,3-dimethyl-1,3-butadiene 2a as the model substrate, we initially carried out the reaction under conditions employing Pd­(OAc)2 and oxygen; however, the desired product 3a was not formed (Table , entry 1). Gratifyingly, upon the addition of Cu­(OAc)2 to the reaction system, the desired product was detected, albeit in low yield (entry 2). This observation suggests that copper acetate plays a crucial role in facilitating the reaction. Considering the potential influence of the copper salt counteranion on reactivity, a range of copper salts was systematically evaluated. Gratifyingly, all common Cu­(I) and Cu­(II) salts enabled the reaction to proceed (entries 3–7). With CuBr as the cocatalyst, the desired product was obtained in 74% yield with good selectivity; no products arising from initial hydroxylation, diamination, or 1,4-difunctionalization were observed (entry 7). Subsequent optimization of the CuBr loading revealed that reducing its amount led to diminished yield (entry 8), whereas increasing the amount of CuBr had no significant beneficial effect on the reaction outcome (entry 9). Building on these optimized conditions, we next investigated the effect of the palladium catalyst. Replacing Pd­(OAc)2 with other common palladium salts resulted in diminished reactivity (entries 10–13). Subsequent experiments showed that the reaction did not occur in the absence of either a palladium salt (entry 14) or oxygen (entry 15), indicating that both are essential.

1. Optimization of Reaction Conditions.

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Entry Pd catalyst (10 mol %) Cu catalyst Yield (%)
1 Pd(OAc)2 - ND
2 Pd(OAc)2 Cu(OAc)2 (0.2 equiv) 6
3 Pd(OAc)2 CuCl2 (0.2 equiv) 36
4 Pd(OAc)2 CuBr2 (0.2 equiv) 53
5 Pd(OAc)2 CuI (0.2 equiv) 44
6 Pd(OAc)2 CuCl (0.2 equiv) 42
7 Pd(OAc)2 CuBr (0.2 equiv) 74
8 Pd(OAc)2 CuBr (0.1 equiv) 51
9 Pd(OAc)2 CuBr (0.5 equiv) 70
10 Pd(TFA)2 CuBr (0.2 equiv) 49
11 PdCl2(MeCN)2 CuBr (0.2 equiv) 45
12 PdBr2 CuBr (0.2 equiv) 65
13 Pd(PPh3)4 CuBr (0.2 equiv) 42
14 - CuBr (0.2 equiv) ND
15 Pd(OAc)2 CuBr (0.2 equiv) ND
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a

Reaction conditions: The reaction was carried out with substrate 1a (0.2 mmol, 1.0 equiv) and 2a (0.4 mmol, 2.0 equiv) in MeCN (1.0 mL) under O2 (1 atm, in sealed tube), in the presence of Pd/Cu at 70 °C for 48 h unless otherwise noted.

b

NMR yields. ND indicates not detected.

c

Ar (1 atm).

With the above optimized reaction conditions in hand, we next investigated a series of nitrogen sources and 2,3-disubstituted 1,3-dienes to explore the substrate scope (Table ). First, sulfamides bearing different substituents were examined. When the amine was substituted with p-methylbenzenesulfonyl, m-methylbenzenesulfonyl, o-methylbenzenesulfonyl, p-methoxylbenzenesulfonyl, benzenesulfonyl or methylsulfonyl groups, the reactions generally proceeded well (3a-3f). However, no desired product was found when the amine was substituted with p-hydroxybenzenesulfonyl (3g) and p-aminobenzenesulfonyl (3h). This is likely because these substrates can coordinate to the PdII, thereby reducing the reactivity of the PdII catalyst. For acyl-protectedamines (namely BocNH2 and AcNH2), no desired products were obtained. Next, a series of 2,3-disubstituted 1,3-dienes were investigated. The 1,2-aminohydroxylation proceeded smoothly for dienes bearing alkyl substituents (3i). However, as the steric bulk of the substituent increased, the yield decreased accordingly (3i vs 3a), which can be attributed to steric hindrance. When the substrate was 1,2-dimethylene-cyclohexane, the yield of the desired product (3j) improved, likely because of the relatively weaker steric hindrance associated with the rigid six-membered ring. Next, a series of unsymmetrically alkyl-substituted dienes were examined, and this aminohydroxylation exhibited alkyl recognition, leading to generally moderate to good chemoselectivity regarding which double bond underwent difunctionalization (3k–3q). Notably, the reaction tolerated a range of functional groups, such as terminal double bonds (3m), acetyloxy groups (3n, 3o), and chlorine substituents (3p, 3q), affording moderate yields. We speculate that the chemoselectivity differences among 3n–3q originate from the distinct coordination effects between the catalytic center and the diene substrates bearing different substituents. Interestingly, when the diene was substituted with methyl and phenoxymethyl groups, the chemoselectivity reversed, favoring difunctionalization at the phenoxymethyl-substituted double bond, which can be attributed to the electronic properties of the phenoxymethyl group (4r). However, when the diene was substituted with methyl and phenyl groups, two products were formed in a 1:1 ratio (3s, 4s), likely due to the electronic effect of the phenyl group. Unfortunately, isoprene was unreactive under the standard conditions (3t); other 1,3-dienes (namely 1,3-pentadiene, 3-methyl-1,3-pentadiene and 2,3-diphenyl-1,3-diene) also failed to react.

2. Substrate Scopec .

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graphic file with name pc6c00059_0006.webp

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a

The chemoselectivity of difunctionalization (which double bond is functionalized) was determined by the 1H NMR ratio of the mixture.

b

Isolated total yield.

c

Unless otherwise noted, the reactions were carried out using amine substrate 1 (0.2 mmol, 1.0 equiv), diene substrate 2 (0.4 mmol, 2.0 equiv), Pd­(OAc)2 (10 mol %), CuBr (0.2 equiv) in MeCN (1.0 mL) at 70 °C for 48 h, under 1 atm O2 in sealed tube. Isolated yield of major product.

As shown in Figure A, a gram scale experiment using 1a and 2a was successfully carried out, affording 3a in 56% yield, demonstrating the practicality of this reaction. In addition, product 3a underwent several transformations, as shown in Figure B. Treatment of 3a with 0.35 equiv of triphosgene (BTC) and 3.0 equiv of triethylamine (NEt3), afforded the oxazolone derivative 5 in 94% yield. Subsequent deprotection of 5 with Na/naphthalene provided alkenyl oxazolone derivative 6 in 81% yield (Figure B, a). Oxidation of 3a with 2 mol % K2OsO4·2H2O, 2.0 equiv of 2,6-lutidine and 4.0 equiv of NaIO4 provided the acetyl β-amino alcohol derivative 7 in 92% yield (Figure B, b). Dihydroxylation of 3a with 2 mol % K2OsO4·2H2O and 2.5 equiv of N-methylmorpholine-N-oxide (NMO) gave product 8 in 86% yield with 1.5:1 diastereoselectivity (Figure B, c).

2.

2

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Gram scale experiment and application. (A) Gram scale experiment. (B) Application.

The mechanism of the aminohydroxylation of dienes was studied as shown in Figure . First, control experiments were carried out, and the results indicated that no desired product would be detected in the absence of PdII, CuI, or oxygen (Figure A). These observations suggest that all three components play significant roles in the catalytic cycle, as mentioned in Table . Given that this type of aerobic oxidation typically generates water, − we considered whether the hydroxyl group in the product originates from water. Accordingly, an isotopic labeling experiment was performed as shown in Figure B: under the standard conditions, 1.0 equiv of H2 18O was additionally introduced into the reaction system. As a result, no 18O-labeled product was observed, indicating that the oxygen atom in the hydroxyl group does not originate from H2O present in the system.

3.

3

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Mechanistic studies and proposed mechanism. (A) Control experiment. (B) Isotopic labeling experiment. (C) Proposed mechanism.

Based on the above results and previous studies, − ,− a mechanism for the PdII/CuI catalyzed 1,2-aminohydroxylation of dienes with oxygen is proposed (Figure C). First, PdII coordinates with substrate 2a to form complex Int-1, which then undergoes aminopalladation with 1a to afford the π-allyl PdII intermediate Int-2. − ,− Among the possible subsequent pathways, Path A is considered the most likely. In Path A, π-allyl PdII intermediate Int-2 is oxidized to π-allyl PdIV intermediate Int-3 ,− by the peroxide CuII species A, which is generated from CuI and oxygen. , Intermediate Int-3 then undergoes reductive elimination to form product 3a, , wherein the 2-hydroxylation occurring (rather than 4-hydroxylation) may be related to hydrogen bonding between the NHTs and OH groups in Int-3. The released PdII then coordinates with substrate, thereby entering the next catalytic cycle. Meanwhile, the released CuII is likely converted to CuI via a disproportionation (the generated CuIII is then further reduced to CuI by reagents in the reaction system, such as excess dienes). , In Path B, π-allyl PdII intermediate Int-2 undergoes ligand exchange with [CuIIOH] species B, generated from peroxide CuII species A and a proton, , to give Int-4. Intermediate Int-4 then undergoes reductive elimination to form product 3a. The released Pd0 is oxidized by CuII to regenerate PdII and CuI, thereby continuing the catalytic cycle. If Path B was operative, H2 18O would partially undergo anion exchange with [CuIIOH] species B in the isotopic labeling experiment, leading to incorporation of 18O into the product. This is inconsistent with our experimental results, indicating that Path B is a less probable route. In Path C, Int-2 directly reacts with H2O in the presence of copper salts and oxygen to afford product 3a, or Int-2 first transforms into aziridine intermediate , and then reacts with H2O to give product 3a. However, this is excluded because it is inconsistent with the isotopic labeling results.

In conclusion, we have developed a PdII/CuI-catalyzed 1,2-aminohydroxylation of 2,3-disubstituted 1,3-dienes using a simple nitrogen source and oxygen as oxidant. This methodology generally proceeds smoothly for a series of benzenesulfonyl-substituted amines and a wide range of dienes bearing various important functional groups. Notably, for 2,3-dialkyl-1,3-dienes bearing distinct alkyl groups, this aminohydroxylation exhibits alkyl-group recognition, preferentially occurring at the less hindered double bond with moderate to good chemoselectivity. Mechanistic studies suggest that this aminohydroxylation of dienes proceeds through hydroxylation of a π-allyl palladium intermediate, a pathway that has rarely been reported. The approach provides a direct and powerful route to the synthesis of β-amino alcohols.

Supplementary Material

pc6c00059_si_001.pdf (3.6MB, pdf)

Acknowledgments

We would like to thank Shanghai Municipal Science and Technology Major Project, Research Foundation of Natural Science Foundation of Hunan Province (No. 2023JJ30500), National Natural Science Foundation of China (No. 22471162), Zhengzhou Industrial Technology Research Institute of Shanghai Jiao Tong University (No. ZZHC-2024-001) for financial support. We thank the Instrumental Analysis Center of Shanghai Jiao Tong University for help with NMR, high-resolution mass spectrometry.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/prechem.6c00059.

  • Experimental procedures and characterization data for all reactions and products, including 1H and 13C NMR spectra, HRMS (PDF)

∥.

(X.Y., Y.W.) These authors contributed equally.

The authors declare no competing financial interest.

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