One-pot Decarbonylative Borylation of Aliphatic Aldehydes

中文 / Bilingual · English version

Chang Lian, Jianning Zhang, Lei Zhang, and Fanyang Mo*

Cite This: J. Org. Chem. 2025, 90, 3841-3847

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ABSTRACT: We present a mild and direct method for the radical borylation of simple aliphatic aldehydes. By employing an enamine and a photocatalyst under light irradiation, aldehydes can be transformed effectively into alkyl boronic esters via a formal decarbonylative process. This alternative route for radical borylation synthesis can not only be applied to the transformation of primary, secondary, and tertiary aldehydes but also be adapted to other radical conversion reactions through the generated alkyl radical intermediate. Mechanistic studies indicate that 4-alkyl-1,4-dihydropyr-idines, formed in situ from the aldehyde and enamine, are the key intermediate for the borylation process.

This work: photo-induced decarbonylation borylation of aldehyde

INTRODUCTION

Alkyl boronic esters, as valuable organic building blocks with significant potential in medicinal chemistry, have broad applications in organic synthesis and drug discovery. ${}^{1 - 7}$ The development of synthetic methodologies for alkyl boronic esters has attracted widespread interest from academic and industrial communities. ${}^{8 - {12}}$ Conventional borylation methods are often constrained by harsh reaction conditions and the use of potentially hazardous reagents. ${}^{{13},{14}}$ In recent years, various innovative borylation strategies have been reported, such as the direct borylation of olefins. ${}^{{15},{16}}$ Among these, the alkyl radical borylation has emerged as a transformative approach characterized by its mild reaction temperature and unique reactivity, serving as an important alternative to traditional methods and transition-metal-catalyzed methods. ${}^{{17} - {32}}$ Various alkyl radical precursors, including NHPI esters, ${}^{8,{17}}$ Katritzky salts, ${}^{{18},{20}}$ and alkyl halides, ${}^{{24},{25},{29}}$ have been harnessed to achieve facile borylation (Scheme 1a) in virtue of their smooth single electron transfer (SET) processes and the stability of the intermediates generated from leaving groups. Unactivated carboxylic acids, alcohols, ketones, and aldehydes are inexpensive and readily available organic feedstocks. However, their direct radical borylation remains elusive, with few reports. MacMillan ${}^{33}$ and Liu groups ${}^{34}$ developed efficient radical borylation of unactivated carboxylic acids through innovative photochemical catalytic cycles. Lin group reported versatile deoxygenative borylation of unactivated alcohols, ketones, and aldehydes through special intermediates in an electrochemical methods. ${}^{35}$ Based on their mechanistic studies, the formation of final benzyl boronic esters relies on the attack of the benzyl anion to HBpin. Despite these advances, a general method for the radical borylation of unactivated aldehydes via common alkyl radicals reacting with boron reagents remains unexplored.

Aliphatic aldehydes are abundant in natural products, and their radical transformations have garnered increasing attention. The C-H functionalization of aldehydes via a radical pathway can construct new C-C(O) bonds efficiently. ${}^{{36} - {39}}$ Another noteworthy reaction type of aldehydes is radical decarbonylation, which can access general C-C bonds. The decarbonylation coupling of aldehydes employing transition-metal catalysts is prevalent with numerous remarkable reports, ${}^{{40} - {46}}$ while its radical transformation is deficient. The radical decarbonylation reactions typically use radical initiators to activate the aldehyde $\mathrm{C}\left( \mathrm{O}\right) - \mathrm{H}$ bond, produce carbonyl radicals, convert to alkyl radicals via decarbonylation, and construct C-C bonds. ${}^{{47} - {49}}$ However, these processes require harsh reaction conditions, such as high temperatures and the use of peroxide compounds, which limit the transformation scopes (Scheme 1b). ${}^{{47},{48}}$ Deng group reported bromo radical-mediated photoredox aldehyde decarbonylation in the water-soluble solvent, realizing the functionalization of special activated alkenes in mild reaction conditions. ${}^{49}$ The general radical approach to realize (formally) decarbonylation of aldehydes is still challenging to be compatible with borylation.

In this study, we devise a new strategy to achieve direct radical borylation of simple aliphatic aldehydes. The approach involves the addition of an enamine, which reacts with aliphatic aldehydes to form 4-alkyl-1,4-dihydropyridines in situ. This 4- alkyl-1,4-DHPs is subsequently oxidized by a photocatalyst, generating alkyl radicals that then react with diboron reagents to produce alkyl boronic esters. Despite its potential, this strategy presents several challenges, including: (1) the

Received: November 2, 2024

Revised: February 10, 2025

Accepted: March 3, 2025

Published: March 11, 2025

Scheme 1. (a) Alkyl Borylation via a Radical Process; (b) Limitations of Traditional Decarbonylation of Aldehyde. This Work: Direct Photocatalyzed Decarbonylation Borylation of Aldehydes difficulty in synchronizing the formation of 4-alkyl-1,4-DHPs with the photocatalytic cycle, requiring the aldehyde and enamines to be added before the photocatalyst in the reaction system; (2) the presence of a free amine group and the high equivalent of enamine, which complicate isolation of borylation products. Nevertheless, the devised strategy is achieved with a broad scope of primary, secondary, and tertiary aldehydes. Furthermore, the generated alkyl radical from simple aldehydes can also be applied to Minisci and halogenation reactions, demonstrating the versatility of the approach.

II RESULTS AND DISCUSSION

We initially selected cyclohexanecarboxaldehyde (1a) as the substrate for borylation with bis(catecholato)diboron $\left( {{\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}}\right)$ under blue LED illumination at room temperature. After numerous screenings, hexamethylphosphoramide (HMPA) was chosen as the solvent, and ethyl 3-aminocrotonate (3a) was added as an additive. The desired borylation product 2a was obtained in 81% GC-FID yield and 73% isolated yield in the presence of the fac-Ir(ppy) ${}_{3}$ photocatalyst (Table 1, entry 1). Other solvents, such as DMF, performed worse than HMPA (entry 2). Attempts to lower the concentration of the reaction system (entry 3) or reduce the amounts of ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ or 3a resulted in lower yields (entries 4 and 5). The use of different boron reagents, such as bis(pinacolato)diboron $\left( {{\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}}\right)$ , did not yield the desired product (entry 6). Iridium catalysts, fac-Ir(ppy), demonstrated superior efficiency compared to other metal or organic photocatalysts (entries 7 and 8). The photoinduced reaction displayed sensitivity to LED wavelengths as changing the wavelength to ${390}\mathrm{\;{nm}}$ from ${467}\mathrm{\;{nm}}$ reduced the yield to 67% (entry 9). Both iridium catalysts and visible light were found to be indispensable for the reaction as no borylation product was formed in the absence of either (entries 10 and 11). Furthermore, the presence of the compound ${\mathrm{O}}_{2}$ was found to be detrimental to the borylation process (entry 12).

Table 1. Optimization of Reaction Conditions ${}^{a}$

${}^{a}$ Standard conditions: cyclohexanecarboxaldehyde 1a (0.3 mmol,1.0 equiv), ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ (1.2 mmol,4.0 equiv), ethyl 3-aminocrotonate (3a,2.4 mmol, 8 equiv), and fac-Ir(ppy) (1 mol %) in HMPA (0.2 M, 1.5 mL), Kessil 467 nm LED lamp, ${\mathrm{N}}_{2}$ atmosphere, room temperature,12 h; then pinacol (2.4 mmol, 8 equiv), NEt ${}_{3}$ (1 mL), 1 h. ${}^{b}$ GC-FID yields were given using $n$ -decane as an internal standard.

Subsequently, we explored the substrate scope by utilizing the optimized conditions (Scheme 2). The reaction exhibited excellent tolerance toward primary aldehydes, allowing for the conversion of long-chain aliphatic aldehydes into the desired formally decarbonylated boronic esters with medium to high yields (2b-2h). Most naturally occurring straight-chain alkyl carboxylic acids in living organisms predominantly consist of an even number of carbon atoms, serving as precursors for the synthesis of various even-carbon aliphatic aldehydes. Through the formal decarbonylation process we developed, the common even-carbon aliphatic aldehydes can be transformed into boronic esters with an odd number of carbon atoms. It demonstrates that the method has potential applications in carbon skeleton construction from synthesized odd-number-carbon aldehydes. Notably, substrates containing unsaturated groups are hard to tolerate diboron reagents because of the formation of 1,2-diboron compounds according to previous reports. ${}^{50}$ Although the yield for product (2i) is diminished, the olefin group can be tolerated, with the $\mathrm{C} = \mathrm{C}$ bond retained. Furthermore, primary aldehydes containing benzene rings were compatible, as were alkyl-, halogen-, and tri- (uoromethyl)substituted benzene rings (2j-2m).

Secondary aldehydes were also tested for the borylation methods, producing the desired borylated products in good yields (2a, 2n-2s). Aliphatic ring aldehydes (2a, 2n-2t) and heterocyclic ring aldehydes (2p, 2q) were well-tolerated in the reaction, showcasing potential applications in the functional-ization of heteroatom rings in pharmaceutical chemistry. Additionally, secondary chain aldehydes proved to be effective substrates in this transformation (2r, 2s).

Scheme 2. Scope Explorations of the Borylation Reaction ${}^{a}$

${}^{a}$ Reaction conditions: aldehyde 1 (0.3 mmol,1.0 equiv), ${\mathrm{B}}_{2}{\text{ cat }}_{2}$ (1.2 mmol,4.0 equiv), ethyl 3-aminocrotonate (3a,2.4 mmol,8 equiv), and fac-Ir(ppy) ${}_{3}$ (1 mol %) in HMPA (0.2 M,1.5 mL), Kessil 467 nm LED lamp, ${\mathrm{N}}_{2}$ atmosphere, room temperature,12 h.

The reactivity of tertiary aldehydes was less favorable, probably due to steric hindrance, yielding lower product yields (2t). A dialdehyde was synthesized through the oxidation of glycol, and it can be converted to a previously unexplored diboron product (2u) that can be utilized in constructing building blocks with the special loop skeleton.

Natural aldehydes are ideal synthetic building blocks because of their diverse and intricate structures. We also attempted several commercially available natural aldehydes (2v-2aa) as substrates, resulting in good yields. It suggested that the methodology provided a viable route to synthesize boronic esters that may be challenging to access through other synthetic procedures.

Previously, we have developed the borylation of Hantzsch esters which was presynthesized from aldehydes. ${}^{27}$ This new method has many advantages compared with the previous one, including: (1) most Hantzsch esters are not commercially available, while aldehydes are commercially available and cheap; (2) the direct borylation can shorten the reaction steps and avoid the heating for Hantzsch esters synthesis as well as its separation; (3) although primary alkyl radical is reactive and hard to harness, we extended the primary aldehyde scope and improved the boronic ester yields. In further validating the

Scheme 3. (a) Gram-Scale Reaction; (b) Application of Synthesis Method in the Minisci Reaction; and (c) Application of Synthesis Method in the Halogenation Reaction utility of this strategy, we successfully conducted a gram-scale synthesis of 2a and obtained a satisfactory yield (Scheme 3a). To our surprise, the application of this synthesis strategy can also be successfully extended to other alkyl radical reactions, facilitating the construction of various $\mathrm{C} - \mathrm{C}$ and $\mathrm{C} - \mathrm{X}$ bonds.

For the $\mathrm{C} - \mathrm{C}$ bond construction, aldehyde $1\mathbf{w}$ can react with 4-methylquinoline to form a Minisci reaction product in a good yield (Scheme 3b). The reaction conditions were slightly modified based on the optimized conditions, using trifluoro-acetic acid (TFA) as the additive and ethanol as the solvent. For the C-X bond construction, the bromination and chlorination of aliphatic aldehydes were achieved, respectively, under mild reaction conditions with $p$ -toluene sulfonyl bromide and benzene sulfonyl chloride as halogenation agents (Scheme 3c). The success of these versatile transformations illustrates the presence of the key alkyl radical intermediate during reaction processes and the practicability of employing aldehydes as general radical precursors.

Scheme 4. (a) Radical Trap Experiment and (b) UV-Vis Spectra

Scheme 5. (a) Analysis of ${}^{1}\mathrm{H}$ NMR Spectroscopy and (b) Borylation of Hantzsch Ester

a) Analysis of ${}^{1}\mathrm{H}$ NMR spectroscopy

Scheme 6. :Plausible Mechanism

In order to verify our proposal for the reaction pathway and conduct mechanistic studies, a series of reactions were designed. To further validate the radical mechanism, TEMPO, a widely used radical scavenger, was added to the reaction mixture, resulting in no desired borylation product but TEMPO trapped product (Scheme 4a). It demonstrated that the alkyl radical was indeed generated in the reaction process. In addition, the light on-off experiment and a series of control experiments with various reagents were designed to help us understand the critical factors influencing the achievement of aliphatic aldehyde borylation (Scheme S1 and S2). The experimental result indicated that visible light and the combination of aldehydes and enamine 3a were indispensable for this radical reaction.

A notable phenomenon was observed during stirring of the aldehyde and enamine mixture. When enamine 3a and aliphatic aldehydes were added to the reaction system and stirred for a few minutes, the color of the mixture transformed into yellow gradually. The UV-vis spectra of different mixtures were measured to explore the color change and possible reaction mechanism (Scheme 4b). Aldehyde 1a and ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ did not exhibit distinct absorption peaks in the UV or visible light regions, whereas enamine 3a had a UV absorption peak below 310 nm. When 1a and 3a were combined, a red-shift occurred, moving 3a’s absorption peak to around ${320}\mathrm{\;{nm}}$ . This phenomenon explained the observed change in color in the reaction mixture. On the other hand, adding ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ to the mixture of 1a and 3a resulted in a significant UV absorption. We also measured the aldehyde conversion along a reagent-adding stepwise process using GC-FID (Scheme S3), which showed that the aldehyde was consumed prominently after the addition of ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ . These results suggest that optically active intermediates may form after the addition of ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ .

To investigate the reaction intermediates, 1a and 3a were added to a reaction tube and stirred in HMPA for ${12}\mathrm{\;h}$ . The crude reaction mixture was then analyzed by ${}^{1}\mathrm{H}$ NMR spectroscopy, and characteristic peaks of the corresponding Hantzsch ester were identified instead of those of Stork enamine (Scheme 5a). To prove that the Hantzsch ester was indeed the intermediate during the transformation, the 4- heptane-substituted Hantzsch ester was synthesized. It was treated with the above optimized borylation conditions instead of the addition of the aldehyde, resulting in a 55% GC-FID yield (Scheme 5b). In comparison, the direct borylation of aliphatic aldehyde 1b produced 2b in a 58% yield under the same conditions. The similar yields of these two reactions suggested the possibility of in situ formation of Hantzsch esters, followed by further borylation.

Based on mechanistic studies, we proposed that 1a and 3a could form a Hantzsch ester intermediate in situ. The intermediate was oxidized by Ir(III)*, generating an alkyl radical. The formed alkyl radical is readily captured by the additive ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ and the aprotic polar solvent HMPA to generate the desired boronate. The mechanism of converting alkyl radicals to boronates has been widely illustrated in previous studies. ${}^{{18},{27},{51}}$ Additionally, DHP cationic species 8 could serve as an electron acceptor to regenerate Ir(III), thereby completing the catalytic cycle. A DFT calculation was also performed to verify the reliability of the key alkyl radical formation processes. The results confirmed that the single-electron oxidation of Hantzsch ester 7 to generate the radical cation intermediate ${7}^{ + }$ , followed by the cleavage of the $\mathrm{C} - \mathrm{C}$ bond to form the alkyl radical and the DHP cationic species 8, were both thermodynamically favorable (Scheme 6). However, it is worth noting that this mechanism differs somewhat from those proposed for the transformation of many classic Hantzsch esters, and we carefully considered these possibilities. For instance, 4-substituted Hantzsch esters can be oxidized by excited photocatalysts, leading to the formation of pyridine ring products and alkyl radicals via proton loss. ${}^{52}$ In our previous work, while we were able to isolate pyridine ring products during subsequent separations, our in situ NMR experiments did not detect characteristic peaks corresponding to the pyridine ring product. ${}^{27}$

Additionally, since ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ is a reducing reagent, it is important to consider what species could serve as the oxidant in this mechanism to complete the catalytic cycle. Some reports suggest that Hantzsch esters can directly absorb light and undergo excitation, leading to radical formation. ${}^{53}$ However, this mechanism still requires clarification regarding the role of the photocatalyst. These individual mechanistic pathways present certain challenges that require further investigation. We believe that the actual transformation is likely a highly complex process, and we look forward to uncovering intriguing aspects of this chemistry in future studies.

CONCLUSIONS

In conclusion, we have developed a mild method for the decarbonylation of aliphatic aldehydes utilizing an enamine and an Ir photocatalyst. This method can tolerate primary, secondary, and tertiary aldehydes as well as natural aldehydes. Additionally, the alkyl radicals generated from aldehydes can also be harnessed to the Minisci reaction and halogenation. Mechanistic investigations reveal that the Hantzsch ester intermediate, formed through the interaction of the aldehyde and enamine, plays a pivotal role in promoting decarbonylation. This method provides an efficient approach for utilizing unactivated aldehydes via a radical mechanism, offering a promising pathway for synthesizing diverse compounds from simple and inexpensive aldehydes.

A ASSOCIATED CONTENT

Data Availability Statement

The data underlying this study are available in the published article and Supporting Information.

(c) Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c02705.

General experimental methods, ${}^{1}\mathrm{H}$ NMR spectra, ${}^{13}\mathrm{C}$ NMR spectra, DFT calculation results, and additional discussion (PDF)

A UTHOR INFORMATION

Corresponding Author

Fanyang Mo - School of Materials Science and Engineering, Peking University, Beijing 100871, P. R. China; © orcid.org/0000-0002-4140-3020; Phone: +86-10- 82529331;

Authors

Chang Lian - Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, P. R. China

Jianning Zhang - Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, P. R. China

Lei Zhang - Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, P. R. China; (c) orcid.org/0000-0001-9031-4318

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.4c02705

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

We are grateful for the financial support from the National Natural Science Foundation of China (grant no. 22071004, 21933001, and 22150013). We are also grateful for the High Performance Computing Platform of Peking University and the Shenzhen Cloud Computing Center for DFT calculations support.

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