Investigation of reaction conditions

Exploratory investigations towards our envisioned Passerini-type reaction involving boronic acids were conducted with phenylpropyl aldehyde (1a), tertbutyl isocyanide (2a) and 4-methoxyphenyl boronic acid (3a) as test substrates (Table 1). To our delights, simple mixing of the three reactants (1a, 2a, and 3a) without any other additive in DCM furnished the desired α-hydroxyketone product 4a in 60% isolated yield (entry 1). A solvent screen of DCE, MeCN, toluene, MeOH, and THF revealed that the best reaction efficiency was endowed by CHCl₃, whereas using MeOH caused a complete reaction inhibition (entries 1−7). As reaction temperature was decreased to 10 °C, the yield of 4a improved to 68% (entry 8). Binary mixture of CHCl₃ and water in a ratio of 7:3 (entries 9−11) minimally but meaningfully enhanced the delivery of 4a to 72% yield (entry 11). This has guided our subsequent study of mixed solvent system with CHCl₃ against various buffer solutions (entries 12−15) where the combination with pH = 8.0 buffer delightfully provided 81% yield of target product (entry 14). We reasoned that a basic reaction medium could sequester the byproduct B(OH)₃ generated during reaction, thus promoting this boronic acid-involved Passerini-type reaction. It was further established that on replacement of tertbutyl isocyanide (2a) with cyclohexyl isocyanide (2b), benzyl isocyanide (2c), or ethyl 2-isocyanoacetate (2d), formation efficiency of α-hydroxyketone product 4a was diminished (entry 16). None of the other ratios of the three reagents resulted in higher yields (entries 17−18).

Table 1

Optimization of the reaction conditions^a.

Entries	Isocyanide	1a:2:3a	Solvent	Temp. (°C)	Yield (%)b
1	2a	1:1.5:1.8	DCM	rt	60
2	2a	1:1.5:1.8	DCE	rt	55
3	2a	1:1.5:1.8	CHCl3	rt	64
4	2a	1:1.5:1.8	MeCN	rt	50
5	2a	1:1.5:1.8	toluene	rt	48
6	2a	1:1.5:1.8	MeOH	rt	N.R
7	2a	1:1.5:1.8	THF	rt	30
8	2a	1:1.5:1.8	CHCl3	10	68
9	2a	1:1.5:1.8	CHCl3/H2O (3:7)	10	62
10	2a	1:1.5:1.8	CHCl3/H2O (1:1)	10	67
11	2a	1:1.5:1.8	CHCl3/H2O (7:3)	10	72
12	2a	1:1.5:1.8	CHCl3/pH = 6.5 buffer (7:3)	10	66
13	2a	1:1.5:1.8	CHCl3/pH = 7.8 buffer (7:3)	10	74
14	2a	1:1.5:1.8	CHCl3/pH = 8.0 buffer (7:3)	10	81
15	2a	1:1.5:1.8	CHCl3/pH = 9.0 buffer (7:3)	10	79
16	2b/2c/2d	1:1.5:1.8	CHCl3/pH = 8.0 buffer (7:3)	10	55/21/trace
17	2a	1:1:1	CHCl3/pH = 8.0 buffer (7:3)	10	52
18	2a	1:1.2:1.8	CHCl3/pH = 8.0 buffer (7:3)	10	62

Scope of aldehydes

Having optimized the model coupling of this Passerini-type reaction, we examined the generality of these conditions with respect to a range of aldehyde components (Fig. 2). Delightfully, diverse aliphatic aldehydes were aptly transformed in moderate to high yields. Phenylpropyl aldehydes with strong electron-withdrawing groups and 3-(furan-2-yl)propanal furnished the α-hydroxyketone products 4b–4d in 66% to 90% yields. The chain length of aldehydes posed no effect on the effectiveness of this reaction, providing respective α-hydroxyketones (4e–4g) in moderate yields. Primary aldehydes bearing ester, adamantyl, and benzyloxy moieties were tolerated well to yield 4h–4j in moderate efficiencies. Secondary aldehydes comprised of acyclic and cyclic analogs (cyclopropyl, cyclohexyl, piperidinyl) were incorporated in 4k–4q with moderate to good yields as well. The diastereomeric ratios (dr) of compounds 4l and 4n are 1.13:1 and 1.38:1. Comparable outcome was observed for a tertiary 1-phenylcyclobutane-1-carbaldehyde substrate, which afforded 4r in 54% yield. It merits mention that transformation of paraformaldehyde has given rise to 4s, which serves as versatile synthetic intermediate for a variety of bioactive molecules. More importantly, this reaction was well suited to diverse aromatic aldehydes when treated in concert with cyclohexyl isocyanide (2b). The electronic property and the position of substituents on the benzene ring had minimal bearing on the efficiency of this transformation. Neutral (4t), electron-rich (4u–4y), or electron-deficient (4z–4aa) functionalities found good compatibility and were left unscathed in respective molecular outputs. The accommodation of halogen substituents (4ab–4ae) signified potential structural elaborations from these handles. Fused ring reactants including 2-naphthaldehyde (4af) and 1-naphthaldehyde (4ag) were also suitable candidates for this MCR.

Fig. 2

Scope of aldehydes^a.

Reaction conditions: ^aaldehyde 1 (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3a (0.36 mmol), and CHCl₃/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours unless otherwise specified; ^bThe dr was determined by ¹H NMR analysis. ^caldehyde 1 (0.2 mmol, 1 equiv), 2b (0.3 mmol), 3a (0.36 mmol), and DCM/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours.

Scope of boronic acids

This protocol featured an admirable scope with respect to arylboronic acid substrates (Fig. 3). For electron-rich congeners, good reactivities were exhibited. Arylboronic acids with electronically neutral meta-para-dimethyl, para-methyl, and para-tertbutyl substituents produced α-hydroxyketones 5a–5c in moderate yields. Analogs with electron-rich substituents such as acetal, alkoxy, and diphenylamino groups reacted smoothly towards products 5d–5l in 51–85% yields. Inclusion of alkenyl or alkynyl group was noteworthy; from which products 5j and 5k were acquired in 80% and 77% yield. This study was auspiciously and effortlessly extendable to a series of heteroarylboronic acids containing furan (5m), thiophene (5n–5p), benzofuran (5q), benzothiophen (5r), protected or unprotected indoles (5s, 5u), 7-azaindole (5t), dibenzothiophene (5w) and carbazole (5x) cores. Remarkably, both aryl and alkyl substituted alkenylboronic acids could rendered the corresponding α-hydroxy enones 5y and 5z in 82% and 63% yields, which broadly expand the scope of the products. For electron-deficient substituted boronic acids, such as the halobenzene boronic acids, only trace amounts of products could be obtained, which probably is due to their low nucleophilicity that cannot capture the nitrilium intermediates. Aliphatic boronic acids, such as phenethylboronic acid and cyclopentylboronic acid, do not react under our standard conditions, perhaps owing to the lack of π electrons which makes 1,4-alkyl shift difficult⁶⁸.

Fig. 3

Scope of boronic acids^a.

Reaction conditions: ^a1a (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol), and CHCl₃/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours unless otherwise specified. ^b1 (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol), and DCM/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours.

Passerini-type reaction of alkynylboron compounds

α-Hydroxy alkynylketones are important intermediates for the synthesis of natural products and drug molecules^82,83. However, the synthesis of such α-hydroxyketones has faced significant challenges and usually multiple steps are required^82,83. We sought to explore the Passerini-type reaction on alkynylboron compounds, if successful, a straightforward and efficient method could be disclosed for the synthesis of α-hydroxy alkynylketones, which further demonstrates the strengths and capability of our protocol (Fig. 4). Alkynyl trifluoroborate salt was employed as the source of alkyne in our transformation owing to the instability of alkynylboronic acid. To our delight, the Passerini-type reaction of alkynyl trifluoroborate salt could proceed smoothly under the action of Lewis acid (Sc(OTf)₃), and the target products (7a–7d) could be obtained in a moderate yield. This reaction could not occur without Lewis acid (Sc(OTf)₃), probably because a four-coordinated boron “ate” nitrilium intermediate could not be generated from potassium phenyltrifluoroborate, aldehyde, and isocyanide. Lewis acid may promote the conversion of potassium phenyltrifluoroborate (6) into phenyldifluoroborane, which could form a four-coordinated boron intermediate⁸⁴.

Fig. 4

Passerini-type reaction of alkynyl trifluoroborate salt.

Reaction conditions: 1 (0.2 mmol, 1 equiv), 2a (0.5 mmol), 6 (0.6 mmol), and THF (1.5 mL) under an argon atmosphere for 12 hours unless otherwise specified.

Late-stage modifications of complex molecules

The excellent functional group compatibility prompted our endeavors to extrapolate this synthesis scheme to late-stage modification of bioactive or therapeutic agents (Fig. 5). A series of bioactive or drug molecules (Ibuprofen, Naproxen, Ketoprofen, Gemfibrozil, Indometacin, L-Menthol and L-Borneol, and Cholesterol) were derivatized into corresponding aldehydes which, upon treatment with 4-methoxyphenyl boronic acid under established Passerini-type coupling conditions, were smoothly incorporated in eventual α-hydroxyketone derivatives 8a–8h. Futhermore, conversions of arylboronic acids that were derived from drug molecules such as Epiandrosterone and Clofibrate had brought forth drug analogs 8i and 8j in moderate yields. It was thus envisioned that this method would simplify access to discover other bioactive molecules. The previous MCRs involving isocyanide exhibit poor stereoselectivity. This Passerini-type reaction of boronic acids showed similar results in terms of stereochemical control. In most cases (4l, 4n, 8a–8c, and 8f–8i), the dr values remained between 1:1 and 2.5:1 (see the Supplementary Information for details).

Fig. 5

Late-stage modifications of bioactive or drug molecules.

Reaction conditions: ^a1a (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol), and CHCl₃/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours unless otherwise specified. ^bThe dr was determined by ¹H NMR analysis. ^c1 (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol) and DCM/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours. ^dThe dr was determined by HPLC analysis.

Gram-scale synthesis and synthetic applications

The practical constraint of this Passerini-type MCR with boronic acids was next evaluated through translation to gram-scale synthesis. As shown in Fig. 6a, reaction efficiencies were preserved on 2 gram-scale (10 mmol, 50 times), thus implying the application potential for industrial production of the α-hydroxyketones.

Fig. 6

Gram-scale synthesis and synthetic applications.

a Gram-scale synthesis. b Transformations of α-hydroxyketones. c Synthesis of Harmandianone. d Syntheis of α-acyloxy lactone. e Synthesis of α, β-unsaturated lactone.

The readiness of α-hydroxyketone products for chemical manipulations was pronounced in production of 1,2-diol (9), 1,2-dione (10), quinoxaline (11), cyclic sulfamate imine (12), and poly-substituted oxazole (13) (Fig. 6b). The innate step economy of MCRs has also presented an abbreviated route towards (±) Harmandianone, a phenylpropanoid derivative isolated from Clausena Harmandiana fruits⁸⁵, from simple building blocks (Fig. 6c). Of further significance, products could be precursors for entities that constitute the structural core of bioactive compounds such as α-acyloxy lactone and α,β-unsaturated lactone. The former (19) was fabricated upon lactonization of α-hydroxyketone 18 formed from methyl 4-oxobutanoate (17) (Fig. 6d). A two-step olefination and ring-closing olefin metathesis of 4a afforded α,β-unsaturated lactone product (±) 22 (Fig. 6e). The high diastereoselectivity of compound 20 may originate from the chelation of hydroxyl, carbonyl oxygen, and magnesium⁸⁶.

In conclusion, we have realized the application of boronic acid as carbon nucleophiles in the manifold of Passerini reaction. Accordingly, this protocol provided simplified modular access of α-hydroxyketones from aldehydes, isocyanide, and boronic acids. The functional group tolerance of this chemistry has supported late-stage diversifications of bioactive products and pharmaceuticals through this three-component coupling reaction. The wealth of follow-up chemical conversions that could be performed on procured α-hydroxyketones has additionally illustrated the utility of this method.

General procedure A for the synthesis of α-hydroxyketones from alkylaldehydes

In air, a 10 mL schlenk tube was charged with arylboronic acids (0.36 mmol, 1.8 equiv). The tube was evacuated and filled with argon for three cycles. Then, chloroform (0.7 mL), pH = 8 buffer (0.3 mL), alkylaldehydes (0.20 mmol, 1 equiv), tertbutyl isocyanide (34 μl, 0.30 mmol, 1.5 equiv) were added under argon. The reaction was allowed to stir at corresponding temperature for 24 hours. Upon completion, proper amount of silica gel was added to the reaction mixture. After removal of the solvent, the crude reaction mixture was purified on silica gel (petroleum ether and ethyl acetate) to afford the desired products.

General procedure B for the synthesis of α-hydroxyketones from arylaldehydes

In air, a 10 mL schlenk tube was charged with arylboronic acids (0.36 mmol, 1.8 equiv). The tube was evacuated and filled with argon for three cycles. Then, dichloromethane (0.7 mL), pH = 8 buffer (0.3 mL), arylaldehydes (0.20 mmol, 1 equiv), cyclohexyl isocyanide (37 μl, 0.30 mmol, 1.5 equiv) were added under argon. The reaction was allowed to stir at room temperature for 24 hours. Upon completion, proper amount of silica gel was added to the reaction mixture. After removal of the solvent, the crude reaction mixture was purified on silica gel (petroleum ether and ethyl acetate) to afford the desired products.

General procedure C for the synthesis of α-hydroxyketones from alkynyl trifluoroborate salt

In air, a 10 mL schlenk tube was charged with alkynyl trifluoroborate salt (0.60 mmol, 3 equiv) and Sc(OTf)₃ (30.0 mg, 0.06 mmol, 0.3 equiv). The tube was evacuated and filled with argon for three cycles. Then, THF (1.5 mL), aldehydes (0.20 mmol, 1 equiv), and tertbutyl isocyanide (57 μl, 0.50 mmol, 2.5 equiv) were added under argon. The reaction was allowed to stir at room temperature for 12 hours. Upon completion, proper amount of silica gel was added to the reaction mixture. After removal of the solvent, the crude reaction mixture was purified on silica gel (petroleum ether and ethyl acetate) to afford the desired products.