Abstract
Multicomponent reactions (MCRs) facilitate the rapid and diverse construction of molecular scaffolds with modularity and step economy. In this work, engagement of boronic acids as carbon nucleophiles culminates in a Passerini-type three-component coupling reaction towards the synthesis of an expanded inventory of α-hydroxyketones with skeletal diversity. In addition to the appealing features of MCRs, this protocol portrays good functional group tolerance, broad substrate scope under mild conditions and operational simplicity. The utility of this chemistry is further demonstrated by amenable modifications of bioactive products and pharmaceuticals as well as in the functionalization of products to useful compounds.
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Introduction
α-Hydroxyketones (also known as acyloins) are structural units ubiquitously found in natural products1,2,3,4,5 and pharmaceuticals6,7. They are also oft-employed synthetic precursors in a panel of high-value transformations (Fig. 1a)8,9,10,11,12,13. The construction of these important molecules is therefore the subject of substantial synthetic efforts14. Traditional benzoin condensation method assembles α-hydroxyketones via condensation of different aldehydes, thus limits its applicability within this substrate class15,16,17. The alternate oxidative pathways that encompass α-hydroxylation of ketones18,19,20,21,22 and ketohydroxylation of olefins23,24,25,26,27 are certainly enabling, but continues to be challenged in terms of substrate diversity and poor selectivity. Hence, devising complementary routes towards these useful entities from readily available starting materials is highly relevant and desirable.
a α-Hydroxyketones in bioactive moleculars or as synthetic precursors. b Classic Passerini or Ugi reaction. c Petasis boronic acid-Mannich reaction. d Passerini-type coupling reaction of boronic acids (this work).
Multicomponent reactions (MCRs) are often prized for their concise and modular features in forging complex molecules with synthetic and biological interest28,29,30,31,32,33,34,35,36. The representative Passerini reaction37,38,39,40,41,42,43,44,45,46 or Ugi reaction47,48,49,50,51,52,53,54 efficiently assembles α-acyloxyamides or α-acylaminoamides from several reactant components via the intermediacy of nitrilium species in single-pot operation (Fig. 1b)55,56,57,58. Interception of this electrophilic intermediate in Passerini reaction pathway by carbon nucleophiles (in place of conventionally used carboxylic acids) would offer an intriguing access to α-hydroxyketone products; yet such synthetic maneuver remains underexplored59,60. Central to the successful establishment of this chemistry would lie in choosing suitable carbon nucleophiles that would not interfere with the formation of the nitrilium intermediate while possess sufficient nucleophilicity to capture this electrophile.
On the other hand, boronic acids are easily available, benign and common building blocks for C-C bond cross-coupling reactions, in both transition-metal catalysis61,62 and metal-free catalysis regimes63,64,65,66,67,68,69,70,71,72,73,74,75. In boronic acid-Mannich reaction (or Petasis reaction), for instance, the nucleophilic feature of boronic acids effects the formation of boron “ate” complex, leading to functionalized amines following 1,3-metallate migration (Fig. 1c)76,77,78,79,80. To this end, a recent endeavor of our group has unraveled a 1,4-metallate shift of boron “ate” nitrilium species generated from nitrile oxide and arylboronic acid, thus mediating stereospecific formation of C-C bond between oxime chlorides and arylboronic acids under metal-free conditions81. Grounded in these knowledges, we envisioned that a boron “ate” nitrilium intermediate could be released from co-treatment of aldehyde, isocyanide, and boronic acid; 1,4-metallate shift of which will invoke C-C bond coupling and α-hydroxyketones could be revealed on hydrolysis (Fig. 1d). Here, we disclose the development of a Passerini-type coupling reaction, which afforded α-hydroxyketones from the combination of readily available aldehydes, isocyanides, and boronic acids (aryl, alkenylboronic acids, and alkynyl trifluoroborate salts) under transition-metal-free conditions. Mild reaction conditions, ease of execution, high functional group tolerance, broad substrate scope, and utility are practical features of this methodology.
Results
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).
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.
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.
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 molecules82,83. However, the synthesis of such α-hydroxyketones has faced significant challenges and usually multiple steps are required82,83. 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.
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).
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.
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.
Methods
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.
Data availability
The data supporting the finding of this study are available within the paper and its Supplementary Information.
References
Escandón-Rivera, S. et al. α-Glucosidase inhibitors from Brickellia cavanillesii. J. Nat. Prod. 75, 968–974 (2012).
Fukuda, T., Matsumoto, A., Takahashi, Y., Tomoda, H. & Ōmura, S. Phenatic acids A and B, new potentiators of antifungal miconazole activity produced by Streptomyces sp. K03-0132. J. Antibiot. 58, 252–259 (2005).
Miles, Z. D. et al. A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis. Nat. Chem. 9, 1235–1242 (2017).
Roush, W. R., Briner, K., Kesler, B. S., Murphy, M. & Gustin, D. J. Studies on the synthesis of aureolic acid antibiotics: acyloin glycosidation studies. J. Org. Chem. 61, 6098–6099 (1996).
Wee, J. L., Sundermann, K., Licari, P. & Galazzo, J. Cytotoxic hypothemycin analogues from Hypomyces subiculosus. J. Nat. Prod. 69, 1456–1459 (2006).
Tanaka, T., Kawase, M. & Tani, S. α-Hydroxyketones as inhibitors of urease. Bioorg. Med. Chem. 12, 501–505 (2004).
Wallace, O. B., Smith, D. W., Deshpande, M. S., Polson, C. & Felsenstein, K. M. Inhibitors of Aβ production: solid-phase synthesis and SAR of α-hydroxycarbonyl derivatives. Bioorg. Med. Chem. Lett. 13, 1203–1206 (2003).
Palomo, C., Oiarbide, M. & García, J. M. α-Hydroxy ketones as useful templates in asymmetric reactions. Chem. Soc. Rev. 41, 4150–4164 (2012).
Ghiringhelli, F., Nattmann, L., Bognar, S. & van Gemmeren, M. The direct conversion of α-hydroxyketones to alkynes. J. Org. Chem. 84, 983–993 (2019).
Kang, S., Han, J., Lee, E. S., Choi, E. B. & Lee, H.-K. Enantioselective synthesis of cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation. Org. Lett. 12, 4184–4187 (2010).
Li, G. et al. Investigation and application of amphoteric α-amino aldehyde: an in situ generated species based on Heyns rearrangement. Org. Lett. 18, 4526–4529 (2016).
Liu, W., Chen, C. & Zhou, P. N,N-dimethylformamide (DMF) as a source of oxygen to access α-hydroxy arones via the α-hydroxylation of arones. J. Org. Chem. 82, 2219–2222 (2017).
Ooi, T., Uraguchi, D., Morikawa, J. & Maruoka, K. Unique synthetic utility of BF3·OEt2 in the highly diastereoselective reduction of hydroxy carbonyl and dicarbonyl substrates. Org. Lett. 2, 2015–2017 (2000).
Hoyos, P., Sinisterra, J.-V., Molinari, F., Alcántara, A. R. & Domínguez de María, P. Biocatalytic Strategies for the asymmetric synthesis of α-hydroxy ketones. Acc. Chem. Res. 43, 288–299 (2010).
Lapworth, A. J. Reactions involving the addition of hydrogen cyanide to carbon compounds. J. Chem. Soc. 83, 995 (1903).
Lapworth, A. J. Reactions involving the addition of hydrogen cyanide to carbon compounds. Part II. cyanohydrins regarded as complex acids. J. Chem. Soc. 85, 1206–1215 (1903).
Staudinger, H. The autooxidation of organic compounds: connection between autooxidation and benzoin formation. Ber. Dtsch. Chem. Ges. 46, 3535–3538 (1913).
Adam, W., Lazarus, M., Saha-Möller, C. R. & Schreier, P. Biocatalytic synthesis of optically active α-oxyfunctionalized carbonyl compounds. Acc. Chem. Res. 32, 837–845 (1999).
Bouma, M. J. & Olofsson, B. In Comprehensive Organic Synthesis II (second edition) (ed Paul Knochel) 213–241 (Elsevier, 2014).
Davis, F. A. & Chen, B. C. Asymmetric hydroxylation of enolates with N-sulfonyloxaziridines. Chem. Rev. 92, 919–934 (1992).
Chuang, G. J., Wang, W., Lee, E. & Ritter, T. A dinuclear palladium catalyst for α-hydroxylation of carbonyls with O2. J. Am. Chem. Soc. 133, 1760–1762 (2011).
Liang, Y.-F. et al. I2- or NBS-catalyzed highly efficient α-hydroxylation of ketones with dimethyl sulfoxide. Org. Lett. 17, 876–879 (2015).
Plietker, B. New oxidative pathways for the synthesis of α-hydroxy ketones—the α-hydroxylation and ketohydroxylation. Tetrahedron 16, 3453–3459 (2005).
Plietker, B. The RuO4-catalyzed ketohydroxylation. part 1. development, scope, and limitation. J. Org. Chem. 69, 8287–8296 (2004).
Huang, J. et al. Dual role of H2O2 in palladium-catalyzed dioxygenation of terminal alkenes. Org. Lett. 19, 3354–3357 (2017).
Plietker, B. RuO4-catalyzed ketohydroxylation of olefins. J. Org. Chem. 68, 7123–7125 (2003).
Wu, X., Gao, Q., Lian, M., Liu, S. & Wu, A. Direct synthesis of α-hydroxyacetophenones through molecular iodine activation of carbon–carbon double bonds. RSC Adv. 4, 51180–51183 (2014).
de Graaff, C., Ruijter, E. & Orru, R. V. A. Recent developments in asymmetric multicomponent reactions. Chem. Soc. Rev. 41, 3969–4009 (2012).
Dömling, A. Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem. Rev. 106, 17–89 (2006).
Dömling, A. & Ugi, I. Multicomponent reactions with isocyanides. Angew. Chem. Int. Ed. 39, 3168–3210 (2000).
Dömling, A., Wang, W. & Wang, K. Chemistry and biology of multicomponent reactions. Chem. Rev. 112, 3083–3135 (2012).
Nair, V. et al. Strategies for heterocyclic construction via novel multicomponent reactions based on isocyanides and nucleophilic carbenes. Acc. Chem. Res. 36, 899–907 (2003).
Touré, B. B. & Hall, D. G. Natural product synthesis using multicomponent reaction strategies. Chem. Rev. 109, 4439–4486 (2009).
Wessjohann, L. A., Rivera, D. G. & Vercillo, O. E. Multiple multicomponent macrocyclizations (MiBs): a strategic development toward macrocycle diversity. Chem. Rev. 109, 796–814 (2009).
Wille, U. Radical cascades initiated by intermolecular radical addition to alkynes and related triple bond systems. Chem. Rev. 113, 813–853 (2013).
Wang, Q., Wang, D.-X., Wang, M.-X. & Zhu, J. Still unconquered: enantioselective Passerini and Ugi multicomponent reactions. Acc. Chem. Res. 51, 1290–1300 (2018).
Passerini, M. Isonitriles. II. Compounds with aldehydes or with ketones and monobasic organic acids. Gazz. Chim. Ital. 51, 181–189 (1921).
Chandgude, A. L. & Dömling, A. Unconventional Passerini reaction toward α-aminoxy-amides. Org. Lett. 18, 6396–6399 (2016).
Denmark, S. E. & Fan, Y. The first catalytic, asymmetric α-additions of isocyanides. Lewis-base-catalyzed, enantioselective Passerini-type reactions. J. Am. Chem. Soc. 125, 7825–7827 (2003).
Mihara, H., Xu, Y., Shepherd, N. E., Matsunaga, S. & Shibasaki, M. A heterobimetallic ga/yb-schiff base complex for catalytic asymmetric α-addition of isocyanides to aldehydes. J. Am. Chem. Soc. 131, 8384–8385 (2009).
Soeta, T., Matsuzaki, S. & Ukaji, Y. A one-pot o-phosphinative Passerini/Pudovik reaction: efficient synthesis of highly functionalized α-(phosphinyloxy)amide derivatives. Chem. Eur. J. 20, 5007–5012 (2014).
Wang, S., Wang, M.-X., Wang, D.-X. & Zhu, J. Asymmetric Lewis acid catalyzed addition of isocyanides to aldehydes – synthesis of 5-amino-2-(1-hydroxyalkyl)oxazoles. Eur. J. Org. Chem. 2007, 4076–4080 (2007).
Yue, T., Wang, M.-X., Wang, D.-X., Masson, G. & Zhu, J. Catalytic asymmetric Passerini-type reaction: chiral aluminum−organophosphate-catalyzed enantioselective α-addition of isocyanides to aldehydes. J. Org. Chem. 74, 8396–8399 (2009).
Yue, T., Wang, M.-X., Wang, D.-X. & Zhu, J. Asymmetric synthesis of 5-(1-hydroxyalkyl)tetrazoles by catalytic enantioselective Passerini-type reactions. Angew. Chem. Int. Ed. 47, 9454–9457 (2008).
Zeng, X. et al. Chiral Brønsted acid catalyzed enantioselective addition of α-isocyanoacetamides to aldehydes. Org. Lett. 12, 2414–2417 (2010).
Zhang, J., Lin, S.-X., Cheng, D.-J., Liu, X.-Y. & Tan, B. Phosphoric acid-catalyzed asymmetric classic Passerini reaction. J. Am. Chem. Soc. 137, 14039–14042 (2015).
Aknin, K. et al. Squaric acid is a suitable building-block in 4C-Ugi reaction: access to original bivalent compounds. Tetrahedron Lett. 53, 458–461 (2012).
Barthelon, A., El Kaïm, L., Gizolme, M. & Grimaud, L. Thiols in Ugi- and Passerini–Smiles-type couplings. Eur. J. Org. Chem. 2008, 5974–5987 (2008).
Chandgude, A. L. & Dömling, A. N-Hydroxyimide Ugi reaction toward α-hydrazino amides. Org. Lett. 19, 1228–1231 (2017).
El Kaïm, L., Grimaud, L. & Oble, J. Phenol Ugi–Smiles systems: strategies for the multicomponent N-arylation of primary amines with isocyanides, aldehydes, and phenols. Angew. Chem. Int. Ed. 44, 7961–7964 (2005).
Keating, T. A. & Armstrong, R. W. Postcondensation modifications of Ugi four-component condensation products: 1-isocyanocyclohexene as a convertible isocyanide. mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J. Am. Chem. Soc. 118, 2574–2583 (1996).
Oh, J., Kim, N. Y., Chen, H., Palm, N. W. & Crawford, J. M. An Ugi-like biosynthetic pathway encodes bombesin receptor subtype-3 agonists. J. Am. Chem. Soc. 141, 16271–16278 (2019).
Waki, M. & Meienhofer, J. Peptide synthesis using the four-component condensation (Ugi reaction). J. Am. Chem. Soc. 99, 6075–6082 (1977).
Zhang, J. et al. Asymmetric phosphoric acid–catalyzed four-component Ugi reaction. Science 361, eaas8707 (2018).
Baker, R. H. & Stanonis, D. The Passerini reaction. III. stereochemistry and mechanism. J. Am. Chem. Soc. 73, 699–702 (1951).
Chéron, N., Ramozzi, R., Kaïm, L. E., Grimaud, L. & Fleurat-Lessard, P. Challenging 50 years of established views on Ugi reaction: a theoretical approach. J. Org. Chem. 77, 1361–1366 (2012).
Iacobucci, C., Reale, S., Gal, J.-F. & De Angelis, F. Insight into the mechanisms of the multicomponent Ugi and Ugi–Smiles reactions by ESI-MS(/MS). Eur. J. Org. Chem. 2014, 7087–7090 (2014).
Maeda, S., Komagawa, S., Uchiyama, M. & Morokuma, K. Finding reaction pathways for multicomponent reactions: the Passerini reaction is a four-component reaction. Angew. Chem. Int. Ed. 50, 644–649 (2011).
El Kaim, L. & Grimaud, L. Beyond the Ugi reaction: less conventional interactions between isocyanides and iminium species. Tetrahedron 65, 2153–2171 (2009).
Banfi, L. & Riva, R. The Passerini reaction. Org. React. 65, 1 (2005).
Lundgren, R. J. & Stradiotto, M. Addressing challenges in palladium-catalyzed cross-coupling reactions through ligand design. Chem. Eur. J. 18, 9758–9769 (2012).
Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).
Barluenga, J., Tomás-Gamasa, M., Aznar, F. & Valdés, C. Metal-free carbon–carbon bond-forming reductive coupling between boronic acids and tosylhydrazones. Nat. Chem. 1, 494–499 (2009).
Roscales, S. & Csákÿ, A. G. Transition-metal-free C–C bond forming reactions of aryl, alkenyl and alkynylboronic acids and their derivatives. Chem. Soc. Rev. 43, 8215–8225 (2014).
Sun, C.-L. & Shi, Z.-J. Transition-metal-free coupling reactions. Chem. Rev. 114, 9219–9280 (2014).
Zhu, C. & Falck, J. R. Transition metal-free ipso-functionalization of arylboronic acids and derivatives. Adv. Synth. Catal. 356, 2395–2410 (2014).
Greb, A. et al. A versatile route to unstable diazo compounds via oxadiazolines and their use in aryl–alkyl cross-coupling reactions. Angew. Chem. Int. Ed. 56, 16602–16605 (2017).
He, Z., Song, F., Sun, H. & Huang, Y. Transition-metal-free Suzuki-type cross-coupling reaction of benzyl halides and boronic acids via 1,2-metalate shift. J. Am. Chem. Soc. 140, 2693–2699 (2018).
Huang, H. et al. Synthesis of aldehydes by organocatalytic formylation reactions of boronic acids with glyoxylic acid. Angew. Chem. Int. Ed. 56, 8201–8205 (2017).
Li, C. et al. Transition-metal-free stereospecific cross-coupling with alkenylboronic acids as nucleophiles. J. Am. Chem. Soc. 138, 10774–10777 (2016).
Peng, C., Zhang, W., Yan, G. & Wang, J. Arylation and vinylation of α-diazocarbonyl compounds with boroxines. Org. Lett. 11, 1667–1670 (2009).
Pérez-Aguilar, M. C. & Valdés, C. Olefination of carbonyl compounds through reductive coupling of alkenylboronic acids and tosylhydrazones. Angew. Chem. Int. Ed. 51, 5953–5957 (2012).
Plaza, M. & Valdés, C. Stereoselective domino carbocyclizations of γ- and δ-cyano-n-tosylhydrazones with alkenylboronic acids with formation of two different C(sp3)–C(sp2) bonds on a quaternary stereocenter. J. Am. Chem. Soc. 138, 12061–12064 (2016).
Tian, D. et al. Stereospecific nucleophilic substitution with arylboronic acids as nucleophiles in the presence of a CONH group. Angew. Chem. Int. Ed. 57, 7176–7180 (2018).
Wu, G., Deng, Y., Wu, C., Zhang, Y. & Wang, J. Synthesis of α-aryl esters and nitriles: deaminative coupling of α-aminoesters and α-aminoacetonitriles with arylboronic acids. Angew. Chem. Int. Ed. 53, 10510–10514 (2014).
Petasis, N. A. & Akritopoulou, I. The boronic acid Mannich reaction: a new method for the synthesis of geometrically pure allylamines. Tetrahedron Lett. 34, 583–586 (1993).
Petasis, N. A. & Zavialov, I. A. A new and practical synthesis of α-amino acids from alkenyl boronic acids. J. Am. Chem. Soc. 119, 445–446 (1997).
Petasis, N. A. & Zavialov, I. A. Highly stereocontrolled one-step synthesis of anti-β-amino alcohols from organoboronic acids, amines, and α-hydroxy aldehydes. J. Am. Chem. Soc. 120, 11798–11799 (1998).
Candeias, N. R., Montalbano, F., Cal, P. M. S. D. & Gois, P. M. P. Boronic acids and esters in the Petasis-borono Mannich multicomponent reaction. Chem. Rev. 110, 6169–6193 (2010).
Wu, P., Givskov, M. & Nielsen, T. E. Reactivity and synthetic applications of multicomponent Petasis reactions. Chem. Rev. 119, 11245–11290 (2019).
Yang, K., Zhang, F., Fang, T., Zhang, G. & Song, Q. Stereospecific 1,4-metallate shift enables stereoconvergent synthesis of ketoximes. Angew. Chem. Int. Ed. 58, 13421–13426 (2019).
Kuethe, J. T. & Comins, D. L. Addition of metallo enolates to chiral 1-acylpyridinium salts: total synthesis of (+)-Cannabisativine. Org. Lett. 2, 855–857 (2000).
Ziegler, F. E., Jaynes, B. H. & Saindane, M. T. A synthetic route to forskolin. J. Am. Chem. Soc. 109, 8115–8116 (1987).
Mundal, D. A., Lutz, K. E. & Thomson, R. J. A direct synthesis of allenes by a traceless Petasis reaction. J. Am. Chem. Soc. 134, 5782–5785 (2012).
Maneerat, W. et al. Phenylpropanoid derivatives from Clausena harmandiana fruits. Phytochem. Lett. 6, 18–20 (2013).
Wildemann, H., Dünkelmann, P., Müller, M. & Schmidt, B. A short olefin metathesis-based route to enantiomerically pure arylated dihydropyrans and α,β-unsaturated δ-valero lactones. J. Org. Chem. 68, 799–804 (2003).
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Financial supports from the National Natural Science Foundation of China (21772046, 2193103) are gratefully acknowledged.
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Q.S. conceived the project. K.Y., F.Z., T.F., C.L., and W.L. performed experiments and prepared the Supplementary Information. Q.S. and K.Y. prepared the manuscript. All authors discussed the results and commented on the manuscript.
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Yang, K., Zhang, F., Fang, T. et al. Passerini-type reaction of boronic acids enables α-hydroxyketones synthesis. Nat Commun 12, 441 (2021). https://doi.org/10.1038/s41467-020-20727-7
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DOI: https://doi.org/10.1038/s41467-020-20727-7
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