Polycyclic N-heterocycles are important structural motifs commonly found in bioactive compounds, however, their selective construction via the cyclization of allenynes remains challenging yet highly desirable. Here we show a homogeneous copper-catalyzed hetero Diels−Alder (HDA) reaction of allenynes with cis-diazenes (PTAD, 4-phenyl-1,2,4-triazoline-3,5-dione), allowing the practical and efficient synthesis of a diverse array of valuable polycyclic N-heterocycles. A temperature-controlled and stereocontrolled chemoselectivity of the reaction was observed, leading to the chemodivergent synthesis of tetracyclic pyrrolidines, pentacyclic triazepanes and tricyclic pyrrolidines. Compared with related Au-catalyzed cyclization of allenynes, this copper catalysis achieves cyclization of allenynes terminating in C–N bond formation via the HDA reaction.
Heterocycles containing C–N bonds are particularly significant structural motifs in organic molecules1,2,3,4,5,6,7. The structurally multiple and interesting family of polycyclic N-heterocycles, such as triazolo[1,2-a]pyridazines8,9,10,11, pyrrolo[2,3-d][1,2,4]triazolo[1,2-a]pyridazine12,13,14, and pyrrolo[2,3-d][1,2,4]triazolo[1,2-a]pyridazine15, are important structural cores that can be regularly found in bioactive natural products as well as in drug candidates. The preparation of structurally diverse heterocycles is important to the discovery of pharmaceutical lead compounds. The synthesis of these skeletons, however, always demands cumbrous synthetic pathways, which is usually time-consuming and labour-intensive. Thus, a practical and efficient strategy capable of selectively forming diverse valuable N-heterocycles from common starting materials, especially those based on assembling structures directly from readily available and easily varied building blocks, are of high value.
Recently, gold-catalyzed cascade cyclization reaction of alkynes, which have proven to be fundamental synthons in organic synthesis, has received enormous attention, and been widely used in the facile synthesis of a diverse array of the valuable cyclic compounds16,17,18,19,20,21. The gold-activated alkyne can be trapped by heteronucleophiles, such as nitrogen, oxygen, or sulfur derivatives, leading to the formation of heterocycles18,22,23,24,25,26,27. For example, generating α-oxo gold carbenes via oxidation of alkynes, as pioneered by the Zhang group28,29, has drawn considerable attention. The generation of α-imino gold carbenes via amination of alkynes have been widely applied to various catalytic reactions30,31,32,33,34. Besides, alkynes can also undergo various types of carbocyclizations, including [2 + 2]-35,36, [3 + 2]-37,38,39, [4 + 2]-40,41,42, and [2 + 2 + 2]-type reactions43,44,45, affording the structurally complex carbocycles. However, the gold-catalyzed cyclization of allenynes has been explored relatively seldom as chemo-, regio-, and stereoselectivity are significant. Realizing this tandem reaction is highly challenging due to two competing reactions. First, the allene functions as a nucleophile attacks Au-activated alkyne to form an allylic cation species. In this context, Toste reported an elegant protocol for the gold-catalyzed cycloisomerization of allenynes, and the resultant allylic cation species were terminated with a 1,5-hydrogen shift (Fig. 1a)46,47,48,49. Second, the alkyne functions as a nucleophile attacks Au-activated allene to generate a vinyl cation species50,51. In this case, Ohno et al. disclosed the gold(I)-catalyzed cyclization of allenynes terminating in C–C bond formation via the vinyl cation species (Fig. 1b)50. Despite these findings, the formed allylic cation or vinyl cation are terminated by deprotonation or nucleophilic attack, and the reactions terminated with C–N bond formation via the hetero Diels−Alder (HDA) reactions has not yet been reported. Furthermore, these allenyne cyclizations have been restricted to noble-metal catalysts, which has severely hampered the practical application of this approach. To our knowledge, non-noble-metal-catalyzed allenyne cyclizations to generate allylic cation intermediates has not been documented to date in homogeneous transition-metal catalysis. In our ongoing program of expanding copper catalysis into N-heterocycle synthesis52,53,54,55,56,57,58,59, we have developed an efficient synthesis of polycyclic N-heterocycles through copper-catalyzed, temperature-controlled regioselective HDA reaction of allenynes with cis-diazenes (PTAD) (Fig. 1c).
The outcome of the process depends on the reaction temperature, with tetracyclic pyrrolidines obtained at room temperature and pentacyclic triazepanes formed at 60 °C. Moreover, this method allows the stereocontrolled synthesis of valuable tricyclic pyrrolidines from an acyclic monosubstituted allenyne. Of note, in all the cases, no intramolecular products were detected46,47,48,49. The chemoselective HDA, and the high synthetic value of the heterocycles, are of great significance. Herein, the modular construction of synthetically valuable polycyclic N-heterocycles through homogeneous copper-catalyzed hetero Diels−Alder reactions of allenynes with PTAD have been described.
Results and discussion
Optimization of the reaction conditions
We started by employing allenyne 1a as the model substrate and PTAD 2a as the dienophile, and the initial reaction was run in DCE using Cu(CH3CN)4PF6 as the catalyst. Gratifyingly, the expected tetracyclic pyrrolidine 3a was indeed obtained in 16% yield (Table 1, entry 1). A subsequent different copper catalysts screening revealed that Cu(OTf)2 gave the best result, thus giving the tetracyclic pyrrolidine 3a in 75% yield (entry 5). We then tried a variety of other Lewis acids, including Zn(OTf)2, Y(OTf)3, and Sc(OTf)3, and general noble metal catalysts such as [Rh(CO)2Cl]2 and PPh3AuCl/AgNTf2, but failed to improve the yield (entries 7–11). Interestingly, pentacyclic triazepane 4a was detected when the reaction was performed at a higher temperature (60 °C) (entry 12). Given the interest of this result, we optimized the reaction conditions towards the selective synthesis of either 3a or 4a. To our delight, the reaction was substantially improved when PTAD 2a (3.0 equiv) was utilized (entry 13). Going a step further, 4.0 equivalents of PTAD 2a was found to be optimal and the yield of 4a was increased to 78% (entries 14 and 15). Further raising the reaction temperature failed to improve the reaction (entry 16).
The temperature turned out to be crucial for the selectivity of this tandem reaction. The chemoselectivity was perfectly controlled via the reaction temperature. Much to our delight, the reaction yield were further improved by using dry DCE as the solvent and 3 Å molecular sieves as an additive (entries 17 and 18).
Substrate scope for the formation of tetracyclic pyrrolidines 3
With the optimal reaction conditions in hand (Table 1, entry 5), the reaction scope of the copper-catalyzed synthesis of tetracyclic pyrrolidines was then explored (Fig. 2). The copper-catalyzed reaction of allenynes which contain different N-protecting groups, such as Ts, Mbs, SO2Ph, Bs, and Ms, furnished the expected tetracyclic pyrrolidines 3a–e in 52–86% yields. Molecular structure of 3d was confirmed by X-ray diffraction60. In entries 6–11, this HDA reaction worked smoothly with allenynes bearing p-phenyl substituents including fluoro, tert-butyl, methoxy and even trifluoromethyl, cyano, methyl formate, leading to the formation of tetracyclic pyrrolidines 3f–k in 54–92% yields. Substitutions on the aromatic ring at different sites were easily allowed, thus yielding tetracyclic pyrrolidines 3l–p in 41–76% yields. The reaction was also extended to the thienyl- and cyclopropyl-substituted allenynes to deliver tetracyclic pyrrolidines 3q and 3r in 43 and 24% yields, respectively. As shown in the cases of 3s–u, substitutions such as Et, tBu, and even NHBoc, on the cyclohexane ring were all smoothly accommodated. In addition, cyclopentyl-substituted allenyne 1 v was also a suitable substrate for this HDA reaction to give the desired tetracyclic pyrrolidine 3 v in 80% yield. We next extended the reaction to a range of PTAD. To our satisfaction, various aryl-substituted PTAD were compatible with this cycloaddition, which delivered the expected tetracyclic pyrrolidines 3w–ad in 39–71% yields. With regard to R2 – dimethyl, the corresponding product 3ae could be obtained in 68% yield. However, with regard to R1 – alkyl, the corresponding product 3af could not be obtained. Importantly, excellent diastereoselectivities (d.r. > 20/1) and unique regioselectivity were achieved in all cases.
Substrate scope for the formation of pentacyclic triazepanes 4
We also probed the substrate scope for the copper-catalyzed synthesis of pentacyclic triazepanes with the same allenynes substrates under the optimal reaction conditions (Table 1, entry 18). As shown in Fig. 3, allenynes bearing different protecting groups (Ts, Mbs, SO2Ph, Bs, and Ms) on nitrogen reacted quite well with PTAD 2a, providing the pentacyclic triazepanes 4a–e in 72–80% yields. Molecular structure of 4e was confirmed by X-ray diffraction60. Various substituted allenynes were then examined. Allenynes with either electron-withdrawing (F, Br, and even CF3, CN, CO2Me, CHO) or electron-donating substituents attached to the para position of the phenyl ring proceeded successfully to provide the pentacyclic triazepanes 4f–l in 67–87% yields. Allenynes with varied phenyl substituents including fluoro, chloro, bromo, and methyl substituents at the 3-position were also suitable substrates to give the corresponding products 4m–p in 60–73% yields. The reaction was also applicable to the 3,4-dichloro-substituted and 3,5-dimethyl-substituted allenynes, which was converted into pentacyclic triazepanes 4q and 4r in 69% yields. The heteroaromatic thienyl and alkyl substituent were well tolerated in this reaction, affording the pentacyclic triazepanes 4s and 4t in 42 and 70% yields, respectively. Interestingly, cyclopentyl-substituted allenyne 1u was also suitable for this reaction, and afforded the expected pentacyclic triazepane 4u in 56% yield. Furthermore, various substituted PTAD reacted satisfactorily, furnishing the resulting tetracyclic pyrrolidines 4v–aa in 68–80% yields. With regard to R2 – dimethyl, the corresponding product 4ab could not be obtained. With regard to R1 – alkyl, the corresponding product 4ac could not be obtained.
Substrate scope for the formation of tricyclic pyrrolidines 6
We then considered the possibility of extending the above HDA reaction to acyclic monosubstituted allenynes. This HDA reaction proceeded smoothly in the presence of 10 mol% Cu(OTf)2 as the catalyst for various acyclic monosubstituted allenynes 5, and the tricyclic pyrrolidines 6 were obtained in generally moderate to good yields with excellent diastereoselectivity. As shown in Fig. 4, this procedure worked well with a range of acyclic monosubstituted allenynes, and the yields ranged from 52 to 78%. Molecular structure of 6n was confirmed by X-ray diffraction60. With regard to R1 - alkyl and R2 - phenyl, the corresponding products 6 s and 6t could not be obtained. The newly formed configuration of tertiary carbon centers were consistent with the routine Diels−Alder reaction mechanism that the PTAD approached from the less hindered face. The regioselectivity of [4 + 2] cycloaddition within the key Cu-containing all-carbon 1,4-dipole intermediate is dominated by steric effects (For details, see the ESI).
Besides, this cycloaddition chemistry is not restricted to highly reactive cyclic diazenes. When tetracyanoethylene 2j as the dienophile, and the reaction was examined in DCE using Cu(OTf)2 as the catalyst, the corresponding benzo[e]isoindole 3ag was also obtained in 52% yield (Fig. 5).
Further synthetic transformation of the as-synthesized products were investigated (Fig. 6). The compound 3a could be easily transformed into the resulting products 7 and 8 in 81 and 74% yields, respectively, by treatment with LiAlH4 and DIBAL-H. Furthermore, the reaction of 3a with Grignard reagents resulted in the formation of 9 in 58–99% yields. The C=C double bond of the 3a could be oxidized by treatment with H2SO4 to deliver the observed product 10 in almost quantitative yield. The molecular structures of 8, 9b and 10 were confirmed by X-ray diffraction60. In addition, the Ns group in tricyclic pyrrolidine 6a, was easily removed by the treatment with p-toluenethiol and K2CO3 to provide the resulting 11 in 76% yield.
On the basis of previous studies on transition-metal-catalyzed allenyne cyclization61, two plausible mechanisms to rationalize the synthesis of tetracyclic pyrrolidine 3a are presented (Fig. 7). In path a, the reaction commences with attacking of allene moiety to the copper-activated triple bond of electron-rich ynamide moiety, giving the endocyclic allylic cation II. Subsequent deprotonation and [1,5]-H shift generates copper-containing diene IV, followed by reacting with PTAD 2a, via HDA reaction, to yield the tetracyclic pyrrolidine 3a. In path b, exocyclic allylic cation V can be generated, further producing the expected copper-containing diene IV upon a loss of a proton.
To further understand the mechanism of the allenyne cyclizations, in particular accounting for the distinct selectivity, several control experiments were explored. First, deuterium labeling experiment was examined with the allenyne [D4]-1a. It was found that <1% deuterium incorporation into the pyrrole ring partner of the desired product was detected when starting from the deuterium-labelled substrate [D4]-1a (91% D), suggesting that path a of Scheme 3 was unlikely, as hydride shift should occur in the formation of copper-containing diene IV (Fig. 8a). Besides, kinetic isotope effect (KIE) studies were also performed with the mixture of allenyne 1a and [D4]-1a, and the KIE data indicated that the cleavage of methylene C(sp3)–H bond was not the rate-determining step (Fig. 8b).
Based on the above experimental observations, a plausible mechanism to rationalize the formation of 3a and 4a are presented (Fig. 9). The electron-rich alkyne moiety of 1a is activated by a cationic copper catalyst to afford copper complex A, followed by intramolecular nucleophilic attack by the allene to generate allylic cation intermediate B. The allylic cation B undergoes a loss of a proton to form copper-containing diene C, followed by reacting with PTAD, via HDA reaction, to deliver the tetracyclic pyrrolidine 3a through vinyl copper intermediate D61. Alternatively, [1,5]-H shift may occur and then form the intermediate E, further reacting with PTAD, via [2 + 2] cycloaddition, to provide the hexacyclic pyrrolidine intermediate F. Subsequent [1,5]-H migration and C–C cleavage allow the formation of the pentacyclic triazepane 4a along with the release of ring strain. The newly generated configuration of tertiary carbon centers (3a) supports the Diels−Alder reaction mechanism that the PTAD approaches from the less hindered face. The formed configuration of tertiary carbon centers (4a) suggests that hydride shift was presumably involved in the formation of seven-membered ring moiety.
In summary, we have developed the modular construction of synthetically valuable polycyclic N-heterocycles through homogeneous copper-catalyzed hetero Diels−Alder reactions of allenynes with PTAD. This reaction shows excellent diastereoselectivities in the ring-formation step and features a broad substrate scope. It is worth noting that the outcome of the procedure can be controlled by adjusting the temperature of the reaction system, giving access to two different N-heterocycle skeletons, namely tetracyclic pyrrolidines and pentacyclic triazepanes, from the same starting materials. This method enables efficient and stereocontrolled access to valuable tricyclic pyrrolidines under mild reaction conditions from an acyclic monosubstituted allenyne. Compared with related Au-catalyzed cyclization of allenynes, this copper catalysis achieves cyclization of allenynes terminating in C–N bond formation via the chemoselective HDA, to the best of our knowledge, which represents the first non-noble metal-catalyzed allenyne cyclizations to generate allylic cation intermediates in homogeneous transition-metal catalysis. Moreover, copper catalysis may be advantageous in catalytic asymmetric reactions over gold catalysis due to the linear coordination favored by gold. The development of copper-catalyzed asymmetric cascade cyclization of allenynes and mechanistic explorations are the themes of continuing study in our laboratory.
Unless otherwise noted, materials were obtained commercially and used without further purification. All the solvents were treated according to general methods. Flash column chromatography was performed over silica gel (300–400 mesh). See Supplementary Methods for experimental details.
1H NMR spectra were recorded on a Bruker AV-400 spectrometer in chloroform-d3. Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The data is being reported as (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, brs = broad singlet, coupling constant(s) in Hz, integration). 13C NMR spectra were recorded on a Bruker AV-400 spectrometer in chloroform-d3. Chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard. Infrared spectra were recorded on a Nicolet iS 10 spectrometer as thin film and are reported in reciprocal centimeter (cm−1). Mass spectra were recorded with Micromass Q-Exactive Focus mass spectrometer using electron spray ionization. More mechanism studies are supplied: see Supplementary Figs. 89–90. Representative synthetic procedures for the preparation of substrates are supplied: see Supplementary Figs. 91–93. General procedure for the synthesis of tetracyclic pyrrolidines 3 are supplied: see Supplementary Fig. 94. General procedure for the synthesis of pentacyclic triazepanes 4 are supplied: see Supplementary Fig. 95. General procedure for the synthesis of tricyclic pyrrolidines 6 are supplied: see Supplementary Fig. 96. Synthetic applications are supplied: see Supplementary Figs. 97–101. Deuterium labeling experiments are supplied: see Supplementary Figs. 102–106. Crystal datas are supplied: see Supplementary Tables 1–6. See Supplementary Methods for the characterization data of compounds not listed in this part.
General procedure for the synthesis of tetracyclic pyrrolidines 3
PTAD (cis-diazenes) 2 (0.3 mmol), and Cu(OTf)2 (0.02 mmol, 7.2 mg) were added in this order to the allenynes 1 (0.2 mmol) in DCE (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. The reaction typically took 1 h. Upon completion, the mixture was then concentrated and the residue was purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate) to afford the desired products 3.
General procedure for the synthesis of pentacyclic triazepanes 4
PTAD (cis-diazenes) 2 (0.8 mmol), 3 Å molecular sieves (40 mg), and Cu(OTf)2 (0.02 mmol, 7.2 mg) were added in this order to the allenynes 1 (0.2 mmol) in dry DCE (4.0 mL) at room temperature. The reaction mixture was stirred at 60 °C (60 °C, heating mantle temperature) and the progress of the reaction was monitored by TLC. The reaction typically took 1 h. Upon completion, the mixture was then concentrated and the residue was purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate) to afford the desired products 4.
General procedure for the synthesis of tricyclic pyrrolidines 6
PTAD (cis-diazenes) 2a (0.3 mmol, 52.5 mg), and Cu(OTf)2 (0.02 mmol, 7.2 mg) were added in this order to the allenynes 5 (0.2 mmol) in dry DCE (8.0 mL) at room temperature. Under N2 atmosphere, the reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. The reaction typically took 1 h. Upon completion, the mixture was then concentrated and the residue was purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate) to afford the desired products 6.
The authors declare that the data supporting the findings of this study are available within the article and the Supplementary Information as well as from the authors upon reasonable request. The compound characterizations are available in Supplementary Data 1. 1H NMR, and 13C NMR are supplied for all compounds: see Supplementary Figs. 1–88. The X-ray crystallographic coordinates for structures 3d, 4e, 6n, 8, 9b, and 10, reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under CCDC 2205946 (3d, Supplementary Data 2), 2192313 (4e, Supplementary Data 3), 2192314 (6n, Supplementary Data 4), 2192316 (8, Supplementary Data 5), 2192317 (9b, Supplementary Data 6) and 2192318 (10, Supplementary Data 7), respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
Hong, F.-L. & Ye, L.-W. Transition metal-catalyzed tandem reactions of ynamides for divergent N-heterocycle synthesis. Acc. Chem. Res. 53, 2003–2201 (2020).
Wang, Y., Zhang, W.-X. & Xi, Z. Carbodiimide-based synthesis of N-heterocycles: moving from two classical reactive sites to chemical bond breaking/forming reaction. Chem. Soc. Rev. 49, 5810–5849 (2020).
Odom, A. L. & McDaniel, T. J. Titanium-catalyzed multicomponent couplings: efficient one-pot syntheses of nitrogen heterocycles. Acc. Chem. Res. 48, 2822–2833 (2015).
Zhu, J. S., Haddadin, M. J. & Kurth, M. J. Davis–beirut reaction: diverse chemistries of highly reactive nitroso intermediates in heterocycle synthesis. Acc. Chem. Res. 52, 2256–2265 (2019).
Zhang, Y. C., Jiang, F. & Shi, F. Organocatalytic asymmetric synthesis of indole-based chiral heterocycles: strategies, reactions, and outreach. Acc. Chem. Res. 53, 425–446 (2020).
Xu, G., Bai, X. & Dang, Q. Aromatic heterocycles as productive dienophiles in the inverse electron-demand Diels–Alder reactions of 1,3,5-triazines. Acc. Chem. Res. 53, 773–781 (2020).
Yamamoto, K., Kuriyama, M. & Onomura, O. Anodic oxidation for the stereoselective synthesis of heterocycles. Acc. Chem. Res. 53, 105–120 (2020).
Mayer, C. D. & Bracher, F. Cytotoxic ring A-modified steroid analogues derived from Grundmann’s ketone. Eur. J. Med. Chem. 46, 3227–3236 (2011).
Su, S. et al. Convergent synthesis of a complex oxime library using chemical domain shuffling. Org. Lett. 7, 2751–2754 (2005).
Wu, J. et al. Synthesis of hexahydropyridazines by [4 + 2] cycloaddition of Donor–Acceptor cyclobutanes and cis-diazenes. Org. Lett. 22, 3140–3144 (2020).
Lei, X., Zaarur, N., Sherman, M. Y. & Porco, J. A. Jr. Stereocontrolled synthesis of a complex library via elaboration of angular epoxyquinol scaffolds. J. Org. Chem. 70, 6474–6483 (2005).
Monge, A. et al. New 5H-pyridazino[4,5-b]indole derivatives. synthesis and studies as inhibitors of blood platelet aggregation and inotropics. J. Med. Chem. 34, 3023–3029 (1991).
Font, M. et al. Indoles and pyridazino [4, 5-b] indoles as nonnucleoside analog inhibitors of HIV-1 reverse transcriptase. Eur. J. Med. Chem. 30, 963–971 (1995).
Avan, I., Guven, A. & Guven, K. Synthesis and antimicrobial investigation of some 5H-pyridazino [4, 5-b] indoles. Turk. J. Chem. 37, 271–291 (2013).
Koini, T., Stumpe, H., Gagstadter, R. & Grubmayr, K. The Diels-Alder adduct of phycocyanobilin dimethyl ester and 4-phenyl-1, 2, 4-triazolin-3, 5-dione: a model intermediate for chromatic adaption of biliprotein chromophores? Tetrahedron Lett 34, 4169–4172 (1993).
Zheng, Z. et al. Homogeneous gold-catalyzed oxidation reactions. Chem. Rev. 121, 8979–9038 (2021).
Ye, L.-W. et al. Nitrene transfer and carbene transfer in gold catalysis. Chem. Rev. 121, 9039–9112 (2021).
Dorel, R. & Echavarren, A. M. Gold(I)-catalyzed activation of alkynes for the construction of molecular complexity. Chem. Rev. 115, 9028 (2015).
Qian, D. & Zhang, J. Gold-catalyzed cyclopropanation reactions using a carbenoid precursor toolbox. Chem. Soc. Rev. 44, 677–698 (2015).
Shen, W.-B. & Tang, X.-T. Recent advances in catalytic asymmetric intermolecular oxidation of alkynes. Org. Biomol. Chem. 17, 7106–7113 (2019).
Ru, G.-X. et al. Recent progress towards the transition-metalcatalyzed Nazarov cyclization of alkynes via metal carbenes. Org. Biomol. Chem. 19, 5274–5283 (2021).
Yang, W. & Hashmi, A. S. K. Mechanistic insights into the gold chemistry of allenes. Chem. Soc. Rev. 43, 2941–2955 (2014).
Alcaide, B. & Almendros, P. Gold-catalyzed cyclization reactions of allenol and alkynol derivatives. Acc. Chem. Res. 47, 939–952 (2014).
Blieck, R., Taillefer, M. & Monnier, F. Metal-catalyzed intermolecular hydrofunctionalization of allenes: easy access to allylic structures via the selective formation of C–N, C–C, and C–O bonds. Chem. Rev. 120, 13545–13598 (2020).
Cañeque, T., Truscott, F. M., Rodriguez, R., Maestri, G. & Malacria, M. Electrophilic activation of allenenes and allenynes: analogies and differences between Brønsted and Lewis acid activation. Chem. Soc. Rev. 43, 2916–2926 (2014).
Mascareñas, J. L., Varela, I. & López, F. Allenes and derivatives in gold(I)- and platinum(II)-catalyzed formal cycloadditions. Acc. Chem. Res. 52, 465–479 (2019).
Obradors, C. & Echavarren, A. M. Gold-catalyzed rearrangements and beyond. Acc. Chem. Res. 47, 902–912 (2014).
Ye, L., Cui, L., Zhang, G. & Zhang, L. Alkynes as equivalents of α-diazo ketones in generating α-oxo metal carbenes: a gold-catalyzed expedient synthesis of dihydrofuran-3-ones. J. Am. Chem. Soc. 132, 3258–3259 (2010).
Ye, L., He, W. & Zhang, L. Gold-catalyzed one-step practical synthesis of oxetan-3-ones from readily available propargylic alcohols. J. Am. Chem. Soc. 132, 8550–8551 (2010).
Gorin, D. J., Davis, N. R. & Toste, F. D. Gold(I)-catalyzed intramolecular acetylenic schmidt reaction. J. Am. Chem. Soc. 127, 11260–11261 (2005).
Yan, Z.-Y., Xiao, Y. & Zhang, L. Gold-catalyzed one-step construction of 2,3-dihydro-1H-pyrrolizines with an electron-withdrawing group in the 5-position: a formal synthesis of 7-methoxymitosene. Angew. Chem. Int. Ed. 51, 8624–8627 (2012).
Zhou, A.-H. et al. Atom-economic generation of gold carbenes: gold-catalyzed formal [3+2] cycloaddition between ynamides and isoxazoles. Chem. Sci. 6, 1265–1271 (2015).
Sahani, R. L. & Liu, R.-S. Development of gold-catalyzed [4+1] and [2+2+1]/[4+2] annulations between propiolate derivatives and isoxazoles. Angew. Chem. Int. Ed. 56, 1026–1030 (2017).
Jin, H. et al. Gold-catalyzed C-H annulation of anthranils with alkynes: a facile, flexible, and atom-economical synthesis of unprotected 7-acylindoles. Angew. Chem. Int. Ed. 55, 794–797 (2016).
González, A. Z., Benitez, D., Tkatchouk, E., Goddard, W. A. & Toste, F. D. Phosphoramidite gold(I)-catalyzed diastereo- and enantioselective synthesis of 3,4-substituted pyrrolidines. J. Am. Chem. Soc. 133, 5500–5507 (2011).
Alcarazo, M., Stork, T., Anoop, A., Thiel, W. & Fürstner, A. Steering the surprisingly modular Π-acceptor properties of N-heterocyclic carbenes: implications for gold catalysis. Angew. Chem. Int. Ed. 49, 2542–2546 (2010).
Huang, X. & Zhang, L. Two-step formal [3+2] cycloaddition of enones/enals and allenyl MOM ether: gold-catalyzed highly diastereoselective synthesis of cyclopentanone enol ether containing an all-carbon quaternary center. J. Am. Chem. Soc. 129, 6398–6399 (2007).
Christian, A. H., Niemeyer, Z. L., Sigman, M. S. & Toste, F. D. Uncovering subtle ligand effects of phosphines using gold(I) catalysis. ACS Catal 7, 3973–3978 (2017).
Jiménez, T., Carreras, J., Ceccon, J. & Echavarren, A. M. Gold(I)-catalyzed inter- and intramolecular additions of carbonyl compounds to allenenes. Org. Lett. 18, 1410–1413 (2016).
Francos, J. et al. Axially chiral triazoloisoquinolin-3-ylidene ligands in gold(I)-catalyzed asymmetric intermolecular (4 + 2) cycloadditions of allenamides and dienes. J. Am. Chem. Soc. 134, 14322–14325 (2012).
Teller, H., Flügge, S., Goddard, R. & Fürstner, A. Enantioselective gold catalysis: opportunities provided by monodentate phosphoramidite ligands with an acyclic TADDOL backbone. Angew. Chem. Int. Ed. 49, 1949–1953 (2010).
Mauleón, P., Zeldin, R. M., González, A. Z. & Toste, F. D. Ligand-controlled access to [4 + 2] and [4 + 3] cycloadditions in gold-catalyzed reactions of allene-dienes. J. Am. Chem. Soc. 131, 6348–6349 (2009).
Marcote, D. C., Varela, I., Fernández-Casado, J., Mascareñas, J. L. & López, F. Gold(I)-catalyzed enantioselective annulations between allenes and alkene-tethered oxime ethers: a straight entry to highly substituted piperidines and aza-bridged medium-sized carbocycles. J. Am. Chem. Soc. 140, 16821–16833 (2018).
Faustino, H., Alonso, I., Mascareñas, J. L. & López, F. Gold(I)-catalyzed cascade cycloadditions between allenamides and carbonyl-tethered alkenes: an enantioselective approach to oxa-bridged medium-sized carbocycles. Angew. Chem. Int. Ed. 52, 6526–6530 (2013).
Peng, S., Cao, S. & Sun, J. Gold-catalyzed regiodivergent [2 + 2 + 2]-cycloadditions of allenes with triazines. Org. Lett. 19, 524–527 (2017).
Cheong, P. H.-Y., Morganelli, P., Luzung, M. R., Houk, K. N. & Toste, F. D. Gold-catalyzed cycloisomerization of 1,5-allenynes via dual activation of an ene reaction. J. Am. Chem. Soc. 130, 4517–4526 (2008).
Lemière, G. et al. Gold(I)- and gold(III)-catalyzed cycloisomerization of allenynes: a remarkable halide effect. Angew. Chem. Int. Ed. 45, 7596–7599 (2006).
Zriba, R., Gandon, V., Aubert, C., Fensterbank, L. & Malacria, M. Alkyne versus allene activation in platinum- and gold-catalyzed cycloisomerization of hydroxylated 1,5-allenynes. Chem. Eur. J. 14, 1482–1491 (2008).
Lin, G.-Y., Yang, C.-Y. & Liu, R.-S. Gold-catalyzed synthesis of bicyclo[4.3.0]nonadiene derivatives via tandem 6-endo-dig/Nazarov cyclization of 1,6-allenynes. J. Org. Chem. 72, 6753–6757 (2007).
Ikeuchi, T., Inuki, S., Oishi, S. & Ohno, H. Gold(I)-catalyzed cascade cyclization reactions of allenynes for the synthesis of fused cyclopropanes and acenaphthenes. Angew. Chem. Int. Ed. 58, 7792–7796 (2019).
Komatsu, H. et al. Construction of tricyclic nitrogen heterocycles by gold(I)-catalyzed cascade cyclization of allenynes and its application to polycyclic Π-electron systems. Angew. Chem. Int. Ed. 60, 27019–27025 (2021).
Shen, W.-B. et al. Copper(I)-catalyzed enyne oxidation/cyclopropanation: divergent and enantioselective synthesis of cyclopropanes. Org. Lett. 23, 1285–1290 (2021).
Shen, W.-B. et al. Cu(I)-catalyzed oxidative cyclization of enynamides: regioselective access to cyclopentadiene frameworks and 2-aminofurans. Org. Lett. 22, 6799–6804 (2020).
Ru, G.-X. et al. Copper catalyzed dearomatization by Michaeltype addition of indolyl ynones: divergent synthesis of functionalized spiroindoles and cyclopenta[c]quinolin-3-ones. Org. Chem. Front. 9, 2621–2626 (2022).
Shen, W.-B. et al. Cu(I)- and Au(I)-catalyzed regioselective oxidation of diynes: divergent synthesis of N-heterocycles. Org. Chem. Front. 8, 4960–4966 (2021).
Shen, W.-B. et al. Highly site selective formal [5+2] and [4+2] annulations of isoxazoles with heterosubstituted alkynes by platinum catalysis: rapid access to functionalized 1,3-oxazepines and 2,5-dihydropyridines. Angew. Chem. Int. Ed. 56, 605–609 (2017).
Shen, W.-B. et al. Divergent synthesis of N-heterocycles via controllable cyclization of azido-diynes catalyzed by copper and gold. Nat. Commun. 8, 1748 (2017).
Zheng, Y., Zhang, T.-T. & Shen, W.-B. Gold-catalyzed oxidative cyclization of amidealkynes: access to functionalized γ-lactams. Org. Biomol. Chem. 19, 9688–9691 (2021).
Zhang, T.-T. et al. Rapid access to functionalized γ-lactams through copper-catalyzed oxidative cyclization of diynes. Synlett 34, 149–152 (2023).
CCDC 2205946 (3d), CCDC 2192313 (4e), CCDC 2192314 (6n), CCDC 2192316 (8), CCDC 2192317 (9b), and CCDC 2192318 (10) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre.
Kawade, R. K. & Liu, R.-S. Gold-catalyzed oxidative cyclization of 4-allenyl-1-ynes with 8-methylquinoline oxide. Org. Lett. 15, 4094–4097 (2013).
We are grateful for the financial support from the National Natural Science Foundation of China (22001059), the Top-Notch Talents Program of Henan Agricultural University (30500739).
The authors declare no competing interests.
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Wei, KF., Liu, Q., Ma, G. et al. Regioselective access to polycyclic N-heterocycles via homogeneous copper-catalyzed cascade cyclization of allenynes. Commun Chem 6, 104 (2023). https://doi.org/10.1038/s42004-023-00910-9