Skip to main content
NCBI home page
JACS Au logoLink to JACS Au
. 2026 Feb 20;6(3):1988–1997. doi: 10.1021/jacsau.6c00074

Synthesis of Spirocyclohexadienones with Diverse Structural Types and Ring Sizes

Yanren Zhu †, Yuxiang Zhao ‡, Lifeng Yao ‡, Enfan Pu †, Shaoxiong Yang †, Yushun Zhang †, Hongbin Zhang †,*, Jingbo Chen †,*
PMCID: PMC13014228  PMID: 41889781

Abstract

Dearomatization reactions represent one of the most straightforward and efficient approaches for transforming complex 3D molecules from planar aromatic systems. Over the past few decades, numerous synthetic methods have been established. However, current synthetic strategies remain confined to constructing only a single type of the common all-carbon, oxa-, or aza-spirocyclic frameworks, predominantly yielding thermodynamically and kinetically favored five- or six-membered rings and typically providing access to no more than three distinct ring sizes. Herein, we report an iodine­(III)-mediated dearomatization of phenol derivatives that enables the construction of three types of spirocycles as well as four distinct ring sizes of all-carbon spirocyclic compounds (three-, four-, five-, and six-membered rings). This strategy effectively controls chemo- and regioselectivity through the combined modulation of substrate structures, steric effects, and reaction conditions. Moreover, these diversely functionalized products can be readily transformed into fused bicyclic ring frameworks that show great potential for synthetic utility in organic synthesis.

Keywords: dearomatization, spirocycles, three types, four distinct ring sizes, chemo- and regioselectivity

graphic file with name au6c00074_0010.jpg

graphic file with name au6c00074_0008.jpg

Introduction

Spirocyclic scaffolds are commonly found in natural products, agrochemicals, and drugs, such as yatakemycin, annosqualine, dalesconol A and B, griseofulvin, carijodienone, and erythratinone. These representative bioactive spirocyclohexenones are displayed in Figure . In recent years, spirocyclic structural units have attracted increasing attention in drug design due to their rigid structure, additional vectors, enhanced three-dimensionality, and unique chemical space, contributing to improved interactions with biological targets. , Moreover, the spirocyclic motif plays a crucial role in organic synthesis, materials science, and especially in medicinal chemistry , due to its ability to regulate physicochemical properties, including basicity, solubility, lipophilicity, and metabolic stability. To date, a variety of efficient strategies have been developed for the synthesis of spirocycles. Among them, the dearomative spirocyclization of arenes has emerged as one of the most powerful and effective approaches. Initially, significant progress was accomplished in the hypervalent iodine-induced dearomative spirocyclization of phenols. Subsequently, transition-metal-catalyzed methods have become indispensable for constructing highly valuable and structurally complex spirocyclohexadienone frameworks. The Ir, Pd, Au, Ag, and other transition-metal-catalyzed approaches have been developed by You, ,,, Luan, Hamada, etc. In addition, radical-mediated functional pathways have also been utilized for the synthesis of spirocycles, including traditional radical reactions as well as photochemical and electrochemical processes. Recently, acid or base and even metalloenzyme-catalyzed spiroannulations of phenol derivatives have been reported by Bower, Ye, etc. (Scheme a). Despite the extensive development of spirocyclization reactions via the dearomatization of planar aromatics, these strategies have been confined to constructing only a single type of the common all-carbon, oxa-, or aza-spirocyclic scaffolds, predominantly yielding thermodynamically and kinetically favored five- or six-membered rings and typically providing access to no more than three distinct ring sizes. In particular, the synthesis of spirocyclic 3- or 4-membered rings is less explored, probably due to the high ring strain of the smaller ring structures. It is worth noting that no unified strategy has yet been reported for the synthesis of spirocycles with a diverse range of structural types and ring sizes.

1.

1

Open in a new tab

Selected natural products and bioactive molecules containing spirocyclohexenone cores.

1. Scientific Context and Synthesis of Spirocycles with Diverse Structural Types and Ring Sizes.

1

Open in a new tab

Indeed, a unified strategy for the synthesis of diverse types and ring sizes of spirocyclic compounds holds particularly significant value, offering intriguing and meaningful advantages in synthetic efficiency, thereby facilitating the rapid construction of various spirocyclic compounds. Previous studies have demonstrated that β-ketoesters and their derivatives (enaminoesters and enamides) are ideal and promising nucleophile species, which can be easily obtained from commercially available aldehydes or carboxylic acids. In this study, we aim to investigate the reactivity of enaminoester-containing phenol derivatives with diverse N-protecting groups and their precursor β-ketoester compounds and to achieve the ultimate goal of establishing a unified synthetic method for constructing various types and sizes of spirocyclic structures (Scheme b). Herein, we develop an unprecedented and versatile strategy for the synthesis of three types (all-carbon, aza-, and oxa-spirocycles) and four sizes (three-, four-, five-, and six-membered rings) of all-carbon spirocycles. This strategy effectively controls chemo- and regioselectivity through the combined modulation of substrate structures, steric effects, and reaction conditions, leading to the formation of C–C, C–N, and C–O bonds via iodine­(III)-mediated dearomatization reactions of phenol derivatives. This protocol enables the practical and divergent synthesis of diversely functionalized spirocyclohexadienones in generally acceptable to good yields with a broad substrate scope under mild conditions. Notably, the extremely challenging all-carbon spirocyclic 3- and 4-membered ring systems, which possess high strain, can also be successfully constructed (Scheme c).

Results and Discussion

To synthesize the relatively accessible 5-membered all-carbon spirocycles, the enaminoester-tethered phenol 1a was selected as the model substrate for optimizing the reaction conditions, and the corresponding results are summarized in Table . We hypothesized that a carefully optimized combination of oxidant, solvent, additive could efficiently drive the desired spirocyclization of phenols through an oxidative coupling reaction. Fortunately, our initial studies revealed that using PIDA as the oxidant in TFE yielded the desired spirocyclic compound 2a in 64% yield (Table , Entry 1). Next, we tested several oxidants for this reaction in TFE at room temperature (Table , Entries 2–5). However, other oxidants were less effective than PIDA. Subsequently, various solvents were tested, and it was found that a mixture of DCM and HFIP (10 mL, v:v = 1/1) was the optimal solvent for obtaining the dearomatized product 2a in 75% yield (Table , Entries 6–11). Among the evaluated reaction additives, K2CO3 was identified as the most effective, affording the desired compound 2a in 78% yield (Table , Entries 12–16). Finally, adjusting the reaction temperature revealed that lowering the temperature to 0 °C could enhance the yield of 2a to 81%, resulting in optimal reaction conditions A (Table , Entry 19).

1. Optimization of Reaction Conditions .

graphic file with name au6c00074_0007.jpg

entry oxidant solvent additive yield of 2a
1 PIDA TFE   64
2 PIFA TFE   41
3 PhI(OPiv)2 TFE   48
4 PhIO TFE   36
5 HTIB TFE   trace
6 PIDA MeOH   23
7 PIDA HFIP   73
8 PIDA DCM   trace
9 PIDA DCM:TFE   63
10 PIDA DCM:HFIP   75
11 PIDA DCM:HFIP   70
12 PIDA DCM:HFIP Et3N 75
13 PIDA DCM:HFIP Na2CO3 74
14 PIDA DCM:HFIP NaHCO3 72
15 PIDA DCM:HFIP K2CO3 78
16 PIDA DCM:HFIP Cs2CO3 76
17, PIDA DCM:HFIP K2CO3 78
18, PIDA DCM:HFIP K2CO3 80
19 , PIDA DCM:HFIP K 2 CO 3 81
20, PIDA DCM:HFIP K2CO3 76
Open in a new tab
a

Reaction conditions: 1a (0.5 mmol, 1.0 equiv), oxidant (1.1 equiv), solvent (10 mL, v:v = 1/1), additive (2.2 equiv), air atmosphere, room temperature, 2 min.

b

Isolated yields.

c

DCM:TFE (10 mL, v:v = 1/1).

d

DCM:HFIP (10 mL, v:v = 1/1).

e

DCM:HFIP (10 mL, v:v = 5/1).

f

K2CO3 (3.3 equiv).

g

The reaction was performed at −10 °C.

h

The reaction was performed at 0 °C.

I

The reaction was performed at 40 °C.

With the optimized reaction conditions in hand, we studied the substrate scope of our transformation (Scheme a). First, we explored the substrate scope of C-2-substituted phenol, which included electron-withdrawing substituents (such as F, Cl, Br, and even CF3) as well as electron-donating groups (such as OMe). These substrates efficiently afforded the desired products 2b–2f in good yields (71–82%). Likewise, substrates with electron-withdrawing or -donating groups at the C-3 position of phenol were smoothly cyclized, providing the spirocyclic products 2g–2n in good yields (76–84%). When aryl-disubstituted enaminoesters were subjected to these conditions, they underwent the dearomative reaction as expected, providing the desired spirocyclic products (2o–2s) in good yields (77–84%). These results demonstrated that the position and electronic properties of substituents on the phenyl ring had no significant effect on the reaction efficiency. In addition, this dearomative reaction was extended to enaminoester-tethered naphthol to produce the corresponding product 2t (66%). Interestingly, phenyl, as an R1 substituent, was also suitable for this reaction and delivered the desired 2u in 81% yield. On the other hand, given the potential influence of N-protecting groups on the chemo- and regioselectivity of the reaction, we shifted our focus to exploring different nitrogen-protecting groups. The tetrahydropyrrolyl-tethered enamine was compatible, affording 2v in 66% yield. However, the substrate bearing a p-toluenesulfonyl (Ts)-protected amine exclusively yielded the regioselectivity-inverted 1-aza-spirocycle 2w in 62% yield, probably due to the strong electron-withdrawing effect of the sulfonyl group, which enhances the nucleophilicity of the nitrogen atom under basic conditions. In view of previously reported similar studies, no further in-depth investigation was conducted in this work. Next, the nitrogen atom of enamines protected by phenyl groups with various electron-neutral, electron-deficient, and electron-rich substituents was tested, and full-carbon spirocycles (2x–2aa) and aza-spirocycles (2x′–2aa′) were obtained with a regioselectivity of approximately 1.3:1. The structure and relative configuration of 2aa′ were further determined by X-ray diffraction analysis. Fascinatingly, the amide-substituted substrate was also well tolerated, affording the full-carbon spirocycle 2ab in good yields (85%) with reversed regioselectivity. These experimental results demonstrate that the regioselectivity can be effectively modulated through subtle adjustments to the substrate structure or the N-protecting group.

2. Synthesis of All-Carbon 5-Membered Spirocycles and 5-Membered Aza-Spirocycles.

2

Open in a new tab

Similar to 1-aza-spirocyclic compounds, 2-aza-spirocycles also serve as core structural motifs in numerous bioactive molecules and natural products and are widely recognized as privileged scaffolds in drug discovery. To access 2-aza-spirocycles, we designed substrate 3 with both thermodynamic advantages and optimal steric properties. Upon further optimization of the reaction conditions, the desired product (4a) was efficiently obtained (Scheme b, see details in the SI, Table S2, Entry 16). The reaction was compatible with a diverse array of functionalities on the phenol ring of enaminoester, including fluoro, chlorine, methoxy, and methyl, obtaining the corresponding products (4b–4f) in acceptable to moderate yields (40–63%). Then, a variety of enaminones with various aromatic ring substituents were well tolerated and afforded the desired products 4g–4p in 47–64% yields. Specifically, the electronic nature (electron-donating or electron-withdrawing) and substituent position (2-, 4-, and bisubstituted) on the benzene ring of enaminones have no significant effect on the reactivity. Furthermore, the reaction tolerated 1-naphthyl-, 2-naphthyl-, thienyl-, furyl-, and cycloalkyl-substituted enaminones, and the desired spirocyclic products 4q–4x were obtained in moderate yields. Moreover, the structure of 4w was further determined by an X-ray diffraction analysis.

Subsequently, as a logical extension of the above encouraging results, we turned our attention toward exploring the synthesis of oxa-spirocycles (Scheme a). By a slight change in the reaction conditions and substrate structure, it is possible to produce oxa-spirocycle products. A comprehensive optimization of the catalytic system was carried out, and the optimal reaction conditions were identified (see details in the SI, Table S3, Entry 11). Following that, a range of alkyl-substituted (methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl) β-ketoesters was tested. Remarkably, these substrates underwent efficient spirocyclization reactions under acidic conditions, delivering the corresponding products (6a–6g) in moderate to good yields (69–82%). Moreover, various substituents on both the aryl moiety of the ketoester side chain and the phenolic core were well tolerated under the reaction conditions, and the corresponding products (6h–6l) were isolated in moderate yields (55–66%).

3. Synthesis of Oxa-Spirocycles and All-Carbon 3-Membered Spirocycles.

3

Open in a new tab

Considering the significant importance of spirocycles with a 3-membered ring size in medicinal chemistry. We further designed substrate 7 for the synthesis of 3-membered all-carbon spirocycles, and subsequent condition screening revealed that the optimal reaction conditions were consistent with condition A (Table , Entry 19). We successfully obtained the 3-membered all-carbon spirocycle 8a in 72% yield under the optimal reaction conditions, and the structure of compound 8a was unambiguously verified by crystallographic analysis. Moreover, enaminoesters bearing a benzoyl-protected amino group, benzyl ester substituents, and various substituted phenol cores were successfully transformed into spirocycles (8b–8h) in moderate yields (55–75%). No aza-spirocycles were detected here, possibly due to the acyl group significantly reducing the nucleophilicity of the nitrogen atom (Scheme b).

Next, we will tackle the most challenging synthesis of spirocyclohexadienones containing four-membered full-carbon rings (Scheme a), a relatively rare structure in natural products. Gratifyingly, enamine substrates 9 smoothly underwent dearomatization, providing 4-membered all-carbon spirocycles 10a and 10b in 40 and 42% yields, respectively. Finally, to further evaluate the viability of this method, enamine derivatives 11 were tested in the dearomative spirocyclization to construct 6-membered spirocycle compounds (Scheme b). Similarly, enamine 11a was also well tolerated, obtaining the desired compound 12a in 59% yield. When the substrate of enamine with phenyl-protected amino group was carried out under conditions A, the reaction concurrently generated all-carbon spirocycle 12b and aza-spirocycle 12b′ in 36 and 28% yields, respectively.

4. Synthesis of All-Carbon 4-Membered Spirocycles, 6-Membered Spirocycles, and Gram-Scale Reaction and Transformation.

4

Open in a new tab

To showcase the versatility and practicality of this strategy, the spiroannulation of compound 1a was carried out on a 5 mmol scale, affording spirocycle 2a in 64% yield (Scheme c). Subsequently, we further illustrated the synthetic usefulness of the products by exploring their practical transformations. Product 2a could undergo a migration-expansion reaction under Brønsted-acid conditions to provide fused bicyclic compound 13 in 68% yield. When 2a was treated with TFA in acetic acid, ketone 14 was obtained in an 80% yield.

On the basis of the above-mentioned results and previous studies, a plausible reaction mechanism has been proposed (Scheme ). First, phenol 1 undergoes a ligand exchange with PIDA to give intermediate I. Subsequently, the cyclohexadienone cation intermediate II was formed via reductive elimination. Notably, when R is a hydrogen atom, the β-carbon of the enamine ester selectively undergoes nucleophilic attack on the dienone cation, leading to the formation of all-carbon spirocyclic product 2. In contrast, when R is a phenyl substituent, in addition to affording product 2 via the above pathway, the nitrogen atom can also act as a nucleophile to attack the carbocation, followed by carbon–carbon double bond isomerization to generate the aza-spirocyclic product 2′.

5. Proposed Reaction Mechanism.

5

Open in a new tab

Conclusion

In conclusion, an unprecedented and versatile strategy for the synthesis of three-type (all-carbon, aza-, and oxa-spirocycles) and four-size (three-, four-, five-, and six-membered rings) full-carbon spirocycles was developed through the combined modulation of substrate structures, steric effects, and reaction conditions to effectively control chemo- and regioselectivity for forming C–C, C–N, and C–O bonds via iodine­(III)-mediated dearomatization reactions of phenol derivatives. A variety of spirocycles was achieved in moderate to good yields, with broad functional group compatibility and excellent substrate scope, under transition-metal-free conditions. The densely functionalized products demonstrate the strong potential of this method for late-stage modifications to achieve high molecular complexity. Furthermore, this protocol offers valuable perspectives into the synthesis of other complex molecular structures, with significant scientific implications.

Supplementary Material

au6c00074_si_001.pdf (12.7MB, pdf)

Acknowledgments

We are grateful to the National Natural Science Foundation of China (22361051, U24A20802, 22461034, 22169016), the Yunnan Fundamental Research Projects (202301BF070001-022, 202301AU070007), the Special Basic Cooperative Research Programs of Yunnan Provincial Undergraduate Universities’ Association (202301BA070001-075), the Yunnan Key Laboratory of Crystalline Porous Organic Functional Materials (202449CE340024), the Key Laboratory of Green Organic Synthesis of Yunnan Education Department, and The Program of Innovative Research Team (in Science and Technology) in the University of Yunnan Province, Yunnan Fundamental Research Projects (202401AS070001) for providing the financial support.

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

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.6c00074.

  • Experimental procedures, crystallographic data, compound characterization data, and copies of NMR spectra of the products (PDF)

§.

Y.Z. and Y.Z. contributed equally to this work. Y.Z. and Y.Z. designed and performed the experimental work. L.Y., E.P., S.Y., and Y.Z. contributed to the analysis and interpretation of data. H.Z. and J.C. conceived the project. J.C. and Y.Z. wrote the manuscript. All authors contributed to or approved the final version of the paper.

The authors declare no competing financial interest.

References

  1. a Rios R.. Enantioselective methodologies for the synthesis of spiro compounds. Chem. Soc. Rev. 2012;41:1060–1074. doi: 10.1039/C1CS15156H. [DOI] [PubMed] [Google Scholar]; b D’yakonov V. A., Trapeznikova O. g. A., de Meijere A., Dzhemilev U. M.. Metal Complex Catalysis in the Synthesis of Spirocarbocycles. Chem. Rev. 2014;114:5775–5814. doi: 10.1021/cr400291c. [DOI] [PubMed] [Google Scholar]; c Smith L. K., Baxendale I. R.. Total syntheses of natural products containing spirocarbocycles. Org. Biomol. Chem. 2015;13:9907–9933. doi: 10.1039/C5OB01524C. [DOI] [PubMed] [Google Scholar]; d Ling T., Rivas F.. All-carbon quaternary centers in natural products and medicinal chemistry: recent advances. Tetrahedron. 2016;72:6729–6777. doi: 10.1016/j.tet.2016.09.002. [DOI] [Google Scholar]; e Kotha S., Panguluri N. R., Ali R.. Design and Synthesis of Spirocycles. Eur. J. Org. Chem. 2017;2017:5316–5342. doi: 10.1002/ejoc.201700439. [DOI] [Google Scholar]; f Reddy C. R., Prajapti S. K., Warudikar K., Ranjan R., Rao B. B.. ipso-Cyclization: an emerging tool for multifunctional spirocyclohexadienones. Org. Biomol. Chem. 2017;15:3130–3151. doi: 10.1039/C7OB00405B. [DOI] [PubMed] [Google Scholar]; g Quintavalla A.. Spirolactones: Recent Advances in Natural Products, Bioactive Compounds and Synthetic Strategies. Curr. Med. Chem. 2018;25:917–962. doi: 10.2174/0929867324666171106162259. [DOI] [PubMed] [Google Scholar]; h Hiesinger K., Dar’in D., Proschak E., Krasavin M.. Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021;64:150–183. doi: 10.1021/acs.jmedchem.0c01473. [DOI] [PubMed] [Google Scholar]
  2. a Parrish J. P., Kastrinsky D. B., Wolkenberg S. E., Igarashi Y., Boger D. L.. DNA Alkylation Properties of Yatakemycin. J. Am. Chem. Soc. 2003;125:10971–10976. doi: 10.1021/ja035984h. [DOI] [PubMed] [Google Scholar]; b Okano K., Tokuyama H., Fukuyama T.. Total Synthesis of (+)-Yatakemycin. J. Am. Chem. Soc. 2006;128:7136–7137. doi: 10.1021/ja0619455. [DOI] [PubMed] [Google Scholar]; c Tichenor M. S., Boger D. L.. Yatakemycin: total synthesis, DNA alkylation, and biological properties. Nat. Prod. Rep. 2008;25:220–226. doi: 10.1039/B705665F. [DOI] [PubMed] [Google Scholar]
  3. Shigehisa H., Takayama J., Honda T.. The first total synthesis of (±)-annosqualine by means of oxidative enamide–phenol coupling: pronounced effect of phenoxide formation on the phenol oxidation mechanism. Tetrahedron Lett. 2006;47:7301–7306. doi: 10.1016/j.tetlet.2006.08.028. [DOI] [Google Scholar]
  4. Zhang Y. L., Ge H. M., Zhao W., Dong H., Xu Q., Li S. H., Li J., Zhang J., Song Y. C., Tan R. X.. Unprecedented Immunosuppressive Polyketides from Daldinia eschscholzii, a Mantis-Associated Fungus. Angew. Chem., Int. Ed. 2008;47:5823–5826. doi: 10.1002/anie.200801284. [DOI] [PubMed] [Google Scholar]
  5. Pirrung M. C., Brown W. L., Rege S., Laughton P.. Total synthesis of (+)-griseofulvin. J. Am. Chem. Soc. 1991;113:8561–8562. doi: 10.1021/ja00022a075. [DOI] [Google Scholar]
  6. Díaz-Marrero A. R., Porras G., Aragón Z., de la Rosa J. M., Dorta E., Cueto M., D’Croz L., Maté J., Darias J.. Carijodienone from the Octocoral Carijoa multiflora. A Spiropregnane-Based Steroid. J. Nat. Prod. 2011;74:292–295. doi: 10.1021/np1007608. [DOI] [PubMed] [Google Scholar]
  7. Xu R.-Q., Gu Q., Wu W.-T., Zhao Z.-A., You S.-L.. Construction of Erythrinane Skeleton via Pd(0)-Catalyzed Intramolecular Dearomatization of para-Aminophenols. J. Am. Chem. Soc. 2014;136:15469–15472. doi: 10.1021/ja508645j. [DOI] [PubMed] [Google Scholar]
  8. Zheng Y.-J., Tice C. M.. The utilization of spirocyclic scaffolds in novel drug discovery. Expert Opin. Drug Discovery. 2016;11:831–834. doi: 10.1080/17460441.2016.1195367. [DOI] [PubMed] [Google Scholar]
  9. a Nam N.-H.. Naturally Occurring NF-κB Inhibitors. Mini-Rev. Med. Chem. 2006;6:945–951. doi: 10.2174/138955706777934937. [DOI] [PubMed] [Google Scholar]; b Roche S. P., Porco J. A. Jr.. Dearomatization Strategies in the Synthesis of Complex Natural Products. Angew. Chem., Int. Ed. 2011;50:4068–4093. doi: 10.1002/anie.201006017. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Zheng Y., Tice C. M., Singh S. B.. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett. 2014;24:3673–3682. doi: 10.1016/j.bmcl.2014.06.081. [DOI] [PubMed] [Google Scholar]
  10. a Swenton J. S., Callinan A., Chen Y., Rohde J. J., Kerns M. L., Morrow G. W.. Intramolecular Anodic Carbon–Carbon Bond Formation from Oxidized Phenol Intermediates. Effect of Oxygenated Substituents on the Yields of Spiro Dienones in Electrochemical and Iodobenzene Diacetate Oxidations. J. Org. Chem. 1996;61:1267–1274. doi: 10.1021/jo951799d. [DOI] [Google Scholar]; b Dohi T., Minamitsuji Y., Maruyama A., Hirose S., Kita Y.. A New H2O2/Acid Anhydride System for the Iodoarene-Catalyzed C–C Bond-Forming Reactions of Phenols. Org. Lett. 2008;10:3559–3562. doi: 10.1021/ol801321f. [DOI] [PubMed] [Google Scholar]; c Zheng Z., Zhang-Negrerie D., Du Y., Zhao K.. The applications of hypervalent iodine­(III) reagents in the constructions of heterocyclic compounds through oxidative coupling reactions. Sci. China:Chem. 2014;57:189–214. doi: 10.1007/s11426-013-5043-1. [DOI] [Google Scholar]; d Yoshimura A., Zhdankin V. V.. Advances in Synthetic Applications of Hypervalent Iodine Compounds. Chem. Rev. 2016;116:3328–3435. doi: 10.1021/acs.chemrev.5b00547. [DOI] [PubMed] [Google Scholar]
  11. Yang Y., Jiang K., Zeng G., Yin B.. Transition Metal-Catalyzed Dearomative Vinylation of Electron Rich Benzenes, Naphthalenes and Indoles with Alkynes. Adv. Synth. Catal. 2023;365:270–294. doi: 10.1002/adsc.202201285. [DOI] [Google Scholar]
  12. a Wu Q.-F., Liu W.-B., Zhuo C.-X., Rong Z.-Q., Ye K.-Y., You S.-L.. Iridium-Catalyzed Intramolecular Asymmetric Allylic Dearomatization of Phenols. Angew. Chem., Int. Ed. 2011;50:4455–4458. doi: 10.1002/anie.201100206. [DOI] [PubMed] [Google Scholar]; b Wu W.-T., Xu R.-Q., Zhang L., You S.-L.. Construction of spirocarbocycles via gold-catalyzed intramolecular dearomatization of naphthols. Chem. Sci. 2016;7:3427–3431. doi: 10.1039/C5SC04130A. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Wang Y., Zhang W.-Y., Xie J.-H., Yu Z.-L., Tan J.-H., Zheng C., Hou X.-L., You S.-L.. Enantioselective Desymmetrization of Bisphenol Derivatives via Ir-Catalyzed Allylic Dearomatization. J. Am. Chem. Soc. 2020;142:19354–19359. doi: 10.1021/jacs.0c09638. [DOI] [PubMed] [Google Scholar]
  13. a Nan J., Zuo Z., Luo L., Bai L., Zheng H., Yuan Y., Liu J., Luan X., Wang Y.. RuII-Catalyzed Vinylative Dearomatization of Naphthols via a C­(sp2)–H Bond Activation Approach. J. Am. Chem. Soc. 2013;135:17306–17309. doi: 10.1021/ja410060e. [DOI] [PubMed] [Google Scholar]; b Gu S., Luo L., Liu J., Bai L., Zheng H., Wang Y., Luan X.. Palladium­(II)-Catalyzed Oxidative Dearomatization of Free Naphthols with Two Alkyne Units. Org. Lett. 2014;16:6132–6135. doi: 10.1021/ol502997d. [DOI] [PubMed] [Google Scholar]; c Zheng H., Bai L., Liu J., Nan J., Zuo Z., Yang L., Wang Y., Luan X.. Pd­(0)-catalyzed chemoselective construction of spirocarbocycles via an alkyne insertion/β-naphthol dearomatization cascade. Chem. Commun. 2015;51:3061–3064. doi: 10.1039/C4CC09099C. [DOI] [PubMed] [Google Scholar]; d Bai L., Yuan Y., Liu J., Wu J., Han L., Wang H., Wang Y., Luan X.. Palladium­(0)-Catalyzed Intermolecular Carbocyclization of (1,n)-Diynes and Bromophenols: An Efficient Route to Tricyclic Scaffolds. Angew. Chem., Int. Ed. 2016;55:6946–6950. doi: 10.1002/anie.201601570. [DOI] [PubMed] [Google Scholar]; e Luo L., Zheng H., Liu J., Wang H., Wang Y., Luan X.. Highly Chemo- and Regioselective Construction of Spirocarbocycles by a Pd(0)-Catalyzed Dearomatization of Phenol-Based Biaryls with 1,3-Dienes. Org. Lett. 2016;18:2082–2085. doi: 10.1021/acs.orglett.6b00710. [DOI] [PubMed] [Google Scholar]; f Fan L., Liu J., Bai L., Wang Y., Luan X.. Rapid Assembly of Diversely Functionalized Spiroindenes by a Three-Component Palladium-Catalyzed C–H Amination/Phenol Dearomatization Domino Reaction. Angew. Chem., Int. Ed. 2017;56:14257–14261. doi: 10.1002/anie.201708310. [DOI] [PubMed] [Google Scholar]; g Hu W., Wang H., Bai L., Liu J., Luan X.. Pd­(0)-Catalyzed Intermolecular Dearomatizing [3 + 2] Spiroannulation of Phenol-Based Biaryls and Allenes. Org. Lett. 2018;20:880–883. doi: 10.1021/acs.orglett.8b00014. [DOI] [PubMed] [Google Scholar]; h Nan J., Yuan Y., Bai L., Liu J., Luan X.. Highly Chemoselective Construction of Spiro­[4,5]­decane-Embedded Polycyclic Scaffolds by a Palladium/Norbornene-Catalyzed C–H Activation/Arene Dearomatization Reaction. Org. Lett. 2018;20:7731–7734. doi: 10.1021/acs.orglett.8b03518. [DOI] [PubMed] [Google Scholar]
  14. a Nemoto T., Ishige Y., Yoshida M., Kohno Y., Kanematsu M., Hamada Y.. Novel Method for Synthesizing Spiro[4.5]­cyclohexadienones through a Pd-Catalyzed Intramolecular ipso-Friedel–Crafts Allylic Alkylation of Phenols. Org. Lett. 2010;12:5020–5023. doi: 10.1021/ol102190s. [DOI] [PubMed] [Google Scholar]; b Nemoto T., Nozaki T., Yoshida M., Hamada Y.. Palladium-Catalyzed Intramolecular ipso-Friedel–Crafts Allylic Alkylation of Phenols via Arylative Activation of Allenes. Adv. Synth. Catal. 2013;355:2693–2700. doi: 10.1002/adsc.201300326. [DOI] [Google Scholar]; c Nemoto T., Zhao Z., Yokosaka T., Suzuki Y., Wu R., Hamada Y.. Palladium-Catalyzed Intramolecular ipso-Friedel–Crafts Alkylation of Phenols and Indoles: Rearomatization-Assisted Oxidative Addition. Angew. Chem., Int. Ed. 2013;52:2217–2220. doi: 10.1002/anie.201209317. [DOI] [PubMed] [Google Scholar]; d Nemoto T., Matsuo N., Hamada Y.. Gold-Catalyzed Carbocyclization of Phenols with a Terminal Alkyne via an Intramolecular ipso-Friedel–Crafts Alkenylation. Adv. Synth. Catal. 2014;356:2417–2421. doi: 10.1002/adsc.201400247. [DOI] [Google Scholar]
  15. a Rousseaux S., García-Fortanet J., Del Aguila Sanchez M. A., Buchwald S. L.. Palladium­(0)-Catalyzed Arylative Dearomatization of Phenols. J. Am. Chem. Soc. 2011;133:9282–9285. doi: 10.1021/ja203644q. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Schmidt B., Berger R., Kelling A., Schilde U.. Pd-Catalyzed [2 + 2+1] Coupling of Alkynes and Arenes: Phenol Diazonium Salts as Mechanistic Trapdoors. Chem. Eur. J. 2011;17:7032–7040. doi: 10.1002/chem.201100609. [DOI] [PubMed] [Google Scholar]; c Ma C., Huang Y., Zhao Y.. Stereoselective 1,6-Conjugate Addition/Annulation of para-Quinone Methides with Vinyl Epoxides/Cyclopropanes. ACS Catal. 2016;6:6408–6412. doi: 10.1021/acscatal.6b01845. [DOI] [Google Scholar]; d Nakayama H., Harada S., Kono M., Nemoto T.. Chemoselective Asymmetric Intramolecular Dearomatization of Phenols with α-Diazoacetamides Catalyzed by Silver Phosphate. J. Am. Chem. Soc. 2017;139:10188–10191. doi: 10.1021/jacs.7b04813. [DOI] [PubMed] [Google Scholar]; e Xia Y., Wang L.-J., Wang J., Chen S., Shen Y., Guo C.-H., Liang Y.-M.. Palladium-Catalyzed Construction of Tetracyclic Scaffolds via the 1,7-Enyne Carbocyclization/Iodophenol Dearomatization Cascade. J. Org. Chem. 2017;82:12386–12394. doi: 10.1021/acs.joc.7b02196. [DOI] [PubMed] [Google Scholar]; f Vacala T. L., Carlson P. R., Arreola-Hester A., Williams C. G., Makhoul E. W., Vadola P. A.. Gold-Catalyzed Dearomative Spirocyclization of N-Aryl Alkynamides for the Synthesis of Spirolactams. J. Org. Chem. 2018;83:1493–1501. doi: 10.1021/acs.joc.7b03125. [DOI] [PubMed] [Google Scholar]; g Yu J.-S., Espinosa M., Noda H., Shibasaki M.. Traceless Electrophilic Amination for the Synthesis of Unprotected Cyclic β-Amino Acids. J. Am. Chem. Soc. 2019;141:10530–10537. doi: 10.1021/jacs.9b05476. [DOI] [PubMed] [Google Scholar]; h Gilmartin P. H., Kozlowski M. C.. Vanadium-Catalyzed Oxidative Intramolecular Coupling of Tethered Phenols: Formation of Phenol-Dienone Products. Org. Lett. 2020;22:2914–2919. doi: 10.1021/acs.orglett.0c00577. [DOI] [PMC free article] [PubMed] [Google Scholar]; i Jia Z.-L., An X.-T., Deng Y.-H., Wang H.-B., Gan K.-J., Zhang J., Zhao X.-H., Fan C.-A.. Palladium-Catalyzed Asymmetric (2 + 3) Annulation of p-Quinone Methides with Trimethylenemethanes: Enantioselective Synthesis of Functionalized Chiral Spirocyclopentyl p-Dienones. Org. Lett. 2020;22:4171–4175. doi: 10.1021/acs.orglett.0c01252. [DOI] [PubMed] [Google Scholar]; j Mu X., Yu H., Peng H., Xiong W., Wu T., Tang W.. Construction of Various Bridged Polycyclic Skeletons by Palladium-Catalyzed Dearomatization. Angew. Chem., Int. Ed. 2020;59:8143–8147. doi: 10.1002/anie.202000953. [DOI] [PubMed] [Google Scholar]; k Lee E., Hwang Y., Kim Y. B., Kim D., Chang S.. Enantioselective Access to Spirolactams via Nitrenoid Transfer Enabled by Enhanced Noncovalent Interactions. J. Am. Chem. Soc. 2021;143:6363–6369. doi: 10.1021/jacs.1c02550. [DOI] [PubMed] [Google Scholar]; l Liu A., Chi D., Chen S.. Palladium-Catalyzed Cascade Allylative Dicarbofunctionalization of Aryl Phenol-Tethered Alkynes with Allyl Iodides: Synthesis of Skipped Dienes. Org. Lett. 2021;23:8333–8337. doi: 10.1021/acs.orglett.1c03073. [DOI] [PubMed] [Google Scholar]; m Li X., Guo J.-X., Zhang J., Chen Q.-Y., He Y.-J., Sha F., Xiang H., Yu P., Liu P.-N.. Asymmetric Dearomatization of Nonfunctionalized 1-Naphthols via Copper-Catalyzed Enantioselective [4 + 1] Spiroannulation. ACS Catal. 2024;14:9244–9253. doi: 10.1021/acscatal.4c01563. [DOI] [Google Scholar]
  16. a Han G., Wang Q., Liu Y., Wang Q.. Copper-Mediated α-Trifluoromethylation of N-Phenylcinnamamides Coupled with Dearomatization: Access to Trifluoromethylated 1-Azaspiro[4.5]­decanes. Org. Lett. 2014;16:5914–5917. doi: 10.1021/ol502921a. [DOI] [PubMed] [Google Scholar]; b Jin D.-P., Gao P., Chen D.-Q., Chen S., Wang J., Liu X.-Y., Liang Y.-M.. AgSCF3-Mediated Oxidative Trifluoromethythiolation of Alkynes with Dearomatization to Synthesize SCF3-Substituted Spiro­[4,5]­trienones. Org. Lett. 2016;18:3486–3489. doi: 10.1021/acs.orglett.6b01702. [DOI] [PubMed] [Google Scholar]; c Yu L.-Z., Xu Q., Tang X.-Y., Shi M.. Iron- or Copper-Catalyzed Trifluoromethylation of Acrylamide-Tethered Alkylidenecyclopropanes: Facile Synthesis of CF3-Containing Polycyclic Benzazepine Derivatives. ACS Catal. 2016;6:526–531. doi: 10.1021/acscatal.5b02400. [DOI] [Google Scholar]; d Zhang Y., Zhang J., Hu B., Ji M., Ye S., Zhu G.. Synthesis of Difluoromethylated and Phosphorated Spiro[5.5]­trienones via Dearomative Spirocyclization of Biaryl Ynones. Org. Lett. 2018;20:2988–2992. doi: 10.1021/acs.orglett.8b01027. [DOI] [PubMed] [Google Scholar]; e Wu J., Ma D., Tang G., Zhao Y.. Copper-Catalyzed Phosphonylation/Trifluoromethylation of N-p-NO2-Benzoylacrylamides Coupled with Dearomatization and Denitration. Org. Lett. 2019;21:7674–7678. doi: 10.1021/acs.orglett.9b03034. [DOI] [PubMed] [Google Scholar]; f Ge Y., Qin C., Bai L., Hao J., Liu J., Luan X.. A Dearomatization/Debromination Strategy for the [4 + 1] Spiroannulation of Bromophenols with α,β-Unsaturated Imines. Angew. Chem., Int. Ed. 2020;59:18985–18989. doi: 10.1002/anie.202008130. [DOI] [PubMed] [Google Scholar]; g Reddy C. R., Kolgave D. H., Subbarao M., Aila M., Prajapti S. K.. Ag-Catalyzed Oxidative ipso-Cyclization via Decarboxylative Acylation/Alkylation: Access to 3-Acyl/Alkyl-spiro[4.5]­trienones. Org. Lett. 2020;22:5342–5346. doi: 10.1021/acs.orglett.0c01588. [DOI] [PubMed] [Google Scholar]; h He F.-S., Su L., Yu F., Tang Z., Wu J.. Construction of sulfonated spiro­[5,5]­trienones from sulfur dioxide via iron-catalyzed dearomative spirocyclization of biaryls. Org. Chem. Front. 2022;9:1937–1942. doi: 10.1039/D2QO00120A. [DOI] [Google Scholar]
  17. a Dong W., Yuan Y., Gao X., Keranmu M., Li W., Xie X., Zhang Z.. Visible-Light-Induced Intermolecular Dearomative Cyclization of 2-Bromo-1,3-dicarbonyl Compounds and Alkynes: Synthesis of Spiro[4.5]­deca-1,6,9-trien-8-ones. Org. Lett. 2018;20:5762–5765. doi: 10.1021/acs.orglett.8b02463. [DOI] [PubMed] [Google Scholar]; b Soni V. K., Hwang H. S., Moon Y. K., Park S.-W., You Y., Cho E. J.. Generation of N-Centered Radicals via a Photocatalytic Energy Transfer: Remote Double Functionalization of Arenes Facilitated by Singlet Oxygen. J. Am. Chem. Soc. 2019;141:10538–10545. doi: 10.1021/jacs.9b05572. [DOI] [PubMed] [Google Scholar]; c Dong W., Yuan Y., Xie X., Zhang Z.. Visible-Light-Driven Dearomatization Reaction toward the Formation of Spiro[4.5]­deca-1,6,9-trien-8-ones. Org. Lett. 2020;22:528–532. doi: 10.1021/acs.orglett.9b04283. [DOI] [PubMed] [Google Scholar]; d Cheng Y.-Z., Feng Z., Zhang X., You S.-L.. Visible-light induced dearomatization reactions. Chem. Soc. Rev. 2022;51:2145–2170. doi: 10.1039/C9CS00311H. [DOI] [PubMed] [Google Scholar]; e Azpilcueta-Nicolas C. R., Meng D., Edelmann S., Lumb J.-P.. Dearomatization of Biaryls through Polarity Mismatched Radical Spirocyclization. Angew. Chem., Int. Ed. 2023;62:e202215422. doi: 10.1002/anie.202215422. [DOI] [PubMed] [Google Scholar]; f Yuan P.-F., Huang X.-T., Long L., Huang T., Sun C.-L., Yu W., Wu L.-Z., Chen H., Liu Q.. Regioselective Dearomative Amidoximation of Nonactivated Arenes Enabled by Photohomolytic Cleavage of N-nitrosamides. Angew. Chem., Int. Ed. 2024;63:e202317968. doi: 10.1002/anie.202317968. [DOI] [PubMed] [Google Scholar]; g Deng C., Wu H., Li S., Chen L., Liu X., Liu P.. Dearomative 1,4-Difunctionalization of Non-Activated Arenes Enabled by Boryl Radical-Mediated Halogen-Atom Transfer. ACS Catal. 2025;15:1294–1304. doi: 10.1021/acscatal.4c06628. [DOI] [Google Scholar]
  18. a Zhang Y., Ma C., Struwe J., Feng J., Zhu G., Ackermann L.. Electrooxidative dearomatization of biaryls: synthesis of tri- and difluoromethylated spiro[5.5]­trienones. Chem. Sci. 2021;12:10092–10096. doi: 10.1039/D1SC02682H. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Li N., Shi Z., Yuan Y., Li Z., Ye K.-Y.. Rapid synthesis of spirodienones via electrochemical dearomative spirocyclization in flow. Org. Chem. Front. 2022;9:6586–6591. doi: 10.1039/D2QO01392D. [DOI] [Google Scholar]; c Wan J.-L., Huang J.-M.. Electrochemical Dearomative Amination of Phenol Derivatives: Access to Spirooxazolidinones. Adv. Synth. Catal. 2023;365:1211–1216. doi: 10.1002/adsc.202300118. [DOI] [Google Scholar]
  19. Farndon J. J., Ma X., Bower J. F.. Transition Metal Free C–N Bond Forming Dearomatizations and Aryl C–H Aminations by in Situ Release of a Hydroxylamine-Based Aminating Agent. J. Am. Chem. Soc. 2017;139:14005–14008. doi: 10.1021/jacs.7b07830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. a Zhang Y.-Q., Chen Y.-B., Liu J.-R., Wu S.-Q., Fan X.-Y., Zhang Z.-X., Hong X., Ye L.-W.. Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides. Nat. Chem. 2021;13:1093–1100. doi: 10.1038/s41557-021-00778-z. [DOI] [PubMed] [Google Scholar]; b Li H.-H., Zhang Y.-P., Zhai T.-Y., Liu B.-Y., Shi C.-Y., Zhou J.-M., Ye L.-W.. Metal-free dearomatization reactions of naphthol-ynamides for the divergent and enantioselective synthesis of azaspirocycles. Org. Chem. Front. 2022;9:3709–3717. doi: 10.1039/D2QO00685E. [DOI] [Google Scholar]
  21. a Tan T.-D., Qian G.-L., Su H.-Z., Zhu L.-J., Ye L.-W., Zhou B., Hong X., Qian P.-C.. Brønsted acid–catalyzed asymmetric dearomatization for synthesis of chiral fused polycyclic enone and indoline scaffolds. Sci. Adv. 2023;9:eadg4648. doi: 10.1126/sciadv.adg4648. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Fu W., Fu Y., Zhao Y., Wang H., Liu P., Yang Y.. A metalloenzyme platform for catalytic asymmetric radical dearomatization. Nat. Chem. 2024;16:1999–2008. doi: 10.1038/s41557-024-01608-8. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Yang T.-T., Zhang Y.-Q., Xie M.-S., Tian Y., Wang D.-C., Guo H.-M.. Dearomative [2 + 1] Spiroannulation of Bromophenols with Electron-Deficient Alkenes. J. Org. Chem. 2024;89:8041–8054. doi: 10.1021/acs.joc.4c00680. [DOI] [PubMed] [Google Scholar]
  22. Gu X., Wei Y., Shi M.. Construction of polysubstituted spiro[2.3] or [3.3] cyclic frameworks fused with a tosylated pyrrolidine promoted by visible-light-induced photosensitization. Org. Chem. Front. 2021;8:6823–6829. doi: 10.1039/D1QO01373D. [DOI] [Google Scholar]
  23. a Gopalaiah K., Kagan H. B.. Use of Nonfunctionalized Enamides and Enecarbamates in Asymmetric Synthesis. Chem. Rev. 2011;111:4599–4657. doi: 10.1021/cr100031f. [DOI] [PubMed] [Google Scholar]; b Sun X., Lyu Y., Zhang-Negrerie D., Du Y., Zhao K.. Formation of Functionalized 2H-Azirines through PhIO-Mediated Trifluoroethoxylation and Azirination of Enamines. Org. Lett. 2013;15:6222–6225. doi: 10.1021/ol4030716. [DOI] [PubMed] [Google Scholar]; c Wang M.-X.. Exploring tertiary enamides as versatile synthons in organic synthesis. Chem. Commun. 2015;51:6039–6049. doi: 10.1039/C4CC10327K. [DOI] [PubMed] [Google Scholar]; d Beltran F., Miesch L.. Tertiary Enamides as Versatile and Valuable Substrates to Reach Chemical Diversity. Synthesis. 2020;52:2497–2511. doi: 10.1055/s-0040-1707403. [DOI] [Google Scholar]; e Lyu M.-Y., Zhong Z., Lo V. K.-Y., Wong H. N. C., Peng X.-S.. Total Synthesis of Cryptotrione. Angew. Chem., Int. Ed. 2020;59:19929–19933. doi: 10.1002/anie.202009255. [DOI] [PubMed] [Google Scholar]; f Bouchet D., Varlet T., Masson G.. Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,β-Substituted Amines. Acc. Chem. Res. 2022;55:3265–3283. doi: 10.1021/acs.accounts.2c00540. [DOI] [PubMed] [Google Scholar]; g Lei T., Cheng Y.-Y., Han X., Zhou C., Yang B., Fan X.-W., Chen B., Tung C.-H., Wu L.-Z.. Lewis Acid-Relayed Singlet Oxygen Reaction with Enamines: Selective Dimerization of Enamines to Pyrrolin-4-ones. J. Am. Chem. Soc. 2022;144:16667–16675. doi: 10.1021/jacs.2c07450. [DOI] [PubMed] [Google Scholar]
  24. a Canesi S., Belmont P., Bouchu D., Rousset L., Ciufolini M. A.. Efficient oxidative spirocyclization of phenolic sulfonamides. Tetrahedron Lett. 2002;43:5193–5195. doi: 10.1016/S0040-4039(02)00949-8. [DOI] [Google Scholar]; b Liang H., Ciufolini M. A.. Oxidative Spirocyclization of Phenolic Sulfonamides: Scope and Applications. Chem. Eur. J. 2010;16:13262–13270. doi: 10.1002/chem.201001402. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au6c00074_si_001.pdf (12.7MB, pdf)

Data Availability Statement

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

Articles from JACS Au are provided here courtesy of American Chemical Society

RESOURCES