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Abbreviation (ISO4): Prog Chem      Editor in chief: Jincai ZHAO

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Progress in Chemistry >

2024 , Vol. 36 >Issue 12: 1785 - 1829

DOI: https://doi.org/10.7536/PC241203

Chemistry: A Century of Life-Special Edition

The Development and Perspective of Dearomatization Reaction

  • Yuan-Zheng Cheng , * ,
  • Muzi Li ,
  • Rui-Xiang Wang ,
  • Long-Hao Zhu ,
  • Wen-Jie Shen ,
  • Xin-Xuan Zou ,
  • Qing Gu ,
  • Shu-Li You , *
Expand
  • New Cornerstone Science Laboratory, State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
* (Yuan-Zheng Cheng);
(Shu-Li You)

Received date: 2024-12-02

  Revised date: 2024-12-20

  Online published: 2025-01-21

Supported by

National Natural Science Foundation of China(22031012)

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Abstract

Representing an important class of ubiquitous chemical feedstock, aromatics have been extensively utilized in the nucleophilic aromatic substitution (SNAr) reactions, nitration reactions, Friedel-Crafts alkylation and acylation reactions, cross-coupling reactions, C-H bond functionalization reactions etc. Dearomatization reaction is another type of transformations of aromatics, in which their aromaticity is destroyed or reduced. Since its first report, dearomatization reaction has served as an efficient platform to create C(sp3)-H-rich spiro, fused and bridged polycyclic structures, widely applied in material and medicinal chemistry. In the past two decades, various dearomatization reactions have been established by using transition-metal catalysis, organocatalysis, enzymatic catalysis, photocatalysis, and electrocatalysis. Diverse polycyclic structures have been obtained by the dearomatization of indoles, pyrroles, (benzo)furans, (benzo)thiophenes, quinolines, pyridines, benzenes, naphthalenes, etc. The coupling reagents, including nucleophiles, electrophiles, dipoles, radicals, and carbenes have been developed to assemble different functional groups on dearomative framework. In this review, we briefly summarized the developed dearomatization reactions, which were categorized by the kinds of aromatic compounds. The remaining challenges and perspectives on the future development of dearomatization reactions are also included here.

Contents

1 Introduction

2 Indoles and pyrroles

2.1 Hydrogenation reactions

2.2 Oxidative dearomatization reactions

2.3 Dearomatization reactions with electrophiles

2.4 Dearomatization reactions with nucleophiles

2.5 Dearomatization reactions with radicals

3 Benzofurans and furans

3.1 Dearomatization reactions with nucleophiles

3.2 Dearomatization reactions with electrophiles

3.3 Dearomatization reactions with radicals

3.4 Cycloaddition dearomatization reactions

4 Benzothiophenes and thiophenes

4.1 Hydrogenation reactions

4.2 Dearomatization reactions with nucleophiles

4.3 Dearomatization reactions with electrophiles

4.4 Dearomatization reactions with radicals

4.5 Cycloaddition dearomatization reactions

4.6 Ring expansion dearomatization reactions

4.7 Dearomatization reactions with carbenes

5 Phenols and naphthols

5.1 Hydrogenation reactions

5.2 Oxidative dearomatization reactions

5.3 Dearomatization reactions with nucleophiles

5.4 Dearomatization reactions with electrophiles

5.5 Dearomatization reactions with radicals

5.6 Dearomatization reactions based on η2 or η6 complex

6 Anilines

6.1 Catalytic hydrogenation reactions

6.2 Oxidative dearomatization reactions

6.3 Dearomatization reactions with nucleophiles

6.4 Dearomatization reactions with radicals

6.5 Dearomatization reactions based on η2 complex

7 Pyridines and (iso)quinolines

7.1 Hydrogenation reactions

7.2 Dearomatization reactions with nucleophiles

7.3 Dearomatization reactions with electrophiles

7.4 Dearomatization reactions with dipoles

7.5 Dearomatization reactions with radicals

8 Benzenes and naphthalenes

8.1 Hydrogenation reactions

8.2 Oxidative dearomatization reactions

8.3 Dearomatization reactions with nucleophiles

8.4 Dearomatization reactions with electrophiles

8.5 Dearomatization reactions with radicals

8.6 Cycloaddition dearomatization reactions

8.7 Dearomatization reactions with carbenes

8.8 Rearrangement dearomatization reactions

9 Other arenes

10 Conclusion and outlook

Key words： aromatic compounds; asymmetric catalysis; dearomatization reactions; saturated polycyclic compounds

Cite this article

Yuan-Zheng Cheng , Muzi Li , Rui-Xiang Wang , Long-Hao Zhu , Wen-Jie Shen , Xin-Xuan Zou , Qing Gu , Shu-Li You . The Development and Perspective of Dearomatization Reaction[J]. Progress in Chemistry, 2024 , 36(12) : 1785 -1829 . DOI: 10.7536/PC241203

1 Introduction

Aromatic compounds, originally a type of organic substance extracted from plant resins, were named for their fragrant smell. In 1825, the British physicist Faraday isolated benzene from coal tar. In 1834, the German chemist Mitscherlich determined the chemical formula of benzene to be C6H6. Since then, the exploration of the structure of benzene has never ceased. In 1865, the German organic chemist Kekule proposed that benzene consists of six carbon atoms connected in an alternating pattern of single and double bonds in a ring. Later, this structural formula was called the Kekule structure. In 1931, the German scientist Hückel proposed that aromatic compounds are planar cyclic conjugated monorings with (4n+2) π electrons. With the development of quantum chemistry, people's understanding of aromatic compounds and aromaticity has deepened, leading to the proposal of concepts such as hyperconjugative aromaticity, three-dimensional aromaticity, metal aromaticity, and global aromaticity.
Nowadays, aromatic compounds are one of the most fundamental bulk chemicals, mainly derived from the coal and petroleum industries. For some common aromatic compounds, such as benzene, the annual production is in the tens of millions of tons. Aromatic compounds are primarily used to manufacture plastics, synthetic fibers, resins, dyes, rubbers, lubricants, pesticides, detergents, and pharmaceuticals, serving various sectors including textiles, automobiles, construction, electrical, and electronics. To meet the growing demands of people's lives, chemical transformations based on aromatic compounds have been successively discovered and widely applied, such as aromatic nucleophilic substitution reactions, nitration reactions, Friedel-Crafts alkylation, acylation reactions, coupling reactions, and C—H bond functionalization reactions. In these reactions, the aromaticity of the reactants is preserved, and the resulting products remain planar structures.
De-aromatization reactions, which achieve the removal or weakening of aromaticity in aromatic compounds, have a long history. In 1884, when Auwers attempted the Reimer-Tiemann reaction with 4-methylphenol, in addition to the 2-formyl product, he also obtained 4-dichloromethylated cyclohexadienone, thus opening the curtain on de-aromatization (Figure 1a)[1]. In 1885, Buchner and Curtius[3] discovered that under continuous boiling conditions, benzene reacted with ethyl diazoacetate to produce ethyl heptatrienoate through a ring-expansion reaction (Figure 1b)[2]. In 1944, Birch found that benzene was reduced to 1,4-cyclohexadiene in sodium/liquid ammonia solution (Figure 1c). In 1957, Blair and Bryce-Smith et al.[4] discovered that benzene, under mercury vapor lamp irradiation, would transform into a yellow compound, fulvene, even though the conversion rate was very low; this reaction was still regarded as the first report of direct isomerization from an aromatic compound to a non-aromatic carbohydrate (Figure 1d). Soon after, photo-promoted cycloaddition reactions between benzene and alkenes developed rapidly (Figure 1e)[5]. However, issues such as poor chemoselectivity and complex product types remained unsolved. In the 1960s, complexes of benzene with transition metals (such as C6H6Cr(CO)3) were synthesized and used for de-aromatization reactions[6].
图1 去芳构化反应的发展历史[1⇓⇓⇓-5]

Fig. 1 The history of dearomatization reactions[1⇓⇓⇓-5]

Defunctionalization reactions have greatly improved the synthesis efficiency of some important natural products. In 1954, Woodward et al.[7]utilized Pictet-Spengler type reactions to develop indole defunctionalization and applied it to the synthesis of strychnine (Figure 2a). In 1960, Day et al.[8]inspired by biosynthetic pathways, used the defunctionalization reaction of phenol as a key step and first completed the total synthesis of the racemate of griseofulvin (Figure 2b).
图2 去芳构化反应在天然产物合成中的应用[7,8]

Fig. 2 The dearomatization reactions in total synthesis[7,8]

Until now, dearomatization reactions have become an efficient method for rapidly obtaining cyclic compounds such as spirocycles, fused rings, and bridged rings, providing novel molecular scaffolds and entities for new drug discovery, and their role in synthetic and medicinal chemistry is becoming increasingly prominent. With the rapid development of transition metal catalysis, small molecule catalysis, and photo/electrocatalysis, the types and systems of dearomatization reactions are advancing, and asymmetric catalytic dearomatization has also made significant progress. This article summarizes dearomatization reactions of aromatic compounds and their derivatives, including indoles, pyrroles, phenols, naphthols, anilines, (benzo)furans, (benzo)thiophenes, (iso)quinolines, pyridines, benzenes, and naphthalenes, based on the types of aromatic systems, and categorizes the commonly used electrophiles and nucleophiles in dearomatization reactions, which is conducive to a deeper understanding of this field.

2 Indole and Pyrrole

2.1 Hydrogenation-Induced Dearomatization Reaction

As early as 1882, Ciamician and Dennsted[9] used acetic acid as a solvent and zinc powder as a reductant to first report the hydrogenation de-aromatization of pyrrole, obtaining a mixture of dihydropyrrole and tetrahydropyrrole (Figure 3). In 1901, Knorr and Rabe[10] replaced acetic acid with hydrochloric acid, developing a pyrrole reduction reaction promoted by metals such as iron/tin, which had better substrate compatibility. In 1912, Willsttter et al.[11] used acetic acid as a solvent and platinum powder as a catalyst to achieve the catalytic hydrogenation of pyrrole, yielding tetrahydropyrrole. The reaction conditions were harsh, and the conversion rate was slow. In 1921, Willsttter et al.[12] found that palladium or platinum, when combined with oxygen, exhibited better catalytic activity. In 1929, Andrews et al.[13] used platinum dioxide for the catalytic hydrogenation of pyrrole under a hydrogen atmosphere, achieving a yield of 65%. However, the catalyst would become deactivated during the reaction, requiring additional supplementation. In 1930, Howard and Cramer[14] reported nickel-catalyzed hydrogenation of pyrrole at 200 ℃. Thereafter, metals such as copper and Raney nickel were also used in the catalytic hydrogenation of pyrrole. However, due to side reactions such as oxidation or polymerization, these reactions did not have ideal yields[15]. Recently developed rhodium catalysts have achieved the hydrogenation conversion of simple pyrroles in equimolar yields[16].
图3 吡咯的氢化反应[9⇓⇓⇓⇓⇓⇓-16]

Fig. 3 Hydrogenation reactions of pyrroles[9⇓⇓⇓⇓⇓⇓-16]

In 1925, Braun and Bayer et al.[18] reported the complete hydrogenation of indole to 2-ethylcyclohexylamine at 200 ℃. Under the same conditions, 2-methylindole and 3-methylindole could only yield octahydroindole derivatives; increasing the reaction temperature to 240 ℃ resulted in the formation of reduced ring-opened products[17]. Subsequently, catalysts such as copper chromite and Raney nickel were used for the selective hydrogenation of indoles (Figure 4).
图4 吲哚的氢化反应[17-18]

Fig. 4 Hydrogenation reactions of indoles[17-18]

In 2000, Ito et al. [19] used the chiral ferrocene-based bidentate phosphine ligand PhTRAP (L1), developing the first example of asymmetric hydrogenation of indole derivatives (Figure 5a). In 2008, the Kuwano group [20] utilized this ligand to report the ruthenium-catalyzed asymmetric hydrogenation of substituted pyrroles (Figure 5b). Asymmetric hydrogenation of indoles catalyzed by iridium and palladium has also been reported [21]. Additionally, after protonation with strong acids, pyrroles can undergo reduction reactions more easily [22]. The resulting tetrahydropyrrole is also protonated by strong acids, avoiding poisoning of the catalyst. In 2011, the Zhou Yonggui group [23] reported the palladium/Tunephos (L2)-catalyzed asymmetric hydrogenation of pyrroles in the presence of ethanesulfonic acid (Figure 5c).
图5 吲哚/吡咯的不对称氢化反应[19,20,23]

Fig. 5 Asymmetric hydrogenation reactions of indoles/ pyrroles[19,20,23]

Initially, Birch reduction was not applicable to simple pyrroles and indoles. In 1960, O'Brien and Smith et al.[24] first reported the Birch reduction of indoles (Figure 6a). The reaction achieved the Birch reduction of indoles by adding a small amount of methanol to the lithium/liquid ammonia solution, but it still could not reduce simple pyrroles. In 1967, the Weiss group[25] found that by changing the order of methanol addition, it was possible to selectively reduce either the benzene ring or the pyrrole ring in indoles. In 1996, Donohoe and Guyo[26] first reported the Birch reduction/sequential alkylation dearomatization reaction of electron-withdrawing group-substituted pyrroles (Figure 6b). When the substituent at the 1-position changed from methyl to Boc, the yield significantly improved. Additionally, lithium/liquid ammonia has also been used for the reduction of pyrroles.
图6 吲哚/吡咯的Birch还原反应[24,26]

Fig. 6 Birch reduction of indoles/pyrroles[24,26]

In 2020, the Song Qiuling research group[27]reported the asymmetric reduction reaction of 2-aryl indoles (Fig. 7). The key to this reaction lies in the fact that chiral phosphoric acid, catecholborane, and water form a Brønsted acid stronger than TsOH.
图7 手性磷酸催化吲哚的不对称还原反应[27]

Fig. 7 CPA catalyzed reduction reactions of indoles[27]

In 2010, the Reissig group[28] reported on the intramolecular reductive cyclization de-aromatization of pyrroles promoted by samarium diiodide (Figure 8). The reaction exhibited poor diastereoselectivity, and when the ring being formed was larger than a seven-membered ring (n = 4), almost no product could be obtained.
图8 二碘化钐促进的吡咯自由基去芳构化反应[28]

Fig. 8 SmI2-mediated radical dearomatization reactions of pyrroles[28]

In 2017, the Studer group[29] used lithium silicide to develop an indole ring-opening reaction (Figure 9a). In 2019, the Yorimitsu group[30] found that lithium powder could also cause indole ring opening (Figure 9b).
图9 吲哚的还原开环/扩环反应[29,30]

Fig. 9 Ring opening and expansion dearomatization reactions of indoles[29,30]

2.2 Oxidative Dearomatization Reactions

Indole can be oxidized to produce indole-2-one, indole-3-one, isatin, and epoxidized indole, among others. As early as 1962, Taylor et al.[31] reported a tert-butyl alcohol chloride-induced oxidative rearrangement and de-aromatization reaction of indole. Subsequently, various oxidation systems have been developed, including: metal oxides, such as NaWO4[32], OsO4[33], and Pb(OAc)4[34]; hypervalent iodine compounds, such as PhI(OAc)2[35], sodium iodide/hydrogen peroxide[36,37]; and other oxidants, such as NBS[38], H2O2[39], etc.
In 2021, Pengfei Li and Jianwei Sun et al.[40]used NIS as an oxidant to develop the asymmetric oxidative rearrangement dearomatization reaction of indoles catalyzed by chiral phosphoric acid (Figure 10). Transition metal-catalyzed oxidative dearomatization reactions of indoles have also been developed. In 2023, Hai Ren et al.[41]reported the oxidative dearomatization reaction of 3-substituted indoles catalyzed by copper under air conditions.
图10 吲哚氧化重排生成吲哚-2-酮[40]

Fig. 10 The oxidative rearrangement of indoles to 2-oxindoles[40]

2-substituted indoles are oxidized to indole-3-one under conditions such as MoO5[42], m-CPBA[43], and TBHP[44]. In recent years, the oxidative dearomatization of 2-substituted indoles catalyzed by transition metals has also been reported. In 2016, the Guchhait group[45] used TBHP/MnO2 as an oxidant to develop the oxidative dearomatization of indoles catalyzed by palladium (Figure 11a). The key to this reaction lies in the peroxidation/Kornblum-DeLaMare reaction at the 3-position of the indole. In 2016, Deng Guojun et al.[46] reported the copper-catalyzed oxidative cyclization and dearomatization of indoles with oxime esters using oxygen. In 2013, Tu Yongqiang and Zhang Shuyu et al.[47] reported the aziridine-promoted oxidative semipinacol rearrangement and dearomatization of 2-cyclobutanol-substituted indoles (Figure 11b). Guan Zhi and He Yanhong et al.[48] achieved the asymmetric oxidation of indoles with ketones under visible light/enzyme co-catalysis in the presence of oxygen. This reaction proceeds through a pseudo-indole ketone intermediate (Figure 11c).
图11 吲哚氧化生成吲哚-3-酮[45,47 -48]

Fig. 11 The oxidation of indoles to 3-oxindoles[45,47 -48]

In 2011, Miller et al. [49] reported the 3-hydroxylation dearomatization reaction of 2-aryltryptamine derivatives catalyzed by chiral amides. The chiral peptide, under the action of N, N'-diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (DMAP), forms a peracid with hydrogen peroxide, catalyzing the reaction (Figure 12a). In 2013, Xiao Wenjing's research group [50] reported the hydroxylation dearomatization reaction of indole derivatives under visible light catalysis in air conditions (Figure 12b). When there is no substituent at the 3-position of the indole, a 3-indolone compound is obtained [51]. In 2015, You Shuli's research group [52] achieved the 3-hydroxylation dearomatization reaction of 3-substituted indoles using tert-butyl hydroperoxide as an oxidant, catalyzed by chiral vanadium (Figure 12c). In 2021, Liu Wen's and You Shuli's research groups [53] collaborated to develop the epoxidation/ring-opening dearomatization reaction of chromanol or 3-indoleacetic acid catalyzed by flavin oxygenase under oxygen conditions.
图12 吲哚氧化生成吲哚-3-醇[49,50,52]

Fig. 12 The oxidation of indoles to 3-OH indolines[49,50,52]

Indole without substituents at the 2 and 3 positions is oxidized into isatin. The currently developed oxidation systems include hypervalent iodine, such as I2/TBHP[54], IBX-SO3K/NaI[55], IBA/O2[56], I2O5[57], PIDA/TEMPO[58], etc., transition metals like PCC-SiO2/AlCl3[59], CeCl3/IBX[60], Pd(OAc)2/TBHP[61], RuCl3/NaIO4[62], etc., and peracids such as m-CPBA[63]. In 2016, the Jiang Zhiyong research group[64] reported the visible light-catalyzed indole oxidation reaction under oxygen conditions. By altering the pH of the reaction, it is possible to selectively oxidize indole into diketone or ortho-aminobenzaldehyde (Figure 13).
图13 吲哚氧化生成靛红[64]

Fig. 13 The oxidation of indoles to isatins[64]

In 1993, the Foote group[65] discovered during the study of indole photooxidation that indole and dimethyldioxirane (DMD) reacted at low temperatures to form an indole epoxide product (Figure 14). This product is unstable and rearranges into 2-indolone, 3-indolone, and 2-methyleneindoline at room temperature.
图14 吲哚氧化生成环氧产物及后续转化[65]

Fig. 14 The oxidation of indoles to epoxide and subsequent transformations[65]

Pyrrole readily undergoes polymerization under oxidative conditions, but under the oxidative conditions of hydrogen peroxide[66], high-valent iodine compounds[67-68], singlet oxygen[69], etc., it can undergo oxidative dearomatization reactions (see Figure 15).
图15 吡咯的氧化去芳构化反应[67-68]

Fig. 15 The oxidative dearomatization reactions of pyrroles[67-68]

2.3 Dearomatization Reactions with Electrophiles

Indole and pyrrole are typically nucleophilic aromatic compounds, which can undergo dearomatization reactions with electrophilic reagents such as fluorination[70], chlorination[71,72-73], bromination[74-75], amination[76⇓-78], sulfuration[79], selenylation[80-81], or aldehydes[82]. In 1975, the Treasurywala group[71] developed a chlorination-induced dearomatization reaction of indoles using tert-butyl hypochlorite (Figure 16a). In 2013, Ma and colleagues[75] achieved an asymmetric bromination dearomatization of tryptamine derivatives using bromide salts under the influence of chiral phosphoric acid (Figure 16b). In 2012, the Antilla group[77] reported a chiral phosphoric acid-catalyzed dearomatization reaction between tryptamine derivatives and azodicarboxylates, synthesizing 3-aminated indoline compounds (Figure 16c). In 2013, the Gong group[81] developed an asymmetric selenylation dearomatization of tryptamine derivatives with arylselenium reagents derived from benzoyl diimides, catalyzed by chiral phosphoric acid (Figure 16d). In 2023, the You group[83] achieved a cascade dearomatization/aza-Prins cyclization/rearrangement reaction of indoles containing olefin side chains with azodicarboxylates under the influence of chiral phosphoric acid. In 2024, the Mei group[84] reported a novel bifunctional amination reagent, azodicarbamide, and by utilizing the differential reactivity of different nitrogen sources, they achieved a sequential diamination dearomatization of indoles catalyzed by chiral phosphoric acid.
图16 吲哚的卤化、胺化、硒化去芳构化反应[71,75,77,81]

Fig. 16 The halogenative, aminative and selenylative dearomatization reactions of indoles[71,75,77,81]

In 2009, the Iwasawa group[85] utilized a dipole formed by platinum and allenyl silanol ether to achieve a [3+2] cyclization dearomatization reaction of 3-methylindole (Figure 17a). In 2014, the Bandini group[86] used allene amine to form an α,β-unsaturated imine in the presence of chiral phosphoric acid, realizing the asymmetric dearomatization reaction of indoles (Figure 17b). In 2019, the Shi Min group[87] designed diindole-substituted allene compounds and developed a desymmetrizing dearomatization reaction of indoles catalyzed by gold or platinum. Also in 2019, the Breit group[88] developed an intramolecular spirocyclization dearomatization reaction of indoles with allenes catalyzed by chiral rhodium. Metals such as gold[89-90] or palladium[91-92] can also be used to catalyze the dearomatization reactions of indoles with allenes.
图17 吲哚与联烯的去芳构化反应[85-86]

Fig. 17 The dearomatization reactions of indoles with allenes[85-86]

Allyl alcohols, propargyl alcohols, benzyl alcohols, and their ester derivatives undergo de-aromatization reactions with indoles under the action of transition metals. In 2005, the Tamaru group[93] used triethylborane to achieve an intermolecular de-aromatization reaction of indoles with allyl alcohols catalyzed by palladium. In 2006, the Trost group[94] designed and developed a cyclohexanediamine-derived diphosphine ligand, which was used to realize the asymmetric de-aromatization reaction of indoles with allyl alcohols catalyzed by palladium (Figure 18a). In 2010, the You Shuli group[95] developed an intramolecular asymmetric de-aromatization reaction of indoles catalyzed by iridium/aminophosphine ligands (Figure 18b). In 2014, the Carreira group[96] used prenyl alcohol as an allyl precursor to develop an isoprenylation de-aromatization reaction of indoles catalyzed by iridium. Metals such as copper[97], nickel[98], and ruthenium[99] have also been used for the catalytic allylation de-aromatization reactions of indoles. In 2014, the You Shuli group[100] utilized in situ generated allylpalladium species as electrophiles to develop an intermolecular allylation de-aromatization reaction of pyrroles catalyzed by chiral palladium (Figure 18c). Additionally, reactions catalyzed by metals such as iridium have been reported successively[101-102]. In 2012, the Rawal group[103] used benzyl carbonate as a benzylation reagent to develop a 3-benzylation de-aromatization reaction of indoles (Figure 18d).
图18 吲哚或吡咯的烯丙基/苄基化去芳构化反应[94-95,100,103]

Fig. 18 The allylic and benzylic dearomatization reactions of indoles/pyrroles[94-95,100,103]

Lewis acids coordinate with alkynes, which can enhance the electrophilicity of alkynes, allowing them to undergo de-aromatization reactions with indoles. In the early stages, such reactions required the use of stoichiometric amounts of Lewis acids such as CpCo(C2H4)2[104]. Subsequently, Lewis acid-catalyzed de-aromatization reactions gradually developed. In 2010, the Wang group[105] activated alkynes through gold, developing intramolecular cyclization and de-aromatization of indole derivatives. In 2012, the Kozlowski group[106] synthesized a series of chiral allene compounds (Figure 19a) via chiral palladium-catalyzed indole and alkyne Aaucy-Marbet-Claisen rearrangement de-aromatization. In 2017, the Wang group[107] achieved intramolecular de-aromatization of tryptamine derivatives and alkynes catalyzed by silver, using chiral phosphoric acid as a ligand, constructing chiral tricyclic skeleton compounds (Figure 19b). In 2020, Liu Yongxiang[108] developed a de-aromatization reaction of ynamine indole derivatives catalyzed by silver/NFSI, where the nucleophile was Hans ester or indole (Figure 19c). In 2022, Liu Yunlin et al.[109] achieved this type of reaction using bismuth trichloride catalyst (Figure 19d). Metal salts of cobalt[110], gold[111], rhodium[112], mercury[113], copper[114], and vanadium[115] have also been used in de-aromatization reactions between indoles and alkynes. Additionally, organometallic complexes formed by C—H bond activation can be used for de-aromatization reactions between indoles and alkynes. In 2023, the Jia Yixia group[116] reported a de-aromatization reaction of C—H bond activation at the 3-position of indole catalyzed by palladium (Figure 19e).
图19 吲哚与炔烃的去芳构化反应[106⇓⇓-109,116]

Fig. 19 The dearomatization reactions of indoles with alkynes[106⇓⇓-109,116]

In 1971, Taylor et al.[117] discovered that α, β-unsaturated carbonyl compounds undergo de-aromatization reactions with indoles under the action of BF3 Et2O. Alcohols and acetic acid can also promote such reactions[118-119]. In 2009, the MacMillan group[120] used chiral secondary amine catalysts to develop a tandem Diels-Alder/amine cyclization reaction between tryptamine derivatives and ethynyl formaldehyde, achieving the synthesis of (+)-minfiensine (strychnine) (Figure 20a). In 2012, the Van der Eycken group[121] achieved domino cyclization de-aromatization of indoles through gold-catalyzed Ugi reactions of 3-indole aldehydes (Figure 20b). In 2015, the Unsworth group[122-123] used silver nitrate as a catalyst to achieve intramolecular de-aromatization reactions of indoles, furans, phenols, or pyrroles with alkynyl ketones in the side chain. In the same year, the You Shuli group[124] developed an intermolecular de-aromatization reaction of pyrroles with enone using silica gel as an acid. In 2020, Wang Rui et al.[125] synthesized pseudoindole-substituted chiral allene compounds through asymmetric de-aromatization reactions of indoles with alkynyl imines catalyzed by chiral phosphoric acid, where the chiral phosphoric acid controlled the addition site of the indole to the alkynyl imine (Figure 20c). In 2021, the Ye Longwu group[126] reported an asymmetric de-aromatization reaction of pyrroles with alkynyl amides in the side chain catalyzed by chiral phosphoric acid, where the alkynyl amide isomerized into an electrophilic azadiene intermediate under acidic conditions (Figure 20d).
图20 吲哚或吡咯与α, β-不饱和羰基化合物的去芳构化反应[120-121,125 -126]

Fig. 20 The dearomatization reactions of indoles/pyrroles with α, β-unsaturated carbonyl compounds[120-121,125 -126]

Metal carbene is a highly electrophilic active species, also used in the dearomatization reactions of indoles or pyrroles. In 1987, the Rogers group[127] discovered dearomatized products in the reaction between pyrrole and carbene. In 1997, the Davies group[128] achieved rhodium-catalyzed cyclization and dearomatization of pyrrole using enol silyl ether-substituted azo esters as carbene precursors. In 2007, this group[129] realized enantioselective control of the reaction by using chiral rhodium catalysts (Figure 21a). In 2008, the Bois group[130] developed a rhodium-catalyzed difunctionalization and dearomatization reaction of pyrrole using PhI(OAc)2 as an oxidant (Figure 21b). In 2010, the Davies group[131] developed a rhodium-catalyzed [3+2] cyclization and dearomatization reaction of indole using vinyl diazoacetate as a carbene precursor; the regioselectivity of the reaction could be controlled by altering the position of substituents on the indole (Figure 21c). In 2020, the Nemoto group[132] developed a chiral silver-catalyzed spirocyclization and dearomatization reaction of indole derivatives with diazoamides in side chains (Figure 21d).
图21 吲哚或吡咯与金属卡宾的去芳构化反应[129⇓⇓-132]

Fig. 21 Transition-metal catalyzed dearomatization reactions of indoles/pyrroles with carbenes[129⇓⇓-132]

Arylmetallic reagents or aryl halides form arylmetallic intermediates with strong electrophilicity, which can undergo arylation and dearomatization reactions with indoles or pyrroles. In 1987, the Halley group[133]used equimolar amounts of aryl lithium reagents to achieve phenylation and dearomatization of indoles. In 1995, the Thiebault group[134]reported an aromatic nucleophilic substitution reaction between 2,4-disubstituted pyrroles and chlorobenzene, resulting in the dearomatization of pyrrole. In 2001, the Mingoia group[135]found that under the action of trifluoromethanesulfonic acid, pyrrole with a phenyl azide side chain underwent intramolecular dearomatization, yielding a mixture of two products (Figure 22a). In 2011, the Bedford group[136]utilized indole as a nucleophile to attack the arylpalladium intermediate formed by oxidative addition of palladium and chlorobenzene, achieving the dearomatization of indole. In 2012, the You Shuli group[137]developed a palladium-catalyzed spirocyclization and dearomatization of indoles using 3-bromobenzene side-chain-containing indoles. In 2015, the Jia Yixia group[138]achieved asymmetric arylation and dearomatization at the 2-position of indole through palladium-catalyzed intramolecular reductive Heck reactions (Figure 22b). In 2019, the Lautens group[139]used nickel catalysts to achieve arylative iodination and dearomatization of indoles (Figure 22c). In 2020, the Zhang Junliang group and the Guo Yinlong group[140]developed an asymmetric coupling spirocyclization and dearomatization reaction between indoles and alkynes using chiral PC-phos (Figure 22d). In 2022, the You Shuli group[141]realized intramolecular coupling and dearomatization of indoles through a desymmetrization strategy. Under basic conditions, pyrrole undergoes intermolecular dearomatization with arylpalladium intermediates (Figure 22e)[142⇓⇓⇓-146].
图22 吲哚或吡咯的芳基化去芳构化反应[135,138⇓ -140,142]

Fig. 22 The arylative dearomatization reactions of indoles/pyrroles[135,138⇓ -140,142]

2.4 Dearomatization Reactions with Nucleophiles

Introducing electron-withdrawing groups at the N-1, C-2 or (and) C-3 positions of indole can reverse its reactivity, allowing it to undergo de-aromatization reactions with nucleophiles. As early as 1962, the Szmuszkovicz group[147] discovered that 3-keto-substituted indole derivatives undergo a de-aromatizing 1,4-addition reaction with Grignard reagents (Figure 23a). In 2012, the Liu Yuanhong group[148] improved the conditions for this reaction and expanded the substrate scope (Figure 23b). In 2003, Vedejs et al.[149] used indole-3-carboxylic acid ethyl esters with an aziridine side chain in a Michael addition reaction with methyl lithium, resulting in de-aromatized indoline compounds, though these were not the major products (Figure 23c). In 2018, the Clayden group[150] achieved intramolecular Michael addition de-aromatization of N-amide-substituted indoles in the presence of LDA (Figure 23d).
图23 金属试剂与3-羰基吲哚的加成去芳构化反应[147⇓⇓-150]

Fig. 23 The dearomatization reactions of 3-carbonyl indoles with metal reagents[147⇓⇓-150]

Electron-withdrawing group-substituted indoles can act as dienophiles in Diels-Alder reactions. Piettere et al.[151] reported the cycloaddition dearomatization reaction of N-Ts-3-aldehyde indole with 1,3-cyclohexadiene under high temperature and pressure (Figure 24a). In this reaction, increasing the pressure and adding a Lewis acid significantly improved the yield and diastereoselectivity control. Using this strategy, they[152] further developed a three-component dearomatization reaction of N-Ts-3-nitroindole, vinyl ether, and acrylate under high-pressure conditions, and found that electron-deficient pyrroles also exhibited good reactivity under these conditions (Figure 24b). The [4+2] cycloaddition between the vinyl ether and the nitroindole/pyrrole generates a nitrated dipole, which then undergoes a [3+2] cycloaddition with the acrylate, producing polycyclic compounds containing indolines/pyrrolines. Gribble et al.[153] also reported the Diels-Alder cycloaddition dearomatization of nitroindoles. In 2015, the Chataigner group[154] discovered that under the catalysis of thiourea, nitroindoles could undergo dearomatization reactions with electron-rich dienes at room temperature and atmospheric pressure. In 2016, the same research team[155] used enamines as nucleophiles to develop a Michael addition dearomatization reaction of nitroindoles. Mancini[156] and the Domínguez group[157] also conducted studies on the Diels-Alder reactions of electron-deficient indoles.
图24 缺电子吲哚的环化去芳构化反应[151-152]

Fig. 24 The annulative dearomatization reactions of electron-poor indoles[151-152]

The catalytic dearomatization of electron-deficient indoles can be achieved through the in situ generation of organometallic reagents. In 2015, the Ito group[158] used a copper-boron species formed from bis(pinacolato)diboron and a copper catalyst to achieve the asymmetric borohydride dearomatization of 2-ester indole compounds (Figure 25a). The addition of sodium tert-butoxide improved the diastereoselectivity of the reaction. Subsequently, this research team[159] also realized the borylative dearomatization of 2-ester indoles. The Xu Senmiao group[160-161] reported the copper-catalyzed borohydration and hydrosilylation dearomatization reactions of 3-ester indoles. Additionally, the Ito group[162-163] achieved the dearomatization of pyrroles using a copper-catalyzed borohydration and hydrosilylation strategy (Figure 25b). In 2021, Brown et al.[164] under nickel catalysis, using N-acyl or N-Boc protected indoles with bis(pinacolato)diboron and aryl bromides, achieved the regioselective borylative arylation dearomatization of indoles (Figure 25c). This reaction controls the regioselectivity of indole insertion into the nickel-boron species through the coordination effect of the acyl group or the steric hindrance of the Boc group. The resulting alkyl-nickel species undergoes a coupling reaction with the aryl bromide to yield the product.
图25 过渡金属催化缺电子吲哚/吡咯的硼化去芳构化反应[158,162⇓ -164]

Fig. 25 Transition-metal catalyzed borylative dearomatization reactions of electron-poor indoles/pyrroles[158,162⇓ -164]

In 1999, the Gribble group[165], in the presence of NaH and using ethyl malonate as a nucleophile, developed a dearomatization reaction for 3-nitroindoles (Figure 26a). Since then, chemists have extensively studied the dearomatization reactions of nitroindoles. In 2014, the Arai group[166]developed a catalytic asymmetric dearomatization reaction for nitroindoles via copper-catalyzed asymmetric [3+2] cyclization with glycinate-derived imine ylides (Figure 26b). In 2016, the Stanley group[167]reported a similar reaction using a Cu(OTf)2/(R)-Difluorphos catalytic system.
图26 3-硝基吲哚的去芳构化反应[165-166]

Fig. 26 The dearomatization reactions of 3-NO2 indoles[165-166]

The cyclization of electron-deficient indoles with dipoles is a relatively common dearomatization reaction. In 2013, the Piettre group[168]achieved a [3+2] cyclization dearomatization reaction between nitroindoles and unstable methylene imine ylides under the action of trifluoroacetic acid (Figure 27a). In 2017, the Wang Rui group[169]developed a [3+2] cyclization dearomatization reaction between nitroindoles and azomethine imines (Figure 27b). In 2024, the Osyanin group[170]used isoquinolinium salts as 1,3-dipoles to achieve a double dearomatization reaction between isoquinolines and nitroindoles (Figure 27c).
图27 硝基吲哚或吡咯的偶极环加成去芳构化反应[168⇓-170]

Fig. 27 The dearomatization reactions of NO2-indoles/ pyrroles with dipoles[168⇓-170]

Trimethylenemethane (TMM) is a highly reactive dipole widely used in [3+n] cyclization reactions of unsaturated bonds. In 2014, the Trost group[171] developed a palladium-catalyzed dearomatization reaction of 3-nitroindoles or pyrroles with TMM, but the enantioselective control was only moderate (Figure 28).
图28 硝基吲哚/吡咯与TMM的去芳构化反应[171]

Fig. 28 The dearomatization reactions of 3-NO2 indoles/ pyrroles with TMM[171]

Alkenylcyclopropanes[172-173], alkenylaziridines[174⇓-176], or alkenyloxiranes, when forming dipoles in situ with palladium, undergo [3+2] cyclo-dearomatization reactions with nitroindoles. In 2018, the You Shuli group[177] reported an asymmetric dearomatization reaction of 3-nitroindoles with alkenyloxiranes catalyzed by palladium, achieving diastereoselectivity inversion by changing the solvent (Figure 29a). In 2022, Jianqiang Zhao and Weicheng Yuan et al.[178] used 2-alkyltrimethylene carbonate as a 1,4-dipole precursor to develop a [4+2] cyclo-dearomatization reaction of 3-nitroindoles catalyzed by palladium (Figure 29b).
图29 钯催化3-硝基吲哚的环化去芳构化反应[177-178]

Fig. 29 Pd-catalyzed annulative dearomatization reactions of 3-NO2 indoles[177-178]

Bandini[179], Chataigner[180], Shi Feng[181], and Ye Zhishi[182] groups have respectively utilized the dipoles generated from the reaction of phosphines with allenes to develop dearomatization reactions of nitroindoles. The Lu Yixin group[183] and the Zhang Junliang group[184] have separately used chiral organic phosphine catalysts to develop asymmetric dearomatization reactions between nitroindoles and allenes (Figure 30).
图30 膦催化硝基吲哚与联烯的去芳构化反应[183-184]

Fig. 30 Phosphine-catalyzed dearomatization reactions of 3-NO2 indoles with allenes[183-184]

In 2015, the Yuan Weicheng group[185] reported the Zn(OTf)2/bisoxazoline-catalyzed asymmetric [3+2] cyclo-dearomatization reaction of nitroindoles with thiocyanates (Figure 31a). In 2020, Lin Guoqiang and Tian Ping et al.[186] used a bifunctional chiral amine catalyst to report the asymmetric [3+2] cyclo-dearomatization reaction of nitroindoles with indolone-derived Morita-Baylis-Hillman carbonates (Figure 31b). Additionally, Li Junlong, Yuan Weicheng, and other groups[187⇓-189] developed the tandem Michael addition/[4+2] cyclo-dearomatization reactions of nitroindoles. In 2021, the You Shuli group and the Yuan Yaofeng group[190] collaborated to report the silver-catalyzed interrupted Barton-Zard type asymmetric dearomatization reaction of 3-nitroindoles/pyrroles with isocyanates (Figure 31c). In 2022, the Yuan Weicheng group[191] extended this reaction to 2-nitroindoles.
图31 硝基吲哚或吡咯的[3+2]串联环化去芳构化反应[185-186,190]

Fig. 31 [3+2] annulative dearomatization reactions of 3-NO2 indoles/pyrroles[185-186,190]

In 2021, the You Shuli group[192] used allyl carbonate as a bifunctional reagent and reported a palladium-catalyzed methoxylation-allylation dearomatization reaction of nitroindoles (Figure 32).
图32 钯催化硝基吲哚与烯丙基碳酸酯的双官能化去芳构化反应[192]

Fig. 32 Pd-catalyzed dearomatization reactions of 3-NO2 indoles with allyl carbonate[192]

Electron-rich indoles undergo polarity inversion in the presence of oxidants, reacting with nucleophiles for dearomatization. In 1980, the Kuroki group[193] achieved a diesterification dearomatization reaction of indoles using carboxylic acids as nucleophiles under the action of the oxidant NIS (Figure 33a). Subsequently, various nucleophiles and oxidation systems such as ethylene glycol/PIFA, methanol/thallium nitrate, and carboxylic acid/PhI(OAc)2 were used in this type of reaction[194⇓-196]. Additionally, indoles can isomerize into pseudoindole intermediates under acidic conditions, which can react with nucleophiles for dearomatization. As early as 1957, Smith et al.[197] discovered that indoles, under the action of hydrochloric acid, transform through a pseudoindole chloride salt intermediate into 2-indole-substituted indoline products. In 2000, the Nakatsuka group[198] reported an isomerization/dearomatization reaction of N-tert-butyloxycarbonyl-protected indoles promoted by aluminum chloride, yielding a mixture of isomers. In 2012, the Vincent group[199] improved the reaction conditions, using iron(III) chloride as a Lewis acid, to obtain 3-arylated indoline products with excellent yields (Figure 33b). In 2022, the same group[200] used trifluoroacetic acid to protonate indoles, generating indolinium cations, which reacted with aromatic rings to achieve intramolecular arylative dearomatization of indoles (Figure 33c).
图33 吲哚的极性反转去芳构化反应[193,199 -200]

Fig. 33 The umpolung dearomatization reactions of indoles[193,199 -200]

2.5 Radical-Involved Dearomatization Reactions

Compared to the ground state, the excited state of indole has higher reactivity and is more prone to undergo dearomatization reactions. As early as the 1970s and 1980s, groups led by Julian[201]and Ikeda[202]used acetophenone or benzophenone as photosensitizers and reported [2+2] cycloaddition dearomatization reactions between indole derivatives and alkenes under ultraviolet light irradiation. Later, Weedon et al.[203]systematically studied the mechanism of this reaction, explaining that the photosensitizer excited indole through a Dexter energy transfer process, thus initiating the reaction.
In 2019, the You Shuli group[204]used iridium complexes as photosensitizers and reported a visible light-induced intramolecular [2+2] cycloaddition dearomatization reaction of indoles with alkenes (Figure 34). Subsequently, Oderinde and Dhar et al.[205]reported that indoles containing alkenes in the amide side chain underwent intramolecular [2+2] cycloaddition dearomatization reactions under visible light catalysis. Fu Qiang et al.[206]reduced the excitation triplet state energy of indole through hydrogen bonding between the acyl group of indole derivatives and trifluoroethanol, achieving an intramolecular [2+2] cycloaddition dearomatization reaction of indoles with terminal alkenes. Tertiary amines are commonly used as reductants in visible light catalysis. Fu Qiang et al.[207]inhibited the quenching of the photosensitizer by amines through hydrogen bonding between the amine and protic solvents, realizing [2+2] cycloaddition dearomatization reactions of indole derivatives containing amino groups with alkenes. In 2020, Rolka and Koenig et al.[208]used 2CzPN as an organic photosensitizer and developed intramolecular [2+2] cycloaddition dearomatization reactions of indoles with alkenes or allenes. Arai and Ohkuma et al.[209]found that Mg(OTf)2could accelerate the intramolecular [2+2] cycloaddition dearomatization reaction of azaindoles with alkenes, suggesting that the chelation effect of Lewis acid with the substrate fixed the conformation of the substrate, promoting the reaction. Paton and Smith et al.[210]developed an interrupted [2+2] cycloaddition reaction of N-acryloylindoles through the conversion of 1,4-diradical intermediates to zwitterions.
图34 可见光诱导吲哚与烯烃的分子内[2+2]环加成去芳构化反应[204]

Fig. 34 Visible-light-induced intramolecular [2+2] cycloaddition dearomatization reactions of indoles with alkenes[204]

In 2019, Guldi and Glorius et al.[211] reported a visible light-induced intermolecular [2+2] cycloaddition dearomatization reaction between N-acetylindole and methyl acrylate (Figure 35a). In 2020, the Glorius group[212] achieved a [2+2] cycloaddition/ring-expansion cascade reaction of indoles catalyzed by Gd(OTf)3 under violet light irradiation. Subsequently, Oderinde et al.[213] reported an energy transfer-mediated intermolecular [2+2] cycloaddition dearomatization reaction of electron-deficient indoles with various alkenes. In 2024, the Feng Xiaoming group[214] synthesized a series of chiral indoles through an asymmetric [2+2] cycloaddition dearomatization/ring-expansion cascade reaction of indoles and alkenes (Figure 35b). The Jiang Zhiyong group[215] found that the two enantiomers of the [2+2] cycloaddition product of indoles and alkenes have different rates of the reverse reaction under chiral phosphoric acid conditions, thereby achieving the de novo deracemization and enantioenriched synthesis of cyclobutanes.
图35 可见光诱导吲哚与烯烃的分子间[2+2]环加成去芳构化反应[211,214]

Fig. 35 Visible-light-induced intermolecular [2+2] cycload- dition dearomatization reactions of indoles with alkenes[211,214]

In 2020, the You Shuli group[216] developed an energy transfer-mediated intramolecular [2+2] cycloaddition dearomatization reaction of indoles with alkynes (Figure 36a). In the same year, they[217] also used oxime ethers as indole diradical acceptors to develop a visible light-induced intramolecular [2+2] cycloaddition or interrupted cycloaddition dearomatization reaction of indoles (Figure 36b). By changing the substituent at the 3-position of indole, it is possible to control whether the 1,4-diradical undergoes coupling cyclization or a 1,5-hydrogen atom transfer process. Companyó and Dell'Amico et al.[218] achieved Paternò-Büchi type dearomatization reactions of indoles by exciting aryl ketones with visible light and reacting them with indoles (Figure 36c). In 2021, the You Shuli group[219] used naphthalene as an indole diradical acceptor to achieve an intramolecular dual dearomatization reaction of indoles and naphthalenes, synthesizing a series of indolines with complex polycyclic skeletons (Figure 36d). In 2021, the You Shuli group[220] reported an energy transfer-mediated [n+2] cycloaddition dearomatization reaction of indoles or pyrroles with vinylcyclopropanes (Figure 36e). By designing substrates to control the reaction pathways of open-shell singlet 1,4- and 1,7-diradical intermediates, [5+2], [2+2], interrupted [5+2], and [5+4] cycloadditions were achieved. Subsequently, Arai and Ohkuma et al.[221] used aryl ketones as photosensitizers to realize intramolecular cycloaddition dearomatization reactions of indoles with vinylcyclopropanes under high-pressure mercury lamp irradiation.
图36 可见光诱导吲哚与其他双自由基受体的环加成去芳构化反应[216⇓⇓⇓-220]

Fig. 36 Visible-light-induced cycloaddition dearomatization reactions of indoles with other biradical acceptors[216⇓⇓⇓-220]

In 2015, the Brasholz group[222]used N-iodoethyl-substituted indoles as radical precursors to achieve a visible light-catalyzed tandem radical addition/dearomatization reaction of indoles in the presence of methyl acrylate (Figure 37a). In 2017, the same group[223]reported a tandem radical addition/dearomatization reaction of 3-iodoethyl-substituted indoles with two molecules of acrylonitrile (Figure 37b). In 2018, the Wang Qingmin group[224]used TMSCN as a nucleophile to achieve an intramolecular spirocyclization dearomatization of indoles containing bromodifluoroacetylamine side chains under visible light catalysis (Figure 37c). In 2020, the Yu Dagan group[225]used DIEPA as a reductant and reported an intramolecular cyclization dearomatization of indoles under visible light catalysis. The 3-position carbanion generated by photoreduction was captured by CO2to synthesize indoline carboxylic acid derivatives (Figure 37d). In 2020, the Zhang Zhaoguo group[226]achieved a radical addition/spirocyclization dearomatization cascade reaction of indoles with alkynes containing a bromide side chain under photocatalytic conditions (Figure 37e). In 2020, Unsworth et al.[227]reported a sulfur radical-initiated intramolecular spirocyclization dearomatization of indoles, where indoles form intramolecular donor-acceptor complexes with ynones, which are triggered by light (Figure 37f). In 2021, the Wang Wei group[228]achieved a diastereoselective intermolecular dearomatization of indoles by introducing a chiral auxiliary at the 3-position of indoles. In 2022, they[229]used different radical precursors to achieve cyano-methylation, sulfonation, trifluoromethylation, stannylation, or borylation dearomatization of indoles. In 2021, Gianetti et al.[230]used nPr-DMQA+as a photocatalyst and reported a red-light-mediated trifluoromethylation/spirocyclization dearomatization of indoles (Figure 37g). In 2022, the Wu Ju group[231]and the Zhu Tingshun group[232]achieved fluoralkylation/spirocyclization dearomatization of indoles under electrochemical conditions. The Wu Ju group[233,234]used sodium azide as a radical precursor or diphenylphosphine oxide as a phosphorylating agent to achieve the synthesis of 2-azido-spiro-indolines and 2-phosphoryl indolines through electrochemically promoted dearomatization reactions of indoles.
图37 吲哚的自由基加成去芳构化反应[222⇓⇓⇓⇓-227]

Fig. 37 The dearomatization reactions of indoles via radical addition[222⇓⇓⇓⇓-227]

In 2004, Royer et al.[235]under electrochemical conditions, oxidized indole into a radical cation, using methanol as a nucleophile, achieving the dimethoxylation and dearomatization of indole (Figure 38a). In 2019, the Vincent group[236]further expanded the scope of electrochemical dearomatization by using alcohols and TMSN3as nucleophiles. In 2023, Lei Aiwen et al.[237]utilized electrochemistry to oxidize indole into an indole radical cation, allowing it to react with a radical derived from para-aminophenol, thus realizing intermolecular dearomatization of indole (Figure 38b). If β-ketonitrile is used as the nucleophile instead of para-aminophenol, the reaction can also proceed, but with different regioselectivity. In 2023, Liu Chengkou et al.[238]achieved intramolecular spirocyclization and dearomatization of indoles through the electrochemical oxidation of indole.
图38 电化学促进吲哚与亲核试剂的去芳构化反应[235,237]

Fig. 38 The electrochemical dearomatization reactions of indoles with nucleophiles[235,237]

In 2018, the Knowles group[239]used TIPS-EBX as an oxidant and reported the asymmetric dearomatization of tryptamine with 2, 2, 6, 6-tetramethylpiperidine N-oxide (TEMPO) via visible light/chiral phosphate co-catalysis (Figure 39). The Xia group[240]used TEMPO as a hydrogen atom transfer reagent to achieve the dearomatization of indoles under visible light catalyzed by chiral phosphoric acid. In 2019, the You group[241]reported the asymmetric dearomatization of indole derivatives using hydroxylamine as a nucleophile via visible light/chiral phosphate co-catalysis. This reaction is applicable to chromanols, tryptamines, and indole derivatives containing an aniline side chain.
图39 光/手性磷酸盐催化吲哚与TEMPO的去芳构化反应[239]

Fig. 39 Photo/chiral phosphonate co-catalyzed dearomatization reactions of indoles with TEMPO[239]

In 2024, the Ren Hai research group[242]developed a copper-catalyzed [3+3] radical cycloaddition dearomatization reaction of indoles based on a benzylic C—H functionalization strategy. In this, the benzylic C—H bond is selectively oxidized to a radical via single electron oxidation and participates in the cycloaddition reaction. Recently, Tang Pingping et al.[243]reported a fluorination trifluoromethoxylation or ditrifluoromethoxylation dearomatization reaction of indoles promoted by silver difluoride using TFMS as the trifluoromethoxy reagent (see Figure 40). The indole is oxidized to a radical cation by silver difluoride, which then couples with the trifluoromethoxy anion.
图40 二氟化银促进吲哚的氟化三氟甲氧基化或双三氟甲氧基化去芳构化反应[243]

Fig. 40 Ag-mediated fluorination/trifluoromethoxylation dearomatization reactions of indoles[243]

In 2023, the You Shuli group[244] used a tridentate amino alcohol ligand to achieve SmI2-mediated intermolecular asymmetric reductive coupling de-aromatization reaction of indoles with ketones (Figure 41).
图41 吲哚的不对称自由基-自由基偶联去芳构化反应[244]

Fig. 41 SmI2-mediated asymmetric dearomatization reactions of indoles via radical coupling[244]

3 Benzofuran and Furan

(Benzo)furan is an important biomass-based platform molecule. Due to its Dewar resonance energy of only 4.3 kcal/mol, furan exhibits the reactivity of compounds such as alkenes, enol ethers, and conjugated dienes, making it very susceptible to de-aromatization reactions.

3.1 Dearomatization Reactions with Nucleophiles

In 1976, the Piancatelli group[245] first discovered that 2-furanmethanol undergoes ring-opening/Nazarov cyclization under acidic conditions, yielding a de-aromatized five-membered carbon ring compound (Figure 42a). After the substrate is protonated, a furan oxonium ion intermediate is formed, which is then attacked by water as a nucleophile, followed by 4π electrocyclization to produce the 4-hydroxycyclopentenone product. The furan oxonium ion can also be captured by other nucleophiles. In 2011, the Yin Biaolin group[246] used aniline in the side chain as a nucleophile to develop an intramolecular arylative dearomatization reaction of furans, synthesizing spiroindolone compounds (Figure 42b).
图42 呋喃的Piancatelli重排去芳构化反应[245-246]

Fig. 42 The dearomatization reactions of furans via Piancatelli rearrangement[245-246]

Similar to alkenes, the C2-C3 double bond of furans can be inserted into arylmetal complexes. In 2016, the Biao-Lin Yin group[247] reported a palladium-catalyzed arylation dearomatization/ring expansion cascade reaction of cyclobutanol-substituted furans (Figure 43a). The reaction proceeds via a spiro π-allylpalladium intermediate with high diastereoselectivity. In the same year, the Biao-Lin Yin group[248] achieved an oxidative coupling dearomatization reaction between arylboronic acids and γ-hydroxyalkyl furans using oxygen as the oxidant (Figure 43b).
图43 钯催化呋喃的1, 4-双官能团化去芳构化反应[247-248]

Fig. 43 Pd-catalyzed 1, 4-difunctionalized dearomatization reactions of furans[247-248]

3.2 Dearomatization Reactions with Electrophiles

In 2005, the Wright group[249]oxidized enol silyl ethers into cationic radicals via electrochemical anodic oxidation, causing a polarity reversal and enabling a dearomatization reaction with furan to produce a series of spirocyclic products (Figure 44a). In 2018, the Yin Biaolin group[250]used furan derivatives containing alkyne amides on the side chain to achieve a palladium/copper-catalyzed cyclization/ring-expansion dearomatization reaction of furan-yne under oxygen (air) conditions (Figure 44b). Subsequently, the Yin Biaolin group[251]developed a palladium-catalyzed 2,5-alkoxylation/alkenylation dearomatization reaction of furan using DDQ as the oxidant and alcohol as the nucleophile (Figure 44c). In the reaction, Li+coordinates with furan, weakening the nucleophilicity of the furan oxygen atom and promoting the Heck migration insertion process of the furan double bond into the alkenylpalladium intermediate.
图44 呋喃与亲电试剂的去芳构化反应[249⇓-251]

Fig. 44 The dearomatization reactions of furans with electrophiles[249⇓-251]

3.3 Radical-Involved Dearomatization Reactions

In 2022, the Studer group[252]used aryl fluorides as acylation reagents and achieved a fluorination-arylation dearomatization reaction of benzofurans through NHC/visible light synergistic catalysis (Figure 45a). The key step in this reaction is the radical-radical coupling process between the radical cation obtained from the photocatalytic oxidation of benzofuran and the carbene radical formed in the NHC catalytic cycle. Radical addition to furan was also utilized in the dearomatization reaction. In 2022, the Yin Baolin group[253]reported a copper-catalyzed 2,5-alkylation-arylation radical dearomatization reaction of furans, completing the construction of the spiro-oxacyclic indole skeleton in one step (Figure 45b).
图45 呋喃与自由基的去芳构化反应[252-253]

Fig. 45 The radical dearomatization reactions of furans[252-253]

3.4 Cycloaddition Dearomatization Reaction

Furan, containing a conjugated diene structural unit, can act as a diene to undergo Diels-Alder reactions, rapidly constructing structurally complex oxygen-bridged cyclic compounds. In 2015, the Kutateladze group[254] reported an intramolecular cycloaddition dearomatization reaction of furan with an imine side chain, yielding [4+2]/[4+4] cycloaddition products with 1:1 chemoselectivity (Figure 46a). The Norrish-Yang type isomer generated under UV light excitation is a key intermediate in this reaction. In 2020, the Mo Dongliang group[255] used o-aminobenzyl chloride as a precursor for the Norrish-Yang type isomer and, under the action of sodium carbonate, achieved intermolecular Diels-Alder reactions of furan (Figure 46b). The reaction exhibited high chemoselectivity, exclusively producing [4+2] cycloaddition products. Benzofuran undergoes [2+2] cycloaddition reactions with alkenes. In 2018, the Meggers group[256] used metal-centered chiral octahedral rhodium Δ-RhS as a Lewis acid, achieving visible-light-promoted asymmetric [2+2] cycloaddition dearomatization reactions of benzofuran (Figure 46c). In 2024, the Liang Wu group[257] used thioxanthone as a photosensitizer, realizing energy transfer-mediated [2+2] cycloaddition dearomatization reactions between benzofuran and maleimide (Figure 46d).
图46 （苯并）呋喃的环加成去芳构化反应[254⇓⇓-257]

Fig. 46 The cycloaddition dearomatization reactions of (benzo)furans[254⇓⇓-257]

In 2017, the You Shuli group[258]achieved the highly stereoselective construction of oxabicyclic compounds containing two consecutive quaternary chiral centers through palladium-catalyzed asymmetric [3+2] cyclo-dearomatization of 2-nitrobenzofurans (Figure 47a). In 2020, the Yu Binxun group[259]
图47 （苯并）呋喃的环化去芳构化反应[258⇓⇓-261]

Fig. 47 The annulative dearomatization reactions of (benzo)furans[258⇓⇓-261]

Using Yb(OTf)3 as the catalyst, the intramolecular click cyclization dearomatization reaction of 2-furylmethanol with azide was accomplished (Figure 47b). Subsequently, the Yu Binxun group[260] achieved an intermolecular click cyclization reaction, stereoselectively synthesizing a series of (E)-fluoroalkenyl triazoles (Figure 47c), initiated by the in situ generated hydrochloric acid from acetyl chloride and hexafluoroisopropanol. In 2023, the Lu Yixin group[261] reported the phosphine-catalyzed asymmetric [3+2] cyclization dearomatization reaction of 2-nitrobenzofuran with vinylcyclopropane (Figure 47d).

4 Benzothiophene and Thiophene

4.1 Hydrogenation Dearomatization Reaction

The de-aromatization reaction of thiophene is an efficient route for the synthesis of sulfur-containing heterocyclic compounds. Under a hydrogen atmosphere, thiophene can be reduced by ruthenium catalysis to produce thiolane (Figure 48a[262]). In 2012, the Glorius group[263] used chiral N-heterocyclic carbenes as ligands and developed an asymmetric hydrogenation reaction of (benzo)thiophenes catalyzed by ruthenium, providing a new strategy for the synthesis of tetrahydrothiophenes and 2,3-dihydrobenzothiophenes (Figure 48b).
图48 （苯并）噻吩的氢化去芳构化反应[262-263]

Fig. 48 The hydrogenative dearomatization reactions of (benzo)thiophenes[262-263]

4.2 Dearomatization Reactions with Nucleophiles

In 2018, the You Jinsong group[264] developed an iridium-catalyzed Heck-type cyclization dearomatization reaction of 2-substituted thiophenes with α, β-unsaturated carboxylic acids, synthesizing thiophene-containing thia-spiro products (Figure 49a). In 2021, Sun Jianwei and Houk et al.[265] used pyrrole as a nucleophilic reagent, reporting a chiral phosphoric acid-catalyzed 1, 10-conjugate addition dearomatization reaction of indole thiophenemethanol (Figure 49b). In this reaction, the indole group at the benzyl position of the thiophene stabilized the thiophene carbocation, achieving chemoselective, regioselective, and stereoselective remote control under mild conditions. In 2022, the Ye Keyin group[266] reported an electrochemical-promoted dearomatization reaction of 2-arylthiophenes (Figure 49c). By altering the substituent at the 5-position of the thiophene, 2,5- or 2,3-difunctionalized dearomatization products could be selectively obtained. In 2023, the Wang Wei group[267] achieved the ring-opening dearomatization of thiophenes or furans by visible light photoredox catalysis that enabled polarity inversion of nucleophilic furans (Figure 49d). Under these reaction conditions, benzo[b]thiophenes or indoles underwent hydrogen functionalization dearomatization via a hydrogen atom transfer (HAT) process.
图49 （苯并）噻吩与亲核试剂的去芳构化反应[264⇓⇓-267]

Fig. 49 The dearomatization reactions of (benzo)thiophenes with nucleophiles[264⇓⇓-267]

In 2023, the Stoltz group[268]used palladium-catalyzed coupling de-aromatization of thiophenes as a key step in the total synthesis of aleutianamine (Figure 50a). In 2024, the Stokes group[269]reported an intramolecular spirocyclization de-aromatization reaction of benzothiophenes catalyzed by TfOH (Figure 50b). This reaction is completed through the nucleophilic attack on the aromatic ring after the benzothiophene is protonated by TfOH.
图50 （苯并）噻吩的芳基化去芳构化反应[268-269]

Fig. 50 The arylative dearomatization reactions of (benzo) thiophenes[268-269]

4.3 Dearomatization Reactions with Electrophiles

In 2024, Yan Hailong et al.[270]used naphthol-derived enyne substrates to develop a quinidine-catalyzed dearomatization reaction of (benzo)thiophenes, synthesizing a series of polycyclic compounds (Figure 51a). In 2024, the Zhao Baoyi group[271]reported an intramolecular [4+3] cycloaddition dearomatization reaction of thiophene with oxiranyl enol silyl ethers catalyzed by Et3SiOTf (Figure 51b).
图51 （苯并）噻吩与亲电试剂的去芳构化反应[270-271]

Fig. 51 The dearomatization reactions of (benzo)thiophenes with electrophiles[270-271]

4.4 Radical-Involved Dearomatization Reactions

In 2024, the Zheng Ke research group[272] discovered that indole oxide anions and hydroxylamine-derived esters can form electron donor-acceptor complexes, which undergo electron transfer under light (Figure 52). Based on this, they developed a highly selective radical relay dearomatization reaction, achieving difunctionalization of naphthalene, benzene, indole, pyrrole, benzofuran, and thiophene.
图52 （苯并）噻吩的自由基去芳构化反应[272]

Fig. 52 The radical dearomatization reactions of (benzo)thiophenes[272]

4.5 Cycloaddition Dearomatization Reaction

The Diels-Alder reaction of thiophene with alkynes for dearomatization, followed by desulfurization, yields the corresponding benzene derivatives[273]. Recently, Yakura and Okitsu et al.[274] reported a tandem intramolecular Diels-Alder/desulfurization reaction between thiophene and alkyne. When thiophene and alkyne are connected via a quaternary ammonium salt, the reaction can be stopped at the dearomatized product (Figure 53a)[275]. In 2023, the Yin Biao-Lin group[276] reported an intramolecular double dearomatization reaction of indole and thiophene catalyzed by visible light (Figure 53b). In the same year, they[277] used 4CzIPN or thioxanthone as photosensitizers to develop energy transfer-mediated intramolecular [2+2] or [4+2] cycloaddition dearomatization reactions of thiophene, furan, benzofuran, naphthalene, and benzene. In 2024, the Maestrik group[278] used Ir(p-Fppy)3 as a photosensitizer, excited allenes through an energy transfer process, allowing them to undergo intramolecular [2+2] cycloaddition with alkenes, followed by a selective retro-[2+2]/[4+2] cycloaddition process, achieving intramolecular dearomatization of benzothiophene or benzofuran (Figure 53c).
图53 （苯并）噻吩的环加成去芳构化反应[275-276,278]

Fig. 53 The cycloaddition dearomatization reactions of (benzo)thiophenes[275-276,278]

4.6 Ring-Expansion Dearomatization Reaction

The cleavage of C—S bonds in sulfur-containing aromatic compounds by transition metals has been extensively studied and applied to the desulfurization of petroleum products[279]. In 1991, Jones et al.[280] reported the insertion reaction of rhodium into the C—S bond of thiophene (Figure 54a). Subsequently, insertion reactions of iron, cobalt, nickel, platinum, molybdenum, and other metals into the C—S bonds of sulfur-containing aromatic compounds were also reported[281]. In 2019, Matsubara and Kurahashi et al.[282] developed a nickel-catalyzed formal [5+2] cycloaddition reaction between benzothiophene and acetylenes (Figure 54b). In 2023, Glorius and Houk et al.[283] reported the visible light-catalyzed insertion of bicyclo[1.1.0]butane into (benzo)thiophene, achieving ring expansion and dearomatization of (benzo)thiophene under mild conditions (Figure 54c). Mechanistic experiments and theoretical calculations supported a photo-redox-induced radical mechanism.
图54 （苯并）噻吩的扩环去芳构化反应[280,282 -283]

Fig. 54 The ring expansion dearomatization reactions of (benzo)thiophenes[280,282 -283]

4.7 Carbene-Involved Dearomatization Reactions

In 2021, the Yamaguchi group[284] used hydrazones as carbene precursors to develop a palladium-catalyzed aza-annulation dearomatization reaction of thiophenes (Figure 55). This reaction is also applicable to the dearomatization of bromonaphthalenes and furans.
图55 钯催化溴代芳烃与对甲苯磺酰腙的氮杂环化反应[284]

Fig. 55 Pd-catalyzed dearomatization reactions of thiophenes with carbenes[284]

5 Phenol, Naphthol, and Their Derivatives

Phenol is one of the most common aromatic compounds, and its dearomatization reactions have been widely used in the synthesis of drug molecules, natural products, and material molecules. For example, in 1969, Corey et al[285] reported an intramolecular spirocyclization dearomatization reaction of phenols containing bromide side chains at the para position under basic conditions, and used this as a key step to synthesize cedrene (Figure 56).
图56 苯酚去芳构化反应在全合成中的应用[285]

Fig. 56 The application of dearomatization reactions of phenols in total synthesis[285]

5.1 Hydrogenation Dearomatization Reaction

In 1946, Stork et al[286] achieved the de-aromatization of β-naphthol for the first time through a palladium/carbon-catalyzed hydrogenation reaction, but this reaction required extremely high pressure and temperature (Figure 57).
图57 萘酚的氢化去芳构化反应[286]

Fig. 57 The hydrogenative dearomatization reactions of naphthols[286]

5.2 Oxidative Dearomatization Reactions

In 2017, Feng Xiaoming et al[287]reported the enantioselective hydroxylation and dearomatization reaction of β-naphthol with oxaziridine catalyzed by scandium/N, N′-oxide (Figure 58).
图58 萘酚的氧化去芳构化反应[287]

Fig. 58 The oxidative dearomatization reactions of naphthols[287]

5.3 Dearomatization Reactions with Nucleophiles

In 2020, Harutyunyan et al.[288] used an equivalent of aluminum chloride to induce the isomerization of naphthol into enone, and through a tandem copper-catalyzed Michael addition or hydrogenation reaction, achieved the dearomatization of β-naphthol (Figure 59).
图59 萘酚的异构化/Michael加成去芳构化反应[288]

Fig. 59 The dearomatization reactions of naphthols via isomerization/Michael addition[288]

Oxidative dearomatization is an essential component of phenol dearomatization reactions. In these reactions, hypervalent iodine reagents are one of the frequently used oxidants, and there are two oxidation mechanisms. The first involves the phenolic hydroxyl group replacing the leaving group in the iodine reagent to form an I—O bond. In 1999, Pelter et al.[289] attempted chiral iodine(III)-mediated asymmetric dearomatization reactions of phenols and their derivatives but could only isolate racemic products. In 2006, Rovis et al.[290] combined intermolecular dearomatization of phenols promoted by iodoacetate with intramolecular Stetter reaction catalyzed by N-heterocyclic carbene, achieving the highly enantioselective synthesis of hydrogenated benzofuranones (Figure 60a). In 2009, the Birman group[291] designed and synthesized a chiral oxazoline-substituted phenyl hypervalent iodine reagent, which was used to develop a tandem oxidative dearomatization/Diels-Alder reaction for ortho-methylphenols (Figure 60b). In 2013, Harned et al.[292] developed a chiral aryl iodine catalyst for the enantioselective oxidative dearomatization of 4-substituted phenols (Figure 60c).
图60 与高价碘形成I—O键的苯酚氧化去芳构化[290⇓-292]

Fig. 60 The dearomatization reactions of phenols via the formation of I—O bond with hypervalent iodine[290⇓-292]

The second method involves the oxidation of phenol into a carbocation using an iodine reagent. In 2010, Canesi et al.[293]used phenyl iodoacetate to oxidize phenolic derivatives, and the resulting carbocations underwent Wagner-Meerwein rearrangement, achieving intramolecular oxidative alkylation and dearomatization of phenols (Figure 61a). In 2013, the Greck group[294]reported an intermolecular oxidative dearomatization reaction between catechol and unsaturated aldehydes using a Jørgensen catalyst, which proceeded through a Diels-Alder/Michael cascade reaction (Figure 61b).
图61 形成苯酚正离子的氧化去芳构化反应[293-294]

Fig. 61 The dearomatization reactions of phenols via the formation of cation with hypervalent iodine[293-294]

In 2008, Kita et al.[295] used stoichiometric chiral hypervalent iodine reagents to develop the oxidative dearomatization reaction of 2-propanoic acid substituted α-naphthol derivatives, obtaining a series of spiro-lactone compounds with high enantioselectivity (Figure 62a). In 2010, Ishihara et al.[296] developed conformationally flexible C2 symmetric chiral aryl iodide catalysts and used these catalysts to achieve the oxidative dearomatization of naphthol derivatives (Figure 62b). In 2023, Xue Xiaosong et al.[297] provided a detailed explanation of the mechanism of this reaction. In 2013, Kita et al.[298] used m-CPBA as an oxidant to develop the oxidative dearomatization of α-naphthol derivatives catalyzed by chiral spirocyclic aryl iodides. In 2019, Houk et al.[299] conducted a detailed study on the mechanism of this reaction.
图62 高价碘催化的萘酚氧化去芳构化反应[295-296]

Fig. 62 Hypervalent iodine catalyzed oxidative dearomatization reactions of naphthols[295-296]

In 2005, Porco et al[300]used oxygen as the oxidant and developed a copper-catalyzed oxidative dearomatization reaction of phenols, achieving the asymmetric total synthesis of (-)-mitorubrin 5, (+)-sclerotiorin, and (+)-8-O-methylsclerotiorinamine 6 (Figure 63a). In 2011, Feringa et al[301]reported a chiral copper-catalyzed Michael addition reaction between Grignard reagents and unsaturated alkenes. The resulting chiral enolate intermediates underwent oxidative dearomatization of naphthols under the oxidation of divalent copper, constructing a series of spiro compounds with multiple chiral centers in excellent yield and selectivity (Figure 63b). In 2012, Katsuki et al[302]reported an iron-Salan complex catalyzed oxidative dearomatization reaction of 1,3-disubstituted-β-naphthols (Figure 63c). This reaction used nitromethane as the nucleophile and oxygen in the air as the oxidant, efficiently and with high enantioselectivity constructing a series of naphthoquinone compounds containing quaternary carbon chiral centers.
图63 金属/氧气催化的苯酚、萘酚氧化去芳构化反应[300⇓-302]

Fig. 63 Transition-metal catalyzed oxidative dearomatization reactions of phenols/naphthols in the presence of O2[300⇓-302]

5.4 Dearomatization Reactions with Electrophiles

In 2016, Sun Wangsheng, Hong Liang, Wang Rui, et al.[303] reported the asymmetric dearomatization reaction of β-naphthol with para-benzoquinone catalyzed by chiral phosphoric acid (Figure 64a). In 2021, the Ye Longwu group[126] used chiral phosphoric acid to enhance the electrophilicity of alkynyl amine, developing an intramolecular asymmetric dearomatization of phenol (Figure 64b). In 2023, the Mei Guangjian group[304-305] utilized azo-substituted alkenes as dipolar reagents, developing a chiral phosphoric acid-catalyzed intermolecular dearomatization/Michael addition cascade reaction of phenols, synthesizing tetrahydroindolones containing quaternary carbon chiral centers with good yields and excellent enantioselectivity control (Figure 64c).
图64 手性磷酸催化苯酚或萘酚与亲电试剂的去芳构化反应[303⇓-305]

Fig. 64 CPA catalyzed dearomatization reactions of phenols/naphthols with electrophiles[303⇓-305]

In 2012, You Shuli et al.[306] developed an iodination-initiated de-aromatization reaction of phenols, utilizing an intramolecular Stetter reaction to synthesize novel tricyclic compounds (Figure 65a). In 2014, the Gulías group[307] reported a rhodium-catalyzed [3+2] cyclization and de-aromatization reaction between 2-alkenylphenols and alkynes (Figure 65b). In the same year, the Hamada group[308] reported an intramolecular cyclization and de-aromatization reaction of phenol derivatives containing alkyne side chains catalyzed by gold (Figure 65c). In 2020, You Shuli and Zhang Liming et al.[309] reported an intramolecular de-aromatization reaction of naphthols with alkynes catalyzed by gold. In 2022, they[310] developed a new type of chiral bifunctional dinaphthyl-2-phosphine catalyst and successfully achieved the asymmetric de-aromatization of naphthols catalyzed by gold.
图65 苯酚与炔烃的环化去芳构化反应[306⇓-308]

Fig. 65 The cyclization dearomatization reactions of phenols with alkynes[306⇓-308]

In 2015, Wang Rui et al.[311]reported the conjugate addition de-aromatization reaction of chiral magnesium-catalyzed β-naphthol with alkynyl benzophenone, obtaining cis-olefin products (Figure 66a). In 2015, Wang Rui et al.[312]designed and synthesized a novel oxazoline ligand, and used this ligand to achieve the asymmetric de-aromatization reaction of magnesium-catalyzed β-naphthol with aziridine. In 2016, You Shuli et al.[313]reported the Michael addition de-aromatization reaction of chiral thiourea-catalyzed β-naphthol with nitroethylene (Figure 66b). In 2018, Wang Rui et al.[314]using quinine-derived chiral urea as a catalyst, reported the asymmetric de-aromatization reaction of 1,3-disubstituted-β-naphthol with 3-bromooxindole, synthesizing a series of products with adjacent quaternary carbon centers in excellent yields, enantioselectivity, and diastereoselectivity (Figure 66c). In 2018, they[315]developed a ligand-controlled β-naphthol de-aromatization and etherification reaction using this strategy. In 2022, Lautens et al.[316]discovered that benzyl hydroxy-substituted β-naphthol forms an enone under acidic conditions through dehydration, thereby developing a rhodium-catalyzed cyclopropanation de-aromatization reaction of naphthol with cyclopropene.
图66 萘酚与Michael受体或烷基溴化物的去芳构化反应[311,313 -314]

Fig. 66 The dearomatization reactions of naphthols with Michael acceptors and alkyl bromides[311,313 -314]

Aryl halides, allyl alcohol esters, and the intermediates formed with transition metals have electrophilicity, which can undergo dearomatization reactions with phenols, naphthols, etc. In 2010, Hamada et al.[317] developed an intramolecular palladium-catalyzed allylic substitution dearomatization reaction of phenols, yielding spiro[4.5]decadienones with good yields and stereoselectivity (Figure 67a). The Buchwald group (Figure 67b)[318] and the You group (Figure 67c)[319] utilized the oxidative addition of bromobenzene to form arylpalladium complexes, advancing the palladium-catalyzed dearomatization of phenols. The latter successfully synthesized the core skeleton of the natural product erythronolide using this strategy. In 2011, You et al.[320] reported an iridium-catalyzed intramolecular allylic substitution dearomatization of phenols, achieving excellent yields and enantioselective control (Figure 67d). In 2011, the Schmidt group[321] reported a [2+2+1] type spirocyclization dearomatization reaction of aryl diazonium salts and two molecules of acetylene under Pd(OAc)2 catalysis. In 2013, You et al.[322] extended this strategy to the dearomatization of naphthols, reporting the palladium-catalyzed allylic substitution dearomatization of 1,3-disubstituted-β-naphthols with linear allyl alcohol carbonates. Mechanistic studies showed that the dearomatized products are thermodynamically more stable, and etherification products can be further converted into dearomatized products. Subsequently, the group developed asymmetric allylic substitution dearomatization reactions of β-naphthols with linear allyl alcohols or esters using palladium/Trost ligands[323] or iridium/Carreira ligands[324]. Zeng Xiaofei, Zhong Guofu, et al.[325] used racemic phosphoric acid as a co-catalyst, reporting the asymmetric allylic substitution dearomatization of β-naphthols with branched allyl alcohols catalyzed by iridium/chiral Carreira ligands. In 2016, You et al.[326] reported the asymmetric intramolecular allylic substitution dearomatization of β-naphthols containing allyl carbonate side chains, obtaining a series of spironaphthalenone compounds with excellent yields, C/O selectivity, enantio- and diastereoselectivity. In the same year, they[327] also developed a zero-valent palladium-catalyzed intermolecular arylation dearomatization reaction of β-naphthols with aryl halides. In 2017, You et al.[328] achieved a tandem C4-arylation/intramolecular aza-Michael addition reaction of α-naphthols catalyzed by zero-valent palladium through substrate design, constructing a series of mesembrine alkaloid derivatives. In 2021, Bin Zhengyang, You Jinsong, et al.[329] reported a [4+1] spirocyclization dearomatization reaction of naphthols with diaryliodonium salts catalyzed by palladium, obtaining a series of spirofluorene-substituted naphthenones under mild conditions, and successfully applied these compounds to thermally activated delayed fluorescence materials. In 2023, the Phipps group[330] used chiral sSPhos, achieving an intramolecular coupling dearomatization reaction of phenols catalyzed by palladium (Figure 67e). In 2017, the Hu Xiangping group[331] reported a copper-catalyzed intermolecular asymmetric propargylation dearomatization reaction of phenols and propargyl alcohols (Figure 67f). In 2015, Tang Wenjun et al.[332] developed a monophosphine ligand and applied it to the asymmetric cross-coupling dearomatization of phenols catalyzed by palladium, completing the enantioselective synthesis of kaurene intermediates, boldenone skeletons, and totaradiol. In the same year, the Luan Xinjun group[333] used chiral N-heterocyclic carbene ligands, achieving the asymmetric dearomatization of axially chiral phenol derivatives catalyzed by palladium. This reaction underwent a dynamic kinetic resolution process, yielding a series of five-membered cyclohexenone spiroindane compounds. Subsequently, they[334] used furanylphosphine ligands, reporting a [3+2] spirocyclization dearomatization reaction of 4-phenylphenol with 1,3-diene benzene catalyzed by palladium.
图67 过渡金属催化的偶联去芳构化反应[317⇓⇓-320]

Fig. 67 Transition-metal catalyzed cross-coupling dearomatization reactions of phenols[317⇓⇓-320]

In 2013, Luan Xinjun et al.[335]reported a ruthenium-catalyzed intermolecular C—H bond activation and dearomatization reaction of 1-aryl-2-naphthols with internal alkynes (Figure 68a). This reaction used copper as an oxidant and involved the cleavage of C(sp2)—H bonds, alkyne migratory insertion, and naphthalene dearomatization. In 2015, You Shuli et al.[336]achieved an asymmetric dearomatization reaction involving the tandem C(sp2)—H functionalization/cyclization of 1-aryl-2-naphthols with internal alkynes under the presence of a chiral Cp-rhodium catalyst and a copper oxidant (Figure 68b). In 2015, Luan Xinjun et al.[337]developed an asymmetric spirocyclization dearomatization reaction of 1-naphthol with internal alkynes using a chiral NHC ligand and palladium catalysis (Figure 68c). This reaction achieved the asymmetric dynamic kinetic transformation of racemic biaryl compounds through the transfer of axial chirality to central chirality. In 2017, Luan Xinjun et al.[338]reported a three-component [2+2+1] spirocyclization dearomatization reaction of 1-bromo-β-naphthol, aryl iodides, and alkynes catalyzed by zero-valent palladium. The reaction underwent Catellani-type C—H bond activation, asymmetric biaryl coupling, alkyne migratory insertion, and aromatic dearomatization. In 2019, Luan Xinjun et al.[339]developed an intermolecular [4+1] spirocyclization reaction of 1-bromo-β-naphthol and aryl iodides catalyzed by palladium. This reaction involved C(sp3)—H activation and naphthol dearomatization, leading to the construction of a series of spirocyclic molecules. In 2020, Luan Xinjun et al.[340]realized a dearomatization reaction based on remote C—H bond arylation directed by alkynes.
图68 萘酚的C—H键活化去芳构化反应[335⇓-337]

Fig. 68 The dearomatization reactions of naphthols via C—H bond activation[335⇓-337]

In 2013, the Toste group[341] reported the asymmetric ortho-fluorination dearomatization reaction of phenol derivatives catalyzed by chiral phosphoric acid (Figure 69a). In 2015, Shuli You et al.[342] used DCDMH as a chlorination reagent and developed the (DHDQ)2PHAL-catalyzed asymmetric chlorination dearomatization reaction of naphthols, which constructed a series of C1 tetrasubstituted chiral naphthoquinone compounds with high yield and enantioselectivity under mild conditions (Figure 69b). In 2018, Dan-Qian Xu et al.[343] reported the chiral copper-catalyzed asymmetric bromination dearomatization reaction of naphthols. In 2018, Dong-Xu Yang, Rui Wang et al.[344] using commercially available halogenation reagents, reported the halogenation dearomatization reaction of chiral β-naphthols catalyzed by copper (Figure 69c). This reaction achieved the transfer from axial chirality to central chirality. In 2018, Rui Wang, Zhao-Qing Xu et al.[345] developed a visible light-promoted intermolecular fluoroalkylation dearomatization reaction of β-naphthols.
图69 萘酚的卤化去芳构化反应[341-342,344]

Fig. 69 The halogenative dearomatization reactions of naphthols[341-342,344]

In 2015, You Shuli et al.[346] used azodicarboxylates as amination reagents and developed an efficient asymmetric amination dearomatization reaction of β-naphthols catalyzed by chiral phosphoric acid (Figure 70a). Almost simultaneously, Luan Xinjun et al.[347] catalyzed this type of reaction using scandium triflate. In 2018, Zhong Cheng, Deng Qinghai et al.[348] reported an amination dearomatization reaction between β-naphthols and aryl azides catalyzed by iron (Figure 70b). In 2019, You Shuli et al.[349a] reported a tandem asymmetric amination/Michael addition dearomatization reaction of α-naphthols catalyzed by chiral phosphoric acid (Figure 70c). In 2023, the Meiguan Jian group[349b] reported a C4 regioselective amination dearomatization reaction of phenols with azodicarboxylates catalyzed by chiral phosphoric acid.
图70 萘酚的胺化去芳构化反应[348-349a]

Fig. 70 The aminative dearomatization reactions of naphthols[348-349a]

In 2017, the Nemoto group[350]used phenol as a nucleophile to attack the carbene intermediate formed by α-diazoacetamide and a chiral silver catalyst, achieving an intramolecular asymmetric dearomatization reaction of phenol (Figure 71a). In 2019, the Wang Donghui group[351a]used o-benzoylhydroxylamine as a carbene precursor and reported a copper-catalyzed intermolecular dearomatization reaction of 2,6-dimethylphenol (Figure 71b). This reaction selectively occurred at the ortho position of the hydroxyl group. In 2024, the Feng Xiaoming group[351b]achieved enantioselective control of this type of reaction using a chiral copper catalyst.
图71 苯酚与卡宾的去芳构化反应[350-351]

Fig. 71 The dearomatization reactions of phenols with carbenes[350-351]

5.5 Radical-Involved Dearomatization Reactions

In 1993, Kakiuchi et al.[352] found that under the action of aluminum halides, β-naphthol can isomerize into cyclohexenone, which can undergo a [2+2] cycloaddition reaction with ethylene under ultraviolet light (Figure 72a). In 2014, the Wang Qingmin group[353] developed a copper-catalyzed tandem alkyl radical addition/dearomatization reaction between phenol derivatives and Togni's trifluoromethylating reagents. In 2016, the Zhang Zhaoguo group[354] applied visible light-induced radicals generated from α-bromoamides to intramolecular spirocyclization dearomatization of phenol derivatives (Figure 72b). In 2018, the Glorius group[355] developed an intramolecular [2+2] cycloaddition dearomatization reaction of naphthyl ethers catalyzed by visible light (Figure 72c). By using catalysts with different triplet energies, [2+2] cycloadducts and rearrangement products could be selectively obtained. In 2024, the Glorius group[356] developed an intermolecular dearomatization reaction between phenols and bicyclo[1.1.0]butane (BCB) via visible light photoredox catalysis, yielding cycloenones fused with a bicyclo[2.1.1]hexane skeleton (Figure 72d).
图72 苯酚或萘酚的自由基去芳构化反应[352,354⇓ -356]

Fig. 72 The radical dearomatization reactions of phenols/ naphthols[352,354⇓ -356]

In 2016, the Dolbier group[357] achieved a photocatalytic tandem fluoralkylation/spirocyclization dearomatization reaction of N-benzyl acrylamides (Figure 73a). Using different fluoralkyl reagents, it was possible to control the retention or elimination of the sulfonyl group in the product. In 2016, the Zhang Zhaoguo group[358] used Ir(ppy)3 as a photocatalyst to achieve an intramolecular spirocyclization dearomatization reaction of benzyl ethers. In 2018, the Zhang Zhaoguo group[359] published a visible light-mediated tandem radical alkyne addition/intramolecular spirocyclization reaction, achieving the dearomatization of phenyl ethers (Figure 73b). In 2020, the Cariou group[360] used iodobenzene and pyran as dual photocatalysts to achieve the intramolecular spirocyclization dearomatization of benzyl ethers under oxygen and blue light. In 2022, the Lei Aiwen group[361] reported an electrochemically promoted spirocyclization dearomatization reaction of benzyl ether derivatives (Figure 73c). This reaction utilized anodic oxidation without the use of expensive oxidants such as high-valent iodine, with hydrogen gas evolved at the cathode.
图73 苯甲醚的自由基去芳构化反应[357,359,361]

Fig. 73 The radical dearomatization reactions of anisoles[357,359,361]

5.6 -Dearomatization Reactions of Metal Complexes2-或η6-金属络合物的去芳构化反应

In 1997, the Harman group[362]found that after benzylic ether coordinates with divalent osmium, defunctionalization can be achieved under acidic conditions (Figure 74a). In 2004, the Harman group[363]discovered that rhenium could also achieve similar transformations. In 2006, the Kündig group[364]achieved a highly regioselective trans-difunctionalization and defunctionalization of benzylic ether by coordinating it with tricarbonyl chromium, where the π electrons of the benzene ring filled the empty d orbitals of chromium, enhancing the electrophilicity of the benzylic ether (Figure 74b). In 2024, the Harman group[365]found that the complex of tungsten with benzylic ether, under the action of trifluoromethanesulfonic acid, would produce two isomers, P-type and D-type (Figure 74c). Although the ratio of 1Dto 1Pis 13, its conjugate acid 2Dis thermodynamically more stable, making the ratio of 2Dto 2Pgreater than 201. The protonated product 3Dof 2Dis highly electrophilic and can react with nucleophiles to yield arylated products.
图74 基于η2-或η6金属络合物的去芳构化反应[362,364 -365]

Fig. 74 The dearomatization reactions of anisoles based on η2 or η6 complex[362,364 -365]

6 Aniline

6.1 Catalytic Hydrogenation De-aromatization Reaction

Aniline can be catalytically hydrogenated to cyclohexylamine under a hydrogen atmosphere by transition metals such as iridium[366], nickel[367], rhodium[368], ruthenium[369-370], cobalt[371], platinum[372], etc. (Figure 75).
图75 苯胺的氢化反应[366⇓⇓⇓⇓⇓-372]

Fig. 75 The hydrogenation reactions of anilines[366⇓⇓⇓⇓⇓-372]

6.2 Oxidative Dearomatization Reactions

In 2005, the Quideau group[373]used IBX to oxidize acetyl-protected aniline, yielding o-quinone imine, 2-hydroxyimine, and a dimeric product of two molecules of aniline, with poor conversion and selectivity (Figure 76a). In 2009, the Canesi group[374]utilized phenyl iodoacetate to oxidize para-methyl-substituted phenylsulfonamide, allowing it to react with the nucleophile ethylene glycol, resulting in an unstable dearomatized intermediate (Figure 76b). Under the influence of trifluoroacetic acid, another hydroxyl group underwent intramolecular Michael addition with the unsaturated imine, leading to a stable product. In 2012, the Fan Renhua group[375]found that after poly-substituted anilines were oxidized by phenyl iodoacetate, they underwent cycloaddition reactions with electron-rich styrenes under the catalysis of AgOTf, producing bridged compounds (Figure 76c). AgOTf, acting as a π-acid, coordinated with the alkyne, promoting intramolecular nucleophilic attack of nitrogen on the alkyne. In 2013, the Fan Renhua group[376]developed a potassium tert-butoxide-promoted sequential Michael addition reaction using cyclohexadiene imine and acetylacetone as substrates, resulting in bridged bicyclic products. Based on this, they reported a tandem oxidative dearomatization and domino Michael addition reaction.
图76 苯胺的氧化去芳构化反应[373⇓-375]

Fig. 76 The oxidative dearomatization reactions of anilines[373⇓-375]

6.3 Dearomatization Reactions with Nucleophiles

In 2009, the Bedford group[377] reported the palladium-catalyzed cross-coupling reaction of N-phenyl-ortho-chloroaniline, yielding two dearomatized products (Figure 77a). In 2015, the Li Jian group[378] achieved the dearomatization of aniline through the Ugi/Himbert tandem reaction (Figure 77b). In 2016, the Meyer group[379] found that N,N-diphenylhydrazine can undergo a [5,5]-σ rearrangement under acidic conditions, leading to the dearomatization product of aniline (Figure 77c). The substituents at the ortho and para positions of the phenyl ring can inhibit side reactions. In 2024, the Wang Youliang group[380] developed a trifluoroacetic acid-promoted nucleophilic dearomatization/inter-ring cyclization tandem reaction of aniline (Figure 77d). Prior to this, inter-ring cyclization of the benzene ring could only be carried out under light conditions.
图77 苯胺的亲核去芳构化反应[377⇓⇓-380]

Fig. 77 The dearomatization reactions of anilines with nucleophiles[377⇓⇓-380]

6.4 Radical-Involved Dearomatization Reactions

In 2017, the Qiu Guansheng research group[381]used K2S2O8as an oxidant and zinc bromide as a bromine source to achieve the spirocyclization dearomatization reaction of N-phenyl propargyl amides. The reaction may proceed through the addition of bromine radicals to the alkyne and radical ipsocyclization, or electrophilic cyclization of bromonium ions with the alkyne. In 2019, the Liu Jinbiao research group[382]used Oxone as an oxidant and N-sulfonyl propargyl aniline as a substrate to achieve radical ipso-cyclization dearomatization of aniline (Figure 78a). To reduce ortho-cyclization, there must be a substituent at the ortho position of the aniline, such as iodine or methyl. The He Yanhong research group[383-384]utilized photocatalysis to generate thiocyanate radicals or bromine radicals, which respectively initiated the cyclization dearomatization of aniline. In 2021, the Liu Jinbiao, Qiu Guansheng, and Zhou Hongwei research groups[385]designed substrates of propargyl anilines containing hydroxyl groups in the side chain, constructing tricyclic skeleton compounds through the ipso-cyclization dearomatization reaction of aniline (Figure 78b). In 2023, the Gong Yuefa research group[386]reported the photo-catalytic para-alkylation dearomatization reaction of aniline (Figure 78c). The reaction underwent a cross-coupling process between cyclohexadienyl alkyl radicals and α-carbonyl alkyl radicals.
图78 苯胺的自由基去芳构化反应[382,385 -386]

Fig. 78 The radical dearomatization reactions of anilines[382,385 -386]

6.5 -Dearomatization Reactions of Metal Complexes2-金属络合物的去芳构化反应

In 1991, the Harman group[387] discovered that aniline and divalent osmium can form a stable η2-complex [Os(NH3)5(η2-benzene)]2+, in which the para position of the benzene ring exhibits strong nucleophilicity and undergoes an addition reaction with maleic anhydride (Figure 79a). The hexacoordinated divalent osmium stabilizes the imine intermediate through a feedback π-bond, which re-aromatizes under basic conditions and is reduced at its uncoordinated double bond in the presence of a reductant. In 1993, the Harman group[388] found that stoichiometric amounts of the Lewis acid TMSOTf or TBSOTf could accelerate the Michael addition reaction rate between the complex and ethyl acrylate (Figure 79b). Similarly, without the presence of an acid, the complex cannot react with MVK; however, upon adding stoichiometric amounts of BF3Et2O or triflic acid, the reaction yields ortho-alkylated dearomatized products with excellent yields (Figure 79c)[389]. Osmium in the product can be removed by oxidation with tetravalent cerium or by heating.
图79 基于η2-锇络合物的去芳构化反应[387⇓-389]

Fig. 79 The dearomatization reactions of anilines based on η2-Os complex[387⇓-389]

In 2010, the Harman group[390] discovered that when [TpW(NO)(PMe3)], forming an η2-tungsten complex with benzene, undergoes ligand exchange with aniline, an N—H bond insertion reaction occurs, yielding a tungsten hydride species (Figure 80a). When exchanging with N,N-dimethyl aniline, the system becomes more chaotic; however, if a weak acid is present to protonate the aniline, the imine intermediate can be stabilized. i-Pr2NH2OTf is the most suitable acid for this purpose, as stronger acids cause the decomposition of the tungsten complex. Under basic conditions, the imine intermediate re-aromatizes; at this point, adding benzyl bromide, allyl bromide, or 1-bromo-2-butanone results in substitution reactions at the para position of the aniline, leading to de-aromatized products with high regio- and stereospecificity (Figure 80b). Under conditions involving Selectfluor/alcohol, NCS/MeOH, or mCPBA, the imine intermediate undergoes a double functionalization reaction of the alkene.
图80 基于η2-钨络合物的去芳构化反应[390]

Fig. 80 The dearomatization reactions of anilines based on η2-W complex[390]

7 Pyridine, Quinoline, and Isoquinoline

Pyridine, quinoline, and isoquinoline are a class of inexpensive and readily available heteroaromatic compounds, from which saturated nitrogen-containing heterocyclic compounds with potential medicinal value can be obtained through dearomatization reactions. Because these aromatic systems have high aromatic stabilization energy and the possibility of coordinating and poisoning metals, achieving their dearomatization is relatively difficult. Currently, dearomatization of pyridine, quinoline, and isoquinoline can be achieved through reactions such as hydrogenation, boronation, silylation, electrophilic substitution, nucleophilic addition, and cyclization.

7.1 Hydrogenation and Dearomatization Reaction

Hydrogenation reactions can conveniently construct six-membered ring amine compounds[391]. In 2003, the Zhou Yonggui group[391a] used hydrogen as a hydrogen source and reported an iridium/bisphosphine ligand-catalyzed asymmetric hydrogenation of quinolines, yielding tetrahydroquinoline (Figure 81a). Subsequently, hydrogenation reactions of pyridines and quinolines catalyzed by ruthenium[392], rhodium[393], palladium[394], and manganese[395] were also reported. In addition to hydrogen, Hantzsch esters, hydrosilanes, and formic acid can also be used as hydrogen sources for the reaction (Figure 81b). Compared to hydrogenation, borohydration and silylation dearomatization reactions have the characteristics of mild conditions and high functional group tolerance, which can be achieved through metal-catalyzed[396] or non-metal[397] processes. In 2012, the Suginome group[398] achieved the rhodium/phosphine ligand-catalyzed borohydration of pyridines, obtaining excellent yields and regioselectivity (Figure 81c).
图81 喹啉或吡啶的氢化去芳构化反应[391a,398]

Fig. 81 The hydrogenative dearomatization reactions of pyridines and quinolines[391a,398]

In 2006, the Rueping group[399]utilized Hantzsch ester as a hydrogen source and chiral phosphoric acid as a catalyst to achieve highly enantioselective transfer hydrogenation of quinolines, yielding chiral tetrahydroquinoline derivatives (Figure 82). This was the first example of using organocatalysis for the hydrogenation of heteroaromatic rings. The reaction mechanism is roughly as follows: the quinoline is protonated by the phosphoric acid, undergoing a 1,4-hydride addition with the Hantzsch ester to form an enamine; in the presence of acid, the enamine isomerizes into an iminium ion, which is then reduced by the Hantzsch ester to produce the final product[400]. In 2022, the You Shuli group[401]synthesized a novel cross-linked chiral phosphoric acid and used it to achieve highly enantioselective transfer hydrogenation of 2-arylquinolines. Experiments involving ten cycles of use demonstrated that this catalyst can be recycled without any reduction in its catalytic efficiency.
图82 手性磷酸催化喹啉的不对称氢化去芳构化反应[399]

Fig. 82 CPA catalyzed hydrogenation reactions of quinolines[399]

7.2 Dearomatization Reactions with Nucleophiles

Pyridine and quinoline are electron-deficient aromatic compounds, often undergoing dearomatization reactions with nucleophiles. Developed nucleophiles include terminal alkynes[402], Grignard reagents[403], organic cyanide ions[404], enol silyl ethers and their derivatives[405], phenylboronic acid[406], indoles[407], and phosphorus nucleophiles[408], etc. For Reissert-type dearomatization reactions, it is necessary to pre-salt pyridine or quinoline, or form salts in the reaction system, to enhance the electrophilicity of the aromatic compound. In 2001, the Shibasaki group[404] achieved an asymmetric Reissert reaction between quinoline and TMSCN under the presence of furanoyl halides, catalyzed by chiral aluminum, obtaining the target product with excellent yield and enantioselectivity control (Figure 83a). The electrophilicity of pyridine and quinoline can also be enhanced by adding acids. In 2020, the Harutyunyan group[403b] used BF3Et2O as a Lewis acid to develop a 4-position addition reaction of quinoline with Grignard reagents, catalyzed by copper/bisphosphine ligands, achieving excellent enantioselective control (Figure 83b).
图83 喹啉与亲核试剂的去芳构化反应[403b-404]

Fig. 83 The dearomatization reactions of quinolines with nucleophiles[403b-404]

7.3 Dearomatization Reactions with Electrophiles

The introduction of a hydroxyl group on the aromatic ring can enhance the nucleophilicity of nitrogen in pyridines and quinolines, allowing it to undergo de-aromatization reactions with electrophiles. Developed electrophiles include propargyl[409]and allyl[410]metal complexes, α,β-unsaturated carbonyl compounds[411]. In 2015, the You Shuli group[410a]achieved an intermolecular asymmetric allylic substitution de-aromatization reaction of 2-hydroxypyridine catalyzed by iridium, which showed good compatibility with cinnamyl alcohol-derived allyl precursors (see Figure 84).
图84 羟基吡啶与亲电试剂的去芳构化反应[410a]

Fig. 84 The dearomatization reactions of 2-OH pyridines with electrophiles[410a]

7.4 Dearomatization Reactions with Dipoles

In 2013, the Piettre group[412]used acetal amine as a dipole precursor to achieve defluorination of 3,5-dinitropyridine promoted by trifluoroacetic acid at room temperature, constructing a tetracyclic structure through three cyclizations (Figure 85a). The Bastrakov group[413]developed a defluorination reaction for 2-substituted pyridines using formaldehyde and sarcosine to generate dipoles in situ (Figure 85b). This reaction undergoes two cyclizations, with substituents being O- or S-containing groups. However, when the substituent is an N-containing group, the reaction mainly yields products that re-aromatize after one cyclization[414]. In 2019, the Xiao-Ming Feng group[415]reported an asymmetric multicomponent cycloaddition defluorination reaction of isoquinoline with isocyanide and Michael acceptors catalyzed by magnesium (Figure 85c), where the isocyanide and 2-methylene malonate diester generated the dipole in situ.
图85 吡啶或异喹啉与偶极子的环加成去芳构化反应[412-413,415]

Fig. 85 The dearomatization reactions of pyridines/isoquinolines with dipoles[412-413,415]

In 2016, the Dowden group[416]reported an iron-catalyzed three-component cycloaddition dearomatization reaction of pyridine with diazo compounds and vinylindolinones. Pyridine and diazo compounds generate a nitrile ylide in situ, which then undergoes a cyclization reaction with vinylindolinones. In 2018, the Guo Hongchao group[417]synthesized N,O-heterooctacycles (Figure 86a) through a [5+3] cycloaddition dearomatization reaction of palladium-catalyzed isoquinoline-type azomethine imines and zwitterionic allylpalladium intermediates. In 2022, the Yoo group[418]synthesized chiral diazocyclooctane derivatives (Figure 86b) via an asymmetric [5+3] cycloaddition dearomatization reaction of copper-catalyzed quinoline zwitterion salts and enolate-substituted diazoacetates. In this reaction, NaBARF makes the copper carbene intermediate more electrophilic, thus avoiding [5+2] cycloaddition.
图86 （异）喹啉盐的去芳构化反应[417-418]

Fig. 86 The dearomatization reactions of (iso)quinoline ylides[417-418]

Although pyridine and quinoline are electron-deficient aromatic systems, the lone pair of electrons on the nitrogen atom is parallel to and directed outward from the aromatic ring, which gives pyridine and quinoline a certain degree of nucleophilicity. In 2017, the Waser group[419] used Yb(OTf)3 as a Lewis acid catalyst to achieve a cycloaddition dearomatization reaction between pyridine or quinoline and cyclopropane derivatives (Figure 87).
图87 Yb(Otf)3催化喹啉或吡啶与环丙烷的去芳构化反应[419]

Fig. 87 Yb(Otf)3 catalyzed dearomatization reactions of pyridines and quinolines with cyclopropanes[419]

7.5 Radical-Involved Dearomatization Reactions

In 2017, the Fu Hua research group[420]reported an oxidation reaction of quinolinium salts under visible light mediation in air conditions, synthesizing 1-alkyl-2-quinolinones with biological and pharmaceutical activity (Figure 88a). Isotope experiments confirmed that the oxygen in the product originated from oxygen. Pyridinium salts and isoquinolinium salts can also undergo this reaction. In 2020, the Li Jinheng research group[421]used sodium phenylsulfinic acid as a radical precursor to achieve a multi-component dearomatization reaction between pyridinium salts and alkenes through visible light photoredox catalysis (Figure 88b). The carbon radical generated by the addition of sulfonyl radicals to alkenes is captured by pyridinium salts, leading to the final products after subsequent processes. In 2020, the Dixon research group[422]used Lewis acids to assist in the single-electron reduction of imines, achieving [3+2] cyclo-dearomatization reactions between quinolines and imines (Figure 88c). In 2022, the Wang Wei research group[423]reported a 5,8-hydroamino dearomatization reaction between quinolines and pyrazoles through visible light photoredox catalysis (Figure 88d). Thiol serves as an HAT reagent, reducing the rate of re-aromatization of the allyl radical intermediate. In 2019, the Koenig research group[424]achieved Birch reduction reactions of various aromatic systems including quinolines and isoquinolines under visible light through a strategy combining energy transfer and redox catalysis (Figure 88e).
图 88 可见光氧化还原催化吡啶或喹啉的去芳构化反应[420⇓⇓⇓-424]

Fig. 88 Photoredox catalyzed dearomatization reactions of pyridines and quinolines[420⇓⇓⇓-424]

In 2019, the Sarlah group built upon their previous work[425], achieving a cis-1, 4-diamination dearomatization reaction of non-activated arenes and heteroarenes (Figure 89a)[426]. This reaction regulates the regioselectivity of palladium-catalyzed amination by altering the position of substituents on the quinoline: when the substituent is at the 2-position, the regioselectivity is only 21; when it is at the 4-position, the selectivity can be increased to >101. Using chiral ligands, the asymmetric dearomatization reaction of naphthalene was successfully achieved. In 2024, the Sarlah group[427]reported a visible light-promoted [4+2] cycloaddition dearomatization reaction between pyridine and MTAD, followed by tandem dihydroxylation or epoxidation of alkenes, to synthesize polysubstituted nitrogen-containing heterocyclic compounds (Figure 89b).
图 89 可见光直接激发吡啶或喹啉的环加成去芳构化反应[426-427]

Fig. 89 The cycloaddition dearomatization reactions of pyridines and quinolines by direct excitation[426-427]

In 2019, the Glorius group[428]developed a photosensitizer-loaded polymer and used it to achieve an intramolecular [4+2] cycloaddition dearomatization reaction between pyridine and α, β-unsaturated amides (Figure 90a). In 2021, the Glorius group[429]used hexafluoroisopropanol (HFIP) to activate quinoline, achieving a visible light-promoted intermolecular [4+2] cycloaddition dearomatization reaction between quinoline and alkenes (Figure 90b). In 2022, the Glorius, Brown, and Houk groups[430]investigated the mechanism of this reaction, finding that the regioselectivity of the reaction is not only greatly related to the position of the substituents on the quinoline ring but also significantly influenced by the polarity of the solvent (Figure 90c). In 2023, the Glorius group[431]achieved a visible light-catalyzed intermolecular [2π+2σ] cycloaddition dearomatization reaction between quinoline derivatives and [1,1,0]-bicyclobutane (BCB) (Figure 90d).
图90 可见光能量转移催化喹啉的环加成去芳构化反应[428⇓⇓-431]

Fig. 90 Energy transfer-mediated cycloaddition dearomatization reactions of quinolines[428⇓⇓-431]

8 Naphthalene and Benzene

Benzene and naphthalene are a class of aromatic systems composed of carbon and hydrogen, with relatively weak nucleophilicity and electrophilicity, and high aromatic stabilization energy. Therefore, achieving the dearomatization reactions of benzene and naphthalene is challenging[432⇓-434].

8.1 Hydrogenation-Induced Dearomatization Reaction

The development of transition metal-catalyzed hydrogenation reactions of benzene and naphthalene is relatively mature. Under a hydrogen atmosphere several times the atmospheric pressure, benzene and naphthalene can be converted to cyclohexane, benzocyclohexane, or decahydronaphthalene (Figure 91a)[435]. The hydrogenation of polysubstituted benzenes or naphthalenes exhibits good cis-selectivity. Using chiral ligands, enantioselective control of the hydrogenative dearomatization reaction can be achieved (Figure 91b)[436]. Functional groups such as carbonyls, esters, and amides are well tolerated in these reactions, but the compatibility with halogens and sterically demanding silyl and boronic esters needs improvement. In addition, the trans-hydrogenation of disubstituted benzenes is also a challenge[437]. In 2023, Li Wei's group[438] used a three-component dearomatization reaction involving a chromium-benzene complex, triphenylsilane, and trifluoroacetic acid to achieve chemoselective 1,2-reduction of benzene (Figure 91c).
图91 萘或苯的氢化去芳构化反应[435-436,438]

Fig. 91 The hydrogenation reactions of benzenes and naphthalenes[435-436,438]

In 2023, the Studer group[439]used water as a hydrogen source and, with the participation of triarylphosphine, developed a visible light photoredox-catalyzed hydrogenation reaction of naphthalene (Figure 92). The phosphorus radical cation generated in the photocatalytic cycle interacts with water molecules to produce an intermediate similar to a free hydrogen atom, reducing naphthalene to benzocyclohexane.
图92 可见光促进萘的氢化反应[439]

Fig. 92 Photocatalyzed hydrogenation reactions of naphthalenes[439]

Unlike hydrogenation dearomatization reactions, the Birch reduction reaction achieves partial hydrogenation of benzene, yielding 1,4-cyclohexadiene. In recent years, Birch-type reduction reactions promoted by visible light and electrochemistry have been reported[424,440⇓⇓⇓ -444]. These reactions have milder conditions, better functional group compatibility, and significantly improved chemoselectivity. In 2020, the Miyake group[442] achieved a Birch reduction of benzene via an organic photocatalytic process using a strategy of two consecutive photo-induced electron transfers (Figure 93a). In 2023, the Chiba group[443] developed a Birch reduction reaction for naphthoic acid derivatives using potassium polysulfide as a photocatalyst in the presence of potassium formate (Figure 93b). In 2019, the Baran group[444] reported an electrochemically promoted Birch reduction of benzene (Figure 93c).
图93 可见光/电促进苯或萘的Birch还原反应[442⇓-444]

Fig. 93 Birch reactions of benzenes/naphthalenes enabled by visible light or electrochemistry[442⇓-444]

8.2 Oxidative Dearomatization Reactions

Benzene and naphthalene can undergo enzymatic or biomimetic catalyzed dihydroxylation de-aromatization reactions[445]. Recently, Costas[446] reported the iron-catalyzed dihydroxylation of naphthalene with hydrogen peroxide, and increasing the amount of hydrogen peroxide can yield tetraol compounds (Figure 94).
图94 仿生催化萘的双羟化去芳构化反应[446]

Fig. 94 The oxidative dearomatization reactions of naphthalenes enabled by biomimetic catalysis[446]

8.3 Dearomatization Reactions with Nucleophiles

In 2005, the Meyers group[447]reported the nucleophilic addition de-aromatization reaction of benzene derivatives with alkyl lithium reagents (Figure 95a). In 2007, the Xi Zhenfeng group[448]developed an intramolecular de-aromatization reaction of benzene derivatives using in situ generated vinyl lithium reagents (Figure 95b). These reactions proceed through the nucleophilic addition to the aromatic ring, forming a carbon anion that subsequently reacts with an electrophile, achieving di-functionalization and de-aromatization of benzene. Introducing strong electron-withdrawing substituents onto the benzene ring can enhance its reactivity. Nitro-substituted benzenes or naphthalenes undergo cyclization and de-aromatization reactions with 1,3-dipoles in the presence of trifluoroacetic acid or palladium catalysts (Figure 95c, 95d)[449⇓-451].
图95 苯与金属试剂或偶极子的亲核去芳构化反应[447⇓⇓⇓-451]

Fig. 95 The dearomatization reactions of benzenes with metal reagents and dipoles[447⇓⇓⇓-451]

Transition metals coordinate with benzene, altering the π electron cloud density on the benzene ring, which can reduce the aromatic stabilization energy of benzene, thereby facilitating the de-aromatization reaction of benzene. Aromatic metal complexes are classified into η2 and η6 types. Metals such as chromium and ruthenium primarily form η6 complexes with benzene. In these complexes, electrons from the aromatic ring flow into the empty orbitals of the metal, reducing the π electron cloud density of the aromatic ring and increasing its electrophilicity[452⇓⇓⇓⇓⇓⇓-459]. In 1992, the Kündig group[452] used a chiral oxazoline-substituted benzo-chromium complex to sequentially react with methyl lithium and allyl bromide, achieving a diastereoselective difunctionalization de-aromatization reaction of benzene (Figure 96a). In 1996, the Kündig group[455] developed an enantioselective phenylation and propargylation de-aromatization reaction of imine-substituted benzene using chiral diether ligands (Figure 96b). In 2024, the Li Wei group[456] developed a three-component de-aromatization reaction involving benzo-chromium complexes, TMSCF3, and alcohols or amines (Figure 96c). The CO in the complex provided the carbonyl group in the product. In 2006, the Pigge group[457] reported an addition de-aromatization reaction of ruthenium-benzene complexes with intramolecular phosphates under NaH conditions, followed by a tandem Wittig reaction, yielding vinyl-substituted spirocyclic pentanamide compounds (Figure 96d).
图96 基于η6型金属络合物的苯与亲核试剂的去芳构化反应[452,455⇓ -457]

Fig. 96 The dearomatization reactions of benzenes with nucleophiles via η6-metal complexes[452,455⇓ -457]

Benzene or naphthalene with a leaving group (Cl or OCOOR) at the benzylic position undergoes oxidative addition with zero-valent palladium to form a de-aromatized allylpalladium intermediate. This intermediate can react with a nucleophile to achieve coupling and de-aromatization of benzene or naphthalene[460-461]. In 2001, the Yamamoto group[460] reported an allylation de-aromatization reaction of benzyl chloride with an allyl stannane reagent catalyzed by palladium (Figure 97a). In 2016, the Tunge group[461] achieved 1,2 or 1,4-dearomatization reactions of naphthalene derivatives containing an allyl carbonate in the side chain under palladium catalysis. The allyl alcohol anion generated in situ served as the nucleophile (Figure 97b).
图97 钯催化苯或萘与亲核试剂的偶联去芳构化反应[460-461]

Fig. 97 Pd-catalyzed cross-coupling dearomatization reactions of benzenes/naphthalenes with nucleophiles[460-461]

8.4 Dearomatization Reactions with Electrophiles

In 2013, the Canesi group[462] utilized the onium ions formed by the oxidation of phenols or anilines with high-valent iodine to achieve the cyclo-dearomatization reaction of benzene (Figure 98a). Electrophiles formed from alkynes and protons or bromonium ions have also been used in the dearomatization reactions of benzene or naphthalene[463-464]. In 2022, the Aggarwal group[465] enhanced the electrophilicity of the bridgehead carbon of aza-BCB using ammonium salts, developing an intramolecular dearomatization reaction of benzene derivatives (Figure 98b).
图98 苯与亲电试剂的去芳构化反应[462,465]

Fig. 98 The dearomatization reactions of benzenes with electrophiles[462,465]

Molybdenum, tungsten, rhenium, osmium, and other metals mainly form η2-type complexes with benzene. In such complexes, the electrons from the metal flow to the aromatic ring, increasing the π electron cloud density of the aromatic ring and enhancing the nucleophilicity of the aromatic compound[466⇓⇓⇓-470]. In 2017, the Harman group[468] reported the de-aromatization reactions of tungsten-benzene complexes with various nucleophiles in the presence of triflic acid (Figure99). In 2020, the Harman group[469] synthesized deuterated cyclohexene from benzene using protonated deuterated methanol as an acid and ammonium borodeuteride as a nucleophile.
图99 基于η2型金属络合物的苯与H+的去芳构化反应[468]

Fig. 99 The dearomatization reactions of benzenes with H+ based on η2-metal complexes[468]

In 2017, Zhang Guozhu et al.[471] utilized the nucleophilic allylchromium intermediate formed by chromium and benzyl bromide to develop an asymmetric reductive coupling dearomatization reaction of naphthalene under the presence of manganese powder and Lewis acid, using a chromium/Nakada ligand catalytic system (Figure 100a). In 2020, Jia Yixia's research group[472] used phenylboronic acid or tetraphenyl boron compounds as arylating agents to achieve a palladium-catalyzed tandem Heck/Suzuki coupling dearomatization reaction of naphthalene (Figure 100b). The dearomatization reaction occurred during the migratory insertion of naphthyl into arylpalladium or alkenylpalladium. A three-component dearomatization reaction took place under standard conditions involving ortho-naphthyl bromobenzene, alkynes, and sodium tetraphenylborate.
图100 过渡金属催化萘与亲电试剂的偶联去芳构化反应[471-472]

Fig. 100 Transition-metal catalyzed cross-coupling dearomati- zation reactions of naphthalenes with electrophiles[471-472]

8.5 Radical-Involved Dearomatization Reactions

The development of samarium diiodide-mediated radical dearomatization reactions occurred relatively early. In 2008, the Reißig group achieved the dearomatization reaction of benzene derivatives with ketones in the side chain promoted by samarium diiodide using tert-butanol as a proton source. The position of the substituents on the benzene ring determined the structure of the products (Figure 101a)[473]. In 2022, the You Shuli group[474] used chiral amino alcohol as a ligand to achieve for the first time the asymmetric dearomatization reaction of benzene and ketones mediated by samarium diiodide (Figure 101b).
图101 二碘化钐介导苯的自由基去芳构化反应[473-474]

Fig. 101 SmI2-mediated radical dearomatization reactions of benzenes[473-474]

In recent years, the development of visible light chemistry has greatly enriched the radical dearomatization reactions of benzene or naphthalene[475⇓⇓⇓⇓-480]. In 2019, Cho et al.[477] discovered a new method for N—O bond cleavage to form nitrogen radicals under oxygen conditions through visible light energy transfer catalysis, and achieved intramolecular spirocyclization dearomatization of benzene (Figure 102a). In 2019, the Samec group[478] used carboxylic acids as precursors for oxygen radicals and developed an intramolecular dearomatization reaction of benzene mediated by visible light (Figure 102b). In 2020, the You Shuli group[479] reported the hydrogen alkylation dearomatization of naphthalene with amino acids under visible light photoredox catalysis, which proceeded via an oxidative quenching mechanism of the photocatalyst by naphthalene (Figure 102c). In 2022, the Li Gang group[480] realized the radical dearomatization reaction of phenyl derivatives with bromobenzene and CO2 in the side chain under visible light catalysis (Figure 102d). In 2024, the Liu Qiang group[481] used N-nitrosoamines as bifunctional reagents, generating N radicals through direct homolysis of the [N]-NO bond under visible light, achieving selective 1, 2- or 1, 4-aminooxylation dearomatization of phenyl derivatives (Figure 102e).
图102 可见光促进苯或萘的自由基去芳构化反应[477⇓⇓⇓-481]

Fig. 102 Visible-light enabled radical dearomatization reactions of benzenes/naphthalenes[477⇓⇓⇓-481]

8.6 Cycloaddition Dearomatization Reaction

As early as the mid-20th century, the cycloaddition reactions of benzene with alkenes under ultraviolet light (254 nm) irradiation had been reported[482⇓⇓-485]. The chemical selectivity of these reactions is generally poor, and visible light catalysis provides a solution[486⇓⇓-489]. In 2022, the Maji group and the Brown group separately reported [4+2] cycloaddition dearomatization reactions of naphthalene with alkenes via visible light energy transfer catalysis (Figure 103a, 103b)[486-487]. In 2023, the Yin Biaolin group[488] developed an intramolecular [4+2] cycloaddition dearomatization reaction between benzene or naphthalene and cinnamamide, in which cinnamamide forms a biradical under the action of a photosensitizer (Figure 103c). In 2023, the Maestri group[489] found that allene amine can be excited by a photosensitizer to form a biradical intermediate, leading to [4+2] cycloaddition dearomatization with benzene or naphthalene (Figure 103d).
图103 能量转移介导苯或萘的环加成去芳构化反应[486⇓⇓-489]

Fig. 103 Energy transfer-mediated cycloaddition dearomatization reactions of benzenes/naphthalenes[486⇓⇓-489]

In 2016, the Sarlah group[490] achieved the de-aromatization reaction of benzene with MTAD mediated by visible light. The de-aromatized product decomposes rapidly above -10 ℃, so it is necessary to use osmium tetroxide and NMO for dihydroxylation of the product. Subsequently, this research team used this strategy to develop a series of functionalized de-aromatization reactions for benzene or naphthalene (Figure 104a)[491⇓⇓⇓⇓⇓⇓-498]. In 2023, the Matsunaga group[499] developed a novel six-membered cyclic azo compound that undergoes [4+2] cycloaddition with benzene or naphthalene under visible light, yielding de-aromatized products stable at room temperature (Figure 104b). In 2024, the You Shuli group[500] reported an asymmetric [4+2] cycloaddition de-aromatization reaction of naphthalene with alkenes catalyzed by gadolinium under visible light, achieving control over multiple selectivities (Figure 104c).
图104 可见光直接激发苯或萘的[4+2]环加成去芳构化反应[498⇓-500]

Fig. 104 [4+2] cycloaddition dearomatization reactions of benzenes/naphthalenes enabled by visible-light excitation[498⇓-500]

In 2023, the Bouffard group[501] used tert-butyl hypochlorite as an oxidant to achieve a [3+2] cycloaddition dearomatization reaction of benzene with triazine compounds. Notably, the dearomatization products and alkynes can be converted into substituted benzenes or naphthalenes, achieving the editing of aromatic ring skeletons (see Figure 105).
图105 苯的[3+2]环加成去芳构化反应及骨架编辑[501]

Fig. 105 [3+2] cycloaddition dearomatization reactions of benzenes and the following skeleton editing[501]

8.7 Carbene-Involved Dearomatization Reactions

Transition metal-catalyzed carbene insertion into benzene or naphthalene for dearomatization reactions is increasingly being reported[502]. In 2020, the Johnson group[503] reported the first intermolecular asymmetric dearomatization of benzene via rhodium-catalyzed carbene insertion (Figure 106a). The two electron-withdrawing groups in the carbene precursor stabilized the dearomatized product, preventing further ring-expanding rearrangement. In 2021, the Nemoto group[504] developed an intramolecular asymmetric dearomatization of benzene using alkynylamines as carbene precursors under silver catalysis, leading to the formation of seven-membered ring compounds after further ring expansion (Figure 106b). In 2024, the Jiao Ning group[505] reported a ring-opening dearomatization of benzene, converting azidobenzene into open-chain unsaturated nitriles (Figure 106c).
图106 卡宾参与的苯去芳构化反应[503⇓-505]

Fig. 106 The dearomatization reactions of benzenes with carbenes[503⇓-505]

8.8 Rearrangement and Dearomatization Reactions

In some special spatial conformations, the benzene ring and side chains undergo rearrangement and dearomatization reactions. In 2019, the Peng Bo group[506] discovered that the intermediate formed by the tin reagent and phenyl hypervalent iodine would undergo a [3,3]-rearrangement, yielding a dearomatized intermediate (Figure 107a). This intermediate isomerizes into stable products upon reaction with nucleophiles or hydrosilanes. In 2020, the Anderson group[507] used a dipole to undergo [3+2] cycloaddition with benzyne, and the resulting cyclized product further underwent an aza-Claisen rearrangement, achieving the dearomatization of benzene (Figure 107b). In 2021, the Ye Longwu group[508] reported the intramolecular asymmetric hydroalkoxylation/Claisen rearrangement dearomatization of benzene catalyzed by chiral phosphoric acid, which involved a kinetic resolution process (Figure 107c). In 2022, the Zhu Shifa group[509] reported the intramolecular [3+2] reaction/aza-Claisen rearrangement dearomatization of nitrobenzene with activated cyclopropane olefins (Figure 107d).
图107 苯的重排去芳构化反应[506⇓⇓-509]

Fig. 107 The rearrangement dearomatization reactions of benzenes[506⇓⇓-509]

9 Dearomatization Reactions of Other Aromatic Rings

Dihydrothiazoles are widely present in natural products and drug molecules, such as mirazole, bisamides, and the β-lactam antibiotics of the penicillin family. In 2016, the Guo Haiming group and the You Shuli group[510] collaborated to discover that, under the catalysis of magnesium and pyridine bisoxazoline ligand L2, 1,1-dicarboxylate cyclobutane as a dipole undergoes a [3+2] cycloaddition dearomatization reaction with benzothiazole, successfully synthesizing a series of dihydrothiazole skeletons with multiple chiral centers, a process involving kinetic resolution (Figure 108a). In 2019, the Guo Haiming group and the You Shuli group[511] collaborated again to report an asymmetric [3+2] cycloaddition dearomatization reaction between benzothiazole and 2-amino-1,1-dicarboxylate cyclopropane catalyzed by copper. Benzisoxazoles are important synthetic building blocks with good coordination properties. Due to the presence of weak N—O bonds, benzisoxazoles easily undergo ring-opening under transition metal catalysis. In 2017, the Luo Yongchun group[512] reported a scandium-catalyzed [4+3] cyclization dearomatization reaction between benzisoxazole and cyclopropane. In 2019, the Liu Ruixiong group[513] developed a gold-catalyzed [4+3] cyclization dearomatization reaction between benzisoxazole and ortho-alkynyl styrene. In 2019, the You Shuli group[514] developed an asymmetric [4+3] cyclization dearomatization reaction between benzisoxazole and alkenyl cyclopropane catalyzed by palladium/PHOX ligand (Figure 108b). NMR experiments showed that triethylboron activated the benzisoxazole. Imidazo[2-a]pyridines are important heteroaromatic compounds, widely found in luminescent materials, natural products, and bioactive molecules. In 2017, the Glorius group[515] achieved the asymmetric hydrogenation of imidazo[2-a]pyridine catalyzed by ruthenium. In 2022, the You Shuli group and the Yuan Yaofeng group[516] collaborated to use silver oxide and chiral squaramide as co-catalysts, achieving an interrupted Barton-Zard reaction between 8-nitroimidazo[2-a]pyridine and α-substituted isocyanates (Figure 108c). In 2024, the You Shuli group[517] reported an asymmetric [3+2] cycloaddition dearomatization reaction between benzimidazole and cyclopropenone catalyzed by phosphorus, where 4Å molecular sieves significantly improved the reaction yield (Figure 108d).
图108 苯并异噁唑/咪唑等与偶极子的去芳构化反应[510,514,516 -517]

Fig. 108 The dearomatization reactions of benzoisoxazoles/ benzimidazoles with dipoles[510,514,516 -517]

In 2017, the You Shuli group[518]applied iridium-catalyzed asymmetric intramolecular allylic substitution reactions to the dearomatization of five-membered nitrogen heterocycles such as benzoxazoles, benzothiazoles, and benzimidazoles (Figure 109a). In 2018, the Simth group[519]achieved an asymmetric Michael addition cyclization reaction between benzothiazoles and β-trifluoromethyl-substituted α,β-unsaturated trichlorophenyl esters catalyzed by isothiourea (Figure 109b). In this reaction, the trichlorophenol leaving group serves both as a Brønsted base, avoiding the need for additional auxiliary bases, and as a Lewis base, catalyzing the isomerization of dihydropyranones to the thermodynamically more stable dihydropyridinones. In 2022, the Hui Xinping group[520]developed a carbene-catalyzed asymmetric Michael addition cyclization reaction between benzoxazoles and α,β-unsaturated aldehydes (Figure 109c).
图109 苯并噁唑/苯并噻唑/苯并咪唑等与亲电试剂的去芳构化反应[518⇓-520]

Fig. 109 The dearomatization reactions of benzoxazoles/ benzothiazoles/benzimidazoles with electrophiles[518⇓-520]

In 2023, the Monge group[521]used a thiourea derived from tert-leucine as a catalyst to achieve the dearomatization reaction of phthalazines with siloxyacetal (Figure 110a). In 2024, the Aponick group[522]developed a copper-catalyzed asymmetric alkyne dearomatization reaction between pyrazines and phenylacetylene (Figure 110b). The product, 2,3-dihydropyrazine, can be further converted into piperazine compounds containing chiral centers and C1-symmetric diamines.
图110 酞嗪/吡嗪与亲核试剂的去芳构化反应[521-522]

Fig. 110 The dearomatization reactions of phthalazines/ pyrazines with nucleophiles[521-522]

In 2023, the Li Jianjun group[523]used cyclohexane as a radical precursor and reported an alkylative dearomatization reaction of benzothiazole derivatives under visible light with iron catalysis (Figure 111a). In 2008, the Davies group[524]utilized diazoacetates as carbene precursors to develop a ring-expansion and carbon-increase dearomatization reaction of isoxazole derivatives with rhodium catalysis, and completed the total synthesis of elisabethin C (Figure 111b). In 2024, the Bi Xiehe group[525]used hydrazones as carbene precursors to achieve a carbon-insertion and ring-expansion dearomatization reaction of (benzo)pyrazoles with rhodium or silver catalysis (Figure 111c). In 2018, the Liu Ruixiong group[526]reported a dearomatization reaction between benzisoxazoles and ynalamides with gold catalysis (Figure 111d). When IPrAuCl was used as the catalyst, a [5+2] cyclization occurred; when P(tBu)2(o-biphenyl)AuCl was used as the catalyst, a [5+1] cyclization occurred. At the same time, the Liu Yuanhong group[527]also reported similar work.
图111 苯并噻唑/异噁唑等与自由基或卡宾的去芳构化反应[523⇓⇓-526]

Fig. 111 The dearomatization reactions of benzothiazoles/ isoxazoles with radicals/carbenes[523⇓⇓-526]

10 Conclusions and Prospects

Defunctionalization reactions transform easily accessible aromatic compounds into three-dimensional molecules, demonstrating broad application prospects in the synthesis of natural products and pharmaceutical development. After 140 years of development, defunctionalization reactions have been applied to aromatic systems such as indoles, pyrroles, (benzo)furan, (benzo)thiophene, quinolines, pyridines, benzene, and naphthalene, constructing structurally diverse polycyclic compounds and significantly shortening the synthetic steps for some natural products. Various coupling reagents, including nucleophiles, electrophiles, dipoles, radicals, and carbenes, have been developed, providing abundant functional group sources for defunctionalization reactions. The gradual establishment of catalytic defunctionalization systems, such as transition metal catalysis, organocatalysis, enzyme catalysis, visible light catalysis, and electrocatalysis, has made the reaction conditions for defunctionalization milder, more atom-economical, and improved the selectivity of defunctionalization reactions. However, defunctionalization reactions still face some challenges. (1) There is a lack of efficient reaction systems for the defunctionalization of relatively inert aromatic compounds like benzene and pyridine. On one hand, benzene and pyridine have high aromatic stabilization energy barriers, requiring harsh reaction conditions for defunctionalization. On the other hand, the product of benzene defunctionalization, cyclohexadiene, is more reactive and will continue to react under reaction conditions, leading to numerous byproducts and difficulty in controlling selectivity. (2) Asymmetric defunctionalization reaction systems are relatively limited. Currently, asymmetric defunctionalization reactions of indoles and naphthols are well-developed, but progress in other aromatic systems is slow. (3) Defunctionalization reactions are mainly used to construct medium-sized rings, such as five-membered and six-membered rings, while methods for synthesizing small and large ring compounds are clearly insufficient. (4) Defunctionalization reactions that form carbon-heteroatom bonds are few, and introducing boron, silicon, sulfur, phosphorus, and other functional groups into defunctionalized products remains highly restricted. We believe that conducting defunctionalization reactions on aromatic compounds in an excited state can both reduce the energy barrier of the transition state and make the energy of the product lower than that of the reactant, which is favorable for the reaction from both kinetic and thermodynamic perspectives. In addition, the rapid development of enzymes, mesoporous materials, and metal-organic framework (MOF) materials in organic chemistry will also bring opportunities to defunctionalization reactions.

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