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Synthesis 2022; 54(02): 315-333
DOI: 10.1055/a-1631-1606
short review

α-Csp3–H Bond Functionalization of Simple Ethers in Radical Reactions

Yanping Feng‡
,
Xiajuan Ye‡
,
Dayun Huang  ∗
,
Sheng-rong Guo∗

This work was funded by the Natural Science Foundation of Zhejiang Province (LY19B020001, LQ18B020001) and Foundation of University Student Innovation Program (2021R434001) for financial support.
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Abstract

The direct α-Csp3–H functionalization of simple ethers is a vital strategy among radical reactions. This review discusses their applications according to the starting materials: (1) reactions with alkenes or alkynes; (2) reactions with other unsaturated compounds; and (3) reactions with nucleophilic partners. Mechanisms like radical addition, C–H activation, elimination, metal-catalyzed coupling, cyclization, oxidation, and rearrangement will be analyzed herein.

1 Introduction

2 Reactions with Alkenes or Alkynes

3 Reactions with Other Unsaturated Compounds

4 Reactions with Nucleophilic Partners

5 Oxidation of Ethers

6 Conclusions


#

Key words

ether - radical - Csp3–H bond functionalization
1

Introduction

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Yanping Fengobtained her B.Sc degree from Lishui University. Her current research interests focus on tandem reactions and green synthetic chemistry. Xiajuan Ye obtained her B.Sc degree from Lishui University. Her current research interests focus on tandem reactions and green synthetic chemistry. Dayun Huang was born in Zhejiang, China. He obtained his B.Sc. degree in chemistry from Xiangtan University and M.Sc. degree from Wenzhou University. He received his Ph.D. degree from Tsinghua University in 2016 under the supervision of Yuefei Hu and then worked at Lishui University as an associate professor. His current research interests focus on tandem reactions and green synthetic chemistry. Sheng-rong Guo was born in Zhangshu, China, in 1976. In 2004, he joined the group of Prof. Ping Zhong and obtained his Master’s degree from Jiangxi Normal University in organic chemistry. Later, he worked under the guidance of Prof. Jiannan Xiang and received his Ph.D. in organic chemistry from Hunan University (China) in 2016. In 2011, he was appointed as lecturer in Lishui University and is currently working as a professor at same university. He visited the University of Wisconsin-Madison (USA) in 2014 and worked with Prof. W. Tang for one year as a visiting scholar. His main research interest is the investigation of new methodologies for C–S bond formation via activation of inactivated chemical bonds.

Simple ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tetrahydropyran, 1,3-dioxolane, diethyl ether, 1,2-dimethoxyethane, and tert-butyl methyl ether (Scheme [1]), are commonly employed as solvents in organic synthesis. In fact, their α-Csp3–H bonds have relatively lower bond dissociation energy, which will facilitate the generation of α-oxyalkyl radicals smoothly under oxidative, light-induced, or electrochemical conditions. In 2021, Wang, Xing, and co-workers[1a] briefly reviewed the use of tert-butyl hydroperoxide (TBHP) as an initiator in radical reactions of alcohols, ketones, nitriles, amides, and ethers. In 2011, the Tu group[1b] reviewed the α-Csp3–H activation of ethers and alcohols, especially highlighting transition-metal-catalyzed C–C bond formation. Because of the great interest in ethers, in 2017, we reviewed the direct α-Csp3–H functionalization of ethers and alcohols via radical pathways with diverse nucleophilic partners, including C–H, N–H, O–H, and S–S compounds.[1c]

Herein, we will discuss advances in simple ethers and their radical applications according to the reaction partners: (1) reactions with alkenes or alkynes; (2) reactions with other unsaturated compounds, and (3) reactions with nucleophilic partners. Ethers are important motifs in various biologically active molecules.[1`] [d] [e] [f] [g] [h] We hope this review will assist future research in this area. Since there are myriad examples of ethers and their reactions in the literature, herein, we discuss only radical reactions of simple ethers. Although this review aims for a thorough coverage of the area, it is not exhaustive in nature.

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Scheme 1 Simple ethers in radical reactions to give C–C,[1h] , [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] , [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] , [42] [43] [44] C–N,[15] , [31] [32] [33] , [41] C–O,[34] [35] [36] [37] , [40] [45] and C–S/Se[38] [39] bonds

# 2

Reactions with Alkenes or Alkynes

One of the most important applications of α,β-unsaturated carboxylic acids is their use in decarboxylative cross-coupling reactions. In the synthesis of alkenes, the use of a high temperature contributes to the E configuration of the final alkene. Commonly, di-tert-butyl peroxide (DTBP),[2a] [c] benzoyl peroxide (BPO),[2b] and K2S2O8 [2d] are employed as oxidants for the generation of α-oxyalkyl radicals (Scheme [2]). Han, Pan, and co-workers[2a] explored a Fe(acac)3-catalyzed decarboxylative cascade of cinnamic acids with cyclic ethers for the synthesis of allyl ethers 2.2. Initially, in the presence of Fe3+, cleavage of DTBP gives a tert-butoxy radical, which reacts with the cyclic ether to generate the α-oxyalkyl radical. Visible-light photoredox reactions are at the forefront of organic chemistry involving radicals as key intermediates. Liu and co-workers[2b] developed a visible-light-induced preparation of ether-attached alkenes at room temperature. Reaction of the tert-butoxy radical and THF, diethyl ether, 1,4-dioxane, or tetrahydropyran forms α-oxyalkyl radicals. Notably, these reactions are all performed under an inert gas atmosphere as atmospheric oxygen will otherwise affect the result. For example, Guo and co-workers[2d] reported a metal-free oxidative decarboxylative coupling in an air atmosphere, in which α-oxyalkyl ketones 2.3 were obtained as the products. Mechanistically (Scheme [2]), using K2S2O8 under thermal conditions, hydrogen abstraction from the ether generates an α-oxyalkyl radical in a process requiring oxygen (in air) as the reagent and includes the formation of C–C and C=O bonds.

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Scheme 2 Radical addition and decarboxylation[2`] [b] [c] [d]

As shown in Scheme [3], radical addition product 3.1 underwent further elimination (denitrification,[2e] β-debromination,[2f] desulfonylation,[2g] or dehydrogenation[2h]) to yield (E)-allyl ethers 3.2 as the final product. Various ethers were used in these transformations. The Yao group[2e] utilized BPO as the sole initiator for the radical process at reflux. Alternatively, the use of UV photolysis instead of heating gave slightly lower yields. The Madsen group[2f] employed Me2Zn/O2 with 10 mol% MnCl2 to obtain pure E-isomers; the use of other radical initiators like BPO, Et2Zn, and Et3B all resulted in lower yields. In the absence of MnCl2, the yield dropped dramatically. It is proposed that Me2Zn reacts with O2 to form a zinc methylperoxide, which triggers homolysis to give the radicals. Guin and Paul[2g] developed a similar tandem reaction by using a catalytic amount of diaryl ketone in the presence of a household fluorescent light bulb. Wang and Gu[2h] developed a method for dehydrogenative olefination by merging rhenium catalysis with a hypervalent iodine(III) reagent (HIR). The cleavage of the I–O bond in the HIR gives an ionic species, which undergoes single electron transfer (SET) with Re2(CO)10 to afford α-oxyalkyl radicals. Interestingly, these (E)-allyl ether syntheses[2`] [f] [g] [h] were not performed under an inert atmosphere. On the other hand, the Liu group[2i] reported the reaction of β-bromo-β-nitrostyrenes with α-oxyalkyl radicals and alcohols (Scheme [3]). During this process, adducts 3.5 from radical addition are trapped by dioxygen to give peroxy radicals that undergo cleavage and elimination of the bromo group to afford acyl nitro compounds 3.6. Since 3.6 are less active than the acyl halide, it is difficult for bulky alcohols to attack to form the corresponding ester. β-Bromo-β-nitrostyrenes bearing electron-withdrawing aryl groups (F, Cl, Br) gave good yields, while those bearing a nitro group afforded a lower yield (15%).

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Scheme 3 Radical addition and elimination[2`] [f] [g] [h] [i]

Radical addition of an α-oxyalkyl radical to an alkene gives γ-oxyalkyl radical 4.1, which subsequently undergoes C–O coupling to enabled the rapid installation of the carbonyl group in 4.2. Liu, Chen, and co-workers[3a] and Li, Zhang, and co-workers[3b] both reported the cobalt-catalyzed oxyalkylation of terminal alkenes. Initially, the cobalt-catalyzed homolytic decomposition of TBHP generates the t-BuO• radical, which abstracts a hydrogen from the ether to give an α-oxyalkyl radical. Radical addition to styrene delivers a better stabilized benzyl radical, which is selectively trapped by the t-BuOO• radical[3a] or O2 [3b] to afford peroxide intermediates. Liu, Chen, and co-workers[3a] required the presence of base, otherwise only trace amounts of product were formed. The Zhang group[3c] devised a CuBr/TBHP-mediated oxyalkylation under aerobic condition; the presence of the copper catalyst is essential to the reaction. Zha, Wang, and co-workers[3d] employed a heterogeneous catalyst, diatomite-supported Mn3O4 nanoparticles (SMONP-1), in a similar oxyalkylation. Control experiments using 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) showed this to be a free-radical process in which where SMONP-1 catalyzed the reaction of ethers and O2 to afford α-oxyalkyl radicals. The Wu group[4] reported the visible-light-mediated three-component reaction of terminal alkenes, CO2, and simple ethers. Mechanistically (Scheme [4]), α-oxyalkyl radicals undergo addition to the alkene to afford 4.4, which is reduced to carbanion intermediate 4.5; CO2 is utilized as the electrophile to give 4.6 during the tandem reaction.

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Scheme 4 Radical addition and alkene difunctionalization[3] [4]

Photoredox catalysis and light-promoted conditions have been widely applied in radical addition reactions with electrophilic alkenes to give ethers 5.2,[5a] [b] , [5`] [f] [g] [h] which rely on SET from the excited state of the catalyst (Scheme [5]). Ravelli and co-workers[5a] and Wu and co-workers[5b] examined the visible-light-driven radical addition to electrophilic alkenes, 2-benzylidenemalononitriles, resulting in alkylation. In other reported examples the electrophilic alkene was dimethyl maleate,[5c] [d] 1,1-bis(phenylsulfonyl)ethylene,[5`] [f] [g] [h] and vinyl ketones and their derivatives.[5`] [j] [k] Cheng, Yu, and Chen[5j] reported the metal-free radical addition to chromones at 140 °C to give C2-substituted chromanone derivatives. Cyclic and acyclic ethers 1,4-dioxane (50%), tetrahydrofuran (86%), tetrahydropyran (73%), 1,3-dioxolane (40%), and diethyl ether (50%) were all compatible. Suryavanshi and More[5k] also designed a metal-free method to achieve the radical 1,6-conjugated addition of para-quinone methides with cyclic ethers. Initially, thermal decomposition of persulfate generates a sulfate anion radical, which could be stabilized by TBACl. Then, the sulfate anion radical abstracts a proton from the cyclic ether to produce the α-oxyalkyl radical.

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Scheme 5 Radical addition to active alkenes[5`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k]

Radical addition-cyclization cascades[6] proceed via a similar mechanism involving radical adducts 6.1 from alkenes and reaction with an acceptor functional group for intramolecular cyclization to give products 6.2 (Scheme [6]); both aryl[6`] [b] [c] [d] [e] , [6g] and alkynyl groups[6f] were good radical acceptors. Miao, Wang, and co-workers[6a] reported a visible-light-induced synthesis of alkylated oxindoles 6.4 using eosin Y as the photocatalyst and TBHP as an oxidant. The scope of the ethers extended to cyclic ethers (62–83%) and an acyclic ether (diethyl ether, 49%). The Yu group[6c] developed the alkylarylation of N-allylbenzamides 6.5 by utilizing copper/DTBP as the oxidative system. The cleavage of the Csp3–H bond in simple ethers and an Csp2–H bond in the aryl group is involved. The Li[6b] and Zhou groups[6d] reported the FeCl3/TBHP system in the radical-initiated addition-cyclization of N-methyl-N-phenylmethacrylamide 6.3 [6b] or N-allylbenzamides 6.5.[6d] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was utilized as a ligand to improve the reaction yield. The Wei group[6f] devised a base-promoted radical cyclization of 1,6-enynes 6.9. As the oxidant, tert-butyl peroxybenzoate (TBPB) performed better than other radical initiators like DTBP, BPO, TBHP, H2O2, and PhI(OAc)2. Control experiments implied that both oxidant and base were necessary. Liu, Tang, and co-workers[6g] designed the metal-free oxidative ring-opening cyclization of methylenecyclopropanes 6.11, via 6.13 and 6.14, to give 3,4-dihydronaphthalenes 6.12. The reactions of diethyl ether (36%) and 1,2-dimethoxyethane (71%) proceeded at the CH2 position. No product was obtained when tetrahydropyran was used. In our opinion, there will be more work performed using CHO, CN, OH, OMe, SMe, and N3 as radical acceptors in the ortho-position of arenes in the future.

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Scheme 6 Annulations of arene or alkyne-containing alkenes[6`] [b] [c] [d] [e] [f] [g]

Xu, Ji, and co-workers[6h] designed a metal-free functionalization of α,α-diarylallyl alcohols with ethers (Scheme [7]). This rearrangement reaction involves the sequence of radical addition to give 7.2, cyclization forming spiro intermediate 7.3, and 1,2-aryl migration giving 7.4. The electronic properties of the aryl ring affects the migration rate, with preferential migration of more electron-poor aryl groups detected. This chemoselective manner suggests that the reaction involves radical intermediate 7.4. The Gu group[6i] studied the distal heteroaryl ipso-migration of the benzothiazolyl group under visible-light irradiation (Scheme [7]). α-Oxyalkyl radicals are generated through hydrogen atom transfer between the ether and the sulfate radical anion. Then, the radical addition to alkenes gives intermediate 7.6, which undergoes cyclization to the heteroaryl group giving 7.7. The homolysis of a C–C bond in 7.7 might be due to ring strain; subsequently, the ring opening yields the more stable radical 7.8, which finally leads to products 7.5. Various ethers were well tolerated and the substrates were not limited to α,α-diaryl alcohols (R = aryl, 37–79%; Me, 52%).

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Scheme 7 Radical cyclization and ring-opening[6h] [i]

Wang and co-workers[7a] [b] and Liang and co-workers[7c] established the base-promoted C–H alkynylation of simple ethers with alkynyl bromides via bromoalkenyl radicals 8.1 (Scheme [8]). Interestingly, no oxidant or metal-catalyst was required for these transformations. The addition of a radical scavenger, TEMPO, to the system resulted in no reaction, which indicates that radical intermediates are involved.[7] Wang and co-workers[7a] found that using their KOAc-mediated thermal reaction under strictly anhydrous and anaerobic conditions gave no product. They also developed a visible-light-induced reaction[7b] using KF but no external photocatalyst. The Ye group[8] reported direct C–H alkynylation to give propargyl ethers 8.3 from the reaction of terminal alkynes with ethers. The H2BIP ligand and cosolvent water were all necessary. Their mechanism studies revealed that the cleavage of C–H bond and generation of α-oxyalkyl radicals is the rate-determining step. A variety of terminal alkynes were utilized and this showed that aryl-substituted acetylenes gave better results (56–82%) than alkyl-substituted acetylenes (11–34%). Significantly, both cyclic and acyclic ethers were suitable coupling patterns.

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Scheme 8 Synthesis of alkynes[7] [8]

Direct radical additions of α-oxyalkyl radicals to alkynes[9] [10] yields functionalized alkenes. Several examples of oxidative,[9a] [b] [d] [e] [g] photocatalytic,[9f] [h] [10] and microwave-promoted synthesis are given in Scheme [9]. Alkoxyalkylations of terminal or internal alkynes with ethers to give allylic ethers 9.1 are well developed.[9] Using cyclic ethers as starting materials, 2-vinyl-substituted heterocycles were obtained in an atom-economical and efficient way, which may be important for the synthesis of natural or biological products. Lu and Tusun,[9a] Zhang and co-workers,[9b] Kang and co-workers,[9e] and Wang and co-workers[9f] reported the catalyzed addition of ethers with various alkynes in the presence of TBHP under mild conditions. Li and Zhang[9c] devised a microwave-assisted addition of cyclic ethers to alkynes; hydrogen abstraction from ethers by oxygen generates the key α-oxyalkyl radicals. Luo and co-workers[10a] investigated selective addition to 3-arylpropynoic acids under visible-light-induced conditions; a variety of 3,3-disubstituted acrylic acids 9.2 were obtained. Surprisingly, this method showed excellent selectivity at C3 and no decarboxylation occurred. Cyclic ethers gave better yields (58–92%) than acyclic ethers (16–54%). The Hong group[10b] devised a photoredox-mediated C2-selective addition to ynones and the product 2-(1-alkoxyalkyl)vinyl ketones 9.3 were obtained with high Z/E selective (Z/E >20:1).

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Scheme 9 Addition to alkyne derivatives[9] [10]

Aryl-substituted alkynes were successfully employed in tandem cyclization with in situ generated α-oxyalkyl radicals (Scheme [10]).[11] [12] The Li group[11a] reported the reaction of N-arylpropynamides and ethers by a copper-catalyzed cascade to give 3-(1-alkoxyalkyl)-1-azaspiro[4.5]trienones 10.1, via a sequence of oxidative Csp3–H cleavage and radical addition to give alkenyl radical 10.2 that undergoes ipso-carbocyclization to give spirocycle 10.3 which undergoes dearomatization to give 10.4. The oxygen atom of newly quinone structure came from the hydroperoxide. It was necessary for the reaction that the N-arylpropynamides were N-substituted (R ≠ H). Li, Wang, and co-workers[11b] developed the metal-free synthesis of 3-(1-alkoxyalkyl)quinolines 10.5 from reactions of N-arylpropargylamines and cyclic ethers. General cyclic ethers, such as tetrahydropyran, 1,4-dioxane, and 1,3-dioxolane were well tolerated, affording 10.5 in 47–67% yields. 1,3-Dioxolane, which can be used as a formyl equivalent, was also a suitable candidate. Notably, due to two different kinds of hydrogens in 1,3-dioxolane, two isomers were obtained in a total yield of 67%. There are many reactions of 1,3-dioxolane[2d] [f] [3] [4] [5b] [e] [j] [n] [p] [6a] [d] [e] , [6`] [h] [i] , [7b] [9b] [d] [10b] [11b] [12b] [13b] [16a] [17b] [21a] [b] [22d] [23a] , [24`] [b] [c] , [24e] [25b] [26a] [29] [30c] [31d] [i] [33b] [39b] [42c] [e] [43b] [e] which demonstrate that the O,O-methylene C–H bond is more reactive than the O-methylene C–H bond, with some exceptions in which the 1,3-dioxolane was also coupled at C4.[22a] [23c] [25a]

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Scheme 10 Addition and cyclization of alkynes[11]
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Scheme 11 ipso-Cyclization (spiro intermediates) and ring-opening[12]

Liu and co-workers,[12a] Pan, Zhu, and Zhang,[12b] and Wang and co-workers[12c] independently reported the reaction of aryl alkynoates with simple ethers under oxidative conditions by radical cascade addition, 1,4-aryl migration, and decarboxylation to give 3-arylallyl ethers 11.1 (Scheme [11]). The mechanism involved a sequence of ipso cyclization to give spiro intermediate 11.2 which undergoes ring opening leading to 11.3 that undergoes decarboxylation to give 3-arylallyl ethers 11.1. Commonly, simple ethers such as 1,4-dioxane, tetrahydropyran, 1,3-dioxolane, and diethyl ether all reacted smoothly to generate the corresponding alkenes in moderate to good yields. A control experiment using fully deuterated THF indicated that the only source of hydrogen in the formed double bond was from ether.[12a] The use of THF in BPO afforded the expected product in a lower yield (20%).[12c]


# 3

Reactions with Other Unsaturated Compounds

Owing to their classical carbene-like reactivity, isocyanides have been recognized as versatile building blocks (Scheme [12]).[13] Zhao, Jia, Li, and co-workers[13a] devised the FeCp2-catalyzed construction of amides 12.1 via the reaction of an aryl isocyanide and THF at reflux (80 °C). Mechanistically, the in situ formed α-oxyalkyl radicals are trapped by the aryl isocyanide to generate an imine-type radical 12.2, which is further oxygenated to hydroperoxide 12.3 in the presence of oxygen. Then, the subsequent hydrogen abstraction and isomerization 12.4 affords final products. She and co-workers,[13b] Gonzalez-Gomez and co-workers,[13c] and Zhu and co-workers[13d] reported the reaction of biphenyl-2-yl isocyanides with ethers by radical insertion/cyclization for the construction of phenanthridines 12.5. Reactions of 1,3-dioxolane delivered a mixture of 1,3-dioxolan-2-yl- and 1,3-dioxolan-4-yl-substituted phenanthridines for the reasons discussed in Section 2. This oxidative cascade was performed under both light-induced[13b] or heating conditions.[13c] [d] The Shao group[13e] developed a microwave-assisted Fe(acac)2-catalyzed preparation of multi-substituted isoquinolines 12.6 via a similar addition-cyclization mechanism. This oxidative cascade reaction employed TBHP as oxidant and DBU as ligand. The use of a series of acyclic ethers was examined and all gave good yields.

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Scheme 12 Reactions of isocyanides[13]

The Inoue group[14a] reported a photoinduced protocol for the carbamoylation reaction between ethers and aryl isocyanates at ambient temperature to give α-alkoxyamides 13.1 (Scheme [13]). The reaction stopped at the monocarbamoylation stage even though excess isocyanate was added. No C–N coupling occurred. In the case of 2-methyltetrahydrofuran, a mixture of isomers was obtained. Zhang and co-workers[14b] investigated three-component reaction of an electrophilic aryl isocyanate, DTBP as the amidation source, and an ether to give N-tert-butyl-α-alkoxyamides 13.2 in good yields. Electron-rich 4-methoxyphenyl isocyanate ( Ar = 4-MeOC6H4) was not sufficiently stable under these strongly oxidative conditions (0% yield of product). However, this reaction went well on a gram scale using p-tolyl isocyanate, DTBP and tetrahydrofuran (10 mmol, 85% yield).

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Scheme 13 Reactions of isocyanates[14]

Averina and co-workers[15] elaborated the synthesis of 5-[hydroxy(tetrahydrofuran-2-yl)amino]isoxazoles 14.1 from the reaction of 5-nitroisoxazoles and THF (Scheme [14]). The process involves the reduction of 5-nitroisoxazole by SnCl2 to give 5-nitrosoisoxazole 14.2 and subsequent radical addition by the tetrahydrofuryl radical 14.3. It is worth noting an electron-withdrawing group (EWG) was necessary for these reactions.

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Scheme 14 Reactions of in situ generated 5-nitrosoisoxazoles[15]

Yoshimitsu, Nagaoka, and co-workers used both Et3B/air[16a] [c] and Et3B/TBHP[16b] as radical initiators to promote radical C–H abstraction from ethers (Scheme [15]). Hydroxyalkylation of simple ethers with aldehydes using Et3B gave 2-alkoxyalkanols 15.2.[16a] [c] The Et3B/TBHP oxidative system was more efficient than Et3B/air.[16b] Using 1,3-dioxolane as the ether and 4-methoxybenzaldehyde under the Et3B/air system resulted in C2/C4-hydroxyalkylation in 79% yield with the 2-substituted product predominating (68%).[16a] Using the Et3B/TBHP system,[16b] aromatic aldehydes were consumed within 5 min (78–82% yield), while aliphatic aldehydes required longer reaction times (70 min, 43–65% yield). The Griesbeck group[16d] studied photochemical reactions between aryl ketones and cyclic ethers. Cyclic ethers such as THF, tetrahydropyran, and 1,4-dioxane were utilized and gave moderate to good yields of 2-alkoxyalkanols 15.2. UV-A light and the Lewis acid catalysts Ti(O i Pr)4 and BF3 were necessary for this methodology.[16d]

Lu, Gong, and co-workers[17a] [b] reported the hydroxyalkylation of cyclic ethers with imines using 2,2′-azobis(isobutyronitrile) (AIBN)[17a] or butanedione/NHS/visible light[17b] as the radical initiator to give 2-alkoxyalkanamines 15.3 (Scheme [15]). Both electron-rich and electron-deficient imines gave the desired products in good yields. Imines are commonly generated from precursor aldehydes or ketones. Dilman and co-workers[17c] and Terent’ev and co-workers[17d] designed a decatungstate photocatalyst[17c] and TBHP,[17d] respectively, as radical initiators in radical additions of in situ generated imines with ethers to give 2-alkoxyalkanamines 15.3. The Tomioka group[17e] reported the Me2Zn-mediated three-component reaction of aldehydes, arylamines, and THF to give 2-(1-aminoalkyl)tetrahydrofurans 15.4; the use of alkyl aldehydes gave lower yields [Ph(CH2)2CHO, 50%; CyCHO­, 44%]. The Wang group[17f] utilized α-amino ketones as the precursors of imines 15.6 under oxidative conditions; this protocol did not require an aldehyde and resulted in α-amino-α-(1,4-dioxan-2-yl) ketones 15.5 in moderate yields.

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Scheme 15 Addition to aldehydes, ketones, or imines[16] [17]

Wang and Wang[18a] devised a tandem reaction of 2-alkynylbenzaldoximes with ethers resulting in 1-(1-alkoxyalkyl)isoquinolines 16.1 (Scheme [16]). Only cyclic ethers were successfully utilized in the cyclization-coupling cascades. AgOTf and Cu(OAc)2 were used as co-catalysts, in which AgOTf promotes the 6-endo cyclization to form isoquinoline N-oxides 16.2. The role of copper/TBHP is the generation of α-oxyalkyl radicals, as well as the key Cu(I) species giving copper species 16.3. Finally, reductive elimination from copper species 16.3 affords the alkylation products. Cu(II) species are regenerated in the presence of TBHP, which completes the catalytic cycle. The reaction of 1,4-dioxane as the ether afforded higher yields than THF. In the alkynyl part of the 2-alkynylbenzaldoximes, both aryl and alkyl groups (R2 = t-Bu, Bu, and cyclopropyl) were tolerated. The Opatz group[18b] employed a UV-A lamp in the light-induced C–C coupling of 2-chlorobenzazole derivatives with simple ethers to give 2-(1-alkoxyalkyl)benzoles 16.4. The radical reaction was promoted by the combination of benzophenone, and sodium acetate in acetonitrile/water. The α-arylation of methyl propyl ether with 2-chlorobenzoxazole provided a mixture of products in 6.25:1.00 ratio and 69% combined yield.

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Scheme 16 Reactions with aryl compounds[18]
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Scheme 17 Radical couplings of arenes[19] [20] [21] [22] [23] [24] [25] [26]

The directed C–H functionalization of arenes is a powerful approach in organic synthesis. Since 2000 there has been impressive progress in the development of Csp3–H functionalization techniques, which can be categorized in three major types: hydrogen atom transfer (HAT), transition-metal-catalyzed C–H activation, and carbene/nitrene insertion.[20a] Distinct from the other two types, HAT possesses a radical mechanism. The hydrogen atom of an ether will be abstracted from the Csp3–H bond by a highly reactive radical species. Oxidants like Selectfluor[20a] [c] [f] [21c] and K2S2O8 [20d] [g] [h] [24a] [26b] have been frequently utilized as a hydrogen­ atom transfer reagents. Scheme [17] summarizes the radical synthesis of α-oxyalkyl-substituted pyridines­,[19] [20b] [d] [e] [h] [21a] [b] quinolines,[20] [21a] [b] isoquinolines,[19c] [20d] [f] [h] , [21`] [b] [c] [d] pyridine N-oxides and N-aminopyridine ylides,[22] benzoxazoles,[21e] [23a] [d] [24e] benzthiazoles,[21b] [e] [f] [23a] [24a] [e] [f] indoles,[23b] [c] quinoxalin-2(1H)-ones,[24b] 2H‑indazole,[24c] boron dipyrromethene,[24d] coumarins[25] and heterocycle-containing phenyl rings.[26] Reactions generally require an oxidant and heating conditions leading to (het)arylmethyl ethers 17.1 regioselectively. Generally, cyclic ethers give better yields in these cross-dehydrogenative couplings (CDC) compared to acyclic ethers. As dehydrogenative coupling avoids the prefunctionalization of substrates, this is an atom-economic reaction that shows great significance in heterocyclic chemistry.

Wu, Wu, and co-workers[27] observed that pyridine or quinoline N-oxides functioned as both starting materials and oxidants in the direct alkylation with simple ethers in the presence of a base giving 2-(alkoxyalkyl)pyridines and -quinolines 18.1 (Scheme [18]). Mechanistically, the N-oxides undergo initial decomposition into benzyl radicals 18.3 and methoxy radical 18.4 via the homolytic cleavage of the N–O bond. These radical intermediates abstract a hydrogen atom from the ether to generate an α-oxyalkyl radical. A wide range of cyclic and acyclic ethers were well tolerated. Diethyl ether and tert-butyl methyl ether, and even ethyl acetate, yielded a single regioisomeric product 18.1 in 40–80% yield. The reaction was also successfully performed on a gram-scale (62%).

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Scheme 18 Alkylations of pyridine or quinoline N-oxides[27]

The Cai group[28] coupled N-methylaniline, without a directing group, with tetrahydrofuran to give N-[(tetrahydrofuran-2-yl)methyl]aniline (19.1) (Scheme [19]); the reaction was also successful with 1,4-dioxane. Mechanistically, the iron catalyst and TBHP oxidant generate a benzyl-type radical 19.2 or imine intermediate 19.3.

The Yan group[29] designed a copper-catalyzed three-component reaction of an isoquinoline, alkyl halide, and ether (Scheme [20]). This reaction is a three-step cascade, involving base-promoted nucleophilic substitution to give N-alkylisoquinolinium 20.2, radical addition giving 20.3, and reduction by DBU to give the final 1-(1-alkoxyalkyl)-2-alkyl-1,2-dihydroisoquinoline 20.1. This 1,2-difunctionalization reaction provides an efficient (10 min) and mild (rt) method for the preparation of various substituted dihydroazaarene derivatives 20.1. Using cyclic ethers as the ether component gave higher yields; acyclic ethers gave low yields or no reaction.

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Scheme 19 Radical coupling of N-methylaniline[28]
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Scheme 20 Three-component reaction of an isoquinoline, ether, and alkyl halide[29]

The Liu group[30a] developed a radical-mediated alkylation of the vinylic C–H of enamides with cyclic ethers to give γ-alkoxyenamides 21.1 (Scheme [21]). Using an ester-substituted enamide (Ar = 4-MeCO2C6H4) with tetrahydrofuran afforded the desired product in only 29% yield due to undesired decomposition. Cyclic enamides reacted with ethers under the same conditions to give products 21.2 in 33–63% yield; the reaction of 9-(acetylamino)-6,7-dihydro-5H-benzo[7]annulene with tetrahydrofuran afforded the corresponding product in low yield (33%). The reactions occur by a similar mechanism involving radical addition to give radical 21.3, SET process giving carbocation 21.4, and dehydrogenation to give cyclic enamides 21.2. Both the Lei[30b] and Yu groups[30c] reported the oxidative C–H alkylation of ketene dithioacetals with ethers to give 1-alkoxyalkyl-substituted ketene dithioacetals 21.5. The Lei group[30b] employed THF and dioxane in a metal-free cross coupling reaction with 2-{2-oxo-2-[4-(trifluoromethyl)phenyl]ethylidene}-1,3-dithiolane giving the corresponding products in 75% and 70% yields, respectively. The Yu group[30c] used simple ethers in similar oxidative C–H alkylation; cyclic ethers worked better than acyclic ethers. The addition of DBU and FeCl3 enhanced the yield in this case. 1,3-Dioxolane and 1,2-dimethoxyethane both contained two different Csp3–H bonds that give two separable isomers in this reaction. The result of the reaction of 1,3-dioxolane with 3,3-bis(methylthio)-1-(4-tolyl)prop-2-en-1-one showed that that the O,O-methylene C–H bond is more reactive than the O-methylene C–H bond. The Li group[30d] achieved direct C–H alkylation of 1,3-dicarbonyls (β-ketone esters, 1,3-diketones, and β-ketone amides) with ethers in the presence of iron catalyst and DTBP to give 2-(1-alkoxyalkyl)-1,3-dicarbonyls 21.6 (Scheme [21]). Notably, both cyclic and acyclic ethers were compatible.

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Scheme 21 Etherification of enol-type compounds[30]

# 4

Reactions with Nucleophilic Partners

As we reported in 2016,[1c] direct reactions between inexpensive ethers and nucleophilic partners (N–H, O–H, S–S, carbenes, F–, Cl–, C–B, metal species) by an oxidative radical process, has emerged as a vital strategy in oxidative cross-couplings.

The direct etherification was extended to sulfonyl amides,[31`] [b] [c] , [31e] [f] [32] saccharin,[31g] and amides[31a] [d] [h] [i] [32] giving N,O-acetals 22.2 (Scheme [22]). This N–H functionalization usually requires an electron-withdrawing group on the amino group. Hu and Buslov,[31a] Yin, He, and co-workers,[31b] Crabtree­, Gunnoe, and co-workers,[31c] and Yu and co-workers[31e] all utilized hypervalent iodine reagents as oxidants to achieve the amination of ethers with amides. The Li group[31d] [i] studied the copper-catalyzed amidation of ethers, using 4-methylpyridine[31d] or 1,10-phenanthroline[31i] as ligands to improve the yield. A quinoline or pyridine moiety was required in the structure of starting materials. The Cheng group[32] described the etherification of hydrazone sulfonamides, via a halogen-bond-promoted mechanism, to give N-(1-alkoxyalkyl)hydrazones 22.3 (Scheme [22]). Mechanistically, in situ generated amidyl anions and perfluorobutyl iodide (halogen bond donor) yield halogen bond adducts 22.4. The, thermal or visible-light-driven electron transfer gives aminyl radicals 22.5 and the perfluorobutyl radical, the latter abstracts the α-H of the ether to afford an α-oxyalkyl radical, which undergoes C–N coupling with aminyl radical 22.5.

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Scheme 22 C–N Coupling of amines[31] [32]

The Kwong group[33a] reported the direct radical amination of THF with indoles or 7-azaindole to give 1-(1-alkoxyalkyl)-substituted product 23.1 (Scheme [23]). Functional groups like ester, keto, and cyano were all compatible in the presence of CuCl2/bipy catalyst. Intermolecular hydrogen abstraction between carbazoles,[33a] azole derivatives,[33b] [c] [e] [f] , [33`] [j] [k] 1,2,4-triazoles,[33i] indazoles,[33i] purines,[33d] [g] [h] and tetrazoles[33l] have also been developed. Guo, Qu, and co-workers[33h] explored the application of (diacetoxyiodo)benzene (DIB) and iodine in the C–N coupling of purine rings and alkyl ethers; irradiation by light (200-W tungsten filament lamp) gave better results in some cases. As the number of carbon atoms in the acyclic ether increased, yield decreased significantly. The Lei group[33j] reported an electrooxidative N-alkylation using Pt as anode and cathode. Their mechanistic study indicates the C–H cleavage of tetrahydrofuran is probably not involved in the rate-determining step.

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Scheme 23 C–N Coupling of nitrogen-containing heterocycles[33]

Scheme [24] shows the oxidative coupling between simple ethers and alcohols[34] (or 2-carbonyl-substituted phenols,[35] in situ generated enols,[35a] N-hydroxyphthalimides,[36`] [b] [c] oximes[36d]) giving O,O-acetals 24.2. For example, the Deng group[34a] elaborated the CuBr2-catalyzed etherification of alcohols under heating using air as oxidant for the generation of α-oxyalkyl radicals 24.1, which are brominated by CuBr2 to form α-oxyalkyl halide as key intermediates. Hence, other copper salts like Cu(acac)2, Cu(OAc)2, CuO, CuI, and Cu powder were not effect for this reaction. Xie and co-workers[36c] also elaborated a copper/O2-mediated oxidative coupling, yielding N-hydroxyimide esters as final products. The radical coupling between simple ethers and hydroxyl compounds was possible using TBHP together with Cu(OAc)2,[35a] CuCl,[35b] Fe(CO)9,[35c] or TBAI.[36a] Kappe, Reddy, and co-workers[35a] and Chang, Wang, and co-workers[35b] reported the selective C–O couplings of salicylaldehydes and ethers. Mechanistically, the reaction of an α-oxyalkyl radical with the copper complex 24.4 yields 24.3, and this is followed by the regeneration of the copper catalyst. Interestingly, the sensitive formyl group of salicylaldehydes still remained intact, despite the oxidative conditions.

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Scheme 24 C–O Coupling of alcohols, phenols, enols, and oximes[34] [35] [36]

Commonly, alcohols[37`] [c] [d] and aldehydes[37e] were easily oxidized to acids,[37] which reacted with α-oxyalkyl radicals to give α-acyloxy ethers 25.1 (Scheme [25]). The Patel group[37f] devised a metal-free synthesis of α-acyloxy ethers by using benzylamines and ethers as starting materials. Mechanistically, the oxidation of benzylamines gives imines 25.3 and subsequent hydrolysis affords benzaldehyde intermediates 25.4, which are oxidized further to benzoic acids 25.5 that couple at the Csp3–H ether bond to give α-acyloxy ethers 25.2. The Patel group[37g] also utilized alkenes or alkynes as the source of the benzoic acid for the synthesis of α-acyloxy ethers 25.6. Mechanistically, the process involves oxidation of the alkene to give α-diketone 25.7, followed by decarbonylation giving benzaldehyde 25.8, and finally further oxidation to the benzoic acid 25.9, the possible source of the carboxy group in the O–C coupling. By comparison, esterification of THF was not as effective as 1,4-dioxane in terms of yield.

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Scheme 25 C–O Coupling of in situ generated acids[37]

As shown in Scheme [26], ethers underwent C–S and C–Se coupling with disulfides,[38`] [b] [c] diselenides,[38d] sodium sulfinates,[38e,f] ArSO2Cl,[38g] [i] or ArSO2NHNH2,[38f] [h] under various reaction conditions. Diverse radical initiators were utilized. In the future, sulfinic acids[38j] may also act as a sulfonyl source and participate the radical chemistry to construct C–S bonds efficiently.

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Scheme 26 C–S and C–Se Coupling[38]

The Tang group[39a] and Guo, Zhao, and co-workers[39b] independently investigated the generation of S[39a] (or Se[39b]) radicals 27.2 and their subsequent cross-coupling with imidazopyridines to give 3-[(1-alkoxyalkyl)thio] (or -seleno) products 27.1 (Scheme [27]). Inexpensive and odorless elemental sulfur (or selenium) was employed. The 3-alkylthiolation (or 3-alkylselenation) of imidazopyridines was performed using oxidants with heating (120–130 °C). Reactions of using THF as the ether gave products in lower yields than 1,4-dioxane; due to the high reaction temperature, the low boiling point of THF might influence the reactivity. Liu, Sun, and co-workers[39c] demonstrated a novel annulation/ring-opening cascade of 1‑(2-aminoaryl)pyrroles and ethers with elemental sulfur. Mechanistically, the tert-butoxyl radical from TBAI/TBHP forms α-oxyalkyl radicals, which are trapped by elemental sulfur. Next radical addition to give 27.4 is followed by SET and nucleophilic addition to give 27.5, and further ring-opening results in N-heterocycle-fused 1,3,6-benzothiadiazepine 27.6 that gives the final product 27.3. Cyclic ethers (THF, 2-methyltetrahydrofuran, 1,3-dioxolane, tetrahydropyran) and linear diethyl ethers were all tolerated in this method.

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Scheme 27 Elemental sulfur or selenium in C–S coupling[39]

The Inoue group[40a] utilized tosyl cyanide as the CN source in the direct cyanation of ethers (Scheme [28]). Benzophenone was excited by light irradiation (UV light, Riko 100-W medium-pressure Hg lamp) and promoted the homolytic cleavage of the C–H bond. The Fuchigami group[40b] studied the electro-organic anodic fluorination of cyclic ethers in Et4NF·4HF. Monofluorinated ethers were obtained in moderate yields and were easily isolated by simple distillation of the electrolytic mixture. The Kamijo group[40c] also reported the application of photo-excited benzophenone in a two-step reaction by C–H bond chlorination to give α-chloro ether 28.2 and nucleophilic substitution giving O,O-acetal 28.3. As the number of carbon atoms in the acyclic ether increased, the yield decreased.

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Scheme 28 Cross-coupling with CN, F, and Cl[40]

The Che group[41a] [b] designed the iron porphyrin catalyst [Fe(TF4DMAP)-Cl] and used it in the amination of ethers with aryl azides to give N,O-acetals 29.2 (Scheme [29]). Mechanistically, the reaction may involve radical recombination of 29.1 and the α-oxyalkyl radical. Wei and co-workers[41c] [d] reported the selective preparation of N 1- 29.3 and N 2-alkylated triazoles 29.4 by the three-component reaction of ethers, TMSN3, and alkynes. The alkyne could be a propynoic acid[41c] or a terminal alkyne.[41d] The best catalyst[41d] was found to be 5 mol% CuCl and it reacted with ethers, TMSN3, and alkynes to selectively afford N 1-alkylated triazoles 29.3, while using 20 mol% CuCl under the same conditions gave N 2-alkylated triazoles 29.4.

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Scheme 29 Reactions with azides or triazoles[41]

As catalytically generated species, metal-bound carbenes 30.1 are efficient for the C–H functionalization of ethers to give β-alkoxy esters 30.2 (Scheme [30]). Catalysts derived from iridium,[42a] rhodium,[42b] [f] [g] silver,[42c] and copper[42d] [e] are particularly effective in the decomposition of diazo compounds to form carbenes. The Lacour group[42h] elaborated a novel carbene insertions for the synthesis of enol acetals. Mechanistically, the ruthenium catalyst precursor reacts with 1,10-phenanthroline to yield intermediate 30.5. Then, electron-deficient 30.5 reacts with the diazo compound to afford metal carbenoid intermediate 30.6. In contrast to classical 3-membered transition states, this mechanism involves a five-membered transition state 30.7. This step is stereodetermining as the s-cis conformation of the carbonyl group in 30.6 is conserved to form the E-configured enol. Various substrates with different ester groups (alkyl, aryl) were well tolerated, while the allyl ester only afforded 30.3 in 15% yield.

Direct formation of C–C bonds in ethers 31.2 starting from unactivated ethers has proven to be a reliable and powerful approach (Scheme [31]);[43] these reactions use transition-metal-catalyzed transformations via 31.1 in which C–Ni[43`] [d] [e] [f] [g] species and radicals[43] serve as the key intermediates. Both Wang and co-workers[43a] and Yang, Xia, and co-workers[43b] investigated catalytic visible-light-induced C–F cleavage and C–C bond formation. The cross-coupling has been described between halides (acyl chlorides,[43c] [d] aryl bromides,[43e] [g] alkyl bromides,[43f] [g] or alkyl chlorides[43f]) and ethers. In particular, the use of Ni and photoredox catalysis has emerged as an important strategy.

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Scheme 30 Reactions with diazo compounds[42]
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Scheme 31 Metal-mediated C–C cross-coupling[43]

The Lei group[44a] elaborated a nickel-catalyzed oxidative C–C coupling between arylboronic acids and ethers to give alkyl benzyl ethers 3.1 (Scheme [32]). Mechanistically, there are two proposed pathways. In path A, aryl radicals 32.2, from arylboronic acids, and α-oxyalkyl radicals are formed, while in path B, α-oxyalkyl radicals are further oxidized to form cations 32.3 and undergo coupling with arylboronic acids. Arylboronic acids bearing electron-withdrawing groups afforded the corresponding products in better yields. The Liu group[44b] developed a mild C–C coupling with nucleophilic potassium trifluoroborates, via the trityl ion mediated C–H functionalization of ethers. During the process, electron-withdrawing groups the aryl group of the potassium aryltrifluoroborate obviously decrease the yield (Ar2 = 4-ClC6H4, 32%) (Scheme [32]).

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Scheme 32 C–C Coupling with boron reagents

# 5

Oxidation of Ethers

As mentioned before, α-oxyalkyl radicals are further oxidized to form cations 33.1, which are then trapped by nucleophiles like water 33.2 [45`] [b] [c] [d] [e] [f] and intramolecular amino group 33.8 (Scheme [33]).[45g] Using O2 as the oxidant, 2-OH-THF 33.2 is generated in a hydrophilic process, which then undergoes oxidation to give 33.3 to form butyrolactone 33.4.[45`] [b] [c] [d] [e] [f] For example, Lin and co-workers[45a] tuned the catalytic microenvironments of metal-organic layers (MOLs) leading to the highly selective formation of butyrolactone 33.4 in quantitative yield. Similarly, the O2-activation of THF was found be achieved in the presence of iron-rich clay,[45b] siloxide complexes of Cr(II) and Cr(IV),[45c] singlet O2 photosensitizer and photoirradiation,[45d] a cobalt catalyst,[45e] or molecular heterogeneous catalysts derived from bipyridine-based organosilica nanotubes.[45f] Many other cyclic/linear aliphatic ethers were examined and gave corresponding lactone products. The Sun group[45g] reported a photo-assisted metal-free multicomponent dehydrogenative condensation of benzaldehydes, thioureas, and cyclic ethers via condensation to give 33.6, oxidation, nucleophilic addition, and intramolecular cyclization of 33.8 to give pyrimidine-2-thiones with excellent stereoselectivities (Scheme [33]).

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Scheme 33 Oxidation and applications[45]

# 6

Conclusions

In summary, we have presented an overview of simple ethers in radical reactions. The employment of inexpensive ethers and new straightforward methods are significant in organic synthesis. Recent applications of simple ethers are summarized according to reaction partners. Mechanisms involving radical addition, C–H activation, elimination, metal-catalyzed coupling, cyclization, oxidation, and rearrangement have been discussed. The activation of ethers can be with a variety of conditions, using a single oxidant [K2S2O8, (NH4)2S2O8, BPO, TBHP, DTBP, BPO, TBPB, PhIPF6, PhI(OAc)2], metal-catalyst/oxidant [Fe(III), Ag(I), Mn(II), Co(II), Ni(II), Cr(II), Pd(II), Ru(III), Cu(I or II), Me2Zn], Et3B/oxidant, BTAI/TBHP, visible-light induced, or electrochemical or microwave-mediated systems. However, the development of a mild, green, and facile catalytic system is still a challenge.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Authors

Dayun Huang
Department of Chemistry, Lishui University
No. 1, Xueyuan Road, Lishui City 323000, Zhejiang Province
P. R. China   

Sheng-rong Guo
Department of Chemistry, Lishui University
No. 1, Xueyuan Road, Lishui City 323000, Zhejiang Province
P. R. China   

Publication History

Received: 22 July 2021

Accepted after revision: 02 September 2021

Accepted Manuscript online:
02 September 2021

Article published online:
20 October 2021

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Yanping Fengobtained her B.Sc degree from Lishui University. Her current research interests focus on tandem reactions and green synthetic chemistry. Xiajuan Ye obtained her B.Sc degree from Lishui University. Her current research interests focus on tandem reactions and green synthetic chemistry. Dayun Huang was born in Zhejiang, China. He obtained his B.Sc. degree in chemistry from Xiangtan University and M.Sc. degree from Wenzhou University. He received his Ph.D. degree from Tsinghua University in 2016 under the supervision of Yuefei Hu and then worked at Lishui University as an associate professor. His current research interests focus on tandem reactions and green synthetic chemistry. Sheng-rong Guo was born in Zhangshu, China, in 1976. In 2004, he joined the group of Prof. Ping Zhong and obtained his Master’s degree from Jiangxi Normal University in organic chemistry. Later, he worked under the guidance of Prof. Jiannan Xiang and received his Ph.D. in organic chemistry from Hunan University (China) in 2016. In 2011, he was appointed as lecturer in Lishui University and is currently working as a professor at same university. He visited the University of Wisconsin-Madison (USA) in 2014 and worked with Prof. W. Tang for one year as a visiting scholar. His main research interest is the investigation of new methodologies for C–S bond formation via activation of inactivated chemical bonds.
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Scheme 1 Simple ethers in radical reactions to give C–C,[1h] , [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] , [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] , [42] [43] [44] C–N,[15] , [31] [32] [33] , [41] C–O,[34] [35] [36] [37] , [40] [45] and C–S/Se[38] [39] bonds
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Scheme 2 Radical addition and decarboxylation[2`] [b] [c] [d]
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Scheme 3 Radical addition and elimination[2`] [f] [g] [h] [i]
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Scheme 4 Radical addition and alkene difunctionalization[3] [4]
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Scheme 5 Radical addition to active alkenes[5`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k]
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Scheme 6 Annulations of arene or alkyne-containing alkenes[6`] [b] [c] [d] [e] [f] [g]
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Scheme 7 Radical cyclization and ring-opening[6h] [i]
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Scheme 8 Synthesis of alkynes[7] [8]
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Scheme 9 Addition to alkyne derivatives[9] [10]
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Scheme 10 Addition and cyclization of alkynes[11]
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Scheme 11 ipso-Cyclization (spiro intermediates) and ring-opening[12]
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Scheme 12 Reactions of isocyanides[13]
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Scheme 13 Reactions of isocyanates[14]
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Scheme 14 Reactions of in situ generated 5-nitrosoisoxazoles[15]
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Scheme 15 Addition to aldehydes, ketones, or imines[16] [17]
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Scheme 16 Reactions with aryl compounds[18]
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Scheme 17 Radical couplings of arenes[19] [20] [21] [22] [23] [24] [25] [26]
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Scheme 18 Alkylations of pyridine or quinoline N-oxides[27]
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Scheme 19 Radical coupling of N-methylaniline[28]
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Scheme 20 Three-component reaction of an isoquinoline, ether, and alkyl halide[29]
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Scheme 21 Etherification of enol-type compounds[30]
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Scheme 22 C–N Coupling of amines[31] [32]
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Scheme 23 C–N Coupling of nitrogen-containing heterocycles[33]
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Scheme 24 C–O Coupling of alcohols, phenols, enols, and oximes[34] [35] [36]
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Scheme 25 C–O Coupling of in situ generated acids[37]
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Scheme 26 C–S and C–Se Coupling[38]
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Scheme 27 Elemental sulfur or selenium in C–S coupling[39]
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Scheme 28 Cross-coupling with CN, F, and Cl[40]
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Scheme 29 Reactions with azides or triazoles[41]
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Scheme 30 Reactions with diazo compounds[42]
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Scheme 31 Metal-mediated C–C cross-coupling[43]
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Scheme 32 C–C Coupling with boron reagents
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Scheme 33 Oxidation and applications[45]