Trisubstituted Alkenes as Valuable Building Blocks

Academic Editor: Gianfranco Favi Received: 16 June 2025 Revised: 10 August 2025 Accepted: 11 August 2025 Published: 13 August 2025 Citation: Tobrman, T.; Hron, V. Trisubstituted Alkenes as Valuable Building Blocks. Molecules 2025,30, 3370. https://doi.org/10.3390/ molecules30163370 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). Review Trisubstituted Alkenes as Valuable Building Blocks Tomáš Tobrman * and Václav Hron Department of Organic Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague, Czech Republic; [email protected] *Correspondence: [email protected] Abstract The stereoselective synthesis of trisubstituted alkenes has become a key topic in modern organic chemistry. At the same time, trisubstituted alkenes also serve as valuable starting materials for a wide range of transformations. However, it remains unclear to what extent these alkenes are utilized in comparison to their monoand disubstituted counterparts. This review aims to provide a comprehensive overview of fundamental transformations involving all-carbon-substituted trisubstituted alkenes. The first section focuses on additions of carbon, oxygen, and nitrogen nucleophiles, as well as halogenation and carboxylation reactions. The second part discusses oxidative cleavage processes, while the final section addresses the cyclization and cycloisomerization reactions of trisubstituted alkenes. Keywords: trisubstituted alkenes; ozonolysis; cyclization; addition 1. Introduction The tetraand trisubstituted double bonds represent a common motif found in natural products and medicinal substances. A typical example is the trisubstituted alkene sponalisolide B, which was isolated in racemic form from the sponge Spongia officinalis (Scheme 1). Sponalisolide B has been shown to function as a quorum sensing inhibitor in Pseudomonas aeruginosa [ 1 ]. Phorbaketal A, another example of a naturally occurring trisubstituted alkene, was isolated from the marine sponge Phorbas sp. and has demonstrated notable anti-inflammatory activity [ 2 ]. Among tetrasubstituted alkenes, tamoxifen is widely used in the treatment of breast cancer [ 3 ]. Another example is diethylstilbestrol (DES), a synthetic estrogen associated with numerous side effects [ 4 ]. Triand tetrasubstituted alkenes are widely employed in materials chemistry, with applications ranging from sensors to optoelectronic devices [5–7]. The notable biological activities of tetraand trisubstituted alkenes have driven the intensive development of stereoselective synthetic methods for their preparation. In principle, trisubstituted alkenes can be synthesized through cross-coupling reactions between electrophilic and nucleophilic reagents, such as the Heck [ 8 – 11 ] and alkyne hydroarylation reactions (Scheme 2) [ 12 – 16 ]. Alternatively, olefination and metathesis [ 17 , 18 ] reactions can be employed. Olefination methods in this context include various transformations, such as Julia [ 19 – 23 ], Still–Gennari [ 24 ], Wittig [ 25 – 27 ] and Horner–Wadsworth–Emmons olefination [ 28 – 30 ]. Comparable methods can be employed for the stereoselective synthesis of tetrasubstituted alkenes [31–38]. A number of papers have already been published in the field of stereoselective synthesis of trisubstituted alkenes. However, an important question remains: what is the use of trisubstituted alkenes in organic synthesis? Therefore, in this review, we sought to answer Molecules 2025,30, 3370 https://doi.org/10.3390/molecules30163370 Molecules 2025,30, 3370 2 of 44 this seemingly simple question. This review article summarizes the important applications of all-carbon trisubstituted alkenes in organic synthesis, with a focus on studies published between 2015 and 2025. First, the addition of C-, O-, and N-nucleophiles to trisubstituted alkenes is discussed. This is followed by the oxidative cleavage of trisubstituted alkenes, and the last section discusses the cycloisomerization and cyclizations of trisubstituted alkenes. Because most of the cited studies include not only trisubstituted alkenes but also diand tetrasubstituted ones, the overview indicates how many of the tested compounds are trisubstituted alkenes. Scheme 1. Naturally occurring trisubstituted alkenes. Scheme 2. General scheme illustrating typical approaches to the stereoselective synthesis of trisubstituted alkenes. 2. Results and Discussion 2.1. Addition Reactions In 2020, Buckley reported a highly regioselective hydrocarboxylation method for the synthesis of alkyl carboxylic acids S3–2 from trisubstituted alkenes (Scheme 3) [ 39 ]. The proposed mechanism involves the addition of a radical anion S3–3 to the alkene, generating the most stable radical S3–4. A relatively broad substrate scope, encompassing 25 alkenes, was explored, including eight examples of trisubstituted alkenes. The corresponding alkyl carboxylic acids were obtained in satisfactory yields as shown by the selected examples. Molecules 2025,30, 3370 3 of 44 Scheme 3. Electrochemical hydroxarboxylation of trisubstituted alkenes. Scheme 4. Transition metal-free carboxylation of acrylates. Recently, Xie co-workers reported a carboxylation–alkylation reaction using thianthrenium salts and carbon dioxide (Scheme 5) [ 41 ]. Of the 41 products, only a single product S5–3 was prepared from the trisubstituted alkene S5–1, with a 10% isolated yield. The primary product of the reaction between triphenyl ethylene and thianthrenium salt S5–2 is a carboxylate salt, which is subsequently converted into an ester S5–3 using trimethylsilyldiazomethane. Hydroxycarboxylation of alkenes was reported by Hattori and Tanaka (Scheme 6) [ 42 ]. The successful progression of the reaction requires the presence of dichloroethyl aluminum in combination with triethyl silane. Triethyl silane serves as a hydride ion source, which reacts with the in situ generated carbocation S6–3 to form carboxylic acids S6–2. The reaction scope primarily focuses on trisubstituted alkenes, with 12 examples tested, but also includes a limited number of tetraand disubstituted alkenes. For cyclic substrates, the reaction predominantly yielded the cis stereoisomer, as illustrated by examples S6–2c and S6–2d. Molecules 2025,30, 3370 4 of 44 Scheme 5. Carboxylative arylation of triphenyl ethylene. Scheme 6. Hydrocarboxylation of trisubstituted alkenes. Photocatalytic carbocarboxylation of trisubstituted alkenes was reported by Da-Gang Yu in 2021 (Scheme 7) [ 43 ]. This catalytic transformation converted alkene S7–1 and amino acid S7–2 into carboxylic acid derivative S7–3 using an iridium complex under blue LED irradiation. Despite the broad substrate scope, which includes over 40 alkenes—primarily 1,1-disubstituted derivatives, only a single trisubstituted alkene S7–1 was tested. The proposed mechanism involves the initial decarboxylation of the amino acid S7–2 to generate a radical species S7–4, which adds to the alkene S7–1 to form a new radical S7–5, which is reduced to anion S7–6. The light-activated iridium catalyst facilitates both the decarboxylation step and a radical–polar crossover process essential for product formation. Scheme 7. Photocatalytic iridium-catalyzed carbocarboxylation of a trisubstituted alkene. Molecules 2025,30, 3370 5 of 44 Recently, a copper-catalyzed asymmetric hydroxymethylation of 1,3-dienes was reported (Scheme 8) [ 44 ]. The reaction employed copper acetate in the presence of eight equivalents of silane and a chiral ligand, delivering high levels of enantioselectivity. This transformation exhibited a broad substrate scope, covering 49 exclusively trisubstituted alkenes. A key feature of the methodology is its excellent enantioselectivity, which exceeds 90% ee in most cases, with only a few exceptions displaying lower values. Mechanistically, the transformation proceeds via the formation of a Cu–H hydride species, which undergoes hydrocupration with the starting alkene S8–1, generating an organocopper intermediate. Subsequent carboxylation yields carboxylic acid derivatives S8–4 and S8–5, which are then reduced to the corresponding silylated alcohols. Final desilylation furnishes the hydroxymethylated product S8–2. The developed method was further applied to the derivatization of terpenoid compounds. In one representative example, Farnesol was first oxidized and converted into the diene S8–1e via a Wittig reaction. Subsequent hydroxymethylation afforded the product S8–2e in high yield and with excellent enantioselectivity. Scheme 8. Copper-catalyzed hydroxymethylation of conjugated dienes. The developed methodology was also applied to the aminomethylation of trisubstituted alkenes (Scheme 9) [ 45 ]. Mechanistically, the reaction proceeds analogously to the previously described hydroxymethylation (Scheme 10). Specifically, the hydrocupration of diene S9–1 generates the allylcopper intermediate S9–3, which reacts with an imine to form complex S9–4. Subsequent ligand substitution then yields the aminomethylated product S9–2. This transformation is characterized by a broad substrate scope, high enantioselectivity, and tolerance to highly functionalized trisubstituted alkenes, including an indomethacin-derived substrate S9–2c. Molecules 2025,30, 3370 6 of 44 Scheme 9. Copper-catalyzed aminomethylation of conjugated dienes. Scheme 10. Copper-catalyzed carboxylative oxytrifluoromethylation of allylamines. The divalent copper complex was also employed in the carboxylative oxytrifluoromethylation of allylamines. The reaction is conducted under a carbon dioxide atmosphere in the presence of Togni’s reagent and DBU, affording cyclic carbamates S10–2 as the final products (Scheme 10) [ 46 ]. The substrate scope was evaluated using 24 alkenes, of which only three were trisubstituted. The starting alkene S10–1a was used as a mixture of Z/Eisomers. In other tested cases, the reaction conditions proved tolerant of various functional groups, including nitro, ester, and amide moieties. A mechanism was proposed in which carbon dioxide is first activated via reaction with the allylamine S10–1c. The activated double bond then undergoes an intramolecular carboxylation, and subsequent trifluoromethylation along with reductive elimination converts the Cu(II) complex S10–3 into the final product S10–2c. Following the carboxylative trifluoromethylation, the formation of cyclic carbamates via the alkylative carboxylation of allylamines has also been reported. This transformation proceeds under visible-light irradiation using a catalytic amount of a palladium complex. However, the substrate scope is limited, with only a single example involving a trisubstituted alkene [47]. Molecules 2025,30, 3370 7 of 44 In 2020, Kobayashi published a study on the photocatalyzed addition of malonates to triand disubstituted alkenes (Scheme 11) [ 48 ]. The reaction was catalyzed using a carbazole-based photocatalyst. Among the 35 alkenes tested, only 3 examples of trisubstituted alkenes were explored, yielding malonates S11–2b–S11–2d. Notably, 1,1-disubstituted alkenes provided significantly higher yields, as demonstrated by the synthesis of derivative S11–2a. From a mechanistic perspective, the authors proposed that the photocatalyst oxidizes the malonate to its corresponding radical, which subsequently adds to the starting alkene. Scheme 11. Photocatalyzed addition of dimethyl malonate to trisubstituted alkenes. Similarly to Kobayashi, Das described the photocatalyzed hydroaminomethylation of primarily disubstituted alkenes using the same photocatalyst (Scheme 12) [ 49 ]. Out of 60 examples, only 2 amino derivatives, S12–2a and S12–2b, were synthesized from trisubstituted alkenes. In the remaining cases, only diand monosubstituted alkenes were used. Like Kobayashi, Das proposed a radical mechanism for the formation of the target alkenes S12–2, which is supported by quantum chemical calculations. The optimized reaction conditions were subsequently applied to the synthesis of pharmaceutical derivatives, such as S12–2c and S12–2d. However, only monoand disubstituted alkenes were used in these examples. Scheme 12. Photocatalyzed hydroaminomethylation of trisubstituted alkenes. Molecules 2025,30, 3370 8 of 44 Trisubstituted alkenes can also participate in halogen addition reactions. A representative example is the synthesis of 2-fluoroalkyl iodides via the reaction of an alkene with iodine in the presence of hydrofluoric acid and an oxidizing agent (Scheme 13) [ 50 ]. The optimized reaction conditions were tested on a total of 15 alkenes; however, only one of the tested substrates was a trisubstituted alkene. The corresponding product, S13–1, was obtained in nearly quantitative isolated yield. According to the authors, the formation of S13–1 proceeds via the in situ transformation of I 2 into IF, which subsequently adds to the double bond. Scheme 13. Transition-metal-free iodofluorination of triphenylethylene. Recently, a cobalt-catalyzed hydrofluorination of alkenes, including trisubstituted examples, was reported. The reaction employs the cobalt–salen complex Cat1, which plays a key role in the formation of the target compounds (Scheme 14) [ 51 ]. Initially, the cobalt complex is converted into the hydride species S14–3, which reacts with isoprenyl alkenes to generate the stabilized radical intermediate S14–4. A subsequent radical–polar crossover leads to the formation of the Co(IV) complex S14–5, which undergoes nucleophilic attack by a fluoride anion. The involvement of a carbocationic intermediate was supported by carbocation rearrangement experiments. This methodology features a broad substrate scope, encompassing 31 alkenes, including 9 trisubstituted ones. The reaction exhibits excellent functional group tolerance; however, sensitive groups such as aldehydes and ketones were not tested. Notably, the process demonstrates high chemoselectivity, as illustrated by substrates bearing multiple unsaturations S14–2c. In addition, the method allows for the efficient synthesis of fluorinated products incorporating 19F atoms. Scheme 14. Cobalt-catalyzed hydrofluorination of trisubstituted alkenes. Molecules 2025,30, 3370 9 of 44 Electrocatalytic transformations have been employed for the straightforward dichlorination of trisubstituted alkenes using a nucleophilic chlorine source (Scheme 15a) [ 52 ]. Among the 26 substrates tested, only three were trisubstituted alkenes: S15–2a,S15–2b, and S15–2c. A gram-scale reaction was demonstrated using indene, which proceeded in high yield and with excellent diastereoselectivity. The proposed mechanism mirrors that of the previously described transformation and is supported by experimental evidence, including cyclic voltammetry data. An extension of the previously reported electrochemical dichlorination is its implementation in the presence of diarylphosphine oxide (Scheme 15b) [ 53 ]. In this variant, lithium chloride serves as the chloride source for the generation of Cl • , and the reaction is catalyzed by manganese triflate. Unfortunately, the substrate scope is limited, with only 1 trisubstituted alkene S15–5 successfully converted out of the 16 alkenes tested. MgCl2(2 equiv.) MnCl2(5 mol%) LiClO4(1 equiv.) MeCN/AcOH (9:1) C(+)/Pt(-), i = 0.8 A, C = 2 F Me Me O Cl Cl NEt2 Me Me Me Cl Cl S15 2a, 82% S15 2b, 89% 1:1 dr S15 1 Cl R3 R2 R1 S15 3R3 R2 R1 Cl Ph Cl S15 2c, 77% 8:1 dr S15 4 Cl Ph O (a) (b) O PhO Me S15 5 Me R2P(O)H (1 equiv.) LiCl (2 equiv.) Mn(OTf)2(5 mol%) bipy (6 mol%) LiClO4 MeCN/AcOH, 22 °C C(+)/Pt( ), Ucell = 2.3 V (Ea,i = 0.9 V) O PhO Cl S15 6a, 65% Me Me PPhOPh O PhO Cl S15 6b, 62% Me Me P O OMe OMe Scheme 15. (a) Electrocatalytic chlorination and (b) electrocatalytic chlorophosphination of trisubstituted alkene. Another example of the transformation of trisubstituted alkenes limited in scope is the addition of iodonium ylides (Scheme 16) [ 54 ]. The authors optimized the reaction conditions to modify a wide range of alkenes, covering over 35 examples; however, only 2 alkenes ,S16–1a and S16–1b, were trisubstituted. The limited use of trisubstituted alkenes may be due to the relatively low yields obtained for products S16–2a and S16–2b. Most reactive disubstituted alkenes afforded products in yields ranging from 50% to 80%. Scheme 16. Addition of an iodonium ylide to trisubstituted alkenes. Molecules 2025,30, 3370 16 of 44 intermediate T1–4a. The universal ruthenium complex (Cat2) has been employed in the oxygenation of alkynes, amidation of aldehydes, and oxidative cleavage of alkenes (Table 1, entry 5) [ 71 ]. In these transformations, sodium iodate serves as the terminal oxidant, converting the precatalyst (Cat6) to a Ru IV O 2 species. A subsequent [3+2] cycloaddition between this complex and the alkene furnishes a Ru(IV) intermediate (T1–5a), which undergoes fragmentation to afford the final oxidation products. However, the optimized reaction conditions were applied to only a single example of a trisubstituted alkene. An alternative method for oxidizing alkenes to carbonyl compounds involves the use of oxygen in the presence of various catalysts. Zhou (2021) reported the oxidation of primarily disubstituted alkenes by oxygen in poly(ethylene glycol) dimethyl ether (PEGDME) (Table 2, entry 1) [ 72 ]. Of the wide range of alkenes tested, only two trisubstituted alkenes were used, which were oxidized to benzophenone (T1-1a) and benzaldehyde (T1-2c) in nearly quantitative yields. The authors proposed that the formation of the peroxide intermediate T2-1b is a key step in the oxidation of the C=C bond. The formation of peroxide T2-1b is facilitated by the oxidation of PEGDME by oxygen to peroxide T2-1a. Additionally, sodium benzenesulfinate can be used for the photochemical oxidation of trisubstituted double bonds, although the scope of the reaction is limited to a single case (Table 2, entry 2) [ 73 ]. Based on the typical reactivity of sulfinic acid salts, it has been proposed that the addition of the PhSO 2• radical produces an intermediate T2–2a, which undergoes nucleophilic substitution. The resulting cyclic peroxide then decomposes into oxidation products T1–2c and T2–2b. Photoinduced oxidation of alkenes was reported by Parasram (Table 2, entry 3) [ 74 ]. The optimized reaction conditions cover a wide range of alkenes, including 1,1-disubstituted, monosubstituted, and trisubstituted alkenes. The tolerance of functional groups is relatively broad, with ester, keto groups, and halogens being tolerated. The authors of the paper also suggested that cleavage of the C=C bond involves the formation of the cyclic intermediate T2–3a. A photochemical oxidative cleavage of di-, tri-, and tetrasubstituted alkenes was reported in 2021 (Table 2, entry 4) [ 75 ]. The transformation is catalyzed by a manganate complex under an oxygen atmosphere. Mechanistic studies suggest that photoexcitation promotes oxidation of the manganese complex to an Mn(III) species, which then engages the alkene to generate a carbon-centered radical intermediate (radical T2–4a). Subsequent reaction with molecular oxygen affords a peroxo complex that undergoes decomposition to deliver the cleavage products. Notably, the reaction proceeds under mild conditions and avoids the use of conventional stoichiometric oxidants such as hydrogen peroxide or ozone. Unfortunately, out of a total of 80 alkenes tested, only 3 were trisubstituted alkenes. Unidative C=C bond grafting has also been demonstrated using a single-atom cobalt catalyst (Scheme 27) [ 76 ]. The catalyst (Co SA –N/C) was obtained via pyrolysis of a bimetal– organic framework (ZnCo-BMOF) and was subsequently employed for the direct transformation of alkenes into oximes. As illustrated in Scheme 19, the reaction conditions were applied to a set of 31 alkenes, including 8 trisubstituted substrates. The proposed mechanism involves the formation of an ArON • radical, which adds to the alkene double bond to afford an intermediate species S27–3. Subsequent cleavage of the C–C bond in this intermediate furnishes the corresponding oxime products. Molecules 2025,30, 3370 17 of 44 Table 1. Overview of the oxidative cleavage of C=C bonds in trisubstituted alkenes. Entry Conditions Intermediates Alkenes Selected Products 1O3 EtOAc:H2O 1/10 2 H 2 O 2 (1.8 equiv.) (c-C6H11Se)2(4 mol%) Fe(NO3)2(4 mol%) Acetone, 80 ◦C, O2 6/27 3 H 2 O 2 (5.0 equiv.) (RSe)2(5 mol%) EtOH, 80–120 ◦ C 13/28 4 H 2 O 2 (3.0 equiv.) Cat5 (10.0 mol%) MeCN, rt 3/10 5 Cat6 (1.0 mol%) TBAI (10 mol%) NaIO4(2.0 equiv.) H2O, rt 1/15 Molecules 2025,30, 3370 18 of 44 Table 2. Overview of the oxidative cleavage of C=C bonds in trisubstituted alkenes. Entry Conditions Intermediate Alkenes Selected Products 1 O2 PEGDME 110 ◦C 2/34 2 PhSO2Na, O2 30 W purple LED, DCE 1/40 3 4-NO2(C6H4)CN (1.5 equiv.) 390 nm MeCN, 23 ◦C 11/39 11/39 4 Mn(dtbpy)2(OTf)2 (2 mol%) MeOH/THF blue light (9 W, 470 nm), 20 ◦C, O2 3/80 Scheme 27. Cobalt-catalyzed oxidative cleavage of alkenes to oximes. Another example of photocatalytic carboxylative C=C bond grafting was reported in 2024 (Scheme 28) [ 77 ]. The reaction requires 1.5 equivalents of methyldicyclohexylamine, which undergoes single-electron transfer (SET) to generate an amine-derived radical. Addition of this radical to the alkene forms the most stable carbon-centered radical intermediate S28–2. Subsequent carboxylation with carbon dioxide yields the corresponding carboxylic acid S28–3. A second SET event, followed by elimination of the imine, furnishes the final product S28–1. Despite the broad substrate scope—exceeding 70 alkenes—only 5 trisubstituted alkenes were included. Molecules 2025,30, 3370 19 of 44 Scheme 28. Photocatalytic cleavage of alkenes via CO2incorporation. 2.3. Ring Formation Involving Trisubstituted Alkenes In addition to undergoing oxidative or otherwise destructive modifications, trisubstituted alkenes can also participate in a wide range of cyclization and cycloisomerization reactions. These transformations may proceed either under transition metal catalysis or under metal-free conditions. A particularly well-explored class of such reactions involves cyclizations leading to indole derivatives, for which a variety of starting materials have been employed. Aniline derivatives bearing trisubstituted double bonds are widely employed in the synthesis of indole derivatives. A particularly straightforward method involves NISinduced cyclization of the starting aniline substrates. However, the reaction has been predominantly studied with disubstituted alkenes, with only four examples of trisubstituted alkenes reported. The proposed mechanism for the formation of indole derivatives involves NIS-mediated generation of the cationic intermediate T3–1a, which subsequently undergoes cyclization to form the iodinated intermediate T3-1b. The final products are obtained through hydrogen iodide elimination followed by aromatization. The formation of the cationic intermediate T3–1a was indirectly supported by the observation of an aryl shift in trisubstituted alkene T3-1e (Table 3, entry 1) [ 78 ]. A similar cyclization was reported by Youn and co-workers (Table 3, entry 2) [ 79 ]. However, unlike the previous approach, the cyclization of aniline derivatives in this case was mediated by silver carbonate in DMF. The proposed mechanism involves a single-electron transfer (SET) process along with a radical–polar crossover. The scope of the reaction was relatively limited, with only eight trisubstituted alkenes successfully undergoing cyclization out of the fifty alkenes tested. The same research group later reported an analogous cyclization coupled with the isomerization of aryl substituents. The reaction was carried out using palladium acetate (5 mol%) and cupric chloride (2.0 equivalents) in 1,2-dichloroethane at 150 ◦ C [ 80 ]. The reaction scope was limited to only four trisubstituted alkenes out of a total of seventeen alkenes tested. The cyclization of aniline derivatives to indoles can also be catalyzed by p-toluenesulfonic acid (Table 3, entry 3) [ 81 ]. This reaction is remarkable in that it is performed in the presence of benzoquinone, which becomes incorporated into the indole framework. The presence of Molecules 2025,30, 3370 20 of 44 the benzoquinone moiety in the product was rationalized by a direct condensation between benzoquinone and aniline, forming intermediate T3–3a, which subsequently cyclizes to the carbocation T3–3b. Notably, the reaction also exhibits a distinctive scope, as it enables the synthesis of indole derivatives bearing the ester functional groups T3–3c and T3–3d. Table 3. Cyclization of trisubstituted alkenes en route to indole derivatives. Entry Conditions Intermediate Alkenes Selected Products 1NIS (2.0 equiv.) DCM, rt 4/41 2Ag2CO3(1.3 equiv.) DMF, 150 ◦C8/50 3 Benzoquinone (1.0 equiv.) TsOH•H2O (20 mol%) 1,4-dioxane, 80 ◦C 12/23 As an extension to previous cyclizations of ortho-substituted anilines, the iodine(III)- mediated cyclization of trisubstituted alkenes has been reported (Scheme 29) [ 82 ]. Through careful optimization of the reaction conditions, the authors found that the highest yields of substituted indoles S29–2 were achieved using 3,5-dimethylphenylλ3 -iodane [3,5Me 2 C 6 H 3 I(OAc) 2 ] in acetonitrile as the solvent. The reaction is notable for its short reaction time (approximately 20 min) and broad substrate scope, encompassing 18 geminally disubstituted alkenes and 9 trisubstituted alkenes. A mechanistic proposal involves the formation of cationic intermediates S29–3 and S29–4, which is followed by the reaction with acetate and elimination to afford the desired products. This methodology was successfully applied to the synthesis of the carbazole alkaloid S29–7, which was obtained in a 36% isolated yield over four steps. Molecules 2025,30, 3370 21 of 44 Scheme 29. Iodine(III)-mediated intramolecular amination of a trisubstituted alkene for the synthesis of an indolo[3,2-a]carbazole alkaloid. An exceptionally broad-scope cyclization of trisubstituted alkenes has been reported by Kim and Cha (Scheme 30) [ 83 ]. The reaction employs the iodine(III) reagent PIFA and proceeds smoothly at room temperature. A distinctive feature of this study is the exclusive use of trisubstituted alkenes S30–1, predominantly as mixtures of E/Zisomers. A detailed investigation of the reaction course revealed that (E)-alkenes afford higher yields of disubstituted indoles compared to (Z)-alkenes. Scheme 30. PIFA-mediated cyclization of trisubstituted alkenes to indole derivatives. Molecules 2025,30, 3370 22 of 44 Indole derivatives can also be synthesized from nitrobenzenes. A representative example is the preparation of indoles S31–3 from benzene derivatives S31–1 and S31–2 (Scheme 31) [ 84 ]. The optimized reaction submodules are notable for their applicability to a wide range of trisubstituted alkenes—14 out of 27 examples. In the case of benzene derivatives S31–1, ester functionalities are well tolerated. In contrast, alkenes S31–2 undergo cyclization to indole derivatives S31–3 with concurrent migration of the alkyl group. According to the proposed mechanism, the nitro group is reduced in situ to either a nitroso or hydroxylamine intermediate, which subsequently undergoes cyclization to form indoles. The authors applied the optimized reaction conditions for the synthesis of rizatriptan; however, in that case, a disubstituted alkene was used as the starting material. Scheme 31. Efficient synthesis of substituted indoles from nitrobenzene derivatives containing a trisubstituted vinyl moiety. Pinacolborane has also been employed in the cyclization of nitrobenzenes to indoles (Scheme 32) [ 85 ]. Optimal conditions involve the use of potassium fluoride in ethanol at 100 ◦ C. Among the alkenes tested—primarily vicinal disubstituted alkenes—five trisubstituted variants were also examined. A detailed mechanistic investigation revealed that pinacolborane first reduces the nitro group to a nitrosobenzene intermediate, which is subsequently converted into an anionic species S32–4. Cyclization of this anionic intermediate is proposed to be the rate-determining step, as supported by Hammett analysis. This is consistent with the observation that the highest yields were obtained for alkenes bearing electron-withdrawing ester and nitrile substituents S32–2b and S32–2c. The final stage of the transformation involves a 1,5-hydrogen shift. Evidence for the formation of the nitroso intermediate was further supported by its successful interception in a [4+2] cycloaddition with 2,3-dimethylbuta-1,3-diene, yielding product S32–10 in 26% isolated yield. In addition, the corresponding hydroxylamine intermediate S32–8 was deoxygenated to the indole product S32–2d in quantitative yield. The reduction and subsequent cyclization of nitrobenzenes bearing a disubstituted vinyl group in the ortho position can also be catalyzed by a palladium complex (Scheme 33) [ 86 ]. In this methodology, molybdenum hexacarbonyl is employed as a source of carbon monoxide. According to the proposed mechanism, carbon monoxide serves a dual role: it reduces the Pd(II) species to a Pd(0)(CO) 2 complex and also mediates the reduction of the intermediate S33–5 to the final product S33–2. The substrate scope with respect to trisubstituted alkenes is narrow, with only 3 examples out of a total of 24 demonstrating successful conversion. Molecules 2025,30, 3370 23 of 44 Scheme 32. Diborane-mediated cyclization of nitrostyrenes. Scheme 33. Palladium-catalyzed intramolecular cyclization of trisubstituted alkenes in the presence of molybdenum hexacarbonyl. A palladium-catalyzed intramolecular cyclization of trisubstituted alkenes S34–1 has also been reported (Scheme 34) [ 87 ]. The scope of the reaction is limited to six examples, all featuring substitution on the aniline core. Notably, the use of ball milling is essential for achieving successful cyclization. Selected indole derivatives S34–2a and S34–2b demonstrate that the reaction conditions are compatible with halogen substituents. The starting trisubstituted alkenes were synthesized via rhodium-catalyzed hydroarylation of disubstituted alkynes under ball-milling conditions. Molecules 2025,30, 3370 24 of 44 Scheme 34. Mechanosynthesis of trisubstituted indoles. The methodology developed for the cyclization of aromatic amines was extended to the synthesis of benzofuran derivatives (Scheme 35) [ 88 ]. The published procedure involves a Pd(0)-catalyzed cyclization of phenols under straightforward reaction conditions. The authors proposed a mechanism that includes the activation of the phenolic O–H bond, followed by the syn-insertion of the double bond and subsequent β -H elimination. The catalytic species is regenerated via reductive elimination of hydrogen. However, the reaction suffers from a limited substrate scope. Of the 27 substrates tested, only 2 were trisubstituted alkenes. The cyclization of an unsymmetrically substituted double bond S35–1 is illustrated in Scheme 35. Scheme 35. Palladium-catalyzed cyclization of phenols for the synthesis of benzofurans. Intermolecular lactonization of alkenes with acetic anhydride was reported by Jiang and co-workers in 2015 (Scheme 36) [ 89 ]. According to the proposed mechanism, manganese dioxide serves as an electron source to generate the carbon-centered radical S36–4 from acetic anhydride. This radical then adds to the alkene, forming the more stabilized intermediate S36–5. A Mn(III)-mediated radical–polar crossover followed by lactone ring closure affords the final products S36–2a and S36–2b. The authors also suggest that lithium bromide may assist in stabilizing the free radicals [ 90 ]. However, the scope of the reaction is largely limited to monosubstituted ethylenes. Only two trisubstituted alkenes out of the 29 tested derivatives were examined—one being the symmetrical triphenylethylene and the other an unsymmetrical derivative. No information is provided regarding the stereochemical purity of alkene S36–1. Molecules 2025,30, 3370 25 of 44 Scheme 36. Cyclization of carboxylic acid derivatives mediated by manganese dioxide. The lactonization of aromatic carboxylic acids was reported in 2018, employing cooperative catalysis by aridine and cobalt (Scheme 37) [ 91 ]. Although the reaction conditions were optimized primarily for benzene derivatives, they were also found applicable for the synthesis of lactones S37–2a and S37–2b from trisubstituted alkenes. Based on a series of experiments, a putative mechanism has been proposed and supported, involving the formation of the carboxylate ion S37–3, which is subsequently oxidized to the radical S37–4 via a single-electron transfer (SET) process. The addition of the radical to the alkene affords the cyclic adduct S37–5 that, presumably through a hydrogen atom transfer (HAT) step, is converted into the reaction product S37–2a. The yields of lactones S37–2a and S37–2b are comparable to those obtained for aromatic derivatives. Lactones with a comparable substrate scope can also be synthesized under electrochemical conditions [92]. An interesting transformation of carboxylic acids and carboxamides into heterocyclic products was reported by Park and co-workers (Scheme 38) [ 93 ]. In their study, carboxylic acids S38–1 and their derivatives S38–2 were subjected to electrochemical cyclization under varying conditions. Depending on the setup, carbon or nickel cathodes in HFIP or acetonitrile were employed for the synthesis of lactones S38–4 and lactams S38–5. In contrast, lactonization carried out in the presence of a nucleophile (MeOH) resulted in the formation of ether products S38–3a and S38–3b. However, it should be noted that the scope of the reaction with respect to trisubstituted alkenes is very limited and involves the formation of 7 compounds out of a total of 59 products prepared. The proposed mechanism involves a radical process and was supported by an electrochemical study. In 2024, Beier and co-workers reported the photochemical generation of a triplet trifluoromethyl nitrene, which was subsequently employed in the aziridination of trisubstituted alkenes (Scheme 39) [ 94 ]. The reaction conditions were evaluated across a broad range of alkene substitution patterns, including vicinally and geminally disubstituted, mono-, tri-, and tetrasubstituted alkenes. The substrate scope included 30 alkenes in total, among which 6 were trisubstituted derivatives. The resulting aziridines were obtained in good yields. However, in the case of stereoisomeric trisubstituted alkenes, the formation of diastereomeric mixtures S39–2a and S39–2c was observed. The authors proposed that the trifluoromethyl nitrene is generated in situ and directly added to the alkene double bond. This mechanistic hypothesis was supported by electron paramagnetic resonance (EPR) spectroscopy and corroborated by quantum chemical calculations. Molecules 2025,30, 3370 32 of 44 A similar cyclization of enynes can also be catalyzed by rhodium complexes. Depending on the structure of the alkene, the cyclization of enyne S36–1 leads to the tricyclic product S47–2 (Scheme 47) [ 103 ]. In contrast, the use of a conjugated diene allows access to the tetracyclic product S47–3. An illustrative example is the synthesis of compounds S47–2a ,S47–2b,S47–3a, and S47–3b, obtained from the corresponding trisubstituted alkenes through reactions 1,1-disubstituted alkenes and substituted buta-1,3-diene. By modifying the reaction conditions—specifically, by using toluene as the solvent—alternative cyclic S47–6 can be formed. The authors also explored an enantioselective version of the transformation. A satisfactory enantiomeric ratio (er ≥ 79:21) was achieved using 2 mol% of the Rh 2 (S-NTTL) 4 complex in dichloromethane. A plausible mechanism was proposed, involving key cyclic intermediates S47–4 and S47–5, which are believed to react with alkenes to afford the final products. Scheme 47. Rhodium-catalyzed [1+2] and [3+4] cycloaddition of enynes. A mechanistically distinct synthesis of indene derivatives is based on triazole precursors S48–1 (Scheme 48) [ 104 ]. The reaction, which predominantly employs trisubstituted alkenes—35 out of the 37 tested—requires a silver catalyst and acetic acid. The authors proposed a mechanism for the formation of indene derivatives S48–2 involving denitrogenation to generate a silver carbene intermediate, S48–3, which subsequently reacts with the trisubstituted double bond. The proposed pathway is supported by quantum chemical calculations and deuterium-labeling experiments. Molecules 2025,30, 3370 33 of 44 Scheme 48. Silver(I)-mediated activation of triazoles en route to indene derivatives. In 2017, the enantioselective cyclization of enals was reported (Scheme 49) [ 105 ]. The reaction is notable for the exclusive use of trisubstituted alkenes, comprising 24 examples—mostly as mixtures of E/Zisomers with E/Zratios ranging from 1:2 to 1:20. According to the authors, the key steps in the formation of the cyclic products S49–2 involve the oxidative addition of cobalt to the C–H bond, resulting in the complex S49–3 . This step is followed by hydrometallation to give the complex S49–4. The proposed mechanism is supported by deuterium-labeling experiments and literature precedents. Scheme 49. Enantioselective cobalt-catalyzed cyclization of trisubstituted alkenes. Trisubstituted alkenes were also employed in the enzyme-catalyzed radical cyclization (Scheme 50) [ 106 ]. The starting alkene S50–1 undergoes cyclization to form lactams with high diastereoselectivity and enantioselectivity. Optimized reaction conditions were investigated for 16 alkenes, of which only three were trisubstituted. Cyclization of these trisubstituted alkenes afforded the products S50–2a,S50–2b, and S50–2c. The reaction is catalyzed by the flavin-dependent ene-reductase GluER-T36A. As part of this experimental study, the formation of radical S50–3 was proposed to occur via electron transfer within a donor–acceptor complex formed between the alkene and the reduced flavin cofactor. The intermediate radical S50–3 undergoes intramolecular cyclization, followed by hydrogen Molecules 2025,30, 3370 34 of 44 atom abstraction (HAT) to yield the final products. It has been proposed that, upon formation of radical S50–3, the enzyme facilitates hydrogen atom transfer selectively from a single rotamer of the prochiral intermediate, with the HAT rate being comparable to the rate of C–C bond rotation. The enantioselectivity of the reaction is independent of the configuration of the trisubstituted double bond, as demonstrated by mechanistic experiments. The same diastereomer is preferentially formed from both Eand Zisomers. Scheme 50. Photocatalytic diastereoselective cyclization of trisubstituted alkenes. Building on previous results [ 106 ], Hyster and colleagues extended the methodology of biocatalytic asymmetric cyclization of chloroacetamides to the synthesis of cyclic lactams S51–2 (Scheme 51) [ 107 ]. The developed reaction conditions were applied to the cyclization of seven trisubstituted alkenes, including one cyclic alkene, which afforded the spirocyclic product S51–2c. The cyclization proceeded with lower enantioselectivity, ranging from 54:46 to 85:15, as illustrated by examples S51–2a and S51–2b. An interesting extension of enzymatically catalyzed radical cyclizations of trisubstituted alkenes is the synthesis of cyclic lactams involving β -scission of the TMS group (Scheme 52a) [ 108 ]. The reaction was primarily explored for the preparation of fivemembered lactams, but it can also be applied to the synthesis of a six-membered derivative S52–2c, albeit with limited stereoselectivity. Conversely, intramolecular cyclization of trisubstituted α , β -unsaturated alkenes affords cyclopentane derivatives S52–4 (Scheme 52b) [ 109 ]. In certain cases, this methodology can also be extended to the formation of cyclohexane derivatives. A logical extension of the hydroamination of trisubstituted alkenes is represented by its intramolecular variant (Scheme 53) [ 110 ]. Reaction conditions enabled the generation of an amidyl radical S53–3, which subsequently underwent intramolecular addition to the C=C double bond, affording carbamates and lactams, respectively. The optimized conditions were applied to a set of 34 alkenes, of which only 5 were trisubstituted. Molecules 2025,30, 3370 35 of 44 Scheme 51. Photoinduced enantioselective cyclization of trisubstituted alkenes. Scheme 52. (a) Enzyme-catalyzed cyclization of chloroacetamides and (b)α,β-unsaturated esters. Molecules 2025,30, 3370 36 of 44 Scheme 53. Intramolecular hydroamination of trisubstituted alkenes. An interesting extension of the intramolecular hydroamination of trisubstituted alkenes involves its combination with intermolecular addition to terminal alkenes (Scheme 54) [ 111 ]. In this transformation, the amidyl radical S54–3 undergoes intramolecular addition to a triple bond, generating the alkyl radical S54–4, which subsequently reacts with an electron-deficient alkene to furnish the target compounds S54–2. The reaction demonstrates a broad substrate scope with respect to trisubstituted alkenes—20 out of 24 tested substrates fall into this category. Another noteworthy feature is the tolerance of highly reactive functional groups, including keto and aldehyde moieties S54–2c and S54–2d, which are often incompatible under radical conditions. Scheme 54. Catalytic hydroamination of trisubstituted alkenes followed by radical addition to the C=C double bond. Enantioselective intramolecular hydroamination of trisubstituted alkenes was reported in 2020 (Scheme 55) [ 112 ]. High enantioselectivity was achieved through the cyclization of sulfonamides in the presence of a sophisticated chiral ligand under low- Molecules 2025,30, 3370 37 of 44 temperature conditions. Elevation of the reaction temperature to ambient levels led to a significant drop in enantioselectivity. This study employed 21 trisubstituted alkenes bearing a dimethylvinyl group and various sulfonamide moieties. Additionally, cyclic sulfonamides bearing cyclobutyl S55–2c and piperidyl S55–2d substituents were also synthesized. The high enantioselectivity was later attributed to noncovalent association between the radical intermediate and the chiral environment provided by the phosphoric acid catalyst [113]. Scheme 55. Enantioselective cyclization of sulfonamides. Chemical modifications of trisubstituted alkenes also include carboxylation reactions, in which various trisubstituted alkenes react with carbon dioxide under appropriate reaction conditions. Transition metal-catalyzed carboxylations include, for example, the lactamization to 2-quinolinones (Scheme 56) [ 114 ]. Although the optimized conditions were evaluated on a broad range of alkenes, mostly disubstituted alkenes, only two trisubstituted alkenes were tested. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis revealed that the reaction proceeds in the absence of a transition metal, and the authors proposed the formation of two key intermediates, S56–3 and S56–4, as essential for the formation of 2-quinolinones. Scheme 56. Transition-metal-free cyclization of trisubstituted alkenes. Recently, Zhang’s research group reported a series of radical cyclizations of trisubstituted alkenes enabled by metalloradical catalysis. This strategy allowed for the synthesis of various bicyclic aziridines [ 115 , 116 ] and cyclopropanes [ 117 , 118 ]. While the reactions were thoroughly investigated for monoand disubstituted alkenes, their applicability to Molecules 2025,30, 3370 38 of 44 trisubstituted alkenes proved limited, with only a single example reported. A notable exception within this body of work is the intramolecular cyclopropanation of enynes S57–2 with the diazo compound S57–1, catalyzed by a 3,5-diMes-ChenPhyrin cobalt complex (Scheme 57) [ 119 ]. The use of a chiral cobalt catalyst ensures high enantioselectivity of the cyclization. The proposed mechanism involves the initial reaction of the diazo compound to generate a cobalt-stabilized radical S57–5, which adds to the alkyne moiety to form a vinyl radical intermediate. This species subsequently undergoes a 5-exo-trig cyclization, followed by a second ring closure, to afford a strained intermediate complex. A β -scission of this complex yields the cyclopropane product alongside regeneration of the catalyst. The mechanism was supported by experimental data, quantum chemical calculations, and EPR spectroscopy. The reaction proceeds with excellent stereoselectivity. Moreover, the authors demonstrated that the C=C double bond in the resulting molecule can be further transformed via oxidative cleavage, epoxidation, or reaction with Grignard reagents. Scheme 57. Radical cyclization of trisubstituted alkenes via metalloradical catalysis. 3. Conclusions In this review, we have summarized the use of trisubstituted alkenes in organic synthesis. The discussed transformations include additions of carbon-, nitrogen-, and Molecules 2025,30, 3370 39 of 44 oxygen-based nucleophiles, as well as carboxylation reactions. The second section focuses on the oxidative cleavage of trisubstituted alkenes, while the final part covers their cyclization, particularly into indole and indene derivatives, along with other fiveand three-membered heterocycles. These transformations can be evaluated in terms of the diversity of accessible structural motifs and their tolerance to functional groups. Another important aspect is the number of trisubstituted alkenes tested under the reported conditions. From the perspective of structural diversity and functional group compatibility, the described methods allow for the preparation of a broad spectrum of acyclic and cyclic products, including various heterocycles. However, in terms of functional group tolerance, the methodologies remain limited and frequently exclude sensitive moieties such as aldehydes and ketones. A notable limitation of many of these transformations is the relatively small number of trisubstituted alkenes that have been explored. In numerous studies, the reaction conditions were optimized primarily using disubstituted alkenes, likely due to their greater availability. When trisubstituted alkenes were included, only a limited number of examples were typically tested. An exception to this trend is seen in cyclization reactions, which have often been studied using extensive libraries of trisubstituted alkenes. This broader applicability is largely due to the tolerance of both (E)- and (Z)-isomers in these reactions, allowing for the use of stereoisomeric mixtures and simplifying practical application. These observations lead to two key conclusions: first, a major limitation of current methodologies involving trisubstituted alkenes lies in their insufficient tolerance—or more precisely, testing—of substrates bearing highly reactive functional groups. Second, the limited availability of stereochemically pure trisubstituted alkenes represents a further bottleneck for broader application. Author Contributions: Conceptualization, writing—review and editing T.T.; writing—review and editing V.H. All authors have read and agreed to the published version of the manuscript. Funding: The work is supported by Operational Programme Johannes Amos Comenius, financed by European Structural and Investment Funds and the Czech Ministry of Education, Youth and Sports (Project No. SENDISO-CZ.02.01.01/00/22_008/0004596). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: No new data were created or analyzed in this study. 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