Synthetic Potential of Regio- and Stereoselective Ring Expansion Reactions of Six-Membered Carbo- and Heterocyclic Ring Systems: A Review

Abstract

Ring expansion reactions fascinate synthetic chemists owing to their importance in synthesizing biologically active compounds and their efficacy in medicinal chemistry. The present review summarizes a number of synthetic methodologies, including stereoselective and regioselective pathways adopted by scientists, for framing medium- to large-size carbo- and heterocycles involving lactams, lactone, azepine and azulene derivatives via ring expansion of six-membered carbo- and heterocycles that have been reported from 2007–2022. Numerous rearrangement and cycloaddition reactions involving Tiffeneau–Demjanov rearrangement, Aza–Claisen rearrangement, Schmidt rearrangement, Beckmann rearrangement, etc., have been described in this regard.

1. Introduction

Ring expansion reactions are among the most efficient reactions in chemistry that facilitate the synthesis of functionalized medium- to large-size ring systems. During recent years, efforts have been put forward by the scientists towards the synthesis of large-size carbo- as well as heterocycles via ring expansion reactions. Six-membered ring expansion reactions are of great importance for synthesizing 7- to 12- and higher-membered rings. The large-size carbo- and heterocyclic rings are of great interest for organic chemists due to their medicinal properties [1]. Benazepril 3 [2] is an angiotensin-converting enzyme inhibitor that has beneficial effects in the medication of diabetic kidney disease, hypertension and heart failure [3]. Paullones [4] are derived from indole [3,2-d]-1-benzoazepin-2-one, which prevents cyclin-dependent kinases (CDKs). Kenpaullone and alsterpaullone (1a,b) [5] have demonstrated the anticancer activity and CDK inhibitory activity [6,7]. Metapramine 2 [8] and opipramol 4 [9] are used to cure depression (Figure 1). Some of the large-size carbocyclic/heterocyclic compounds exhibit various biological activities, such as antitumor activity [10], inhibition of HIV-1 replication [11], antinociception activity [12], antiepileptic activity [13], inhibition of α-glucosidase [14] and inhibition of cytidine deaminase.

Herein, we report the recent synthetic approaches used for the formation of large-size ring lactams, lactones, O, N, S-containing heterocyclic rings, substituted azulenes and azepine derivatives. A number of rearrangements, including Aza–Claisen rearrangement [15], Beckmann rearrangement [16], Tiffeneau–Demjanov rearrangement [17], Schmidt rearrangement and cycloaddition reactions (10 + 4) [18] and (6 + 6) [19], are discussed in the current review.

2. Literature Review

2.1. Ring Expansion Reactions for the Synthesis of Lactams

The effect of nonbonded, attractive cation–π interactions on the reactions of hydroxyl alkyl azides and cyclic ketones has been explored via computational and experimental sources. An attractive asymmetric pathway to lactams from the hydroxyalkyl azide-mediated ring expansion reaction of cyclic ketones was reported by Katz et al. The reaction of 2-aryl-1,3-hydroxyalkyl azide 6 with 4-tert-butylcyclohexanone 5 afforded the diastereomers of lactams 7a and 7b in maximum yields (99%) with 43:57 diastereomeric ratio. The solvent study revealed that out of different solvents such as toluene, diglyme, CH₂Cl₂, (C₅H₅)₂O and n-C₅H₁₂, CH₂Cl₂ provided a 99% yield. The reaction proceeded well via asymmetric ring expansion reaction using BF₃^.OEt₂, followed by the hydrolysis of intermediate iminium ethers using aqueous potassium hydroxide (Scheme 1) [20].

Beckmann rearrangement is the rearrangement of an oxime functional group to an amide, which usually leads to ring expansion. Hadimani et al. reported the formation of lactam by ring expansion of acyloxy nitroso compound. 1-Nitrosocyclohexyl acetate 8 was treated with triphenylphosphine (TPP) in the presence of benzene, which gave seven-membered Beckmann rearrangement ring 9 in a 55% yield, along with triphenylphosphine oxide. Consequently, the intermediate 9 underwent acid-catalyzed hydrolysis (HCl 1M) to produce caprolactam 10 (Scheme 2) [16].

Medium and macrocyclic ring scaffolds have contributed significantly to medicinal chemistry [21]. Unsworth and his colleagues developed the synthetic approach for a wide range of medium-size lactams possessing medicinal lead-like properties. The lead-likeness of the medium-size lactams is analyzed through lead-likeness and molecular analysis (LLAMA). The 10-membered ring lactam 12 was obtained in an 84% (maximum) yield by ring expansion of β-keto ester 11 with acid chloride in the presence of MgCl₂, pyiridine and dichloromethane, followed by the addition of piperidine and CH₂Cl₂. Room temperature was maintained for 1–2 h to carry out the reaction (Scheme 3). After achieving satisfactory results, authors applied this protocol on different substrates, affording substituted lactams in a 12–84% yield. This methodology demonstrates the worth of ring expansion reactions for synthesizing the medicinally appropriate compounds [22].

The effective and flexible protocol for the generation of benzannulated medium ring lactams from bicyclic scaffolds through oxidative dearomatization ring-expanding rearomatization reaction (ODRE) was outlined by Guney et al. A wide range of benzannulated lactams was attained in a 53–89% yield range by maintaining temperatures at 0–24 °C. However, the excellent yield (89%) of benzannulated lactam 14 was achieved by the reaction of chromanone-derived compound 13 with bis(trifluoroacetoxy)iodobenzene (PhI(TFA)₂) in nitromethane as solvent for 0.5–2 h (Scheme 4). In contrast, the halobenzocyclooctanols and halobenzosuberanols afforded 10- and 11-membered benzannulated lactams in 70–90% yield [23].

Xu et al. scrutinized the catalyst-free electrochemical ring expansion reaction for synthesizing the synthetically challenging annulated medium-size lactams via carbon–carbon bond cleavage. Highly functionalized medium-size lactam 16 was obtained in a 98% yield when CF₃-aryl-substituted substrate 15 was electrolyzed in the electrolytic solution of n-Bu₄NBF₄ in CH₃CN/H₂O without using any catalysts or bases at 25 °C (Scheme 5). The electrolytic reaction shows compatibility with the electron-rich and electron-poor groups at either para- or metapositions of aniline to obtain a wide range of products (30–98%) [24].

The compounds containing the benzazepines motif have exhibited considerable importance in medicinal chemistry. For example, benazepril [2] is an angiotensin-converting enzyme inhibitor utilized to cure heart failure, hypertension [3] and diabetic kidney disease. Paullones [4] are the derivatives of indole [3,2-d]-1-benzoazepin-2-one that inhibit cyclin-dependent kinases (CDKs). Zarraga and coworkers performed the reaction of oxime 17 with POCl₃ in order to obtain polyheterocyclic lactam. The reaction mixture was refluxed at 70 °C in dry THF for 1.5 h, giving a 67% yield of polyheterocyclic lactam 18. The corresponding lactam was achieved by a tandem process involving Beckmann rearrangement/expansion and subsequent cyclization of nitrogen atom and primary halide fragment of 17 (Scheme 6) [5].

2.2. Ring Expansion Reactions for the Synthesis of Lactones

1,3-Benzoxazine, a class of cyclic compounds, has obtained appreciable attention because of its ring-opening polymerization that synthesizes polymers with excellent characteristics, such as thermal stability [25], high mechanical strength and durability under humid environment [26]. Endo and coworkers outlined the synthesis of eight-membered ring lactone by using benzoxazine as starting material. The solution of 1,3-benzoxazine 19 in acetic anhydride was refluxed using p-toluenesulfonic acid (1 mol%) as catalyst. The reaction mixture underwent ring expansion to afford eight-membered ring lactone 20, containing a tertiary amine group in the ring, in a maximum of 70% yield with 90% conversion in 1 h (Scheme 7). For this purpose, the temperature outside the container was maintained at 150 °C [27].

Shintani et al. in 2011 reported a ring expansion reaction by treating valerolactones 21 and aziridines 22 via (6 + 3) cyclization reaction, which resulted in the synthesis of nine atoms containing cyclic rings, referred to as “azlactones” 23 (Scheme 8). These azlactones are regarded as 1,4-oxanones, and they cannot be obtained simply by other reported methodologies in the past [28].

2.3. Ring Expansion Reactions for the Formation of Azulenes Derivatives

Azulenes are composed of a five-membered ring fused to a seven-membered ring and are important colored compounds that are used for indicators [29], dyes [30] and imaging. Furthermore, these compounds show prominent biological and electronic properties. Gorgensen and colleagues synthesized a series of polysubstituted azulene derivatives through organocatalytic (10 + 4) cycloaddition of indene-2-carbaldehyde and chromen-4-one. The electron-deficient substituents provided azulenes in excellent yields (up to 98%), while electron-rich substituents gave different azulenes in the 45–83% yield range. The substituted azulene 27 was obtained in a 98% yield by reaction of substituted indene-2-carbaldehyde 24 with substituted chromen-4-one 25 in the presence of 15 mol% pyrrolidine 26, 15 mol% p-MeOBzOH, CDCl₃ and molecular sieves at 40 °C. (Scheme 9) [18].

2.4. Ring Expansion Reactions for the Synthesis of Azepine Derivatives

The azepines class of heterocycles has gained tremendous importance due to wide-ranging biological activities. For example, some compounds are used to cure cardiovascular diseases and some are the inhibitors of cytidine deaminase [31]. A general approach towards the formation of 1,3-diazepin-2-one derivatives by the ring expansion reaction of pyrimidines using different nucleophiles was developed by Shutalev and coworkers. They synthesized different diazepinone derivatives in good-to-excellent yields under different reaction conditions. The reaction of 28a,b (where R = CH₃ & Ph respectively) and sodium diethyl malonate proceeded in THF at room temperature gives diazepinones 29a and 29b in 90% and 92% yields, respectively. 4-Mesyloxymethyl-pyrimidines 28a,b reacted with potassium phthalimide 30 and refluxed in acetonitrile (MeCN) to afford the desired products 31a, b in 96% yields. The pyrimidines 28a,b refluxed in tetrahydrofuran in the presence of succinimide 32 and sodium hydride provided the diazepinones 33a and 33b in 93% and 92% yields, respectively. The 4-unsbstituted diazepinones 34a and 34b were attained in 66% and 72% yields, respectively, on refluxing 28a,b with NaBH₄ in THF. (Scheme 10) [32].

Fesenko et al. reported the nucleophilic-dependent diastereoselectivity of the ring expansion of pyrimidines with nucleophiles to synthesize polysubstituted1,3-diazepine. Several functionalized polysubstituted 1,3-diazepin-2-ones were obtained in excellent yields (80–97%) by the reaction of pyrimidines with different nucleophiles. The treatment of tetrahydropyrimidine 35 with MeONa in methanol gave a single cis-diastereomer 36 in a 93% yield. The reaction of 35 with EtONa in ethanol synthesized a diastereoselective (cis/trans = 93/7) 4-ethoxydiazepine 37 in a 97% yield.

When 35 was treated with sodium cyanide (NaCN) in DMSO at room temperature, a mixture of cis- and transdiastereomers (cis/trans = 94/6) 38 was obtained in an 80% yield. The transdiastereomer 39 was obtained in an 83% yield by the reaction of 35 with PhSNa, synthesized by the reaction of PhSH with sodium hydride in THF. The pyrimidine 35 and potassium phthalimide 30 were refluxed in acetonitrile, and the full trans-isomer 40 was obtained in a 95% yield (Scheme 11) [33].

Tetrahydrodiazepinones are essential biologically active heterocycles that have been rarely studied in the past due to the scarcity of their precursors. In order to obtain medicinally important diazepinones, Fesenko and coworker carried out the synthesis of diversely substituted 1,2,3,4-tetrahydropyrimidinones by reacting α-tosyl ketone enolates with N-[(2-benzoyloxy-1-tosyl)ethyl]urea. The synthesized tetrahydropyrimidinones 41 were then subjected to treatment with different nucleophiles, i.e., potassium phthalimide, sodium salt of diethyl malonate, sodium cyanide and sodium thiophenolate, to furnish tetrahydro-1,3-diazepinones 42, 43, 44 and 45 in good yields (Scheme 12) [34].

Dihydropyrimidinones are easily accessible organic compounds; however, their extended seven-membered rings are rarely obtained. In order to obtain seven-membered cyclic system of Biginelli compounds, substituted Biginelli compounds 46 were treated with nucleophilic substances which first underwent removal of the proton, resulting in the generation of bicyclic intermediate as a result of subsequent nucleophilic substitution reaction. The intermediate then underwent ring expansion to give diazepinones 47 [35,36]. Shutalev et al., in 2008, employed easily accessible pyrimidinone derivative 48 to treat it with non-nucleophilic strong base, i.e., NaH, which furnished tricyclic bis-diazepinone derivative 49 as a result of tandem reaction (Scheme 13) [37].

Shutalev and coworkers outlined the synthetic protocol of diazepine by ring expansion of acyl-substituted pyrimidines. A series of diazepines was attained in a 43–96% yield range by applying different reaction conditions. The maximum (96%) yield of 1,3-diazepine 51 was obtained on refluxing 5-acyl-substituted pyrimidine 50a with potassium phthalimide 30 in acetonitrile solvent for 1 h. Another diazepine derivative 52 was obtained in a 96% yield by the reaction of 50b with thiophenol and sodium hydride in tetrahydrofuran (THF) for 2 h (Scheme 14). This protocol has a wide substrate scope, allowing the formation of substituted diazepines (80–96%) [38].

2.5. Ring Expansion Reaction for the Synthesis of Tropone Derivatives

Tropones have gained significant importance owing to their unique structural features, along with their remarkable biological activities. They are found to be essential structural motifs of various naturally occurring and medicinally important organic compounds. The ring elongation reaction of alkynyl quinols results in the synthesis of tropone derivatives. Considering the wide applications of tropone derivatives, Zhao et al., in 2015, reported the synthesis of tropone derivatives by employing the ring elongation reaction of alkynyl quinols in the presence of various gold catalysts and a diverse range of solvents. The optimization reactions revealed that the utilization of PPh₃AuNTf catalyst and DCE solvent resulted in high yields of target molecules (Scheme 15) [39].

In 2021, Du et al. reported the ring extension reaction of alkynyl quinols by employing a highly efficient catalyst, i.e., an MCM-41-based confined complex of gold carrying altered benzylidene phosphine. MCM-41-BnPh₂-AuX is regarded as a productive catalyst owing to its large surface area, resistance to high temperature and facile recycling properties. Taking into account the usage of this effective catalyst, Du et al. synthesized and then incorporated this catalyst into the expansion reaction of alkynyl quinols. The reaction conditions were optimized by using various solvents and by varying X in gold complex catalyst. However, the highest yield (91%) was obtained by using DCE as solvent, along with the incorporation of NTf₂ in MCM-41-BnPh₂-AuX (Scheme 16) [40].

2.6. Miscellaneous Ring Expansion Reactions

Benzoazocine-containing drugs and alkaloids exhibit numerous biological activities, e.g., antitumor activity [10], antinociception activity [12], inhibition of α-glucosidase [14], acetylcholinesterase [41] and inhibition of HIV-1 replication [11]. Voskressensky and coworkers reported the synthesis of benzoazocines via the ring enlargement of substituted tetrahydroisoquinolines and activated alkynes. A total of 37–83% of substituted tetrahydrobenzoazocines was achieved by the reaction of different tetrahydroisoquinolines with alkynes using acetonitrile as solvent. The tetrahydroisoquinoline 57 was refluxed with alkyne 58 in acetonitrile, giving corresponding tetrahydrobenzoazocines 59 in an 83% yield. In addition, the maximum (83%) yield of 61 was obtained by the reaction of 57 and 60 (Scheme 17). Acetonitrile was selected as the appropriate solvent for this reaction [42].

The seven-membered carbocyclic rings are mostly found in potent medicinal scaffolds such as thapsigargins [43], colchicines [44], hinokitiol [45], etc. The ring expansion reaction for the formation of dihydrotropones conducted by the rearrangement of spirocyclohexadienones was performed by Guillou and coworkers. To achieve the targeted dihydrotropone 63, authors utilized spirocyclichexadienone 62 as the starting precursor. For this protocol, MeONa in methanol was selected as an effective reaction media. An excellent yield (75%) of dihydrotropone 63 was attained by the rearrangement of spirocyclichexadienone 62 within 30 min by keeping the temperature at 40 °C (Scheme 18) [46].

Free radical ring expansion reactions of five and six-membered rings have extended the use of radical chemistry for framing the large cyclic compounds. Xu et al. reported the ring expansion reaction promoted by free radical and associated cyclization of 1,3-diketone derivatives. A 68–72% yield range of targeted nine-membered ring compounds was attained under optimized reaction conditions (Bu₃SnH, AIBN, C₆H₆ and 80 °C). The compound 56 was refluxed in benzene using tri-n-butyltin hydride (Bu₃SnH) and azobisisobutyronitrile (AIBN) as catalyst. As a result, targeted derivative 57 was achieved as the major product, along with direct reduction product 58 in a 12% yield by maintaining the temperature at 80 °C (Scheme 19) [47].

Seven-membered carbocycles gained substantial attention due to their remarkable biological activities. Maruoka and colleagues made a novel contribution to the stereoselective construction of seven-membered ring compounds through direct Tiffeneau–Demjanov-type ring enlargement. The authors performed the reaction between t-butyl α-benzyl diazoacetate 67 and 4-phenylcyclohexanone 68. Resultantly, the corresponding product with one all-carbon quaternary center was obtained in a 95% yield. To facilitate this approach, optimized reaction conditions involved 20 mol% BF₃^.OEt₂ (catalyst), CH₂Cl₂ (solvent), 30 min and −78 °C temperature (Scheme 20). The 40–95% yield range proved the effectivity of this methodology [17].

Ballesteros-Garrido et al. reported the synthesis of medium-size rings by using rhodium-catalyzed ring expansion reaction in one pot. Several functionalized nine-membered ring compounds were isolated in the low-to-high yields (31–85%) by the reaction of α-diazodicarbonyls with cyclic acetals. α-diazo β-ketoester 70 underwent reaction with 1,3,5-trioxane 71 at 60 °C using (Rh₂(OAc)₄) (1 mol%) as catalyst (Scheme 21). Toluene proved to be a suitable solvent for this reaction. Consequently, an 85% yield of corresponding product 72 was achieved as a single product [48].

Seven-membered ring compounds possessing enormous biological activities have attracted the attention of chemists to develop synthetic routes for their preparation. Silva et al. reported the metal-free, versatile and efficient method for synthesizing hetero- and carbocycles containing seven-membered rings. 1-Vinylcycloalkanol derivative 73 underwent hydroxy(tosyloxy)iodobenzene (HTIB)-promoted ring expansion. As a result, a mixture of O-heterocycles 74, 75 and 76 was attained in a 72–88% yield range (Scheme 22). The reaction parameters for the corresponding reaction include HTIB, a hypervalent iodine reagent and methanol as solvent. The easy availability of starting materials is the salient feature of this protocol [49].

Seven-membered heterocycles are core structures of numerous naturally occurring biologically potent organic compounds. Cancer is the most prevent and deadly disease in the recent era, and continuous efforts are in progress to devise anticancerous agents [50]. For example, theaflavin is known to inhibit the proliferation of cancerous cells [51]. Similarly, TAK-779 is highly effective against human immunodeficiency virus [52]. There have been numerous reports concerning the synthesis of seven-membered cyclic organic compounds via utilization of titanium, palladium or mercury metals. Silva et al., in 2008, carried out the ring expansion reaction of six-membered cyclic rings by devising a metal-free synthetic approach. For this purpose, they treated silyl or methyl ether of vinylcycloalkanols in the presence of HTIB (PhI(OH)OTs) and methanol to furnish lactone-based cyclic compounds 77. Similarly, the reaction to silyl enol ether of vinylcycloalkanols 73 with iodine’s reagent by using methanol as solvent in the presence of p-TsOH led to the synthesis of methoxy ketone 74 in a 61% yield. However, the reaction of vinylcycloalkanol with 2.5 equivqlents of HTIB in the presence of methanol achieved dimethoxyketone 75 in a 75% yield (Scheme 23) [53].

Oxygen, sulfur and nitrogen constituting heterocycles are diversely and abundantly found in various pharmaceutically important organic compounds. For example, bauhiniastatin is a naturally occurring seven-membered cyclic ring that has been found to be a potent cytotoxic agent. Taking into account the unparalleled pharmacological applications of seven-membered cyclic rings, Khan et al. in 2021 attempted their synthesis via ring expansion reaction by utilizing an iodine reagent, i.e., HTIB (PhI(OH)OTs), as catalyst. HTIB (PhI(OH)OTs) is regarded as Koser’s reagent and has been found to be highly effective as an alternative to expensive metal catalysts that were previously employed for the synthesis of seven-membered heterocyclic rings. Khan et al. reacted ketone 78 with potassium tert-butoxide, Ph₃PCH₃Br and diethyl ether, which resulted in the synthesis of chromane intermediate 79. The synthesized chromane was then treated with HTIB catalyst in the presence of acetonitrile and water as solvent to synthesize seven-membered heterocycle 80 in a good yield (Scheme 24) [54].

Seven-membered sulfonamides possess enormous biological activities, such as the inhibition of HIV-1 protease [55] calcium-sensing receptor agonists [56] and apical sodium-dependent bile acid transporter (ASBT) inhibition [57]. Moreover, they act as synthetic intermediates for synthesizing biologically active scaffolds. Xia et al. reported the reactions of N-sulfonylimines with diazomethane under metal-free conditions providing enesulfonamides in a 45–99% yield range. The reaction worked efficiently by using Cs₂CO₃ as base and 1,4-dioxane at 60 °C. A maximum (99%) yield of enesulfonamide 83 was obtained under argon atmosphere (Scheme 25) [58].

Tricyclic dibenzazepines and dibenzoxepines derivatives are therapeutic agents and possess a wide range of pharmaceutical properties, for example, metapramine [59] and opipramol [9] display analgesic and anxiolytic properties, respectively. In addition, oxcarbazepine, an antiepileptic drug (AED) [13], is used as monotherapy for medication of partial seizures in adults. Mancheno and coworkers reported the facile and effortless way to synthesize dibenzazepines and dibenzoxepines oxidative C-H bond rearrangement and ring expansion using copper catalyst. The tricyclic product 86 was obtained in a 75% yield by the reaction of 84 with TMS-CHN₂ 85 in acetonitrile. The reaction was completed in 18 h using 10 mol% Cu(OTf)₂ as catalyst, 30 mol% of 2,2-bipyridine as ligand and Ph(CO₂)₂ as additive (Scheme 26). Electron-donating (OMe, Ph, Me) and electron-withdrawing (F, Br) substituents were well-tolerated in the corresponding reaction, giving 55–74% yields of respective products. The substitution of O by N-Ph group gave a 55% yield, while the substitution of sulfur gave a 36% yield of the corresponding product [8].

The insertion of isolated alkynes into the carbon–carbon σ-bond of unstrained cyclic β-dicarbonyl compounds without use of transition metals is outlined by Zhou et al. The reaction of different alkynes and dicarbonyl compounds consequently gave corresponding ring expansion products in a 49–86% yield range. It was noted that electron-donating and -withdrawing substituents on aryl groups of alkynes gave respective products in good yields. The insertion of alkynes 87 into cyclic β-diketone 88 was facilitated under optimized reaction conditions (Cs₂CO₃, DMAc, 80 °C). The 2.0 equiv cesium carbonate (Cs₂CO₃) was used as base and dimethylacetamide (DMAc) as an effective solvent, as compared with DMF, DMSO and toluene, to attain the required product 89 in an 86% yield (Scheme 27). Due to mild reaction conditions and easily accessible starting precursors, this approach is applicable to organic synthesis [60].

The existence of 8- to 12-membered medium-ring heterocycles in natural products demonstrates several biological activities. Clayden and coworkers reported an effective method to synthesize medium (8- to 12-membered) benzo-fused nitrogen-containing heterocyclic rings via n → n + 3 ring expansion of metalated urea. A series of substituted nine-membered benzodiazonines in a 50–90% yield proved the substrate scope and efficacy of this protocol. The reaction was processed in tetrahydrofuran in the presence of lithium diisopropylamide (LDA) as base and N,N^’-dimethylpropylideneurea (DMPU) as additive. By maintaining temperature at −78 °C, product 91 was attained through migratory ring expansion reaction of urea derivative in 1–16 h. The investigation of bases such as LDA and sec-BuLi was conducted. LDA was selected as a suitable base for this reaction (Scheme 28) [61].

The pyrrole-annulated medium-sized rings have attracted considerable attention, as they are found in pharmaceutical agents, naturally occurring products and biologically active compounds. For example, some of the compounds show useful effects on the central nervous system and some are agonists of the farnesoid X receptor [62]. The enantioselective construction of pyrrole-annulated seven-membered rings by allylic dearomatization or retro-Mannich/hydrolysis via iridium catalyst was reported by Huang et al. The targeted product 95 was obtained in a 77% yield and an enantioselectivity value of 99% ee by the reaction of 92 with 2 mol% of iridium catalyst (Ir(COD)Cl)₂ and 4 mol% of ligand 93. The reaction worked well by utilizing 100 mol% (Cs₂CO₃) as base in THF through an intermediate 94, followed by the Boc protection of amino group by using Boc₂O and triethylamine (Et₃N) (Scheme 29). The reaction was completed in 4–12 h by keeping the temperature at 50 °C [63].

Oxetanes are abundantly present in several medicinal drugs [64]. Shibata and coworkers reported a simple method for the formation of 12-membered trifluoromethyl heterocycles through nondecarboxylative palladium-catalyzed (6 + 6) annulation of 6-membered trifluoromethylbenzo[d][1,3]oxazinones and several vinyl oxetanes. Vinyl oxetanes containing electron-rich (4-OCH₃, 2-OMe, 4-CH₃) and electron-poor (4-Cl, 4-Br, 4-F) substituents on aryl ring gave respective products in good-to-excellent yields (66–93%). The impact of different solvents (THF, CH₂Cl₂, 1,4-dioxane, MeCN and toluene) was examined, and results declare that 1,4-dioxane gave the maximum yield, as compared with other solvents. Highly functionalized trifluoromethyl 12-membered ring heterocycle 98 was obtained in an excellent yield (93%) by the reaction of 96 with substituted vinyl oxetane 97 using 5 mol% Pd(PPh₃)₄ via Pd-catalyzed non-decarboxylative (6 + 6) annulation (Scheme 30) [19].

Most of the pharmaceutically important organic compounds contain saturated cyclic rings having nitrogen and oxygen atoms. The synthesis of heterocycles containing more carbon atoms is a very interesting task, which can be easily accomplished by employing the ring closing strategy on open-chain starting materials. However, Grant et al., in 2008, reported the synthesis of these heterocycles by subjecting lactams or lactones to the ring-expansion reaction. For this purpose, they treated N-sulfonyllactams 99 and easily available lactones with tert-butyl propiolate 100 in the presence of n-butyl lithium and boron triflouride diethyl etherate, which gave acyclic adducts 101 in good yields. The synthesized adducts were then made to react with pyridinium acetate, which resulted in the synthesis of six or seven carbon-containing cyclized ethers or amines upon cyclization 102 (Scheme 31). The higher carbon-containing cyclic rings are synthesized as a result of ring elongation methodology, which proceeds via nucleophile-catalyzed reaction [65].

Selenium-incorporated heterocycles have gained considerable significance due to their significant biological applications and extraordinary chemical properties [66]. However, there are few reports concerning the synthesis of selenium-based cyclic rings. Thus, in 2008, Sashida et al. reacted tertrahydroselenopyranone 103 with diversely substituted ethynyl lithiums to synthesize selenium-incorporated eight-membered heterocyclic ring 105. The reaction was carried out under different conditions, and the highest yield (95%) was obtained when the reaction between the two substrates was carried out by substituting R = Ph and by employing THF as solvent at −40 °C in the presence of sulfuric acid as proton source (Scheme 32) [67].

A wide variety of medicinal drugs constitute fluorine constituting organic compounds, which emphasizes the synthesis of fluorine-based organic molecules. According to the reported data by the FDA in 2018, almost 47% percent of approved drugs include fluorine/CF₃ in their structural formula [68]. Considering the wide applicability of fluorine-based organic molecules, Uno et al. carried out the ring extension reaction of trifluoromethyl-benzo [1,3]-oxazinones by employing an optically active ligand as catalyst. In this regard, they reacted [1,3]-oxazinones with vinyl-substituted ethylene carbonates in the presence of palladium acetate and (R)-Tol-BINAP, which led to the synthesis of a nine-membered heterocycle, i.e., dextrorotary and levorotatory mirror images of trifluoromethyl-substituted [1,5]-oxazonines in high enantiomeric excess (up to 98% ee). In the first step, double removal of carboxylic acid results in ring elongation to furnish phenyl sunstituted (R)-108. The nonreactive starting material in the second cycle is then converted to (S)-108 in 88% yield with -89%ee without utilizing another optically active ligand. (Scheme 33). However, thiophene substituted ethylene carbonate resulted in -98% ee of target molecule in 81% yield [69].

3. Conclusions

In summary, the synthesis of biologically active carbocyclic/heterocyclic compounds has been achieved by numerous pathways. The current review article outlines a wide range of reactions to demonstrate the synthetic importance of functionalized carbocyclic/heterocyclic molecules formed via six-membered ring expansion reactions that covers the literature reported from 2017 to 2022. The use of catalysts and ligands and the effect of different substituents on product yields while conducting reactions were also illustrated in this review. Moreover, such ring expansion reactions will provide meticulous guidelines for synthetic and pharmaceutical chemists to yield valuable ring expansion products.