Sustainable Transition Metal Free Synthesis of Substituted γ-Lactones

Sustainable Transition Metal Free Synthesis of Substituted γ-Lactones | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sustainable Transition Metal Free Synthesis of Substituted γ-Lactones Smita R. Waghmare, Harsh K. Gaikwad, Vishal Deore This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7365888/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A novel and efficient methodology has been established for the synthesis of substituted γ-lactone scaffolds using a metal-free iodine/DMSO system. This approach offers a straightforward, practical, and environmentally benign alternative to conventional methods, delivering γ-lactones in good to excellent yields. The reaction employs molecular iodine as a catalyst and dimethyl sulfoxide (DMSO) as the solvent—both of which are inexpensive, commercially available, and non-toxic. Notably, this method eliminates the need for transition metals or complex catalytic systems, making it a cost-effective and sustainable route for lactone synthesis. In the broader context of green and sustainable chemistry, the development of methodologies that minimize environmental impact while maximizing efficiency remains a key objective. This protocol addresses those goals by utilizing simple, readily available starting materials and operating under mild reaction conditions, ensuring tolerance for various functional groups. The iodine/DMSO system reduces chemical waste and avoids hazardous reagents, aligning with the principles of atom economy and environmental safety. The use of iodine, a non-toxic halogen, further enhances the method’s appeal from a sustainability standpoint. Moreover, the operational simplicity and scalability of this process make it suitable for applications in both research and industrial settings. Given the importance of γ-lactone structures in pharmaceuticals, natural products, and fine chemicals, this methodology represents a valuable tool for synthetic chemists. Overall, the iodine/DMSO protocol offers a reliable, metal-free, and eco-friendly alternative for constructing γ-lactones, with strong potential for broader application and further development in modern organic synthesis. γ-Lactones Iodine catalyst DMSO Metal-free synthesis Substituted lactones Organic synthesis green chemistry Figures Figure 1 Introduction Lactones are a class of organic compounds known as cyclic esters, formed when a hydroxyl group (-OH) and a carboxylic acid group (-COOH) within the same molecule undergo intramolecular esterification, releasing a molecule of water. The ring size of lactones can vary widely, ranging from 3 to over 20 members. However, three-membered lactone rings are highly strained and thus extremely unstable. In contrast, five- and six-membered lactones are the most stable and easiest to synthesize due to minimal ring strain. Larger ring lactones, though more complex to synthesize, are commonly found in nature. 1 – 3 A notable example is the antibiotic erythromycin, which contains a 14-membered macro lactone ring as part of its structure. Lactones are typically named based on the corresponding carboxylic acid, with the suffix “-lactone.” Greek letters are used to indicate the position of ring closure, which correlates with ring size. For instance, γ-lactones possess five-membered rings, while δ- and ε-lactones contain six- and seven-membered rings, respectively. Examples include γ-butyrolactone and δ-valerolactone. Lactone functionality is widespread in nature and is found in a broad range of biologically active compounds. They play crucial roles in natural products, often contributing to the pharmacological activity of antibiotics, alkaloids, and pheromones. Functionalized γ-lactones have been identified as flavour compounds and sex-attractant pheromones in various insect species. Moreover, several lactone derivatives function as plant growth regulators. Examples include biologically significant compounds such as (+)-Eeldonolide, (−)-Methylenolactocin, (+)-Hexanolide, and the Japanese beetle sex pheromone. The representative structures are shown in Fig. 1 Due to their structural diversity and biological relevance, lactones are valuable intermediates in organic synthesis, particularly in the development of pharmaceuticals, agrochemicals, and natural product derivatives. The physiological activity of lactones is closely linked to their optical purity and stereochemical configuration. This is particularly true in the case of insect sex attractant pheromones, where even slight differences in stereochemistry can significantly impact biological activity across various species. Among the different types of lactones, α-lactones represent a particularly important subgroup due to their potent bioactivity and their role in chemical communication among insects. In recent years, there has been growing interest in the synthesis of optically pure lactones, especially for their potential application as natural insect attractants in biological traps designed to control harmful agricultural pests. These eco-friendly alternatives to synthetic pesticides offer a more sustainable and targeted approach to pest management. However, the synthesis of enantiomerically pure lactones is often complex and challenging. Common methods include the transformation of naturally occurring chiral compounds, microbial reduction of γ-keto acids, and enzymatic resolution. While these techniques can yield high stereoselectivity, they are typically multistep, time-consuming processes that require substrate-specific conditions and the use of expensive chiral reagents or catalysts. As a result, the large-scale application of these methods remains limited by cost and practicality. Continued research into more efficient, cost-effective, and sustainable synthetic routes is therefore essential. Advances in green chemistry and biocatalysis may help overcome these challenges and unlock the potential of optically active lactones as environmentally friendly solutions in pest control and other biologically relevant applications. Due to the wide-ranging applications of γ-lactones, numerous synthetic methods have been developed, particularly via transition metal catalysis. Metals such as gold, 4 palladium, 5 copper, 6 cobalt, 7 silver, 8 cobalt 9 and rhodium 10 have been effectively utilized in various catalytic systems for the formation of γ-lactones. Notably, Ishii and co-workers reported the synthesis of α-hydroxy-γ-lactones using a cobalt(II)/N-hydroxyphthalimide (NHPI)/O₂ catalytic system, 9 demonstrating a useful oxidative approach to access these compounds. In addition to metal catalysis, recent advances in organocatalysis 10 and photocatalysis 11 have opened up new strategies for γ-lactone synthesis. 12 For instance, MacMillan and colleagues employed an iridium-based photocatalyst in an elegant transformation to construct γ-lactones, showcasing the potential of photoredox catalysis in lactone chemistry. Similarly, Kokotos and co-workers developed a photoorganocatalytic route for the selective synthesis of lactones through C–H activation followed by alkylation of alcohols. 13 This method not only avoids the use of metals but also provides a more environmentally benign alternative. Despite these significant advances, including a variety of efficient protocols and catalytic systems, there is still a persistent need for the development of simpler, more sustainable, and highly efficient synthetic methodologies for accessing γ-lactone frameworks. The continued interest in γ-lactones stems from their presence in a wide array of natural products and biologically active compounds, as well as their utility as key intermediates in pharmaceuticals, agrochemicals, and fine chemicals. Therefore, the design of novel catalytic systems or reaction conditions that can overcome current limitations—such as harsh reaction conditions, limited substrate scope, or high cost of catalysts—remains an area of great research interest. Developing such methodologies would not only expand the synthetic utility of γ-lactones but also align with the broader goals of green and sustainable chemistry. Result and Discussion As illustrated in Scheme I, the synthesis of lactones (compound 3) was carried out using different solvents to evaluate the influence of solvent choice on the reaction outcome. Phenylacetic acid served as the starting material, which underwent esterification with various alcohols in the presence of concentrated sulfuric acid as a catalyst. In this procedure, the alcohols not only acted as reactants but also served as solvents, thereby playing a dual role in facilitating the reaction. The resulting esters subsequently cyclized to form the desired lactones. By conducting the reaction in a range of alcohol-based solvents, the effect of solvent nature—such as polarity and steric properties—on the efficiency and yield of lactone formation was systematically studied. Table I: Solvent effect Sr. No Solvent Temp Time (hr) Yield (%) 1. DMSO RT 5–24 No reaction 2. DMSO 75 0 C 2.5 24 3. MeOH RT 5 23 4. Pyridine RT 5–24 No reaction 5. DCM RT 5–24 No reaction Methanol was used as a solvent and reactant to synthesize methyl phenyl acetate, which was obtained in an excellent yield of 85% with a boiling point of 218°C. Similarly, ethanol gave ethyl phenyl acetate in 83% yield with a boiling point of 229°C, while isopropanol resulted in the formation of isopropyl phenyl acetate with the highest yield among the three, 86%, and a boiling point of 250°C. All of these esters possess an aromatic ring, which is relevant for subsequent transformations. To further explore the scope of the reaction, a non-aromatic ester, ethyl hexanoate [2B], was also synthesized and subjected to the same allylation process as the aromatic esters. Allylation was performed on each of these esters using carefully selected bases. The esters were first dissolved in appropriate solvents and stirred magnetically for 20–30 minutes to promote carbanion formation. The formation of a carbanion intermediate was visually indicated by a change in the reaction mixture—either becoming turbid or developing a reddish hue. Following allylation, the resulting allylated esters [2] were subjected to iodine treatment in a 1:1 molar ratio. This step facilitated the intramolecular cyclization process known as iodolactonization , which leads to the formation of γ-lactones (compounds [3]). Although the methodology of allylation and iodolactonization is well-established, the novelty of this work lies in the exploration of different solvent systems to assess their influence on the overall efficiency and outcome of the reaction. To remove any excess iodine from the reaction mixture, a saturated solution of sodium thiosulfate was used. This ensured cleaner reaction profiles and improved isolation of the desired lactone products. Scheme I: Table II: Synthesis of alkyl phenyl acetate Sr. No R Time (hr) Product Yield (%) Physical constant ( 0 C) 1. -CH 3 5 Methyl Phenyl Acetate 85 218 2. -CH 2 -CH 3 5 Ethyl Phenyl Acetate 83 229 3. -CH-(CH 3 ) 2 5 Isopropyl Phenyl acetate 86 250 In an effort to explore alternative allylating agents, cinnamyl bromide was used in place of conventional reagents such as allyl chloride and allyl bromide for the allylation of methyl phenyl acetate. Cinnamyl bromide was synthesized from cinnamaldehyde (compound 4) as shown in Scheme II. The transformation involved the reduction of cinnamaldehyde using a 1:1 molar ratio of sodium borohydride (NaBH₄) in methanol, in the presence of a catalytic amount of 10% sodium hydroxide (NaOH) in methanol. The NaOH served to stabilise NaBH₄ during the reduction process. Scheme II This reaction yielded cinnamyl alcohol (compound 5) in 65% yield. Subsequently, cinnamyl alcohol was subjected to bromination using bromine (Br₂) in carbon tetrachloride (CCl₄). The reaction was conducted by slowly warming the mixture from 0°C to room temperature over a period of 3.5 hours. Despite careful monitoring and controlled conditions, the yield of cinnamyl bromide was found to be relatively low, at only 18%, indicating inefficiencies in the bromination step under these conditions. The cinnamyl bromide obtained was then used for allylation of methyl phenyl acetate. However, the yield of the resulting allylated product was significantly lower, only 15% compared to those obtained using allyl chloride or allyl bromide in earlier experiments. This substantial decrease in yield suggests that cinnamyl bromide is less efficient for this transformation, possibly due to steric or electronic factors. As a result of the poor yield, the subsequent iodolactonization step, which would lead to the formation of the corresponding lactone, was not carried out. The overall inefficiency of this pathway indicates that while cinnamyl bromide is a potential allylating agent, it may not be suitable for this particular synthetic route under the studied conditions. Experimental Details A) Synthesis of Lactone from Phenylacetic Acid 1) Esterification of Phenylacetic Acid to Methyl Phenyl Acetate The synthesis began with the esterification of phenylacetic acid to obtain methyl phenyl acetate. For this, 0.5 g of phenylacetic acid was weighed and transferred into a round-bottom flask. Methanol was added both as the solvent and as the alcohol component for ester formation. To catalyse the reaction, 1 mL of concentrated sulfuric acid was introduced into the mixture. The reaction mixture was then subjected to reflux for 5 hours under constant stirring. This facilitated the conversion of phenylacetic acid into its corresponding ester, methyl phenyl acetate, through a typical acid-catalysed esterification process. After completion of the reaction, the mixture was cooled and processed for work-up. During the extraction phase, the reaction mixture was carefully washed with a saturated sodium bicarbonate solution. This step was crucial for neutralizing any residual sulfuric acid and removing any unreacted phenylacetic acid, thus purifying the organic layer containing the desired ester. Following separation and drying, methyl phenyl acetate was obtained in an excellent yield of 85%. The purity of the product was confirmed by its physical properties, including its boiling point and characteristic odour. This step represents a key intermediate stage in the synthesis of γ-lactones, as the methyl ester serves as a substrate for subsequent transformations such as allylation and iodolactonization. The high yield and simplicity of the procedure make it an efficient and practical approach for ester synthesis in preparative organic chemistry. 2) Synthesis of (α-propene) Methyl Phenyl Acetate To synthesize (α-propene) methyl phenyl acetate, 0.5 g of methyl phenyl acetate was taken in a round-bottom flask. Two pellets of potassium hydroxide (KOH) were added as the base, and the mixture was dissolved in dimethyl sulfoxide (DMSO) as the solvent. The reaction mixture was stirred magnetically for 20–30 minutes to allow deprotonation and carbanion formation at the benzylic position. After this pre-activation phase, allyl bromide was added slowly to the reaction mixture. The reaction was carried out under controlled conditions, and upon completion, the mixture was worked up using diethyl ether for extraction. The desired allylated product, (α-propene) methyl phenyl acetate, was isolated and obtained in a yield of 65%. This reaction demonstrates efficient C–C bond formation via base-induced nucleophilic substitution, offering a useful route for further transformation toward lactone synthesis. Spectral Characterisation NMR data:- 7.4 δ m 5H ; 5.8 δ dd 1H J = 15 Hz, 6Hz ; 5.9 δ dd 1H J = 15 Hz, 6Hz; 5.2 δ m 1H; 3.6 δ s 3H; 2.5 δ dd 1H J = 6Hz, 7Hz; 4.5 δ dd 1H J = 6Hz. 3) Synthesis of Lactone from (α-2-propene) Methyl Phenyl Acetate Using Different Solvents To synthesize lactone, 0.2 g of (α-2-propene) methyl phenyl acetate was dissolved in four different solvents under varying conditions. In each case, 0.2 g of iodine was added in a 1:1 molar ratio to initiate iodolactonization. The reaction mixtures were stirred under their respective conditions, allowing cyclization to occur. After completion, excess iodine was removed by treating the mixtures with a saturated solution of sodium thiosulfate. The resulting products were extracted using diethyl ether. This step aimed to evaluate the influence of solvent choice on the efficiency and yield of lactone formation. Spectral Characterisation IR data : 1) DMSO as solvent At room temperature: 3030, 2950, 1737.5, 1641.3, 1600.8, 1548.7, 704 cm − 1 At 75 0 C: 3028, 2925, 1776.5, 1735, 1645.2, 162.7, 704.0 cm − 1 Here 1776.5 cm − 1 shows that lactone is present. 2) MeOH as solvent 3030, 2950, 1778.2, 1735, 1641, 1602, 704 cm − 1 Here 1778.2 cm − 1 shows that lactone is present. Here 1735 cm − 1 shows that ester is present. 3) Pyridine as solvent 3030, 295., 1716.5, 1602, 702.9 cm − 1 Here 1737.7 cm − 1 shows that ester is present. 3) DCM as solvent 3030, 2950, 1716.5, 1602, 702.9 cm − 1 Here 1716.5 cm − 1 shows that acid is present. B) Synthesis of Lactone from Aliphatic Ester Ethyl Hexanoate via (α-2-Propene) Intermediate To synthesize a lactone from the aliphatic ester ethyl hexanoate, a base-induced allylation reaction was first carried out. In a dry round-bottom flask, 1.44 g of sodium hydride (NaH) was initially washed with dry petroleum ether to remove any residual mineral oil. Dimethylformamide (DMF) was then added as the solvent, followed by the addition of 2 mL of ethyl hexanoate. The reaction mixture was stirred magnetically for 20 minutes to allow deprotonation of the ester. Subsequently, 1.5 mL of allyl chloride was added immediately under strictly anhydrous conditions. The molar ratio of NaH, ester, and allyl chloride was maintained at 5:1:1. The reaction was kept at room temperature for 5 hours to ensure completion. Upon completion, the reaction was carefully quenched by adding cold water dropwise to neutralize the unreacted NaH. The mixture was then extracted with diethyl ether to isolate the organic product. The desired allylated intermediate, corresponding to (α-2-propene) ethyl hexanoate, was obtained in a good yield of 71%. However, due to time constraints, the subsequent step of iodolactonization to obtain the final lactone could not be performed. Spectral Characterisation NMR data: 5.8 δ m 2H, 5.2 δ m 1H, 4.2 δ q 2H J = 3Hz, 2.4 δ m 1H J = 5 Hz, 2.3 δ m 2H J = 5. 1.5 δ sextet 2H J = 7, 1.7 δ quintet 2H, 1.2 δ t 3H, 0.96 δ t 3H, 2.6 δ m 2H. C) Synthesis of Cinnamyl Bromide from Cinnamaldehyde via Cinnamyl Alcohol 1) Reduction of Cinnamaldehyde to Cinnamyl Alcohol : Cinnamyl bromide was synthesized via a two-step process, beginning with the reduction of cinnamaldehyde to cinnamyl alcohol. For this, 1 g of cinnamaldehyde was taken in a round-bottom flask and dissolved in methanol. A catalytic amount of 10% sodium hydroxide (NaOH) solution was added to stabilize the reducing agent. Sodium borohydride (NaBH₄) was then added gradually in equimolar proportion (1:1) over a period of 30 minutes, while the reaction mixture was maintained in an ice bath at 0°C. The reaction was allowed to proceed for 5 hours under constant stirring. After completion, the reaction mixture was extracted using diethyl ether to isolate the organic phase. The desired product, cinnamyl alcohol, was obtained with a moderate yield of 65%. This alcohol was subsequently used in the bromination step to produce cinnamyl bromide for further synthetic transformations. Spectral Characterisation: NMR data: 7.3δ m 5H, 6.6 δ d 1H, 6.4 δ dt 1H, 4.3 δ d 2H, 2.3 δ s 1H. 2) Bromination of Cinnamyl Alcohol For the synthesis of cinnamyl bromide, 0.5 g of cinnamyl alcohol was dissolved in carbon tetrachloride (CCl₄), and the solution was cooled in an ice bath to maintain a temperature of 0°C. Separately, 0.2 mL of bromine was dissolved in CCl₄ and added dropwise to the chilled cinnamyl alcohol solution with constant stirring. After the complete addition of bromine, the reaction mixture was allowed to gradually reach room temperature and was left undisturbed for 48 hours to ensure completion. Following the reaction, the mixture was extracted using diethyl ether to isolate the organic components. Thin-layer chromatography (TLC) analysis revealed five distinct spots, indicating a mixture of products. These components were separated using column chromatography. Cinnamyl bromide was obtained as a yellowish solid with a melting point of 35°C. However, the yield was relatively low, with only 20% of the desired product being recovered. 3) Allylation of Methyl Phenyl Acetate Using Cinnamyl Bromide To perform the allylation reaction, 0.1 g of methyl phenyl acetate was dissolved in dimethyl sulfoxide (DMSO) in a round-bottom flask. An equimolar amount of potassium hydroxide (KOH) pellets was added (1:1 ratio) to generate the carbanion intermediate. The mixture was stirred magnetically for 20 minutes at room temperature to allow for complete deprotonation. Separately, cinnamyl bromide was dissolved in DMSO and then added to the reaction mixture. The reaction was allowed to proceed at room temperature for 3.5 hours under constant stirring. Upon completion, the reaction mixture was extracted using diethyl ether to isolate the organic components. The allylated product was obtained but in very low yield, with only 10% recovery. The low yield may be attributed to the reduced reactivity or steric hindrance of cinnamyl bromide compared to simpler allyl halides, making this approach less efficient for further transformations. Conclusions In conclusion, we have successfully developed a new, simple, and mild methodology for the synthesis of γ-lactones using iodine as a catalyst in dimethyl sulfoxide (DMSO). This approach offers a practical and efficient alternative to existing methods, eliminating the need for expensive transition metal catalysts or photocatalysts. The reaction proceeds under mild conditions and employs easily accessible starting materials, making it cost-effective and environmentally friendly. The versatility of the method was demonstrated through its application in various solvents, allowing us to study the influence of solvent choice on reaction efficiency and yield. The process is operationally straightforward, requiring no elaborate setup or special reaction conditions. Importantly, this method is compatible with a broad range of substrates, highlighting its potential utility in both academic research and industrial synthesis. Our findings suggest that iodine, a readily available and inexpensive reagent, can serve as an effective catalyst for lactone formation through iodolactonization. The reaction conditions are robust and reproducible, making this methodology attractive for further synthetic applications. Ongoing research in our laboratory is focused on investigating the detailed mechanism of this transformation, as well as expanding the substrate scope to include more complex and functionalized molecules. These studies aim to deepen our understanding of the reaction pathway and further enhance the applicability of this protocol in synthetic organic chemistry. Declarations Author Contribution Author 1 Smita R Waghmare: Conceptualisation, Methodology, Experimental Investigation, Data Curation, Writing – Original Draft Preparation.Author 2 Harsh Gaikwad: Formal Analysis, Validation, Writing – Review & Editing.Author 3 Name Vishal Deore: Supervision, Resources, Project Administration.All authors have read and approved the final manuscript. Acknowledgement The authors would like to thank Prof P. D. Lokhande from Savitribai Phule Pune University for his constant support and guidance Data Availability “Data is provided within the manuscript or supplementary information files” References Brown HC, Kulkarni SV, Racheria US. J Org Chem. 1994;59:364. Yang CG, Reich NW, Shi Z, He C. Org Lett. 2005;7:4553. Genin E, Toullee PY, Antioniotti S, Brancour C, Genet JP, Michelet V. J Am Chem Soc. 2006;128:3112. Genin E, Toullec PY, Antoniotti S, Brancour C, Genêt J-P, Michelet V, Zhang G, Cui L, Wang Y, Zhang L, Shu C, Liu M-Q, Sun Y-Z, Ye L-W, editors. Am. Chem. Soc. 2006, 128 , 3112. (b) Zhang G, Cui L, Wang Y, Zhang L J . Am. Chem. Soc. 2010, 132 , 1474. (c) Shu C, Liu M-Q, Sun Y-Z, Ye L-W Org . Lett. 2012, 14 , 4958. (a) Trend RM, Ramtohul YK, Ferreira EM; Stoltz, B Angew. Chem., Int. Ed. 2003, 42 , 2892. (b) Li J, Yang W, Yang S, Huang L, Wu W, Sun Y, Jiang H. 2014, 53 , 7219. (c) Zheng, M.; Chen, P.; Huang, L.; Wu, W.; Jiang, H. Org. Lett. 2017, 19 , 5756. (d) Li, M.-B.; Inge, A. 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Scheme Scheme 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files FinalsupplementaryFile.docx Scheme.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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12:26:17","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":68982,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7365888/v1/f778211e8d5fa2f292b68e1c.html"},{"id":92083611,"identity":"f549d8b5-0cad-45f6-8cb7-4935d24e2734","added_by":"auto","created_at":"2025-09-24 12:26:17","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":306148,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7365888/v1/aadba927b41a834fff72e0b3.jpeg"},{"id":94825451,"identity":"729fba97-6acc-4b3f-8637-37dea8a50ae9","added_by":"auto","created_at":"2025-10-31 06:50:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1066506,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7365888/v1/2ed4eb2a-2215-4e3f-8bba-2136c4ebce6f.pdf"},{"id":92083623,"identity":"a0bdc484-cd52-4c0c-b9d1-2d3258e36e45","added_by":"auto","created_at":"2025-09-24 12:26:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":3659141,"visible":true,"origin":"","legend":"","description":"","filename":"FinalsupplementaryFile.docx","url":"https://assets-eu.researchsquare.com/files/rs-7365888/v1/67163c9e3ccb1966eed81cb7.docx"},{"id":92083608,"identity":"1991a9a1-32af-4986-b0cf-89233b5c5106","added_by":"auto","created_at":"2025-09-24 12:26:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":106592,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme.docx","url":"https://assets-eu.researchsquare.com/files/rs-7365888/v1/eb4dba8b6ad8940bc501736f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sustainable Transition Metal Free Synthesis of Substituted γ-Lactones","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLactones are a class of organic compounds known as cyclic esters, formed when a hydroxyl group (-OH) and a carboxylic acid group (-COOH) within the same molecule undergo intramolecular esterification, releasing a molecule of water. The ring size of lactones can vary widely, ranging from 3 to over 20 members. However, three-membered lactone rings are highly strained and thus extremely unstable. In contrast, five- and six-membered lactones are the most stable and easiest to synthesize due to minimal ring strain. Larger ring lactones, though more complex to synthesize, are commonly found in nature.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e A notable example is the antibiotic erythromycin, which contains a 14-membered macro lactone ring as part of its structure.\u003c/p\u003e\u003cp\u003eLactones are typically named based on the corresponding carboxylic acid, with the suffix \u0026ldquo;-lactone.\u0026rdquo; Greek letters are used to indicate the position of ring closure, which correlates with ring size. For instance, γ-lactones possess five-membered rings, while δ- and ε-lactones contain six- and seven-membered rings, respectively. Examples include γ-butyrolactone and δ-valerolactone. Lactone functionality is widespread in nature and is found in a broad range of biologically active compounds. They play crucial roles in natural products, often contributing to the pharmacological activity of antibiotics, alkaloids, and pheromones. Functionalized γ-lactones have been identified as flavour compounds and sex-attractant pheromones in various insect species. Moreover, several lactone derivatives function as plant growth regulators. Examples include biologically significant compounds such as (+)-Eeldonolide, (\u0026minus;)-Methylenolactocin, (+)-Hexanolide, and the Japanese beetle sex pheromone. The representative structures are shown in Fig.\u0026nbsp;1\u003c/p\u003e\u003cp\u003eDue to their structural diversity and biological relevance, lactones are valuable intermediates in organic synthesis, particularly in the development of pharmaceuticals, agrochemicals, and natural product derivatives.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe physiological activity of lactones is closely linked to their optical purity and stereochemical configuration. This is particularly true in the case of insect sex attractant pheromones, where even slight differences in stereochemistry can significantly impact biological activity across various species. Among the different types of lactones, α-lactones represent a particularly important subgroup due to their potent bioactivity and their role in chemical communication among insects. In recent years, there has been growing interest in the synthesis of optically pure lactones, especially for their potential application as natural insect attractants in biological traps designed to control harmful agricultural pests. These eco-friendly alternatives to synthetic pesticides offer a more sustainable and targeted approach to pest management. However, the synthesis of enantiomerically pure lactones is often complex and challenging. Common methods include the transformation of naturally occurring chiral compounds, microbial reduction of γ-keto acids, and enzymatic resolution. While these techniques can yield high stereoselectivity, they are typically multistep, time-consuming processes that require substrate-specific conditions and the use of expensive chiral reagents or catalysts. As a result, the large-scale application of these methods remains limited by cost and practicality. Continued research into more efficient, cost-effective, and sustainable synthetic routes is therefore essential. Advances in green chemistry and biocatalysis may help overcome these challenges and unlock the potential of optically active lactones as environmentally friendly solutions in pest control and other biologically relevant applications.\u003c/p\u003e\u003cp\u003eDue to the wide-ranging applications of γ-lactones, numerous synthetic methods have been developed, particularly via transition metal catalysis. Metals such as gold,\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e palladium,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e copper,\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e cobalt,\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e silver,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e cobalt\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and rhodium\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e have been effectively utilized in various catalytic systems for the formation of γ-lactones. Notably, Ishii and co-workers reported the synthesis of α-hydroxy-γ-lactones using a cobalt(II)/N-hydroxyphthalimide (NHPI)/O₂ catalytic system,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e demonstrating a useful oxidative approach to access these compounds. In addition to metal catalysis, recent advances in organocatalysis\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and photocatalysis\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e have opened up new strategies for γ-lactone synthesis.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e For instance, MacMillan and colleagues employed an iridium-based photocatalyst in an elegant transformation to construct γ-lactones, showcasing the potential of photoredox catalysis in lactone chemistry. Similarly, Kokotos and co-workers developed a photoorganocatalytic route for the selective synthesis of lactones through C\u0026ndash;H activation followed by alkylation of alcohols.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e This method not only avoids the use of metals but also provides a more environmentally benign alternative. Despite these significant advances, including a variety of efficient protocols and catalytic systems, there is still a persistent need for the development of simpler, more sustainable, and highly efficient synthetic methodologies for accessing γ-lactone frameworks. The continued interest in γ-lactones stems from their presence in a wide array of natural products and biologically active compounds, as well as their utility as key intermediates in pharmaceuticals, agrochemicals, and fine chemicals. Therefore, the design of novel catalytic systems or reaction conditions that can overcome current limitations\u0026mdash;such as harsh reaction conditions, limited substrate scope, or high cost of catalysts\u0026mdash;remains an area of great research interest. Developing such methodologies would not only expand the synthetic utility of γ-lactones but also align with the broader goals of green and sustainable chemistry.\u003c/p\u003e"},{"header":"Result and Discussion","content":"\u003cp\u003eAs illustrated in Scheme I, the synthesis of lactones (compound 3) was carried out using different solvents to evaluate the influence of solvent choice on the reaction outcome. Phenylacetic acid served as the starting material, which underwent esterification with various alcohols in the presence of concentrated sulfuric acid as a catalyst. In this procedure, the alcohols not only acted as reactants but also served as solvents, thereby playing a dual role in facilitating the reaction. The resulting esters subsequently cyclized to form the desired lactones. By conducting the reaction in a range of alcohol-based solvents, the effect of solvent nature\u0026mdash;such as polarity and steric properties\u0026mdash;on the efficiency and yield of lactone formation was systematically studied.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable I: Solvent effect\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSr. No\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSolvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTemp\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTime (hr)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYield (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDMSO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u0026ndash;24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo reaction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDMSO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75\u003csup\u003e0\u003c/sup\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePyridine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u0026ndash;24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo reaction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u0026ndash;24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo reaction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eMethanol was used as a solvent and reactant to synthesize methyl phenyl acetate, which was obtained in an excellent yield of 85% with a boiling point of 218\u0026deg;C. Similarly, ethanol gave ethyl phenyl acetate in 83% yield with a boiling point of 229\u0026deg;C, while isopropanol resulted in the formation of isopropyl phenyl acetate with the highest yield among the three, 86%, and a boiling point of 250\u0026deg;C. All of these esters possess an aromatic ring, which is relevant for subsequent transformations. To further explore the scope of the reaction, a non-aromatic ester, ethyl hexanoate [2B], was also synthesized and subjected to the same allylation process as the aromatic esters. Allylation was performed on each of these esters using carefully selected bases. The esters were first dissolved in appropriate solvents and stirred magnetically for 20\u0026ndash;30 minutes to promote carbanion formation. The formation of a carbanion intermediate was visually indicated by a change in the reaction mixture\u0026mdash;either becoming turbid or developing a reddish hue.\u003c/p\u003e\u003cp\u003eFollowing allylation, the resulting allylated esters [2] were subjected to iodine treatment in a 1:1 molar ratio. This step facilitated the intramolecular cyclization process known as \u003cb\u003eiodolactonization\u003c/b\u003e, which leads to the formation of γ-lactones (compounds [3]). Although the methodology of allylation and iodolactonization is well-established, the novelty of this work lies in the exploration of different solvent systems to assess their influence on the overall efficiency and outcome of the reaction.\u003c/p\u003e\u003cp\u003eTo remove any excess iodine from the reaction mixture, a saturated solution of sodium thiosulfate was used. This ensured cleaner reaction profiles and improved isolation of the desired lactone products.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eScheme I:\u003c/h2\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable II: Synthesis of alkyl phenyl acetate\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSr. No\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTime (hr)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eProduct\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYield (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhysical constant (\u003csup\u003e0\u003c/sup\u003eC)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-CH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMethyl Phenyl Acetate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e218\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-CH\u003csub\u003e2\u003c/sub\u003e-CH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEthyl Phenyl Acetate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e229\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-CH-(CH\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIsopropyl Phenyl acetate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e250\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn an effort to explore alternative allylating agents, cinnamyl bromide was used in place of conventional reagents such as allyl chloride and allyl bromide for the allylation of methyl phenyl acetate. Cinnamyl bromide was synthesized from cinnamaldehyde (compound 4) as shown in Scheme II. The transformation involved the reduction of cinnamaldehyde using a 1:1 molar ratio of sodium borohydride (NaBH₄) in methanol, in the presence of a catalytic amount of 10% sodium hydroxide (NaOH) in methanol. The NaOH served to stabilise NaBH₄ during the reduction process.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eScheme II\u003c/h3\u003e\n\u003cp\u003e\u003c/p\u003e\u003cp\u003eThis reaction yielded cinnamyl alcohol (compound 5) in 65% yield. Subsequently, cinnamyl alcohol was subjected to bromination using bromine (Br₂) in carbon tetrachloride (CCl₄). The reaction was conducted by slowly warming the mixture from 0\u0026deg;C to room temperature over a period of 3.5 hours. Despite careful monitoring and controlled conditions, the yield of cinnamyl bromide was found to be relatively low, at only 18%, indicating inefficiencies in the bromination step under these conditions. The cinnamyl bromide obtained was then used for allylation of methyl phenyl acetate. However, the yield of the resulting allylated product was significantly lower, only 15% compared to those obtained using allyl chloride or allyl bromide in earlier experiments. This substantial decrease in yield suggests that cinnamyl bromide is less efficient for this transformation, possibly due to steric or electronic factors.\u003c/p\u003e\u003cp\u003eAs a result of the poor yield, the subsequent iodolactonization step, which would lead to the formation of the corresponding lactone, was not carried out. The overall inefficiency of this pathway indicates that while cinnamyl bromide is a potential allylating agent, it may not be suitable for this particular synthetic route under the studied conditions.\u003c/p\u003e"},{"header":"Experimental Details","content":"\u003cp\u003e\u003cb\u003eA) Synthesis of Lactone from Phenylacetic Acid\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e1) Esterification of Phenylacetic Acid to Methyl Phenyl Acetate\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe synthesis began with the esterification of phenylacetic acid to obtain methyl phenyl acetate. For this, 0.5 g of phenylacetic acid was weighed and transferred into a round-bottom flask. Methanol was added both as the solvent and as the alcohol component for ester formation. To catalyse the reaction, 1 mL of concentrated sulfuric acid was introduced into the mixture. The reaction mixture was then subjected to reflux for 5 hours under constant stirring. This facilitated the conversion of phenylacetic acid into its corresponding ester, methyl phenyl acetate, through a typical acid-catalysed esterification process. After completion of the reaction, the mixture was cooled and processed for work-up. During the extraction phase, the reaction mixture was carefully washed with a saturated sodium bicarbonate solution. This step was crucial for neutralizing any residual sulfuric acid and removing any unreacted phenylacetic acid, thus purifying the organic layer containing the desired ester. Following separation and drying, methyl phenyl acetate was obtained in an excellent yield of 85%. The purity of the product was confirmed by its physical properties, including its boiling point and characteristic odour. This step represents a key intermediate stage in the synthesis of γ-lactones, as the methyl ester serves as a substrate for subsequent transformations such as allylation and iodolactonization. The high yield and simplicity of the procedure make it an efficient and practical approach for ester synthesis in preparative organic chemistry.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2) Synthesis of (α-propene) Methyl Phenyl Acetate\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo synthesize (α-propene) methyl phenyl acetate, 0.5 g of methyl phenyl acetate was taken in a round-bottom flask. Two pellets of potassium hydroxide (KOH) were added as the base, and the mixture was dissolved in dimethyl sulfoxide (DMSO) as the solvent. The reaction mixture was stirred magnetically for 20\u0026ndash;30 minutes to allow deprotonation and carbanion formation at the benzylic position. After this pre-activation phase, allyl bromide was added slowly to the reaction mixture. The reaction was carried out under controlled conditions, and upon completion, the mixture was worked up using diethyl ether for extraction. The desired allylated product, (α-propene) methyl phenyl acetate, was isolated and obtained in a yield of 65%. This reaction demonstrates efficient C\u0026ndash;C bond formation via base-induced nucleophilic substitution, offering a useful route for further transformation toward lactone synthesis.\u003c/p\u003e\n\u003ch3\u003eSpectral Characterisation\u003c/h3\u003e\n\u003cp\u003eNMR data:- 7.4 δ m 5H ; 5.8 δ dd 1H J\u0026thinsp;=\u0026thinsp;15 Hz, 6Hz ; 5.9 δ dd 1H J\u0026thinsp;=\u0026thinsp;15 Hz, 6Hz; 5.2 δ m 1H; 3.6 δ s 3H; 2.5 δ dd 1H J\u0026thinsp;=\u0026thinsp;6Hz, 7Hz; 4.5 δ dd 1H J\u0026thinsp;=\u0026thinsp;6Hz.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3) Synthesis of Lactone from (α-2-propene) Methyl Phenyl Acetate Using Different\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003eSolvents\u003c/h3\u003e\n\u003cp\u003eTo synthesize lactone, 0.2 g of (α-2-propene) methyl phenyl acetate was dissolved in four different solvents under varying conditions. In each case, 0.2 g of iodine was added in a 1:1 molar ratio to initiate iodolactonization. The reaction mixtures were stirred under their respective conditions, allowing cyclization to occur. After completion, excess iodine was removed by treating the mixtures with a saturated solution of sodium thiosulfate. The resulting products were extracted using diethyl ether. This step aimed to evaluate the influence of solvent choice on the efficiency and yield of lactone formation.\u003c/p\u003e\n\u003ch3\u003eSpectral Characterisation\u003c/h3\u003e\n\u003cp\u003e\u003cb\u003eIR data\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cb\u003e1) DMSO as solvent\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAt room temperature: 3030, 2950, 1737.5, 1641.3, 1600.8, 1548.7, 704 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAt 75\u003csup\u003e0\u003c/sup\u003eC: 3028, 2925, 1776.5, 1735, 1645.2, 162.7, 704.0 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Here 1776.5 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e shows that lactone is present.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2) MeOH as solvent\u003c/b\u003e\u003c/p\u003e\u003cp\u003e3030, 2950, 1778.2, 1735, 1641, 1602, 704 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Here 1778.2 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e shows that lactone is present. Here 1735 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e shows that ester is present.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3) Pyridine as solvent\u003c/b\u003e\u003c/p\u003e\u003cp\u003e3030, 295., 1716.5, 1602, 702.9 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Here 1737.7 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e shows that ester is present.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3) DCM as solvent\u003c/b\u003e\u003c/p\u003e\u003cp\u003e3030, 2950, 1716.5, 1602, 702.9 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Here 1716.5 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e shows that acid is present.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eB) Synthesis of Lactone from Aliphatic Ester Ethyl Hexanoate via (α-2-Propene)\u003c/h2\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003eIntermediate\u003c/h2\u003e\u003cp\u003eTo synthesize a lactone from the aliphatic ester ethyl hexanoate, a base-induced allylation reaction was first carried out. In a dry round-bottom flask, 1.44 g of sodium hydride (NaH) was initially washed with dry petroleum ether to remove any residual mineral oil. Dimethylformamide (DMF) was then added as the solvent, followed by the addition of 2 mL of ethyl hexanoate. The reaction mixture was stirred magnetically for 20 minutes to allow deprotonation of the ester.\u003c/p\u003e\u003cp\u003eSubsequently, 1.5 mL of allyl chloride was added immediately under strictly anhydrous conditions. The molar ratio of NaH, ester, and allyl chloride was maintained at 5:1:1. The reaction was kept at room temperature for 5 hours to ensure completion. Upon completion, the reaction was carefully quenched by adding cold water dropwise to neutralize the unreacted NaH. The mixture was then extracted with diethyl ether to isolate the organic product.\u003c/p\u003e\u003cp\u003eThe desired allylated intermediate, corresponding to (α-2-propene) ethyl hexanoate, was obtained in a good yield of 71%. However, due to time constraints, the subsequent step of iodolactonization to obtain the final lactone could not be performed.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eSpectral Characterisation\u003c/h3\u003e\n\u003cp\u003eNMR data: 5.8 δ m 2H, 5.2 δ m 1H, 4.2 δ q 2H J\u0026thinsp;=\u0026thinsp;3Hz, 2.4 δ m 1H J\u0026thinsp;=\u0026thinsp;5 Hz, 2.3 δ m 2H J\u0026thinsp;=\u0026thinsp;5. 1.5 δ sextet 2H J\u0026thinsp;=\u0026thinsp;7, 1.7 δ quintet 2H, 1.2 δ t 3H, 0.96 δ t 3H, 2.6 δ m 2H.\u003c/p\u003e\u003cp\u003e\u003cb\u003eC) Synthesis of Cinnamyl Bromide from Cinnamaldehyde via Cinnamyl Alcohol\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e1) Reduction of Cinnamaldehyde to Cinnamyl Alcohol\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eCinnamyl bromide was synthesized via a two-step process, beginning with the reduction of cinnamaldehyde to cinnamyl alcohol. For this, 1 g of cinnamaldehyde was taken in a round-bottom flask and dissolved in methanol. A catalytic amount of 10% sodium hydroxide (NaOH) solution was added to stabilize the reducing agent. Sodium borohydride (NaBH₄) was then added gradually in equimolar proportion (1:1) over a period of 30 minutes, while the reaction mixture was maintained in an ice bath at 0\u0026deg;C. The reaction was allowed to proceed for 5 hours under constant stirring. After completion, the reaction mixture was extracted using diethyl ether to isolate the organic phase. The desired product, cinnamyl alcohol, was obtained with a moderate yield of 65%. This alcohol was subsequently used in the bromination step to produce cinnamyl bromide for further synthetic transformations.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSpectral Characterisation:\u003c/h2\u003e\u003cp\u003eNMR data: 7.3δ m 5H, 6.6 δ d 1H, 6.4 δ dt 1H, 4.3 δ d 2H, 2.3 δ s 1H.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2) Bromination of Cinnamyl Alcohol\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor the synthesis of cinnamyl bromide, 0.5 g of cinnamyl alcohol was dissolved in carbon tetrachloride (CCl₄), and the solution was cooled in an ice bath to maintain a temperature of 0\u0026deg;C. Separately, 0.2 mL of bromine was dissolved in CCl₄ and added dropwise to the chilled cinnamyl alcohol solution with constant stirring. After the complete addition of bromine, the reaction mixture was allowed to gradually reach room temperature and was left undisturbed for 48 hours to ensure completion.\u003c/p\u003e\u003cp\u003eFollowing the reaction, the mixture was extracted using diethyl ether to isolate the organic components. Thin-layer chromatography (TLC) analysis revealed five distinct spots, indicating a mixture of products. These components were separated using column chromatography. Cinnamyl bromide was obtained as a yellowish solid with a melting point of 35\u0026deg;C. However, the yield was relatively low, with only 20% of the desired product being recovered.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3) Allylation of Methyl Phenyl Acetate Using Cinnamyl Bromide\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo perform the allylation reaction, 0.1 g of methyl phenyl acetate was dissolved in dimethyl sulfoxide (DMSO) in a round-bottom flask. An equimolar amount of potassium hydroxide (KOH) pellets was added (1:1 ratio) to generate the carbanion intermediate. The mixture was stirred magnetically for 20 minutes at room temperature to allow for complete deprotonation. Separately, cinnamyl bromide was dissolved in DMSO and then added to the reaction mixture. The reaction was allowed to proceed at room temperature for 3.5 hours under constant stirring.\u003c/p\u003e\u003cp\u003eUpon completion, the reaction mixture was extracted using diethyl ether to isolate the organic components. The allylated product was obtained but in very low yield, with only 10% recovery. The low yield may be attributed to the reduced reactivity or steric hindrance of cinnamyl bromide compared to simpler allyl halides, making this approach less efficient for further transformations.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, we have successfully developed a new, simple, and mild methodology for the synthesis of γ-lactones using iodine as a catalyst in dimethyl sulfoxide (DMSO). This approach offers a practical and efficient alternative to existing methods, eliminating the need for expensive transition metal catalysts or photocatalysts. The reaction proceeds under mild conditions and employs easily accessible starting materials, making it cost-effective and environmentally friendly. The versatility of the method was demonstrated through its application in various solvents, allowing us to study the influence of solvent choice on reaction efficiency and yield. The process is operationally straightforward, requiring no elaborate setup or special reaction conditions. Importantly, this method is compatible with a broad range of substrates, highlighting its potential utility in both academic research and industrial synthesis.\u003c/p\u003e\u003cp\u003eOur findings suggest that iodine, a readily available and inexpensive reagent, can serve as an effective catalyst for lactone formation through iodolactonization. The reaction conditions are robust and reproducible, making this methodology attractive for further synthetic applications.\u003c/p\u003e\u003cp\u003eOngoing research in our laboratory is focused on investigating the detailed mechanism of this transformation, as well as expanding the substrate scope to include more complex and functionalized molecules. These studies aim to deepen our understanding of the reaction pathway and further enhance the applicability of this protocol in synthetic organic chemistry.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor 1 Smita R Waghmare: Conceptualisation, Methodology, Experimental Investigation, Data Curation, Writing \u0026ndash; Original Draft Preparation.Author 2 Harsh Gaikwad: Formal Analysis, Validation, Writing \u0026ndash; Review \u0026amp; Editing.Author 3 Name Vishal Deore: Supervision, Resources, Project Administration.All authors have read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank Prof P. D. Lokhande from Savitribai Phule Pune University for his constant support and guidance\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003e\u0026ldquo;Data is provided within the manuscript or supplementary information files\u0026rdquo;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrown HC, Kulkarni SV, Racheria US. J Org Chem. 1994;59:364.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang CG, Reich NW, Shi Z, He C. Org Lett. 2005;7:4553.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGenin E, Toullee PY, Antioniotti S, Brancour C, Genet JP, Michelet V. J Am Chem Soc. 2006;128:3112.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGenin E, Toullec PY, Antoniotti S, Brancour C, Gen\u0026ecirc;t J-P, Michelet V, Zhang G, Cui L, Wang Y, Zhang L, Shu C, Liu M-Q, Sun Y-Z, Ye L-W, editors. Am. Chem. Soc. 2006, \u003cem\u003e128\u003c/em\u003e, 3112. 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Catal.\u003c/em\u003e 2017, \u003cem\u003e359\u003c/em\u003e, 3883. (e) Triandafillidi, I.; Kokotou, M. G., Kokotos, C. G. \u003cem\u003eOrg. Lett.\u003c/em\u003e 2018, \u003cem\u003e20\u003c/em\u003e, 36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJeffrey JL, Terrett JA, MacMillan DWC. Science. 2015;349:1532.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaplaneris N, Bisticha A, Papadopoulos GN, Limnios D, Kokotos CG. Green Chem. 2017;19:4451.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Scheme ","content":"\u003cp\u003eScheme 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"γ-Lactones, Iodine catalyst, DMSO, Metal-free synthesis, Substituted lactones, Organic synthesis, green chemistry","lastPublishedDoi":"10.21203/rs.3.rs-7365888/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7365888/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA novel and efficient methodology has been established for the synthesis of substituted γ-lactone scaffolds using a metal-free iodine/DMSO system. This approach offers a straightforward, practical, and environmentally benign alternative to conventional methods, delivering γ-lactones in good to excellent yields. The reaction employs molecular iodine as a catalyst and dimethyl sulfoxide (DMSO) as the solvent\u0026mdash;both of which are inexpensive, commercially available, and non-toxic. Notably, this method eliminates the need for transition metals or complex catalytic systems, making it a cost-effective and sustainable route for lactone synthesis. In the broader context of green and sustainable chemistry, the development of methodologies that minimize environmental impact while maximizing efficiency remains a key objective. This protocol addresses those goals by utilizing simple, readily available starting materials and operating under mild reaction conditions, ensuring tolerance for various functional groups. The iodine/DMSO system reduces chemical waste and avoids hazardous reagents, aligning with the principles of atom economy and environmental safety. The use of iodine, a non-toxic halogen, further enhances the method\u0026rsquo;s appeal from a sustainability standpoint. Moreover, the operational simplicity and scalability of this process make it suitable for applications in both research and industrial settings. Given the importance of γ-lactone structures in pharmaceuticals, natural products, and fine chemicals, this methodology represents a valuable tool for synthetic chemists. Overall, the iodine/DMSO protocol offers a reliable, metal-free, and eco-friendly alternative for constructing γ-lactones, with strong potential for broader application and further development in modern organic synthesis.\u003c/p\u003e","manuscriptTitle":"Sustainable Transition Metal Free Synthesis of Substituted γ-Lactones","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-24 12:26:12","doi":"10.21203/rs.3.rs-7365888/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"89b3bb68-f0db-434c-9619-03e561c8147a","owner":[],"postedDate":"September 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-30T15:23:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-24 12:26:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7365888","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7365888","identity":"rs-7365888","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}