Letter Cite This: Org. Lett. 2018, 20, 36−39
pubs.acs.org/OrgLett
Photocatalytic Synthesis of γ‑Lactones from Alkenes: HighResolution Mass Spectrometry as a Tool To Study Photoredox Reactions Ierasia Triandafillidi, Maroula G. Kokotou, and Christoforos G. Kokotos* Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece S Supporting Information *
ABSTRACT: A mild photocatalytic manifold for the synthesis of γ-lactones has been developed. Utilizing Ru(bpy)3Cl2 as the photocatalyst, a cheap and reproducible synthetic protocol for γ-lactones has been introduced. Mechanistic studies revealed the successful monitoring of photocatalytic reactions and radical intermediates via high-resolution mass spectrometry.
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lactones,14 while Zhu employed bromodifluoroamides of acetic acid to access lactams.15 γ-Lactones are very important moieties in natural products, products of biological importance, perfumes, and food additives.16 Thus, many synthetic approaches for the synthesis of lactones have been devised, utilizing as starting materials carboxylic acids,17 alkynes,18 alcohols,19 and so on. However, olefins are among the most popular synthetic blocks. Our laboratory has developed photocatalytic protocols for the synthesis of useful organic compounds.20 In this study, we report an intermolecular synthesis of γ-lactones via photoredox catalysis, taking advantage of the ATRA reaction (Scheme 1, bottom). We began our investigation for the synthesis of γ-lactone 2a. A number of photocatalysts were tested with Ru(bpy)3Cl2 affording the highest yield (Table 1, entries 1−3).21 If the catalyst or visible light was omitted, no reaction took place (Table 1, entries 4 and 5). When the reaction took place under blue or green LED irradiation, the yield decreased slightly (Table 1, entries 6 and 7). Furthermore, a quick screening of solvents did not afford lactone 2a in better yield (Table 1, entries 8−11). Having in hand the optimum reaction conditions, the substrate scope of the reaction was sought (Schemes 2 and 3). The substitution pattern on the aliphatic group was studied. First, terminal alkenes with a linear or cyclic aliphatic chain (1a−e) were tested, affording lactones 2a−e in excellent yields. Substitution on the alkene (1f−i) did not affect the efficiency of the synthetic method, and γ-lactones 2f−i were isolated in high yields. Substrates carrying functional groups, such as ether, substituted amine, ester, or amide (1j−n), were well tolerated. Thus, the substitution pattern does not affect the outcome of the reaction. In an effort to expand the limits of the synthetic method, 1,2- and 1,1-disubstituted alkenes were employed.
he atom-transfer radical addition (ATRA) to olefins by haloalkanes constitutes a powerful and highly atomeconomical method for the one-step synthesis of C−C and C− X bonds. During the last 80 years, pioneering contributions by Kharasch,1 Curran,2 Oshima,3 Renaud,4 and others5 have forged the area, making ATRA reactions a common practice. In a standard ATRA reaction, toxic, hazardous, or stoichiometric reagents, such as organotin,2 peroxide,1 and triethylborane,3 are usually employed. Among other less common initiators, photoredox catalysis6 has provided elegant solutions to ATRA reactions, employing photocatalysts based on iridium,7 ruthenium,7 or copper (Scheme 1, A).8 Recently, Scheme 1. ATRA Approaches for the Synthesis of γ-Lactones
Melchiorre and Cozzi utilized photo-organocatalysis to address this reaction.9 The corresponding ATRA with derivatives of iodoacetic acid has been less studied (Scheme 1, B). Esters of iodoacetic acid have been employed utilizing stoichiometric amounts of initiators,10 triethylborane,11 Ti,12 or Cu,13 leading to either the ATRA product or the cyclized lactone. Using iodoacetic acid and stoichiometric AIBN, Oshima synthesized © 2017 American Chemical Society
Received: October 18, 2017 Published: December 7, 2017 36
DOI: 10.1021/acs.orglett.7b03256 Org. Lett. 2018, 20, 36−39
Letter
Organic Letters
Cyclic olefins afforded lactones 2o and 2p in good yield, forming a bicyclic compound. Diethyl malonate analogue 1q gave the desired lactone 2q in good yield. On the other hand, norbornene could not lead to the desired cyclized product due to high ring strain. The iodo compound 2r was isolated in high yield instead. When 1,1-disubstituted alkenes (1s, 1t) were tested, a mixture (1:1) of lactone and alkenoic acid, as the product of competitive elimination reaction, was isolated. Since the nature of C−X is very crucial for photocatalysis, other compounds substituted with halogen acetic acid derivatives were tested (Scheme 3). Ethyl iodoacetate led also to lactone 2a, albeit in lower yield. It seems that the basic reaction conditions, due to sodium ascorbate, slowly hydrolyzed the ester, affording the desired lactone. When the iodo group was replaced by bromoacetic acid, the yield of lactone 2a decreased. This can be attributed to the difference in strength of the corresponding C−X bond (BDEs). Finally, 2bromopropionic acid was employed, and disubstituted lactone 2u was isolated in moderate yield. The nature of the C−X bonds plays some role both for the photocatalytic step and the cyclization, as a leaving group, hinting at iodo incorporation before cyclization. Since photoredox catalysis has brought forth a revolution in the field of photochemistry for organic synthesis, tools to probe their mechanisms are required. Thus, mechanistic studies to probe the mechanism of the photocatalytic reaction were conducted. Initially, the quantum yield (Φ) of the reaction was calculated.22 On the basis of the literature,20−22 the measurement of the quantum yield, under air (reaction conditions) or Ar, led to Φ < 1, which hints that a closed catalytic cycle is followed. Along the same lines, photoredox reactions are usually probed by utilizing fluorescence quenching studies. Increasing the amount of added decene did not lead to any significant fluorescence quenching. On the other hand, increasing the amount of added iodoacetic acid or sodium ascorbate led to a distinct decrease of the fluorescence of the catalyst.21 Although the measurement of the quantum yield and the fluorescence-quenching studies are useful for parts of the mechanism, it is necessary to monitor intermediates throughout the reaction. For example, in the ATRA reaction that was developed above, one could argue that iodine is first incorporated in the alkene scaffold (proper ATRA product) and then the intramolecular SN2 reaction (carboxylate to iodide) occurs to afford the lactone. An alternative mechanism that one could propose would be the carboxylate to ring close to the lactone product on the carbocation formed, without requiring the incorporation of the iodine. In order to address this issue and distinguish between the two pathways, one has to continuously monitor the photoredox reaction. Thus, highresolution mass spectrometry (HRMS) and 19F NMR studies were carried out that led us to identify more intermediates of the reaction mechanism. 19F NMR studies were first employed to identify the intermediate of the reaction.21 Starting from alkene 1j (DMSO-d6 was used as the solvent), the reaction was studied periodically, identifying that except from the starting material and the product, another peak was observed. This peak can be attributed to the intermediate iodo acid (the product of the ATRA reaction). We then turned our attention to monitoring the reaction with HRMS.23,24 In accordance with the 19F NMR studies,21 the presence of the iodo intermediate was also verified via HRMS (Figure 1, A). Also, the desired cyclized product and the
Table 1. Optimization of the Reaction Conditions for the Synthesis of γ-Lactones from Alkenesa
entry
catalyst (mol %)
solvent
yieldb (%)
1 2 3 4 5c 6d 7e 8 9 10 11
Ir(ppy)3 (1) Ru(bpy)3Cl2 (1) thioxanthone (10) no Ru(bpy)3Cl2 (1) Ru(bpy)3Cl2 (1) Ru(bpy)3Cl2 (1) Ru(bpy)3Cl2 (1) Ru(bpy)3Cl2 (1) Ru(bpy)3Cl2 (1) Ru(bpy)3Cl2 (1)
MeOH/MeCN MeOH/MeCN MeOH/MeCN MeOH/MeCN MeOH/MeCN MeOH/MeCN MeOH/MeCN DMSO MeOH MeCN CHCl3
97 98 78 − − 80 62 72 94 12 18
a
All reactions were carried out with decene (0.50 mmol), catalyst, solvent (6.0 mL), iodoacetic acid (1.00 mmol), and sodium ascorbate (1.00 mmol). bIsolated yield. cReaction in dark. dReaction with blue LED. eReaction with green LED.
Scheme 2. Substrate Scope of the Photocatalytic Synthesis of γ-Lactones from Alkenes
Scheme 3. Additional Scope with Different Halogen Groups
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DOI: 10.1021/acs.orglett.7b03256 Org. Lett. 2018, 20, 36−39
Letter
Organic Letters
Figure 2. HRMS studies. (A) [Ru(bpy)3]2+ at 0 min, theoretical m/z 285.0547. (B) [Ru(bpy)3]1+ after 30 min, theoretical m/z 570.1100.
Scheme 4. Proposed Reaction Mechanism
Figure 1. HRMS studies. (A) Iodo compound after 30 min. (B) Cyclic compound after 30 min. (C) Radical compound after 30 min. (D) Radical compound after 60 min. (E) Iodo compound after 60 min. (F) Cyclic compound after 60 min.
ascorbate), the carboxylic group is deprotonated and attacks the good leaving group, leading to γ-lactone. In conclusion, a cheap photocatalytic protocol for the synthesis of lactones from alkenes was developed. This synthetic protocol utilizes Ru(bpy)32+ as the photocatalyst. This method reports the addition of iodoacetic acid in olefins followed by an in situ cyclization in the reaction conditions to afford the desired lactones in high to excellent yields. HRMS can be employed for probing reaction mechanisms in photoredox reactions.
intermediate radical (product of the ATRA addition of α-oxo radical to alkene) can be observed via HRMS (Figure 1, B and C). Similarly, after 60 min, the same intermediates can be identified (Figure 1, D−F). Thus, photoredox reactions may be studied via HRMS in order to identify proposed radical intermediates. Furthermore, the fate of the ruthenium photocatalyst can be probed to check whether an oxidative or reductive cycle is followed (Figure 2). Initially, [Ru(bpy)3]2+ is present at 0 min (Figure 2, A). After 30 min (random choice of reaction time),21 [Ru(bpy)3]1+ can be identified (Figure 2, B), while no [Ru(bpy)3]3+ is found. Utilizing all these data, the following mechanism can be proposed (Scheme 4). Upon irradiation, Ru(bpy)32+ is excited, and the excited photocatalyst is reduced by ascorbate leading to B,9b,25 which reacts with iodoacetic acid to form electrophilic radical A and regenerate the photocatalyst. Radical A reacts with the alkene leading to radical C, observed via HRMS. Then, propagation with iodoacetic acid leads to iodo compound D. The corresponding carbocation of C is not formed. We think this is possible only when styrene derivatives are employed (benzylic carbocation) and not when aliphatic alkenes are used, as in our case. Under the basic reaction conditions (sodium
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03256. Experimental procedure, full optimization data, characterization data, and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Christoforos G. Kokotos: 0000-0002-4762-7682 38
DOI: 10.1021/acs.orglett.7b03256 Org. Lett. 2018, 20, 36−39
Letter
Organic Letters Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge financial support through the Latsis Foundation programme “EPISTHMONIKES MELETES 2015” (PhotoOrganocatalysis: Development of new environmentally friendly methods for the synthesis of compounds for the pharmaceutical and chemical industry). We also thank Prof. V. Constantinou from the Agricultural University of Athens for access to the fluorescence spectrometer. I.T. thanks the Hellenic Foundation for Research and Innovation (ΕΛΙΔΕΚ), and M.G.K. thanks the National Scholarship Foundation (IKY) for financial support. COST Action C−H Activation in Organic Synthesis (CHAOS) CA15106 is acknowledged for helpful discussions.
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DOI: 10.1021/acs.orglett.7b03256 Org. Lett. 2018, 20, 36−39
