Access to Alkyl-Substituted Lactone via Photoredox-Catalyzed

Letter Cite This: Org. Lett. 2017, 19, 5900-5903

pubs.acs.org/OrgLett

Access to Alkyl-Substituted Lactone via Photoredox-Catalyzed Alkylation/Lactonization of Unsaturated Carboxylic Acids Wanxing Sha, Shengyang Ni, Jianlin Han,* and Yi Pan* School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Nanjing University, Nanjing 210093, China S Supporting Information *

ABSTRACT: An efficient photoredox-catalyzed alkylation/lactonization reaction of unsaturated carboxylic acids by using alkyl N-hydroxyphthalimide esters as alkylation reagents has been developed. Varieties of redox-active esters derived from aliphatic carboxylic acids were proved viable in this method, affording alkyl substituted lactones in moderate to good yields. This redoxneutral procedure features mild conditions and operational simplicity, which provides a new strategy for the synthesis of alkyl substituted lactones. synthesis of γ-lactones (Scheme 1a).15 In 2014, Koike, Akita and co-workers used alkenoic acids and Umemoto’s reagent as

I

n the past decade, visible light-induced photoredox catalysis has gained a great achievement due to mild reaction conditions and low-energy irradiation.1 Meanwhile, the application of this strategy to radical decarboxylation reactions has resulted in a significant advancement of this field.2 Generally, radical decarboxylation of carboxylic acids has several advantages for organic synthesis, such as abundance in nature, inexpensive materials, CO2 as the traceless, nontoxic byproduct and easy conversion to activated alkyl radical through elimination of CO2. Recently, the alkyl N-hydroxyphthalimide esters (NHP esters) derived from alkyl carboxylic acids and N-hydroxyphthalimide (NHPI) were demonstrated to be very efficient alkyl sources in alkylation cross-coupling reactions. For example, the Baran group3 and Weix group4 have successfully developed a series of Ni-catalyzed alkyl-aryl, alkyl−alkyl, alkyl-boryl and alkyl-alkenyl cross-coupling reactions using alkyl NHP esters as alkyl reagents. On the other hand, Chen,5 Overman,6 Fu7 and other8 groups have also independently applied the alkyl NHP esters in photoredox catalyzed coupling reactions. Lactones are abundant in natural products, pharmaceuticals, and other bioactive compounds.9 Several strategies have been developed for the construction of lactone derivatives.10 Among them, using unsaturated carboxylic acids to assemble modified lactones has been extensively explored, as an additional functional group could be introduced along with the formation of lactones in one reaction. However, those reports mainly focused on halolactonization,11 and trifluoromethyllactonization12 of unsaturated carboxylic acids.13 Apart from that, the synthesis of alkyl γ-lactones has received less attention in the past years.14 In particular, there are still few examples of lactonization by photoredox catalysis. In 2013, Wu, Liu and co-workers reported a visible-light photoredox catalyzed lactonization reaction of styrenes with α-bromo esters for the © 2017 American Chemical Society

Scheme 1. Photoredox-Catalyzed Lactonization

starting materials for the synthesis of CF3-substituted lactones via photoredox catalysis (Scheme 1b).16a The Xiao group also reported a photoredox catalyzed arylation−lactonization reaction of alkenoic acids by using diazonium salts as aryl sources (Scheme 1b).16b To the best of our knowledge, there is still no report on alkylation-initiated lactonization of unsaturated Received: September 16, 2017 Published: October 17, 2017 5900

DOI: 10.1021/acs.orglett.7b02899 Org. Lett. 2017, 19, 5900−5903

Letter

Organic Letters

With the optimized conditions in hand, we then explored the reactivity of various unsaturated carboxylic acids with cyclopentyl NHP ester 2a as the reaction partner, and the results are summarized in Scheme 2. As shown in Scheme 2, both

carboxylic acids by photoredox catalysis. Thus, we herein report the first example of an efficient, visible-light, photoredox catalyzed, alkylation-initiated lactonization of unsaturated carboxylic acids by using alkyl NHP esters as an alkyl agent (Scheme 1c). This photoredox-catalyzed reaction could be carried out at room temperature, affording alkyl γ-lactones with good chemical yields. Furthermore, this process represents a new strategy for the synthesis of alkyl γ-lactones. At the outset, we selected 4-(4-fluorophenyl)pent-4-enoic acid 1a and alkyl NHP ester 2a as model substrates for the optimization of reaction conditions (Table 1). The reaction

Scheme 2. Scope of Unsaturated Carboxylic Acidsa,b

Table 1. Optimization of Reaction Conditionsa

entry

photocatalyst (mol %)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Ir(ppy)2(dtbbpy)PF6 (2) Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2) fac-Ir(ppy)3 (2) rhodamine B (2) fluorescein (2) eosin Y (2) rose bengal (2) Ir(ppy)2(dtbbpy)PF6 (1) Ir(ppy)2(dtbbpy)PF6 (1) Ir(ppy)2(dtbbpy)PF6 (1) Ir(ppy)2(dtbbpy)PF6 (1) Ir(ppy)2(dtbbpy)PF6 (2) Ir(ppy)2(dtbbpy)PF6 (3) Ir(ppy)2(dtbbpy)PF6(2) Ir(ppy)2(dtbbpy)PF6 (2) Ir(ppy)2(dtbbpy)PF6 (2)

additive (equiv)

H2O H2O H2O H2O H2O H2O H2O H2O H2O

(50) (50) (50) (50) (50) (100) (100) (100) (100)

time (h)

yieldb (%)

12 12 12 12 12 12 12 12 12 12 24 24 24 24 24 24 24

21 trace trace nr nr nr nr 19c 43c 56c,d 67c,d 73c,d 71c,d 77c,d 44d c,d c−e

a

Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Ir(ppy)2(dtbbpy)PF6 (0.004 mmol, 2 mol %), TsOH·H2O (0.04 mmol, 0.2 equiv), H2O (20 mmol, 100 equiv), CH3CN (2 mL), at room temperature, 5 W blue LEDs, 24 h, under argon atmosphere. bIsolated yield.

electron-donating (methyl) and electron-withdrawing groups (halo) on the benzene moieties almost had no obvious effect on the reaction outcome (3aa−fa). Then, 5-phenylhex-5-enoic acid (1g) was used in the reaction to construct a six-membered lactone cycle. We found that such an unsaturated carboxylic acid was compatible with the current catalytic system to give the corresponding lactone in moderate yield (47%, 3ga). As the isobenzofuran-1-ones motif is popular in organic and bioorganic chemistry, which attracts us to try the ortho-vinyl benzoic acids in the current system. Fortunately, the reactions with these substrates proceeded smoothly to give the product in moderate to excellent yields regardless of the electronegativity of substituted groups on the alkenoic acids (3ha−la). Furthermore, several alkyl NHP esters were tested as substrates for this reaction, and the results are shown in Scheme 3. Initially, primary alkyl NHP esters bearing methyl, ethyl, and propyl could work very well in this reaction, resulting in the corresponding products 3cb−cd with moderate to good yields (58−73%). Next, we tried to use aryl ethyl and aryl propyl NHP esters for this catalytic system, and good results were obtained (3ce−cg). Besides primary alkyl NHP esters, the secondary alkyl NHP esters were also effective substrates for this reaction (3ch−cl). Especially, the substrates bearing cyclobutyl 2i and cyclohexyl 2j−k could be well tolerated, and the corresponding product 3ci−ck could be found in 66−81% yields. Unsymmetric substrate 2l was used as a substrate for the investigation of stereoselectivity of this reaction. The result discloses that the reaction showed almost no stereoselectivity; and the two diastereomers of 3cl were obtained in a 1:1 ratio. The tertiary alkyl NHP ester also worked in this reaction, and a good yield was obtained (75%, 3 cm). Usually the

a

Reaction conditions: 1a (0.1 mmol), 2a (1.0 equiv), photocatalyst (2 mol %), CH3CN (2 mL), at room temperature, 5 W blue LEDs under argon atmosphere. bIsolated yields. cTsOH·H2O (0.2 equiv). d 2a (2.0 equiv). eIn the dark.

proceeded to afford the expected product 3aa with 21% yield in the presence of a catalytic amount of Ir(ppy)2(dtbbpy)PF6 under an argon atmosphere (entry 1). This reaction did not take place with other photocatalysts, such as Ir[dF(CF3)ppy]2(dtbbpy)PF6, fac-Ir(ppy)3, and others (entries 2−7). According to our recent work on lactonization, we supposed that addition of TsOH·H2O can improve the yield.17 However, no satisfactory result was obtained after only addition of TsOH· H2O (entry 8). Glorius and co-workers found that H2O plays a key role in their phtoredox-catalyzed oxyalkylation of styrenes with alkyl NHP esters.8e Considering these reaction conditions, we tried to add TsOH·H2O and H2O into our current reaction simultaneously. The corresponding product was obtained with improved yield (43%, entry 9). Increasing the amount of 2a to 2.0 equiv and prolonging the reaction time also increased the chemical yields (entries 10 and 11). Further reaction condition optimization found that the use of 2 mol % of photocatalyst was the best choice, and a 73% yield was achieved (entries 12 and 13). Adding 100 equiv of H2O can further increase the reaction yield to 77% (entry 14). Finally, control experiments demonstrated that the TsOH·H2O, photocatalyst and visible light were all essential for this reaction (entries 15−17). 5901

DOI: 10.1021/acs.orglett.7b02899 Org. Lett. 2017, 19, 5900−5903

Letter

Organic Letters Scheme 3. Scope of Alkyl NHP Estersa,b

Scheme 4. Mechanistic Investigation

Scheme 5. Proposed Mechanism

a

Reaction conditions: 1c (0.2 mmol), 2 (0.4 mmol), Ir(ppy)2(dtbbpy)PF6 (0.004 mmol, 2 mol %), TsOH·H2O (0.04 mmol, 0.2 equiv), H2O (20 mmol, 100 equiv), CH3CN (2 mL), at room temperature, 5 W blue LEDs, 24 h, under argon atmosphere. bIsolated yield.

stability of alkyl radical should be primary < secondary < tertiary. However, the alkyl-substituted N-acyloxyphthalimides are the active alkyl radical precursors and can generate alkyl radical easily. Thus, the reaction of primary, secondary, tertiary alkyl-substituted N-acyloxyphthalimides gave the similar yields.5b Even the methyl radical could be generated, and the corresponding product was obtained in 56% yield (3cb). Similar yields of 3cc, 3cj and 3 cm, were found, which is mainly due to the high reactivity of N-acyloxyphthalimides. The yield of 3cc looks a litter bit higher. To confirm this result, we carried out the reaction again, and a similar yield (70%) was obtained. The chemical structure of these lactone products 3 has been confirmed by X-ray single-crystal analysis of 3ck (see the Supporting Information). To validate a probable mechanism of this reaction, a radical scavenger TEMPO (2,2,6,6,-tetramethyl-1-piperidinyloxy) was added into the catalytic system. Although no TEMPO-trapped compounds were detected, the formation of 3aa was suppressed, which indicates that a single-electron-transfer radical process may be involved (Scheme 4a). To confirm the formation of alkyl radical, another radical scavenger, 1,1-diphenylalkene, was added to the reaction. Almost no desired product 3aa was found, while the product 4a was isolated with 43% yield (Scheme 4b). Next, we replaced H2O with H218O to investigate the source of oxygen atom in the ester group. The result showed that both of 3aa and 3aa′ were found in the reaction mixture with the ratio of 1.8:1 determined by HRMS (Scheme 4c). According to the above experimental results and previous studies,5−8,11 a possible mechanism is shown in Scheme 5. Initially, the photoredox catalyst Ir(ppy)2(dtbbpy)PF6 is irradiated to the activated state A, from which 2a could

abstract an electron to form the radical alkyl intermediate C. Subsequently, the alkyl radical C adds to the alkenyl of 1a to generate the intermediate D. Then, Ir intermediate B abstracts one electron from intermediate D to generate intermediate E and regenerate the Ir(ppy)2(dtbbpy)PF6 catalyst for the next cycle. Next, the reaction chooses path a to generate intermediate F, which is catalyzed by acid to generate product 3aa with loss of H2O on the base of above experimental results. On the other hand, the process maybe also proceed via path b to generate the product 3aa. In summary, we have developed a novel photoredoxcatalyzed reaction for the synthesis of alkyl-substituted lactones through alkylation−lactonization of alkenoic acids. The use of TsOH·H2O and H2O plays a vital role in this reaction. This reaction was conducted at room temperature and was compatible with various alkenoic acids and multiple alkyl NHP esters including primary, secondary, and tertiary alkylsubstituted esters. This reaction represents the first example of alkylation initiated lactonization of unsaturated carboxylic acids, which provides a new path to alkyl-substituted lactones.

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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.7b02899. 5902

DOI: 10.1021/acs.orglett.7b02899 Org. Lett. 2017, 19, 5900−5903

Letter

Organic Letters

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Experimental procedures, full spectroscopic data for compounds 3 and 4, X-ray analysis of 3ck, and 1H and 13 C NMR spectra (PDF) X-ray data for 3ck (CIF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jianlin Han: 0000-0002-3817-0764 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21472082). The support from Collaborative Innovation Center of Solid-State Lighting and Energy-Saving Electronics, the Jiangsu 333 program (Y.P.) and Changzhou Jin-Feng-Huang program (J.H.) are also acknowledged.

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DOI: 10.1021/acs.orglett.7b02899 Org. Lett. 2017, 19, 5900−5903