Letter pubs.acs.org/OrgLett
Phosphine-Catalyzed Domino β/γ-Additions of Benzofuranones with Allenoates: A Method for Unsymmetrical 3,3-Disubstituted Benzofuranones Zhusheng Huang, Xiuqin Yang, Fulai Yang, Tao Lu, and Qingfa Zhou* State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China S Supporting Information *
ABSTRACT: A phosphine-catalyzed domino process of benzofuranones with allenoates has been developed which furnishes highly functionalized unsymmetrical 3,3-disubstituted benzofuranones in synthetically useful yields. The mechanism for the transformation is a tandem β-umpolung/γ-umpolung process. operational ease, and low cost.7 In this context, nucleophilic phosphine-catalyzed γ-addition reactions have been extensively investigated and were independently reported by the groups of Trost and Lu in the 1990s.8 Then Kwon and co-workers and Shi and co-workers simultaneously reported the phosphinecatalyzed β-umpolung additions of ethyl 2-alkyl-2,3-butadienoate.9 Very recently, the Huang group and the Lu group independently reported β-umpolung additions of hydrazones or arylcyanoacetates to allenoates, which are very scarce examples of phosphine-promoted β-umpolung additions.10 However, to the best of our knowledge, the phosphine-mediated domino βand γ-addition reaction of allenoates has not been reported until now. Herein, we describe the first phosphine-catalyzed domino β- and γ-addition reaction of benzofuranones to allenoates for the construction of highly functionalized unsymmetrical 3,3-disubstituted benzofuranones. At the outset of our study, we first chose 1a and 2a as the standard substrates to search for suitable reaction conditions for the synthesis 3a, and the results are shown in Table 1. The reaction of 1a with 2a in the presence of PPh3 (5 mol %) in CH2Cl2 at room temperature for 48 h afforded 3a as a white solid in 65% yield (entry 1, Table 1), and the structure and stereochemistry of compound 3 were characterized by a combination of NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction.11 Increasing the PPh3 loading to 20 mol % gave a better result (entry 3). However, the yield decreased obviously when more catalyst loading was used, such as 50 or 100 mol % (entries 4 and 5). Subsequently, PPh2 Et with relatively stronger nucleophilicity was tested in the reaction, and it afforded the product 3a in lower yield, but no product was obtained when the stonger nucleophilic PPhEt2 or PBu3 was used as catalyst in place of PPh3. Other nucleophilic bases, such as DBU, Et3N, and DABCO, were also tested, and no product was formed.
3,3-Disubstituted benzofuranone is an important structural motif found in many natural products, pharmaceuticals, and biologically active compounds (Figure 1).1 It is also an
Figure 1. Natural products containing benzofuranone rings.
important synthon that can undergo synthetically useful transformations to other valuable heterocycles, such as aplysin, isoaplysin, sesquiterpene, and isolaurinterol.2 Owing to its great importance, there are a lot of methods developed for the synthesis of diverse 3,3-disubstituted benzofuranones. These methods mainly involved the condensation of 2-(2hydroxyphenyl)acetic acid derivatives;3 the cascade reaction of α-hydroxy acid esters and phenols;4 transition-metalcatalyzed inter- or intramolecular heteroannulation of prefunctionalized substrates;5 and modification of the preconstructed heterocyclic rings.6 Despite significant advances in the synthesis of 3,3-disubstituted benzofuranones, synthesis of unsymmetrical 3,3-disubstituted benzofuranone motifs from readily accessible benzofuranones still remains a daunting challenge. Notably, most of the above-mentioned methods require tedious prefunctionalization steps or have limited substrate scope, which severely restricts application in organic and pharmaceutical synthesis. Therefore, developing a method to build functionalized unsymmetrical 3,3-disubstituted benzofuranones in one step from readily available starting materials with broad substrate scope would be highly appealing. Recently, nucleophilic phosphine catalysis has become a powerful tool in organic synthesis because of its high versatility, © 2017 American Chemical Society
Received: May 17, 2017 Published: June 9, 2017 3524
DOI: 10.1021/acs.orglett.7b01482 Org. Lett. 2017, 19, 3524−3527
Letter
Organic Letters Table 1. Survey on Conditions for Formation of 3aa
Scheme 1. Synthesis of Unsymmetrical 3,3-Disubstitued Benzofuranonesa−c
entry
base
equiv
solvent
time (h)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18c 19d 20e 21f
PPh3 PPh3 PPh3 PPh3 PPh3 PPh2Et PPhEt2 PBu3 DBU Et3N DABCO PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3
0.05 0.10 0.20 0.50 1.00 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20
DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DMF toluene MeCN DMSO THF Et2O toluene toluene toluene toluene
48 24 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12
65 72 95 79 74 40 NR NR trace trace trace trace 97 13 trace 61 14 71 51 43 88
a
Typical conditions: base reagent was added to a stirred solution of 1a (0.2 mmol) and 2a (0.44 mmol) in solvent (2.0 mL) under Ar atmosphere and at room temperature. bIsolated yield based on 1a. c The reaction was performed at 0 °C. dThe reaction was performed at reflux. eUsing 0.2 mmol of 2a. fUsing 0.4 mmol of 2a.
a
Typical conditions: PPh3 (0.04 mol, 10.5 mg) was added to a stirred solution of 1 (0.2 mmol) and 2 (0.44 mmol) in solvent (2.0 mL) under Ar atmosphere and at room temperature. bIsolated yield based on 1. cBased on the 1H NMR assay of the crude product.
Solvents were subsequently screened. Toluene was proved to be the best solvent for the reaction. The temperature has a great effect on the reaction. For example, both lowering the reaction temperature to 0 °C and raising the temperature to reflux led to a lower yield in toluene. Thus, we established the optimal reaction conditions: 20 mol % of PPh3 as the catalyst in toluene as the solvent at room temperature for the synthesis of compound 3. Following the above optimized conditions, a range of allenoates were first investigated to couple with benzofuranone 1a, and the results are outlined in Scheme 1. The allenoates bearing various straight-chain alkyl units, namely ethyl, methyl, normal-propyl and normal-butyl, gave the products in good yields. The variation of ester group to phenethyl and benzyl was well tolerated in the reactions and gave the corresponding products in good yields. The nature of the substituent on the benzene ring of the benzyl allenoate had slight impact on the yields. For example, 4-methylbenzyl buta2,3-dienoate and 4-chlorobenzyl buta-2,3-dienoate gave the products 3h and 3i in yields of 75% and 72%, respectively, and they both afforded carbon−carbon double-bond migration isomers 3h′ and 3i′. However, only a trace product was formed when a bulk ester group in 1, such as tert-butyl, was introduced. Examining substituted benzofuranones, we found that all tested substituted benzofuranones were found to be applicable to this reaction to give products 3 in good to excellent yields under the optimized reaction conditions. The nature of the substituent on
benzofuranones had no obvious effect on the yields. For example, for substrates with a I or NO2 group attached on the benzene ring, the corresponding products were obtained in yields of 79% and 81%, respectively. A carbon−carbon doublebond migration isomer was also observed when 5-iodobenzofuran-2(3H)-one was used as reactant. It is highlighted here that a free OH group attached on the benzene ring also gave the corresponding product 3j in a yield of 94% under our reaction conditions. In addition, 5,7-dibromo- or 5,7-diiodosubstituted benzofuranones also participated in the reaction and gave the corresponding 3n and 3o in yields of 69% and 76%, respectively. We also tested the feasibility of this reaction using benzofuran-3(2H)-one. Treatment of benzofuran-3(2H)-one 4 with 2a under the present reaction conditions furnished double γ-addition product 5 in 58% yield (Scheme 2). The products of the domino process possess an all-carbon quaternary center at the 3-position with a latent allyl group and a vinyl group; these structures are not only interesting from a biological point of view but also synthetically valuable. To Scheme 2. Reaction of Benzofuran-3(2H)-one 4 with 2a
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DOI: 10.1021/acs.orglett.7b01482 Org. Lett. 2017, 19, 3524−3527
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Organic Letters
BINAP was used in place of PPh3. The β-addition product 12 was treated with allenoate 2a, and the product 3a was formed effectively. In addition, we found that the structure of lactones is vital for the present process. For example, no reaction was found when ethyl 2-phenylacetate 13 or ethyl 2-(4nitrophenyl)acetate 14 was used in place of benzofuran2(3H)-one compound 3a, while the O-β-addition product 16 was the sole product when the ethyl 2-(2-hydroxyphenyl)acetate 15 was used as the reaction partner. On the basis of our results and the previous studies, we proposed a reasonable mechanism for these domino processes (Scheme 5). In the presence of tertiary phosphine, the β-
demonstrate the synthetic potential of this catalytic system, the gram-scale preparation of highly functionalized 3a was investigated. The reaction of 10 mmol (1.34 g) of the starting material (1a) proceeded smoothly, delivering the corresponding product 3a (3.76 g) in a yield of 78% (Scheme 3), showing Scheme 3. Gram-Scale and Synthetic Transformations
Scheme 5. Proposed Mechanism for the Formation of 3
the reaction to be a practical tool for the synthesis of highly functionalized unsymmetrical 3,3-disubstituted benzofuranones. Treatment of product 3a with Et3N led to smooth carbon− carbon double migrations and furnished a 3,3-vinyl-disubstituted benzofuranone 6. However, 3c was treated with Pd/C under an atmosphere of H2 in MeOH at room temperature, leading to a vinyl- and alkyl-substituted benzofuranone 7 in 95% yield. Interestingly, benzofuranone derivatives 8a and 8b were obtained by treatment of 3a or 3c in toluene under reflux, which could be formed by a Cope rearrangement. To our surprise, a novel compound 9 was formed when 3a was disposed with NaBH4 in MeOH. To understand these domino processes, 3-phenylbenzofuran2(3H)-one 10 was synthesized and treated with allenoate 1a under the above conditions (Scheme 4). The γ-addition product 11 was formed, and no β-addition product was found. This implied that the β-addition process may proceed first, followed by the γ-addition process. Catching the βaddition product is the key to understand the present process. We found that only the β-addition product 12 was given when
phosphonium dienolate intermediate, formed though conjugate addition of the phosphine to the allenoate, proceeds subsequent transformation to give β-addition product first.10a The β-addition product then reacts with another βphosphonium dienolate intermediate and proceeds through a subsequent transformation to lead to the formation of γaddition product 3.8a In conclusion, the first phosphine-catalyzed β/γ domino process of allenoates with benzofuranones has been developed, which shows an extra example on current phosphine chemistry and a useful method for constructing functionalized unsymmetrical 3,3-disubstituted benzofuranones. The potential utility of this domino process indicates that the synthesized unsymmetrical 3,3-disubstituted benzofuranones could be transformed into other interesting heterocycles and performed on a gram scale.
Scheme 4. Control Experiments
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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.7b01482. Detailed experimental procedures, characterization data, and 1H and 13C NMR spectra of key substrates and final products (PDF) X-ray data of 3a (CIF) 3526
DOI: 10.1021/acs.orglett.7b01482 Org. Lett. 2017, 19, 3524−3527
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Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grant Nos. 21102179 and 21572271), Qing Lan Project of Jiangsu Province.
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DOI: 10.1021/acs.orglett.7b01482 Org. Lett. 2017, 19, 3524−3527
