Letter pubs.acs.org/OrgLett
Highly Diastereoselective Crown Ether Catalyzed Arylogous Michael Reaction of 3‑Aryl Phthalides Marina Sicignano, Antonella Dentoni Litta, Rosaria Schettini, Francesco De Riccardis, Giovanni Pierri, Consiglia Tedesco, Irene Izzo, and Giorgio Della Sala* Dipartimento di Chimica e Biologia “A. Zambelli”, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy S Supporting Information *
ABSTRACT: The first arylogous Michael reaction of 3-aryl phthalides has been developed. The reaction, promoted by catalytic amounts of KOH or K3PO4 and dibenzo-18-crown-6, affords the corresponding 3,3-disubstituted phthalides in good to high yields and as single diastereomers in nearly all studied cases.
I
unsaturated ketones, we considered the 3-aryl phthalides (1) as potential candidate donors (Scheme 1). These compounds are easy to prepare and have never been previously utilized in the arylogous Michael additions.11
sobenzofuran-1(3H)-ones, also known as phthalides, are important lactones widely distributed in plants1 and extensively used in medicinal chemistry.2 The bicyclic pharmacophore is a valuable building block for the synthesis of bioactive natural products/pharmaceuticals,3 and the 3-substituted phthalides hold a special place in current studies for their intriguing chemical properties.4 While most of the stereoselective methods to prepare 3-substituted phthalides involve the stereocontrolled construction of the lactone ring,2d,5 the synthesis of 3,3-disubstituted phthalides implies challenging stereocontrolled procedures.6 A much less exploited route envisions a C-3 alkyl group stereoselective insertion to an unsubstituted or a 3-monosubstituted phthalide. The arylogous Michael reaction (AMR) of phthalides with electron-poor alkenes represents an expedient way to insert alkyl groups to the weakly acidic C-3 position. Unfortunately, the strong bases required (LDA or metal alkoxides) yield Michael adducts with no stereoselectivity (as in the case of 3-phenylthio-phthalides).7 Other activating groups at C-3, such as cyano, sulfonyl, phosphonyl, and benzotriazolyl, act as nucleofuges yielding naphthoquinols after cyclization of the adducts.8 The only effective C-3 activating/stereodirecting group in the Michael addition is the alkoxycarbonyl residue, which enables the reaction under mild conditions. Indeed, the amine-catalyzed reaction of phthalide-3-carboxylic acid esters with activated acceptors such as chalcones and nitroalkenes in nonpolar solvents furnished Michael adducts in high diastereoselectivity.9,10 However, with less reactive substrates, such as aliphatic α,β-unsaturated ketones, very polar solvents and high temperatures are needed, and Michael adducts were obtained in a 1:1 diastereomeric ratio.9 With the aim of obtaining high diastereoselectivities in the Michael reaction of weakly activated phthalides with diverse α,β© 2017 American Chemical Society
Scheme 1. Diastereoselective AMR of 3-Aryl Phthalides
Preliminary studies in our laboratory showed that mild amine catalysis does not promote Michael addition. No traces of addition products were detected in the reaction of 3-phenylphthalide 1a with the chalcone 2a in the presence of 1 equiv of triethylamine in toluene after 24 h. During our studies on macrocycle phase-tranfer catalyzed reactions,12 we disclosed that crown ethers are excellent catalysts for the KF-promoted diastereoselective vinylogous Mukaiyama− Michael reaction of γ-butenolides.13 In view of the analogy of phthalides with γ-butenolides, we decided to examine the use of crown ethers in the base-promoted diastereoselective AMR of 3aryl phthalides under mild conditions. To our delight, the reaction of 1a with 2a in the presence of catalytic amounts of KOH and dicyclohexane-18-crown-6 (4a) (10 mol % of both) in toluene at room temperature cleanly yielded the desired adduct 3aa with high diastereoselectivity (95:5 dr; Table 1, entry 1). We Received: July 11, 2017 Published: August 9, 2017 4383
DOI: 10.1021/acs.orglett.7b02113 Org. Lett. 2017, 19, 4383−4386
Letter
Organic Letters next surveyed diverse crown ethers derived from 18-crown-6 and 15-crown-5 (Table 1).
Table 2. Screening of Reaction Conditions in the AMR Catalyzed by 4ca
Table 1. Screening of Crown Ethers in the AMR of 1a with 2aa
entry
catalyst
t (h)
yield (%)b
drc
1 2 3 4 5 6 7 8 9
4a 4b 4c 4d 4e 4f 4g 4h −
5 5 5 6 20 20 20 20 116
99 95 95 97 94 95 90 95 −
95:5 98:2 98:2 97:3 96:4 96:4 95:5 97:3 −
entry
solvent
base
t (h)
yield (%)b
drc
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15d 16e
toluene CH3CN DMF CH2Cl2 DCE Et2O THF MTBE mesitylene o-xylene m-xylene p-xylene mesitylene mesitylene mesitylene mesitylene
KOH KOH KOH KOH KOH KOH KOH KOH KOH KOH KOH KOH PhOK K3PO4 KOH KOH
5 4 68 6 20 20 44 20 20 7 7 7 140 140 20 116
95 74 58 94 90 94 83 89 96 89 88 87 64 91 83 61
98:2 79:21 72:28 95:5 96:4 98:2 94:6 95:5 98:2 97:3 98:2 97:3 >98:2 >98:2 >98:2 >98:2
a Reaction conditions: 1a (0.20 mmol), 2a (0.20 mmol), base (0.020 mmol), 4c (0.020 mmol), solvent (1.0 mL). bIsolated yields. c Determined by 1H NMR analysis of the crude product. dReaction performed at 0 °C. eReaction performed at −20 °C.
improvement of the yield was achieved in mesitylene, which was chosen as the preferred solvent for further studies. A large screening of bases gave frustrating results for the majority of them. No traces of any product were observed in the reaction promoted by weak inorganic bases such as KF, K2CO3, K2HPO4, and KH2PO4. Bases of intermediate strength, such as PhOK and K3PO4, promoted the formation of 3aa as a single diastereomer, albeit with long reaction times (entries 13 and 14, Table 2). However, with PhOK, the yield was only moderate, while a high yield was obtained with K3PO4. Lowering the temperature to 0 °C gave 3aa as a single diastereomer even with KOH, but with the advantage of a shorter reaction time compared to K3PO4 (entry 15, Table 2). At −20 °C the yield decreased (entry 16, Table 2). The (R*,S*) relative configuration of the diastereomer 3aa was determined by X-ray crystal structure (Figure 1).14
a Reaction conditions: 1a (0.20 mmol), 2a (0.20 mmol), KOH (0.020 mmol), catalyst (0.020 mmol), toluene (1.0 mL). bIsolated yields. c Determined by 1H NMR analysis of the crude product.
18-Crown-6 (4b) and dibenzo-18-crown-6 (4c) exhibited higher diastereoselectivity than dicyclohexane-18-crown-6 (cf. entries 2, 3 with entry 1, Table 1). With more hindered derivative 4d, no improvements were observed (entry 4, Table 1). Slightly lower diastereoselectivities and yields were generally observed with 15-crown-5 derivatives 4e−h (entries 5−8, Table 1). The role of the crown ether catalysts was confirmed by an experiment performed in the absence of the macrocycle, which failed to furnish any product (entry 9, Table 1). Although crown ethers 4b and 4c displayed comparable performances in toluene, we chose the latter as an ideal catalyst for further investigations, ensuring generally better results in other solvents. Thus, we next studied the effect of solvent, temperature, and base in the AMR of 1a and 2a catalyzed by 4c (Table 2). In polar solvents such as CH3CN and DMF, the yields and the diastereoselectivities were disappointing (entries 2, 3, Table 2). In halogenated and ethereal solvents, good yields were achieved, but the diastereoselectivities were slightly lower compared to toluene (entries 4−8, Table 2), except for diethyl ether, with a 98:2 diastereomeric ratio (entry 6). Aromatic solvents performed generally better, with yields and diastereoselectivity very close to those obtained in toluene (entries 9−12, Table 2). A slight
Figure 1. Single-crystal X-ray structure of 3aa. 4384
DOI: 10.1021/acs.orglett.7b02113 Org. Lett. 2017, 19, 4383−4386
Letter
Organic Letters Scheme 2. Scope of the AMR of 3-Aryl Phthalides Catalyzed by 4ca,b,c
a
Reaction conditions: 1a (0.20 mmol), 2a (0.20 mmol), base (0.020 mmol), 4c (0.020 mmol), mesitylene (1.0 mL). bIsolated yields. Diastereomeric ratios determined by 1H NMR analysis of the crude product. dAt the 1.00 mmol scale, 3aa was obtained with 90% yield and >98:2 dr after 20 h. eAt the 1.00 mmol scale, 3aa was obtained with 92% yield and >98:2 dr after 44 h. c
with shorter times even at 0 °C. As an exception, a smooth reaction of 1a with 2g was achieved at 0 °C even with K3PO4. On the other hand, the use of K3PO4 provided slightly better yields and a higher diastereomeric ratio for the product 3ag. The AMR reaction was successfully applied to different 3-aryl phthalides 1b−f, affording in all cases adducts 3bd−3fd as single diastereomers. As expected, the presence of electronreleasing groups on the aromatic ring resulted in lower reactivity at the C-3 position and longer reaction times. However, the p-methoxysubstituted product 3bd was obtained in excellent yield with K3PO4 at room temperature, although with a longer reaction time compared to KOH at 0 °C. The reaction of p-tolylphthalide 3c with 2d was performed with KOH at room temperature, in order to achieve a good yield. KOH at 0 °C afforded good yields of 3dd and 3ed. The presence of an ortho-methyl substituent on the aromatic ring was well tolerated in the reaction promoted by KOH at 0 °C (product 3fd). In the same case, K3PO4 was ineffective. For the Michael reaction studied in the present contribution we assumed a phase-transfer catalytic process involving the formation of a ion pair between the K+/crown complex and the arylogous enolate generated after deprotonation of phthalides. Further evidence was provided by tetrabutylammonium bromide (TBAB) as a different phasetransfer catalyst in the presence of KOH. Albeit less efficient than crown ethers (in the AMR of 1a with 2a, 3aa was obtained with a 70% yield and 92:8 dr after 68 h at room temperature), TBAB exhibited a certain degree of catalytic activity.16
Having established KOH (at 0 °C) and K3PO4 (at rt) as the most effective bases in the AMR of 1a and 2a in mesitylene, we evaluated the scope of the reaction under both conditions (Scheme 2). 1a reacted satisfactorily with both aliphatic and aromatic α,β-unsaturated ketones and with other unsaturated Michael acceptors (such as 3-crotonyl-2-oxazolidinone, 2f, and diethyl benzylidenemalonate, 2g), yielding adducts 3aa−ag as single diastereomers in nearly all cases. Traces of a minor diastereomers were only detected in the reaction with 2e and 2g (products 3ae and 3ag). The assumed (R*,S*) configuration was confirmed by crystallization of the major diastereomer 3ag that was subjected to X-ray analysis (Figure 2).15 Generally K3PO4-promoted reactions turned out to be slower and were performed at rt. Those induced by KOH proceeded
Figure 2. Single-crystal X-ray structure of 3ag. 4385
DOI: 10.1021/acs.orglett.7b02113 Org. Lett. 2017, 19, 4383−4386
Letter
Organic Letters In summary, we have developed the first example of an arylogous Michael reaction of 3-aryl phthalides. While amine organocatalysts turned out to be unable to promote the process, crown ethers proved to be efficient catalysts. The reaction of diverse 3-aryl phthalides and electrophilic alkenes under mild conditions afforded 3,3-disubstituted phthalides as single diastereomers in nearly all cases. The application of chiral macrocycles in asymmetric arylogous reactions is currently underway in our laboratory.
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(4) For reviews, see: (a) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213. (b) Willis, M. C. Angew. Chem., Int. Ed. 2010, 49, 6026. (c) Di Mola, A.; Palombi, L.; Massa, A. Curr. Org. Chem. 2012, 16, 2302. (d) Xiong, M. J.; Li, Z. H. Curr. Org. Chem. 2007, 11, 833. (5) For selected examples, see: (a) Niedek, D.; Schuler, S. M. M.; Eschmann, C.; Wende, R. C.; Seitz, A.; Keul, F.; Schreiner, P. R. Synthesis 2016, 49, 371. (b) Reddy, M. C.; Jeganmohan, M. Chem. Commun. 2015, 51, 10738. (c) Yang, J.; Yoshikai, N. J. Am. Chem. Soc. 2014, 136, 16748. (d) Shimogaki, M.; Fujita, M.; Sugimura, T. Eur. J. Org. Chem. 2013, 2013, 7128. (e) Reddy, R. S.; Kiran, I. N. C.; Sudalai, A. Org. Biomol. Chem. 2012, 10, 3655. (f) Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J. Org. Chem. 2010, 75, 368. (g) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 15608. (h) Zhang, B.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2009, 11, 4712. (i) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46, 7664. (j) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Chem. - Eur. J. 2007, 13, 4356. (k) Pedrosa, R.; Sayalero, S.; Vicente, M. Tetrahedron 2006, 62, 10400. (l) Watanabe, M.; Hashimoto, N.; Araki, S.; Butsugan, Y. J. Org. Chem. 1992, 57, 742. (6) (a) Tanaka, K.; Osaka, T.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9, 1307. (b) Sakamoto, M.; Sekine, N.; Miyoshi, H.; Mino, T.; Fujita, T. J. Am. Chem. Soc. 2000, 122, 10210. (c) Takahashi, M.; Sekine, N.; Fujita, T.; Watanabe, S.; Yamaguchi, K.; Sakamoto, M. J. Am. Chem. Soc. 1998, 120, 12770. (d) Lee, J. H.; Park, Y. S.; Nam, M. H.; Lee, S. H.; Cho, M. Y.; Yoon, C. M. Bull. Korean Chem. Soc. 2005, 36, 496. (7) Kraus, G.; Sugimoto, H. Synth. Commun. 1977, 7, 505. (8) (a) Kraus, G.; Sugimoto, H. Tetrahedron Lett. 1978, 19, 2263. (b) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178. (c) Watanabe, M.; Morimoto, H.; Nogami, K.; Ijichi, S.; Furukawa, S. Chem. Pharm. Bull. 1993, 41, 968. (d) Katritzky, A. R.; Zhang, G.; Xie, L. Synth. Commun. 1997, 27, 3951. (9) Heisler, T.; Janowski, W. K.; Prager, R. H.; Thompson, M. J. Aust. J. Chem. 1989, 42, 37. During this study moderate enantioselectivities were also reported in the reactions catalyzed by cinchonine and cinchonidine (65% ee and 67% ee respectively). (10) For enantio- and diastereoselective Michael additions of phthalide-3-carboxylic acid esters catalyzed by chiral amine, see: (a) Luo, J.; Wang, H.; Zhong, F.; Kwiatkowski, J.; Xu, L.-W.; Lu, Y. Chem. Commun. 2013, 49, 5775. (b) Luo, J.; Jiang, C.; Wang, H.; Xu, L.W.; Lu, Y. Tetrahedron Lett. 2013, 54, 5261. (11) (a) Karthikeyan, J.; Parthasarathy, K.; Cheng, C.-H. Chem. Commun. 2011, 47, 10461. (b) Lv, G.; Huang, G.; Zhang, G.; Pan, C.; Chen, F.; Cheng, J. Tetrahedron 2011, 67, 4879. (c) Ye, Z.; Lv, G.; Wang, W.; Zhang, M.; Cheng, J. Angew. Chem., Int. Ed. 2010, 49, 3671. (d) Amaladass, P.; Clement, J. A.; Mohanakrishnan, A. K. Eur. J. Org. Chem. 2008, 2008, 3798. (e) Chang, H.-T.; Jeganmohan, M.; Cheng, C.H. Chem. - Eur. J. 2007, 13, 4356. (f) Mohanakrishnan, A. K.; Amaladass, P. Tetrahedron Lett. 2005, 46, 4225. (12) (a) Schettini, R.; De Riccardis, F.; Della Sala, G.; Izzo, I. J. Org. Chem. 2016, 81, 2494. (b) Schettini, R.; Nardone, B.; De Riccardis, F.; Della Sala, G.; Izzo, I. Eur. J. Org. Chem. 2014, 2014, 7793. (c) Schettini, R.; D’Amato, A.; De Riccardis, F.; Della Sala, G.; Izzo, I. Synthesis 2017, 49, 1319. (d) Della Sala, G.; Nardone, B.; De Riccardis, F.; Izzo, I. Org. Biomol. Chem. 2013, 11, 726. (13) Della Sala, G.; Sicignano, M.; Schettini, R.; De Riccardis, F.; Cavallo, L.; Minenkov, Y.; Batisse, C.; Hanquet, G.; Leroux, F.; Izzo, I. J. Org. Chem. 2017, 82, 6629. (14) CCDC 156087 contains the supplementary crystallographic data for compound 3aa. These data are provided free of charge by The Cambridge Crystallographic Data Centre. (15) Interestingly the compound 3ag crystallizes with two crystallographically independent molecules in the unit cell, which differ slightly in the molecular conformation (see Supporting Information for details). In Figure 2 only one conformer is shown. CCDC 1560874 contains the supplementary crystallographic data for 3ag. These data are provided free of charge by The Cambridge Crystallographic Data Centre. (16) For details on AMR catalyzed by tetrabutylammonium bromide, see the Supporting Information.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02113. Experimental procedures, characterization data of the unknown compounds, and copies of NMR spectra (PDF) Crystallographic data for 3aa and 3ag (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Francesco De Riccardis: 0000-0002-8121-9463 Irene Izzo: 0000-0002-0369-0102 Giorgio Della Sala: 0000-0001-5020-8502 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the University of Salerno (FARB), Regione Campania under POR Campania FESR 2007/2013O.O. 2.1 (Farma-BioNet - CUP B25C13000230007, and CUP B46D14002660009) are acknowledged. We thank Dr. Patrizia Iannece (Dipartimento di Chimica e Biologia “A. Zambelli”, Università degli Studi di Salerno) for HRMS measurements.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02113 Org. Lett. 2017, 19, 4383−4386
