Letter Cite This: Org. Lett. 2017, 19, 5872-5875
pubs.acs.org/OrgLett
Switchable Chemoselectivity for Organocatalytic, Asymmetric Malononitrile Addition to ortho-Formyl Chalcones Sanjay Maity, Mithu Saha, Gurupada Hazra, and Prasanta Ghorai* Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal By-pass Road, Bhauri, Bhopal 462066, India S Supporting Information *
ABSTRACT: Chemoselective 1,2- and 1,4-addition of malononitriles to ortho-formyl chalcones using cinchona alkaloid based bifunctional chiral organocatalysts has been shown by tuning the electronic nature of the malononitriles. Alkyl (hard) malononitriles undergo an asymmetric 1,2addition followed by oxa-Michael reaction cascade to afford 1,3-disubstituted isobenzofurans with high enantio- and diastereoselectivity. Aryl (soft) malononitriles proceed through 1,4-addition followed by an aldol reaction cascade to provide indanols, having three consecutive stereocenters, in good yields and with good to excellent enantio- and diastereoselectivites.
C
Scheme 1. Catalytic Enantio- and Diastereoselective Synthesis of the Isobenzofuran and Indanol Moiety
hemoselective formation of complex carbo- and heterocyclic skeletons from a multifunctional substrate via a chemical cascade process is an attractive strategy in modern organic synthesis.1 It is even more impressive if the method is an asymmetric organocatalytic, affording an enantioenriched product with multiple stereocenters.2 Tuning the chemoselectivity of such a reaction in a simple and predictable manner has been drawing more attention. The lethal combination of the electronic and steric effect in the reactants could provide the desired chemoselectivity. In this context, our aim is to control the 1,2- vs 1,4-addition of a carbon nucleophile on an enone-containing aldehyde to construct new C−C and C−O bonds in an asymmetric fashion. The basic chemistry of a hard−soft acid− base principle is the origin of chemoselectivity.3 We hypothesized the tuning of electronic nature of the malononitriles (the carbon nucleophile) to achieve the desired selectivity of 1,2- (hard) vs 1,4- (soft) addition to provide 1,3-disubstituted isobenzofurans and indanols, respectively, from a common substrate (orthoformyl chalcone; Scheme 1). Addition of unsubstituted malononitriles to aldehydes is well-known with the Knoevenagel reaction,3 but enantioselective 1,2-addition of substituted malononitriles is unknown, probably due to the faster reversible reaction. In this case, the intermediate alcoholate is trapped through an oxa-Michael cascade reaction in an asymmetric pathway. Organocatalyzed 1,4-addition of unsubstituted malononitrile to an enone is reported;4 however, 1,4-addition of substituted malononitrile is unknown to the best of our knowledge.5 Isobenzofuran is a well-known heterocycle that is frequently found in natural products and drug molecules, such as RPR 225, 370, an oxygen-bridged analogue of farnesyl transferase inhibitors, and citalopram, an antidepression drug (Figure 1a).6 For the synthesis of chiral disubstituted isobenzofurans, very few methods are reported, mostly, by chiral pool approach.7 However, © 2017 American Chemical Society
catalytic enantio- and diastereoselective synthesis of such a moiety is still elusive. Indane moiety is often found in bioactive compounds and drug molecules such as Crixivan, HIV protease inhibitor and leading drug for AIDS treatment (Figure 1b).8 Recently, chiral indanes are used as a chiral ligand in asymmetric catalysis. Some chiral organocatalysts, such as oxazaborolidine and Ricci’s thiourea, were designed based on these chiral indane scaffolds.9 Due to Received: September 13, 2017 Published: October 24, 2017 5872
DOI: 10.1021/acs.orglett.7b02862 Org. Lett. 2017, 19, 5872−5875
Letter
Organic Letters
1). Next, an array of chiral organic bases and bifunctional catalysts (C2−C7) were examined in toluene at rt. After a few screenings of the catalysts, quinine-derived organic base C3 was the best catalyst, which furnished desired isobenzofuran in 90% NMR yield (entry 3) with 85% ee and 10:1 dr. A quick study of reaction parameters such as solvent, temperature, and catalyst loading [see Supporting Information (SI)] revealed that the presence of C3 (10 mol %) as catalyst and mesitylene as solvent is the best reaction conditions in terms of enantio- and diastereoselectivity (94% ee, 13:1 dr; entry 11). With the optimized reaction conditions (entry 11, Table 1), we examined the scope of the reaction. A wide range of substitutions on the aryl moiety of the substrate was executed and found quite general concerning yield, ee, and dr (Scheme 2).
Figure 1. Natural products, bioactive molecules, and ligands possessing (a) chiral 1,3-dihydroisobenzofuran and (b) indanol moiety.
Scheme 2. Substrate Scope: Disubstituted Isobenzofuransa−d
these extensive utilities of chiral indane, synthesis of many racemic and asymmetric approaches were attempted by using transition metal complexes.10 Very recently, Enders et al. reported a Michael addition of indoles and dicarbonyls followed by aldol reaction cascade to synthesize chiral indane scaffolds using chiral thiourea.11 To evaluate our hypothesis, we started our investigation with ortho-formyl chalcone 1b and 2-methyl malononitrile 2a as starting substrates, aiming to synthesize 1,3-disubstituted 1,3dihydroisobenzofuran 3 (Table 1). Various cinchona-derived organic bases (C1−C3) and bifunctional organocatalysts (C4C7)12−14 in toluene as a solvent at rt were screened. In the presence of chiral base C1, the reaction proceeded smoothly to afford desired isobenzofuran 3ba with moderate selectivity (entry Table 1. Optimization of the Reaction Conditionsa
entry
C
solvent
t (h)
yield (%)b
drc
eed
1 2 3 4 5 6 7 9 10 11 12f
C1 C2 C3 C4 C5 C6 C7 C3 C3 C3 C3
toluene toluene toluene toluene toluene toluene toluene xylene benzene msle msl
12 18 12 12 10 16 12 15 20 18 30
35 62 90 35 32 45 40 92 89 90 88
3:1 2:1 10:1 1:1 1:1 1:1 2:1 12:1 12:1 13:1 10:1
54 40 85 44 93 62 80 91 90 94 94
a
Reactions performed on 0.02 mmol scale of aldehyde. bYield calculated based on 1H NMR spectroscopy of the crude reaction mixture using diphenyl acetonitrile as the internal standard. c Diastereomeric ratio determined by 1H NMR analysis of the crude reaction mixture. dEnantiomeric excess determined by HPLC analysis on a chiral stationary phase. eMesitylene. fReaction performed at 0 °C. a
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), C3 (0.01 mmol, 10 mol %) in mesitylene at rt. bDiastereomeric ratio determined by 1H NMR analysis of the crude reaction mixtures. cUnless stated, yields are of pure isolated major diastereomers. dEnantiomeric excess of the major diastereomers determined by chiral HPLC analysis. eCombined yield of both the diastereomers. 5873
DOI: 10.1021/acs.orglett.7b02862 Org. Lett. 2017, 19, 5872−5875
Letter
Organic Letters Various electron-withdrawing groups, such as p-Br (3ba), p-Cl (3ca), p-F (3da), and p-CF3 (3ha), and electron-donating groups, such as p-Me (3fa), p-OMe (3ga), and 3,4-di-OMe (3ma) reacted smoothly to provide the desired products with enantio- and diastereoselectivities. Heteroaryls such as furyl (3ia) and thiophenyl (3ja) were also well tolerated under these reaction conditions. Irrespective of the position of the substitution such as m-CF3 (3ka), o-Cl (3la), 3,4-di-OMe (3ma), or 2,4-di-Cl (3na), the reaction worked well and led to the corresponding products with good ee, albeit in moderate dr due to steric hindrance in the transition state. Substitutions on the central aryl moiety were also explored and had very good enantio- and diastereoselectivities with high yields (3oa−ra). For practical utility, gram-scale synthesis was performed with 1b, which afforded 3ba in 78% yield with 10:1 dr and 87% ee. The structure and the cis-stereochemistry of the product were confirmed by a crystal structure of 3ba (Figure 2).15
Phenyl malononitrile (3a) reacted smoothly under the standard reaction conditions to afford desired indanol in 93% yield with 20:1 dr and 66% ee (see SI). After that, all the above-listed catalysts were surveyed in mesitylene at rt and low temperature; unfortunately, an increase in ee was not observed (see SI). Replacement of the phenyl substitution by p-fluorophenyl (3b) was planned to make the malononitrile softer for the better orbital overlap. Our investigation using 3b as a nucleophile at standard reaction conditions provided a sharp increase in ee of desired indanol 4bb from 66 to 84% ee with 15:1 dr (Scheme 4). After Scheme 4. Reverse Additiona−d
Figure 2. Crystal structure of 3ba.
Next, we focused on substitutions on malononitrile moiety (Scheme 3). Ethyl (3bb), allyl (3cb), and benzyl (3db) showed a Scheme 3. Substrate Scope: Substitution on the Malononitrilea a
Reaction conditions: 1 (0.1 mmol), 3a or 3b (0.15 mmol, 1.5 equiv), C7 (0.01 mmol, 10 mol %) in mesitylene at −30 °C. bC3 as catalyst. c Unless stated, yields are of pure isolated major diastereomers. d Enantiomeric excess of the major diastereomers determined by chiral HPLC analysis.
a
various reaction parameters were screened (see SI), catalyst C7 in mesitylene as solvent at −30 °C was the optimum reaction conditions that furnished indanol 4bb with 96% ee and 13:1 dr. Using the optimized reaction conditions, we explored the scope of the substrate (Scheme 4). Substituents such as p-Br (4bb), p-Cl (4cb), p-I (4eb), or p-Me (4fb) were well executed to furnish desired indanols with high enantio- and diastereoselectivities. Strong electron-withdrawing substituents such as p-F (4db) or pCF3 (4gb) also worked smoothly to provide the corresponding indanols, albeit in a slight decrease in ee. Heteroaryl such as furyl (4hb) was also tolerated in these reaction conditions. To prove the electronic effect on the arylmalononitrile nucleophile, p-Br (3c) and p-OMe (3d) substituted aryl malononitriles were investigated for the current reaction. However, 4bc and 4bd were obtained with decreases in ee. The structure and the relative configuration of the major diastereomer was confirmed by X-ray crystallography of 4bb (Figure 3).15 To explain the observed absolute stereochemistry of the products, a transition state model was proposed as previously shown by bifunctional organocatalysts.12−14 In conclusion, a highly enantio- and diastereoselective substrate-dependent switchable chemoselective malononitrile addition (1,2 and 1,4) cascade for the synthesis of 1,3dihydroisobenzofurans and indanols is reported. The basic
Reaction conditions are the same as those in Scheme 2.
moderate selectivity. Unfortunately, ethynyl (3eb), acetyl (3fb), and isopropyl (3gb) substitution failed to furnish the desired product. After the successful synthesis of substituted 1,3-dihydroisobenzofurans with high enantio- and diastereoselectivities, we switched the reactivity toward 1,4-addition followed by aldol reaction for the synthesis of highly substituted indanols. From DFT, it was revealed that there would be an orbital overlap between electrophile and nucleophile for 1,4-addition, whereas electrostatic interaction was needed for favoring 1,2-addition.16 We then made soft malonate as the carbon nucleophile by replacing the aliphatic substitution with an aromatic one. 25874
DOI: 10.1021/acs.orglett.7b02862 Org. Lett. 2017, 19, 5872−5875
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Organic Letters
(f) Oliva, C. G.; Silva, A. M. S.; Resende, D. I. S.P.; Paz, F. A. A. F.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2010, 2010, 3449. (g) De Fusco, C.; Lattanzi, A. Eur. J. Org. Chem. 2011, 2011, 3728. (h) Li, X.-M.; Wang, B.; Zhang, J.-M.; Yan, M. Org. Lett. 2011, 13, 374. (i) Yang, W.; Jia, Y.; Du, D.M. Org. Biomol. Chem. 2012, 10, 332. (j) Molleti, N.; Rana, N. K.; Singh, V. K. Org. Lett. 2012, 14, 4322. (k) Yan, L.; Wang, H.; Xiong, F.; Tao, Y.; Wu, Y.; Chen, F. Tetrahedron: Asymmetry 2017, 28, 921. (5) Only example of organocatalyzed enantioselective 1,4-addition of substituted malononitrile: Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 16050. (6) Dihydroisobenzofuran moieties present in natural products and drug molecules: (a) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213. (b) Lovey, R. G.; Elliott, A. J.; Kaminski, J. J.; Loebenberg, D.; Parmegiani, R. M.; Rane, D. F.; Girijavallabhan, V. M.; Pike, R. M.; Guzik, H. J. Med. Chem. 1992, 35, 4221. (c) Agranat, I.; Caner, H.; Caldwell, J. Nat. Rev. Drug Discovery 2002, 1, 753. (7) Synthesis of dihydroisobenzofurans: (a) Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.; Salomone, A. J. Org. Chem. 2006, 71, 3984. (b) Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. J. Org. Chem. 2010, 75, 897. (c) Delacroix, T.; Berillon, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 2000, 65, 8108. (d) Luzzio, F. A.; Okoromoba, O. E. Tetrahedron Lett. 2011, 52, 6530. (e) Ha, T. M.; Wang, Q.; Zhu, J. Chem. Commun. 2016, 52, 11100. (f) Shen, H.; Fu, J.; Gong, J.; Yang, Z. Org. Lett. 2014, 16, 5588. (g) Yuan, H.; Gong, J.; Yang, Z. Org. Lett. 2016, 18, 5500. (8) Indane moieties as HIV inhibitor: Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E. Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 4096. (9) Indane-based chiral ligands and catalysts: (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (b) Kerr, M. S.; Read de Alaniz, J. R.; Rovis, T. J. Org. Chem. 2005, 70, 5725. (c) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576. (d) Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464. (e) Loh, C. C. J.; Badorrek, J.; Raabe, G.; Enders, D. Chem. - Eur. J. 2011, 17, 13409. (f) Loh, C. C. J.; Raabe, G.; Enders, D. Chem. - Eur. J. 2012, 18, 13250. (10) (a) Borie, C.; Ackermann, L.; Nechab, M. Chem. Soc. Rev. 2016, 45, 1368. (b) Gabriele, B.; Mancuso, R.; Veltri, L. Chem. - Eur. J. 2016, 22, 5056. (c) Qian, H.; Zhao, W.; Sung, H. H-Y.; Williams, I. D.; Sun, J. Chem. Commun. 2013, 49, 4361. (d) Rincón, Á .; Carmona, V.; Torres, M. R.; Csákÿ, A. G. Synlett 2012, 23, 2653. (e) Sánchez-Larios, E.; Gravel, M. J. Org. Chem. 2009, 74, 7536. (f) Giorgi, G.; Arroyo, F. J.; López-Alvarado, P.; Menéndez, J. C. Synlett 2010, 2010, 2465. (11) (a) Loh, C. C. J.; Atodiresei, I.; Enders, D. Chem. - Eur. J. 2013, 19, 10822. (b) Loh, C. C. J.; Hack, D.; Enders, D. Chem. Commun. 2013, 49, 10230. (c) Loh, C. C. J.; Chauhan, P.; Hack, D.; Lehmann, C.; Enders, D. Adv. Synth. Catal. 2014, 356, 3181. (12) Recent reviews on chiral aminothiourea catalysis: (a) Connon, S. J. Chem. Commun. 2008, 2499. (b) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593. Chiral aminosquaramide catalysis: (c) Malerich, J.; Hagihara, K.; Rawal. J. Am. Chem. Soc. 2008, 130, 14416. (d) Storer, R. I.; Aciro, C.; Jones, L. H. Chem. Soc. Rev. 2011, 40, 2330. (13) Recent bifunctional organocatalytic oxa-Micheal reactions: (a) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008, 130, 46. (b) Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2011, 133, 16711. (c) Kobayashi, Y.; Taniguchi, Y.; Hayama, N.; Inokuma, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2013, 52, 11114. (14) Our contribution on asymmetric oxa-Michael addition reaction: (a) Ravindra, B.; Das, B. G.; Ghorai, P. Org. Lett. 2014, 16, 5580. (b) Maity, S.; Parhi, B.; Ghorai, P. Angew. Chem., Int. Ed. 2016, 55, 7723. (c) Parhi, B.; Maity, S.; Ghorai, P. Org. Lett. 2016, 18, 5220. (d) Reddy, R. R.; Gudup, S. S.; Ghorai, P. Angew. Chem., Int. Ed. 2016, 55, 15115. (e) Hazra, G.; Maity, S.; Bhowmick, S.; Ghorai, P. Chem. Sci. 2017, 8, 3026. (f) Midya, A.; Maity, S.; Ghorai, P. Chem. - Eur. J. 2017, 23, 11216. (15) CCDC numbers for compound 3ba and 4bb are 1546570 and 1546569, respectively. (16) For DFT study, see SI.
Figure 3. Crystal structure of 4bb.
chemistry of hard−soft acid−base principle originated this chemoselectivity. To the best of our knowledge, this is the first example of enantioselective 1,2-addition of substituted malononitriles and 1,4-addition of substituted malononitrile; this is also the first catalytic enantio- and diastereoselective synthesis of 1,3dihydroisobenzofurans. Besides asymmetric organocatalysis, this finding might add value to the area of physical organic chemistry.
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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.7b02862. Experimental procedures, characterization data (PDF) Copies of NMR spectra for all products (PDF) X-ray data for TRYA2 (CIF) X-ray data for f1 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Prasanta Ghorai: 0000-0001-5120-2700 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is funded by SERB (EMR/2016/005995), New Delhi, and IISER Bhopal. S.M. thanks UGC. M.S. thanks IISERB. G.H. thanks CSIR, New Delhi, India, for doctoral fellowships. We thank Mr. L.M. Jha, IISERB, for crystal data, and Dr. Mithu Saha for DFT calculation.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02862 Org. Lett. 2017, 19, 5872−5875
