FULL PAPER DOI: 10.1002/asia.201402567
Asymmetric Michael Addition/Intramolecular Cyclization Catalyzed by Bifunctional Tertiary Amine–Squaramides: Construction of Chiral 2-Amino4H-chromene-3-Carbonitrile Derivatives Yu Gao and Da-Ming Du*[a] Abstract: The efficient asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones catalyzed by a chiral bifunctional tertiary amine– squaramide catalyst for the synthesis of chiral 2-amino-4H-chromene-3-carbonitrile derivatives was developed. The corresponding products were obtained in good to excellent yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) for most of the bisarylidenecyclopentanones.
Introduction
squaramides as a novel type of good hydrogen-bonding organocatalyst have been successfully applied in various asymmetric reactions.[6] Our group has also reported several chiral squaramide-catalyzed asymmetric Michael addition reactions in recent years.[7] A highly enantioselective Michael addition of malononitrile to chalcones catalyzed by a chiral quinine-derived squaramide catalyst was developed in our preliminary report.[7i] This organocatalytic reaction led to chiral g-cyanocarbonyl compounds in good yields with high enantioselectivities. On the basis of this concept and background, we envisioned that Cinchona alkaloid based squaramides as bifunctional organocatalysts could be used to catalyze the cascade Michael addition/intramolecular cyclization of malononitrile with dienones. With our continued interest in asymmetric catalysis and with further endeavors in the synthesis of 2-amino-4H-chromene derivatives, herein we wish to report the first example of the organocatalytic asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones catalyzed by tertiary amine–squaramide catalysts to afford chiral 2-aminio-4Hchromene-3-carbonitrile derivatives in good to excellent yields with excellent enantioselectivities (up to 99 % yield, 98 % ee).
Optically active 4H-chromene skeletons constitute important structural motifs in a variety of natural products and biologically active drugs.[1] In particular, chiral 2-amino-4Hchromene-3-carbonitriles are versatile and useful building blocks for the preparation of natural products and candidate drugs, such as EAAT inhibitors and Bcl-2 inhibitors.[2] Several asymmetric strategies have been developed for the synthesis of chiral 2-amino-4H-chromene-3-carbonitriles, such as the use of transition-metal complexes as catalysts and organocatalyzed methods.[3] Among them, Michael addition/ cyclization of malononitrile with bisarylidenecyclopentanones is an important and straightforward way to access these interesting molecules. To date, only one group has illustrated the asymmetric synthesis of 2-amino-4H-chromene-3-carbonitriles derived from bisarylidenecyclopentanones.[4] Considering the importance of these products, it is still desirable to develop more and effective new organocatalytic protocols to achieve this transformation for the preparation of optically active 2-amino-4H-chromene-3-carbonitrile derivatives. Recently, the development of chiral bifunctional catalysts as powerful hydrogen-bond-donating organocatalysts has received growing attention.[5] Among these catalysts, chiral squaramides such as thiourea catalysts have great potential in catalytic asymmetric reactions. These tertiary amine– squaramides have been demonstrated to activate both donors and acceptors simultaneously and effectively. Chiral
Results and Discussion Initially, we selected the Michael addition/cyclization of 2,5dibenzylidenecyclopentanone (1 a) with malononitrile (2) as a model reaction. The model reaction proceeded well in CH2Cl2 in the presence of catalyst I (1 mol %, Figure 1) for 24 h at room temperature. Desired product 3 a was obtained in 92 % yield with 94 % ee. To identify a more efficient catalyst, we screened a small library of squaramide and thiourea organocatalysts. The results are presented in Table 1. A quinine-based squaramide bearing a 4-CF3 group on the aromatic ring gave a slightly better result than that obtained
[a] Y. Gao, Prof. Dr. D.-M. Du School of Chemical Engineering and Environment Beijing Institution of Technology 5 South Zhongguancun Street, Beijing 100081 (China) Fax: (+ 86) 010-6891-4985 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402567.
Chem. Asian J. 2014, 9, 2970 – 2974
Keywords: asymmetric catalysis · chromenes · cyclization · Michael addition · squaramides
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Yu Gao and Da-Ming Du
Figure 1. The screened organocatalysts.
conditions, hydroquinine-derived squaramide II afforded adduct 3 a in 93 % yield with 89 % ee, and V afforded adduct 3 a in 94 % yield with 94 % ee (Table 1, entries 2 and 5). These results indicate that quinine-derived squaramides exhibit a slight higher enantioselectivity than hydroquinine-derived squaramides. In contrast to squaramides, thioureas displayed much lower enantioselectivities (Table 1, entries 3, 6, and 9). Upon using cyclohexylamine-derived VII and sulfonamide-derived VIII, no better enantioselectivity was achieved (Table 1, entries 7 and 8). From the above evaluation, squaramide IV was identified as the optimal catalyst. With the optimal catalyst in hand, we investigated the effect of solvent and catalyst loading on the model reaction in search for the optimal reaction conditions. The results are shown in Table 2. Variation of the solvent had some effect on the stereoselectivity. All solvents gave excellent enantioselectivities, but only CH2Cl2 gave excellent yields (Table 2, entries 1–5). Common solvents such as ClCH2CH2Cl, CHCl3, toluene, and chlorobenzene afforded moderate to good yields (62–86 %) with excellent enantioselectivities (94–96 % ee). Noticeably, upon performing the reaction in THF or CH3CN, desired product 3 a was not obtained (Table 2, entries 6 and 7). Furthermore, if the loading of malononitrile was raised from 0.3 to 0.4 mmol, no better result was achieved (Table 2, entry 8). Upon using 0.2 mmol malononitrile, product 3 a was obtained in only 72 % yield (Table 2, entry 9). Having established the optimal reaction conditions, we explored the scope of the asymmetric Michael addition/intramolecular cyclization of malononitrile with bisarylidenecyclopentanone for the synthesis of chiral 2-amino-4H-chromene-3-carbonitrile derivatives. The results are summarized
Table 1. Screening of organocatalysts for the asymmetric Michael addition/intramolecular cyclization.[a]
Entry
Catalyst
Yield[b] [%]
ee[c] [%]
1 2 3 4 5 6 7 8 9
I II III IV V VI VII VIII IX
92 93 89 95 94 95 90 55 95
94 89 88 98 94 85 79 85 83
[a] Reactions were performed with 1 a (0.2 mmol) and malononitrile (0.3 mmol) in the presence of catalyst I (1 mol %) in CH2Cl2 (1 mL) at room temperature. [b] Yield of isolated product after purification by column chromatography. [c] Determined by HPLC analysis with the use of a Daicel Chiralpak AD-H column.
with a squaramide bearing a 3,5-(CF3)2 group (Table 1, entry 1 vs. 4 and entry 2 vs. 5). Under otherwise identical
Abstract in Chinese:
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Table 2. Optimization of the reaction conditions.[a]
Entry
Solvent
Yield[b] [%]
ee[c] [%]
1 2 3 4 5 6 7 8[d] 9[e]
CH2Cl2 ClCH2CH2Cl CHCl3 toluene chlorobenzene THF CH3CN CH2Cl2 CH2Cl2
95 72 62 66 86 – – 92 72
98 94 96 95 95 – – 91 91
(81–98 % ee; Table 3, entries 1–9). The position of the substituent had a certain effect on the enantioselectivity. Generally, the positions of the substituents on the aromatic rings have a strong influence on the enantioselectivity. Upon performing reactions with 1 b and 1 c bearing electron-withdrawing halogen substituents in the para position of the aromatic aldehydes, desired products 3 b and 3 c were obtained with high enantioselectivities (94 and 92 % ee, respectively; Table 3, entries 2 and 3). If the halogen substituents were in the ortho positions of the aromatic aldehydes, corresponding products 3 f and 3 i were obtained with only 86 and 81 % ee (Table 3, entries 6 and 9). The position of the electron-donating Me substituent had no effect on the enantioselectivity (Table 3, entry 4 vs. 5). In addition, we also examined a small library of bisarylidenecyclohexanones 1 j–n. The substrates exhibited comparable reactivity, and products 3 j–n were obtained in excellent yields with moderate-to-good enantioselectivities (Table 3, entries 10–14). Furthermore, a bisarylidenecyclopentanone derived from different aromatic aldehydes was also evaluated. Unfortunately, two different products were obtained that could not be separated by silica gel column chromatography (Table 3, entry 15). From the 1H NMR spectrum, the ratio of the two products was 1.2: 1. Additionally, the reaction between acyclic 1,5-diphenylpenta-1,4-dien-3-one and malononitrile did not give the desired product. To highlight the synthetic value of this methodology, as shown in Scheme 1, the substrate scope was further extend to heterocyclic dienones. Upon using (3E,5E)-3,5-dibenzylidenetetrahydro-4H-pyran-4-one (1 p), product 3 p was obtained in good yield with excellent stereoselectivity (97 % ee). (3Z,5Z)-3,5-Dibenzylidenetetrahydro-4H-thiopyran-4-one (1 q) reacted with malononitrile to afford product 3 q in good yield (85 %) with good enantioselectivity (83 % ee). On the basis of the experimental results described above, a catalytic reaction mechanism for the asymmetric induction in this system is hypothesized and is shown in Figure 2. We envision that chiral squaramide IV acts as a bifunctional catalyst. Malononitrile is deprotonated by the basic nitrogen
[a] Unless noted otherwise, reactions were performed with 1 a (0.2 mmol) and malononitrile (0.3 mmol) in the presence of catalyst IV (1 mol %) in CH2Cl2 (1 mL) at room temperature. [b] Yield of isolated product after purification by column chromatography. [c] Determined by HPLC analysis with the use of a Daicel Chiralpak AD-H column. [d] Malononitrile (0.4 mmol). [e] Malononitrile (0.2 mmol).
Table 3. Scope of the asymmetric Michael addition/cyclization for the synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives.[a]
Entry
Ar1
Ar2
n
Product
Yield[b] [%]
ee[c] [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
C6H5 4-ClC6H4 4-BrC6H4 4-MeC6H4 2-MeC6H4 2-ClC6H4 2-MeOC6H4 2-naphthyl 2-BrC6H4 C6H5 4-BrC6H4 2-BrC6H4 2-ClC6H4 2-MeC6H4 C6H5
C 6H5 4-ClC6H4 4-BrC6H4 4-MeC6H4 2-MeC6H4 2-ClC6H4 2-MeOC6H4 2-naphthyl 2-BrC6H4 C 6H5 4-BrC6H4 2-BrC6H4 2-ClC6H4 2-MeC6H4 4-ClC6H4
1 1 1 1 1 1 1 1 1 2 2 2 2 2 1
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o
95 91 95 98 88 68 96 88 99 97 94 93 90 95 40[d]
98 94 92 93 94 86 91 87 81 81 80 23 32 61 –
Yu Gao and Da-Ming Du
[a] Reactions were performed with dienone 1 (0.2 mmol) and malononitrile (0.3 mmol) in the presence of catalyst IV (1 mol %) in CH2Cl2 (1 mL) at room temperature. [b] Yield of isolated product after purification by column chromatography. [c] Determined by HPLC analysis with the use of a Daicel Chiralpak AD-H column. [d] Total yield of two isomers.
in Table 3. Bisarylidenecyclopentanones 1 a–i were first evaluated. Among them, bisarylidenecyclopentanones 1 a–i derived from aromatic aldehydes bearing electron-neutral, electron-withdrawing, and electron-donating substituents reacted smoothly with 2 to afford corresponding products 3 a– i in good-to-high yields with excellent enantioselectivities
Chem. Asian J. 2014, 9, 2970 – 2974
Scheme 1. Michael addition/intramolecular cyclization of malononitrile with heterocyclic dienones.
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Experimental Section General procedure for the asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones 1 A mixture of dienone 1 a (0.2 mmol), malononitrile (0.3 mmol), and catalyst IV (0.002 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 24 h. Next, the mixture was separated directly by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1), and product 3 a was obtained as a white solid (62.3 mg, 95 % yield); m.p. 226–227 8C; ½a25 D = + 19.5 1 H NMR (c = 0.06, CH2Cl2); (400 MHz, [D6]DMSO): d = 7.38–7.35 (m, 6 H; ArH), 7.29–7.25 (m, 1 H; ArH), 7.23–7.19 (m, 3 H; ArH), 6.92 (s, 2 H; NH2), 6.40 (s, 1 H; CH), 4.28 (s, 1 H; CH), 2.90–2.76 (m, 2 H; CH2), 2.38 (dd, J1 = 16.8 Hz, J2 = 7.2 Hz, 1 H; CH2), 2.03 (dd, J1 = 17.2 Hz, J2 = 6.4 Hz, 1 H, CH2) ppm; 13C NMR (100 MHz, [D6]DMSO): d = 161.2, 146.1, 143.1, 138.0, 137.4, 129.1, 128.4, 128.1, 127.5, 126.9, 122.8, 121.1, 116.7, 56.4, 41.2, 28.2, 26.9 ppm; HPLC (Daicel Chiralpak AD-H column, nhexane/2-propanol = 80:20, flow rate = 1.0 mL min1, l = 254 nm): tR = 8.2 (minor), 12.4 min (major); 98 % ee.
Figure 2. Proposed reaction mechanism.
atom of the tertiary amine; furthermore, the squaramide moiety acts as a Brønsted acid and activates dienone 1 a through double hydrogen bonding. The deprotonated malononitrile first attacks the activated dienone from the Re face to afford (S)-configured intermediate B. Enolization of the carbonyl triggers a cascade sequence, which is followed by attack of the oxygen atom on the carbonyl group to form intermediate C. Finally, product 3 a is formed after tautomerization with release of catalyst IV. The catalyst that is regenerated can then be used in the next catalytic cycle.
Acknowledgements We are grateful for financial support from the National Natural Science Foundation of China (Grant No. 21272024).
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Conclusions In conclusion, we developed an efficient enantioselective Michael addition/intramolecular cyclization of malononitrile with dienones by using a chiral bifunctional tertiary amine– squaramide catalyst for the synthesis of chiral 2-amino-4Hchromene-3-carbonitrile derivatives. This reaction proceeded well at low catalyst loading (1 mol %) with a broad scope of substrates under convenient and mild conditions and afforded the corresponding adducts in good to excellent yields with excellent enantioselectivities (up to 98 % ee). This protocol provides easy and straightforward entry to 2-amino4H-chromene-3-carbonitrile derivatives. Further studies on bifunctional tertiary amine–squaramide-catalyzed asymmetric synthesis of 4H-chromene derivatives are currently underway in our laboratory.
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hedron Lett. 2011, 52, 3905; m) W. Li, H. Liu, X. F. Jiang, J. Wang, ACS Catal. 2012, 2, 1535; n) J. W. Xie, X. Huang, L. P. Fan, D. C. Xu, X. S. Li, H. Su, Y. H. Wen, Adv. Synth. Catal. 2009, 351, 3077; o) Y. Gao, W. Yang, D.-M. Du, Tetrahedron: Asymmetry 2012, 23, 339; p) Y. Gao, D.-M. Du, Tetrahedron: Asymmetry 2012, 23, 1343; q) Y. Gao, D.-M. Du, Tetrahedron: Asymmetry 2013, 24, 1312. [4] a) Z.-P. Hu, C.-L. Lou, J.-J. Wang, C.-X. Chen, M. Yan, J. Org. Chem. 2011, 76, 3797; b) Z.-P. Hu, J. Li, X.-G. Yin, X.-J. Zhang, M. Yan, ARKIVOC 2013, partACHTUNGRE(iii),1. [5] For selected examples, see: a) Y. Yang, S. Dong, X. Liu, L. Lin, X. Feng, Chem. Commun. 2012, 48, 5040; b) Z. Wang, Z. Yang, D. Chen, X. Liu, L. Lin, X. Feng, Angew. Chem. Int. Ed. 2011, 50, 4928; Angew. Chem. 2011, 123, 5030; c) M. Wang, L. Lin, J. Shi, X. Liu, Y. Kuang, X. Feng, Chem. Eur. J. 2011, 17, 2365; d) P. He, X. Liu, J. Shi, L. Lin, X. Feng, Org. Lett. 2011, 13, 936; e) Z. Dong, L. Wang, X. Chen, X. Liu, L. Lin, X. Feng, Eur. J. Org. Chem. 2009, 5192; f) J. Liu, Z. Yang, X. Liu, Z. Wang, Y. Liu, S. Bai, L. Lin, X. Feng, Org. Biomol. Chem. 2009, 7, 4120; g) X. Liu, L. Lin, X. Feng, Chem. Commun. 2009, 6145; h) Y. Takemoto, Org. Biomol. Chem. 2005, 3, 4299; i) M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520; Angew. Chem. 2006, 118, 1550; j) S. J. Connon, Chem. Eur. J.
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2006, 12, 5418; k) W.-Y. Siau, J. Wang, Catal. Sci. Technol. 2011, 1, 1298. [6] For reviews on squaramides, see: a) R. I. Storer, C. Aciro, L. H. Jones, Chem. Soc. Rev. 2011, 40, 2330; b) J. Alemn, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17, 6890; for pioneering reports in organocatalysis, see: c) J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416; d) Y. Zhu, J. P. Malerich, V. H. Rawal, Angew. Chem. Int. Ed. 2010, 49, 153; Angew. Chem. 2010, 122, 157. [7] Organocatalytic reactions with the use of squaramide catalysts reported by our group: a) W. Yang, D.-M. Du, Org. Lett. 2010, 12, 5450; b) W. Yang, D.-M. Du, Adv. Synth. Catal. 2011, 353, 1241; c) W. Yang, D.-M. Du, Chem. Commun. 2011, 47, 12706; d) W. Yang, D.-M. Du, Adv. Synth. Catal. 2013, 355, 3670; e) W. Yang, D.-M. Du, Org. Biomol. Chem. 2012, 10, 6876; f) W. Yang, D.-M. Du, Org. Lett. 2013, 15, 1190; g) W. Yang, D.-M. Du, Chem. Commun. 2013, 49, 8842; h) H.-X. He, W. Yang, D.-M. Du, Adv. Synth. Catal. 2013, 355, 1137; i) W. Yang, D.-M. Du, Org. Biomol. Chem. 2012, 10, 332. Received: May 24, 2014 Published online: August 14, 2014
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Asymmetric Michael Addition/Intramolecular Cyclization Catalyzed by Bifunctional Tertiary Amine–Squaramides: Construction of Chiral 2-Amino4H-chromene-3-Carbonitrile Derivatives Yu Gao and Da-Ming Du*[a] Abstract: The efficient asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones catalyzed by a chiral bifunctional tertiary amine– squaramide catalyst for the synthesis of chiral 2-amino-4H-chromene-3-carbonitrile derivatives was developed. The corresponding products were obtained in good to excellent yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) for most of the bisarylidenecyclopentanones.
Introduction
squaramides as a novel type of good hydrogen-bonding organocatalyst have been successfully applied in various asymmetric reactions.[6] Our group has also reported several chiral squaramide-catalyzed asymmetric Michael addition reactions in recent years.[7] A highly enantioselective Michael addition of malononitrile to chalcones catalyzed by a chiral quinine-derived squaramide catalyst was developed in our preliminary report.[7i] This organocatalytic reaction led to chiral g-cyanocarbonyl compounds in good yields with high enantioselectivities. On the basis of this concept and background, we envisioned that Cinchona alkaloid based squaramides as bifunctional organocatalysts could be used to catalyze the cascade Michael addition/intramolecular cyclization of malononitrile with dienones. With our continued interest in asymmetric catalysis and with further endeavors in the synthesis of 2-amino-4H-chromene derivatives, herein we wish to report the first example of the organocatalytic asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones catalyzed by tertiary amine–squaramide catalysts to afford chiral 2-aminio-4Hchromene-3-carbonitrile derivatives in good to excellent yields with excellent enantioselectivities (up to 99 % yield, 98 % ee).
Optically active 4H-chromene skeletons constitute important structural motifs in a variety of natural products and biologically active drugs.[1] In particular, chiral 2-amino-4Hchromene-3-carbonitriles are versatile and useful building blocks for the preparation of natural products and candidate drugs, such as EAAT inhibitors and Bcl-2 inhibitors.[2] Several asymmetric strategies have been developed for the synthesis of chiral 2-amino-4H-chromene-3-carbonitriles, such as the use of transition-metal complexes as catalysts and organocatalyzed methods.[3] Among them, Michael addition/ cyclization of malononitrile with bisarylidenecyclopentanones is an important and straightforward way to access these interesting molecules. To date, only one group has illustrated the asymmetric synthesis of 2-amino-4H-chromene-3-carbonitriles derived from bisarylidenecyclopentanones.[4] Considering the importance of these products, it is still desirable to develop more and effective new organocatalytic protocols to achieve this transformation for the preparation of optically active 2-amino-4H-chromene-3-carbonitrile derivatives. Recently, the development of chiral bifunctional catalysts as powerful hydrogen-bond-donating organocatalysts has received growing attention.[5] Among these catalysts, chiral squaramides such as thiourea catalysts have great potential in catalytic asymmetric reactions. These tertiary amine– squaramides have been demonstrated to activate both donors and acceptors simultaneously and effectively. Chiral
Results and Discussion Initially, we selected the Michael addition/cyclization of 2,5dibenzylidenecyclopentanone (1 a) with malononitrile (2) as a model reaction. The model reaction proceeded well in CH2Cl2 in the presence of catalyst I (1 mol %, Figure 1) for 24 h at room temperature. Desired product 3 a was obtained in 92 % yield with 94 % ee. To identify a more efficient catalyst, we screened a small library of squaramide and thiourea organocatalysts. The results are presented in Table 1. A quinine-based squaramide bearing a 4-CF3 group on the aromatic ring gave a slightly better result than that obtained
[a] Y. Gao, Prof. Dr. D.-M. Du School of Chemical Engineering and Environment Beijing Institution of Technology 5 South Zhongguancun Street, Beijing 100081 (China) Fax: (+ 86) 010-6891-4985 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402567.
Chem. Asian J. 2014, 9, 2970 – 2974
Keywords: asymmetric catalysis · chromenes · cyclization · Michael addition · squaramides
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Yu Gao and Da-Ming Du
Figure 1. The screened organocatalysts.
conditions, hydroquinine-derived squaramide II afforded adduct 3 a in 93 % yield with 89 % ee, and V afforded adduct 3 a in 94 % yield with 94 % ee (Table 1, entries 2 and 5). These results indicate that quinine-derived squaramides exhibit a slight higher enantioselectivity than hydroquinine-derived squaramides. In contrast to squaramides, thioureas displayed much lower enantioselectivities (Table 1, entries 3, 6, and 9). Upon using cyclohexylamine-derived VII and sulfonamide-derived VIII, no better enantioselectivity was achieved (Table 1, entries 7 and 8). From the above evaluation, squaramide IV was identified as the optimal catalyst. With the optimal catalyst in hand, we investigated the effect of solvent and catalyst loading on the model reaction in search for the optimal reaction conditions. The results are shown in Table 2. Variation of the solvent had some effect on the stereoselectivity. All solvents gave excellent enantioselectivities, but only CH2Cl2 gave excellent yields (Table 2, entries 1–5). Common solvents such as ClCH2CH2Cl, CHCl3, toluene, and chlorobenzene afforded moderate to good yields (62–86 %) with excellent enantioselectivities (94–96 % ee). Noticeably, upon performing the reaction in THF or CH3CN, desired product 3 a was not obtained (Table 2, entries 6 and 7). Furthermore, if the loading of malononitrile was raised from 0.3 to 0.4 mmol, no better result was achieved (Table 2, entry 8). Upon using 0.2 mmol malononitrile, product 3 a was obtained in only 72 % yield (Table 2, entry 9). Having established the optimal reaction conditions, we explored the scope of the asymmetric Michael addition/intramolecular cyclization of malononitrile with bisarylidenecyclopentanone for the synthesis of chiral 2-amino-4H-chromene-3-carbonitrile derivatives. The results are summarized
Table 1. Screening of organocatalysts for the asymmetric Michael addition/intramolecular cyclization.[a]
Entry
Catalyst
Yield[b] [%]
ee[c] [%]
1 2 3 4 5 6 7 8 9
I II III IV V VI VII VIII IX
92 93 89 95 94 95 90 55 95
94 89 88 98 94 85 79 85 83
[a] Reactions were performed with 1 a (0.2 mmol) and malononitrile (0.3 mmol) in the presence of catalyst I (1 mol %) in CH2Cl2 (1 mL) at room temperature. [b] Yield of isolated product after purification by column chromatography. [c] Determined by HPLC analysis with the use of a Daicel Chiralpak AD-H column.
with a squaramide bearing a 3,5-(CF3)2 group (Table 1, entry 1 vs. 4 and entry 2 vs. 5). Under otherwise identical
Abstract in Chinese:
Chem. Asian J. 2014, 9, 2970 – 2974
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Table 2. Optimization of the reaction conditions.[a]
Entry
Solvent
Yield[b] [%]
ee[c] [%]
1 2 3 4 5 6 7 8[d] 9[e]
CH2Cl2 ClCH2CH2Cl CHCl3 toluene chlorobenzene THF CH3CN CH2Cl2 CH2Cl2
95 72 62 66 86 – – 92 72
98 94 96 95 95 – – 91 91
(81–98 % ee; Table 3, entries 1–9). The position of the substituent had a certain effect on the enantioselectivity. Generally, the positions of the substituents on the aromatic rings have a strong influence on the enantioselectivity. Upon performing reactions with 1 b and 1 c bearing electron-withdrawing halogen substituents in the para position of the aromatic aldehydes, desired products 3 b and 3 c were obtained with high enantioselectivities (94 and 92 % ee, respectively; Table 3, entries 2 and 3). If the halogen substituents were in the ortho positions of the aromatic aldehydes, corresponding products 3 f and 3 i were obtained with only 86 and 81 % ee (Table 3, entries 6 and 9). The position of the electron-donating Me substituent had no effect on the enantioselectivity (Table 3, entry 4 vs. 5). In addition, we also examined a small library of bisarylidenecyclohexanones 1 j–n. The substrates exhibited comparable reactivity, and products 3 j–n were obtained in excellent yields with moderate-to-good enantioselectivities (Table 3, entries 10–14). Furthermore, a bisarylidenecyclopentanone derived from different aromatic aldehydes was also evaluated. Unfortunately, two different products were obtained that could not be separated by silica gel column chromatography (Table 3, entry 15). From the 1H NMR spectrum, the ratio of the two products was 1.2: 1. Additionally, the reaction between acyclic 1,5-diphenylpenta-1,4-dien-3-one and malononitrile did not give the desired product. To highlight the synthetic value of this methodology, as shown in Scheme 1, the substrate scope was further extend to heterocyclic dienones. Upon using (3E,5E)-3,5-dibenzylidenetetrahydro-4H-pyran-4-one (1 p), product 3 p was obtained in good yield with excellent stereoselectivity (97 % ee). (3Z,5Z)-3,5-Dibenzylidenetetrahydro-4H-thiopyran-4-one (1 q) reacted with malononitrile to afford product 3 q in good yield (85 %) with good enantioselectivity (83 % ee). On the basis of the experimental results described above, a catalytic reaction mechanism for the asymmetric induction in this system is hypothesized and is shown in Figure 2. We envision that chiral squaramide IV acts as a bifunctional catalyst. Malononitrile is deprotonated by the basic nitrogen
[a] Unless noted otherwise, reactions were performed with 1 a (0.2 mmol) and malononitrile (0.3 mmol) in the presence of catalyst IV (1 mol %) in CH2Cl2 (1 mL) at room temperature. [b] Yield of isolated product after purification by column chromatography. [c] Determined by HPLC analysis with the use of a Daicel Chiralpak AD-H column. [d] Malononitrile (0.4 mmol). [e] Malononitrile (0.2 mmol).
Table 3. Scope of the asymmetric Michael addition/cyclization for the synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives.[a]
Entry
Ar1
Ar2
n
Product
Yield[b] [%]
ee[c] [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
C6H5 4-ClC6H4 4-BrC6H4 4-MeC6H4 2-MeC6H4 2-ClC6H4 2-MeOC6H4 2-naphthyl 2-BrC6H4 C6H5 4-BrC6H4 2-BrC6H4 2-ClC6H4 2-MeC6H4 C6H5
C 6H5 4-ClC6H4 4-BrC6H4 4-MeC6H4 2-MeC6H4 2-ClC6H4 2-MeOC6H4 2-naphthyl 2-BrC6H4 C 6H5 4-BrC6H4 2-BrC6H4 2-ClC6H4 2-MeC6H4 4-ClC6H4
1 1 1 1 1 1 1 1 1 2 2 2 2 2 1
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o
95 91 95 98 88 68 96 88 99 97 94 93 90 95 40[d]
98 94 92 93 94 86 91 87 81 81 80 23 32 61 –
Yu Gao and Da-Ming Du
[a] Reactions were performed with dienone 1 (0.2 mmol) and malononitrile (0.3 mmol) in the presence of catalyst IV (1 mol %) in CH2Cl2 (1 mL) at room temperature. [b] Yield of isolated product after purification by column chromatography. [c] Determined by HPLC analysis with the use of a Daicel Chiralpak AD-H column. [d] Total yield of two isomers.
in Table 3. Bisarylidenecyclopentanones 1 a–i were first evaluated. Among them, bisarylidenecyclopentanones 1 a–i derived from aromatic aldehydes bearing electron-neutral, electron-withdrawing, and electron-donating substituents reacted smoothly with 2 to afford corresponding products 3 a– i in good-to-high yields with excellent enantioselectivities
Chem. Asian J. 2014, 9, 2970 – 2974
Scheme 1. Michael addition/intramolecular cyclization of malononitrile with heterocyclic dienones.
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Experimental Section General procedure for the asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones 1 A mixture of dienone 1 a (0.2 mmol), malononitrile (0.3 mmol), and catalyst IV (0.002 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 24 h. Next, the mixture was separated directly by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1), and product 3 a was obtained as a white solid (62.3 mg, 95 % yield); m.p. 226–227 8C; ½a25 D = + 19.5 1 H NMR (c = 0.06, CH2Cl2); (400 MHz, [D6]DMSO): d = 7.38–7.35 (m, 6 H; ArH), 7.29–7.25 (m, 1 H; ArH), 7.23–7.19 (m, 3 H; ArH), 6.92 (s, 2 H; NH2), 6.40 (s, 1 H; CH), 4.28 (s, 1 H; CH), 2.90–2.76 (m, 2 H; CH2), 2.38 (dd, J1 = 16.8 Hz, J2 = 7.2 Hz, 1 H; CH2), 2.03 (dd, J1 = 17.2 Hz, J2 = 6.4 Hz, 1 H, CH2) ppm; 13C NMR (100 MHz, [D6]DMSO): d = 161.2, 146.1, 143.1, 138.0, 137.4, 129.1, 128.4, 128.1, 127.5, 126.9, 122.8, 121.1, 116.7, 56.4, 41.2, 28.2, 26.9 ppm; HPLC (Daicel Chiralpak AD-H column, nhexane/2-propanol = 80:20, flow rate = 1.0 mL min1, l = 254 nm): tR = 8.2 (minor), 12.4 min (major); 98 % ee.
Figure 2. Proposed reaction mechanism.
atom of the tertiary amine; furthermore, the squaramide moiety acts as a Brønsted acid and activates dienone 1 a through double hydrogen bonding. The deprotonated malononitrile first attacks the activated dienone from the Re face to afford (S)-configured intermediate B. Enolization of the carbonyl triggers a cascade sequence, which is followed by attack of the oxygen atom on the carbonyl group to form intermediate C. Finally, product 3 a is formed after tautomerization with release of catalyst IV. The catalyst that is regenerated can then be used in the next catalytic cycle.
Acknowledgements We are grateful for financial support from the National Natural Science Foundation of China (Grant No. 21272024).
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Conclusions In conclusion, we developed an efficient enantioselective Michael addition/intramolecular cyclization of malononitrile with dienones by using a chiral bifunctional tertiary amine– squaramide catalyst for the synthesis of chiral 2-amino-4Hchromene-3-carbonitrile derivatives. This reaction proceeded well at low catalyst loading (1 mol %) with a broad scope of substrates under convenient and mild conditions and afforded the corresponding adducts in good to excellent yields with excellent enantioselectivities (up to 98 % ee). This protocol provides easy and straightforward entry to 2-amino4H-chromene-3-carbonitrile derivatives. Further studies on bifunctional tertiary amine–squaramide-catalyzed asymmetric synthesis of 4H-chromene derivatives are currently underway in our laboratory.
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2006, 12, 5418; k) W.-Y. Siau, J. Wang, Catal. Sci. Technol. 2011, 1, 1298. [6] For reviews on squaramides, see: a) R. I. Storer, C. Aciro, L. H. Jones, Chem. Soc. Rev. 2011, 40, 2330; b) J. Alemn, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17, 6890; for pioneering reports in organocatalysis, see: c) J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416; d) Y. Zhu, J. P. Malerich, V. H. Rawal, Angew. Chem. Int. Ed. 2010, 49, 153; Angew. Chem. 2010, 122, 157. [7] Organocatalytic reactions with the use of squaramide catalysts reported by our group: a) W. Yang, D.-M. Du, Org. Lett. 2010, 12, 5450; b) W. Yang, D.-M. Du, Adv. Synth. Catal. 2011, 353, 1241; c) W. Yang, D.-M. Du, Chem. Commun. 2011, 47, 12706; d) W. Yang, D.-M. Du, Adv. Synth. Catal. 2013, 355, 3670; e) W. Yang, D.-M. Du, Org. Biomol. Chem. 2012, 10, 6876; f) W. Yang, D.-M. Du, Org. Lett. 2013, 15, 1190; g) W. Yang, D.-M. Du, Chem. Commun. 2013, 49, 8842; h) H.-X. He, W. Yang, D.-M. Du, Adv. Synth. Catal. 2013, 355, 1137; i) W. Yang, D.-M. Du, Org. Biomol. Chem. 2012, 10, 332. Received: May 24, 2014 Published online: August 14, 2014
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