DOI: 10.1002/chem.201403505

Communication

& Cascade Aminocatalysis

Organocatalytic Cascade Reactions: Towards the Diversification of Hydroisochromenes and Chromenes through Two Different Activation Modes David Cruz Cruz, Rasmus Mose, Clarisa Villegas Gmez, Stine V. Torbensen, Martin S. Larsen, and Karl Anker Jørgensen*[a] Abstract: The organocatalytic enantioselective syntheses of functionalized hydroisochromenes and chromenes by trienamine-mediated [4+2]-cycloaddition/nucleophilic ring-closing and iminium-ion/aminal-mediated oxa-Michael/Michael/nucleophilic ring-closing with 2-nitroallylic alcohols are presented. The corresponding cycloadducts, with up to five stereocenters, are formed in good yield and excellent enantioselectivities. The synthetic applications of the obtained products have been demonstrated.

Organocatalytic cascade reactions constitute a powerful tool to construct complex molecules from simple precursors. These stereoselective atom- and step-economic transformations, which avoid time-consuming protection/deprotection steps and isolation of intermediates continue to be a demanding area of research.[1] Current progress in this field has been circumscribed by the discovery and development of new catalytic activation concepts. In this sense, activation modes such as dienamine,[2] vinylogous-iminium-ion,[3] linear trienamine,[4] cross trienamine[5] and tetraenamine[6] have emerged as successful strategies in aminocatalysis and offer new challenges to perform new cascade reactions. In attempts to develop reaction strategies for the construction of molecules with complex and structural diversity we have initiated a program to explore organocatalytic cascade reactions for the diversification of optically active functionalized fused heterocycles, which are considered as important core structures and synthetic building blocks. The strategy presented is based on the reaction of electron-deficient alkenes containing a remote nucleophilic center, with conjugated aldehydes that have been activated by an amino catalyst. The purpose of the development of such reaction strategies is to generate diversified bicyclic scaffolds (Scheme 1, center). Recently, an organocatalytic cascade reaction between cyanoacrylamides and 2,4-dienals for the asymmetric synthesis of highly function[a] Dr. D. Cruz Cruz, R. Mose, Dr. C. Villegas Gmez, S. V. Torbensen, M. S. Larsen, Prof. Dr. K. A. Jørgensen Center for Catalysis, Department of Chemistry, Aarhus University, 8000 Aarhus C (Denmark) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403505. Chem. Eur. J. 2014, 20, 11331 – 11335

alized hydroisoquinolines through a [4+2]-cycloaddition/ringclosing sequence has been reported (Scheme 1, top).[7] This cascade sequence, which is based on a trienamine intermediate I, was expected to exhibit a reactive pattern that could provide attractive bicyclic frameworks. Applying this methodology, the cascade reaction proceeded in good yields and excellent stereoselectivities. In this work we envisioned that 2-nitroallylic alcohols[8] could be employed as electron-deficient alkenes II for the reaction with the two different classes of intermediates I, formed by the reaction with 2,4-dienals[4c,f] or 2’-hydroxy-cinnamaldehydes[9] for the asymmetric synthesis of hydroisochromenes or chromenes. These reactions are expected to proceed by [4+2]-cycloaddition-nucleophilic ring-closing reaction or an oxa-Michael/Michael/nucleophilic ring-closing sequence, respectively. We figured that the first aminocatalytic cascade strategy proceeds via a trienamine intermediate; while an iminium-ion/ aminal[10] intermediate can be rationalized for the second sequence (Scheme 1, bottom). Hydroisochromenes and chromenes are important classes of heterocyclic scaffolds, which exhibit diverse biological activities.[11] Herein we report the results of our investigations of both trienamine and iminium-ion/aminal organocatalytic cascade strategies. This study shows the versatility of the asymmetric aminocatalysis towards the diversification of privileged structures. We initially focused our attention on the development of the [4+2]-cycloaddition/nuclephilic ring-closing sequence. To find the optimal conditions we chose to study the cascade reaction between (E)-5-methylhexa-2,4-dienal (1 a) and (E)-2-nitroalcohol 2 a (Table 1). In a first approach, when the reaction was carried out with 20 mol % of TMS-protected prolinol catalyst 3 a and o-fluorobenzoic acid (OFBA) as additive in CDCl3, only traces of the desired product 4 a were observed after 93 h at room temperature (entry 1). However, when the temperature was increased to 40 8C or 55 8C, product 4 a was obtained in moderate yield with excellent enatioselectivity (entries 2, 3). Under these conditions, we noticed that part of the aldehyde was degraded and no improvement in stereoselectivity was observed by changing the additive to for example, mandelic acid (MA) (entry 4); however, when diphenylthiourea (DPTU) was used, a slightly better yield and excellent enantioselectivity was achieved (entry 5). By switching the equivalents of the reactants (3 equiv for 1 a and 1 equiv for 2 a) we observed 60 % conversion and 75:25 d.r. Increasing the reaction temper-

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Communication

Scheme 1. Proposed organocatalytic cascade reaction strategies.

ature to 70 8C, the screened solvents (toluene, CH3CN, EtOAc, and dichloroethane (DCE)) showed toluene to be the best, giving good yield and diastereoselectivity, and excellent enantioselectivity of 4 a (entry 8). Higher temperatures only caused a decrease in yield and enantioselectivity (entries 12, 13). After developing the best reaction conditions for the [4+2]cycloaddition/nucleophilic ring-closing sequence, we turned our attention to finding the optimal conditions for the oxa-Michael/Michael/nucleophilic-ring closing cascade sequence. For this purpose the reaction between (E)-2’-hydroxy-3-phenylpropenal (5 a) and (E)-2-nitroallylic alcohol 2 a were chosen as reaction partners for the initial investigations (Table 2). Pleasingly, in the presence of 20 mol % of the catalyst 3 b, full conversion was observed after 70 h in CDCl3 at 40 8C, affording the desired product 6 a in 50 % yield, 80:20 d.r. and 97 % ee (Table 2, entry 1). To improve the reactivity and yield, several additives were tested. When OFBA was used, both reactivity and yields were improved; however, the enantioselectivity slightly decreased. It was also observed that no improveChem. Eur. J. 2014, 20, 11331 – 11335

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ment in enantioselectivity was observed when NaOAc, Et3N, and DPTU were applied. Finally, good yield and diastereoselectivity, and excellent enantioselectivity, were obtained after 24 h by using PhCO2Na. Table 3 and Table 4 present the scope and limitations of both cascade sequences investigated. Delightfully, through a [4+2] cycloaddition/ring closing sequence, a variety of substitution patterns were well-tolerated in both dienals 1 and nitroallylic alcohols 2. Electron-deficient and electron-rich substituents on the aromatic ring of 2 could be applied, affording the corresponding hydroisochromenes 4 b– e with high levels of enantiocontrol (89–93 % ee), moderate to good yields, and good diastereoselectivities (70:30–77:23 d.r.). Heteroaromatic rings in 2 were also compatible with the methodology, affording 4 f, g with excellent enantioselectivities (91– 96 % ee) and good diastereoselectivities and yields. Next, a series of dienals 1, acting as trienamine precursors were examined. Pleasingly, alkyl and aryl substituents at g- and d-positions of 1 proved to be beneficial to the reaction, providing the corresponding adducts 4 h–k in good yields (61– 85 %) and excellent enantioselectivities (92– > 99 % ee). Interestingly, polycyclic products could also be obtained. Lower stereoselectivity and moderate yield were observed for the tricyclic compound 4 l; however the tetracyclic indole derivative 4 m was obtained in excellent yield and stereoselectivity. Having proved the generality of the [4+2]-cycloadition/nucleophilic ring-closing sequence via trienamine activation, we focused on the scope of the oxa-Michael/Michael/nucleophilic ring-closing cascade reaction. Under optimized reaction conditions, several substituted aldehydes 5 and the corresponding nitroallylic alcohols 2 reacted smoothly through the organocatalytic iminium-ion/aminal activation, affording the functionalized chromenes 6 (Table 4). The same substitution patterns in 2 applied to the synthesis of hydroisochromenes were also compatible with this methodology. Thus, both electron-withdrawing and electron-donating groups on the aromatic ring, as well as heteroaromatic substituents lead to high levels of stereocontrol (85– > 99 % ee and 71:29–77:23 d.r.) and good yields of the chromenes 6 b–h were obtained.

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Communication Table 1. Screening of the reaction conditions for the [4+2]-cycloaddition/nucleophilic ring-closing reaction of (E)-5-methylhexa-2,4-dienal 1 a and (E)-2-nitroallylic alcohol 2 a.

Entry [a]

1 2[a] 3[a] 4[a] 5[a] 6[b] 7[b] 8[b] 9[b] 10[b] 11[b] 12[b] 13[b]

Solvent

Additive

T [8C]/t [h]

d.r.[c]

ee[d]

Conv/yield [%]

CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 toluene CH3CN EtOAc DCE toluene toluene

OFBA OFBA OFBA MA DPTU DPTU SC DPTU DPTU DPTU DPTU DPTU DPTU

rt/93 40/46 55/24 55/24 55/24 55/24 55/24 70/20 70/20 70/20 70/20 85/20 95/20

– 70:30 72:28 70:30 72:28 75:25 74:26 80:20 – 80:20 80:20 80:20 80:20

– 96 94 93 98 nd nd 96 – nd nd 94 90

– nd[e]/34 nd[e]/38 nd[e]/30 nd[e]/39 60/nd 50/nd > 95/70 – 55/nd 75/51 > 95/63 > 95/60

[a] Reactions were performed with 1 a (0.1 mmol), 2 a (0.1 mmol), 3 a (0.02 mmol), additive (0.02 mmol) in solvent (0.5 mL). [b] 1 a (0.3 mmol) and 2 a (0.1 mmol). [c] Determined by 1H NMR spectroscopy on the crude reaction mixture. [d] Determined by chiral ultraperformance convergence chromatography (UPC2). [e] Conversion was not determined due to partly decomposition of 1 a. OFBA = o-fluorobenzoic acid, MA = mandelic acid, DPTU = N,N’-diphenylthiourea. SC = Schreiner’s catalyst (N,N’-bis[3,5bis(trifluoromethyl)phenyl]thiourea.

The absolute configuration of the compounds 4 b and 6 b obtained by both trienamine and iminiumion/aminal organocatalytic activations were established unambiguously by X-ray analysis.[12] The remaining products were assigned by analogy. For the structures of 6 it should be noted that for the X-ray structure of 6 b’, the absolute configuration at the hydroxyl stereocenter is inverted, relative to the structure given in the manuscript (see the Supporting Information). To demonstrate the synthetic potential of the cascade products, selected transformations were performed on the corresponding 4 a and 6 a cycloadducts. The hydroxyl group could be reduced to the corresponding saturated products 8 and 11 in excellent yields by reaction with Et3SiH and BF3·Et2O (Scheme 2, [Eq. (I) and (V)]). An oxidation at the same positions could also be achieved under Dess–Martin conditions, affording the lactones 7 and 10 also with very good yields (Scheme 2, [Eq. (II) and (IV)]). Both reduction and oxidation reactions showed the presence of only one diastereoisomer for 7, 8, 10, and 11, demonstrating that the stereocenters containing the hydroxyl group are responsible for the diastereomeric ratio obtained for 4 and 6 in Table 3 and 4, respectively. A stereoselective epoxidation at the double

Table 2. Screening of the reaction conditions for the oxa-Michael-Michael/nucleophilic ring-closing reaction of 2’-hydroxy-3-phenylpropenal 5 a and (E)-2-nitroallylic alcohol 2 a.

Entry[a]

Additive

t [h]

dr[b]

ee[c]

Conv[b]/yield [%]

1 2 3 4 5 6

– OFBA NaOAc Et3N PhCO2Na DPTU

70 24 72 24 24 72

80:20 80:20 80:20 80:20 80:20 80:20

97 94 93 16 96 98

> 95/50 94/66 > 95/60 > 95/57 > 95/74 68/24

[a] Reactions were performed with 5 a (0.12 mmol), 2 a (0.1 mmol), 3 b (0.02 mmol), additive (0.02 mmol) and solvent (0.2 mL). [b] Determined by 1 H NMR spectroscopy on the crude reaction mixture. [c] Determined by chiral ultraperformance convergence chromatography (UPC2). OFBA = ofluorobenzoic acid, DPTU = N,N’-diphenylthiourea.

Finally, a variety of substituted aldehydes 5 were evaluated. Gratifyingly, electron-rich and electron-poor substituents in different positions on the aromatic ring could be applied to this methodology, providing the cycloadducts 6 i–l in excellent enantioselectivities (94–98 % ee) and good diastereoselectivities and yields (61:39–85:15 d.r. and 61–80 %). Chem. Eur. J. 2014, 20, 11331 – 11335

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Scheme 2. Synthetic transformations of products 4 a and 6 a.

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Communication Table 3. Scope of the [4+2]-cycloaddition/nucleophilic ring-closing reaction.[a]

Table 4. Scope of the oxa-Michael-Michael/nucleophilic ring-closing reaction.[a]

[a] Reaction conditions: 5 (0.12 mmol), 2 (0.1 mmol), 3 (0.02 mmol), PhCO2Na (0.02 mmol) and 0.2 mL of CDCl3. The reported yields are for the mixture of diastereoisomers. The d.r. was determined by 1H NMR spectroscopy on the crude mixture. The ee values (major diastereoisomer) were determined by chiral ultraperformance convergence chromatography (UPC2).

Acknowledgements

[a] Reaction conditions: 1 (0.3 mmol), 2 (0.1 mmol), 3 (0.02 mmol) and DPTU (0.02 mmol) in 0.5 mL of toluene. The reported yields are for the mixture of diastereoisomers. The d.r. was determined by 1H NMR spectroscopy on the crude mixture. The ee values (major diastereoisomer) were determined by chiral ultraperformance convergence chromatography (UPC2).

This work was made possible by grants from Aarhus University and Carlsberg Foundation. The authors thank Dr. Jacob Overgaard for performing the X-ray analyses.

bond of 8 was achieved, leading to the compound 9 with five stereocenters (see the Supporting Information) (Scheme 2, [Eq. (III)]). Finally, the corresponding amine 12 was obtained in quantitative yield by a selective reduction of the nitro group of 10 with Zn0 (Scheme 2, [Eq. (VI)]). In conclusion, we have developed both organocatalytic [4+2] cycloaddition/nucleophilic ring-closing and oxa-Michael/ Michael/nucleophilic ring-closing sequences for the asymmetric construction of hydroisochromenes and chromenes through organocatalytic trienamine and iminium-ion-aminal activation modes, respectively. In both cases the reactions proceed efficiently with high levels of stereocontrol. The synthetic application of the obtained cycloadducts was proved with selected transformations, which proceed with high yield without affecting the stereoselectivity. These reaction concepts represent an important study for the diversification of privileged structures. Chem. Eur. J. 2014, 20, 11331 – 11335

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Keywords: aminocatalysis · asymmetric catalysis · cascade reactions · chromenes hydroisochromenes [1] a) C. M. R. Volla, I. Atodiresei, M. Rueping, Chem. Rev. 2014, 114, 2390 – 2431; b) B. Westermann, M. Ayaz, S. S. van Berkel, Angew. Chem. 2010, 122, 858 – 861; Angew. Chem. Int. Ed. 2010, 49, 846 – 849; c) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167 – 178. [2] a) D. B. Ramachary, Y. V. Reddy, Eur. J. Org. Chem. 2012, 865 – 887. [3] a) X. Tian, Y. Liu, P. Melchiorre, Angew. Chem. 2012, 124, 6545 – 6548; Angew. Chem. Int. Ed. 2012, 51, 6439 – 6442; b) Y. Hayashi, D. Okumara, S. Umemiya, T. Uchimaru, ChemCatChem 2012, 4, 959 – 962; c) X. Tian, P. Melchiorre, Angew. Chem. 2013, 125, 5468 – 5471; Angew. Chem. Int. Ed. 2013, 52, 5360 – 5363; d) L. Dell’Amico, Ł. Albrecht, T. Naicker, P. H. Poulsen, K. A. Jørgensen, J. Am. Chem. Soc. 2013, 135, 8063 – 8070; e) K. S. Halskov, T. Naicker, M. E. Jensen, K. A. Jørgensen, Chem. Commun. 2013, 49, 6382 – 6384; f) M. J. Lear, Y. Hayashi, ChemCatChem 2013, 5, 3499 – 3501. [4] a) E. Arceo, P. Melchiorre, Angew. Chem. 2012, 124, 5384 – 5386; Angew. Chem. Int. Ed. 2012, 51, 5290 – 5292; b) Z.-J. Jia, H. Jiang, J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-C. Chen, K. A. Jørgensen, J. Am.

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Communication Chem. Soc. 2011, 133, 5053 – 5061; c) Z.-J. Jia, Q. Zhou, Q.-Q. Zhou, P.-Q. Chen, Y.-C. Chen, Angew. Chem. 2011, 123, 8797 – 8800; Angew. Chem. Int. Ed. 2011, 50, 8638 – 8641; d) Y. Liu, M. Nappi, E. Arceo, S. Vera, P. Melchiorre, J. Am. Chem. Soc. 2011, 133, 15212 – 15218; e) Ł. Albrecht, F. Cruz-Acosta, A. Fraile, A. Albrecht, J. Christensen, K. A. Jørgensen, Angew. Chem. 2012, 124, 9222 – 9226; Angew. Chem. Int. Ed. 2012, 51, 9088 – 9092; f) L. Prieto, G. Talavera, U. Uria, E. Reyes, J. L. Vicario, L. Carrillo, Chem. Eur. J. 2014, 20, 2145 – 2148. [5] K. S. Halskov, T. K. Johansen, R. L. Davis, M. Steurer, F. Jensen, K. A. Jørgensen, J. Am. Chem. Soc. 2012, 134, 12943 – 12946. [6] a) J. Stiller, P. H. Poulsen, D. C. Cruz, J. Dourado, R. L. Davis, K. A. Jørgensen, Chem. Sci. 2014, 5, 2052 – 2056; b) Q.-Q. Zhou, Y.-C. Xiao, X. Yuan, Y.-C. Chen, Asian J. Org. Chem. 2014, 3, 545 – 549. [7] C. V. Gmez, D. C. Cruz, R. Mose, K. A. Jørgensen, Chem. Commun. 2014, 50, 6035 – 6038.

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[8] a) G. Talavera, E. Reyes, J. L. Vicario, L. Carrillo, Angew. Chem. 2012, 124, 4180 – 4183; Angew. Chem. Int. Ed. 2012, 51, 4104 – 4107; b) A. Parra, S. Reboredo, J. Alemn, Angew. Chem. 2012, 124, 9872 – 9874; Angew. Chem. Int. Ed. 2012, 51, 9734 – 9736. [9] L. Zu, S. Zhang, H. Xie, W. Wang, Org. Lett. 2009, 11, 1627 – 1630. [10] Previous studies have showed this activation mode, see ref. [9]. [11] For recent review on the importance of isochromenes, see: a) J.-M. Gao, S.-X. Yang, J.-C. Qin, Chem. Rev. 2013, 113, 4755 – 4811. For recent review on the importance of chromenes, see: b) S. A. Patil, R. Patil, L. M. Pfeffer, D. D. Miller, Future Med. Chem. 2013, 5, 1647 – 1660; c) Y.-L. Shi, M. Shi, Org. Biomol. Chem. 2007, 5, 1499 – 1504. [12] See the Supporting Information for details about the X-ray analyses. Received: May 13, 2014 Published online on July 22, 2014

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Organocatalytic cascade reactions: towards the diversification of hydroisochromenes and chromenes through two different activation modes.

The organocatalytic enantioselective syntheses of functionalized hydroisochromenes and chromenes by trienamine-mediated [4+2]-cycloaddition/nucleophil...
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