aldol cascade reactions

Tetrahedron Letters 56 (2015) 105–108

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Facile synthesis of spiro chromanone-tetrahydrothiophenes with three contiguous stereocenters via sulfa-Michael/aldol cascade reactions Ya-Jian Hu, Xiao-Bing Wang ⇑, Su-Yi Li, Sai-Sai Xie, Kelvin D. G. Wang, Ling-Yi Kong ⇑ State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People’s Republic of China

a r t i c l e

i n f o

Article history: Received 17 September 2014 Revised 4 November 2014 Accepted 6 November 2014 Available online 13 November 2014

a b s t r a c t A novel sulfa-Michael/aldol cascade reaction of (E)-3-arylidenechroman-4-ones with 1,4-dithiane-2, 5-diol has been developed. This method provides a new practical and facile approach to 40 -hydroxy-20 aryl-40 ,50 -dihydro-20 H-spiro[chroman-3,30 -thiophen]-4-ones with three contiguous stereocenters in high yields. The transformation is atom-economic with good to excellent diastereoselectivities. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Cascade reaction Chromanones Diastereoselectivity Sulfa-Michael/aldol reaction Tetrahydrothiophene

Spiro heterocycles constitute a structurally unique class of natural and pharmacological molecules. They have attracted a great deal of attention due to their interesting conformational features and wide spectrum of biological activities.1 As valuable synthetic targets, the construction of this structure is both attractive and challenging in the synthetic community.2 Among many spiro heterocycles, spiro chromanone analogues are found in many biological, natural and synthetic products, and they often show a broad range of favourable properties, such as antitumor,3 antimicrobial,4 Acetyl-CoA carboxylase (ACC) inhibiting activities5 and inhibition of human telomerase.6 As a consequence, the interest in their synthesis has significantly intensified over the past few decades.7 Moreover, tetrahydrothiophenes, especially the polysubstituted tetrahydrothiophenes, are also important units of many natural products and pharmaceutical agents, such as essential coenzyme biotin with important biological functions,8 chiral organocatalyst,9 potential inhibitors of HIV,10 glucosidase inhibitors,11 antitumor natural product12 and human A3 adenosine receptor ligands.13 In view of the importance of the two types of heterocycles, it is rational to envisage that a combination of the two privileged motifs in a spiro structure may bring out some advantages to assemble drug-like molecules.2c,7a

Recently, much progress has been reported towards highly functionalized tetrahydrothiophene analogues from commercially available 1,4-dithiane-2,5-diol (the dimer of 2-mercaptoacetaldehyde) and a,b-unsaturated compounds via tandem sulfa-Michael/ aldol condensation reaction in a one-pot manner.14 Based on these precedents, we envisaged that Michael addition of 2-mercaptoacetaldehyde to (E)-3-arylidenechroman-4-ones followed by intramolecular aldol reaction would generate highly functionalized spiro chromanone-tetrahydrothiophenes. In continuation of our research interest in developing new methodologies towards novel structures via the cascade process,15 herein we describe the preparation of a new family of spiro chromanone-tetrahydrothiophenes with three contiguous stereocenters in high yields and diastereoselective manners via sulfa-Michael/aldol cascade reaction. (Scheme 1). Initially, (E)-3-arylidenechroman-4-one derivatives were prepared by condensation of appropriate chroman-4-ones and various

O R1

⇑ Corresponding authors. Tel./fax: +86 25 8327 1405 (L.-Y.K.). E-mail addresses: [email protected] (X.-B. Wang), [email protected] (L.-Y. Kong). http://dx.doi.org/10.1016/j.tetlet.2014.11.026 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

HO

R2 O

+

S S

O

Et3 N, toluene OH

80 οC

OH S

R1 O

R2

Scheme 1. General synthesis of spiro chromanone-tetrahydrothiophenes.

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Y.-J. Hu et al. / Tetrahedron Letters 56 (2015) 105–108

Table 1 Screening of reaction conditions

Table 2 Scope of Sulfa-Michael/aldol cascade reaction O

O

HO +

O

S S

OH S

Base (0.2eq) OH

O

solvent

R

R1

O

HO

2

O

+

O

S S

Et3 N, toluene 80 oC

OH

OH S

R1 R2

O 3-29

1

3

2

Entrya

Base

Solvent

T (°C)

t (h)

Yieldb (%)

drc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19d 20e

Et3N Et3N Et3N Et3N Et3N Et3N DIPEA DABCO DBU DMAP Pyrrolidine Piperidine K2CO3 NaOAc Et3N Et3N Et3N Et3N Et3N Et3N

Toluene DCM DMF EtOH CH3CN THF Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene

rt rt rt rt rt rt rt rt rt rt rt rt rt rt 40 60 80 100 80 80

6 3 3 2 2 12 11 8 7 7 10 9 6 6 5 3 1 1 1 2

70 40 66 65 68 46 68 62 66 59 65 55 58 57 75 87 95 92 95 84

90:10 71:29 82:18 86:14 88:12 89:11 85:15 83:17 81:19 82:8 83:17 85:15 89:11 86:14 97:3 99:1 98:2 92:8 95:5 97:3

The bold entry is the optimized condition for the reaction. a Unless otherwise specified, the reactions were carried out with 1 (0.2 mmol), 2 (0.1 mmol), base (20 mol %), in the solvent (1 mL). b Isolated yield of the isomers. c Determined by 1H NMR analysis of the crude mixture. d 30 mol % catalyst was used. e 10 mol % catalyst was used.

substituted benzaldehydes following the reported procedure.16 Next, 1,4-dithiane-2,5-diol 2 and (E)-3-benzylidenechroman-4one 1 were chosen as reactants for screening reaction conditions and the results are summarized in Table 1. We were pleased to find that the reaction with 20 mol % Et3N in toluene at rt for 6 h proceeded as expected affording the spirocyclic product 3a in 70% yield and 90:10 diastereoselectivity (Table 1, entry 1). The mixture of diastereomers was inseparable and the ratio was determined by integration of characteristic signals in 1H NMR spectra of the crude product. Encouraged by this promising result, we attempted to test the effect of various solvents including dichloromethane, dimethyl formamide, ethanol, acetonitrile and tetrahydrofuran. These experiments revealed that the domino reaction could be carried out in various protic and aprotic solvents with low to moderate conversions and moderate to good diastereoselectivities (Table 1, entries 2–6), and toluene might be the best suitable solvent in terms of both reactivity and selectivity. With the optimized solvent in hand, we further investigated the effect of different bases to enhance the efficiency of the reaction. Unfortunately, the attempt did not work efficiently (Table 1, entries 7–14). However, to our delight, the reaction went smoothly and furnished the desired product in much shorter time with significantly higher yield and better diastereoselectivity when the temperature was elevated (Table 1, entries 15–18). Subsequently, increasing loading of catalyst had little impact on the efficiency of the reaction (Table 1, entry 19), whereas reducing the catalyst loading decreased the yield and prolonged the reaction time (Table 1, entry 20). Thus, the best condition was achieved when the reaction was performed at 80 °C and the loading of the catalyst Et3N was maintained at 20 mol % (Table 1, entry 17).

Entrya

R1

R2

Product

t (min)

Yieldb (%)

drc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

H H H H H H H H H H H H H H H H H H H H H H H H H 6-Me 6-Cl

Ph 4-MeC6H4 3-MeC6H4 2-MeC6H4 4-iPrC6H4 4-FC6H4 3-FC6H4 2-F C6H4 4-ClC6H4 3-ClC6H4 2-ClC6H4 4-BrC6H4 4-OHC6H4 4-MeOC6H4 3-MeOC6H4 2-MeOC6H4 4-OH,3MeOC6H3 3,4,5-Tri-MeOC6H2 4-NMe2C6H4 2-Furyl 2-Thienyl 3-Thienyl 2-Pyridyl 2-naphthyl PhCH@CHA Ph Ph

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

60 80 40 50 90 40 30 40 30 40 30 30 100 120 50 50 40 40 100 40 50 50 80 30 50 80 40

95 93 93 94 90 96 98 97 99 96 96 95 85 89 95 93 96 94 83 90 93 96 88 98 97 87 88

98:2 98:2 85:15 84:16 96:4 96:4 99:1 98:2 93:7 92:8 87:13 96:4 86:14 98:2 92:8 98:2 89:11 88:12 96:4 95:5 94:6 93:7 92:8 93:7 93:7 95:5 76:24

a All reactions were carried out in toluene (1 mL) with various (E)-3-arylidenechroman-4-ones (0.2 mmol), 2 (0.1 mmol) in the presence of 20 mol % Et3N at 80 °C. b Isolated yield of the isomers. c Determined by 1H NMR analysis of the crude product.

Having established the best protocol for the reaction, we decided to explore the scope and generality of this domino reaction and the results are outlined in Table 2.17 In all the cases, the reaction was completed in two hours, affording the corresponding spirocyclic products in generally good to excellent yields (up to 99%) and high levels of diastereoselectivity (up to 99:1). Various electron-withdrawing and electron-donating substituents were appended to the benzene ring of the benzylidene-chroman-4-ones, and it was revealed that the reaction could go smoothly to give the desired products in 83–99% yields and 86:14 dr to 99:1 dr (Table 2, entries 2–19). Notably, satisfying results were also achieved with the arylidene-chroman-4-one bearing heteroaromatic rings (Table 2, entries 20–23). Sterically hindered naphthylienechroman-4-one was also compatible with the reaction conditions (Table 2, entry 24). Additionally, alkenylidene chroman-4-ones derived from cinnamaldehyde could also be utilized as a suitable reactant in the cascade sulfa-Michael/aldol reaction to furnish the desired product while no 1,6-adduct was detected (Table 2, entry 25). Furthermore, 6-Me and 6-Cl substituted benzylidene chroman-4-ones were also examined and turned out to be tolerated in the reaction. However, the 6-Cl substituted substrate gave lower diastereoselectivity compared to the latter (Table 2, entries 26-27). The structures of 40 -hydroxy-20 -aryl-40 ,50 -dihydro-20 H-spiro [chroman-3,30 -thiophen]-4-ones were characterized by 1H NMR, 13 C NMR and HRMS studies. The relative configuration of the product was confirmed by HMBC correlations and ROESY correlations as illustrated for compound 3 as a representative example

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3.57

3.13

HO O

4.84

S

7.49 5.61

O

4.33 3.98

7.18-7.28 7.49

7.18-7.28

HMBC

7.18-7.28

NOESY

Figure 1. Key HMBC and ROESY correlations of compound 3.

2-mercaptoacetaldehyde from 1,4-dithiane-2,5-diol 2 undergoes the intramolecular sulfa-Michael addition to 3-benzylidenechroman-4-one 1 to generate the enolate intermediate II. Subsequently, intramolecular aldol reaction delivers the final spiro chromanone-tetrahydrothiophene product. This cascade reaction is diastereoselective with one diastereomer formed predominantly in spite of three stereocenters in the product. The relative configurations of the stereocenters of compound 3 show the trans-relationship between the chromanone carbonyl and the benzene ring. This is ascribable to the steric hindrance between the two moieties.14i Presumably, the trans-stereochemical relationship between the benzene ring and the hydroxyl group arises from the preferential annulation of intermediate II, which is in accord with lesser unfavourable steric interactions between the two parts. In conclusion, we have developed a practical sulfa-Michael/ aldol cascade reaction furnishing a new library of densely functionalized spiro chromanone-tetrahydrothiophenes bearing three contiguous stereocenters with high yields in a diastereoselective fashion for the first time. The process goes in a one-pot manner, proceeds rapidly and allows multiple bond-forming events to occur in a single vessel with lower costs and greatly simplified work-up manipulation. Moreover, the transformation is atomeconomic with high efficiency, as all atoms of the reactants are incorporated into the structure of the product. In addition, further investigation on its asymmetric version is currently ongoing, and the results will be reported in due course.

Figure 2. ORTEP diagram of compound 26 (CCDC 1022005).

(Fig. 1). Finally, the structure of the product 26 was unambiguously determined by X-ray diffraction analysis (Fig. 2).18 On the basis of our experimental results, a proposed mechanism of the current cascade reaction is outlined in Scheme 2, taking compound 3 as an example. First, the in situ generated

O HO

S HS S 2

S

CHO

CHO I

OH

Et3 N O

O

3

intramolecular Aldol reaction

1

sulfa-Michael additon

Et3 NH

OH S

O

O

O S

O

II Scheme 2. Proposed mechanism.

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Acknowledgments This research work was financially supported by the Program for Changjiang Scholars and Innovative Research Team in University (IRT1193), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11. 026. References and notes 1. For selected examples, see: (a) Brodney, M. A.; Barreiro, G.; Ogilvie, K.; HajosKorcsok, E.; Murray, J.; Vajdos, F.; Ambroise, C.; Christoffersen, C.; Fisher, K.; Lanyon, L.; Liu, J.; Nolan, C. E.; Withka, J. M.; Borzilleri, K. A.; Efremov, I.; Oborski, C. E.; Varghese, A.; O’Neill, B. T. J. Med. Chem. 2012, 55, 9224; (b) Hu, X.-L.; Bian, X.-Q.; Wu, X.; Li, J.-Y.; Hua, H.-M.; Pei, Y.-H.; Han, A.-H.; Bai, J. Tetrahedron Lett. 2014, 55, 3864; (c) Hunt, K. W.; Cook, A. W.; Watts, R. J.; Clark, C. T.; Vigers, G.; Smith, D.; Metcalf, A. T.; Gunawardana, I. W.; Burkard, M.; Cox, A. A.; Geck Do, M. K.; Dutcher, D.; Thomas, A. A.; Rana, S.; Kallan, N. C.; DeLisle, R. K.; Rizzi, J. P.; Regal, K.; Sammond, D.; Groneberg, R.; Siu, M.; Purkey, H.; Lyssikatos, J. P.; Marlow, A.; Liu, X.; Tang, T. P. J. Med. Chem. 2013, 56, 3379; (d) Morita, H.; Mori, R.; Deguchi, J.; Oshimi, S.; Hirasawa, Y.; Ekasari, W.; Widyawaruyanti, A.; Hadi, A. H. J. Nat. Med. 2012, 66, 571; (e) Rapposelli, S.; Breschi, M. C.; Calderone, V.; Digiacomo, M.; Martelli, A.; Testai, L.; Vanni, M.; Balsamo, A. Eur. J. Med. Chem. 2011, 46, 966; (f) Schlager, T.; Schepmann, D.; Lehmkuhl, K.; Holenz, J.; Vela, J. M.; Buschmann, H.; Wunsch, B. J. Med. Chem. 2011, 54, 6704; (g) Toledo, M. A.; Pedregal, C.; Lafuente, C.; Diaz, N.; MartinezGrau, M. A.; Jimenez, A.; Benito, A.; Torrado, A.; Mateos, C.; Joshi, E. M.; Kahl, S. D.; Rash, K. S.; Mudra, D. R.; Barth, V. N.; Shaw, D. B.; McKinzie, D.; Witkin, J. M.; Statnick, M. A. J. Med. Chem. 2014, 57, 3418; (h) Wu, Q.; Wu, Z.; Qu, X.; Liu, W. J. Am. Chem. Soc. 2012, 134, 17342; (i) Yeung, B. K.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.; Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.; Schmitt, E. K.; Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.; Winzeler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana, T. T.; Keller, T. H. J. Med. Chem. 2010, 53, 5155. 2. For reviews, see: (a) Gavaskar, D.; Raghunathan, R.; Suresh Babu, A. R. Tetrahedron Lett. 2014, 55, 2217; (b) Hirschhäuser, C.; Parker, J. S.; Perry, M. W. D.; Haddow, M. F.; Gallagher, T. Org. Lett. 2012, 14, 4846; (c) Hu, J.; Liu, D.; Xu, W.; Zhang, F.; Zheng, H. Tetrahedron 2014, 70, 7511; (d) Pati, A.; Mohapatra, S.; Behera, R. K. J. Heterocycl. Chem. 2011, 48, 1234; (e) Rajesh, R.; Suresh, M.; Selvam, R.; Raghunathan, R. Tetrahedron Lett. 2014, 55, 4047; (f) Rios, R. Chem. Soc. Rev. 2012, 41, 1060; (g) Sun, H.; Wang, X.; Chen, Y.; Ouyang, L.; Liu, J.; Zhang, Y. Tetrahedron Lett. 2014, 55, 5434; (h) Zou, Y.; Hu, Y.; Liu, H.; Shi, D. ACS Comb. Sci. 2012, 14, 38. 3. Dean, F. M. Naturally Occurring Oxygen Ring Compounds; Butterworths: London, 1963. 4. Arumugam, N.; Raghunathan, R.; Shanmugaiah, V.; Mathivanan, N. Bioorg. Med. Chem. Lett. 2010, 20, 3698. 5. (a) Shinde, P.; Srivastava, S. K.; Odedara, R.; Tuli, D.; Munshi, S.; Patel, J.; Zambad, S. P.; Sonawane, R.; Gupta, R. C.; Chauthaiwale, V.; Dutt, C. Bioorg. Med. Chem. Lett. 2009, 19, 949; (b) Takeru, Y.; Hideki, J.; Kenji, N.; Koji, Y.; Tomoharu, I.; Mitsuru, O.; Hideaki, I.; Jun, S.; Jun, K.; Lihu, Y. WO 2007011809, 2007. 6. Tsang, K. Y.; Brimble, M. A. Tetrahedron 2007, 63, 6015. 7. For reviews, see: (a) Gao, Y.; Ren, Q.; Wu, H.; Li, M.; Wang, J. Chem. Commun. 2010, 9232; (b) Liu, T.-L.; He, Z.-L.; Wang, C.-J. Chem. Commun. 2011, 9600; (c)

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