Download PDF
Synlett 2016; 27(07): 1083-1090
DOI: 10.1055/s-0035-1560602
letter
© Georg Thieme Verlag Stuttgart · New York

Four-Component Reaction of Substituted β-Nitrostyrenes, Cyclohexanones, Activated Methylene Compounds, and Ammonium Acetate: Efficient Strategy for Construction of Tetrahydroindole Skeletons

Shuwen Xue
a   School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China   Email: wangcd@yzu.edu.cn
,
Yan Li
a   School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China   Email: wangcd@yzu.edu.cn
,
Lizhong Wang
b   Department of Environmental and Chemical Engineering, Taizhou Polytechnic College, Taizhou 225300, P. R. of China
,
Jiaming Liu
a   School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China   Email: wangcd@yzu.edu.cn
,
Xushun Qing
a   School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China   Email: wangcd@yzu.edu.cn
,
Cunde Wang*
a   School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China   Email: wangcd@yzu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 04 December 2015

Accepted after revision: 29 December 2015

Publication Date:
21 January 2016 (online)

    Permissions and Reprints All articles of this category


Abstract

An efficient one-pot four-component reaction was developed for the synthesis of two different stereochemical classes of substituted 2-aminotetrahydroindoles from substituted β-nitrostyrenes, cyclohexanones, ammonium acetate, and activated methylene compounds, such as Meldrum’s acid, 4-hydroxycoumarin, cyclohexanediones, cyclopentane-1,3-dione, or alkyl cyanoacetates. Both electron-donating and electron-withdrawing groups are tolerated in the aryl ring of the β-nitrostyrene. The reaction utilizes the triethylamine-promoted formation of new C–C and C–N bonds, and simultaneous aromatization in a domino fashion.

Key words

indoles - multicomponent reactions - domino reactions - cyclizations

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1560602.
  • Supporting Information
 

  • References

  • 3 Sun L, Tran N, Liang C, Hubbard S, Tang F, Lipson K, Schreck R, Zhou Y, McMahon G, Tang C. J. Med. Chem. 2000; 43: 2655
    CrossrefSearch in Google Scholar
  • 6 Taber DF, Tirunahari PK. Tetrahedron 2011; 67: 7195
    CrossrefPubMedSearch in Google Scholar
  • 9 Mamedov VA, Berdnikov EA, Tsuboi S, Hamamoto H, Komiyama T, Gorbunova EA, Gubaidullin AT, Litvinov IA. Russ. Chem. Bull. 2006; 55: 1455
    CrossrefSearch in Google Scholar
  • 10 Yedukondalu M, Sridhar R, Jawahar Luther B, Basaveswara Rao MV. J. Appl. Chem. (Lumami, India) 2014; 3: 1295 ; http://www.joac.info/ContentPaper/2014/347.pdf
    Search in Google Scholar
  • 13 Trofimov BA, Mikhaleva AI, Ivanov AV, Shcherbakova VS, Ushakov IA. Tetrahedron 2015; 71: 124
    CrossrefSearch in Google Scholar
    • 14a Tietze LF, Dietz S, Böhnke N, Düfert MA, Objartel I, Stalke D. Eur. J. Org. Chem. 2011; 6574
    • 14b Xiong G, Wei M, Zhou Y, Li Y, Zhang F, Gong Y. Synthesis 2011; 3439
      Thieme Connect
    • 14c Song W, Lu W, Wang J, Lu P, Wang Y. J. Org. Chem. 2010; 75: 3481
      CrossrefSearch in Google Scholar
    • 14d Ghabraie E, Balalaie S, Bararjanian M, Bijanzadeh HR, Rominger F. Tetrahedron 2011; 67: 5415
      CrossrefSearch in Google Scholar
  • 16 C7a-Substituted 3-Aryl-5,6,7,7a-tetrahydro-4H-indol-2-amines 4a–r and C7-Substituted 3-Aryl-5,6-dihydro-1H-indol-2-amines 5a–x; General Procedure Et3N (7.5 mmol, 0.757 g) was added to a mixture of the appropriate substituted β-nitrostyrene (3 mmol), cycloalkanone (3 mmol), and NH4OAc (3 mmol, 0.231 g) in EtOH (15 mL), and the mixture was stirred at 65 °C for 2 h. The appropriate activated methylene compound (Meldrum’s acid, 4-hydroxy-2H-chromen-2-one, cyclohexane-1,3-dione, cyclopentane-1,3-dione, or cyanoacetate) (3 mmol) was added, and the mixture was stirred for about 24 h until the reaction was complete (TLC; hexanes–EtOAc, 1:1). The mixture was then filtered, and the residue was washed with cold EtOAc (10 mL) to give a white solid product 4a–r. Subsequently, the filtrate was concentrated under reduced pressure, and the residue was mixed with H2O (10 mL) and extracted with CH2Cl2 (2 × 10 mL). The organic phase was washed successively with H2O (10 mL) and brine (5 mL) then dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography [silica gel, EtOAc–hexanes (1:1)] to give the desired product 5a–x. 5-[2-Amino-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-7aH-indol-7a-yl]-2,2-dimethyl-1,3-dioxane-4,6-dione (4a) White solid; yield: 0.541g (65%); mp 225.3–225.6 °C (MeOH–CH2Cl2). IR (KBr): 3209, 3143, 2939, 2852, 1677, 1610, 1551, 1519, 1479, 1206, 1077, 830, 747 cm–1. 1H NMR (600 MHz, DMSO-d6 ): δ = 9.57 (s, 1 H), 7.83 (s, 1 H), 7.61 (s, 1 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 8.4 Hz, 2 H), 3.80 (s, 3 H), 3.46 (d, J = 12.0 Hz, 1 H), 2.62 (d, J = 11.4 Hz, 1 H), 2.35 (td, J = 13.2, 6.0 Hz, 1 H), 1.80 (d, J = 11.4 Hz, 1 H), 1.58 (d, J = 13.2 Hz, 1 H), 1.54 (s, 6 H), 1.47–1.41 (m, 1 H), 1.05–0.98 (m, 1 H), 0.89 (t, J = 11.4 Hz, 1 H). 13C NMR (150 MHz, DMSO-d6 ): δ = 171.70, 163.61, 159.24, 130.69, 121.50, 120.15, 114.35, 99.14, 86.89, 71.02, 70.97, 55.19, 27.51, 27.26, 22.27. HRMS (ESI): m/z [M + Na]+ calcd for C21H24N2NaO5: 407.1583; found: 407.1578. 5-[2-Amino-3-(4-methoxyphenyl)-1,4,5,6-tetrahydro-7H-indol-7-ylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (5a) White solid; yield: 0.091 g (11%); mp 189.4–189.5 °C (MeOH–CH2Cl2). IR (KBr): 3380, 3234, 2932, 1677, 1605, 1556, 1481, 1450, 1256, 1076, 938, 786 cm–1. 1H NMR (600 MHz, DMSO-d6 ): δ = 11.35 (s, 1 H), 7.79 (s, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 7.8 Hz, 2 H), 3.80 (s, 3 H), 2.90 (t, J = 6.0 Hz, 2 H), 2.60 (t, J = 6.6 Hz, 2 H), 1.76 (t, J = 6.6 Hz, 2 H), 1.59 (s, 6 H). 13C NMR (150 MHz, DMSO-d6 ): δ = 163.82, 158.62, 154.73, 144.64, 130.13, 126.50, 122.78, 116.25, 114.29, 100.24, 83.89, 55.17, 31.59, 25.83, 24.43, 23.37. HRMS (ESI): m/z [M + Na]+ calcd for C21H22N2NaO5: 405.1426; found: 405.1418
  • 17 CCDC 930559 (4d), 933723 (5a), 979509 (5c), 992839 (5s), 990834 (5t) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.