CC BY ND NC 4.0 · SynOpen 2018; 02(01): 0036-0040
DOI: 10.1055/s-0036-1591918
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Iodine as a New Catalyst for the Condensation of 2-Hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone with Cyclic Enaminones: Synthesis of Spiro-dihydropyridine Derivatives under Acid-Free Conditions

,
Vahid Saberi
,
Seyedmahmoudreza Keshavarz
Further Information

Publication History

Received: 05 November 2017

Accepted after revision: 16 January 2018

Publication Date:
01 February 2018 (online)

 

Abstract

Iodine has been used as a new catalyst for the synthesis of spiro-dihydropyridine derivatives by the condensation of cyclic enaminones and 2-hydroxy-2,2-bisindan-1,1′,3,3′-tetrone.


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The properties of molecular iodine, including its Lewis acidity, lead to a range of applications in organic synthesis.[1] [2] [3] [4] Nitrogen-containing heterocyclic compounds have been of interest for the development of organic synthesisthrough decades.[5–8] Among them, 1,4-dihydropyridines (1,4-DHPs; Figure [1]) are an important class of compounds in the field of vasodilation and bronchodilation, being potent calcium antagonists and calcium channel blockers.[9] [10] [11] [12]

Zoom Image
Figure 1 Selected examples of dihydropyridines

Spiro-heterocycles, due to their steric constraints, represent an important class of substances that often have interesting biological properties.[13] [14] [15] Among them, spiro-dihydropyridine derivatives serve as important building blocks in a wide range of biologically active compounds.[16] There are several synthetic methods available for the preparation of functionalized dihydropyridines.[17]

2-Hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone can be readily generated by acid or base catalyzed condensation of ninhydrin with 1,3-indanedione.[18] Activation of 2-hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone for electrophilic reactions has been achieved under acidic conditions such as AcOH/H2SO4 for addition of phenols,[19] AcOH for enol condensation,[20] triflic acid,[21] acidic magnetic nanoparticle for synthesis of pyrazoles,[22] and silica-sulfuric acid for synthesis of dihydropyridines.[23] However, the use of acidic conditions can cause rearrangements and can also require high temperatures in some cases.

In the present work, in a continuation of our ongoing research program in the field of synthesis of spiro-heterocyclic compounds, we report the reaction of 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone 1 and cyclic enaminones 2aj in the presence of molecular iodine under mild reaction conditions to form spiro-dihdydropyridines 3aj (Scheme [1]).

Zoom Image
Scheme 1 Synthesis spiro-dihydropyridines

Firstly, 1,3-indandione was reacted with ninhydrin in the presence of triethylamine in EtOH at room temperature, to afford 2-hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone 1. The reaction of compound 1 was tested initially with 6-aminouracil in dimethyl sulfoxide (DMSO) at 120 °C without catalyst. However, these conditions did not afford the desired product 3a (Table [1], entry 2). The use of an acidic catalyst such as p-TSA or acetic acid gave 3a in moderate yields (entries 3 and 4). Our group has previously used molecular iodine as a catalyst[1] [24] and when we examined the use of iodine in DMSO at 120 °C the reaction proceeded in excellent yield (entry 5). To study the effect of temperature, an additional experiment was performed at 100 °C, resulting in 91% yield of 3a after 4 hours (entry 8). However, when the reaction was performed at lower temperatures, the yield decreased dramatically (entries 9 and 10). When solvents such as N,N-dimethylformamide (DMF) and toluene were examined, again a decrease in the yield of the reaction was observed (entries 11 and 12). Therefore, 20 mol% I2 in DMSO at 100 °C was established as the optimal conditions for the current methodology.

Table 1 Optimization of Reaction Conditions for the Preparation of 3a a

Entry

Solvent

Catalyst

Catalyst (%)

Temp. (°C)

Time (h)

Yield (%)b

1

DMSO

none

100

24

2

DMSO

none

120

24

3

DMSO

p-TSA

100

120

12

42

4

DMSO

HOAc

100

120

12

37

5

DMSO

I2

100

120

12

94

6

DMSO

I2

20

120

12

92

7

DMSO

I2

10

120

12

65

8

DMSO

I2

20

100

4

91

9

DMSO

I2

20

80

4

44

10

DMSO

I2

20

50

4

23

11

DMF

I2

20

100

4

67

12

toluene

I2

20

100

4

35

a Reagents and conditions: 1 (1 mmol), 2a (1 mmol), solvent (4 mL), in a capped vial.

b Isolated yield.

To investigate the scope of this reaction, a range of cyclic enaminones was used; the results are summarized in Table [2]. All derivatives 3aj were obtained in high yields, although in the case of compounds 3i and 3j the yield of the reaction decreased slightly, presumably because the nitrogen of the 6-aminocoumarin is further substituted and therefore more sterically hindered.

All novel compounds 3af were fully characterized by elemental analysis, IR, 1H NMR, 13C NMR spectroscopic analysis and HRMS. For example, the HRMS spectrum of 3a displayed m/z [M+H]+ at 398.0775 and the IR spectrum showed absorption bands at 3249, 1710, 1690, and 1666 cm–1 assigned to NH stretching and five-membered ketone, amide, and α,β-unsaturated ketone carbonyl groups, respectively. The 1H-decoupled 13C NMR spectrum of 3a showed 18 distinct resonances, with a signal at 56 ppm being attributed to the spiro- carbon.

Finally, to investigate the scalability of our reaction, the reaction was conducted on a gram scale under the optimized reaction conditions and no significant changes in either reaction time or yield were observed (Scheme [2]).

Table 2 Synthesis of 3aj a

Entry

Cyclic Enaminones

Product

Yield (%)b

1

2a

3a

91

2

2b

3b

88

3

2c

3c

85

5

2d

3d

92

5

2e

3e

86

6

2f

3f

80

7

2g

3g

73

8

2h

3h

83

9

2i

3i

61

10

2j

3j

57

a Reagents and conditions: 1 (1 mmol), 2aj (1 mmol), DMSO (4 mL), I2 (20 mol%) in a capped vial.

b Isolated yield.

Zoom Image
Scheme 2

Although we have not established the mechanism of the reaction experimentally, a plausible mechanism is proposed in Scheme [3]. The reaction between molecular iodine and hydroxy compound 1 could produce two intermediates, Path A gives intermediate 4, which is reported to be formed under acidic conditions,[19] [21] and Path B leads to intermediate 5. Michael addition of enaminone 2a to either the double bond of 4 or the carbocationic center of 5 gives intermediate 7, which undergoes intramolecular cyclocondensation to produce the desired product.

In conclusion, we have developed an efficient methodology for the synthesis of spiro-dihydropyridines in high yield from 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone as starting material.[25] [26] Activation of 2-hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone with molecular iodine as a mild catalyst under acid-free reaction conditions and a simple work-up procedure are features of this method.

Zoom Image
Scheme 3 Proposed mechanism of formation of spiro-dihydropyrans 3

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Supporting Information

  • References

  • 1 Moghaddam FM. Khodabakhshi MR. Aminaee M. Tetrahedron Lett. 2014; 55: 4720
  • 2 Alizadeh A. Saberi V. Mokhtari J. Synlett 2013; 24: 1825
  • 3 Zhang J. Gao Q. Wu X. Geng X. Wu YD. Wu A. Org. Lett. 2016; 18: 1686
  • 4 Hao WJ. Wang SY. Ji SJ. ACS Catal. 2013; 3: 2501
  • 5 Deiters A. Martin SF. Chem. Rev. 2004; 104: 2199
  • 6 Thansandote P. Lautens M. Chem. Eur. J. 2009; 15: 5874
  • 7 Zhu L. Cheng L. Zhang Y. Xie R. You J. J. Org. Chem. 2007; 72: 2737
  • 8 Martín R. Rodriguez RiveroM. Buchwald SL. Angew. Chem. Int. Ed. 2006; 45: 7079
    • 9a Safak C. Simsek R. Mini-Rev. Med. Chem. 2006; 6: 747
    • 9b Katoh M. Nakajima M. Shimada N. Yamazaki H. Yokoi T. Eur. J. Clin. Pharmacol. 2000; 55: 843
    • 9c Ruggenenti P. Perna A. Benini R. Remuzzi G. J. Am. Soc. Nephrol. 1998; 9: 2096
    • 10a Glossmann H. Ferry DR. Goll A. Striessnig J. Zernig G. Arzneim.-Forsch. 1985; 35: 1917
    • 10b Matowe WC. Akula M. Knaus EE. Wolowyk MW. Proc. West. Pharmacol. Soc. 1989; 32: 305
  • 11 Vo D. Matowe WC. Ramesh M. Iqbal N. Wolowyk MW. Howlett SE. Knaus EE. J. Med. Chem. 1995; 38: 2851
    • 12a Vo D. Nguyen JT. McEwen C.-A. Shan R. Knaus EE. Drug Dev. Res. 2002; 56: 1
    • 12b Edraki N. Mehdipour AR. Khoshneviszadeh M. Miri R. Drug Discovery Today 2009; 14: 1058
  • 13 Zhang YL. Li YF. Wang JW. Yu B. Shi YK. Liu HM. Steroids 2016; 109: 22
  • 14 Parameswarappa SG. Pigge FC. J. Org. Chem. 2012; 77: 8038
  • 15 Tejedor D. Cotos L. Méndez-Abt G. García-Tellado F. J. Org. Chem. 2014; 79: 10655
  • 16 Auria-Luna F. Marqués-López E. Mohammadi S. Heiran R. Herrera RP. Molecules 2015; 20: 15807
    • 17a Senczyszyn J. Brice H. Clayden J. Org. Lett. 2013; 15: 1922
    • 17b Debnath K. Singha K. Pramanik A. RSC Adv. 2015; 5: 31866
    • 17c Sarkar P. Mukhopadhyay C. Tetrahedron Lett. 2016; 57: 4306
    • 18a Campagna F. Carotti A. Casini G. Ferappi M. Gazz. Chim. Ital. 1983; 113: 507
    • 18b Schoenberg A. Singer E. Chem. Ber. 1970; 103: 3871
  • 19 Das S. Pramanik A. Fröhlich R. Patra A. Tetrahedron 2004; 60: 10197
  • 20 Das S. Fröhlich R. Pramanik R. J. Chem. Res. 2005; 9: 572
  • 21 Das S. Fröhlich R. Pramanik R. J. Chem. Res. 2007; 1: 5
  • 22 Ashis K. Mukherjee S. Pramanik R. RSC Adv. 2015; 130: 107847
  • 23 Ashis KR. Pramanik R. Mol. Diversity 2015; 3: 459
    • 24a Moghaddam FM. Bardajee RG. Ismaili H. Dokht M. Taimoory S. Synth. Commun. 2006; 36: 2543
    • 24b Moghaddam FM. Khodabakhshi MR. Aminaee M. Tetrahedron Lett. 2014; 55: 4720
  • 25 Typical procedure for the synthesis of spiro-dihydropyridines 3a–j: A mixture of 2-hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone 1 (1 mmol), cyclic enaminone 2af (1 mmol) and molecular iodine (20 mol%) in DMSO (4 mL) was stirred at 100 °C for 4 h. After completion of the reaction (monitored by TLC, ethyl acetate/n-hexane, 1:2) the reaction mixture was allowed to cool to room temperature. Water was added and the precipitate was filtered off and washed with acetone to give the product 3aj.
  • 26 Synthesis of 2-hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone 1: A mixture of 1,3-indandione (10 mmol), ninhydrin (10 mmol), and triethylamine (1 mmol) in EtOH (50 mL) was stirred at room temperature for 5 h. The precipitate was filtered and washed with EtOH (2 × 5 mL) to give 1. Yellow powder; mp 187–190 °C; 1H NMR (500 MHz, CDCl3): δ = 8.00–7.93 (m, 2 H, Ar), 7.92–7.83 (m, 6 H, Ar), 5.47 (s, 1 H, OH), 3.96 (s, 1 H, CH); 13C NMR (125 MHz, CDCl3): δ = 197, 196, 142, 141, 137, 136, 124, 124, 76, 53. Analytical data for spiro[indene-2,5′-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine]-1,2′,3,4′,6′(1′H,3′H,11′H)-pentaone (3a): Yield: 0.361 g (91%); red powder; mp 212–215 °C (dec.); IR (KBr): 3249, 2917, 1710, 1690, 1666 cm–1; 1H NMR (500 MHz, D2O): δ = 7.89–7.85 (m, 4 H, Ar-H), 7.36 (d, J = 6.9 Hz, 1 H, Ar-H), 7.24–7.17 (m, 2 H, Ar-H), 7.00 (d, J = 6.9 Hz, 1 H, Ar-H); 13C NMR (125 MHz, D2O): δ = 209, 187, 173, 170, 165, 162, 141, 138, 137, 136, 131, 130, 122, 119, 119, 100, 92, 56; Anal. Calcd for C22H11N3O5: C, 66.50; H, 2.79; N, 10.58. Found: C, 65.90; H, 2.81; N, 10.61; HRMS: m/z [M+H]+ calcd. for C22H11N3O5: 398.0777; found: 398.0775.

  • References

  • 1 Moghaddam FM. Khodabakhshi MR. Aminaee M. Tetrahedron Lett. 2014; 55: 4720
  • 2 Alizadeh A. Saberi V. Mokhtari J. Synlett 2013; 24: 1825
  • 3 Zhang J. Gao Q. Wu X. Geng X. Wu YD. Wu A. Org. Lett. 2016; 18: 1686
  • 4 Hao WJ. Wang SY. Ji SJ. ACS Catal. 2013; 3: 2501
  • 5 Deiters A. Martin SF. Chem. Rev. 2004; 104: 2199
  • 6 Thansandote P. Lautens M. Chem. Eur. J. 2009; 15: 5874
  • 7 Zhu L. Cheng L. Zhang Y. Xie R. You J. J. Org. Chem. 2007; 72: 2737
  • 8 Martín R. Rodriguez RiveroM. Buchwald SL. Angew. Chem. Int. Ed. 2006; 45: 7079
    • 9a Safak C. Simsek R. Mini-Rev. Med. Chem. 2006; 6: 747
    • 9b Katoh M. Nakajima M. Shimada N. Yamazaki H. Yokoi T. Eur. J. Clin. Pharmacol. 2000; 55: 843
    • 9c Ruggenenti P. Perna A. Benini R. Remuzzi G. J. Am. Soc. Nephrol. 1998; 9: 2096
    • 10a Glossmann H. Ferry DR. Goll A. Striessnig J. Zernig G. Arzneim.-Forsch. 1985; 35: 1917
    • 10b Matowe WC. Akula M. Knaus EE. Wolowyk MW. Proc. West. Pharmacol. Soc. 1989; 32: 305
  • 11 Vo D. Matowe WC. Ramesh M. Iqbal N. Wolowyk MW. Howlett SE. Knaus EE. J. Med. Chem. 1995; 38: 2851
    • 12a Vo D. Nguyen JT. McEwen C.-A. Shan R. Knaus EE. Drug Dev. Res. 2002; 56: 1
    • 12b Edraki N. Mehdipour AR. Khoshneviszadeh M. Miri R. Drug Discovery Today 2009; 14: 1058
  • 13 Zhang YL. Li YF. Wang JW. Yu B. Shi YK. Liu HM. Steroids 2016; 109: 22
  • 14 Parameswarappa SG. Pigge FC. J. Org. Chem. 2012; 77: 8038
  • 15 Tejedor D. Cotos L. Méndez-Abt G. García-Tellado F. J. Org. Chem. 2014; 79: 10655
  • 16 Auria-Luna F. Marqués-López E. Mohammadi S. Heiran R. Herrera RP. Molecules 2015; 20: 15807
    • 17a Senczyszyn J. Brice H. Clayden J. Org. Lett. 2013; 15: 1922
    • 17b Debnath K. Singha K. Pramanik A. RSC Adv. 2015; 5: 31866
    • 17c Sarkar P. Mukhopadhyay C. Tetrahedron Lett. 2016; 57: 4306
    • 18a Campagna F. Carotti A. Casini G. Ferappi M. Gazz. Chim. Ital. 1983; 113: 507
    • 18b Schoenberg A. Singer E. Chem. Ber. 1970; 103: 3871
  • 19 Das S. Pramanik A. Fröhlich R. Patra A. Tetrahedron 2004; 60: 10197
  • 20 Das S. Fröhlich R. Pramanik R. J. Chem. Res. 2005; 9: 572
  • 21 Das S. Fröhlich R. Pramanik R. J. Chem. Res. 2007; 1: 5
  • 22 Ashis K. Mukherjee S. Pramanik R. RSC Adv. 2015; 130: 107847
  • 23 Ashis KR. Pramanik R. Mol. Diversity 2015; 3: 459
    • 24a Moghaddam FM. Bardajee RG. Ismaili H. Dokht M. Taimoory S. Synth. Commun. 2006; 36: 2543
    • 24b Moghaddam FM. Khodabakhshi MR. Aminaee M. Tetrahedron Lett. 2014; 55: 4720
  • 25 Typical procedure for the synthesis of spiro-dihydropyridines 3a–j: A mixture of 2-hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone 1 (1 mmol), cyclic enaminone 2af (1 mmol) and molecular iodine (20 mol%) in DMSO (4 mL) was stirred at 100 °C for 4 h. After completion of the reaction (monitored by TLC, ethyl acetate/n-hexane, 1:2) the reaction mixture was allowed to cool to room temperature. Water was added and the precipitate was filtered off and washed with acetone to give the product 3aj.
  • 26 Synthesis of 2-hydroxy-2,2′-bisindan-1,1′,3,3′-tetrone 1: A mixture of 1,3-indandione (10 mmol), ninhydrin (10 mmol), and triethylamine (1 mmol) in EtOH (50 mL) was stirred at room temperature for 5 h. The precipitate was filtered and washed with EtOH (2 × 5 mL) to give 1. Yellow powder; mp 187–190 °C; 1H NMR (500 MHz, CDCl3): δ = 8.00–7.93 (m, 2 H, Ar), 7.92–7.83 (m, 6 H, Ar), 5.47 (s, 1 H, OH), 3.96 (s, 1 H, CH); 13C NMR (125 MHz, CDCl3): δ = 197, 196, 142, 141, 137, 136, 124, 124, 76, 53. Analytical data for spiro[indene-2,5′-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine]-1,2′,3,4′,6′(1′H,3′H,11′H)-pentaone (3a): Yield: 0.361 g (91%); red powder; mp 212–215 °C (dec.); IR (KBr): 3249, 2917, 1710, 1690, 1666 cm–1; 1H NMR (500 MHz, D2O): δ = 7.89–7.85 (m, 4 H, Ar-H), 7.36 (d, J = 6.9 Hz, 1 H, Ar-H), 7.24–7.17 (m, 2 H, Ar-H), 7.00 (d, J = 6.9 Hz, 1 H, Ar-H); 13C NMR (125 MHz, D2O): δ = 209, 187, 173, 170, 165, 162, 141, 138, 137, 136, 131, 130, 122, 119, 119, 100, 92, 56; Anal. Calcd for C22H11N3O5: C, 66.50; H, 2.79; N, 10.58. Found: C, 65.90; H, 2.81; N, 10.61; HRMS: m/z [M+H]+ calcd. for C22H11N3O5: 398.0777; found: 398.0775.

Zoom Image
Figure 1 Selected examples of dihydropyridines
Zoom Image
Scheme 1 Synthesis spiro-dihydropyridines
Zoom Image
Scheme 2
Zoom Image
Scheme 3 Proposed mechanism of formation of spiro-dihydropyrans 3