Synthesis of New Bis-Iminodihydrofurans

Abstract

A new synthetic pathway to new bis-iminodihydrofurans is proposed, which involves the synthesis of N-substituted iminodihydrofurans from reaction of iminodihydrofurans with 2-cyanoacetohydrazide and their condensation with tertiary α-hydroxyketones. This sequence of reactions opens the new approach to the synthesis of novel polyheteroconjugated systems consisting from iminodihydrofuran rings. The methodology is simple, rapid and inexpensive affording high yields of the potentially bioactive products.

Keywords:
iminodihydrofurans; 2-cyanoacetohydrazide; N-substituted iminodihydrofurans; tertiary α-hydroxyketones; bis-iminodihydrofurans

Introduction

2-Oxo-2,5-dihydrofuran subunit has been found both in several bioactive natural (ascorbic, penicillic and tetronic acids), synthetic products^1-11 and in a number of drugs with diverse biological activities, such as antifungal, antibacterial and anti-inflammatory.^1,2,12-14

The 2-imino-2,5-dihydrofuran structure is related to 2-oxo-2,5-dihydrofuran fragment. The synthesis, structure and reactivity of 2-imino-2,5-dihydrofurans have been studied intensively in the last decade.^15-28 Many of these compounds have antibacterial activity.^29,30 On the other hand, N-substituted derivatives of iminodihydrofurans have not been studied extensively.^31,32

In continuation of our current studies on the chemistry of iminodihydrofurans (1a,b),¹⁷ we studied their interaction with 2-cyanoacetohydrazide, which was known in coumarine series.³³ Synthesized N-substituted iminodihydrofurans condensed with tertiary a-hydroxyketones to give bis-iminodihydrofurans. In the literature, bis-iminodihydrofurans have been the subject of some reports.^22,34-36

Results and Discussion

The simple and easy synthesis of a new series of bis-iminodihydrofurans 5a-e begins with the preparation of N-substituted iminodihydrofurans 3a,b. The latter were easily obtained by interaction of iminodihydrofurans 1a,b with 2-cyanoacetohydrazide (2) at room temperature, in glacial acetic acid. Compounds 3a,b exist as two (E and Z) stereoisomer types (Scheme 1).

Scheme 1
Preparation of N-substituted iminodihydrofurans 3a,b.

Next, bis-iminodihydrofuran compounds 5a-e were obtained, in cascade reaction, from tertiary α-hydroxyketones 4a-d and N-substituted iminodihydrofuran derivatives 3a,b in the presence of a catalytic amount of sodium methoxide in methanol. It has been used a method involving the condensation of tertiary α-hydroxyketones with N-(alkyl)-2-cyanoacetamides.¹⁷

The cyclization between the hydroxyl group of compounds 4a-e and the cyano group of compounds 3a,b followed by a Knoevenagel condensation afforded the bis-iminolactones 5a-e in good yields (90-96%, Scheme 2). The ease of ring formation was due to the presence of a gem-dialkyl producing a Thorpe-Ingold conformational effect,^37,38 which states that alkyl substitution on a central methylene causes compression of the internal angle, that leads to an easier ring formation. The suggested mechanism is described in literature.¹⁷

Scheme 2
Preparation of bis-iminodihydrofurans 5a-e.

The structures of the products were determined from their elemental analyses and spectroscopic data. Compounds 4b and 5b have asymmetric carbon atom. The specific rotation were measured for these compounds. They are optically inactive compounds.

Conclusions

We have developed a mild and efficient, environmentally friendly strategy for synthesis of potentially bioactive bis-iminodihydrofurans from readily available starting materials. This sequence of reactions opens a new approach to the synthesis of a novel polyheteroconjugated systems consisting from iminodihydrofuran rings. The methodology is simple, rapid and inexpensive affording high yields of the cyclized products with operational simplicity.

Experimental

All solvents were dried by standard methods. Melting points were measured on an Electrothermal 9100 apparatus (Bibby Scientific Limited, Staffordshire, UK). Elemental analyses for C, H and N were obtained using a Heraeus CHN-O-Rapid analyzer (Heraeus Holding GmbH, Hanau, Germany). Infrared (IR) spectra were recorded on a Specord 75 IR spectrometer (Analytik Jena AG, Jena, Germany). Proton (¹H) nuclear magnetic resonance (NMR) spectra were recorded at 300 MHz on a Varian Mercury 300 VX spectrometer (Palo Alto, CA, USA) with dimethyl sulfoxide (DMSO)-d₆ and DMSO-d₆:carbon tetrachloride (CCl₄), 1:3 (v/v) as solvent and tetramethylsilane (TMS) as internal standard. Monitoring of the reaction course and the purity of the products was carried out by thin layer chromatography (TLC), on silufol UV254 plates, eluent acetone:benzene 1:2 (v/v) and visualized using iodine vapor. Specific optical rotation was decided on a Polartronic H532 polarimeter (Schmidt + Haensch GmbH & Co., Berlin, Germany). Tertiary a-hydoxy ketones were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without further purification.

The starting compounds 1a,b and 2 were synthesized by using a published procedure.^17,39

General procedure for synthesis of compounds 3a,b

To a well-stirred warm (40-50 ºC) 10 mmol solution of 2-imino-2,5-dihydrofuran (1a,b) in 10 mL glacial acetic acid was added 2-cyanoacetohydrazide (2) (1 g, 10 mmol). The reaction mixture was stirred at room temperature for 2 h. The product, which precipitated in the course of the reaction, was filtered and washed with water. Purification was performed by recrystallization.

Physical and spectral data for the synthesized compounds 3a,b

2-(2-(2-Cyanoacetyl)hydrazono)-4,5,5-trimethyl-2,5-dihydrofuran-3-carboxamide (3a)

White solid; mp: 237-238 ºC (from water); yield (2.4 g, 96%); IR υ / cm^-1 1620, 1640, 1680, 1685, 2220, 3250, 3280; ¹H NMR (300 MHz, DMSO-d₆) δ 1.48 (s, 1.8H) and 1.52 (s, 4.2H, 2CH₃), 2.32 (s, 0.9H) and 2.36 (s, 2.1H, CH₃), 3.62 (s, 1.4H) and 3.92 (s, 0.6H, CH₂), 7.34 (bs, 1H), 7.43 (bs, 0.3H) and 8.18 (bs, 0.7H, NH₂), 9.96 (s, 0.3H) and 10.64 (s, 0.7H, NH); anal. calcd. for C₁₁H₁₄N₄O₃ (250.26): C, 52.79; H, 5.64; N, 22.39%; found: C, 52.89; H, 5.88; N, 22.51%.

2-(2-(2-Cyanoacetyl)hydrazono)-N-4,5,5-tetramethyl-2,5-dihydrofuran-3-carboxamide (3b)

White solid; mp: 268-269 ºC (from water); yield (2.51 g, 95%); IR υ / cm^-1 1620, 1644, 1680, 1690, 2225, 3250, 3275; ¹H NMR (300 MHz, DMSO-d₆) δ 1.48 (s, 1.8H) and 1.52 (s, 4.2H, 2CH₃), 2.32 (s, 0.9H) and 2.36 (s, 2.1H, CH₃), 2.75 (d, 3.3H) and 2.82 (d, 0.7H, J 4.9 Hz, NCH₃), 3.62 (s, 1.4H) and 3.92 (s, 0.6H, CH₂), 8.62 (bs, 0.3H) and 8.88 (bs, 0.7H, NH), 9.98 (s, 0.3H) and 10.68 (s, 0.7H, NH); anal. calcd. for C₁₂H₁₆N₄O₃ (264.28): C, 54.53; H, 6.10; N, 21.19%; found: C, 54.65; H, 6.24; N, 21.29%.

General procedure for the synthesis of compounds 5a-d

A mixture of the appropriate tertiary α-hydroxyketones 4a-d (5 mmol) and 2-(2-(2-cyanoacetyl)hydrazono)-4,5,5-trimethyl-2,5-dihydrofuran-3-carboxamide 3a (1.25 g, 5 mmol) with a solution of sodium methoxide (0.115 g, 0.5 mmol) in absolute methanol (15 mL) was stirred at 35-40 ºC for 5h. After solvent evaporation, water was poured onto the residue, the resulting precipitate was filtered and washed with water.

2-(2-(2-Imino-4,5,5-trimethyl-2,5-dihydrofuran-3-carbonyl)hydrazono)-4,5,5-trimethyl-2,5-dihydrofuran-3-carboxamide (5a)

White solid; mp: 303-305 ºC (from ethanol); yield (1.5 g, 90%); IR υ / cm^-1 1620, 1644, 1680, 1690, 3255, 3275; ¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (s, 6H, 2CH₃), 1.51 (s, 6H, 2CH₃), 2.36 (s, 3H, CH₃), 2.40 (s, 3H, CH₃), 7.36 (bs, 1H) and 8.26 (bs, 1H, NH₂), 7.39 (s, 1H, NH), 12.25 (s, 1H, NH); anal. calcd. for C₁₆H₂₂N₄O₄ (334.38): C, 57.47; H, 6.63; N, 16.76%; found: C, 57.58; H, 6.75; N, 16.89%.

2-(2-(5-Ethyl-2-imino-4,5-dimethyl-2,5-dihydrofuran-3-carbonyl)hydrazono)-4,5,5-trimethyl-2,5-dihydrofuran-3-carboxamide (5b)

White solid; mp: 309-310 ºC (from ethanol); yield (1.57 g, 90%), [α]_D²⁰ 0 (c 0.5, DMSO); IR υ / cm^-1 1622, 1645, 1680, 1685, 3254, 3278; ¹H NMR (300 MHz, DMSO-d₆:CCl₄, 1:3) δ 0.78 (t, 3H, J 4.2 Hz, CH₂CH₃), 1.42 (s, 3H, 2CH₃), 1.51 (s, 6H, 2CH₃), 1.80 (q, 2H, J 5.4 Hz, CH₂CH₃), 2.37 (s, 6H, 2CH₃), 7.37 (bs, 1H) and 8.28 (bs, 1H, NH₂), 7.39 (s, 1H, NH), 12.26 (s, 1H, NH); anal. calcd. for C₁₇H₂₄N₄O₄ (348.40): C, 58.61; H, 6.94; N, 16.08%; found: C, 58.78; H, 7.09; N, 16.27%.

2-(2-(2-Imino-4-methyl-1-oxaspiro[4.4]non-3-enecarbonyl)hydrazono)-4,5,5-trimethyl-2,5-dihydrofuran-3-carboxamide (5c)

White solid; mp: 281-282 ºC (from ethanol); yield (1.6 g, 89%); IR υ / cm^-1 1625, 1640, 1680, 1685, 3250, 3275; ¹H NMR (300 MHz, DMSO-d₆:CCl₄, 1:3) δ 1.42 (m, 2H) and 1.58-1.85 (m, 6H, m(CH₂)₄), 1.45 (s, 6H, 2CH₃), 2.38 (s, 6H, 2CH₃), 7.36 (bs, 1H) and 8.25 (bs, 1H, NH₂), 7.39 (s, 1H, NH), 12.25 (s,1H, NH); anal. calcd. for C₁₈H₂₄N₄O₄ (360.41): C, 59.99; H, 6.71; N, 15.55%; found: C, 60.08; H, 6.85; N, 15.69%.

2-(2-(2-Imino-4-methyl-1-oxaspiro[4.5]dec-3-enecarbonyl)hydrazono)-4,5,5-trimethyl-2,5-dihydrofuran-3-carboxamide (5d)

White solid; mp: 274-275 ºC (from ethanol); yield (1.72 g, 92%); IR υ /cm^-1 1620, 1642, 1684, 1691, 3254, 3280; ¹H NMR (300 MHz, DMSO-d₆:CCl₄, 1:3) δ 1.27 (m, 1H), 1.47(m, 2H) and 1.58-1.82 (m, 7H, (CH₂)₅), 1.45 (s, 6H), 2.36 (s, 3H), 2.38 (s, 3H), 7.36 (bs, 1H) and 8.25 (bs, 1H, NH₂), 7.39 (s, 1H, NH), 12.25 (s, 1H, NH); anal. calcd. for C₁₉H₂₆N₄O₄ (374.44): C, 60.95; H, 6.99; N, 14.96%; found: C, 61.04; H, 7.07; N, 15.14%.

2-(2-(2-Imino-4,5,5-trimethyl-2,5-dihydrofuran-3-carbonyl)hydrazono)-N-4,5,5-tetramethyl-2,5-dihydofuran-3-carboxamide (5e)

White solid; mp: 224-225 ºC (from ethanol); yield (1.58 g, 91%); IR υ / cm^-1 1620, 1644, 1682, 1690, 3252, 3281; ¹H NMR (300 MHz, DMSO-d₆:CCl₄, 1:3) δ 1.45 (s, 6H, 2CH₃), 1.50 (s, 6H, 2CH₃), 2.38 (s, 3H, CH₃), 2.40 (s, 3H, CH₃), 2.85 (d, 3H, J 3.4 Hz, NCH₃), 7.39 (s, 1H, NH), 8.78 (bs, 1H, NH), 12.25 (s, 1H, NH); anal. calcd. for C₁₇H₂₄N₄O₄ (348.40): C, 58.61; H, 6.94; N, 16.08%; found: C, 58.66; H, 7.12; N, 16.19%.

Supplementary Information

Supplementary information is available free of charge at http://jbcs.sbq.org.br as a PDF file.

https://minio.scielo.br/documentstore/1678-4790/6YbZWRSmyqRCDWpzqJMvWPt/e7078209bc0bee55e77b25f7e1398205a830389b.pdf

Acknowledgments

We are grateful to PhD Henrik Panosyan for NMR analyses (Molecular Structure Research Centre, Scientific-Technological Center of Organic and Pharmaceutical Chemistry, Yerevan, Armenia).

References

• ¹
  Rao, Y. S.; Chem. Rev. (Washington, DC, U. S.) 1964, 64, 353.
• ²
  Rao, Y. S.; Chem. Rev. (Washington, DC, U. S.) 1976, 76, 625.
• ³
  Avetisyan, A. A.; Dangyan, M. T.; Russ. Chem. Rev. 1977, 46, 643.
• ⁴
  Ortega, M. J.; Zubia, E.; Ocana, J. M.; Naranjo, S.; Salva, J.; Tetrahedron 2000, 56, 3963.
• ⁵
  Rossi, R.; Bellina, F.; Targets Heterocycl. Syst. 2001, 5, 169.
• ⁶
  Jung, J. H.; Pummangura, S.; Chaichantipyuth, S.; Patarapanich, C.; Fanwick, P. E.; Chang, C. J.; McLaughlin, J. L.; Tetrahedron 1990, 46, 5043.
• ⁷
  Dawidson, B. S.; Ireland, C. M.; J. Nat. Prod. 1990, 53, 1036.
• ⁸
  Miao, S.; Andersen, R. J.; J. Org. Chem. 1991, 56, 6275.
• ⁹
  Kuhnt, D.; Anke, T.; Besl, H.; Bross, M.; Herrmann, R.; Mocek, U.; Steffan, B.; Steglich, W.; J. Antibiot. 1990, 43, 1413.
• ¹⁰
  Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H.; Phytochemistry 1982, 21, 695.
• ¹¹
  Avetisyan, A. A.; Tokmadzhyan, G. G.; Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 1987, 23, 595.
• ¹²
  Larock , R. C.; Riefling, B.; Fellows, C. A.; J. Org. Chem. 1978, 43, 131.
• ¹³
  Caine, D.; Frobese, A. S.; Ukachukwu, V. C.; J. Org. Chem. 1983, 48, 740.
• ¹⁴
  Desmond, R.; Dolling, U.; Marcune, B.; Tillyer, R.; Tschaen, D.; WO Pat. Appl. 96/08482, 1996 (CA 125:P86474).
• ¹⁵
  Villemin, D.; Liao, L.; Synth. Commun. 2001, 31, 1771.
• ¹⁶
  Villemin, D.; Liao, L.; Synth. Commun. 2003, 33, 1575.
• ¹⁷
  Avetissyan, A.; Karapetyan, L.; Synth. Commun. 2009, 39, 7.
• ¹⁸
  Avetisyan, A. A.; Alvandzhyan, A. G.; Avetisyan, K. S.; Russ. J. Org. Chem. 2009, 45, 1871.
• ¹⁹
  Avetisyan, A. A; Karapetyan, L. V.; Tadevosyan, M. D.; Russ. J. Org. Chem. 2009, 45, 1031.
• ²⁰
  Avetisyan, A. A; Karapetyan, L. V.; Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2010, 46, 15.
• ²¹
  Avetisyan, A. A.; Karapetyan, L. V.; Tadevosyan, M. D.; Russ. Chem. Bull. 2010, 59, 974.
• ²²
  Cheikh, N.; Bar, N.; Choukchou-Braham, N.; Mostefa-Kara, B.; Lohier, J. F.; Sopkova, J.; Villemin, D.; Tetrahedron 2011, 67, 1540.
• ²³
  Mal'kina, A. G.; Sokolyanskaya, L. V.; Kudyakova, R. N.; Sinegovskaya, L. M.; Albanov, A. I., Shemyakina, O. A.; Trofimov, B. A.; Russ. J. Org. Chem. 2005, 41, 61.
• ²⁴
  Trofimov, B. A.; Mal'kina, A. G.; Shemyakina, O. A.; Borisova, A. P.; Nosyreva, V. V.; Dyachenko, O. A.; Kazheva, O. N.; Alexandrov, G. G.: Synthesis 2007, 17, 2641.
• ²⁵
  Trofimov, B. A.; Mal'kina, A. G.; Shemyakina, O. A.; Nosyreva, V. V.; Borisova, A. P.; Khutsishvili, S. S.; Krivdin, L. B.; Synthesis 2009, 18, 3136.
• ²⁶
  Trofimov, B. A.; Mal'kina, A. G.; Borisova, A. P.; Shemyakina, O. A.; Nosyreva, V. V.; Albanov, A. I.; Synthesis 2010, 18, 3174.
• ²⁷
  Mal'kina, A. G.; Borisova, A. P.; Nosyreva, V. V.; Shemyakina, O. A.; Albanov, A. I.; Trofimov, B. A.; Arkivoc 2011, ix, 281.
• ²⁸
  Kobayashi, K.; Matsumoto, K.; Konishi, H.; Heterocycles 2011, 83, 99.
• ²⁹
  Avetisyan, A. A; Karapetyan, L. V.; Paronikyan, R. V.; Stepanyan, H. M.; Pharm. Chem. J. 2011, 45, 156.
• ³⁰
  Avetisyan, A. A; Karapetyan, L. V.; Paronikyan, R. V.; Stepanyan, H. M.; Pharm. Chem. J. 2011, 45, 723.
• ³¹
  Avetisyan, A. A.; Karapetyan, L. V.; Heterocycl. Commun. 2012, 18, 263.
• ³²
  Tang, Y.; Li, Ch.; Tetrahedron Lett. 2006, 47, 3823.
• ³³
  Gorobets, N. Y.; Borisov, A. V.; Silin, A. V.; Nikitchenko, V. M.; Kovalenko, S. N.; Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2002, 38, 1389.
• ³⁴
  Avetisyan, A. A.; Karapetyan, L. V.; Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2012, 48, 1613.
• ³⁵
  Skvortsov, Y. M.; Fartisheva, O. M.; Mal'kina, A. G.; Trofimov, B. A.; Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 1985, 21, 1393.
• ³⁶
  Trofimov, B. A.; Mal'kina, A. G.; Shemyakina, O. A.; Kudyakova, R. N.; Sokolyanskaya, L. V.; Sinegovskaya, L. M.; Albanov, A. I.; Smirnov, V. I.; Kazheva, O. N.; Chekhlov, A. N.; Russ. J. Org. Chem. 2005, 41, 884.
• ³⁷
  Beesley, R. M.; Ingold, C. K.; Thorpe, J. F.; J. Chem. Soc. 1915, 107, 1080.
• ³⁸
  Ingold, C. K.; J. Chem. Soc. 1921, 119, 305.
• ³⁹
  Organic Reactions, vol. 3; Koshechkova, K. A., ed.; Foreign Literature: Moscow, Russia, 1951, p. 366.

Publication Dates

• Publication in this collection
  May 2016

History

• Received
  07 Aug 2015
• Accepted
  11 Dec 2015