Formation of macrocyclic lactones in the Paternò–Büchi dimerization reaction

  1. Junya Arimura1,
  2. Tsutomu Mizuta1,
  3. Yoshikazu Hiraga1 and
  4. Manabu Abe1,2

1Department of Chemistry, Graduate School of Science, Hiroshima University (HIRODAI), 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
2Japan Science and Technology Agency, CREST, 5 Sanbancho, Chiyodaku, Tokyo, 102-0075, Japan

  1. Author email
  2. Corresponding author email

This article is part of the Thematic Series "Photocycloadditions and photorearrangements"

Guest Editor: A. G. Griesbeck
Beilstein J. Org. Chem. 2011, 7, 265–269. doi:10.3762/bjoc.7.35
Received 11 Nov 2010, Accepted 02 Feb 2011, Published 28 Feb 2011

Abstract

Furan-2-ylmethyl 2-oxoacetates 1a,b, in which the furan ring and the carbonyl moiety were embedded intramolecularly, were synthesized from commercially available furan-2-ylmethanol and their photochemical reaction (hν > 290 nm) was investigated. Twelve-membered macrocyclic lactones 2a,b with Ci symmetry including two oxetane-rings, which are the Paternò–Büchi dimerization products, were isolated in ca. 20% yield. The intramolecular cyclization products, such as 3-alkoxyoxetane and 2,7-dioxabicyclo[2.2.1]hept-5-ene derivatives, were not detected in the photolysate.

Keywords: furans; macrocyclic lactone; oxetane; Paternò–Büchi reaction; photochemical reaction

Findings

Photochemical [2 + 2] cycloaddition reaction of alkenes with carbonyls, so-called Paternò–Büchi reaction [1-13], is one of the most efficient methods for preparing synthetically useful four-membered heterocyclic compounds, i.e., oxetanes. The Paternò–Büchi reaction of furan with a triplet carbonyl, such as n,π* triplet benzophenone, produces regioselectively 2-alkoxyoxetanes 2OX (Scheme 1). The regioselective formation is rationalized by the relative stability of the intermediary triplet biradicals, BR versus BR’, and also by the relative nucleophilicity of the furan-ring carbons, i.e., C1 versus C2 (Scheme 1) [14-18].

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Scheme 1: Reaction of furan with triplet excited carbonyls, regioselectivity.

Biradical BR, in principle, possess two resonance forms, i.e., 1,4-biradical form and 1,6-biradical form. The 1,4-biradical form affords oxetane 2OX after the intersystem crossing (ISC). Alternatively, 2,7-dioxabicyclo[2.2.1]hept-5-ene OBH would be formed from the 1,6-biradical form. The regioisomeric oxetane 3OX should be formed via the regioisomeric biradical BR’. Biradical BR is energetically more stable than BR’, because BR can undergo radical delocalization. The electrophilic oxygen of the excited carbonyl should preferably interact with more nucleophilic C1 carbon to give selectively the biradical BR. Thus, only the 2-alkoxyoxetane 2OX has been observed in the Paternò–Büchi reactions reported so far [19-27]. Thus, in this study, furan-2-ylmethyl 2-oxoacetates 1a,b and 2-(furan-2-yl)ethyl 2-oxo-2-phenylacetate 1c [28] were synthesized, in which the furan ring and the carbonyl moiety are connected intramolecularly, and their photochemical reactions were investigated to see whether the reaction proceeds intramolecularly to produce the 3-alkoxyoxetane derivative A and/or the dioxabicyclo[2.2.1]hept-5-ene derivative B, or intermolecularly to give the 2-alkoxyoxetane derivative C (Scheme 2).

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Scheme 2: Possible pathways for the photochemical reaction of furan derivatives 1a–c.

Compounds 1ac [28] were synthesized from furan-2-ylmethanol or furan-2-ylethanol [29] (Scheme 3). Compound 1a (R = Ph) was irradiated in degassed benzene with a high-pressure Hg lamp with a Pyrex filter (Scheme 3). Interestingly, the Paternò–Büchi dimer product 2a (R = Ph), which possesses Ci symmetry, was obtained as the major product and contains the biologically important macrocyclic lactone structure [30-33]. The structure of 2a was unequivocally determined by the X-ray crystallographic analysis (Figure 1). The one-step preparation of the highly functionalized twelve-membered macrocyclic lactone is synthetically attractive. Intramolecular products, such as compounds A and B, were not detected in the photolysate, although intramolecular cyclization products are known to be products in the photoreaction of 3-substituted furan derivatives [11,21]. Furan-2-carbaldehyde (3) was the only assignable product during the photochemical reaction, which was monitored by 1H NMR spectroscopy (Figure 2). The intermolecular Paternò–Büchi reaction product, i.e., C in Scheme 2, was also not observed in the photolysate. This result suggests that the intramolecular Paternò–Büchi reaction of C is faster than the first intermolecular Paternò–Büchi reaction of 1a. The photoreaction of 1b (R = Me) gave 2b and 3 in 25% and 18%, respectively (Scheme 3). The dimerization product 2c was not observed in the reaction of 1c. Only polymeric products were present in the photolysate. Although the dimerization is sensitive to the chain-length, the Paternò–Büchi dimerization reaction could in future be applicable to the synthesis of a variety of macrocyclic lactones.

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Scheme 3: Synthesis and the photochemical reaction of furan-2-ylmethyl 2-oxoacetates 1a,b.

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Figure 1: X-ray crystal structure of the macrocyclic lactone 2a.

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Figure 2: 1H NMR spectra (500 MHz) for (a) the photolysate of 1a after 4 h irradiation in degassed and dried C6D6 solution, (b) for isolated macrocyclic lactone 2a, and (c) for furan-2-carbaldehyde (3).

To investigate the effects of concentration, solvent, and temperature on the formation of 2a, the photochemical reaction of 1a was conducted under the variety of conditions (Table 1). The yield of intermolecular product 2a was expected to be improved when the concentration of 1a was increased; however, no concentration effect was observed (entry 2). Under the reaction conditions, the formation of polymeric products increased as evidenced by 1H NMR analysis of the photolysate. Even with low concentrations of 1a (entry 3), the intramolecular photoproducts A and B were not detected by 1H NMR (500 MHz). To investigate the medium effect on the formation of 2a, the photochemical reaction of 1a was performed in several solvents (entries 4–6). The yield of 2a decreased with increasing solvent polarity; 16% in toluene (entry 4) and 10% in CH3CN (entry 6). Temperature had no effect on the yield of 2a (entries 7–9).

Table 1: Formation of 2a in the photochemical reaction of 1a under the various conditionsa.

entry solvent concentration of 1a (mM) temperature (°C) yield of 2a (%)b
1 benzene 80 15 18
2 benzene 800 15 8
3 benzene 8 15 17
4 toluene 80 15 16
5 CH2Cl2 80 15 10
6 CH3CN 80 15 10
7 benzene 80 50 5
8 toluene 80 −35 18
9 toluene 80 −75 14

aThe photochemical reactions of 1a were performed for 4 h with a high-pressure Hg lamp (300 W) with a Pyrex filter under a dry nitrogen atmosphere in dried and degassed solvent. bThe yields of 2a were determined on the basis of 1H NMR (500 MHz) peak areas; error ± 3%. Dimethyl fumarate was used as an internal standard.

In summary, the intramolecular products such as A and B were not observed in the photochemical reaction of furan derivatives 1a,b, but interestingly the Paternò–Büchi dimers 2a,b with the Ci symmetry, i.e., macrocyclic lactones, were isolated in ca. 20% yield. The results indicate that the intramolecular reactions, which produce 3-alkoxyoxetanes and 2,7-dioxabicyclo[2.2.1]hept-5-ene (Scheme 1 and Scheme 2), are slower than the intermolecular reaction which leads to the preferential formation of 2-alkoxyoxetane C which is followed by a second Paternò–Büchi reaction to give the observed macrocyclic lactones 2. This finding should stimulate future experimental and computational studies on the mechanistically and synthetically fascinating formation of macrocyclic lactone derivatives.

Experimental

NMR and MS measurements were made using JEOL JMN-LA500 and Thermo Fisher Scientific LTD Orbitrap XL spectrometers, respectively, at the Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University.

The furan derivatives 1ac (129 mg, 0.561 mmol) were dissolved in benzene (7.0 ml) and the degassed reaction mixture was irradiated with a high-pressure Hg lamp (300 W, hν > 290 nm) with a Pyrex filter. After 13 h, the solvent was removed in vacuo and dimethyl fumarate added as an internal standard. 1H NMR (500 MHz, CDCl3) was measured to determine the ratio of products. After the photoreaction, the residue was purified by repeated column chromatography and PTLC (hexane–EtOAc = 2:1) to give 2a,b as colorless crystals.

2a: 1H NMR (500 MHz, CDCl3) δ 7.55–7.51 (m, 4H), 7.40–7.31 (m, 6H), 6.35 (dd, J = 3.1, 1.1 Hz, 2H), 5.28 (dd, J = 12.5, 0.9 Hz, 2H), 4.82 (dt, J = 3.0, 0.9 Hz, 2H), 4.67 (dd, J = 3.0, 1.1 Hz, 2H), 3.71 (d, J = 12.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 171.6 (C), 148.7 (CH), 136.0 (CH), 128.6 (CH), 128.4 (CH), 125.7 (CH), 112.6 (C), 102.1 (CH), 90.7 (C), 61.4 (CH2), 55.2 (CH); HRMS (ESI) m/z calcd for C26H20O8Na (M + Na)+ 483.10504, found 483.10526.

2b: 1H NMR (500 MHz, CDCl3): δ 6.66 (dd, J = 3.0, 1.2 Hz, 2H), 5.23 (dt, J = 3.0, 0.8 Hz, 2H), 5.14 (dd, J = 12.5, 0.8 Hz, 2H), 4.27 (dd, J = 3.0, 1.2 Hz, 2H), 3.77 (d, J = 12.5 Hz, 2H), 1.57 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 173.3 (C), 149.8 (CH), 112.7 (C), 101.3 (CH), 88.1 (C), 61.5 (CH2), 53.1 (CH), 21.2 (CH3); HRMS (ESI) m/z calcd for C16H16O8Na (M + Na)+ 359.07374, found 359.07391.

Supporting Information

Supporting Information File 1: Experimental section for preparation of compounds 1ac, the detail of the X-ray structure of compound 2a, and 1H NMR and 13C NMR spectra for compounds 2a,b.
Format: PDF Size: 338.1 KB Download
Supporting Information File 2: X-Ray crystallographic data for compound 2a.
Format: CIF Size: 16.9 KB Download

Acknowledgements

M. A. acknowledges financial support in the form of a Grant-in-Aid for Scientific Research on Innovative Areas "π-Space" (No 21108516), the Scientific Research (B) (No. 19350021), and Tokuyama Science Foundation.

References

  1. Paternò, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341–361.
    Return to citation in text: [1]
  2. Büchi, G.; Inman, C. G.; Lipinsky, E. S. J. Am. Chem. Soc. 1954, 76, 4327–4331. doi:10.1021/ja01646a024
    Return to citation in text: [1]
  3. Yang, N. C.; Nussim, M.; Jorgenson, M. J.; Murov, S. Tetrahedron Lett. 1964, 5, 3657–3664. doi:10.1016/S0040-4039(01)89388-6
    Return to citation in text: [1]
  4. Arnold, D. R. The Photocycloaddition of Carbonyl Compounds to Unsaturated Systems: The Syntheses of Oxetanes. In Advances in Photochemistry; Noyes, W. A.; Hammond, G. S.; Pitts, J. N., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 1968; Vol. 6, pp 301–349. doi:10.1002/9780470133361.ch4
    Return to citation in text: [1]
  5. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum Press: New York, 1984; pp 425–487.
    Return to citation in text: [1]
  6. Griesbeck, A. G. Photochemical Oxetane Formation: Intermolecular Reactions. In CRC Handbook of Organic Photochemistry and Photobiology; Horspool, W. M.; Song, P.-S., Eds.; CRC Press: Boca Raton, 1995; pp 522–535.
    Return to citation in text: [1]
  7. Griesbeck, A. G. In CRC Handbook of Organic Photochemistry and Photobiology; Horspool, W. M.; Song, P.-S., Eds.; CRC Press: Boca Raton, 1995; pp 550–559.
    Return to citation in text: [1]
  8. Griesbeck, A. G.; Bondock, S. Oxetane Formation: Stereocontrol. In CRC Handbook of Organic Photochemistry and Photobiology, 2nd ed.; Horspool, W. M.; Lenci, F., Eds.; CRC Press: Boca Raton, 2004; chapter 59.
    Return to citation in text: [1]
  9. Griesbeck, A. G.; Bondock, S. Oxetane Formation: Intermolecular Additions. In CRC Handbook of Organic Photochemistry and Photobiology, 2nd ed.; Horspool, W. M.; Lenci, F., Eds.; CRC Press: Boca Raton, 2004; chapter 60.
    Return to citation in text: [1]
  10. Abe, M. Photochemical Oxetane Formation: Addition to Heterocycles. In CRC Handbook of Organic Photochemistry and Photobiology, 2nd ed.; Horspool, W. M.; Lenci, F., Eds.; CRC Press: Boca Raton, 2004; chapter 62.
    Return to citation in text: [1]
  11. Porco, J. A.; Schreiber, S. L. The Paternò–Büchi Reaction. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 151–192. doi:10.1016/B978-0-08-052349-1.00123-2
    Return to citation in text: [1] [2]
  12. Bach, T. Synthesis 1998, 683–703. doi:10.1055/s-1998-2054
    Return to citation in text: [1]
  13. Hei, X.-M.; Song, Q.-H.; Li, X.-B.; Tang, W.-J.; Wang, H.-B.; Guo, Q.-X. J. Org. Chem. 2005, 70, 2522–2527. doi:10.1021/jo048006k
    Return to citation in text: [1]
  14. Abe, M.; Kawankami, T.; Ohata, S.; Nozaki, K.; Nojima, M. J. Am. Chem. Soc. 2004, 126, 2838–2846. doi:10.1021/ja039491o
    Return to citation in text: [1]
  15. Griesbeck, A. G.; Abe, M.; Bondock, S. Acc. Chem. Res. 2004, 37, 919–928. doi:10.1021/ar040081u
    Return to citation in text: [1]
  16. Abe, M. J. Chin. Chem. Soc. (Taipei, Taiwan) 2008, 55, 479–486.
    Return to citation in text: [1]
  17. Abe, M. Chapter 7. Formation of a Four-Membered Ring: Oxetanes. In Handbook of Synthetic Photochemistry; Albini, A.; Fagnoni, M., Eds.; Wiley-VCH: Weinheim, 2009; pp 217–239. doi:10.1002/9783527628193.ch7
    Return to citation in text: [1]
  18. Shima, K.; Sakurai, H. Bull. Chem. Soc. Jpn. 1966, 39, 1806–1808. doi:10.1246/bcsj.39.1806
    Return to citation in text: [1]
  19. Whipple, E. B.; Evanega, G. R. Tetrahedron 1968, 24, 1299–1310. doi:10.1016/0040-4020(68)88081-0
    Return to citation in text: [1]
  20. Jarosz, S.; Zamojski, A. Tetrahedron 1982, 38, 1447–1451. doi:10.1016/0040-4020(82)80228-7
    Return to citation in text: [1]
  21. Schreiber, S. L.; Hoveyda, A. H.; Wu, H.-J. J. Am. Chem. Soc. 1983, 105, 660–661. doi:10.1021/ja00341a077
    Return to citation in text: [1] [2]
  22. Cantrell, T. S.; Allen, A. C.; Ziffer, H. J. Org. Chem. 1989, 54, 140–145. doi:10.1021/jo00262a032
    Return to citation in text: [1]
  23. Hambalek, R.; Just, G. Tetrahedron Lett. 1990, 31, 5445–5448. doi:10.1016/S0040-4039(00)97868-7
    Return to citation in text: [1]
  24. Griesbeck, A. G.; Buhr, S.; Fiege, M.; Schmickler, H.; Lex, J. J. Org. Chem. 1998, 63, 3847–3854. doi:10.1021/jo971767l
    Return to citation in text: [1]
  25. Hu, S.; Neckers, D. C. J. Chem. Soc., Perkin Trans. 2 1999, 1771–1778. doi:10.1039/a901092k
    Return to citation in text: [1]
  26. D’Auria, M.; Racioppi, R.; Romaniello, G. Eur. J. Org. Chem. 2000, 3265–3272. doi:10.1002/1099-0690(200010)2000:19<3265::AID-EJOC3265>3.0.CO;2-6
    Return to citation in text: [1]
  27. Zhang, Y.; Xue, J.; Gao, Y.; Fun, H.-K.; Xu, J.-H. J. Chem. Soc., Perkin Trans. 1 2002, 345–353. doi:10.1039/B109697D
    Return to citation in text: [1]
  28. Howard, B. E.; Woerpel, K. A. Tetrahedron 2009, 65, 6447–6453. doi:10.1016/j.tet.2009.05.066
    Return to citation in text: [1] [2]
  29. Loiseau, F.; Simone, J.-M.; Carcache, D.; Bobal, P.; Neier, R. Monatsh. Chem. 2007, 138, 121–129. doi:10.1007/s00706-006-0578-x
    Return to citation in text: [1]
  30. Miyauchi, H.; Ikematsu, C.; Shimazaki, T.; Kato, S.; Shinmyozu, T.; Shimo, T.; Somekawa, K. Tetrahedron 2008, 64, 4108–4116. doi:10.1016/j.tet.2008.02.005
    Return to citation in text: [1]
  31. Denmark, S. E.; Muhuhi, J. M. J. Am. Chem. Soc. 2010, 132, 11768–11778. doi:10.1021/ja1047363
    Return to citation in text: [1]
  32. Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040–6041. doi:10.1021/ja034030o
    Return to citation in text: [1]
  33. Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313–10318. doi:10.1021/ja047190o
    Return to citation in text: [1]

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