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Catalyst-free transformations of diethyl 2-ethoxymethylenemalonate and diethyl polyfluorobenzoylmalonates in water
Tetrahedron Letters 53 (2012) 1961–1963
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free transformations of diethyl 2-ethoxymethylenemalonate and diethyl polyfluorobenzoylmalonates in water Denis N. Bazhin ⇑, Yulia S. Kudyakova, Yanina V. Burgart, Victor I. Saloutin I.Ya. Postovsky Institute of Organic Synthesis, the Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy str., 620990, Ekaterinburg, Russian Federation
a r t i c l e
i n f o
Article history: Received 24 December 2011 Revised 20 January 2012 Accepted 3 February 2012 Available online 11 February 2012 Keywords: Water chemistry Cyclotrimerization Dealkoxycarbonylation b-Keto esters
a b s t r a c t The unusual transformation of diethyl 2-ethoxymethylenemalonate into triethyl 1,3,5-benzenetricarboxylate is described. This one-pot reaction proceeds in water without any catalyst in a good yield. One of the proposed intermediates of this process is also used under similar conditions to give the desired trisubstituted benzene. A catalyst-free, efficient, practical, and convenient process in water based on deethoxycarbonylation has been developed to form ethyl polyfluorobenzoylacetates in a high yield from diethyl polyfluorobenzoylmalonates. Ó 2012 Elsevier Ltd. All rights reserved.
Cycloaddition reactions allow for the rapid construction of highly functionalized arenes in one step. A three-component coupling of alkynes is a well-known synthetic method to obtain trisubstituted benzenes.1–4 Although the transition metal catalyzed cyclotrimerization of alkynes has made great advances, the regioselectivity of the process can still be troublesome. Also, alkenes and acetals bearing electron-withdrawing substituents have become useful synthons for comparable benzene-ring formation methodologies.5 Selective preparation of symmetric triethyl benzenetricarboxylate was observed in the reaction of ethyl 3-ethoxyacrylate with benzylmethylammonium ethoxide.5f The trisannelation reaction of acrylates through acetal formation has also been reported.5g Self-condensation of enaminones or enamino esters in the presence of pyridinium chloride has been described to form trisubstituted benzenes.5b Some non-metal catalyzed reactions are represented in the literature in which various species initiate trimerization of unsaturated compounds.3,4,6 To our knowledge, there is only one example of 1,3,5-trisubstituted benzene formation from an alkyne in the absence of any added catalyst. The transformation of 1-phenyl-2-propyn-1-one in pressurized hot water to produce 1,3,5tribenzoylbenzene in 65–74% yield has been reported;7 the authors of that work suggested a mechanism involving three consecutive Michael additions with formation of the enol benzoylacetaldehyde to give acetophenone as a by-product. Carrying out processes in water is an important approach in organic chemistry that meets the requirements of green ⇑ Corresponding author. Tel.: +7 343 362 3425; fax: +7 343 374 5954. E-mail address: [email protected] (D.N. Bazhin). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2012.02.015
CO2Et OEt EtO2C
i
CO2Et
45-52%
CO2Et
EtO2C
1
3 ii
88-90%
O
H
EtO2C
CO2Et
i 62-65%
2 i : H2O, reflux; ii : NaOH, H2O, r.t. Scheme 1. Synthesis of triethyl 1,3,5-benzenetricarboxylate (3).
chemistry. Water is a non-toxic and non-flammable solvent.8 While investigating transformations of diethyl 2-ethoxymethylenemalonate in water, we surprisingly obtained a cyclotrimerization product 3 in a good yield (Scheme 1). This result is very different from that obtained using aqueous alkali with the ethoxymethylene derivative at room temperature which resulted in diethyl 2-hydroxymethylenemalonate.9 In this work, we report the one-step synthesis of triethyl 1,3,5benzenetricarboxylate from diethyl 2-ethoxymethylenemalonate and suggest a possible mechanism for this transformation. The cyclotrimerization of diethyl 2-ethoxymethylenemalonate has been carried out under reflux in water without any catalysts.
1962
D. N. Bazhin et al. / Tetrahedron Letters 53 (2012) 1961–1963
H
O
1,4-Michael addition 1 + H2O
EtO2C
CO2Et 2
retro-aldol condensation
de-ethoxycarbonylation
+ H2O
malonic ester
O
CO2Et H
A
3 intramolecular cyclization EtO2C
CO2Et C
Figure 1. ORTEP view of ethyl (2Z)-3-hydroxy-(2,3,4,5-tetrafluorobenzyl)-prop2-enoate (5a) (thermal ellipsoids at 50% probability).
+A CO2Et
CO2Et
O
aldol condensation
+A
O
aldol EtO2C condensation B
Scheme 2. A possible mechanism for the cyclotrimerization of compound 1.
X F
O
X
i
F EtO2C
EtO2C
CO2Et 4a,b
O 5a,b, 96-98%
X = H (a), F (b), i : H2O, reflux, 5 h. Scheme 3. Deethoxycarbonylation of diethyl polyfluorobenzoylmalonates.
The ease of product isolation is one of advantages of the reaction. After cooling, the product crystallizes directly from the reaction mixture which makes this method efficient. The purity of the product obtained was established by GC–MS, 1 H NMR spectroscopy, and X-ray analysis confirmed the structure (see Supplementary data). Thus, it was demonstrated that only one isomer of the trisubstituted benzene was obtained under the reaction conditions. Based on several experiments the yield of triethyl 1,3,5-benzenetricarboxylate was 46–52%. The process could be readily scaledup to several tens of grams. Malonic ester was a by-product identified by GC–MS (yield 5–8%). A possible mechanism for this transformation includes several stages. It is known that the ethoxy-bearing alkene carbon atom of 2-ethoxymethylenemalonic ester (1) is the most reactive center. In reactions with various nucleophiles (C–, P–, S–, N–, O–) and under mild conditions, addition–elimination on the activated C@C bond of 1 occurs.10 Taking this into consideration, we assume that in the first step, water, acting as nucleophile, attacks the methine carbon atom of the double bond of compound 1. Thus, b-tricarbonyl compound 2 is a possible intermediate in this reaction (Scheme 2). Compound 2 (enol form) is known from previous work.9 In order to confirm the subsequent cyclotrimerization of 2 into symmetrical triethyl 1,3,5-benzenetricarboxylate we realized a similar process in water (Scheme 1). The product obtained as a result of this conversion was compound 3 and this fact makes our suggestion about the mechanism and intermediates of the process reasonable. In the mechanism under consideration we expect that deethoxycarbonylation of b-tricarbonyl compound 2 occurs with the
formation of the corresponding b-aldehydo ester. To our knowledge, the dealkoxycarbonylation of malonic ester derivatives is realized according to known methods using acid catalysis or NaCl/DMSO, H2O/DMSO.11 This transformation probably proceeds by a step-wise mechanism (Scheme 2). The process is thought to initiate the self-aldol (Knöevenagel) condensation of ethyl a-formylacetate (A) to form initially the intermediate B and then C. Subsequent intermolecular aldol cyclization of intermediate C gave the aromatic product 3. As the ionic dissociation of water is endothermic, its ion product of 10 14 at 25 °C increases with temperature that facilitates various acid- or base-catalyzed organic reactions in water in the absence of added catalysts.12 It is known that similar trimerization of aformylacetophenones occurs under basic conditions giving 1,3,5tribenzoylbenzene in a high yield.13 However catalyst-free condensation of compounds with reactive methylene groups (C–H acids) using water as the solvent is preferred.14 The mechanism is similar to that of the metal-catalyzed acetal trimerizations described in a recent paper.5c Our attempts to extend this approach and to synthesize 1,3,5triacyl substituted benzenes from ethyl 2-ethoxymethyleneacyl acetates were unsuccessful and gave a complex mixture consisting mainly of dicarbonyl derivatives. We are also interested in this transformation of b-tricarbonyl compounds based on the malonic ester in terms of fluorine-containing b-keto ester synthesis.15 It was previously shown that pentafluorobenzoylmalonic ester, under acid catalysis, gave the pentafluorobenzoylmethyl ketone as a by-product.15a Interest in the use of ethyl tetrafluorobenzoylacetate is the result of its use as an intermediate in the synthesis of Levofloxacin and a number of other derivatives of quinolone antibiotics.16 In this study we performed the conversion of diethyl (polyfluorobenzoyl)malonates into the corresponding b-keto esters.17 The reaction proceeded in water under reflux at atmospheric pressure in a quantitative yield (Scheme 3). However, all our attempts to extend this method to nonfluoro- or polyfluoroacylmalonic esters failed. It should be added here that products 5a,b were isolated without neutralization, purification, and distillation procedures. X-ray diffraction analysis carried out on a crystal of compound 5a unambiguously showed this keto ester existed in the enol form (Fig. 1).18 The difference in the b-keto esters 5a,b from the proposed intermediate A (Scheme 2) is their resistance to self-condensation and further dealkoxycarbonylation to polyfluorobenzoylmethylketones. In conclusion, we have presented the one-step synthesis of triethyl 1,3,5-benzenetricarboxylate from diethyl 2-ethoxymethylenemalonate. This transformation is catalyst-free, proceeds in water, and is simple, convenient, and ecologically friendly. In addition, the conversion of b-tricarbonyl compounds in water without catalysts is a preparative process for the synthesis of ethyl polyfluorobenzoylacetates.
D. N. Bazhin et al. / Tetrahedron Letters 53 (2012) 1961–1963
Acknowledgement This study was financially supported by the Russian Foundation for Basic Research-Ural (Project No. 10-03-96017) and the Program of Presidium UB of RAS No. 12-G-3-1020. Supplementary data CCDC 857487 (for 3, see Supplementary data) and CCDC 797287 (for 5a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2012.02.015. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. (a) Galan, B.; Rovis, T. Angew. Chem. Int. Ed. 2009, 48, 2830–2834; (b) Wu, C.-Y.; Lin, Y.-C.; Chou, P.-T.; Wang, Y.; Liu, Y.-H. Dalton Trans. 2011, 40, 3748–3753; (c) Qiu, Z.; Xie, Z. Angew. Chem. Int. Ed. 2009, 48, 5729–5732. 2. For papers on metal-catalyzed syntheses of triethyl 1,3,5benzenetricarboxylate from alkynes, see: (a) Cheng, J.; Tang, L.; Li, J. J. Nanosci. Nanotechnol. 2011, 11, 5159–5168; (b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605–613; (c) Dutta, B.; Curchod, B.; Campomanes, P.; Solari, E.; Scopelliti, R.; Rothlisberger, U.; Severin, K. Chem. Eur. J. 2010, 16, 8400–8409; (d) Kawata, A.; Kuninobu, Y.; Takai, K. Chem. Lett. 2009, 38, 836–837; (e) Yoshida, K.; Morimoto, I.; Mitsudo, K.; Tanaka, H. Tetrahedron 2008, 64, 5800– 5807; (f) Miyake, Y.; Nomaguchi, Y.; Yuki, M.; Nishibayashi, Y. Organometallics 2007, 26, 3611–3613; (g) Lombardo, M.; Pasi, F.; Trombini, C.; Seddon, K. R.; Pitner, W. R. Green Chem. 2007, 9, 321–322; (h) Cadierno, V.; Garcia-Garrido, S. E.; Gimeno, J. J. Am. Chem. Soc. 2006, 128, 15094–15095; (i) Yong, L.; Kirleis, K.; Butenschoen, H. Adv. Synth. Catal. 2006, 348, 833–836; (j) Xue, P.; Sung, H. S. Y.; Williams, I. D.; Jia, G. J. Organomet. Chem. 2006, 691, 1945–1953; (k) Weng, W.; Guo, C.; Celenligil-Cetin, R.; Foxman, B. M.; Ozerov, O. V. Chem. Commun. 2006, 197–199.; (l) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M. Chem. Eur. J. 2005, 11, 1145–1156; (m) Ruba, E.; Schmid, R.; Kirchner, K.; Calhorda, M. J. J. Organomet. Chem. 2003, 682, 204–211; (n) Ardizzoia, G. A.; Brenna, S.; Cenini, S.; LaMonica, G.; Masciocchi, N.; Maspero, A. J. Mol. Catal. A 2003, 204– 205, 333–340; (o) Han, W. S.; Lee, S. W. J. Organomet. Chem. 2003, 678, 102– 107; (p) Yong, L.; Butenschoen, H. Chem. Commun. 2002, 2852–2853.; (q) Ardizzoia, G. A.; Brenna, S.; LaMonica, G.; Maspero, A.; Masciocchi, N. J. Organomet. Chem. 2002, 649, 173–180; (r) Slugovc, C.; Doberer, D.; Gemel, C.; Schmidt, R.; Kirchner, K.; Winkler, B.; Stelzer, F. Monatsh. Chem. 1998, 129, 221– 233; (s) Meriwether, L. S.; Colthup, E. C.; Kennerly, G. W.; Reusch, R. N. J. Org. Chem. 1961, 26, 5155–5163. 3. (a) Zhou, Q.-F.; Yang, F.; Guo, Q.-X.; Xue, S. Synlett 2007, 215–218.; (b) Balasubramanian, K. K.; Selvaraj, S.; Venkataramani, P. S. Synthesis 1980, 29–30.
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4. Yang, J.; Verkade, J. G. Organometallics 2000, 19, 893–900. 5. (a) Joseph, D.; Jankowski, R.; Prim, D.; Mahuteau, J.; Chiaroni, A. Tetrahedron Lett. 2002, 43, 8051–8054; (b) Al-Zaydi, K. M.; Nhari, L. M.; Borik, R. M.; Elnagdi, M. H. Green Chem. Lett. Rev. 2010, 3, 93–99; (c) Maeda, S.; Obora, Y.; Ishii, Y. Eur. J. Org. Chem. 2009, 24, 4067–4072; (d) Jiang, H.-F.; Shen, Y.-X.; Wang, Z.-Y. Tetrahedron 2008, 64, 508–514; (e) Jiang, H.-F.; Shen, Y.-X.; Wang, Z.-Y. Tetrahedron Lett. 2007, 48, 7542–7545; (f) Croxall, W. J.; Van Hook, J. O. J. Am. Chem. Soc. 1950, 72, 803; (g) Tamaso, K.-i.; Hatamoto, Y.; Sakaguchi, S.; Obora, Y.; Ishii, Y. J. Org. Chem. 2007, 72, 3603–3605.; (h) Abdel-Khalik, M. M.; Elnagdi, M. H. Synth. Commun. 2002, 32, 159–164; (i) Kanner, C. B.; Pandit, U. K. Tetrahedron 1982, 38, 3597–3604. 6. Labuschagne, A. J. H.; Malherbe, J. S.; Meyer, C. J.; Schneider, D. F. Synth. Commun. 2002, 32, 297–304. 7. Tanaka, M.; Nakamura, K.; Iwado, T.; Sato, T.; Okada, M.; Sue, K.; Iwamura, H.; Hiaki, T. Chem. Eur. J. 2011, 17, 606–612. 8. (a) Breslow, R. Handbook of Green Chemistry In Reactions in Water; Wiley-VCH: Weinheim, 2010; Vol. 5,; (b) Polshettiwar, V; Varma, R. S. Chem. Soc. Rev. 2008, 37, 1546–1557; (c) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68–82. 9. Katagiri, N.; Akatsuka, H.; Haneda, T.; Kaneko, C.; Sera, A. J. Org. Chem. 1988, 53, 5464–5470. 10. (a) Ilangovan, A.; Kumar, R. Chem. Eur. J. 2010, 16, 2938–2943; (b) Guillou, S.; Janin, Y. L. Chem. Eur. J. 2010, 16, 4669–4677; (c) Tabouazata, M.; El Louzi, A.; Ahmar, M.; Cazes, B. Synlett 2008, 2495–2499.; Xu, Y.-S.; Zeng, C.-C.; Jiao, Z.-G.; Hu, L.-M.; Zhong, R.-g. Molecules 2009, 14, 868–883; (e) Tabouazat, M.; Louzi, A. E.; Ahmar, M.; Cazes, B. Synlett 2009, 1405–1408. 11. Krapcho, A. P. Synthesis, 1982, 893–914. 12. Kerton, F. M. In Alternative Solvents for Green Chemistry; Clark, J. H., Kraus, G. A., Eds.; RSC: Cambridge, 2009; pp 44–65. 13. Harnisch, H. Liebigs Ann. Chem. 1972, 765, 8–14. 14. (a) Yadav, L. D. S.; Singh, S.; Rai, V. K. Green Chem. 2009, 11, 878–882; (b) Jung, E. J.; Park, B. H.; Lee, Y. R. Green Chem. 2010, 12, 2003–2011; (c) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Green Chem. 2001, 3, 229–232; (d) Bigi, F.; Conforti, M. L.; Maggi, R.; Piccinno, A.; Sartori, G. Green Chem. 2000, 2, 102–103. 15. (a) Filler, R.; Rao, Y. S.; Biezais, A.; Miller, F. N.; Beacaire, V. D. J. Org. Chem. 1970, 35, 930–935; (b) Chu, D. T. W.; Fernandes, P. B.; Maleczka, R. E.; Nordeen, C. W., Jr.; Pernet, A. G. J. Med. Chem. 1987, 30, 504–509; (c) Xu, J.; Cole, D. C.; Chang, C.-P. B.; Ayyad, R.; Asselin, M.; Hao, W.; Gibbons, J.; Jelinsky, S. A.; Saraf, K. A.; Park, K. J. Med. Chem. 2008, 51, 4115–4121; (d) Chu, D. T. W.; Maleczka, R. E. J. Heterocycl. Chem. 1987, 24, 453–456; (e) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. Synthesis 1993, 290–292.; (f) Osadchii, S. A.; Barkhash, V. A. Zh. Org. Khim. 1970, 6, 1627–1636; (g) Prudchenko, A. T.; Barkhash, V. A.; Vorozhtsov, N. N. Izv. Akad. Nauk SSSR, Ser. Khim. 1965, 1798–803.; (h) Vorozhtsov, N. N.; Barkhash, V. A.; Prudchenko, A. T.; Shchegoleva, G. S. Zh. Obsh. Khim. 1965, 35, 1501–1502. 16. (a) Hayakawa, I.; Hiramitsu, T.; Tanaka, Y. Chem. Pharm. Bull. 1984, 32, 4907– 4913; Atarashi, S.; Yokohama, S.; Yamazaki, K.; Sakano, K.-i.; Imamura, M.; Hayakawa, I. Chem. Pharm. Bull. 1987, 35, 1896–1902; (c) Dinakaran, M.; Senthilkumar, P.; Yogeeswari, P.; China, A.; Nagaraja, V.; Sriram, D. Bioorg. Med. Chem. Lett. 2008, 18, 1229–1236. 17. Compounds 4a,b were synthesized according to our recent paper: Bazhin, D. N.; Schegol’kov, E. V.; Kudyakova, Yu. S.; Burgart, Ya. V.; Saloutin, V. I. Russ. Chem. Bull., Int. Ed. 2011, 60, 929–932. 18. b-Keto esters 5a,b exist in both keto and enol forms in CDCl3. In previous papers15,16 only the 1H NMR spectra of compounds 5a,b were reported.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free transformations of diethyl 2-ethoxymethylenemalonate and diethyl polyfluorobenzoylmalonates in water Denis N. Bazhin ⇑, Yulia S. Kudyakova, Yanina V. Burgart, Victor I. Saloutin I.Ya. Postovsky Institute of Organic Synthesis, the Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy str., 620990, Ekaterinburg, Russian Federation
a r t i c l e
i n f o
Article history: Received 24 December 2011 Revised 20 January 2012 Accepted 3 February 2012 Available online 11 February 2012 Keywords: Water chemistry Cyclotrimerization Dealkoxycarbonylation b-Keto esters
a b s t r a c t The unusual transformation of diethyl 2-ethoxymethylenemalonate into triethyl 1,3,5-benzenetricarboxylate is described. This one-pot reaction proceeds in water without any catalyst in a good yield. One of the proposed intermediates of this process is also used under similar conditions to give the desired trisubstituted benzene. A catalyst-free, efficient, practical, and convenient process in water based on deethoxycarbonylation has been developed to form ethyl polyfluorobenzoylacetates in a high yield from diethyl polyfluorobenzoylmalonates. Ó 2012 Elsevier Ltd. All rights reserved.
Cycloaddition reactions allow for the rapid construction of highly functionalized arenes in one step. A three-component coupling of alkynes is a well-known synthetic method to obtain trisubstituted benzenes.1–4 Although the transition metal catalyzed cyclotrimerization of alkynes has made great advances, the regioselectivity of the process can still be troublesome. Also, alkenes and acetals bearing electron-withdrawing substituents have become useful synthons for comparable benzene-ring formation methodologies.5 Selective preparation of symmetric triethyl benzenetricarboxylate was observed in the reaction of ethyl 3-ethoxyacrylate with benzylmethylammonium ethoxide.5f The trisannelation reaction of acrylates through acetal formation has also been reported.5g Self-condensation of enaminones or enamino esters in the presence of pyridinium chloride has been described to form trisubstituted benzenes.5b Some non-metal catalyzed reactions are represented in the literature in which various species initiate trimerization of unsaturated compounds.3,4,6 To our knowledge, there is only one example of 1,3,5-trisubstituted benzene formation from an alkyne in the absence of any added catalyst. The transformation of 1-phenyl-2-propyn-1-one in pressurized hot water to produce 1,3,5tribenzoylbenzene in 65–74% yield has been reported;7 the authors of that work suggested a mechanism involving three consecutive Michael additions with formation of the enol benzoylacetaldehyde to give acetophenone as a by-product. Carrying out processes in water is an important approach in organic chemistry that meets the requirements of green ⇑ Corresponding author. Tel.: +7 343 362 3425; fax: +7 343 374 5954. E-mail address: [email protected] (D.N. Bazhin). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2012.02.015
CO2Et OEt EtO2C
i
CO2Et
45-52%
CO2Et
EtO2C
1
3 ii
88-90%
O
H
EtO2C
CO2Et
i 62-65%
2 i : H2O, reflux; ii : NaOH, H2O, r.t. Scheme 1. Synthesis of triethyl 1,3,5-benzenetricarboxylate (3).
chemistry. Water is a non-toxic and non-flammable solvent.8 While investigating transformations of diethyl 2-ethoxymethylenemalonate in water, we surprisingly obtained a cyclotrimerization product 3 in a good yield (Scheme 1). This result is very different from that obtained using aqueous alkali with the ethoxymethylene derivative at room temperature which resulted in diethyl 2-hydroxymethylenemalonate.9 In this work, we report the one-step synthesis of triethyl 1,3,5benzenetricarboxylate from diethyl 2-ethoxymethylenemalonate and suggest a possible mechanism for this transformation. The cyclotrimerization of diethyl 2-ethoxymethylenemalonate has been carried out under reflux in water without any catalysts.
1962
D. N. Bazhin et al. / Tetrahedron Letters 53 (2012) 1961–1963
H
O
1,4-Michael addition 1 + H2O
EtO2C
CO2Et 2
retro-aldol condensation
de-ethoxycarbonylation
+ H2O
malonic ester
O
CO2Et H
A
3 intramolecular cyclization EtO2C
CO2Et C
Figure 1. ORTEP view of ethyl (2Z)-3-hydroxy-(2,3,4,5-tetrafluorobenzyl)-prop2-enoate (5a) (thermal ellipsoids at 50% probability).
+A CO2Et
CO2Et
O
aldol condensation
+A
O
aldol EtO2C condensation B
Scheme 2. A possible mechanism for the cyclotrimerization of compound 1.
X F
O
X
i
F EtO2C
EtO2C
CO2Et 4a,b
O 5a,b, 96-98%
X = H (a), F (b), i : H2O, reflux, 5 h. Scheme 3. Deethoxycarbonylation of diethyl polyfluorobenzoylmalonates.
The ease of product isolation is one of advantages of the reaction. After cooling, the product crystallizes directly from the reaction mixture which makes this method efficient. The purity of the product obtained was established by GC–MS, 1 H NMR spectroscopy, and X-ray analysis confirmed the structure (see Supplementary data). Thus, it was demonstrated that only one isomer of the trisubstituted benzene was obtained under the reaction conditions. Based on several experiments the yield of triethyl 1,3,5-benzenetricarboxylate was 46–52%. The process could be readily scaledup to several tens of grams. Malonic ester was a by-product identified by GC–MS (yield 5–8%). A possible mechanism for this transformation includes several stages. It is known that the ethoxy-bearing alkene carbon atom of 2-ethoxymethylenemalonic ester (1) is the most reactive center. In reactions with various nucleophiles (C–, P–, S–, N–, O–) and under mild conditions, addition–elimination on the activated C@C bond of 1 occurs.10 Taking this into consideration, we assume that in the first step, water, acting as nucleophile, attacks the methine carbon atom of the double bond of compound 1. Thus, b-tricarbonyl compound 2 is a possible intermediate in this reaction (Scheme 2). Compound 2 (enol form) is known from previous work.9 In order to confirm the subsequent cyclotrimerization of 2 into symmetrical triethyl 1,3,5-benzenetricarboxylate we realized a similar process in water (Scheme 1). The product obtained as a result of this conversion was compound 3 and this fact makes our suggestion about the mechanism and intermediates of the process reasonable. In the mechanism under consideration we expect that deethoxycarbonylation of b-tricarbonyl compound 2 occurs with the
formation of the corresponding b-aldehydo ester. To our knowledge, the dealkoxycarbonylation of malonic ester derivatives is realized according to known methods using acid catalysis or NaCl/DMSO, H2O/DMSO.11 This transformation probably proceeds by a step-wise mechanism (Scheme 2). The process is thought to initiate the self-aldol (Knöevenagel) condensation of ethyl a-formylacetate (A) to form initially the intermediate B and then C. Subsequent intermolecular aldol cyclization of intermediate C gave the aromatic product 3. As the ionic dissociation of water is endothermic, its ion product of 10 14 at 25 °C increases with temperature that facilitates various acid- or base-catalyzed organic reactions in water in the absence of added catalysts.12 It is known that similar trimerization of aformylacetophenones occurs under basic conditions giving 1,3,5tribenzoylbenzene in a high yield.13 However catalyst-free condensation of compounds with reactive methylene groups (C–H acids) using water as the solvent is preferred.14 The mechanism is similar to that of the metal-catalyzed acetal trimerizations described in a recent paper.5c Our attempts to extend this approach and to synthesize 1,3,5triacyl substituted benzenes from ethyl 2-ethoxymethyleneacyl acetates were unsuccessful and gave a complex mixture consisting mainly of dicarbonyl derivatives. We are also interested in this transformation of b-tricarbonyl compounds based on the malonic ester in terms of fluorine-containing b-keto ester synthesis.15 It was previously shown that pentafluorobenzoylmalonic ester, under acid catalysis, gave the pentafluorobenzoylmethyl ketone as a by-product.15a Interest in the use of ethyl tetrafluorobenzoylacetate is the result of its use as an intermediate in the synthesis of Levofloxacin and a number of other derivatives of quinolone antibiotics.16 In this study we performed the conversion of diethyl (polyfluorobenzoyl)malonates into the corresponding b-keto esters.17 The reaction proceeded in water under reflux at atmospheric pressure in a quantitative yield (Scheme 3). However, all our attempts to extend this method to nonfluoro- or polyfluoroacylmalonic esters failed. It should be added here that products 5a,b were isolated without neutralization, purification, and distillation procedures. X-ray diffraction analysis carried out on a crystal of compound 5a unambiguously showed this keto ester existed in the enol form (Fig. 1).18 The difference in the b-keto esters 5a,b from the proposed intermediate A (Scheme 2) is their resistance to self-condensation and further dealkoxycarbonylation to polyfluorobenzoylmethylketones. In conclusion, we have presented the one-step synthesis of triethyl 1,3,5-benzenetricarboxylate from diethyl 2-ethoxymethylenemalonate. This transformation is catalyst-free, proceeds in water, and is simple, convenient, and ecologically friendly. In addition, the conversion of b-tricarbonyl compounds in water without catalysts is a preparative process for the synthesis of ethyl polyfluorobenzoylacetates.
D. N. Bazhin et al. / Tetrahedron Letters 53 (2012) 1961–1963
Acknowledgement This study was financially supported by the Russian Foundation for Basic Research-Ural (Project No. 10-03-96017) and the Program of Presidium UB of RAS No. 12-G-3-1020. Supplementary data CCDC 857487 (for 3, see Supplementary data) and CCDC 797287 (for 5a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2012.02.015. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. (a) Galan, B.; Rovis, T. Angew. Chem. Int. Ed. 2009, 48, 2830–2834; (b) Wu, C.-Y.; Lin, Y.-C.; Chou, P.-T.; Wang, Y.; Liu, Y.-H. Dalton Trans. 2011, 40, 3748–3753; (c) Qiu, Z.; Xie, Z. Angew. Chem. Int. Ed. 2009, 48, 5729–5732. 2. For papers on metal-catalyzed syntheses of triethyl 1,3,5benzenetricarboxylate from alkynes, see: (a) Cheng, J.; Tang, L.; Li, J. J. Nanosci. Nanotechnol. 2011, 11, 5159–5168; (b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605–613; (c) Dutta, B.; Curchod, B.; Campomanes, P.; Solari, E.; Scopelliti, R.; Rothlisberger, U.; Severin, K. Chem. Eur. J. 2010, 16, 8400–8409; (d) Kawata, A.; Kuninobu, Y.; Takai, K. Chem. Lett. 2009, 38, 836–837; (e) Yoshida, K.; Morimoto, I.; Mitsudo, K.; Tanaka, H. Tetrahedron 2008, 64, 5800– 5807; (f) Miyake, Y.; Nomaguchi, Y.; Yuki, M.; Nishibayashi, Y. Organometallics 2007, 26, 3611–3613; (g) Lombardo, M.; Pasi, F.; Trombini, C.; Seddon, K. R.; Pitner, W. R. Green Chem. 2007, 9, 321–322; (h) Cadierno, V.; Garcia-Garrido, S. E.; Gimeno, J. J. Am. Chem. Soc. 2006, 128, 15094–15095; (i) Yong, L.; Kirleis, K.; Butenschoen, H. Adv. Synth. Catal. 2006, 348, 833–836; (j) Xue, P.; Sung, H. S. Y.; Williams, I. D.; Jia, G. J. Organomet. Chem. 2006, 691, 1945–1953; (k) Weng, W.; Guo, C.; Celenligil-Cetin, R.; Foxman, B. M.; Ozerov, O. V. Chem. Commun. 2006, 197–199.; (l) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M. Chem. Eur. J. 2005, 11, 1145–1156; (m) Ruba, E.; Schmid, R.; Kirchner, K.; Calhorda, M. J. J. Organomet. Chem. 2003, 682, 204–211; (n) Ardizzoia, G. A.; Brenna, S.; Cenini, S.; LaMonica, G.; Masciocchi, N.; Maspero, A. J. Mol. Catal. A 2003, 204– 205, 333–340; (o) Han, W. S.; Lee, S. W. J. Organomet. Chem. 2003, 678, 102– 107; (p) Yong, L.; Butenschoen, H. Chem. Commun. 2002, 2852–2853.; (q) Ardizzoia, G. A.; Brenna, S.; LaMonica, G.; Maspero, A.; Masciocchi, N. J. Organomet. Chem. 2002, 649, 173–180; (r) Slugovc, C.; Doberer, D.; Gemel, C.; Schmidt, R.; Kirchner, K.; Winkler, B.; Stelzer, F. Monatsh. Chem. 1998, 129, 221– 233; (s) Meriwether, L. S.; Colthup, E. C.; Kennerly, G. W.; Reusch, R. N. J. Org. Chem. 1961, 26, 5155–5163. 3. (a) Zhou, Q.-F.; Yang, F.; Guo, Q.-X.; Xue, S. Synlett 2007, 215–218.; (b) Balasubramanian, K. K.; Selvaraj, S.; Venkataramani, P. S. Synthesis 1980, 29–30.
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