DOI: 10.1002/chem.201303385
Communication
& Asymmetric Synthesis
Catalytic and Asymmetric Fluorolactonisations of Carboxylic Acids through Anion Phase Transfer Dixit Parmar, Modhu Sudan Maji, and Magnus Rueping*[a] Halocyclisation reactions have experienced a tremendous amount of attention as it provides a powerful oppurtunity to simultaneous form two new bonds in a predictable manner.[7] Halolactonisations constitute a major component of this field.[8] Whilst the heavier halogens (Cl, Br, I) have enjoyed much success in participating in both racemic and asymmetric halolactonisations the extension of these procedures towards fluorolactonisations has ultimately proved challenging. With alkene counterparts, the sparse literature generally provides a limited scope and either employs harsh conditions or non-commercial electrophilic fluorine sources.[9] Cyclisations involving the more reactive allene partners have also been studied, but further progress towards milder conditions is still a challenge to be met.[10] With this in mind, we sought to develop a mild metalfree procedure for the fluorolactonisation of unsaturated carboxylic acids and herein we report our progress towards this goal (Figure 1).
Abstract: Catalytic fluorolactonisations of aromatic carboxylic acids have been developed. The reactions proceed under mild conditions using the commercially available reagent Selectfluor. A weak phase transfer of the reagent mediated by Na2CO3 allows the reaction to be conducted in non-polar solvents. Furthermore, by the use of a catalytic amount of (DHQ)2PHAL (hydroquinine 1,4-phthalazinediyl diether), the first asymmetric fluorolactonisation has been achieved. The corresponding isobenzofuran core can be found in many biologically active molecules.
The significance of organofluorine compounds has increased considerably in recent years due to the realisation of fluorine’s unique electronic properties and the ability to induce conformational changes to a molecule.[1] Fluorine-containing molecules can be found in many diverse applications, such as pharmaceuticals, fine chemicals and materials.[2] [F18]-labelled compounds have also found use as imaging agents by using positron emission tomography (PET).[3] Despite the increasing importance of fluorinated molecules, the introduction of fluorine[4] into molecules in a selective manner under mild conditions is still a challenge to be overcome. The difficulty in the introduction of fluorine into compounds has been in part due to the reagents employed suffering from being difficult to prepare, hard to handle or incompatible with reaction conditions. For example, early research on electrophilic fluorination reactions typically involved the highly toxic elemental fluorine gas. The advent of milder and safer electrophilic fluorinating agents (e.g., Selectfluor)[5] has no doubt opened up the avenues for incorporating fluorine by using standard laboratory equipment and procedures. However, the mild nature of these reagents can sometimes lead to low reactivity, which may be overcome by high reaction temperatures. More recently electrophilic fluorine sources have been elegantly combined with transition metal catalysts,[6] but the use of these metals may be undesirable for some processes.
Figure 1. Overview of halolactonisations.
Lactones are a class of structural motifs that are incredibly versatile and thus they have become highly useful synthetic intermediates.[11] In particular, the g-lactone moiety when fused to an aromatic ring system is a privileged structure that appears in numerous natural products.[12] They have also been shown to exhibit useful properties, such as anti-tumour,[13] anti-HIV,[14] and also the ability to inhibit ATP synthesis in the chloroplast (Figure 2).[15] Our study began by examining the fluorolactonisation of benzoic acid 1 a with Selectfluor and Na2CO3 as a base (Table 1). Initial experiments had revealed only inorganic bases to be suitable for the reaction and from various bases tested, Na2CO3 was found to be optimal. Literature precedent for the use of Selectfluor shows that the most common solvents utilised with the reagent are highly polar, for example, water or acetonitrile.[5c] This is due to its’ poor solubility in non-polar media. In our initial solvent evaluation (Table 1, entries 1 and 2)
[a] Dr. D. Parmar, Dr. M. S. Maji, Prof. Dr. M. Rueping Institut fr Organische Chemie RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) Fax: (+ 49) 241-8092665 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303385. Chem. Eur. J. 2014, 20, 83 – 86
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Communication product dropped dramatically. Hexane also demonstrated equal reactivity to Et2O (Table 1, entry 9) providing the desired product in 77 % yield after 18 h. This last result was striking considering that all three reaction components (Selectfluor, Na2CO3 and 1 a) are insoluble in the solvent. The importance of the base was highlighted in entry 10 (Table 1), as when removed no reaction occurred. Finally, N-fluorobenzenesulfonimide (NFSI) was also tested for reactivity, and although some starting material was consumed, no appreciable amounts of the product could be isolated (Table 1, entry 11). It was decided that both hexane and Et2O were suitable solvents and so with these optimal reaction conditions now in hand, we investigated the scope of the fluorolactonisation. In general, the reaction exhibited a broad scope towards a variety of substituents on both the aromatic backbone (R1) and the alkene (R2). Aromatic substitution on the alkene worked well with various groups at the 4-position tolerated in good yields (2 a–2 d; Figure 3). Substitution at the 6-position of the aromatic backbone (2 e–2 h; Figure 3) was also seen to be functioning
Figure 2. Examples of pharmacologically active natural products containing the isobenzofuran core.
Table 1. Selected optimisation of solvents and fluorinating agents.
Entry
Solvent
Fluorinating agent [(equiv)]
Yield [%]
1 2 3[b] 4 5 6 7 8 9 10[b] 11
MeCN EtOAc NaHCO3 (aq) toluene CHCl3 Et2O Et2O Et2O hexane hexane hexane
Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (3) Selectfluor (1.5) Selectfluor (1.5) NFSI (1.5)
33 14 44[c] 45 46 44 79[d] 18 77 – n.d.[e]
[a] Determined by 1H NMR spectroscopy using 1,3,5-(OMe)3C6H3 as an internal standard. [b] Na2CO3 was not used. [c] Isolated yield. [d] Reaction was carried out for 48 h. [e] Unidentified products.
reactions in polar organic solvents proved to be fast. However, only low yields of the desired product were isolated. The reaction in a saturated solution of NaHCO3 (Table 1, entry 3) showed more promise and gave the product in a modest 44 % isolated yield. This led us to consider less polar solvents in an attempt to reduce the reactivity of the reagent. Remarkably, our further solvent screening revealed that in fact non-polar solvents gave both cleaner reactions and superior yields of desired lactone 2 a. The reaction was seen to proceed efficiently in a variety of less-polar media (Table 1, entries 4–6) even though Selectfluor is not known to be soluble in the solvent. Diethyl ether (Et2O) showed the best reactivity and when the reaction was left to stir for 48 h (Table 1, entry 7) the product was obtained in 79 % yield. It was found that the use of more Selectfluor was detrimental and accordingly the yield of the Chem. Eur. J. 2014, 20, 83 – 86
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Figure 3. Substrate scope of fluorolactonisations.
efficiently, including electron-withdrawing and -donating groups. When substitution was placed at the 2-position of the aromatic group attached to the alkene (2 i and 2 j; Figure 3) slightly lower yields were obtained. It was thought this may be due to an increased steric hindrance at the fluorinating centre. Halogen substitution was accepted at the 7-position of the aromatic backbone (2 k and 2 l; Figure 3) and the use of alkyl 84
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Communication substitution on the alkene (2 m and 2 n; Figure 3) also gave the desired products. It is worth noting that although most substrates worked equally as efficient in both solvents some substrates did show a preference for one particular solvent. This could be simply due to solubility since in general the starting materials are more soluble in Et2O. Intrigued by the mechanism of the reaction we conducted a test experiment to determine the importance of the base. We decided to prepare the sodium salt (3) of carboxylic acid 1 a to test under our reaction conditions. When 3 was treated with only Selectfluor in hexane the desired lactonised product 2 a was isolated in 65 % yield (Figure 4). This result is comparable to when 1 a is treated with Selectfluor and base indicating that the sodium salt 3 is involved in the reaction. Figure 6. Possible mechanisms for the fluorolactonisation.
also be in operation.[17] Cyclisation of the carboxylic acid and loss of NaBF4 ultimately yields the product 2 a. Alternatively, pathway B would see the carboxylate 3 undergo anion exchange with 4 to yield species 6. This would ultimately also lead to the product. The fact that there is only a low concentration of the “active” reagent in solution is most likely the reason for the observation of only small amounts of by-products in the reaction. Recently, the phase-transfer of Selectfluor has been shown to occur with phosphoric acids.[18] The authors propose that phosphates can displace the tetraborofluorate anions, which in turn renders the Selectfluor reagent soluble. Our work suggests that the phase-transfer may also be possible with carboxylates. Keen to expand the utility of our reaction conditions we next investigated the possibility of using it to carry out an asymmetric fluorolactonisation. For the heavier halogens, this process has been well studied.[8a] We hoped that the low solubility may allow for a catalytic ligand to be used. The use of cinchona alkaloids with Selectfluor is well documented[19] and typically these are used in stoichometric quantities in combination with Selectfluor; however, recently a catalytic procedure has been reported.[20] Treating 1 a under the standard conditions at room temperature in the presence of 20 mol % (DHQ)2PHAL (hydroquinine 1,4-phthalazinediyl diether) afforded the enantiomerically enriched fluorolactone 2 a in 50 % yield and 27 % ee (Figure 7). It was found that in the presence of (DHQ)2PHAL the reaction rate was slower and by using higher quantities of the chiral catalyst lower reactivity was observed. We assume that the presence of (DHQ)2PHAL reduces the solubility of the starting material. To the best of our knowl-
Figure 4. Mechanistic investigations.
To shed further light on the possible mechanism, a 19F NMR study was conducted. Taking the Selectfluor reagent firstly in CDCl3 resulted in the reagent depositing at the bottom of the solution. Its complete insolubility was confirmed by analysis of the 19F NMR spectra, which showed no peaks.[16] In a separate vial, the Selectfluor reagent was mixed with Na2CO3 for 1 h. This time the clear solution had become cloudy indicating the precipitation of an insoluble species. Analysis of the NMR spectra this time showed two peaks in an approximate 4:1 ratio that are proposed to come from intermediate 4 (Figure 5).
Figure 5. 19F NMR study.
Taking all the observations together, we postulate that the first step of the reaction involves a phase transfer of Selectfluor mediated by Na2CO3 (Figure 6). The carbonate anion displaces one of the weakly co-ordinating tetraborofluorate anions (BF4 ) and this allows the active reagent (4) into solution. The next step of the reaction involves a deprotonation of the carboxylic acid to form the sodium salt (cf. 3). This is then proposed to follow one of two pathways. Pathway A sees 4 to go on to fluorinate the substrate to presumably form an acyclic bfluoro-carbenium ion 5. However, a cyclic fluoronium ion may Chem. Eur. J. 2014, 20, 83 – 86
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Figure 7. Asymmetric fluorolactonisation.
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Communication edge this is the first example of an asymmetric fluorolactonisation. In conclusion, we have developed the first fluorolactonisations of aromatic carboxylic acids to give fluorinated isobenzofurans. Mechanistic studies suggest that the reaction proceeds through a weak phase transfer, which allows non-polar solvents to be used and allows the products to be formed in high yields. Furthermore, preliminary experiments have demonstrated that in combination with a cinchona alkaloid the reaction can be carried out in an asymmetric manner for the first time. The reaction uses a mild and safe reagent with an operationally simple procedure. The scope, mechanism and asymmetric transformation are currently being investigated in our laboratory and will be reported in due course.
[7] A. N. French, S. Bissmire, T. Wirth, Chem. Soc. Rev. 2004, 33, 354 – 362. [8] a) S. Ranganathan, K. M. Muraleedharan, N. K. Vaish, N. Jayaraman, Tetrahedron 2004, 60, 5273 – 5308; b) C. K. Tan, L. Zhou, Y.-Y. Yeung, Synlett 2011, 1335 – 1339; c) M. S. Laya, A. K. Banerjee, E. V. Cabrera, Curr. Org. Chem. 2009, 13, 720 – 730. [9] a) L. F. Lourie, Y. A. Serguchev, G. V. Shevchenko, M. V. Ponomarenko, A. N. Chernega, E. B. Rusanov, J. A. K. Howard, J. Fluorine Chem. 2006, 127, 377 – 385; b) M. Okada, Y. Nakamura, H. Horikawa, T. Inoue, T. Taguchi, J. Fluorine Chem. 1997, 82, 157 – 161; c) M. Sawaguchi, S. Hara, T. Fukuhara, N. Yoneda, J. Fluorine Chem. 2000, 104, 277 – 280; d) Y. A. Serguchev, L. F. Lourie, G. V. Polishchuk, A. N. Chernega, Mendeleev Commun. 2002, 12, 115 – 117; e) Y. A. Serguchev, L. F. Lourie, M. V. Ponomarenko, E. B. Rusanov, N. V. Ignat’ev, Tetrahedron Lett. 2011, 52, 5166 – 5169. [10] a) C. Zhou, Z. Ma, Z. Gu, C. Fu, S. Ma, J. Org. Chem. 2008, 73, 772 – 774; b) H. Cui, Z. Chai, G. Zhao, S. Zhu, Chin. J. Chem. 2009, 27, 189 – 194; c) B. L, C. Fu, S. Ma, Org. Biomol. Chem. 2010, 8, 274 – 281; d) H. Cui, Z. Chai, Y. Lu, P. Li, G. Zhao, S. Zhu, Chin. J. Chem. 2011, 29, 2744 – 2748. [11] For selected examples of the use of lactones as synthetic intermediates see: a) D. Mal, P. Pahari, Chem. Rev. 2007, 107, 1892 – 1918; b) B. A. Egan, M. Paradowski, L. H. Thomas, R. Marquez, Org. Lett. 2011, 13, 2086 – 2089; c) E. del Olmo, M. G. Armas, M. I. Ybarra, J. L. Lopez, P. Oporto, A. Gimenez, E. Deharo, A. San Feliciano, Bioorg. Med. Chem. Lett. 2003, 13, 2769 – 2772; d) D. Parmar, L. A. Duffy, D. V. Sadasivam, H. Matsubara, P. A. Bradley, R. A. Flowers, D. J. Procter, J. Am. Chem. Soc. 2009, 131, 15467 – 15473; e) D. Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley, D. J. Procter, J. Am. Chem. Soc. 2011, 133, 2418 – 2420; f) D. Parmar, H. Matsubara, K. Price, M. Spain, D. J. Procter, J. Am. Chem. Soc. 2012, 134, 12751 – 12757. [12] a) M. Azuma, M. Yoshida, S. Horinouchi, T. Beppu, Agric. Biol. Chem. 1990, 54, 1441 – 1446; b) G. Brader, S. Vajrodaya, H. Greger, M. Bacher, H. Kalchhauser, O. Hofer, J. Nat. Prod. 1998, 61, 1482 – 1490; c) A. Arnone, G. Assante, G. Nasini, S. Strada, A. Vercesi, J. Nat. Prod. 2002, 65, 48 – 50; d) G. Strobel, E. Ford, J. Worapong, J. K. Harper, A. M. Arif, D. M. Grant, P. C. W. Fung, R. M. W. Chau, Phytochemistry 2002, 60, 179 – 183; e) D. Mal, P. Pahari, S. R. De, Tetrahedron 2007, 63, 11781 – 11792; f) J. J. Beck, S.-C. Chou, J. Nat. Prod. 2007, 70, 891 – 900; g) T.-H. Chou, I.S. Chen, T.-L. Hwang, T.-C. Wang, T.-H. Lee, L.-Y. Cheng, Y.-C. Chang, J.-Y. Cho, J.-J. Chen, J. Nat. Prod. 2008, 71, 1692 – 1695. [13] L. P. L. Logrado, C. O. Santos, L. A. S. Romeiro, A. M. Costa, J. R. O. Ferreira, B. C. Cavalcanti, O. M. de Moraes, L. V. Costa-Lotufo, C. Pessoa, M. L. dos Santos, Eur. J. Med. Chem. 2010, 45, 3480 – 3489. [14] K. Yoganathan, C. Rossant, S. Ng, Y. Huang, M. S. Butler, A. D. Buss, J. Nat. Prod. 2003, 66, 1116 – 1117. [15] X.-Z. Huang, Y. Zhu, X.-L. Guan, K. Tian, J.-M. Guo, H.-B. Wang, G.-M. Fu, Molecules 2012, 17, 4219 – 4224. [16] See Supporting Information for more details. [17] a) M. D. Struble, M. T. Scerba, M. Siegler, T. Lectka, Science 2013, 340, 57 – 60; b) U. Hennecke, Science 2013, 340, 41 – 42. [18] a) V. Rauniyar, A. D. Lackner, G. L. Hamilton, F. D. Toste, Science 2011, 334, 1681 – 1684; b) T. Honjo, R. J. Phipps, V. Rauniyar, F. D. Toste, Angew. Chem. 2012, 124, 9822 – 9826; Angew. Chem. Int. Ed. 2012, 51, 9684 – 9688; c) R. J. Phipps, K. Hiramatsu, F. D. Toste, J. Am. Chem. Soc. 2012, 134, 8376 – 8379; d) R. J. Phipps, F. D. Toste, J. Am. Chem. Soc. 2013, 135, 1268 – 1271; e) U. Hennecke, Angew. Chem. 2012, 124, 4608 – 4610; Angew. Chem. Int. Ed. 2012, 51, 4532 – 4534. [19] a) D. Cahard, C. Audouard, J.-C. Plaquevent, N. Roques, Org. Lett. 2000, 2, 3699 – 3701; b) D. Cahard, C. Audouard, J. C. Plaquevent, L. Toupet, N. Roques, Tetrahedron Lett. 2001, 42, 1867 – 1869; c) N. Shibata, E. Suzuki, Y. Takeuchi, J. Am. Chem. Soc. 2000, 122, 10728 – 10729. [20] O. Lozano, G. Blessley, T. Martinez del Campo, A. L. Thompson, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman, V. Gouverneur, Angew. Chem. 2011, 123, 8255 – 8259; Angew. Chem. Int. Ed. 2011, 50, 8105 – 8109.
Experimental Section Representative procedure for the fluorolactonisation The substrate (0.1 mmol, 1 equiv), Selectfluor (53 mg, 0.15 mmol, 1.5 equiv) and Na2CO3 (16 mg, 0.15 mmol, 1.5 equiv) were placed in a screw-cap vial. The vessel was evacuated and refilled with an atmosphere of N2 before the addition of solvent (3 mL). The reaction was stirred for 24 h at 23 8C before being filtered through cotton wool. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (SiO2, n-hexane/EtOAc = 9:1) to yield the product. Further details for the synthesis and characterisation of compounds studied in this manuscript can be found in the Supporting Information.
Acknowledgements D. P. and M. S. M. would like to thank the Alexander von Humboldt Foundation for providing us both with a Humboldt Research Fellowship Award. Keywords: asymmetric synthesis cyclisation · fluorination · lactones
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carboxylic
acids
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[1] a) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004; b) D. O’Hagan, ChemBioChem 2005, 6, 763. [2] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320 – 330; b) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305 – 321; c) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359 – 4369. [3] P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem. 2008, 120, 9136 – 9172; Angew. Chem. Int. Ed. 2008, 47, 8998 – 9033. [4] T. Furuya, C. A. Kuttruff, T. Ritter, Curr. Opin. Drug Discovery Dev. 2008, 11, 803 – 819. [5] a) R. E. Banks, J. Fluorine Chem. 1998, 87, 1 – 17; b) R. P. Singh, J. n. M. Shreeve, Acc. Chem. Res. 2004, 37, 31 – 44; c) P. T. Nyffeler, S. G. Durn, M. D. Burkart, S. P. Vincent, C.-H. Wong, Angew. Chem. 2005, 117, 196 – 217; Angew. Chem. Int. Ed. 2005, 44, 192 – 212; d) M. Schueler, Spec. Chem. Mag. 2006, 26, 20; e) S. Stavber, Molecules 2011, 16, 6432 – 6464. [6] a) G. Liu, Org. Biomol. Chem. 2012, 10, 6243 – 6248; b) C. Hollingworth, V. Gouverneur, Chem. Commun. 2012, 48, 2929 – 2942; c) M. F. Kuehnel, D. Lentz, T. Braun, Angew. Chem. 2013, 125, 3412 – 3433; Angew. Chem. Int. Ed. 2013, 52, 3328 – 3348.
Chem. Eur. J. 2014, 20, 83 – 86
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Received: August 28, 2013 Published online on December 4, 2013
86
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication
& Asymmetric Synthesis
Catalytic and Asymmetric Fluorolactonisations of Carboxylic Acids through Anion Phase Transfer Dixit Parmar, Modhu Sudan Maji, and Magnus Rueping*[a] Halocyclisation reactions have experienced a tremendous amount of attention as it provides a powerful oppurtunity to simultaneous form two new bonds in a predictable manner.[7] Halolactonisations constitute a major component of this field.[8] Whilst the heavier halogens (Cl, Br, I) have enjoyed much success in participating in both racemic and asymmetric halolactonisations the extension of these procedures towards fluorolactonisations has ultimately proved challenging. With alkene counterparts, the sparse literature generally provides a limited scope and either employs harsh conditions or non-commercial electrophilic fluorine sources.[9] Cyclisations involving the more reactive allene partners have also been studied, but further progress towards milder conditions is still a challenge to be met.[10] With this in mind, we sought to develop a mild metalfree procedure for the fluorolactonisation of unsaturated carboxylic acids and herein we report our progress towards this goal (Figure 1).
Abstract: Catalytic fluorolactonisations of aromatic carboxylic acids have been developed. The reactions proceed under mild conditions using the commercially available reagent Selectfluor. A weak phase transfer of the reagent mediated by Na2CO3 allows the reaction to be conducted in non-polar solvents. Furthermore, by the use of a catalytic amount of (DHQ)2PHAL (hydroquinine 1,4-phthalazinediyl diether), the first asymmetric fluorolactonisation has been achieved. The corresponding isobenzofuran core can be found in many biologically active molecules.
The significance of organofluorine compounds has increased considerably in recent years due to the realisation of fluorine’s unique electronic properties and the ability to induce conformational changes to a molecule.[1] Fluorine-containing molecules can be found in many diverse applications, such as pharmaceuticals, fine chemicals and materials.[2] [F18]-labelled compounds have also found use as imaging agents by using positron emission tomography (PET).[3] Despite the increasing importance of fluorinated molecules, the introduction of fluorine[4] into molecules in a selective manner under mild conditions is still a challenge to be overcome. The difficulty in the introduction of fluorine into compounds has been in part due to the reagents employed suffering from being difficult to prepare, hard to handle or incompatible with reaction conditions. For example, early research on electrophilic fluorination reactions typically involved the highly toxic elemental fluorine gas. The advent of milder and safer electrophilic fluorinating agents (e.g., Selectfluor)[5] has no doubt opened up the avenues for incorporating fluorine by using standard laboratory equipment and procedures. However, the mild nature of these reagents can sometimes lead to low reactivity, which may be overcome by high reaction temperatures. More recently electrophilic fluorine sources have been elegantly combined with transition metal catalysts,[6] but the use of these metals may be undesirable for some processes.
Figure 1. Overview of halolactonisations.
Lactones are a class of structural motifs that are incredibly versatile and thus they have become highly useful synthetic intermediates.[11] In particular, the g-lactone moiety when fused to an aromatic ring system is a privileged structure that appears in numerous natural products.[12] They have also been shown to exhibit useful properties, such as anti-tumour,[13] anti-HIV,[14] and also the ability to inhibit ATP synthesis in the chloroplast (Figure 2).[15] Our study began by examining the fluorolactonisation of benzoic acid 1 a with Selectfluor and Na2CO3 as a base (Table 1). Initial experiments had revealed only inorganic bases to be suitable for the reaction and from various bases tested, Na2CO3 was found to be optimal. Literature precedent for the use of Selectfluor shows that the most common solvents utilised with the reagent are highly polar, for example, water or acetonitrile.[5c] This is due to its’ poor solubility in non-polar media. In our initial solvent evaluation (Table 1, entries 1 and 2)
[a] Dr. D. Parmar, Dr. M. S. Maji, Prof. Dr. M. Rueping Institut fr Organische Chemie RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) Fax: (+ 49) 241-8092665 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303385. Chem. Eur. J. 2014, 20, 83 – 86
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Communication product dropped dramatically. Hexane also demonstrated equal reactivity to Et2O (Table 1, entry 9) providing the desired product in 77 % yield after 18 h. This last result was striking considering that all three reaction components (Selectfluor, Na2CO3 and 1 a) are insoluble in the solvent. The importance of the base was highlighted in entry 10 (Table 1), as when removed no reaction occurred. Finally, N-fluorobenzenesulfonimide (NFSI) was also tested for reactivity, and although some starting material was consumed, no appreciable amounts of the product could be isolated (Table 1, entry 11). It was decided that both hexane and Et2O were suitable solvents and so with these optimal reaction conditions now in hand, we investigated the scope of the fluorolactonisation. In general, the reaction exhibited a broad scope towards a variety of substituents on both the aromatic backbone (R1) and the alkene (R2). Aromatic substitution on the alkene worked well with various groups at the 4-position tolerated in good yields (2 a–2 d; Figure 3). Substitution at the 6-position of the aromatic backbone (2 e–2 h; Figure 3) was also seen to be functioning
Figure 2. Examples of pharmacologically active natural products containing the isobenzofuran core.
Table 1. Selected optimisation of solvents and fluorinating agents.
Entry
Solvent
Fluorinating agent [(equiv)]
Yield [%]
1 2 3[b] 4 5 6 7 8 9 10[b] 11
MeCN EtOAc NaHCO3 (aq) toluene CHCl3 Et2O Et2O Et2O hexane hexane hexane
Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (1.5) Selectfluor (3) Selectfluor (1.5) Selectfluor (1.5) NFSI (1.5)
33 14 44[c] 45 46 44 79[d] 18 77 – n.d.[e]
[a] Determined by 1H NMR spectroscopy using 1,3,5-(OMe)3C6H3 as an internal standard. [b] Na2CO3 was not used. [c] Isolated yield. [d] Reaction was carried out for 48 h. [e] Unidentified products.
reactions in polar organic solvents proved to be fast. However, only low yields of the desired product were isolated. The reaction in a saturated solution of NaHCO3 (Table 1, entry 3) showed more promise and gave the product in a modest 44 % isolated yield. This led us to consider less polar solvents in an attempt to reduce the reactivity of the reagent. Remarkably, our further solvent screening revealed that in fact non-polar solvents gave both cleaner reactions and superior yields of desired lactone 2 a. The reaction was seen to proceed efficiently in a variety of less-polar media (Table 1, entries 4–6) even though Selectfluor is not known to be soluble in the solvent. Diethyl ether (Et2O) showed the best reactivity and when the reaction was left to stir for 48 h (Table 1, entry 7) the product was obtained in 79 % yield. It was found that the use of more Selectfluor was detrimental and accordingly the yield of the Chem. Eur. J. 2014, 20, 83 – 86
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Figure 3. Substrate scope of fluorolactonisations.
efficiently, including electron-withdrawing and -donating groups. When substitution was placed at the 2-position of the aromatic group attached to the alkene (2 i and 2 j; Figure 3) slightly lower yields were obtained. It was thought this may be due to an increased steric hindrance at the fluorinating centre. Halogen substitution was accepted at the 7-position of the aromatic backbone (2 k and 2 l; Figure 3) and the use of alkyl 84
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Communication substitution on the alkene (2 m and 2 n; Figure 3) also gave the desired products. It is worth noting that although most substrates worked equally as efficient in both solvents some substrates did show a preference for one particular solvent. This could be simply due to solubility since in general the starting materials are more soluble in Et2O. Intrigued by the mechanism of the reaction we conducted a test experiment to determine the importance of the base. We decided to prepare the sodium salt (3) of carboxylic acid 1 a to test under our reaction conditions. When 3 was treated with only Selectfluor in hexane the desired lactonised product 2 a was isolated in 65 % yield (Figure 4). This result is comparable to when 1 a is treated with Selectfluor and base indicating that the sodium salt 3 is involved in the reaction. Figure 6. Possible mechanisms for the fluorolactonisation.
also be in operation.[17] Cyclisation of the carboxylic acid and loss of NaBF4 ultimately yields the product 2 a. Alternatively, pathway B would see the carboxylate 3 undergo anion exchange with 4 to yield species 6. This would ultimately also lead to the product. The fact that there is only a low concentration of the “active” reagent in solution is most likely the reason for the observation of only small amounts of by-products in the reaction. Recently, the phase-transfer of Selectfluor has been shown to occur with phosphoric acids.[18] The authors propose that phosphates can displace the tetraborofluorate anions, which in turn renders the Selectfluor reagent soluble. Our work suggests that the phase-transfer may also be possible with carboxylates. Keen to expand the utility of our reaction conditions we next investigated the possibility of using it to carry out an asymmetric fluorolactonisation. For the heavier halogens, this process has been well studied.[8a] We hoped that the low solubility may allow for a catalytic ligand to be used. The use of cinchona alkaloids with Selectfluor is well documented[19] and typically these are used in stoichometric quantities in combination with Selectfluor; however, recently a catalytic procedure has been reported.[20] Treating 1 a under the standard conditions at room temperature in the presence of 20 mol % (DHQ)2PHAL (hydroquinine 1,4-phthalazinediyl diether) afforded the enantiomerically enriched fluorolactone 2 a in 50 % yield and 27 % ee (Figure 7). It was found that in the presence of (DHQ)2PHAL the reaction rate was slower and by using higher quantities of the chiral catalyst lower reactivity was observed. We assume that the presence of (DHQ)2PHAL reduces the solubility of the starting material. To the best of our knowl-
Figure 4. Mechanistic investigations.
To shed further light on the possible mechanism, a 19F NMR study was conducted. Taking the Selectfluor reagent firstly in CDCl3 resulted in the reagent depositing at the bottom of the solution. Its complete insolubility was confirmed by analysis of the 19F NMR spectra, which showed no peaks.[16] In a separate vial, the Selectfluor reagent was mixed with Na2CO3 for 1 h. This time the clear solution had become cloudy indicating the precipitation of an insoluble species. Analysis of the NMR spectra this time showed two peaks in an approximate 4:1 ratio that are proposed to come from intermediate 4 (Figure 5).
Figure 5. 19F NMR study.
Taking all the observations together, we postulate that the first step of the reaction involves a phase transfer of Selectfluor mediated by Na2CO3 (Figure 6). The carbonate anion displaces one of the weakly co-ordinating tetraborofluorate anions (BF4 ) and this allows the active reagent (4) into solution. The next step of the reaction involves a deprotonation of the carboxylic acid to form the sodium salt (cf. 3). This is then proposed to follow one of two pathways. Pathway A sees 4 to go on to fluorinate the substrate to presumably form an acyclic bfluoro-carbenium ion 5. However, a cyclic fluoronium ion may Chem. Eur. J. 2014, 20, 83 – 86
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Figure 7. Asymmetric fluorolactonisation.
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Communication edge this is the first example of an asymmetric fluorolactonisation. In conclusion, we have developed the first fluorolactonisations of aromatic carboxylic acids to give fluorinated isobenzofurans. Mechanistic studies suggest that the reaction proceeds through a weak phase transfer, which allows non-polar solvents to be used and allows the products to be formed in high yields. Furthermore, preliminary experiments have demonstrated that in combination with a cinchona alkaloid the reaction can be carried out in an asymmetric manner for the first time. The reaction uses a mild and safe reagent with an operationally simple procedure. The scope, mechanism and asymmetric transformation are currently being investigated in our laboratory and will be reported in due course.
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Experimental Section Representative procedure for the fluorolactonisation The substrate (0.1 mmol, 1 equiv), Selectfluor (53 mg, 0.15 mmol, 1.5 equiv) and Na2CO3 (16 mg, 0.15 mmol, 1.5 equiv) were placed in a screw-cap vial. The vessel was evacuated and refilled with an atmosphere of N2 before the addition of solvent (3 mL). The reaction was stirred for 24 h at 23 8C before being filtered through cotton wool. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (SiO2, n-hexane/EtOAc = 9:1) to yield the product. Further details for the synthesis and characterisation of compounds studied in this manuscript can be found in the Supporting Information.
Acknowledgements D. P. and M. S. M. would like to thank the Alexander von Humboldt Foundation for providing us both with a Humboldt Research Fellowship Award. Keywords: asymmetric synthesis cyclisation · fluorination · lactones
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Chem. Eur. J. 2014, 20, 83 – 86
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Received: August 28, 2013 Published online on December 4, 2013
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