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Mild and metal-free oxy- and amino-fluorination for the synthesis of fluorinated heterocycles† Dixit Parmar and Magnus Rueping*
Received 2nd July 2014, Accepted 16th September 2014 DOI: 10.1039/c4cc05027d www.rsc.org/chemcomm
A mild intramolecular fluoro-cyclisation reaction of benzylic alcohols and amines has been developed. This strategy uses commercially available Selectfluor to trigger electrophilic cyclisations to afford fluorinated heterocycles containing 1,3-disubstitution. The dual role of the reagent as a fluorine source and a base is shown to be crucial for reactivity.
The attention focused on synthetic routes to organofluorine compounds has increased exponentially in recent years due to the realisation of the unique ability of fluorine to significantly modify the properties of molecules.1 The presence of fluorine in a molecule is known to alter important parameters such as electronics, lipophilicity, metabolism and conformation.2 This can be incredibly useful since fluorine-containing groups can be found in many diverse applications, such as natural products,3 pharmaceuticals,4 fine chemicals and materials. [F18]-labeled compounds have also found use as imaging agents by using positron emission tomography (PET).5 Over the past few years, significant gains have been made to introduce fluorine into molecules using both electrophilic6 and nucleophilic7 sources of fluorine. More recently, transition metals have also greatly assisted the process of delivering fluorine.8 Although these developments have opened up routes to fluorinated molecules, the challenge for the selective and predictable introduction under mild and operationally simple conditions is still to be overcome.9 Isobenzofurans and isoindolines are heterocyclic skeletons that feature at the forefront of a broad spectrum of applications. Isobenzofurans are well known for being versatile building blocks as well as precursors for the generation of reactive intermediates. They are also present in a number of natural products and biologically active molecules.10 For example, pestacin is a naturally occurring compound possessing antioxidant and antimycotic activities which result from an unusual C–H oxidation (Fig. 1a).10a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074, Aachen, Germany. E-mail: [email protected]; Fax: +49-241-8092665; Tel: +49-241-8094686 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc05027d
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Equally prominent, isoindolines have been receiving increasing levels of synthetic interest because of the realisation of their potential. For example, isoindolines also feature in a number of natural products and have been shown to possess biological activities (Fig. 1a).11 Furthermore, isoindolines are widely recognized as stable, easy-to-handle precursors to isoindoles, which are commonly used in cycloaddition reactions. Isoindoles are also known for their strong fluorescence and this property has been exploited in organic light-emitting diodes.12 Despite the attention received by these compounds from the synthetic community,13 routes to access them are rather limited. In particular, the synthesis of 1,3-di-substituted variants is particularly difficult especially in a diastereoselective manner. A method to access these frameworks that allows for straightforward introduction of substituents onto the skeleton would be a highly advantageous process for the advancement of their applications.
Fig. 1 (a) Selected examples of molecules and properties associated with the products; (b) overview of this work.
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In line with our continued interest in the synthesis of fluorinated small molecules,14 we proposed the use of an electrophilic fluorination–cyclisation strategy of O-15 and N-16 nucleophiles to access fluorinated variants of these important motifs. We envisioned that treatment of easily prepared substrates in the presence of an electrophilic fluorine source would result in regioselective fluorination of the alkene followed by concomitant cyclisation of the pendant nucleophile (Fig. 1b). Crucial to the success of the reaction would be the ability to minimize unwanted reactivity of the electrophilic reagent with the nucleophile. For example, benzylic alcohols and amines are well known to be easily oxidised by electrophilic fluorinating agents.17 Our study began by investigating the fluoro-cyclisation of benzylic alcohol 1a with a variety of electrophilic fluorinating agents. The initial results obtained with the commonly used fluorinating agents such as N-fluorobenzenesulfonimide (NFSI) and N-fluoropyridinium (N-fluoropyr) in combination with Na2CO3 as a base failed to yield any appreciable amount of the desired product 2a (Table 1, entries 1 and 2). Using the stronger fluorinating agent Selectfluor in a variety of solvents also was not initially fruitful (Table 1, entries 3–5). At the time, we suspected that the desired reactivity was not being achieved due to the poor solubility of Selectfluor. Changing the solvent to MeCN led to a modest yield of 51% of the desired product (Table 1, entry 6). Interestingly, when tBuOK was used as the base in MeCN, the desired reaction was once again completely absent (Table 1, entry 7). We speculated that the use of a strong base may result in the deprotonation of the alcohol and formation of an alkoxide species which was detrimental to reactivity. The use of a weak base may be sufficiently tolerated if it functions as a proton scavenger but unfortunately a screen of alternative weak bases failed to significantly improve upon the result obtained with Na2CO3. At this point, we recognised that Selectfluor upon fluorination liberates a tertiary amine base and that perhaps we could harness this by-product to act as our proton scavenger. Pleasingly, the simple use of Selectfluor in MeCN resulted in an excellent yield of the desired product (Table 1, entry 8).
Table 1
Selected optimisation of solvents and fluorinating agentsa
Entry
F+ source
Base
Solvent
Yieldb (%)
1 2 3 4 5 6 7 8
NFSI N-Fluoropyr Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor
Na2CO3 Na2CO3 Na2CO3 — Na2CO3 Na2CO3 tBuOK —
CH2Cl2 CH2Cl2 Hexane NaHCO3 (aq.) Acetone MeCN MeCN MeCN
o5 o5 o5 o5 o5 51c o5 95 (91)c
a Reaction conditions: a mixture of 1a (1 equiv.), Selectfluor (1.2 equiv.) and base (1.2 equiv.) were reacted under N2 at room temperature. b Yield based on NMR analysis. c Yield of isolated product.
Chem. Commun.
Fig. 2
Fluoro-cyclisations to access fluorinated isobenzofurans.
With the optimised conditions in hand, we looked towards exploring the scope of the fluoro-cyclisations to access a variety of isobenzofurans 2 (Fig. 2). We found the reaction to proceed smoothly for a broad scope of substituents. In general, aromatic groups with various substituents were well tolerated at the both 1- and 3-positions. At the 3-position, alongside the neutral and electronrich aromatics (2a, 2b, and 2e), electron-poor (2c and 2d) aromatics also worked well. Alkyl substitution was also well tolerated (2f and 2g) at this position including di-alkyl substitution (2h). In addition, it was shown that an unsubstituted substrate also smoothly underwent fluorocyclisation (2i). The diastereoselectivity was determined by analysis of signals in the 1H-NMR spectra and the relative stereochemistry of the major diastereoisomer was determined by NOE studies on 2e and assumed to be constant for all the entries in the series.18 In all cases, a consistently modest ratio of diastereoisomers was observed. Attempts to enhance the ratio by altering the reaction temperature failed to yield any improvements. With the scope explored for benzylic alcohols 1 we envisioned that the extension to benzylic amines would allow access to the
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Fig. 4 Proposed mechanism and model for diastereoselectivity for the fluoro-cyclisation.
Fig. 3
Fluoro-cyclisations to access fluorinated isoindolines.
corresponding fluorinated isoindolines. In contrast to the benzylic alcohols, we required the use of a compatible protecting group for the benzylic amines. The electron-withdrawing tosyl group was quickly identified as being suitable for the desired reactivity.19,20 Treatment of a range of benzylic amines 3 led to an efficient fluorination–cyclisation to yield fluorinated isoindolines 4 in good yields (Fig. 3). In general, the reaction proceeded smoothly in all cases to yield 1,3-disubstituted products. Aromatic groups containing a wide range of substituents and substitution patterns were well tolerated (4a–e) including the presence of fluorine on the aromatic ring (4f). Once again, the diastereoselectivity was determined by analysis of signals in the 19F-NMR spectra and was found to be rather low for all cases. It is assumed that the major diastereoisomer contains the same relative configuration as in the case of the isobenzofurans. A proposed mechanism is depicted in Fig. 4. The first step involves regioselective fluorination at the terminus of the alkene to give the acyclic b-fluoro-carbenium ion 6. Recent studies have proven that cyclic fluoronium ions can be formed under special circumstances; however this is not thought to be the case here.21 Interception of this cationic intermediate by the alcohol (or amine) nucleophile results in cyclisation to form the protonated species 7. The by-product (5) released upon fluorination by Selectfluor is a tertiary amine base similar in structure to DABCO. We propose that the basic residue 5 is responsible for scavenging the proton from 7 to ultimately yield the products 2. The modest diastereoselectivity can be proposed to occur from an anti-orientation of the aromatic substituents during ring closure; however, the energy difference between this
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and the cis-orientation is likely to be low. For the isoindolines, the presence of the tosyl group on the nitrogen may result in the lower selectivity observed. In conclusion, we have developed an operationally simple and mild route to access fluorinated isobenzofurans and isoindolines. The reaction involves an electrophilic oxy- and aminofluorination process mediated by commercially available Selectfluor. The protocol has been shown to be useful for accessing 1,3-substituted products containing both alkyl and aromatic substituents. In addition to being metal-free, the methodology requires no additional base by exploiting the basic by-product of the reagent Selectfluor as a proton scavenger. The scope, utility and asymmetric transformation is currently being investigated in our laboratory and will be reported in due course. D. P. would like to thank the Alexander von Humboldt Foundation for the Humboldt Research Fellowship Award for Postdoctoral Researchers.
Notes and references 1 (a) T. Hiyama, Organofluorine Compounds. Chemistry and Applications, Springer, Berlin, 2000; (b) R. D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, 2004; (c) P. Kirsch, Modern Fluoroorganic Chemistry. Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, 2013. 2 (a) M. R. C. Gerstenberger and A. Haas, Angew. Chem., Int. Ed. Engl., 1981, 20, 647–667; (b) D. O’Hagan, ChemBioChem, 2005, 6, 763; (c) K. Mueller, C. Faeh and F. Diederich, Science, 2007, 317, 1881–1886; (d) W. K. Hagmann, J. Med. Chem., 2008, 51, 4359–4369; (e) K. L. Kirk, Org. Process Res. Dev., 2008, 12, 305–321; ( f ) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320–330. 3 (a) D. B. Harper and D. O’Hagan, Nat. Prod. Rep., 1994, 11, 123–133; (b) D. O’Hagan and D. B. Harper, J. Fluorine Chem., 1999, 100, 127–133. ´nchez-Rosello ´, J. L. Acen ˜a, C. del Pozo, A. E. Sorochinsky, 4 J. Wang, M. Sa S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2013, 114, 2432–2506. 5 P. W. Miller, N. J. Long, R. Vilar and A. D. Gee, Angew. Chem., Int. Ed., 2008, 47, 8998–9033. 6 (a) R. E. Banks, J. Fluorine Chem., 1998, 87, 1–17; (b) R. P. Singh and J. n. M. Shreeve, Acc. Chem. Res., 2004, 37, 31–44; (c) P. T. Nyffeler, S. G. Duron, M. D. Burkart, S. P. Vincent and C.-H. Wong, Angew. Chem., Int. Ed., 2005, 44, 192–212; (d) S. Stavber and M. Zupan, Acta Chim. Slov., 2005, 52, 13–26; (e) S. Stavber, Molecules, 2011, 16, 6432–6464; ( f ) S. D. Taylor, C. C. Kotoris and G. Hum, Tetrahedron, 1999, 55, 12431–12477; ( g) T. Umemoto, Adv. Org. Synth., 2006, 2, 159–181.
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Mild and metal-free oxy- and amino-fluorination for the synthesis of fluorinated heterocycles† Dixit Parmar and Magnus Rueping*
Received 2nd July 2014, Accepted 16th September 2014 DOI: 10.1039/c4cc05027d www.rsc.org/chemcomm
A mild intramolecular fluoro-cyclisation reaction of benzylic alcohols and amines has been developed. This strategy uses commercially available Selectfluor to trigger electrophilic cyclisations to afford fluorinated heterocycles containing 1,3-disubstitution. The dual role of the reagent as a fluorine source and a base is shown to be crucial for reactivity.
The attention focused on synthetic routes to organofluorine compounds has increased exponentially in recent years due to the realisation of the unique ability of fluorine to significantly modify the properties of molecules.1 The presence of fluorine in a molecule is known to alter important parameters such as electronics, lipophilicity, metabolism and conformation.2 This can be incredibly useful since fluorine-containing groups can be found in many diverse applications, such as natural products,3 pharmaceuticals,4 fine chemicals and materials. [F18]-labeled compounds have also found use as imaging agents by using positron emission tomography (PET).5 Over the past few years, significant gains have been made to introduce fluorine into molecules using both electrophilic6 and nucleophilic7 sources of fluorine. More recently, transition metals have also greatly assisted the process of delivering fluorine.8 Although these developments have opened up routes to fluorinated molecules, the challenge for the selective and predictable introduction under mild and operationally simple conditions is still to be overcome.9 Isobenzofurans and isoindolines are heterocyclic skeletons that feature at the forefront of a broad spectrum of applications. Isobenzofurans are well known for being versatile building blocks as well as precursors for the generation of reactive intermediates. They are also present in a number of natural products and biologically active molecules.10 For example, pestacin is a naturally occurring compound possessing antioxidant and antimycotic activities which result from an unusual C–H oxidation (Fig. 1a).10a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074, Aachen, Germany. E-mail: [email protected]; Fax: +49-241-8092665; Tel: +49-241-8094686 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc05027d
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Equally prominent, isoindolines have been receiving increasing levels of synthetic interest because of the realisation of their potential. For example, isoindolines also feature in a number of natural products and have been shown to possess biological activities (Fig. 1a).11 Furthermore, isoindolines are widely recognized as stable, easy-to-handle precursors to isoindoles, which are commonly used in cycloaddition reactions. Isoindoles are also known for their strong fluorescence and this property has been exploited in organic light-emitting diodes.12 Despite the attention received by these compounds from the synthetic community,13 routes to access them are rather limited. In particular, the synthesis of 1,3-di-substituted variants is particularly difficult especially in a diastereoselective manner. A method to access these frameworks that allows for straightforward introduction of substituents onto the skeleton would be a highly advantageous process for the advancement of their applications.
Fig. 1 (a) Selected examples of molecules and properties associated with the products; (b) overview of this work.
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In line with our continued interest in the synthesis of fluorinated small molecules,14 we proposed the use of an electrophilic fluorination–cyclisation strategy of O-15 and N-16 nucleophiles to access fluorinated variants of these important motifs. We envisioned that treatment of easily prepared substrates in the presence of an electrophilic fluorine source would result in regioselective fluorination of the alkene followed by concomitant cyclisation of the pendant nucleophile (Fig. 1b). Crucial to the success of the reaction would be the ability to minimize unwanted reactivity of the electrophilic reagent with the nucleophile. For example, benzylic alcohols and amines are well known to be easily oxidised by electrophilic fluorinating agents.17 Our study began by investigating the fluoro-cyclisation of benzylic alcohol 1a with a variety of electrophilic fluorinating agents. The initial results obtained with the commonly used fluorinating agents such as N-fluorobenzenesulfonimide (NFSI) and N-fluoropyridinium (N-fluoropyr) in combination with Na2CO3 as a base failed to yield any appreciable amount of the desired product 2a (Table 1, entries 1 and 2). Using the stronger fluorinating agent Selectfluor in a variety of solvents also was not initially fruitful (Table 1, entries 3–5). At the time, we suspected that the desired reactivity was not being achieved due to the poor solubility of Selectfluor. Changing the solvent to MeCN led to a modest yield of 51% of the desired product (Table 1, entry 6). Interestingly, when tBuOK was used as the base in MeCN, the desired reaction was once again completely absent (Table 1, entry 7). We speculated that the use of a strong base may result in the deprotonation of the alcohol and formation of an alkoxide species which was detrimental to reactivity. The use of a weak base may be sufficiently tolerated if it functions as a proton scavenger but unfortunately a screen of alternative weak bases failed to significantly improve upon the result obtained with Na2CO3. At this point, we recognised that Selectfluor upon fluorination liberates a tertiary amine base and that perhaps we could harness this by-product to act as our proton scavenger. Pleasingly, the simple use of Selectfluor in MeCN resulted in an excellent yield of the desired product (Table 1, entry 8).
Table 1
Selected optimisation of solvents and fluorinating agentsa
Entry
F+ source
Base
Solvent
Yieldb (%)
1 2 3 4 5 6 7 8
NFSI N-Fluoropyr Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor
Na2CO3 Na2CO3 Na2CO3 — Na2CO3 Na2CO3 tBuOK —
CH2Cl2 CH2Cl2 Hexane NaHCO3 (aq.) Acetone MeCN MeCN MeCN
o5 o5 o5 o5 o5 51c o5 95 (91)c
a Reaction conditions: a mixture of 1a (1 equiv.), Selectfluor (1.2 equiv.) and base (1.2 equiv.) were reacted under N2 at room temperature. b Yield based on NMR analysis. c Yield of isolated product.
Chem. Commun.
Fig. 2
Fluoro-cyclisations to access fluorinated isobenzofurans.
With the optimised conditions in hand, we looked towards exploring the scope of the fluoro-cyclisations to access a variety of isobenzofurans 2 (Fig. 2). We found the reaction to proceed smoothly for a broad scope of substituents. In general, aromatic groups with various substituents were well tolerated at the both 1- and 3-positions. At the 3-position, alongside the neutral and electronrich aromatics (2a, 2b, and 2e), electron-poor (2c and 2d) aromatics also worked well. Alkyl substitution was also well tolerated (2f and 2g) at this position including di-alkyl substitution (2h). In addition, it was shown that an unsubstituted substrate also smoothly underwent fluorocyclisation (2i). The diastereoselectivity was determined by analysis of signals in the 1H-NMR spectra and the relative stereochemistry of the major diastereoisomer was determined by NOE studies on 2e and assumed to be constant for all the entries in the series.18 In all cases, a consistently modest ratio of diastereoisomers was observed. Attempts to enhance the ratio by altering the reaction temperature failed to yield any improvements. With the scope explored for benzylic alcohols 1 we envisioned that the extension to benzylic amines would allow access to the
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Fig. 4 Proposed mechanism and model for diastereoselectivity for the fluoro-cyclisation.
Fig. 3
Fluoro-cyclisations to access fluorinated isoindolines.
corresponding fluorinated isoindolines. In contrast to the benzylic alcohols, we required the use of a compatible protecting group for the benzylic amines. The electron-withdrawing tosyl group was quickly identified as being suitable for the desired reactivity.19,20 Treatment of a range of benzylic amines 3 led to an efficient fluorination–cyclisation to yield fluorinated isoindolines 4 in good yields (Fig. 3). In general, the reaction proceeded smoothly in all cases to yield 1,3-disubstituted products. Aromatic groups containing a wide range of substituents and substitution patterns were well tolerated (4a–e) including the presence of fluorine on the aromatic ring (4f). Once again, the diastereoselectivity was determined by analysis of signals in the 19F-NMR spectra and was found to be rather low for all cases. It is assumed that the major diastereoisomer contains the same relative configuration as in the case of the isobenzofurans. A proposed mechanism is depicted in Fig. 4. The first step involves regioselective fluorination at the terminus of the alkene to give the acyclic b-fluoro-carbenium ion 6. Recent studies have proven that cyclic fluoronium ions can be formed under special circumstances; however this is not thought to be the case here.21 Interception of this cationic intermediate by the alcohol (or amine) nucleophile results in cyclisation to form the protonated species 7. The by-product (5) released upon fluorination by Selectfluor is a tertiary amine base similar in structure to DABCO. We propose that the basic residue 5 is responsible for scavenging the proton from 7 to ultimately yield the products 2. The modest diastereoselectivity can be proposed to occur from an anti-orientation of the aromatic substituents during ring closure; however, the energy difference between this
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and the cis-orientation is likely to be low. For the isoindolines, the presence of the tosyl group on the nitrogen may result in the lower selectivity observed. In conclusion, we have developed an operationally simple and mild route to access fluorinated isobenzofurans and isoindolines. The reaction involves an electrophilic oxy- and aminofluorination process mediated by commercially available Selectfluor. The protocol has been shown to be useful for accessing 1,3-substituted products containing both alkyl and aromatic substituents. In addition to being metal-free, the methodology requires no additional base by exploiting the basic by-product of the reagent Selectfluor as a proton scavenger. The scope, utility and asymmetric transformation is currently being investigated in our laboratory and will be reported in due course. D. P. would like to thank the Alexander von Humboldt Foundation for the Humboldt Research Fellowship Award for Postdoctoral Researchers.
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