DOI: 10.1002/chem.201403021
Communication
& Click Chemistry
Regioselective Conversion of Arenes to N-aryl-1,2,3-triazoles Using C H Borylation Rajavel Srinivasan,* Anthony G. Coyne, and Chris Abell*[a] Abstract: A one-pot protocol for the synthesis of N-aryl 1,2,3-triazoles from arenes by an iridium-catalyzed C H borylation/copper catalyzed azidation/click sequence is described. 1 mol % of Cu(OTf)2 was found to efficiently catalyze both the azidation and the click reaction. The applicability of this method is demonstrated by the late-stage chemoselective installation of 1,2,3-triazole moiety into unactivated molecules of pharmaceutical importance.
The discovery of the CuI-catalyzed 1,3-dipolar cycloaddition between an alkyne and an azide independently by Sharpless and co-workers[1a] and Meldal and co-workers[1b] and popularly known as the “click” reaction is known for its fidelity and robustness. This reaction has found widespread application in medicinal chemistry,[2a,b] chemical biology,[2c,d] and materials science[2e,f] and consequently revived the use of azides. However, unlike other aryl functionalities, such as nitrile, halides, phenols, amines, acids, and ethers, there are not many methods available to synthesize aryl azides from fundamental or feedstock building blocks, such as an unactivated arene. This might in part be due to a reluctance of the synthetic community to work with azides, some of which are known to be “explosive” under certain conditions.[3] This property of the azides has severely limited their application. The ever-expanding application of click chemistry mainly in the fields of drug discovery and compound-library synthesis[4] creates demand for simple and quick methods to generate diverse azides from readily available starting materials. Furthermore, approaches, in which the azides could be generated and used in situ for the next reaction without being isolated or purified, making the synthesis safer, simpler, and quicker, may attract the attention of process chemists. There have been several examples of arenes functionalized with 1,2,3-triazoles at the meta position (Figure 1).[5a–e] Herein, we present a simple protocol for the regioselective conversion of an aryl meta C H to the corresponding 1,2,3-triazole by direct C H borylation followed by CuII-catalyzed azidation of the aryl boronate. The azidation has been achieved by using
Figure 1. Representative of arenes functionalized with N-aryl-1,2,3-triazoles at meta position.
just 1 mol % of Cu(OTf)2 using air as the sole oxidant. The azides generated were not isolated or purified and were “clicked” in situ with a range of alkynes to furnish 1,2,3-triazoles in moderate to good yields. This is the first report, in which an aryl C H is functionalized to a 1,2,3-triazole in a onepot sequence, adding new methodology to the tool box of azide/click chemistry and bringing together the fields of click chemistry and C H activation. Finally, the applicability of this method is demonstrated by introduction of a 1,2,3-triazole into more complex molecules and by derivatizing 3-azidonicotine generated through the C H borylation/azidation sequence to various functionalized products (Scheme 1). Several groups have demonstrated the in situ generation of azides and their trapping with alkynes in a one-pot or a multicomponent fashion to create 1,2,3-triazoles. For example, Fokin and co-workers[6] and Lutz and co-workers[7] have used
[a] Dr. R. Srinivasan, Dr. A. G. Coyne, Prof. Dr. C. Abell Department of Chemistry, University of Cambridge Lensfield Road, Cambridge CB2 1EW (UK) E-mail: [email protected] [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403021. Chem. Eur. J. 2014, 20, 11680 – 11684
Scheme 1. Comparison between the existing methods and the C H activation method to generate 1,2,3-triazoles.
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Communication alkyl and aryl halides, respectively, for the in situ generation of azides and have “clicked” them with alkynes. Moses and coworkers[8] used anilines, whereas Wittmann and co-workers[9] used aliphatic amines for this purpose. More recently, Guo and co-workers[10a] and Yang et al.[10b] have demonstrated the generation of azides from commercially available boronic acids by Chan–Lam-based oxidative coupling[11] and used them in situ to make 1,2,3-triazoles. Even though all the above-mentioned methods are simple and attractive, they all need arenes with a functionalized handle, such as a halide, amine, or boronic acid(ester), to generate the azide. The commercial availability and substrate scope of these azide precursors limit the applicability of the methods. Another drawback of all the existing approaches to generate aryl azides from aryl boronic acids is the requirement of high loading of copper catalyst (10 mol %), and in some cases, the use of additives, such as CsF[12] and higher temperatures for effective conversion.[10b] It should be noted that the use of higher concentrations of copper catalyst in the presence of an anionic azide source, such as sodium azide or trimethylsilyl azide, results in the generation of higher concentrations of copper(II) azide, which is shock sensitive when dry, potentially making the reaction more hazardous particularly on a large scale.[13] Iridium-catalyzed direct C H borylation has proven to be a successful approach to functionalize unactivated (hetero)arenes.[14] The use of the [Ir(cod)(OMe)]2/dtdpy (dtdpy = 4,4’-ditert-butyl-2,2’-dipyridyl; cod = 1,5-cyclooctadiene) catalytic system developed by Hartwig and co-workers remains the most common choice for C H borylation.[14a] The regiochemistry of this reaction is controlled by steric factors rather than electronic or directing effects, and the borylation occurs at the arene carbon, which is least hindered.[14f,g, h] This selectivity has been exploited for the regioselective derivatization of an aryl C H to phenol,[15a] amino and ether,[15b] halide,[15c,d] nitrile,[15e] trifluoromethyl,[15f,g] alkyl,[15h] and aryl[15i,j,k] groups in a one-pot fashion, which are difficult to access by traditional chemical methods. However, this method has not been explored for the synthesis of 1,2,3-triazoles via an azide intermediate, which we describe herein. 3-Chloroanisole was used as the substrate in the optimization studies because of the presence of both electron-withdrawing and electron-donating groups on the same molecule. At first, 3-chloroanisole was subjected to a C H borylation reaction by using the standard conditions as described by Hartwig and co-workers by using B2Pin2 as the borylation agent in the presence of 0.25 mol % of [Ir(OMe)(cod)]2 and 0.5 mol % of dtdpy in THF, heating at 80 8C for 18 h (Scheme 2). After the completion of the reaction (as was monitored by 1H NMR spectroscopy), the volatiles were removed, and the reaction mixture was subjected to the screening conditions summarized in Table 1. Various copper catalysts were assessed to determine the most effective conversion of aryl boronate 1 B to aryl azide 1Az. Sodium azide was used as the azide source. Among the conditions screened, it was found that just 1 mol % of copper(II) triflate in ethanol at 40 8C in the presence of air as an oxidant could effect 94 % conversion by 1H NMR analysis (entry 1 in Table 1) of 1 B to 1Az in just 4 h. The protodeboronated Chem. Eur. J. 2014, 20, 11680 – 11684
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Table 1. Optimization of one-pot conversion of the crude C H borylated intermediate to 1,2,3-triazole.
Entry Catalyst[a]
Solvent t Conv. of 1 B to 1Az Yield of triazole 2 a [h] [%][b] [%][c]
1 2 3 4 5
ethanol ethanol ethanol ethanol ethanol
6 7 8 9[d]
Cu(OTf)2 CuSO4·5 H2O Cu(OAc)2 Cu(acac)2 copper(II) d-gluconate Cu(OTf)2 Cu(OTf)2 – Cu(OTf)2
4 6 6 6 8
94 89 68 48 31
75 71 n.d.[e] n.d. n.d.
THF 24 CH3CN 24 ethanol 24 ethanol 9
14 21 0 33
n.d. n.d. 0 n.d.
[a] Catalyst (1.0 mol %) was used. [b] Conversion was determined by H NMR spectroscopy. [c] Isolated yields after silica-gel chromatography. [d] Reaction was performed under N2. [e] n.d. = not determined.
1
compound (6 %) was also detected. CuSO4·5 H2O catalyzed 89 % conversion of 1 B to 1Az in 6 h. In contrast, other copper(II) sources, such as Cu(OAc)2 and Cu(acac)2 (acac = acetylacetonate), gave much poorer conversion of 68 and 48 %, respectively. Copper(II) d-gluconate gave the lowest conversion of only 31 %. When the solvent was varied, it was found that ethanol gave the best conversions, ahead of THF, which in turn was better than acetonitrile. Halogenated solvents, such as CH2Cl2 and CHCl3, were avoided, considering the risk of formation of highly sensitive azidomethanes in the presence of sodium azide.[3d] In the absence of any copper source, azide 1Az was not detected even after 24 h of reaction (by NMR spectroscopy). When the reaction was performed under N2, the conversion was poor (33 % after 9 h compared to 96 % in 4 h when carried out open to air). Having optimized conditions for the in situ conversion of the aryl boronate 1 B to aryl azide 1Az, the click reaction was then initiated by adding phenyl acetylene and 3 mol % of aqueous sodium ascorbate solution to the same reaction pot containing the aryl azide. No additional copper catalyst was added, because the reaction mixture already contained 1 mol % of the catalyst. After 8 h, complete conversion of azide 1Az to 1,4-substituted-1,2,3-triazole 2 a was achieved in an overall yield (for three steps) of 75 % (entry 1, Table 1). The presence of the iridium catalyst and other by-products from the borylation step did not appear to greatly affect either the azidation reaction or the click reaction. Importantly, only the expected 1,4-disubstituted regioisomer was formed in the click reaction. By using the optimized conditions, various 1,2,3-triazoles were synthesized as summarized in Scheme 2. Initially, the arenes were subjected to the C H borylation (Hartwig’s conditions)[14a] to give the aryl boronates (see the Supporting Infor-
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Communication ents, such as CH3, CF3, CN, OCH3, OCF3, CO2R, NR2, F, Cl, and Br, were tolerated under these reaction conditions. Arenes containing electron-withdrawing and/or electron-donation groups performed well. Heterocycles, such as pyridines and quinolones,[14h,i] underwent the reaction sequence in modest yields (entries 2 q, 2 r, and 2 s). Alkynes with different steric and electronic properties underwent the click reaction effectively (see the Supporting Information). The minor drawbacks of this approach are: 1) the low yield (Scheme 2, entry 2 b) in the case of a volatile azide intermediates (such as 1-azido-3,5-dimethylbenzene), which could be lost during the azidation sequence, which was performed open under air; and 2) contamination by pinacol (< 3 %) in a few final compounds even after chromatographic purification. This contamination can be removed azeotropically with water on a rotary evaporator.[15l] A control reaction was performed between the purified azide and alkyne in the presence of the iridium-catalytic system, but in the absence of any copper source. This confirmed that iridium did not have any effect on the click reaction. Late-stage modification of complex molecules is of interest to pharmaceutical companies seeking to develop structure–activity relationships (SAR), but at the same time presents a significant challenge to synthetic chemists. By using the approach Scheme 2. Conversion of (hetero)arenes to 1,2,3-triazoles. [a] Isolated yields after silica-gel chromatography. [b] Azidation carried out by using methanol as solvent. [c] Cu(OTf)2 (3 mol %) was used in the azidation sequence. described herein, ()-a-toco[d] Azidation and click reaction carried out in 0.5 mol % scale. [e] [Ir(cod)(OMe)]2 (3 mol %) and dtdpy (6 mol %) pherol nicotinate and ( )-nicoused in the borylation sequence, and Cu(OTf)2 (3 mol %) in the azidation sequence. tine were each modified with a 1,2,3-triazole moiety selectively in the meta-position, without the need to introduce a handle mation). Volatiles were then removed in vacuo, and the residue for the modification. A number of compounds containing the was dissolved in ethanol and added to a mixture of sodium 1,2,3-triazole scaffold are pharmaceutically active.[2a] We have azide (1.5 equiv) and 1 mol % of Cu(OTf)2, and heated at 40 8C for a period of 4–12 h in the presence of air to give the aryl synthesized a resveratrol analogue[16a] and an intermediate en azide. Thereafter, 3 mol % of sodium ascorbate and 1.2 equivaroute to a combretastatin analogue[16b] in 71 and 42 % yield, relent of alkyne was added, and the resulting mixture was stirred spectively, from arene precursors by using our approach. Both at room temperature for 12 h. The 1,4-disubsituted-1,2,3-trithe above-mentioned compounds are anti-cancer leads azoles (click product) were isolated in 33–88 % yield. Substitu(Scheme 3). Chem. Eur. J. 2014, 20, 11680 – 11684
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Communication The method was further evaluated for scale-up starting with 10 mmol (1.81 g) of 1,2,3-trichlorobenzene by using the standard conditions outlined in Scheme 2. The azide formed was trapped in situ by using N,N-dimethyl propargyl amine to give the desired 1,2,3-triazole in 78 % isolated yield (Scheme 5).
Scheme 5. Evaluation of a scale-up reaction.
Scheme 3. Late-stage modification/synthesis of medicinally important compounds.
Apart from making 1,2,3-triazoles, azides are also versatile intermediates for a number of chemical transformations. We chose ( )-nicotine to demonstrate this. ( )-Nicotine and its derivatives are known to be powerful ligands, which modulate nicotinic acetylcholine receptors and have potential effects on the central nervous system.[17a] Moreover, every year, 2 800 tons of nicotine is used as an insecticide.[17b] We subjected ( )-nicotine to C H borylation/azidation sequence and isolated the only regioselective product 3-azidonicotine formed in 62 % yield. The azido group was transformed into a variety of functionalities including amine, amide,[18a] sulfonamide, 1,5-substituted triazole,[18b] and 5-iodo-1,2,3-triazole[18c] (Scheme 4). All the nicotine derivatives synthesized herein were previously unknown and may have potential application in medicine and agriculture.
To conclude, we have demonstrated the first one-pot protocol for the conversion of an aryl C H bond to a 1,2,3-triazole in a regioselective manner utilizing the C H borylation/azidation/click sequence. Only 1 mol % of Cu(OTf)2 was required to catalyze both the azidation, as well the subsequent click reaction, making it a safer process. The method was applied to the direct synthesis of known medicinally important compounds and late-stage modification of more complex molecules. The ease of generating an aryl azide regioselectively from the C H of an (hetero)arene and derivatizing the azide into various functionalities was demonstrated by using ( )-nicotine. We believe this methodology will simplify the ways to make polysubstituted aryl azides/1,2,3-triazoles and may be amenable for scale-up chemistry.
Acknowledgements We thank Dr. John Skidmore for proofreading this manuscript. A.C. would like to thank the BBSRC for funding (Grant code BB/I019669/1). Keywords: azidation · C H borylation · click chemistry · synthetic methods
Scheme 4. Derivatization of ( )-nicotine C H bond. Reaction conditions: a) Pd/C (10 wt %), H2, MeOH, 2 h, 92 %; b) thiobenzoic acid, 16 h, 61 %; c) Pd/ C (10 wt %), H2, 2 h then p-TsCl, THF, 8 h, 59 %; d) 1-iodo-2-phenylethyne, CuI, THF, 16 h, 50 %; e) phenylacetylene, Me4NOH, DMSO, 16 h, 66 %. [a–e performed at 20 8C]. Chem. Eur. J. 2014, 20, 11680 – 11684
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[1] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708; Angew. Chem. Int. Ed. 2002, 41, 2596; b) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057. [2] For recent reviews, see: a) S. G. Agalave, S. R. Maujan, V. S. Pore, Chem. Asian J. 2011, 6, 2696; b) S. K. Mamidyala, M. G. Finn, Chem. Soc. Rev. 2010, 39, 1252; c) E. M. Sletten, C. R. Bertozzi, Acc. Chem. Res. 2012, 45, 630; d) A. H. El-Sagheer, T. Brown, Acc. Chem. Res. 2012, 45, 1258; e) K. D. Hnni, D. A. Leigh, Chem. Soc. Rev. 2010, 39, 1240; f) P. L. Golas, K. Matyjaszewski, Chem. Soc. Rev. 2010, 39, 1338. [3] a) S. Brse, K. Banert, Organic Azides: Syntheses and Applications, John Wiley & Sons, Chichester, 2010; b) S. Brse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem. 2005, 117, 5320; Angew. Chem. Int. Ed. 2005, 44, 5188; c) E. F. V. Scriven, K. Turnbull, Chem. Rev. 1988, 2, 351; d) J. Wiss, C. Fleury, U. Onken, Org. Process Res. Dev. 2006, 10, 349. [4] a) N. P. Grimster, B. Stump, J. S. Fotsing, T. T. Weide, J. G. Talley, Y. Yamauchi, A. Namecz, C. Kim, K. Y. Ho, K. B. Sharpless, P. Taylor, V. V. Fokin, J. Am. Chem. Soc. 2012, 134, 6732; b) L. P. Tan, H. Wu, P. Y. Yang, K. A. Kalesh, X. Zhang, M. Hu, R. Srinivasan, S. Q. Yao, Org. Lett. 2009, 11, 5102; c) R. Srinivasan, L. P. Tan, H. Wu, P. Y. Yang, K. A. Kalesh, S. Q. Yao,
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Received: April 10, 2014 Published online on July 22, 2014
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& Click Chemistry
Regioselective Conversion of Arenes to N-aryl-1,2,3-triazoles Using C H Borylation Rajavel Srinivasan,* Anthony G. Coyne, and Chris Abell*[a] Abstract: A one-pot protocol for the synthesis of N-aryl 1,2,3-triazoles from arenes by an iridium-catalyzed C H borylation/copper catalyzed azidation/click sequence is described. 1 mol % of Cu(OTf)2 was found to efficiently catalyze both the azidation and the click reaction. The applicability of this method is demonstrated by the late-stage chemoselective installation of 1,2,3-triazole moiety into unactivated molecules of pharmaceutical importance.
The discovery of the CuI-catalyzed 1,3-dipolar cycloaddition between an alkyne and an azide independently by Sharpless and co-workers[1a] and Meldal and co-workers[1b] and popularly known as the “click” reaction is known for its fidelity and robustness. This reaction has found widespread application in medicinal chemistry,[2a,b] chemical biology,[2c,d] and materials science[2e,f] and consequently revived the use of azides. However, unlike other aryl functionalities, such as nitrile, halides, phenols, amines, acids, and ethers, there are not many methods available to synthesize aryl azides from fundamental or feedstock building blocks, such as an unactivated arene. This might in part be due to a reluctance of the synthetic community to work with azides, some of which are known to be “explosive” under certain conditions.[3] This property of the azides has severely limited their application. The ever-expanding application of click chemistry mainly in the fields of drug discovery and compound-library synthesis[4] creates demand for simple and quick methods to generate diverse azides from readily available starting materials. Furthermore, approaches, in which the azides could be generated and used in situ for the next reaction without being isolated or purified, making the synthesis safer, simpler, and quicker, may attract the attention of process chemists. There have been several examples of arenes functionalized with 1,2,3-triazoles at the meta position (Figure 1).[5a–e] Herein, we present a simple protocol for the regioselective conversion of an aryl meta C H to the corresponding 1,2,3-triazole by direct C H borylation followed by CuII-catalyzed azidation of the aryl boronate. The azidation has been achieved by using
Figure 1. Representative of arenes functionalized with N-aryl-1,2,3-triazoles at meta position.
just 1 mol % of Cu(OTf)2 using air as the sole oxidant. The azides generated were not isolated or purified and were “clicked” in situ with a range of alkynes to furnish 1,2,3-triazoles in moderate to good yields. This is the first report, in which an aryl C H is functionalized to a 1,2,3-triazole in a onepot sequence, adding new methodology to the tool box of azide/click chemistry and bringing together the fields of click chemistry and C H activation. Finally, the applicability of this method is demonstrated by introduction of a 1,2,3-triazole into more complex molecules and by derivatizing 3-azidonicotine generated through the C H borylation/azidation sequence to various functionalized products (Scheme 1). Several groups have demonstrated the in situ generation of azides and their trapping with alkynes in a one-pot or a multicomponent fashion to create 1,2,3-triazoles. For example, Fokin and co-workers[6] and Lutz and co-workers[7] have used
[a] Dr. R. Srinivasan, Dr. A. G. Coyne, Prof. Dr. C. Abell Department of Chemistry, University of Cambridge Lensfield Road, Cambridge CB2 1EW (UK) E-mail: [email protected] [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403021. Chem. Eur. J. 2014, 20, 11680 – 11684
Scheme 1. Comparison between the existing methods and the C H activation method to generate 1,2,3-triazoles.
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Communication alkyl and aryl halides, respectively, for the in situ generation of azides and have “clicked” them with alkynes. Moses and coworkers[8] used anilines, whereas Wittmann and co-workers[9] used aliphatic amines for this purpose. More recently, Guo and co-workers[10a] and Yang et al.[10b] have demonstrated the generation of azides from commercially available boronic acids by Chan–Lam-based oxidative coupling[11] and used them in situ to make 1,2,3-triazoles. Even though all the above-mentioned methods are simple and attractive, they all need arenes with a functionalized handle, such as a halide, amine, or boronic acid(ester), to generate the azide. The commercial availability and substrate scope of these azide precursors limit the applicability of the methods. Another drawback of all the existing approaches to generate aryl azides from aryl boronic acids is the requirement of high loading of copper catalyst (10 mol %), and in some cases, the use of additives, such as CsF[12] and higher temperatures for effective conversion.[10b] It should be noted that the use of higher concentrations of copper catalyst in the presence of an anionic azide source, such as sodium azide or trimethylsilyl azide, results in the generation of higher concentrations of copper(II) azide, which is shock sensitive when dry, potentially making the reaction more hazardous particularly on a large scale.[13] Iridium-catalyzed direct C H borylation has proven to be a successful approach to functionalize unactivated (hetero)arenes.[14] The use of the [Ir(cod)(OMe)]2/dtdpy (dtdpy = 4,4’-ditert-butyl-2,2’-dipyridyl; cod = 1,5-cyclooctadiene) catalytic system developed by Hartwig and co-workers remains the most common choice for C H borylation.[14a] The regiochemistry of this reaction is controlled by steric factors rather than electronic or directing effects, and the borylation occurs at the arene carbon, which is least hindered.[14f,g, h] This selectivity has been exploited for the regioselective derivatization of an aryl C H to phenol,[15a] amino and ether,[15b] halide,[15c,d] nitrile,[15e] trifluoromethyl,[15f,g] alkyl,[15h] and aryl[15i,j,k] groups in a one-pot fashion, which are difficult to access by traditional chemical methods. However, this method has not been explored for the synthesis of 1,2,3-triazoles via an azide intermediate, which we describe herein. 3-Chloroanisole was used as the substrate in the optimization studies because of the presence of both electron-withdrawing and electron-donating groups on the same molecule. At first, 3-chloroanisole was subjected to a C H borylation reaction by using the standard conditions as described by Hartwig and co-workers by using B2Pin2 as the borylation agent in the presence of 0.25 mol % of [Ir(OMe)(cod)]2 and 0.5 mol % of dtdpy in THF, heating at 80 8C for 18 h (Scheme 2). After the completion of the reaction (as was monitored by 1H NMR spectroscopy), the volatiles were removed, and the reaction mixture was subjected to the screening conditions summarized in Table 1. Various copper catalysts were assessed to determine the most effective conversion of aryl boronate 1 B to aryl azide 1Az. Sodium azide was used as the azide source. Among the conditions screened, it was found that just 1 mol % of copper(II) triflate in ethanol at 40 8C in the presence of air as an oxidant could effect 94 % conversion by 1H NMR analysis (entry 1 in Table 1) of 1 B to 1Az in just 4 h. The protodeboronated Chem. Eur. J. 2014, 20, 11680 – 11684
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Table 1. Optimization of one-pot conversion of the crude C H borylated intermediate to 1,2,3-triazole.
Entry Catalyst[a]
Solvent t Conv. of 1 B to 1Az Yield of triazole 2 a [h] [%][b] [%][c]
1 2 3 4 5
ethanol ethanol ethanol ethanol ethanol
6 7 8 9[d]
Cu(OTf)2 CuSO4·5 H2O Cu(OAc)2 Cu(acac)2 copper(II) d-gluconate Cu(OTf)2 Cu(OTf)2 – Cu(OTf)2
4 6 6 6 8
94 89 68 48 31
75 71 n.d.[e] n.d. n.d.
THF 24 CH3CN 24 ethanol 24 ethanol 9
14 21 0 33
n.d. n.d. 0 n.d.
[a] Catalyst (1.0 mol %) was used. [b] Conversion was determined by H NMR spectroscopy. [c] Isolated yields after silica-gel chromatography. [d] Reaction was performed under N2. [e] n.d. = not determined.
1
compound (6 %) was also detected. CuSO4·5 H2O catalyzed 89 % conversion of 1 B to 1Az in 6 h. In contrast, other copper(II) sources, such as Cu(OAc)2 and Cu(acac)2 (acac = acetylacetonate), gave much poorer conversion of 68 and 48 %, respectively. Copper(II) d-gluconate gave the lowest conversion of only 31 %. When the solvent was varied, it was found that ethanol gave the best conversions, ahead of THF, which in turn was better than acetonitrile. Halogenated solvents, such as CH2Cl2 and CHCl3, were avoided, considering the risk of formation of highly sensitive azidomethanes in the presence of sodium azide.[3d] In the absence of any copper source, azide 1Az was not detected even after 24 h of reaction (by NMR spectroscopy). When the reaction was performed under N2, the conversion was poor (33 % after 9 h compared to 96 % in 4 h when carried out open to air). Having optimized conditions for the in situ conversion of the aryl boronate 1 B to aryl azide 1Az, the click reaction was then initiated by adding phenyl acetylene and 3 mol % of aqueous sodium ascorbate solution to the same reaction pot containing the aryl azide. No additional copper catalyst was added, because the reaction mixture already contained 1 mol % of the catalyst. After 8 h, complete conversion of azide 1Az to 1,4-substituted-1,2,3-triazole 2 a was achieved in an overall yield (for three steps) of 75 % (entry 1, Table 1). The presence of the iridium catalyst and other by-products from the borylation step did not appear to greatly affect either the azidation reaction or the click reaction. Importantly, only the expected 1,4-disubstituted regioisomer was formed in the click reaction. By using the optimized conditions, various 1,2,3-triazoles were synthesized as summarized in Scheme 2. Initially, the arenes were subjected to the C H borylation (Hartwig’s conditions)[14a] to give the aryl boronates (see the Supporting Infor-
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Communication ents, such as CH3, CF3, CN, OCH3, OCF3, CO2R, NR2, F, Cl, and Br, were tolerated under these reaction conditions. Arenes containing electron-withdrawing and/or electron-donation groups performed well. Heterocycles, such as pyridines and quinolones,[14h,i] underwent the reaction sequence in modest yields (entries 2 q, 2 r, and 2 s). Alkynes with different steric and electronic properties underwent the click reaction effectively (see the Supporting Information). The minor drawbacks of this approach are: 1) the low yield (Scheme 2, entry 2 b) in the case of a volatile azide intermediates (such as 1-azido-3,5-dimethylbenzene), which could be lost during the azidation sequence, which was performed open under air; and 2) contamination by pinacol (< 3 %) in a few final compounds even after chromatographic purification. This contamination can be removed azeotropically with water on a rotary evaporator.[15l] A control reaction was performed between the purified azide and alkyne in the presence of the iridium-catalytic system, but in the absence of any copper source. This confirmed that iridium did not have any effect on the click reaction. Late-stage modification of complex molecules is of interest to pharmaceutical companies seeking to develop structure–activity relationships (SAR), but at the same time presents a significant challenge to synthetic chemists. By using the approach Scheme 2. Conversion of (hetero)arenes to 1,2,3-triazoles. [a] Isolated yields after silica-gel chromatography. [b] Azidation carried out by using methanol as solvent. [c] Cu(OTf)2 (3 mol %) was used in the azidation sequence. described herein, ()-a-toco[d] Azidation and click reaction carried out in 0.5 mol % scale. [e] [Ir(cod)(OMe)]2 (3 mol %) and dtdpy (6 mol %) pherol nicotinate and ( )-nicoused in the borylation sequence, and Cu(OTf)2 (3 mol %) in the azidation sequence. tine were each modified with a 1,2,3-triazole moiety selectively in the meta-position, without the need to introduce a handle mation). Volatiles were then removed in vacuo, and the residue for the modification. A number of compounds containing the was dissolved in ethanol and added to a mixture of sodium 1,2,3-triazole scaffold are pharmaceutically active.[2a] We have azide (1.5 equiv) and 1 mol % of Cu(OTf)2, and heated at 40 8C for a period of 4–12 h in the presence of air to give the aryl synthesized a resveratrol analogue[16a] and an intermediate en azide. Thereafter, 3 mol % of sodium ascorbate and 1.2 equivaroute to a combretastatin analogue[16b] in 71 and 42 % yield, relent of alkyne was added, and the resulting mixture was stirred spectively, from arene precursors by using our approach. Both at room temperature for 12 h. The 1,4-disubsituted-1,2,3-trithe above-mentioned compounds are anti-cancer leads azoles (click product) were isolated in 33–88 % yield. Substitu(Scheme 3). Chem. Eur. J. 2014, 20, 11680 – 11684
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Communication The method was further evaluated for scale-up starting with 10 mmol (1.81 g) of 1,2,3-trichlorobenzene by using the standard conditions outlined in Scheme 2. The azide formed was trapped in situ by using N,N-dimethyl propargyl amine to give the desired 1,2,3-triazole in 78 % isolated yield (Scheme 5).
Scheme 5. Evaluation of a scale-up reaction.
Scheme 3. Late-stage modification/synthesis of medicinally important compounds.
Apart from making 1,2,3-triazoles, azides are also versatile intermediates for a number of chemical transformations. We chose ( )-nicotine to demonstrate this. ( )-Nicotine and its derivatives are known to be powerful ligands, which modulate nicotinic acetylcholine receptors and have potential effects on the central nervous system.[17a] Moreover, every year, 2 800 tons of nicotine is used as an insecticide.[17b] We subjected ( )-nicotine to C H borylation/azidation sequence and isolated the only regioselective product 3-azidonicotine formed in 62 % yield. The azido group was transformed into a variety of functionalities including amine, amide,[18a] sulfonamide, 1,5-substituted triazole,[18b] and 5-iodo-1,2,3-triazole[18c] (Scheme 4). All the nicotine derivatives synthesized herein were previously unknown and may have potential application in medicine and agriculture.
To conclude, we have demonstrated the first one-pot protocol for the conversion of an aryl C H bond to a 1,2,3-triazole in a regioselective manner utilizing the C H borylation/azidation/click sequence. Only 1 mol % of Cu(OTf)2 was required to catalyze both the azidation, as well the subsequent click reaction, making it a safer process. The method was applied to the direct synthesis of known medicinally important compounds and late-stage modification of more complex molecules. The ease of generating an aryl azide regioselectively from the C H of an (hetero)arene and derivatizing the azide into various functionalities was demonstrated by using ( )-nicotine. We believe this methodology will simplify the ways to make polysubstituted aryl azides/1,2,3-triazoles and may be amenable for scale-up chemistry.
Acknowledgements We thank Dr. John Skidmore for proofreading this manuscript. A.C. would like to thank the BBSRC for funding (Grant code BB/I019669/1). Keywords: azidation · C H borylation · click chemistry · synthetic methods
Scheme 4. Derivatization of ( )-nicotine C H bond. Reaction conditions: a) Pd/C (10 wt %), H2, MeOH, 2 h, 92 %; b) thiobenzoic acid, 16 h, 61 %; c) Pd/ C (10 wt %), H2, 2 h then p-TsCl, THF, 8 h, 59 %; d) 1-iodo-2-phenylethyne, CuI, THF, 16 h, 50 %; e) phenylacetylene, Me4NOH, DMSO, 16 h, 66 %. [a–e performed at 20 8C]. Chem. Eur. J. 2014, 20, 11680 – 11684
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Received: April 10, 2014 Published online on July 22, 2014
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