- Email: [email protected]
A convenient one-pot synthesis of boroxoles from diboronic acid
Accepted Manuscript A convenient one-pot synthesis of boroxoles from diboronic acid Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan, Frédéric Gaigne, Véronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe Vatinel, Jean-François Fournier, Branislav Musicki, Gilles Ouvry, Claire BouixPeter, Loic Tomas, Craig S. Harris PII: DOI: Reference:
S0040-4039(17)31000-6 http://dx.doi.org/10.1016/j.tetlet.2017.08.011 TETL 49201
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
28 June 2017 1 August 2017 5 August 2017
Please cite this article as: Lafitte, G., Kunihiro, K., Bonneaud, C., Dréan, B., Gaigne, F., Parnet, V., Pierre, R., Raffin, C., Vatinel, R., Fournier, J-F., Musicki, B., Ouvry, G., Bouix-Peter, C., Tomas, L., Harris, C.S., A convenient one-pot synthesis of boroxoles from diboronic acid, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/ j.tetlet.2017.08.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
A convenient one-pot synthesis of boroxoles using diboronic acid
Leave this area blank for abstract info.
Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan, Frédéric Gaigne, Véronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe Vatinel, Jean-François Fournier, Branislav Musicki, Gilles Ouvry, Claire Bouix-Peter, Loic Tomas, Craig S. Harris
Tetrahedron Letters
1
TETRAHEDRON LETTERS
Pergamon
A convenient one-pot synthesis of boroxoles from diboronic acid Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan, Frédéric Gaigne, Véronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe Vatinel, Jean-François Fournier, Branislav Musicki, Gilles Ouvry, Claire Bouix-Peter, Loic Tomas,* Craig S. Harris * Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France Abstract— The preparation of the boroxole motif traditionally relies on a 3-step process and the use of n-butyl lithium that can limit substrate scope. Herein during our exploration toward novel RORγ inhibitors, we identified a convenient one-pot preparation of the motif in good yields with good substrate scope. © 2017 Elsevier Science. All rights reserved
Psoriasis is a chronic inflammatory disease involving marked immunological changes that affects 2%-3% of the Caucasian population and is characterised by thick, red and scaly lesions.1 IL-17-targeting biologics have been successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease.2 The Retinoid-related Orphan Receptor γt (RORγt), a subfamily of nuclear hormone receptors, is known as the master regulator of IL-17 family cytokines. Therefore, inhibition of the RORγt receptor represents an interesting opportunity for the treatment of psoriasis. Bis-aryl sulfonamides have been described by multiple groups as potent RORγt modulators.3 Our internal research program extensively explored bicyclic heteroaromatic sulfonamides.4,5 As part of this approach boroxole 1 was envisaged as a possible interesting target molecule (Figure 1). Boroxoles6 have recently risen to fame in dermatology with the approval of Crisaborole for the topical treatment of atopic dermatitis.7
Figure 1. Targeted boroxole 1
Retrosynthetic analysis of 1 drove us to consider an ambitious and direct approach starting from commercially-available 3,4dibromobenzenesulfonyl chloride (7) and 4-ethyl-N-isobutylaniline (6), easily prepared through reductive amination of 4ethylaniline. From inspection of the literature,8 Singh et al reported an excellent yield and selectivity at C-4 for a Sonagashira coupling using 1,2-dibromo-4-nitrobenzene as the substrate. Given the fact the C-4-bromine atom of sulfonamide 5 is also directly activated by the sulfonamide group, we anticipated that we should be able differentiate between them to afford Sonagahira product 4 using commercially-available, 4-ethynyltetrahydro-2H-pyran. We anticipated that the hydration step of 4 as high risk as there were very few clear examples of Markovnikov hydration selectivity of alkynes separated by aromatic moieties and secondary alkyl groups.9-11 However, given the fact 4 was prepared very quickly in just three steps and the wealth of options to evaluate9-11 we were certain we could find conditions that would provide 3 in sufficient yield. Finally, after reduction to afford 2, we anticipated that using the 4-step literature protocol involving protection of the alcohol, borylation using trimethoxyborane after lithium halogen exchange, deprotection and cyclocondensation to the boroxole under acid catalysis would afford 1 (Scheme 1).12 ——— * Craig Harris. Tel.: +33 (0)4 93 95 7042; fax: +33 (0)4 93 95 7071; e-mail: [email protected] Keywords: Diboronic acid, boroxole formation; one-pot
2
Tetrahedron Letters
Scheme 1. Retrosynthetic analysis of 1 Sulfonamide 5 was easily prepared in 70% yield from 7 and 6. The Sonagashira coupling of 5 was surprisingly very inefficient and not as selective as we anticipated. However, we managed to isolate sufficient 4 to progress the reaction. During the evaluation of the hydration step, we came across several issues. Under Bronsted acid-catalysed conditions, we principally obtained the desired regiochemistry but the competing Fries rearrangement product dominated the reaction profile affording 9 as the only product.13 To overcome this issue, we tried several conditions and found that the combination of 1,3bis(2,6-diisopropylphenyl-imidazol-2-ylidene)gold(I) chloride and silver hexafluoroantimoniate 10 afforded 3 albeit in very poor yield and selectivity. Finally, our attempts to convert 3 to desired target 1 following the closest literature process failed.12
Scheme 2. First route for the preparation of 1. Reagents and conditions: a) Pyridine, THF, r.t., 19 h (quant.); b) 4Ethynyltetrahydro-2H-pyran, CuI, Pd(PPh3)2Cl2, DMF, 60°C, 1 h, 34% (4), 8% (8); c) Sulfuric acid, dioxane, 100 °C, 65%; d) IPrAuCl, AgSbF6, 1,4-dioxane, H2O, 120 °C, 3 h, 41%; e) NaBH4, THF, MeOH, 0 °C, 1 h, 60%; f) MOM-Cl, DIPEA, THF, 67%; g) n-Bu-Li, B(OMe)3, THF -78 °C-r.t., 0% (f) 6N HCl, r.t., 16 h To avoid the Fries’ product, we decided to prepare the imidazole sulfonamide 10, with the knowledge that if we had difficulty to displace the imidazole with 6,14 we could activate the imidazole group by methylation for the coupling reaction downstream.15 To our surprise, the selectivity of the Sonagashira step was greatly improved from 34% to 72% of 11. We opted to trial directly the gold catalyzed conditions10 and obtained desired ketone 13 as the sulfonic acid in excellent conversion, albeit in 59:41 ratio in favour of the undesired isomer 14. In situ activation of the sulfonic acid was achieved using the Vilsmeier reagent16 followed by coupling with aniline 8 and reduction to afford 2 in poor overall yield. With 2 in hand, we decided to see if we could apply Molander’s borylation conditions using dibronic acid and second generation Buchwald catalyst17 anticipating that if transformation to the boronic acid takes place we could expect in situ cyclisation to
Tetrahedron Letters
3
desired boroxole 1. To our delight, the reaction proceeded as expected affording an excellent conversion to 1 in a nonoptimised yield of 32% (Scheme 2).
Scheme 2. Adapted route for the preparation of 1. Reagents and conditions: a) Imidazole, Et3N, DCM, r.t., 19 h, quant.; b) 4Ethynyltetrahydro-2H-pyrane, CuI, Pd(PPh3)2Cl2, DMF, 60 °C, 1 h, 72% (11) 5% (12); c) IPrAuCl, AgSbF6, 1,4-dioxane, H2O, 120 °C, 3 h, 41%; (d) Vilsmeier salt, Et3N, DCM, r.t., 1 h, followed by 4-ethyl-N-isobutylaniline (8), pyridine, 100°C, microwave, 15 min., 28%; e) NaBH4, THF, MeOH, 0 °C, 1 h, 55%); f) Tetrahydroxydiboron, XPhos Pd G2, XPhos KOAc, EtOH, 80 °C, 1 h, 32% With this knowledge in hand, we decided to explore substrate scope of the one-pot borylation-cyclocondensation step. While the authors acknowledge a recent process using B2pin2 was reported by Huang et al,18 we anticipated that the use of diboronic acid directly is much more atom economic and should avoid contamination of boroxole products with pinacol. Both bromides and iodides were equally good substrates for this process (Table 1, entries 1 and 2). Increasing steric hindrance at the benzylic position with one, two methyl groups or a cyclopropyl group was also afforded boroxole product with acceptable to good yields (Table 1, entries 4, 6 and 7). Unfortunately, going from aryl-bromide to aryl-chloride gave lower yield despite the utilization of XPhos Pd G2 catalyst (Table 1, entry 4 v 5). Six and seven membered boroxoles were also isolated albeit in moderate yield using this convenient one-pot approach (entries 7-8). Table 1. One pot synthesis of boroxoles using diboronic acid
Entry
Aryl halide
Isolated Yield (%)
1
59
2
69
3
35
4
57
5
OH Cl
32
4
Tetrahedron Letters 6
42
7
51
8
37
9
45
In conclusion, during our exploration to prepare and test boroxole 1 for RORγ activity, we successfully employed diboronic acid to the convenient and functional group tolerant one pot borylation-cyclocondensation reaction18 to prepare a range of novel boroxoles in moderate to good yield. Work in ongoing in the laboratory to enlarge substrate scope. Supplementary data Full experimental procedures and supporting LCMS, 1H-NMR characterisation data are available for a selection of compounds described in this letter is available at no extra charge via the on-line version. References and notes 1. Greb, J. E.; Goldminz, A. M.; Elder, J. T.; Lebwohl, M. G.; Gladman, D. D.; Wu, J. J.; Mehta, N. N.; Finlay, A. Y.; Gottlieb, A. B. Nat. Rev. Disease Primers 2016, 2, 1-17. 2. Smith, S. H.; Peredo, C. E.; Takeda, Y.; Bui, T.; Neil, J.; Rickard, D.; Millerman, E.; Therrien, J. P.; Nicodeme, E.; Brusq, J. M.; Birault, V.; Viviani, F.; Hofland, H.; Jetten, A.M.; Cote-Sierra, J. PLoS ONE 2016, 11, 1-18. 3. (a) Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.; Shukla, L. WO2013/160418; 31 Oct. 2013; (b) Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.; Shukla, L. WO2013/160419; 31 Oct. 2013; (c) Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.WO2013/045431; 04 Apr. 2013; (d) Fauber, B.; Rene, O; Bodil van Niel, M.; Gaines, S.; Killen, J.; Ward, S. US2014/0163024 12 Jun. 2014; (e) Fauber, B.; Rene, O; Bodil van Niel, M.; Ward, S. US2014/0163110 12 Jun. 2014; (f) Bodil van Niel, M.; Fauber, B.; Rene, O; Ward, S. WO2014/140059 18 Sept. 2014; (g) Fauber, B. P.; Rene, O.; Burton, B.; Everett, C.; Gobbi, A.; Hawkins, J.; Johnson, A. R.; Liimatta, M.; Lockey, P.; Norman, M.; Wong, H. Bioorg. Med. Chem. Lett. 2014, 24, 2182-2187; (h) Fauber, B. P.; Rene, O.; de Leon Boenig, G.; Burton, B.; Deng, Y.; Eidenschenk, C.; Everett, C.; Gobbi, A.; Hymowitz, S. G.; Johnson, A. R.; La, H.; Liimatta, M.; Lockey, P.; Norman, M.; Ouyang, W;; Wang, W.; Wong, H. Bioorg. Med. Chem. Lett. 2014, 24, 3891-3897; (i) van Niel, M. B.; Fauber, B. P.; Cartwright, M.; Gaines, S.; Killen, J. C.; Rene, O.; Ward, S. I.; de Leon Boenig, G.; Deng, Y.; Eidenschenk, C.; Everett, C.; Garcia, E.; Ganguli, A.; Gobbi, A.; Hawkins, J.; Johnson, A. R.; Kiefer, J. R.; La, H.; Lockey, P.; Norman, M.; Ouyang, W.; Qin, A.; Wakes, N.; Waszkowycz, B.; Wong, H. Bioorg. Med. Chem. Lett. 2014, 24, 5769-5776. 4. (a) Musicki, B. WO2016/097389; 23 Jun. 2016; (b) Musicki, B. WO2016/097391; 23 Jun. 2016; (c) Musicki, B. WO2016/097392; 23 Jun. 2016; (a) Musicki, B. WO2016/097393; 23 Jun. 2016; (a) Musicki, B. WO2016/097394; 23 Jun. 2016. 5. Full account of the medicinal chemistry including SAR and SPR will be published elsewhere shortly. 6. For review articles on boroxoles, please consult: a) Adamczyk-Woźniak, A.; Borys, K. M.; Sporzyński, A. Chem. Rev. 2015, 115, 5224−5247; b) Liu, T. C.; Tomsho, J. W.; Benkovic S. J. Bioorg. Med. Chem. 2015, 23, 44624473; c) Baker, Stephen J.; Tomshob, J. W.; Benkovicc, S. J. Chem. Soc. Rev. 2011, 40, 4279–4285. 7. Paller, A. S.; Tom, W. L.; Lebwohl, M. G.; Blumenthal, R. L.; Boguniewicz, M.; Call, R. S.; Eichenfield, L. F.; Forsha, D.; Rees, W. C.; Simpson, E. L.; Spellman, M. C.; Stein Gold, L. F.; Zaenglein, A. L.; Hughes, M. H.; Zane, L. T.; Hebert, A. A. J. Am. Acad. Dermatol. 2016, 75, 494-503. 8. Singh, R.; Just, G. J. Org. Chem. 1989, 54, 4453-4457. 9. Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149-6153 10. Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448-449. 11. For review articles see a) Goodwin, J. A.; Aponick A. Chem. Commun. 2015, 51, 8370-8741; b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180-3211. 12. a) Jacobs, R. T.; Plattner, J. J.; Nare, B.; Wring, S. A.; Chen, D.; Freund, Y.; Gaukel, E. G.; Orr, M. D.; Perales, J. B.; Jenks, M.; Noe, R. A.; Sligar, J. M.; Zhang, Y-K.; Bacchi, C. J.; Yarlett, N.; Don, R. Future Med. Chem. 2011, 3, 1259-1278; b) Ye, L.; Ding, D.; Feng, Y.; Xie, D.; Wu, P.; Guo, H.; Meng, Q.; Zhou, H. Tetrahedron 2009, 65,
Tetrahedron Letters
13. 14. 15. 16. 17. 18. .
5
8738-8744; c) Gunasekera, D. S.; Gerold, D. J.; Aalderks, N. S.; Chandra, J. S.; Maanu, C. A.; Kiprof, P.; Zhdankin, V. V.; Reddy, M. V. R. Tetrahedron 2007, 63, 9401-9405. a) Searles, S. Jr.; Nukina, S. Chem. Rev. 2007, 59, 1077-1103; b) Sharma, A.; Jain, S.; Sirohi, R.; Kishore, D. Org. Chem. Int. 2011, 614627, 5 pp. Staab, H. A.; Wendel, K. Chem. Ber. 1960, 93, 2902-2915 Vilkas, E. Bull. Soc. Chim. Fr. 1978, 1-2, Pt. 2, 37-8. Dunetz, J. R.; Magano, J.; Weisenburger, G. A. Org. Proc. Res. Dev. 2016, 20, 140-177. Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge M. T. J. Am. Chem. Soc., 2012, 134, 1166711673. For recent one-pot protocol described using B2pin2 as the borylating agent see: Zhu, Jianan; Wei, Ying; Lin, Dongqing; Ou, Changjin; Xie, Linghai; Zhao, Yu; Huang, Wei. OBC 2015, 13, 11362-11368
6
Tetrahedron Letters
•
•
•
An efficient one-pot process to prepare boroxoles directly from diboronic acid is disclosed This mild process avoids the necessity of carrying out a halogen-lithium exchange under cryogenic conditions A diverse range of boroxoles were prepared in acceptable yield with good substrate scope
S0040-4039(17)31000-6 http://dx.doi.org/10.1016/j.tetlet.2017.08.011 TETL 49201
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
28 June 2017 1 August 2017 5 August 2017
Please cite this article as: Lafitte, G., Kunihiro, K., Bonneaud, C., Dréan, B., Gaigne, F., Parnet, V., Pierre, R., Raffin, C., Vatinel, R., Fournier, J-F., Musicki, B., Ouvry, G., Bouix-Peter, C., Tomas, L., Harris, C.S., A convenient one-pot synthesis of boroxoles from diboronic acid, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/ j.tetlet.2017.08.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
A convenient one-pot synthesis of boroxoles using diboronic acid
Leave this area blank for abstract info.
Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan, Frédéric Gaigne, Véronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe Vatinel, Jean-François Fournier, Branislav Musicki, Gilles Ouvry, Claire Bouix-Peter, Loic Tomas, Craig S. Harris
Tetrahedron Letters
1
TETRAHEDRON LETTERS
Pergamon
A convenient one-pot synthesis of boroxoles from diboronic acid Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan, Frédéric Gaigne, Véronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe Vatinel, Jean-François Fournier, Branislav Musicki, Gilles Ouvry, Claire Bouix-Peter, Loic Tomas,* Craig S. Harris * Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France Abstract— The preparation of the boroxole motif traditionally relies on a 3-step process and the use of n-butyl lithium that can limit substrate scope. Herein during our exploration toward novel RORγ inhibitors, we identified a convenient one-pot preparation of the motif in good yields with good substrate scope. © 2017 Elsevier Science. All rights reserved
Psoriasis is a chronic inflammatory disease involving marked immunological changes that affects 2%-3% of the Caucasian population and is characterised by thick, red and scaly lesions.1 IL-17-targeting biologics have been successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease.2 The Retinoid-related Orphan Receptor γt (RORγt), a subfamily of nuclear hormone receptors, is known as the master regulator of IL-17 family cytokines. Therefore, inhibition of the RORγt receptor represents an interesting opportunity for the treatment of psoriasis. Bis-aryl sulfonamides have been described by multiple groups as potent RORγt modulators.3 Our internal research program extensively explored bicyclic heteroaromatic sulfonamides.4,5 As part of this approach boroxole 1 was envisaged as a possible interesting target molecule (Figure 1). Boroxoles6 have recently risen to fame in dermatology with the approval of Crisaborole for the topical treatment of atopic dermatitis.7
Figure 1. Targeted boroxole 1
Retrosynthetic analysis of 1 drove us to consider an ambitious and direct approach starting from commercially-available 3,4dibromobenzenesulfonyl chloride (7) and 4-ethyl-N-isobutylaniline (6), easily prepared through reductive amination of 4ethylaniline. From inspection of the literature,8 Singh et al reported an excellent yield and selectivity at C-4 for a Sonagashira coupling using 1,2-dibromo-4-nitrobenzene as the substrate. Given the fact the C-4-bromine atom of sulfonamide 5 is also directly activated by the sulfonamide group, we anticipated that we should be able differentiate between them to afford Sonagahira product 4 using commercially-available, 4-ethynyltetrahydro-2H-pyran. We anticipated that the hydration step of 4 as high risk as there were very few clear examples of Markovnikov hydration selectivity of alkynes separated by aromatic moieties and secondary alkyl groups.9-11 However, given the fact 4 was prepared very quickly in just three steps and the wealth of options to evaluate9-11 we were certain we could find conditions that would provide 3 in sufficient yield. Finally, after reduction to afford 2, we anticipated that using the 4-step literature protocol involving protection of the alcohol, borylation using trimethoxyborane after lithium halogen exchange, deprotection and cyclocondensation to the boroxole under acid catalysis would afford 1 (Scheme 1).12 ——— * Craig Harris. Tel.: +33 (0)4 93 95 7042; fax: +33 (0)4 93 95 7071; e-mail: [email protected] Keywords: Diboronic acid, boroxole formation; one-pot
2
Tetrahedron Letters
Scheme 1. Retrosynthetic analysis of 1 Sulfonamide 5 was easily prepared in 70% yield from 7 and 6. The Sonagashira coupling of 5 was surprisingly very inefficient and not as selective as we anticipated. However, we managed to isolate sufficient 4 to progress the reaction. During the evaluation of the hydration step, we came across several issues. Under Bronsted acid-catalysed conditions, we principally obtained the desired regiochemistry but the competing Fries rearrangement product dominated the reaction profile affording 9 as the only product.13 To overcome this issue, we tried several conditions and found that the combination of 1,3bis(2,6-diisopropylphenyl-imidazol-2-ylidene)gold(I) chloride and silver hexafluoroantimoniate 10 afforded 3 albeit in very poor yield and selectivity. Finally, our attempts to convert 3 to desired target 1 following the closest literature process failed.12
Scheme 2. First route for the preparation of 1. Reagents and conditions: a) Pyridine, THF, r.t., 19 h (quant.); b) 4Ethynyltetrahydro-2H-pyran, CuI, Pd(PPh3)2Cl2, DMF, 60°C, 1 h, 34% (4), 8% (8); c) Sulfuric acid, dioxane, 100 °C, 65%; d) IPrAuCl, AgSbF6, 1,4-dioxane, H2O, 120 °C, 3 h, 41%; e) NaBH4, THF, MeOH, 0 °C, 1 h, 60%; f) MOM-Cl, DIPEA, THF, 67%; g) n-Bu-Li, B(OMe)3, THF -78 °C-r.t., 0% (f) 6N HCl, r.t., 16 h To avoid the Fries’ product, we decided to prepare the imidazole sulfonamide 10, with the knowledge that if we had difficulty to displace the imidazole with 6,14 we could activate the imidazole group by methylation for the coupling reaction downstream.15 To our surprise, the selectivity of the Sonagashira step was greatly improved from 34% to 72% of 11. We opted to trial directly the gold catalyzed conditions10 and obtained desired ketone 13 as the sulfonic acid in excellent conversion, albeit in 59:41 ratio in favour of the undesired isomer 14. In situ activation of the sulfonic acid was achieved using the Vilsmeier reagent16 followed by coupling with aniline 8 and reduction to afford 2 in poor overall yield. With 2 in hand, we decided to see if we could apply Molander’s borylation conditions using dibronic acid and second generation Buchwald catalyst17 anticipating that if transformation to the boronic acid takes place we could expect in situ cyclisation to
Tetrahedron Letters
3
desired boroxole 1. To our delight, the reaction proceeded as expected affording an excellent conversion to 1 in a nonoptimised yield of 32% (Scheme 2).
Scheme 2. Adapted route for the preparation of 1. Reagents and conditions: a) Imidazole, Et3N, DCM, r.t., 19 h, quant.; b) 4Ethynyltetrahydro-2H-pyrane, CuI, Pd(PPh3)2Cl2, DMF, 60 °C, 1 h, 72% (11) 5% (12); c) IPrAuCl, AgSbF6, 1,4-dioxane, H2O, 120 °C, 3 h, 41%; (d) Vilsmeier salt, Et3N, DCM, r.t., 1 h, followed by 4-ethyl-N-isobutylaniline (8), pyridine, 100°C, microwave, 15 min., 28%; e) NaBH4, THF, MeOH, 0 °C, 1 h, 55%); f) Tetrahydroxydiboron, XPhos Pd G2, XPhos KOAc, EtOH, 80 °C, 1 h, 32% With this knowledge in hand, we decided to explore substrate scope of the one-pot borylation-cyclocondensation step. While the authors acknowledge a recent process using B2pin2 was reported by Huang et al,18 we anticipated that the use of diboronic acid directly is much more atom economic and should avoid contamination of boroxole products with pinacol. Both bromides and iodides were equally good substrates for this process (Table 1, entries 1 and 2). Increasing steric hindrance at the benzylic position with one, two methyl groups or a cyclopropyl group was also afforded boroxole product with acceptable to good yields (Table 1, entries 4, 6 and 7). Unfortunately, going from aryl-bromide to aryl-chloride gave lower yield despite the utilization of XPhos Pd G2 catalyst (Table 1, entry 4 v 5). Six and seven membered boroxoles were also isolated albeit in moderate yield using this convenient one-pot approach (entries 7-8). Table 1. One pot synthesis of boroxoles using diboronic acid
Entry
Aryl halide
Isolated Yield (%)
1
59
2
69
3
35
4
57
5
OH Cl
32
4
Tetrahedron Letters 6
42
7
51
8
37
9
45
In conclusion, during our exploration to prepare and test boroxole 1 for RORγ activity, we successfully employed diboronic acid to the convenient and functional group tolerant one pot borylation-cyclocondensation reaction18 to prepare a range of novel boroxoles in moderate to good yield. Work in ongoing in the laboratory to enlarge substrate scope. Supplementary data Full experimental procedures and supporting LCMS, 1H-NMR characterisation data are available for a selection of compounds described in this letter is available at no extra charge via the on-line version. References and notes 1. Greb, J. E.; Goldminz, A. M.; Elder, J. T.; Lebwohl, M. G.; Gladman, D. D.; Wu, J. J.; Mehta, N. N.; Finlay, A. Y.; Gottlieb, A. B. Nat. Rev. Disease Primers 2016, 2, 1-17. 2. Smith, S. H.; Peredo, C. E.; Takeda, Y.; Bui, T.; Neil, J.; Rickard, D.; Millerman, E.; Therrien, J. P.; Nicodeme, E.; Brusq, J. M.; Birault, V.; Viviani, F.; Hofland, H.; Jetten, A.M.; Cote-Sierra, J. PLoS ONE 2016, 11, 1-18. 3. (a) Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.; Shukla, L. WO2013/160418; 31 Oct. 2013; (b) Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.; Shukla, L. WO2013/160419; 31 Oct. 2013; (c) Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.WO2013/045431; 04 Apr. 2013; (d) Fauber, B.; Rene, O; Bodil van Niel, M.; Gaines, S.; Killen, J.; Ward, S. US2014/0163024 12 Jun. 2014; (e) Fauber, B.; Rene, O; Bodil van Niel, M.; Ward, S. US2014/0163110 12 Jun. 2014; (f) Bodil van Niel, M.; Fauber, B.; Rene, O; Ward, S. WO2014/140059 18 Sept. 2014; (g) Fauber, B. P.; Rene, O.; Burton, B.; Everett, C.; Gobbi, A.; Hawkins, J.; Johnson, A. R.; Liimatta, M.; Lockey, P.; Norman, M.; Wong, H. Bioorg. Med. Chem. Lett. 2014, 24, 2182-2187; (h) Fauber, B. P.; Rene, O.; de Leon Boenig, G.; Burton, B.; Deng, Y.; Eidenschenk, C.; Everett, C.; Gobbi, A.; Hymowitz, S. G.; Johnson, A. R.; La, H.; Liimatta, M.; Lockey, P.; Norman, M.; Ouyang, W;; Wang, W.; Wong, H. Bioorg. Med. Chem. Lett. 2014, 24, 3891-3897; (i) van Niel, M. B.; Fauber, B. P.; Cartwright, M.; Gaines, S.; Killen, J. C.; Rene, O.; Ward, S. I.; de Leon Boenig, G.; Deng, Y.; Eidenschenk, C.; Everett, C.; Garcia, E.; Ganguli, A.; Gobbi, A.; Hawkins, J.; Johnson, A. R.; Kiefer, J. R.; La, H.; Lockey, P.; Norman, M.; Ouyang, W.; Qin, A.; Wakes, N.; Waszkowycz, B.; Wong, H. Bioorg. Med. Chem. Lett. 2014, 24, 5769-5776. 4. (a) Musicki, B. WO2016/097389; 23 Jun. 2016; (b) Musicki, B. WO2016/097391; 23 Jun. 2016; (c) Musicki, B. WO2016/097392; 23 Jun. 2016; (a) Musicki, B. WO2016/097393; 23 Jun. 2016; (a) Musicki, B. WO2016/097394; 23 Jun. 2016. 5. Full account of the medicinal chemistry including SAR and SPR will be published elsewhere shortly. 6. For review articles on boroxoles, please consult: a) Adamczyk-Woźniak, A.; Borys, K. M.; Sporzyński, A. Chem. Rev. 2015, 115, 5224−5247; b) Liu, T. C.; Tomsho, J. W.; Benkovic S. J. Bioorg. Med. Chem. 2015, 23, 44624473; c) Baker, Stephen J.; Tomshob, J. W.; Benkovicc, S. J. Chem. Soc. Rev. 2011, 40, 4279–4285. 7. Paller, A. S.; Tom, W. L.; Lebwohl, M. G.; Blumenthal, R. L.; Boguniewicz, M.; Call, R. S.; Eichenfield, L. F.; Forsha, D.; Rees, W. C.; Simpson, E. L.; Spellman, M. C.; Stein Gold, L. F.; Zaenglein, A. L.; Hughes, M. H.; Zane, L. T.; Hebert, A. A. J. Am. Acad. Dermatol. 2016, 75, 494-503. 8. Singh, R.; Just, G. J. Org. Chem. 1989, 54, 4453-4457. 9. Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149-6153 10. Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448-449. 11. For review articles see a) Goodwin, J. A.; Aponick A. Chem. Commun. 2015, 51, 8370-8741; b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180-3211. 12. a) Jacobs, R. T.; Plattner, J. J.; Nare, B.; Wring, S. A.; Chen, D.; Freund, Y.; Gaukel, E. G.; Orr, M. D.; Perales, J. B.; Jenks, M.; Noe, R. A.; Sligar, J. M.; Zhang, Y-K.; Bacchi, C. J.; Yarlett, N.; Don, R. Future Med. Chem. 2011, 3, 1259-1278; b) Ye, L.; Ding, D.; Feng, Y.; Xie, D.; Wu, P.; Guo, H.; Meng, Q.; Zhou, H. Tetrahedron 2009, 65,
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8738-8744; c) Gunasekera, D. S.; Gerold, D. J.; Aalderks, N. S.; Chandra, J. S.; Maanu, C. A.; Kiprof, P.; Zhdankin, V. V.; Reddy, M. V. R. Tetrahedron 2007, 63, 9401-9405. a) Searles, S. Jr.; Nukina, S. Chem. Rev. 2007, 59, 1077-1103; b) Sharma, A.; Jain, S.; Sirohi, R.; Kishore, D. Org. Chem. Int. 2011, 614627, 5 pp. Staab, H. A.; Wendel, K. Chem. Ber. 1960, 93, 2902-2915 Vilkas, E. Bull. Soc. Chim. Fr. 1978, 1-2, Pt. 2, 37-8. Dunetz, J. R.; Magano, J.; Weisenburger, G. A. Org. Proc. Res. Dev. 2016, 20, 140-177. Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge M. T. J. Am. Chem. Soc., 2012, 134, 1166711673. For recent one-pot protocol described using B2pin2 as the borylating agent see: Zhu, Jianan; Wei, Ying; Lin, Dongqing; Ou, Changjin; Xie, Linghai; Zhao, Yu; Huang, Wei. OBC 2015, 13, 11362-11368
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An efficient one-pot process to prepare boroxoles directly from diboronic acid is disclosed This mild process avoids the necessity of carrying out a halogen-lithium exchange under cryogenic conditions A diverse range of boroxoles were prepared in acceptable yield with good substrate scope