Regioselective palladium-catalyzed CH arylation of 4-alkoxy and 4-thioalkyl pyrazoles

Tetrahedron Letters 58 (2017) 4587–4590

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Regioselective palladium-catalyzed CAH arylation of 4-alkoxy and 4-thioalkyl pyrazoles William F. Vernier ⇑, Laurent Gomez Discovery Chemistry, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA 92131, United States

a r t i c l e

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Article history: Received 10 August 2017 Revised 6 October 2017 Accepted 17 October 2017 Available online 19 October 2017

a b s t r a c t A methodology for the palladium-catalyzed regioselective CAH arylation of electron rich pyrazoles has been developed. New ligands and mild conditions (70–90 °C) have been identified for this transformation. An intramolecular application of the methodology provided a novel synthetic route for the regioselective synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles and 1,5-dihydroisothiochromeno[4,3-c]pyrazoles. Ó 2017 Elsevier Ltd. All rights reserved.

Keywords: CAH arylation Pyrazoles Sphos Qphos Palladium

Pyrazoles are widely used in the medicinal chemistry community because of their good metabolic stability and favorable physicochemical properties.1 Not surprisingly, this heterocycle appears in numerous marketed therapeutics. In particular, several drugs containing 5-aryl pyrazoles have reached the market (Fig. 1). In addition, several 5-(het)aryl pyrazoles are currently being investigated in clinical trials.2 Pyrazoles have traditionally been synthesized by the condensation of hydrazines and 1,3-bis-electrophiles leading to poor regiochemical control in many cases.3 Methods have been developed to improve the regiochemical control, but the preliminary synthesis of organometallic derivatives is typically needed.4 In recent years, transition-metal catalyzed CAH activation reactions have emerged as a powerful methodology to straightforwardly introduce aryls to various heterocycles.5 In their seminal paper, Miura and co-workers described the CAH arylation of imidazoles at the 5-position with aryl bromides or iodides.6 Sames and co-workers next reported an application of the CAH activation methodology to the synthesis of 5-aryl pyrazoles (Scheme 1).7 More recently, the scope of this type of reaction has been expanded and improved conditions have been identified.8 Although very useful, the existing conditions require high temperatures with a limited choice of ligands and have not been applied to many heterocycles. Also, to the best of our knowledge, direct CAH arylation has not been investigated with electron rich ⇑ Corresponding author. E-mail address: [email protected] (W.F. Vernier). https://doi.org/10.1016/j.tetlet.2017.10.047 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

pyrazoles. Herein, we report our research effort aimed at identifying mild and general conditions for the direct arylation of 4-alkoxy and 4-thio substituted pyrazoles. The identified conditions were also applied to an expedient synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles and 1,5-dihydroisothiochromeno [4,3-c]pyrazoles via intramolecular cyclization. This approach constitutes a novel and efficient synthetic route to these biologically relevant heterocyclic systems. 4-(Benzyloxy)-1-methyl-1H-pyrazole (1) was synthesized according to literature procedures9 (see ESI) and selected as the starting material for reaction optimization. We also wished to investigate and develop reaction conditions that can easily be applied to the synthesis of ‘‘druglike” molecules. Therefore, we chose to conduct our optimization study with a heterocycle and selected 5-bromo-2-methylpyridine (2). Traditionally, pyrazole CAH arylation reactions have required the use of pivalic acid as a co-catalyst and 1.5 eq. of the aryl bromide. In an initial round of optimization, we observed that for our substrate, pivalic acid was not necessary and led to increased formation of by-product 4a (Table 1, entries 1 and 2). In addition, less than 1.5 eq. of the aryl bromide could be used and Pd(OAc)2 was the superior Pd source (see Table 1; and ESI S8). Finally, higher Pd and ligand loading did not significantly improve the conversion. We focused next on evaluating the influence of the base and solvent. Among the bases investigated Bu4NOAc performed the best with complete conversion and improved regiochemistry (Entries 2–5). This result confirms the beneficial effect of this base as previously observed by other groups8a,8g For the solvent, NMP and dioxane were far

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W.F. Vernier, L. Gomez / Tetrahedron Letters 58 (2017) 4587–4590 Table 1 Optimization of the palladium-catalyzed CAH arylation of alkoxypyrazoles.a

Fig. 1. Selected examples of 5-aryl pyrazoles that have reached the market.

Entry

Ligand

Base

Temp. (°C)

Conversion (3a/4a)b

1c,d 2d 3d 4d 5d 6d,e 7d,f 8d 9g 10g,h 11g 12g 13g 14g 15g 16g

PBuAd2 PBuAd2 PBuAd2 PBuAd2 PBuAd2 PBuAd2 PBuAd2 tBu2PMe PBuAd2 PBuAd2 Davephos BippyPhos Sphos Amphos Qphos Josiphos

K2CO3 K2CO3 Bu4NOAc KOAc KF K2CO3 Bu4NOAc K2CO3 Bu4NOAc Bu4NOAc Bu4NOAc Bu4NOAc Bu4NOAc Bu4NOAc Bu4NOAc Bu4NOAc

100 100 90 90 90 90 90 90 70 70 70 70 70 70 70 70

75(69)/22(11) 79/16 90/10 48/0 52/0 40/0 46/0 66/1 94(78)/2 82/1 93(79)/2 93(82)/5 92(79)/5 52/0 95(82)/3 5/0

a Reactions were conducted on a 0.1 mmol scale for 18 h. The ratio of 1/2/catalyst/ligand/base was 1/1.05/0.075/0.05/3 unless otherwise noted. b Analysis by UPLC/MS using uncorrected AUC at 254 nM. Isolated yield after column chromatography in parenthesis. c t-BuCO2H (0.25 eq.) used as an additive. d 2 (1.2 eq.) was used. e DMA was used. f Toluene was used. g 16 h reaction time. h NMP was used.

Scheme 1. Palladium-catalyzed CAH arylation of imidazoles and pyrazoles.

superior to DMA and toluene (Entries 2, 3, 6, 7; and 22 and 24, ESI S8). To further improve the methodology, the temperature was decreased and 1.05 eq. of aryl bromide 2 was used for the rest of the optimization. Under these milder conditions, dioxane gave slightly better conversion than NMP (Entries 9–10). These conditions also had the added benefit of minimizing the formation of by-product 4a. With the optimized solvent and base in hand, we next evaluated a set of ligands. We were able to confirm that previously identified di(1-adamantyl)-n-butylphosphine (PBuAd2, cataCXium A)7 and Davephos8a (Fig. 2) were competent for this transformation (Entries 9 and 11). We also identified three new ligands (BippyPhos10 Sphos11 and Qphos12) that gave conversions and isolated yields similar to the known ligands (Entries 12, 13 and 15). For the rest of the study, we selected dioxane as the solvent to simplify the work-up and Sphos as the ligand due to lower cost and the fact that it has not previously been studied for the CAH arylation of pyrazoles. It should be noted that on a 1 mmol scale, the temperature and reaction time needed to be increased to 80 °C and 72 h, respectively, to obtain 3 in 77% isolated yield using the above optimized conditions. In a few cases where the yield was not satisfactory, Qphos was also examined. With the optimal reaction conditions in hand, we next studied the substrate scope (Scheme 2). For the aryl bromide, electron rich and electron deficient aryl groups were well tolerated (3d and 3e). Various functional groups including chlorine, methoxy and ester

Fig. 2. Highly competent ligands used in this study.

(3b, 3d and 3e) were also tolerated. Steric hindrance on the aryl bromide was tolerated as compound 3c with an ortho-substituent was obtained in 71% yield. However, steric hindrance on the pyrazole seemed to be less tolerated as compounds 3i and 3j were obtained in lower yield. Pyrimidine and chloropyridine were tolerated, although moderate yields were obtained (3f, 3g, and 3h). In general, thioethers required higher temperatures and longer reaction times compared to the ethers (3j and 3k). In the case of 3h, the yield was greatly improved by using Qphos instead of Sphos as the ligand. However, the yields were still moderate in the cases of 3g and 3j when using Qphos. We next investigated if this methodology could be applied to an intramolecular cyclization to afford 1,5-dihydroisochromeno [4,3-c]pyrazoles and 1,5-dihydroisothiochromeno[4,3-c]pyrazoles.

W.F. Vernier, L. Gomez / Tetrahedron Letters 58 (2017) 4587–4590

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Scheme 4. Synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles and 1,5-dihydroisothiochromeno[4,3-c]pyrazoles via intramolecular cyclization.

Scheme 2. Substrate scope for the CAH arylation of 4-alkoxy and 4-thio pyrazoles.

Those analogs have previously been investigated as inhibitors of the nicotinic acetylcholine receptor13 and COX-2.14 Reported syntheses involves the condensation of hydrazines with 1,3-diketone 7 (Scheme 3). The limitations of this synthetic route are the length of synthesis and poor control of regiochemistry when R2 substituents are not electron withdrawing. We were pleased to find that using our optimized conditions, 4((2-bromobenzyl)oxy)-1-methyl-1H-pyrazole 9 cyclized readily to give the desired 1,5-dihydroisochromeno[4,3-c]pyrazoles 10 with complete control of the regiochemistry. The substrate scope for this cyclization is shown in Scheme 4. Electron donating and withdrawing substituents on the aryl bromide were tolerated, as well as chlorine (10c–e). Unlike the intermolecular cases, larger groups on the pyrazole were well tolerated (10b and 10f). The methodology was also successfully applied to the formation of a 7-membered ring to afford 10g in moderate yield. For the thioethers, higher temperature was required for the cyclization and lower yields were observed due to increased decomposition and lower

Scheme 3. Synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles via condensation with hydrazines.

Fig. 3. Application of the optimized conditions to other substrates.a Reaction conditions: azole (1 mmol), aryl bromide (1.05 eq.), Pd(OAc)2 (5 mol%), QPhos (7.5 mol%), Bu4NOAc (3 eq.), dioxane (0.4 M). Isolated yield after column chromatography. bYield was determined by 1H NMR analysis of the crude product using CH2Br2 as the internal standard.

a

conversion (10h and 10i). When using Qphos instead of Sphos as the ligand, the conversion and the yield of 10d were improved. On the other hand, the yield for 10i with the sterically demanding benzyl substituent was lower when using the bulkier ligand. To evaluate the generality of the methodology, we next applied the optimized conditions to substrates that have been previously studied by other groups (Fig. 3).8,15 Three pyrazoles that do not bear an electron-rich substituent at the C4 position and one imidazole were selected; it should be noted that the reactions were run with less aryl bromide or azole and at lower temperatures (for 3m–o) than previously reported. We were pleased to find that the yields obtained were comparable to the reported yields. In conclusion, we have developed general and mild conditions for the highly regioselective direct arylation of electron rich pyrazoles. Three new ligands have been identified for this transformation providing more options for reaction optimization and future applications. The developed conditions show a number of

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advantages, including the minimization of bisarylated by-product formation, low cost of the catalytic system, and good functional group tolerance. The methodology was successfully applied to the synthesis of biologically relevant 1,5-dihydroisochromeno [4,3-c]pyrazoles and 1,5-dihydroisothiochromeno[4,3-c]pyrazoles via intramolecular cyclization and should be highly valuable to medicinal chemists wishing to install heteroaryl groups at the C5 position of pyrazoles.

6. 7. 8.

Acknowledgments We thank Dart Neuroscience for supporting this investigation and Dr. Guy Breitenbucher for his assistance and feedback. A. Supplementary data Starting material synthesis, additional table entries, experimental procedures and spectra for all new compounds. Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.tetlet.2017.10.047.

9.

References 1. (a) St. Jean DJ, Fotsch C. J Med Chem. 2012;55:6002–6020; (b) Ioannidis S, Lamb ML, Almeida L, et al. Bioorg Med Chem Lett. 2010;20:1669–1673. 2. Afuresertib (GSK2110183) an Akt inhibitor in phase 2, Nelotanserin an inverse agonist of 5-HT2A in phase 2, and PF-05180999 an inhibitor of cyclic nucleotide phosphodiesterase-2 (PDE2) discontinued after phase 1. 3. (a) Elguero J. In: Katritzky AR, Rees CW, Scriven EFV, eds. Comprehensive Heterocyclic Chemistry II, Vol. 3. New York: Pergamon Press; 1996:58–61; (b) Fustero S, Román R, Sanz-Cervera JF, et al. J Org Chem. 2008;73:3523–3529; (c) Fustero S, Sanchez-Rosello M, Barrio P, Simon-Fuentes A. Chem Rev. 2011;111:6984–7034. 4. (a) Font-Sanchis E, Cespedes-Guirao FJ, Sastre-Santos A, Fernandez-Lazaro F. J Org Chem. 2007;72:3589–3591; (b) Despotopoulou C, Klier L, Knochel P. Org Lett. 2009;11:3326–3329; (c) Kirkham JD, Edeson SJ, Stokes S, Harrity JPA. Org Lett. 2012;14:5354–5357; (d) Fricero P, Bialy L, Brown AW, Czechtizky W, Mendez M, Harrity JPA. J Org Chem. 2017;82:1688–1696. 5. (a) Alberico D, Scott M, Lautens M. Chem Rev. 2007;107:174–238; (b) Satoh T, Miura M. Chem Lett. 2007;36:200–205; (c) Joo JM, Guo P, Sames D. J Org Chem. 2013;78:738–743;

10. 11. 12.

13.

14.

15.

(d) Rossi R, Bellina F, Lessi M, Manzini C. Adv Synth Catal. 2014;356:17–117; (e) Rossi R, Lessi M, Manzini C, Marianetti G, Bellina F. Synthesis. 2016;48:3821–3862. Pivsa-Art S, Satoh T, Kawamura Y, Miura M, Nomura M. Bull Chem Soc Jpn. 1998;71:467–473. Goikhman R, Jacques TL, Sames D. J Am Chem Soc. 2009;131:3042–3048. (a) Mateos C, Mendiola J, Carpintero M, Minguez JM. Org Lett. 2010;12:4924–4927; (b) Rene O, Fagnou K. Adv Synth Catal. 2010;352:2116–2120; (c) Beladhria A, Beydoun K, Ben Ammar H, Ben Salem R, Doucet H. Synthesis. 2011;2553–2560; (d) Gaulier SM, McKay R, Swain NA. Tetrahedron Lett. 2011;52:6000–6002; (e) Yang Y, Kuang C, Jin H, Yang Q, Zhang Z. Beilstein J Org Chem. 2011;1656–1662; (f) Yan T, Chen L, Bruneau C, Dixneuf PH, Doucet H. J Org Chem. 2012;77:7659–7664; (g) Bellina F, Lessi M, Manzini C. Eur J Org Chem. 2013;5621–5630; (h) Smari I, Youssef C, Yuan K, et al. Eur J Org Chem. 2014;1778–1786; (i) Iaroshenko VO, Gevorgyan A, Davydova O, Villinger A, Langer P. J Org Chem. 2014;79:2906–2915; (j) Takfaoui A, Zhao L, Touzani R, Dixneuf PH, Doucet H. Tetrahedron Lett. 2014;55:1697–1701; (k) Kumpulainen ETT, Pohjakallio A. Adv Synth Catal. 2014;356:1555–1561; (l) Brahim M, Ben Ammar H, Soule J-F, Doucet H. Tetrahedron. 2016;72:4312–4320. (a) Westaway SM, Preston AGS, Barker MD, et al. J Med Chem. 2016;59:1370–1387(b) Schultz-Fademrecht C, Klebl B, Choidas A, et al. MaxPlanck-Gesellschaft zur Förderung der Wissenschaften E.V. Preparation of quinoline carboxamide compounds as Axl inhibitors for treating hyperproliferative disorders. WO2012028332; 2012. Singer RA, Dore M, Sieser JE, Berliner MA. Tetrahedron Lett. 2006;47:3727–3731. Barder TE, Walker SD, Martinelli JR, Buchwald SL. J Am Chem Soc. 2005;127:4685–4696. (a) Shelby Q, Kataoka N, Mann G, Hartwig J. J Am Chem Soc. 2000;122:10718–10719; (b) Kataoka N, Shelby Q, Stambuli JP, Hartwig JF. J Org Chem. 2002;67:5553–5566. Herbert B, Schumacher R, Dai G, Xie W, Memory Pharmaceuticals Corporation. Preparation of (1,4-diazabicyclo[3.2.2]non-6-en-4-yl)-heterocyclyl-methanone ligands for nicotinic acetylcholine receptors useful for the treatment of disease. WO2009055437; 2009. (a) Talley JJ, Bertenshaw SR, Graneto MJ, Rogier DJ, Searle GD and Company. Benzopyranopyrazolyl derivatives for the treatment of inflannation. WO1996009304; 1996.; (b) Bertenshaw SR, Talley JT, Rogier DJ, Graneto MJ, Koboldt CM, Zhang Y. Bioorg Med Chem Lett. 1996;6:2827–2830; (c) Metz S, Clare M, Crich JZ, et al. Substituted pyrazolo compounds for the treatment of inflammation. WO2003024936; 2003. We are thankful to the reviewer for this suggestion.