Nair, Reji

Wang, Yong

eScholarship - University of California

UC San DiegoUC San Diego Previously Published WorksTitleSynthesis of 4-carboxy-4-pyridylpiperidines through palladium-catalyzed Î±-arylation of estersPermalinkhttps://escholarship.org/uc/item/2tg1429jJournalTetrahedron Letters, 48(7)ISSN00404039AuthorsWang, YongNair, RejiPublication Date2007-02-01DOI10.1016/j.tetlet.2006.12.052 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaTetrahedron Letters 48 (2007) 1191–1193Synthesis of 4-carboxy-4-pyridylpiperidines throughpalladium-catalyzed a-arylation of estersYong Wanga,* and Reji NairbaDiabetes Chemistry, La Jolla Laboratories, Pfizer Global Research and Development, 10770 Science Center Drive,San Diego, CA 92121, USAbSan Diego State University, San Diego, CA 92182, USAReceived 21 November 2006; revised 11 December 2006; accepted 12 December 2006Abstract—A concise synthesis of 4-carboxy-4-pyridylpiperidines has been achieved. Key step is the palladium-catalyzed a-arylationof esters under basic conditions. 2006 Elsevier Ltd. All rights reserved.NBocCO2MeArNBocCO2MePd2dba3 (2 mol%), P(tBu) 3 (4 mol%), tolueneLHMDS, ArX, 23 ºC, 12 h.4Scheme 1.4-Arylpiperidines are important building blocks foundin several important pharmaceuticals. Examples includethe analgesic Trefentanil (1),1 Pethidine (2),2 and theantidiarrheal Loperamide (3) (Fig. 1).3 Thus, synthesisof these building blocks is of intense interest in discoverychemistry.In our small molecule drug discovery efforts we targetedthe synthesis of 4-carboxy-4-pyridylpiperidines as build-ing blocks. 4-Carboxy-4-pyridylpiperidine derivativeshas been prepared by condensation of 2-pyr-idylacetonitirle with di-(2-chloroethyl)-methylamines.4However, few pyridylacetonitriles are commerciallyavailable. As a result, parallel synthesis is severely lim-ited. Hence we sought to develop a general new protocol0040-4039/$ - see front matter  2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.tetlet.2006.12.052* Corresponding author. Tel.: +1 858 638 3691; e-mail: yong.wang01@pfizerNNN NNOOFNCTrefantanil (1) PethidinFigure 1.to allow us to carry parallel medicinal chemistry. Hereinwe reported the synthesis of 4-carboxy-4-pyridylpiperi-dine analogues through palladium-catalyzed a-arylationof esters..comNONOClO2EtLoperamide (3)e (2)Table 1. Palladium-catalyzed a-arylation of estersaEntry ArX Product Isolated yield1NBrNBocMeO2CN5912 NBrNBocMeO2CN6463NBrNBocMeO2CN7954NBr ONBocMeO2CNO8945NCl ONBocMeO2CNO8936 NFBrNBocMeO2CNF9937NBrCF3NBocMeO2CNF3C10728N ClNBocMeO2CN11869NBrNBocMeO2CN129210NNC Br NBocMeO2CNNC130a Reactions were conducted for 12 h at room temperature using 1 equiv of halide and 2 equiv of ester and 2.2 equiv of LHMDS, 2 mol % Pd2dba3 and4 mol % P(t-Bu)3 in toluene.1192 Y. Wang, R. Nair / Tetrahedron Letters 48 (2007) 1191–1193Hartwig5 and Buchwald6 have recently described their a-arylation of esters. However, application of this versatilepalladium-catalyzed reaction to heterocyclic arrays ofpharmaceutical interest is quite limited. Thus, arylationof N-Boc-4-methoxycarbonylpiperidine (4) with a seriesof chloropyridine and bromopyridine, LHMDS, and acatalytical amount of Pd2dba3 and P(t-Bu)3 was carriedout (Scheme 1). The results are summarized in Table 1.7NBocCO2MeNBocOHLiAlH4, THF, 0 ºC72%A. MsCl, Et3N, DMAP, CH2Cl288%B. LiEt3BH, THF, reflux55%NBocN N NO O O8 14 15Scheme 2.Y. Wang, R. Nair / Tetrahedron Letters 48 (2007) 1191–1193 1193The reactions of ester 4 with unsubstituted pyridylbromides went smoothly at room temperature in moder-ate to excellent yield (entries 1 and 2). Pyridyl halideswith electron-donating groups gave excellent yields andshort reaction times (entries 3–5). Chloropyridine worksequally well as bromopyridine (entries 4 and 5). Halideswith electron-withdrawing groups also gave good yields(entries 6 and 7). No byproduct from the competingnucleophilic attack on the pyridyl halide was observed.However, for halides bearing cyano groups, no product13 was observed due to the nucleophilic attack on thecyano group to form amidine (entry 10). The reactions ofester 4 with bicyclic quinolyl halide also gave an excellentyield (entries 8 and 9). Attempts to change reaction con-ditions to improve the yield (for example, use tert-butylester instead of methyl ester and replacing LHMDS withNaHMDS) were not successful.4-Carboxy-4-pyridylpiperidine is an important inter-mediate in the synthesis of other biologically activepharmaceuticals. The ester group can be transformed toother functional groups such as amide, alcohol, methylor other heterocyclic groups. Scheme 2 illustrates theexample of transformation to the methyl group. 4-Methyl-4-phenylpiperidine has been made by Friedel–Crafts arylation of the tertiary alcohol in the presenceof substituted benzene and aluminum trichloride.8 How-ever, this protocol is not amenable for electron-deficientsystems such as pyridine. This transformation wasachieved in a three-step sequence.9 First, reduction ofthe ester with lithium aluminum hydride to give primaryalcohol 14 in a 72% yield. Second, treatment of the alco-hol with methanesulfonyl chloride in the presence ofEt3N and 5% DMAP furnished the mesylate in an88% yield; finally, reduction of mesylate to the corre-sponding methyl group was achieved with super-hydridein reflux for 12 h to furnish the desired product 15 in a55% yield.10 Direct deoxygentation of alcohol throughB(C6F5)3 and triethylsilane was not successful.11In conclusion, we have developed a protocol for synthe-sizing 4-carboxy-4-pyridylpiperidines. The key step isthe palladium-catalyzed arylation of ester under basicconditions. This method should be of application tothe synthesis of other 4-carboxy-4-heteroarylpiperidineintermediates (such as pyrimidine, oxazole, imidazole),which will be reported in due course. Further modifica-tion to expand the scope of this protocol by carrying outpalladium-catalyzed a-arylation under neutral condi-tions is underway.References and notes1. Lemmons, H. J.; Dyck, J. B.; Shafer, S. L.; Stanski, D. R.Clin. Pharmacol. Ther. 1994, 56, 261.2. Watts, R. W. Aust Prescr. 2004, 27, 34.3. Adelstein, G. W.; Yen, C. H.; Dejani, E. Z.; Bianchi, R. G.J. Med. Chem. 1976, 19, 1221.4. Dummel, R.; Wrinkler, W.; Mosher, H. J. Am. Chem. Soc.1955, 1936.5. Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc.2001, 123, 8410.6. Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001,123, 7996.7. Representative procedure, 1-tert-butyl 4-methyl 4-(6-methylpyridin-2-yl)piperidine-1,4-dicarboxylate (7): To asolution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxy-late (4) (430 mg, 1.77 mmol), 2-bromo-5-methylpyridine(152 mg, 0.88 mmol), Pd2dba3 (32 mg, 0.035 mmol), P-(t-Bu)3 (0.070 mL, 0.07 mmol; 1.0 M in toluene) in toluene(5 mL) was added LHMDS (1.9 mL, 1.9 mmol; 1.0 M intoluene) dropwise at room temperature. The solutionturned from dark red to dark brown. After 24 h, themixture was quenched with saturated aqueous ammoniumchloride. The mixture was partitioned between EtOAc andwater. The combined organic extracts were dried oversodium sulfate and concentrated to give a residue, whichwas purified by silica gel chromatography (10% EtOAc/hexanes) to give the product as a colorless oil (280 mg,95%). 1H NMR (400 MHz, CDCl3) d ppm 1.45 (s, 9H),1.98–2.11 (m, 2H), 2.31 (s, 3H), 2.33–2.37 (m, 2H), 3.03–3.11 (m, 2H), 3.62 (s, 3H), 3.77–3.80 (m, 2H), 7.21 (d,J = 8.08 Hz, 1H), 7.48 (dd, J = 8.08, 2.27 Hz, 1H), 8.40 (d,J = 1.52 Hz, 1H). LC–MS (EI) m/z 335.1 [M+H].8. Harriman, G. C.; Shao, J.; Luly, J. R. Tetrahedron Lett.2000, 41, 8853.9. (a) Zhao, D.; Kuethe, J. T.; Journet, M.; Peng, Z.;Humphery, G. R. J. Org. Chem. 2006, 71, 4336; (b)Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41,3064.10. All compounds were characterized via NMR (Bruker AM400) and LC/MS. tert-Butyl 4-(hydroxymethyl)-4-(6-methoxypyridin-2-yl)piperidine-1-carboxylate (14): 1HNMR (400 MHz, CDCl3): d 1.32 (s, 9H), 1.87–2.01 (m,2H), 2.21–2.34 (m, 2H), 3.28–3.37 (m, 2H), 3.51–3.55 (m,2H), 3.76 (s, 2H), 3.85 (s, 3H); 4.11 (s, 1H), 6.47 (d,J = 8.34 Hz, 1H), 6.70 (d, J = 7.58 Hz, 1H), 7.39 (t,J = 7.83 Hz, 1H). LC–MS (EI) m/z 323.1 [M+H]. tert-Butyl 4-(6-methoxypyridin-2-yl)-4-methylpiperidine-1-carb-oxylate (15): 1H NMR (400 MHz, CDCl3): d 1.25 (s, 3H),1.44 (s, 9H), 1.57–1.70 (m, 2H), 2.20–2.36 (m, 2H), 3.15–3.30 (m, 2H), 3.59 (br s, 2H), 3.90 (s, 3H), 6.55 (d,J = 8.34 Hz, 1H), 6.83 (d, J = 7.58 Hz, 1H), 7.52 (t,J = 7.83 Hz, 1H). LC–MS (EI) m/z 307.1 [M+H].11. Gevorgyan, V.; Liu, J.-X.; Rubin, M.; Benson, S.;Yamamoto, Y. Tetrahedron Lett. 1999, 40, 8919.

Synthesis of 4-carboxy-4-pyridylpiperidines through palladium-catalyzed Î±-arylation of esters

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