Synthesis of 1,4-Disubstituted Pyrazolo[3,4-d]pyrimidines from 4,6-Dichloropyrimidine-5-carboxaldehyde: Insights into Selectivity and Reactivity

Dedicated to Prof. Scott E. Denmark on the occasion of his 60^th birthday

Abstract

Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5-carboxaldehyde with both aromatic and aliphatic hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective, high-yielding, and operationally simple manner are presented. For aromatic hydrazines, the reaction is performed at a high temperature in the absence of an external base. For aliphatic hydrazines, the reaction proceeds at room temperature in the presence of an external base. The observed selectivity and reactivity­ trends are rationalized through consideration of the proposed­ reaction mechanism. The 1-substituted 4-chloropyrazolo[3,4-d]pyrimidine products serve as versatile synthetic intermediates, through further functionalization of the 4-chloride moiety, enabling the rapid generation of a structurally diverse array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines.

Key words

condensation - hydrazines - hydrazones - nucleophilic aromatic substitution - pyrazolo[3,4-d]pyrimidines

• References

• 1a Meng F, Hou J, Shao YX, Wu PY, Huang M, Zhu X, Cai Y, Li Z, Xu J, Liu P, Luo HB, Wan Y, Ke H. J. Med. Chem. 2012; 55: 8549
• 1b Verhoest PR, Fonseca KR, Hou X, Proulx-LaFrance C, Corman M, Helal CJ, Claffey MM, Tuttle JB, Coffman KJ, Liu S, Nelson F, Kleiman RJ, Menniti FS, Schmidt CJ, Vanase-Frawley M, Liras S. J. Med. Chem. 2012; 55: 9045
• 1c Claffey MM, Helal CJ, Verhoest PR, Kang Z, Fors KS, Jung S, Zhong J, Bundesmann MW, Hou X, Lui S, Kleiman RJ, Vanase-Frawley M, Schmidt AW, Menniti F, Schmidt CJ, Hoffman WE, Hajos M, McDowell L, O’Conner RE, MacDougall-Murphy M, Fonseca KR, Becker SL, Nelson FR, Liras S. J. Med. Chem. 2012; 55: 9055
• 2 Manetti F, Santucci A, Locatelli GA, Maga G, Spreafico A, Serchi T, Orlandini M, Bernardini G, Caradonna NP, Spallarossa A, Brullo C, Schenone S, Bruno O, Ranise A, Bondavalli F, Hoffmann O, Bologna M, Angelucci A, Botta M. J. Med. Chem. 2007; 50: 5579
• 3 Das J, Moquin RV, Pitt S, Zhang R, Shen DR, McIntyre KW, Gillooly K, Doweyko AM, Sack JS, Zhang H, Kiefer SE, Kish K, McKinnon M, Barrish JC, Dodd JH, Schieven GL, Leftheris K. Bioorg. Med. Chem. Lett. 2008; 18: 2652
• 4 Tan TM. C, Yang F, Fu H, Raghavendra MS, Lam Y. J. Comb. Chem. 2007; 9: 210
• 5 Settimo FD, Primofiore G, Motta CL, Taliani S, Simorini F, Marini AM, Mugnaini L, Lavecchia A, Novellino E, Tuscano D, Martini C. J. Med. Chem. 2005; 48: 5162
• 6a Neustadt BR, Hao J, Lindo N, Greenlee WJ, Stamford AW, Tulshian D, Ongini E, Hunter J, Monopoli A, Bertorelli R, Foster C, Arik L, Lachowicz J, Ng K, Feng KI. Bioorg. Med. Chem. Lett. 2007; 17: 1376
• 6b Harris JM, Neustadt BR, Zhang H, Lachowicz J, Cohen-Williams M, Varty G, Hao J, Stamford AW. Bioorg. Med. Chem. Lett. 2011; 21: 2497
• 7 Baraldi PG, Bovero A, Fruttarolo F, Romagnoli R, Tabrizi MA, Preti D, Varani K, Borea PA, Moorman AR. Bioorg. Med. Chem. 2003; 11: 4161
• 8 Kelley JL, Davis RG, McLean EW, Glen RC, Soroko FE, Cooper BR. J. Med. Chem. 1995; 38: 3884
• 9 Burch HA. J. Med. Chem. 1968; 11: 79
• 10 Deng X, Okram B, Ding Q, Zhang J, Choi Y, Adrián FJ, Wojciechowski A, Zhang G, Che J, Bursulaya B, Cowan-Jacob SW, Rummel G, Sim T, Gray NS. J. Med. Chem. 2010; 53: 6934
• 11a Manetti F, Brullo C, Magnani M, Mosci F, Chelli B, Crespan E, Schenone S, Naldini A, Bruno O, Trincavelli ML, Maga G, Carraro F, Martini C, Bondavalli F, Botta M. J. Med. Chem. 2008; 51: 1252
• 11b Radi M, Dreassi E, Brullo C, Crespan E, Tintori C, Bernardo V, Valoti M, Zamperini C, Daigl H, Musumeci F, Carraro F, Naldini A, Filippi I, Maga G, Schenone S, Botta M. J. Med. Chem. 2011; 54: 2610
• 12a Richard DJ, Verheijen JC, Curran K, Kaplan J, Toral-Barza L, Hollander I, Lucas J, Yu K, Zask A. Bioorg. Med. Chem. Lett. 2009; 19: 6830
• 12b Zask A, Verheijen JC, Curran K, Kaplan J, Richard DJ, Nowak P, Malwitz DJ, Brooijmans N, Bard J, Svenson K, Lucas J, Toral-Barza L, Zhang WG, Hollander I, Gibbons JJ, Abraham RT, Ayral-Kaloustian S, Mansour TS, Yu K. J. Med. Chem. 2009; 52: 5013
• 12c Nowak P, Cole DC, Brooijmans N, Bursavich MG, Curran KJ, Ellingboe JW, Gibbons JJ, Hollander I, Hu YB, Kaplan J, Malwitz DJ, Toral-Barza L, Verheijen JC, Zask A, Zhang WG, Yu K. J. Med. Chem. 2009; 52: 7081
• 12d Zask A, Kaplan J, Verheijen JC, Richard DJ, Curran K, Brooijmans N, Bennett EM, Toral-Barza L, Hollander I, Ayral-Kaloustian S, Yu K. J. Med. Chem. 2009; 52: 7942
• 12e Verheijen JC, Richard DJ, Curran K, Kaplan J, Lefever M, Nowak P, Malwitz DJ, Brooijmans N, Toral-Barza L, Zhang WG, Lucas J, Hollander I, Ayral-Kaloustian S, Mansour TS, Yu K, Zask A. J. Med. Chem. 2009; 52: 8010
• 12f Gilbert AM, Nowak P, Brooijmans N, Bursavich MG, Dehnhardt C, Santos ED, Feldberg LR, Hollander I, Kim S, Lombardi S, Park K, Venkatesan AM, Mallon R. Bioorg. Med. Chem. Lett. 2010; 20: 636
• 12g Curran KJ, Verheijen JC, Kaplan J, Richard DJ, Toral-Barza L, Hollander I, Lucas J, Ayral-Kaloustian S, Yu K, Zask A. Bioorg. Med. Chem. Lett. 2010; 20: 1440
• 13 Link W, Oyarzabal J, Serelde BG, Albarran MI, Rabal O, Cebriá A, Alfonso P, Fominaya J, Renner O, Peregrina S, Soilán D, Ceballos PA, Hernández AI, Lorenzo M, Pevarello P, Granda TG, Kurz G, Carnero A, Bischoff JR. J. Biol. Chem. 2009; 284: 28392
• 14 Carraro F, Pucci A, Naldini A, Schenone S, Bruno O, Ranise A, Bondavalli F, Brullo C, Fossa P, Menozzi G, Mosti L, Manetti F, Botta M. J. Med. Chem. 2004; 47: 1595
• 15 Traxler P, Bold G, Frei J, Lang M, Lydon N, Mett H, Buchdunger E, Meyer T, Mueller M, Furet P. J. Med. Chem. 1997; 40: 3601
• 16 Markwalder JA, Arnone MR, Benfield PA, Boisclair M, Burton CR, Chang CH, Cox SS, Czerniak PM, Dean CL, Doleniak D, Grafstrom R, Harrison BA, Kaltenbach III RF, Nugiel DA, Rossi KA, Sherk SR, Sisk LM, Stouten P, Trainor GL, Worland P, Seitz SP. J. Med. Chem. 2004; 47: 5894
• 17a Boyd S, Campbell L, Liao W, Meng Q, Peng Z, Wang X, Waring MJ. Tetrahedron Lett. 2008; 49: 7395
• 17b Wainwright P, Maddaford A, Simms M, Forrest N, Glen R, Hart J, Zhang X, Pryde DC, Stephenson PT, Middleton DS, Guyot T, Sutton SC. Synlett 2011; 1900
• 17c Slavish PJ, Price JE, Hanumesh P, Webb TR. J. Comb. Chem. 2010; 12: 807
• 17d Bio MM, Waters M, Javadi G, Song ZJ, Zhang F, Thomas D. Synthesis 2008; 891
• 17e Quiroga J, Trilleras J, Insuasty B, Abonía R, Nogueras M, Marchal A, Cobo J. Tetrahedron Lett. 2008; 49: 3257
• 17f Boudet N, Knochel P. Org. Lett. 2006; 8: 3737
• 17g Seela F, Steker H. Helv. Chim. Acta 1986; 69: 1602
• 18 Dang Q, Liu Y, Sun Z. Tetrahedron Lett. 2001; 42: 8419
• 19 Evans LE, Cheeseman MD, Jones K. Org. Lett. 2012; 14: 3546
• 20 Madroñero R, Vega S. Synthesis 1987; 628
• 21 Babu S, Morrill C, Almstead NG, Moon YC. Org Lett. 2013; 15: 1882
• 22 Hayes R, Meth-Cohn O. Tetrahedron Lett. 1982; 23: 1613
• 23 We considered the possibility of 6 serving as an intermediate capable of converting to 4 at elevated temperatures. To test this hypothesis, isolated 6a was heated at 180 °C in MeCN for 20 min, in both the presence and the absence of 1 equiv of HCl (4 M in 1,4-dioxane). In both cases, formation of 4a was not observed (¹H NMR of the crude reaction mixture). In both cases, 6a did, however, undergo 70–80% conversion to a new product, identified by both UPLC/MS and ¹H NMR (taken of the crude reaction mixture) as 4-chloro-6-{(4-methoxyphenyl)[1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}pyrimidine-5-carbonitrile.
• 24 We also investigated the corresponding reactions of 2q–t in the absence of an external base. In cases where 2 was an HCl salt (2s and 2t), exclusive formation of hydrazone 3 was observed. When 2 was used in its free base form (2q and 2r), a mixture of 1 and 4 (ca. 1:2) was observed, along with several unidentified minor byproducts. When 2.1 equiv of 2q and 2r were used instead of 1.05 equiv, 4 was formed quantitatively. In the latter case 2q and 2r presumably functioned as the external base, thus leading to similar results as those obtained in Table 6.
• 25 Another possible explanation is that the isolated yields reported in reference 17a were obtained after silica gel chromatography, whereas those reported in Table 6 were not. We observed that the products shown in Table 6 were partially unstable to silica gel chromatography, with an approximately 25% loss of material when this purification method was attempted.
• 26 Nigst TA, Antipova A, Mayr H. J. Org. Chem. 2012; 77: 8142
• 27 We also evaluated the corresponding reaction of 1 with 2v at 0 °C. We observed a mixture of 4v and 5v, again favoring 5v. The majority of the material, however, formed an unidentified intermediate(s), which did not significantly react further until the reaction warmed to r.t.
• 28a Paul S, Gupta M, Gupta R, Loupy A. Tetrahedron Lett. 2001; 42: 3827
• 28b Selvi ST, Nadaraj V, Mohan S, Sasi R, Hema M. Bioorg. Med. Chem. 2006; 14: 3896
• 28c Mali JR, Pratap UR, Jawale DV, Mane RA. Tetrahedron Lett. 2010; 51: 3980
• 28d Nadaraj V, Selvi ST. Pharm. Chem. 2010; 2: 315
• 29 Suzuki N. Chem. Pharm. Bull. 1980; 28: 761
• 30 An equivalent of i-Pr₂NEt was employed in entry 17 (Table 8) because THF was unable to reach 200 °C in our microwave reactor unless this additive was present. It is thus unclear whether or not the presence of i-Pr₂NEt is necessary to minimize chloride hydrolysis, as we were unable to perform the corresponding reaction carried out in the absence of i-Pr₂NEt. MeCN, on the other hand, could be heated to 200 °C in the absence of i-Pr₂NEt. The corresponding reactions to entries 8, 9, and 16 (Table 8), performed with one equivalent of i-Pr₂NEt, exhibited no change in product distribution relative to that shown in Table 8.
• 31 The reactions illustrated in this scheme represent unoptimized procedures carried out on a small scale (0.2–0.5 mmol).
• 32 Ismail ZH, Abdel-Gawad SM, Abdel-Aziem A, Ghorab MM. Phosphorus, Sulfur Silicon Relat. Elem. 2003; 178: 1795
• 33 Qu GR, Xia R, Yang XN, Li JG, Wang DC, Guo HM. J. Org. Chem. 2008; 73: 2416
• 34 Miyashita A, Suzuki Y, Ohta K, Higashino T. Heterocycles 1994; 39: 345
• 35 Miyashita A, Matsuda H, Suzuki Y, Iwamoto K, Higashino T. Chem. Pharm. Bull. 1994; 42: 2017
• 36 Sugimoto O, Sudo M, Tanji K. Tetrahedron 2001; 57: 2133