We developed and presented here a ferrocene-catalyzed C-H imidation of 7-deazapurines (pyrrolo[2,3-d]pyrimidines) with N-imidyl peroxyesters. The reactions occur regioselectively at position 8 in 7-deazapurines, leading to a series of 8-succinimido-, phtalimido-, or naphthalimido-7-deazapurine derivatives. Attempted hydrazinolysis of resulting 8-imidyl-7-deazapurines led to corresponding 8-amino-7-deazapurine, which was very unstable and quickly decomposed.

Department of Organic Chemistry Faculty of Science Charles University Prague Hlavova 8 12843 Prague 2 Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Gilead and IOCB Research Center Flemingovo nám 2 16610 Prague 6 Czech Republic

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De Coen L. M.; Heugebaert T. S. A.; García D.; Stevens C. V. Synthetic Entries to and Biological Activity of Pyrrolopyrimidines. Chem. Rev. 2016, 116, 80–139. 10.1021/acs.chemrev.5b00483. PubMed DOI

Ding S.; Wu T. Y. H.; Brinker A.; Peters E. C.; Hur W.; Gray N. S.; Schultz P. G. Synthetic Small Molecules That Control Stem Cell Fate. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 7632–7637. 10.1073/pnas.0732087100. PubMed DOI PMC

Traxler P.; Allegrini P. R.; Brandt R.; Brueggen J.; Cozens R.; Fabbro D.; Grosios K.; Lane H. A.; McSheehy P.; Mestan J.; Meyer T.; Tang C.; Wartmann M.; Wood J.; Caravatti G. AEE788: A Dual Family Epidermal Growth Factor receptor/ErbB2 and Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor with Antitumor and Antiangiogenic Activity. Cancer Res. 2004, 64, 4931–4941. 10.1158/0008-5472.can-03-3681. PubMed DOI

Jiao X.; Kopecky D. J.; Liu J.; Liu J.; Jaen J. C.; Cardozo M. G.; Sharma R.; Walker N.; Wesche H.; Li S.; Farrelly E.; Xiao S.-H.; Wang Z.; Kayser F. Synthesis and Optimization of Substituted Furo[2,3-d]-pyrimidin-4-amines and 7H-pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 Inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 6212–6217. 10.1016/j.bmcl.2012.08.020. PubMed DOI

Scott J. S.; Degorce S. L.; Anjum R.; Culshaw J.; Davies R. D. M.; Davies N. L.; Dillman K. S.; Dowling J. E.; Drew L.; Ferguson A. D.; Groombridge S. D.; Halsall C. T.; Hudson J. A.; Lamont S.; Lindsay N. A.; Marden S. K.; Mayo M. F.; Pease J. E.; Perkins D. R.; Pink J. H.; Robb G. R.; Rosen A.; Shen M.; McWhirter C.; Wu D. Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265PDiffuse Large B-Cell Lymphoma. J. Med. Chem. 2017, 60, 10071–10091. 10.1021/acs.jmedchem.7b01290. PubMed DOI

Riggs J. R.; Nagy M.; Elsner J.; Erdman P.; Cashion D.; Robinson D.; Harris R.; Huang D.; Tehrani L.; Deyanat-Yazdi G.; Narla R. K.; Peng X.; Tran T.; Barnes L.; Miller T.; Katz J.; Tang Y.; Chen M.; Moghaddam M. F.; Bahmanyar S.; Pagarigan B.; Delker S.; LeBrun L.; Chamberlain P. P.; Calabrese A.; Canan S. S.; Leftheris K.; Zhu D.; Boylan J. F. The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen. J. Med. Chem. 2017, 60, 8989–9002. 10.1021/acs.jmedchem.7b01223. PubMed DOI

Vazquez M. L.; Kaila N.; Strohbach J. W.; Trzupek J. D.; Brown M. F.; Flanagan M. E.; Mitton-Fry M. J.; Johnson T. A.; TenBrink R. E.; Arnold E. P.; Basak A.; Heasley S. E.; Kwon S.; Langille J.; Parikh M. D.; Griffin S. H.; Casavant J. M.; Duclos B. A.; Fenwick A. E.; Harris T. M.; Han S.; Caspers N.; Dowty M. E.; Yang X.; Banker M. E.; Hegen M.; Symanowicz P. T.; Li L.; Wang L.; Lin T. H.; Jussif J.; Clark J. D.; Telliez J.-B.; Robinson R. P.; Unwalla R. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases. J. Med. Chem. 2018, 61, 1130–1152. 10.1021/acs.jmedchem.7b01598. PubMed DOI

Chakka N.; Bregman H.; Du B.; Nguyen H. N.; Buchanan J. L.; Feric E.; Ligutti J.; Liu D.; McDermott J. S.; Zou A.; McDonough S. I.; Dimauro E. F. Discovery and Hit-to-lead Optimization of Pyrrolopyrimidines as Potent, State-dependent Na(v)1.7 Antagonists. Bioorg. Med. Chem. Lett. 2012, 22, 2052–2062. 10.1016/j.bmcl.2012.01.015. PubMed DOI

Lee J.-H.; Shin S. C.; Seo S. H.; Seo Y. H.; Jeong N.; Kim C.-W.; Kim E. E.; Keum G. Synthesis and in Vitro Antiproliferative Activity of C5-benzyl Substituted 2-amino-pyrrolo[2,3-d]pyrimidines as Potent Hsp90 Inhibitors. Bioorg. Med. Chem. Lett. 2017, 27, 237–241. 10.1016/j.bmcl.2016.11.062. PubMed DOI

Perlíková P.; Hocek M. Pyrrolo[2,3-d]pyrimidine (7-deazapurine) as a Privileged Scaffold in Design of Antitumor and Antiviral Nucleosides. Med. Res. Rev. 2017, 37, 1429–1460. 10.1002/med.21465. PubMed DOI PMC

Bourderioux A.; Nauš P.; Perlíková P.; Pohl R.; Pichová I.; Votruba I.; Džubák P.; Konečný P.; Hajdúch M.; Stray K. M.; Wang T.; Ray A. S.; Feng J. Y.; Birkus G.; Cihlar T.; Hocek M. Synthesis and Significant Cytostatic Activity of 7-hetaryl-7-deazaadenosines. J. Med. Chem. 2011, 54, 5498–5507. 10.1021/jm2005173. PubMed DOI

Wu R.; Smidansky E. D.; Oh H. S.; Takhampunya R.; Padmanabhan R.; Cameron C. E.; Peterson B. R. Synthesis of a 6-Methyl-7-deaza Analogue of Adenosine That Potently Inhibits Replication of Polio and Dengue Viruses. J. Med. Chem. 2010, 53, 7958–7966. 10.1021/jm100593s. PubMed DOI PMC

Nauš P.; Caletková O.; Konečný P.; Džubák P.; Bogdanová K.; Kolář M.; Vrbková J.; Slavětínská L.; Tloušt’ová E.; Perlíková P.; Hajdúch M.; Hocek M. Synthesis, Cytostatic, Antimicrobial, and anti-HCV Activity of 6-substituted 7-(het)aryl-7-deazapurine Ribonucleosides. J. Med. Chem. 2014, 57, 1097–1110. 10.1021/jm4018948. PubMed DOI

Tumkevicius S.; Dodonova J. Functionalization of Pyrrolo[2,3-d]pyrimidine by Palladium-catalyzed Cross-coupling Reactions (review). Chem. Heterocycl. Compd. 2012, 48, 258–279. 10.1007/s10593-012-0986-2. DOI

Krömer M.; Klečka M.; Slavětínská L.; Klepetářová B.; Hocek M. Chemoselective Synthesis of 4,5-Diarylpyrrolo[2,3-d]pyrimidines (6,7-Diaryl-7-deazapurines) by Consecutive Suzuki and Liebeskind-Srogl Cross-Couplings. Eur. J. Org. Chem. 2014, 7203–7210. 10.1002/ejoc.201402882. DOI

Dodonova J.; Tumkevicius S. Fused Pyrrolo[2,3-d]pyrimidines (7-Deazapurines) by Palladium-Catalyzed Direct N–H and C–H Arylation Reactions. Synthesis 2017, 49, 2523–2534. 10.1055/s-0036-1588734. DOI

Prieur V.; Rubio-Martínez J.; Font-Bardia M.; Guillaumet G.; Pujol M. D. Microwave-Assisted Synthesis of Substituted Pyrrolo[2,3-d ]pyrimidines. Eur. J. Org. Chem. 2014, 1514–1524. 10.1002/ejoc.201301496. DOI

Tumkevicius S.; Dodonova J.; Kazlauskas K.; Masevicius V.; Skardziute L.; Jursenas S. Synthesis and Photophysical Properties of Oligoarylenes with a Pyrrolo[2,3-d]pyrimidine Core. Tetrahedron Lett. 2010, 51, 3902–3906. 10.1016/j.tetlet.2010.05.093. DOI

Prieur V.; Heindler N.; Rubio-Martínez J.; Guillaumet G.; Pujol M. D. One-pot Synthesis of 4-aminated Pyrrolo[2,3-d]pyrimidines from Alkynylpyrimidines Under Metal-catalyst-free Conditions. Tetrahedron 2015, 71, 1207–1214. 10.1016/j.tet.2015.01.012. DOI

Gayakhe V.; Sanghvi Y. S.; Fairlamb I. J. S.; Kapdi A. R. Catalytic C–H bond functionalisation of purine and pyrimidine nucleosides: a synthetic and mechanistic perspective. Chem. Commun. 2015, 51, 11944–11960. 10.1039/c5cc03416g. PubMed DOI

Liang Y.; Wnuk S. Modification of Purine and Pyrimidine Nucleosides by Direct C-H Bond Activation. Molecules 2015, 20, 4874–4901. 10.3390/molecules20034874. PubMed DOI PMC

Abdoli M.; Mirjafary Z.; Saeidian H.; Kakanejadifard A. New Developments in Direct Functionalization of C–H and N–H Bonds of Purine Bases via Metal Catalyzed Cross-coupling Reactions. RSC Adv. 2015, 5, 44371–44389. 10.1039/c5ra04406e. DOI

Klečka M.; Pohl R.; Klepetářová B.; Hocek M. Direct C-H Borylation and C-H Arylation of Pyrrolo[2,3-d]pyrimidines: Synthesis of 6,8-disubstituted 7-deazapurines. Org. Biomol. Chem. 2009, 7, 866–868. 10.1039/b900218a. PubMed DOI

Klečka M.; Slavětínská L. P.; Hocek M. Modification of Pyrrolo[2,3-d ]pyrimidines by C-H Borylation Followed by Cross-Coupling or Other Transformations: Synthesis of 6,8-Disubstituted 7-Deazapurine Bases. Eur. J. Org. Chem. 2015, 7943–7961. 10.1002/ejoc.201501177. DOI

Sabat N.; Klečka M.; Slavětínská L.; Klepetářová B.; Hocek M. Direct C-H Amination and C-H Chloroamination of 7-deazapurines. RSC Adv. 2014, 4, 62140–62143. 10.1039/c4ra13143f. DOI

Kavoosi S.; Rayala R.; Walsh B.; Barrios M.; Gonzalez W. G.; Miksovska J.; Mathivathanan L.; Raptis R. G.; Wnuk S. F. Synthesis of 8-(1,2,3-triazol-1-yl)-7-deazapurine Nucleosides by Azide-alkyne Click Reactions and Direct C-H Bond Functionalization. Tetrahedron Lett. 2016, 57, 4364–4367. 10.1016/j.tetlet.2016.08.053. PubMed DOI PMC

Sabat N.; Slavětínská L. P.; Klepetářová B.; Hocek M. C-H Phosphonation of Pyrrolopyrimidines: Synthesis of Substituted 7- and 9-Deazapurine-8-phosphonate Derivatives. J. Org. Chem. 2016, 81, 9507–9514. 10.1021/acs.joc.6b01970. PubMed DOI

Klečka M.; Pohl R.; Čejka J.; Hocek M. Direct C-H Sulfenylation of Purines and Deazapurines. Org. Biomol. Chem. 2013, 11, 5189–5193. 10.1039/c3ob40881g. PubMed DOI

Sabat N.; Slavětínská L. P.; Hocek M. Ir-catalyzed C–H Silylations of Phenyldeazapurines. Tetrahedron Lett. 2015, 56, 6860–6862. 10.1016/j.tetlet.2015.10.089. DOI

Wang S.; Ni Z.; Huang X.; Wang J.; Pan Y. Copper-catalyzed Direct Amidation of Heterocycles with N-fluorobenzenesulfonimide. Org. Lett. 2014, 16, 5648–5651. 10.1021/ol502724u. PubMed DOI

Kawakami T.; Murakami K.; Itami K. Catalytic C-H Imidation of Aromatic Cores of Functional Molecules: Ligand-accelerated Cu Catalysis and Application to Materials- and Biology-oriented Aromatics. J. Am. Chem. Soc. 2015, 137, 2460–2463. 10.1021/ja5130012. PubMed DOI

Boursalian G. B.; Ngai M.-Y.; Hojczyk K. N.; Ritter T. Pd-catalyzed Aryl C-H Imidation with Arene as the Limiting Reagent. J. Am. Chem. Soc. 2013, 135, 13278–13281. 10.1021/ja4064926. PubMed DOI PMC

Song L.; Zhang L.; Luo S.; Cheng J.-P. Visible-light Promoted Catalyst-free Imidation of Arenes and Heteroarenes. Chem.—Eur. J. 2014, 20, 14231–14234. 10.1002/chem.201404479. PubMed DOI

Kim H.; Kim T.; Lee D. G.; Roh S. W.; Lee C. Nitrogen-centered Radical-mediated C-H Imidation of Arenes and Heteroarenes via Visible Light Induced Photocatalysis. Chem. Commun. 2014, 50, 9273–9276. 10.1039/c4cc03905j. PubMed DOI

Foo K.; Sella E.; Thomé I.; Eastgate M. D.; Baran P. S. A Mild, Ferrocene-catalyzed C-H Imidation of (hetero)arenes. J. Am. Chem. Soc. 2014, 136, 5279–5282. 10.1021/ja501879c. PubMed DOI PMC

Farrugia L. J. WinGX and ORTEP for Windows: an update. J. Appl. Crystallogr. 2012, 45, 849–854. 10.1107/s0021889812029111. DOI

Diana P.; Barraja P.; Lauria A.; Almerico A. M.; Dattolo G.; Cirrincione G. Protonation of aminoindoles. Tetrahedron 2000, 56, 5177–5183. 10.1016/s0040-4020(00)00180-0. DOI

Hino T.; Nakagawa M.; Hashizume T.; Yamaji N.; Miwa Y. Autoxidation of 2-aminoindoles to 3-oxo-derivatives. Tetrahedron Lett. 1970, 11, 2205–2208. 10.1016/s0040-4039(01)98190-0. DOI