Synthesis 2018; 50(17): 3420-3429
DOI: 10.1055/s-0036-1591594
paper
© Georg Thieme Verlag Stuttgart · New York

Iridium-Catalysed C–H Borylation of 2-Pyridones; Bisfunctionalisation of CC4

Aurélien Honraedt
a  School of Chemistry, University of Bristol, BS8 1TS, Bristol, UK   Email: hugo.regocampello@bristol.ac.uk   Email: t.gallagher@bristol.ac.uk
,
Worawat Niwetmarin
a  School of Chemistry, University of Bristol, BS8 1TS, Bristol, UK   Email: hugo.regocampello@bristol.ac.uk   Email: t.gallagher@bristol.ac.uk
,
Cecilia Gotti
b  CNR, Institute of Neuroscience, Biometra Department, University of Milan, 20129 Milan, Italy
,
Hugo Rego Campello*
a  School of Chemistry, University of Bristol, BS8 1TS, Bristol, UK   Email: hugo.regocampello@bristol.ac.uk   Email: t.gallagher@bristol.ac.uk
,
Timothy Gallagher*
a  School of Chemistry, University of Bristol, BS8 1TS, Bristol, UK   Email: hugo.regocampello@bristol.ac.uk   Email: t.gallagher@bristol.ac.uk
› Author Affiliations
Financial support from the Royal Thai Government, University of Bristol and EPSRC (EP/N024117/1) is acknowledged.
Further Information

Publication History

Received: 06 April 2018

Accepted after revision: 18 May 2018

Publication Date:
29 June 2018 (eFirst)

Abstract

The high regioselectivity associated with the iridium-catalysed borylation of pyridones has been exploited to provide a very direct and efficient entry to C(10) doubly substituted CC4 variants of cytisine. Two approaches have been evaluated based on (i) C–H activation of cytisine (or an N-substituted derivative) followed by N-alkylation (to enable dimer formation) and (ii) direct C–H activation and borylation of CC4 itself. Both approaches provide access to C(10)-functionalized CC4 derivatives, but direct borylation of CC4 allows for a wider range of functional group interconversions to be tolerated.

Supporting Information

 
  • References

    • 1a Ishiyama T. Takagi J. Hartwig JF. Miyaura N. Angew. Chem. Int. Ed. 2002; 41: 3056
    • 1b Chotana GA. Rak MA. Smith MR. J. Am. Chem. Soc. 2005; 127: 10539

    • For reviews; see:
    • 1c Mkhalid IA. I. Barnard JH. Marder TB. Murphy JM. Hartwig JF. Chem. Rev. 2010; 110: 8902
    • 1d Hartwig JF. Chem. Soc. Rev. 2011; 40: 1992
    • 1e A Co-catalysed protocol has recently been reported and applied to substituted pyridines, see: Ren HL. Zhou YP. Bai YP. Cui CM. Driess M. Chem. Eur. J. 2017; 23: 5663

      For mechanistic and regioselectivity and related studies, see
    • 2a Tamura H. Yamazaki H. Sato H. Sakaki S. J. Am. Chem. Soc. 2003; 125: 16114
    • 2b Mkhalid IA. I. Coventry DN. Albesa-Jove D. Batsanov AS. Howard JA. K. Perutz RN. Marder TB. Angew. Chem. Int. Ed. 2006; 45: 489
    • 2c Vanchura BA. Preshlock SM. Roosen PC. Kallepalli VA. Staples RJ. Maleczka RE. Singleton DA. Smith MR. Chem. Commun. 2010; 7724
    • 2d Tajuddin H. Harrisson P. Bitterlich B. Collings JC. Sim N. Batsanov AS. Cheung MS. Kawamorita S. Maxwell AC. Shukla L. Morris J. Lin ZY. Marder TB. Steel PG. Chem. Sci. 2012; 3: 3505
    • 2e Roosen PC. Kallepalli VA. Chattopadhyay B. Singleton DA. Maleczka RE. Smith MR. J. Am. Chem. Soc. 2012; 134: 11350
    • 2f Konishi S. Kawamorita S. Iwai T. Steel PG. Marder TB. Sawamura M. Chem. Asian J. 2014; 9: 434
    • 2g Sadler SA. Tajuddin H. Mkhalid IA. I. Batsanov AS. Albesa-Jove D. Cheung MS. Maxwell AC. Shukla L. Roberts B. Blakemore DC. Lin ZY. Marder TB. Steel PG. Org. Biomol. Chem. 2014; 12: 7318
    • 2h Green AG. Liu P. Merlic CA. Houk KN. J. Am. Chem. Soc. 2014; 136: 4575
    • 2i Chattopadhyay B. Dannatt JE. Andujar-De Sanctis IL. Gore KA. Maleczka RE. Singleton DA. Smith MR. J. Am. Chem. Soc. 2017; 139: 7864
    • 2j For general rules on regioselectivity, see: Larsen MA. Hartwig JF. J. Am. Chem. Soc. 2014; 136: 4287
    • 2k For an unusual para-selective borylation, see: Saito Y. Segawa Y. Itami K. J. Am. Chem. Soc. 2015; 137: 5193

      For recent examples involving heterocyclic substrates, including pyridines, see ref. 2g and
    • 3a Fischer DF. Sarpong R. J. Am. Chem. Soc. 2010; 132: 5926
    • 3b Egan BA. Burton PM. RSC Adv. 2014; 4: 27726
    • 3c Eastabrook AS. Wang C. Davison EK. Sperry J. J. Org. Chem. 2015; 80: 1006
    • 3d Baggett AW. Vasiliu M. Li B. Dixon DA. Liu SY. J. Am. Chem. Soc. 2015; 137: 5536
    • 3e Sadler SA. Hones AC. Roberts B. Blakemore D. Marder TB. Steel PG. J. Org. Chem. 2015; 80: 5308
    • 3f For mechanistic studies using 1,10-phenanthroline as ligand in hetereocylic systems, see: Johannson Seechurn CC. C. Sivakumar V. Satoskar D. Colacot TJ. Organometallics 2014; 33: 3514
  • 4 Miura W. Hirano K. Miura M. Synthesis 2017; 49: 4745 ; note these authors used gel permeation chromatography to isolate the boronate ester product derived from N-Boc cytisine
  • 5 Miura W. Hirano K. Miura M. Org. Lett. 2016; 18: 3742

    • Borylation of 2-pyridones is commonly done by a palladium-catalysed reaction with the corresponding halogenated 2-pyridone and bis(pinacolatodiboron) (B2pin2). For selected examples, see:
    • 6a Hong JB. Davidson JP. Jin QW. Lee GR. Matchett M. O’Brien E. Welch M. Bingenheimer B. Sarma K. Org. Process Res. Dev. 2014; 18: 228
    • 6b Kaila N. Follows B. Leung L. Thomason J. Huang A. Moretto A. Janz K. Lowe M. Mansour TS. Hubeau C. Page K. Morgan P. Fish S. Xu X. Williams C. Saiah E. J. Med. Chem. 2014; 57: 1299
    • 6c Lou Y. Han XC. Kuglstatter A. Kondru RK. Sweeney ZK. Soth M. McIntosh J. Litman R. Suh J. Kocer B. Davis D. Park J. Frauchiger S. Dewdney N. Zecic H. Taygerly JP. Sarma K. Hong J. Hill RJ. Gabriel T. Goldstein DM. Owens TD. J. Med. Chem. 2015; 58: 512
    • 6d Zhao XG. Xin MH. Huang W. Ren YL. Jin Q. Tang F. Jiang HL. Wang YZ. Yang J. Mo SF. Xiang H. Bioorg. Med. Chem. 2015; 23: 348

      For the tandem one/pot iridium-borylation/bromination conditions used, see:
    • 7a Murphy JM. Liao X. Hartwig JF. J. Am. Chem. Soc. 2007; 129: 15434
    • 7b For a one-pot protocol to prepare arylboronic acids and aryl trifluoroborates, see: Murphy JM. Tzschucke CC. Hartwig JF. Org. Lett. 2007; 9: 757

    • In situ bromination proved to be more reliable than isolation of the intially formed boronate esters, which may link to stability issues. 2-Boronate derivatives of pyridines are known to be unstable towards protodeborylation; see ref. 2g and
    • 7c Cox PA. Leach AG. Campbell AD. Lloyd-Jones GC. J. Am. Chem. Soc. 2016; 138: 9145
  • 8 Catalyst inhibition by coordination of 1a would explain the issues we have observed for unsubstituted (i.e., NH) pyridones. No C–H activation of substrate 1b (which is otherwise a viable substrate) was observed when a mixture of 1a and 1b was used, suggesting that 1a deactivates the Ir catalyst. Catalyst inhibition via coordination of an azinyl N to a vacant coordination site on Ir also retards reactions involving pyridines, see refs 2g and 2j.
  • 9 In the case of simple pyridone substrates (Table 1), no mono C–H insertion at C(3) and/or C(6) was detected, demonstrating that initial reaction occurs at C(4) and/or C(5) (to give 2 and 3). This then leads to subsequent activation of (and reaction at) C(6) or C(3), respectively, leading to the double C–H insertion products 4 and 5. Reaction of 1b with 0.5 equiv of B2pin2 led to a lower conversion and reaction of 1b with 1.0 equiv of B2pin2 led to faster conversion (24 h instead of 48 h). In both cases, the same proportions of products 25 were observed. Monobromides 2 and 3 did not undergo further (i.e., additional) substitution when exposed to the bromination conditions shown in Scheme 1.

    • For overviews on nAChRs as therapeutic targets, see:
    • 10a Lloyd GK. Williams M. J. Pharmacol. Exp. Ther. 2000; 292: 461
    • 10b Jensen AA. Frolund B. Lijefors T. Krogsgaard-Larsen P. J. Med. Chem. 2005; 48: 4705
    • 10c Gotti C. Zoli M. Clementi F. Trends Pharmacol. Sci. 2006; 27: 482
    • 10d Albuquerque EX. Pereira EF. R. Alkondon M. Rogers SW. Physiol. Rev. 2009; 89: 73
    • 10e Taly A. Corringer PJ. Guedin D. Lestage P. Changeux JP. Nat. Rev. Drug Discovery 2009; 8: 733
    • 10f Miwa JM. Freedman R. Lester HA. Neuron 2011; 70: 20
    • 11a Jha P. Nat. Rev. Cancer 2009; 9: 655
    • 11b Jha P. Lancet 2015; 385: 918 ; See also WHO Framework Convention on Tobacco Control. Geneva: World Health Organization (2003)

      Cytisine is sold within Eastern Europe under the tradename Tabex® for use in smoking cessation therapy. For a recent review of cytisine, see:
    • 12a Rouden J. Lasne MC. Blanchet J. Baudoux J. Chem. Rev. 2014; 114: 712

    • For recent clinical trials reports and overviews associated with cytisine and smoking cessation, see:
    • 12b Etter JF. Arch. Intern. Med. 2006; 166: 1553
    • 12c West R. Zatonski W. Cedzynska M. Lewandowska D. Pazik J. Aveyard P. Stapleton J. N. Engl. J. Med. 2011; 365: 1193
    • 12d Walker N. Howe C. Glover M. McRobbie H. Barnes J. Nosa V. Parag V. Bassett B. Bullen C. N. Engl. J. Med. 2014; 371: 2353
    • 13a Coe JW. Brooks PR. Vetelino MG. Wirtz MC. Arnold EP. Huang JH. Sands SB. Davis TI. Lebel LA. Fox CB. Shrikhande A. Heym JH. Schaeffer E. Rollema H. Lu Y. Mansbach RS. Chambers LK. Rovetti CC. Schulz DW. Tingley FD. O’Neill BT. J. Med. Chem. 2005; 48: 3474
    • 13b Reus VI. Obach RS. Coe JW. Faessel H. Rollema H. Watsky E. Reeves K. Drugs Today 2007; 43: 65
  • 14 Sala M. Braida D. Pucci L. Manfredi I. Marks MJ. Wageman CR. Grady SR. Loi B. Fucile S. Fasoli F. Zoli M. Tasso B. Sparatore F. Clementi F. Gotti C. Br. J. Pharmacol. 2013; 168: 835 ; CC4 7 was reported to bind to the α4β2 and α7 nicotinic acetylcholine receptors with K i values of 26 nM and 13000 nM, respectively. This compares to K i values for cytisine 6a of 2.1 nM (at α4β2) and 228 nM (at α7). Correspondingly, whereas CC4 is less potent at α4β2, this dimeric ligand is more selective for this receptor than for α7 when compared to cytisine (and indeed varenicline, see Figure 1)
  • 15 Rucktooa P. Haseler CA. van Elk R. Smit AB. Gallagher T. Sixma TK. J. Biol. Chem. 2012; 287: 23283 ; See also ref. 17b for earlier docking studies. Details of our computational studies will be reported elsewhere
    • 16a Lester HA. Dibas MI. Dahan DS. Leite JF. Dougherty DA. Trends Neurosci. 2004; 27: 329
    • 16b Blum AP. Lester HA. Dougherty DA. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 13206
    • 16c Blum AP. Puskar NL. Tavares XD. Nakamura DT. Xiu XN. Lester HA. Dougherty DA. Biophys. J. 2010; 98: 132A
    • 16d Blum AP. Van Arnam EB. German LA. Lester HA. Dougherty DA. J. Biol. Chem. 2013; 288: 6991
    • 17a Chellappan SK. Xiao YX. Tueckmantel W. Kellar KJ. Kozikowski AP. J. Med. Chem. 2006; 49: 2673
    • 17b Kozikowski AP. Chellappan SK. Xiao YX. Bajjuri KM. Yuan HB. Kellar KJ. Petukhov PA. ChemMedChem 2007; 2: 1157
    • 17c Durkin P. Magrone P. Matthews S. Dallanoce C. Gallagher T. Synlett 2010; 2789
  • 18 Pd-catalysed methylation using MeI and aryl boronate esters have been reported, see: Doi H., Ban I., Nonoyama A., Sumi K., Kuang C. X., Hosoya T., Tsukada H., Suzuki M.; Chem. Eur. J.; 2009, 15: 4165; Synthesis of the C(10) methylated adduct 12b was attempted using this approach, however, this reaction failed when applied to bisboronate 11.
    • 19a Wysocki J. Schlepphorst C. Glorius F. Synlett 2015; 26: 1557
    • 19b Messaoudi S. Brion JD. Alami M. Adv. Synth. Catal. 2010; 352: 1677
    • 19c Passarella D. Favia R. Giardini A. Lesma G. Martinelli M. Silvani A. Danieli B. Efange SM. N. Mash DC. Bioorg. Med. Chem. 2003; 11: 1007
  • 20 We have carried out preliminary pharmacological evaluation (using binding methods obtained as described earlier[14]) of two ligands 12d and 12g shown in this paper. Ligand 12d had K i values of 4142 nM at human α4β2; 45610 nM at human α7. Ligand 12g had K i values of 7360 nM at human α4β2; 45890 nM at human α7. This indicates that these two substitution changes (NHAc and CO2Me respectively) lead to both a significant reduction of binding affinity at each of α4β2 and α7, as well as a loss of subtype selectivity by one to two orders of magnitude across these two nicotinic receptors, as compared to CC4. Details of a more extensive study to understand the structure-activity relationships involved here will be published in due course.