Synlett 2015; 26(18): 2570-2574
DOI: 10.1055/s-0035-1560320
letter
© Georg Thieme Verlag Stuttgart · New York

The Synthesis of 3,3-Dimethyl Aza- and Diazaindolines Using a Palladium-Catalysed Intramolecular Reductive Cyclisation

James E. H. Day*
a   Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK   Email: james.day@astx.com
,
Martyn Frederickson
a   Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK   Email: james.day@astx.com
,
Colin Hogg
b   Onyx Scientific Limited, Silverbriar, Enterprise Park East, Sunderland, Tyne & Wear, SR5 2TQ, UK
,
Christopher N. Johnson
a   Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK   Email: james.day@astx.com
,
Alistair Meek
b   Onyx Scientific Limited, Silverbriar, Enterprise Park East, Sunderland, Tyne & Wear, SR5 2TQ, UK
,
Julian Northern
b   Onyx Scientific Limited, Silverbriar, Enterprise Park East, Sunderland, Tyne & Wear, SR5 2TQ, UK
,
Michael Reader
a   Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK   Email: james.day@astx.com
,
Gary Reid
b   Onyx Scientific Limited, Silverbriar, Enterprise Park East, Sunderland, Tyne & Wear, SR5 2TQ, UK
› Author Affiliations
Further Information

Publication History

Received: 09 July 2015

Accepted after revision: 22 August 2015

Publication Date:
22 September 2015 (online)


Abstract

A range of azaindolines was prepared in three steps from heterocyclic amines using halogenation, alkylation with 3-bromo-2-methylpropene, and a palladium-catalysed reductive cyclisation. The chemistry proved applicable to a multigram-scale operation.

 
  • References and Notes

  • 1 Gribble GW. J. Chem Soc., Perkin Trans. 1 2000; 1045
  • 2 Song JJ, Reeves JT, Gallou F, Tan Z, Yee NK, Senanayake CH. Chem. Soc. Rev. 2007; 36: 1120
  • 3 Wipf P, Maciejewski JP. Org. Lett. 2008; 10: 4383
  • 4 Gonzalez-Lopez de Turiso F, Shin Y, Brown M, Cardozo M, Chen YL, Fong D, Hao X, He X, Henne K, Hu YL. J. Med. Chem. 2012; 55: 7667
  • 5 Qiao JX, Wang TC, Ruel R, Thibeault C, L’heureux A, Schumacher WA, Spronk SA, Hiebert S, Bouthillier G, Lloyd J, Pi Z, Schnur DM, Abell LM, Hua J, Price LA, Liu E, Wu Q, Steinbacher TE, Bostwick JS, Chang M, Zheng J, Gao Q, Ma B, McDonnell PA, Huang CS, Rehfuss R, Wexler RR, Lam PY. S. J. Med. Chem. 2013; 56: 9275
  • 6 Genin MJ, Chidester CG, Constance G, Rohrer DC, Romero DL. Bioorg Med. Chem. Lett. 1995; 5: 1875
  • 7 Leroi C, Bertin D, Dufils PE, Gigmes D, Marque S, Tordo P, Courturier JL, Guerret O, Ciufolini MA. Org. Lett. 2003; 5: 4943
  • 8 Johnston JN, Plotkin MA, Viswanathan R, Prabhakaran EN. Org. Lett. 2001; 3: 1009
  • 9 Mo D.-L, Ding C.-H, Dai L.-X, Hou X.-L. Chem. Asian J. 2011; 6: 3200
  • 10 Viswanathan R, Prabhakaran EN, Plotkin MA, Johnston JN. J. Am. Chem. Soc. 2003; 125: 163
  • 11 Pfefferkorn JA, Choi C. Tetrahedron Lett. 2008; 49: 4372
  • 12 Takamatsu K, Hirano K, Satoh T, Miura M. J. Org. Chem. 2015; 80: 3242
  • 13 Liu KG, Lo JR, Robichaud AJ. Tetrahedron 2010; 66: 573
  • 14 Vu AT, Cohn ST, Zhang P, Kim CY, Mahaney PE, Bray JA, Johnston GH, Koury EJ, Cosmi SA, Deecher DC, Smith VA, Harrison JE, Leventhal L, Whiteside GT, Kennedy JD, Trybulski EJ. J. Med. Chem. 2010; 53: 2051
  • 15 Larock RC, Babu S. Tetrahedron Lett. 1987; 28: 5291
  • 16 Jhoti H, Williams G, Rees DC, Murray CW. Nat. Rev. Drug Discovery 2013; 12: 644
  • 17 Chessari G, Buck IM, Day JE. H, Day PJ, Iqbal A, Johnson CN, Lewis EJ, Martins V, Miller D, Reader M, Rees DC, Rich SJ, Tamanini E, Vitorino M, Ward GA, Williams PA, Williams G, Wilsher NE, Woolford AJ.-A. J. Med. Chem. 2015; 58: 6574
  • 18 Pd(OAc)2 (0.005 mmol, 2 mol%), Et3N (0.625 mmol), substrate (0.25 mmol), sodium formate (0.06 M), n-Bu4NCl (0.25 mmol), and DMF (0.06 M) at 80 °C.
  • 19 Bell IM, Gallicchio SN, Wood MR, Quigley AG, Stump CA, Zartman CB, Fay JF, Li C.-C, Lynch JJ, Moore EL, Mosser SD, Prueksaritanont T, Regan CP, Roller S, Salvatore CA, Kane SA, Vacca JP, Selnick HG. ACS Med. Chem. Lett. 2010; 1: 24
  • 20 General Iodination Procedure NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloropyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL), and the mixture was stirred and held at reflux overnight. Upon cooling to r.t. the solvent was removed in vacuo and the residue partitioned between EtOAc (250 mL), sat. Na2S2O3 (100 mL), and H2O (250 mL). The organic layer was separated, washed with H2O (2 × 250 mL), separated, and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica gel. Elution with 30–50% EtOAc in PE afforded a pale orange solid that was rinsed with 25% EtOAc in PE (80 mL). The solids were collected by filtration and sucked dry to afford 2-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid. The mother liquors were concentrated to dryness in vacuo and the residues subjected to column chromatography on silica. Elution with 30–50% EtOAc in PE afforded further pure material (1.90 g). Combined yield 9.22 g, 36%. 1H NMR (400 MHz, DMSO-d 6): δ = 8.20 (s, 1 H), 6.64 (s, 1 H), 6.50 (br s, 2 H). MS: m/z = 255, 257 [M + H]+.
  • 21 General Alkylation Procedure KOt-Bu (4.56 g, 40.73 mmol) was added to a stirred solution of 2-chloro-5-iodopyridin-4-ylamine (8.62 g, 33.94 mmol) in anhydrous THF (140 mL), and the mixture was stirred at r.t. for 15 min. 3-Bromo-2-methylpropene (5.51 g, 40.73 mmol) was added, and the mixture was stirred at r.t. overnight. The solvent was removed in vacuo and the residues partitioned between CH2Cl2 (100 mL) and H2O (100 mL). The organic layer was separated, the solvent removed in vacuo, and the residues subjected to column chromatography on silica. Elution with 5–20% EtOAc in PE afforded (2-chloro-5-iodopyridin-4-yl)-(2-methylallyl)amine (7.93 g, 76%) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d 6): δ = 8.23 (s, 1 H), 6.49 (t, J = 6.4 Hz, 1 H), 6.39 (s, 1 H), 4.84 (s, 1 H), 4.73 (s, 1 H), 3.82 (d, J = 5.7 Hz, 2 H), 1.69 (s, 3 H). MS: m/z = 309, 311 [M + H]+.
  • 22 General Palladium-Catalysed Cyclisation Pd(OAc)2 (300 mg, 1.34 mmol), sodium formate (2.40 g, 30.53 mmol), n-Bu4NCl (8.48 g, 30.53 mmol), and Et3N (10.6 mL, 76.32 mmol) were added to a solution of (2-chloro-5-iodopyridin-4-yl)-(2-methylallyl)amine (7.85 g, 25.44 mmol) in toluene (200 mL) and H2O (10 mL), and the mixture was stirred and held at 100 °C under a nitrogen atmosphere overnight. The mixture was filtered whilst still hot and the solids rinsed with toluene (50 mL), H2O (50 mL), and EtOAc (50 mL). The organic solvent was removed in vacuo, the aqueous residues were diluted with H2O (100 mL), and extracted with EtOAc (2 × 200 mL). The organic layer was separated, the solvent was removed in vacuo, and the residues subjected to column chromatography on silica. Elution with 30–100% EtOAc in PE afforded 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (4.12 g, 89%) as a colourless solid. 1H NMR (400 MHz, DMSO-d 6): δ = 7.72 (s, 1 H), 6.75 (br s, 1 H), 6.33 (s, 1 H), 3.32 (s, 2 H,), 1.25 (s, 6 H). MS: m/z = 183, 185 [M + H]+.
  • 23 Cyclisation Product (Table 1, Entry 1) 1H NMR (400 MHz, DMSO-d 6): δ = 6.94 (d, J = 7.8 Hz, 1 H), 6.57–6.47 (m, 1 H), 6.44 (d, J = 2.0 Hz, 1 H), 5.74 (s, 1 H), 3.21 (d, J = 1.8 Hz, 1 H), 1.20 (s, 6 H). MS: m/z = 182 [M + H]+.
  • 24 Cyclisation Product (Table 1, Entry 2) 1H NMR (400 MHz, DMSO-d 6): δ = 7.72 (s, 1 H), 6.75 (br s, 1 H), 6.33 (s, 1 H), 3.32 (s, 2 H), 1.25 (s, 6 H). MS: m/z = 183 [M + H]+.
  • 25 Cyclisation Product (Table 1, Entry 3) 1H NMR (400 MHz, DMSO-d 6): δ = 7.71 (s, 1 H), 6.74 (s, 1 H), 6.48 (s, 1 H), 3.31 (s, 1 H), 1.25 (s, 6 H). MS: m/z = 228 [M + H]+.
  • 26 Cyclisation Product (Table 1, Entry 4) 1H NMR (270 MHz, CDCl3): δ = 7.09–7.06 (d, J = 8.0 Hz, 1 H), 6.51–6.48 (d, J = 8.0 Hz, 1 H), 5.05 (br s, 1 H), 3.37 (s, 2 H), 1.28 (s, 6 H). MS: m/z = 183 [M + H]+.
  • 27 Cyclisation Product (Table 1, Entry 5) 1H NMR (400 MHz, DMSO-d 6): δ = 7.72–7.64 (m, 1 H), 6.87 (t, J = 2.2 Hz, 1 H), 6.05 (s, 1 H), 3.30 (m, 2 H), 1.20 (s, 6 H). MS: m/z = 228 [M + H]+.
  • 28 Cyclisation Product (Table 1, Entry 6) 1H NMR (270 MHz, CDCl3): δ = 7.74 (s, 1 H), 5.79 (br s, 1 H), 3.46 (s, 2 H), 1.35 (s, 6 H). MS: m/z = 184 [M + H]+.
  • 29 Cyclisation Product from HCl Deprotection (Table 1, Entry 7) 1H NMR (270 MHz, CD3OD): δ = 6.92 (s, 1 H), 3.79 (s, 2 H), 1.44 (s, 6 H). MS: m/z = 184 [M + H]+.
  • 30 Negishi E.-I. Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley-Interscience; New York: 2002
  • 31 Liu P, Huang L, Lu Y, Dilmeghani M, Baum J, Xiang T, Adams J, Tasker A, Larsen R, Faul MM. Tetrahedron Lett. 2007; 48: 2307
  • 32 2-Chloro-3-iodopyridin-4-ylamine isolated in 33% yield. 1H NMR (400 MHz, DMSO-d 6): δ = 7.75 (d, J = 5.5 Hz, 1 H), 6.53 (m, 3 H), MS: m/z = 255 [M + H]+.
  • 33 Larger-Scale Palladium Cyclisation To a 10 L flange flask fitted with stirrer bar and nitrogen inlet/outlet was added (2-chloro-5-iodopyridin-4-yl)-(2-methylallyl)amine hydrochloride (217 g, 0.629 mol), Pd(OAc)2 (7 g, 0.031 mol), sodium formate (51.3 g, 0.755 moles), TBACl (210 g, 0.755 mol), Et3N (350 mL, 2.52 mol), toluene (4.9 L), and H2O (242 mL). The reaction mixture was heated at 100 °C (oil bath) overnight after which time NMR confirmed no starting material remaining, bulk material worked up. The reaction mixture was cooled to r.t. and stood overnight. To the cooled reaction mixture was added H2O (500 mL) and Et2O (2.5 L), organic layer removed and aqueous re-extracted with Et2O (1.5 L). Organic extracts combined, washed with sat. brine solution (1.5 L), removed, dried over MgSO4, filtered, and evaporated to dryness at 40 °C to give 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (76.2 g, 66%) as a yellow solid, the analytical data matched those from the smaller scale.