In Situ Preparation and Consumption of O-Mesitylsulfonylhydroxylamine (MSH) in Continuous Flow for the Amination of Pyridines
Received: 08 February 2017
Accepted after revision: 28 March 2017
02 May 2017 (eFirst)
The paper demonstrates a safe method in which highly unstable O-mesitylsulfonylhydroxylamine (MSH) can be prepared and consumed in continuous flow. MSH was prepared in situ and used for the flow amination of a range of pyridines, which were subsequently transformed into useful pyrazolopyridine building blocks.
References and Notes
- 1 Mendiola J. Rincon JA. Mateos C. Soriano JF. de Frutos O. Niemeier JK. Davis EM. Org. Process Res. Dev. 2009; 13: 263
- 2a Kendall JD. O’Connor PD. Marshall AJ. Frederick R. Marshall ES. Lill CL. Lee WJ. Kolekar S. Chao M. Malik A. Yu SQ. Chaussade C. Buchanan C. Rewcastle GW. Baguley BC. Flanagan JU. Jamieson SM. F. Denny WA. Shepherd PR. Bioorg. Med. Chem. 2012; 20: 69
- 2b Takahashi Y. Hibi S. Hoshino Y. Kikuchi K. Shin K. Murata-Tai K. Fujisawa M. Ino M. Shibata H. Yonaga M. J. Med. Chem. 2012; 55: 5255
- 2c Kendall JD. Marshall AJ. Giddens AC. Tsang KY. Boyd M. Frederick R. Lill CL. Lee WJ. Kolekar S. Chao M. Malik A. Yu S. Chaussade C. Buchanan CM. Rewcastle GW. Baguley BC. Flanagan JU. Denny WA. Shepherd PR. MedChemComm 2014; 5: 41
- 2d Moller D. Salama I. Kling RC. Hubner H. Gmeiner P. Bioorg. Med. Chem. 2015; 23: 6195
- 2e Tang J. Wang BX. Wu T. Wan JT. Tu ZC. Njire M. Wan BJ. Franzblauc SG. Zhang TY. Lu XY. Ding K. ACS Med. Chem. Lett. 2015; 6: 814
- 2f Degorce SL. Boyd S. Curwen JO. Ducray R. Halsall CT. Jones CD. Lach F. Lenz EM. Pass M. Pass S. Trigwell C. J. Med. Chem. 2016; 59: 4859
- 3a Ley SV. Chem. Rec. 2012; 12: 378
- 3b Movsisyan M. Delbeke EI. P. Berton J. Battilocchio C. Ley SV. Stevens CV. Chem. Soc. Rev. 2016; 45: 4892
- 3c Porta R. Benaglia M. Puglisi A. Org. Process Res. Dev. 2016; 20: 2
- 4 Tamura Y. Minamikawa J. Ikeda M. Synthesis 1977; 1
- 5 Huisgen R. Grashey R. Krischke R. Tetrahedron Lett. 1962; 387
- 6 Roy PJ. Dufresne C. Lachance N. Leclerc JP. Boisvert M. Wang ZY. Leblanc Y. Synthesis 2005; 2751
- 7 O’Brien AG. Levesque F. Seeberger PH. Chem. Commun. 2011; 47: 2688
- 8 Legault C. Charette AB. J. Org. Chem. 2003; 68: 7119
- 9 Carpino LA. J. Am. Chem. Soc. 1960; 82: 3133
- 10 Tamura Y. Minamika J. Sumoto K. Fujii S. Ikeda M. J. Org. Chem. 1973; 38: 1239
- 11 When MSH (1) was isolated as a damp solid and analyzed by ion chromatography, no anions were observed, indicating the formation of free MSH and not a salt.
- 12 It should be noted that, when damp solid MSH was dissolved in acetonitrile and pumped through the Vapourtec Knauer pump heads, decomposition occurred presumably due to the mechanical action of the pistons. Both the batch and the flow deprotection of 7 required 15 minutes. Warming of the first reaction coil above 30 °C resulted in the decomposition of MSH. Combining the inlet solutions of pyridine 2a and sodium hydroxide was not tolerated and also resulted in decomposition.
- 13 1-Aminopyridin-1-ium 2,4,6-trimethylbenzenesulfonate Salts 3, General Flow Procedure All reactions were performed using a commercially available Vapourtec R-series set-up equipped with four pumps. (E)-Ethyl N-(mesitylsulfonyl)oxyacetimidate (7) was dissolved in MeCN (1 M) and filtered. Perchloric acid (neat, 11.6 M) was mixed with the first inlet via a Y-piece with flow rates of 1.228 mL/min and 0.106 mL/min, respectively. Pyridine 2 was dissolved in MeCN (2M), filtered and introduced into a second Y-piece at a flow rate of 0.614 mL/min. Sodium hydroxide (1 M, aq.) was diluted with DMF to a concentration of 0.667 M and introduced in a third Y-piece at a flow rate of 1.840 mL/min. The stoichiometric ratio of all four inlets was 1:1:1:1. The system solvent was MeCN for the first three inlets and H2O/DMF (2:1) for the fourth inlet. The PFA (polyfluoroalkoxy alkane polymer) reactor coils, with volumes of 20 mL, 2 mL and 10 mL, respectively, were all set to a temperature of 30 °C. The reaction mixture from the first two inlet streams had a residency time of 15 min in the first reactor, of 1.02 min in the second and of 2.64 min in the third. 1-Amino-3-bromopyridin-1-ium 2,4,6-Trimethylbenzenesulfonate (3a) The reaction was performed by adapting the general flow procedure to the reaction of 3-bromopyridine (2a) with MSH. The outlet solution (25 mL, collected over 3.6 min) was concentrated in vacuo to give an orange solid (3.6 min collection time, >99%). 1H NMR (400 MHz, DMSO-d 6): δ = 2.18 (s, 9 H, 3 × CH3), 6.77 (s, 2 H, NH2), 7.93 (dd, J = 4, 8 Hz, 1 H, ArH), 7.95 (s, 2 H, ArH), 8.49 (d, J = 8 Hz, 1 H, ArH), 8.81 (d, J = 8 Hz, 1 H, ArH), 9.17 (s, 1 H, ArH). 13C NMR (101 MHz, d6-DMSO): δ = 20.3, 22.7, 121.4, 128.6, 129.9, 135.8, 136.4, 138.6, 141.4, 142.5, 166.0. HRMS (FAB): m/z calcd for C5H6BrN2 +: 172.97144; found: 172.97105; m/z calcd for C9H11O3S–: 199.04289; found: 199.04277. DSC showed small exotherm with 61 J/g onset 249 °C and larger exotherm with 573 J/g onset 299 °C.
- 14 It should also be noted that combining any of the three inlet solutions, in order to simplify the set-up, led to decomposition and poor yield.