Communication
Green Chemistry
reduced pressure, (3-((2-morpholinoethyl) amino)-2-(pyridine-
2 P. T. Anastas and J. C. Warner, Green Chemistry: Theory and
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3 B. Gutmann, D. Cantillo and C. O. Kappe, Angew. Chem.,
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2-yl)imidazo[1,2-a]pyridin-6-yl)methanol
4g
(309
mg,
0.874 mmol, 87% yield) was isolated as a beige powder.
Representative flow procedure using formaldehyde (Scheme 5,
entry 4s)
4 A. T. Baviskar, C. Madaan, R. Preet, P. Mohapatra, V. Jain,
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729–737.
10 D. Flesch, S.-y. Cheung, J. Schmidt, M. Gabler, P. Heitel,
J. Kramer, A. Kaiser, M. Hartmann, M. Lindner,
K. Lüddens–Dämgen, J. Heering, C. Lamers, H. Lüddens,
M. Wurglics, E. Proschak, M. Schubert–Zsilavecz and
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Two stock 10 mL solutions were prepared. The first solution
contained 5-methanolyl-2-aminopyridine (248 mg, 2.00 mmol)
and 2-isocyano-2-methylpropane (0.452 mL, 4.00 mmol) in
ethanol (10.0 mL total volume) as a clear yellow solution. The
second solution contained HCl (0.160 mL, 0.200 mmol, 1.25 M
in ethanol) and aqueous 37% wt. formaldehyde (0.166 mL,
2.24 mmol) in ethanol (10.0 mL total volume) as a colourless,
clear solution. 5.00 mL from each solution was pumped into
the flow reactor, heated to 130 °C, at a flow rate of 0.100 mL
per minute per line for 50 min. Ethanol was then collected for
25 min to account for the 5 mL dead volume in the reactor,
before the product solution was collected for 61 min 45 s
(12.35 mL crude product mixture collected as a golden clear
solution). A 10 µL aliquot was removed from the solution and
diluted with 1 mL methanol for quantitative HPLC analysis
against a concentration gradient of the amidine starting
material. 94% consumption of the starting material was
observed, by quantitative HPLC analysis. The solvent was
removed in vacuo, and the product was isolated by flash
column chromatography, using a gradient elution of 5 to 10%
ethanol in ethyl acetate. Following solvent removal under
reduced pressure, (3-(tert-butylamino)imidazo[1,2-a]pyridin-6-
yl) methanol 4s (192 mg, 0.876 mmol, 88% yield) was isolated
as a white crystalline solid.
11 K. Mizushige, T. Ueda, K. Yukiiri and H. Suzuki,
Cardiovasc. Drug Rev., 2002, 20, 163–174.
12 C. W. McNamara, M. C. Lee, C. S. Lim, S. H. Lim,
J. Roland, O. Simon, B. K. Yeung, A. K. Chatterjee,
S. L. McCormack, M. J. Manary, A.-m. Zeeman,
K. J. Dechering, T. S. Kumar, P. P. Henrich, K. Gagaring,
M. Ibanez, N. Kato, K. L. Kuhen, C. Fischli, A. Nagle,
M. Rottmann, D. M. Plouffe, B. Bursulaya, S. Meister,
L. Rameh, J. Trappe, D. Haasen, M. Timmerman,
R. W. Sauerwein, R. Suwanarusk, B. Russell, L. Renia,
F. Nosten, D. C. Tully, C. H. Kocken, R. J. Glynne,
C. Bodenreider, D. A. Fidock, T. T. Diagana and
E. A. Winzeler, Nature, 2013, 504, 248–253.
Notes
The data that support the findings of this study are available
within the article and its ESI.†
Conflicts of interest
13 N. Desroy, B. Heckmann, R. C. X. Brys, A. M. Joncour,
C. Peixoto, X. M. Bock and C. G. Housseman, WO2014/
139882A1, 2014.
There are no conflicts to declare.
14 C. Wallrapp, E. Thoenes and P. Geigle, WO2008/116648A2,
2008.
Acknowledgements
15 S. Régnier, W. S. Bechara and A. B. Charette, J. Org. Chem.,
2016, 81, 10348–10356.
16 Z. Fei, Y.-p. Zhu, M.-c. Liu, F.-c. Jia and A.-x. Wu,
Tetrahedron Lett., 2013, 54, 1222–1226.
17 P. R. Adiyala, G. S. Mani, J. B. Nanubolu, K. C. Shekar and
R. A. Maurya, Org. Lett., 2015, 17, 4308–4311.
We thank the EPSRC for funding via Prosperity Partnership
EP/S035990/1. The authors would also like to thank Steve
Richards (PDS-ASD-Global Spectroscopy-NMR UK, GSK) for his
assistance with NMR analysis, and PDS API chemistry, GSK for
consultation regarding the use of flow chemistry apparatus.
18 A. R. Katritzky, Y.-j. Xu and H. Tu, J. Org. Chem., 2003, 68,
4935–4937.
19 K. Groebke, L. Weber and F. Mehlin, Synlett, 1998, 661–663.
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