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PleaseRd So Cn oA t da vd aj un s ct ems argins
DOI: 10.1039/C5RA18386C
Journal Name
ARTICLE
collected in a fraction collector. Samples were purified using
preparative HPLC/MS to yield the final compound.
General Procedure for Oxadiazole Formation.
A stock solution of carboxylic and DIPEA (0.60 M and 1.8 in
DMA, respecitvely, 166.7 μL, 0.10 mmol carboxylic acid (1.0
eq) and 0.3 mmol DIPEA (3.0 eq)) and HATU (0.50 M in DMA,
Acknowledgements
The acknowledgements come at the end of an article after the
conclusions and before the notes and references.
200 μL, 0.10 mmol, 1.0 eq) were aspirated from their
respective source vials, mixed through a PFA mixing tube (0.2
mm inner diameter), and loaded into an incubation chamber
held at 30 °C for 5 minutes. The reaction segment was mixed
with a stock solution of hydroxyamidine (0.60 M, 166.7 μL,
Notes and References
1
M. Werner, C. Kuratli, R. E. Martin, R. Hochstrasser, D.
Wechsler, T. Enderle, A. I. Alanine, H. Vogel, Angew. Chem.
Int. Ed, 2014, 53, 1704-1708.
0.10 mmol, 1.0 eq), loaded into an injection loop for one
minute, followed by injection into the flow reactor (Hastelloy
coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at
2
3
4
S. V. Ley, D. E. Fitzpatrick, R. J. Ingham, R. M. Myers, Angew.
Chem. Int. Ed., 2015, 54, 3449-3464.
T. Rodrigues, P. Schneider, G. Schneider, Angew. Chem. Int.
Ed. 2014, 53, 5750-5758.
S. Hordhoff, S. Bulat, S. Cerezo-Galvez, O. Hill, B. Hoffman-
Enger, M. Lopez-Canet, C. Rosenbaum, C. Rummey, M.
Thiemann, V. G. Matassa, P. J. Edwards, A. Feurer, Bio. Med.
Chem. Lett. 2009, 19, 6340-6345.
-1
175 °C, and passed through the reactor at 163 μL min (11
minute residence time) pressurized to 1000 psi using a back-
pressure regulator. Upon exiting the reactor, the reaction was
loaded directly into an injection loop and purified using
preparative HPLC/MS to yield the final compound.
5
6
7
8
9
Y. Wang, K. Sarris, D. R. Sauer, S. W. Djuric, Tetrahedron Lett.
2
007, 48, 5181–5184.
Y. Wang, K. Sarris, D. R. Sauer, S. W. Djuric. Tetrahedron Lett.
007, 48, 2237–2240.
Y. Wang, D. R. Sauer, S. W. Djuric, Tetrahedron Lett. 2005,
, 105–108.
General Procedure for Monocyclic Triazole Formation.
2
A stock solution of carboxylic and DIPEA (0.60 M and 1.8 in
DMA, respecitvely, 166.7 μL, 0.10 mmol carboxylic acid (1.0
eq) and 0.3 mmol DIPEA (3.0 eq)) and HATU (0.50 M in DMA,
4
7
N. P. Tu, P. A. Searle, K. Sarris, J. Lab. Automation, 2015, in
press.
Select reviews on flow chemistry: D. T. McQuade, P. H.
Seeberger, J. Org. Chem. 2013, 78, 6384-6389. J. C. Pastre, D.
L. Browne, S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849–8869. J.
200 μL, 0.10 mmol, 1.0 eq) were aspirated from their
respective source vials, mixed through a PFA mixing tube (0.2
mm inner diameter), and loaded into an incubation chamber
held at 30 °C for 5 minutes. The reaction segment was mixed
with a stock solution of hydrazonamide (0.60 M, 166.7 μL, 0.10
mmol, 1.0 eq), loaded into an injection loop for one minute,
followed by injection into the flow reactor (Hastelloy coil, 0.75
mm inner diameter, 1.8 mL internal volume) set at 175 °C, and
Wegner, S. Ceylan, A. Kirschning, Chem. Commun. 2011, 47,
583−4592. B. P. Mason, K. E. Price, J. L. Steinbacher, A. R.
4
Bogdan, D. T. McQuade, Chem. Rev., 2007, 107, 2300–2318.
Microreactors in Organic Synthesis and Catalysis (Ed.: T.
Wirth),Wiley-VCH, Weinheim, 2008. V. Hessel, P. Lob, H.
Lowe, Curr. Org. Chem. 2005,
Chem. Eng. Technol. 2005, 28, 267. B. Ahmed-Omer, J. C.
Brandt, T. Wirth, Org. Biomol. Chem. 2007, , 733.
0 J. E. Hochlowski, P. A. Searle, N. P. Tu, J. Y. Pan, S. G.
Spanton, S. W. Djuric, J. Flow Chem. 2011, , 56-61.
9, 765. V. Hessel, H. Lowe,
-1
passed through the reactor at 163 μL min (11 minute
residence time) pressurized to 1000 psi using a back-pressure
regulator. Upon exiting the reactor, the reaction was loaded
5
1
2
directly into an injection loop and purified using preparative 11 J. D. Sutherland, N. P. Tu, T. A. Nemcek, P. A. Searle, J. E.
Hochlowski, S. W. Djuric, J. Y. Pan, Journal of Laboratory
HPLC/MS to yield the final compound.
Automation, 2014, 19, 176-182.
2 A. R. Bogdan, N. W. Sach, Adv. Synth. Catal. 2009, 351
49−854.
3 C. M. Thompson, J. L. Poole, J. L. Cross, I. Akritopoulou-Zanze,
S. W. Djuric, Molecules 2011, 16, 9161−9177.
4 P. P. Lange, A. R. Bogdan, K. James, Adv. Synth. Catal., 2012,
1
1
1
1
,
General Procedure for Bicyclic Triazole Formation.
8
A stock solution of carboxylic and DIPEA (0.60 M and 1.8 in
DMA, respecitvely, 166.7 μL, 0.10 mmol carboxylic acid (1.0
eq) and 0.3 mmol DIPEA (3.0 eq)) and HATU (0.50 M in DMA,
354, 2373-2379.
5 A. R. Bogdan, K. James, Chem. Eur. J. 2010, 16, 14506
−14512.
2
00 μL, 0.10 mmol, 1.0 eq) were aspirated from their 16 A. R. Bogdan, K. James, Org. Lett. 2011, 13, 4060−4063.
1
1
1
7 N. Hawbaker, E. Wittgrove, B. Christensen, B., N. W. Sach, D.
G. Blackmond, Org. Process Res. Dev. 2015, ASAP.
8 The compounds per hour rate is limited by the preparative
HPLC method. A standard HPLC method is 10 minutes long.
9 On average, libraries are run using 15-20 mg of core per
reaction.
respective source vials, mixed through a PFA mixing tube (0.2
mm inner diameter), and loaded into an incubation chamber
held at 30 °C for 5 minutes. The reaction segment was mixed
with a stock solution of 2-hydrazinopyridine (0.60 M, 166.7 μL,
0.10 mmol, 1.0 eq), loaded into an injection loop for one
2
2
0 P. P. Lange, K. James, ACS Comb. Sci. 2012, 14, 570-578.
1 D. Grant, R. Dahl, N. D. P. Cosford, Org. Chem., 2008, 73
219-7223.
2 Dimethylacetamide (DMA) was chosen as the reaction
solvent due to the high solubility of compounds and due to
its compatibility with the integrated purification.
minute, followed by injection into the flow reactor (Hastelloy
coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at
,
7
-1
250 °C, and passed through the reactor at 90 μL min (20
2
minute residence time) pressurized to 1000 psi using a back-
pressure regulator. Upon exiting the reactor, the reaction was
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