Organic Process Research & Development
Article
30 °C for 6 h. The reaction was quenched by exposure to air,
and the solvent was removed in vacuo. Purification via flash
column chromatography (C18) yielded the cross-coupled
product.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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sı
Heterogeneous Flow Conditions. A reaction solution
was prepared using methyl-(R)-4-bromo-3-((tert-
butoxycarbonyl)amino)butanoate (635 g, 2.25 mmol, 1.5
equiv), Ir[dF(CF3)ppy]2(dtbbpy) (17 mg, 0.015 mmol, 1
mol %), 4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl)benzenesulfonamide (669 g, 1.5 mmol, 1 equiv),
lutidine (0.35 mL, 3 mmol, 2 equiv), tris(trimethylsilyl)silane
(0.7 mL, 2.25 mmol, 1.5 equiv), Ni(OAc)2·4H2O (3.7 mg,
0.015 mmol, 0.01 equiv), and 4,4′-di-tert-butyl-2,2′-bipyridine
(4 mg, 0.015 mmol, 0.01 equiv). The reaction components
were dissolved in DME (3 mL, 0.5 M), sonicated until
homogeneous, and degassed via nitrogen sparging for 20 min.
The reaction mixture was pumped through a 2 mL reactor coil
(internal diameter 2.0 mm) for 30 min (0.1 mL/min, 20 min
residence time) at 30 °C under irradiation from an 18 W 385
nm LED lamp. After the reaction was complete, the reaction
mixture was diluted with ethyl acetate and washed with water
and brine. The organic phase was dried with sodium sulfate
and filtered, and the solvent was removed in vacuo. Purification
via column chromatography yielded the pure product as a
white solid (700 mg, 80% yield).
Experimental methods, characterization data and spectra
of all isolated compounds, and optimization details of
AUTHOR INFORMATION
Corresponding Author
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David W. C. MacMillan − Merck Center for Catalysis at
Princeton University, Princeton, New Jersey 08544, United
Authors
Tomer M. Faraggi − Merck Center for Catalysis at Princeton
University, Princeton, New Jersey 08544, United States
Caroline Rouget-Virbel − Merck Center for Catalysis at
Princeton University, Princeton, New Jersey 08544, United
States
Juan A. Rincón − Centro de Investigación Eli Lilly,
Mario Barberis − Centro de Investigación Eli Lilly,
Alcobendas-Madrid 28108, Spain
Homogeneous Flow Conditions. A reaction solution was
prepared using methyl-(R)-4-bromo-3-((tert-butoxycarbonyl)-
amino)butanoate (7.62 g, 27 mmol, 1.5 equiv), Ir[dF(CF3)-
ppy]2(dtbbpy) (202 mg, 0.18 mmol, 1 mol %), 4-(5-(4-
bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-
benzenesulfonamide (8 g, 18 mmol, 1 equiv), lutidine (4.2 mL,
36 mmol, 2 equiv), tris(trimethylsilyl)silane (8.33 mL, 27
mmol, 1.5 equiv), Ni(OAc)2·4H2O (45 mg, 0.18 mmol, 0.01
equiv), and 4,4′-di-tert-butyl-2,2′-bipyridine (48 mg, 0.18
mmol, 0.01 equiv). The reaction components were dissolved
in DMA (90 mL, 0.2 M), sonicated until homogeneous, and
degassed via nitrogen sparging for 20 min. The reaction
mixture was pumped through a 10 mL reactor coil (internal
diameter 2.0 mm) for 8 h (0.225 mL/min, 45 min residence
time) at 40 °C under irradiation from an 18 W 385 nm LED
lamp. After the reaction was complete, the reaction mixture
was diluted with ethyl acetate and washed with water and
brine. The organic phase was dried with sodium sulfate and
filtered, and the solvent removed in vacuo. Purification via
column chromatography yielded the pure product as a white
solid (6 g, 60% yield).
Carlos Mateos − Centro de Investigación Eli Lilly, Alcobendas-
Madrid 28108, Spain
Susana García-Cerrada − Centro de Investigación Eli Lilly,
Alcobendas-Madrid 28108, Spain
Javier Agejas − Centro de Investigación Eli Lilly, Alcobendas-
Madrid 28108, Spain
Oscar de Frutos − Centro de Investigación Eli Lilly,
Alcobendas-Madrid 28108, Spain
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors are grateful for financial support provided by the
National Institute of General Medical Sciences (NIGMS), the
NIH (under Award R35GM134897-01), the Princeton
Catalysis Initiative, and kind gifts from Eli Lilly, Merck,
Janssen, BMS, Genentech, Celgene, and Pfizer. T.M.F.
acknowledges Princeton University, E. Taylor, and the Taylor
family for an Edward C. Taylor Fellowship. This work was
supported by Eli Lilly and Company through the Lilly
Research Award Program (LRAP).
Methyl-(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-(4-sul-
famoylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-
1
propanoate (60): H NMR (500 MHz, CDCl3): δ 7.94−7.87
(m, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.15 (s, 4H), 6.76 (s, 1H),
5.03 (d, J = 8.4 Hz, 1H), 4.90 (d, J = 20.5 Hz, 2H), 4.60 (d, J =
7.3 Hz, 1H), 3.72 (d, J = 4.9 Hz, 3H), 3.10 (ddd, J = 69.8,
13.8, 6.0 Hz, 2H), 1.42 (s, 9H). 13C NMR (126 MHz, CDCl3):
δ 172.17, 155.14, 144.93, 142.49, 141.65, 138.21, 130.14,
129.11, 127.65, 125.62, 106.62, 80.35, 60.57, 54.43, 52.58,
38.45, 28.42, 21.21, 14.33. HRMS (ESI-TOF) m/z calcd for
C25H27F3SN4NaO6 ([M + Na]+), 591.1501; found, 591.1486.
IR (film): λ(max) 2980, 1700, 1500, 1368, 1238, 1163, 976, 739
cm−1 Chiral HPLC OJ column, 20% IPA/hexanes, 1.0 mL/
min, >99% ee, tR(minor) = 9.22 min, tR(major) = 24.74 min.
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