Organic Process Research & Development
Article
complexes as catalysts for vinylic hydrogen substitution reactions. J.
Am. Chem. Soc. 1974, 96, 1133.
(15) Hunt, A. R.; Stewart, S. K.; Whiting, A. Heck versus Suzuki
palladium catalysed cross-coupling of a vinylboronate ester with aryl
halides. Tetrahedron Lett. 1993, 34, 3599.
(
3) (a) de Meijere, A.; Meyer, F. E. Fine Feathers Make Fine Birds:
The Heck Reaction in Modern Garb. Angew. Chem., Int. Ed. Engl.
995, 33, 2379. (b) Whitcombe, N. J.; Hii, K.; Gibson, S. Advances in
the Heck chemistry of aryl bromides and chlorides. Tetrahedron 2001,
7, 7449. (c) Littke, A.; Fu, G. Palladium-Catalyzed Coupling
Reactions of Aryl Chlorides. Angew. Chem., Int. Ed. 2002, 41, 4176.
d) Jagtap, S. Heck ReactionState of the Art. Catalysts 2017, 7, 267.
4) Beletskaya, I. P.; Cheprakov, A. V. The Heck Reaction as a
Sharpening Stone of Palladium Catalysis. Chem. Rev. 2000, 100, 3009.
5) Jutand, A.; Mosleh, A. Rate and Mechanism of Oxidative
(16) (a) Camp, D.; Matthews, C. F.; Neville, S. T.; Rouns, M.; Scott,
R. W.; Truong, Y. Development of a Synthetic Process towards a
Hepatitis C Polymerase Inhibitor. Org. Process Res. Dev. 2006, 10, 814.
(b) Schils, D.; Stappers, F.; Solberghe, G.; Heck, R. V.; Coppens, M.;
Van den Heuvel, D.; Van der Donck, P.; Callewaert, T.; Meeussen, F.;
De Bie, E.; Eersels, K.; Schouteden, E. Ligandless Heck Coupling
between a Halogenated Aniline and Acrylonitrile Catalyzed by Pd/C:
Development and Optimization of an Industrial-Scale Heck Process
for the Production of a Pharmaceutical Intermediate. Org. Process Res.
Dev. 2008, 12, 530.
1
5
(
(
(
Addition of Aryl Triflates to Zerovalent Palladium Complexes.
Evidence for the Formation of Cationic (σ-Aryl)palladium Com-
plexes. Organometallics 1995, 14, 1810.
(17) Bosse, F.; Das, P.; Belfiore, L. A. Annealing Effects on the Solid
́
State Properties of Transition-Metal Coordination Complexes and
Networks Based on Diene Polymers with Palladium Chloride. J.
Polym. Sci., Part B: Polym. Phys. 1996, 34, 909.
(6) Fu, X.; Zhang, S.; Yin, J.; McAllister, T. L.; Jiang, S. A.; Tann, C.-
H.; Thiruvengadam, T. K.; Zhang, F. First examples of a tosylate in
the palladium-catalyzed Heck cross coupling reaction. Tetrahedron
Lett. 2002, 43, 573.
(18) Blackmond, D. G.; Rosner, R.; Pfaltz, A. Comprehensive
Kinetic Screening of Catalysts Using Reaction Calorimetry. Org.
Process Res. Dev. 1999, 3, 275.
(7) Hansen, A. L.; Skrydstrup, T. Regioselective Heck Couplings of
α,β-Unsaturated Tosylates and Mesylates with Electron-Rich Olefins.
Org. Lett. 2005, 7, 5585.
(19) The choice of amine can dramatically affect the fate of the
reaction. For additional information, see: Singer, R. A. Commercial
Development of Axitinib (AG-013736): Optimization of a Con-
vergent Pd-Catalyzed Coupling Assembly and Solid Form Challenges.
Transition Metal-Catalyzed Couplings in Industry, Case Studies from the
Pharmaceutical Industry; Magano, J., Dunetz, J., Eds.; Wiley: 2013, p
(8) Kikukawa, K.; Matsuda, T. Reaction of diazonium salts with
transition metals, I. Arylation of olefins with arenediazonium salts
catalyzed by zero valent palladium. Chem. Lett. 1977, 6, 159.
(
9) (a) Ozawa, F.; Kubo, A.; Hayashi, T. Catalytic asymmetric
arylation of 2,3-dihydrofuran with aryl triflates. J. Am. Chem. Soc.
991, 113, 1417. (b) Dounay, A. B.; Overman, L. E. The asymmetric
1
(
65.
1
20) While this addition sequence is optimal for our calorimetry
intramolecular Heck reaction in natural product total synthesis. Chem.
Rev. 2003, 103, 2945. (c) McCartney, D.; Guiry, P. J. The asymmetric
Heck and related reactions. Chem. Soc. Rev. 2011, 40, 5122.
studies, it will cause accumulation of reactive chemicals and thus
should be avoided for scale-up.
(21) (a) Bollyn, M. DMSO Can Be More than a Solvent: Thermal
(
10) Colacot, T. J. The 2010 Nobel Prize in Chemistry: Palladium-
Catalysed Cross-Coupling. Platinum Met. Rev. 2011, 55, 84.
11) (a) Beller, M.; Zapf, A.; Magerlein, W. Efficient Synthesis of
Analysis of Its Chemical Interactions with Certain Chemicals at
Different Process Stages. Org. Process Res. Dev. 2006, 10, 1299.
(
̈
(b) Wang, Z.; Richter, S. M.; Gates, B. D.; Grieme, T. A. Safety
Fine Chemicals and Organic Building Blocks Applying Palladium-
Concerns in a Pharmaceutical Manufacturing Process Using Dimethyl
Sulfoxide (DMSO) as a Solvent. Org. Process Res. Dev. 2012, 16, 1994.
Catalyzed Coupling Reactions. Chem. Eng. Technol. 2001, 24, 575.
(b) de Vries, J. G. The Heck reaction in the production of fine
(c) Wang, Z.; Richter, S. M.; Bellettini, J. R.; Pu, Y. M.; Hill, D. R.
chemicals. Can. J. Chem. 2001, 79, 1086. (c) Prashad, M. Palladium-
Catalyzed Heck Arylations in the Synthesis of Active Pharmaceutical
Ingredients. Top. Organomet. Chem. 2004, 6, 181. (d) Farina, V. High-
Turnover Palladium Catalysts in Cross-Coupling and Heck
Chemistry: A Critical Overview. Adv. Synth. Catal. 2004, 346, 1553.
Safe Scale-Up of Pharmaceutical Manufacturing Processes with
Dimethyl Sulfoxide as the Solvent and a Reactant or a Byproduct.
Org. Process Res. Dev. 2014, 18, 1836. (d) Yang, Q.; Cabrera, P. J.; Li,
X.; Sheng, M.; Wang, N. X. Safety Evaluation of the Copper-Mediated
Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroace-
tate. Org. Process Res. Dev. 2018, 22, 1441.
(e) Hansen, M. M.; Kallman, N. J.; Koenig, T. M.; Linder, R. J.;
Richey, R. N.; Rizzo, J. R.; Ward, J. A.; Yu, H.; Zhang, T. Y.; Mitchell,
D. Double Heck Route to a Dibenzoxepine and Convergent Suzuki
Cross-Coupling Strategy for the Synthesis of an MR Antagonist. Org.
Process Res. Dev. 2017, 21, 208.
(22) Wang, Z.; Richter, S. M.; Rozema, M. J.; Schellinger, A.; Smith,
K.; Napolitano, J. G. Potential Safety Hazards Associated with Using
Acetonitrile and a Strong Aqueous Base. Org. Process Res. Dev. 2017,
2
(
1, 1501.
(12) (a) Yang, Q.; Ulysse, L. G.; McLaws, M. D.; Keefe, D. K.;
23) Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.;
Haney, B. P.; Guzzo, P. R.; Liu, S. Initial Process Development and
Scale-Up of the Synthesis of a triple reuptake inhibitor ALB109780.
Org. Process Res. Dev. 2012, 16, 499. (b) Venkatraman, S.; Tweedie,
S.; McLaws, M.; Lathbury, D. Continuous Flow Chemistry of Metal
Mediated Carboxylation and α-Arylation Reactions. ACS Symp. Ser.
Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W.
Critical Assessment of Pharmaceutical Processes-A Rationale for
Changing the Synthetic Route. Chem. Rev. 2006, 106, 3002.
(
24) Quantitative GC analysis was performed using acetophenone as
an internal standard.
25) (a) Curtiss, L. A.; Redfern, P. C.; Frurip, D. J. Theoretical
2
(
014, 1181, 441.
(
13) (a) Brown Ripin, D. H.; Bourassa, D. E.; Brandt, T.; Castaldi,
Methods for Computing Enthalpies of Formation of Gaseous
Compounds. Rev. Comput. Chem. 2007, 15, 147. (b) Boese, A. D.;
Oren, M.; Atasoylu, O.; Martin, J. M. L. W3 theory: Robust
computational thermochemistry in the kJ/mol accuracy range. J.
Chem. Phys. 2004, 120, 4129.
M. J.; Frost, H. N.; Hawkins, J.; Johnson, P. J.; Massett, S. S.;
Neumann, K.; Phillips, J.; Raggon, J. W.; Rose, P. R.; Rutherford, J. L.;
Sitter, B.; Stewart, A. M., III; Vetelino, M. G.; Wei, L. Evaluation of
Kilogram-Scale Sonagashira, Suzuki, and Heck Coupling Routes to
Oncology Candidate CP-724,714. Org. Process Res. Dev. 2005, 9, 440.
(26) (a) Ryberg, P. Development of a Highly Efficient Regio- and
(b) Houpis, I. N.; Shilds, D.; Nettekoven, U.; Schnyder, A.; Bappert,
E.; Weerts, K.; Canters, M.; Vermuelen, W. Utilization of Sequential
Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific
Synthesis of Trisubstituted Olefins. Org. Process Res. Dev. 2009, 13,
Stereoselective Heck Reaction for the Large-Scale Manufacture of an
α4β2 NNR Agonist. Transition Metal-Catalyzed Couplings in Industry,
Case Studies from the Pharmaceutical Industry; Magano, J., Dunetz, J.,
Eds.; Wiley: 2013, p 147. (b) Lipshutz, B. H. Applying the
Hydrophobic Effect to Transition Metal-Catalyzed Couplings in
Water at Room Temperature. Transition Metal-Catalyzed Couplings in
Industry, Case Studies from the Pharmaceutical Industry; Magano, J.,
Dunetz, J., Eds.; Wiley: 2013, p 299.
5
(
98.
14) Yang, Q.; Canturk, B.; Gray, K.; McCusker, E.; Sheng, M.; Li,
F. Evaluation of Potential Safety Hazards Associated with the Suzuki−
Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species.
Org. Process Res. Dev. 2018, 22, 351.
H
Org. Process Res. Dev. XXXX, XXX, XXX−XXX