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Negishi-Coupling Alcázar et al. developed a continuous flow procedure for the synthesis of organozinc reagents, which were then employed in the Negishi reaction.² The same group showed that the efficiency of nickel- and palladium-catalyzed Negishi reactions can be enhanced by irradiation with blue light.³ Below, we show an example where a Suzuki-coupling-hydrogenation sequence failed to give the desired product using classical methods, while the product was successfully isolated in 46% yield after a two-step one flow Negishi-coupling procedure. Reactor Constructions 3D printed photoreactors were assembled following a procedure from the Noel research group.⁹ The reactor for the synthesis of organozinc reagents is very similar to the one described in reference 2b. The tube-in-flask diazomethane generator is described in reference.⁸ Construction of C(sp²)-C(sp³) bonds is relatively difficult in comparison to C(sp²)-C(sp²) bonds. Recently, photoredox catalytic and other photochemical methodologies, together with technological achievements expanded the scope of C(sp²)-C(sp³) bond constructions.¹ Herein, we show how photochemical and general flow methodologies were employed in the synthesis of novel compounds (screening libraries and DEL building blocks) with high fsp3 content. Furthermore, we demonstrate the application of the Minisci reaction in the preparation of biologically active compounds. In the same project in situ generated diazomethane was used for the preparation of amino acid derivatives. Thiazoles and Pyrazoles Thiazoles and pyrazoles are among the most frequently utilized ring systems in small molecule drugs.⁴ Nevertheless, these structures have been scarcely utilized in Negishi-couplings. We have started a systematic investigation in this area to access building blocks for DNA-encoded libraries. The obtained α-heteroaryl acetates provide opportunity for derivatization both on the heteroaryl ring or at the acetate motif. Thiazoles Pyrazoles – where light matters Towards Amino Acid Analogues . A flow photochemical benzylic bromination was described by Kappe et al ⁵ The method is good yielding, scalable and the reaction proceeds in CH₃CN without the need for radical initiators. We surmised that similar treatment of α-heteroaryl acetates would provide α-bromo-α-heteroaryl acetates, and those would lead us to the synthesis of novel unnatural amino acids. Synthesis of Biologically Active Compounds One of our medicinal chemistry project focuses on the synthesis of biologically active compounds to target the treatment of high mortality tumor diseases. As depicted on the scheme our synthetic strategy relied on two key intermediates which were prepared through photoredox Minisci reaction and by homologation of amino acids, respectively. Minisci Reaction - Key Intermediate I. The Minisci reaction allows the introduction of an alkyl group into nitrogen heterocycles without the need for prefunctionalization.⁶ Traditional procedures require harsh reaction conditions and often provide low yields, however, photoredox Minisci reactions can be performed under mild conditions with good selectivity and improved yields.⁷ The Synthesis of α-halo Ketones - Key Intermediate II. Diazomethane is an explosive and toxic gas, and at the same time a useful methylating agent. The Kappe group described a tube-in-flask reactor in which safe handling of anhydrous diazomethane was realized, and a method for the synthesis of α-halo ketones was developed.⁸ We adapted Kappe’s procedure for the synthesis of dipeptides derived α-halo ketones. Conclusions • The Negishi reaction was successfully applied in cases where other methods failed. • The Negishi reaction between (2-ethoxy-2-oxoethyl)zinc(II) bromide and small heterocycles afforded α-heteroaryl acetates. These compounds provide an easy entry to further derivatization. • Key intermediates of novel biologically active compounds were accessed through photoredox Minisci reaction and through homologation of dipeptides with diazomethane. Acknowledgement We thank Dr. Doris Dallinger and Prof. Oliver Kappe for helpful discussions about diazomethane chemistry. We are grateful to our colleagues at ComInnex Inc. who provided assistance in some of the experimental work. The ComInnex Analytical Group is acknowledged for compound characterization support. This work is partly supported by Hungarian grant (National Research, Development and Innovation Office: National Competitiveness and Excellence Program, #NVKP16-1-2016-0036). References 1 (a) M. H. Shaw, J. Twilton, and D. W. C. MacMillan J. Org. Chem. 2016, 81, 6898-6926; (b) D. Cambié, C. Bottecchia, N. J. W. Straathof, V. Hessel, T. Noel Chem. Rev. 2016, 116, 10276-10341. 2 (a) N. Alonso, L. Z. Miller, J. de M. Munoz, J. Alcázar, D. T. McQuade Adv. Synth. Catal. 2014, 356, 3737-3741; (b) M. Berton, L. Huck, J. Alcázar Nat. Protoc. 2018, 13, 324-334. 3 (a) I. Abdiaj, A. Fontana, M. V. Gomez, A. de la Hoz, J. Alcázar Angew. Chem. Int. Ed. 2018, 57, 8473-8477; (b) I. Abdiaj, L. Huck, J. M. Mateo, A. de la Hoz, M. V. Gomez, A. Díaz-Ortiz, J. Alcázar Angew. Chem. Int. Ed. 2018, 57, 13231-13236. 4 R. D. Taylor, M. MacCoss, A. D. G. Lawson J. Med. Chem. 2014, 57, 5845–5859. 5 D. Cantillo, O. de Frutos, J. A. Rincon, C. Mateos, C. O. Kappe J. Org. Chem. 2014, 79, 223-229. 6 M. A. J. Duncton Med. Chem. Commun. 2011, 2, 1135-1161 7 (a) R. A. Garza-Sanchez, A. Tlahuext-Aca, G. Tavakoli, F. Glorius ACS Catal. 2017, 7, 4057-4061; (b) T. C. Sherwood, N. Li, A. N. Yazdani, T. G. M. Dhar J. Org. Chem. 2018, 83, 3000-3012. 8 D. Dallinger, O. Kappe Nat. Protoc. 2017, 12, 2138-2147. 9 X.-J. Wei, W. Boon, V. Hessel, T. Noel ACS Catal. 2017, 7, 7136-7140. Custom Chemistry Research www.cominnex.com Introduction NHBoc O OH Cl O O NHBoc O Cl 42% 1) TEA, THF 2) CH 2 N 2 generated from a) Diazald, DMF b) MeOH : H2O (1:2) HCl N H O H N Boc O 32% O N Boc H N O Cl 32% Cl Boc N H N O O Cl 33% Boc N H H N O O Cl 23% N S Ph EtO O N S Ph EtO O 290 mg (35%) N S EtO O Br PhB(OH) 2 CsF, Pd(dppf)Cl 2, 50 °C, THF N Boc O O N O O DCC (3 equiv) N-hydroxyphthalimide (3 equiv) DMAP (5 mol%), CzIPN (5 mol%) DMSO Blue LED (32 W) 30-34 °C, 32 h in situ N Boc O HO 700 mg, 80% N-Boc-proline (3 equiv) DCC (3 equiv) N-hydroxyphthalimide (3 equiv), DMAP (5 mol%), CzIPN (5 mol%) DMSO Blue LED (32 W) 30-34 °C, 32 h N Boc (3 equiv) N S Br EtO O N Boc N S X N S O OEt N S O OEt Br Pd(dba) 2 (5 mol%) X-Phos (10 mol%) THF, 30 °C R R N S O OEt X = Cl, 85% (23% isolated) OEt O BrZn + 2 equiv. X = Cl, 0% N S O OEt Cl N S O OEt Cl X = Br, 82% (44% isolated) X = Br, 71% (62% isolated) X = Br, 59% S N N S N S BocN X = Cl, >95% X = Cl, >95% Pd(dppf)Cl 2 (5 mol%) O OEt Organozinc reagents were prepared in flow Negishi couplings were performed in batch Catalyst: Pd(dba) 2 /X-Phos or Pd(dppf)Cl 2 Blue light irradiation did not influence the reaction Reactions times generally <1 h HPLC yields are given N HN X OEt O BrZn Pd(dba) 2 (5 mol%) X-Phos (10 mol%) THF, rt, blue LED + N HN OEt O X = I, 78% X = Cl, 0% 2 equiv. N N O OEt X = Br, >95% N HN OEt O X = Br 52% with light on (37% isolated) 22% without light Light irradiation has a positive effect Reaction times generally <1 h HPLC yields are given N S O OEt N S O OEt Br NBS (1.05 equiv.) CH 3 CN (0.5 M) 80 W CFL, 60 min N S O OEt Br Br + 1:0.3 0.92 mmol, 75%* * 60% corrected yield based on 1H NMR 0.71 mmol Br, 0.21 mmol diBr in 246 mg isolated material N S O OEt N N N S O OEt N N Boc K 2 CO 3 CH 3 CN D, 3 h N H N Boc DIPEA CH 3 CN rt, 3 h N S O OEt Br N H N 58% 66% N S R 1 R 2 N H N S R 1 R 2 N O R 3 H N R 4 H N R 3 O R 4 + Cl Intermediate I. Intermediate II. General structure of target compounds Boc N N N O OEt N N Cl O OEt Boc N ZnI Pd 2 (dba) 3 , X-Phos blue LED or Boc N I Zn LiCl THF 46% N N N O R 1 ca. 100 compounds N N O OEt Boc N N N Cl O OEt Boc N B O O PdCl 2 (PPh 3 ) 2 KF, H 2 O Dioxane, 100°C, on. + Pd(dba) 2 /X-Phos was found to be optimal Blue light irradiation did not influence the yield significantly 25 min residence time in flow 9 h flow process gave 3.64 g product after purification Batch and flow yields are similar, but flow is more practical for scale-up R 2 3.64 g 83% PHOTOCHEMISTRY AND FLOW TECHNOLOGY FOR EARLY PHASE DRUG DISCOVERY 1 1 1 1 1 2 1 Balázs Fődi, Gergő Ignácz, Anna Dávid, Ármin Szabolcs, Béla Bertók, Timothy Noel, Gellért Sipos 1 2 Cominnex Inc., Zahony u. 7., 1031 Budapest, Hungary Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands [email protected]
