Site-selective Suzuki-Miyaura coupling of heteroaryl halides - understanding the trends for pharmaceutically important classes

Abstract

Suzuki-Miyaura cross-coupling reactions of heteroaryl polyhalides with aryl boronates are surveyed. Drawing on data from literature sources as well as bespoke searches of Pfizer's global chemistry RKB and CAS Scifinder® databases, the factors that determine the site-selectivity of these reactions are discussed with a view to rationalising the trends found.

Scheme 1. The Handy and Zhang method for site-selectivity prediction based on the ¹H NMR δ _H values for the corresponding non-halogenated heteroarenes – as applied to (a) 2,3-, (b) 3,4-, and (c) 2,4-dibromopyrroles, the last of which displays solvent dependent selectivity.^,

Fig. 1. Houk's ‘distortion–interaction’ DFT approach to computationally predicting the most favourable position for OA by bis-ligated Pd-catalysts in heteroaryl polyhalides.

Fig. 2. The Houk ‘distortion–interaction’ DFT approach to site-selectivity prediction – as applied to (a) benzofuran 8, (b) furan 9 and (c) isothiazole 10.

Scheme 2. The site-selectivity of SMC reactions can be determined by substituents: e.g. (a) 3,6-dichloropyrimidines containing 1°, 2° or 3° amine substituents at C4 (11a–c) generally react at C3, but (b) when the C4 substituent is non-basic (13a–c) reaction is at C6 presumably for steric reasons.

Scheme 3. Carboxylic ester, -amide and -acid modulation of site-selectivity: e.g. 2,6-dichloro nicotinic acid (18) and its derivatives can undergo SMC reactions at C2 or C6 selectively depending on the conditions (a–d).

Scheme 4. A subtle interplay of steric and electronic factors can control SMC reaction site-selectivity: e.g. (a) methyl 1,4-ditrifloxy phenyl-2-carboxylate (21) and (b) phenyl 1,4-ditrifloxynaphthalene-2-carboxylate (23) undergo SMC at C4 and C1 respectively.^,

Scheme 5. Ligand-dependent site-selectivity: e.g. 3,5-dichloropyridazine 25 undergoes SMC (a) at C3 with Pd(OAc)₂/dppf, (→ 26) and (b) at C5 with Pd(OAc)₂/Qphos (→ 27).

Scheme 6. Ligand-dependent site-selectivity: (a) 2,4-diiodooxazole, (b) 2,5-dibromoimidazole, (c) 2,4-dibromoimidazole, and (d) 2,4- and 2,5-dibromothiazoles.

Scheme 7. Control of site-selectivity in the SMC reaction of 4-trifloxychlorobenzene (36) according to the conditions: (a) ligand,^, and (b) solvent control.

Scheme 8. The BDE of the C–Hal bond clearly influences the site of SMC reaction for pyridine derivatives: e.g. (a) 5-bromo-2-chloropyridine (39), and (b) 2-bromo-3-iodopyridine (41) undergo SMC at C5 (→ 40) and C3 (→ 42) respectively.

Scheme 9. The high intrinsic electrophilicity of certain ring positions (e.g. C2 in quinoxalines and quinazolines) can perturb the BDE sufficiently to override the usual ArBr > ArCl order of reactivity: e.g. (a) 6-bromo-2-chloroquinoxaline (43), and (b) 6-bromo-2-chloro-8-fluoroquinazoline (45) undergo SMC at C2.^,

Scheme 10. The intrinsic electrophilicity of C1 in isoquinolines is sufficient to override the usual ArBr > ArCl order of halide reactivity for (a) 1-chloro-5-bromoisoquinoline (47), and (b) 1,3-dichloro-6-bromoisoquinoline (49), but not for (c) 1-chloro-3-tert-butyl-6-bromoisoquinoline (51), or (d) 1-chloro-7-bromoisoquinoline (53a) or 1,4-dichloro-7-bromoisoquinoline (53b).

Scheme 11. The intrinsic electrophilicity of C2 in quinolines is sufficient to override the usual ArBr > ArCl order of halide reactivity e.g. for (a) 2,4-dichloro-8-bromo-7-methoxyquinoline (55), but 2-chloro-6-bromoquinoline (57) can react (b) at C2 (→ 58) using Pd(PPh₃)₄, or (c) at C6 (→ 59) using Pd(dppf)Cl₂, and 2-chloro-7-bromo-5-isopropylquinoline reacts at C7 (60 → 61).

Scheme 12. The site-selectivity for SMC reactions of 2-(4-bromophenyl)-5-chloropyrazine (62) are ligand-dependent: it undergoes SMC (a) at C2 with Pd(Xantphos®)Cl₂ (→ 63) and (b) at C4′ with Pd(Qphos)₂ (→ 64).

Fig. 3. Coupling outcomes for pyridines.

Scheme 13. (a) 2-Bromo-3-iodopyridine undergoes SMC reactions at C3 (41 → 65), and (b) 2-chloro-3,4-diiodopyridine reacts at C4 then C3 then C2 (66 → 67).^,,

Scheme 14. (a) A 3-CF₃ group directs OA of 2,6-dichloropyridine to C2 (68 → 69), whereas (b) reaction occurs at C4 in the benzene analogue (70 → 71).

Fig. 4. Coupling outcomes for pyridazines, pyrimidines and pyrazines.

Scheme 15. Example of SMC reaction of 3,5-dichloropyridazine at C3, (25 → 72) from Pfizer RKB.

Scheme 16. 3-Chloro-5-bromo-6-phenylpyridazine undergoes SMC reaction at C5 (73 → 74).

Scheme 17. 5-Bromo-2-chloropyrimidine undergoes SMC at C5 (75 → 76).

Scheme 18. A 3-OMe group directs OA of 2,5-dibromopyrazine to C2 (77 → 78).

Fig. 5. Coupling outcomes for pyrroles, furans and thiophenes.

Scheme 19. A methyl ester at C2 directs OA of 3,4-dibromopyrrole to C3 (79 → 80).

Scheme 20. A 3-ethoxycarbonyl group directs OA of 3,4-dibromofuran to C5 (81 → 82).

Scheme 21. A 3-alkyl group directs OA of 2,5-dibromothiophene to C5 (83 → 84).

Fig. 6. Coupling outcomes for imidazoles, pyrazoles, (is)oxazoles and (iso)thiazoles.

Fig. 7. Coupling outcomes for quinolines.

Scheme 22. (a) 2-Bromo-4-iodoquinoline undergoes SMC at C4 (85 → 86), and (b) 3,4-dichloro-7-bromoquinoline reacts at C7 (87 → 88).

Fig. 8. Coupling outcomes for isoquinolines.

Scheme 23. 4,7-Dibromo-1-chloroisoquinoline undergoes SMC at C7 (89 → 90).

Fig. 9. Coupling outcomes for benzodiazines.

Scheme 24. 6-Bromo-2,4-dichloroquinazoline undergoes SMC at C4 (91 → 92).

Fig. 10. Coupling outcomes for indoles, benzoxazoles, benzothiazoles and benzodiazoles.

Scheme 25. A 3,5,7-trichlorobenzothiophene undergoes SMC at C3 (93 → 94).

Scheme 26. 6-Bromo-3-iodo-1-H-indazole undergoes SMC at C3 (95 → 96).

Fig. 11. Coupling outcomes for azaquinolines and azaisoquinolines.

Scheme 27. A SMC reaction of 3,7-dibromo-5-azaquinoline with pinacolatoborane (97 → 98).