摘要：Matthew T. Gill,[a]Lucy A. Tomczyk,[a]Andres R. Gomez-Angel,[a]James D. Firth,[a]David C. Blakemore,[b]John M. Humphrey,[b]Ricardo
转自：康龙化成
Synthesis of α-Aryl and α-Heteroaryl 4-Silyloxy Piperidines via a One-Pot Negishi Cross-Coupling Approach
Matthew T. Gill,[a] Lucy A. Tomczyk,[a] Andres R. Gomez-Angel,[a] James D. Firth,[a] David C. Blakemore,[b] John M. Humphrey,[b] Ricardo Lira,[b] and Peter O'Brien*[a]
[a] Department of Chemistry, University of York, York YO10 5DD, U.K.; [b] Medicine Design, Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340, USA
—Chem. Eur. J. 2025, 10.1002/chem.202500863
Recommended by Rui Jin
KEY WORDS: Negishi coupling,lithiation, α-arylation, Pd catalysis, diastereoselective (反应类型), C(sp2)-C(sp3)(成键类型), 4-substituted piperidines, aryl bromide (原料), α-Aryl and α-Heteroaryl 4-Silyloxy Piperidines (产物),one-pot approach, 2,4-cis-diastereoselectivity (其他)
ABSTRACT: The direct α-arylation of a protected 4-hydroxy piperidine via a one-pot Negishi cross-coupling reaction is described. The methodology uses a single solvent, toluene, for the lithiation / transmetallation / Negishi sequence and 20 examples are presented. Of note, the high-yielding cross-coupling of a range of pharmaceutically relevant heteroaryl bromides is reported. The reactions show high levels of 2,4-cis-diastereoselectivity and further functionalizations are also described. Piperidine is the most common nitrogen heterocycle in approved drugs and our approach delivers such heterocycles via a direct diastereoselective α-functionalization of 4-substituted N-Boc piperidines; as such, the approach is ready to be utilized in the pharmaceutical industry.
Background and this work
:
(A) Pharmaceutically relevant or naturally occurring 4-heteroatom-substituted 2-aryl piperidines.
(B) Lithiation / transmetallation / Negishi cross-coupling of TIPS- and TBS-protected 4-hydroxy N-Boc piperidines.
Conditions: (i) 6 (1.0 eq.), s-BuLi (1.3 eq.), TMEDA (1.3 eq.), -78 oC, toluene, 3 hours; (ii) ZnCl2 (1.3 eq.), THF, -78 oC, 30~60 minutes then rt, 30~60 minutes; (iii) ArBr (1.3 eq.), [Pd(allyl)Cl]2 (2.5 mol%), RuPhos (5 mol%), 100 oC, 16~18 hours.
Substrate scope: lithiation /
transmetallation / Negishi cross‐coupling of TBS‐protected 4‐hydroxy N‐Boc piperidine
Further functionalizations of 2,4‐disubstituted compounds (selected examples):
Summary and Comments:
In summary, Peter O'Brien et al have developed a practical method for the direct α-arylation of TBS-protected 4-hydroxy piperidine. For this, toluene was identified as the key solvent as it was compatible with all parts of the lithiation / transmetallation / Negishi arylation sequence. Of note, for the Negishi cross-coupling step, optimization of the palladium source and ligand allowed a range of pharmaceutically relevant nitrogen-containing heteroaryl bromides to be successfully cross-coupled. In total, the synthesis of 20 examples of 2,4-disubstituted 2-aryl- and 2-heteroaryl-substituted piperidines with excellent levels of 2,4-cis-diastereoselectivity are showcased. Further functionalizations of some of the products show additional potential utility of this methodology. Overall, our method delivers a much-needed simple and practical approach for the direct diastereoselective α-functionalization of 4-substituted N-Boc piperidines and the methodology is now ready to be deployed in drug discovery programs.
来源：新浪财经
