Letter pubs.acs.org/OrgLett
Synthesis of Substituted Cyclopropanecarboxylates via Room Temperature Palladium-Catalyzed α‑Arylation of Reformatsky Reagents Stephen N. Greszler,* Geoff T. Halvorsen, and Eric A. Voight Centralized Lead Optimization − Discovery Chemistry & Technology, AbbVie, Inc., 1 N. Waukegan Road, North Chicago, Illinois 60064, United States S Supporting Information *
ABSTRACT: The room temperature palladium-catalyzed cross-coupling of aromatic and heteroaromatic halides with Reformatsky reagents derived from 1-bromocyclopropanecarboxylates provides an exceptionally mild method for enolate αarylation. The method is tolerant of a wide range of functionalities and dramatically shortens many of the existing routes to access widely used 1,1-disubstituted cyclopropanecarboxylate derivatives.
T
elaborate molecules (Scheme 1). Commonly employed methods include Corey−Chaykovsky cyclopropanation3a,d,4 and fre-
he ubiquity of the cyclopropane moiety renders it a frequent target for both traditional synthetic chemists, who take advantage of its unique steric and electronic properties,1 and medicinal chemists, who further appreciate its enhanced metabolic stability and molecular rigidity over unsubstituted methylene units.1a−d,2 Common among bioactive compounds, 1,1-disubstituted cyclopropanecarboxylate derivatives have received significant attention from the synthetic community and pharmaceutical industry. Recent targets of interest containing this structural motif include EP4 antagonist 1,3a milnacipran 2, a serotonin−norepinephrin reuptake inhibitor,3b NPY Y5 receptor ligand 3,3c and NK1 receptor antagonist 43d (Figure 1). Synthetic methods to access 1-arylcyclopropane esters and their derivatives often rely on lengthy sequences with limited functional group compatibility. Their incorporation into structure−activity relationship studies is also frequently challenged by the requirement for strongly basic conditions that complicate the late-stage introduction of these units into
Scheme 1. Synthetic Approaches to Arylcyclopropylesters
quently low-yielding bis-α-alkylations of phenylacetic acid derivatives (Scheme 1, eq 1).5 Recently, a palladium-catalyzed coupling of cyclopropylnitriles with aryl bromides was reported that allows efficient access to the corresponding 1,1-disubstituted cyclopropanes (Scheme 1, eq 2).6 While providing rapid entry into this class of substrates, significant limitations arise from the reaction conditions (LiHMDS, 80 °C), which preclude the use of base-sensitive functionalities. Particularly limited utility with heteroaromatic substrates has been demonstrated. Furthermore, the analogous couplings with ester enolates, while potentially more synthetically useful, reportedly failed to afford the desired products after extensive screening,6 and thus a general and mild method to directly access this subset of 1,1,-disubstituted cyclopropanes is still unknown.7,8 Based on these limitations, Figure 1. Pharmaceutically relevant 1,1-disubstituted cyclopropanecarboxylate derivatives. © 2017 American Chemical Society
Received: March 9, 2017 Published: May 1, 2017 2490
DOI: 10.1021/acs.orglett.7b00707 Org. Lett. 2017, 19, 2490−2493
Letter
Organic Letters we identified an opportunity to significantly expand the synthetic accessibility of 1-arylcyclopropane carboxylates, substrates that serve as precursors to the widely utilized primary amines through Curtius rearrangement,5a,9 as obvious coupling partners in amide ligation, and as viable substrates in recent C−H activation methodologies.10 We speculated that a Negishi coupling of aryl halides with a Reformatsky reagent11 derived from α-bromo and α-cyclopropylesters might offer a general entry into the corresponding 1,1-disubstituted cyclopropanes. Organozinc reagents offer many attractive features in cross-coupling methodology, including low basicity and high functional group compatibility, which enhance their utility in reactions with complex molecules.12 Nevertheless, at the outset of this work, we were surprised to discover only two known reports of the arylation of α-cyclopropylester enolates, which were both limited in scope to iodide coupling partners and employed elevated temperatures (95 or 65 °C).7e,f Nishii’s report of a diastereoselective coupling of aryl and styrenyl iodides with Reformatsky reagents bearing phenyl or fused cyclohexyl substitution on the cyclopropane ring was an important demonstration of the potential utility of this coupling stragtegy;7f however, an expansion of the analogous coupling to aryl bromides and heteroaromatic substrates has not been reported. Examples of cross-couplings within the broader class of tertiary cyclopropylzinc reagents are similarly sparse.13 Herein, we report a general and rapid room temperature palladium-catalyzed direct arylation of these Reformatsky reagents in THF that exhibits excellent tolerance of base-sensitive coupling partners and high yields with wide functional group compatibility. We first investigated the direct insertion of zinc into commercially available 5a. Activation of zinc dust with bromine,14 followed by heating to 60 °C in THF, reliably afforded the corresponding Reformatsky reagent 6a. We also observed facile insertion of zinc into benzyl and tert-butyl derivatives 5b and 5c, which can be synthesized in two steps from commercial 2,4dibromobutyryl chloride.15 We were pleased to discover in our initial attempts that complete conversion and nearly quantitative yield were achieved in less than 5 min at rt when a cross-coupling between the Reformatsky reagent 6a and methyl 4-bromobenzoate was performed using 2 mol % of Pd(dba)2 and 2 mol % of Q-Phos7a in THF (Scheme 2).
Table 1. Deviation from Standard Conditions
entry
deviation from std. cond.
time (min)/yield (%)a,b
1 2 3 4 5 6 7 8 9 10
none Pd(dba)2/Q-Phos (0.5 mol %) Pd(dba)2/Q-Phos (0.1 mol %) Pd2(dba)3 (1 mol %)/Q-Phos (2 mol %) Pd(OAc)2/Q-Phos (2 mol %) Pd(dba)2/Xantphos (2 mol %) Pd(dba)2/BINAP (2 mol %) Pd(dppf)Cl2 (2 mol %) [t-Bu3PPdBr]2 (2 mol %) 1.1 equiv of 6a
