A number of amine and phosphorus ligands were investigated (Entries 4–9), 12 among which TMEDA 9a, 9b, 13 (40 mol %) provided the highest yields of 2 a using either a standard Grignard reagent (PMPBr/Mg, 86 %, Entry 8), or the turbo-Grignard (PMPBr/Mg/LiCl, 79 %, Entry 9). Notably, no reaction was seen using Cu(acac) 2 (Entry 3).
Our studies began with the coupling of iodo-BCP 1 a with p-methoxyphenylmagnesium bromide (1.6 equiv, 0.7 mL h −1), which afforded small amounts of coupled product 2 a using Fe(acac) 3 or FeCl 3 (20 mol %) as catalyst (Table 1, Entries 1, 2) the main byproduct was the dehalogenated BCP 3. 11 The chemistry proceeds under mild conditions and short reaction times, displays wide functional group tolerance, and is applicable to the synthesis of drug-like molecules. Here we describe the development of iron-catalyzed cross-coupling reactions of iodo-BCPs with both aryl and heteroaryl Grignard reagents, which represents the first general procedure for the direct cross-coupling of iodo-BCP electrophiles. While isolated examples of Fe-catalyzed Kumada couplings of tertiary alkyl bromides and chlorides have been described, 9d, 10 the equivalent reaction of tertiary iodides is, to our knowledge, unknown. Iron-catalyzed Kumada cross-couplings of aryl Grignard reagents with secondary alkyl iodides are an efficient means to achieve sp 3–sp 2 C−C bond formation, 9 and we questioned whether the tertiary iodide resident in an iodo-BCP could engage in this coupling manifold. We targeted an alternative, catalytic method to access all-carbon disubstituted BCPs ( 2, Figure 1 c) directly from iodo-BCPs 1, under mild conditions and without recourse to organolithium reagents. 1e, 4a However, the conditions needed for lithiation of the iodo-BCP again limit scope and scalability. 7 As direct palladium-catalyzed cross-coupling of iodo-BCPs can suffer from competing ring fragmentation, 8 approaches to all-carbon disubstituted BCPs from iodo-BCPs have to date necessitated lithiation of the iodide, followed by cross-coupling as the nucleophilic component (Figure 1 b, or reaction with other carbon-based electrophiles). We recently described efficient and functional group-tolerant conditions to access these compounds by atom transfer radical addition of C–I bonds to propellane, under photoredox catalysis 6 or using triethylborane as initiator. 1e, 4a, 5 While such methods can generate useful products, the harsh conditions required to achieve the initial nucleophilic addition limit the suitability of this chemistry for industrial applications.Ī) Examples of bicyclopentanes (BCPs) in medicinal chemistry b) known cross-coupling of metallated BCPs c) this work: Direct iron-catalyzed cross-coupling of iodo-BCPs with aryl/ heteroaryl Grignard reagents.ġ-Iodobicyclopentanes (iodo-BCPs, 1) are attractive substrates for the introduction of carbon substituents on the BCP skeleton.
These challenges have inspired the development of a number of methods to synthesize 1,3- C-disubstituted BCPs in which installation of the carbon substituents relies on addition of an organometallic nucleophile to the strained C1–C3 σ-bond of propellane, 1e, 4 followed by palladium-catalyzed cross-coupling of the resulting metallated BCP (Figure 1 b).
2 However, access to promising BCP-bearing compounds 2b, 3 can be impeded by lengthy and unscalable reaction sequences, in particular where two carbon substituents are required. 1 Incorporation of these sp 3-rich motifs into drug leads often results in pharmacological benefits such as improved solubility, membrane permeability and metabolic stability. 1,3-Disubstituted bicyclopentanes (BCPs) are of high interest in drug discovery as bioisosteres for 1,4-disubstituted arenes and alkynes (Figure 1 a).
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