Synthesis of All‐Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron‐Catalyzed Kumada Cross‐Coupling

Abstract 1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo[1.1.1]pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues.

1,3-Disubstituted bicyclo[1.1.1]pentanes(BCPs) are of high interest in drug discovery as bioisosteres for 1,4disubstituted arenes and alkynes (Figure 1 a). [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. [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.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.
1-Iodobicyclo[1.1.1]pentanes(iodo-BCPs, 1) are attractive substrates for the introduction of carbon substituents on the BCP skeleton.We recently described efficient and functional group-tolerant conditions to access these compounds by atom transfer radical addition of C-I bonds to [1.1.1]propellane,under photoredox catalysis [6] or using triethylborane as initiator. [7]1e, 4a] However, the conditions needed for lithiation of the iodo-BCP again limit scope and scalability.
We targeted an alternative, catalytic method to access allcarbon disubstituted BCPs (2, Figure 1 c) directly from iodo-BCPs 1, under mild conditions and without recourse to organolithium reagents.Iron-catalyzed Kumada cross-couplings of aryl Grignard reagents with secondary alkyl iodides are an efficient means to achieve sp 3 -sp 2 C À C bond formation, [9] and we questioned whether the tertiary iodide resident in an iodo-BCP could engage in this coupling manifold.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.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. [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.
9i, 17] The formation of iron nanoparticles may also be observed, in particular under a "rapid addition" (of Grignard) regime. [18]13a] The presence of substoichiometric TMEDA is also clearly beneficial to reaction efficiency, [9j, 20] although its role is unclear given evidence that it may not be ligated to the metal during the coupling process. [21]17a, 24] When combined with our previous methods for iodo-BCP synthesis, the Kumada cross-coupling offers a powerful method for the mild and rapid generation of valuable, pharmaceutically-relevant 1,3-C-difunctionalized BCPs.To demonstrate potential utility, we targeted BCP analogues of the anti-inflammatory drug flurbiprofen, and the anti-neoplastic agent brequinar (Scheme 2 a).The requisite iodo-  BCPs 1 k and 1 i were synthesized in excellent yields from reaction of [1.1.1]propellanewith commercially available ethyl iodopropanoate 6 (80 %), and iodoquinoline 7 (85 %), [8] using Et 3 B initiation and photoredox catalysis (Ir(ppy) 3 /blue LEDs), respectively.Kumada cross-coupling of iodo-BCP ester 1 k with PhMgBr, followed by hydrolysis, furnished BCP-flurbiprofen 8 in 78 % yield; coupling of 2-pyridyl iodo-BCP 1 i with 4-fluorophenylmagnesium bromide afforded brequinar analogue 9 (66 %). [25]Finally, access to aryl-BCPs featuring substituents not tolerated under Kumada coupling could be achieved by ipso-substitution [26] of aryl silane 2 m (Scheme 2 b), for example with halides suitable for further elaboration by cross-coupling (10, 11), [27] or an electronwithdrawing acetyl group (12). [28]n conclusion, we have developed a mild, efficient ironcatalyzed cross-coupling of iodo-BCPs and (hetero)aryl Grignard reagents, which represents the first such example of Kumada cross-coupling of tertiary iodides.The reaction is rapid, exhibits good functional group tolerance, and performs well on gram scale.
Applications to the functionalization of pharmaceutical derivatives, including the synthesis of two BCP drug analogues, demonstrate the potential of this transformation to access highly functionalized 1,3-C-disubstituted BCPs of direct relevance in medicinal chemistry settings.