Medicinal chemists always gladly adopt useful synthetic tools which allow them to create new chemical bonds in a selective manner. The last decades have resulted in tremendous advances in the area, particularly well demonstrated with regard to transformations carried out under transition metal catalysis. The collaborative work of researchers around the world has contributed to the development of metal-catalyzed methods giving access to new carbon-carbon and carbon-heteroatom bonds. These methodologies have promptly proved their synthetic usefulness and eventually led to extensive application in both academic laboratories and industrial production plants. The pioneers who have developed the transformations gave their names to the reactions which currently rank as the most versatile synthetic methods for coupling sp2-hybridized carbon atoms in drug discovery (Scheme 1).1
Scheme 1. Most popular name cross-coupling reactions.
The challenges in compound development from early stages of drug discovery through clinical trials to eventually become a drug to a degree is correlated with structural complexity which can be illustrated using calculated parameters such as F(sp3) and the number of stereogenic centers (Table 1). However, molecules with certain values of these descriptors have a higher likelihood to demonstrate better transition through the process of drug discovery. In contrast to mostly flat aromatic compounds, scaffolds maintaining a greater saturation level display a general tendency towards higher selectivity, resulting from fewer unspecific interactions, and exhibit improved physicochemical properties (higher solubility and lower melting points).
Although greater three-dimensionality broadens structural availability by accessing wider chemical space, its complete exploration has been limited by the lack of convenient synthetic methods.2,3
Table 1. Mean F(sp3) values for compounds at different stages of drug discovery process.
Naturally, Pd-mediated reactions have been expanded to sp3-sp2 C-C bond formation4–7 but the substrate scope for these methods remains narrow and therefore their synthetic utility is rather limited. The problem with alkyl partners (alkyl halide or alkyl organometallic) is associated with their tendency to undergo β-hydride elimination from the formed alkylpalladium species (1 or 2, see Scheme 2) and their lower reactivity during transmetallation step, especially in case of alkyl boronates. Moreover, the undesired β-hydride elimination is a reversible step and may lead to isomeric coupling products 3 and 4 which are often difficult to separate. Although related transformations employing Cu, Ni, Co and Fe-based catalysts showing high chemoselectivity have also been described including asymmetric variants of the reaction, many examples revealed some of the limitations mentioned above which are inherent to the nature of alkyl components.8
Scheme 2. Catalytic cycle of Pd-mediated cross-coupling with alkyl organometallics
An attractive platform which circumvents all those drawbacks is offered by reactions proceeding via a different mechanistic pathway based on single electron transfer (SET) and exploiting the chemistry of radicals. In the most recently developed transformations, two distinct catalytic cycles are merged: photocatalyst which upon excitation engages SET process leading to alkyl radical formation and metal-based catalyst capable to use the generated radicals to construct new C-C linkages under mild conditions. Photocatalysts of choice are iridium and ruthenium complexes or purely organic photocatalysts (Scheme 3). Suitable coupling catalysts are based on nickel, providing a competitive option compared to expensive palladium complexes and elaborated ligands. The SET process reduces the activation energy barrier required to initiate the reaction, obviating the need for strong bases or pyrophoric reagents. Moreover, the radical mechanistic pathway significantly broadens the scope of alkyl substrates and enables to couple partners with less accessible secondary and tertiary carbon atoms in high yields.9
Scheme 3. Commonly used photocatalysts.
Itis postulated that alkyl radical 5 generated from an appropriate feedstock can undergo recombination at Ni0 compound 6 to form alkyl-NiI intermediate 7, which is then attacked by aryl halide in an oxidative addition step (Scheme 4). The resulting high-valent nickel complex 8 undergoes subsequently reductive elimination to form the coupling product 3 and NiI. An electron originating from the photoredox cycle reduces nickel’s oxidation state in a SET process and closes the catalytic cycle. A homolytic Ni-C bond cleavage in intermediate 8 leads to a mixture of alkyl radical and NiII complex 9 which all remain in a rapid equilibrium. Previously hypothesized mechanism has assumed that the oxidative addition precedes the recombination of alkyl radical at the ligated Ni0 center. However, computational studies have revealed that the recombination requires lower activation energy and therefore it is more likely to proceed as depicted below.10
Scheme 4. An example of catalytic cycle under dual catalysis conditions.
Over the last decade, several convenient methodologies of alkyl radical formation under photoredox catalysis have been developed and employed in cross-coupling reactions (Scheme 5). For instance, alcohols converted to corresponding oxalates can be easily activated to afford carbon centered radicals.11 Equally, secondary potassium alkyltrifluoroborates have been reported to be useful radical precursors generated under similar mild conditions.10,12 Carboxylic acids have been found as exceptionally practical alkyl radical surrogates owing to their great bench stability and broad commercial availability.13 Recently, inactivated primary amines have also been utilized in a similar manner to yield alkyl radicals by activation through the formation of Katritzky’s pyridinium salts.14 An application of chiral ligands allows to accomplish the coupling in a stereocontrolled manner and the recent advances in the field have been comprehensively reviewed.15
Scheme 5. Selected examples of alkyl partners in cross-coupling reactions under dual catalysis.
In another study, driven by curiosity how alkyl radicals formed during the classic Barton decarboxylation can be utilized in the coupling reaction, Baran and co-workers have investigated the reaction of redox-active esters and organozinc species in the presence of an inexpensive nickel source (Scheme 6). Redox-active esters are defined as ester compounds capable of accepting one electron in the SET process, yielding a radical anion which quickly decomposes to give an alkyl radical. Interestingly, it was found that the transformation proceeds effectively in the absence of an orthogonal photocatalyst and affords the desired coupling product, revealing a dual role of the nickel catalyst in the process.16
Scheme 6. Inspiration of Barton’s decarboxylation reaction and similarities with Baran’s redox-active esters.
Acids had to be transformed to the corresponding N-hydroxyphthalimide esters before coupling with a number of arylzinc reagents, resulting in the desired product formation in moderate to good yields (Scheme 7). An array of simple linear, carbo- and heterocyclic secondary alkyl carboxylic acids provided the corresponding arylation products. Additionally, aryl and heteroaryl partners exhibiting distinct electronic properties were also well tolerated.16
Scheme 7. Nickel-catalyzed cross-coupling with secondary alkyl redox-active esters and arylzinc reagents.
Most remarkably, it was found that no functional group stabilizing the alkyl radical is required to enable its generation, contrary to what was demonstrated in MacMillan’s higher atom economy decarboxylative arylation. It was illustrated by comparing the results of the cross-coupling reaction leading to compound 10 (Scheme 8). On the other hand, the method utilizing redox-active esters obliges to pre-functionalize the free carboxylic group, usually repurposing methods well known in the peptide synthesis. However, the sequence including the carboxylate activation and coupling reaction can be carried out in one pot without isolation of the intermediate ester, obtaining the product with relatively similar results.16
Scheme 8. Comparison of the conditions in decarboxylative cross-coupling reactions.
The methodology was promptly expanded to construct challenging C(sp3)-C(sp3) bonds using primary and secondary alkylzinc reagents. As a result, the method extends the standard retrosynthetic toolbox to unusual and nonobvious disconnections. The scope of alkyl partners derived from acids was explored and found to be broad again: primary, secondary and tertiary alkyl carboxylic acids could be employed to generate new connections, often difficult to obtain otherwise (Scheme 9).17
Scheme 9. Two synthetic approaches towards [2.2.2]-bicyclooctane derivative.
The high functional group tolerance allows to carry out the reaction with the reagents harboring various types of moieties, including olefins, alkynes, ketals, oxiranes, amides, as well as alkyl and aryl halides. As a consequence, the method was successfully applied in late-stage functionalization of complex molecules, such as simple tri- or penta-peptides using solid state synthesis and approved drug analogue 11 (Scheme 10).17 Recently, an asymmetric modification of the method has been published by Fu’s group, providing an elegant synthetic avenue to chiral amines.18
Scheme 10. Synthesis of cetirizine analogue 11 utilizing decarboxylative cross-coupling reaction.
Naturally, the method still requires organozinc species which are not very widely available commercially, meaning that the more exotic derivatives must be prepared prior to use in the cross-coupling reaction. Fortunately, aryl and heteroaryl boronic acids were found to be equally viable partners for redox-active esters in the described reaction. Suzuki coupling substrates are of course readily available from commercial sources and show an enormous potential for scalability, owing to their high stability and compatibility with a number of functionalities. Moreover, the method offers minimal experimental precaution requirements and allows to conduct the reaction using wet solvents under air atmosphere, as exemplified by the synthesis of 12 (Scheme 11).19
Scheme 11. Decarboxylative cross-coupling reaction using arylboronic acids
Although the reaction with boronic acids requires elevated temperatures to proceed, which is associated with higher energy demand during the transmetallation step, the desired products were isolated in yields comparable to those obtained for zinc-based counterparts.
Arylation of tertiary carbon centers has been exemplified in the case of selected bridgehead systems, but the researchers openly admitted that these disconnections pose a challenge for the investigated catalytic system. Interestingly, changing the metal to iron can help to overcome the obstacle and provides complementary catalytic activity which extends the system’s utility to the demanding realm of C-C couplings, at least to a certain degree (Scheme 12).20
Scheme 12. Scope and limitation of Fe- and Ni-catalyzed tertiary carbon arylation.
The kinetic studies confirmed that the reaction under iron catalysis proceeds faster, allowing the use of lower catalyst loadings in comparison to the Ni catalytic system. The reaction can be accomplished in the presence of Fe catalysts, using both organozinc and highly nucleophilic Grignard reagents (the latter were not compatible with the Ni-promoted transformation). Additionally, a highly convenient one-pot protocol is available for creation of the arylation products directly from acids. Generally, the products were produced in both catalytic modes with similar results using stepwise approach, the striking difference in the catalysts’ activity only noticed when operating with the in situ protocol (Scheme 13).20
Scheme 13. One-pot carboxylic acid activation followed by decarboxylative cross-coupling under Fe- and Ni-catalysis.
SET-mediated transformations undeniably provide a remarkable technology to functionalize sp3 hybridized carbon centers under mild conditions. The concept of Baran’s redox-active esters21 offers a practical and user-friendly synthetic toolbox for the installation of alkyl fragments into aromatic or aliphatic compounds. The transformation remains fully operative with a variety of nucleophiles adopted from analogous C(sp2)-C(sp2) Negishi, Kumada, and Suzuki cross-coupling reactions. The methodology is of broad scope and has been used to convert a variety of alkyl carboxylic acids into desired products in the presence of inexpensive Ni and Fe catalysts and without the need for any photocatalyst. Wide commercial availability and good bench stability of carboxylic acids makes them an attractive feedstock of alkyl radicals. However, redox-active esters must be synthesized prior to use in the coupling reaction, which naturally lowers the atom economy of the process, though the arylation can be conducted with in situ generated activated acid. Great simplicity of the experimental protocols, low-cost reagents and great modularity of all described methods can definitely be appreciated in compound library synthesis allowing late-stage functionalization using advanced building blocks. Moreover, the necessity for increased sp3 hybridized carbon count in new drug candidates will surely result in widespread employment of similar methodologies in drug discovery programs.
CASE STUDY
A few years ago, Selvita successfully adopted the methodology and applied it in a gram-scale custom synthesis of benzene derivative which was substituted with a long alkyl chain. One of proposed synthetic approaches assuming another disconnection strategy (Sonogashira reaction and hydrogenation) was abandoned due to high cost of needed reagents. Instead, the same aryl bromide was converted into aryl zinc reagent using Knochel’s protocol and mixed in the presence of a catalytic amount of NiCl2(glyme) with redox-active ester derived from cheaper pimelic acid monoethyl ester. The desired product was isolated in respectable amount of 10.2 g and in satisfying yield (48%).
AUTHOR
Grzegorz Zieliński
Team Leader, Selvita Chemistry Department
REFERENCES
(1) Synthetic Methods in Drug Discovery Vol 1; 2016; Vol. 1. https://doi.org/10.1039/9781782622086.
(2) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52 (21), 6752–6756. https://doi.org/10.1021/jm901241e.
(3) Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. MedChemComm 2013, 4 (3), 515–519. https://doi.org/10.1039/C2MD20347B.
(4) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-Organometallics as Reaction Partners. Chem. Rev. 2011, 111 (3), 1417–1492. https://doi.org/10.1021/cr100327p.
(5) Frisch, A. C.; Beller, M. Catalysts for Cross-Coupling Reactions with Non-Activated Alkyl Halides. Angew. Chem. Int. Ed. 2005, 44 (5), 674–688. https://doi.org/10.1002/anie.200461432.
(6) Rudolph, A.; Lautens, M. Secondary Alkyl Halides in Transition-Metal-Catalyzed Cross-Coupling Reactions. Angew. Chem. Int. Ed. 2009, 48 (15), 2656–2670. https://doi.org/10.1002/anie.200803611.
(7) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances in Homogeneous Nickel Catalysis. Nature 2014, 509 (7500), 299–309. https://doi.org/10.1038/nature13274.
(8) Manolikakes, G. 3.08 Coupling Reactions Between Sp3 and Sp2 Carbon Centers. In Comprehensive Organic Synthesis II (Second Edition); Knochel, P., Ed.; Elsevier: Amsterdam, 2014; pp 392–464. https://doi.org/10.1016/B978-0-08-097742-3.00312-8.
(9) Zhu, C.; Yue, H.; Chu, L.; Rueping, M. Recent Advances in Photoredox and Nickel Dual-Catalyzed Cascade Reactions: Pushing the Boundaries of Complexity. Chem. Sci. 2020, 11 (16), 4051–4064. https://doi.org/10.1039/D0SC00712A.
(10) Primer, D. N.; Karakaya, I.; Tellis, J. C.; Molander, G. A. Single-Electron Transmetalation: An Enabling Technology for Secondary Alkylboron Cross-Coupling. J. Am. Chem. Soc. 2015, 137 (6), 2195–2198. https://doi.org/10.1021/ja512946e.
(11) Zhang, X.; MacMillan, D. W. C. Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: Sp3–Sp2 Cross-Coupling of Oxalates with Aryl Halides. J. Am. Chem. Soc. 2016, 138 (42), 13862–13865. https://doi.org/10.1021/jacs.6b09533.
(12) Tellis, J. C.; Primer, D. N.; Molander, G. A. Single-Electron Transmetalation in Organoboron Cross-Coupling by Photoredox/Nickel Dual Catalysis. Science 2014, 345 (6195), 433–436. https://doi.org/10.1126/science.1253647.
(13) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C. Merging Photoredox with Nickel Catalysis: Coupling of α-Carboxyl Sp3-Carbons with Aryl Halides. Science 2014, 345 (6195), 437–440. https://doi.org/10.1126/science.1255525.
(14) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C–N Bond Activation. J. Am. Chem. Soc. 2017, 139 (15), 5313–5316. https://doi.org/10.1021/jacs.7b02389.
(15) Lipp, A.; Badir, S. O.; Molander, G. A. Stereoinduction in Metallaphotoredox Catalysis. Angew. Chem. Int. Ed. 2021, 60 (4), 1714–1726. https://doi.org/10.1002/anie.202007668.
(16) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S. Practical Ni-Catalyzed Aryl–Alkyl Cross-Coupling of Secondary Redox-Active Esters. J. Am. Chem. Soc. 2016, 138 (7), 2174–2177. https://doi.org/10.1021/jacs.6b00250.
(17) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. A General Alkyl-Alkyl Cross-Coupling Enabled by Redox-Active Esters and Alkylzinc Reagents. Science 2016, 352 (6287), 801–805. https://doi.org/10.1126/science.aaf6123.
(18) Yang, Z.-P.; Freas, D. J.; Fu, G. C. The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions. J. Am. Chem. Soc. 2021, 143 (7), 2930–2937. https://doi.org/10.1021/jacs.0c13034.
(19) Wang, J.; Qin, T.; Chen, T.-G.; Wimmer, L.; Edwards, J. T.; Cornella, J.; Vokits, B.; Shaw, S. A.; Baran, P. S. Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids. Angew. Chem. Int. Ed. 2016, 55 (33), 9676–9679. https://doi.org/10.1002/anie.201605463.
(20) Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T.-G.; Dixon, D. D.; Creech, G.; Baran, P. S. Redox-Active Esters in Fe-Catalyzed C–C Coupling. J. Am. Chem. Soc. 2016, 138 (35), 11132–11135. https://doi.org/10.1021/jacs.6b07172.
(21) Sandfort, F.; O’Neill, M. J.; Cornella, J.; Wimmer, L.; Baran, P. S. Alkyl−(Hetero)Aryl Bond Formation via Decarboxylative Cross-Coupling: A Systematic Analysis. Angew. Chem. Int. Ed. 2017, 56 (12), 3319–3323. https://doi.org/10.1002/anie.201612314.