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Synlett 2022; 33(02): 103-108
DOI: 10.1055/a-1404-2763
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EuCheMS Organic Division Young Investigator Workshop

Alkyl Halides as Substrates for Photocatalytic Minisci-Type C–H Alkylation of Hetarenes

Jędrzej Predygier‡
a   Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b   Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
,
Joanna Szczepanik‡
a   Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
c   Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
,
Maciej Giedyk  ∗
a   Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
› Author Affiliations

We gratefully acknowledge funding from the National Science Centre, Poland (SONATA 2018/31/D/ST5/00306) for the financial support.
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Dedicated to Professor Daniel Gryko on the occasion of his 50th birthday

Abstract

Alkyl halides are readily available starting materials for various synthetic transformations, including Minisci-type C–H functionalizations of hetarenes. The existing methods, however, often require harsh reaction conditions, such as the use of acids, sacrificial electron donors, or radical precursors in excess amounts. Here, we outline recent developments in this field and we highlight our group̓s efforts to achieve fully catalytic photoredox Minisci-type alkylations supported by noncovalent interactions under mild aqueous conditions.


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Key words

C–H functionalization - Minisci reaction - alkyl bromides - hetarenes - photoredox catalysis - alkylation

Introduction: Minisci-Type C–H Alkylation

Hetarenes are present as structural motifs in a myriad of natural products, agrochemicals, and other biologically active compounds.[1] [2] Their prevalence in medicinally important molecules has been clearly demonstrated in a study by GlaxoSmithKline that showed that successful drug candidates contain an average of 0.38 to 0.69 hetaryl rings per molecule.[1] This ubiquity of hetarene-containing structures creates a constant demand for more efficient and more sustainable methods for the direct synthesis or late-stage modification of such molecules.

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Dr. Maciej Giedyk (right) graduated with a Master of Engineering degree in chemistry from the Warsaw University of Technology, Poland, in 2012. He completed his Ph.D. studies at the Institute of Organic Chemistry of the Polish Academy of Sciences under the supervision of Professor Dorota Gryko in 2016, working on the synthesis and catalytic properties of vitamin B12 derivatives. At the beginning of 2018, he took up a postdoctoral position in the group of Professor Burkhard König at the University of Regensburg. In 2019, he was appointed an assistant professor at the Institute of Organic Chemistry of the Polish Academy of Sciences. His research interests include light-induced processes, the chemistry of organic halides, cobalt-catalysis, and microheterogeneous solutions.
Joanna Szczepanik (bottom left) and Jędrzej Predygier (upper left) are master’s students and research-team members with a keen interest in developing synthetic methodologies and, in particular, in photocatalysis.

Radical C–H alkylation, commonly known as the Minisci-type reaction, has been recognized as a useful tool for appending aliphatic substituents to aromatic heterocycles. It is a radical process in which a carbon-centered alkyl radical adds to a protonated hetarene of electrophilic character (Scheme [1]). In the next step, the intermediate radical cation follows one of the two possible pathways, either losing a proton and becoming a neutral radical susceptible to oxidation or undergoing hydrogen-atom-transfer (HAT) to form the corresponding cation. Overall, both pathways lead to the same final product, the C–H functionalized hetarene in its protonated form. Unlike electrophilic alkylation, the Minisci reaction does not tend to cause isomerization of the alkyl substituent or rearrangement of the final product. The nucleophilic nature of the intermediate alkyl radical guides the regioselectivity of the reaction which, in the case of pyridine and its derivatives, occurs at the 2- and 4-positions exclusively.[3]

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Scheme 1 General mechanistic pathways of Minisci-type reactions

Although initial reports on radical additions to hetarenes date back to 1964,[4] [5] the original synthetic method was presented in 1968 by the group led by Francesco Minisci.[6] Nucleophilic radicals were generated from cyclohexanone peroxide in the presence of a Fe(II) salt, and the reaction was carried out in an acidic solution, permitting the conversion of pyridine or quinolone into their respective deri­vatives in yields of 70–80%.

Minisci and other researchers soon extended this pioneering development to other sources of alkyl radicals such as alcohols, carboxylic acids, esters, amides, alkyl halides, peroxides, N-chloroamines, or oxaziridines.[7] [8] Recently, modern methods for the generation of alkyl radicals, such as electrochemistry[9–11] or photochemistry,[12,13] have further cemented the Minisci-type reaction as a preferred method for C–H alkylation of aromatic heterocycles with a broad range of applications in medicinal chemistry.[14]


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Alkyl Halides as Substrates in Minisci-Type Reactions

Aliphatic halides have attracted considerable attention as cheap, stable, and readily available precursors of nucleophilic radicals for the alkylation of hetarenes.[15] [16] [17] In the late 1980s, Minisci and co-workers generated alkyl radicals from the corresponding iodides through iodine-atom abstraction by aryl[18] or methyl[19] radicals. Recently, methods involving catalysis by copper[20] or palladium[21] compounds have been reported. Those approaches, however, involve harsh conditions, such as the use of excess acids, strong bases, or oxidants or high temperatures.

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Scheme 2 Photocatalytic Minisci-type alkylation of hetarenes catalyzed by a binuclear gold–phosphine complex

A solution arose with the development of photocatalysis, which emerged as a convenient approach for the activation of relatively stable carbon–halogen bonds. Light-induced processes were promptly adapted to Minisci-type reactions, and several methods have been established. McCallum and Barriault reported that alkyl-centered radicals generated from bromides undergo Minisci-type additions catalyzed by binuclear Au(I) phosphine complexes (Scheme [2]).[22] In its excited state [Au2(dppm)2]Cl2 [dppm = CH2(PPh2)2] exhibits a reductive potential of –1.63 V vs. SCE, similar to those of more common transition-metal photocatalysts such as [Ru(bpy)3]Cl2 or fac-Ir(ppy)3 (ppy = 2-phenylpyridyl); this value is insufficient to permit efficient excited-state quenching with nonactivated bromoalkanes, which have redox potentials of about –2.0 V vs. SCE. Upon excitation, however, aurophilic Au–Au interactions between the gold atoms provide an open coordination site, permitting the association of a haloalkane. The resulting exciplex is capable of inducing inner-sphere electron transfer, affording reactive alkyl radicals that attack protonated hetarenes. In this way, the authors successfully carried out arylations of various hetarenes in very good to moderate yields under UVA irradiation.

The challenge of using visible light instead of high-energy UV radiation was addressed in 2017 by Frenette, Fadeyi, and their co-workers, who reported a Minisci-type alkylation with alkyl iodides catalyzed by a complex of Earth-abundant manganese (Scheme [3]).[23] Binuclear metal complexes are known to undergo photoinduced homolysis of the weak metal–metal bond, and metal-centered radicals generated in this way readily abstract halogen atom from alkyl halides to provide the corresponding alkyl radicals with concomitant formation of an M–X bond.[24] Mn2(CO)10 is a readily available catalyst of this type. As the most efficient among the 16 or so nonprecious metal catalysts that were screened, it provided the desired products from a wide scope of alkyl iodides. The researchers carried out meticulous investigations to support their proposed reaction mechanism, including laser flash photolysis and density functional theory calculations. Their studies indicated a blue-light-mediated chain mechanism with initial iodine abstraction as the rate-limiting step. In terms of limitations, the method requires alkyl iodides, and no reaction is observed when nonactivated alkyl bromides are used as substrates.

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Scheme 3 Manganese-catalyzed Minisci-type alkylation of hetarenes under blue-light irradiation

In 2018, Nuhant and co-workers used an iridium photoredox catalyst to convert alkyl iodides into radicals for Minisci-type reactions (Scheme [4]).[25] Remarkably, due to the unconventional use of basic conditions, this method permits the introduction of small alkyl groups bearing acid-sensitive substituents (oxetanes, Boc-carbamates, spirocyclic systems, or aldehydes) that are typically not tolerated. A few examples of alkyl bromides also proved to be competent substrates, although they gave yields approximately 20% lower than those from their iodide analogues.

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Scheme 4 Photocatalytic Minisci-type alkylation of indoles in basic conditions. ppy = 2-phenylpyridyl; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridyl.

There have been several recent reports on Minisci-type reactions involving silicon compounds as halogen-abstracting agents (Scheme [5]). In 2018, Wang and co-workers reported a system consisting of an iridium photocatalyst and tris(trimethylsilyl)silane (TTMSS) as a primary radical source that permitted the generation of alkyl radicals from the corresponding alkyl bromides.[26] By inducing a halogen-atom transfer as the key mechanistic step, it was possible to bypass the problem of the innate inability of Ir-based photoredox catalysts to undergo efficient excited-state quenching by nonactivated alkyl bromides under standard (acidic and oxidative) Minisci-type conditions. The reaction tolerates primary, secondary, tertiary, or benzyl bromides, as well as a range of heterocycles, mostly derivatives of pyridine. Several alkyl iodides were also tested but gave lower yields than the analogous bromides. Similar reaction conditions have been recently used by Xu and co-workers in C−H alkylations or aroylations of hetarenes, leading to a total of 56 different products.[27] Their report was soon followed by one from ElMarrouni’s group, who used the organic photocatalyst 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4-CzIPN) as a single-electron-transfer (SET) mediator and potassium persulfate as an oxidant.[28] Compared with previous methods, the reaction times were considerably shorter and the need for a rare-earth metal photocatalyst was eliminated. However, all three methods share the same disadvantage, namely, the need for an excess amount of the silane, which requires careful handling due to its flammability.

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Scheme 5 Photoredox Minisci-type alkylation with tris(trimethylsilyl)silane (TTMSS) as a primary radical source. dF(CF3)ppy = 3,5-difluoro-2-[5-(trifluoromethyl)phenyl]pyridinato; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridyl.

One of the most recent reports in the field discloses the formation of electron donor–acceptor (EDA) complexes[29] that permit photocatalytic Minisci-type alkylation to proceed without the addition of an external photocatalyst. In the approach developed by Hong and co-workers, protonated hetarenes form an EDA complex with a bromide anion, which, upon excitation followed by intramolecular SET forms a bromine radical (Scheme [6]).[30] Subsequent reaction with TTMSS completes the initiation step and leads to a chain reaction between an N-amidopyridinium salt and various alkyl bromides, providing straightforward access to C4-alkylated pyridines. It is worth highlighting that full C4 regioselectivity was preserved in all the reported examples.

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Scheme 6 Catalytic Minisci-type alkylation under photocatalyst-free conditions involving intermediate EDA complexes

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Merging Photoredox/Bromide Catalysis in Water to Avoid the Need for Stoichiometric Radical Promoters, Oxidants, or Acids

Given that the methods discussed above are all constrained by requirements for acids, bases, or silane-based radical promotors, finding mild conditions for photocatalytic Minisci-type reactions involving nonactivated alkyl bromides as substrates remained a formidable challenge. We tackled it by resorting to micellar systems, which had been recently reported to be successful media for photoredox reactions.[31] [32] [33] We reasoned that compartmentalization of the reacting species in a micellar solution, combined with the use of bromide-anion catalysis, might facilitate the desired C–C coupling due to favorable kinetic effects (Scheme [7]).[34] After performing a careful optimization, we established reaction conditions involving an iridium photocatalyst, anionic sodium dodecylsulfate (SDS) as a surfactant, and a catalytic amount of CBr4.

The developed method permits the use of a variety of secondary or primary alkyl bromides in the coupling reaction. Several functional groups in the bromide moiety were well tolerated, including free hydroxy, chloro, or trifluoromethyl groups, as well as double bonds or primary or secondary amides. In terms of the hetarene substrate, the reaction proceeded not only with simple heterocycles such as lepidine, phenanthridine, or quinoline, but also with analogues of pyridine containing ester or cyano substituents. Gratifyingly, the method also permitted C–H functionalization of caffeine, an important central-nervous-system stimulant. On the other hand, we found that tertiary or benzylic bromides, as well as those bearing an acetal unit, were incompatible as substrates. Limitations on the hetarene included those with aldehyde, ketone, or halo substituents, and substrates lacking hydrogen atoms at the C2 position.

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Scheme 7 Photocatalytic Minisci-type alkylation with alkyl bromides in structured aqueous solutions. (a) Examples showing the reaction scope. (b) A plausible reaction mechanism.

Mechanistic investigations including a radical-clock reaction, Stern–Volmer fluorescence-quenching experiments, and kinetic studies confirmed the involvement of carbon-centered radicals in the reaction mechanism. They also showed that the excited state of the photocatalyst is preferentially quenched by CBr4, which provides the starting concentration of co-catalytic bromide anions in the initiation step. The ability of bromide anions to engage in SET with the excited iridium complex (despite the slight endergonicity of this step) is due to a beneficial preorganization of the components in the reaction mixture and to halogen bonding between CBr4 and Br–. This might decrease the hydrophilic character of the latter species, slow down the migration to the water bulk, and, consequently, render Br– more accessible to the excited Ir(III)* photocatalyst. This, in turn, raises the concentration of the photocatalyst in its reduced form, facilitating consecutive excitation and providing bromine radicals capable of abstracting a hydrogen atom from the pyridinium radical cation intermediate. Alternatively, stepwise deprotonation followed by oxidation by the Br– radical leads to the desired protonated product. The catalytic activity of Br– and the decisive role of the spatial arrangement in the micellar solution have been further emphasized in kinetic studies as well as by control experiments.


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Conclusions

In summary, we have briefly overviewed recent progress in Minisci-type C–H functionalization of hetarenes with alkyl halides. In particular, we have highlighted our recent contribution to the field: the use of dual photoredox/bromide catalysis in micellar solutions. This new method eliminates previously unavoidable requirements such as the need for excess acid or base or the use of high reaction temperatures, stoichiometric radical promoters, or UV irradiation. The method permits valorization of nonactivated alkyl bromides by exploiting noncovalent interactions such as the hydrophobic effect, Coulombic attraction, and halogen bonding, which provide favorable preorganization of the components of the reaction mixture.

Although further advancements are still needed, the advantages of mild reaction conditions, commercially available blue LEDs as energy sources, and water as a solvent hold promise for practical applications of this method in late-stage functionalization of biologically or functionally relevant hetarenes.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Maciej Giedyk
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw
Poland   

Publication History

Received: 11 February 2021

Accepted after revision: 02 March 2021

Accepted Manuscript online:
02 March 2021

Article published online:
16 March 2021

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Dr. Maciej Giedyk (right) graduated with a Master of Engineering degree in chemistry from the Warsaw University of Technology, Poland, in 2012. He completed his Ph.D. studies at the Institute of Organic Chemistry of the Polish Academy of Sciences under the supervision of Professor Dorota Gryko in 2016, working on the synthesis and catalytic properties of vitamin B12 derivatives. At the beginning of 2018, he took up a postdoctoral position in the group of Professor Burkhard König at the University of Regensburg. In 2019, he was appointed an assistant professor at the Institute of Organic Chemistry of the Polish Academy of Sciences. His research interests include light-induced processes, the chemistry of organic halides, cobalt-catalysis, and microheterogeneous solutions.
Joanna Szczepanik (bottom left) and Jędrzej Predygier (upper left) are master’s students and research-team members with a keen interest in developing synthetic methodologies and, in particular, in photocatalysis.
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Scheme 1 General mechanistic pathways of Minisci-type reactions
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Scheme 2 Photocatalytic Minisci-type alkylation of hetarenes catalyzed by a binuclear gold–phosphine complex
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Scheme 3 Manganese-catalyzed Minisci-type alkylation of hetarenes under blue-light irradiation
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Scheme 4 Photocatalytic Minisci-type alkylation of indoles in basic conditions. ppy = 2-phenylpyridyl; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridyl.
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Scheme 5 Photoredox Minisci-type alkylation with tris(trimethylsilyl)silane (TTMSS) as a primary radical source. dF(CF3)ppy = 3,5-difluoro-2-[5-(trifluoromethyl)phenyl]pyridinato; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridyl.
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Scheme 6 Catalytic Minisci-type alkylation under photocatalyst-free conditions involving intermediate EDA complexes
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Scheme 7 Photocatalytic Minisci-type alkylation with alkyl bromides in structured aqueous solutions. (a) Examples showing the reaction scope. (b) A plausible reaction mechanism.