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Synthesis 2023; 55(21): 3470-3486
DOI: 10.1055/a-2134-0307
special topic
C–H Bond Functionalization of Heterocycles

Carbon–Carbon Bond Forming Reactions in Diazines via Transition-Metal-Catalyzed C–H Bond Activation

Rafael Gramage-Doria  ∗
,
Christian Bruneau 

Financial support from the Agence Nationale de la Recherche (ANR-19-CE07-0039), Centre National de la Recherche Scientifique (CNRS), and University of Rennes is acknowledged.
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Abstract

An overview of the key achievements concerning C–C bond-forming processes with diazines (pyridazines, pyrimidines, and pyrazines) and benzodiazines (cinnolines, phthalazines, quinazolines, and quinoxalines) under transition-metal-catalyzed C–H activation is presented. The focus is on examples in which C–H functionalization takes place in the diazine or benzodiazine core because of the relevance of these compounds in material science and as active pharmaceutical ingredients. These metal-catalyzed protocols benefit from the biased reactivity of the C–H bonds targeted or from the presence of a rationally designed directing group proximate to the C–H bond to be functionalized. As such, innovative alkylations, alkenylations, alkynylations, arylations, and carboxylations are accomplished within such skeletons in a step- and atom-economy fashion.

1 Introduction

2 Transition-Metal-Catalyzed C–H Alkylation of Diazines

3 Transition-Metal-Catalyzed C–H Alkynylation of Diazines

4 Transition-Metal-Catalyzed C–H Alkenylation of Diazines

5 Transition-Metal-Catalyzed C–H Arylation of Diazines

6 Transition-Metal-Catalyzed C–H Carboxylation of Diazines

7 Conclusion


#

Key words

diazines - C–H activation - arylation - alkenylation - alkylation - metal catalyst
1

Introduction

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Rafael Gramage-Doria received his Ph.D. from the University of Strasbourg (France) with Dr. Dominique Matt and Prof. Dominique Armspach. After postdoctoral fellowships with Prof. Joost N. H. Reek at the University of Amsterdam (Netherlands) and Prof. Takashi Ooi at Nagoya University (Japan), he joined in 2015 the Institute of Chemical Sciences of the University of Rennes (France) as a CNRS researcher, where he completed his Habilitation (2019). His research interests include transition metal catalysis for fine chemicals and green chemistry applications, C–H bond functionalization, coordination chemistry, and supramolecular and bio-inspired catalysis.

Aromatic heterocycles containing more than one nitrogen atom are present in numerous molecules presenting a wide range of properties with applications in biological, optical, and electronic fields. This is especially the case for diazine and benzodiazine derivatives featuring two nitrogen atoms in a six-membered aromatic ring (Figure [1]).[1] [2]

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Figure 1 Structural motifs of diazines and benzodiazines

Functionalization of these primary substrate cores, which are known as electron-poor heterocycles, have been achieved with various transition-metal-free methods including nucleophilic aromatic substitution of hydrogen,[3] radical (Minisci-type) transformations,[4] and deprotonative metalation (lithiation, magnesiation, zincation) followed by quenching by an electrophile.[5] Transition-metal-catalyzed cross-coupling reactions between a diazine halide and an organometallic reagent (Suzuki–Miyaura, Stille, Negishi, Corriu–Kumada coupling), or a terminal alkyne (Sonogashira coupling), or an olefin (Heck coupling), have also been used for the formation of new carbon–carbon bonds in diazines,[6] but most of them generate harmful byproducts in stoichiometric amounts.

More straightforward and atom-economic coupling methods based on direct C–H bond activation[7`] [b] [c] [d] [e] [f] [g] have recently appeared making possible the unprecedented functionalization of diazines.[7h–k] In this review article we wish to focus on the transition-metal-catalyzed C–H bond functionalization of diazines and benzodiazines leading to the formation of new C–C bonds, namely alkenylation, arylation, and carboxylation. Functional diazines such as diazinones, diazine-diones, and diazine N-oxides presenting either modified reactivities or directing group properties are beyond the scope of this short review. Note that all metal-catalyzed radical processes have not been included.


# 2

Transition-Metal-Catalyzed C–H Alkylation of Diazines

The synthesis of alkylated diazines relies on two types of reactions: metal-catalyzed hydroarylation of alkenes or direct alkylation with alkyl halides. A catalytic system based on [RhCl(cod)]2, a diphosphine, and a base catalyzes the ortho-selective alkylation of various diazines with ethyl acrylate and dimethyl acrylamide.[8] The regioselectivity of the alkylation is dictated by the migratory insertion of the electron-deficient double bond into a Rh–H bond generated by oxidative addition of the diazine to the metal center. Linear alkylated products were obtained in the presence of potassium pivalate as the base whereas branched isomers were obtained when the more basic potassium phosphate was used (Scheme [1], top). The efficiency of the formation of branched products was improved by using the less basic 1,2-bis[3,5-bis(difluoromethylphenyl)phosphino]ethane (dArFpe) together with K3PO4 as the base, as compared to 1,2-bis(diphenylphosphino)ethane (dppe), which gave good yields in the formation of linear products using PivOK as the base. The reaction mechanism involves a Rh(I)/Rh(III) catalytic cycle initiated by C–H activation in the diazine core followed by migratory insertion of the olefin with the regioselectivity controlled by the nature of the base (Scheme [2], bottom). Finally reductive elimination affords the product while regenerating the active Rh(I) complex (Scheme [1], bottom). It is interesting to note that 3,4-dihydroquinazolines were alkylated with various terminal alkenes at the sp2C(2) position of the heterocycle with a catalyst based on [RhCl(cyclooctene)]2 and tricyclohexylphosphine at 150 °C in THF.[9] In the presence of an excess of olefin and prolonged reaction time, aromatization of the 2-alkyl-3,4-dihydroquinazolines led to 2-alkylquinazoline via a cascade rhodium-catalyzed hydrogen transfer process. This aromatization could also be efficiently achieved by adding MnO2 as oxidant.

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Scheme 1Rhodium-catalyzed alkylation of diazines with ethyl acrylate (top) and plausible reaction mechanism (bottom); Rh = [RhCl(cod)]2 (10 mol%)
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Scheme 2Copper-catalyzed enantioselective alkylation of pyridazines (top) and plausible reaction mechanism (bottom); Cu = Cu(OAc)2 (6 mol%)

Enantioselective alkylation of pyridazines by styrenes has been successfully achieved with a chiral copper catalyst at room temperature (Scheme [2], top).[10] This reaction involves a dearomatization/reoxidation sequence starting with the formation of a copper hydride in the presence of dimethoxymethylsilane (DMMS) followed by regioselective insertion of the styrene double bond, which generates a chiral α-methylbenzylcopper species with high enantioselectivity due to the presence of the optically pure (S,S)-Ph-BPE ligand (Scheme [2], bottom). This intermediate reacts with a copper-coordinated pyridazine to form a dearomatized N-cuprate leading to the formation of the optically active alkylated dihydropyridazine after σ-bond metathesis with the silane. Further oxidation at room temperature gives the final optically active benzylated pyridazine.

The palladium-catalyzed methylation/alkenylation of 5-iodo-2,4-dimethoxypyrimidine based on the Catellani strategy[11] was achieved via the Heck-type alkenylation with tert-butyl acrylate and the alkylation with methyl tosylate[12] (Scheme [3], top). The benzylation of the analogue 5-bromo-2,4-dimethoxypyrimidine was carried out in 57% yield under similar conditions with p-methoxybenzyl chloride as alkylating agent.[13] As depicted in Scheme [3] (bottom) the reaction starts with a Pd(0) species that undergoes oxidative addition at the substrate followed by norbornene coordination and migratory insertion enabling methylation at the neighboring C–H bond after activation of Pd(II) to Pd(IV) with the alkylating agent MeOTs. Reversible norbornene release followed by a palladium-catalyzed Heck process with the acrylate derivatives forms the final product with regeneration of the active Pd(0) species.

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Scheme 3 Palladium-catalyzed alkylation/alkenylation based on the Catellani strategy (top) and plausible reaction mechanism (bottom); Pd = Pd2(dba)3 (5 mol%)

The direct alkylation of diazines with unactivated alkyl halides is not well documented. Some modest results have been obtained using copper catalysis, for instance using BrCF2CO2Et as the reagent gave the 5-substituted quinoxaline in 35% yield and the proposed mechanism was based on radical processes.[14] The monoperfluoroalkylation of pyrazine and pyrimidine has been performed with C6F13Br as the alkylating agent and a stoichiometric amount of Cs2CO3 at 130 °C with a heterogeneous nanocatalyst containing 10 mol% cobalt that could be recycled several times (Scheme [4]).[15] Mechanistic investigation ruled out the involvement of radicals.

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Scheme 4Perfluoroalkylation of diazines with a cobalt nanocatalyst; Co = cobalt nanocatalyst (10 mol%)

# 3

Transition-Metal-Catalyzed C–H Alkynylation of Diazines

Transition-metal-catalyzed alkynylation has been performed with diazines featuring a pendant chelating functional group. Using this strategy, regioselective directed C–H bond activation/alkynylation could take place. Thus, NiCl2 in combination with bis(2-(dimethylamino)ethyl) ether (BDMAE) was utilized in the regioselective ortho-alkynylation of the quinoxaline core substituted by a bidentate N-(quinolin-8-yl)amide by TIPS-protected bromoacetylene (Scheme [5], top).[16] The overall reaction mechanism follows oxidative addition of the bromoalkyne at Ni going from +2 to +4 formal oxidation state ending up with a reductive elimination and regeneration of the active Ni(II) species (Scheme [5], bottom). With copper catalysts known to also activate the C–H bond of terminal alkynes, pyridazines and pyrimidine equipped with the PIP substituent were alkynylated in moderate yields (Scheme [6]).[17] The chelating 2-(pyridin-2-yl)propan-2-ylamido group (PIP) linked to a monocyclic diazine triggers ortho-directed C–H activation on the diazine structure via a concerted metalation deprotonation mechanism in the presence of a base.

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Scheme 5Nickel-catalyzed alkynylation of quinoxaline directed by the Q chelating group (top) and plausible reaction mechanism (bottom); Ni = NiCl2 (10 mol%)
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Scheme 6Copper-catalyzed alkynylation of diazines directed by the PIP chelating group; Cu = Cu(OAc)2 (30 mol%)

# 4

Transition-Metal-Catalyzed C–H Alkenylation of Diazines

There are essentially two types of reactions to connect an olefinic substituent to an aromatic core: either (i) cross coupling with an olefin, described as a dehydrogenative Heck reaction, or (ii) hydroarylation of alkynes, both methods involve C–H bond activation and C–C bond formation. Complexes of palladium, rhodium, and ruthenium are the catalysts of choice for these activations, but a few examples with 3d metals, such as nickel and cobalt, have also been reported.

4.1

Alkenylation with Olefins

The alkenylation of pyrimidine with electron-deficient ethyl acrylate[18] and dimethylacrylamide[19] was initially carried out with 10 mol% Pd(OAc)2 associated with 1,10-phenanthroline or an N-protected amino acid, such as Ac-Val-OH, and Ag2CO3 and/or air as oxidant. In both cases, selective alkenylation took place selectively at C5 of the pyrimidine but modest yields below 30% were obtained (Scheme [7], top). The origin of the regioselectivity towards olefination at C5 was studied by DFT calculations identifying the C–H activation step via concerted-metalation deprotonation (CMD) as the rate-determining one (Scheme [7], bottom).[19] Functionalization at the other C–H bonds was more energetically demanding likely due to the influence of the ligands coordinating to palladium.

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Scheme 7Palladium-catalyzed alkenylation of pyrimidine (top) and plausible key intermediate (bottom); Pd = Pd(OAc)2 (10 mol%)

Improved productivities were obtained from 2-aminopyrimidines with a catalytic system based on Pd(OAc)2 avoiding the use of an external ligand but operating in air in the presence of additional Cu(OAc)2 as oxidant in acetic acid as solvent at 120 °C. With this procedure, excellent yields of 5-alkenylated pyrimidines of biological interest were obtained in excellent yields (Scheme [8], top).[20] The regioselectivity of this reaction results from dearomatization at the substrate occurring simultaneously to the electrophilic C–H palladation (Scheme [8], bottom). A Heck-type process is operative in which migratory insertion of the olefin follows β-hydride syn elimination forming the product and palladium hydride species. Reductive elimination at palladium forms acetic acid and Pd(0) that is chemically oxidized with copper salts (Scheme [8], bottom). A related catalytic system containing silver acetate as oxidant and PivOH made possible the selective monoalkenylation of 2,6-dimethylpyrazine with tert-butyl acrylate at 140 °C in DMF in 52% yield.[21]

Fused bicyclic diazines have also been alkenylated with electron-deficient olefins using palladium catalysts. With the help of a designed U-shaped template (1 equiv.) added to Pd(OAc)2 (10 mol%), N-protected glycine Ac-Gly-OH (20 mol%), and AgOAc (2.5 equiv.), the regioselective alkenylation of 2-methoxyquinoxaline with methyl acrylate was achieved at 80 °C in hexafluoroisopropanol at 80 °C forming the corresponding 8-alkenylated quinoxaline in 83% yield (Scheme [9]).[22] In this case, the regioselectivity of the reaction is controlled by the ability of the U-shaped template to bind in a ditopic fashion to the substrate via a Pd···N interaction and the palladium active site via a nitrile···Pd interaction. The geometry and distance between the substrate binding site and the catalytically active palladium site enables the formation of large palladacycle species responsible of such precise regioselectivity. A highly functionalized quinazoline has been alkenylated by methyl vinyl sulfone in the presence of a catalytic system based on Pd(OCOCF3)2 (10 mol%) operating under strong oxidative conditions in the presence of 2 equiv. of potassium persulfate. A late-stage functionalization of the anti-cancer drug gefitinib was thus obtained in 30% yield (Scheme [10]).[23]

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Scheme 8Palladium-catalyzed alkenylation of 2-aminopyrimidines (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)
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Scheme 9 Template-enabled remote C–H olefination of a quinoxaline derivative under palladium catalysis (top) and postulated key palladacycle intermediate (bottom); Pd = Pd(OAc)2 (10 mol%)

Styrenes are also convenient substrates to perform the alkenylation of diazines. This was demonstrated in the olefination of 6,7-difluoroquinoxalines by styrenes with extended electronic conjugation leading to fluorophores with high potential for bioimaging applications. The palladium catalyst consisted of Pd(OCOCF3)2 (5 mol%), 1,10-phenanthroline (10 mol%), and AgF (5 equiv.) with DMF as the solvent at 130 °C for 7 h. Depending on the substitution pattern at position 5 of the initial quinoxaline, symmetrical and unsymmetrical molecules were obtained in excellent yields (Scheme [11]).[24] The reaction appears to undergo a Fujiwara–Moritani-type mechanism although no discussion was reported.

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Scheme 10 C–H olefination of gefitinib under palladium catalysis; L = 3-methyl-2-isopropyl-2-(phenylthio)acetic acid, Pd = Pd(OCOCF3)2 (10 mol%)
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Scheme 11 C–H olefination of 6,7-difluoroquinoxalines with styrenes under palladium catalysis; Pd = Pd(OCOCF3)2 (5 mol%)

Whereas the alkylation of diazines was selectively achieved at the vicinal carbon of nitrogen atoms in the presence of Rh(I) catalysts, their alkenylation was possible with Rh(III) catalysts but required the presence of a directing group. However, the reaction of simple diazines with acrylates was sensitive to the nature of the diazine and the directing group. For instance, using [Cp*RhCl2]2 as catalyst precursor, AgSbF6 as chloride abstractor, and Cu(OAc)2 as oxidant with a tertiary amide at C4 of the pyrimidine led to alkenylation at C5 in 70% yield with ethyl acrylate whereas the same directing group at C2 of pyrazine gave alkylation at C3 in 63% yield (Scheme [12], top).[25] In contrast when the pyrazine was substituted by a secondary amide at C2, a further cyclization, which required the presence of both rhodium and copper catalysts, was observed in 43% yield (Scheme [12], top).[26] In these cases, the key rhodacycle intermediate is the same, with a β-hydride elimination step explaining the olefinated product whereas a protonation step instead leads to the alkylated product (Scheme [12], bottom). The olefinated/cyclized product arises from an N–H deprotonation after olefination and syn-addition of the olefin that explains the formation of the E isomer after β-hydride elimination (Scheme [12], bottom). The Cu(II) salt enables oxidation of Rh(I) to the catalytically active Rh(III).

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Scheme 12 Amide-directed C–H olefination of pyrimidine, C–H alkylation of pyrimidine, and C–H olefination/cyclization of pyrazine derivatives under rhodium catalysis (top) and key mechanistic considerations (bottom); Rh = [Cp*RhCl2]2 = (2.5 mol%)

# 4.2

Alkenylation with Alkynes

With alkynes as coupling partners the alkenylation of unsubstituted monocyclic diazines, namely pyrazine and pyrimidine, leads to the introduction of a linear olefinic substituent. On the other hand, diazines substituted by a (hetero)aromatic group in most cases give cyclized products with the formation of two C–C bonds or an additional C–heteroatom bond. The first example of diazine alkenylation via transition metal catalysis was reported in 2008. Pyrazine reacted with 1,2-dipropylacetylene in the presence of catalytic amounts of two metal catalysts, Ni(cod)2 (3 mol%) and ZnMe2 (6 mol%), and P i Pr3 (12 mol%) in toluene at 100 °C; 2-(1-propylpent-1-enyl)pyrazine was selectively obtained in 65% yield with an E/Z stereoisomer ratio of 97:3 (Scheme [13], top). In this process, the Ni(0) catalyst activates the triple bond and the pyridine is activated by the zinc Lewis acid facilitating the regioselective oxidative addition of the C2–H bond of pyrazine to form a Ni(II) intermediate.[27] It can be noted that a second molecule of alkyne could be involved forming a 1,2,3,4-tetrapropylbutadien-1-yl substituted pyrazine in 10% with ZnMe2 that could become the major product using AlMe3 as Lewis acid. The Co(acac)3 complex with dppp (5 mol%) and MeAl(2,6-di t Bu-4-MeC6H2O)2 (MAD) as Lewis acid were also found to be very efficient for the same alkenylation reaction of pyrazine at C2 and pyrimidine at C4 (Scheme [13], top).[28] In both cases, the Lewis acid (ZnMe2 or MAD) is expected to bind to the nitrogen atom of the heteroaromatic ring leading to a C–H metalation step followed by hydrometalation across the alkyne coordinating to the metal center and further reductive elimination as the plausible reaction mechanism (Scheme [13], bottom).

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Scheme 13 C–H alkenylation of diazines with alkynes under nickel catalysis and under cobalt catalysis, respectively (top) and plausible reaction mechanism (bottom); Ni = Ni(cod)2 (3 mol%), Co = Co(acac)3 (5 mol%)

Several groups have shown that Rh(III) catalysts are able to promote the dehydrogenative coupling/annulation of pyrazines with internal alkynes.[29] [30] [31] Starting from a pyrazine core substituted by a proximal indole, the reaction with diphenylacetylene provided a tetracyclic heteroaromatic in 75% yield in the presence of 4 mol% [Cp*RhCl2]2 and 3 equiv. of silver acetate as oxidant (Scheme [14], top).[29] This reactivity has been explained by initial rhodium-mediated C–H bond activation of indole directed by coordination of one nitrogen atom of the pyrazine to form a rhodacycle followed by insertion of the triple bond, rollover cyclorhodation, and elimination (Scheme [14], bottom).

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Scheme 14 C–H dehydrogenative/cyclizing alkenylation of a pyrazine derivative under rhodium catalysis (top) and plausible reaction mechanism (bottom); Rh = [Cp*RhCl2]2 (4 mol%)

The same strategy based on a rollover mechanism was extended to pyrazines disubstituted by imidazole and imidazolium motifs in positions 2,6 and 2,5 to form highly condensed conjugated systems with fluorescence properties. A catalytic system containing silver triflate and sodium acetate was active for the imidazolium and benzimidazolium salts whereas Cu(OAc)2 was more efficient for the neutral imidazoles (Scheme [15], top).[30] The reaction mechanism is similar to the one described in Scheme [14] but involving a 4 C–H bond activation events thanks to rhodium via 2 rollovers, and 2 annulations (Scheme [15], bottom).

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Scheme 15 C–H dehydrogenative/cyclizing alkenylation of pyrazine imidazolium salts with alkynes under rhodium catalysis (top) and plausible reaction mechanism (bottom); Rh = [Cp*RhCl2]2 (3 mol%)

The cross dehydrogenative coupling of 4-anilinoquinazolines with internal alkynes offers an excellent example of site-selectivity in C–H bond activation/annulation controlled by the catalytic system. ortho C–H selective annulation on the aniline fragment was observed with a palladium catalyst in DMF giving indole-substituted quinazolines, whereas a ruthenium catalyst in PEG-400 gave annulation at the peri C–H bond of the quinazoline ring to furnish pyrido-fused quinazolines (Scheme [16], top). This is due to the different behaviour of the same directing group in each catalytic system. With palladium, a six-membered palladacycle is formed with the quinazoline as directing group activating the aniline ortho-C–H bond. With ruthenium the formation of a five-membered ruthenacycle upon activation of the peri-C–H bond of the quinazoline directed by the amino group of aniline is favored (Scheme [16], bottom). In both cases, a broad scope of alkynes and substituted quinazolines were evidenced and the different families of products corresponding to concomitant C–C and C–N bond formation were obtained in 55–68% yields (Scheme [16], top).[31]

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Scheme 16 Site-selective dehydrogenative cyclizing coupling of 4-anilinoquinazolines and alkynes under palladium and ruthenium catalysts (top) and plausible reaction mechanism for the ruthenium-catalyzed methodology (bottom); Ru = [RuCl2(p-cymene)]2 (5 mol%), Pd = Pd(OAc)2 (10 mol%)

#
# 5

Transition-Metal-Catalyzed C–H Arylation of Diazines

Two strategies have been investigated to perform the (hetero)arylation of diazines via C–H bond activation in the presence of transition metal catalysts: (i) oxidative C–H/C–H cross coupling of diazines with (hetero)arenes directly from unactivated substrates, which represents the most attractive approach from an atom- and step-economy point of view,[32] and (ii) (hetero)arylation with (pseudo)halides

5.1

Metal-Catalyzed Arylation via Oxidative Coupling

The first dehydrogenative cross coupling of diazines involved 2-methylthiophene as coupling partner in the presence of Pd(II) associated with a phenanthroline ligand, PivOH as proton shuttle, and AgOAc as oxidant to close the catalytic cycle (Scheme [17], top).[33] With this catalytic system using a large excess of diazine as solvent, diazines were selectively arylated at the α-position of one nitrogen atom, pyrazine being more reactive than pyrimidine and pyridazine. Quinoxaline was arylated by 2-methylthiophene in 45% yield under the same conditions. Other reaction conditions for the oxidative coupling of quinoxaline with 1,2-dichlorobenzene using Pd(OAc)2 without the use of the N,N-chelating phenanthroline ligand and working under air at higher temperature gave the 2-arylated quinoxaline product in only 24% yield (Scheme [17], top).[34] The mechanism for this type of reaction involves initial coordination of the nitrogen from the diazine to the palladium catalyst followed by a palladium shift/deprotonation at the neighboring α-position. A trans-effect at palladium is also postulated for enabling η6-binding of the substrate to the palladium. Next, electrophilic palladation with the coupling partner H-Het/Ar precedes the reductive elimination and the formed Pd(0) species are in situ oxidized with silver(I) salts.

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Scheme 17 Oxidative C–H/C–H cross-coupling of diazines enabling formal (hetero)arylation under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)

A system consisting of Pd(OAc)2/AgOPiv/PivOH was also shown to be efficient for the oxidative homocoupling of diazine derivatives at 140 °C (Scheme [18]). The C–C coupling took place at a vicinal carbon with respect to the nitrogen atom, more precisely at C4 of pyrimidine and C2 of 2,6-dimethylpyrazine to give the corresponding 2,2′-bis-diazines in 42% and 39% yields, respectively.[35] The selectivity for these examples is explained as discussed in Scheme [17] (bottom).

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Scheme 18 Oxidative C–H/C–H homocoupling of diazines enabling formal (hetero)arylation under palladium catalysis; Pd = Pd(OAc)2 (0.1 mmol)
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Scheme 19 Oxidative C–H/C–H coupling of quinoxaline enabling formal (hetero)arylation under iridium catalysis (top) and plausible reaction mechanism (bottom); Ir = [IrCp*Cl2]2 (1 mol%)

Besides palladium catalysts, the Ir(III) complex [IrCp*Cl2]2 in the presence of NaOTf in tert-amyl alcohol has made possible the oxidative coupling of pyrrole and indoles with quinoxaline under mild conditions at 110 °C. The new C–C bond connects C2 of the diazine and C3 of the cross-coupling partner (Scheme [19], top).[36] In this case, the reaction begins with C–H functionalization at the most acidic indole C3 site whereas the sodium triflates activates C2 of the diazine that undergoes C–C bond formation followed by β-hydride elimination and regeneration of the catalytically active Ir(III) species with concomitant formation of H2 in each catalytic cycle (Scheme [19], bottom).


# 5.2

Metal-Catalyzed Arylation via Coupling with (Pseudo)halide (Hetero)aryl Coupling Partners

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Scheme 20 C–H arylation of pyridazine and pyrimidine under copper catalysis (top) and plausible reaction mechanism (bottom); Cu = CuI (10 mol%)

The interest in biaryl derivatives for various applications has triggered the search for efficient synthetic strategies. Indeed, the arylation of N-heterocyclic substrates based on C–H bond activation was rapidly investigated as soon as efficient transition metal catalysts were discovered for the arylation of aromatics.[37] In 2008, a copper iodide/phenanthroline catalytic system performed the first phenylation of pyrimidine and pyridazine by phenyl iodide in the presence of Et3COLi as a base in N,N′-dimethylpropyleneurea (DMPU) at 125 °C. The more acidic C–H bond of the diazine was activated leading to the formation of an organocopper(I) intermediate at C4 for pyridazine and C5 for pyrimidine (Scheme [20], top).[38] The best yield obtained with pyridazine was attributed to the higher acidity of the C4 proton. The mechanism operating likely involves base-assisted C–H metalation followed by copper transmetalation and Ullmann-type arylation (Scheme [20], bottom). Related versions with CuCl2 and MnCl2 as the precatalysts, respectively, have been reported.[39] [40]

Mono- and diarylation of pyrazine and quinoxaline were next achieved in good yields with Ph2Zn as aryl source in the presence of the Ni(0) precursor Ni(cod)2 associated with PCy3 (Scheme [21], top).[41] In this reaction, the formation of an intermediate 3,4-dihydropyrimidine from 2-methylpyrimidinev was observed (Scheme [21], bottom), which directed the mechanism towards formation of an azanickelacyclopropane that undergoes further transmetalation with diphenylzinc rather than a direct C–H bond activation via classical deprotonation or oxidative addition.

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Scheme 21 C–H arylation of pyrazine and quinoxaline under nickel catalysis; Ni = Ni(COD)2 (5 mol%)

Rh(I) complexes, already mentioned in the alkylation of diazines, also promote the arylation of diazines at vicinal positions to the nitrogen atom in these heterocycles. Disappointingly, the arylation of 2,3-dimethylpyrazine and 4,6-dimethylpyrimidine with 2-bromonaphththalene at 175 °C for 24 h led to the corresponding naphthyl-substituted product in only 26% and 33% yield, respectively.[42] On the other hand, catalytic amounts of Rh2(OAc)4 and 1,3-bis(mesityl)imidazolium chloride (IMes·HCl) in the presence of 2.5 equiv. of t BuONa allowed monoarylation at the peri-position of phenazine, an extended quinoxaline structure, with phenyl bromide in 73% yield (Scheme [22], top).[43] Although no mechanistic cycle was proposed, key rhodacycle species, either dimeric or monomeric, for the C–H activation step were postulated (Scheme [22], bottom). It must be underlined that the use of the catalytic system [RhCl(coe)]2/ PCy3/NEt3 was unsuccessful for the phenylation of quinazoline with PhI at 150 °C in THF, whereas under similar conditions 3,4-dihydroquinazoline was directly phenylated to give 2-phenylquinazoline in 78% yield, probably via cross coupling giving phenyldihydroquinazoline followed by dehydrogenative aromatization.[42]

Palladium catalysis proved very efficient for diazine arylation based on coordination of a nitrogen atom and/or the easy deprotonation of specific acidic protons of these N-heterocycles without the introduction of a directing group orientating the C–H bond activation. For instance, 2-aminopyrimidines were arylated with aryl halides in the presence of Pd(OAc)2 as catalyst precursor associated with pyridine as ligand, Na2CO3 as a base, and Ag2CO3 as halide abstractor (Scheme [23], top).[20] The reaction tolerated both electron-donating and -withdrawing groups on the aryl group. It was assumed to proceed via a Pd(II)/Pd(IV) catalytic cycle with initial oxidative addition involving the aryl halide, subsequent C–H activation involving dearomatization, base-assisted aromatization, and ending with reductive elimination and regeneration of the active Pd(II) species upon reaction with silver salts (Scheme [23], bottom). Only secondary amines were reactive, which suggests that the carbonate-assisted deprotonation of the amino group enhances the electronic density at C5 favoring palladation at this position.

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Scheme 22 C–H arylation of phenazine under rhodium catalysis (top) and key rhodacycle species involved in the C–H activation step (bottom); Rh = Rh2(OAc)4 (3 mol%)
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Scheme 23 C–H 5-arylation of 2-aminopyrimidines under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%), B = base

Condensed 3-aminoimidazo[1,2-a]pyrazines were regioselectively arylated at the vicinal carbon of the pyrazine ring that is not involved in the bicyclic structure. The catalytic system was based on Pd(OAc)2 and triphenylphosphine in the presence of PivOH and K2CO3 (Scheme [24], top).[44] The use of excess aryl bromide (2.5 equiv.) as the arylating agent gave a variety of C6-arylated 3-aminoimidazo[1,2-a]pyrazines in 46–74% yields. The mechanism of the reaction involves initial formation of Pd(II) species upon oxidative addition with aryl halide, halide/carboxylate exchange at palladium, concerted metalation deprotonation at the most acidic C–H bond of the diazine substrate, and finally reductive elimination and regeneration of the Pd(0) species (Scheme [24], bottom). It is noteworthy that when R1 (Scheme [24], top) was an aryl group, arylation could also take place at the ortho-position of this group depending on the nature of the catalytic system, but the use of PPh3 as ligand and PivOH completely inhibited the formation of this regioisomer.

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Scheme 24 C–H arylation of imidazopyrazines under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)

A related catalytic system using an optically pure bidentate phosphine-phosphine oxide ligand produced a racemic mixture of 5-aryl-2-phenylimidazo[1,2-a]pyrimidine in 11% yield as a side product, the major product, 3-aryl-2-phenylimidazo[1,2-a]pyrimidine, resulting from arylation of the imidazole ring was obtained in 50% yield (68:32 er) (Scheme [25]).[45]

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Scheme 25 C–H arylation of an imidazopyrimidine derivative under palladium catalysis; Pd = Pd(OAc)2 (10 mol%)

Quinoxaline-6,7-dicarbonitriles readily undergo selective C–H diarylation at both C5 and C8 under palladium catalysis in the presence of an aryl bromide as the coupling partner (Scheme [26]).[46] The most appropriate catalytic system was Pd(OAc)2 as the catalyst precursor and P t Bu2Me as the ligand in a 1:2 ratio together with a combination of PivOH and K2CO3 in excess. Modified reactions replacing the palladium precursor with Pd2dba3 and the base with K3PO4 enabled the same type of reactivity with 6,7-dinitroquinoxalines (Scheme [27]). These reactions were compatible with thiophene as the heteroarylating source. These methodologies afforded poly(hetero)aromatic products relevant for materials science as they are strong electron acceptors.

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Scheme 26 C–H arylation of dicyanoquinoxalines under palladium catalysis; Pd = Pd(OAc)2 (10 mol%)
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Scheme 27 C–H arylation of dinitroquinoxalines under palladium catalysis; Pd = Pd2dba3 (10 mol%)

6-Bromoquinoxaline was found to undergo a sequence of cross-coupling and annulation with 1-(2-bromophenyl)-1-phenylethene under palladium catalysis affording an original poly(hetero)aromatic system (Scheme [28], top).[47] The authors demonstrated the importance of using bis[(2-diphenylphosphino)phenyl] ether (DPEphos) as the ligand, yet the product was formed in a poor yield. The reaction mechanism (Scheme [28], bottom) likely operates by first reacting with the 1-(2-bromophenyl)-1-phenylethene reagent via oxidative addition at palladium, intramolecular C–H activation, and formation of a five-membered ring palladacycle, which was characterized by the authors. A Heck-type event occurs between the palladium-ligated olefin and the C–Br bond of the diazine leading to the arylated olefin backbone that places the C–H bond at C5 of the quinoxaline near to the palladium to enable a second C–H activation step. Final reductive elimination affords the final product with concomitant formation of Pd(0) species.

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Scheme 28 Sequential Heck/C–H arylation of 6-bromoquinoxaline under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)

In 2020, the Yu group reported a palladium tridentate template comprising of a nitrile group that enabled selective C–H arylation in remote positions of heterocycles under palladium catalysis.[48] Particularly, by means of a mediator (NBE-CO2Me, NBE = norbornene) and a very specific set of reagents, it was possible to perform the very challenging C7-arylation of 2-methoxyquinoxaline although in a modest yield of 43% (Scheme [29]). The reaction mechanism resembles the action mode already described in Scheme [9] (bottom) but with an additional switch in the C–H activation step from C8 to C7 due to a Catellani-type mechanism involving the norbornene derivative.

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Scheme 29 Remote C–H arylation of 2-methoxyquinoxaline under palladium catalysis; Pd = Pd(OAc)2 (10 mol%)
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Scheme 30 Intramolecular C–H arylation of N-(2-iodophenyl)diazinecarboxamides under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)

Iodine-containing diazines underwent intramolecular C–H arylation under palladium catalysis provided that the amide behaved as an ortho-directing group (Scheme [30], top).[49] C–H arylation of N-(2-iodophenyl)-N-methylpyrimidine-5-carboxamide gave the corresponding product in higher yield (79%) compared to N-(2-iodophenyl)-N-methylpyrazine-2-carboxamide (49%). In the case of pyridazine a mixture of regioisomers was observed in almost statistical ratio with an overall 52% yield. The reaction is thought to proceed via initial oxidative addition of the C–I bond to palladium and intramolecular C–H activation via the concerted metalation deprotonation pathway; upon reductive elimination, Pd(0) and the product are formed (Scheme [30], bottom).

Similarly, a directing group strategy was applied to the ruthenium-catalyzed C–H arylation of N,N-diethylpyrazine-2-carboxamide (Scheme [31]).[50] In this case, the arylating coupling partner is derived from boroneopentylate and the tertiary amide behaved as an ortho-directing group within the diazine core leading to the C3-arylated product in poor yield when using RuH2(CO)(PPh3)3 as the metal pre-catalyst in toluene solvent.

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Scheme 31 Intermolecular C–H ortho-arylation of N,N-diethylpyrazine-2-carboxamide by amide chelation under ruthenium catalysis; Ru = RuH2(CO)(PPh3)3 (10 mol%)

Analogously, an iron-catalyzed methodology was applied to the selective ortho-C–H arylation of 2-(1-(phenyl­imino)ethyl)pyrazine containing an imine group that behaves as directing group (Scheme [32]).[51] A bipyridine ligated iron complex is assumed to be the active species and excess PhMgBr (6 equiv.) as the arylating coupling partner was employed with 20 mol% of KF as additive using a mixture of chlorinated solvents. A final hydrolysis step was performed to obtain the ketone-containing diazine derivative in 25% yield.

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Scheme 32 Intermolecular C–H ortho-arylation of 2-(1-(phenylimino)ethyl)pyrazine by imine chelation under iron catalysis; Fe = Fe(acac)3 (10 mol%)

In the same vein, the Ackermann group reported a manganese-catalyzed C–H arylation with secondary amides behaving as ortho-directing groups.[52] This protocol was applied to N-butylpyrimidine-4-carboxamide with 4-methoxyphenylmagnesium bromide as the arylating agent leading to the corresponding product in 50% yield after 16 hours at 60 °C (Scheme [33], top). Interestingly, similar efficiencies (53% yield) were reached under flow conditions in less than 2 hours at 80 °C. The catalytically active system required the presence of catalytic amounts of MnCl2 and a phenanthroline-type ligand in 1:2 ratio as well as over-stoichiometric amounts of TMEDA and 1,2-dichloro-2-methylpropane. According to computational calculations and experimental data, the reaction mechanism operates via a manganese(II/III/I) catalytic cycle as shown in Scheme [33] (bottom). The role of the tetrahydrofuran solvent is key to stabilize otherwise inaccessible intermediates and transition states. On the other hand, the 1,2-dichloro-2-methylpropane reagent served as an oxidant. Note that one Ar-H is formed as side product at each turnover during the manganese-mediated C–H activation step and that the final reductive elimination takes place in a pentacoordinated manganese(III) species.

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Scheme 33 Intermolecular C–H ortho-arylation of pyrimidine by amide chelation under manganese catalysis (top) and plausible reaction mechanism (bottom); Mn = MnCl2 (10 mol%), S = THF solvent

The Larrosa group developed palladium-catalyzed C–H arylation mediated by a carboxylic acid as the ortho-directing groups.[53] In this context, they reported a single case of pyridazine-4-carboxylic acid that gave selectively the C5-arylated derivative in 29% yield when using 1-chloro-3-fluorobenzene as an aryl chloride coupling partner (Scheme [34]). In addition, the authors demonstrated the relevance of generating the active species by in situ combination of Pd(OAc)2 with a trialkylphosphine ligand.

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Scheme 34 Intermolecular C–H ortho-arylation of pyridazine-4-carboxylic acid by chelation under palladium catalysis; Pd = Pd(OAc)2 (5 mol%)

Maiti and co-workers developed selective C–H arylations in the pyridazine core under palladium catalysis.[54] By benefiting from the directing ability of a rationally placed 1,2,4-triazole motif near the C–H activation site, a large number of functionalized pyridazines were regioselectively arylated (Scheme [35], top). Importantly, the reaction conditions did not require the use of any phosphine ligand. A reaction time of 12 hours was needed, and the yields were relatively high. The reaction mechanism is thought to begin with a C–H activation step mediated by palladium at the C8–H in the pyridazine ring fused to the triazole ring (Scheme [35], bottom). After oxidative addition with the aryl iodide coupling partner and subsequent reductive elimination, the final arylated diazine product is formed and Pd(OAc)I undergoes a final anion metathesis to regenerate the active Pd(OAc)2 catalyst.

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Scheme 35 Intermolecular C–H arylation of pyridazine-fused 1,2,4-triazoles under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)

The Bristol-Myers Squibb Company developed palladium-catalyzed C–H arylations on a quinazoline derivative in order to access libraries structurally related to the IKur inhibitor BMS-919373.[55] The key precursor contains a C4 2-picolylamine group that behaved as directing group in order to obtain selective C5 arylation (Scheme [36], top). The catalysis performed well only with the more reactive (hetero)aryl iodides as coupling partners under phosphine-free palladium conditions with anisole as the solvent. Analogous 2-methyl- and 2-phenylquinazoline derivatives afforded comparable levels of reactivity (Scheme [36], middle). The reaction mechanism for this palladium-catalyzed C–H arylation of quinazoline starts with the coordination of palladium to the N,N-chelating fragment in the substrate (Scheme [36], bottom). C–H activation at the C5 site leads to a C,N,N-pincer-like palladabicyclic species that undergoes oxidative addition with the aryl iodide and final reductive elimination to form the 5-arylquinazoline and the active Pd(OAc)2 catalyst.

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Scheme 36 Intermolecular C–H bond (hetero)arylation of a biologically important quinazoline derivative under palladium catalysis (top), application to a less sophisticated system (middle), and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)

They also noted that raising the number of equivalents of base to five as well as doubling the amounts of palladium precursor led an additional C–N bond-forming reaction between phenyl group introduced at C5 and the amine group of the directing group (Scheme [37], top).[56] As such, the original late-stage functionalization is targeted using palladium-catalyzed C–H arylation methodology. Regarding the reaction mechanism (Scheme [37], bottom), once the C–H arylation takes place (Scheme [36]), palladium coordinates to the N,N-chelating fragment leading to ortho-C–H activation in the newly installed aryl motif followed by reductive C–N elimination. The remaining palladium species is reoxidized by the excess aryl iodide as observed by the formation of biphenyl as side product during the catalysis.

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Scheme 37 Inter- and intramolecular C–H functionalization of a biologically important quinazoline derivative under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)

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# 6

Transition-Metal-Catalyzed C–H Carboxylation of Diazines

In 2010, the Nolan group reported what is so far the only example of C–H carboxylation within the diazine core, namely pyridazine (Scheme [38], top).[57] The catalyst design is based on a gold-carbene complex that catalyzes the CO2 insertion at the most acidic C–H bond leading to pyridazine-4-carboxylic acid, a useful heteroaromatic carboxylic acid scaffold, in 82% yield. The protocol required one equivalent of KOH in the gold-catalyzed step and acidic treatment in the second step. This reaction aims to create value from the greenhouse gas CO2. The reaction mechanism of this gold-catalyzed C–H functionalization of diazine is depicted in Scheme [38] (bottom). The gold-hydroxide carbene complex abstracts the hydrogen from the substrate with formation of water as side product and formation of a new Au–C bond. CO2 inserts into this bond to give a carboxylate bonded gold carbene species that undergoes ligand exchange with hydroxide forming back the active gold-carbene species and the carboxylated product that can be protonated during the workup at the end of the reaction.

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Scheme 38 Gold-catalyzed C–H carboxylation of pyridazine with CO2 under gold catalysis (top) and plausible reaction mechanism (bottom); Au = (I t Bu)AuOH (1.5 mol%)

# 7

Conclusion

We have summarized the main discoveries concerning the selective C–H functionalization of diazines enabling formation of new C–C bond-forming processes. In particular, C–H olefinations and C–H arylations appear to be the most reliable so far, although examples of alkylation, alkynylation, and carboxylation are known. However, in general, the yields obtained from all the above-discussed metal-catalyzed methodologies are rather modest compared to the non-heteroaromatic versions. This clearly highlights the difficulty to directly perform C–H functionalizations on diazines. On the other hand, since diazine motifs are important building blocks in a variety of fields, it is of high interest and urgency to further develop technologies to circumvent the poor reactivity encountered not to mention to address selectivity issues when multiple C–H sites are available for reaction. Interestingly, as diazines are also used as directing groups for C–H functionalizations,[58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] examples merging this strategy with direct C–H functionalization at the diazine core in a one-pot or cascade manner might be appealing to undertake.[75] With this review, we hope to stimulate the scientific community to developing efficient tools to tackle C–H functionalizations of diazines en route to complex structures.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Rafael Gramage-Doria
Univ Rennes, ISCR UMR 6226
35000 Rennes
France   

Publication History

Received: 22 May 2023

Accepted after revision: 20 July 2023

Accepted Manuscript online:
20 July 2023

Article published online:
12 September 2023

© 2023. Thieme. All rights reserved

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Rafael Gramage-Doria received his Ph.D. from the University of Strasbourg (France) with Dr. Dominique Matt and Prof. Dominique Armspach. After postdoctoral fellowships with Prof. Joost N. H. Reek at the University of Amsterdam (Netherlands) and Prof. Takashi Ooi at Nagoya University (Japan), he joined in 2015 the Institute of Chemical Sciences of the University of Rennes (France) as a CNRS researcher, where he completed his Habilitation (2019). His research interests include transition metal catalysis for fine chemicals and green chemistry applications, C–H bond functionalization, coordination chemistry, and supramolecular and bio-inspired catalysis.
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Figure 1 Structural motifs of diazines and benzodiazines
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Scheme 1Rhodium-catalyzed alkylation of diazines with ethyl acrylate (top) and plausible reaction mechanism (bottom); Rh = [RhCl(cod)]2 (10 mol%)
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Scheme 2Copper-catalyzed enantioselective alkylation of pyridazines (top) and plausible reaction mechanism (bottom); Cu = Cu(OAc)2 (6 mol%)
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Scheme 3 Palladium-catalyzed alkylation/alkenylation based on the Catellani strategy (top) and plausible reaction mechanism (bottom); Pd = Pd2(dba)3 (5 mol%)
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Scheme 4Perfluoroalkylation of diazines with a cobalt nanocatalyst; Co = cobalt nanocatalyst (10 mol%)
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Scheme 5Nickel-catalyzed alkynylation of quinoxaline directed by the Q chelating group (top) and plausible reaction mechanism (bottom); Ni = NiCl2 (10 mol%)
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Scheme 6Copper-catalyzed alkynylation of diazines directed by the PIP chelating group; Cu = Cu(OAc)2 (30 mol%)
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Scheme 7Palladium-catalyzed alkenylation of pyrimidine (top) and plausible key intermediate (bottom); Pd = Pd(OAc)2 (10 mol%)
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Scheme 8Palladium-catalyzed alkenylation of 2-aminopyrimidines (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)
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Scheme 9 Template-enabled remote C–H olefination of a quinoxaline derivative under palladium catalysis (top) and postulated key palladacycle intermediate (bottom); Pd = Pd(OAc)2 (10 mol%)
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Scheme 10 C–H olefination of gefitinib under palladium catalysis; L = 3-methyl-2-isopropyl-2-(phenylthio)acetic acid, Pd = Pd(OCOCF3)2 (10 mol%)
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Scheme 11 C–H olefination of 6,7-difluoroquinoxalines with styrenes under palladium catalysis; Pd = Pd(OCOCF3)2 (5 mol%)
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Scheme 12 Amide-directed C–H olefination of pyrimidine, C–H alkylation of pyrimidine, and C–H olefination/cyclization of pyrazine derivatives under rhodium catalysis (top) and key mechanistic considerations (bottom); Rh = [Cp*RhCl2]2 = (2.5 mol%)
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Scheme 13 C–H alkenylation of diazines with alkynes under nickel catalysis and under cobalt catalysis, respectively (top) and plausible reaction mechanism (bottom); Ni = Ni(cod)2 (3 mol%), Co = Co(acac)3 (5 mol%)
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Scheme 14 C–H dehydrogenative/cyclizing alkenylation of a pyrazine derivative under rhodium catalysis (top) and plausible reaction mechanism (bottom); Rh = [Cp*RhCl2]2 (4 mol%)
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Scheme 15 C–H dehydrogenative/cyclizing alkenylation of pyrazine imidazolium salts with alkynes under rhodium catalysis (top) and plausible reaction mechanism (bottom); Rh = [Cp*RhCl2]2 (3 mol%)
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Scheme 16 Site-selective dehydrogenative cyclizing coupling of 4-anilinoquinazolines and alkynes under palladium and ruthenium catalysts (top) and plausible reaction mechanism for the ruthenium-catalyzed methodology (bottom); Ru = [RuCl2(p-cymene)]2 (5 mol%), Pd = Pd(OAc)2 (10 mol%)
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Scheme 17 Oxidative C–H/C–H cross-coupling of diazines enabling formal (hetero)arylation under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)
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Scheme 18 Oxidative C–H/C–H homocoupling of diazines enabling formal (hetero)arylation under palladium catalysis; Pd = Pd(OAc)2 (0.1 mmol)
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Scheme 19 Oxidative C–H/C–H coupling of quinoxaline enabling formal (hetero)arylation under iridium catalysis (top) and plausible reaction mechanism (bottom); Ir = [IrCp*Cl2]2 (1 mol%)
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Scheme 20 C–H arylation of pyridazine and pyrimidine under copper catalysis (top) and plausible reaction mechanism (bottom); Cu = CuI (10 mol%)
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Scheme 21 C–H arylation of pyrazine and quinoxaline under nickel catalysis; Ni = Ni(COD)2 (5 mol%)
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Scheme 22 C–H arylation of phenazine under rhodium catalysis (top) and key rhodacycle species involved in the C–H activation step (bottom); Rh = Rh2(OAc)4 (3 mol%)
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Scheme 23 C–H 5-arylation of 2-aminopyrimidines under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%), B = base
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Scheme 24 C–H arylation of imidazopyrazines under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)
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Scheme 25 C–H arylation of an imidazopyrimidine derivative under palladium catalysis; Pd = Pd(OAc)2 (10 mol%)
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Scheme 26 C–H arylation of dicyanoquinoxalines under palladium catalysis; Pd = Pd(OAc)2 (10 mol%)
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Scheme 27 C–H arylation of dinitroquinoxalines under palladium catalysis; Pd = Pd2dba3 (10 mol%)
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Scheme 28 Sequential Heck/C–H arylation of 6-bromoquinoxaline under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)
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Scheme 29 Remote C–H arylation of 2-methoxyquinoxaline under palladium catalysis; Pd = Pd(OAc)2 (10 mol%)
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Scheme 30 Intramolecular C–H arylation of N-(2-iodophenyl)diazinecarboxamides under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)
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Scheme 31 Intermolecular C–H ortho-arylation of N,N-diethylpyrazine-2-carboxamide by amide chelation under ruthenium catalysis; Ru = RuH2(CO)(PPh3)3 (10 mol%)
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Scheme 32 Intermolecular C–H ortho-arylation of 2-(1-(phenylimino)ethyl)pyrazine by imine chelation under iron catalysis; Fe = Fe(acac)3 (10 mol%)
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Scheme 33 Intermolecular C–H ortho-arylation of pyrimidine by amide chelation under manganese catalysis (top) and plausible reaction mechanism (bottom); Mn = MnCl2 (10 mol%), S = THF solvent
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Scheme 34 Intermolecular C–H ortho-arylation of pyridazine-4-carboxylic acid by chelation under palladium catalysis; Pd = Pd(OAc)2 (5 mol%)
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Scheme 35 Intermolecular C–H arylation of pyridazine-fused 1,2,4-triazoles under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)
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Scheme 36 Intermolecular C–H bond (hetero)arylation of a biologically important quinazoline derivative under palladium catalysis (top), application to a less sophisticated system (middle), and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (5 mol%)
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Scheme 37 Inter- and intramolecular C–H functionalization of a biologically important quinazoline derivative under palladium catalysis (top) and plausible reaction mechanism (bottom); Pd = Pd(OAc)2 (10 mol%)
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Scheme 38 Gold-catalyzed C–H carboxylation of pyridazine with CO2 under gold catalysis (top) and plausible reaction mechanism (bottom); Au = (I t Bu)AuOH (1.5 mol%)