Advances in Metal-Catalyzed Cross-Coupling Reactions of Halogenated Quinazolinones and Their Quinazoline Derivatives

Halogenated quinazolinones and quinazolines are versatile synthetic intermediates for the metal-catalyzed carbon–carbon bond formation reactions such as the Kumada, Stille, Negishi, Sonogashira, Suzuki-Miyaura and Heck cross-coupling reactions or carbon-heteroatom bond formation via the Buchwald-Hartwig cross-coupling to yield novel polysubstituted derivatives. This review presents an overview of the application of these methods on halogenated quinazolin-4-ones and their quinazolines to generate novel polysubstituted derivatives.


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Lapatinib 3, a 6-heteroaryl substituted 4-anilinoquinazoline derivative is an oral dual tyrosine kinase inhibitor (TKI) that targets both EGFR and HER2 to inhibit the proliferation of breast cancer cells [3]. The 6-alkynylated 4-aminoquinazolines 4 and 5 (Figure 2), on the other hand, serve as selective inhibitors of Aurora A [4]. Likewise, the 4-anilinoquinazoline derivative 6 (CP-724,714) is a selective ErbB2 angiogenesis inhibitor under investigation for the treatment of breast, ovarian and other types of cancer [5]. During the course of the exploration of non-anilinoquinazoline scaffold, trisubstituted quinazoline derivatives such as 4-(3-bromophenyl)-8-(trifluoromethyl)-2-phenylquinazoline 7a and 4-(3-bromophenyl)-2-(thiophen-2-yl)-8-(trifluoromethyl)quinazoline 7b ( Figure 3) were prepared as part of a series of liver X-receptor modulators [6]. Likewise, the 4-alkynylquinazolines 8 were found to be potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors [7]. New findings on the biological and photophysical properties of polycarbo-substituted quinazolinones and quinazolines reveal a need to increase the diversity of substituents around these heterocyclic scaffolds. To this end, halogenated quinazolinones and quinazoline derivatives have established themselves as important intermediates for the synthesis of polycarbo-and polyheteroatom-substituted derivatives with potential application in material and medicinal chemistry. The versatility of the halogenated heterocycles as synthetic intermediates is a consequence of Csp 2 -X bonds, which enable further elaboration into polycarbo-substituted or polyheteroatom-substituted derivatives. Despite the importance of metal catalysed cross-coupling reactions in synthesis, there is no comprehensive review in the literature on the application of these methods on halogenated quinazolinones and quinazolines to afford polysubstituted derivatives. Only a few examples of transition metal mediated cross-coupling of halogenated quinazolinones or quinazolines are described in a monograph by de Vries [8] and the review paper by Connolly et al. [9]. Most of the review articles in the literature on quinazolinones and quinazolines, on the other hand, only focus on the conventional and microwave syntheses of heteroatom-substituted derivatives as well as their medicinal applications [10][11][12]. This prompted us to compile a comprehensive review on the application of the Kumada, Stille, Negishi, Sonogashira, Suzuki-Miyaura and Heck cross-coupling as well as the Buchwald-Hartwig cross-coupling and palladium-catalysed cyanation in the synthesis of polycarbo-or polyheteroatom-substituted quinazolinones and quinazolines derivatives from the corresponding halogenated precursors.

Reactivity of Halogenated Quinazolinones and Quinazoline Derivatives in Cross-Coupling Reactions
The use of halogenated quinazolinones and quinazolines as intermediates in transition metal-catalyzed cross-coupling reactions to form Csp 2 -Csp 2 , Csp 2 -Csp or Csp 2 -heteroatom bond(s) takes advantage of the ease of displacement of iodine, bromine, or chlorine atom(s) on the aryl or heteroaryl moiety by nucleophiles or metal catalysts. The order of reactivity of Csp 2 -halogen bonds in transitional metal-mediated cross-coupling for aryl/heteroaryl halides, C-I > C-Br >> C-Cl, generally allows selective coupling with iodides or bromides in the presence of chlorides [13,14]. Theoretical calculations at B3LYP level, on the other hand, reveal that the bond dissociation energy of the C(4)-Cl bond (84.8 kcal/mol) of 6-bromo-2,4-dichloroquinazoline is larger than that of the weaker Csp 2 -Br bond (83 kcal/mol at B3LYP) [15]. The Csp 2 -Cl bond of the 4-chloroquinazoline moiety is, however, highly activated relative to other chlorinated or brominated positions due to α-nitrogen effect and additional activation resulting from the coordination of palladium(0) with the N-3 lone pair electron density in the oxidative-addition step [15][16][17]. Among the cross-coupling reactions with organometallic reagents that involve halogenoquinazolinones and halogenoquinazolines as well as their tosylate derivatives, Sonogashira and Suzuki-Miyaura cross-coupling reactions and to some extent the Heck reaction are more prevalent. Only limited examples involving the application of the Kumada, Stille and Negishi cross-coupling reactions in the synthesis of polycarbo-substituted quinazolinones and quinazolines exist in the literature. This also applies for the miscellaneous methods such as Buchwald-Hartwig cross-coupling and palladium catalysed cyanation of halogenated quinazolinones and quinazoline derivatives.

Application of Cross-Coupling Reactions in the Synthesis of Substituted Quinazolinones and Quinazolines
The development of metal-catalyzed cross-coupling reactions over the past decade has revolutionized the way carbon-carbon and carbon-heteroatom bonds are formed. Kumada, Negishi, Heck, Suzuki-Miyaura, Stille and Sonogashira cross-coupling reactions represent powerful synthetic tools for the construction of carbosubstituted quinazolinones and/or quinazolines. The Buchwald-Hartwig cross-coupling and Pd-catalyzed cyanation, on the other hand, have also been employed for the synthesis of novel heteroatom-or cyano-substituted quinazolinones and quinazoline derivatives.

Application of Kumada Cross-Coupling Reaction in the Synthesis of Polysubstituted Quinazolines
Kumada cross-coupling involves the reaction of arylhalides or triflates with Grignard reagents in the presence of palladium catalyst. Despite its relatively early discovery, the application of the Kumada reaction is only limited to the transformation of halogenated quinazolines because of the incompatibility of Grignard reagents with the amide group of quinazolinones. The reducing ability of the Grignard reagents, on the other hand, has been found to cause the precipitation of palladium black and, in turn, arrest the catalytic turnover. A modification of this reaction involving the cross-coupling of 2,4-dichloroquinazoline (R = H) or its 2,4-dichloro-6,7-dimethoxyquinazoline derivative (R = OMe) 9 with tert-butylmagnesium chloride in the presence of copper(I) iodide as catalyst in tetrahydrofuran (THF) at room temperature afforded the 4-substituted quinazoline derivatives 10a (92%) and 10b (63%) in less than an hour (Scheme 1) [18]. The selectivity of Csp 2 -Csp 2 bond formation in this case is attributed to the increased reactivity of the C-4 position of the quinazoline ring due to the α-nitrogen effect. Anhydrous manganese chloride (MnCl2) or manganese chloride tetrahydrate (MnCl2.4H2O) have also been employed to promote the cross-coupling of 4-chloro-2-phenylquinazoline with phenylmagnesium chloride in THF for 1.5 h to afford 2,4-diphenylquinazoline in 71% yield [19]. Despite its efficiency, this method makes use of an excess of the Grignard reagent (4 equiv.), which only tolerates limited functional groups on both of the coupling partners. The mild reaction conditions as well as the lower cost of copper(I) iodide and manganese chloride nevertheless, render these modified methods an attractive alternative for the synthesis of carbosubstituted quinazolines using palladium or nickel salts. Scheme 1. CuI-catalyzed cross-coupling of 9 with tert-butylmagnesium chloride.
The high nucleophilicity of the readily accessible Grignard reagents generally limits the application of the Kumada cross-coupling towards the synthesis of novel polycarbo-substituted quinazolinones.

Application of Negishi Cross-Coupling in the Synthesis of Polysubstituted Quinazolines
The Negishi cross-coupling reaction of aryl or vinyl halides/triflates with organozinc reagents in the presence of palladium [Pd 0 , Pd 2+ ] or nickel source [Ni 0 , Ni 2+ ] as catalyst and a phosphine ligand is a versatile and efficient method for the synthesis of a variety of heterocyclic motifs [20]. Organozinc reagents can be prepared either from the corresponding organohalide (RX) by reductive metalation [21] or from other organometalic compounds, often RLi, by transmetalation [22]. The cross-coupling reaction normally occurs at or slightly above room temperature to avoid the degradation of the zinc compound at high temperature. This reaction has thus far only been employed for the synthesis of carbo-substituted quinazolines from the corresponding halogenated precursors. The Negishi cross-coupling between the 4-substituted 2-chloro-6,7-dimethoxyquinazolines 11 and CH3ZnCl reagent generated in situ from methyl lithium and zinc(II) chloride in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) as a Pd(0) catalyst source in dioxane, for example, previously afforded compounds 12 (Scheme 2) [17].  (2-Pyridyl)zinc chloride prepared, in turn, from 2-bromopyridine by halogen-metal exchange with isopropylmagnesium chloride followed by addition of zinc chloride [24], was reacted with 2-chloro-5iodo-6,7-dimethoxyquinazolin-4-amine 16 in the presence of palladium acetate-triphenylphosphine catalyst complex in THF under reflux to afford a mixture of the cross-coupled product 17 and the reduced derivative 18 (Scheme 4) [25]. The latter was formed as a sole product by treatment of 16 with 2-iodopyridine in the presence of activated zinc and Pd(OAc)2-PPh3 mixture in DMF.
Despite high sensitivity of organozinc reagents to air and moisture, their high compatibility with various functional groups make the Negishi cross-coupling reaction a powerful tool for the formation of carbon-carbon bonds.

Application of Stille Cross-Coupling in the Synthesis of Polysubstituted Quinazolines
The Stille cross-coupling which involves the reaction between organostannanes and organic halides or tosylates in the presence of Pd catalyst [26] has thus far only been employed for the synthesis of polysubstituted quinazolines from the corresponding halogenated precursors. 5-Chlorotriazoloquinazoline, for example, was subjected to Stille cross-coupling with heterarylstannanes using Pd(PPh3)4-CuI catalyst mixture in DMF at 70 °C to afford a series of 5-heteraryl-substituted triazoloquinazolines in 20%-78% yields [23]. Under the same reaction conditions, the analogous 5-tosyltriazoloquinazoline 19 reacted with heterarylstannanes 20 to afford the corresponding 5-heteraryl-substituted derivatives 21 in reasonable yields (Scheme 5) [23]. A modification of the Stille cross-coupling involving the use of 6-bromo-2,4-dichloroquinazoline 22 as substrate and trimethylalane (1.2 equiv.) as coupling partner in the presence of Pd(PPh3)4 as a source of active Pd(0) catalyst to afford a mixture of the C-4 substituted 23 (47%) and C-6 cross-coupled product 24 (16%) has been described before (Scheme 6) [16]. The preponderance of the C-4 cross-coupled product is a consequence of the increased reactivity of the C(4)-Cl bond due to the α-effect and strong coordination of Pd(0) with N-3 lone pair electrons in the oxidative-addition step. The 2-position of the pyrimidine ring, on the other hand, is generally known to be less reactive to oxidative addition of Pd than the 4-position [27].
Sonogashira cross-coupling of the 2-substituted 4-chloroquinazolines 37 with terminal alkynes 38 using Pd(PPh3)4 and CuI in the presence of cesium carbonate (Cs2CO3) in dry DMF at room temperature afforded a series of the corresponding 4-alkynylquinazolines 39 in high yields (Scheme 11) [31]. Attempted Sonogashira cross-coupling of 4-chloro-2-trichloromethylquinazoline 40 with phenylacetylene 41 using triethylamine as a base, Pd(PPh3)4 as a source of the reactive Pd(0) species and CuI as a co-catalyst in THF did not afford the expected cross-coupled product [31]. The use of Cs2CO3 as a base, Pd(OAc)2 as a catalyst in DMF, on the other hand, afforded the cross-coupled product 42 in low yield (15%) along with other undesirable products 43-45 (Scheme 12). The presence of trichloromethyl group at position 2 of 40 was found to complicate the outcome of this reaction. Likewise, 4-bromo-and 4-iodo-2-trichloromethylquinazolines prepared, in turn, from 2-trichloromethyl quinazolin-4(3H)-ones using tetrabutylammonium bromide (TBABr) and tetrabutylammonium iodide (TBAI) in the presence of P2O5 in toluene under reflux were cross-coupled with cyclopropylacetylene and phenylacetylene to afford the corresponding 4-alkynyl-2-trichloromethylquinazolines in 15% and 9%, respectively [31]. These poor yields indicate that the 4-chloroquinazoline moiety is preferred over the 4-bromo-or 4-iodoquinazoline framework in the cross-coupling reactions.

Application of Heck Cross-Coupling in the Synthesis of Polysubstituted Quinazolinones and Quinazolines
The Heck reaction which involves Pd-catalyzed [Pd(PPh3)4, PdCl2(PPh3)2, or Pd(OAc)2] carbon-carbon bond formation through inter-or intramolecular cross-coupling reaction between organohalides or triflates with alkenes is a powerful tool for the construction of alkenyl-and aryl-substituted alkenes. 2-Substituted 6-iodoquinazolin-4(3H)-one 57 was previously reacted with unprotected allyl amidines or guanidines 58 in the presence of palladium acetate as active Pd(0) source, tri-(o-tolyl)phosphine as ligand and triethylamine in acetonitrile at 80 °C to afford a series of the 6-vinyl substituted products 59 as potential vitronectin receptor (ανβ, integrin) antagonists (Scheme 17) [38]. To our knowledge, this represents the only example of the application of the Heck cross-coupling reactions on halogenated quinazolinones to afford alkenyl-substituted derivatives.  The Heck cross-coupling reaction has, however, been applied extensively on the synthesis of poly-carbosubstituted derivatives from the corresponding halogenated quinazoline precursors. For example, initial hydro-zirconation of the terminal alkynes 60 followed by a Heck-type cross-coupling involving the reaction of the incipient alkene-like intermediate with 6,7-dialkoxy-4-iodoquinazolines 61 in THF at room temperature afforded the analogous 4-alkenyl-6,7-dialkoxyquinazolines 62 (Scheme 18) [7]. Of interest is that compounds 62 serve as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors [7].

Palladium Catalyzed Cyanation in the Synthesis of Polysubstituted Quinazolines
Cyanation of aromatic halides in the presence of palladium(0) catalyst source has proven to be superior to the Rosemund-Von Braun reaction which employs stoichiometric amount of CuCN under high temperature conditions accompanied by tedious work-up [56]. An excess of the strong σ-donor cyanide ion which has high affinity for palladium tend to poison the catalyst and, in turn, retard the progress of reaction [56]. A microwave assisted cyanation of 8-bromo-6-fluoro-2-methylquinazolino-4(3H)-one 104 using zinc cyanide in the presence of tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3)-xanthphos catalyst complex afforded the C8-CN substituted product 105, exclusively (Scheme 36) [55]. Zn(CN)2 in this case serves as a source of low concentration of cyanide ion during the reaction to avoid poisoning the catalyst. A series of 2-substituted 4-tosylquinazolines 106 was recently subjected to copper(I) cyanide (2 equiv.) in the presence of palladium(II) acetate-bis(diphenylphosphino)ferrocene (DPPF) catalyst complex and cesium carbonate in toluene under reflux to yield the corresponding 4-cyanoquinazoline 107 in moderate to high yields (Scheme 37) [57]. Under the same conditions, 4-chloro-2-(4methoxyphenyl)quinazoline was found to be less reactive and to afford the corresponding 4-cyanoquinazoline in 11% yield. The nitrile group offers a useful functionality for subsequent manipulations to important functional groups such as hydrolysis into acids, hydration into amides, reduction into amines or aldehydes, and cycloaddition into various heterocycles.

Conclusions and Perspective
The observed reactivity of the dihalogenated quinazolinones in metal catalyzed C-C bond formation follows a similar trend to that observed for the other aryl/heteroaryl halides (C-I > C-Br >> C-Cl), whereby selective coupling occurs with the more intrinsically reactive iodides or bromides in the presence of chlorides. The C(4)-Cl bond of quinazoline derivatives, on the other hand, is highly activated than the other positions bearing Cl or Br due to α-nitrogen effect and in general, the oxidative addition of Pd(0) to a C(4)-Cl bond occurs easily at room temperature without the use of specialized and expensive ligands. Moreover, the 4-chloroquinazoline moiety is preferred over the 4-bromo-or 4-iodoquinazoline framework in the cross-coupling reactions [31]. Despite the successes in site-selective or sequential metal-catalyzed halogen substitution reactions, the application of this strategy towards the synthesis of polysubstituted quinazolinones and quinazolines from the corresponding di-or trihalogenated precursors in a single-pot operation remains a challenge. In our view, this could be realized through the use of di-or trihalogenated quinazolinones or quinazolines bearing mixed halogen atoms to increase the diversity of substitution on the heterocyclic scaffold/s to afford compounds with interesting biological or photophysical properties. Heterocyclic compounds with intramolecular charge transfer properties continue to attract considerable attention for potential applications in organic electroluminescent diodes, organic solar cells, polarity probes and nonlinear optics. Polycarbo-substituted quinazolinones and quinazoline derivatives comprise electron-deficient heterocyclic scaffolds (quinazolinone or quinazoline framework) as electron-acceptors linked directly to the aryl ring or through π-conjugated bridge/s to comprise donor-π-acceptor systems with intramolecular charge transfer properties. Given the need for efficient methods for the incorporation of quinazolinone and quinazoline moieties in pharmaceutical compounds or materials, it can be expected that growth and exciting new advances will continue in this important subdomain of metal-catalyzed cross-coupling research.