Synthesis of two nitrogen-containing polyaromatic compounds through gold catalysis/DBU-promoted cyclizations †

This work reports an eﬃcient synthesis of novel benzo[7,8]- indolizino[2,3,4,5-ija ]quinazoline derivatives between 2-(2-ethynyl-aryl)acetonitriles 1 and anthranils 2. The synthetic approach involves the initial formation of 7-formylindole intermediates that can be implemented by DBU to activate a novel indole–nitrile– aldehyde cyclization.

Nitrogen-doped polyarenes have attracted immense interest owing to their significance as electronic and pharmaceutical materials. 1,2Nevertheless, synthetic procedures to access such heteroaromatic compounds are long and tedious. 1,2Reported examples are largely limited to those polyarenes containing only one nitrogen atom.There is considerable interest in synthesizing polyarenes containing two or more nitrogen atoms, but little success is achieved toward material application. 3Fig. 1 shows those polyarenes containing two nitrogen atoms, which have optoelectronic applications. 4New convenient syntheses of such N-doped polyarenes are highly desired to expand the present small scope.
Scheme 1 (eqn ( 1)) shows a recent example of synthesizing fused four-membered benzenes such as benzo [7,8]indolizino- [2,3,4,5-ija]quinoline (I) containing one nitrogen atom that is embedded in an indole moiety. 5We are aware that the twonitrogen-containing analogues C 13 H 8 N 2 , such as species IV-VII, have not been reported in the literature (eqn ( 4)).Incorporation of one additional nitrogen in polyaromatic frameworks can alter the optoelectronic properties.The LUMO-HOMO energy levels will be significantly decreased if a pyridine ring replaces a benzene ring. 4old catalysis proves to be a powerful tool to access all-carbon fused benzene rings; 6 however, their applications to the synthesis of nitrogen-containing fused benzenes are not well explored.Recently, Hashmi reported 7 gold-catalyzed synthesis of new indole derivatives such as 2-amino-7-formylindole products (III) from the reactions of alkynes with anthranils (eqn (2)).So far, this catalytic reaction has no imminent impact on materials and medicinal chemistry.This work reports the new development of this catalytic reaction to access two-nitrogen containing fused benzenes such as benzo [7,8]indolizino [2,3,4,5-ija]quinazoline (4a), which is unprecedented in the literature (eqn (3)).This reaction sequence comprises two separate steps involving the initial treatment of 2-(2-ethynylaryl)acetonitriles 1a with anthranil 2a with a suitable gold catalyst in hot DCE, followed by a novel DBU-promoted 8 indole-nitrile-aldehyde cyclization; intermediate 3a can be isolated and well characterized.
The generality of this new catalysis is assessed using various 2-(2-ethynylaryl)acetonitriles 1 and anthranil 2a; the results are summarized in Scheme 2. The operation used IPrAuCl/AgNTf 2 in 10 mol% and 20 mol%, respectively, in the first step, and DBU (1.0 equiv.) in the second step.For substrates 1b-1d bearing various 5-phenyl substituents (R 1 = OMe, F, and Cl), their standard operations yielded the desired products 4b-4d in 62-67% yields.We prepared additional substrates 1e and 1f containing 4-phenyl substituents (R 2 = F and Cl), which delivered the desired products 4e and 4f in 56 and 55% yields, respectively.We also prepared substrates 1g and 1h bearing 3-phenyl substituents (R 3 = F and Cl), and the corresponding products 4g and 4h were obtained in 61 and 57% yields, respectively.Substrate 1i, bearing a phenylethynyl group, afforded the desired product 4i, albeit with only 21% yield.Another internal alkyne substrate, 1j (R 4 = n-butyl), failed to form the C(2)-substituted 7-formylindole intermediate through the C(a)-addition.The low efficiency of internal alkyne substrates is due to a distinct C(b)-regioselectivity for the anthranil attack on gold-p-alkyne, whereas our target 4 is produced from the alkynyl C(a)-regioselectivity.This assessment is further manifested by our control experiments (vide infra, eqn ( 5)-( 7)).
Scheme 5 depicts the chemical functionalization of compounds 4a and 5o.Treatment of species 4a with PhCOCl (1.5 equiv.)yielded a new acylation product 6a in 50% yield.Treatment of compound 4a with HCl/NaNO 2 , produced a nitrosyl-derived product 6b in 84% yield.Bromo-containing species 5o was active towards the Sonogashira reaction to yield the cross-coupling product 7a in 76% yield.The Suzuki-Miyaura cross-coupling of compound 5o with phenylboronic acid led to the formation of product 7b in 69% yield.Furthermore, the Stillecoupling reaction on species 5o with tributyl(vinyl)tin, delivered product 7c in 74% yield.The molecular structures of 6a, 6b, 7a and 7c were elucidated using X-ray diffraction. 11his gold catalysis and DBU-promoted cyclization involves an initial formation of 7-formylindole 3a (Scheme 6); its formation mechanism follows an early proposal in Hashmi's work 6 (see eqn ( 2)).The second step comprises an intramolecular reaction among indole, nitrile and aldehyde; such a three-component cyclization is unprecedented in the literature.We postulate an initial deprotonation of the indole N-H group of intermediate 3a to form an amide anion A that attacks the nitrile group to generate an imino anion B; this step does not require a gold catalyst according to our control experiment in eqn (5).A final intramolecular cyclization is likely to occur between this imino anion B and the aldehyde to generate an oxy anion C, which upon protonation by the DBU/H + complex will generate the last intermediate D. A final aromatization of this intermediate D delivers the observed product 4a.
Photophysical properties of representatives 4a-4c, 5a and 5m were measured to examine their potential material applications.Fig. 2 shows the electronic absorption and emission spectra, and Table S1 (see ESI †) shows their corresponding wavelengths, absorption efficiencies and Stokes shifts.All these compounds have very similar values despite various substituents (Cl, F and OMe) on three different benzene rings.One strong absorption band is observed at 268-274 nm, corresponding to p-p* transition with large coefficients (log e = 4.47-4.91).The emission spectra are centered at 565-572 nm in the yellow-orange region.Notably, the Stokes shifts are quite large up to 291-299 nm À1 , which reflects a fast relaxation process from the initial state to the emissive state.
In summary, we have developed new gold catalysis between 2-cyanomethyl-1-ethynylbenzene with anthranils to construct benzo [7,8]indolizino [2,3,4,5-ija]quinazoline frameworks.In this reaction sequence, anthranils attack the gold-p-alkyne intermediate at the alkyne C(a)-regioselectivity forming 7-formylindole intermediates that can be isolated and characterized.Internal alkyne substrates are not efficient because the alkyne C(b)-regioselectivity occurs to yield 7-formylindole intermediates that are not active towards the DBU-activated cyclizations.The use of readily available substrates 1 and 2 to access two-nitrogen containing fused benzenes highlights the significance of this work.