Copper(II)-Catalyzed (3+2) Cycloaddition of 2H-Azirines to Six-Membered Cyclic Enols as a Route to Pyrrolo[3,2-c]quinolone, Chromeno[3,4-b]pyrrole, and Naphtho[1,8-ef]indole Scaffolds

A method for the [2+3] pyrroline annulation to the six-membered non-aromatic enols using 3-aryl-2H-azirines as annulation agents is developed in the current study. The reaction proceeds as a formal (3+2) cycloaddition via the N1-C2 azirine bond cleavage and is catalyzed by both Cu(II) and Cu(I) compounds. The new annulation method can be applied to prepare pyrrolo[3,2-c]quinoline, chromeno[3,4-b]pyrrole, and naphtho[1,8-ef]indole derivatives in good to excellent yields from enols of the quinolin-2-one, 2H-chromen-2-one, and 1H-phenalen-1-one series.


Introduction
2H-Azirines are widely used for the preparation of various 4-7-membered N-, N,N-, and N,O-heterocycles of varying degrees of unsaturation and different heteroatom arrangements [1,2]. The ability of azirines to open at any of the three bonds of the ring under the action of electrophilic and nucleophilic reagents, as well as transition metal compounds, underlies a powerful strategy for the synthesis of azete [3], pyrrole [4][5][6], oxazole [7][8][9], imidazole [10][11][12], 1,2,3-triazole [13], pyridine [14] derivatives, and other heterocycles, which are hardly accessible with conventional methods. Some of the azirine-ring opening reactions can be applied for the synthesis of ortho-fused, spiro-fused, and bridged heterocycles. These heteropolycycles can be the result of both intramolecular and intermolecular reactions of azirines [1]. Among them, intermolecular cycloaddition reactions are of particular interest, since they satisfy the requirements of green chemistry being atom-economical processes. In contrast to the (2+3)-and (2+4)-cycloaddition reactions of azirines with 1,3-dipoles and 1,3-dienes (or their aza-analogs) [15][16][17][18][19], in which azirines, without the ring opening, provide the incorporation of a diatomic N-C fragment in the resulting heterocycle, the reaction sequence "azirine-ring opening/cycloaddition" provides the incorporation of all atoms of the azirine ring into a new heterocyclic system. This annulation strategy includes transition-metal-catalyzed reactions of azirines with cyclic diazo compounds [20][21][22], Y(OTf) 3 -catalyzed [3+6] cycloaddition of azirines to fulvenes [23] leading to 3,4-dihydro-2H-cyclopenta[c]pyridine derivatives, photoinduced (3+2) cycloaddition of nitrile ylides, generated via the azirine-ring opening (C2-C3 azirine bond cleavage), to quinones [24] or N-benzylmaleimide [25], synthesis of cycloalkane-fused pyrroles by the Fe(III)-catalyzed decarboxylative (3+2) cycloaddition of the 2H-azirines to cyclic βketoacids (N1-C3 azirine bond cleavage) [26], and synthesis of pyrrolo [3,4-b]pyrrole derivatives via Cu(I)-catalyzed (3+2) cycloaddition of azirines to the enol carbon-carbon double bond of 3-methoxycarbonyl-substituted tetramic acids (Scheme 1, reaction 1) [27]. The last of these methods can be effectively applied to the pyrroline annulation of tetronic and thiotetronic acids as well [28]. However, attempts to extend this method to six-membered enols of the quinoline-3-carboxylate series unexpectedly encountered a serious problem associated with the involvement of the ester substituent in the transformation (Scheme 1, reaction 2a). This reaction also proceeds through azirine N1-C2 bond cleavage under both Cu(I) and Cu(II) catalysis, but exclusively produces the furo-annulation product [29]. A visible-light-promoted (3+2) cycloaddition of azirines, derived in situ from vinyl azides, to α-hydroxybenzoquinones is the only successful example of azirine cycloaddition to a multiple bond of a six-membered cyclic enol to date (Scheme 1, reaction 2b) [30]. However, this reaction cannot serve as an alternative to the method of copper-catalyzed annulation of enols with azirines, since it proceeds via the cleavage of not a single N-C2 azirine bond, but a multiple N-C3 bond, and provides a pyrrole ring with another substitution pattern. Thus, the search for the effective conditions for (3+2) cycloadditions of azirines to unsaturated cyclic systems, including cyclic enols, the elucidation of mechanisms of these reactions, assessing their scope and limitations still remains an outstanding challenge.
six-membered enols of the quinoline-3-carboxylate series unexpectedly encountered a serious problem associated with the involvement of the ester substituent in the transformation (Scheme 1, reaction 2a). This reaction also proceeds through azirine N1-C2 bond cleavage under both Cu(I) and Cu(II) catalysis, but exclusively produces the furo-annulation product [29]. A visible-light-promoted (3+2) cycloaddition of azirines, derived in situ from vinyl azides, to α-hydroxybenzoquinones is the only successful example of azirine cycloaddition to a multiple bond of a six-membered cyclic enol to date (Scheme 1, reaction 2b) [30]. However, this reaction cannot serve as an alternative to the method of copper-catalyzed annulation of enols with azirines, since it proceeds via the cleavage of not a single N-C2 azirine bond, but a multiple N-C3 bond, and provides a pyrrole ring with another substitution pattern. Thus, the search for the effective conditions for (3+2) cycloadditions of azirines to unsaturated cyclic systems, including cyclic enols, the elucidation of mechanisms of these reactions, assessing their scope and limitations still remains an outstanding challenge.
In this study, we describe a method for the pyrroline annulation of six-membered non-aromatic enols of the quinolin-2-one, 2H-chromen-2-one, and 1H-phenalen-1-one series. Additionally, a reaction mechanism is presented that allows us to define the scope of this method. In this study, we describe a method for the pyrroline annulation of six-membered non-aromatic enols of the quinolin-2-one, 2H-chromen-2-one, and 1H-phenalen-1-one series. Additionally, a reaction mechanism is presented that allows us to define the scope of this method.

Results and Discussion
Our initial interest in (3+2)-cycloaddition reactions of azirines 2 was related to their possible use for the rapid assembly of 1H-pyrrolo[3,2-c]quinoline framework 3 from 4hydroxyquinolone derivatives 1 (Scheme 2). The structural motif of 1H-pyrrolo [3,2-c] quinoline has always attracted the attention of synthetic chemists [31,32], as it is included in many bioactive, natural products [33][34][35][36] and synthetic compounds that possess enzyme modulator [37], antitumor [38], and 5-hydroxytryptamine(6) receptor antagonist activities [39]. The attractiveness of the mentioned approach to these compounds lies in the easy availability of quinolones 1, which can be prepared from isatoic anhydrides. It should also be noted that the synthesis of pyrroline-fused systems bearing a bridgehead hydroxy group is a challenge, since conventional annulation methods either produce unsatisfactory results [40] or require the use of an aggressive medium, such as liquid ammonia [41].

Results and Discussion
Our initial interest in (3+2)-cycloaddition reactions of azirines 2 was related to their possible use for the rapid assembly of 1H-pyrrolo [3,2-c]quinoline framework 3 from 4-hydroxyquinolone derivatives 1 (Scheme 2). The structural motif of 1H-pyrrolo [3,2-c]quinoline has always attracted the attention of synthetic chemists [31,32], as it is included in many bioactive, natural products [33][34][35][36] and synthetic compounds that possess enzyme modulator [37], antitumor [38], and 5-hydroxytryptamine(6) receptor antagonist activities [39]. The attractiveness of the mentioned approach to these compounds lies in the easy availability of quinolones 1, which can be prepared from isatoic anhydrides. It should also be noted that the synthesis of pyrroline-fused systems bearing a bridgehead hydroxy group is a challenge, since conventional annulation methods either produce unsatisfactory results [40] or require the use of an aggressive medium, such as liquid ammonia [41]. In our initial experiments, we synthesized 3-(4-methoxyphenyl)-substituted quinolin-2-one 1a from N-methylisatoic anhydride and methyl 4-methoxyphenylacetate according to the procedure described in the literature [42]. Enol 1a turned out to be inactive toward azirine 2a when heated at 100 °C in methanol, toluene, or 1,2-dichloroethane (DCE). At higher temperatures, the formation of azirine decomposition products without enol involvement was observed. The reaction between 1a and 2a commenced at 100 °C in methanol when catalytic amounts of the Cu(I)-NHC complex IPrCuCl (5 mol%) were added, and resulted in the formation of the desired annulation product, pyrroloquinolone 3a, in 98% yield in 20 min (Table 1, entry 2). It was notable that a close to quantitative yield of 3a was also achieved with all tested copper(II) catalysts (entries 3-5). The optimal ratio 1a/2a was observed to be 1:1.6, whereas the reaction between equimolar amounts of the reagents provided only 65% yield (entry 6). Replacing anhydrous methanol with 96% aqueous ethanol led to a decrease in the yield (entry 7). A high yield of 3a in the CuCl2-catalyzed reaction was obtained by increasing the amount of the azirine to 2 equiv. To our surprise, cobalt(II) acetate as well as nickel(II) and iron(III) acetylacetonates also catalyzed the reaction, albeit with less efficiency (entries 9−11). As a result, we used the 1:1.6 mixture of enol 1 and azirine 2 in the presence of copper(II) acetate monohydrate (5 mol%) as a catalyst at 100 °C in methanol as optimal conditions for the further experiments. In our initial experiments, we synthesized 3-(4-methoxyphenyl)-substituted quinolin-2-one 1a from N-methylisatoic anhydride and methyl 4-methoxyphenylacetate according to the procedure described in the literature [42]. Enol 1a turned out to be inactive toward azirine 2a when heated at 100 • C in methanol, toluene, or 1,2-dichloroethane (DCE). At higher temperatures, the formation of azirine decomposition products without enol involvement was observed. The reaction between 1a and 2a commenced at 100 • C in methanol when catalytic amounts of the Cu(I)-NHC complex IPrCuCl (5 mol%) were added, and resulted in the formation of the desired annulation product, pyrroloquinolone 3a, in 98% yield in 20 min (Table 1, entry 2). It was notable that a close to quantitative yield of 3a was also achieved with all tested copper(II) catalysts (entries 3-5). The optimal ratio 1a/2a was observed to be 1:1.6, whereas the reaction between equimolar amounts of the reagents provided only 65% yield (entry 6). Replacing anhydrous methanol with 96% aqueous ethanol led to a decrease in the yield (entry 7). A high yield of 3a in the CuCl 2 -catalyzed reaction was obtained by increasing the amount of the azirine to 2 equiv. To our surprise, cobalt(II) acetate as well as nickel(II) and iron(III) acetylacetonates also catalyzed the reaction, albeit with less efficiency (entries 9-11). As a result, we used the 1:1.6 mixture of enol 1 and azirine 2 in the presence of copper(II) acetate monohydrate (5 mol%) as a catalyst at 100 • C in methanol as optimal conditions for the further experiments.
The scope of hydroxyquinolones 1 was then evaluated under the optimized conditions using 3-(p-tolyl)-2H-azirine (2a) as the reaction partner (Scheme 3). The reaction displayed a low sensitivity to the electronic effects of the aryl substituent at C3 of the enol (compounds 3a-f). In addition, the annulation product 3g was synthesized from a quinolone with a 2-thienyl substituent at the C3 in 92% yield. The reaction was observed to be tolerant to the presence of a substituent at any position of the benzene ring of the quinolone moiety and provided high product yields (compounds 3h-k). Additional orthoand peri-fusion (as in quinolone 1m) also did not influence the product yield (compound 3m).  The scope of hydroxyquinolones 1 was then evaluated under the optimized conditions using 3-(p-tolyl)-2H-azirine (2a) as the reaction partner (Scheme 3). The reaction displayed a low sensitivity to the electronic effects of the aryl substituent at C3 of the enol (compounds 3a−f). In addition, the annulation product 3g was synthesized from a quinolone with a 2-thienyl substituent at the C3 in 92% yield. The reaction was observed to be tolerant to the presence of a substituent at any position of the benzene ring of the quinolone moiety and provided high product yields (compounds 3h−k). Additional ortho-and peri-fusion (as in quinolone 1m) also did not influence the product yield (compound 3m).
The structures of compounds 3a−p were established using NMR spectroscopy and HRMS methods. The structure of compound 3e was additionally verified by X-ray diffraction analysis. The structures of compounds 3a-p were established using NMR spectroscopy and HRMS methods. The structure of compound 3e was additionally verified by X-ray diffraction analysis.
The comparison of the obtained results with the data of our previous work [29] (Scheme 1, reaction 2a) revealed a dramatic dependence of the reaction outcome on the nature of the C3 substituent in quinolones 1: 3-alkoxycarbonyl-substituted derivatives produced the products of furo-annulation, while 3-aryl-substituted derivatives exclusively produced pyrroline-fused products 3. In order to find out how general this pattern was for six-membered enols, we examined compounds 4 and 7, having carbonyl substituents both at the αand β-carbon atoms of the enol moiety (Scheme 4). The Cu(OAc) 2 -and IPrCuCl-catalyzed reactions of chromenone 4 with azirine 2a, conducted in methanol at 100 • C, resulted in a complex, inseparable mixture of products. IPrCuCl did not catalyzed the reaction in DCE at all, but, to our delight, the target chromenopyrrole 6a was obtained in 67% yield in DCE using Cu(OAc) 2 ×H 2 O (5 mol%) as a catalyst. According to the 1 H NMR spectrum of the reaction mixture, no traces of the furo-annulated product, compound 5, were detected. The reaction of chromenone 4 with azirines 2b-d occurred with almost the same efficiency, producing chromenopyrroles 6b-d in 60-70% yields. The structure of compound 6c was confirmed by X-ray diffraction analysis.
Phenalenone 7 with a similarly substituted enol moiety included in the orthoand perifused system also reacted well with azirine 2a, producing the tetracyclic annulation adduct 8 in a 60% yield. In this reaction, copper(II) hexafluoroacetylacetonate (10 mol%) was used as a catalyst since it provided a slightly higher product yield than copper(II) acetate. The comparison of the obtained results with the data of our previous work [29] (Scheme 1, reaction 2a) revealed a dramatic dependence of the reaction outcome on the nature of the C3 substituent in quinolones 1: 3-alkoxycarbonyl-substituted derivatives produced the products of furo-annulation, while 3-aryl-substituted derivatives exclusively produced pyrroline-fused products 3. In order to find out how general this pattern was for six-membered enols, we examined compounds 4 and 7, having carbonyl substituents both at the α-and β-carbon atoms of the enol moiety (Scheme 4). The Cu(OAc)2-and IPrCuCl-catalyzed reactions of chromenone 4 with azirine 2a, conducted Thus, the substitution pattern of the enol moiety of six-membered cyclic enols controlled the outcome of their catalytic annulation with azirines directing the reaction toward either pyrroline-or furane-fused products. In the presence of an aryl substituent at the β-position of the enol moiety of quinolones 1, its (2+3) cycloaddition to azirines 2 smoothly proceeded to afford pyrroline-annulated products 3. In contrast, the CO 2 Me group in the same position directs the process toward the formation of furo-annulated products as follows from the results of the previous studies [29]. However, this switching does not occur if the α-carbon of the enol moiety is adjacent to the endocyclic carbonyl carbon atom. We proposed the reaction mechanism (Scheme 5) to address the observed reactivity of non-aromatic six-membered cyclic enols toward azirines under copper catalysis. The key step of the reaction was the azirine-ring opening across the N1-C2 bond to form radical 9 under the action of copper(I) enolate 1-Cu(I)/4-Cu(I). The latter resulted from the oxidative homocoupling of the enol with the copper(II) catalyst. Such an oxidation with copper(II) acetylacetonate was previously reported for tetramic acids [27]. Indeed, enol 1a reacts with Cu(OAc) 2 in boiling MeOH, but, unfortunately, our attempts to isolate the oxidative coupling product failed because of the low selectivity of the reaction, which yielded an inseparable mixture of products. Intramolecular radical attack in intermediate 9 afforded copper(I) iminide 10,11. 3-Aryl-substituted iminide 10 underwent the cyclization at the keto group followed by a copper-hydrogen exchange to produce cycloadduct 3. The expected intramolecular nucleophilic attack of the iminide nitrogen on the ester carbonyl in intermediate 11 to form furo-annulation product 5 did not occur because of two reasons: (1) the additional activation of the electrophilic keto group by the lactone carbonyl group, and (2) stabilization of alcoholate 13 by the chelation of the copper by the lactone carbonyl group. As a result, the cyclization in the keto group proceeded rapidly and irreversibly. The copper-hydrogen exchange between alcoholate 13 and enol 4 afforded the final cycloadduct 6 and regenerated enolate 4-Cu(I).
Molecules 2022, 27, x FOR PEER REVIEW 6 of 18 in methanol at 100 °C, resulted in a complex, inseparable mixture of products. IPrCuCl did not catalyzed the reaction in DCE at all, but, to our delight, the target chromenopyrrole 6a was obtained in 67% yield in DCE using Cu(OAc)2H2O (5 mol%) as a catalyst. According to the 1 H NMR spectrum of the reaction mixture, no traces of the furo-annulated product, compound 5, were detected. The reaction of chromenone 4 with azirines 2b−d occurred with almost the same efficiency, producing chromenopyrroles 6b−d in 60−70% yields. The structure of compound 6c was confirmed by X-ray diffraction analysis.
Phenalenone 7 with a similarly substituted enol moiety included in the ortho-and peri-fused system also reacted well with azirine 2a, producing the tetracyclic annulation adduct 8 in a 60% yield. In this reaction, copper(II) hexafluoroacetylacetonate (10 mol%) was used as a catalyst since it provided a slightly higher product yield than copper(II) acetate.
Thus, the substitution pattern of the enol moiety of six-membered cyclic enols controlled the outcome of their catalytic annulation with azirines directing the reaction toward either pyrroline-or furane-fused products. In the presence of an aryl substituent at the β-position of the enol moiety of quinolones 1, its (2+3) cycloaddition to azirines 2 smoothly proceeded to afford pyrroline-annulated products 3. In contrast, the CO2Me group in the same position directs the process toward the formation of furo-annulated products as follows from the results of the previous studies [29]. However, this switching does not occur if the α-carbon of the enol moiety is adjacent to the endocyclic carbonyl carbon atom. We proposed the reaction mechanism (Scheme 5) to address the observed reactivity of non-aromatic six-membered cyclic enols toward azirines under copper catalysis. The key step of the reaction was the azirine-ring opening across the N1-C2 bond to form radical 9 under the action of copper(I) enolate 1-Cu(I)/4-Cu(I). The latter resulted from the oxidative homocoupling of the enol with the copper(II) catalyst. Such an oxidation with copper(II) acetylacetonate was previously reported for tetramic acids [27]. Indeed, enol 1a reacts with Cu(OAc)2 in boiling MeOH, but, unfortunately, our attempts to isolate the oxidative coupling product failed because of the low selectivity of the reaction, which yielded an inseparable mixture of products. Intramolecular radical attack in intermediate 9 afforded copper(I) iminide 10,11. 3-Aryl-substituted iminide 10 underwent the cyclization at the keto group followed by a copper-hydrogen exchange to Thus, the lactone carbonyl in intermediate 11 acted as a directing group, enabling the annulation of the pyrroline ring even though the enol system bears an ester substituent at the β-C enol atom. The reaction of methoxycarbonyl-substituted 6-membered cyclic enols, having no directing carbonyl group, should proceed through a furo-annulation involving the CO 2 Me group. This important conclusion was supported by the reaction between thiochromene-based enol 14 and azirine 2a (Scheme 6). This reaction afforded carbamate 15 as a sole product in the presence of copper(II) acetylacetonate under the standard conditions. Compound 15 can be transformed under acidic conditions into thiochromenofuran 16 in good yields.
An unexpected result was obtained in the reaction of 4-hydroxyisoquinolinone 17 with azirine 2a catalyzed with Cu(acac) 2 (5 mol%) (Scheme 6). The formation of a furofused product (similar to 15) did not occur from compound 17, despite the presence of the methoxycarbonyl group at the β-C atom and the absence of the directing carbonyl group at the α-C atom of the enol moiety. Instead, pyrrolino-annulated 1:2 adduct 18 was isolated in 27% yield. Optimization experiments showed that the use of other copper(II) catalysts (Cu(OAc) 2 , Cu(hfacac) 2 ) did not enhance the efficiency of the reaction, whereas NHC complex IPrCuCl (5 mol%) allowed a slight increase in the yield of 18 (32%). This product resulted from the addition of two molecules of azirine 2a to isoquinolone 17, one of which modified the methoxycarbonyl group of 17 and another one formed the pyrroline ring. The abnormal reaction course can be rationalized in terms of rapid copper-hydrogen exchange in intermediate 20, which is more rapid than the furan ring closure. The (2+3) cycloaddition of aminovinyl-substituted enol 21 to azirine 2a afforded compound 18. The Z configuration of the C=C bond in compound 18 was established based on 2D 1 H-1 H-NOESY spectrum data (see the Supplementary Materials).
produce cycloadduct 3. The expected intramolecular nucleophilic attack of the iminide nitrogen on the ester carbonyl in intermediate 11 to form furo-annulation product 5 did not occur because of two reasons: (1) the additional activation of the electrophilic keto group by the lactone carbonyl group, and (2) stabilization of alcoholate 13 by the chelation of the copper by the lactone carbonyl group. As a result, the cyclization in the keto group proceeded rapidly and irreversibly. The copper-hydrogen exchange between alcoholate 13 and enol 4 afforded the final cycloadduct 6 and regenerated enolate 4-Cu(I).

Scheme 5. Plausible mechanism.
Thus, the lactone carbonyl in intermediate 11 acted as a directing group, enabling the annulation of the pyrroline ring even though the enol system bears an ester substituent at the β-C enol atom. The reaction of methoxycarbonyl-substituted 6-membered cyclic enols, having no directing carbonyl group, should proceed through a furo-annulation involving the CO2Me group. This important conclusion was supported by the reaction between thiochromene-based enol 14 and azirine 2a (Scheme 6). This

General Instrumentation
Melting points were determined on a melting-point apparatus and were uncorrected. 1 H (400 MHz) and 13 C (100 MHz) NMR spectra were recorded on a Bruker Avance 400 spectrometer in solvent indicated below. 1 H NMR spectra were calibrated according to the residual peaks of CDCl 3 (δ = 7.26 ppm), DMSO-d 6 (δ = 2.50 ppm). 13 C{1H} NMR spectra were calibrated according to the carbon atom peaks of CDCl 3 (δ = 77.0 ppm), DMSO-d 6 (δ = 40.0 ppm). High-resolution mass spectra were recorded with a Bruker maXis HRMS-QTOF, electrospray ionization. X-ray diffraction analysis was performed with an Agilent Technologies Xcalibur Eos (for 3e) and Agilent Technologies Supernova (for 6c) diffractometers. Crystallographic data for the structures 3e (CCDC 1535459) and 6c (CCDC 2182542) were deposited at the Cambridge Crystallographic Data Centre. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO 2 ALUGRAM SIL G/UV 254 . Column chromatography was performed on silica gel 60 M (0.04-0.063 mm). Methanol was refluxed for 2 h with magnesium turnings and then distilled. 1,2-Dichloroethane was washed with concentrated H 2 SO 4 , water, then distilled from P 2 O 5 and stored over anhydrous K 2 CO 3 .