Iridium-Catalyzed Tandem Dehydrogenation/Hydroarylation Approach to Synthetically Versatile C2-Alkenyl N–H Indoles

Rúa Jenaro de la Fuente, s/n – Campus Vida – Universidade de Santiago de Compostela – 15782 Santiago de Compostela – www.usc.es/ciqus Tandem An Iridium-Catalyzed Dehydrogenation/Hydroarylation Approach to Synthetically Versatile C2-Alkenyl N–H Indoles Carlos Lázaro-Milla, José L. Mascareñas, Fernando López Peer reviewed version This is the peer reviewed version of the following article: Lázaro-Milla, C.; Mascareñas, J. L.; López, F. (2024), Iridium-Catalyzed Tandem Dehydrogenation/Hydroarylation Approach to Synthetically Versatile C2-Alkenyl N–H Indoles. ACS Catal., 14: 2872–2882, which has been published in final form at https://doi.org/10.1021/acscatal.3c05841. This article may be used for non-commercial purposes in accordance with ACS Terms and Conditions for Use of Self-Archived Versions. How to cite: Lázaro-Milla, C.; Mascareñas, J. L.; López, F. (2024), Iridium-Catalyzed Tandem Dehydrogenation/Hydroarylation Approach to Synthetically Versatile C2-Alkenyl N–H Indoles. ACS Catal., 14: 2872–2882. DOI: 10.1021/acscatal.3c05841 Copyright information: © 2024 ACS. This article may be used for non-commercial purposes in accordance with ACS Terms and Conditions for Use of Self-Archived Versions An Iridium-Catalyzed Tandem Dehydrogenation / Hydroarylation Approach to Synthetically Versatile C2-Alkenyl N-H Indoles Carlos Lázaro-Milla,†,§ José L. Mascareñas*† and Fernando López*†,‡ † Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS) and Departamento de Química Orgánica. Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain § Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain ‡ Misión Biológica de Galicia, Consejo Superior de Investigaciones Científicas (CSIC), 36080, Pontevedra, Spain KEYWORDS Iridium, Hydroarylation, indoles, C-H functionalization, cycloadditions. Dedicated, in memoriam, to Dr. Alejandro Gutiérrez González ABSTRACT: Readily available N-carbamoyl indolines can be converted into highly valuable 2-alkenyl and 2-alkyl indoles in a one pot reaction, through an auto-tandem catalytic cascade promoted by an iridium complex. The process entails a dehydrogenation reaction initiated by an iridium-promoted C(sp3)-H activation, the addition of the resulting indole to an alkyne -or alkenepartner, and a spontaneous loss of the carbamoyl directing group. Interestingly, the resulting C2-alkenyl indoles can participate in a variety of metal-catalyzed annulations initiated by C−H activation, including formal [4+1] and [4+2] cycloadditions, as well as cross-dehydrogenative cyclizations, thus enabling a divergent access to a collection of functionally rich nitrogen-containing heterocycles. Tandem reactions involving transition metal catalysts are highly attractive synthetic transformations because of their capacity to enhance the structural and functional complexity of readily available precursors in an atomand step-economical manner.1 Most of these reactions involve different types of metal catalysts operating in an orthogonal or sequential manner. One-pot tandem processes promoted by a single transition metal reagent that operates under unaltered reaction conditions, namely, auto-tandem processes, are much less common.1a,2 This is the case of reactions that combine metal-catalyzed alkane dehydrogenations with a second catalytic event that requires the presence of the newly generated unsaturation. Most of these tandem processes have been carried out using two different catalysts and, even in some cases, they need to operate in a flask-separated manner because of incompatibility issues.3 Examples in which these types of tandem reactions are promoted by a single metal catalyst are very rare, especially when they involve C−H activation processes. Indeed, the only example involving a dehydrogenation and a C-H activation of the in situ generated alkene was reported more than 25 years ago by Murai and coworkers, and consists of a Rh-catalyzed dehydrogenation/carbonylation sequence on piperazine precursors (Scheme 1, equation 1).4 Suginome and Ohmura reported a related tandem methodology to build N-methyl indoles from 2-ethyl-Nmethylanilines, which involves an iridium-catalyzed dehydrogenation / intramolecular hydrocarbonation sequence (Scheme 1, equation 2).5 Elegantly, they also used a similar strategy for the synthesis of 2,3-dihydrobenzofurans from alkyl aryl ethers (Scheme 1, equation 3).6 However, in contrast to the Murai’s method, in these iridiumpromoted reactions, the alkenyl moiety created in the dehydrogenation step is used as a hydrocarbonation partner, rather than as substrate for the C−H activation. Therefore, and despite the well-known ability of Ir(I) complexes to oxidatively insert into C(sp2)-H bonds, tandem processes involving oxidative additions of in situ generated alkenyl C−H bonds to this metal center have never been described.7 Herein we demonstrate that iridium catalysts can promote one-pot, intermolecular reactions entailing a tandem sequence that involves a dehydrogenation, a C−H activation and an alkyne (or alkene) addition step. Specifically, we show that this cascade process can be leveraged to transform N-carbamoyl indolines into 2-alkenyl and 2-alkyl N-H indoles (Scheme 1, equation 4). The reaction also entails an intriguing, spontaneous loss of the N-linked directing group at the end of the sequential process. The results also raised interesting mechanistic aspects, especially with regard to the nature and order of the catalytic events. Importantly, we also demonstrate that this type of N-H indole products, which are not trivially made using alternative methods,8 hold an unanticipated but powerful and versatile synthetic potential, and can engage in a variety of metal-catalyzed annulations that lead to different types of pyridoindole, pyrroloindoline and benzocarbazoles derivatives in excellent yields (Scheme 1, equation 4). Finally, we have used our Ir-catalyzed tandem process for a two-step, one pot synthesis of the bio-relevant carbazole Sorazolon E. Scheme 1. Previous metal catalyzed dehydrogenation / hydrocarbonation methods and current process. N H N NH OAr +R 1 R 2 1 (E)-3 HH OOTBS [IrCl(C 2 H 4 ) 2 ] 2 (5%) DTBM-Segphos (10%) TBE, p-xylene, 135 ºC O TBSO [IrCl(C 2 H 4 ) 2 ] 2 (3%) DTBM-Segphos (10 %) TBE, mesitylene, 150 ºC N R 2 Me R 3 This work: Tandem dehydrogenation / C-H functionalization of indoline 1a. Synthetic potential of alkenyl indoles 3 Previous metal catalyzed dehydrogenation / C-H functionalization 4-6 N N Ph R O [Rh 4 (CO)] 12 (3%) H 2 C=CH 2 , CO (15 atm) TBE, toluene, 160 ºC N N Ph R OO (1) (2) (3) (4) N R 2 R 3 R 1 R 2 R 1 2 N N Ph R O N R 2 R 3 [Rh] [Ir] [Ir] O OR H H H N R 2 R 1 R 4 R 3 N O R 2 R 1 N HR 2 [Rh] [4+2] [Rh] [4+1] [Ru] R R 1 R 1 R 1 R 1 R 1 [Ir(I)] Our research started after observing that the reaction of the N-carbamoyl indoline 1a with diphenylacetylene (2a), in presence of [Ir(cod)OH]2 / rac-Binap, and at 120 ºC, instead of providing hydroalkylation products,9 led to the C2-alkenylated N-H indole (E)-3aa, in a moderate 44% yield (55% conversion), together with traces of indole (4) as side product (Table 1, entry 1).10 Changing the solvent from dioxane to 1,2-DCE, under otherwise identical conditions, led to full recovery of the starting material (entry 2). However, the reaction works in toluene, resulting in a slightly higher yield of 3aa (51% yield, 61% conversion), together with a 9% yield of indole (4, entry 3). Curiously, the addition of small amounts of water (20 equivalents) allowed full conversion of 1a and a significant increase of the reaction yield (73 %, entry 4). Moreover, the reaction could be equally performed at lower temperatures, just by increasing the reaction times (entries 5 and 6). On the contrary, the use of alternative protic additives, such as MeOH, instead of water, had a negative impact in the yield (entry 7 and Table S2).11 In all these reactions, we could detect cis-stilbene in the crude reaction mixtures, suggesting that diphenylacetylene 2a acts both as a hydrocarbonation partner and a hydride scavenger. The use of other common hydrogen scavengers, such as t-butyl ethylene (TBE), was less effective (entry 8). We next analysed the influence of electron-donating (p-OMe, 1a’) or electron-withdrawing groups (p-CF3, 1a’’) at the phenyl ring of the N-aryl carboxamide moiety. Interestingly, while the presence of the para-methoxy group did not have any significant effect on the reaction (entry 9), the incorporation of a CF3 group proved to be advantageous, leading to an improved 85% yield (entry 10). Substrate 1a’’’, bearing an N-Benzyl carboxamide (entry 11), or just indoline, that lacks directing groups (entry 12), failed to give any conversion. The use of the bisphosphine ligand is key for the observed reactivity, as in its absence the reaction provides a poor 5% conversion (entry 13). Not only Binap, but also related ligands such as DM-Binap, H8-Binap or Segphos provided similar results (Table S1). However, structurally different bisphosphines like DPPF, Xantphos or dppe, among others, led to very poor yields (Table S1). Thus, rac-Binap was selected as the optimal ligand for the process. Finally, we also confirmed that the use of an iridium-based catalyst is essential, since a similar rhodium complex [Rh(OH)(cod)]2 failed to yield any product (entry 14). Table 1. Preliminary screening of a tandem Dehydrogenative hydroarylation of indolines 1.a Ph Ph [Ir(OH)(cod)] 2 (5 mol%) rac-Binap (10 mol%) Additive (0-20 equiv) Solvent (0.1M), Temp 2a N H N NH OR + Ph Ph N H + 1(E)-3aa 4 entry 1, R Solv. Add. T (°C) t (h) Conv. (%) 3aa (%) 4 (%) 1 1a, Ph Diox - 120 4 55 44 2 2 1a, Ph DCE - 120 4 0 0 0 3 1a, Ph Tol - 120 4 63 51 9 4 1a, Ph Tol H 2 O 120 3 100 73 4 5 1a, Ph Tol H 2 O 100 24 100 70 3 6 1a, Ph Tol H2O 90 24 100 72 3 7 1a, Ph Tol MeOH 120 4 25 12 2 8 1a, Ph Tol TBEb 120 3 59 45 3 9 1a’, p-MeOC6H4 Tol H2O 110 1 100 72 9 10 1a’’, p-CF3C6H4 Tol H2O 110 1 100 85 6 11 1a’’’, Bn Tol H2O 110 24 0 0 2 12 Indolinec Tol H2O 110 24 0 0 0 13d 1a’’, p-CF3C6H4 Tol H2O 110 24 5 0 0 14e 1a’’, p-CF3C6H4 Tol H2O 110 1 0 0 1 a Conditions: N-carbamoyl indoline (1, 1 equiv), 2a (3 equiv), additive (0-20 equiv), [Ir(OH)(cod)]2 (5%), rac-Binap (10%). b Carried out using TBE (8 equiv) as additive. Equal results were obtained using TBE and H2O (20 equiv). c Carried out using NH-indoline as 1. d Carried out without rac-Binap. e [Rh(OH)(cod)]2 instead of [Ir(OH)(cod)]2. After this screening, we analysed the scope of the Ircatalyzed tandem process, initially using different 1,2-disubstituted alkyne partners (Scheme 2). Thus, we were glad to observe that several symmetrical bis-aryl alkynes (2b-f), bearing either electron-donating (e.g, p-MeO, mMe) or electron-withdrawing groups (e.g. m-F, p-CF3), as well as bromine or chlorine atoms (e.g. p-Br, o-Cl), participate in the process, providing the expected (E)-C2-alkenylated-NH-indoles, 3ab–3ag, in good yields. Alkynes with larger aromatic substituents such as a β-naphthyl moiety, or with alkyl, instead of aryl groups, were also successful partners. Thus, the reaction of 1a’’ with symmetrically aliphatic alkynes such as 3-hexyne (2i) or with 4-octyne (2j) gave the respective indole products 3ai and 3aj in good to excellent yields. Non-symmetrical internal alkynes, such as a bis-aryl alkyne bearing two different electron donating groups at the aryl rings (e.g. o-Me and p-MeO groups, 2k) led to a 1:1 mixture of the corresponding regioisomers (3ak, 3ak’). One of the isomers, 3ak’, could be characterized by X-ray analysis.11 The regioselectivity can be improved by differentiating the electron character of the substituents (3al:3al’ = 1.5:1), and, fully controlled by playing with steric differences. Thus, the reaction of 1a’’ with but-1-yn-1-ylbenzene (2m) delivered exclusively the product 3am, wherein the new C−C bond was formed at the less sterically hindered alkyne site. The structure of 3am was unambiguously determined by X-ray crystallography, which also confirmed the E-stereochemistry of the alkene moiety.11 Remarkably, the reaction of dialkyl alkynes like 2-hexyne also proceeded with complete regioselectivity toward the less congested product 3an, which was isolated in 95% yield. Curiously, when trimethylsilylphenylacetylene (2o) was used as alkyne partner, the product 3ao, bearing the bulkier TMS group at the indole-adjacent position was obtained with excellent yield and complete regioselectivity. Terminal alkynes, such as phenylacetylene, are not suitable substrates for this reaction, probably due to the facile insertion of Ir(I) complexes into the C(sp)-H bond, which leads to secondary reactions.12 Nonetheless, the product (3ap) can be easily obtained from its TMS analogue (e g. 3ao) by desilylation with a fluoride source.11 Scheme 2. Tandem dehydrogenative / hydroarylation process with diverse alkynes a [Ir(OH)(cod)] 2 (5 mol%), rac-Binap (10 mol%) Toluene (0.1M), H 2 O (20 equiv), 110 ºC, 1 h 2 N H N NHAr O + R 2 R 1 1a'' (Ar = p-CF 3 C 6 H 4 )3 R 1 R 2 N HN H N H N HN H N H CF 3 CF 3 OMe OMe Br Br Me Me N H F F N H Cl Cl N H Me Me N H Me Me 3aa, 85% 3ad, 72% 3ab, 81% 3ag, 83% 3ah, 96% 3ac, 83% 3ae, 70% 3af, 56% 3aj, 90% 3ai, 80% N H 3ak, 44% OMe Me N H OMe 3ak', 44% + 3ak : 3ak' = 1:1 b Me N HN H + CF 3 CF 3 3al 3al' 3al : 3al' = 1.5:1, 68% c N H Ph TMS N H Ph Et N HMe 3am, 72% 3ao, 86% 3an, 95% N H Ph H 3ap, 0% (61%) d N H Ph Ph N H Ph Ph N HN HN H COOMe MeO R Me F F 3ca, 98% 3ba, 73% 3da (R = NO 2 ), 64% 3fa, 75% 3ga, 53% 3ea (R = Br), 80% Ph Ph Ph Ph Ph Ph RR N H Ph Ph Me 3ha, 0% e a Conditions: All reactions were conducted with 3 equiv of alkyne 2. b Isomers can be independently isolated. c Yield of the mixture of isomers. d Yield of 3ap obtained through a fluoride (TBAF, THF, 60 ºC) promoted desilylation of 3ao (see the Supp. Info for details). e The 3-methyl indoline precursor (1h) was recovered (85%), together with a 10% yield of its 3-methyl NH-indole derivative. We next explored the behaviour of differently functionalized indolines, using diphenylacetylene as an alkyne partner. Gratifyingly, indolines bearing both electronwithdrawing and electron-donating groups in any of their C4 to C7 positions give the expected (E)-C2-alkenylatedNH-indoles (3ba – 3ga) in good to high yields. The structure of (E)-3ca could be further confirmed by X-ray single crystal analysis. Worth to note, a C3-methyl substituted indoline (1h) did not participate in the process (3ha, 0% yield), possibly due to steric hindrance imposed by this group. At this stage, it was pertinent to find out whether the method could also be extended to alkene partners. Nicely, the tandem reaction works using methyl acrylate, with the expected indole 6aa obtained in 43% yield (58% conversion, Scheme 3). This value could be improved by carrying out the reaction with higher excess of alkene, at 120 ºC for 24 hours (71 % yield). The reaction works with other alkenes bearing electron-withdrawing groups, phenyl sulfone or a phosphonate ester (6aa-6ae, 68-99% yield). Furthermore, although styrene did not participate in the process, non-conjugated alkenes like norbornene, quantitatively afforded the desired C2-alkylated indole (6af). Scheme 3. Tandem dehydrogenative hydroarylation using alkene partners a 5 N H N NH OAr + 1a (Ar = p-CF 3 C 6 H 4 ) 6 R R N HCO 2t Bu N HCO 2 Me N HCO 2 Bn N HSO 2 Ph N HPO(OEt) 2 6aa, 71% (58) b 6ab, 94% 6ac, 82% 6ad, 68% 6ae, 99% 6af, 99% H 2 O (20 equiv) Toluene (0.1M), 120 ºC, 24 h [Ir(OH)(cod)] 2 (5 mol%) rac-Binap (10 mol%) N H a Conditions. Reactions were conducted with 8 equiv. of alkene, unless otherwise noted. b Carried out at 110 ºC with 3 equiv of 5a. Regarding the mechanism, two hypothetical alternatives were initially considered. The first one (Scheme 4, path A) would involve an initial dehydrogenation of indoline 1,13 followed by a hydroarylation of the alkyne (or alkene) partner with the generated indole intermediate (Int1). This path involves two C−H activations promoted by the Ir(I) catalyst, one in the Csp3−H bond of the initial indoline and the other in the Csp2−H of the indole resulting from the dehydrogenation. The C2-alkenylated indole product (Int-2) would then loss the carbamate, releasing the observed product 3. Alternatively, path B would consist of an initial hydrocarbonation to give Int-3, followed by a dehydrogenation to Int-2. The first step of this path, leading to Int-3, would indeed be consistent with previously reported C2-alkylation of indolines with alkenes.9a Scheme 4. Proposed pathways for the formation of C2-functionalized-NH-indoles 3 R R N H N DG R RN DG R R N DG C(sp3)-H act. Dehydrogenation N DG R R C(sp3)-H act. Alkenylation C(sp3)-H activation Dehydrogenation N DG R R R R R R Path APath B 1 2 Int-1 Int-23Int-2 C(sp2)-H activation Alkenylation Int-3 - DG - DG To gain insights into the real mechanism, we synthesized the carbamoyl indole precursor Int-1 (DG = CONHp-CF3C6H4, path A), which was submitted to the reaction conditions (Scheme 5, b). We observed the formation of the C2-alkenylated indole 3aa in good yield, a result which supports path A. Interestingly, whereas the precursor indoline 1a’’ doesn't evolve if the reaction is performed in the absence of Binap (Table 1 entry 13), the indole Int-1 reacts with diphenylacetylene (2a) when treated with [Ir(OH)(cod)]2 (5 mol%) in toluene at 110 °C, to give the C2alkenylated indole product 3aa in 80% yield (Scheme 5, c). This result highlights a crucial role of Binap for the dehydrogenation step. Control experiments confirmed that the presence of the carbamoyl directing group is essential to observe any reactivity, either with indoline or indoles. The intrinsic reactivity profiles of 1a’’ and Int-1 were evaluated by submitting them to standard conditions, but in the absence of diphenylacetylene (Scheme 5, d and e). While in the case of indoline 1a’’, we observed no conversion, the indole Int-1, gave a considerable amount of the deprotected indole 4 (39% yield). This result suggests that the release of the directing group occurs only after the oxidative aromatization. Finally, and in consonance with the above control reactions, the 3,3-dimethylindoline 1i, for which the dehydrogenation is not feasible, was fully recovered when treated under standard reaction conditions. Scheme 5. Control mechanistic experiments a-f a Ph Ph N 1a'' 1a'' (fully recovered) N DG 2a N H N DG Ph Ph 3aa, 80 %, E/Z = 90:10 + Ph Ph 2a N H N DG Ph Ph 3aa, 78 %, E/Z = 60:40 + N DG N DG Int-1 (47% recovered) Ph Ph [Ir(OH)(cod)] 2 (5 mol%) rac-Binap (10 mol%) H 2 O (20 equiv) Toluene (0.1M), 110 ºC, 1 h 2a N DG + 1a'' N H Ph Ph 3aa, 85 %, E/Z = 95:5 Int-1 Int-1 Int-1 DG a) b) c) d) e) Ph Ph 2a N DG + 1i 1i (100% recovered) Me Me N DG Me Me f) 4 (39%) [Ir(OH)(cod)] 2 (5 mol%) rac-Binap (10 mol%) H 2 O (20 equiv) [Ir(OH)(cod)] 2 (5 mol%) H 2 O (20 equiv) [Ir(OH)(cod)] 2 (5 mol%) rac-Binap (10 mol%) H 2 O (20 equiv) Toluene (0.1M), 110 ºC, 1 h [Ir(OH)(cod)] 2 (5 mol%) rac-Binap (10 mol%) H 2 O (20 equiv) Toluene (0.1M), 110 ºC, 24 h [Ir(OH)(cod)] 2 (5 mol%) rac-Binap (10 mol%) H 2 O (20 equiv) Toluene (0.1M), 110 ºC, 24 h + Toluene (0.1M), 110 ºC, 1 h Toluene (0.1M), 110 ºC, 1 h a DG = CONHpCF 3 C 6 H 4 . Therefore, these results suggest a catalytic cycle involving the initial reaction of indoline 1 with in situ generated hydroxoiridium complex to yield an amidoiridium complex A (Scheme 6). Oxidative addition of the methylene C(sp3)-H bond to this Ir(I) complex forms alkyl-(hydrido)iridium(III) species B that undergoes a β-hydride elimination towards the amidoiridium bis-hydride species C. A migratory insertion of the alkyne unit to give D (or its regioisomer D’11), followed by reductive elimination accounts for an overall redox neutral process, and is in consonance with the detection of cis-stylbene in the crude reaction mixture (GC-MS and NMR). The resulting amidoiridium complex E might be in equilibrium with its protonated species Int-1, as the corresponding indole was confirmed to work in the alkenylation process (Scheme 5, b). An oxidative addition step from E results in the alkenyl- (hydrido)iridium(III) species F. The insertion of a second unit of alkyne and a subsequent reductive elimination would deliver the amidoiridium intermediate H,14 which undergoes the hydrolysis of the carbamoyl directing group to yield the observed product 3 and resetting the catalytic cycle. The detection of p-CF3-aniline by GC-MS in the crude mixtures is consistent with this decarbamoylation. Scheme 6. Mechanistic proposal N ON Ar [Ir] A NN [Ir] OAr H B C NN [Ir] OAr H H NN OAr H R R [Ir] H N ON Ar [Ir] E [Ir] −OH H 2 O N ON H Ar N ON Ar H E NN [Ir] OAr H NN [Ir] OAr R R H G N ON Ar R R H [Ir] H H 2 O N H R R H ArNH 2 3 CO 2 H 2 O D F 1 R H H R Dehydrogenation Hydroindolation P P Ir [Ir] = RR Int-1 RR H 2 O With an optimal and versatile protocol for the practical assembly of N-unsubstituted C2-alkenyl indoles, the stage was set to explore the synthetic possibilities of these products. We were especially attracted by the possibility of performing formal annulation reactions initiated by a C−H activation of the alkenyl moiety. Although this type of processes have been used for C2−aryl indoles,15 related methodologies with C2-alkenyl indoles are essentially unknown. Indeed, the synthetic derivatizations of these systems have been limited to particular thermal Diels-Alder cycloadditions and acid-promoted condensations.16 We initially explored the viability of formal metal-promoted annulations with alkynes to give could pyrido[1,2a]indole products of type 7 (Scheme 7), scaffolds that are frequently found in relevant natural and synthetic products.17 Moreover, due to their luminescent properties, this type of products have also been used in the construction of relevant molecular materials.18 Initial transformation attempts, carried out using indole 3aa and alkyne 2b (bis-pmethoxyphenylacetylene), and several palladium catalysis previously used in related transformations of C2-aryl indoles,18b, 19 were unsuccessful.11 However, we were glad to observe that the desired [4+2] annulation could be performed under rhodium(III) catalysis. In particular, using the catalyst generated from [Cp*RhCl2]2, AgOAc, and K2CO3, in p-xylene at 110 ºC, the desired pyrido[1,2-a]indole 7ab was obtained in 57% yield (Scheme 7, equation 1).20, 15k Its structure was unambiguously confirmed by X-ray analysis.11 Importantly, this catalytic system can also promote alternative annulations of 3aa with partners other than alkynes. For instance, the use of a CO (1 atm), instead of the alkyne, allowed the quantitative formation of the pyrrolo[1,2-a]indole-3-one derivative 8aa, which results from a formal [4+1] annulation (Scheme 7, equation 2).15k It is also possible to use diazocompounds such as dimethyl diazomalonate as coupling partners, to give pyrrolo[1,2-a]indole products like 10aa in quantitative yield (Scheme 7, equation 3). This type of formal [4+1] annulations had never been described, even with C2-aryl indoles.21 Curiously, when using as partner the keto-ester diazo derivative 9b, instead of the formal [4+1] cycloadduct, we observed the pyrido[1,2-a]indole 11ab (58% yield, Scheme 7, equation 4).15l Its structure could be unambiguously determined by X-ray crystallography.11 The efficiency of this particular annulation could be further improved by changing the Rh(III) precatalyst to an iridium counterpart, [Cp*IrCl2]2, using AcOH as additive and 1,2-DCE as solvent. Under these conditions, the pyridoindole 11ab was obtained in 99% yield. Moreover, with this iridium catalyst,15m the participation of other diketo diazocompounds like 9c, is also viable, affording the expected formal [4+2] annulation product 11ac in 87% yield (Scheme 7, equation 4). Its structure was also confirmed by X-ray analysis.11 Scheme 7. Rh(I) and Ir(I)-catalyzed formal cycloadditions of C2-alkenyl indoles 3 with alkynes, CO and diazomethane derivates N HPh Ph N Ph Ph Ar Ar [Cp*RhCl 2 ] 2 (2.5%) AgOAc (3 equiv) K 2 CO 3 (2 equiv) Ar Ar p-xylene, 110ºC, 6h N Ph Ph Rh 3aa Ar = p-MeOPh (2b) 7ab, 57% I N O Ph Ph 8aa, 99% CO (1 atm) Cp* N Ph Ph EE 10aa, 69% E N 2 E 9a N Ph Ph E' Me 11ab, 58% 11ab, 99% {with [Cp*IrCl 2 ] 2 (2.0%), AgOAc (30%), AcOH, (1 equiv), 1,2-DCE, 110 ºC} 11ac, 87% {with [Cp*IrCl 2 ] 2 (2.0%), AgOAc (30%), AcOH, (1 equiv), 1,2-DCE, 110 ºC} Ac N 2 E' E = CO 2 Me 9b, E' = CO 2 Et 9c, E' = COMe N Ph Ph Rh Cp* E E N Rh EE Ph Ph Cp* N H E' Ph Ph N Rh Ph Ph Cp* O N Rh Ar Ar Ph Ph II III IV V Cp* VI [4 + 2] [4 + 1] [4 + 1] [4 + 2] (1) (2) (3) (4) 11ab via: via: via: via IV, V and: N R 1 R 2 R 5 R 5 N O R 1 R 2 N R 1 R 2 CO 2 Et Me 11cb (R 1 , R 2 = Ph; R 3 = OMe; R 4 = H), 75% 11eb (R 1 , R 2 = Ph; R 3 = H; R 4 = Br), 99% R 3 R 4 11hb (R 1 , R 2 = 2-Naphthyl; R 3 , R 4 = H), 89% 11mb (R 1 = Et; R 2 = Ph; R 3 , R 4 = H), 86% 11ib (R 1 , R 2 = Et; R 3 , R 4 = H), 72% a 8ca (R 1 , R 2 = Ph; R 3 = OMe; R 4 = H), 70% 8ea (R 1 , R 2 = Ph; R 3 = H; R 4 = Br), 90% 8ah (R 1 , R 2 = 2-Naphthyl; R 3 , R 4 = H), 79% 8am (R 1 = Et; R 2 = Ph; R 3 , R 4 = H), 90% 8ai (R 1 , R 2 = Et; R 3 , R 4 = H), 35% R 3 R 4 R 3 R 4 7ca (R 1 , R 2 , R 5 = Ph; R 3 = OMe; R 4 = H), 64% 7eb (R 1 , R 2 = Ph; R 3 = H; R 4 = Br; R 5 = p-MeOC 6 H 4 , 79% 7hb (R 1 , R 2 = 2-Naphthyl; R 3 , R 4 = H; R 5 = p-MeOC 6 H 4 ), 95% 7mb, (R 1 = Et; R 2 = Ph; R 3 , R 4 = H; R 5 = p-MeOC 6 H 4 ), 36%, 7cd (R 1 , R 2 = Ph; R 3 = OMe; R 4 = H; R 5 = p-CF 3 C 6 H 4 ), 88% 7cj (R 1 , R 2 = Ph; R 3 = OMe; R 4 = H; R 5 = n-Pr), 52% 7ab O Me a Carried out with 9b (6 equiv), [Cp*IrCl 2 ] 2 (4 mol%), AgOAc (60 mol%) and AcOH (2 equiv). Mechanistically, we propose that all these reactions involve an initial N−H indole metalation, followed by a C−H activation to give a common five-membered metallacyclic intermediate of type I (Scheme 7). A migratory insertion of the alkyne or of carbon monoxide would respectively deliver rhodacyclic intermediates II and III that, after their corresponding reductive eliminations, provide products 7 and 8. In the case of the diazoderivatives (9), the reaction of intermediate I with diazomalonate would evolve to the corresponding metal carbene (IV), prior to a migratory insertion towards V. At this point, if a C-N reductive elimination takes place, the reaction affords the product 10. However, with ketodiazomethanes the reaction seems to proceed via an alternative protodemetallation path towards VI, a process that is more efficient using the Ir(III) catalyst and AcOH as proton source. Importantly, these transformations are not limited to the diphenyl substituted indole 3aa. Indeed, as it is preliminary outlined in Scheme 7, several pyrido[1,2-a]indoles derivatives of type 7, exhibiting a variety of substitutions were synthesized in good to excellent yields. Likewise, different type of pyrrolo[1,2-a]indolones 8 and pyrido[1,2a]indoles 11, respectively resulting from [4+1] and [4+2] cycloadditions between 3 and carbon monoxide or the diazo ester 9b, could also be obtained in good yields. Electron-activated alkenes, like methyl acrylate, can also be used as coupling partners in the Rh(III)-catalyzed reactions of the alkenylindoles 3. However, instead of a formal annulation process, the Heck-like addition product (E,E)-12aa was obtained, as single stereoisomer (Scheme 8). The formation of this diene indicates that the putative intermediate VII prefers to evolve now through a β-hydride elimination. Curiously, by replacing the Ag(I) oxidant by Cu(OAc)2 and using DMF as the solvent, we exclusively obtained the unexpected carbazole, 13aa, whose structure was unambiguously confirmed by X-ray crystallographic analysis.11 This type of carbazoles are appealing structures that can exhibit intriguing physical properties, particularly as light emitting materials for electroluminescence devices.18 Control experiments confirmed that 13aa derives from the initially formed diene 12aa,11 which would probably undergo a formylation at its C3 position, with DMF serving as formyl source,22 prior to a Rh-promoted cyclodehydration. Scheme 8. Rh-catalyzed C-H-olefin functionalization with methyl acrylate as coupling partner N H R 1 R 2 MeO 2 C N HR 1 R 2 CO 2 Me [Cp*RhCl 2 ] 2 (2.5%) Cu(OAc) 2 (2 equiv) DMF, 140 ºC, 24 h CO 2 Me N H [Cp*RhCl 2 ] 2 (2.5%) AgOAc (3 equiv) p-xylene, 110 ºC, 6h 3+ N Rh CO 2 Me R 2 R 1 VII Cp* 12ca (R 1 , R 2 = Ph; R 3 = OMe), 78% 12ah (R 1 , R 2 = 2-Naphthyl; R 3 = H), 50% 12am (R 1 = Et; R 2 = Ph; R 3 = H), 65% 12aa (R 1 , R 2 = Ph; R 3 = H), 66% 13ca (R 1 , R 2 = Ph; R 3 = OMe), 59% 13ah (R 1 , R 2 = 2-Naphthyl; R 3 = H), 44% 13aa (R 1 , R 2 = Ph; R 3 = H), 50% R 2 R 1 R 3 R 3 5a R 3 Further exploration of the synthetic potential of indoles 3 led us to find out that they can also engage in interesting ruthenium(II)-promoted transformations. Thus, treatment of 3aa with catalytic amounts of [Ru(p-cymene)Cl2]2, in the presence of Cu(OAc)2 and NaOAc, leads to the benzo[c]carbazole derivative 14aa (55% yield), which was also characterized by X-ray analysis (Scheme 9, equation 1). The reaction could also be extended to other related alkenylindoles.23 Control experiments suggest that this novel process might involve an initial E-to-Z isomerization of 3aa,11 which enables a subsequent dehydrogenative ring closure. Indeed, the Ru-catalyzed dehydrogenative coupling of an independently prepared cis isomer (Z-3aa),11,24 gave the benzocarbazole 14aa in 58% yield (Scheme 9, equation 2). The dehydrogenative step from Z-3 would consist of an initial ortho-C-H activation of the terminal phenyl group to give the seven-membered ruthenacyclic IX. Protonation followed by a second concerted metalation deprotonation at the indole C3-position would deliver the ruthenacycle XI that, upon C-C reductive elimination, yields the observed product. Scheme 9. Ru-catalyzed dehydrogenative ring closure for Benzo[c]carbazole formation N HN HAr 1 14aa (R 1 , R 2 = H, Ar 1 , Ar 2 = Ph), 55% E-3aa - E-3ad NaOAc (1 equiv) DCE, 110 ºC, 24 h [Ru(p-cymene)Cl 2 ] 2 (2.5%) Cu(OAc) 2 ·H 2 O (2 equiv) N H Ar1 N [Ru] Ar1 AcO N HAr1 [Ru] AcO N H [Ru] Ar1 Z-3aa N H Ph Ph DMF, 130 ºC Pd(OAc) 2 (5%) PCy 3 (15%) N HPh Ph E-3aa Z-3aa IX X XI (1) (2) 14aa Ar 1 Ar 2 14ea (R 1 = H, R 2 = Br, Ar 1 , Ar 2 = Ph), 57% R 1 R 2 R 1 R 2 14ca (R 1 = OMe, R 2 = H, Ar 1 , Ar 2 = Ph), 41% 14ah (R 1 , R 2 = H, Ar 1 , Ar 2 = 2-Naphthyl), 36% Ar2Ar2 Ar2Ar2 NaOAc (1 equiv) DCE, 110 ºC, 24 h [Ru(p-cym)Cl 2 ] 2 (2.5%) Cu(OAc) 2 (2 equiv) 58% KOH (6 equiv) Indoles 3 can also be manipulated using metal-free methods (Scheme 10).25 Thus, treatment of 3aa with ethyl acetoacetate and diphenyl phosphoric acid led to the polysubstituted carbazole 15, whereas the reaction with benzyloxyacetaldehyde in presence of p-TSA produces 16 (Scheme 10, equations 1 and 2). Product 3aa could also be transformed into γ-carboline derivatives, like 17 (Scheme 10, equation 3), which exhibit a skeletal framework that is very common in antivirals and antiproliferative agents.26 Finally, the synthetic utility of our tandem process was further demonstrated by the synthesis of Sorazolon E, a carbazole isolated from Sorangium Cellulosum that exhibits antibacterial activities, as well as cytotoxicity against mice fibroblast cell lines. Treatment of 1a’’ with dimethylacetylene (2q) under standard conditions gave the expected (E)-2-alkenyl-indole 3aq. Then, replacement of toluene by a THF solution of glyoxal and tartaric acid, and further heating at 120 ºC for 3 h, provided Sozarolon E in 61% overall yield (Scheme 10, equation 4). The procedure is much faster and efficient that previous protocols, based on Wittig reactions that produce mixture of both (E) and (Z) isomers.27 Scheme 10. Metal-free synthesis of carbazole derivatives via C3-indole derivatization. Synthesis of Sorazolon E N H Ph Ph O BnO EtOAc, 120 ºC N H Ph Ph N H Ph Ph EtOAc-Decalin, O 2 180 ºC, 4 days N H N Ph Ph Me O OEt OMe COOEt POCl 3 , DMF, rt, 2 h then 3aa 15, 61% 17, 54% 16, 72% (PhO) 2 PO 2 H (15%) N 1a'' O O THF, 120 ºC,3 h Me Me Sorazolon E DG N H Me Me N H OH 61% 3aq NH 2 OH·HCl, NaOAc dioxane, 140 ºC p-TSA·H 2 O (20%) (1) (2) (3) (4) Tartaric acid (25%) 2q (3 equiv) Me Me a) a) [Ir(OH)(cod)] 2 (5%), rac-Binap (10%), H 2 O (20 equiv), Toluene, 110 ºC, 1 h In conclusion, we have uncovered a one-pot, auto-tandem catalytic process that allows to couple readily available N-carbamoyl indolines with alkynes or activated alkenes to give a variety of highly valuable (E)-C2-alkenyl and alkyl NH-indoles. The success of the reaction relies on a sequential orchestration of several reactions that occur with a perfect timing and orthogonality, namely: a dehydrogenation initiated by an iridium promoted C(sp3)-H activation, the regeneration of the Ir(I) catalyst by excess of the unsaturated partner, a hydroarylation triggered by a C(sp2)-H activation, and a final, spontaneous decarbamoylation. Despite the distinct nature of the organometallic steps involved in the process, they can be promoted by the same Ir catalyst, which is quite uncommon in other cascade processes. We have also demonstrated that the produced C2alkenylindoles present a rich and versatile chemistry, and can be readily transformed into a variety of highly appealing azaheterocycles. For instance, using a common Rh(III) catalytic conditions, they can engage in a variety of novel [4+2] and [4+1] annulations with alkynes, carbon monoxide and diazomethane derivatives, all of them involving C−H activations. On the other hand, in the presence of Ru-catalysts they can undergo cross-dehydrogenative cyclizations towards benzocarbazole derivatives. Finally, using other reagents they can be converted into different type of polysubstituted carbazoles. Eventually, we also demonstrate the utility of the tandem methodology in a two-step, one-pot synthesis of Sorazolon E. AUTHOR INFORMATION Corresponding Author