Base-Mediated Domino [5 + 3 + 1] Annulation for Highly π

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Cu(I)-/Base-Mediated Domino [5 + 3 + 1] Annulation for Highly π‑Extended Carbazole Frameworks and DFT Mechanistic Insights Tej Narayan Poudel,† Sangita Karanjit,‡ Hari Datta Khanal,† Ramuel John Inductivo Tamargo,† and Yong Rok Lee*,† †

School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Shomachi, Tokushima 770-8505, Japan

‡

Org. Lett. Downloaded from pubs.acs.org by DURHAM UNIV on 09/04/18. For personal use only.

S Supporting Information *

ABSTRACT: An efficient synthesis of highly π-extended carbazoles is described via an unexpected domino [5 + 3 + 1] annulation approach. The Cu(I)-/base-promoted reactions of 2-nitrocinnamaldehydes with benzyl cyanides provide diverse benzo[b]carbazoles. The reaction is proposed to proceed via a sequential Michael addition/intramolecular addition of an enol into a nitro group, 6π- electrocyclization, and the final oxidative aromatization as supported by density functional theory calculations. Some of the synthesized carbazoles showed significant potential in fluorescence sensing of Cu2+ ions.

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Recently, our group reported novel methodologies for the construction of carbazoles and indoles starting from 2nitrocinnamaldehyde or 2-nitrochalcone via transition-metalfree annulation reactions.13 On the basis of the reported literature from our group, formation of indole can be generally anticipated in the reaction of o-nitrocinnamaldehyde or onitrochalcone and benzyl cyanide (Scheme 1a). Surprisingly,

arbazole and related compounds constitute an important class of alkaloids that exhibit a wide variety of biological and pharmacological activities and unique thermal and electric properties.1 Specifically, benzo[b]carbazoles display a broad range of activities including antitumor, anticancer, antiinflammatory, antifungal, antiestrogenic, and kinase inhibitory activities.2 In addition, highly π-extended benzocarbazoles are widely used as building blocks for organic light-emitting diodes, semiconductors, polymers, and chemiluminescent and electroluminescent materials.3 Moreover, they can be utilized for the development of dye-sensitized solar cells and fluorescent reagents.4 Due to the highly useful nature of carbazole-based frameworks, a number of methods for their syntheses, including indole-to-carbazole strategies, have been developed.5−9 For the synthesis of aryl-annulated carbazoles such as benzo[b]carbazoles, a few methods have been employed.10−12 These approaches include domino isomerization/cyclodehydration of 2-[(indoline-3-ylidene)(methyl)]benzaldehydes,10 intramolecular dehydro-Diels−Alder reactions of ynamides,11 and thermal biradical cyclizations of enyne−ketenimines.12a Although a few synthetic protocols via intramolecular cyclization of presynthesized building blocks have been demonstrated, the development of novel and efficient approaches to aryl-annulated carbazole derivatives with diverse substitution patterns from commercially available feedstock is still highly desirable. To the best of our knowledge, there is no report on an assembly of simple, cheap, and commercially available starting materials to construct polyarylannulated complex carbazoles via a one-pot domino reaction. Moreover, to date, the direct installation of a versatile cyano substituent on the aryl-annulated carbazoles has not been reported. © XXXX American Chemical Society

Scheme 1. (a) Anticipated Annulation for the Construction of Indoles. (b) Observed Domino [5 + 3 + 1] Annulation for Highly π-Extended Carbazole Frameworks

we observed an unexpected domino [5 + 3 + 1] annulation reaction with the involvement of 2 equiv of benzyl cyanides for the formation of highly π-extended carbazoles (Scheme 1b). This unique annulation reaction involves a series of Michael addition/intramolecular nucleophilic addition of an enol to a nitro-group/reduction of a −NO2 to −NH group/intramolecular Baeyer−Villiger oxidation/carboxylic acid and Received: July 26, 2018

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DOI: 10.1021/acs.orglett.8b02363 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditions for the Synthesis of 3aa

entry

1a/2a (mmol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0 0.5:1.0

catalyst (mol %)

base (1 equiv)

solvent

conditions

yieldb (%)

FeCl3 (5 mol %) Fe(OTf3) (5 mol %) In(OTf3) (5 mol %) InCl3 (5 mol %) CuBr2 (5 mol %) CuCl2 (5 mol %) Cu(OAc)2 (5 mol %) Cu(OTf)2 (5 mol %) CuI (5 mol %) CuI (10 mol %) CuI (2 mol %) CuI (5 mol %) CuI (5 mol %) CuI (5 mol %) Cul (5 mol %) CuI (5 mol %)

TEA DBU NaOMe K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF toluene 1,4-dioxane CH3CN DMSO

reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h reflux, 6 h 80 °C, 8 h reflux, 6 h reflux, 6 h 80 °C, 8 h

0 7 15 27 46 52 48 50 51 56 54 55 57 61 58 54 30c 21 45 53 16

a

Reaction conditions: 1a and 2a in solvent (5 mL). bIsolated yield. cUnreacted 1a was recovered.

HCN elimination/6π-electrocyclization/oxidation reactions. This method affords diverse polyaryl-annulated tetracyclic benzo[b]carbazoles, pentacyclic naphtho[2,1-b]-, naphtho[1,2b]-, and dibenzo[a,h]carbazoles, and hexacyclic benzo[a]naphtho[1,2-h]carbazoles in a one-pot operation. To optimize the reaction conditions, (E)-3-(2-nitrophenyl)acrylaldehyde (1a) and 2 equiv of 2-phenylacetonitrile (2a) were treated with different catalysts and bases at different temperature (Table 1). The reaction with 1 equiv of triethylamine (TEA) in refluxing THF for 6 h was unsuccessful (entry 1). However, with DBU, NaOMe, and K2CO3 in refluxing THF, desired product 3a was obtained in 7, 15, and 27% yields, respectively (entries 3−5). With Cs2CO3 (1 equiv), the yield of 3a improved to 46% (entry 5).14 Combinations of 5 mol % of catalysts such as FeCl3, Fe(OTf)3, In(OTf)3, InCl3, CuBr2, CuCl2, Cu(OAc)2, and Cu(OTf)2 with 1 equiv of Cs2CO3 in refluxing THF significantly enhanced the yield of the product (entries 6−13). The best yield of product 3a (61%) was obtained using CuI (5 mol %) and Cs2CO3 (1.0 equiv) in refluxing THF for 6 h (entry 14). Neither increasing the loading of CuI to 10 mol % (entry 15) nor decreasing the loading to 2 mol % (entry 16) improved the yield. With a 1:1 ratio of 1a and 2a, the yield of the product decreased to 30%, and unreacted 1a was recovered (entry 17). In other solvents, such as toluene, 1,4-dioxane, acetonitrile, and DMSO, 3a was obtained in 21, 45, 53, and 16% yields, respectively (entries 18−21). The structure of 3a was determined by an analysis of its spectral data and X-ray crystallographic analysis of structurally related compound 4j (Figure S9). With the optimized reaction conditions in hand, the substrate scope of this tandem annulation reaction was explored using (E)-3-(2-nitrophenyl)acrylaldehyde (1a) with

various 2-phenylacetonitriles 2a−l (Scheme 2). The tandem annulation reactions of 1a with 2b−l bearing electron-donating Scheme 2. Construction of Various Benzo[b]carbazoles 3b− l from 1a and 2b−l

as well as electron-withdrawing substituents were successful. The reaction of 1a with 2b−g, which possess electron-donating methyl, ethyl, isopropyl, and methoxy substituents on the aromatic ring of the 2-phenylacetonitrile, afforded the desired aryl-annulated benzo[b]carbazoles 3b−g in 55−64% yields. Moreover, ethynyl- and phenyl-substituted 2-phenylacetonitriles 2h and 2i provided products 3h and 3i in 64 and 58% yields, respectively. In addition, treatment of 1a with 2j−l, which possess an electron-withdrawing trifluoromethoxy, chloride, and trifluoromethyl group, also afforded the expected products 3j, 3k, and 3l in 61, 55, and 63% yields, respectively. B

DOI: 10.1021/acs.orglett.8b02363 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

en-1-one (5) (Scheme 4). Interestingly, the reaction of 5 with 2a or 2b under the optimized reaction conditions afforded

Next, we explored the scope of this cascade annulation by employing substituted (E)-3-(2-nitrophenyl)acrylaldehyde derivatives 1a−f as shown as in Scheme 3. For example, the

Scheme 4. Control Reactions of 5 with 2a or 2b for the Synthesis of 3a and 3b

Scheme 3. Construction of Various Benzo[b]carbazoles, Naphtho[2,1-b]carbazoles, Naphtho[1,2-b]carbazoles, Dibenzo[a,h]carbazoles, and Benzo[a]naphtho[1,2h]carbazoles from 1a−f and 2a,b,g,m,n

products 3a and 3b in 48 and 51% yields, respectively. These results show that the benzoyl group was cleaved from substrate 5 during the formation of products 3a and 3b. As an application of this method, solvatochromic and fluorescencesensing properties of the synthesized compounds were also investigated (see Figures S1−S8). On the basis of the observed products and the results of the control experiments, a mechanism for the formation of product 3a was proposed (Scheme 5). In a basic medium, a putative Scheme 5. Proposed Reaction Mechanism for the Formation of 3a

reaction of (E)-3-(3-methoxy-2-nitrophenyl)acrylaldehyde (1b), which possesses an electron-donating methoxy group on the aromatic ring, with 2-phenylacetonitriles 2a or 2b provided the desired products 4a and 4b in 63 and 60% yields, respectively. Furthermore, reactions of (E)-3-(2-nitro-4(trifluoromethyl)phenyl)acrylaldehyde (1c) and (E)-3-(4chloro-2-nitrophenyl)acrylaldehyde (1d), which have an electron-withdrawing trifluoromethyl or chloride substituent on their aromatic rings with 2a, 2b, or 2g, afforded the expected products 4c−f in 55−64% yields. These tandem annulation reactions provide rapid access to tetracyclic benzo[b]carbazole derivatives with diverse substitution patterns in good yields. Having confirmed the generality of the tandem annulation, we next explored the versatility of this synthetic methodology for the construction of pentacyclic naphtho[1,2-b]- and naphtho[2,1-b]carbazole derivatives. When 2-(naphthalen-1-yl)acetonitrile (2m) was employed as the substrate in combination with different (E)-3-(2nitrophenyl)acrylaldehyde derivatives 1a−c and (E)-3-(5chloro-2-nitrophenyl)acrylaldehyde (1e), pentacyclic naphtho[2,1-b]-carbazole derivatives 4g−j were obtained in 58−65% yields. In addition, the reaction of 2-(naphthalen-2-yl)acetonitrile (2n) with 1a and 1b afforded the desired naphtho[1,2-b]carbazoles 4k and 4l in 59 and 61% yields, respectively. The versatility of this synthetic methodology was further extended to the synthesis of pentacyclic dibenzo[a,h]carbazoles and hexacyclic benzo[a]naphtho[1,2-h]carbazole derivatives. The reactions of (E)-3-(1-nitronaphthalen-2-yl)acrylaldehyde (1f) with 2a, 2b, or 2g afforded diverse and complex pentacyclic dibenzo[a,h]carbazoles 4m−o in 40−48% yields. In addition, the reaction of 1f with 2m provided hexacyclic benzo[a]naphtho[1,2-h]carbazole 4p in 45% yield. To elucidate the reaction mechanism, control experiments were carried out using (E)-3-(2-nitrophenyl)-1-phenylprop-2-

ketenimine anion derived from 2a′ undergoes 1,4-addition with 1a to generate enol 6. Intramolecular addition of enol 6 to the nitro group affords intermediate 7. Elimination of water from 7 in the presence of CuI generates intermediate 8 (path a), which undergoes Baeyer−Villiger oxidation via the formation of 2,5-dioxa-3-azabicyclo[2.1.0]pentane to form an ester intermediate 9 or 10. Alternatively, the rearrangement of the −O−N−OH of 7 into an −N−O−OH functionality followed by base-induced elimination of H2O2 generates 12 via 11 (path b). Intermolecular Baeyer−Villiger oxidation of 12 by H2O2 affords 9 or 10. To experimentally verify this, we have C

DOI: 10.1021/acs.orglett.8b02363 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

path b, the relative energy of 11 is only 7 kcal/mol higher than 7. The formation of H2O2 from 11 (path b) is more difficult (TS4, 34.1 kcal/mol) than the formation of 8 (TS4, 14.8 kcal/ mol). Interestingly, the calculations showed that 11 can be converted to 8 through the elimination of H2O (TS3′, 10.8 kcal/mol), which confirms that “path a” is more likely to occur than “path b”. The energy calculation of the subsequent steps showed nucleophilic addition of the ketenimine to the imine/ elimination of carboxylic acid/tautomerization/1,4-HCN elimination/6π-electrocyclization, and aerobic oxidation (Figure 1b) proceeded smoothly in the presence of CuI. In summary, we have developed a noble, operationally simple, mild, and cost-effective Cu(I)-catalyzed domino annulation reaction for the synthesis of diverse, polysubstituted aryl-annulated carbazole derivatives starting from readily available 2-nitrocinnamaldehydes and benzyl cyanides in good yield. As demonstrated by the DFT calculations, this unique tandem annulation reaction involves a sequential Michael addition/intramolecular nucleophilic addition of an enol to a nitro group/reduction of an −NO2 to −NH group/ intramolecular Baeyer−Villiger oxidation/carboxylic acid and HCN elimination/6π-electrocyclization/oxidation. The synthesized compounds exhibited excellent fluorescence-sensing properties for the Cu2+ ions and significant solvatochromic properties.

carried out the reaction between 1a, 2a (2 equiv), and 2naphthylboronic acid (1 equiv) under the standard reaction conditions. In this case, 3a was obtained in 60% yield along with the recovery of 2-naphthylboronic acid (98%) (see Scheme S1). The absence of formation of 2-naphthol indicates that “path a” is favored over the elimination of H2O2. Furthermore, addition of a second equivalent of ketenimine anion 2a′ on 9 or 10 gives intermediate 13, which subsequently undergoes elimination of the carboxylate group to form 14. Tautomerization of 14 followed by elimination of HCN gives intermediate 16 via 15. Finally, 6π-electrocyclization of 16 to 17 followed by air oxidation furnishes the final product 3a. Density functional theory (DFT) calculations were carried out to validate the proposed mechanisms for the formation of 9 (Figure 1a). The calculations were initially performed

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02363. Experimental procedures, characterization data, computational data and energy diagrams, fluorescence study and X-ray crystallographic structure and data for 4j (PDF) Accession Codes

Figure 1. Energy profile from DFT calculations of the proposed reaction mechanism [calculated values under CuI conditions are given in parentheses (red)].

CCDC 1584684 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

without CuI, and then the steps with high energy demands were calculated in the presence of CuI to investigate its role in the reaction. The 1,4-addition of 2a′ to 1a was calculated as the first step. Ketenimine 2a′ was taken as the model compound, which had an activation barrier of 47.2 kcal/mol (TS1) for the intermolecular addition with 1a. The reaction of enol 6 onto the nitro group via the six-membered transition state of TS2 has an activation energy of 21.5 kcal/mol. In TS2, the C−N bond is formed by the simultaneous migration of hydrogen from the −OH of the enol to the nitro group in the presence of base. For the conversion of 7 to 9, the feasibility of paths a and b was calculated. In path a, the generation of Noxide intermediate 8 (path a) is facile via TS3 (14.8 kcal/mol) under the reaction conditions through the elimination of H2O. The intramolecular Baeyer−Villiger oxidation of in situ generated N-oxide intermediate 8 leads to 9 through a comparatively high energy barrier (67.9 kcal/mol, TS5) in the absence of CuI. However, the step is aided by the addition of CuI showing a 20 kcal/mol decrease in the calculated energy barrier. This might be due to coordination of Cu+ to the oxygen atom of the 2,5-dioxa-3-azabicyclo[2.1.0]pentane facilitating the dissociation of the N−O bond in TS5-CuI. In

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Tej Narayan Poudel: 0000-0002-0390-107X Hari Datta Khanal: 0000-0001-9955-1256 Yong Rok Lee: 0000-0002-4048-8341 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2018R1A2B2004432) and by the Korean Ministry of Education, Science, and Technology (2012M3A7B4049675). We thank Professor Kosuke Namba (Tokushima University) D

DOI: 10.1021/acs.orglett.8b02363 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters for valuable discussions and providing us the opportunity to use the computational research facility in his group.

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DOI: 10.1021/acs.orglett.8b02363 Org. Lett. XXXX, XXX, XXX−XXX