[1 + 2 + 3] Annulation as a General Access to Indolo[3,2-b]carbazoles

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

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[1 + 2 + 3] Annulation as a General Access to Indolo[3,2‑b]carbazoles: Synthesis of Malasseziazole C Jinhuan Dong,† Dawei Zhang,*,‡ Yang Men,† Xueming Zhang,‡ Zhongyan Hu,† and Xianxiu Xu*,† †

College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China ‡ College of Chemistry, Jilin University, Changchun 130012, China

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S Supporting Information *

ABSTRACT: A formal [1 + 2 + 3] annulation of methyleneindolinones with o-alkenyl arylisocyanides has been developed for the general and efficient synthesis of both symmetrical and unsymmetrical indolo[3,2-b]carbazoles. The chemoselectivity of this domino reaction was tuned by a tethered alkenyl group, which enables successive formation of three new bonds and two rings from readily accessible starting materials in a single operation. Furthermore, this methodology was used as a key step in the synthesis of the alkaloid malasseziazole C.

T

Scheme 1. Domino Reactions of Isocyanides with Metheneindolinones

he indolo[3,2-b]carbazole (ICZ) framework exists in natural products (such as malasseziazoles A−C1), optoelectronic materials,2 and biologically active molecules.3 As a consequence, a plethora of synthetic methods for the construction of these ICZs have been reported.3a,4 They mainly rely on (i) the formation of two pyrrole rings from substituted p-phenylenediamine,5 terphenyl,6 or cyclohexane1,4-dione bis(phenylhydrazone) derivatives,7 (ii) the formation of the central ring from indole8 or bis(indolyl)methane derivatives,9 and (iii) modification of the preformed ICZs.10 Despite intensive research efforts, most of these methods have been applied to the synthesis of symmetrical ICZs.4,8a Therefore, the development of general and efficient strategies for the rapid synthesis of unsymmetrical ICZs, especially those with diverse functional groups at both terminal benzene rings, is still highly desirable. Isocyanides are versatile synthons in chemical synthesis.11 To date, various isocyanide-based annulations such as [3 + 2],12 [3 + 3],13 [3 + 6],14 [4 + 2],15 [1 + 4],16 [1 + 5],17 and [1 + 2 + 2]18 annulations have been developed for the synthesis of diverse classes of heterocycles. Moreover, a number of isocyanide-based double annulations were also developed for the construction of structurally complex molecules.19 Recently, the research group of Li and Jia reported versatile isocyanide annulations with methyleneindolinones for the divergent synthesis of fused quinolines,20 spirooxindoles,21 and fused indoles22 (Scheme 1, eqs 1−4). With the aid of different Lewis acids, isocyanide insertions can be selectively achieved in these transformations.20−22 Very recently, we developed a formal [1 + 2 + 3] annulation of oalkenylaryl isocyanides with α,β-unsaturated ketones for the expeditious synthesis of carbazoles.23 Considering that methyleneindolinones are reactive Michael acceptors and © XXXX American Chemical Society

also inspired by Li and Jia’s work,20−22 we envisioned that [1 + 2 + 3] annulation of o-alkenylaryl isocyanides with methyleneindolinones would deliver ICZs in a single step. As a continuation of our studies on the domino reactions of functionalized isocyanides,24 we herein report a new and general strategy for the efficient synthesis of both symmetrical and unsymmetrical indolo[3,2-b]carbazole derivatives from the domino reaction of o-alkenylaryl isocyanides with methylReceived: November 14, 2018

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DOI: 10.1021/acs.orglett.8b03646 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

catalyst-free conditions (61%, Table 1, entry 1). Therefore, both conditions were performed depending on the cases. The scope of methyleneindolinones 1 was first examined, and the results are summarized in Scheme 2. This [1 + 2 + 3]

eneindolinones (Scheme 1, eq 5). It is notable that the tethered alkenyl moiety on isocyanides modulated a pathway distinct from those reported by Li and Jia,20−22 delivering valuable fused pentacyclic frameworks through a one-pot transformation of readily available raw materials (Scheme 1, eqs 1−4 vs 5). Furthermore, the facile synthesis of indolocarbazole alkaloid malasseziazole C was accomplished via this [1 + 2 + 3] annulation as the key step. Initially, methyleneindolinone 1a25 and o-alkenyl arylisocyanide 2a26 were selected as model substrates to optimize the reaction conditions (Table 1). When a mixture of 1a (0.3

Scheme 2. Substrate Scope of Methyleneindolonones 1a,b

Table 1. Optimization of Reaction Conditionsa

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

catalyst

KAuCl4 In(OTf)3 AgOTf FeCl3 Zn(OTf)2 Zn(OAc)2 ZnCl2 ZnCl2 ZnCl2 ZnCl2 ZnCl2 ZnCl2 ZnCl2 ZnCl2 ZnCl2

solvent

temp (°C)

time (h)

yield of 3ab (%)

EtOH EtOH toluene toluene toluene toluene toluene toluene toluene CF3Ph EtOH dioxane DME THF DME DME DME DME

100 130 130 130 130 130 130 130 130 130 130 130 130 130 100 150 130 130

48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 27 48

61 56 5 trace 4 6 6 27 42 20 23 56 67 40 36 68 69c 37

a

Reaction conditions A: 1 (0.3 mmol), 2a (0.6 mmol), and ZnCl2 (0.09 mmol) in DME (1 mL) at 130 °C. Reaction conditions B: 1 (0.3 mmol), 2a (0.6 mmol) in EtOH (1 mL) at 100 °C. bIsolated yields; the yields in parentheses were obtained with conditions B.

annulation generally tolerates a wide range of substrates 1, and a series of polysubstituted ICZs 3a−v were obtained in moderate to good yields. Various methyleneindolinones 1 bearing different R1 groups such as phenyl (1a), electron-rich aryls (1b, 1c, 1g, 1i, and 1j), or electron-poor aryls (1d−f, 1h), β-naphthyl (1k), heteroaryls (1l and 1m), vinyl group (1n), and ethoxy group (1o) were all effective reactants. The annulation tolerates methyleneindolinones 1 with various R2 groups on the benzene ring such as fluoro (1p), chloro (1q), methyl (1r), and methoxyl (1s). Furthermore, the nitrogen substituent R3 can also be alkyl (1t and 1u), albeit with low product yields (3t and 3u). The reactions depicted in Scheme 2 gave the ICZs products 3 in moderate to good yields. In some cases, a pyrrolo[3,4-b]indole24a byproduct ((E)-methyl 2-(2-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)-2,4dihydropyrrolo[3,4-b]indole-1-carboxylate) generated from the homodimerization of isocyanide 2a was also produced. Generally, the yields of ICZs 3 are higher in the presence of ZnCl2 (conditions A) than under the catalyst-free conditions (conditions B). Subsequently, the reaction scope of this annulation was further investigated with respect to isocyanides 2; some selected results are summarized in Scheme 3. The reaction tolerates isocyanides 2 bearing various R3 and R4 groups. Isocyanides 2b, 2c, and 2d bearing both electron-donating and -withdrawing R3 groups at the 4- and 5-positions give ICZs 3v−x in good yields. Isocyanides 2e and 2f with acetyl or ethoxycarbonyl R4 groups also afford ICZs 3y and 3z8b in good yields. Additionally, unsymmetrical ICZs 3aa and 3ab bearing

a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (30 mol %), and solvent (3 mL). bIsolated yields. cDME (1 mL) was used.

mmol) and 2a (0.6 mmol) was treated at 100 °C in ethanol for 48 h according to our previous [1 + 2 + 3] conditions,23 ICZ 3a was obtained in 61% yield (Table 1, entry 1). Elevating the temperature to 130 °C led to a slightly lower yield (Table 1, entry 2). Solvent screening revealed that ethanol is the best medium, although only a moderate yield of 3a was obtained (see Table S1). Gold Lewis acid catalyzed conditions21 were then tested, but only 5% yield of 3a was obtained (Table 1, entry 3). ZnCl2 was found to be the optimal catalyst after screening a series of Lewis acids (Table 1, entries 4−9). To our delight, the yield of 3a was improved to 67% when the reaction was performed in DME (Table 1, entries 10−14). Lowering the temperature to 100 °C led to a lower yield of 3a (Table 1, entry 15), whereas at 150 °C, ICZ 3a was obtained in a comparable yield (Table 1, entries 16 vs 13). Increasing the concentration from 0.1 to 0.3 M led to a slightly higher yield with shorter reaction time (Table 1, entries 17 vs 13). In the absence of ZnCl2, 3a was obtained in lower yield (Table 1, entry 18). In the presence of ZnCl2 (30 mol %), the yield of 3a is 69% (Table 1, entry 17), which is only slightly higher than the B

DOI: 10.1021/acs.orglett.8b03646 Org. Lett. XXXX, XXX, XXX−XXX

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(6) (Scheme 5). Malasseziazole C (6) is an indolo[3,2b]carbazole alkaloid, isolated by Steglich et al. in 2005.29 It was Scheme 5. Synthesis of Malasseziazole C

a

Reaction conditions A: 1 (0.3 mmol), 2 (0.6 mmol), and ZnCl2 (0.09 mmol) in DME (1 mL) at 130 °C, 27−38 h. bIsolated yields.

differently substituted terminal benzene rings are produced in moderate yields. On the basis of our previous23 and present results, as well as literature precedent,27 a possible mechanistic pathway is proposed in Scheme 4. First, nucleophilic attack of isocyanide

first synthesized by Knö lker and co-workers in 2015, employing a Pd-promoted (2.0 equiv) 2-fold oxidative cyclization as the key step.30 As depicted in Scheme 5, the indolo[3,2-b]carbazole-6,12-diester 3o was obtained in 54% yield from the catalyst-free [1 + 2 + 3] annulation of the readily available substrates 1o and 2a (condition B, 2.5 mmol scale). One of the ester groups was transformed to the aldehyde 5 in high overall yield by a known reduction and oxidation sequence.8b,30 The other ester group was finally hydrolyzed to give the final malasseziazole C (6) in excellent yield. The spectroscopic data of malasseziazole C (6) were consistent with those of the documents.29,30 In summary, a formal [1 + 2 + 3] annulation of methyleneindolinone with o-alkenyl arylisocyanides was developed as a general method for the efficient synthesis of both symmetrical and unsymmetrical indolo[3,2-b]carbazoles. This strategy features high chemical efficiency, readily available starting materials, broad substrate scope, as well as good atom economy, enabling three new chemical bonds and two rings to be successively constructed in a single operation. Compared with previous work,20−22 the tethered alkenyl moiety of isocyanide plays a vital role on the chemoselectivity of this domino process. Furthermore, a total synthesis of alkaloid malasseziazole C was accomplished by using this [1 + 2 + 3] annulation strategy as the key step.

Scheme 4. Proposed Mechanism

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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.8b03646. Experimental procedures and characterization data for all compounds (PDF)

2 onto 1 generates the zwitterionic intermediate I. Cyclization of I then gives intermediate II, which undergoes 1,3-proton shift to afford the formal [1 + 4] product 2-amino furo[2,3b]indole III.24 Next, an intramolecular Diels−Alder reaction occurs to produce intermediate IV, followed by C−O scission, 1.3-proton shift, and elimination of water to give the final ICZ 3.27 To our knowledge, while furo[3,4-b]indoles are reactive dienes, the Diels−Alder reaction of furo[2,3-b]indoles with dienophiles has few precedents.28 Finally, the synthetic potential of this domino reaction was demonstrated by the synthesis of the alkaloid malasseziazole C

Accession Codes

CCDC 1573550 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 CamC

DOI: 10.1021/acs.orglett.8b03646 Org. Lett. XXXX, XXX, XXX−XXX

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xianxiu Xu: 0000-0001-7435-7449 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support provided by the NSFC (21672034) and Shandong Normal University (108-100801) is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03646 Org. Lett. XXXX, XXX, XXX−XXX