Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of 3,3′-Biindoles through a Copper-Catalyzed Friedel− Crafts Propargylation/Hydroamination/Aromatization Sequence Tian-Ren Li,† Mao-Mao Zhang,† Bao-Cheng Wang,† Liang-Qiu Lu,*,† and Wen-Jing Xiao†,‡ †
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China ‡ Hubei Key Laboratory for Processing and Application of Catalytic Materials, Huanggang Normal College, Huanggang 438000, China S Supporting Information *
ABSTRACT: A copper-catalyzed Friedel−Crafts propargylation/ hydroamination/aromatization sequence is described. In the presence of a catalytic amount of CuI, this sequential reaction can convert ethynyl benzoxazinanones and indoles into a diverse set of 3,3′biindoles with high efficiency and selectivity. Moreover, the synthesis of other indole−heteroaryl molecules and the catalytic asymmetric formation of axially chiral 3,3′-biindoles are demonstrated.
T
Scheme 1. Reaction Design: Synthesis of 3,3′-Biindoles
he construction of heteroaryl−heteroaryl scaffolds is a fundamentally important task in chemical sciences due to their ubiquity and unique biological and catalytic properties.1 Among them, 3,3′-biindoles and their derivatives, a common structural motif in many natural alkaloids2 and artificial functional molecules,3 have received increasing attention from synthetic chemists.4−6 Generally, direct coupling reactions of two indole units are used for the synthesis of 3,3′-biindoles (Scheme 1a).4 However, except for the oxidative homocoupling reactions of simple indoles,4b,c,e Pd-, In-, or I2-catalyzed crosscoupling processes always require the prefunctionalization of one or both indoles.4a,d,f In addition to coupling reactions, Aucatalyzed5a or Brønsted acid catalyzed5b cyclizations of o-amino aryl alkynes are efficient routes to 3,3′-biindoles (Scheme 1b). Additionally, reductive cyclizations of nitrobenzene derivatives have been well established as another reliable tool for accessing these compounds.6 Although they are efficient, the drawbacks accompanying these strategies, such as limited diversity of products and the requirement of multistep procedures and excess oxidative or reductive reagents, stimulate the development of new methods for the synthesis of 3,3′-biindoles. Recently, we have developed an ethynyl benzoxazinanone reagent (1a) that can be used as a versatile synthon for constructing many aza-heterocycles.7,8 Along with our ongoing program on transition-metal-catalyzed cyclizations,7,9 herein, we plan to develop a novel sequential reaction of this reagent with a wide range of indoles to access 3,3′-biindoles. As illustrated in Scheme 1c, we expect that 1a first reacts with the catalyst to generate transient Cu−allenylidene species A.10 It would then undergo a Friedel−Crafts propargylation with Cu indole 211 to afford intermediate B, which can be converted to indoline−indole compound 4 through a Cu-catalyzed hydroamination.7c Finally, a 1,3-proton shift on 4 driven by aromatization would furnish the desired product 3. If feasible, this Cu-catalyzed sequential reaction would serve as a new © XXXX American Chemical Society
route to significant 3,3′-biindole products while featuring an inexpensive metal catalyst and high synthetic efficiency. To examine this idea, we initially performed the reaction with ethynyl benzoxazinanone 1a and indole 2a as model substrates at room temperature in the presence of CuI and a box ligand Received: April 8, 2018
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DOI: 10.1021/acs.orglett.8b01100 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters L1 (entry 1 of Table 1). The reaction proceeded well, and the desired 3,3′-biindole 3a was obtained in 86% yield after the
Scheme 2. Representative 3,3′-Biindole Products from Various Indolesa
Table 1. Selected Condition Optimizationa
entry 1 2 3 4 5 6 7 8d
variation of the standard conditions none L2 instead of L3 instead of L4 instead of L5 instead of without CuI without L1 without L1
L1 L1 L1 L1
yieldb (%)
timec (h)
86 80 78 73 57 0 88 91
0.2 0.5 1 1 0.5 2 3
a
Standard conditions: 1a (0.2 mmol), 2a (0.24 mmol), CuI (5 mol %), L1 (6 mol %) and i-Pr2NEt (0.4 mmol, 2.0 equiv) in MeOH (2 mL) at ambient temperature; then, Cs2CO3 (2.0 equiv). bIsolated yield. cReaction time for the first step. di-PrOH as solvent. L5: 1,2bis(diphenylphosphanyl)ethane.
a
Reaction conditions are the same as in entry 8 in Table 1, and the time for the first step is provided. bThe yield in parentheses is the result of a gram-scale reaction, and the details are shown in the Supporting Information. c50 °C.
corresponding indoline−indole intermediate was quenched with 2.0 equiv of Cs2CO3 as a base. With this impressive result in hand, the ligand effect on the reaction efficiency was investigated. We found that pybox ligands L2−4 were also amenable to this reaction, and they afforded good, but relatively low, reaction efficiencies compared with box ligand L1 (Table 1, entries 2−4: 73−78% yields). When a phosphine ligand L5 was used instead of nitrogen ligands, only a moderate yield was obtained (Table 1, entry 5:57% yield). Moreover, control experiments revealed that a copper salt was essential for this transformation (Table 1, entry 6:0% yield). Interestingly, a higher yield was achieved in the absence of a ligand; however, a prolonged reaction time was necessary (Table 1, entry 7: 88% yield). Furthermore, the isolated yield could be slightly enhanced to 91% by simply switching the solvent from MeOH to i-PrOH, which might be due to its low nucleophilicity, thus decreasing the formation of byproducts.12 Having established the optimal reaction conditions, we began to probe the generality of this Cu-catalyzed sequential reaction. As highlighted in Scheme 2, a variety of indoles with different substitution patterns can successfully participate in this transformation and afford structurally diverse 3,3′-biindole products in good yields. For example, 2-arylindoles are well tolerated and provide 85−93% yields of the desired products (products 3aa−ad).13 In addition to aryl groups, aliphatic substituents, such as t-Bu, Et, and Me, and functional groups, such as ether and hydroxyl, were found to be compatible with the copper catalyst system (products 3ae−ai, 79−92% yields). Variations in the electronic properties and substitution positions of the indoles ring were also investigated under the optimal conditions. As indicated in Scheme 2, no substantial effect on the reaction efficiency was observed; the corresponding 3,3′-biindoles were provided in generally high yields
(products 3ai−ao, 78−92% yields). Moreover, the success of this sequential reaction can be extended to N-H and N-allyl indole substrates, which afforded biindole products in satisfactory yields (products 3ap, 86% yield; product 3aq, 89% yield). Notably, this reaction can be performed on a gram scale. With the model reaction as an example, product 3aa could be prepared in 84% yield with a prolonged reaction time. Next, we turned our attention to examining the scope of ethynyl benzoxazinanones for this sequential reaction. As summarized in Scheme 3, the reaction with different ethynyl benzoxazinanones proceeded well, producing a set of 3,3′biindole compounds in high yields. For instance, substrates 2 with various substituents at the para-position of the tosyl amide Scheme 3. Representative 3,3′-Biindole Products from Various Ethynyl Benzoxazinanonesa
a
B
Reaction conditions are the same as in entry 8 in Table 1 DOI: 10.1021/acs.orglett.8b01100 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters were well-tolerated in this transformation; the corresponding 3,3′-biindole products 3bi−ei were furnished in 81−94% yields. Additionally, variations of the substituent position were proven compatible with this reaction, delivering the desired products in good yields (3fi, 75% yield; 3gj, 77% yield). Interestingly, the tosyl groups of biindole products 3ei and 3fi were cleaved during the sequential reaction, possibly during the base treatment. Moreover, this reaction method can be further applied to the synthesis of other significant indole−heteroaryl molecules. For example, when pyrrole 5a or furan 5b reacted with ethynyl benzoxazinanone 1a under the standard reaction conditions, the corresponding pyrrole−indole and furan−indole products 6aa and 6ab could be generated in 92% and 65% yields, respectively (eqs 1 and 2). In addition, as shown in eq 3, a
this strategy can be further extended to the production of other indole-heteroaryl compounds (i.e., 3-furylindole and 3pyrrolylindole) from readily available starting materials. Moreover, the catalytic asymmetric process proved to be feasible, affording axially chiral 3,3′-biindole with moderate enantiocontrol.
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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.8b01100. Experimental procedures; spectral data (PDF) Accession Codes
CCDC 1811791 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 data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Liang-Qiu Lu: 0000-0003-2177-4729 Wen-Jing Xiao: 0000-0002-9318-6021
terminally substituted propargyl substrate 1h was examined, and no reaction occurred at room temperature or even 50 °C. This result implied that the formation of Cu−allenylidene intermediates from terminally unsubstituted propargyl substrates was crucial for the present transformation. Axial chirality is an important property of rotationally hindered biaryl compounds, which are extensively used in chiral catalysts and ligands and are common in natural products and pharmaceutical candidates.14 However, the asymmetric construction of axially chiral arylindoles, especially via catalytic processes, has been rarely reported.3b,15 Herein, we conducted a preliminary investigation on the asymmetric preparation of chiral 3,3′-biindoles. The reaction of ethynyl benzoxazinanone 1a and 2-methylindole 2i was performed at 0 °C in methanol in the presence of CuI and chiral pybox ligand L3, and then Cs2CO3 was introduced to promote the 1,3-H transfer process after the disappearance of starting material 1a. As a result, only racemic product 3ai was observed. When a “proton shuttle” strategy with a catalytic amount of BINOL-derived phosphoric acid (PA) was employed instead of the Cs2CO3 condition,16 chiral biindole product 3ai′ was indeed successfully achieved in a good yield, albeit with a moderate enantioselectivity (eq 4). In summary, we have described a Cu-catalyzed Friedel− Crafts propargylation/hydroamination/aromatization sequence of ethynyl benzoxazinanones and indoles. This protocol allows the facile synthesis of a variety of 3,3′-biindole products in one pot with high reaction efficiency and selectivity. The success of
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Nos. 21572074, 21772052, and 21772053), the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019), the Foundation for the Author of National Excellent Doctoral Dissertation of PR China (NO. 201422), and the Natural Science Foundation of Hubei Province (Nos. 2015CFA033 and 2017AHB047) for support of this research.
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DOI: 10.1021/acs.orglett.8b01100 Org. Lett. XXXX, XXX, XXX−XXX
