Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of cis-5,5a,6,10b-Tetrahydroindeno[2,1‑b]indoles through Palladium-Catalyzed Decarboxylative Coupling of Vinyl Benzoxazinanones with Arynes Shengguo Duan,† Bin Cheng,*,† Xiaoguang Duan,† Bian Bao,† Yun Li,† and Hongbin Zhai*,†,‡,⊥ †
The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China ‡ Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China ⊥ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China S Supporting Information *
ABSTRACT: A novel palladium-catalyzed decarboxylative coupling reaction of vinyl benzoxazinanones with arynes which may feature an intramolecular nucleophilic attack of an amino group at the central carbon of πallylpalladium intermediate has been developed. The cis-5,5a,6,10btetrahydroindeno[2,1-b]indoles were generated in moderate to good yields. One key to the success of the present reaction was to achieve comparable rates for the palladium-catalyzed decarboxylation and aryne formation steps.
he chemistry of allylic palladium is one of the most useful, popular, and intriguing subjects in organic chemistry.1 In general, allylation products could be obtained via nucleophilic attack to a π-allylpalladium intermediate at one of the two terminal carbons of allylic moiety (Figure 1a, left side). But since the study of Hegedus in 1980,2 scientists have discovered that nucleophiles could also attack the central carbon of the allylic
T
moiety in some particular cases (Figure 1a, right side).3,4 In all previous cases, the palladacyclobutane intermediate ended up with either being terminated by cyclopropane formation2,3 or forming a new π-allylpalladium intermediate4 that could participate in further reactions. Since Tunge5 first studied vinyl benzoxazinanones in 2008, the reaction of palladium-catalyzed decarboxylation of vinyl benzoxazinanones has attracted considerable attention from the organic chemistry community.6 The Pd-stabilized zwitterionic intermediates can react with a variety of electrophilic or nucleophilic reagents or two reagents embodied in the same molecule to form cyclic products (Figure 1b, route (i)).5,6 It can also undergo direct cyclization to form 1,2-dihydroquinoline derivatives via palladium extrusion in the absence of other reaction partners (Figure 1b, route (ii)).5 In general, the reported reactions of this type with a vinyl benzoxazinanone as a substrate all involved nucleophilic attack at a terminal carbon (C1 or C3) of the π-allylpalladium intermediate. Herein, we report a novel palladium-catalyzed reaction of vinyl benzoxazinanones with aryne precursors that involves capture of an aryne species with a palladacyclobutane intermediate; the latter was produced through an intramolecular nucleophilic attack to a decarboxylation-derived π-allylpalladium intermediate at its central carbon atom (Figure 1b, route (iii)). The reaction provides a one-step access to cis-5,5a,6,10b-tetrahydroindeno[2,1-b]indoles 3, which widely exists in biologically active compounds7a and natural products such as yeuhchukene7b and fischerindole I.7c
Figure 1. Reactions involving an allylic palladium intermediate.
Received: January 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00192 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Since the discovery of o-(trimethylsilyl)aryl triflate as a new aryne precursor by Kobayashi in 1983, its applications in transition-metal-catalyzed coupling reactions have spurred great attention.8 As the continuation of our interest in developing facile synthetic methods to construct heterocyclic compounds with arynes,9 we decided to explore the new chemistry of palladacyclobutane intermediate and our initial efforts commenced with investigating the coupling reaction of aryne precursor 1a with vinyl benzoxazinanone 2a in the presence of both CsF and a palladium catalyst, Pd(PPh3)4 (Table 1, entry
no appreciable enhancement for the yields of 3aa (entries 5−11). Finally, we were delighted to find that the yield of 3aa could be increased to 70% when the quantity of the fluoride source was reduced to 1.5 equiv and that of 2a was increased to 3.0 equiv (entries 12 and 13). With the optimal reaction conditions determined (Table 1, entry 13), the substrate scope for the vinyl benzoxazinanones 2 was scrutinized (Scheme 1). First, the protecting group on the Scheme 1. Substrate Scope of Vinyl Benzoxazinanones 2
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
c,d
Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd(PPh3)4 Pd(PPh3)4
1 2e 3d 4 5 6 7 8 9 10 11 12f 13f,g
ligand
dppf (±)-BINAP P(OEt)3 P(4-MeOC6H4)3 P(4-CF3C6H4)3 o-phenanthroline
yieldb (%) 16 31 39 42 0 5 3 9 19 12 0 50 70 (67h)
a
Reaction conditions: 1a (0.15 mmol), 2a (0.23 mmol, 1.5 equiv), [Pd] (5 mol %), ligand (5 mol % for entries 6−7, 10 mol % for entries 8−10), and KF/18-C-6 (0.30 mmol, 2.0 equiv) in THF/MeCN (1/3, 3 mL) heated at 70 °C. bDetermined by 1H NMR using 4(dimethylamino)benzaldehyde as the internal standard. cCsF (2.0 equiv) was used instead of KF/18-C-6 (2.0 equiv). dMeCN was used as the solvent. eTHF was used as the solvent. fKF/18-C-6 (0.23 mmol, 1.5 equiv) was used. g2a (0.45 mmol, 3.0 equiv) was used. hIsolated yield. dppf = 1,1′-bis(diphenyphosphino)ferrocene; (±)-BINAP = (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
1).10 Excitingly, tetracycle 3aa bearing a cis-5,5a,6,10btetrahydroindeno[2,1-b]indole skeleton was isolated in 16% yield as our first trial; the structure was unambiguously confirmed by X-ray crystallographic analysis. We speculated that the reaction should have involved the formation of a palladacyclobutane intermediate via intramolecular nucleophilic attack of nitrogen to the central carbon of the π-allylpalladium moiety followed by insertion of aryne and reductive elimination (Figure 1b, route (iii)). In view of the intriguing structure of the cis-5,5a,6,10btetrahydroindeno[2,1-b]indole product and the novel reaction mode of π-allylpalladium intermediate, we then focused on optimizing the reaction conditions (Table 1). KF/18-C-6 exhibited greater performance than CsF as the fluoride source, 70 °C was the best choice for the reaction temperature, and a mixed solvent of THF/MeCN (1/3) was found to be better than any single solvent (entries 2−4, also see the Supporting Information (SI) for the screening experiments in more details). Because ligands usually have significant effects on the metalcatalyzed coupling reactions, we tested the combinations of Pd2(dba)3 with many different ligands, but there was essentially
nitrogen atom of the vinyl benzoxazinanones was examined. As summarized in Scheme 1a, the palladium-catalyzed decarboxylative coupling reaction could be applied to a series of sulfonyl protecting groups. The substrates with an electron-donating group on the benzene ring of the phenylsulfonyl protecting group (3aa and 3ab) gave higher yields than those with an electron-withdrawing group (3ad). Furthermore, methylsulfonyl-protected substrate 2e resulted in a 43% yield, while a carboxamide-protected substrate 2f gave a moderate yield of 53%. Note that electron-donating protecting groups such as benzyl group cannot function in this decarboxylative coupling reaction. All of the experimental results indicated that the efficiency of this coupling reaction was strongly influenced by the protecting groups on the nitrogen atom of the vinyl benzoxazinanones. The identity of the protecting groups on the nitrogen atom could significantly affect the rate of the B
DOI: 10.1021/acs.orglett.8b00192 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters decarboxylation step, which should match that of aryne formation; otherwise, the Pd-stabilized zwitterionic intermediates could self-polymerize or self-cyclize5 and arynes could trimerize,11 all leading to lower yields of the desired coupling products. A methyl group at the 4-, 5-, or 6-position of the vinyl benzoxazinanones was well-tolerated, and the resulting coupling product yields were 49−80% (Scheme 1b). It was obvious that the yield of 3ai was higher than that of 3ag and 3ah. We speculated that the methyl group at the 6-position played an important role, and its steric hindrance made the π-allylpalladium moiety closer to the nucleophilic nitrogen (Scheme 2a). The
Scheme 3. Substrate Scope of the Aryne Precursors 1
Scheme 2. Conformations of the Pd-Stabilized Zwitterionic Intermediates a
Isolated as a 1:1 mixture of 8- and 9-tert-butyl-substituted regioisomers.
Scheme 4. Proposed Mechanism
conformation of intermediate 2i-A2 was more favorable for nucleophilic attack at the central carbon of the π-allylpalladium moiety than 2i-A1. When R3 was a fluoro or methoxy group, the yields of 3aj and 3ak were relatively low because it would be detrimental to the desired reaction if the rate of decarboxylation was too fast (2j) or too slow (2k) compared to that of the aryne generation. It is interesting to note that, contrary to the case of 3ak, the yield of 3al containing a methoxy group at the 6-position was higher (75%), reminiscent of the case of 3ai (Scheme 1b). Substrate 2m, bearing a methyl group at the internal sp2carbon of the alkene moiety, formed the tetracyclic product 3am in high yield (Scheme 1c). The steric effect between the 6-H on the benzene ring and the methyl group directly connected to the vinyl group promoted the intramolecular nucleophilic attack at the central carbon of the π-allylpalladium intermediate, analogous to the case of 3ai and 3al, even though a fully substituted carbon center was constructed in this particular case (Scheme 2b). Further, a series of arynes were reacted with 2a (Scheme 3). In all cases, the reaction proceeded smoothly and the polycyclic compounds 3ba−ga were obtained in moderate yields. When ptert-butyl-o-(trimethylsilyl)aryl triflate (1g) was used as the aryne precursor, two regioisomeric products (i.e., 3ga1 and 3ga2) were formed with a ratio of ca. 1:1, as determined by an analysis of the 1 H NMR integrals. A plausible mechanism was proposed in Scheme 4.2−6 The Pdstabilized zwitterionic intermediates A1/A2 can be readily formed by decarboxylation of 2 in the presence of Pd(0). On one hand, the nitrogen could attack at the terminal carbon of the π-allylpalladium moiety to form 1,2-dihydroquinoline derivative 5 via palladium extrusion (route (i)).5 Indeed, we were able to detect compound 5 in the reaction system. On the other hand, the nitrogen could also attack at the central carbon of the πallylpalladium to generate palladacyclobutane intermediates B (route (ii)).2−4 It seems that insertion of highly reactive aryne is much more favorable over the cyclopropanation process. The
product 3 can be obtained from D1/D2 upon palladium extrusion via reductive elimination. It is plausible that the 6/5/3tricyclic ring system of 6 is too strained to be formed through reductive elimination. Although there are some indirect evidences to support the current mechanism,12 other possible mechanisms13 cannot be ruled out at this time. In summary, we have developed a palladium-catalyzed decarboxylative coupling of vinyl benzoxazinanones with arynes, providing rapid access to cis-5,5a,6,10b-tetrahydroindeno[2,1b]indoles in moderate to good yields. The reaction process may involve a nucleophilic attack at the central carbon of vinyl benzoxazinanone-derived π-allylpalladium that generates a palladacyclobutane intermediate, further reaction of which with an aryne leads to an array of complex polycyclic heterocycles. One key to the success of the present reaction was to achieve comparable rates for the palladium-catalyzed decarboxylation and aryne formation steps. Our new findings will enrich the knowledge of π-allylpalladium chemistry.
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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.8b00192. Detailed experimental procedures and full spectroscopic data for all compounds are available (PDF) C
DOI: 10.1021/acs.orglett.8b00192 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Accession Codes
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CCDC 1570678 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 Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Bin Cheng: 0000-0002-8276-6653 Yun Li: 0000-0003-2236-9880 Hongbin Zhai: 0000-0003-2198-1357 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the NSFC (21732001, 21672017, 21290183, 21472072), Shenzhen Science and Technology Innovation Committee (JCYJ20150529153646078, JSGG20160229150510483), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT_15R28), and “111” Program of MOE for financial support.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00192 Org. Lett. XXXX, XXX, XXX−XXX
