Letter pubs.acs.org/OrgLett
Chiral Diphosphine−Palladium-Catalyzed Sequential Asymmetric Double-Friedel−Crafts Alkylation and N‑Hemiketalization for Spiropolycyclic Indole Derivatives Nai-Kai Li, Jun-Qi Zhang, Bing-Bing Sun, Hai-Yan Li, and Xing-Wang Wang* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People’s Republic of China S Supporting Information *
ABSTRACT: An efficient cascade asymmetric Friedel−Crafts alkylation/N-hemiketalization/Friedel−Crafts alkylation reaction of 3-alkylindoles with oxindolyl β,γ-unsaturated α-ketoesters has been developed in the presence of a chiral diphosphine− palladium(II) catalyst. A series of enantiomerically enriched spiro-polycyclic indole derivatives have been constructed in high yields with excellent enantioselectivities and diastereoselectivities.
P
molecular coupling reaction,6 the catalytic asymmetric dearomatization (CADA) reaction also provided a useful alternative for C2-functionalized polycyclic indole derivatives.3,7 Despite these advances, development of direct access to optically active C-2- and N-1-functionalized polycyclic indole derivatives remains a challenging topic. In a review of Xiao’s (Box)/Cu(II) catalysis for enantioselective synthesis of pyrrolo[1,2-a]indole derivatives8 and other reports,9−12 we are eager to investigate chiral Lewis acid catalyzed cascade Friedel−Crafts alkylation/N-hemiketalization/Friedel−Crafts alkylation reaction of 3-alkylindoles with oxindolyl β,γ-unsaturated α-ketoesters for construction of multifunctionalized optically active spiro [oxindole−pyrrolo(1,2-a)-indole] derivatives, which is catalyzed by a chiral Segphos−dicationic palladium(II) complex in a multistep process (Scheme 1).13 As illustrated in Table 1, the feasibility of this proposed cascade reaction was first valuated between isatin-derived β,γ-unsaturated α-ketoester 1a and 3-methylindole 2a with a chiral box−Cu(II). The reaction proceeded smoothly and afforded Friedel−Crafts alkylation/N-hemiketalization product 3aa in 72% yield with 70:30 dr and 55% ee (Table 1, entry 1). We then investigated this reaction by the use of (R)-BINAP/Pd(PPh3)2Cl2 in combination with AgSbF6, and the corresponding reaction went smoothly at room temperature but still gave 3aa as the major product (Table 1, entry 2). Subsequently, several other diphosphine ligands L3− L7 were screened, and (R)-DM-SegPhos L6 turned out to be the optimal ligand in terms of enantioselectivity, although poor yield
olycyclic indole backbones exist in a large number of important molecules, such as natural products, pharmacologically active reagents, and dyes (Figure 1).1 Thus, approaches
Figure 1. Selected biologically active C-2 functionalized polycyclic indole derivatives.
to polycyclic indole derivatives with various substituents at the N1, C-2, and C-3 positions of the indolyl backbones have been reported in recent decades.2 Among them, necleophilic addition reactions of C-3 position of indoles, such as allylic alkylation3 and Friedel−Crafts alkylation reaction2 of indoles with activated electrophiles, provide a wide and direct access to C-3functionalized polycyclic indole derivatives due to efficient C-3 nucleophilicity. By contrast, asymmetric C-2 and N-1 alkylation reactions4 giving polycyclic indole structures have been less reported, although much effort has been devoted to this attractive research field and several robust methods have been documented so far. From 2004, the Pictet−Spengler-type reaction5 of 3substituted indoles represented a successful strategy for indolo[2,3-a]quinolizidines through C-2 alkylations. In addition, apart from some domino alkylation reactions initiated by intra© XXXX American Chemical Society
Received: February 5, 2017
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DOI: 10.1021/acs.orglett.7b00368 Org. Lett. XXXX, XXX, XXX−XXX
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was found that 4aa was furnished as the sole spiro-polycyclic indole product in 80% yield with 96% ee (Table 1, entry 15). More reaction parameters, including catalyst loading, reaction substrate concentration, and reaction temperature as well as additives, were further delicately optimized, and the results are summarized in Table 2. When the catalyst loading was decreased
Scheme 1. Proposed Cascade Process
Table 2. Optimization of Other Reaction Parametersa
Table 1. Optimization of the Reaction Conditionsa
a Unless otherwise noted, reactions were carried out with 1a (0.05 mmol), 2a, Pd(PPh3)2Cl2, L6, and corresponding additive in PhCF3. b Isolated yield of 4aa with >20:1 dr. cDetermined by 1H NMR analysis. dDetermined by chiral HPLC. eYield of 3aa.
to 5 mol %, we found that both the yield and enantioselectivity were unaffected (Table 2, entries 1−5). Then two other silver salts were tested instead of AgSbF6, and the results showed that AgSbF6 was still the best cocatalyst (Table 2, entries 8 and 9 vs entry 2). When the reaction temperature and substrate ratio of 2a to 1a were further investigated, it was disclosed that a stepwise temperature increase promoted a maximal level of chiral induction, albeit with prolonged reaction time (Table 2, entry 12 vs entries 2 and 6). The optimal reaction conditions were finally established by the use of L6/Pd(PPh3)2Cl2 (5 mol %) and AgSbF6 (10 mol %) as catalysts with a substrate ratio of 2a/1a to 3:1 and reaction temperature elevation from 25 to 90 °C in PhCF3 (0.1 M) (Table 2, entry 12). With the optimized conditions in hand, we proceeded to investigate the utility of the cascade process for construction of optically active spiro-polycyclic indoles. As shown in Table 3, most of the reactions proceeded smoothly to afford the corresponding spiro-polycyclic indoles 4 in excellent yields with high enantioselectivites and diastereoselectivities. The corresponding N-protected substrates 1a−e and unprotected 1f all gave the desired products 4aa−fa in good yields with high enantioselectivities (Table 3, entries 1−6). The substrate 1g bearing a methyl group at the 5-position of the oxindolyl ring gave the desired products 4ga in 83% yield with 87% ee (Table 3, entry 7), while the other substrates 1h−k bearing various substituents
a Unless otherwise noted, reactions were carried out with 1a (0.025 mmol), 2a (0.05 mmol, 2 equiv), metal (10 mol %) and L (10 mol %) in corresponding solvent (0.5 mL) at 25 °C. bIsolated yield. c Determined by chiral HPLC. dWithout AgSbF6. eAt 50 °C.
of the desired product 4aa was obtained (Table 1 entry 7 vs entries 2−6 and 8). To further optimize the reaction conditions, more metal sources and solvents were investigated (Table 1, entries 9−14). Finally, the use of PhCF3 as the reaction medium resulted in a considerable improvement in both reactivity and enantioselectivity of the desired product 4aa (Table 1, entry 14). While the reaction temperature was increased from 25 to 50 °C, it B
DOI: 10.1021/acs.orglett.7b00368 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 4. Substrate Scope of 3-Substituted Indoles 2a
Table 3. Substrate Scope of Oxindolyl β,γ-Unsaturated αKetoester 1a
entry
1 (R1, R2)
t25 °C/t90 °C (h)
4
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1a (Me, H) 1b (Bn, H) 1c (Ally, H) 1d (MOM, H) 1e (Ac, H) 1f (H, H) 1g (Me, 5-Me) 1h (Me, 5-OMe) 1i (Me, 5-F) 1j (Me, 5-Cl) 1k (Me, 5-Br) 1l (Me, 6-Cl) 1m (Me, 7-Me) 1n (Me, 7-F) 1o (Me, 5,6-2F)
1/3 2/12 1/3 15d/8 4/0 1/2 1/2 3/2 1/2 3/3 4/2 0.5/3 3/5 0.5/1 5/6
4aa 4ba 4ca 4da 4ea 4fa 4ga 4ha 4ia 4ja 4ka 4la 4ma 4na 4oa
95 89 80 81 96 80 83 88 82 86 94 85 92 95 81
97 96 95 89 87 86 87 97 99 97 95 87 95 92 99
entry 1 2 3 4 5 6 7 8 9 10
2 (R1, R2) 2b (4-Br, Me) 2c (5-Me, Me) 2d (5-Ph, Me) 2e (5-OMe, Me) 2f (5-Br, Me) 2g (6-Cl, Me) 2h (6-Br, Me) 2i (6-I, Me) 2j (H, n-hexyl) 2k (H, iPr)
t25 °C/t90 °C (h) d
18 /5 2/5 7/3 2/3 5/3 3/3 2/5 24d/12 10d/12 24e/12
4
yieldb (%)
eec (%)
4ab 4ac 4ad 4ae 4af 4ag 4ah 4ai 4aj 4ak
85 88 94 93 92 87 92 90 91 20:1 dr. c Determined by chiral HPLC. dAt 50 °C. eReactions were carried out with 2k (4 equiv) and 10 mol % catalyst.
chemistry of the other compounds was assigned by analogy to them. Based on the profound insight into the mechanism of the cascade transformation, we suspected that trapping the in situ generated iminium species with another aromatic compound could practically provide a significant opportunity for diversityoriented synthesis of aryl-substituted spiro polycyclic indoles. When two different 3-methylindoles were successively introduced to the “one-pot” reaction, a messy reaction system was observed. We then tried to fufill the diversity-oriented synthesis via a stepwise approach between another aromatic compound and isolated product 3aa. As shown in Scheme 2, 3-methylindoles 2c, 2e, and 2f were first selected to test this transformation, and the corresponding products were successfully obtained in excellent yields with high enantioselectivities. Furthermore,
a
Unless otherwise noted, the reaction conditions are the same as those for entry 12 in Table 2. bIsolated yield of 4 with >20:1 dr. c Determined by chiral HPLC. dAt 50 °C.
(5-OMe, 5-F, 5-Cl, or 5-Br) were quite well-tolerated, respectively, giving the desired products 4ha−ka in 82−94% yields with >20:1 dr and 95−97% ee (Table 3, entries 8−11). We also investigated the substrates 1l−n bearing various substituents (−Cl, −Me, or −F) at the 6- or 7-position of the oxindolyl ring, and the substrates showed good performance for this transformation, furnishing the desired products 4la−na in 85−95% yields with 87−95% ee, respectively (Table 3, entries 12−14). Finally, the substrate 1o bearing a 5,6-diflouro moiety was also investigated, affording the desired products 4oa in 81% yield with >20:1 dr and 99% ee (Table 3, entry 15). We also investigated the substrate scope of 3-substituted indoles 2 with oxindolyl β,γ-unsaturated α-ketoester 1a under otherwise identical reaction conditions. As shown in Table 4, 3methylindole 2b bearing a −Br group at the 4-position of the indole ring is obvious unsuitable, and the corresponding reaction led to the product 4ab in 85% yield with 65% ee (Table 4, entry 1). The substrates 2c−f bearing various substituents (−Me, −Ph, −OMe, or −Br) at the 5-position of the indole ring were welltolerated, giving the desired products 4ac−af in good to high yields with high enantioselectivities (Table 4, entries 2−5). The reactions of substrates 2g−i bearing 6-Cl, 6-Br, and 6-I substituents were also smoothly carried out, providing the corresponding desired products 4ag−ai in 87−92% yields with >20:1 dr and 94−98% ee, respectively (Table 4, entries 6−8). In addition, 3-hexylindole 2j was employed for this transformation, and the corresponding product 4aj was obtained in 91% yield with 82% ee (Table 4, entry 9). Sterically hindered 3isopropylindole 2k was then tested for this transformation, but the catalytic results were unsatisfactory (Table 4, entry 10). Finally, single crystals of compounds 4ag and 4ah were obtained, and their absolute configurations were unambiguously determined as (3S,3′R) by X-ray crystallographic analysis.14 Stereo-
Scheme 2. Further Transformation of 3aa with Diverse Aromatic Compounds
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DOI: 10.1021/acs.orglett.7b00368 Org. Lett. XXXX, XXX, XXX−XXX
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pyrrole and dimethyl resorcinol were respectively chosen to react with 3aa, affording the corresponding 2-pyrrolyl- or 2,4dimethoxyphenyl-substituted spiro [oxindole−pyrrolo[1,2-a]indole] derivatives 5a and 5b with high enantioselectivities. On the other hand, when N-(p-tolyl)acetamide 6 was introduced to the reaction, the dehydration product 7 was obtained instead of the Friedel−Crafts alkylation product, probably due to the insufficient nucleophilicity of N-(p-tolyl)acetamide (Scheme 2). Brønsted acid p-TsOH was further applied into the reaction between indole and 3aa, Friedel−Crafts alkylation product 5d was obtained in 46% yield with >20:1 dr and 91% ee (See section 2.5 in SI). In order to further illuminate the stereocontrol of L6− Pd(II)-catalyzed three-component Friedel−Crafts alkylation/Nhemiketalization/Friedel−Crafts alkylation cascade reaction, we carried out a reaction between 3-methylindole 2a with aryl β,γunsaturated α-ketoester 9. The reaction proceeded smoothly to give 2-indolylpyrrolo[1,2-a]indole 10 in 72% yield with only 19% ee (See section 2.6 in SI). In comparison with Xiao’s work on the chiral Box−copper(II)-catalyzed highly enantioselective Friedel−Crafts alkylation/N-hemiketalization cascade reaction of 3substituted indole with aryl β,γ-unsaturated α-ketoester, it implied that chiral diphosphine−palladium(II) catalyst displays advantages for the use of isatin-derived electrophiles but is not particularly effective for simple γ-aryl substrates. In summary, we have developed an efficient cascade asymmetric Friedel−Crafts alkylation/N-hemiketalization/Friedel−Crafts alkylation reaction of 3-alkylindoles with oxindolyl β,γ-unsaturated α-ketoesters, which is catalyzed by a chiral diphosphine−palladium(II) catalyst. A series of enantiomerically enriched spiro-polycyclic indole derivatives have been constructed in high yields with excellent enantioselectivities and diastereoselectivities. Further studies on the broad application in the synthesis of these kinds of bioactive molecules are currently in progress in our laboratory.
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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.7b00368. Experimental details, compound characterization, and Xray crystallographic data (PDF) X-ray data for 4ag (CIF) X-ray data for 4ah (CIF)
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xing-Wang Wang: 0000-0002-6004-8458 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21572150), the major basic research project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (13KJA150004), the Program for New Century Excellent Talents in University (NCET-12-0743), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). D
DOI: 10.1021/acs.orglett.7b00368 Org. Lett. XXXX, XXX, XXX−XXX
