Cycloaddition of Indoles with Epoxides

DOI: 10.1002/chem.201502448

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Asymmetric Synthesis of Furo[3,4-b]indoles by Catalytic [3+ +2] Cycloaddition of Indoles with Epoxides Weiliang Chen,[a] Yong Xia,[a] Lili Lin,[a] Xiao Yuan,[a] Songsong Guo,[a] Xiaohua Liu,[a] and Xiaoming Feng*[a, b] Abstract: A highly efficient N,N’-dioxide–NiII catalyst system for the catalytic [3+ +2] cycloaddition of indoles with epoxides through C¢C cleavage of oxiranes was accomplished under mild conditions. It provided a promising approach for chiral furo[3,4-b]indoles in up to 98 % yield with up to 91 % enantiomeric excess (ee) and > 95:5 diastereomeric ratio (d.r.).

The catalytic asymmetric dearomatization reaction of indoles represents an attractive and useful tactic for the conversion of indoles into optically active polycyclic C2-, C3-fused indoline motifs,[1] which are privileged molecular architectures in biologically active heterocyclic compounds and organic electronics.[2] As a result, various methodologies have been developed, including alkylative dearomatization,[3] oxidative dearomatization,[4] dearomatic annulation, and so on.[5, 6] In terms of chemical efficiency, the enantioselective C2-, C3-annulation of indoles by means of cycloaddition reactions has received a growing acclaim.[5, 7] Carbonyl ylides are promising 1,3-dipolar building block for annulation, and have been utilized to construct many complex oxa-heterocyclic skeletons.[8] Among these oxa-heterocyclic skeletons, 1H-furo[3,4-b]indole exhibits considerable biological activity, and has been employed as anti-infective, immune, and antitumor agents as shown in Figure 1.[9] Moreover, 1Hfuro[3,4-b]indole, which was achieved by cycloaddition of a carbonyl ylide and indole, is a key intermediate to access a variety of natural products, for instance, vindoline,[8c,d] (+ +)-fendleridine, and (+ +)-1-acetylaspidoalbidine,[8e] aspido-sperma, and so forth.[8g] In these impressive studies, diazo compounds or oxadiazole derivatives were employed to generate carbonyl ylides to access natural products; in addition the asymmetric cycload-

dition of indole and epoxide by C¢C bond cleavage of oxiranes have advantages in atom-economy and safety. In 2012, the Zhang group reported a NiII-catalyzed regio- and diastereoselective [3+ +2] cycloaddition of indoles and oxiranes.[10, 11] However, when the enantioselective variant of this reaction was tested, only 19 % ee was obtained by the application of BOX as the chiral ligand (Scheme 1a). On the other hand, we have achieved the catalytic asymmetric [3+ +2] cycloaddition of oxiranes with alkynes and aldehydes recently.[12] In this context, we present herein our ongoing efforts in developing an efficient N,N’-dioxide–NiII complex for the catalytic asymmetric [3+ +2] cycloaddition of indoles with oxiranes by selective C¢C bond

[a] W. Chen,+ Y. Xia,+ Dr. L. Lin, X. Yuan, S. Guo, Prof. Dr. X. Liu, Prof. Dr. X. Feng Key Laboratory of Green Chemistry & Technology Ministry of Education, College of Chemistry Sichuan University, Chengdu 610064 (P. R. China) Fax: (+ 86) 28-8541-8249 E-mail: [email protected]

Entry[a]

Metal salts

Ligand

Solvent

Yield [%][b]

ee [%][c,d]

1 2 3 4 5 6 7 8 9 10 11 12 13[e]

Sc(OTf)3 Co(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O Ni(ClO4)2·6H2O

L-PrPr2 L-PrPr2 L-PrPr2 L-PiPr2 L-RaPr2 L-PrEt2 L-PrMe2 L-PrPh L-PrPr3 L-PrPr3 L-PrPr3 L-PrPr3 L-PrPr3

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DCE TCE toluene TCE

40 63 72 59 66 85 76 84 83 84 76 48 87

race 82 83 40 43 65 60 15 85 87 88 53 90

[a] Unless otherwise noted, all reactions were performed with L–metal (10 mol %, 1.05:1), 1 a (0.10 mmol) in solvent (0.5 mL) at 30 8C for 48 h. [b] Isolated yield. [c] Determined by chiral HPLC analysis. [d] > 19:1 d.r. was obtained in all cases determined by 1H NMR analysis. [e] LiNTf2 (15 mol %) was added. DCE = dichloroethane, TCE = 1,1,2,2-tetrachloroethane.

[b] Prof. Dr. X. Feng Collaborative Innovation Centre of Chemical Science and Engineering Tianjin (P. R. China) [+] These individuals contributed equally to this work Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201502448. Chem. Eur. J. 2015, 21, 15104 – 15107

Table 1. Optimization of different chiral N,N’-dioxide-metal complexes.

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Figure 1. Selected 1H-furo[3,4-b]indoles with biological and pharmacological activity.

Scheme 1. The asymmetric synthesis of chiral furo[3,4-b]indoles.

and ee was realized, when L-PrPr3, with an isopropyl group at para-position of L-PrPr2, was employed, and 83 % yield with 85 % ee was obtained (Table 1, entry 9). Further attempts to improve the results were focused on the solvents. Except for reactivity, CHCl2CHCl2 was more efficient in enantioselectivity than other solvents (Table 1, entries 9–12). As predicted,[12] the addition of LiNTf2 (15 mol %) enhanced the yield and enantioselectivity to 87 % yield and 90 % ee, respectively (Table 1, entry 13). With the optimal conditions identified, various substituted indoles with N–Me protecting groups were investigated, and the results are listed in Scheme 2.[14] C4-Subsituted indoles underwent the reaction efficiently, giving high yields (80–91 %) and enantioselectivities (88–90 % ee), while the diastereoselectivities were quite different, which might arise from the steric hinderance of bromine (Scheme 2, 3 a–3 c). It seemed that indoles with electron-withdrawing groups exhibited slight higher enantioselectivities than those with electron-donating groups (Scheme 2, 3 d, 3 e, 3 h versus 3 f and 3 i). Except for indoles with a 5-Br group, C5-, C6- and C7-subsituted indoles performed well, affording the corresponding products in excellent yields, enantioselectivities and diastereoselectivities (86–96 % yield, 86–91 % ee and > 95:5 d.r.; Scheme 2, 3 d–3 l). Compared to other positions, lower diastereoselectivities were observed, when the indoles with substituents at C6 position were tested (Scheme 1, 3 b, 3 e, 3 f, 3 g versus 3 h, 3 i). To evaluate the

cleavage of epoxides (Scheme 1b).[13] A variety of chiral 1Hfuro[3,4-b]indoles were obtained in high yields with excellent enantioselectivities and diastereoselectivities (up to 98 % yield, 91 % ee, > 95:5 d.r.). We initially carried out the screening of an efficient Lewis acid for catalytic [3+ +2] cycloaddition of epoxides 1 a and indoles 2 a at 30 8C in CH2Cl2 with L-PrPr2 as a ligand. As shown in Table 1, Sc(OTf)3 showed moderate reactivity (40 % yield), but only a racemic product was obtained (Table 1, entry 1). Co(ClO4)2·6H2O gave a lower yield and ee, compared with Ni(ClO4)2·6H2O (Table 1, entries 2 versus 3). Investigation of ligands showed that l-proline derived L-PrPr2 was superior to (S)pipecolic acid derived L-PiPr2 and l-ramipril derived L-RaPr2 in both the reactivity and selectivity (Table 1, entry 3 versus entries 4 and 5). With the decrease of steric hinderance at the orthoposition of a phenyl ring from iPr to Et, Me and H, the enantioselectivity decreased from 83 to 65, 60 and 15 % ee, respectively (Table 1, entries 3 versus 6–8). A further improvement of yield Scheme 2. Substrate scope of indoles for the catalytic asymmetric [3 + 2] cycloaddition. Chem. Eur. J. 2015, 21, 15104 – 15107

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Communication effect of C3-substituents of indole, 3-ethyl-1-methyl-1H-indole was tested, which gave the corresponding product in 96 % yield, 90 % ee and > 95:5 d.r. (Scheme 1, 3 m).[15] Additionally, when 1,2,3-trimethylindole was used, the corresponding product 3 n was obtained in 78 % yield with 56 % ee and > 95:5 d.r.. The absolute configuration of the product 3 a (2R,3S,4R) was determined by X-ray crystallographic analysis.[16] The other products exhibited a similar Cotton effect in their circular dichroism (CD) spectra (see the Supporting Information for details). Subsequently, we investigated the substrate scope of the epoxides. When dimethyl 3-(3,4-dimethylphenyl)oxirane-2,2-dicarboxylate was employed, the corresponding product 3 o was obtained in 73 % yield with 90 % ee and > 95:5 d.r. (Scheme 3a). However, epoxides without electron-donating groups gave inferior results.[17]

Figure 2. Proposed catalytic model and X-ray structure of the product 3 a.

upper right corner to the Re face, affording product 3 a (2R,3S,4R). In summary, we have developed an efficient catalytic system for furo[3,4-b]indoles through asymmetric [3+ +2] cycloaddition of indoles and epoxides by C¢C cleavage of oxiranes for the first time. In the presence of the L-PrPr3–NiII complex, a variety of corresponding chiral furo[3,4-b]indoles were obtained in excellent yields (up to 98 %) with high enantioselectivities (up to 91 % ee) and diastereoselectivities (up to > 95:5 d.r.). Additionally, a transition-state model was proposed to explain the original asymmetric introduction. This, along with the asymmetric cycloaddition of epoxides with other classes of dipolarophiles, constitutes the subject of our sustained efforts.

Experimental Section

Scheme 3. a) Catalytic asymmetric [3 + 2] cycloaddition of indole with oxirane; b) gram-scaled version of the reaction; c) transformation of ester to alcohol.

To evaluate the synthetic value of this catalytic system, a gram-scale reaction was performed (Scheme 3 b). In the presence of the L-PrPr3–Ni(ClO4)2·6H2O complex (10 mol %), the starting material 1 a (3 mmol) reacted with 1.5 equivalents of 2 a, and the corresponding product 3 a was obtained in 89 % yield (1.05 g) with 89 % ee and > 95:5 d.r.. By a simple recrystallization using petroleum ether and ethyl acetate, enantiopure product 3 a could be obtained in 73 % yield. Furthermore, this enantiopure product 3 a could be efficiently transformed into diols 4 upon treatment with NaBH4 in methanol with the retention of stereochemistry (76 % yield, > 99 % ee, Scheme 3c). Based on the absolute configuration of 3 a, and our previous reports,[12, 18] a plausible catalytic model was proposed (Figure 2). In the complex, L-PrPr3 binds the Ni2 + ion with all of the oxygen atoms in a tetradentate manner. NiII coordinates to the carbonyl group of the epoxide, and the active carbonyl ylide is formed. Then the indole attacks the oxirane from the Chem. Eur. J. 2015, 21, 15104 – 15107

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Typical experimental procedure for asymmetric synthesis of furo[3,4-b]indoles by catalytic [3+ +2] cycloaddition of indoles with epoxides N,N’-dioxide L-PrPr3 (7.4 mg, 0.105 mmol), Ni(ClO4)2·6H2O (3.7 mg, 0.01 mmol), LiNTf2 (15 mol %) and 4 æ MS (20.0 mg) were stirred in CHCl2CHCl2 (0.5 mL) at 35 8C under N2 atmosphere for 0.5 h, then 1,3-dimethyl-1H-indole (21.8 mL, 0.15 mmol) was added. After the decrease of temperature to 30 8C, dimethyl 3-(p-tolyl)oxirane-2,2-dicarboxylate 1 a (25.0 mg, 0.1 mmol) was added. The mixture was stirred at 30 8C for 48 h. The reaction mixture was purified by flash chromatography (petroleum ether:ethyl acetate = 10:1) on silica gel to afford the desired product.

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Received: June 24, 2015 Published online on September 4, 2015

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