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Catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles† Hong-Hao Zhang, Xiao-Xue Sun, Jing Liang, Yue-Ming Wang, Chang-Chun Zhao* and Feng Shi* The first catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles was established in the presence of chiral phosphoric acid, which tolerates a wide range of substrates with generally excellent diastereoselectivity and good enantioselectivity (up to >95 : 5 dr, 89 : 11 er). This approach will greatly enrich the chemistry of the catalytic asymmetric Povarov reaction, in particular ketone-involved transformations. Furthermore, this protocol represents the first diastereo- and enantio-
Received 14th August 2014, Accepted 2nd October 2014
selective construction of a spiro[indolin-3,2’-quinoline] framework bearing an indole moiety. This novel type of spiro-compound not only contains two chiral centers, including one quaternary stereogenic
DOI: 10.1039/c4ob01741b
center, but also integrates two biologically important structures of spiro[indolin-3,2’-quinoline] and
www.rsc.org/obc
indole, which may find medicinal applications after bioassay.
Introduction The Povarov reaction,1 namely, the inverse electron-demand aza-Diels–Alder reaction (IEDDA reaction) between 2-azadienes and electron-rich olefins, has proven to be a robust method for constructing a tetrahydroquinoline (THQ) scaffold, which is present in a wide range of biologically important natural alkaloids and man-made heterocycles.2 In recent years, elegant developments have been achieved in the enantioselective Povarov reaction of aldehyde-derived 2-azadienes in the presence of chiral organocatalysts or metal-based catalysts (eqn (1)).3
School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116, China. E-mail: [email protected], [email protected]; Fax: +86 (516)83500065; Tel: +86 (516) 83403165 † Electronic supplementary information (ESI) available: Experimental details, characterization, original NMR and HPLC spectra of products 3. CCDC 1015572. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01741b
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On the other hand, the catalytic asymmetric Povarov reaction of ketone-derived 2-azadienes has gained little success because of its low reactivity and rigid structure (eqn (2)).4 Nevertheless, a ketone-involved asymmetric Povarov reaction will provide easy access to chiral tetrahydroquinolines with at least one quaternary stereogenic center. In particular, if cyclic ketone-derived 2-azadienes are employed as substrates, a specific type of privileged chiral spiro-tetrahydroquinoline architecture will be constructed. Therefore, the catalytic asymmetric Povarov reaction of ketonederived 2-azadienes is in great demand, but full of challenges.
Recently, some breakthroughs have been made in this research field. Our group employed isatins as a type of active ketone to an organocatalytic three-component Povarov reaction, which afforded an enantioenriched spiro[indolin-3,2′-quinoline] scaffold with excellent stereoselectivity (eqn (3)).4a Huang and coworkers also utilized pyruvates as another class of activated ketones for an enantioselective four-component Povarov reaction, giving chiral tetrahydroquinolines with quaternary stereogenic centers (eqn (4)).4b Despite these creative works, the catalytic
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Table 1
Scheme 1 Design of catalytically asymmetric ketone-involved Povarov reaction leading to a Spiro-THQ Structure.
asymmetric ketone-involved Povarov reactions are still underdeveloped and highly desirable. In addition, chiral spirooxindole-based THQs5 and indolerelated molecules6–8 exhibit versatile bioactivities. These two intriguing class of compounds inspired us to envision that the integration of the two biologically important scaffolds into a novel type of spiro-THQ structure (I) might lead to interesting or promising bioactivities (Scheme 1). Our continuous efforts on chiral phosphoric acid (CPA)9 catalyzed enantioselective transformations10 promoted us to devise that this spiro [indolin-3,2′-quinoline] architecture linked to an indole moiety could be constructed by an asymmetric Povarov reaction of isatinderived 2-azadienes with 3-vinylindoles in the presence of CPA. Herein, we report the first catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles, which not only provides easy access to chiral spiro[indolin-3,2′quinoline] framework bearing an indole moiety with good diastereo- and enantioselectivity (up to >95 : 5 dr, 89 : 11 er), but will also significantly enrich the research contents of the catalytic asymmetric ketone-involved Povarov reaction.
Results and discussion This study commenced with the reaction of isatin-derived 2-azadiene 1a and 3-vinylindole 2a in the presence of a wide range of BINOL-derived CPAs 4a–4g in toluene (Table 1, entries 1–7), which afforded the desired spiro[indolin-3,2′-quinoline] 3aa linked with an indole moiety, as expected. Although the diastereoselectivity was excellent in all cases (>95 : 5 dr), the yield and enantioselectivity ranged from low to moderate. Among the CPAs 4a–4g, 3,3′-bis(1-naphthyl)- and 3,3′-bis(triphenylsilyl)-substituted CPAs 4c and 4f exhibited the highest capability for enantioselective control, delivering the spiro-product in 74 : 26 er albeit with poor yields (entries 3 and 6). To improve the yield and enantioselectivity, the backbone of catalyst 4c was changed to a structurally more rigid SPINOL11 framework (entry 8). However, this type of spiro-CPA 5a showed lower catalytic activity than its BINOL-derived counterpart 4c in terms of both reactivity and enantioselectivity (entry 8 vs. 3). Therefore, CPA 4c was employed as
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Screening of the catalysts and solventsa
Entry
Cat.
Solvent
Yieldb (%)
drc
erd
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
4a 4b 4c 4d 4e 4f 4g 5a 4c 4c 4c 4c 4c 4c 4c 4c 4c
Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene CHCl3 EtOAc CH3CN PhF PhCl PhBr o-Xylene m-Xylene p-Xylene
62 58 37 41 50 33 39 26 57 65 96 54 50 17 38 47 58
>95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5
60 : 40 64 : 36 74 : 26 66 : 34 57 : 43 74 : 26 51 : 49 68 : 32 56 : 44 62 : 38 52 : 48 63 : 37 62 : 38 73 : 27 79 : 21 76 : 24 75 : 25
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in a solvent (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2a) without additives at 45 °C for 11 h, and the mole ratio of 1a : 2a was 1 : 1.5. b Isolated yields. c The diastereomeric ratio (dr) was determined by HPLC. d The enantiomeric ratio (er) was determined by HPLC.
the optimal catalyst to further screen the different classes of solvents (entries 3 and 9–11). The preliminary results showed that acetonitrile, being a polar non-protonic solvent, could offer the designed Povarov reaction with an excellent yield of 95%, but with almost no enantioselective induction (entry 11), while toluene, being a nonpolar arene-type solvent, was still the most suitable in terms of enantioselectivity (entry 3). A wide range of arenes, including halogenated aromatics and analogues of toluene, were further evaluated by the model reaction (entries 12–17); It was found that xylenes were superior to toluene in regards to the enantioselectivity (entries 15–17 vs. 3). Among the various arenes, o-xylene delivered the spiro-product with the highest enantioselectivity of 79 : 21 er; however, the yield was still not improved (entry 15). Considering the relatively better performance of o-xylene in enantioselective control, the subsequent optimization of the reaction conditions were carried out in this solvent (Table 2). Because isatin-derived 2-azadiene 1a has a tendency to hydrolyze to the corresponding aniline and isatin in the presence of an acid, molecular sieves (MS), as water absorbers, were added to the reaction mixture with the aim of increasing the yield (entries 2–4). Among the tested MS, the 3 Å MS indeed
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Table 2
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Further optimization of the reaction conditionsa
Entry
1a : 2a
x (mol%)
Yieldb (%)
drc
erd
1 2e 3f 4g 5h 6 7 8 9 10 11 12 13 14
1 : 1.5 1 : 1.5 1 : 1.5 1 : 1.5 1 : 1.5 2:1 1:3 1:6 1:3 1:3 1:3 1:3 1:3 1:3
10 10 10 10 10 10 10 10 5 15 20 30 35 40
38 46 26 39 50 34 60 72 30 61 67 67 68 68
>95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5
79 : 21 69 : 31 56 : 44 63 : 37 73 : 27 72 : 28 76 : 24 72 : 28 63 : 37 79 : 21 82 : 18 83 : 17 84 : 16 84 : 16
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in o-xylene (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2a) without additives at 45 °C for 11 h. b Isolated yields. c The diastereomeric ratio (dr) was determined by HPLC. d The enantiomeric ratio (er) was determined by HPLC. e 3 Å MS (100 mg) was used as an additive.f 4 Å MS (100 mg) was used as an additive. g 5 Å MS (100 mg) was used as an additive. h at 60 °C.
benefited the yield, but the enantioselectivity dramatically decreased (entry 2 vs. 1). Subsequently, in the absence of MS, the reaction temperature was elevated from 45 °C to 60 °C, which also enhanced the yield to a moderate level but with deteriorated enantioselectivity (entry 5 vs. 1). Then, the mole ratio of the two reactants was modulated at 45 °C (entries 6–8), suggesting that increasing the stoichiometry of 3-vinylindole 2a could greatly ameliorate the yield but with certain degree of erosion in enantioselectivity (entries 7 and 8 vs. 1). At this stage, it appears that the yield and enantioselectivity somewhat restrict each other, and a compromise between them should be made. Therefore, a mole ratio of 1 : 3 was chosen as the optimal one for its relatively good yield and considerable enantioselectivity (entry 7). Finally, the catalyst loading was carefully investigated (entries 9–14). Lowering the catalyst loading was detrimental to the reaction (entry 9 vs. 7), while properly raising the catalyst loading was beneficial to the reaction, particularly with regards to the enantioselectivity (entries 10–13 vs. 7). This afforded the desired spiro-product in a good yield of 68% with a considerable enantioselectivity of 84 : 16 er (entry 13). Under optimal reaction conditions, the investigation was carried out on the substrate scope of the catalytic asymmetric isatin-involved Povarov reaction with 3-vinylindole. As shown in Table 3, this protocol was applicable to a wide range of isatin-derived 2-azadienes 1 with various R/R1/R2 groups at different positions of the molecules, delivering the desired spiro[indolin-3,2′-quinolines] 3 bearing an indole backbone with generally excellent diastereoselectivity and moderate to good enantioselectivity (>95 : 5 dr, >81 : 19 er in most cases).
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Table 3
Substrate scope of isatin-derived 2-azadiene 1a
Entry
R/R1/R2 (1)
3
Yieldb (%)
drc
erd
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
H/H/p-OMe (1a) p-tBu/H/p-OMe (1b) m-Me/H/p-OMe (1c) m-Cl/H/p-OMe (1d) p-Cl/H/p-OMe (1e) p-Br/H/p-OMe (1f) m,p-Cl2/H/p-OMe (1g) H/5-Me/p-OMe (1h) H/6-Me/p-OMe (1i) H/7-Me/p-OMe (1j) H/6-OMe/p-OMe (1k) H/6-Br/p-OMe (1l) H/7-Br/p-OMe (1m) H/7-F/p-OMe (1n) H/7-CF3/p-OMe (1o) H/H/p-OEt (1p) H/H/p-OPh (1q) H/H/p-Me (1r) H/H/m,p-(OMe)3 (1s) H/H/H (1t) H/H/p-F (1u)
3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma 3na 3oa 3pa 3qa 3ra 3sa 3ta 3ua
68 50 73 60 50 55 51 75 65 51 67 81 60 56 55 50 69 54 67 Trace Trace
>95 : 5 >95 : 5 81 : 19 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 85 : 15 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 — —
84 : 16 84 : 16 84 : 16 83 : 17 83 : 17 83 : 17 81 : 19 72 : 28 87 : 13 87 : 13 89 : 11 85 : 15 85 : 15 82 : 18 82 : 18 82 : 18 71 : 29 79 : 21 84 : 16 — —
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in o-xylene (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2a) at 45 °C for 11 h, and the mole ratio of 1 : 2 is 1 : 3. b Isolated yields. c The diastereomeric ratio (dr) was determined by 1 H NMR. d The enantiomeric ratio (er) was determined by HPLC.
Firstly, the effect of different substituents R that are linked to the benzyl motif was studied (Table 3, entries 1–7). The investigation revealed that the variation of these substituents, including electronically neutral (entry 1), rich (entries 2 and 3) and poor (entries 4–7) ones, had little influence on the stereoselectivity of the reaction. In detail, all these substrates 1a–1g afforded the spiro-products in >95 : 5 dr (except for 1c) and 81 : 19 to 84 : 16 er, but electron-neutral or -rich substituents exhibited slight superiority over their electron-poor counterparts with regards to enantioselectivity (entries 1–3 vs. 4–7). Moreover, it appeared that the position of the substituents exerted no effect on the enantioselectivity, as exemplified by 1d and 1e (entries 4 and 5), while the disubstituted substrate 1g was inferior to its mono-substituted analogues in terms of enantioselectivity (entry 7 vs. 4–5). Secondly, the impact of the substituents R1 linked to the isatin moiety on the reaction was investigated. As shown in entries 8–15, electronically different substituents at the C5, C6 and C7 positions of isatin moiety could be tolerated by the reaction with generally good stereoselectivity (up to >95 : 5 dr, 89 : 11 er). The position of the substituents appeared to have a delicate effect on the enantioselectivity. For instance, C5-substituted substrate 1h exhibited considerably lower enantioselective
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control than its C6- or C7-substituted counterparts 1i–1j (entry 8 vs. 9–10), whereas there was no remarkable difference in enantioselectivity between C6- and C7-substituted substrates (entry 9 vs. 10 and 12 vs. 13). In addition, the electronic nature of the substituents obviously affected the enantioselectivity because electron-donating groups, such as methyl group, delivered higher enantioselectivity than electronwithdrawing groups at the same C7-position (10 vs. 13–15). Finally, several anilines with different R2 groups were employed in the reaction to investigate the impact of this group on the reaction (entries 16–21). Obviously, substrates 1p–1s bearing electron-donating R2 groups offered the spiroproducts in excellent diastereoselectivity and considerable enantioselectivity (entries 16–19). Among them, trisubstituted aniline-derived substrate 1s afforded the highest stereoselectivity of >95 : 5 dr and 84 : 16 er (entry 19). However, when substrates 1t–1u with electron-neutral or withdrawing R2 groups were utilized in the reaction, only a trace of the desired product was obtained (entries 20 and 21). These results indicated that the electronic nature of the R2 group imposed a significant effect on the reactivity. Generally speaking, by varying the R/R1/R2 group, this approach could serve as an efficient method to synthesize chiral spiro[indolin-3,2′-quinolines] bearing an indole moiety with structural diversity. Moreover, 5-bromo-substituted 3-vinylindole 2b proved to be a suitable reaction component, which participated in the catalytic asymmetric Povarov reaction with isatin-derived 2-azadienes 1a with an excellent diastereoselectivity of >95 : 5 dr and acceptable enantioselectivity of 80 : 20 er (eqn (5)).
The absolute configuration of spiro[indolin-3,2′-quinoline] 3aa (92 : 8 er after recrystallization) was assigned to be (2′R,4′S) by single-crystal X-ray diffraction (in Scheme 2).12 The configurations of other spiro-products 3 were designated by analogy. Based on the experiment results, we suggested possible transition states to explain the stereochemistry of this catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles. As illustrated in Scheme 2, catalyst 4c simultaneously formed a dual hydrogen-bonding interaction with the two substrates. Because of the chiral environment created by the (R)-BINOL backbone and the bulky 3,3′-substitutents of CPA 4c, an enantioselective vinylogous Mannich reaction occurred to generate a transient intermediate A, which subsequently underwent a stereoselective intramolecular Friedel– Crafts reaction to afford the final (2′R,4′S)-configured spiroproduct. In the suggested reaction pathway, CPA 4c acted as a bifunctional catalyst to form two hydrogen bonds with the substrates or the intermediate, which significantly contributed to the excellent diastereoselectivity and good enantioselectivity observed.
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Scheme 2 Absolute configuration of compound 3aa and the proposed transition states of the reaction.
Because a non-asymmetric version of the Povarov reaction is still of significant interest from a synthetic point of view, we also investigated the performance of the racemic reaction using racemic phosphoric acid (±)-PA as a catalyst. As shown in Table 4, this reaction was also amenable to a variety of Table 4 Performance of the racemic Povarov reactiona
Entry
R/R1/R2 (1)
R3 (2)
(±)-3
drb
Yieldc (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
H/H/p-OMe (1a) p-tBu/H/p-OMe (1b) m-Me/H/p-OMe (1c) m-Cl/H/p-OMe (1d) p-Cl/H/p-OMe (1e) p-Br/H/p-OMe (1f) m,p-Cl2/H/p-OMe (1g) H/5-Me/p-OMe (1h) H/6-Me/p-OMe (1i) H/7-Me/p-OMe (1j) H/6-OMe/p-OMe (1k) H/6-Br/p-OMe (1l) H/7-Br/p-OMe (1m) H/7-F/p-OMe (1n) H/7-CF3/p-OMe (1o) H/H/p-OEt (1p) H/H/p-OPh (1q) H/H/p-Me (1r) H/H/m,p-(OMe)3 (1s) H/H/H (1t) H/H/p-F (1u) H/H/p-OMe (1a)
H (2a) 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a Br (2b)
(±)-3aa (±)-3ba (±)-3ca (±)-3da (±)-3ea (±)-3fa (±)-3ga (±)-3ha (±)-3ia (±)-3ja (±)-3ka (±)-3la (±)-3ma (±)-3na (±)-3oa (±)-3pa (±)-3qa (±)-3ra (±)-3sa (±)-3ta (±)-3ua (±)-3ab
>95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 — — >95 : 5
74 64 67 64 57 59 62 80 69 50 74 76 69 67 64 62 64 59 58 Trace Trace 52
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in o-xylene (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2) at 45 °C for 11 h, and the mole ratio of 1 : 2 is 1 : 3. b The diastereomeric ratio (dr) was determined by 1H NMR. c Isolated yields.
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substrates, delivering the racemic products (±)-3 with structural diversity in generally good yield (52%–80%) and excellent diastereoselectivity (all >95 : 5 dr). Nevertheless, substrates 1t–1u were still unable to participate in the reaction (entries 20 and 21).
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Conclusions In summary, we have established the first catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles, which tolerates a wide range of substrates in generally excellent diastereoselectivity and good enantioselectivity (up to >95 : 5 dr, 89 : 11 er). This approach is expected to significantly enrich the chemistry of the catalytic asymmetric Povarov reaction, especially ketone-involved transformations. Furthermore, this protocol also represents the first diastereo- and enantioselective construction of a spiro[indolin-3,2′-quinoline] framework bearing an indole moiety. This novel type of spiro-compound not only contains two chiral centers, including one quaternary stereogenic center, but also integrates the two biologically important structures of spiro[indolin-3,2′-quinoline] and indole, which may find medicinal applications after bioassay.
Experimental General information The 1H and 13C NMR spectra were measured at 400 and 100 MHz respectively. The solvent used for NMR spectroscopy was CDCl3 with tetramethylsilane as the internal reference. HRMS (ESI) was determined by a micrOTOF-QII HRMS/MS instrument (Bruker). The enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography (chiral HPLC). The chiral columns used for determining the enantiomeric excesses by chiral HPLC were Chiralpak AD-H and IA columns. The optical rotation values were measured with instruments operating at λ = 589 nm, corresponding to the sodium D line at the indicated temperatures. Analytical grade solvents for column chromatography and commercially available reagents were used as received. All commercially available starting materials were directly used. Substrates 1 and 2 were synthesized according to the literature methods.13 General procedure for the catalytic asymmetric Povarov reaction of isatin-derived 2-azadiene 1 with 3-vinylindole 2 to synthesize spiro-product 3 (Table 3) To a stirred solution of isatin-derived 2-azadienes 1 (0.1 mmol) and the catalyst 4c (0.035 mmol) in o-xylene (2 mL) at 45 °C, a solution of 3-vinylindoles 2 (0.3 mmol) in a mixed solvent of o-xylene (0.8 mL) and 1,4-dioxane (0.2 mL) was added dropwise through syringe pump for 10 h. After the addition of 3-vinylindoles 2 was completed, the reaction mixture was then further stirred for one hour. The resulting solution was concentrated under reduced pressure to obtain a residue, which
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was purified through flash column chromatography on silica gel to afford the pure spiro-product 3. General procedure for the racemic Povarov reaction of isatin-derived 2-azadiene 1 with 3-vinylindole 2 to synthesize spiro-product (±)-3 (Table 4) To a stirred solution of isatin-derived 2-azadienes 1 (0.1 mmol) and racemic phosphoric acid (0.035 mmol) in o-xylene (2 mL) at 45 °C, a solution of 3-vinylindoles 2 (0.3 mmol) in a mixed solvent of o-xylene (0.8 mL) and 1,4-dioxane (0.2 mL) was added dropwise through syringe pump for 10 h. After completing the addition of 3-vinylindoles 2, the reaction mixture was stirred for another hour. The resulting solution was concentrated under the reduced pressure to give the residue, which was purified by flash column chromatography on silica gel to afford pure spiro-product (±)-3. These products were used as the racemic standards for HPLC determination. Selected examples of characterization of compounds 3 (2′R,4′S)-1-Benzyl-4′-(1H-indol-3-yl)-6′-methoxy-3′,4′-dihydro1′H-spiro[indoline-3,2′-quinolin]-2-one (3aa). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 68% (33.1 mg); >95 : 5 dr; yellow 1 solid; [α]20 D = +132.7 (c 0.59, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.06 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.39–7.36 (m, 2H), 7.33 (d, J = 4.3 Hz, 4H), 7.31–7.26 (m, 1H), 7.20–7.15 (m, 3H), 7.07–7.00 (m, 2H), 6.72 (d, J = 7.8 Hz, 1H), 6.66 (dd, J = 8.5, 2.9 Hz, 1H), 6.61–6.54 (m, 2H), 5.17 (dd, J = 12.6, 5.2 Hz, 1H), 5.00–4.81 (m, 2H), 4.03 (s, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.20 (dd, J = 13.7, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.1, 152.4, 142.1, 136.7, 136.3, 136.0, 132.0, 129.3, 128.9, 127.7, 127.4, 125.4, 123.6, 123.0, 122.8, 121.9, 119.9, 119.3, 117.8, 114.7, 113.2, 111.3, 109.2, 60.1, 55.8, 43.7, 39.0, 30.7; IR (KBr): 3646, 3309, 2922, 2360, 1702, 1607, 1497, 1351, 1289, 1231, 1173, 1098, 1037, 986, 858, 808, 741, 697, and 669 cm−1; ESI FTMS exact mass calcd for (C32H27N3O2 − H)− requires m/z 484.2020, found m/z 484.2026; enantiomeric ratio: 84 : 16, determined by HPLC (Daicel Chirapak IA, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.21 min (minor), tR = 10.37 min (major). (2′R,4′S)-1-(4-(tert-Butyl)benzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ba). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 50% (27.1 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +167.9 (c 0.32, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.12 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 9.4, 6.1 Hz, 4H), 7.28 (s, 2H), 7.23–7.16 (m, 2H), 7.14 (d, J = 2.5 Hz, 1H), 7.07–7.00 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.67 (dd, J = 8.5, 2.6 Hz, 1H), 6.61–6.55 (m, 2H), 5.18 (dd, J = 12.5, 5.1 Hz, 1H), 4.93 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.5 Hz, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.21 (dd, J = 13.7, 5.3 Hz, 1H), 1.61 (s, 1H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 150.6, 142.3, 136.7, 136.3, 132.9, 132.0, 129.2, 127.2, 125.7, 123.5, 122.9, 122.6, 121.9, 120.0, 119.3, 118.0, 114.7, 114.6, 113.2, 111.2, 109.2,
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60.1, 55.8, 43.3, 39.0, 34.5, 31.3, 30.7, 29.7; IR (KBr): 3651, 3298, 2959, 2360, 1704, 1605, 1628, 1498, 1353, 1264, 1290, 1237, 1174, 1097, 1038, 987, 861, 806, and 742 cm−1; ESI FTMS exact mass calcd for (C36H35N3O2 − H)− requires m/z 540.2646, found m/z 540.2673; enantiomeric ratio: 84 : 16, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 7.27 min (minor), tR = 9.24 min (major). (2′R,4′S)-4′-(1H-Indol-3-yl)-6′-methoxy-1-(3-methylbenzyl)3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ca). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 73% (36.7 mg); 81 : 19 dr; yellow sticky oil; [α]20 D = +197.7 (c 0.31, Acetone); 1 H NMR (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.40–7.34 (m, 2H), 7.25–7.12 (m, 6H), 7.12–7.07 (m, 1H), 7.06–7.00 (m, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.70–6.64 (m, 1H), 6.62–6.54 (m, 2H), 5.18 (dd, J = 12.5, 5.1 Hz, 1H), 4.93 (d, J = 15.5 Hz, 1H), 4.81 (d, J = 15.5 Hz, 1H), 4.05 (s, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.33 (s, 3H), 2.21 (dd, J = 13.7, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 142.2, 138.6, 136.7, 136.3, 135.9, 132.0, 129.3, 128.7, 128.5, 128.2, 126.7, 125.4, 124.5, 123.5, 122.9, 122.6, 121.9, 119.9, 119.3, 118.0, 114.7, 114.6, 113.2, 111.2, 109.2, 60.1, 55.8, 43.7, 39.1, 30.7, 21.5; IR (KBr): 3651, 3319, 2922, 2361, 1698, 1603, 1628, 1499, 1437, 1344, 1291, 1235, 1177, 1098, 1035, 811, 745, and 696 cm−1; ESI FTMS exact mass calcd for (C33H29N3O2 − H)− requires m/z 498.2176, found m/z 498.2195; enantiomeric ratio: 84 : 16, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.23 min (minor), tR = 12.72 min (major). (2′R,4′S)-1-(3-Chlorobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3da). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 60% (31.2 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 H NMR D = +43.3 (c 0.80, CHCl3); (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.41–7.34 (m, 2H), 7.29 (dd, J = 7.9, 5.5 Hz, 4H), 7.23–7.16 (m, 2H), 7.14 (dd, J = 6.5, 1.6 Hz, 1H), 7.07–7.02 (m, 2H), 6.73–6.63 (m, 2H), 6.61–6.55 (m, 2H), 5.15 (dd, J = 12.5, 5.1 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.08 (s, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.18 (dd, J = 13.7, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 178.8, 152.5, 143.4, 136.7, 136.0, 135.4, 130.9, 129.0, 127.9, 127.4, 126.6, 125.9, 125.3, 125.0, 122.8, 122.7, 122.0, 119.9, 119.3, 117.7, 114.9, 114.6, 113.2, 112.5, 111.3, 59.9, 55.7, 43.7, 38.9, 30.6; IR (KBr): 3651, 3525, 3441, 3274, 2923, 1705, 1629, 1490, 1353, 1235, 1173, 1095, 1013.99 1037, 987, 801, 743, and 567 cm−1; ESI FTMS exact mass calcd for (C32H26ClN3O2 − H)− requires m/z 518.1630, found m/z 518.1631; enantiomeric ratio: 83 : 17, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.57 min (minor), tR = 15.83 min (major). (2′R,4′S)-1-(4-Chlorobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ea). Flash column chromatography eluent, petroleum ether–ethyl acetate
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= 6/1; Reaction time = 11 h; yield: 50% (26.1 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +226.3 (c 0.31, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.10 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.40–7.35 (m, 2H), 7.32–7.26 (m, 4H), 7.22–7.13 (m, 3H), 7.06–7.01 (m, 2H), 6.71–6.64 (m, 2H), 6.61–6.54 (m, 2H), 5.15 (dd, J = 12.5, 5.1 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.03 (s, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.21–2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 141.8, 136.7, 136.2, 134.5, 133.6, 132.0, 129.3, 129.0, 128.8, 126.6, 125.3, 123.7, 123.2, 122.6, 122.0, 119.9, 119.3, 117.9, 114.7, 114.6, 113.2, 111.2, 109.0, 60.1, 55.8, 43.0, 39.0, 30.7; IR (KBr): 3659, 3525, 3443, 3043, 2360, 1629, 1538, 1353, and 568 cm−1; ESI FTMS exact mass calcd for (C32H26ClN3O − H)− requires m/z 518.1630, found m/z 518.1630; enantiomeric ratio: 83 : 17, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.73 min (minor), tR = 16.07 min (major). (2′R,4′S)-1-(4-Bromobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3fa). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 55% (31.2 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +449.5 (c 0.41, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.45 (d, J = 8.3 Hz, 3H), 7.37 (t, J = 8.4 Hz, 2H), 7.24–7.12 (m, 5H), 7.07–7.00 (m, 2H), 6.72–6.62 (m, 2H), 6.61–6.53 (m, 2H), 5.15 (dd, J = 12.6, 5.1 Hz, 1H), 4.90 (d, J = 15.7 Hz, 1H), 4.79 (d, J = 15.7 Hz, 1H), 4.06 (s, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.18 (dd, J = 13.7, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 141.8, 136.7, 136.2, 135.0, 132.0, 129.3, 129.2, 125.3, 123.7, 123.2, 122.6, 122.0, 121.6, 119.9, 119.3, 117.9, 114.7, 114.6, 113.2, 111.3, 109.0, 60.1, 55.8, 43.1, 39.0, 30.7; IR (KBr): 3659, 3525, 3441, 3292, 2923, 1707, 1629, 1488, 1352, 1291, 1235, 1173, 1071, 1097, 1011, 1038, 799, 743, and 580 cm−1; ESI FTMS exact mass calcd for (C32H26BrN3O2 − H)− requires m/z 564.1110, found m/z 564.1086; enantiomeric ratio: 83 : 17, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.74 min (minor), tR = 16.07 min (major). (2′R,4′S)-1-(3,4-Dichlorobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ga). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 51% (28.3 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +146.0 (c 0.35, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.47–7.42 (m, 2H), 7.41–7.34 (m, 3H), 7.22 (td, J = 7.8, 1.3 Hz, 1H), 7.19–7.13 (m, 3H), 7.08–7.01 (m, 2H), 6.72–6.64 (m, 2H), 6.61–6.55 (m, 2H), 5.14 (dd, J = 12.6, 5.2 Hz, 1H), 4.89 (d, J = 15.8 Hz, 1H), 4.79 (d, J = 15.7 Hz, 1H), 4.05 (s, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.2 Hz, 1H), 2.23–2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 141.5, 136.7, 136.3, 136.1, 133.0, 131.9, 130.9, 129.4, 126.8, 126.6, 125.3, 123.8, 123.4, 122.6, 122.0, 119.9, 119.3, 117.8, 114.8, 114.6, 113.3, 111.3, 108.8, 60.1, 55.8, 42.7, 39.1, 30.7; IR (KBr): 3666, 3525, 3441, 3273, 2923, 2360, 1707, 1629, 1498, 1354, 1236, 1173, 1097, 1031, 988, 872, 806, 742, and 567 cm−1; ESI FTMS exact mass calcd for (C32H25Cl2N3O2 − H)− requires m/z 552.1240, found m/z
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552.1230; enantiomeric ratio: 81 : 19, determined by HPLC (Daicel Chirapak IA, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.92 min (minor), tR = 14.61 min (major). (2′R,4′S)-1-Benzyl-4′-(1H-indol-3-yl)-6′-methoxy-5-methyl3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ha). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 75% (37.5 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +60.5 (c 0.56, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.15 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 11.2, 6.3 Hz, 5H), 7.28 (dd, J = 8.4, 4.5 Hz, 1H), 7.23–7.20 (m, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.67 (dd, J = 8.5, 2.7 Hz, 1H), 6.64–6.54 (m, 3H), 5.17 (dd, J = 12.5, 5.2 Hz, 1H), 4.96 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.28 (s, 3H), 2.20 (dd, J = 13.7, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.1, 152.3, 139.6, 136.8, 136.4, 136.1, 132.7, 132.0, 129.5, 128.8, 127.6, 127.4, 126.6, 125.5, 124.4, 122.7, 121.9, 120.0, 119.2, 118.0, 114.7, 113.2, 111.3, 109.0, 60.2, 55.8, 43.7, 39.1, 30.8, 21.0; IR (KBr): 3553, 3482, 3416, 3234, 2920, 1701, 1617, 1637, 1497, 1438, 1455, 1383, 1342, 1265, 1288, 1242, 1149, 1182, 1011, 1038, 988, 809, 742, 697, and 620 cm−1; ESI FTMS exact mass calcd for (C33H29N3O2 − H)− requires m/z 498.2176, found m/z 498.2176; enantiomeric ratio: 72 : 28, determined by HPLC (Daicel Chirapak OD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.21 min (minor), tR = 10.37 min (major).
Acknowledgements We are grateful for financial support from National Natural Science Foundation of China (21372002 and 21232007), Open Foundation of Jiangsu Key Laboratory (K201314), PAPD and Qing Lan Project of Jiangsu Province, and the Graduate Students Project of Jiangsu Normal University (2014YZD012).
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Catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles† Hong-Hao Zhang, Xiao-Xue Sun, Jing Liang, Yue-Ming Wang, Chang-Chun Zhao* and Feng Shi* The first catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles was established in the presence of chiral phosphoric acid, which tolerates a wide range of substrates with generally excellent diastereoselectivity and good enantioselectivity (up to >95 : 5 dr, 89 : 11 er). This approach will greatly enrich the chemistry of the catalytic asymmetric Povarov reaction, in particular ketone-involved transformations. Furthermore, this protocol represents the first diastereo- and enantio-
Received 14th August 2014, Accepted 2nd October 2014
selective construction of a spiro[indolin-3,2’-quinoline] framework bearing an indole moiety. This novel type of spiro-compound not only contains two chiral centers, including one quaternary stereogenic
DOI: 10.1039/c4ob01741b
center, but also integrates two biologically important structures of spiro[indolin-3,2’-quinoline] and
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indole, which may find medicinal applications after bioassay.
Introduction The Povarov reaction,1 namely, the inverse electron-demand aza-Diels–Alder reaction (IEDDA reaction) between 2-azadienes and electron-rich olefins, has proven to be a robust method for constructing a tetrahydroquinoline (THQ) scaffold, which is present in a wide range of biologically important natural alkaloids and man-made heterocycles.2 In recent years, elegant developments have been achieved in the enantioselective Povarov reaction of aldehyde-derived 2-azadienes in the presence of chiral organocatalysts or metal-based catalysts (eqn (1)).3
School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116, China. E-mail: [email protected], [email protected]; Fax: +86 (516)83500065; Tel: +86 (516) 83403165 † Electronic supplementary information (ESI) available: Experimental details, characterization, original NMR and HPLC spectra of products 3. CCDC 1015572. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01741b
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On the other hand, the catalytic asymmetric Povarov reaction of ketone-derived 2-azadienes has gained little success because of its low reactivity and rigid structure (eqn (2)).4 Nevertheless, a ketone-involved asymmetric Povarov reaction will provide easy access to chiral tetrahydroquinolines with at least one quaternary stereogenic center. In particular, if cyclic ketone-derived 2-azadienes are employed as substrates, a specific type of privileged chiral spiro-tetrahydroquinoline architecture will be constructed. Therefore, the catalytic asymmetric Povarov reaction of ketonederived 2-azadienes is in great demand, but full of challenges.
Recently, some breakthroughs have been made in this research field. Our group employed isatins as a type of active ketone to an organocatalytic three-component Povarov reaction, which afforded an enantioenriched spiro[indolin-3,2′-quinoline] scaffold with excellent stereoselectivity (eqn (3)).4a Huang and coworkers also utilized pyruvates as another class of activated ketones for an enantioselective four-component Povarov reaction, giving chiral tetrahydroquinolines with quaternary stereogenic centers (eqn (4)).4b Despite these creative works, the catalytic
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Table 1
Scheme 1 Design of catalytically asymmetric ketone-involved Povarov reaction leading to a Spiro-THQ Structure.
asymmetric ketone-involved Povarov reactions are still underdeveloped and highly desirable. In addition, chiral spirooxindole-based THQs5 and indolerelated molecules6–8 exhibit versatile bioactivities. These two intriguing class of compounds inspired us to envision that the integration of the two biologically important scaffolds into a novel type of spiro-THQ structure (I) might lead to interesting or promising bioactivities (Scheme 1). Our continuous efforts on chiral phosphoric acid (CPA)9 catalyzed enantioselective transformations10 promoted us to devise that this spiro [indolin-3,2′-quinoline] architecture linked to an indole moiety could be constructed by an asymmetric Povarov reaction of isatinderived 2-azadienes with 3-vinylindoles in the presence of CPA. Herein, we report the first catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles, which not only provides easy access to chiral spiro[indolin-3,2′quinoline] framework bearing an indole moiety with good diastereo- and enantioselectivity (up to >95 : 5 dr, 89 : 11 er), but will also significantly enrich the research contents of the catalytic asymmetric ketone-involved Povarov reaction.
Results and discussion This study commenced with the reaction of isatin-derived 2-azadiene 1a and 3-vinylindole 2a in the presence of a wide range of BINOL-derived CPAs 4a–4g in toluene (Table 1, entries 1–7), which afforded the desired spiro[indolin-3,2′-quinoline] 3aa linked with an indole moiety, as expected. Although the diastereoselectivity was excellent in all cases (>95 : 5 dr), the yield and enantioselectivity ranged from low to moderate. Among the CPAs 4a–4g, 3,3′-bis(1-naphthyl)- and 3,3′-bis(triphenylsilyl)-substituted CPAs 4c and 4f exhibited the highest capability for enantioselective control, delivering the spiro-product in 74 : 26 er albeit with poor yields (entries 3 and 6). To improve the yield and enantioselectivity, the backbone of catalyst 4c was changed to a structurally more rigid SPINOL11 framework (entry 8). However, this type of spiro-CPA 5a showed lower catalytic activity than its BINOL-derived counterpart 4c in terms of both reactivity and enantioselectivity (entry 8 vs. 3). Therefore, CPA 4c was employed as
9540 | Org. Biomol. Chem., 2014, 12, 9539–9546
Screening of the catalysts and solventsa
Entry
Cat.
Solvent
Yieldb (%)
drc
erd
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
4a 4b 4c 4d 4e 4f 4g 5a 4c 4c 4c 4c 4c 4c 4c 4c 4c
Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene CHCl3 EtOAc CH3CN PhF PhCl PhBr o-Xylene m-Xylene p-Xylene
62 58 37 41 50 33 39 26 57 65 96 54 50 17 38 47 58
>95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5
60 : 40 64 : 36 74 : 26 66 : 34 57 : 43 74 : 26 51 : 49 68 : 32 56 : 44 62 : 38 52 : 48 63 : 37 62 : 38 73 : 27 79 : 21 76 : 24 75 : 25
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in a solvent (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2a) without additives at 45 °C for 11 h, and the mole ratio of 1a : 2a was 1 : 1.5. b Isolated yields. c The diastereomeric ratio (dr) was determined by HPLC. d The enantiomeric ratio (er) was determined by HPLC.
the optimal catalyst to further screen the different classes of solvents (entries 3 and 9–11). The preliminary results showed that acetonitrile, being a polar non-protonic solvent, could offer the designed Povarov reaction with an excellent yield of 95%, but with almost no enantioselective induction (entry 11), while toluene, being a nonpolar arene-type solvent, was still the most suitable in terms of enantioselectivity (entry 3). A wide range of arenes, including halogenated aromatics and analogues of toluene, were further evaluated by the model reaction (entries 12–17); It was found that xylenes were superior to toluene in regards to the enantioselectivity (entries 15–17 vs. 3). Among the various arenes, o-xylene delivered the spiro-product with the highest enantioselectivity of 79 : 21 er; however, the yield was still not improved (entry 15). Considering the relatively better performance of o-xylene in enantioselective control, the subsequent optimization of the reaction conditions were carried out in this solvent (Table 2). Because isatin-derived 2-azadiene 1a has a tendency to hydrolyze to the corresponding aniline and isatin in the presence of an acid, molecular sieves (MS), as water absorbers, were added to the reaction mixture with the aim of increasing the yield (entries 2–4). Among the tested MS, the 3 Å MS indeed
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Table 2
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Further optimization of the reaction conditionsa
Entry
1a : 2a
x (mol%)
Yieldb (%)
drc
erd
1 2e 3f 4g 5h 6 7 8 9 10 11 12 13 14
1 : 1.5 1 : 1.5 1 : 1.5 1 : 1.5 1 : 1.5 2:1 1:3 1:6 1:3 1:3 1:3 1:3 1:3 1:3
10 10 10 10 10 10 10 10 5 15 20 30 35 40
38 46 26 39 50 34 60 72 30 61 67 67 68 68
>95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5
79 : 21 69 : 31 56 : 44 63 : 37 73 : 27 72 : 28 76 : 24 72 : 28 63 : 37 79 : 21 82 : 18 83 : 17 84 : 16 84 : 16
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in o-xylene (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2a) without additives at 45 °C for 11 h. b Isolated yields. c The diastereomeric ratio (dr) was determined by HPLC. d The enantiomeric ratio (er) was determined by HPLC. e 3 Å MS (100 mg) was used as an additive.f 4 Å MS (100 mg) was used as an additive. g 5 Å MS (100 mg) was used as an additive. h at 60 °C.
benefited the yield, but the enantioselectivity dramatically decreased (entry 2 vs. 1). Subsequently, in the absence of MS, the reaction temperature was elevated from 45 °C to 60 °C, which also enhanced the yield to a moderate level but with deteriorated enantioselectivity (entry 5 vs. 1). Then, the mole ratio of the two reactants was modulated at 45 °C (entries 6–8), suggesting that increasing the stoichiometry of 3-vinylindole 2a could greatly ameliorate the yield but with certain degree of erosion in enantioselectivity (entries 7 and 8 vs. 1). At this stage, it appears that the yield and enantioselectivity somewhat restrict each other, and a compromise between them should be made. Therefore, a mole ratio of 1 : 3 was chosen as the optimal one for its relatively good yield and considerable enantioselectivity (entry 7). Finally, the catalyst loading was carefully investigated (entries 9–14). Lowering the catalyst loading was detrimental to the reaction (entry 9 vs. 7), while properly raising the catalyst loading was beneficial to the reaction, particularly with regards to the enantioselectivity (entries 10–13 vs. 7). This afforded the desired spiro-product in a good yield of 68% with a considerable enantioselectivity of 84 : 16 er (entry 13). Under optimal reaction conditions, the investigation was carried out on the substrate scope of the catalytic asymmetric isatin-involved Povarov reaction with 3-vinylindole. As shown in Table 3, this protocol was applicable to a wide range of isatin-derived 2-azadienes 1 with various R/R1/R2 groups at different positions of the molecules, delivering the desired spiro[indolin-3,2′-quinolines] 3 bearing an indole backbone with generally excellent diastereoselectivity and moderate to good enantioselectivity (>95 : 5 dr, >81 : 19 er in most cases).
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Table 3
Substrate scope of isatin-derived 2-azadiene 1a
Entry
R/R1/R2 (1)
3
Yieldb (%)
drc
erd
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
H/H/p-OMe (1a) p-tBu/H/p-OMe (1b) m-Me/H/p-OMe (1c) m-Cl/H/p-OMe (1d) p-Cl/H/p-OMe (1e) p-Br/H/p-OMe (1f) m,p-Cl2/H/p-OMe (1g) H/5-Me/p-OMe (1h) H/6-Me/p-OMe (1i) H/7-Me/p-OMe (1j) H/6-OMe/p-OMe (1k) H/6-Br/p-OMe (1l) H/7-Br/p-OMe (1m) H/7-F/p-OMe (1n) H/7-CF3/p-OMe (1o) H/H/p-OEt (1p) H/H/p-OPh (1q) H/H/p-Me (1r) H/H/m,p-(OMe)3 (1s) H/H/H (1t) H/H/p-F (1u)
3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma 3na 3oa 3pa 3qa 3ra 3sa 3ta 3ua
68 50 73 60 50 55 51 75 65 51 67 81 60 56 55 50 69 54 67 Trace Trace
>95 : 5 >95 : 5 81 : 19 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 85 : 15 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 — —
84 : 16 84 : 16 84 : 16 83 : 17 83 : 17 83 : 17 81 : 19 72 : 28 87 : 13 87 : 13 89 : 11 85 : 15 85 : 15 82 : 18 82 : 18 82 : 18 71 : 29 79 : 21 84 : 16 — —
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in o-xylene (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2a) at 45 °C for 11 h, and the mole ratio of 1 : 2 is 1 : 3. b Isolated yields. c The diastereomeric ratio (dr) was determined by 1 H NMR. d The enantiomeric ratio (er) was determined by HPLC.
Firstly, the effect of different substituents R that are linked to the benzyl motif was studied (Table 3, entries 1–7). The investigation revealed that the variation of these substituents, including electronically neutral (entry 1), rich (entries 2 and 3) and poor (entries 4–7) ones, had little influence on the stereoselectivity of the reaction. In detail, all these substrates 1a–1g afforded the spiro-products in >95 : 5 dr (except for 1c) and 81 : 19 to 84 : 16 er, but electron-neutral or -rich substituents exhibited slight superiority over their electron-poor counterparts with regards to enantioselectivity (entries 1–3 vs. 4–7). Moreover, it appeared that the position of the substituents exerted no effect on the enantioselectivity, as exemplified by 1d and 1e (entries 4 and 5), while the disubstituted substrate 1g was inferior to its mono-substituted analogues in terms of enantioselectivity (entry 7 vs. 4–5). Secondly, the impact of the substituents R1 linked to the isatin moiety on the reaction was investigated. As shown in entries 8–15, electronically different substituents at the C5, C6 and C7 positions of isatin moiety could be tolerated by the reaction with generally good stereoselectivity (up to >95 : 5 dr, 89 : 11 er). The position of the substituents appeared to have a delicate effect on the enantioselectivity. For instance, C5-substituted substrate 1h exhibited considerably lower enantioselective
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control than its C6- or C7-substituted counterparts 1i–1j (entry 8 vs. 9–10), whereas there was no remarkable difference in enantioselectivity between C6- and C7-substituted substrates (entry 9 vs. 10 and 12 vs. 13). In addition, the electronic nature of the substituents obviously affected the enantioselectivity because electron-donating groups, such as methyl group, delivered higher enantioselectivity than electronwithdrawing groups at the same C7-position (10 vs. 13–15). Finally, several anilines with different R2 groups were employed in the reaction to investigate the impact of this group on the reaction (entries 16–21). Obviously, substrates 1p–1s bearing electron-donating R2 groups offered the spiroproducts in excellent diastereoselectivity and considerable enantioselectivity (entries 16–19). Among them, trisubstituted aniline-derived substrate 1s afforded the highest stereoselectivity of >95 : 5 dr and 84 : 16 er (entry 19). However, when substrates 1t–1u with electron-neutral or withdrawing R2 groups were utilized in the reaction, only a trace of the desired product was obtained (entries 20 and 21). These results indicated that the electronic nature of the R2 group imposed a significant effect on the reactivity. Generally speaking, by varying the R/R1/R2 group, this approach could serve as an efficient method to synthesize chiral spiro[indolin-3,2′-quinolines] bearing an indole moiety with structural diversity. Moreover, 5-bromo-substituted 3-vinylindole 2b proved to be a suitable reaction component, which participated in the catalytic asymmetric Povarov reaction with isatin-derived 2-azadienes 1a with an excellent diastereoselectivity of >95 : 5 dr and acceptable enantioselectivity of 80 : 20 er (eqn (5)).
The absolute configuration of spiro[indolin-3,2′-quinoline] 3aa (92 : 8 er after recrystallization) was assigned to be (2′R,4′S) by single-crystal X-ray diffraction (in Scheme 2).12 The configurations of other spiro-products 3 were designated by analogy. Based on the experiment results, we suggested possible transition states to explain the stereochemistry of this catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles. As illustrated in Scheme 2, catalyst 4c simultaneously formed a dual hydrogen-bonding interaction with the two substrates. Because of the chiral environment created by the (R)-BINOL backbone and the bulky 3,3′-substitutents of CPA 4c, an enantioselective vinylogous Mannich reaction occurred to generate a transient intermediate A, which subsequently underwent a stereoselective intramolecular Friedel– Crafts reaction to afford the final (2′R,4′S)-configured spiroproduct. In the suggested reaction pathway, CPA 4c acted as a bifunctional catalyst to form two hydrogen bonds with the substrates or the intermediate, which significantly contributed to the excellent diastereoselectivity and good enantioselectivity observed.
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Scheme 2 Absolute configuration of compound 3aa and the proposed transition states of the reaction.
Because a non-asymmetric version of the Povarov reaction is still of significant interest from a synthetic point of view, we also investigated the performance of the racemic reaction using racemic phosphoric acid (±)-PA as a catalyst. As shown in Table 4, this reaction was also amenable to a variety of Table 4 Performance of the racemic Povarov reactiona
Entry
R/R1/R2 (1)
R3 (2)
(±)-3
drb
Yieldc (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
H/H/p-OMe (1a) p-tBu/H/p-OMe (1b) m-Me/H/p-OMe (1c) m-Cl/H/p-OMe (1d) p-Cl/H/p-OMe (1e) p-Br/H/p-OMe (1f) m,p-Cl2/H/p-OMe (1g) H/5-Me/p-OMe (1h) H/6-Me/p-OMe (1i) H/7-Me/p-OMe (1j) H/6-OMe/p-OMe (1k) H/6-Br/p-OMe (1l) H/7-Br/p-OMe (1m) H/7-F/p-OMe (1n) H/7-CF3/p-OMe (1o) H/H/p-OEt (1p) H/H/p-OPh (1q) H/H/p-Me (1r) H/H/m,p-(OMe)3 (1s) H/H/H (1t) H/H/p-F (1u) H/H/p-OMe (1a)
H (2a) 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a Br (2b)
(±)-3aa (±)-3ba (±)-3ca (±)-3da (±)-3ea (±)-3fa (±)-3ga (±)-3ha (±)-3ia (±)-3ja (±)-3ka (±)-3la (±)-3ma (±)-3na (±)-3oa (±)-3pa (±)-3qa (±)-3ra (±)-3sa (±)-3ta (±)-3ua (±)-3ab
>95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5 — — >95 : 5
74 64 67 64 57 59 62 80 69 50 74 76 69 67 64 62 64 59 58 Trace Trace 52
a Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in o-xylene (3 mL, including 0.2 mL 1,4-dioxane to increase the solubility of 2) at 45 °C for 11 h, and the mole ratio of 1 : 2 is 1 : 3. b The diastereomeric ratio (dr) was determined by 1H NMR. c Isolated yields.
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substrates, delivering the racemic products (±)-3 with structural diversity in generally good yield (52%–80%) and excellent diastereoselectivity (all >95 : 5 dr). Nevertheless, substrates 1t–1u were still unable to participate in the reaction (entries 20 and 21).
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Conclusions In summary, we have established the first catalytic asymmetric Povarov reaction of isatin-derived 2-azadienes with 3-vinylindoles, which tolerates a wide range of substrates in generally excellent diastereoselectivity and good enantioselectivity (up to >95 : 5 dr, 89 : 11 er). This approach is expected to significantly enrich the chemistry of the catalytic asymmetric Povarov reaction, especially ketone-involved transformations. Furthermore, this protocol also represents the first diastereo- and enantioselective construction of a spiro[indolin-3,2′-quinoline] framework bearing an indole moiety. This novel type of spiro-compound not only contains two chiral centers, including one quaternary stereogenic center, but also integrates the two biologically important structures of spiro[indolin-3,2′-quinoline] and indole, which may find medicinal applications after bioassay.
Experimental General information The 1H and 13C NMR spectra were measured at 400 and 100 MHz respectively. The solvent used for NMR spectroscopy was CDCl3 with tetramethylsilane as the internal reference. HRMS (ESI) was determined by a micrOTOF-QII HRMS/MS instrument (Bruker). The enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography (chiral HPLC). The chiral columns used for determining the enantiomeric excesses by chiral HPLC were Chiralpak AD-H and IA columns. The optical rotation values were measured with instruments operating at λ = 589 nm, corresponding to the sodium D line at the indicated temperatures. Analytical grade solvents for column chromatography and commercially available reagents were used as received. All commercially available starting materials were directly used. Substrates 1 and 2 were synthesized according to the literature methods.13 General procedure for the catalytic asymmetric Povarov reaction of isatin-derived 2-azadiene 1 with 3-vinylindole 2 to synthesize spiro-product 3 (Table 3) To a stirred solution of isatin-derived 2-azadienes 1 (0.1 mmol) and the catalyst 4c (0.035 mmol) in o-xylene (2 mL) at 45 °C, a solution of 3-vinylindoles 2 (0.3 mmol) in a mixed solvent of o-xylene (0.8 mL) and 1,4-dioxane (0.2 mL) was added dropwise through syringe pump for 10 h. After the addition of 3-vinylindoles 2 was completed, the reaction mixture was then further stirred for one hour. The resulting solution was concentrated under reduced pressure to obtain a residue, which
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was purified through flash column chromatography on silica gel to afford the pure spiro-product 3. General procedure for the racemic Povarov reaction of isatin-derived 2-azadiene 1 with 3-vinylindole 2 to synthesize spiro-product (±)-3 (Table 4) To a stirred solution of isatin-derived 2-azadienes 1 (0.1 mmol) and racemic phosphoric acid (0.035 mmol) in o-xylene (2 mL) at 45 °C, a solution of 3-vinylindoles 2 (0.3 mmol) in a mixed solvent of o-xylene (0.8 mL) and 1,4-dioxane (0.2 mL) was added dropwise through syringe pump for 10 h. After completing the addition of 3-vinylindoles 2, the reaction mixture was stirred for another hour. The resulting solution was concentrated under the reduced pressure to give the residue, which was purified by flash column chromatography on silica gel to afford pure spiro-product (±)-3. These products were used as the racemic standards for HPLC determination. Selected examples of characterization of compounds 3 (2′R,4′S)-1-Benzyl-4′-(1H-indol-3-yl)-6′-methoxy-3′,4′-dihydro1′H-spiro[indoline-3,2′-quinolin]-2-one (3aa). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 68% (33.1 mg); >95 : 5 dr; yellow 1 solid; [α]20 D = +132.7 (c 0.59, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.06 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.39–7.36 (m, 2H), 7.33 (d, J = 4.3 Hz, 4H), 7.31–7.26 (m, 1H), 7.20–7.15 (m, 3H), 7.07–7.00 (m, 2H), 6.72 (d, J = 7.8 Hz, 1H), 6.66 (dd, J = 8.5, 2.9 Hz, 1H), 6.61–6.54 (m, 2H), 5.17 (dd, J = 12.6, 5.2 Hz, 1H), 5.00–4.81 (m, 2H), 4.03 (s, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.20 (dd, J = 13.7, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.1, 152.4, 142.1, 136.7, 136.3, 136.0, 132.0, 129.3, 128.9, 127.7, 127.4, 125.4, 123.6, 123.0, 122.8, 121.9, 119.9, 119.3, 117.8, 114.7, 113.2, 111.3, 109.2, 60.1, 55.8, 43.7, 39.0, 30.7; IR (KBr): 3646, 3309, 2922, 2360, 1702, 1607, 1497, 1351, 1289, 1231, 1173, 1098, 1037, 986, 858, 808, 741, 697, and 669 cm−1; ESI FTMS exact mass calcd for (C32H27N3O2 − H)− requires m/z 484.2020, found m/z 484.2026; enantiomeric ratio: 84 : 16, determined by HPLC (Daicel Chirapak IA, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.21 min (minor), tR = 10.37 min (major). (2′R,4′S)-1-(4-(tert-Butyl)benzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ba). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 50% (27.1 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +167.9 (c 0.32, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.12 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 9.4, 6.1 Hz, 4H), 7.28 (s, 2H), 7.23–7.16 (m, 2H), 7.14 (d, J = 2.5 Hz, 1H), 7.07–7.00 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.67 (dd, J = 8.5, 2.6 Hz, 1H), 6.61–6.55 (m, 2H), 5.18 (dd, J = 12.5, 5.1 Hz, 1H), 4.93 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.5 Hz, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.21 (dd, J = 13.7, 5.3 Hz, 1H), 1.61 (s, 1H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 150.6, 142.3, 136.7, 136.3, 132.9, 132.0, 129.2, 127.2, 125.7, 123.5, 122.9, 122.6, 121.9, 120.0, 119.3, 118.0, 114.7, 114.6, 113.2, 111.2, 109.2,
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60.1, 55.8, 43.3, 39.0, 34.5, 31.3, 30.7, 29.7; IR (KBr): 3651, 3298, 2959, 2360, 1704, 1605, 1628, 1498, 1353, 1264, 1290, 1237, 1174, 1097, 1038, 987, 861, 806, and 742 cm−1; ESI FTMS exact mass calcd for (C36H35N3O2 − H)− requires m/z 540.2646, found m/z 540.2673; enantiomeric ratio: 84 : 16, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 7.27 min (minor), tR = 9.24 min (major). (2′R,4′S)-4′-(1H-Indol-3-yl)-6′-methoxy-1-(3-methylbenzyl)3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ca). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 73% (36.7 mg); 81 : 19 dr; yellow sticky oil; [α]20 D = +197.7 (c 0.31, Acetone); 1 H NMR (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.40–7.34 (m, 2H), 7.25–7.12 (m, 6H), 7.12–7.07 (m, 1H), 7.06–7.00 (m, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.70–6.64 (m, 1H), 6.62–6.54 (m, 2H), 5.18 (dd, J = 12.5, 5.1 Hz, 1H), 4.93 (d, J = 15.5 Hz, 1H), 4.81 (d, J = 15.5 Hz, 1H), 4.05 (s, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.33 (s, 3H), 2.21 (dd, J = 13.7, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 142.2, 138.6, 136.7, 136.3, 135.9, 132.0, 129.3, 128.7, 128.5, 128.2, 126.7, 125.4, 124.5, 123.5, 122.9, 122.6, 121.9, 119.9, 119.3, 118.0, 114.7, 114.6, 113.2, 111.2, 109.2, 60.1, 55.8, 43.7, 39.1, 30.7, 21.5; IR (KBr): 3651, 3319, 2922, 2361, 1698, 1603, 1628, 1499, 1437, 1344, 1291, 1235, 1177, 1098, 1035, 811, 745, and 696 cm−1; ESI FTMS exact mass calcd for (C33H29N3O2 − H)− requires m/z 498.2176, found m/z 498.2195; enantiomeric ratio: 84 : 16, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.23 min (minor), tR = 12.72 min (major). (2′R,4′S)-1-(3-Chlorobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3da). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 60% (31.2 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 H NMR D = +43.3 (c 0.80, CHCl3); (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.41–7.34 (m, 2H), 7.29 (dd, J = 7.9, 5.5 Hz, 4H), 7.23–7.16 (m, 2H), 7.14 (dd, J = 6.5, 1.6 Hz, 1H), 7.07–7.02 (m, 2H), 6.73–6.63 (m, 2H), 6.61–6.55 (m, 2H), 5.15 (dd, J = 12.5, 5.1 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.08 (s, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.18 (dd, J = 13.7, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 178.8, 152.5, 143.4, 136.7, 136.0, 135.4, 130.9, 129.0, 127.9, 127.4, 126.6, 125.9, 125.3, 125.0, 122.8, 122.7, 122.0, 119.9, 119.3, 117.7, 114.9, 114.6, 113.2, 112.5, 111.3, 59.9, 55.7, 43.7, 38.9, 30.6; IR (KBr): 3651, 3525, 3441, 3274, 2923, 1705, 1629, 1490, 1353, 1235, 1173, 1095, 1013.99 1037, 987, 801, 743, and 567 cm−1; ESI FTMS exact mass calcd for (C32H26ClN3O2 − H)− requires m/z 518.1630, found m/z 518.1631; enantiomeric ratio: 83 : 17, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.57 min (minor), tR = 15.83 min (major). (2′R,4′S)-1-(4-Chlorobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ea). Flash column chromatography eluent, petroleum ether–ethyl acetate
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Organic & Biomolecular Chemistry
= 6/1; Reaction time = 11 h; yield: 50% (26.1 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +226.3 (c 0.31, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.10 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.40–7.35 (m, 2H), 7.32–7.26 (m, 4H), 7.22–7.13 (m, 3H), 7.06–7.01 (m, 2H), 6.71–6.64 (m, 2H), 6.61–6.54 (m, 2H), 5.15 (dd, J = 12.5, 5.1 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.03 (s, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.21–2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 141.8, 136.7, 136.2, 134.5, 133.6, 132.0, 129.3, 129.0, 128.8, 126.6, 125.3, 123.7, 123.2, 122.6, 122.0, 119.9, 119.3, 117.9, 114.7, 114.6, 113.2, 111.2, 109.0, 60.1, 55.8, 43.0, 39.0, 30.7; IR (KBr): 3659, 3525, 3443, 3043, 2360, 1629, 1538, 1353, and 568 cm−1; ESI FTMS exact mass calcd for (C32H26ClN3O − H)− requires m/z 518.1630, found m/z 518.1630; enantiomeric ratio: 83 : 17, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.73 min (minor), tR = 16.07 min (major). (2′R,4′S)-1-(4-Bromobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3fa). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 55% (31.2 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +449.5 (c 0.41, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.45 (d, J = 8.3 Hz, 3H), 7.37 (t, J = 8.4 Hz, 2H), 7.24–7.12 (m, 5H), 7.07–7.00 (m, 2H), 6.72–6.62 (m, 2H), 6.61–6.53 (m, 2H), 5.15 (dd, J = 12.6, 5.1 Hz, 1H), 4.90 (d, J = 15.7 Hz, 1H), 4.79 (d, J = 15.7 Hz, 1H), 4.06 (s, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.18 (dd, J = 13.7, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 141.8, 136.7, 136.2, 135.0, 132.0, 129.3, 129.2, 125.3, 123.7, 123.2, 122.6, 122.0, 121.6, 119.9, 119.3, 117.9, 114.7, 114.6, 113.2, 111.3, 109.0, 60.1, 55.8, 43.1, 39.0, 30.7; IR (KBr): 3659, 3525, 3441, 3292, 2923, 1707, 1629, 1488, 1352, 1291, 1235, 1173, 1071, 1097, 1011, 1038, 799, 743, and 580 cm−1; ESI FTMS exact mass calcd for (C32H26BrN3O2 − H)− requires m/z 564.1110, found m/z 564.1086; enantiomeric ratio: 83 : 17, determined by HPLC (Daicel Chirapak AD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.74 min (minor), tR = 16.07 min (major). (2′R,4′S)-1-(3,4-Dichlorobenzyl)-4′-(1H-indol-3-yl)-6′-methoxy3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ga). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 51% (28.3 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +146.0 (c 0.35, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.11 (s, 1H), 7.47–7.42 (m, 2H), 7.41–7.34 (m, 3H), 7.22 (td, J = 7.8, 1.3 Hz, 1H), 7.19–7.13 (m, 3H), 7.08–7.01 (m, 2H), 6.72–6.64 (m, 2H), 6.61–6.55 (m, 2H), 5.14 (dd, J = 12.6, 5.2 Hz, 1H), 4.89 (d, J = 15.8 Hz, 1H), 4.79 (d, J = 15.7 Hz, 1H), 4.05 (s, 1H), 3.55 (s, 3H), 2.68 (t, J = 13.2 Hz, 1H), 2.23–2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.0, 152.4, 141.5, 136.7, 136.3, 136.1, 133.0, 131.9, 130.9, 129.4, 126.8, 126.6, 125.3, 123.8, 123.4, 122.6, 122.0, 119.9, 119.3, 117.8, 114.8, 114.6, 113.3, 111.3, 108.8, 60.1, 55.8, 42.7, 39.1, 30.7; IR (KBr): 3666, 3525, 3441, 3273, 2923, 2360, 1707, 1629, 1498, 1354, 1236, 1173, 1097, 1031, 988, 872, 806, 742, and 567 cm−1; ESI FTMS exact mass calcd for (C32H25Cl2N3O2 − H)− requires m/z 552.1240, found m/z
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552.1230; enantiomeric ratio: 81 : 19, determined by HPLC (Daicel Chirapak IA, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.92 min (minor), tR = 14.61 min (major). (2′R,4′S)-1-Benzyl-4′-(1H-indol-3-yl)-6′-methoxy-5-methyl3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one (3ha). Flash column chromatography eluent, petroleum ether–ethyl acetate = 6/1; Reaction time = 11 h; yield: 75% (37.5 mg); >95 : 5 dr; 1 yellow sticky oil; [α]20 D = +60.5 (c 0.56, Acetone); H NMR (400 MHz, CDCl3) δ ( ppm): 8.15 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 11.2, 6.3 Hz, 5H), 7.28 (dd, J = 8.4, 4.5 Hz, 1H), 7.23–7.20 (m, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.67 (dd, J = 8.5, 2.7 Hz, 1H), 6.64–6.54 (m, 3H), 5.17 (dd, J = 12.5, 5.2 Hz, 1H), 4.96 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 3.54 (s, 3H), 2.68 (t, J = 13.1 Hz, 1H), 2.28 (s, 3H), 2.20 (dd, J = 13.7, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ( ppm): 179.1, 152.3, 139.6, 136.8, 136.4, 136.1, 132.7, 132.0, 129.5, 128.8, 127.6, 127.4, 126.6, 125.5, 124.4, 122.7, 121.9, 120.0, 119.2, 118.0, 114.7, 113.2, 111.3, 109.0, 60.2, 55.8, 43.7, 39.1, 30.8, 21.0; IR (KBr): 3553, 3482, 3416, 3234, 2920, 1701, 1617, 1637, 1497, 1438, 1455, 1383, 1342, 1265, 1288, 1242, 1149, 1182, 1011, 1038, 988, 809, 742, 697, and 620 cm−1; ESI FTMS exact mass calcd for (C33H29N3O2 − H)− requires m/z 498.2176, found m/z 498.2176; enantiomeric ratio: 72 : 28, determined by HPLC (Daicel Chirapak OD-H, hexane–isopropanol = 70/30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.21 min (minor), tR = 10.37 min (major).
Acknowledgements We are grateful for financial support from National Natural Science Foundation of China (21372002 and 21232007), Open Foundation of Jiangsu Key Laboratory (K201314), PAPD and Qing Lan Project of Jiangsu Province, and the Graduate Students Project of Jiangsu Normal University (2014YZD012).
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