Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipole and Base Catalyzed

Letter pubs.acs.org/OrgLett

Isatin N,N′‑Cyclic Azomethine Imine 1,3-Dipole and Base Catalyzed Michael Addition with β‑Nitrostyrene via C3 Umpolung of Oxindole Xiao Wang,†,‡ Lin Wu,†,‡ Peng Yang,†,‡ Xiang-Jia Song,†,‡ Hong-Xia Ren,†,‡ Lin Peng,† and Li-Xin Wang*,† †

Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *

ABSTRACT: A new isatin N,N′-cyclic azomethine imine 1,3dipole was devised, and an unusual Michael addition with βnitrostyrene catalyzed by tributylamine under mild conditions has been developed. The new reaction featured the C3 umpolung of oxindole and an unusual formation of double bond. Notably, this new synthon performed as a donor rather than an acceptor. This protocol provided a promising method for the preparation of various 3-aminooxindoles with good yields in moderate diastereoselectivities.

3,3-Disubstituted oxindoles are privileged structural motifs widely found in natural products and pharmaceuticals.1 Among those structures, quaternary 3-aminooxindoles have drawn a great deal of attention from both synthetic and medicinal chemists due to their frequent occurrence in biological and pharmaceutical compounds (Figure 1).2 Several methods

Scheme 1. Reaction Modes for N,N′-Cyclic Azomethine Imines

Figure 1. Representative biologically active compounds containing 3aminooxindoles scaffold.

their wide applications in cycloadditions with dipolarophiles,7,8 they are seldom reported as an acceptor for nucleophilic additions (Scheme 1),9 and the reported nucleophiles were limited to TMSCF3,9a TMSCN,9b,c phosphites or diarylphosphoryl oxygen,9d and tetraarylborates.9e Based on recent progress in the chemistry of 1,3-dipoles10 and our first study on the new isatin N,N′-cyclic azomethine imine 1,3-dipole 2 (Scheme 1),11g we hope to open further applications of this synthon for the construction of 3-aminooxindoles with potential biological and pharmaceutical activities. Herein, a [3 + 2]-cycloaddition with generally used vinyl component was chosen. Inspired by our former work in cyclizations11 and β-

including addition of 3-aminooxindoles,3 amination of 3monosubstituted oxindoles with azodicarboxylate and nitrosobenzene,4 nucleophilic additions to isatin imines,5 and cycloadditions of isatin azomethine ylides 6 have been developed for the syntheses of various quaternary 3-aminooxindoles. Despite those achievements, more effective and creative methods to access 3-aminooxindoles are still in great demand. N,N′-Cyclic azomethine imines 1 (Scheme 1), mainly prepared by the condensation of pyrazolidin-3-one with aldehydes, have been increasingly employed in constructing pyrazolones and related dinitrogen fused heterocycles. Despite © 2017 American Chemical Society

Received: April 8, 2017 Published: June 1, 2017 3051

DOI: 10.1021/acs.orglett.7b01063 Org. Lett. 2017, 19, 3051−3054

Letter

Organic Letters

Table 2. Further Optimization of Reaction Conditionsa

nitrostyrene participating reactions,12 we started to investigate the reaction between N,N′-cyclic azomethine imine 2 and βnitrostyrene 3. The reaction proceeded smoothly under mild conditions. However, only an unexpected Michael addition analogous product 4 with an unusual formation of double bond was obtained, and no anticipated [3 + 2]-cycloadduct was detected. Compared with previously reported nucleophilic additions of the commonly used azomethine imines 1, the new isatin azomethine imine 2 underwent an unusual addition via oxindole C3 umpolung and performed as a donor rather than an acceptor (Scheme 1). This abnormal observation prompted us to further study the reaction under various conditions. Considering the slight solubility of the new dipole in most solvents under room and lower temperature, we chose more soluble chloroform as a model solvent and screened the effects of various catalysts on the reaction between 2a and β-nitrostyrene 3a at a relatively higher temperature (45 °C), and the results were summarized in Table 1. Remarkably, bases affected the yields significantly, Table 1. Screenings of Catalysta

entry

temp (°C)

solvent

time (h)

yieldb (%)

drc (4a/4a′)

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

45 45 45 45 45 45 45 45 25 60 80 45 45

CHCl3 DCE dioxane THF CH3CN DMSO DMF DMAC DMAC DMAC DMAC DMAC DMAC

13 10 60 60 12 5 5 6 20 3 1 6 10

85 86 85 80 69 75 70 82 75 71 66 74 74

1.4:1 1:1.1 1.6:1 1.9:1 2.1:1 2.1:1 2.8:1 3.4:1 3.3:1 2.6:1 2.3:1 2.8:1 2.8:1

a Unless otherwise specified, all reactions were carried out with 0.1 mmol of 2a and 0.15 mmol of 3a in the presence of 20 mol % of Bu3N in 1 mL of solvent at specified temperature. bYield of the diastereoisometric mixture. cDetermined by HPLC. dThe reaction was carried out with 0.1 mmol of 2a and 0.12 mmol of 3a. ePerformed in the presence of 10 mol % Bu3N.

entry

cat.

time (h)

yieldb (%)

drc (4a/4a′)

1 2 3 4 5 6 7 8 9 10 11

DABCO Et3N Bu3N DMAP DBU pyridine NaOH K2CO3 NaH Na3PO4 CH3COOK

30 13 13 48 5 48 20 30 32 32 48

84 80 85 84 62 nrd 44 27 78 70 nrd

1.4:1 1.3:1 1.4:1 1.4:1 1:1.4

established as 2a/3a/Bu3N = 1:1.5:0.2 molar ratio, in DMAC at 45 °C (Table 2, entry 8). Under the optimal reaction conditions, the generality of substrate scope was broadened, and the results were listed in Table 3. Generally, most isatin N,N′-cyclic azomethine imines 2 and β-nitrostyrenes 3 were well tolerated, and fair to good yields and moderate diastereoselectivities were obtained (Table 3, entries 1−18). The electronic characteristics and positions of the substituents at the aromatic ring of β-nitrostyrene slightly affected the yields and diastereoselectivities (Table 3, entries 1−12). Heterocyclic nitrostyrene 3m gave the corresponding 3aminooxindole in 73% yield with 3.8:1 dr (Table 3, entry 13). However, the aliphatic cyclohexyl nitroolefin 3n gave only a 37% yield while the best diastereoselectivity (dr = 1:4.9) (Table 3, entry 14). The scope of isatin N,N′-cyclic azomethine imines 2 were also studied (Table 3, entries 15−19). N-H 2b and Nallyl 2c could smoothly afford the desired products with moderate results (Table 3, entries 15 and 16). The substituents, whether electron-drawing or -donating on the aromatic ring, had slight influences on yields and diastereoselectivities (Table 3, entries 17 and 18). Especially, 2f, bearing a substituent on the pyrazolidinone ring (R3 = Me), was totally inactive, and no other reaction was detected (Table 3, entry 19). Based on the results and single crystal X-ray of major isomer 4t (Figure 2),13 we proposed a plausible catalytic mechanism as illustrated in Scheme 2. The reaction was initiated by the resonance of 2a to form I. After tautomerism in the presence of a base, the delocalized and more stable intermediate II was formed. Intermediate II underwent Michael addition with βnitrostyrene 3a with a double bond shift to generate the final product (Scheme 2). To achieve an asymmetric version of the new reaction, a series of organocatalysts, such as cinchonas, bifunctional cinchona thioureas, and chiral squaramides have also been screened. However, only chiral squaramide 5f gave the desired

1.0:1 1.1:1 1.2:1 1.0:1

a

Unless otherwise specified, all reactions were carried out with 0.1 mmol of 2a and 0.15 mmol of 3a in the presence of 20 mol % of catalyst in 1 mL of CHCl3 at 45 °C. bYield of the diastereoisometirc mixture. cDetermined by HPLC. dNo reaction.

but slightly for the diastereoselectivities. When DABCO, Et3N, Bu3N, and DMAP were used, all gave good results (Table 1, entries 1−4). However, pyridine did not give the expected product even after 48 h (Table 1, entry 6). Other bases were also tested, but no better results were obtained (Table 1, entries 7−11). Bu3N gave a better result and was chosen as the optimal catalyst for further optimization. Other experimental parameters such as solvent, temperature, substrate ratio, and catalyst loading were also studied (Table 2). Notably, the solvents affected the diastereoselectivities significantly (Table 2, entries 1−8). In dioxane and THF, only 1.6−1.9:1 dr were detected (Table 2, entries 3 and 4). Polar solvents such as CH3CN, DMSO, DMF, and dimethylacetamide (DMAC) gave better diastereoselectivities (Table 2, entries 5−8). A higher or lower reaction temperature all gave lower yields and diastereoselectivities (Table 2, entries 9−11). Unfortunately, no significant improvement was achieved when the substrate ratio and catalyst loading were tuned (Table 2, entries 12 and 13), and the optimal reaction conditions were 3052

DOI: 10.1021/acs.orglett.7b01063 Org. Lett. 2017, 19, 3051−3054

Letter

Organic Letters Table 3. Generality of the Substrate Scopea

entry

2 (R1, R2, R4)

3 (R3)

time (h)

4

yieldb (%)

drc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2a (Bn, H, H) 2b (H, H, H) 2c (allyl, H, H) 2d (Bn, 6-Br, H) 2e (Bn, 7-Me, H) 2f (Bn, H, Me)

3a (C6H5) 3b (2-ClC6H4) 3c (2-BrC6H4) 3d (2-MeOC6H4) 3e (3-ClC6H4) 3f (3-BrC6H4) 3g (4-FC6H4) 3h (4-ClC6H4) 3i (4-BrC6H4) 3j (4-MeC6H4) 3k (4-MeOC6H4) 3l (3,4,5-(MeO)3C6H4) 3m (2-thienyl) 3n (2-cyclohexyl) 3a (C6H5) 3a (C6H5) 3a (C6H5) 3a (C6H5) 3a (C6H5)

6 10 10 6 12 12 12 12 12 7 7 7 6 6 24 8 8 12 24

4a, 4a′ 4b, 4b′ 4c, 4c′ 4d, 4d′ 4e, 4e′ 4f, 4f′ 4g, 4g′ 4h, 4h′ 4i, 4i′ 4j, 4j′ 4k, 4k′ 4l, 4l′ 4m, 4m′ 4n, 4n′ 4o, 4o′ 4p, 4p′ 4q, 4q′ 4r, 4r′ 4s, 4s′

82 72 66 84 67 64 78 69 64 82 83 80 73 37 60 80 70 76 nrd

3.4:1 1.8:1 1.2:1 2.0:1 2.7:1 3.0:1 2.1:1 2.3:1 2.2:1 2.8:1 2.4:1 1.7:1 3.8:1 1:4.9 1.6:1 2.5:1 1.7:1 3.1:1

Reactions were carried out with 0.1 mmol of 2 and 0.15 mmol of 3 in the presence of 20 mol % Bu3N in 1 mL of DMAC at 45 °C. bIsolated yield of diastereoisomeric mixture. cDetermined by HPLC. dNo reaction.

a

Scheme 3. Catalytic Enantioselective Variant

Figure 2. X-ray crystal structure of major isomer 4t.

Scheme 2. Plausible Reaction Mechanism good diastereoselectivities. Notably, this new synthon performed as a donor, quite different from the reported 1,3dipoles. Further studies on the new reaction and application of the newly designed synthon are systematically underway 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.7b01063. Experimental procedures and detailed characterization data of all compounds (PDF) X-ray crystal details for 4t (CIF)

chiral product in 59% ee (Scheme 3; details in Supporting Information). In conclusion, we have disclosed an unusual Michael reaction between isatin N,N′-cyclic azomethine imine 1,3-dipoles and βnitrostyrenes under mild conditions. The new reaction featured the C3 umpolung of oxindole and an unusual formation of double bond. A variety of isatin N,N′-cyclic azomethine imine 1,3-dipoles and β-nitrostyrenes were tolerated in the protocol and afforded 3-aminooxindoles in good yields with moderate to

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Li-Xin Wang: 0000-0003-0830-7421 3053

DOI: 10.1021/acs.orglett.7b01063 Org. Lett. 2017, 19, 3051−3054

Letter

Organic Letters Notes

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The authors declare no competing financial interest.

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DOI: 10.1021/acs.orglett.7b01063 Org. Lett. 2017, 19, 3051−3054