Asymmetric Mannich reaction: highly enantioselective synthesis of 3-amino-oxindoles via chiral squaramide based H-bond donor catalysis

Abstract

We describe here a simple and facile asymmetric Mannich reaction catalyzed by chiral Cinchona alkaloid based squaramide containing H-bond donor catalysts, wherein, the reaction of 1,3-diketones with isatin (N-Boc) ketimines led to the formation of 3-aminooxindole derivatives. These derivatives were obtained in high yields with excellent enantioselectivities under mild conditions using 3 mol% of the catalyst. This protocol provides valuable and easy access to chiral 3-substituted 3-aminooxindole derivatives.

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Chiral 3-substituted 3-amino-2-oxindoles are highly privileged structural motifs usually present in numerous biologically active natural products and pharmaceuticals.^1,2 A potential cholecystokinin-B/gastrin receptor antagonist, AG-041R, having a 3-aminooxindole scaffold, is known to exhibit chondrogenic and anticancer activities (Fig. 1).³ Certain bioactive alkaloids such as psychotrimine⁴ and (+)-folicanthine⁵ are synthesized using a 3-substituted-3-aminooxindole intermediate. There are several routes reported for the asymmetric synthesis of 3-aminooxindoles, for instance, amination reaction using mono or bimetallic Schiff base catalyst⁶ and asymmetric addition of arylboronic acids to isatin ketimines using Pd(II)-catalyst.⁷ Moreover, in recent times, the organocatalyst mediated addition of various nucleophiles to isatin ketimines have gained substantial momentum.⁸ These include, chiral phosphoric acid catalyzed asymmetric addition of indole or pyrrole,⁹ thiourea catalyzed enantioselective addition of phenols and naphthols,¹⁰ asymmetric cyanation reaction using chiral thiourea¹¹ and enantioselective addition of alcohol and thiol¹² to isatin (N-Boc) ketimines. Among them, chiral thiourea containing H-bond donor catalysts have predominantly gained popularity as the most versatile ligands, and in 2012, Wang et al. reported a high yield and high enantioselective asymmetric addition of 1,3-dicarbonyl compounds to N-alkoxycarbonyl ketimines derived from isatins.¹³

Fig. 1 Biologically active 3-aminooxindole and indole derivatives.

During the past half a decade, Rawal and co-workers and others have independently demonstrated the successful implementation of chiral squaramide catalysts as powerful organocatalyst for synthesis of numerous chiral compounds.^14,15 Over the past couple of years, Trivedi's group has studied various types of benzyl amines as well as ferrocenyl amine containing chiral squaramide catalysts for asymmetric Michael addition reactions.¹⁶ Upon scrutiny of the literature, it was observed that the chiral squaramide based catalyst have not been investigated for the addition of 1,3-dicarbonyl compounds onto isatin ketimines. In continuation of our research interest on chiral squaramide catalysis, a study on the effect of squaramide organocatalyst for asymmetric enantioselective addition of 1,3-diketones to N-alkoxycarbonyl ketimines derived from isatins was undertaken. Therefore, we, herein, report a highly enantioselective method for the synthesis of 3-aminooxindoles catalyzed by cinchona alkaloid based squaramide catalyst.

A model reaction of pentane-2,4-dione 3a with isatin (N-Boc) ketimine 2a was chosen to screen the chiral organocatalysts as shown in Fig. 2. In the first instance, the model reaction was conducted in dichloromethane solvent in the presence of 10 mol% catalyst at room temperature and the results are summarized in Table 1. It was observed from the catalyst screening studies that the bifunctional squaramide catalysts (1a–i) gave the desired product 4a in high yield with good to excellent enantioselectivities (Table 1, entries 1–9). Catalyst 1g was found to be superior, among all the catalysts screened, to give the product in 96% yield with 97% enantioselectivity. With the most effective catalyst 1g in hand, the effect of solvent and catalyst loading (mol%) was studied on the yield and enantioselectivity of the reaction.

Fig. 2 Structures of squaramide based bifunctional catalysts screened.

Table 1 Catalyst screening and optimization of reaction conditions for the asymmetric Mannich reaction of N-Boc ketimine 2a to pentane-2,4-dione^a

Entry	Catalyst (mol%)	Solvent	Time (h)	Yield^b (%)	ee^c^,^d (%)
a Unless otherwise indicated, reactions were carried out with N-Boc ketimine 2a (0.25 mmol) and pentane-2,4-dione 3a (0.3 mmol) in solvent (1.5 ml) at room temperature. b Isolated yield after column chromatography purification. c The ee values were determined by chiral HPLC analysis using a Daicel Chiralpak IC. d The absolute configuration of the product 4a was determined by comparison of its retention time with literature data according to ref. 13.
1	1a (10)	CH2Cl2	4	92	93 (S)
2	1b (10)	CH2Cl2	4	94	95 (S)
3	1c (10)	CH2Cl2	4	92	95 (S)
4	1d (10)	CH2Cl2	5	91	92 (S)
5	1e (10)	CH2Cl2	5	93	94 (S)
6	1f (10)	CH2Cl2	4	95	92 (S)
7	1g (10)	CH2Cl2	4	96	97 (S)
8	1h (10)	CH2Cl2	4	92	90 (R)
9	1i (10)	CH2Cl2	4	94	93 (R)
10	1g (10)	CHCl3	4	95	95 (S)
11	1g (10)	PhCH3	9	92	91 (S)
12	1g (10)	EtOAc	8	89	92 (S)
13	1g (10)	THF	8	90	84 (S)
14	1g (10)	CH3CN	12	90	87 (S)
15	1g (10)	Et2O	24	85	82 (S)
16	1g (10)	CH3OH	6	88	21 (S)
17	1g (10)	H2O	4	86	73 (S)
18	1g (10)	H2O + ^iPrOH	4	83	44 (S)
19	1g (5)	CH2Cl2	7	95	97 (S)
20	1g (3)	CH2Cl2	10	99	>99(S)
21	1g (1)	CH2Cl2	22	92	95 (S)

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The reaction was conducted in various protic and aprotic solvents. The non-polar and polar aprotic solvents such as chloroform, toluene, ether, THF, acetonitrile and ethyl acetate gave the product in good yields with high enantioselectivities (Table 1, entries 10–15). A remarkable decrease in both yield and enantioselectivity was observed in the case of protic solvent such as methanol, water and water: ⁱPrOH mixture (Table 1, entry 16–18). It can be assumed that the hydrogen-bond interaction between the solvent and the substrate might perturb the efficient accumulation of the reactants surrounding the bifunctional catalyst in polar solvents. Dichloromethane was found to be the best solvent, among various solvents screened, for the reaction conducted at room temperature. Sequential variation of different mole ratio from 1 mol% to 10 mol% provided the optimum yield of 99% and >99% enantioselectivity using 3 mol% of the catalyst (Table 1, entry 18). Further lowering of the catalyst loading from 3 to 1 mol% resulted in a decreased yield and enantioselectivity, although with an extended reaction time (Table 1, entry 19). A 3 mol% catalyst loading was thus found suitable and effective for the Mannich reaction. The optimized set of reaction conditions as established on the basis of all of the above results were, pentane-2,4-dione 3a (0.3 mmol) and isatin (N-Boc) ketimine 2a (0.25 mmol) in 1.5 ml CH₂Cl₂ with 3 mol% of catalyst 1g at room temperature.

The reactivities of different ketimines, 2a–g, were examined under the optimized conditions for the enantioselective nucleophilic addition reaction. The results are depicted in Table 2. Based on the results, both enantioselectivity and the reactivity of ketimines were influenced by the substituent groups at 1-position of ketimine. The reactions proceeded smoothly with –CH₃, –CH₂C₆H₅, allyl and propargyl groups as the substituted groups at the 1-position of ketimine and gave the products in high yields and excellent enantioselectivities, respectively (Table 2, entries 1, 4, 6 and 7). The unsubstituted ketimines exhibited good reactivity and the product 4b was obtained in 90% yield and 86% ee (Table 2, entry 2). High yields and good enantioselectivity was obtained for 1-ethyl ketimine (Table 2, entry 3). Meanwhile, substitution of acetyl group at 1-position led to moderate yield with poor enantioselectivity for the product 4e (Table 2, entry 5). Based on the reactivity assessment of (N-Boc) ketimines 2a–g, ketimine 2a gave the best result under the optimized conditions.

Table 2 Reactivities Evaluation of Ketimines 2a–g^a

Entry	R1	Product	Time (h)	Yield^b (%)	ee^c^,^d (%)
a Unless otherwise indicated, reactions were carried out with N-Boc ketimine 2a–g (0.25 mmol) and pentane-2,4-dione 3a (0.3 mmol) in CH2Cl2 (1.5 ml) at room temperature. b Isolated yield after column chromatography purification. c The ee values were determined by chiral HPLC analysis using a Daicel Chiralpak IC column. d The absolute configuration of the product 4a was determined by comparison of its retention time with literature data according to ref. 13 and the configurations of other products were tentatively assigned by analogy.
1	CH3 (2a)	4a	10	99	>99
2	H (2b)	4b	24	90	86
3	C2H5 (2c)	4c	15	92	92
4	CH2C6H5 (2d)	4d	12	96	99
5	C(O)CH3 (2e)	4e	34	85	33
6	C3H5 (2f)	4f	16	91	96
7	C3H4 (2g)	4g	18	93	98

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Next, the scope of asymmetric Mannich reaction of different (N-Boc) ketimines derived from various substituted N-methyl isatins with 1,3-diketones was examined and results are given in Scheme 1. Various N-Boc ketimines having electron donating and withdrawing groups reacted smoothly with pentane-2,4-dione 3a to give the desired products in high yields and good to excellent enantioselectivities. Particularly, (N-Boc) ketimines bearing electron donating groups such as methyl and methoxy groups at 5th position gave the products in high yields and good enantioselectivities (Scheme 1, compound 5a and 5b). (N-Boc) ketimines bearing halogens such as fluoro, chloro, bromo and iodo groups at 5th or 7th position proceeded smoothly and high yields with excellent enantioselectivities were obtained (Scheme 1, compound 5c–5g). (N-Boc) ketimines with electron withdrawing groups such as nitro and OCF₃ also gave good yields with 92% and 97% enantioselectivities respectively (Scheme 1, compound 5h and 5i). In addition, it turned out that this asymmetric addition of pentane-2,4-dione to disubstitued ketimine i.e., 4,7-dichloro (N-Boc) ketimine, also followed the similar reaction pattern, affording the addition product in 78% yield and 94% ee (Scheme 1, compound 5j). Further, various 1,3-diketones were also explored for this reaction. The Mannich reaction of dimethyl malonate to ketimine 2a proceeded smoothly and afforded the desired product with excellent enantioselectivity (Scheme 1, compound 5k). Furthermore, symmetrical and unsymmetrical 1,3-diketones were also employed in this reaction. Symmetrical diketone such as 1,3-diphenylpropane-1,3-dione underwent the Mannich reaction with ketimine 2a to give the product in 93% yield with 96% enantioselectivity (Scheme 1, compound 5l). Similarly, unsymmetrical diketones such as methyl acetoacetate, ethyl acetoacetate and tertiary butyl acetoacetate gave the corresponding products in good yields with moderate diastereoselectivity and excellent enantioselectivity (Scheme 1, compound 5m–5o). Interestingly, the Mannich reaction of (N-Boc) ketimine with 1-benzoylacetone proceeded smoothly and the product was obtained in good yield with excellent enantio- and diastereoselectivity (Scheme 1, compound 5p). The absolute configuration of the product 5g was unambiguously determined as S on the basis of single crystal X-ray analysis (Fig. 3).

Scheme 1 Scope of the asymmetric Mannich reaction of diketones to N-Boc Ketimines^a. ^aUnless otherwise indicated, reactions were carried out with N-Boc ketimine 2 (0.25 mmol) and 1,3-diketone 3 (0.3 mmol) in CH₂Cl₂ (1.5 ml) at room temperature. ^bIsolated yield after column chromatography purification. ^cThe ee values were determined by chiral HPLC analysis using a Daicel Chiralpak IC and AD-H columns. ^dThe absolute configuration of the product 5a was determined by comparison of its retention time with literature data according to ref. 13 and the configurations of other products were tentatively assigned by analogy.

Fig. 3 X-ray structure of compound 5g (ORTEP diagram).

Fig. 4 shows a possible transition state structure on the basis of X-ray diffraction analysis of product 5g.¹⁷ The rigid squaramide unit forms a hydrogen bonding interaction through the NH group with the exocyclic amide carbonyl and imine nitrogen of the ketimine moiety. This H-bonding aggregation in turn facilitates the nucleophilic attack of the active methylene group of the 1,3-diketone onto the imine carbon by increasing its electrophilicity, wherein, simultaneous hydrogen bond formation takes place via the tertiary amino nitrogen of cinchona alkaloid part of the squaramide catalyst with the enol form of the 1,3-diketone and the acidic proton gets deprotonated thereby increasing the nucleophilicity of the active methylene carbon. The resultant deprotonated 1,3-diketone (pentane-2,4-dione) undergoes a nucleophilic attack onto the activated ketimine via the Si-face resulting in the S-configured product.

Fig. 4 Proposed transition state model.

Conclusions

In summary, we have described the catalytic activity of chiral squaramide catalysts, 1a–i, for asymmetric Mannich reaction of 1,3-diketones with isatin (N-Boc) ketimines in dichloromethane at room temperature. Chiral squaramide catalyst 1g showed high efficiency and excellent enantioselectivity with broad substrate scope. The corresponding 3-substituted 3-aminooxindole derivatives were obtained in high yields and excellent enantioselectivities under mild conditions with low catalyst loading (3 mol%). This method affords valuable and simple access to enantiomerically pure 3-substituted-3-aminooxindole derivatives. Further studies on chiral squaramides are currently underway in our laboratory to expand their application in asymmetric catalysis.

Acknowledgements

K. S. R. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for the award of a Senior Research Fellowship. R. T. acknowledges the XII five year plan project CSC, (CSC-0125) of CSIR-IICT for financial support.

Notes and references

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17. CCDC number of the 5g is CCDC 1451822.†.

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Footnote

† Electronic supplementary information (ESI) available: General method, experimental procedure and compound characterizations, ¹H and ¹³C NMR spectra, HPLC chromatograms and X-ray crystallographic data. CCDC 1451822. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra16877a

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