Enantioselective assembly of functionalized carbocyclic spirooxindoles using an L-proline derived thiourea organocatalyst

Abstract

Sequential vinylogous Michael addition–cyclization reactions of vinyl malononitriles with isatylidene malononitrile were accomplished using L-proline derived bifunctional thiourea. Cyclohexylidine malononitrile afforded exclusively the single diastereomer with good to excellent enantioselectivity (up to 99% ee) for diverse oxindole spirocyclohexene derivatives. Tetralone derived α,α-dicyano alkene was also employed to access spirocyclic oxindole scaffolds with an excellent level of stereoselectivity (up to 99% ee).

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Introduction

The majority of drug molecules are either natural products or derivatives inspired by active pharmacophores present in natural products. Thus nature inspires synthetic chemists to create unique molecular scaffolds to diversify structural complexity.¹ Construction of these molecules would require the development of novel synthetic strategies. Various natural products contain an oxindole scaffold with an interesting spiromolecular architecture.² The ubiquitous presence of spirocylohexaneoxindoles with multifunctional and multistereogenic centres in bioactive molecules attracts the attention of synthetic chemists.³ These motifs stimulate interest in the development of synthetic strategies to diversify the molecular complexity. As a consequence, various enantioselective synthetic transformations have been reported for the synthesis of carbocyclic spirooxindoles.⁴ Among various strategies, cascade/domino reactions are found to be more useful since they provide oxindoles with varying degrees of substitution.⁵ Intrigued by this report, various groups developed organocatalysed assembly of diverse spirocyclohexane derivatives with multistereogenic centres.⁶ In these reports excellent synthetic utility of Michael addition has been realised by using several Michael variants such as donors and acceptors for asymmetric transformations.⁷ α,α-Dicyanoalkene is an effective donor which can be used for direct vinylogous Michael type reactions. Enantioselective allylic amination is the first report which revealed the vinylogous Michael addition of α,α-dicyanoalkene.⁸

Since then, vinylogous malononitrile has been considered as an effective nucleophile for the development of numerous elegant transformations.⁹ Recently vinylogous malononitrile has been effectively utilized for the construction of spirocylic oxindoles.¹⁰ Alternatively, electrophilic isatylydine dicyanoalkene 1a was also employed for the synthesis of similar spirooxindoles.¹¹ However, enantioselective synthesis of densely functionalized spirooxindoles with diene moiety has remained a challenge until recently.

In 2010, Hairbabu et al. reported racemic reaction between vinylogous malononitrile and isatylidine dicyanoalkene to construct spirooxindole containing diene moiety.¹² The report by Wang and co-workers disclosed the synthesis of identical scaffold with moderate diastereoselectivity (dr 7.9 : 1) and good enantioselectivity using hydroquinine derived thiourea organocatalyst at 50 °C.¹³ In our continued effort in developing applications of L-proline derived thiourea, we wish to report here the facile construction of densely functionalised spirooxindoles with diene at ambient temperature.

Results and discussion

Our initial investigation commenced with the addition of N-methyl isatylidene malononitrile 1a to the stirred solution of cyclohexanone malononitrile 2a in the presence of 10 mol% of chiral bases 4a–4e in toluene at 25 °C (Table 1, entries 1–5). Although very good yield of spirooxindole comprising diene 3aa was obtained, the enantioselectivity was found to be moderate (Table 1, entries 1–3). Chinconidine and β-ICD failed to induce any level of enantioselectivity (Table 1, entries 4 and 5).

Table 1 Organocatalyst screening of cascade reaction between isatylidine malononitrile 1a and cyclohexanone malononitrile 2a^a

Entry	Catalyst	Time (h)	Yield^b (%)	dr	ee^c (%)
a The reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), and catalyst (0.01 mmol) in 1 mL of PhCH3 at 25 °C.b Isolated yield.c Determined using chiral stationary phase.
1	4a	3	90	1 : 1	34
2	4b	3	91	1 : 1	47
3	4c	3	91	1 : 1	44
4	4d	3	90	1 : 1	rac
5	4e	3	89	1.2 : 1	rac
6	4f	5	89	1.5 : 1	rac
7	4g	5	90	2 : 1	35
8	4h	5	91	1.7 : 1	47
9	4i	10	88	4 : 1	68
10	4j	5	89	4 : 1	40
11	4k	5	90	1.5 : 1	43
12	4l	12	90	5.6 : 1	20
13	4m	10	89	4 : 1	11

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To identify the suitable catalyst to promote enantioselectivity, we turned our attention to bifunctional organocatalysts. Employment of Takemoto thiourea 4f and organocatalysts (4g and 4h) derived from quinine and quinidine did not bring in desired level of enantioselectivity. These results motivated us to evaluate L-proline derived bifunctional thiourea 4i in constructing 3aa.

We were happy to note the observed enantioselectivity using catalyst 4i was found to be 68% and diastereoselectivity was better than previously employed organocatalysts and chiral bases (Table 1, entries 1–8). Intrigued by these results, we wanted to prove the requirement of additional stereogenic centre in catalyst 4i. Hence, thioureas 4j and 4k were evaluated (Table 1, entries 10 and 11). The observed results indicate that it is necessary to have a chiral centre on the carbon bearing thiourea moiety in order to get good asymmetric induction. In addition, similar pyrrolidine moiety containing bifunctional catalysts 4l and 4m were also screened (Table 1, entries 12 and 13). These results showcase the potential of catalyst 4i in achieving good enantioselectivity in construction of spirooxindoles. Encouraged by these results, optimization of reaction conditions were carried out using L-proline derived thiourea 4i.

Initially, identification of suitable reaction medium was undertaken. Replacing toluene with trifluoromethyl benzene retarded the enantioselectivity to 48% (Table 2, entries 1 and 2). Similarly use of methylene chloride lowered the enantioselectivity although rate of the reaction increased (Table 2, entry 3). Protic solvents such as methanol dramatically improved the conversion however; diastereoselectivity and enantioselectivity were significantly lower (Table 2, entry 4). Among ethereal solvents, THF negatively influenced the stereoselectivity. The use of MTBE or diethyl ether had little influence either on the yield or enantioselectivity (Table 2, entries 5–7). Thus toluene was found to be the most suitable reaction medium in obtaining spirooxindole 3aa. Either increasing or decreasing the catalyst loading at room temperature did not change the outcome drastically (Table 2, entries 8 and 9). In order to obtain product 3aa in enantiomerically pure manner, reaction was carried out at 0 °C. It is evident that lowering of temperature is indeed required to improve diastereo and enantioselectivities (Table 2, entry 10). Excellent diastereoselectivity (20 : 1) and enantioselectivity (99%) were obtained using 10 mol% of organocatalyst 4i at 0 °C. Thus, densely functionalised spirooxindole containing diene moiety was synthesized via sequential vinylogous Michael addition–cyclisation of N-methyl isatylidine malononitrile 1a and vinylogous malononitrile 2a using L-proline derived bifunctional thiourea 4i.

Table 2 Optimization studies of reaction conditions using organocatalyst 4i^a

Entry	Solvent	mol%	T °C	Time (h)	Yield^b (%)	dr	ee^c (%)
a The reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), and catalyst 4i (0.01 mmol) in 1 mL of appropriate solvent at mentioned temperature.b Isolated yield.c Determined using chiral stationary phase.
1	PhCH3	10	25	10	88	4 : 1	68
2	PhCF3	10	25	10	90	4.2 : 1	48
3	CH2Cl2	10	25	6	84	3.8 : 1	21
4	CH3OH	10	25	0.5	89	1 : 1	34
5	THF	10	25	6	85	1 : 1	21
6	MTBE	10	25	5	88	4 : 1	55
7	Et2O	10	25	5	89	5 : 1	67
8	PhCH3	20	25	9	82	4.2 : 1	65
9	PhCH3	5	25	9	84	4 : 1	40
10	PhCH3	10	0	24	86	20 : 1	99

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Under the optimized reaction conditions, various vinylogous malononitriles were subjected to cascade Michael-cyclisation reaction using 10 mol% of organocatalyst 4i in toluene at 0 °C.

While cyclohexanone derived malononitrile 2a yielded the expected product 3aa in excellent enantioselectivity, heteroatom containing malononitriles (2b and 2c) afforded the respective products in moderate enantioselectivities (Table 3, entries 1–3). We were delighted to observe no effect of heteroatom in tetralone derived vinylogous malononitriles (5a–5c). The cyclised products 6aa–6ac were obtained in very good enantioselectivities without compromising the yields (Table 3, entries 4–6). Hence nucleophiles 2a and 5a were chosen to assemble the structurally diverse spirooxindoles. Structure of the product 6aa was confirmed by X-ray crystallography analysis (Fig. 1).

Table 3 Nucleophilic scope of cascade reaction between N-methyl isatylidene malononitrile 1a and vinylogous malononitrile 2/5^a

Entry	2 or 5	3 or 6	Time (h)	Yield^b (%)	ee^c (%)
a The reactions were carried out with 1a (0.1 mmol), 2 or 5 (0.1 mmol), and catalyst 4i (0.01 mmol) in 1 mL of PhCH3 at 0 °C.b Isolated yield.c Determined using chiral stationary phase.
1	2a	3aa	24	86	99
2	2b	3ab	24	91	35
3	2c	3ac	24	91	40
4	5a	6aa	27	92	96
5	5b	6ab	48	86	94
6	5c	6ac	48	89	91

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Fig. 1 ORTEP diagram of compound 6aa.

Intrigued by the importance of multicomponent assembly process of more than two reactants and possible better pharmacological activity of unprotected oxindole derivatives, a cascade reaction was carried out to construct molecular scaffold 3a and 6a (Table 4).¹⁴ Mixture of isatin 7a, malononitrile and 2-cyclohexylidenemalononitrile 2a was treated with 10 mol% of 4i in toluene at 0 °C. Product 3a was isolated with 88% yield and 99% ee. Under identical conditions N-methyl isatin 1a also underwent multicomponent reaction with respective nucleophile 2a and 5a smoothly to yield 3aa and 6aa in excellent yield and stereoselectivity (up to 99% ee). We wish to highlight here that many existing enantioselective transformations involving oxindole skeletons require the N1-protection in order to achieve best enantioselectivity possible.¹⁵ Our results demonstrate the capability of L-proline derived organocatalyst 4i in inducing very good enantioselectivity in spirooxindoles without the need of N-1 protection.¹⁶

Hence substrate scope on isatin derivatives was carried out using multicomponent strategy by employing organocatalyst 4i under established conditions. The results are depicted in Table 4. Encouraged by this fruitful results substrate scope was carried out. 5-Halogen substituted such as fluoro, chloro and bromo isatins 7b–7d yielded the corresponding products 3b–3d with almost similar enantioselectivity and very good yields (Table 4, entries 2–4). Electron withdrawing 5-nitro isatin 7e and electron releasing 5-methoxy isatin 7f produced the corresponding products with very good yields fair enantioselectivities (Table 4, entries 5–6). However, lowering of reaction temperature for these substrates to −10 °C brought in desired level of enantioselectivity up to 92% ee.

Table 4 Substrate scope of enantioselective multicomponent reaction using organocatalyst 4i^a

Entry	R1, R2	3 or 6	Time (days)	Yield^b (%)	ee^c (%)
a The reactions were carried out with 1 (0.1 mmol), 2 or 5 (0.1 mmol), and catalyst 4i (0.01 mmol) in 1 mL of PhCH3 at 0 °C.b Isolated yield.c Determined using chiral stationary phase.d Particulars in the parenthesis were obtained when reaction was carried out at −10 °C.e Reaction was carried out using 0.5 mmol of 7a in 5 mL of PhCH3 at 0 °C.
1	H, H 7a	3a	1.5	88	99
2	5-F, H 7b	3b	1	91	93
3	5-Cl, H 7c	3c	1	90	96
4	5-Br, H 7d	3d	1	89	90
5^d	5-NO2, H 7e	3e	1(4)	92(85)	77(90)
6^d	5-OMe, H 7f	3f	1(4)	90(87)	73(92)
7	H, H 7a	6a	2	88	99
8	H, 5-F 7b	6b	2	80	88
9	H, 5-Cl 7c	6c	2	82	96
10	H, 4-Br 7d	6d	1	90	90
11	H, 5-Br 7e	6e	2	79	90
12^d	H, 5-NO2 7f	6f	2(4)	80(85)	84(91)
13^d	H, 5-Ome 7g	6g	2(4)	89(91)	71(93)
14	H, CH2CO2Me 7h	6h	4	89	99
15	H, allyl 7i	6i	4	85	99
16	H, propargyl 7j	6j	4	87	94
17	H, benzyl 7k	6k	4	87	80
18^e	H, H 7a	6a	2	83	98

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Since cyclohexylidenemalononitrile 2a was well explored in the recently reported literature,¹³ we turned our attention to the tetralone based vinyl malononitrile nucleophile 5a for exploring the substrate diversity. Various substituted isatins were subjected to the enantioselective multicomponent reaction and in all the cases very good yields were obtained. Reaction proceeded smoothly with excellent enantioinduction to yield the cyclised product 6a, when isatin was employed (Table 4, entry 7). 5-Fluoro and 5-chloro isatins afforded the corresponding products 6c and 6d with 96% and 90% of enantioselectivity respectively (Table 4, entries 8–9). Irrespective to the position of substitution, both 4-bromo and 5-bromo isatins provided the respective products with 90% ee (Table 4, entry 10–11).

Only moderate enantioselectivities were observed for both electron releasing and electron withdrawing group containing iastins as substrates but enantioselectivity was improved by reducing the reaction temperature to −10 °C (Table 4, entries 12–13). Effect of N-substitution in the enantioselectivity of cascade reaction was identified by employing various N-protected isatins. Product 6h was isolated with 99% of enantioselectivity when methyl acetate was used as N-protection in isatin (Table 4, entry 14). N-Allyl and N-propargyl protected isatins afforded the products with excellent enantioselectivities while N-benzyl isatin provided only 80% ee for the respective product (Table 4, entries 15–17). To further validate this methodology, the reaction was scaled up and the product 6a was obtained without substantial loss in both yield and enantioselectivity (Table 4, entry 18). Thus, one-pot three component enantioselective reaction was accomplished with the range of substrates using organocatalyst 4i.

Conclusions

In conclusion, enantioselective multicomponent reaction which involves sequential vinylogous Michael addition and cyclisation process for the construction of multifunctional spirooxindole scaffolds has been developed. Vinylogous nucleophiles, cyclohexylidene malononitrile 2a and tetralone based malononitrile 5a provided the products with good yields (up to 92%) and good to excellent enantioselectivities (up to 99% ee) using L-proline derived organocatalyst 4i.

Experimental

General remarks

All reactions were carried out in an oven dried flask. Solvents used for reactions and column chromatography were commercial grade and distilled prior to use. Toluene and THF were dried over sodium/benzophenone, CH₂Cl₂ and CHCl₃ over CaH₂. Solvents for HPLC bought as analytical grade and used without further purification. TLC was performed on pre-coated silica gel aluminium plates with 60_F254 indicator, visualised by irradiation with UV light. Column chromatography was performed using silica gel 60–100 mesh. ¹H-NMR and ¹³C-NMR were recorded on a 500 MHz instrument using DMSO-d₆ and CDCl₃ as solvent and multiplicity as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), dt (doublet of triplet) bs (broad singlet). Coupling constants J were reported in Hertz. High resolution mass spectra were obtained by ESI using Q-TOF mass spectrometer. IR spectra were reported in terms of frequency of absorption (cm⁻¹). The enantiomeric excess is obtained by HPLC analysis using a chiral stationary phase column (CHIRALPAK AD-H, AS-H and OD-H). Optical rotation was recorded using polarimeter at a wavelength of 589 nm.

(A) General procedure for reaction between isatylidine malononitrile 1a and vinylogous malononitriles 2 or 5. To a stirred solution of 4i (0.01 mmol, 10 mol%) and isatylidine malononitrile 1a (20.9 mg, 0.1 mmol) in PhCH₃ (1.0 mL) and vinylogous nucleophile 2 or 5 (0.1 mmol) was added. The solution was stirred at 0 °C temperature for mentioned days. After the reaction was completed (monitored by TLC), the resulting mixture was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel to give the product 3aa–3ac or 6aa–6ac.
3′-Amino-1-methyl-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (3aa). Prepared according to general procedure A using 2a (14.6 mg, 0.1 mmol) and the reaction completed after 24 h. After column chromatography, desired product was obtained as white solid (45 mg, 86% yield). Mp: 257–259 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 7.55 (s, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.65 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 5.93–5.92 (m, 1H), 3.27 (s, 3H), 2.95 (d, J = 10.7 Hz, 1H), 2.16–2.11 (m, 1H), 1.93–1.85 (m, 1H), 1.63–1.60 (m, 1H), 1.47–1.44 (m, 2H), 0.40 (q, J = 11.2 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 172.03, 144.66, 142.63, 131.49, 125.80, 125.10, 124.30, 124.15, 122.24, 115.94, 111.03, 110.55, 110.23, 82.12, 54.75, 42.68, 40.39, 40.23, 40.06, 39.89, 39.72, 39.56, 39.39, 37.51, 27.10, 24.98, 23.86, 20.60. IR: 3411, 3327, 3232, 2945, 2217, 1717, 1607, 1363, 758. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −26.0 (c = 1.0, acetone).
(3R,8a′R)-6′-Amino-1-methyl-2-oxo-1′,8a′-dihydrospiro[indoline-3,8′-isochromene]-5′,7′,7′(3′H)-tricarbonitrile (3ab). Prepared according to general procedure A using 2b (14.8 mg, 0.1 mmol) and the reaction completed after 24 h. After column chromatography, desired product was obtained as white solid (46 mg, 91% yield). Mp: 193–198 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 7.83 (s, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 5.93 (d, J = 1.0 Hz, 1H), 4.26 (d, J = 17.5 Hz, 1H), 4.01 (d, J = 18.0 Hz, 1H), 3.66–3.63 (m, 1H), 3.17 (s, 3H), 2.41 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 172.12, 144.36, 143.54, 131.81, 125.10, 124.41, 124.07, 121.36, 120.95, 115.49, 110.68, 110.62, 11.06, 80.37, 65.84, 63.88, 52.11, 42.85, 35.99, 27.31. IR: 3612.26, 3420.78, 3333.63, 3208.32, 3056.97, 2925.76, 2845.07, 2205.09, 1716.74, 1643.16, 1609.38, 1585.23, 1491.25, 1470.96, 1422.83, 1372.42, 1349.43, 1299.70, 1264.85, 1193.71, 1160.36, 1133.22, 1089.74, 1042.46, 1024.27, 971.34, 903.93, 859.15, 753.97, 737.36, 702.00. HRMS (ESI): m/z calculated for C₂₀H₁₅N₅O₂ + Na⁺: 357.1223, found: 357.1226. The ee was determined to be 35% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 80/20, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 19.8 min, t_R (major) = 16.8 min. [α]²⁵_D = −104.0 (c = 1.0, acetone).
(3R,8a′R)-6′-Amino-1-methyl-2-oxo-1′,8a′-dihydrospiro[indoline-3,8′-isothiochromene]-5′,7′,7′(3′H)-tricarbonitrile (3ac). Prepared according to general procedure A using 2c (16.4 mg, 0.1 mmol) and the reaction completed after 24 h. After column chromatography, desired product was obtained as white solid (47 mg, 91% yield). Mp: 219–24 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 7.73 (s, 2H), 7.52 (t, J = 10.0 Hz, 1H), 7.28 (d, J = 12.5 Hz, 1H), 7.18 (t, J = 9.5 Hz, 1H), 7.05 (d, J = 9.5 Hz, 1H), 6.95 (d, J = 9.5 Hz, 1H), 6.14 (d, J = 3.0 Hz, 1H), 3.30 (s, 3H), 3.17–3.10 (m, 3H), 2.41 (m, 1H), 1.66 (t, J = 9.0 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 171.12, 144.36, 143.54, 131.81, 125.10, 124.41, 124.07, 121.36, 120.95, 115.49, 110.68, 110.62, 110.06, 80.37, 65.84, 63.88, 52.11, 42.85, 35.99, 27.31. IR: 3631.10, 3428.16, 3334.56, 3220.09, 3057.62, 2921.68, 2886.37, 2804.06, 2362.55, 2338.72, 2211.05, 1715.56, 1639.39, 1610.57, 1491.17, 1470.59, 1422.56, 1372.22, 1352.29, 1307.48, 1254.43, 1241.61, 1186.88, 1160.96, 1138.51, 1086.02, 1026.08, 939.93, 880.21, 790.19, 752.63, 735.31, 701.61. HRMS (ESI): m/z calculated for C₂₀H₁₅N₅OS + Na⁺: 396.0890, found: 396.0888. The ee was determined to be 40% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 80/20, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 27.8 min, t_R (major) = 19.4 min. [α]²⁵_D = −58.0 (c = 1.0, acetone).
(R)-3′-Amino-1-methyl-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6aa). Prepared according to general procedure A using 5a (19.4 mg, 0.1 mmol) and the reaction completed after 27 h. After column chromatography, desired product was obtained as white solid (51 mg, 92% yield). Mp: 208–214 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 7.98 (s, 2H), 7.56–7.52 (m, 2H), 7.34–7.30 (m, 2H), 7.29–7.26 (m, 2H), 7.20 (t, J = 7.5 Hz, 2H), 3.29 (s, 3H), 2.64–2.59 (m, 1H), 2.43–2.36 (m, 1H), 2.11–2.04 (m, 1H), 1.81–1.75 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 171.09, 147.92, 144.34, 136.65, 132.16, 130.95, 128.83, 128.73, 128.20, 126.96, 124.69, 124.62, 124.55, 123.71, 123.63, 117.36, 111.20, 110.65, 75.70, 56.52, 44.11, 28.36, 27.35, 25.17. IR: 3963.99, 3856.05, 3692.02, 3432.62, 3314.32, 3231.42, 3054.37, 3022.80, 2945.83, 2206.05, 1708.84, 1639.99, 1610.54, 1579.33, 1488.73, 1468.96, 1422.38, 1367.97, 1353.93, 1264.48, 1221.16, 1131.88, 1085.48, 1046.34, 1022.41, 889.65, 870.54, 773.12, 760.02, 732.93, 701.67. HRMS (ESI): m/z calculated for C₂₅H₁₇N₅O + Na⁺: 426.1325, found: 426.1323. The ee was determined to be 99.7% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 30.1 min, t_R (major) = 26.9 min. [α]²⁵_D = −70 (c = 1.0, acetone).
(R)-9-Amino-1′-methyl-2′-oxospiro[benzo[c]chromene-7,3′-indoline]-8,8,10-(6H)-tricarbonitrile (6ab). Prepared according to general procedure A using 5b (19.6 mg, 0.1 mmol) and the reaction completed after 48 h. After column chromatography, desired product was obtained as white solid (56 mg, 86% yield). Mp: 237–241 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 7.66 (s, 2H), 7.66 (dd, J = 9.5, 1.5 Hz, 1H), 7.57 (td, J = 10.0, 1.5 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.32–7.27 (m, 2H), 7.20 (td, J = 9.5, 1.5 Hz, 1H), 7.11 (td, J = 10.0, 1.5 Hz, 1H), 6.93 (dd, J = 10.0, 1.0 Hz, 1H), 4.42–4.26 (m, 2H), 3.28 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 169.60, 154.40, 148.59, 144.17, 131.90, 130.38, 125.67, 124.68, 124.13, 124.07, 121.91, 121.85, 120.07, 116.71, 116.46, 115.39, 110.47, 110.18, 109.97, 73.09, 64.19, 55.37, 43.84, 26.98. IR: 3426.66, 3357.34, 3307.63, 3226.27, 3202.40, 3065.04, 2883.56, 2834.31, 2801.96, 2632.43, 2363.05, 2335.40, 2208.06, 1709.98, 1636.24, 1610.18, 1577.31, 1468.24, 1426.89, 1369.19, 1248.00, 1218.92, 1159.41, 1131.55, 1090.00, 1045.64, 1024.19, 891.17, 783.57, 752.72, 690.68. HRMS (ESI): m/z calculated for C₂₄H₁₅N₅O₂ + Na⁺: 428.1118, found: 428.1107. The ee was determined to be 94% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 80/20, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 35.8 min, t_R (major) = 13.7 min. [α]²⁵_D = −85.0 (c = 1.0, acetone).
(R)-9-Amino-1′-methyl-2′-oxospiro[benzo[c]thiochromene-7,3′-indoline]-8,8,10-(6H)-tricarbonitrile (6ac). Prepared according to general procedure A using 5c (21.2 mg, 0.1 mmol) and the reaction completed after 48 h. After column chromatography, desired product was obtained as white solid (60 mg, 89% yield). Mp: 235–240 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 8.12 (s, 2H), 7.57–7.53 (m, 2H), 7.38 (dd, J = 8.5, 1.5 Hz, 1H), 7.34–7.27 (m, 4H), 7.20 (t, J = 9.0, 1H), 3.33 (s, 4H), 3.29–3.04 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 170.14, 147.78, 144.05, 133.49, 131.81, 130.41, 130.29, 128.81, 128.23, 126.83, 125.90, 124.11, 122.80, 119.78, 116.56, 110.46, 110.37, 109.95, 75.91, 57.43, 56.01, 43.77, 26.98, 26.48. IR: 3679.36, 3308.62, 3194.52, 2953.88, 2921.22, 2852.87, 2214.83, 1713.23, 1659.43, 1605.77, 1571.82, 1486.57, 1464.90, 1368.56, 1349.03, 1260.94, 1244.86, 1214.61, 1157.85, 1130.28, 1085.95, 1043.57, 1021.82, 970.75, 889.92, 862.51, 788.84, 756.30, 702.68. HRMS (ESI): m/z calculated for C₂₃H₁₅N₅OS + Na⁺: 444.0186, found: 444.0183. The ee was determined to be 92% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 80/20, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 18.2 min, t_R (major) = 12.7 min. [α]²⁵_D = −59.0 (c = 1.0, acetone).

(B) General procedure for enantioselective three component reaction. To a stirred solution of 4i (4.61 mg, 0.01 mmol, 10 mol%) and isatin 7 (0.1 mmol) in PhCH₃ (1.0 mL), malononotrile (0.12 mmol) and vinylogous nucleophile 2a (14.6 mg, 0.1 mmol) or 5a (19.4 mg, 0.1 mmol) was added. The solution was stirred at 0 °C temperature for mentioned days. After the reaction was completed (monitored by TLC), the resulting mixture was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel to give the product 3a–3f or 6a–6k.
(1′R,8a′R)-3′-Amino-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (3a). Prepared according to general procedure B using 7a (14.7 mg, 0.1 mmol) and the reaction completed after 1.5 days. After column chromatography, desired product was obtained as white solid (60 mg, 88% yield). Mp: 238–240 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 11.36 (s, 1H), 7.52 (s, 2H, D₂O exchangeable), 7.36 (t, J = 7.6 Hz, 1H), 7.07–7.00 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 5.93–5.91 (m, 1H), 2.16–2.12 (m, 1H), 1.94–1.85 (m, 1H), 1.64–1.54 (m, 2H), 1.50–1.40 (m, 1H), 0.52–0.42 (m, 1H, s), 1.41 (m, 1H). ¹³C NMR (500 MHz, DMSO-d₆): δ = 173.21, 142.84, 142.24, 130.76, 125.40, 124.90, 123.63, 122.86, 122.43, 115.46, 110.63, 110.58, 110.16, 81.58, 56.02, 54.54, 42.14, 36.94, 24.49, 23.38, 20.18, 18.46. IR: 3339, 3200, 2934, 2216, 1733, 1614, 619. HRMS (ESI): m/z calculated for C₂₀H₁₅N₅O + Na⁺: 364.0394, found: 364.0396. The ee was determined to be 99% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 0.8 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = min. [α]²⁵_D = −43.3 (c = 1.0, acetone).
(1′R,8a′R)-3′-Amino-5-fluoro-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (3b). Prepared according to general procedure B using 7b (16.5 mg, 0.1 mmol) and the reaction completed after 1 day. After column chromatography, desired product was obtained as white solid (57 mg, 91% yield). Mp: 258–263 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 11.44 (s, 1H), 7.59 (s, 2H), 7.30–7.24 (m, 1H), 7.06–7.03 (m, 1H), 6.60 (dd, J = 8.8, 2.8 Hz, 1H), 5.96 (t, J = 2.4 Hz, 1H), 2.94–2.91 (m, 1H), 2.18–2.08 (m, 1H), 1.66–1.38 (m, 3H), 0.53–0.43 (m, 1H). ¹³C NMR (75 MHz, DMSO-d₆): δ = 178.29, 175.51, 164.39, 162.02, 147.23, 144.57, 130.14, 129.49, 129.10, 129.02, 122.89, 122.66, 120.55, 117.83, 117.57, 117.06, 116.98, 115.58, 115.26, 86.65, 64.94, 60.11, 47.21, 42.12, 29.72, 28.62, 27.26, 25.94, 25.37, 19.27. IR: 3324.73, 3217.55, 2363.22, 2218.62, 1715.48, 1645.68, 1597.25, 1480.98, 1450.35, 1393.60, 1355.03, 1301.61, 1255.69, 1219.47, 1184.90, 1116.39, 1082.72, 1044.80, 981.05, 948.98, 871.46, 827.13, 741.39. HRMS (ESI): m/z calculated for C₂₀H₁₄FN₅O + Na⁺: 382.0285, found: 382.0281. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 23.2 min, t_R (major) = 20.8 min. [α]²⁵_D = −69 (c = 1.0, acetone).
(1′R,8a′R)-3′-Amino-5-chloro-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (3c). Prepared according to general procedure B using 7c (18.1 mg, 0.1 mmol) and the reaction completed after 1 day. After column chromatography, desired product was obtained as white solid (48 mg, 90% yield). Mp: 145–150 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 11.57 (s, 1H), 7.63 (s, 2H), 7.48 (dd, J = 8.4, 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H) 6.77 (d, J = 2.0 Hz, 1H), 5.97 (t, J = 2.4 Hz, 1H), 2.94–2.91 (m, 1H), 2.18–2.14 (m, 2H), 1.67–1.42 (m, 3H), 0.54–0.44 (m, 1H). ¹³C NMR (75 MHz, DMSO-d₆): δ = 178.09, 147.23, 136.19, 131.85, 130.13, 129.88, 129.55, 120.52, 117.52, 115.50, 115.26, 86.62, 64.95, 59.95, 47.20, 42.13, 29.71, 28.61, 25.95, 25.36, 19.28. IR: 3342.42, 3245.19, 3215.48, 2927.36, 2858.99, 2213.26, 1725.19, 1641.99, 1612.18, 1474.43, 1393.98, 1298.61, 1246.57, 1213.31, 1184.88, 1123.38, 1095.48, 1049.40, 970.03, 876.95, 823.62, 770.19, 735.59, 695.28. HRMS (ESI): m/z calculated for C₂₀H₁₄ClN₅O + Na⁺: 397.9892, found: 397.9889. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −125.0 (c = 1.0, acetone).
(1′R,8a′R)-3′-Amino-5-bromo-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (3d). Prepared according to general procedure B using 7d (22.6 mg, 0.1 mmol) and the reaction completed after 1 day. After column chromatography, desired product was obtained as white solid (42 mg, 89% yield). ¹H NMR (500 MHz, DMSO-d₆): δ = 11.58 (s, 1H), 7.63 (s, 2H), 7.61 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 2.95–2.92 (m, 1H), 2.19–2.12 (m, 1H), 1.98–1.86 (m, 1H), 1.67–1.65 (m, 1H), 1.60–1.57 (m, 1H), 1.51–1.46 (m, 1H), 0.54–0.44 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 173.24, 142.87, 142.49, 134.28, 127.90, 125.40, 125.19, 124.76, 115.76, 114.80, 112.51, 110.76, 110.53, 81.89, 55.15, 42.48, 37.42, 24.98, 23.87, 20.67. IR: 3882.48, 3852.49, 3716.54, 3641.48, 3590.45, 3500.87, 3432.70, 3395.77, 3318.52, 3216.41, 3062.29, 2943.16, 2863.46, 2833.83, 2766.99, 2600.47, 2540.92, 2433.17, 2362.99, 2336.38, 2215.29, 1711.43, 1645.63, 1613.87, 1470.66, 1438.86, 1391.27, 1353.52, 1300.62, 1267.76, 1243.76, 1215.61, 1186.41, 1096.66, 1046.09, 945.98, 872.03, 829.88, 736.30. The ee was determined to be 90% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 37.4 min, t_R (major) = 25.3 min. [α]²⁵_D = −89.0 (c = 1.0, acetone).
(1′R,8a′R)-3′-Amino-5-nitro-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (3e). Prepared according to general procedure B using 7e (19.2 mg, 0.1 mmol) at −10 °C and the reaction completed after 4 days. After column chromatography, desired product was obtained as white solid (59 mg, 85% yield). ¹H NMR (400 MHz, DMSO-d₆): δ = 12.15 (s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.93 (s, 1H), 7.69 (s, 2H), 7.67 (d, J = 2.00 Hz, 1H), 3.00–2.98 (m, 1H), 2.28–2.24 (m, 1H), 2.17–2.12 (m, 1H), 1.64–1.62 (m, 1H), 1.59–1.55 (m, 1H), 1.51–1.47 (m, 3H). ¹³C NMR (75 MHz, DMSO-d₆): δ = 174.11, 143.28, 142.22, 129.09, 128.65, 128.60, 125.61, 125.35, 125.06, 120.99, 117.45, 116.34, 115.65, 81.89, 55.03, 42.33, 37.47, 24.93, 23.80, 20.56. IR: 336.98, 3219.63, 2939.84, 2862.41, 2231.00, 2207.39, 1743.36, 1626.97, 1591.65, 1528.11, 1477.27, 1447.30, 1395.79, 1338.09, 1312.87, 1289.92, 1253.08, 1182.91, 1124.90, 1076.43, 1026.68, 1000.49, 935.71, 894.37, 836.12, 734.94. The ee was determined to be 90% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 0.8 mL min⁻¹, λ = 254 nm): t_R (minor) = 49.2 min, t_R (major) = 34.1 min. [α]²⁵_D = −53.0 (c = 1.0, acetone).
(1′R,8a′R)-3′-Amino-5-methoxy-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (3f). Prepared according to general procedure B using 7f (17.7 mg, 0.1 mmol) at −10 °C and the reaction completed after 4 days. After column chromatography, desired product was obtained as white solid (mg, 87% yield). Mp: 190–195 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 11.20 (s, 1H), 7.56 (s, 2H, D₂O exchange), 6.93–6.99 (m, 2H), 6.42 (d, J = 2.0 Hz, 1H), 5.93–5.92 (m, 1H), 3.68 (s, 1H), 3.36 (s, 1H), 2.91–2.89 (m, 1H), 2.17–2.12 (m, 1H), 1.96–1.90 (m, 1H), 1.66–1.45 (m, 3H), 0.54–0.44 (m, 1H). ¹³C NMR (75 MHz, DMSO-d₆): δ = 178.17, 160.26, 147.52, 141.27, 130.58, 129.00, 128.92, 120.64, 119.29, 118.03, 116.20, 115.85, 115.39, 86.64, 60.52, 59.98, 47.38, 42.16, 29.75, 28.65, 25.43. IR: 3330.37, 3208.93, 3068.47, 2931.22, 2209.74, 1714.91, 1642.79, 1597.06, 1487.60, 1445.16, 1393.08, 1302.95, 1269.25, 1208.50, 1087.98, 1032.74, 875.24, 820.49, 743.11. HRMS (ESI): m/z calculated for C₁₀H₆O₂N₂Cl₂ + Na⁺: 278.9695, found: 278.9698. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −151.0 (c = 1.0, acetone).
(R)-3′-Amino-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6a). Prepared according to general procedure B using 7a (14.7 mg, 0.1 mmol) and the reaction completed after 2 days. After column chromatography, desired product was obtained as white solid (65 mg, 88% yield). Mp: 115–1120 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 11.48 (s, 1H), 7.97 (s, 2H), 7.51 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.0 Hz, 1H), 7.28–7.21 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 2.65–2.62 (m, 1H), 2.46–2.39 (m, 1H), 2.11–2.08 (m, 1H), 1.83–1.80 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 172.86, 147.94, 142.98, 136.63, 132.05, 131.00, 128.68, 128.60, 128.19, 126.97, 124.86, 124.69, 124.52, 123.96, 117.44, 111.47, 111.33, 110.80, 75.60, 58.17, 43.95, 40.44, 40.28, 40.20, 40.11, 39.94, 39.77, 39.61, 39.44, 28.41, 25.26. IR: 3330.94, 3238.10, 2927.37, 2207.05, 1725.44, 1639.97, 1620.79, 1582.93, 1471.00, 1428.25, 1384.54, 1323.80, 1291.21, 1263.59, 1224.25, 1193.17, 1159.84, 1104.73, 1043.11, 946.43, 894.24, 868.94, 736.25, 702.28. HRMS (ESI): m/z calculated for C₂₄H₁₅N₅O + Na⁺: 412.1169, found: 412.1158. The ee was determined to be 99% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −86.2 (c = 1.0, acetone).
(R)-3′-Amino-5-fluoro-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6b). Prepared according to general procedure B using 7a (16.5 mg, 0.1 mmol) and the reaction completed after 2 days. After column chromatography, desired product was obtained as white solid (64 mg, 80% yield). Mp: 201–206 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 11.54 (s, 1H), 8.04 (s, 2H), 7.53 (d, J = 8.0 Hz 1H), 7.35–7.22 (m, 4H), 7.23–7.22 (m, 1H), 7.09 (dd, J = 4.5, 9.0 Hz 1H), 7.04 (d, J = 8.0 Hz, 1H), 2.65–2.61 (m, 1H), 2.48–2.47 (m, 1H), 2.14–2.09 (m, 1H), 1.90–1.84 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 172.70, 159.68, 157.78, 147.71, 139.45, 136.77, 130.91, 129.03, 128.79, 128.20, 126.95, 125.78, 125.71, 124.75, 123.30, 118.93, 118.74, 117.32, 112.72, 112.66, 112.59, 112.38, 111.06, 110.66, 75.69, 58.40, 43.81, 28.35, 25.22. IR: 3302.35, 3252.15, 3079.07, 2896.40, 2834.18, 2338.06, 2200.89, 1736.98, 1628.11, 1573.36, 1547.76, 1483.24, 1455.74, 1368.29, 1330.69, 1269.76, 1244.08, 1183.78, 1077.75, 959.80, 869.44, 828.46, 797.87, 773.51, 730.79, 697.79. HRMS (ESI): m/z calculated for C₂₄H₁₄FN₅O + Na⁺: 430.0291, found: 430.0293. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −114.2 (c = 1.0, acetone).
(R)-3′-Amino-5-chloro-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6c). Prepared according to general procedure B using 7a (18.1 mg, 0.1 mmol) and the reaction completed after 2 days. After column chromatography, desired product was obtained as white solid (59 mg, 82% yield). Mp: 122–126 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 11.29 (s, 1H), 8.00 (s, 2H), 7.51 (dd, J = 1.0, 8.00 Hz, 1H), 7.32 (td, J = 7.5, 1.0 Hz, 1H), 7.27 (t, J = 7.5, 1.5 Hz, 1H), 7.22–7.21 (m, 1H), 7.03 (dd, J = 8.5, 2.5 Hz, 1H), 6.99–6.97 (m, 1H), 6.82 (d, J = 2.5 Hz, 1H), 2.66–2.61 (m, 1H), 2.49–2.44 (m, 1H), 2.14–2.09 (m, 1H), 1.88–1.82 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 172.58, 156.02, 147.96, 136.69, 136.15, 131.02, 128.67, 128.19, 126.95, 125.61, 124.69, 124.18, 117.41, 116.30, 111.97, 111.78, 111.30, 110.82, 75.58, 58.43, 43.95, 28.38, 25.27. IR: 3853.89, 3332.76, 3243.08, 3057.94, 2927.82, 2340.65, 2205.51, 1725.73, 1638.82, 1618.49, 1580.87, 1474.87, 1435.85, 1382.77, 1360.53, 1294.84, 1265.07, 1227.48, 1191.14, 1167.81, 1122.07, 1078.05, 1043.67, 1004.38, 947.79, 887.19, 868.24, 851.66, 821.72, 799.96, 765.34, 734.05, 702.27. HRMS (ESI): m/z calculated for C₂₄H₁₄ClN₅O + Na⁺: 446.0779, found: 446.0772. The ee was determined to be 99% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −61.2 (c = 1.0, acetone).
(R)-3′-Amino-4-bromo-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6d). Prepared according to general procedure B using 7a (22.6 mg, 0.1 mmol) and the reaction completed after 2 days. After column chromatography, desired product was obtained as white solid (55 mg, 90% yield). Mp: 130–134 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 11.81 (s, 1H), 7.91 (s, 2H), 7.52 (d, J = 6.5 Hz, 1H), 7.36–7.34 (m, 3H), 7.30–7.22 (m, 2H), 7.08 (d, J = 6.0 Hz, 1H), 2.62 (d, J = 13.5 Hz, 1H), 2.12–2.06 (m, 1H), 1.61 (d, J = 16.0 Hz, 1H), 1.17–1.16 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 172.09, 147.59, 145.76, 136.96, 133.52, 131.45, 130.72, 128.70, 128.01, 126.88, 125.07, 124.18, 120.23, 118.06, 117.52, 111.50, 111.06, 110.44, 78.25, 60.71, 43.62, 28.28, 25.01. HRMS (ESI): m/z calculated for C₂₄H₁₄BrN₅O + Na⁺: 490.0274, found: 490.0268. The ee was determined to be 90% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 23.2 min, t_R (major) = 16.5 min. [α]²⁵_D = −145 (c = 1.0, acetone).
(R)-3′-Amino-5-bromo-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6e). Prepared according to general procedure B using 7a (22.6 mg, 0.1 mmol) and the reaction completed after 2 days. After column chromatography, desired product was obtained as white solid (63 mg, 79% yield). Mp: 176–181 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 11.69 (s, 1H), 8.11 (s, 2H), 7.65 (dd, J = 10.5, 2.5 Hz, 2H), 7.55–7.53 (m, 1H), 7.34–7.22 (m, 4H), 7.06 (d, J = 10.5 Hz, 1H), 2.68–2.62 (m, 1H), 2.51–2.44 (m, 1H), 2.25–2.11 (m, 1H), 1.90–1.83 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 171.91, 147.24, 141.95, 136.23, 134.40, 130.32, 128.58, 128.31, 127.71, 126.95, 126.44, 126.19, 124.24, 122.76, 116.80, 114.65, 113.07, 110.49, 110.10, 75.10, 57.65, 43.32, 27.83, 24.72. IR: 3629.52, 3505.55, 3433.69, 3329.07, 3216.14, 2922.64, 2861.60, 2583.36, 2339.25, 2214.78, 1710.93, 1645.56, 1614.44, 1597.57, 1470.72, 1436.94, 1392.76, 1300.06, 1276.00, 1243.12, 1215.68, 1185.80, 1097.32, 871.23, 828.99, 766.59, 736.20. HRMS (ESI): m/z calculated for C₂₄H₁₄N₆O₃ + Na⁺: 490.0274, found: 490.0275. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −110 (c = 1.0, acetone).
(R)-3′-Amino-5-nitro-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6f). Prepared according to general procedure B using 7a (19.2 mg, 0.1 mmol) and the reaction completed after 2 days. After column chromatography, desired product was obtained as white solid (mg, 85% yield). Mp: 174–178 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 12.24 (s, 1H), 8.41 (dd, J = 8.5, 3.0 Hz, 2H), 8.16 (s, 2H), 8.08 (d, J = 2.5 Hz, 1H), 7.56–7.54 (m, 1H), 7.37–7.23 (m, 4H), 2.70–2.53 (m, 2H), 2.20–2.11 (m, 1H), 1.93–1.86 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 172.72, 148.74, 147.07, 143.15, 136.36, 130.22, 129.04, 128.47, 127.75, 126.49, 124.66, 124.33, 121.99, 120.08, 116.67, 111.53, 110.23, 109.97, 75.14, 57.48, 43.20, 27.75, 24.71. IR: 3960.98, 3916.02, 3883.73, 3853.35, 3830.68, 3780.68, 3739.27, 3703.85, 3631.86, 3589.21, 3504.07, 3429.65, 3224.51, 3124.64, 2909.27, 2829.46, 2802.67, 2767.60, 2708.29, 2588.70, 2336.13, 2237.21, 2033.85, 1982.75, 1739.90, 1599.95, 1523.74, 1466.72, 1393.90, 1337.35, 1294.73, 1203.02, 1180.46, 1122.31, 1080.26, 990.56, 943.18, 905.39, 838.39, 783.69, 743.88, 700.46. HRMS (ESI): m/z calculated for C₂₄H₁₄N₆O₃ + Na⁺: 457.0668, found: 457.0669. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −71.0 (c = 1.0, acetone).
(R)-3′-Amino-5-methoxy-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6g). Prepared according to general procedure B using 7a (17.7 mg, 0.1 mmol) and the reaction completed after 2 days. After column chromatography, desired product was obtained as white solid (56 mg, 91% yield). Mp: 160–165 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 8.00 (s, 1H), 7.53 (d, J = 9.5 Hz, 1H),7.36–7.23 (m, 3H),7.07–6.99 (m, 2H), 6.84 (s, 1H), 3.73 (s, 3H), 2.68–2.64 (m, 1H), 2.47 (t, J = 7.5 Hz, 1H),2.14 (t, J = 15.1 Hz, 1H), 1.89–1.85 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 177.31, 160.76, 152.69, 141.43, 140.90, 135.76, 133.41, 132.93, 131.68, 130.35, 129.42, 128.94, 122.14, 121.08, 116.71, 116.51, 116.04, 115.55, 80.35, 63.17, 48.69, 33.11, 30.01. IR: 3433.18, 3382.94, 3210.93, 3052.84, 2952.24, 2886.91, 2833.40, 2338.39, 2214.94, 1726.11, 1619.79, 1599.03, 1572.63, 1538.09, 1487.04, 1438.77, 1366.30, 1340.56, 1302.89, 1267.86, 1208.48, 1030.49, 936.02, 896.24, 867.31, 808.37, 772.58, 730.43, 707.68. HRMS (ESI): m/z calculated for C₂₅H₁₇N₅O₂ + Na⁺: 442.1274, found: 442.1267. The ee was determined to be 99.3% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 95/5, 1 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −95.0 (c = 1.0, acetone).
(R)-Methyl 2-(3′-amino-2′,2′,4′-tricyano-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-1-yl)acetate (6h). Prepared according to general procedure B using 7a (21.2 mg, 0.1 mmol) and the reaction completed after 4 days. After column chromatography, desired product was obtained as white solid (51 mg, 89% yield). Mp: 176–180 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 8.15 (s, 1H), 7.55–7.51 (m, 2H), 7.36–7.22 (m, 6H), 4.82 (s, 2H), 2.66–2.62 (dt, J = 15.0, 4.5 Hz, 1H), 2.46–2.49 (td, J = 14.5, 6.5 Hz, 1H), 2.13–2.06 (m, 1H), 2.00–1.94 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 171.62, 168.20, 147.78, 143.14, 136.68, 132.15, 130.90, 128.79, 128.22, 126.99, 124.98, 124.76, 124.67, 123.70, 123.62, 117.33, 111.08, 110.83, 110.39, 75.73, 57.57, 53.00, 43.75, 42.01, 28.36, 24.77. IR: 3336.64, 3202.56, 3060.03, 2955.42, 2925.20, 2854.53, 2202.81, 1723.85, 1639.10, 1610.42, 1582.40, 1485.33, 1468.32, 1446.26, 1362.02, 1305.63, 1265.24, 1216.98, 1183.12, 1093.53, 1061.42, 1014.85, 943.68, 886.61, 854.80, 733.78, 698.62. HRMS (ESI): m/z calculated for C₂₇H₁₉N₅O₃ + Na⁺: 484.1380, found: 484.1369. The ee was determined to be 96% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 80/20, 0.8 mL min⁻¹, λ = 254 nm): t_R (minor) = 39.2 min, t_R (major) = 35.5 min. [α]²⁵_D = −178.2 (c = 1.0, acetone).
(R)-1-Allyl-3′-amino-2-oxo-9′,10′-dihydro-2′H-spiro[indoline-3,1′-phenanthrene]-2′,2′,4′-tricarbonitrile (6i). Prepared according to general procedure B using 7a (18.5 mg, 0.1 mmol) and the reaction completed after 4 days. After column chromatography, desired product was obtained as white solid (62 mg, 85% yield). Mp: 139–144 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 8.02 (s, 2H), 7.52 (t, J = 8.5 Hz, 2H),7.34–7.31 (m, 2H), 7.27 (t, J = 15 Hz, 1H),7.22–7.19 (m, 3H), 5.91–5.83 (m, 1H), 5.35 (dd, J = 17.0, 1.0 Hz, 1H), 5.25 (dd, J = 10.5, 1.0 Hz, 1H), 4.54 (dd, J = 16.5, 5.0 Hz, 1H), 4.41 (dd, J = 16.5, 5.5 Hz, 1H),2.64–2.59 (m, 1H), 2.45–2.38 (m, 1H),2.12–2.02 (m, 1H), 1.80–1.74 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 170.99, 147.92, 143.37, 136.62, 132.08, 131.47, 130.94, 128.91, 128.76, 128.21, 126.99, 124.75, 124.69, 123.72, 123.59, 118.45, 117.36, 111.23, 110.75, 75.67, 57.67, 56.51, 44.00, 42.97, 28.38, 25.14, 19.04. IR: 3331.33, 3256.96, 3067.15, 2933.34, 2217.02, 1796.52, 1714.64, 1610.88, 1588.57, 1555.69, 15 114.39, 1487.32, 1468.31, 1433.34, 1364.30, 1278.94, 1249.28, 1225.05, 1174.96, 1125.50, 1106.89, 1030.78, 986.96, 932.25, 901.87, 876.66, 852.84, 799.06, 755.00, 732.86, 702.69. HRMS (ESI): m/z calculated for C₂₇H₂₀ON₅ + Na⁺: 430.1661, found: 430.1659. The ee was determined to be 99% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 80/20, 0.5 mL min⁻¹, λ = 254 nm): t_R (minor) = 21.3 min, t_R (major) = 18.9 min. [α]²⁵_D = −126.0 (c = 1.0, acetone).
(R)-3′-Amino-2-oxo-1-(prop-2-ynyl)-9′,10′-dihydro-2′H-spiro[indoline-3,1′phenanthrene]-2′,2′,4′-tricarbonitrile (6j). Prepared according to general procedure B using 7a (18.7 mg, 0.1 mmol) and the reaction completed after 4 days. After column chromatography, desired product was obtained as white solid (64 mg, 87% yield). Mp: 183–188 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 8.03 (s, 2H), 7.59–7.52 (m, 2H), 7.37–7.20 (m, 6H), 4.78–4.67 (m, 2H), 2.60 (d, 1H), 2.43–2.36 (td, J = 14, 6.0 Hz, 1H), 2.09 (t, J = 12.5 Hz, 1H), 1.73 (d, J = 17.5 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 170.66, 147.87, 142.40, 136.59, 132.14, 130.88, 128.92, 128.80, 128.22, 127.01, 125.05, 124.77, 124.71, 123.72, 123.35, 117.32, 111.26, 111.07, 110.32, 57.46, 43.79, 30.19, 28.33, 24.99. IR: 3745.98, 3297.13, 3054.69, 2932.56, 2218.84, 1724.78, 1612.48, 1573.39, 1554.87, 1487.60, 1468.57, 1430.29, 1364.41, 1338.85, 1264.59, 1185.14, 1162.91, 1111.34, 1046.92, 899.14, 731.85, 701.99. HRMS (ESI): m/z calculated for C₂₇H₁₈ON₅ + Na⁺: 428.1506, found: 428.1504. The ee was determined to be 94% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 0.3 mL min⁻¹, λ = 254 nm): t_R (minor) = 43.3 min, t_R (major) = 39.4 min. [α]²⁵_D = −98.2 (c = 1.0, acetone).
(R)-3′-Amino-1-benzyl-2-oxo-9′,10′-dihydro-2′H spiro[indoline-3,1′phenanthrene]-2′,2′,4′-tricarbonitrile (6k). Prepared according to general procedure B using 7a (23.7 mg, 0.1 mmol) and the reaction completed after 4 days. After column chromatography, desired product was obtained as white solid (53 mg, 87% yield). Mp: 211–216 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 8.03 (s, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.48–7.43 (m, 3H), 7.40–7.25 (m, 6H), 7.22–7.17 (m, 3H), 5.11–5.02 (m, 2H), 2.63–2.58 (m, 1H), 2.44–2.37 (m, 1H), 2.09–2.05 (m, 1H), 1.77–1.64 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆): δ = 171.48, 147.94, 143.38, 136.60, 135.92, 132.09, 130.93, 129.19, 128.97, 128.79, 128.29, 128.21, 128.13, 128.07, 128.05, 128.02, 127.00, 124.82, 124.77, 123.79, 123.52, 117.36, 111.23, 110.75, 75.67, 57.61, 44.26, 43.89, 28.35, 25.12. IR: 3499.91, 3161.10, 3060.63, 2885.20, 2841.28, 2363.21, 2337.45, 2224.64, 1696.55, 1607.39, 1485.47, 1461.44, 1346.00, 1300.19, 1267.57, 1248.38, 1210.44, 1168.25, 1138.54, 1101.43, 1080.71, 1031.23, 1008.21, 937.44, 911.74, 878.43, 851.29, 755.19, 729.57, 696.81. HRMS (ESI): m/z calculated for C₃₁H₂₁ON₅ + Na⁺: 502.1638, found: 502.1638. The ee was determined to be 90% by chiral HPLC analysis (Chiralcel AD-H, hexane/isopropanol 90/10, 0.7 mL min⁻¹, λ = 254 nm): t_R (minor) = 30.5 min, t_R (major) = 20.5 min. [α]²⁵_D = −152 (c = 1.0, acetone).

Acknowledgements

This work was supported by Department of Science & Technology, Government of India, New Delhi (Grant no. SR/S1/OC-60/2006). We thank Dr M. S. Moni and Dr C. Baby at Sophisticated Analytical Instrument Facility (SAIF), IIT Madras for NMR analysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 985882. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra13711f

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