Molecular diversity of the cyclization reaction of 3-methyleneoxindoles with 2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitriles

Abstract

The cyclization reaction of 3-methyleneoxindoles with 2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitrile in ethanol in the presence of DBU at room temperature afforded functionalized 3′-iminospiro[indoline-3,2′-phenanthrenes] in good yields. However, the similar reaction of ethyl 2-cyano-2-(3,4-dihydronaphthalen-1(2H)-ylidene)acetate resulted in functionalized 3-oxospiro[indoline-3,2′-phenanthrenes] and benzo[d]phenanthro[2,3-f][1,3]diazepines depending on the structures of substrates. Furthermore, the cycloaddition reaction of 3-phenacylideneoxindole with ethyl 2-cyano-2-(3,4-dihydronaphthalen-1(2H)-ylidene)acetate produced the spiro[indoline-3,2′-phenanthrene]-4′-carbonitrile derivatives. The stereochemistry of the cyclic spirooxindoles was clearly elucidated by ¹H NMR data and fourteen single crystal structures.

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Introduction

α,α-Dicyanoalkenes are one kind of valuable synthetic block.¹ The electron-deficient α,α-dicyanoalkenes not only behave as good hydride acceptors in conjugate reduction reactions, but also act as versatile direct vinylogous donors in Michael addition reactions with excellent chemo- and stereo-selectivity.^2,3 Because the γ-C–H of α,α-dicyanoalkenes could be easily deuterated in the presence of organic bases, they can act as versatile direct vinylogous donors in Michael addition reactions and behave as good hydride acceptors in conjugate reduction reactions.^4–6 In recent years, much attention has been paid to the various synthetic protocols of the direct vinylogous Michael addition of α,α-dicyanoalkenes to different electrophilic reagents providing γ-carbon-functionalized exocyclic or acyclic activated alkenes.^7–12 Very recently, we found that the domino reactions of 3-phenacylideneoxindoles with various vinyl malononitriles provided a convenient synthetic protocol for a series of the functionalized spiro[indoline-3,2′-naphthalene], spiro[benzo[7]annulene-2,3′-indoline], and spiro[indoline-3,7′-isoquinoline] derivatives.¹³ In order to develop the synthetic value of this methodology and provide more efficient synthetic reactions for various spirooxindoles,^14,15 we systematically investigated the base promoted sequential cyclization reaction of 3-methyleneoxindoles with 2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitrile and its derivatives, which was generated from the condensation of 1-tetralone with malononitrile or ethyl cyanoacetate. Herein, we wish to report the convenient synthesis of several kinds of functionalized spiro[indoline-3,2′-phenanthrenes] depending to the molecular structure of the substrates and reaction conditions.

Results and discussion

According to the previously established reaction conditions of the cycloaddition reaction of vinyl malononitrile with 3-methyleneoxindole,¹³ a mixture of 3-phenacylideneoxindole and 2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitrile in ethanol in the presences of DBU as base promoter was carried out. The cycloaddition reactions proceeded smoothly at room temperature to give the cyclic spirooxindoles 1a–1h in good yields (Table 1). ¹H NMR spectra clearly indicated a mixture of cis/trans-isomers with nearly 1 : 1 ratio was obtained in all cases. It is also interesting to find that one imino group exists in the molecule, which did not transfer to amino group through enamine-imine tautomerization as that in the similar cyclic spirooxindoles.¹³ In order to determine the configuration of the product, the single crystal structures of the cis-isomer of the compounds 1b, 1c, 1d, 1e, 1f (Fig. 1), 1j and trans-isomer of compound 1h (Fig. 2) were successfully determined by X-ray diffraction method. From the Fig. 1, it can be seen that the benzoyl group, the phenyl group of the oxindole moiety and the bridging hydrogen atom exists on the cis-positions in the newly-formed cyclohexyl ring in the cis-isomer. On the contrary, the benzoyl group exist in trans-configuration to the two neighboring bulky groups in the trans-isomer.

Table 1 Synthesis of 3′-iminospiro[indoline-3,2′-phenanthrenes] 1a–1h^a

Entry	Comp	R	R′	Ar	Yield^b (%, ratio of cis/trans-isomer)
a Reaction condition: 3-phenacylidieneoxindole (1.0 mmol), vinyl malononitrile (1.0 mmol), DBU (0.1 mmol) in EtOH (10.0 mL), rt, 6 h.b Isolated yield. The ratio of cis/trans isomers was determined by ^1H NMR spectra.
1	1a	H	H	p-CH3C6H4	76 (1 : 1)
2	1b	H	Bn	p-CH3OC6H4	80 (1 : 1)
3	1c	CH3	Bn	C6H5	76 (1 : 1)
4	1d	CH3	Bn	p-ClC6H4	72 (1 : 1)
5	1e	F	Bn	p-CH3C6H4	85 (1 : 1)
6	1f	Cl	H	p-CH3C6H4	73 (1 : 1)
7	1g	Cl	H	p-CH3OC6H4	78 (1 : 1)
8	1h	Cl	Bn	p-CH3C6H4	79 (1 : 1)
9	1i	Cl	n-Bu	p-CH3OC6H4	66 (1 : 1)
10	1j	CH3	n-Bu	p-ClC6H4	76 (11 : 9)

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Fig. 1 Molecular structure of compound 1f (cis-isomer).

Fig. 2 Molecular structure of compound 1h (trans-isomer).

In order to develop the scope of this reaction, another common used 3-methyleneoxindole, ethyl 2-(2-oxoindolin-3-ylidene)acetates, were also utilized to react with vinyl malononitrile under similar reaction conditions. The results are summarized in Table 2. It is interesting to find that ethyl 2-(2-oxoindolin-3-ylidene)acetates with N-benzyl, and N-butyl group resulted in the expected 3′-iminospiro[indoline-3,2′-phenanthrenes] 2a–2d in good yields, in which a mixture of cis/trans-isomers with a ratio of 1 : 1 to 1 : 2.2 exists in the obtained samples. The cis-isomer of spiro compounds 2b, 2c and trans-isomer of spiro compound 2c were also determined by the X-ray diffraction method. From the Fig. 3 it can be seen that the phenyl group of oxindole moiety, ethoxycarbonyl group and bridge-head hydrogen atom exist in the cis-configuration. When ethyl 2-(2-oxoindolin-3-ylidene)acetates with free NH group was employed in the reaction, the unexpected densely substituted benzo[d]phenanthro[2,3-f][1,3]diazepine-15-carboxylates 3a–3d were produced as main products. Their structures were established on the spectroscopy and single crystal structure of compound 3a (Fig. 3). This fact reflects the different reactivity of the oxindoles with N-groups to oxindoles with free NH groups. A literature survey indicated that indolinone derivatives without N-substituents occasionally underwent ring-expansion process to give other nitrogen-containing benzo-fused heterocycles in basic medium.¹⁶

Table 2 Synthesis of 3′-iminospiro[indoline-3,2′-phenanthrenes] 2a–2d and benzo[d]phenanthro[2,3-f][1,3]diazepine 3a–3d^a

Entry	Comp	R	R′	Yield^b (%)
a Reaction condition: ethyl 2-(2-oxoindolin-3-ylidene)acetate (1.0 mmol), vinyl malononitrile (1.0 mmol), DBU (0.1 mmol) in EtOH (10.0 mL), rt, 6 h.b Isolated yield. The ratio of cis/trans isomers was determined by ^1H NMR.
1	2a	H	Bn	66
2	2b	CH3	Bn	59 (1.6 : 1)
3	2c	Cl	Bn	51 (2.2 : 1)
4	2d	F	n-Bu	72 (1 : 1)
5	3a	Cl	H	65
6	3b	CH3	H	66
7	3c	F	H	63
8	3d	H	H	64

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Fig. 3 Molecular structure of compound 3a.

To further highlight the applicability of this reaction, the cycloaddition reaction of 3-phenacylideneoxindole with ethyl 2-cyano-2-(3,4-dihydronaphthalen-1(2H)-ylidene)acetate was also investigated. The obtained interesting results are summarized in Table 3. Firstly, the cyano group is retained in the obtained spiro[indoline-3,2′-phenanthrenes] 4a–4h, while the ethoxycarbonyl group take part in the cyclization process to give the products 4a–4h with a carbonyl group. Secondly, ¹H NMR spectra clearly indicated only one diastereoisomer existed in the obtained spiro[indoline-3,2′-phenanthrenes] 4a–4h. Molecular structure of single crystals 4d and 4h have been determined by X-ray diffraction method, in which the benzoyl group and phenyl group of oxindole moiety exist in trans-position (Fig. 4). Thus, we tentatively suggested that only trans-isomer predominately existed in the obtained spiro[indoline-3,2′-phenanthrenes] 4a–4h.

Table 3 Synthesis of spiro[indoline-3,2′-phenanthrenes] 4a–4h^a

Entry	Comp	R	R′	Ar	Yield^b (%)
a Reaction condition: 3-phenacylidieneoxindole (1.0 mmol), vinyl cyanoacetate (1.0 mmol), DBU (0.1 mmol) in EtOH (10.0 mL), rt, 6 h.b Isolated yield. The ratio of cis/trans isomers was determined by ^1H NMR.
1	4a	H	Bn	p-ClC6H4	70
2	4b	CH3	H	C6H5	63
3	4c	CH3	n-Bu	p-ClC6H4	77
4	4d	F	H	p-CH3C6H4	62
5	4e	F	n-Bu	C6H5	79
6	4f	Cl	H	p-CH3C6H4	70
7	4g	Cl	n-Bu	p-CH3OC6H4	76
8	4h	Cl	Bn	p-CH3C6H4	81

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Fig. 4 Molecular structure of compound 4h (trans-isomer).

In order to explain the formation of the different kinds of polysubstituted spiro[indoline-3,2′-phenanthrenes], a plausible reaction mechanism is rationally proposed on the basis of the previously reported cyclization reactions of vinyl malononitrile (Scheme 1).^7–13 At first, the active γ-C–H of vinyl malononitrile was deuterated by DBU to give a carbanion intermediate (A). Secondly, the carbanion (A) attacked the exocyclic carbon atom of the 3-methyleneoxindole to give a new adduct intermediate (B). In the case of existing two cyano groups, the intramolecular addition of carbanion (B) to one cyano group resulted in a cyclized imino intermediate (C), which in turn attracted one proton from the conjugated Lewis acid to afford the obtained products 1 and 2. If there is no N-substituted group in the oxindole moiety, the product 2 was unstable and converted to the benzo-fused diazepine 3 through a ring rearrangement of the oxindole moiety. A literature survey indicated that indolinone derivatives without N-substituents occasionally underwent ring-expansion process in basic medium to give other nitrogen-containing benzo-fused heterocycles.¹⁶ Here, a similar ring-expansion of spirooxindole 2 to benzo-fused diazepine 3 was observed. On the other hand, if there is one ester group in the intermediate (B), the nucleophilic addition of carbanion (B) to carbonyl group of the est moiety afforded the cyclic intermediate (D). Then, the departure of ethoxide ion from the cyclic intermediate (D) resulted in spirocyclic oxindole 4 as the final product. Depending on the reaction conditions and structures of the substrates, the sequential cyclization reaction stopped at the different stages to give the different kinds of the products. When reactions of ethyl 2-(2-oxoindolin-3-ylidene)acetate with 2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitrile were carried out in ethanol in the presence of less weak base piperidine at room temperature, the protonated intermediates (B1–B3) can be successfully separated out in about 37%, 44% and 50% yields, respectively. The single crystal structure of the compound B3 was determined by X-ray determination (Fig. 5). This result provided an important support to the above proposed reaction mechanism.

Scheme 1 The proposed reaction mechanism for cyclization reaction.

Fig. 5 Molecular structure of one protonated intermediate (B3).

In conclusion, we have systematically examined the base promoted sequential cyclization reaction of 3-methyleneoxindoles with 2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitrile and its ester derivatives. This reaction resulted in several kinds of functionalized spiro[indoline-3,2′-phenanthrene] and benzo[d]phenanthro[2,3-f][1,3]diazepine derivatives depending to the molecular structure of the substrates and reaction conditions. Totally, fourteen single crystal structures were successfully determined by X-ray diffraction method. The reaction mechanism is also rationally proposed on the basis of capture of the reaction intermediate and the stereochemistry of the reaction was clearly elucidated. This reaction will become an efficient protocol for the synthesis of novel functionalized spirocyclic oxindoles and the potential uses of the reaction in synthetic and medicinal chemistry may be significant.

Experimental section

1. Typical procedure for the synthesis of spirocyclic oxindoles 1a–1h

A mixture of vinyl malononitrile (1.0 mmol) and 3-methyleneoxindole (1.0 mmol) and DBU (0.1 mmol) in ethanol (10.0 mL) was stirred at room temperature for about six hours. The resulting precipitate was collected by filtration and washed with cold alcohol to give the pure product for analysis. In few cases, the crude product was subjected to chromatography with a mixture of light petroleum and ethyl acetate to give the product for analysis.

3′-Imino-1′-(4-methylbenzoyl)-2-oxo-3′,9′,10′,10a′-tetrahydro-1′H-spiro[indoline-3,2′-phenanthrene]-4′-carbonitrile (1a). White solid, 76%, mp 221–223 °C; ¹H NMR (600 MHz, DMSO-d₆) δ cis-isomer: 10.67 (brs, 1H, NH), 10.17 (s, 1H, NH), 8.34 (d, J = 7.8 Hz, 1H, ArH), 7.92–7.88 (m, 2H, ArH), 7.58–7.53 (m, 1H, ArH), 7.45–7.42 (m, 1H, ArH), 7.34–7.31 (m, 3H, ArH), 7.22 (t, J = 7.8 Hz, 1H, ArH), 7.01–6.98 (m, 1H, ArH), 6.96–6.93 (m, 1H, ArH), 6.82 (d, J = 7.8 Hz, 1H, ArH), 4.63 (d, J = 10.2 Hz, 1H, CH), 3.43–3.41 (m, 1H, CH), 2.97–2.89 (m, 2H, CH), 2.38 (s, 3H, CH₃), 2.06–1.99 (m, 1H, CH), 1.76–1.70 (m, 1H, CH); trans-isomer: 10.43 (s, 1H, NH), 10.06 (s, 1H, NH), 8.28 (d, J = 7.8 Hz, 1H, ArH), 7.19 (t, J = 7.8 Hz, 1H, ArH), 6.91–6.88 (m, 1H, ArH), 6.79 (d, J = 7.8 Hz, 1H, ArH), 4.71 (d, J = 10.2 Hz, 1H, CH), 3.34–3.32 (m, 1H, CH). Ratio of cis/trans isomers = 1 : 1. ¹³C NMR (100 MHz, DMSO-d₆) δ: 197.9, 197.1, 175.3, 174.6, 167.0, 163.6, 163.3, 145.1, 145.0, 142.5, 142.3, 141.4, 140.7, 135.2, 135.0, 133.3, 132.8, 130.8, 130.7, 129.9, 129.8, 129.6, 129.5, 129.2, 129.1, 129.0, 128.9, 127.4, 126.8, 126.6, 124.3, 122.3, 121.9, 117.2, 116.4, 110.8, 110.4, 108.0, 104.9, 59.6, 58.2, 56.5, 49.0, 48.5, 38.7, 29.4, 29.1, 28.2, 21.6, 19.0; IR (KBr) ν: 3241, 2925, 2208, 1736, 1671, 1604, 1470, 1448, 1405, 1379, 1356, 1329, 1301, 1268, 1228, 1203, 1180, 1120, 1093, 1060, 1046, 997, 958, 931, 887, 818, 781, 754 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₀H₂₃N₃NaO₂ ([M + Na]⁺): 480.1682. Found: 480.1675.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21272200) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra for all compounds. Crystallographic data 1b (CCDC 973205), 1c (CCDC 973206), 1d (CCDC 973207), 1e (CCDC 973208), 1f (CCDC 1437649), 1h (CCDC 973209), 1j (CCDC 1437650), 2b (CCDC 1437651), 2c-cis-isomer (CCDC 1437652), 2c-trans-isomer (CCDC 1437653), 3a (CCDC 1437654), 4d (CCDC 1437655) 4h (CCDC 1437656), and B3 (CCDC 1437658) have been deposited at the Cambridge Crystallographic Database Centre. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra00476h

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