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Synlett 2016; 27(03): 383-386
DOI: 10.1055/s-0035-1560963
letter
© Georg Thieme Verlag Stuttgart · New York

A One-Pot, Multicomponent Synthesis of 5′-Amino-2,2′-dioxospiro[indoline-3,3′-pyrrole]-4′-carbonitriles

Mehdi Adib*
a   School of Chemistry, College of Science, University of Tehran, P. O. Box 14155-6455 Tehran, Iran   Email: madib@khayam.ut.ac.ir
,
Zahra Yasaei
a   School of Chemistry, College of Science, University of Tehran, P. O. Box 14155-6455 Tehran, Iran   Email: madib@khayam.ut.ac.ir
,
Peiman Mirzaei
b   Department of Chemistry, Shahid Beheshti University, Tehran   Iran
› Author Affiliations
Further Information

Publication History

Received: 17 August 2015

Accepted after revision: 20 October 2015

Publication Date:
11 December 2015 (online)

 
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Abstract

A novel, one-pot, multicomponent synthesis of 5′-amino-2,2′-dioxospiro[indoline-3,3′-pyrrole]-4′-carbonitriles is described. The Knoevenagel condensation reaction between isatin derivatives and malononitrile gave the corresponding cyclic arylmethylidenemalononitriles that, on treatment with isocyanides, afforded 2,2′-dioxospiro-bis-γ-lactams in good to excellent yields.


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Key words

isatins - isocyanides - spiro compounds - lactams - multicomponent reactions

Spiro[indoline-3,3′-pyrrole] motifs are found in many natural products and biologically active synthetic compounds. For example, indole alkaloids strychnofoline, spirotryprostatin A, and spirotryprostatin B have been shown to possess antimitotic properties, so are of interest as anticancer drugs.[1] Rhynchophylline is a noncompetitive NMDA antagonist and calcium channel blocker,[2] and horsfiline presents analgesic effects.[3] Synthetic compound MI-219 is a potent, highly selective, and orally active inhibitor of the MDM2–p53 interaction, which has been studied as a new agent for cancer treatment (Figure [1]).[4] A prominent structural feature of all these natural and synthetic products is the presence of a spiro[indoline-3,3′-pyrrole] core. Thus, development of new approaches for the preparation of these spiro compounds have attracted a great deal of attention.[5] [6] [7] [8] [9] [10] [11]

Zoom Image
Figure 1 Examples of natural products and synthetic molecules with a spiro[indoline-3,3′-pyrrole] core structure

In a continuation of our studies on the development of efficient methods for the synthesis of biologically active heterocyclic compounds from readily accessible precursors,[12] we have recently described a one-pot and four-component synthesis of pyrrolo[1,2-a]quinoline-3-carbonitriles. The 2-arylmethylidenemalononitriles generated in situ from Knovenagel condensation reaction of malononitrile and aromatic aldehydes were treated with quinoline and cyclohexyl isocyanide under solvent-free conditions to afford the corresponding pyrrolo[1,2-a]quinolines.[13] We were prompted to investigate whether isatin derivatives could play the role of the carbonyl component in this multicomponent reaction, which would lead to a new skeleton. Thus, a mixture of isatin 1a and malononitrile 2 were condensed at 100 °C under solvent-free conditions to give cyclic arylmethylidenemalononitrile 3 within 10 minutes. Quinoline 4 and cyclohexyl isocynide 5a were then added to the mixture, which was stirred at 100 °C for a further 24 hours. TLC monitoring of the reaction mixture indicated formation of a new product (Table [1], entry 2), which was purified. Identification of its structure by NMR spectroscopy revealed that it was 5′-amino-1′-cyclohexyl-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (6a), obtained in 20% yield and not the expected spiro[pyrroloquinoline-2,3′-indoline] 7 (Scheme [1]). However, further investigations showed that the presence of quinoline in this reaction was crucial; omission of the base led to a very low yield of the product (entry 8). To improve the yield of 6a, the effects of different bases, reaction temperatures, reaction times and solvents were examined in this model reaction, for which the reaction conditions would be optimized. By varying the parameters, the highest yield was obtained with one equivalent of pyridine as base, EtOH–H2O (1:1) as the reaction medium, at 80 °C after 20 hours; under these conditions, 6a was obtained in 85% yield (entry 9).

Table 1 Optimization of the Reaction Conditions for Synthesis of 6a a

Entry

Solvent

Base

T (°C)

t (h)

Yield of 6a (%)b

 1

CH3CN

quinoline

reflux

24

trace

 2

none

quinoline

100

24

20

 3

CH2Cl2

quinoline

reflux

24

trace

 4

toluene

quinoline

60

24

trace

 5

toluene

quinoline

reflux

24

trace

 6

EtOH–H2O

quinoline

60

 6

70

 7

EtOH–H2O

quinoline

80

20

82

 8

EtOH–H2O

–

80

20

trace

 9

EtOH–H2O

pyridine

80

20

85

10

EtOH–H2O

DMAP

80

20

50

11

EtOH–H2O

isoquinoline

80

20

83

a Reaction conditions: isatin (1 mmol), malononitrile (1 mmol), cyclohexyl isocynide (1.1 mmol), base (1 mmol).

b Isolated yield.

Zoom Image
Scheme 1 Condensation of isatin and malononitrile followed by treatment with quinoline and cyclohexyl isocynide

After optimization of the reaction conditions, to explore the generality of the reaction, a series of 5′-amino-2,2′-dioxospiro[indoline-3,3′-pyrrole]-4′-carbonitriles 6 was prepared from isatins 1a–f and isocynides 5a and 5b (Figure [2]). Thus, a mixture of isatin 1, malononitrile 2, isocynide 5, and pyridine in EtOH–H2O (1:1) was stirred at 80 °C for 20 or 24 h to afford the corresponding spiro[indoline-3,3′-pyrrole] derivatives 6a–l. TLC and NMR spectroscopic analysis of the reaction mixtures clearly indicated the formation of 6 in good to excellent yields.[14] The results are summarized in Table [2].

Zoom Image
Figure 2 Starting materials for the multicomponent reaction

Table 2 Synthesis of 5′-Amino-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitriles 6a–l

Entry

R1

R2

R3

6

t (h)

Yield of 6 (%)a

 1

H

H

Cy

6a

20

85

 2

Me

H

Cy

6b

20

95

 3

Et

H

Cy

6c

20

85

 4

Bn

H

Cy

6d

20

85

 5

i-Pr

H

Cy

6e

20

89

 6

H

NO2

Cy

6f

24

85

 7

H

H

t-Bu

6g

24

90

 8

Me

H

t-Bu

6h

24

85

 9

Et

H

t-Bu

6i

24

72

10

Bn

H

t-Bu

6j

24

82

11

i-Pr

H

t-Bu

6k

24

70

12

H

NO2

t-Bu

6l

24

87

a Isolated yield.

The structures of the isolated products were deduced on the basis of IR, 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis. The IR spectrum of 6e showed the stretching bands for N−H bonds at 3343, 3265, and 3191, nitrile bond at 2187, and C=O bonds at 1739 and 1667 cm–1. The mass spectrum of 6e displayed the molecular ion [M+] peak at m/z 364, which was consistent with the 1:1:1 adduct of N-isopropylisatin (1e), malononitrile (2), and cyclohexyl isocynide (5a). Fragment ions such as 321 [M+ – C3H7], 282 [M+ – C6H10], 239 [M+ – (C6H11 + C3H6), M+ – (C6H10 + C3H7), or M+ – (NH2C=NCy)], 212 [M+ – (NHC=NCyCO)], 197 [M+ – (CyN=C=O + C3H6) or M+ – (Me2CHN=C=O + C6H12)] were consistent with the structure of 6e. The 1H NMR spectrum of 6e exhibited characteristic multiplets at δ = 1.02–2.10 and 3.78–3.90 ppm for the cyclohexyl moiety along with a doublet at δ = 1.39 ppm and a septet at δ = 4.49 ppm (J = 6.9 Hz) for the isopropyl group. Characteristic signals were seen at δ = 7.02–7.35 ppm for the four protons of the phenylene moiety of the oxindole ring, as well as a fairly sharp singlet at δ = 7.79 ppm for the NH2 group. The 1H-decoupled 13C NMR spectrum of 6e showed characteristic signals at δ = 19.4, 19.5, 25.0, 25.7, 29.0, 29.2, 44.6, and 53.0 ppm for the cyclohexyl and isopropyl substituents. Distinguishing signals were observed at δ = 53.6 ppm for the spiro-carbon atom, δ = 117.9 ppm for the nitrile group, and δ = 171.9 and 172.1 ppm due to the two amide carbonyls of the two fused rings. Two other carbon atoms of the pyrroline ring appeared as a shielded signal at δ = 61.6 ppm and a deshielded signal at δ = 160.4 ppm (due to the C=CN2 carbon atoms, respectively), as well as six other distinct resonances (4 × CH and 2 × C) arising from the phenylene moiety of the oxindole ring, in agreement with the proposed structure.[14]

Zoom Image
Scheme 2 Proposed mechanism for the formation of 5′-amino-2,2′-dioxospiro[indoline-3,3′-pyrrole]-4′-carbonitriles 6

A reasonable mechanistic rationalization for the formation of the spiro-bis-γ-lactams is provided in Scheme [2]. First, Knoevenagel reaction of isatin 1 and malononitrile 2 gives the condensation product 3. Next, the α,β-unsaturated system may undergo nucleophilic addition of the isocyanide 5 followed by protonation to form the positively charged isonitrilium intermediate 8. The isonitrilium moiety may undergo hydrolysis to produce amide intermediate 9. One of the nitrile groups of 9 can then undergo nucleophilic addition of the adjacent amide functionality, which is facilitated by the added base, to give the imino amide intermediate 10. This imino amide can then tautomerize under the reaction conditions to afford 5′-amino-2,2′-dioxo-spiro[indoline-3,3′-pyrrole]-4′-carbonitriles 6.

In conclusion, we have developed a novel, one-pot and multicomponent approach for the preparation of spiro[indoline-3,3′-pyrrole] derivatives. To our knowledge, this is the first report of the synthesis of 2,2′-dioxospiro[indoline-3,3′-pyrrole] derivatives with the two carbonyl functions located next to the spiro-carbon atom.[15] The mild conditions and good to excellent yields of the products are the main advantages of this reaction. In view of the general biological activities of oxindoles and 2-pyrrolinones, combination of these structures in a single entity might lead to enhanced properties.


#

Acknowledgment

This research was supported by the Research Council of the University of Tehran.

  • References and Notes

  • 4 Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah RB, Pienta KJ, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 3933
    CrossrefSearch in Google Scholar
  • 6 Edmondson S, Danishefsky SJ, Sepp-Lorenzino S, Rosen N. J. Am. Chem. Soc. 1999; 121: 2147
    CrossrefSearch in Google Scholar
  • 8 Zhang H, Ma X, Kang H, Hong L, Wang R. Chem. Asian J. 2013; 8: 542
    CrossrefSearch in Google Scholar
  • 13 Adib M, Azimzadeh M, Rahimi-Nasrabadi M, Zhu LG. J. Chem. Res. 2014; 38: 423
    Search in Google Scholar
  • 14 Preparation of Spiro[indoline-3,3′-pyrrole] Derivatives 6a–l; Typical Procedure for 6a: A mixture of isatin (1 mmol) and malononitrile (1 mmol) in H2O–EtOH (1:1, 4 mL) was stirred at 80 °C for 10 min. Cyclohexyl isocyanide (1.1 mmol) and pyridine (1 mmol) were added to the mixture, which was then stirred at 80 °C for 20 h. Upon completion of the reaction, as indicated by TLC, the mixture was cooled to room temperature, brine (5 mL) was added, and the mixture was stirred for 5 min. The product was extracted into EtOAc (3 × 5 mL), followed by drying over Na2SO4. After filtration, the solvent was removed under the reduced pressure and the residue was crystallized from EtOAc–n-hexane (1:1) to afford 6a as colorless crystals. Compounds 6e and 6k were purified accordingly. Other p­roducts were purified by column chromatography (EtOAc–n-hexane, 1:4). 5′-Amino-1′-cyclohexyl-1-ethyl-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (6c): Yield: 0.298 g (85%); white crystals; mp 200–202 °C. IR (KBr): 3335, 3297 and 3185 (NH), 2191 (CN), 1735 and 1664 (C=O), 1600, 1453, 1353, 1089, 999, 941, 832, 750, 680, 626 cm–1. 1H NMR (300.1 MHz, DMSO-d 6): δ = 1.05–2.10 [t, J = 7.1 Hz, 3 H, CH3; m, 10 H, CH(CH 2)5], 3.20–3.90 [q, J = 7.1 Hz, 2 H, CH2; m, 1 H, CH(CH2)5], 7.05–7.20 (m, 3 H, 3 × CH), 7.36 (t, J = 7.1 Hz, 1 H, CH), 7.80–7.89 (br. s, 2 H, NH2). 13C NMR (75.5 MHz, DMSO-d 6): δ = 13.0 (CH3), 25.0 (CH2), 25.6 (2 × CH2), 28.9 and 29.1 (2 × CH2), 35.1 (CH2), 53.0 [CH(CH2)5], 53.3 (C−C=O), 61.6 (N2C=C), 109.8 (CH), 117.9 (CN), 123.3 and 123.9 (2 × CH), 127.5 (C), 130.0 (CH), 143.9 (C−N), 160.4 (N2 C=C), 171.8 and 172.0 (2 × C=O). MS: m/z (%) = 350 (42) [M+], 281 (48), 268 (100), 239 (42), 225 (34), 212 (20), 198 (44), 183 (39), 160 (33), 128 (19), 97 (18), 83 (28), 69 (34), 55 (80), 41 (80). Anal. Calcd for C20H22N4O2 (350.41): C, 68.55; H, 6.33; N, 15.99. Found: C, 68.49; H, 6.37; N, 15.86. 5′-Amino-1′-cyclohexyl-1-isopropyl-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (6e): Yield: 0.324 g (89%); white crystals; mp 196 °C. IR (KBr): 3343, 3265 and 3191 (NH), 2187 (CN), 1739 and 1667 (C=O), 1598, 1450, 1306, 1230, 1171, 1092, 1001, 937, 808, 743, 677 cm–1. 1H NMR (300.1 MHz, DMSO-d 6): δ = 1.02–2.10 [d (1.39), J = 6.9 Hz, 6 H, C(CH3)2; m, 10 H, CH(CH 2)5], 3.78–3.90 [m, 1 H, CH(CH2)5], 4.49 (sept, J = 6.9 Hz, 1 H, CH), 7.02–7.13 (m, 2 H, 2 × CH), 7.25 (d, J = 6.9 Hz, 1 H, CH), 7.35 (t, J = 6.9 Hz, 1 H, CH), 7.79 (s, 2 H, NH2). 13C NMR (75.5 MHz, DMSO-d 6): δ = 19.4 and 19.5 [C(CH3)2], 25.0 (CH2), 25.7 (2 × CH2), 29.0 and 29.2 (2 × CH2), 44.6 [C(CH3)2], 53.0 [CH(CH2)5], 53.6 (C−C=O), 61.6 (N2C=C), 110.9 (CH), 117.9 (CN), 123.0 and 124.1 (2 × CH), 127.8 (C), 129.9 (CH), 143.7 (C−N), 160.4 (N2 C=C), 171.9 and 172.1 (2 × C=O). MS: m/z (%) = 364 (33) [M+], 321 (15), 282 (100), 239 (47), 212 (41), 197 (30), 170 (35), 143 (19), 128 (14), 116 (19), 105 (22), 81 (19), 67 (27), 55 (47), 41 (52). Anal. Calcd for C21H24N4O2 (364.44): C, 69.21; H, 6.64; N, 15.37. Found: C, 69.18; H, 6.71; N, 15.30.
  • 15 To our knowledge, there are two reports concerning the synthesis of 2-oxo-2′-thioxospiro[indoline-3,3′-pyrrole] derivatives with carbonyl and thiocarbonyl functions located next to the spiro-carbon atom; see ref. 11.

  • References and Notes

  • 4 Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah RB, Pienta KJ, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 3933
    CrossrefSearch in Google Scholar
  • 6 Edmondson S, Danishefsky SJ, Sepp-Lorenzino S, Rosen N. J. Am. Chem. Soc. 1999; 121: 2147
    CrossrefSearch in Google Scholar
  • 8 Zhang H, Ma X, Kang H, Hong L, Wang R. Chem. Asian J. 2013; 8: 542
    CrossrefSearch in Google Scholar
  • 13 Adib M, Azimzadeh M, Rahimi-Nasrabadi M, Zhu LG. J. Chem. Res. 2014; 38: 423
    Search in Google Scholar
  • 14 Preparation of Spiro[indoline-3,3′-pyrrole] Derivatives 6a–l; Typical Procedure for 6a: A mixture of isatin (1 mmol) and malononitrile (1 mmol) in H2O–EtOH (1:1, 4 mL) was stirred at 80 °C for 10 min. Cyclohexyl isocyanide (1.1 mmol) and pyridine (1 mmol) were added to the mixture, which was then stirred at 80 °C for 20 h. Upon completion of the reaction, as indicated by TLC, the mixture was cooled to room temperature, brine (5 mL) was added, and the mixture was stirred for 5 min. The product was extracted into EtOAc (3 × 5 mL), followed by drying over Na2SO4. After filtration, the solvent was removed under the reduced pressure and the residue was crystallized from EtOAc–n-hexane (1:1) to afford 6a as colorless crystals. Compounds 6e and 6k were purified accordingly. Other p­roducts were purified by column chromatography (EtOAc–n-hexane, 1:4). 5′-Amino-1′-cyclohexyl-1-ethyl-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (6c): Yield: 0.298 g (85%); white crystals; mp 200–202 °C. IR (KBr): 3335, 3297 and 3185 (NH), 2191 (CN), 1735 and 1664 (C=O), 1600, 1453, 1353, 1089, 999, 941, 832, 750, 680, 626 cm–1. 1H NMR (300.1 MHz, DMSO-d 6): δ = 1.05–2.10 [t, J = 7.1 Hz, 3 H, CH3; m, 10 H, CH(CH 2)5], 3.20–3.90 [q, J = 7.1 Hz, 2 H, CH2; m, 1 H, CH(CH2)5], 7.05–7.20 (m, 3 H, 3 × CH), 7.36 (t, J = 7.1 Hz, 1 H, CH), 7.80–7.89 (br. s, 2 H, NH2). 13C NMR (75.5 MHz, DMSO-d 6): δ = 13.0 (CH3), 25.0 (CH2), 25.6 (2 × CH2), 28.9 and 29.1 (2 × CH2), 35.1 (CH2), 53.0 [CH(CH2)5], 53.3 (C−C=O), 61.6 (N2C=C), 109.8 (CH), 117.9 (CN), 123.3 and 123.9 (2 × CH), 127.5 (C), 130.0 (CH), 143.9 (C−N), 160.4 (N2 C=C), 171.8 and 172.0 (2 × C=O). MS: m/z (%) = 350 (42) [M+], 281 (48), 268 (100), 239 (42), 225 (34), 212 (20), 198 (44), 183 (39), 160 (33), 128 (19), 97 (18), 83 (28), 69 (34), 55 (80), 41 (80). Anal. Calcd for C20H22N4O2 (350.41): C, 68.55; H, 6.33; N, 15.99. Found: C, 68.49; H, 6.37; N, 15.86. 5′-Amino-1′-cyclohexyl-1-isopropyl-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (6e): Yield: 0.324 g (89%); white crystals; mp 196 °C. IR (KBr): 3343, 3265 and 3191 (NH), 2187 (CN), 1739 and 1667 (C=O), 1598, 1450, 1306, 1230, 1171, 1092, 1001, 937, 808, 743, 677 cm–1. 1H NMR (300.1 MHz, DMSO-d 6): δ = 1.02–2.10 [d (1.39), J = 6.9 Hz, 6 H, C(CH3)2; m, 10 H, CH(CH 2)5], 3.78–3.90 [m, 1 H, CH(CH2)5], 4.49 (sept, J = 6.9 Hz, 1 H, CH), 7.02–7.13 (m, 2 H, 2 × CH), 7.25 (d, J = 6.9 Hz, 1 H, CH), 7.35 (t, J = 6.9 Hz, 1 H, CH), 7.79 (s, 2 H, NH2). 13C NMR (75.5 MHz, DMSO-d 6): δ = 19.4 and 19.5 [C(CH3)2], 25.0 (CH2), 25.7 (2 × CH2), 29.0 and 29.2 (2 × CH2), 44.6 [C(CH3)2], 53.0 [CH(CH2)5], 53.6 (C−C=O), 61.6 (N2C=C), 110.9 (CH), 117.9 (CN), 123.0 and 124.1 (2 × CH), 127.8 (C), 129.9 (CH), 143.7 (C−N), 160.4 (N2 C=C), 171.9 and 172.1 (2 × C=O). MS: m/z (%) = 364 (33) [M+], 321 (15), 282 (100), 239 (47), 212 (41), 197 (30), 170 (35), 143 (19), 128 (14), 116 (19), 105 (22), 81 (19), 67 (27), 55 (47), 41 (52). Anal. Calcd for C21H24N4O2 (364.44): C, 69.21; H, 6.64; N, 15.37. Found: C, 69.18; H, 6.71; N, 15.30.
  • 15 To our knowledge, there are two reports concerning the synthesis of 2-oxo-2′-thioxospiro[indoline-3,3′-pyrrole] derivatives with carbonyl and thiocarbonyl functions located next to the spiro-carbon atom; see ref. 11.

   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Examples of natural products and synthetic molecules with a spiro[indoline-3,3′-pyrrole] core structure
Zoom Image
Scheme 1 Condensation of isatin and malononitrile followed by treatment with quinoline and cyclohexyl isocynide
Zoom Image
Figure 2 Starting materials for the multicomponent reaction
Zoom Image
Scheme 2 Proposed mechanism for the formation of 5′-amino-2,2′-dioxospiro[indoline-3,3′-pyrrole]-4′-carbonitriles 6