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Facile and Convenient One-Pot Process for the Synthesis of Spirooxindole Derivatives in High Optical Purity Using (−)-(S)-Brevicolline as an Organocatalyst

Academy Street 3, Institute of Chemistry, Academy of Science of Moldova, MD-2028 Chisinau, Moldova
Author to whom correspondence should be addressed.
Symmetry 2011, 3(2), 165-170;
Received: 10 March 2011 / Revised: 11 April 2011 / Accepted: 12 April 2011 / Published: 20 April 2011
(This article belongs to the Special Issue Asymmetric Organocatalysis)


The paper presents an application of the asymmetry approach to spirooxindoles via Brevicolline, Cinchonidine or Cinchonine catalyzed one-pot multicomponent synthesis. Brevicolline, in comparison with Cinchonidine or Cinchonine, catalyzes the reaction of isatins, acetylacetone/ethyl 3-oxobutanoate and malononitrile, with the formation of spiro[oxindole-3,4′-4′H-pirane] derivatives in an optically active form in very good to excellent yields.

Graphical Abstract

1. Introduction

Asymmetric catalysis with the participation of organic compounds is one of the most rapidly developing areas of modern chemistry [1,2,3,4,5]. A special position among these catalysts is occupied by alkaloids, with the vast majority of research, until recently, being focused on the discovery of new properties of the well-studied cinchona alkaloids and related compounds [6,7,8,9,10,11]. The cupreine-catalyzed synthesis of optically active spiro[pyran-oxindoles] as promising candidates for chemical biology and drug discovery has been reported recently [12]. This important trend towards obtaining single-enantiomer drugs has brought the asymmetric synthesis to the forefront. Nowadays it has become an important subject in drug discovery and development [13].

2. Results and Discussion

In this paper we report an application of the alkaloids Cinchonidine 1a, Cinchonine 1b and Brevicolline 1c (see Figure 1) as new catalysts to a known synthesis of spiro[oxindole-3,4′-4′H-pyrane] derivatives 5a,b,c [12].
Our initial studies were performed only on catalysts Cinchonidine 1a and Cinchonine 1b because related C6′-OH cinchona alkaloids were used by Wei-Cheng Yuan et al. [12] for organocatalytic studies in the reaction of N-substituted isatines, acetylacetone and malononitrile.
The presence of water in the reaction media (after forming isatylidene malononitrile) at room temperature had a negative effect on the enantioselectivity for the spirane 5a (see Scheme 1). Finally, the reaction of N-Bn isatine 2a carried out in dichloromethane (DCM) as a solvent using 10 mol% of 1a as catalyst at room temperature (rt) gave a spirane 5a with 85% yield, but low enantioselectivity (2% ee).
When the temperature was decreased to 0 °C in the presence of the freshly activated 4 Å MS, the spirane 5a was obtained with 80% yield and 23% ee (Table 1, entry 1). However, the use of 1b as a catalyst at rt gave the results practically similar to those as with the use of 1a. The % ee’s was also confirmed by HPLC using Chiralpak IA column. (Table 1, entry 2).
We envisioned that Brevicolline 1c (see Figure 1) could be also useful for such catalytic processes. (S)-Brevicolline possessing the core of (S)-nicotine structure was isolated by us from the plant Carex brevicollis DC (Cyperacee). 1H NMR, and IR data of our alkaloid match exactly with those reported earlier for 1c [14,15,16]. The melting point and optical rotation, however, differ slightly from literature data. A higher melting point (232–233 °C instead of 223–224 °C) and an increased [α]20D (−154.16 instead of −145.8) indicate higher purity. The 100% ee measurement was confirmed by HPLC [17].
When we were working with Brevicolline 1c at 0 °C in DCM, the reaction time for 5a increased and the yield was lower (50%), however the enantioselectivities were slightly higher than those obtained using 1a, b (Table 1, compare entries 1, 2 and 3).
When we increased the molar ratio up to 50 mol% of catalysts 1ac, but kept the amount of 4 Å MS as well as temperature 0 °C constant, only a small change in % ee towards an increase was observed. Therefore, the rest of the investigation was carried out with 10 mol% of catalysts 1ac.
Further, we studied the influence of the ethyl acetoacetate as nucleophilic component on the selectivity of the reaction N-Bn isatine 2a with malononitrile.
In all the tested cases the product 5b was obtained with very good to excellent yields (Table 1, entries 4, 5 and 6). Slightly higher enantioselectivity has been observed in the reaction between N-Bn isatine, ethyl acetoacetate, and malononitrile using 1c as a catalyst than in the reaction with catalysts 1a, b.
The effect of the unprotected isatine 2b in the enantiochemical outcome of the reaction was studied. Entries 7–9 in Table show the addition of malononitrile together with acetylacetone to isatine 2b in the presence of Cinchonidine, Cinchonine or Brevicolline, respectively.
In the cases of Cinchonidine and Cinchonine, good conversions (up to 67%), but low enantioselectivities were obtained.
The highest enantiomeric excess (based on the specific rotation [α]20D = +46.8 compared with [α]20D = +21.0; ee = 78% [12]) was obtained for product 5c when Brevicolline 1c was used as catalyst. The 94% ee measurement was confirmed by HPLC using Chiralpak IA.
At this point, the distinguishing features of the active species inducing chirality are not understood. However, we believe that the induced chirality is due to the intermolecular cycloaddition involving hydrogen-bonding interactions of the CN group with chiral N-methylpyrrolidinyl core as well as keto-enol tautomerism equilibrium via the interaction with the NH group [18]. This creates a chiral pocket which influences the selectivity of β-dicarbonyl group transfer from acetylacetone/ethyl 3-oxobutanoate to isatylidene malononitrile derivatives. Tracer experiments to clarify the mechanisms and further studies on the reactivity of Brevicolline as organocatalyst are in progress.
We have also observed that all catalysts 1ac can be recovered during the isolation of products 5ac.

3. Experimental

3.1. General Data

Solvents and commercially available reagents were purchased from Aldrich (Germany), Across (Belgium) and Lancaster (Great Britain). Brevicolline was extracted from Carex brevicollis and purified by crystallization according to [14,15,16]. Dichloromethane was dried and distilled before using. The molecular sieves have been heated up to 180 °C for two hours. Thin-layer chromatography was carried out on Merck aluminum sheets, silica gel 60 F254. Column chromatography was performed on Fluka silica gel 60, 70–230 mesh. Melting points were determined on a Boëtius melting point apparatus (PHMK, VEB Wägetechnik Rapido, Radebeul, Germany) and are uncorrected. 1H- and 13C-NMR spectra were recorded on a Bruker Avance III 400 spectrometer operating at 400.13 MHz for 1H and 100.61 MHz for 13C. Chemical shifts δ are given in ppm referring to the signal center using the solvent peaks for reference: DMSO-d6 2.50 ppm/39.52 ppm. The NMR signals were assigned by two-dimensional 1H,1H COSY and 1H, 13C correlation spectra (HSQC, HMBC) using standard pulse sequences. IR spectra were recorded on apparatus “Perkin-Elmer Spectrum 100 FTIR”. The specific rotation has been recorded on “Jasco-P-2000” in MeOH.

3.2. General Procedure for Preparing of Compounds (5)

Malononitrile (0.89 mmol), catalyst (10 mol%) and molecular sieves to the suspension of the corresponding oxindoles (0.89 mmol) in dry DCM (4 mL) were added at vigorous stirring. The reaction mixture was put into the ice bath and after cooling acetylacetone (or ethyl acetoacetate) was added. After six hours of stirring at 0 °C (monitored by TLC) the solvent was evaporated and the residue was purified by column chromatography (DCM/MeOH 0–2%).
5′-Acetyl-2′-amino-6′-methyl-spiro[oxindole-3,4′-4′H-pyran]-3′carbonitrile (5a)
M.p. 249–252 °C (MeOH); 1H-NMR (DMSO-d6) δ 2.09 (s, 3H, CCH3), 2.29 (s, 3H, COCH3), 6.78 (d, 1H, J = 8.0 Hz, Hind), 6.92 (td, 1H, J = 8.0, 2.0 Hz, Hind), 7.04 (d, 1H, J = 8.0 Hz, Hind), 7.12 (s, 2H, NH2), 7.16 (td, 1H, J = 8.0, 2.0 Hz, Hind), 10.39 (s, 1H, NH); 13C-NMR (DMSO-d6) δ 19.71 (CCH3), 31.68 (COCH3), 49.90 (C3), 57.31 (CCN), 109.91 (CHind), 115.32 (CCH3), 117.92 (CN), 122.32 (CHind), 123.86(CHind), 128.98 (CHind), 134.48 (Cind), 142.45 (Cind), 156.30 (C6′), 159.75 (CNH2), 178.88 (CONH), 197.97 (COCH3); IR cm−1 3376.8, 3343.4 (NH2), 3113.0 (NH), 2187.1 (CN), 1706.0 (CONH), 1679.1 (CO).
5′-Acetyl-2′-amino-1-benzyl-6′-methyl-spiro[oxindole-3,4′-4′H-pyran]-3′carbonitrile (5b)
M.p. 209 °C (sub), 229 °C (dec) (DCM/MeOH); 1H-NMR (DMSO-d6) δ 2.12 (s, 3H, CCH3), 2.37 (s, 3H, COCH3), 4.86 (d, 1H, J = 16.0 Hz, CHHN), 4.95 (d, 1H, J = 16.0 Hz, CHHN), 6.69 (d, 1H, J = 7.6 Hz, Hind), 6.99 (t, 1H, J = 7.4, Hz, Hind), 7.09–7.16 (m, 4H, NH2, Hind,), 7.24–7.33 (m, 3H, HAr), 7.47 (d, 2H, J = 7.4 Hz, HAr); 13C-NMR (DMSO-d6) δ 19.93 (CCH3), 31.72 (COCH3), 44.00 (CH2), 49.52 (C3), 57.09 (CCN), 109.38 (CHind), 115.32 (CCH3), 117.78 (CN), 122.92 (CHind), 123.51 (CHind), 127.48 (CAr), 127.59 (CHAr), 128.72 (CHAr), 128.82 (CAr), 133.76 (CHind), 136.42 (Cind), 143.10 (Cind), 156.76 (C6′), 159.76 (CNH2), 177.42 (CONH), 197.32 (COCH3); IR cm−1 3361.3, 3292.6 (NH2), 3144.4 (NH), 2192.6 (CN), 1709.1 (CONH), 1676.2 (CO).
Ethyl 6′-amino-1-benzyl-5′-cyano-2′-methyl-spiro[oxindole-3,4′-4′H-pyran]-3′carboxylate (5c)
M.p. 204 °C (sub), 222 °C (dec) (DCM/MeOH); 1H-NMR (DMSO-d6) δ 0.58 (t, 3H, J = 7.0 Hz, CH2CH3), 2.34 (s, 3H, COCH3), 3.51–3.55 (m, 1H, CHHCH3), 3.77–3.81 (m, 1H, CHHCH3), 4.78 (d, 1H, J = 15.8 Hz, CHHN), 5.01 (d, 1H, J = 15.8 Hz, CHHN), 6.86 (d, 1H, J = 7.8 Hz, Hind), 7.02 (t, 1H, J = 7.4, Hz, Hind), 7.16 (d, 1H, J = 6.8 Hz, Hind), 7.21 (t, 1H, J = 7.6, Hz, Hind), 7.26 (s, 2H, NH2), 7.27–7.34 (m, 3H, HAr), 7.47 (d, 2H, J = 7.0 Hz, HAr); 13C-NMR (DMSO-d6) δ 13.56 (CH2CH3), 19.12 (CCH3), 43.90 (NCH2), 49.03 (C3), 56.72 (CCN), 60.58 (CH2CH3), 105.07 (CCH3), 109.38 (CHind), 117.98 (CN), 123.19 (CHind), 123.80 (CHind), 127.81 (CAr), 128.00 (CHAr), 128.86 (CHAr), 129.12 (CAr), 134.12 (CHind), 136.64 (Cind), 143.24 (Cind), 159.30 (C6′), 159.68 (CNH2), 164.85 (COCH2), 177.42 (CONH); IR cm−1 3377.9, 3246.5 (NH2), 3187.3 (NH), 2193.1 (CN), 1710.3 (CONH), 1665.5 (CO).

4. Conclusions

We have demonstrated that Brevicolline, Cinchonidine and Cinchonine can be used as organocatalysts to achieve asymmetric induction in one-pot multicomponent synthesis of spiro [oxindole-3,4′-4′H-pyrane] derivatives. Although currently the enantioselectivity obtained is moderate to good, several important parameters have been studied. The useful insight into the understanding of the application of Brevicolline, Cinchonidine and Cinchonine has led to the “design” of other inductors, which can afford higher enantioselectivities. The results of these studies will be reported in the near future.


The authors (F.M. and N.S.) gratefully acknowledge generous financial support from the Royal Society International Joint Project 2009-2011(Ref. No. JP090309).

References and Notes

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Figure 1. Catalysts used in this study.
Figure 1. Catalysts used in this study.
Symmetry 03 00165 g001
Scheme 1. One-pot multicomponent synthesis.
Scheme 1. One-pot multicomponent synthesis.
Symmetry 03 00165 sch001
Table 1. Scope of one-pot multicomponent synthesis of spiro[oxindole-3,4′-4′H-pyrane] derivatives.
Table 1. Scope of one-pot multicomponent synthesis of spiro[oxindole-3,4′-4′H-pyrane] derivatives.
EntryCatalystIsatineDicarbonyl compoundProductaYield (%)[α]Db/cee (%)
11a2a4a5a80+2 (c 0.35)b23
21b2a4a5a77+1.8 (c 0.84)b21/
31c2a4a5a50+3.7 (c 0.6) b43
41a2a4b5b87+2.27 (c 0.9)c8
51b2a4b5b98+0.98 (c 1.16)c3
61c2a4b5b68+3.5 (c 0.33)c12
71a2b4a5c60+6.32 (c 0.17)d22
81b2b4a5c67+2.16 (c 0.35)e8
91c2b4a5c62+46.8 (c 0.12) e94
a Of the isolated products after column chromatography; b Based on the specific rotation measured using Jasco-P-2000 polarimeter compared with [α]D = +8.1 (c 0.37 MeOH); ee = 94% [12]; c Based on the specific rotation measured using Jasco-P-2000 polarimeter compared with [α]D = +21.3 (c 0.14 MeOH); ee = 74% [12]; d Based on the specific rotation measured using Jasco-P-2000 polarimeter compared with [α]D = +21.0 (c 0.15 MeOH); ee = 78% [12]; e The ee measurement was confirmed by HPLC using Chiralpak IA column; i-propanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, tR (major) = 19.25 min, tR (minor) = 25.26 min.

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MDPI and ACS Style

Macaev, F.; Sucman, N.; Shepeli, F.; Zveaghintseva, M.; Pogrebnoi, V. Facile and Convenient One-Pot Process for the Synthesis of Spirooxindole Derivatives in High Optical Purity Using (−)-(S)-Brevicolline as an Organocatalyst. Symmetry 2011, 3, 165-170.

AMA Style

Macaev F, Sucman N, Shepeli F, Zveaghintseva M, Pogrebnoi V. Facile and Convenient One-Pot Process for the Synthesis of Spirooxindole Derivatives in High Optical Purity Using (−)-(S)-Brevicolline as an Organocatalyst. Symmetry. 2011; 3(2):165-170.

Chicago/Turabian Style

Macaev, Fliur, Natalia Sucman, Felix Shepeli, Marina Zveaghintseva, and Vsevolod Pogrebnoi. 2011. "Facile and Convenient One-Pot Process for the Synthesis of Spirooxindole Derivatives in High Optical Purity Using (−)-(S)-Brevicolline as an Organocatalyst" Symmetry 3, no. 2: 165-170.

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