One-pot four component domino strategy for the synthesis of novel spirooxindole pyrrolizine linked 1,2,3-triazoles via stereo- and regioselective [3 + 2] cycloaddition reaction in acidic medium

Abstract

An efficient, one-pot four component condensation procedure for the synthesis of selective spirooxindole pyrrolizine linked 1,2,3-triazole conjugates via [3 + 2] cycloaddition has been reported using coumarin-3-carboxylic acid (1), N-propargylated isatin (2), L-proline/sarcosine (3) and aryl azides (4) using Cu(I) as a catalyst in the presence of glacial CH₃COOH at 60 °C. The structures of the compounds synthesized herein were confirmed by ¹H NMR, ¹³C NMR, mass spectra and X-ray crystallographic techniques.

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Introduction

In biology-oriented synthesis, the underlying scaffold classes of natural products are useful starting points for the synthesis of compounds with focused structural diversity.¹ Oxindole or spirooxindole² core structures represent an interesting synthetic challenge due to their biological activity in natural products such as spirotryprostatins A and B,³ horsfiline,⁴ rhynchophylline,⁵ formosanine⁶ and elacomine^7,8 (Fig. 1). Also, coumarin containing natural products⁹ as well as their synthetic hetero fused analogs are endowed with a wide array of biological properties which include antidiabetic,¹⁰ anticoagulant,¹¹ anticancer,¹² antitubercular,¹³ anti-HIV¹⁴ and AChE inhibition.¹⁵ 1,2,3-Triazole based heterocycles exhibit important biological activities such as antiviral, agonist, antibacterial, anti-HIV, DNA labeling, etc.¹⁶ One of the most efficient approaches for the synthesis of 1,2,3-triazole frameworks is the 1,3-dipolar cycloaddition reaction of azides with alkynes.¹⁷

Fig. 1 Examples of natural products, pharmaceutical leads, and luminescent molecules containing an oxindole or spirooxindole core structure.

In continuation of our interest in the synthesis of novel heterocycles employing multicomponent reactions¹⁸ we decided to explore a new protocol for the synthesis of novel spirooxindole pyrrolizine linked 1,2,3-triazole conjugates via [3 + 2] cycloaddition reaction by one-pot four component condensation of coumarin-3-carboxylic acid, N-propargylated isatin, L-proline/sarcosine and aryl azides.

Results and discussion

The present manuscript describes a first protocol for the synthesis of novel coumarin fused spirooxindole pyrrolizine linked 1,2,3-triazole conjugates via one-pot, four component condensation of coumarin-3-carboxylic acid (1), N-propargylated isatin (2), L-proline (3a)/sarcosine (3b) and aryl azides (4) using Cu(I) as catalyst in glacial CH₃COOH as reaction medium at 60 °C. The condensation involves two sequential [3 + 2] cycloaddition reactions of azide–alkyne and azomethine ylide–alkene, in one-pot to give the desired products.

The four component condensation of coumarin-3-carboxylic acid (1.0 mmol) (1), N-propargylated isatin (1.0 mmol) (2), L-proline (1.0 mmol) (3a) and 4-fluorophenyl azide (1.0 mmol) (4a) was examined in different solvents and also under solvent-less condition in presence of Cu(I) and acid catalyst. Initially, this four component reaction was attempted in MeOH : H₂O (1 : 1, v/v) at 80 °C in presence of aq. solution of CuSO₄·5H₂O (10 mol%) and aq. solution of sodium ascorbate (20 mol%) in glacial CH₃COOH (10 mol%) as catalyst. The reaction was complete after 3 h, but yielded a mixture of products as evident by TLC using ethyl acetate : petroleum ether (30 : 70, v/v) as eluent. The reaction was quenched by water. The solid so obtained after filtration was subjected to flash column chromatography. Two different products were separated from column chromatography and characterized as 1-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)indoline-2,3-dione (6a) in 16% yield and 1′-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-6b,7,8,9-tetrahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-2′,6(6aH,11aH)-dione (5a) in 52% yield (Scheme 1) by spectroscopic analysis (Table 1, entry 1).

Scheme 1 Synthesis 1′-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-6b,7,8,9-tetrahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-2′,6(6aH,11aH)-dione (5a).

Table 1 Optimization of reaction conditions for the synthesis 1′-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-6b,7,8,9-tetrahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-2′,6(6aH,11aH)-dione (5a)

Entry	Solvent	Catalyst^a	Catalyst (mol%)	Temp. (°C)	Time (min)	Yield (%)
a Aq. CuSO4·5H2O (10 mol%) and aq. sodium ascorbate (20 mol%) were added in all reactions.b Incomplete.c Mixture of products.
1	MeOH : H2O	CH3COOH	10	80	180	52^b
2	MeOH : H2O	HCl	10	80	180	41^b
3	MeOH : H2O	H2SO4	10	80	180	35^b
4	MeOH : H2O	p-TSA	10	80	180	38^b
5	H2O	CH3COOH	10	100	120	31^b
6	—	CH3COOH	10	RT	90	67
7	—	CH3COOH	10	60	35	89
8	—	CH3COOH	20	60	35	88
9	—	[NMP]H2PO4	10	60	120	27^c
10	—	[BMIM]HSO4	10	60	120	23^c

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The yield of our desired product 5a, however, was only 52%. In order to achieve high reaction yield in less time the same model reaction was further explored with different acid catalysts like conc. HCl, conc. H₂SO₄ and p-TSA (10 mol%) in presence of Cu(I). All the reactions were incomplete even after 3 h and yielded 41, 35 and 38% of 5a along with traces of 6a, respectively (Table 1, entries 2–4). The above reaction was attempted in water at 100 °C using glacial CH₃COOH (10 mol%) as catalyst under otherwise identical conditions, was also incomplete after 3 h, but afforded 31% of 5a after separation (Table 1, entry 5). The reaction was attempted using glacial CH₃COOH (10 mol%) as catalyst in the absence of any solvent at ambient temperature. The reaction was found to be complete in 90 min and afforded the desired product 5a in 72% of yield (Table 1, entry 6). Subsequently, the same reaction was attempted at 60 °C. The reaction was complete in 35 min and yielded the desired product 5a in 89% after a simple work-up (Table 1, entry 7). The above reaction was performed using 20 mol% of glacial CH₃COOH was complete in 60 min and gave 88% of 5a (Table 1, entry 8). The reaction was also attempted in [NMP]H₂PO₄ and [bmim]HSO₄ as catalyst in an analogous manner but resulted in formation of mixture of products (Table 1, entries 9 and 10). All these results are compiled in Table 1.

Thus, condensation of one-pot four components protocol using CuSO₄·5H₂O (10 mol%) and sodium ascorbate (20 mol%) in 10 mol% of glacial CH₃COOH at 60 °C proved to be the optimum reaction condition. Subsequently, reactions were carried out with differently substituted aryl azides. All the reactions were facile with both electron rich and electron deficient aryl azides and afforded the desired products 5a–5f in high yields (Table 2, entries 1–6). Further, with a view to extend the scope of the above one-pot four component protocol, coumarin-3-carboxylic acid was replaced with 7-hydroxy coumarin-3-carboxylic acid and 6-bromocoumarin-3-carboxylic acid. The reactions were carried out under otherwise identical conditions. All the reactions proceeded smoothly and afforded corresponding triazoles containing spirooxindole pyrrolizines 5g–5k and 5l–5p in high yields (Table 2, entries 7–16). Subsequently, the scope of reaction was investigated with sarcosine (3b) also in place of L-proline (3a) under otherwise identical conditions. The reactions were complete and yielded corresponding triazole containing spirooxindole pyrrolidines 5q–5r (Table 2, entries 17 and 18). Structural assignments have been made on the basis of IR, ¹H NMR, ¹³C NMR and mass spectra (Scheme 2).

Table 2 Synthesis of 1′-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)-6b,7,8,9-tetrahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-2′,6(6aH,11aH)-diones^a

Entry	R	R′	3	Ar	Time (min)	Product	Yield (%)
a All the reactions carried out in glacial CH3COOH at 60 °C in presence of CuSO4·5H2O (10 mol%) and sodium ascorbate (20 mol%).
1	H	H	3a	4-FC6H4	35	5a	89
2	H	H	3a	4-(OCH3)C6H4	45	5b	85
3	H	H	3a	4-(NO2)C6H4	35	5c	90
4	H	H	3a	4-(CH3)C6H4	50	5d	86
5	H	H	3a	7-Chloroquinoline	40	5e	89
6	H	H	3a	4-BrC6H4	35	5f	85
7	OH	H	3a	4-FC6H4	35	5g	87
8	OH	H	3a	4-BrC6H4	35	5h	88
9	OH	H	3a	4-(NO2)C6H4	30	5i	83
10	OH	H	3a	4-(CH3)C6H4	45	5j	86
11	OH	H	3a	4-ClC6H4	35	5k	87
12	OH	H	3a	7-Chloroquinoline	35	5l	90
13	H	Br	3a	4-ClC6H4	30	5m	89
14	H	Br	3a	4-BrC6H4	35	5n	88
15	H	Br	3a	7-Chloroquinoline	35	5o	85
16	H	Br	3a	4-(OCH3)C6H4	45	5p	84
17	H	H	3b	4-(CH3)C6H4	65	5q	71
18	H	H	3b	4-(NO2)C6H4	55	5r	78

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Scheme 2 Synthesis of 1′-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)-6b,7,8,9-tetrahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-2′,6(6aH,11aH)-diones (5a–5r).

The two-dimensional NMR spectra of HMBC and COSY correlations are useful in the signal assignment of 5a, and various characteristic signals are shown in Fig. 2. The ¹H NMR spectrum of 5a revealed quartet at δ 4.67–4.55 for two protons of N–CH₂. A doublet at δ 4.14 (J = 11.45 Hz) can be readily assigned to 11-CH on the basis of its multiplicity. From the H,H-COSY of 11-CH, the doublet of doublet at δ 3.40 (J = 11.22, 2.75 Hz) is due to 6-CH. The coupling constant value of 11.45 and 11.22 Hz suggests that 11-H and 6-H are cis to each other (Fig. 2). Further, it is evident from the H,H-COSY of 6-CH that the triplet of doublet at δ 4.43 ppm (³J_H–H = 7.42, 3.66 Hz) accounting for one proton is due to 7-CH. Aromatic protons appeared as a multiplet in the region of δ 7.77–6.04. One proton at C-4′ carbon of triazole appears at δ 7.48 which confirms the formation of triazole ring. Nine aliphatic protons of pyrrolizine protons appeared in the region of δ 4.42–1.57. Further, the off-resonance decoupled ¹³C NMR of the product exhibited signal at δ 76.0 which corresponds to the spiro C₁ of the pyrrolizidine ring of 5a. The downfield signals at δ 175.3 and δ 167.5 of the product 5a are arising from the carbonyl carbon of oxindole and coumarin ring. The signal at δ 150.7 corresponds to the O–C of chromene ring of 5a. The coupling between ¹³C–F signals appeared at δ 161.7 (¹J = 245.3 Hz), δ 116.7 (²J = 23.0 Hz), δ 122.8 (³J = 8.6 Hz) and δ 132.9 (⁴J = 2.8 Hz). From the C,H-HMBC, the correlation between the H of C-11 interacting with spiro carbon of C-13 at δ 76.4 suggests the formation of product 5a proceeding via path a. In case of path b, the correlation must have appeared between the H of C-6 with spiro carbon of C-13 at 76.4. The mass spectrum of 5a showed a molecular ion peak at m/z 522.1936 (M⁺).

Fig. 2 HMBC and COSY correlations useful in the signal assignments of 5a and various characteristic ¹H and ¹³C NMR peaks.

Additionally, the structures of the synthesized novel triazole containing spiro-oxindole pyrrolizine derivatives (5) have been confirmed by the single crystal X-ray diffraction analysis of compound 5e (Fig. 3). All our attempts to obtain single crystal of compound 5a were not successful. Single crystal of 5e suitable for X-ray diffraction was obtained by layering method of CH₂Cl₂/hexane solutions at −4 °C. The crystal packing shows four molecules in a unit cell and the structural resolution of 5e showed one disordered molecule of DCM solvent is located in the crystal (the crystal refinement data is listed in ESI Table S1†). The crystal structure shows that spiro carbon of propargyl isatin and pyrrolizine ring deviate by an angle 110.26° (see ESI, Fig. S55a†). The compounds also reveal two types of interactions, namely, intermolecular and intramolecular hydrogen bonding (for details, see ESI Fig. S55b and c†) (Table 2).

Fig. 3 X-ray crystal structure of 5e.†

A plausible reaction mechanism for the formation of triazole containing spiro-oxindole pyrrolizine heterocycles 5 is depicted in Scheme 3. The triazoles 6, formed by [3 + 2] cycloaddition of propargylated isatin azides in presence of Cu(I), undergo condensation with L-proline to give the spiro intermediate 7. The decarboxylation of 7 gave the reactive ylide 8,¹⁹ which undergoes [3 + 2] cycloaddition with 1. The ylide 8 can undergo [3 + 2] cycloaddition with 1 by two ways, path a and path b to give the products 5 and 9, respectively. However, in the case of path a, the secondary orbital interactions²⁰ between the aromatic rings of coumarin-3-carboxylic acid and carbonyl group of isatin in the transition state stabilize the intermediate and result in the formation of 5 but in case of path b no such stabilization by secondary orbital interactions are observed as shown in Scheme 3. Therefore formation of 5 was observed exclusively. The formation of 5 was also confirmed by HMBC as discussed earlier besides spectral data and X-ray analysis.

Scheme 3 Plausible mechanism for the formation of 5.

The role of Cu(I)²¹ in catalyzing only the first part of the pathway was also confirmed by an independent reaction of 6 with coumarin-3-carboxylic acid and L-proline. The reaction was attempted both in the presence and absence of CuSO₄·5H₂O (10 mol%) and sodium ascorbate (20 mol%). The reactions resulted in the formation in 89 and 90% yield of 5, respectively, in 35 min, which suggests that Cu(I) was catalyzing only [3 + 2] azide–alkyne cycloaddition and has no effect on [3 + 2] cycloaddition reaction of azomethine ylide and alkene.

Experimental

Silica gel 60 F₂₅₄ (precoated aluminium plates) from Merck were used to monitor reaction progress. Melting points were determined on Buchi melting point 545 apparatus and are uncorrected. IR (CHCl₃) spectra were recorded on a Perkin Elmer FT-IR spectrophotometer, and the values are expressed as ν_max (cm⁻¹). The ¹H and ¹³C spectra were recorded on Jeol JNM ECX-400P at 400 MHz and 100 MHz, respectively. Chemical shift values are recorded on δ scale, and the coupling constants (J) are in Hertz. Mass spectra were recorded at Bruker Micro TOF Q – II. The aryl azides and N-propargylated isatin were prepared from aromatic amines and isatin by reported procedure.²²

Data collection and refinement

The intensity data for compound 5e was collected on an Oxford Xcalibur CCD diffractometer equipped with graphite monochromatic MoK_α radiation (λ 0.71073 Å) at 293(2) K. The multiscan absorption correction was applied. The crystal structure of 5e was solved by direct methods and refined by full-matrix least squares refinement techniques on F2 using SHELXL-97.²³ The coordinates of non-hydrogen atoms were refined anisotropically using SHELXL-97. The positions of hydrogen atoms were obtained from difference Fourier maps and were included in the final cycles of refinement. All calculations were done using the Wingx software package.²³ Complete crystallographic data (excluding factors) of 5e has been deposited.†

General procedure for the synthesis of 1′-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)-6b,7,8,9-tetrahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-2′,6(6aH,11aH)-diones (5a–5r)

An equimolar mixture of coumarin-3-carboxylic acid (1) (1.0 mmol), N-propargylated isatin (2) (1.0 mmol), L-proline (3a)/sarcosine (3b) (1.0 mmol) and aryl azides (4) (1.0 mmol) was dissolved in glacial CH₃COOH (10 mol%) in a 50 mL round-bottomed flask. The reaction contents were stirred magnetically in a pre-heated oil-bath maintained at 60 °C. Aqueous solution of CuSO₄·5H₂O (10 mol%) followed by an aqueous solution of sodium ascorbate (20 mol%) were then added to the reaction mixture and the heating was continued. All the reactions were complete in 35–50 min (Table 2). The progress of the reaction was monitored by TLC (ethyl acetate : petroleum ether, 30 : 70, v/v). After completion of the reaction, the reaction mixture was allowed to cool at room temperature and was quenched with water (∼5 mL). The precipitate formed was collected by filtration at the pump and washed with water. The crude material was purified by flash chromatography over silica gel (230–400 mesh) to afford pure products. The products were characterized by IR, ¹H NMR, ¹³C NMR and mass spectra. Product 5e was also analyzed by X-ray diffraction studies.

Conclusion

In conclusion, we have developed a facile synthesis of novel structurally diverse triazole containing spiro-oxindole pyrrolizine heterocycles by condensation of substituted coumarin-3-carboxylic acid (1), N-propargylated isatin (2), L-proline (3a)/sarcosine (3b) and aryl azides (4) using Cu(I) as catalyst in glacial CH₃COOH at 60 °C. All the reactions were facile and gave high yields by simple work-up. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass analysis.

Acknowledgements

R. M. thanks C.S.I.R., New Delhi, India for the grant of Senior Research Fellowship. S. K. thanks C.S.I.R., New Delhi, India for the grant of Junior Research Fellowship.

References

1. E. Ruijter, R. Scheffelaar and R. V. A. Orru, Angew. Chem., Int. Ed., 2011, 50, 6234–6246.
2. B. Yu, D.-Q. Yu and H.-M. Liu, Eur. J. Med. Chem., 2015, 97, 673–698.
3. (a) C.-B. Cui, H. Kakeya and H. Osada, Tetrahedron, 1996, 52, 12651–12666; (b) H. Wang and A. Ganesan, J. Org. Chem., 2000, 65, 4685–4693.
4. (a) A. Jossang, P. Jossang, H. A. Hadi, T. Sbvenet and B. Bodo, J. Org. Chem., 1991, 56, 6527–6529; (b) M. G. Kulkani, A. P. Dhondge, S. W. Chavhan, A. S. Borhade, Y. B. Shaikh, D. R. Birhade, M. P. Desai and N. R. Dhatrak, Beilstein J. Org. Chem., 2010, 6, 876–879.
5. J. Zhou and S. Zhou, J. Ethnopharmacol., 2010, 132, 15–27.
6. Y. Ban, N. Taga and T. Oishi, Tetrahedron Lett., 1974, 130, 187–190.
7. C. Pellegrini, M. Weher and H.-J. Borschberg, Helv. Chim. Acta, 1996, 79, 151–168.
8. N. R. Ball-Jones, J. J. Badillo and A. K. Franz, Org. Biomol. Chem., 2012, 10, 5165–5181.
9. A. Cervi, P. Aillard, N. Hazeri, L. Petit, C. L. L. Chai, A. C. Willis and M. G. Banwell, J. Org. Chem., 2013, 78, 9876–9882.
10. X.-H. Zhang, J.-F. Yan, L. Fan, G.-B. Wang and D.-C. Yang, Acta Pharm. Sin. B, 2011, 1, 100–105.
11. N. M. Pecheniuk, H. Deguchi and J. H. Griffin, J. Thromb. Haemostasis, 2005, 3, 340–345.
12. D. Kaminskyy, D. Khyluk, O. Vasylenko, L. Zaprutko and R. Lesyk, Sci. Pharm., 2011, 79, 763–777.
13. K. A. Badiola, D. H. Quan, J. A. Triccas and M. H. Todd, PLoS One, 2014, 9, 1–20.
14. Y. Zheng, C. M. Tice and S. B. Singh, Bioorg. Med. Chem. Lett., 2014, 24, 3673–3682.
15. (a) Y. A. Al-Soud, H. H. Al-Sa'doni, H. A. S. Amajaour, K. S. M. Salih, M. S. Mubarak, N. A. Al-Masoudic and I. H. Jaber, Z. Naturforsch., B: J. Chem. Sci., 2008, 63, 83–89; (b) S. S. Sahoo, S. Shukla, S. Nandy and H. B. Sahoo, Eur. J. Exp. Biol., 2012, 2, 899–908.
16. S. Haider, M. S. Alam and H. Hamid, Inflammation and Cell Signaling, 2014, 1, 95–107.
17. (a) R. Huisgen, Angew. Chem., Int. Ed., 1963, 2, 633–696; (b) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596–2599; (c) D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo, E. Zunino and L. Vaccaro, J. Org. Chem., 2005, 70, 6526–6529.
18. (a) M. Rajeswari, J. Sindhu, H. Singh and J. M. Khurana, RSC Adv., 2015, 5, 39686–39691; (b) J. Sindhu, H. Singh and J. M. Khurana, Mol. Diversity, 2014, 18, 345–355; (c) J. Sindhu, H. Singh, J. M. Khurana, C. Sharma and K. R. Aneja, Chin. Chem. Lett., 2015, 26, 50–54.
19. (a) S. Kanchithalaivan, R. V. Sumesh and R. R. Kumar, ACS Comb. Sci., 2014, 16, 566–572; (b) G. P. Rizzi, J. Org. Chem., 1970, 35, 2069–2072; (c) A. M. D'Souza, N. Spiccia, J. Basutto, P. Jokisz, L. S.-M. Wong, A. G. Meyer, A. B. Holmes, J. M. White and J. H. Ryan, Org. Lett., 2011, 13, 486–489; (d) M. F. Aly, G. M. El-Nagger, T. I. El-Emary, R. Grigg, S. A. M. Metwally and S. Sivagnanam, Tetrahedron, 1994, 50, 895–906; (e) I. Coldham and R. Hufton, Chem. Rev., 2005, 105, 2765–2809.
20. (a) L. Srinu, S. Thennarasu and P. T. Perumal, Tetrahedron Lett., 2012, 53, 7052–7055; (b) Y. Apeloig and E. Matzner, J. Am. Chem. Soc., 1995, 117, 5375–5376; (c) A. Arrieta and F. P. Cossio, J. Org. Chem., 2001, 66, 6178–6180; (d) J. I. Garcia, J. A. Mayoral and L. Salvatella, Eur. J. Org. Chem., 2005, 85–90.
21. F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless and V. V. Fokin, J. Am. Chem. Soc., 2004, 127, 210–216.
22. (a) N. D. Obushak, N. T. Pokhodylo, N. I. Pidlypnyi and V. S. Matiichuk, Russ. J. Org. Chem., 2008, 44, 1522–1527; (b) H. Singh, J. Sindhu, J. M. Khurana, C. Sharma and K. R. Aneja, Eur. J. Med. Chem., 2014, 77, 145–154.
23. (a) L. J. Farrugia, WinGX Version 1.80.05: An Integrated System of Windows Programs for the solution, Refinement and Analysis of Single Crystal X-Ray Diffraction Data, Department of Chemistry, University of Glasgow, Glasgow, 1997–2009; (b) G. M. Sheldrick, Acta Crystallogr., 2008, 64, 112–122.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1407486. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra26093k

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