New Preparation of Ferrocene Carboxylic Acid Benzotriazol-1-yl Ester

Abstract

Ferrocene and its derivatives are very useful in the fields of chemistry, biomedicine and materials. Herein, a ferrocene derivative was synthesized in one step from benzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate and ferrocenecarboxylic acid. Its accurate structure was determined by ¹H and ¹³C NMR and further confirmed by X-ray diffraction analysis of the corresponding single crystal.

1. Introduction

In the 1950s, iron bis-cyclopentadienyl was first synthesized [1,2], and this unique compound received much attention in the world [3,4,5]. The initially proposed structure was reassigned as a sandwich-like model by Woodward and co-workers [6], and later confirmed by the X-ray diffraction of its crystal [7,8,9]. Since the discovery of this unique complex called ferrocene [10,11], new advances in the synthesis of analogs and their properties’ studies [12,13] were achieved. No doubt, ferrocene opened up an era of organometallic chemistry and continues to play an important role in many fields, such as asymmetric catalysis [14] and ATP bioconjugates [15] up until now.

2. Results and Discussion

In connection with our continuous research on the synthesis of natural products [16,17,18,19,20,21,22] and fluorescent probes [23,24,25,26,27], a ferrocene derivative (1, Scheme 1) was obtained serendipitously. When benzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate (PyBoP) was added to a mixture of ferrocenecarboxylic acid [28], N,N-diisopropylethyl amine (DIPEA) and 4-dimethylamino pyridine (DMAP) in CH₂Cl₂, compound 1 was formed as an orange solid. This compound had been previously obtained through a different condition [29].

As shown in Table 1, the reaction could be optimized, and the yield of compound 1 was thus eventually raised to 65%. The extension of the reaction time did not lead to a yield increase (entry 1 vs. 2). While a lower yield of 1 was obtained in the diluted solution (entry 3), an excess of PyBoP resulted in more generation of 1 (entry 4). The omission of DMAP even led to a further increase in 1 (entry 5). However, the excess either of DIEPA or DMAP provided inferior results (entries 6 and 7). The replacement of DMAP with 4-pyrrolidinopyridine (PPY) produced a similar result (entries 2, 4 vs. 8). Pleasingly, the addition of 1.5 equivalent of PyBoP can lead to a significant increase in 1 even with the decreased amount of DIEPA and PPY (entry 9).

Its molecular structure was determined by single crystal X-ray diffraction [30]. As shown in Figure 1, two cyclopentadienyl groups were coordinated with an iron atom, which formed a pentagonal prism. The distances of ten Fe–C bonds were from 2.020 to 2.056 Å and the C–C distances of two cyclopentadienyl groups were from 1.384 to 1.428 Å, which were similar to the reported values. The dihedral angle between the C8/C9/C10/C11/C12 and C13/C14/C15/C16/C17 planes was 2.70°, which indicated two cyclopentadienyl groups almost parallel to each other. The dihedral angle between the C1/C2/C3/C4/C5/C6/N1/N2/N3 and C8/C9/C10/C11/C12 planes was 86.48°, which indicated the benzotriazole group and cyclopentadienyl group were almost vertical to each other.

3. Materials and Methods

For product purification by flash column chromatography, silica gel (200~300 mesh) and petroleum ether (bp. 60~90 °C) were used. All solvents were purified and dried using standard techniques and distilled prior to use. The following chemicals were purchased and used as received. All of the experiments were conducted under an argon or nitrogen atmosphere in oven-dried or flame-dried glassware with magnetic stirring, unless otherwise specified. Organic extracts were dried over Na₂SO₄, unless otherwise noted. ¹H and ¹³C NMR spectra were taken on a Bruker AM-400 with TMS as an internal standard and CDCl₃ as solvent unless otherwise noted. The X-ray diffraction studies were carried out on a Bruker SMART Apex CCD area detector diffractometer equipped with a graphite-monochromated Cu-Kα radiation source (see Supplementary Materials).

To a mixture of ferrocenecarboxylic acid (230 mg, 1.0 mmol), DIPEA (0.15 mL, 0.9 mmol, 0.9 equiv.) and PPY (30 mg, 0.2 mmol, 0.2 equiv.) in anhydrous CH₂Cl₂ (4 mL), PyBoP (520 mg, 1.0 mmol, 1.0 equiv.) was added at 0 °C. The temperature was then raised to room temperature, and the resulting mixture was stirred for 10 h. The reaction mixture was cooled down to 0 °C and quenched with saturated NH₄Cl (5 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic phase was dried over Na₂SO₄ and then concentrated under reduced pressure to produce a crude product, which was purified by flash column chromatography (petroleum ether/EtOAc = 8:1 →petroleum ether/EtOAc = 4:1) on silica gel to produce 1 as an orange solid (180 mg, 52% yield). ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.49–7.42 (m, 2H), 5.10 (t, J = 2.0 Hz, 2H), 4.70 (t, J = 2.0 Hz, 2H), 4.45 (s, 5H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 168.3, 143.6, 128.9, 128.6, 124.7, 120.5, 108.4, 73.5 (2C), 71.0 (2C), 70.9 (5C), 63.8 ppm.

This product was dissolved in EtOAc (0.25 mL), CH₂Cl₂ (0.25 mL) and hexane (0.5 mL). After 4 days, single crystals were obtained by slow evaporation of the solvent at room temperature.

Author Contributions

Y.P. conceived and designed the experiments; L.-J.X. and L.-Y.Z. performed the experiments; L.-Y.Z., L.-J.X., Y.-W.W. and Y.P. analyzed the data; Y.-W.W. and Y.P. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank Analytical and Testing Center of Southwest Jiaotong University for the NMR test.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

Footnotes

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Figure, Scheme and Table

Scheme 1. Preparation of ferrocene derivative 1.

Figure 1. X-ray crystal structure of ferrocene derivative 1.

Table 1

Optimization of reaction.

Entry a	PyBoP (equiv.)	DIPEA (equiv.)	DMAP (equiv.)	PPY (equiv.)	1 Yield b
1 c	1.0	1.8	0.6	/	23%
2	1.0	1.8	0.6	/	25%
3 d	1.0	1.8	0.6	/	14%
4	1.5	1.8	0.6	/	30%
5	1.5	1.8	/	/	42%
6	1.0	3.6	0.6	/	9%
7	1.0	1.8	1.5	/	6%
8	1.0	1.8	/	0.6	35%
9	1.5	0.9	/	0.2	52%

^a To a solution of PyBoP and DIPEA in CH₂Cl₂ (4 mL), ferrocenecarboxylic acid (1 mmol) and DMAP or PPY were added at 0 °C, then stirred at 22 °C for 10 h. ^b Isolated yield is shown. ^c Stirred at 14 °C for 28 h. ^d CH₂Cl₂ (10 mL).

Supplementary Materials

The following are available online: Copies of ¹H, ¹³C NMR spectra and the cif file of 1.

References and Note

1. Miller, S.A.; Tebboth, J.A.; Tremaine, J.F. Dicyclopentadienyliron. J. Chem. Soc.; 1952; pp. 632-635. [DOI: https://dx.doi.org/10.1039/jr9520000632]

2. Kealy, T.J.; Pauson, P.L. A new type of organo-iron compound. Nature; 1951; 168, pp. 1039-1040. [DOI: https://dx.doi.org/10.1038/1681039b0]

3. Pauson, P.L. Ferrocene—how it all began. J. Organomet. Chem.; 2001; 637–639, pp. 3-6. [DOI: https://dx.doi.org/10.1016/S0022-328X(01)01126-3]

4. Fischer, E.O.; Jira, R. How metallocene chemistry and research began in Munich. J. Organomet. Chem.; 2001; 637–639, pp. 7-12. [DOI: https://dx.doi.org/10.1016/S0022-328X(01)01127-5]

5. Rosenblum, M. The early ferrocene days—A personal recollection. J. Organomet. Chem.; 2001; 637–639, pp. 13-15. [DOI: https://dx.doi.org/10.1016/S0022-328X(01)01128-7]

6. Wilkinson, G.; Rosenblum, M.; Whiting, M.C.; Woodward, R.B. The structure of iron bis-cyclopentadienyl. J. Am. Chem. Soc.; 1952; 74, pp. 2125-2126. [DOI: https://dx.doi.org/10.1021/ja01128a527]

7. Fischer, E.O.; Pfab, W. Cyclopentadien-Metallkomplexe, ein neuer Typ metallorganischer Verbindungen. Z. Naturforschg.; 1952; 7, pp. 377-379. Available online: https://zfn.mpdl.mpg.de/data/Reihe_B/7/ZNB-1952-7b-0377.pdf (accessed on 8 December 2022). [DOI: https://dx.doi.org/10.1515/znb-1952-0701]

8. Eiland, P.F.; Pepinsky, R. X-ray examination of iron biscyclopentadienyl. J. Am. Chem. Soc.; 1952; 74, 4971. [DOI: https://dx.doi.org/10.1021/ja01139a527]

9. Dunitz, J.D.; Orgel, L.E. Iron bis-cyclopentadienyl: A molecular sandwich. Nature; 1953; 171, pp. 121-122. [DOI: https://dx.doi.org/10.1038/171121a0]

10. Woodward, R.B.; Rosenblum, M.; Whiting, M.C. A new aromatic system. J. Am. Chem. Soc.; 1952; 74, pp. 3458-3459. [DOI: https://dx.doi.org/10.1021/ja01133a543]

11. Seeman, J.I.; Cantrill, S. Wrong but seminal. Nat. Chem.; 2016; 8, pp. 193-200. [DOI: https://dx.doi.org/10.1038/nchem.2455] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26892545]

12. Wilkinson, G. The preparation and some properties of ruthenocene and ruthenicinium salts. J. Am. Chem. Soc.; 1952; 74, pp. 6146-6147. [DOI: https://dx.doi.org/10.1021/ja01143a538]

13. Heinze, K.; Lang, H. Ferrocene – beauty and function. Organometallics; 2013; 32, pp. 5623-5625. [DOI: https://dx.doi.org/10.1021/om400962w]

14. Gao, D.-W.; Gu, Q.; Zhen, C.; You, S.-L. Synthesis of planar chiral ferrocenes via transition-metal-catalyzed direct C−H bond functionalization. Acc. Chem. Res.; 2017; 50, pp. 351-365. [DOI: https://dx.doi.org/10.1021/acs.accounts.6b00573]

15. Martic, S.; Rains, M.K.; Freeman, D.; Kraatz, H.-B. Use of 5′-γ-ferrocenyl adenosine triphosphate (Fc-ATP) bioconjugates having poly(ethylene glycol) spacers in kinase-catalyzed phosphorylations. Bioconj. Chem.; 2011; 22, pp. 1663-1672. [DOI: https://dx.doi.org/10.1021/bc200229y]

16. Cao, J.-S.; Zeng, J.; Xiao, J.; Wang, X.-H.; Wang, Y.-W.; Peng, Y. Total synthesis of linoxepin facilitated by Ni-catalyzed tandem reductive cyclization. Chem. Commun.; 2022; 58, pp. 7273-7276. [DOI: https://dx.doi.org/10.1039/D2CC02221D] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35674204]

17. Zhang, H.-Q.; Yan, C.-X.; Xiao, J.; Wang, Y.-W.; Peng, Y. Recent advances on the total synthesis of 2,7′-cyclolignans. Org. Biomol. Chem.; 2022; 20, pp. 1623-1636. [DOI: https://dx.doi.org/10.1039/D1OB02457D]

18. Zhuang, Z.; Luo, Z.; Yao, S.; Wang, Y.; Peng, Y. A concise synthesis of sacidumlignan B. Molecules; 2022; 27, 5775. [DOI: https://dx.doi.org/10.3390/molecules27185775]

19. Luo, L.; Zhai, X.-Y.; Wang, Y.-W.; Peng, Y.; Gong, H. Divergent total syntheses of C3a-C7′linked diketopiperazine alkaloids (+)-asperazine and (+)-pestalazine A enabled by a Ni-catalyzed reductive coupling of tertiary alkyl chloride. Chem.-Eur. J.; 2019; 25, pp. 989-992. [DOI: https://dx.doi.org/10.1002/chem.201805682]

20. Xiao, J.; Cong, X.-W.; Yang, G.-Z.; Wang, Y.-W.; Peng, Y. Divergent asymmetric syntheses of podophyllotoxin and related family members via stereoselective reductive Ni-catalysis. Org. Lett.; 2018; 9, pp. 3965-3968.

21. Xiao, J.; Cong, X.-W.; Yang, G.-Z.; Wang, Y.-W.; Peng, Y. Stereoselective synthesis of Podophyllum lignans core by intramolecular reductive nickel-catalysis. Chem. Commun.; 2018; 54, pp. 2040-2043. [DOI: https://dx.doi.org/10.1039/C8CC00001H] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29412213]

22. Peng, Y.; Xiao, J.; Xu, X.-B.; Duan, S.-M.; Ren, L.; Shao, Y.-L.; Wang, Y.-W. Stereospecific synthesis of tetrahydronaphtho[2,3-b]furans enabled by a nickel-promoted tandem reductive cyclization. Org. Lett.; 2016; 18, pp. 5170-5173. [DOI: https://dx.doi.org/10.1021/acs.orglett.6b02665]

23. Xu, H.; Zhang, C.; Zhang, Y.-Q.; Suo, S.-N.; Wang, Y.-W.; Peng, Y. A red-NIR fluorescence probe for rapid and visual detection of acrolein. Chem. Commun.; 2022; 58, pp. 10080-10083. [DOI: https://dx.doi.org/10.1039/D2CC03480H]

24. Feng, Y.-A.; Xu, H.; Zhou, Y.; Wang, B.-J.; Xiao, J.; Wang, Y.-W.; Peng, Y. Ratiometric detection and bioimaging of endogenous alkaline phosphatase by a NIR fluorescence probe. Sens. Actuators B; 2022; 358, 131505. [DOI: https://dx.doi.org/10.1016/j.snb.2022.131505]

25. Xu, H.; Wu, S.-L.; Lin, N.-J.; Lu, Y.; Xiao, J.; Wang, Y.-W.; Peng, Y. A NIR fluorescent probe for rapid turn-on detection and bioimaging of hypochlorite anion. Sens. Actuators, B.; 2021; 346, 130484. [DOI: https://dx.doi.org/10.1016/j.snb.2021.130484]

26. Feng, X.; Wang, Y.-W.; Feng, W.; Peng, Y. Development of BINOL-Si complexes with large stokes shifts and their application as chemodosimeters for nerve agent. Chin. Chem. Lett.; 2020; 31, pp. 2960-2964. [DOI: https://dx.doi.org/10.1016/j.cclet.2020.05.042]

27. Wang, B.-J.; Liu, R.-J.; Fang, J.; Wang, Y.-W.; Peng, Y. A water-soluble dual-site fluorescent probe for the rapid detection of cysteine with high sensitivity and specificity. Chem. Commun.; 2019; 55, pp. 11762-11765. [DOI: https://dx.doi.org/10.1039/C9CC06468K] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31513186]

28. Burns, A.S.; Rychnovsky, S.D. Total synthesis and structure revision of (−)-illisimonin A, a neuroprotective sesquiterpenoid from the fruits of Illicium simonsii. J. Am. Chem. Soc.; 2019; 141, pp. 13295-13300. [DOI: https://dx.doi.org/10.1021/jacs.9b05065]

29. Kraatz, H.-B.; Lusztyk, J.; Enright, G.D. Ferrocenoyl amino acids: A synthetic and structural study. Inorg. Chem.; 1997; 36, pp. 2400-2405. [DOI: https://dx.doi.org/10.1021/ic961454t]

30. CCDC-2225030 (1) contain the supplementary crystallographic data for this paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.