Synthesis of both enantiomers of ferrocene[1,2-c]1H-quinolin-2-one by diastereoselective deproto-zincation of sugar-derived ferrocene esters

Abstract

The diastereoselective deproto-metallation of several sugar-derived ferrocene esters using lithium-zinc bases was studied. While bis[(R)-1-phenylethyl]amino as the ligand afforded the diacetone-D-glucose-based (S_P)-2-iodoferrocene ester in 91% de after iodination, the R_P was synthesized from α-D-glucofuranose using 2,2,6,6-tetramethylpiperidino as the ligand. Both (R_P)- and (S_P)-ferrocene[1,2-c]1H-quinolin-2-one were reached by subsequent cyclizing couplings, albeit their racemization was noted.

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Metallocenes have been intensively studied due to their varied applications in fields such as catalysis, materials science,¹ and bioorganometallic chemistry.² In particular, planar-chiral ferrocenes have attracted the attention of chemists because of their use in homogeneous asymmetric catalysis.³

The presence of a heteroatom-containing substituent on ferrocenes usually directs lithiation onto the adjacent position. With the aim of obtaining enantio-enriched planar-chiral derivatives, reactions of ferrocenes bearing various chiral directing groups have been documented.^3b,c We have recently contributed to these studies by identifying sugar-derived esters as suitable groups to induce ferrocene diastereoselective deproto-metallations. With TMPLi (TMP = 2,2,6,6-tetramethylpiperidino) not being efficient enough to achieve this goal, we turned to the synergic (concerning both efficiency and chemoselectivity) lithium-cadmium base (TMP)₃CdLi followed by iodination.⁴ Herein, the use of lithium-zinc combinations as non-toxic basic alternatives to achieve chemo- and diastereoselective syntheses of 2-iodoferrocene esters is described. In order to access the targets such as ferrocene[1,2-c]1H-quinolinones 1 from the latter, coupling-cyclization one-pot sequences are next considered (Scheme 1).

Scheme 1 Retrosynthetic route for 1

We thus turned our attention to a variety of chiral ferrocene esters, prepared from ferrocenecarboxylic acid and the corresponding secondary alcohols 2a–g depicted in Scheme 2 under classic conditions.⁵ The metallation reactions were attempted in THF (tetrahydrofuran) at room temperature for 2 h before interception with iodine (Table 1).

Scheme 2 The chiral alcohols used to prepare the ferrocene esters.

Table 1 Metallation of the chiral ferrocenecarboxylates 3a–g using the lithium-zinc base prepared from ZnCl₂·TMEDA (1 equiv) and TMPLi (3 equiv) before trapping with I₂ (3 equiv)

Entry	3	4, yield (%), de^a (%)	5, yield (%), ee^b (%)
a Wherever possible, determined from the integration of the ^1H NMR spectrum of the crude mixture. b Determined by HPLC analysis on a chiral stationary phase (AS-H column, eluent: hexane–isopropanol 9 : 1, 1 mL min^−1, λ = 252 nm). c Absolute configuration assigned on the basis of reported data.^8 d Estimated yield, due to the presence of starting material. e Reduction performed on a fraction. f Using ZnCl2·TMEDA (1.5 equiv) and TMPLi (4.5 equiv). g Both diastereomers separated by column chromatography purification over silica gel.
1	3a	4a, 86, 20	61, 22 (R)^c
2	3b	4b, 50^d, 17	(S)^c^,^e
3	3c	4c, 86, 54	(S)^c^,^e
4	3d	4d, 87, 56	96, 57 (S)^c
5	3e	4e, 64^d	86, 32 (S)^c
6^f	3f	4f, 70	91, 11 (S)^c
7^g	3g	R P- 4g, 35 and SP-4g, 12^d	81, 96 (R) and 88, 92 (S)^c

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From the α-D-xylofuranose derivative 3a, using the lithium-zinc base prepared in situ from ZnCl₂·TMEDA (1 equiv, TMEDA = N,N,N',N'-tetramethylethylenediamine) and TMPLi (3 equiv)⁶ afforded 4a in 86% yield but with a moderate 20% de. Subsequent reduction to 2-iodoferrocenemethanol (5) using DIBAL-H,⁷ analysis by HPLC using a chiral stationary phase, and comparison with the literature showed the predominant formation of 4a as the R_P diastereomer (Table 1, entry 1). When the α-D-mannofuranose derivative 3b was treated similarly, the metallation proved incomplete, affording 4b in 50% yield and a low 17% de in favor of the S_P diastereomer (Table 1, entry 2). Under the conditions used to functionalize 3a and 3b, the iodo derivatives 4c and 4d were synthesized from the inexpensive α-D-glucofuranose derivatives 3c and 3d in 86 and 87% yield and 54 and 56% de, respectively (major S_P diastereomer, Table 1, entries 3 and 4). Involving the α-D-allofuranose derivative 3e in the reaction, a good conversion was observed but with a disappointing 32% de in favor of the S_P diastereomer (Table 1, entry 5). In order to evaluate more metal-coordinating groups, the α-D-xylofuranose derivative 3f was tested using 1.5 equiv of base, giving 4f in 70% yield and a low de (Table 1, entry 6). With the α-D-glucofuranose derivative 3g, both diastereomers were separated and the major one, isolated in 35% yield, proved to be the R_P (Table 1, entry 7).

A thorough study was then undertaken in order to evaluate the parameters responsible for the diastereoselectivity observed from the promising 3c (Table 2). In order to check the importance of the structural composition of the base, (TMP)₂BuZnLi^6b was tested; a similar yield and de were obtained (Table 2, entry 2). Using hexane containing TMEDA (5 equiv)⁹ instead of THF still led to 4c but in lower yield and de (Table 2, entry 3). The presence of TMEDA¹⁰ in THF, due to the zinc source used, did not change the diastereoselectivity, as shown by employing ZnCl₂ instead of ZnCl₂·TMEDA (Table 2, entries 4 and 5). The addition of TMPLi (1 or 2 equiv) to a mixture of (TMP)₂Zn and 3c was attempted, and led to 89 and 87% yields, and 64 or 72% de, respectively (Table 2, entries 6 and 7), as if TMPLi (or aggregates containing LiCl)^6c was superior to mixed ferrocenyl-TMP zincates when performing the diastereoselective reaction. Similarly, the addition of TMPLi (3 equiv) to a mixture of ZnCl₂·TMEDA and 3c led to an improved de (Table 2, entry 8). The sequential addition of (TMP)₂Zn and TMPLi (2 equiv) was also attempted using 1,2-dimethoxyethane, 1,4-dioxane, and dimethoxymethane as solvents, but the reaction only proceeded with the latter, affording 4c in 32% yield and 51% de (Table 2, entry 9). Mixing the reagents in different orders at −30 or −50 °C before warming to rt did not change the diastereoselectivity significantly (Table 2, entries 10–13).

Table 2 Metallation of the chiral ferrocenecarboxylate 3c using the lithium-zinc base prepared from ZnCl₂·TMEDA (1 equiv), RLi (2 equiv) and R'Li (n equiv) before trapping with I₂ (3 equiv)

Entry	R	R'(n)	Solvent, conditions	Yield (%), de^a (%)
a Determined from the integration of the ^1H NMR spectrum of the crude mixture. b Determined after reduction using DIBAL-H by HPLC analysis on a chiral stationary phase (AS-H column, eluent: hexane–isopropanol 9 : 1, 1 mL min^−1, λ = 252 nm). c In hexane containing TMEDA (5 equiv). d Base prepared from ZnCl2 instead of ZnCl2·TMEDA. e TMEDA slowly added at −30 °C. f Sequential addition of RLi and, 10 min later, R'Li. g Substrate mixed with ZnCl2·TMEDA before reaction (no RLi used). h Using dimethoxymethane as solvent. i Containing TMEDA (1 equiv). j Base transferred to the substrate. k Using (R)-PEAH. l Using (S)-PEAH.
1	TMP	TMP(1)	THF, rt, 2 h	86, 54 (S^b)
2	TMP	Bu(1)	THF, rt, 2 h	89, 55 (S^b)
3	TMP	TMP(1)	^c, rt, 2 h	50, 42 (S^b)
4^d	TMP	TMP(1)	THF, rt, 2 h	84, 56 (S^b)
5^d^e	TMP	TMP(1)	THF, −30 °C to rt, 2 h	46, 53 (S^b)
6^f	TMP	TMP(1)	THF, rt, 2 h	89, 64 (S^b)
7^f	TMP	TMP(2)	THF, rt, 2 h	87, 72 (S^b)
8	^g	TMP(3)	THF, −30 °C to rt, 2 h	70, 68 (S^b)
9^d^f	TMP	TMP(2)	^h, rt, 2 h	32, 51 (S^b)
10^f	TMP	TMP(2)	THF, −30 °C to rt, 2 h	51, 52 (S^b)
11	TMP	TMP(2)	THF, −30 °C to rt, 2 h	64, 56 (S^b)
12^d	TMP	TMP (2)	THF,^i −30 °C to rt, 2 h	30, 56 (S^b)
13^j	TMP	TMP(2)	THF, −50 °C to rt, 2 h	71, 56 (S^b)
14	PEA^k	PEA^k(1)	THF, rt, 2 h	67, 79 (S^b)
15	PEA^l	PEA^l(1)	THF, rt, 2 h	24, 10 (S^b)
16^f	PEA^k	PEA^k(2)	THF, rt, 2 h	85, 91 (S^b)

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Double asymmetric induction¹¹ using commercial (R)- and (S)-bis[1-phenylethyl]amine (PEAH) as the ligand source instead of TMPH was next attempted. Thus, when the substrate was reacted with a base obtained from ZnCl₂·TMEDA (1 equiv) and (R)- or (S)-PEALi (3 equiv), 4c was obtained in 67 and 24% yield, and 79 and 10% de, respectively (Table 2, entries 14 and 15). With the sequential addition of the zinc diamide (1 equiv) and lithium amide (2 equiv) to the substrate being more efficient in the case of TMPH (Table 2, entry 7), we applied a similar protocol using (R)-PEAH; under these conditions, both a good yield and de were obtained (Table 2, entry 16).

When applied to the ester 3g, the sequential addition of (TMP)₂Zn (either prepared from ZnCl₂·TMEDA or ZnCl₂) and TMPLi (2 equiv) afforded R_P-4g in 51 and 57% yield, respectively.

In order to access the quinolinones 1, the iodides S_P-4c and R_P-4g were reacted with 2-aminophenylboronic acid. Using catalytic Pd(dba)₂ (dba = dibenzylidene acetone) and triphenylphosphine, dioxane as solvent, and CsF in order to avoid the use of basic reagents,¹² led to the carboxamides R_P-1 and S_P-1 through the Suzuki cross-coupling and subsequent cyclization of the amino group with the ester function (Scheme 3).

Scheme 3 Cyclizing Suzuki couplings giving 1.

The crystals were analysed by X-ray diffraction and a structure referring to the non-chiral space group R3̄ was obtained (Fig. 1). This result is not sufficient to claim racemization,¹³ but led us to check this possibility using HPLC analysis on the chiral phases. The interconversion (R_P-1vs.S_P-1) was noted in solution;¹⁴ without solvent, it could be stopped at temperatures below −20 °C.

Fig. 1 ORTEP diagrams (30% probability) of R_P-1 and S_P-1.

Lithiation experiments on aryl carboxamides showed that the orientation of the functional group has an impact on the efficiency of the ortho-metallations, which increases with the coplanarity of the oxygen and activated hydrogen within the ring.¹⁵ A rationalization of the diastereoselectivity observed using 3c was thus attempted by identifying more stable conformers. Geometrical (local stabilization) optimization was performed by changing the dihedral angle between the upper plane of the ferrocenyl moiety and the ester carbonyl group (B3LYP/6-31G(d), structure of the ferrocenyl group fixed). The dihedral angle was fixed with 30° intervals from 0° to 330°. The two most stable structures, with dihedral angles of 0° (to give the major diastereomer) and 180° (to give the minor diastereomer), were identified and calculated in greater detail (M06/LanL2DZ(Fe)&6-31G(d)) at around 0° and 180°. The conformation with a dihedral angle of −6° proved to be 4.6 kcal mol⁻¹ lower in energy that of 190° (Fig. 2, left).¹⁶ These calculated results are in accordance with the observed diastereoselectivity in the deproto-metallation of 3c using the lithium-zinc combination (Scheme 4). It is interesting to note that the structure obtained by the X-ray diffraction of the suitable crystals of 3c corresponds to the most stable conformer (Fig. 2, right).

Fig. 2 The calculated most stable conformer (M06/LanL2DZ(Fe)&6-31G(d)) and ORTEP diagram (30% probability) of 3c.

Scheme 4 The observed diastereoselectivity in the deproto-metallation of 3c.

Conclusions

Sugar-based ferrocene esters were deproto-metallated by using mixed lithium-zinc amido-based bases, with diastereoselectivities up to 91% under the “double asymmetric induction” protocol.

Acknowledgements

The authors gratefully acknowledge the Institut Universitaire de France, Région Bretagne (financial support for A.S. and G.D.), University of Rennes 1 and CNRS (financial support for G.D. and D.V.R.). This research has also been performed as part of the Indo-French “Joint Laboratory for Sustainable Chemistry at Interfaces”. The calculations were performed by using the RIKEN Integrated Cluster of Clusters (RICC) facility.

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16. The calculations using the SCRF method (PCM, solvent = THF) gave similar results. For details, see the ESI.†.

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Footnote

† Electronic Supplementary Information (ESI) available: procedures, X-ray diffraction analysis and CIF files of 1 (CCDC 872139) and 3c (CCDC 798863), NMR spectra of 1, geometrical optimization of 3c and computational details. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21045b/

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