Synthesis and properties of novel chiral imidazolium-based ionic liquids derived from carvone

Abstract

A large series of novel chiral imidazolium ionic liquids were synthesized using the terpenoid carvone as the chiral substrate. Their specific rotations were characterized and their potential use in chiral recognition was demonstrated by studying interactions with racemic Mosher's acid salt.

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Introduction

Over the past few years, chiral ionic liquids (CILs), have received considerable attention as promising materials for a variety of applications.¹ Although a limited number of CILs have been designed and synthesized, they have already shown successful results as chiral solvents for optical resolution,² as green organic catalysts in asymmetric synthesis³ and as a chiral stationary phase in chromatography.⁴

Most of the known chiral ionic liquids are derived from chiral pools.⁵ The latter provide limited scope for further structural modifications. Carvone (1) is a terpenoid found naturally in many essential oils.⁶

It's commercially available in both enantiomeric forms, and provides an easy and cost effective access to optically pure functionalized compounds.

Results and discussions

We anticipated that we could use carvone for the design and synthesis of novel chiral ionic liquids with the possibility of an easy structural refinement. Accordingly target new CILs R-5 and R-6 derived from (R)-carvone (R)-1 were prepared as outlined in Scheme 1.

Scheme 1 General synthetic procedure used to prepare the new CLIs derived from (R)-carvone (R)-1.

The series of enantiomers S-5 and S-6 were also prepared by using a similar procedure starting from (S)-carvone. To distinguish between them, those compounds derived from (R)-carvone were named using the prefix R and those derived from (S)-carvone were named by using the prefix S.

First the (R)-carvone ketone group was regioselectively reduced by treatment with NaBH₄ in the presence of CeCl₃ (ref. 7) to afford the known allylic alcohol R-2. Treatment of R-2 with m-CPBA in CH₂Cl₂ (ref. 8) gave the epoxy-alcohol R-3.⁹ The next step consisted in the introduction of an imidazole heterocycle that would allow ionic liquids preparation by a direct quaternization reaction. Using imidazole as a nucleophile,¹⁰ the epoxide R-3 was opened in a regioselective manner to yield diol R-4, which incorporates 4 chiral centers. The imidazolium halides R-5 were then prepared by direct alkylation of R-4 with the corresponding alkyl halides. However, other new CILs, the bridged oxabicycles R-11 (Scheme 2), were also obtained when long reaction times were employed or when an alkyl bromide was used as alkylating agent.

Scheme 2 Preparation of halide salts by direct alkylation.

When R-4 was heated with the alkyl chlorides 7–9 for 3–7 days, the corresponding dihydroxylated salts R-5a–c were obtained (Table 1). However, the use of longer reaction times (8–9 days) or the bromide 10, afforded the bridged oxabicycles R-11a–c. These unexpected results can be explained by an electrophilic addition of the neighboring hydroxyl group to the isopropenyl double bond, through a cis-1,3-diaxial attack.

Table 1 Preparation and characterization of both series of CILs

Compounds	RX	t (d)	CIL	Rto (%)	[α]^20D
R-4	7	5	R-5a	66	−43
R-4	8	3	R-5b	61	−27
R-4	9	7	R-5c	76	−28
R-4	8	9	R-11a	89	−51
R-4	10	3	R-11b	91	−52
R-4	9	9	R-11c	79	−53
S-4	7	6	S-5a	90	+42
S-4	8	2	S-5b	82	+28
S-4	9	7	S-5c	75	+27
S-4	8	8	S-11a	40	+50
S-4	10	3	S-11b	74	+50
S-4	9	9	S-11c	77	+52

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When the above procedure was developed starting from (S)-carvone (S)-1 instead of (R)-carvone (R)-1, the corresponding enantiomers S-5a–c and S-11a–c were obtained, as indicated in Scheme 3.

Scheme 3 Preparation of halide salts from (S)-carvone (S)-1.

Table 1 shows the results of the quaternization reactions and the characterization of both series of enantiomeric CILs.

Finally, a series of different anions were introduced by metathesis reactions carried out by treatment of the dihydroxylated halide salts R-5a–c and the bridged oxabicycles R-11b, R-11c with different inorganic salts (Schemes 4 and 5). A similar procedure was applied starting from corresponding enantiomers S-5a–c and S-11b, S-11c. The inorganic salts used in each case and the optical rotations of the CILs obtained are indicated in Table 2. The structures of all the novel CILs were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR, IR and high resolution MS.

Scheme 4 Metathesis reactions from dihydroxylated chlorides R-5a–c.

Scheme 5 Metathesis reactions from oxabicycles R-11b, R-11c.

Table 2 Metathesis reactions and optical rotations of the obtained CILs

Starting material	Inorganic salt	CIL	R [α]^20D	S [α]^20D
5a	NaBF4	6a	−35	+33
5a	LiNTf2	6b	−22	+21
5a	NaMSO4	6c	−32	+31
5b	NaTFA	6d	−26	+27
5b	LiNTf2	6e	−15	+14
5b	NaMSO4	6f	−26	+25
5c	NaTFA	6g	−34	+33
5c	LiNTf2	6h	−14	+15
5c	NaMSO4	6i	−20	+21
11b	NaBF4	12a	−53	+52
11b	NaTFA	12b	−42	+41
11b	LiNTf2	12c	−56	+54
11b	NaMSO4	12d	−53	+55
11c	NaTFA	12e	−42	+43
11c	LiNTf2	12f	−20	+19
11c	NaMSO4	12g	−29	+30

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Altogether, 44 new enantiomerically pure salts based on imidazolium cation derived from carvone incorporating [Cl], [Br], [BF₄], [NTf₂], [TFA] and [MSO₄] anions were prepared, 22 from (R)-carvone and 22 from (S)-carvone. All of them were found to be liquid at room temperature except chlorides 5a.

The enantiomeric recognition ability of all the new synthesized CILs was tested by investigating their diastereomeric interaction with the racemic substrate Mosher's acid potassium salt, by ¹H and ¹⁹F NMR. First chlorides R-5a and S-5a were dissolved in (CD₃)₂CO and stirred with racemic Mosher's carboxylate using different concentrations of CIL. Due to the chiral environment produced by the CILs, the NMR signals corresponding to the MeO and CF₃ groups of the racemic substrate were split (Table 3).

Table 3 Splitting of MeO and CF₃ NMR signals of Mosher's salt in the presence of the CILs R-5a and S-5a

[R-5a] (equiv.)	[H2O] (%)	Δδ (^19F) [Hz]	Δδ (^1H) [Hz]
0	0	14	2
1.5	0	15	3.9
2.25	0	18	3.1
2.25	0.04	0	0

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[S-5a] (equiv.)	[H2O] (%)	Δδ (^19F) [Hz]	Δδ (^1H) [Hz]
0	0	30	4.2
1.25	0	36	4.6
2.25	0	34	4.4
2.25	0.04	0	0

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The highest splitting was observed for the CF₃ signal of S-5a that showed a Δδ = 36 when a concentration of 1.25 equiv. of CIL was used (Fig. 1).

Fig. 1 ¹⁹F NMR signals of Mosher's salts CF₃ group in the presence of 1.25 equiv. of CIL S-5a.

The high chiral discrimination ability of CIL S-5a prompted us to use it in the determination of the ee value of enantiomerically enriched mixtures of Mosher's carboxylate with approximately R/S = 1 : 2, and 2 : 1 (Fig. 2 and 3).

Fig. 2 ¹⁹F NMR spectrum of an (S)-enriched sample of Mosher's acid potassium salt in the presence of CIL S-5a.

Fig. 3 ¹⁹F NMR spectrum of an (R)-enriched sample of Mosher's acid potassium salt in the presence of CIL S-5a.

As we can see in Fig. 1 and 2, the integration of the CF₃ signal of each enantiomer of Mosher's carboxylate can provide the exact amount of enantiomers, hence could be used for ee determination.

The bridged oxabicycle S-11a also proved to induce high chiral discrimination (Fig. 4).

Fig. 4 ¹⁹F NMR signals of Mosher's salts CF₃ group in the presence of 1.25 equiv. of CIL S-11a.

Conclusion

In summary, 44 new enantiomerically pure salts based on imidazolium cation derived from carvone incorporating [Cl], [Br], [BF₄], [NTf₂], [TFA] and [MSO₄] anions were prepared, 22 from (R)-carvone and 22 from (S)-carvone. All of them were found to be liquid at room temperature except chlorides.

Their enantiomeric recognition ability was tested by investigating their diastereomeric interaction with the racemic substrate Mosher's acid potassium salt, by ¹H and ¹⁹F NMR.

The high chemical shift dispersion induced by some of CILs shows their potential applications in optical resolution of racemates and in determining the enantiomeric excess of enantiomerically enriched carboxylates by NMR spectroscopy. We are currently studying the application of these CILs as reaction media and as catalysts in asymmetric synthesis.

Experimental section

See ESI.†

Acknowledgements

We thank the Xunta de Galicia (CN 2012/184, EM2013/031, REGALIs Network R2014/015) and the Ministerio de Economía y Competitividad of Spain (DPI2012-38841-C02-02) for their financial support. The work of the NMR, SC-XRD and MS divisions of the research support services of the University of Vigo (CACTI) is also gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectroscopic data of all new compounds. See DOI: 10.1039/c6ra00654j

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