Ir-Catalyzed Chemo-, Regio-, and Enantioselective Allylic Enolization of 6,6-Dimethyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-one Involving Keto-Enol Isomerization

Abstract

The utilization of 6,6-dimethyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-one made from an unsymmetrical 4,4-dimethylcyclohexane-1,3-dione in iridium-catalyzed allylic enolization involving keto-enol isomerization is accomplished under mild conditions. The chemoselectivity, regioselectivity, and enantioselectivity are facilitated by the quaternary carbon and adjusting the reaction conditions. This method provides the substituted 2-(but-3-en-2-yl)-3-hydroxy-6,6-dimethylcyclohex-2-en-1-ones in good to high yields with high level of chemo-, regio-, and enantioselectivities. The chiral carbon-fluorine bond formation is induced by an adjacent chiral carbon center of the allylated 3-hydroxy-6,6-dimethylcyclohex-2-en-1-one, as well.

1. Introduction

Enol is of great importance to synthetic chemistry since it could undergo various transformation [1,2]. As a result, new method for introducing enol moiety into organic compounds is highly desirable. To date, acyclic enol as a nucleophile was used in transition-metal catalyzed allylic substitution [3,4,5,6,7,8,9,10,11,12,13,14].

Very few cyclic enol such as 5,5-dimethylcyclohexane-1,3-dione was used in allylic substitution under Pd [15,16,17,18] and Ru [19] catalysis (eq-1 and eq-2 in Scheme 1). Interestingly, the racemic allylated 3-hydroxy-5,5-dimethylcyclohex-2-en-1-one was observed in eq-2 of Scheme 1. Iridium-catalyzed allylic substitution has become a powerful tool for the synthesis of optically active compounds [20,21]. In general, 4,4-dimethylcyclohexane-1,3-dione that is structurally unsymmetrical could carry out keto-enol isomerization to form either 3-hydroxy-6,6-dimethylcyclohex-2-en-1-one or 3-hydroxy-4,4-dimethylcyclohex-2-en-1-one [3,22] (Scheme 2); thus, stereoselective introduction of cyclic enol moiety into allyl products is a changeling task. We speculated that unsymmetrical 3-hydroxy-4,4-dimethylcyclohex-2-en-1-one may undergo enantioselective allylic substitution under Ir catalysis to form two chiral centers. In this paper, we describe Ir-catalyzed enantioselective allylic enolization of 6,6-dimethyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-one involving keto-enol isomerization.

2. Results and Discussion

We initiated with a model reaction of 6,6-dimethyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-one 1a [22], which derived from 4,4-dimethylcyclohexane-1,3-dione 1b and hexamethyldisilazane (HMDS), with (E)-cinnamyl methyl carbonate 2a in the presence of CsF and an iridacycle [23] prepared from [Ir(COD)Cl]₂ and Feringa’s ligand L1 [24,25] (Figure 1). When the reaction was conducted in dichloromethane (DCM) at −20 °C, the formation of 3-hydroxy-6,6-dimethyl-2-(1-phenylallyl)cyclohex-2-en-1-one 3a was observed. Its enolated isomer, either 4,4-dimethyl-2-(1-phenylallyl)cyclohexane-1,3-dione 3a″ or 3-hydroxy-4,4-dimethyl-2-(1-phenylallyl) cyclohex-2-en-1-one 3a‴ was not found. These results suggested that it is difficult to form 3a‴ due to the repulsion between methyl and hydroxyl group. The structure of 3a was established by 2D ¹H NMR and X-ray analysis of 3j (entry 1 and Figure S2; Supplementary Materials). Inspired by these results, various solvents were examined and they revealed that toluene is a proper solvent (entry 4); whereas other solvents such as DCM and acetonitrile offered 3a in poor yields with good to high ee values (entries 1, 3, and 4); THF is not favorable for this reaction (entry 2). Base plays an important role in the allylic enolization, thus, a series of bases including CsF, CsCl, Cs₂CO₃, CsOH, K₂CO₃, and 1,8-diazabicyclo [5.4.0]-7-undecene (DBU) was tested and Cs₂CO₃ led to the better results than the others (entries 5–8); DBU is not effective for the reaction (entry 9). The reaction was performed at a temperature ranging from −20 °C to 35 °C, and we found that the reaction at 25 °C gave superior results (entries 6, 10–13). Notably, the incomplete conversion of 1a led to a 75% yield (entry 12). Iridium salts such as [Ir(Cp*)Cl₂]₂ and Ir(COD)(acac) were surveyed, [Ir(Cp*)Cl₂]₂ was not suitable for this reaction (entry 14); Ir(COD)(acac) gave 3a in a poor yield but with high ee value (entry 15). Ligand is crucial to Ir-catalyzed asymmetric allylic substitution [20,21]. Therefore, structurally varying ligands such as L1, L2 [25], L3 [26], L4 [27], and L5 [28] (Figure 1) were explored. L1 led to a better ee value than L2; and L2 gave a higher yield than that of L1 (entry 12 vs. entry 16); L3 gave a moderate ee value; both L4 and L5 are ineffective for this reaction (entries 16–19). Moreover, either 4,4-dimethylcyclohexane-1,3-dione 1b or 2,2-dimethylcyclohexan-1-one 1c was also tested under the optimal conditions and no corresponding product was detected; these results suggested that 1a is requirable for this reaction (entry 20).

Having established the optimal reaction conditions shown in the entry 12 of Table 1, we further surveyed the scope of various allylic substrates 2. When 2a and substrates 2b–2c, 2e–2h having an electron-rich substituent (e.g., p-Et, p-iso-Propyl, p-MeO, m-Me, m-MeO, and m-EtO) on the phenyl ring were employed, the corresponding 3a–3c, 3e–3h were obtained in moderate to good yields with high regio- and enantioselectivities.

Interestingly, substrate 2d bearing a bulky tert-butyl group and 2i attaching 3,4-di-Me groups on the phenyl ring were used, 3d and 3i were also achieved in good to high yield with a high level of regio- and enantioselectivities. However, the substrates 2j–2l containing the electron-poor substituent (e.g., m-Br, m-Cl, and p-Br) on the phenyl ring were utilized, the allyl products 3j–3l were obtained in moderate to good yields with slight lowering ee values but with high regioselectivities. Naphthyl-substituted substrate 2m and heteroaryl-substituted substrates (2n and 2o) offered 3m, 3n–3o in good yield with high regio- and enantioselectivity. In particular, aliphatic-substituted substrate 2p gave 3p in a moderate yield with high regio- and enantioselectivity (Scheme 3).

The scale-up synthesis of enolated allyl product such as 3d was conducted under the optimal conditions as shown in Scheme 3. 1a (318 mg, 1.5 mmol) and the allylic substrate 2d (744 mg, 3 mmol) were employed and 3d (351 mg, 75% yield, 93% ee and 3d/3d′ = 20/1) was obtained (Scheme 4).

The application of the enolated product 3d made by this method is shown in Scheme 3. The absolute configuration of 3j was determined as S by its X-ray analysis [29] (Figure 2).

The enantioselective fluorination of 3d was realized by a treatment of 3d with N-fluorobenzenesulfonimide (NFSI, 0.15 mmol) in the presence of K₂CO₃ (0.25 mmol), tetrabutylammonium iodide (TBAI, 0.01 mmol) and THF/H₂O (7/3) at room temperature and it gave the fluorinated 5 in an 86% yield with 99% ee and dr 3/1 (Scheme 4).

For a possible mechanism, we outline that it begins by insertion of iridium into the allyl-oxygen bond in the presence of Cs₂CO₃ and toluene to yield an ionized (π-allyl)-Ir-complex (Int A). The treatment of 1 with Cs₂CO₃ liberates 1′, the later attacks Int A to produce 3″, which leads to enolization to provide 3, regenerating the catalyst. The quaternary carbon center adjacent to the carbonyl group on the six-membered ring plays a significant role in the formation of enol 3 (or 3‴) because of the resonance effect [19] and steric effect (Scheme 5).

3. Materials and Methods

3.1. Reagents and General Methods

All manipulations were carried out under the argon atmosphere using standard Schlenk techniques. All glassware were oven or flame dried immediately prior to use. All solvents were purified and dried according to standard methods prior to use, unless stated otherwise.

¹H NMR spectra were obtained at 400 MHz or 600 MHz and recorded relative to the tetramethylsilane signal (0 ppm) or residual protio-solvent (7.26 ppm for CDCl₃). ¹³C NMR spectra were obtained at 100 MHz or 150 MHz, and chemical shifts were recorded relative to the solvent resonance (CDCl₃, 77.16 ppm). ¹⁹F NMR spectra were obtained at 376 MHz or 565 MHz. Data for NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br = broad singlet, coupling constant(s) in Hz, integration).

The phosphoramidite ligands [24,27,30], substituted allylic carbonates [31], were prepared according to the known procedures. Other chemicals were purchased from commercial suppliers and used without further purification, unless mentioned.

3.2. Synthetic Procedures

General Procedure for the Synthesis of 3: [Ir(COD)Cl]₂ (0.004 mmol, 4 mol%), phosphoramidite ligand L1 (0.008 mmol, 8 mol%) were dissolved in THF (0.5 mL) and n-propylamine (0.3 mL) in a dry Schlenk tube filled with argon. The reaction mixture was heated at 50 °C for 30 min and then the volatile solvents were removed under vacuum to give a yellow solid. After that, allylic carbonate 2 (0.20 mmol), cesium carbonate (Cs₂CO₃, 0.12 mmol), and toluene (1.0 mL) were added. In another dry Schlenk tube, 6,6-dimethyl-3-((trimethylsilyl) oxy) cyclohex-2-en-1-one 1a was prepared from 4,4-dimethylcyclohexane-1,3-cyclohexanedione (0.10 mmol) and hexamethyldisilazane (HMDS) (0.15 mmol) in DCM (2.0 mL), under stirring for 2.5 h at room temperature, and the solvent was removed under vacuum to give a light-yellow liquid which was transferred through a syringe into the above mentioned Schlenk tube. The reaction was stirred at room temperature for 12 h. Then the mixture was washed with brine. After the organic phase was collected, the aqueous phase was extracted with DCM. The combined organic phase was dried over anhydrous Na₂SO₄ and concentrated on a rotary evaporator. The crude residue was purified by flash column chromatography (petroleum ether/ethyl acetate) to give the desired products 3.

(S)-3-Hydroxy-6,6-dimethyl-2-(1-phenylallyl)cyclohex-2-en-1-one (3a), white solid; m.p.: 103–105 °C; 75% yield (19.2 mg); HPLC ee: 91% [Daicel CHIRALPAK AD-H (0.46 cm × 25 cm); n-hexane/2-propanol = 90/10; flow rate = 1.0 mL/min; detection wavelength = 254 nm; t_R = 6.77 (minor), 8.22 (major) min]. [α]_D²⁰ = +22.3 (c 1.0, CHCl₃). ¹H NMR (600 MHz, CD₃CN) δ 7.28–7.24 (m, 2H), 7.21 (d, J = 7.8 Hz, 2H), 7.17–7.13 (m, 1H), 6.49–6.43 (m, 1H), 5.11–5.05 (m, 2H), 4.88 (d, J = 7.8 Hz, 1H), 2.57–2.54 (m, 2H), 1.82 (t, J = 6.0 Hz, 2H), 1.06 (d, J = 6.0 Hz, 6H).¹³C NMR (150 MHz, CD₃CN) δ 212.6, 172.2, 144.4, 140.2, 128.5, 127.9, 126.1, 115.9, 115.4, 44.2, 39.8, 34.7, 27.7, 24.8, 24.8. IR (KBr): ν_max (cm⁻¹) = 3648, 3523, 3442, 1715, 1627, 1400, 1275, 1260, 764, 749. HRMS (ESI⁺) calcd for C₁₇H₂₀NaO₂ [M+Na]⁺: 279.1356, Found: 279.1362.

(S)-3-Hydroxy-2-(1-(4-isopropylphenyl)allyl)-6,6-dimethyl-cyclohex-2-en-1-one (3c), pale yellow solid; m.p.: 99–101 °C; 78% yield (23.2 mg); HPLC ee: 90% [Daicel CHIRALPAK AD-H (0.46 cm × 25 cm); n-hexane/2-propanol = 90/10; flow rate = 1.0 mL/min; detection wavelength = 254 nm; t_R = 6.56 (minor), 7.41 (major) min]. [α]_D²⁰ = −5.5 (c 1.0, CHCl₃). ¹H NMR (600 MHz, DMSO-d₆) δ 10.45 (s, 1H), 7.10–7.00 (m, 4H), 6.44–6.38 (m, 1H), 5.02–4.93 (m, 2H), 4.76 (d, J = 9.0 Hz, 1H), 2.52–2.50 (m, 3H), 1.73 (t, J = 6.6 Hz, 2H), 1.17 (d, J = 7.2 Hz, 6H), 0.99 (d, J = 3.6 Hz, 6H). ¹³C NMR (150 MHz, DMSO-d₆) δ 201.1, 170.6, 145.4, 141.5, 140.5, 127.3, 126.0, 115.0, 114.9, 43.5, 34.2, 33.4, 26.9, 25.3, 25.2, 24.5, 24.4. IR (KBr): ν_max (cm⁻¹) = 3498, 3431, 3011, 1676, 1632, 1413, 1265, 1243, 743. HRMS (ESI⁺) calcd for C₂₀H₂₆NaO₂ [M + Na]⁺: 321.1825, Found: 321.1823.

(S)-3-Hydroxy-2-(1-(4-methoxyphenyl)allyl)-6,6-dimethyl-cyclohex-2-en-1-one (3e), yellow solid; m.p.: 75–77 °C; 70% yield (20.1 mg); HPLC ee: 83% [Daicel CHIRALPAK AD-H (0.46 cm × 25 cm); n-hexane/2-propanol = 90/10; flow rate = 1.0 mL/min; detection wavelength = 254 nm; t_R = 10.52 (minor), 12.24 (major) min]. [α]_D²⁰ = +6.8 (c 1.0, CHCl₃). ¹H NMR (600 MHz, CD₃CN) δ 7.01 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H), 6.36–6.30 (m, 1H), 5.00–4.89 (m, 2H), 4.71 (d, J = 7.8 Hz, 1H), 3.65 (s, 3H), 2.45–2.42 (m, 2H), 1.70 (t, J = 6.0 Hz, 2H), 0.95 (d, J = 4.2 Hz, 6H). ¹³C NMR (150 MHz, CD₃CN) δ 202.2, 176.0, 158.2, 140.6, 135.9, 128.8, 116.0, 115.0, 113.7, 55.3, 43.3, 39.7, 34.5, 27.6, 24.7, 24.7. IR (KBr): ν_max (cm⁻¹) = 3523, 3129, 3006, 2990, 1607, 1509, 1400, 1275, 1260, 764, 749. HRMS (ESI⁺) calcd for C₁₈H₂₂NaO₃ [M + Na] ⁺: 309.1461, Found: 309.1462.

(S)-2-(1-(3-Ethoxyphenyl)allyl)-3-hydroxy-6,6-dimethyl-cyclohex-2-en-1-one (3h), yellow solid; m.p.: 83–85 °C; 76% yield (22.8 mg); HPLC ee: 89% [Daicel CHIRALPAK AD-H (0.46 cm × 25 cm); n-hexane/2-propanol = 90/10; flow rate = 1.0 mL/min; detection wavelength = 254 nm; t_R = 8.08 (major), 8.64 (minor) min]. [α]_D²⁰ = −21.5 (c 1.0, CHCl₃). ¹H NMR (600 MHz, DMSO-d₆) δ 10.45 (s, 1H), 7.12–7.07 (m, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.65–6.63 (m, 2H), 6.42–6.36 (m, 1H), 5.00–4.97 (m, 2H), 4.75 (d, J = 9.0 Hz, 1H), 3.93 (dd, J = 6.6, 2.4 Hz, 2H), 2.50–2.49 (m, 2H), 1.72 (t, J = 6.6 Hz, 2H), 1.29 (t, J = 6.6 Hz, 3H), 0.99 (d, J = 3.6 Hz, 6H). ¹³C NMR (150 MHz, DMSO-d₆) δ 201.0, 172.3, 159.7, 146.3, 140.5, 129.7, 120.4, 116.1, 115.6, 114.4, 112.1, 63.9, 44.4, 40.0, 34.8, 27.8, 25.1, 15.1. IR (KBr): ν_max (cm⁻¹) = 3498, 3465, 3009, 1665, 1620, 1342, 1298, 1213, 734. HRMS (ESI⁺) calcd for C₁₉H₂₄NaO₃ [M + Na]⁺: 323.1618, Found: 323.1617.

4. Conclusions

In conclusion, we developed Ir-catalyzed allylic enolization of 6,6-dimethyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-one involving keto-enol isomerization, which afforded the enolated allyl products in good to high yields with high regio- and enantioselectivities. This method allows the use of 6,6-dimethyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-one, tolerates numerous functionalized groups, and provides a new way for the construction of a chiral carbon-fluorine center.

Author Contributions

Conceptualization, X.-M.Z.; methodology, X.-L.W. and J.-T.C.; validation, X.-L.W. and J.-T.C.; investigation, X.-L.W.; resources, X.-M.Z. and S.-C.Z.; writing—original draft preparation, X.-L.W.; writing—review and editing, X.-M.Z. and S.-C.Z.; supervision, X.-M.Z. and S.-C.Z. 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

The authors are grateful to the Chinese National Science Foundation (NSF) (grant number 21971193).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Figures, Schemes and Table

Scheme 1. Cyclohexane-1,3-dione derivatives employed in allylic substitution under Pd, Ru, and Ir catalysis.

Scheme 2. Keto-enol isomerization of 4,4-dimethylcyclohexane-1,3-dione.

Figure 1. Ligands used in this reaction.

Scheme 3. Scope of the allylic substrates 2. Reaction conditions: [Ir(COD)Cl]2 (0.004 mmol), L1 (0.008 mmol), 1a (0.1 mmol), 2 (0.2 mmol), Cs2CO3 (0.12 mmol), and PhMe (1 mL). Yield referred to isolated yield and ee was determined by a chiral HPLC.

Scheme 4. Scale-up synthesis of 3d and its fluorination for the synthesis of 5 with a chiral C-F center.

Figure 2. X-ray molecular structure of 3j.

Scheme 5. Possible mechanism.

Table 1

Screening reaction conditions for Ir-catalyzed reaction between 6,6-dimethyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-one 1a and allylic substrate 2a ^a.

[Image omitted. Please see PDF.]
Entry	Ir catalyst	Ligand	Base	Solvent	Temp (°C)	3a/3a′b	Yield b (%)	ee c (%)
1	[Ir(COD)Cl]2	L1	CsF	DCM	−20	>20/1	13	85
2	[Ir(COD)Cl]2	L1	CsF	THF	−20	-	-	-
3	[Ir(COD)Cl]2	L1	CsF	CH3CN	−20	>20/1	18	73
4	[Ir(COD)Cl]2	L1	CsF	Toluene	−20	>20/1	21	91
5	[Ir(COD)Cl]2	L1	CsCl	Toluene	−20	>20/1	19	70
6	[Ir(COD)Cl]2	L1	Cs2CO3	Toluene	−20	>20/1	27	91
7	[Ir(COD)Cl]2	L1	CsOH	Toluene	−20	>20/1	49	71
8	[Ir(COD)Cl]2	L1	K2CO3	Toluene	−20	>20/1	31	80
9	[Ir(COD)Cl]2	L1	DBU	Toluene	−20	-	nr	-
10	[Ir(COD)Cl]2	L1	Cs2CO3	Toluene	0	>20/1	52	87
11	[Ir(COD)Cl]2	L1	Cs2CO3	Toluene	10	>20/1	60	92
12	[Ir(COD)Cl]2	L1	Cs2CO3	Toluene	25	>20/1	75	91
13	[Ir(COD)Cl]2	L1	Cs2CO3	Toluene	35	>20/1	86	85
14	[Ir(Cp*)Cl2]2	L1	Cs2CO3	Toluene	25	-	nr	-
15	Ir(COD)(acac)	L1	Cs2CO3	Toluene	25	>20/1	19	93
16	[Ir(COD)Cl]2	L2	Cs2CO3	Toluene	25	>20/1	78	87
17	[Ir(COD)Cl]2	L3	Cs2CO3	Toluene	25	>20/1	30	78
18	[Ir(COD)Cl]2	L4	Cs2CO3	Toluene	25	-	-	-
19	[Ir(COD)Cl]2	L5	Cs2CO3	Toluene	25	-	-	-
20 d	[Ir(COD)Cl]2	L1	Cs2CO3	Toluene	25	-	nr	-

^a Reaction conditions: Ir salt (0.004 mmol), ligand (0.008 mmol), 1a (0.10 mmol), 2a (0.20 mmol), base (0.12 mmol), and solvent (1 mL). ^b Isolated yield. ^c Determined by a chiral HPLC. ^d Either 1b or 1c instead of 1a was used.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27206981/s1, experimental details, NMR spectra, X-ray Crystallographic Information, HPLC Spectra, HRMS data for new products.

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