Asymmetric cyclopropanation of chalcones using chiral phase-transfer catalysts

Graphical abstract

Abstract

The first phase-transfer catalyzed cyclopropanation reaction of chalcones using bromomalonates as the nucleophiles in a Michael Initiated Ring Closing reaction (MIRC) was developed. Key to success was the use of a free OH-containing cinchona alkaloid ammonium salt catalyst and carefully optimized liquid/liquid reaction conditions. The reaction performed well for electron neutral and electron deficient chalcones giving the products in yields up to 98% and with enantiomeric ratios up to 91:9.

Introduction

Chiral cyclopropanes are highly versatile organic molecules. Their importance is a result of their unique reactivity which makes them outstanding synthons to access complex molecular scaffolds¹ and because of their presence in different biologically active compounds.² Although a variety of versatile strategies for the stereoselective syntheses of chiral cyclopropanes have been reported,^1–3 the development of novel strategies to access these important compounds is a worthwhile goal. Asymmetric phase-transfer catalysis has proven its potential in numerous demanding applications^4–7 and a variety of carefully fine-tuned catalysts have been reported in the past.^4–9 Surprisingly, the use of (chiral) phase-transfer catalysts (PTCs) to facilitate (stereoselective) cyclopropanation reactions has so far been limited to a few examples only.^10–12 Based on our recent success in developing novel TADDOL-derived PTCs⁹ and the knowledge gathered therein we have now undertaken systematic investigations concerning the PT-catalyzed Michael Initiated Ring Closing (MIRC) reaction of bromomalonates 1 with trans-chalcones (2) to furnish cyclopropanes 3 in the presence of a variety of known chiral quaternary ammonium salt PTCs (Scheme 1). The asymmetric cyclopropanation of chalcones with malonates is an unprecedented reaction and should therefore broaden the application scope of asymmetric phase-transfer catalysis toward such interesting chiral moieties.

Scheme 1.

Targeted phase-transfer catalyzed MIRC-reaction of bromomalonates with chalcones.

Results and discussion

Table 1 gives an overview of the most significant results obtained in the course of a thorough and systematic screening. Initial studies were carried out using diethyl bromomalonate (1a) as the nucleophile in the presence of differently substituted cinchona alkaloid catalysts 4 and 5 under liquid/solid conditions (entries 1–9). The first challenge to be addressed was the identification of reaction conditions suppressing the rapid base-catalyzed dimerization of 1.¹³ Although the combination of different solvents with solid Cs₂CO₃ furnished the targeted product 3 in reasonable yields only very low selectivities were obtained. Out of different other solvent/solid base combinations only the use of K₃PO₄/toluene in combination with the free OH-containing quinidine-derived catalyst 4c furnished 3 in moderate selectivity at room temperature (entry 9).

Table 1.

Identification of the most-active catalyst and optimum reaction conditions in the phase-transfer catalyzed MIRC-reaction of bromomalonates 1 with 2

Entry	1	Cat.	Solv.	Base (equiv)	Concd.	Yielda (%)	er b (+/−)
1	1a	4a	CH2Cl2	Cs2CO3 (4×)	Ac	70	51:49
2			THF			77	43:57
3			Toluene			30	44:56
4		4b	THF			45	46:54
5		4c				40	44:56
6		5a				41	51:49
7		5c				14	52:48
8		5d				55	57:43
9		4c	Toluene	K3PO4 (10×)		45	31:69
10		4a		K3PO4 (50%) (10×)		84	50:50
11		4b				36	38:62
12		4c				48	26:74
13		4d				57	40:60
14		4e				44	31:69
15		4f				67	50:50
16		5b				30	70:30
17		5d				45	73:27
18		6				57	47:53
19		4c	Mesitylene			43	24:76
20			Toluene	Li2CO3 (50%) (10×)		7	21:79
21				K2CO3 (50%) (10×)		35	24:76
22			Mesitylene			54	22:78
23	1b					n.r.	—
24	1c					63	17:83
25					Bc	10	17:83
26					Cc	54	15:85
27					Dc	83	15:85
28					Ec	82	13:87
29					Fc	39	10:90
30		5d			Ec	61	75:25

^aIsolated yield.

^bDetermined by HPLC using a chiral stationary phase.

^cA: 3 equiv 2, rt, 22 h, 0.15 M; B: 3 equiv 1a, RT, 22 h, 0.15 M; C: 3 equiv 2, rt, 46 h, 0.075 M; D: 6 equiv 2, rt, 46 h, 0.075 M; E: 6 equiv 2, 0 °C, 46 h, 0.075 M; F: 6 equiv 2, −20 °C, 46 h, 0.075 M.

During the course of our investigations the Adamo group reported the first PT-catalyzed cyclopropanation of highly electrophilic 4-nitro-5-styrylisoxazoles using cinchona alkaloid-derived PTCs under liquid/liquid (toluene/aq K₃PO₄) conditions.¹¹ Interestingly, applying analogous conditions to our reaction (entries 10–18), the presence of the free sec-9-OH-group in the cinchona alkaloid catalyst was found to be crucial to achieve reasonable selectivities. Whereas O-alkylated derivatives (e.g., 4a) as well as our standard TADDOL-based catalyst 6 gave racemic 3 only, the bifunctional quinidine and quinine-derived catalysts 4c and 5d were found to be the most active ones, giving 3 with enantiomeric ratios up to 74:26 at room temperature (entries 12, 17). Compared to the corresponding cinchonine and cinchonidine based catalysts 4b and 5b the 6′-OMe group of 4c and 5d has a beneficial effect on yield and selectivity. In sharp contrast, a 9-O-protected free 6′-OH based catalyst (4f, entry 15) was found to be absolutely nonselective.¹⁴ Further investigations using 4c under liquid/liquid biphasic conditions (entries 19–22) allowed us to identify the combination of mesitylene and aqueous K₂CO₃ as the most promising one with respect to yield and enantioselectivity (entry 22). Testing the influence of different ester-groups we found that the t-butyl ester 1b did not give any product at all whereas the methyl ester 1c performed reasonably well at room temperature already (entry 24). To improve yield and enantioselectivity different ratios of reagents, temperature, reaction time, and dilution were investigated (entries 24–29). Initially we employed an excess of 2 which could easily be recovered after the reaction. As the dimerization of 1 was found to be the major yield-limiting side reaction,¹³ the use of an excess of 1 was tested next. However, the yield dropped significantly under a variety of conditions (e.g., entry 25) and besides vast amounts of the unwanted dimer various decomposition products were observed. Test reactions revealed that product 3 undergoes further (most presumably ring opening) reactions with an excess of 1 under the reaction conditions. Thus, ensuring a permanent excess of the Michael acceptor 2 was found to be crucial to warrant good yields (entry 27). In addition, higher dilution and prolonged reaction time combined with a slightly reduced reaction temperature allowed us to isolate (−)-3 in high yields and with good enantioselectivities up to 90:10 (entries 28 and 29).¹⁵ Surprisingly, where the pseudoenantiomeric 4c and 5d performed similarly under Adamo’s conditions (entries 12 and 17), the quinine-derived 5d was found to be less selective than 4c under our optimized conditions (entry 30 vs 28).

Having identified suitable high-yielding and selective conditions for the cyclopropanation of the parent chalcone 2, a series of differently substituted chalcone derivatives was screened next (Table 2). Where electron neutral and electron deficient chalcones were well-tolerated (no matter which aryl group was modified) (entries 1–7), more electron rich electrophiles did not undergo the cyclopropanation reaction. Instead the main product in these experiments was the dimerization of bromomalonate 1c, thus illustrating again the high dependence of this reaction on the electrophilicity of the Michael acceptor and seemingly small changes in the electronic nature of the reagents have a dramatic influence on the outcome of the reaction.

Table 2.

Scope of the phase-transfer catalyzed MIRC-reaction of 1c with different chalcones

Entry	Chalcone	Ar1	Ar2	Prod.	Yielda (%)	er b (+/−)
1	2	Ph	Ph	3c	82	13:87
2	7	4-ClC6H4	Ph	8	98	12:88
3	9	Ph	4-ClC6H4	10	91	11:89
4	11	Ph	4-FC6H4	12	72	13:87
5	13	3-NO2C6H4	Ph	14	59	9:91
6	15	4-NO2C6H4	Ph	16	58	10:90
7	17	Ph	4-MeC6H4	18	72	16:84
8	19	4-OH-C6H4	Ph	20	Nrc	Nd
9	21	Ph	4-OH-C6H4	22	Nrc	Nd
10	23	4-MeO-C6H4	Ph	24	Nrc	Nd
11	25	Ph	4-MeO-C6H4	26	Nrc	Nd

^aIsolated yield.

^bDetermined by HPLC using a chiral stationary phase.

^cOnly dimerization of 1c.

Conclusion

Summarizing, the first phase-transfer catalyzed cyclopropanation reaction of bromomalonates and chalcones proceeding via a Michael Initiated Ring Closing (MIRC) reaction has been developed. Key to success was the use of a free OH-containing cinchona alkaloid ammonium salt catalyst and carefully optimized liquid/liquid reaction conditions. The exact role of the free-OH group is not clear yet. However, based on recent reports two possible modes of action seem reasonable.⁵ The free OH-group can either cause an additional coordination of the bromomalonate nucleophile thus achieving a better control of the orientation of the nucleophile compared to the standard ion pair formation achieved with classical chiral PTCs or an activation/coordination of the chalcone, thus resulting in a highly ordered transition state during the reaction.⁵ The reaction performed well for electron neutral and electron deficient chalcones giving the products in yields up to 98% and with enantiomeric ratios up to 91:9. In contrast, electron rich chalcones could not be successfully employed yet due to the lower reactivity of these Michael acceptors. Further investigations to expand this methodology toward other starting materials are currently undertaken and will be reported in due course.

Experimental section

General procedure for the phase-transfer catalyzed cyclopropanation using bromomalonates and chalcones

Reactions were usually carried out using less than 0.5 mmol bromomalonate (1). First 10 equiv K₂CO₃ (50% aq solution) was added to a solution of catalyst (10 mol %) in mesitylene (assuring a dilution of 0.075 M based on the amount of 1 used in the reaction). After flushing the solution with Argon, the corresponding chalcone derivative (6 equiv) was added. The vigorously stirred solution (>1200 rpm) was cooled to 0 °C (Ar-atmosphere). Subsequently, the bromomalonate was added in 3 portions (3 × 0.33 equiv over 24 h). The biphasic mixture was stirred for a total of 46 h at 0 °C. After extraction with CH₂Cl₂/H₂O, the combined organic phases were dried over Na₂SO₄, evaporated to dryness and purified by column chromatography using heptanes/EtOAc = 40:1–10:1 as the eluent. The excess chalcone could easily be recovered hereby.

Cyclopropane (−)-3c

Obtained as a colorless oil in 82% yield (136 mg, 0.40 mmol) and with er = 87:13 upon reacting chalcone 2 (615 mg, 2.96 mmol) with bromomalonate 1c (104 mg, 0.49 mmol) in 6.4 mL mesitylene with 0.82 mL aqueous K₂CO₃ solution (50% w/w). Analytical data are in accordance with those reported in the literature.¹⁶ ${[\alpha ]}_{\text{D}}^{20}$ −25.9 (c 0.44, CHCl₃); ¹H NMR (300 MHz, δ, CDCl₃, 298 K): 3.55 (s, 3H), 3.72 (s, 3H), 3.88 (d, J = 7.7 Hz, 1H), 4.14 (d, J = 7.7 Hz, 1H), 7.27–7.34 (m, 5H), 7.48–7.56 (m, 2H), 7.59–7.66 (m, 1H), 8.07–8.13 (m, 1H) ppm; ¹³C NMR (75 MHz, δ, CDCl₃, 298 K): 35.1, 36.6, 46.0, 53.0, 53.1, 127.8, 128.4, 128.5, 128.6, 128.8, 133.4, 133.8, 136.7, 166.1, 166.6, 193.9 ppm; IR (film): ν = 3064, 3032, 2995, 2953, 2916, 2846, 2358, 2341, 1735, 1678, 1597, 1581, 1449, 1437, 1352, 1267, 1219, 1178, 1117, 1024, 1010, 943, 916, 739 cm⁻¹; The enantioselectivity was determined by HPLC (Chiralcel OD-R, eluent: H₂O/AcN = 55:45, 0.7 mL/min, 10 °C, retention times: (+)-enantiomer 36.4 min, (−)-enantiomer 39.6 min); HRMS (ESI): m/z calcd for C₂₀H₁₈O₅: 339.1227 [M+H]⁺; found: 339.1227.

Supplementary data

Supplementary data

Analytical data and experimental details can be found in the supporting material.