Chiral 2-Amino Alcohol Derivatives Catalyze the Enantioselective α-Chlorination of β-Ketoesters

Abstract

The enantioselective ${\alpha}$-chlorination of cyclic ${\beta}$-ketoesters catalyzed by chiral 2-aminoalcohol derivatives (2f) has been developed. For the optically active ${\alpha}$-chlorinated products, the isolated yields are in the range of 85-94% and the enantiomeric excesses are up to 84% ee.

Introduction

The enantioselective construction of C-X stereogenicity has gained considerable momentum in modern organic syn-thesis, drug, discovery and sciences.1-5 For the enantioselec-tive α-chlorination of β-ketoesters, several metal-mediated approaches have been reported.6-11 However, the organo-catalytic enantioselective α-chlorination is still rare.

In 2005, the first enantioselective α-chlorination of β- ketoesters with polyhalogenated quinolinone as the halogen source catalyzed by O-benzoylquinine was achieved by Melchiorre et al.12 Feng et al. reported further developments on a highly enantioselective α-chlorination of β-ketoesters by using (S)-pipecolic acid derived N,N'-dioxide as organo-catalyst and N-chlorosuccinimide (NCS) as the chlorinating reagent at −20 °C.13 Furthermore, Etayo et al. also reported the examples of highly enantioselective chlorination of cyclic β-ketoesters catalyzed by chiral amino diol derivatives using NCS as the chlorine Source.14 However, multi-step synthesis and complex structure catalysts were the main drawbacks of these methods.

In this paper we disclose that the commercially available chiral 2-aminoalcohol derivatives catalyze the asymmetric chlorination applicable to cyclic β-ketoesters producing the corresponding optically active α-halogenated compounds in good yields and moderate to good enantioselectivities using NCS (3a) as the chlorine source.

 

Results and Discussion

A series of screening experiments were performed in order to examine the catalytic efficiency of several commercially available chiral 2-aminoalcohol derivatives (2a-i). The ethyl-2-oxocyclopentane carboxylate (1a) was chosen as the model substrate with NCS (3a) as chlorine donor in toluene at room temperature. The results were shown in Table 1.

As shown in Table 1, all catalysts led to good yields. The size of R3 played an important role in controlling the enantioselectivity. For example, catalyst 2b containing the largest R3 group gave better result (Table 1, entry 2), and the catalyst 2c containing the smallest R3 group showed the lowest catalytic selectivity with 13% ee (Table 1, entry 3). R1 group has little influence on the enantioselectivity (Table 1, entries 1 and 5).

Table 1.a2a-i (20 mol %), 1a (1.0 mmol), NCS (3a, 1.2 mmol), toluene (5 mL) at room temperature. bIsolated yield. cEnantiomeric excess determined by GC using a chiraldex® G-TA column. dReaction temperature at 0 °C

By comparing catalysts 2f and 2b or catalysts 2g and 2a, it was obvious that the introduction of a methyl group on the nitrogen atom has a beneficial effect on both conversion and enantioselectivity of products (Table 1, entries 1-2, 6 and 8). Nevertheless, the catalysts with two alkyl groups on the nitrogen atom only obtained mediate enantioselectivity (Table 1, entries 9-10). Lowering the temperature from room temperature to 0 °C in all cases led to an improvement in enantioselectivity (Table 1, entry 7).

Table 2.aIsolated yield. bEnantiomeric excess determined by GC using a Chiraldex® G-TA column

The effects of solvent and chlorine donor on the 2f-catalyzed asymmetric α-chlorination of 1a at 0 °C were studied. The results showed that NCS was the best choice (Table 2, entry 1). The use of reagents 3b-d, which have nitrogen-chlorine bonds, afforded product 4a with good yield but had a detrimental effect on the enantioselectivity (Table 2, entries 2-4). Using 3e as chlorine donor, no enantio-meric excess product was obtained (Table 2, entry 5). The effects of solvent on the reaction were also studied. The best result was given when the reaction was performed in cyclo-hexane (Table 2, entry 6).

Under our optimized reaction conditions, we investigated 2f-catalyzed enentioselective α-chlorination of various cyclic β-ketoesters with NCS (3a) in cyclohexane at 0 °C to afford the optically active α-chlorinated adducts 4a-i in high yields (Table 3). The substrates with sterically more bulky ester groups gave the higher enantioselectivities (Table 3, entry 2). Substrates 1f and 1h bearing an electron withdrawing bromine atom and substrates 1g and 1i with electron donat-ing groups such as MeO substituent on the benzene ring produced the similar enantioselectivities. Six-membered ring esters were less enantioselective than five-membered ring ones (Table 3, entries 5-9).

 

Conclusion

In summary, we have presented the enantioselective chlori-nation of cyclic β-ketoesters using inexpensive commercial-ly available NCS as chlorine source and 2f as the catalyst. The reactions proceeded smoothly to afford the correspond-ing optically active α-chlorinated products in high yields with moderate to good enantioselectivities.

Table 3aReaction conditions: 2f (20 mol %), 1a-i (1.0 mmol.), NCS (1.2 mmol.), cyclohexane (5 mL) at 0 °C. bIsolated yield. cEnantiomeric excess determined by GC using a Chiraldex® G-TA column (4a-d), or by HPLC using a Chiralpak IB column (4e), AD-H column (4h), and Chiralpak OD-H column (4f-g, i).

 

Experimental

General Methods. The reagents were purchased from Merck, 1H and 13C spectra were recorded in CDCl3 on a 400 MHz instrument at 400 MHz (1H) and 100 MHz (13C) with TMS as internal standard. High performance liquid chromatography (HPLC) was performed on an Agilent 1100 liquid chromato-graph; HPLC analysis using Diacel chiralcel IB, OD or AD-H column. Gas chromatography analyses were performed using a Varian CP-3800 instrument equipped using an Astec Chiraldex® G-TA 30 m × 0.25 mm capillary column. Flash column chromatography was performed with 300- and 400-mesh silica gel.

General Procedure for Organocatalytic Asymmetric α-Chlorination of β-Ketoesters 4a-i. To a solution of chiral 2-amino alcohol derivatives (2f) (45.4 mg, 0.2 mmol) in the cyclohexane (5 mL), the corresponding β-ketoester (1 mmol) was added and the mixture was stirred for 10 min at 0 °C. Then NCS (159.6 mg, 1.2 mmol) was added and stirring was continued for the indicated time. The crude reaction mixture was added to a silica gel column and eluted using dichloromethane/hexanes (1:1 or 2:1) as eluent depending on the product polarity. After evaporation of the solvent under vacuum the enantiomeric excess of the corresponding isolated α-chloro-β-ketoester was determined by GC or HPLC analysis using chiral stationary phases.

Ethyl of 2-Chloro-2-oxocyclopentanecarboxylic acid 4a: Colourless oil, GC conditions: Chiraldex® G-TA; T1 = 50 °C, t1 = 1 min, v1 = 8 °Cmin−1, T2 = 150 °C, t2 = 15 min, v2 = 10 °Cmin−1, T3 = 50 °C t3 = 1 min; tR = 20.0 [minor], tR = 22.6 [major]; 1H NMR (CDCl3, 400 MHz) δ 1.35 (t, 3H), 2.06–2.20 (m, 2H), 2.37–2.45 (m, 2H), 2.49–2.60 (m, 1H), 2.68–2.77 (m, 1H), 4.21 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 18.8, 27.5, 35.8, 38.2, 60.9, 84.1, 166.1, 206.8; Elemental analysis found C, 50.40, H, 5.83, Cl, 18.63, C13H13ClO5; Requires C, 50.41, H, 5.82, Cl, 18.60.

Tert-Butyl of 2-Chloro-2-oxocyclopentanecarboxylic acid 4b: Yellowish solid, GC conditions: Chiraldex® G-TA; T1 = 50 °C, t1 =1 min, v1 = 8 °C min−1, T2 = 135 °C, t2 = 25 min, v2 = 10 °C min−1, T3 = 50 °C, t3 = 1 min; tR = 23.2 [major], tR = 23.5 [minor]; 1H NMR (CDCl3, 400 MHz) δ 1.48 (s, 9H), 2.06–2.19 (m, 2H), 2.35–2.46 (m, 2H), 2.47–2.59 (m, 1H), 2.67–2.77 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 19.0, 27.7, 35.6, 38.5, 70.3, 84.1, 166.1, 206.8; Elemental analysis found C, 54.93, H, 6.93, Cl, 16.21, C13H13ClO5; Requires C, 54.92, H, 6.91, Cl, 16.21.

Methyl of 2-Chloro-2-oxocyclohexanecarboxylic acid 4c: Colourless oil, GC conditions: Chiraldex® G-TA; T1 = 50 °C, t1 = 1 min, v1 = 8 °C min−1, T2 = 150°C, t2 = 15 min, v2 = 10 °C min−1, T3 = 50 °C, t3 = 1 min; tR = 21.7 [minor], tR = 25.0 [major]. 1H NMR (CDCl3, 400 MHz) δ 1.65-1.78 (m, 1H), 1.84-2.01 (m, 3H), 2.14 (ddd, 14.0 Hz, 8.0 Hz, 3.2 Hz, 1H), 2.42 (ddd, J = 13.7 Hz, 6.6 Hz, 6.6 Hz, 1H), 2.72-2.89 (m, 2H), 3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 21.9, 26.5, 38.6, 39.5, 53.3, 73.2, 166.8, 200.0; Elemental analysis found: C, 50.39, H, 5.80, Cl, 18.58 C8H11ClO3; Requires C, 50.41, H, 5.82, Cl, 18.60

Isopropyl of 2-Chloro-2-oxocyclohexanecarboxylic acid 4d: Colourless oil. GC conditions: Chiraldex® G-TA; T1 = 50 °C, t1 = 1 min, v1 = 8 °C min−1, T2 = 150 °C, t2 = 10 min, v2 = 10 °C min−1, T3 = 50 °C, t3 = 1 min; tR = 20.9 [minor], tR = 23.9 [major]. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H), 2.03–2.20 (m, 2H), 2.33–2.44 (m, 2H), 2.50–2.61 (m, 1H), 2.73 (ddd, J = 14.4 Hz, 9.2 Hz, 8.0 Hz, 1H), 5.11 (sept, J = 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.0, 21.5, 21.6, 35.5, 38.3, 69.9, 71.1, 166.8, 206.2; Elemental analysis found C, 54.91, H, 6.89, Cl, 16.19 C10H15ClO3; Requires C, 54.92, H, 6.91, Cl, 16.21

Methyl of 2-Chloro-1-oxo-indan-2-carboxylic acid 4e: Pale yellow oil. HPLC conditions: Daicel Chiralpak IB, hexane/i-PrOH = 96/4, 1.0 mL/min, 230 nm; tR = 9.9 [major], tR = 11.6 [minor]. 1H NMR (CDCl3, 400 MHz) δ 3.58 (d, J =17.6 Hz, 1H), 3.83 (s, 3H), 4.11 (d, J = 17.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H); Elemental analysis found C, 58.80, H, 4.02, Cl, 15.77 C11H9ClO3; Requires C, 58.81, H, 4.04, Cl, 15.78.

Methyl of 5-Bromo-2-chloro-1-oxo-indan-2-carboxylic acid 4f: White solid. HPLC conditions: Daicel Chiralpak AD-H, hexane/i-PrOH = 90/10, 0.7 mL/min, 254 nm; tR = 16.9 [major], tR = 20.6 [minor]. 1H NMR (CDCl3, 400 MHz) δ 3.54 (d, J = 18.0 Hz, 1H), 3.83 (s, 3H), 4.11 (d, J = 18.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ 42.9, 54.0, 67.3, 127.0, 129.5, 131.0, 132.1, 132.3, 151.9, 167.5, 193.7; Ele-mental analysis found: C, 43.52, H, 2.64, Br, 26.34, Cl, 15.77 C11H8BrClO3; Requires C, 43.53, H, 2.66, Br, 26.32, Cl, 15.76.

Methyl of 2-Chloro-5,6-dimethoxy-1-oxo-indan-2-carbox-ylic acid 4g: Pale yellow solid. HPLC conditions: Daicel Chiralpak AD-H, hexane/i-PrOH = 80/20, 0.7 mL/min, 254 nm; tR = 18.3 [major], tR = 20.7 [minor]. 1H NMR (CDCl3, 400 MHz) δ 3.49 (d, J = 17.2 Hz, 1H), 3.82 (s, 3H), 3.92 (s, 3H), 4.01 (s, 3H), 4.04 (d, J = 17.2 Hz, 1H), 6.86 (s, 1H), 7.24 (s, 1H). 13C NMR (CDCl3, 100 MHz) δ 43.0, 54.0, 56.2, 56.5, 68.4, 105.6, 107.0, 125.0, 146.5, 150.3, 157.1, 167.8, 193.5; Elemental analysis found C, 54.82, H, 4.61, Cl, 12.45 C13H13ClO5; Requires C, 54.84, H, 4.60, Cl, 12.45.

Methyl of 2-Chloro-7-bromo-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid 4h: White solid, HPLC conditions: Daicel Chiralpak AD-H; hexane/i-PrOH = 80/20, 1.0 mL/min, 254 nm; tR = 12.0 [major], tR = 13.1 [minor]. 1H NMR (CDCl3, 400 MHz) δ 2.49-2.55 (m, 1H), 2.93-3.10 (m, 2H), 3.17-3.26 (m, 1H), 3.85 (s, 3H), 7.18 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 8.20 (bs, 1H). 13C NMR (CDCl3, 100 MHz) δ 25.0, 29.8, 34.8, 54.0, 70.2, 121.5, 130.5, 131.5, 131.5, 137.1, 141.2, 167.5, 186.3; Elemental analysis found C, 45.36, H, 3.15, Br, 25.13, Cl, 11.14 C12H10BrClO3; Requires C, 45.39, H, 3.17, Br, 25.16, Cl, 11.16.

Methyl of 2-Chloro-7-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid 4i: White solid. HPLC conditions: Daicel Chiralpak OD-H; hexane/i-PrOH = 98/2, 1.0 mL/min, 254 nm; tR = 20.0 [major], tR = 21.9 [minor]. 1H NMR (CDCl3, 400 MHz) δ 2.47-2.54 (m, 1H), 2.90-3.00 (m, 2H), 3.16-3.24 (m, 1H), 3.83 (s, 3H), 3.85 (s, 3H), 7.13 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.9, 35.5, 53.8, 55.5, 70.6, 110.5, 123.0, 130.0, 130.5, 135.3, 158.7, 168.0, 187.5; Elemental analysis found C, 58.08, H, 4.89, Cl, 13.20 C13H13ClO4; Requires C, 58.11, H, 4.88, Cl, 13.19.