10.1002/ejoc.202000976
European Journal of Organic Chemistry
FULL PAPER
times: 96.7 min (minor), 97.4 min (major)]; IR (thin film): 1732
(146 mg, 0.36 mmol) in dichloromethane (10.0 mL) at –25 °C
and stirred at this temperature for another 16 h. After 16 h the
reaction was concentrated under reduced pressure to about 2
1
cm-1; H NMR (400 MHz, CDCl3, TMS, Major isomer): δ 7.12-
7.04 (m, 2H), 6.87-6.80 (m, 2H), 3.78 (s, 3H), 3.66 (s, 3H), 2.76-
2.60 (m, 1H), 2.36-2.24 (m, 1H), 2.06-1.90 (m, 1H), 1.65-1.51 (m, mL. The reaction was diluted with 1% EtOAc/hexane (30 mL)
1H), 1.20 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3, Major isomer): δ 177.5, 158.2, 139.0, 128.1,
114.1, 55.5, 51.6, 43.0, 37.9, 37.4, 22.9, 18.1; (M + H)+ HRMS
m/z calcd for (C14H21O3)+: 237.1491; Found: 237.1482.
and passed through a plug of neutral silica (15 g), eluting with
1% EtOAc/hexane (500 mL). Removal of solvent under reduced
pressure afforded (R,Z)-2h as a low melting white solid (467 mg,
57%) with a Z:E ratio of 98:2 as determined by GC-MS analysis;
Rf = 0.6 (EtOAc/hexane 1:9); HPLC analysis: 90% ee [Daicel
(2R,4R)-Methyl
4-(4-methoxyphenyl)-2-methylpentanoate
[4f]: Following general procedure, the heterodimer (R,Z)-2f (49
mg, 0.22 mmol), of 95% ee and Z:E = 93:7, in MeOH (3.0 mL)
was added to the 10 wt% Pd/C catalyst (12 mg, 0.011 mmol)
(reaction time: 3 h). Regular silica gel column purification of
ester using 2% EtOAc/hexane afforded 4f as a light yellow liquid
(34 mg, 64% in two steps), dr = 73:27 (by GC-MS of crude
ester); Rf = 0.4 (EtOAc/hexane 1:19); Chiral GC analysis: 99%
ee [Supelco Chiraldex BDM column; GC Conditions: Split ratio:
1:20; make up flow: 25 mL/min; H2 flow: 45 mL/min; air flow: 450
mL/min; injector temperature: 250 °C, pressure: 12.3-18.5 psi ;
oven temperature: 50-180 °C, 1 °C/min; detector temperature:
250 °C; retention times: 97.1 min (major), 97.2 min (minor)]; IR
Chiralpak OB-H column; 1 mL/min; solvent system: 2%
isopropanol in hexane; retention times: 12.1 min (minor), 15.1
min (major)]; [α]D24 = 16.7 (c = 1.04, CH2Cl2); IR (thin film):
1
1700 cm-1; H NMR (400 MHz, CDCl3, TMS): δ 7.47-7.39 (m,
2H), 7.35-7.28 (m, 2H), 4.24 (q, J = 7.6 Hz, 1H), 1.98 (s, 3H),
1.58 (d, J = 7.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.5,
143.7, 134.7, 133.1, 128.7, 128.6, 107.2, 50.3, 15.4, 12.4; (M +
H)+ HRMS m/z calcd for (C12H12ClO2)+: 223.0526; Found:
223.0522.
(2S,4S)-Methyl 4-(4-chlorophenyl)-2-methylpentanoate [4g]:
Following general procedure, the heterodimer (S,Z)-2g (81 mg,
0.36 mmol), of 82% ee and Z:E = 98:2, in MeOH (5 mL) was
added to the 10 wt% Pd/C catalyst (19 mg, 0.018 mmol)
(reaction time: 10 min). Crude GC-MS: acid:β-lactone = 93:7;
Regular silica gel column purification of ester using 2%
EtOAc/hexane afforded 4g as a light yellow liquid (63 mg, 72%
in two steps), dr = 66:34 (by GC-MS of crude ester); Rf = 0.5
(EtOAc/hexane 1:19); Chiral GC analysis: 91% ee [Supelco
Chiraldex BDM column; GC Conditions: Split ratio: 1:20; make
up flow: 25 mL/min; H2 flow: 45 mL/min; air flow: 450 mL/min;
injector temperature: 250 °C, pressure: 12.3-18.5 psi; oven
1
(thin film): 1732 cm-1; H NMR (400 MHz, CDCl3, TMS, Major
isomer): δ 7.12-7.04 (m, 2H), 6.87-6.80 (m, 2H), 3.78 (s, 3H),
3.66 (s, 3H), 2.75-2.60 (m, 1H), 2.36-2.23 (m, 1H), 2.06-1.90 (m,
1H), 1.65-1.51 (m, 1H), 1.20 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3, Major isomer): δ 177.5,
158.2, 139.0, 128.1, 114.1, 55.4, 51.6, 43.0, 37.9, 37.4, 22.9,
18.1; (M + H)+ HRMS m/z calcd for (C14H21O3)+: 237.1491;
Found: 237.1483.
Methyl 4-chlorophenylketene [1c][28]: Yellow oil (64%); 1H
NMR (400 MHz, CDCl3, TMS): δ 7.29-7.23 (m, 2H), 6.95-6.88 (m, temperature: 50-180 °C, 1 °C/min; detector temperature: 250 °C;
2H), 1.97 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 204.9, 132.2,
129.8, 129.2, 125.0, 33.7, 8.9; MS (EI 70 eV): m/z 166.0.
retention times: 91.2 min (minor), 91.6 min (major)]; IR (thin
film): 1732 cm-1; 1H NMR (400 MHz, CDCl3, TMS, Major isomer):
δ 7.30-7.23 (m, 2H), 7.14-7.06 (m, 2H), 3.66 (s, 3H), 2.79-2.64
(m, 1H), 2.35-2.20 (m, 1H), 2.10-1.91 (m, 1H), 1.67-1.52 (m, 1H),
1.21 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3, Major isomer): δ 177.2, 145.3, 128.8, 128.6, 127.3,
51.7, 42.6, 37.8, 37.7, 22.7, 18.1; (M + H)+ HRMS m/z calcd for
(C13H18ClO2)+: 241.0995; Found: 241.0991.
(S,Z)-4-(1-(4-Chlorophenyl)ethylidene)-3-methyloxetan-2-one
[(S,Z)-2g]: Following general procedure, propionyl chloride (0.65
mL, 7.35 mmol) in dichloromethane (2.0 mL) was added over 8
h to a solution of methyl 4-chlorophenylketene 1c (612 mg, 3.68
mmol), Hünig's base (1.28 mL, 7.35 mmol) and Me-quinidine
(124 mg, 0.37 mmol) in dichloromethane (10.0 mL) at –25 °C
and stirred at this temperature for another 16 h. After 16 h the
reaction was concentrated under reduced pressure to about 2
mL. The reaction was diluted with 1% EtOAc/hexane (30 mL)
and passed through a plug of neutral silica (15 g), eluting with
1% EtOAc/hexane (500 mL). Removal of solvent under reduced
pressure afforded (S,Z)-2g as a low melting white solid (461 mg,
56%) with a Z:E ratio of 98:2 as determined by GC-MS analysis;
Rf = 0.6 (EtOAc/hexane 1:9); HPLC analysis: 82% ee [Daicel
(2R,4R)-Methyl 4-(4-chlorophenyl)-2-methylpentanoate [4h]:
Following general procedure, the heterodimer (R,Z)-2h (77 mg,
0.34 mmol), of 90% ee and Z:E = 98:2, in MeOH (3.5 mL) was
added to the 10 wt% Pd/C catalyst (18 mg, 0.017 mmol)
(reaction time: 10 min). Crude GC-MS: acid:β-lactone = 90:10;
Regular silica gel column purification of ester using 2%
EtOAc/hexane afforded 4h as a light yellow liquid (55 mg, 66%
in two steps), dr = 65:35 (by GC-MS of crude ester); Rf = 0.5
(EtOAc/hexanes 1:19); Chiral GC analysis: 99% ee [Supelco
Chiraldex BDM column; GC Conditions: Split ratio: 1:20; make
up flow: 25 mL/min; H2 flow: 45 mL/min; air flow: 450 mL/min;
injector temperature: 250 °C, pressure: 12.3-18.5 psi; oven
temperature: 50-180 °C, 1 °C/min; detector temperature: 250 °C;
retention times: 91.2 min (major), 91.7 min (minor)]; IR (thin
film): 1732 cm-1; 1H NMR (400 MHz, CDCl3, TMS, Major isomer):
δ 7.30-7.23 (m, 2H), 7.14-7.06 (m, 2H), 3.66 (s, 3H), 2.79-2.64
(m, 1H), 2.37-2.20 (m, 1H), 2.10-1.91 (m, 1H), 1.67-1.53 (m, 1H),
1.21 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3, Major isomer): δ 177.2, 145.3, 128.8, 128.6, 127.2,
51.7, 42.6, 37.8, 37.7, 22.7, 18.1; (M + H)+ HRMS m/z calcd for
(C13H18ClO2)+: 241.0995; Found: 241.0992.
Chiralpak OB-H column;
1 mL/min; solvent system: 2%
isopropanol in hexane; retention times: 11.6 min (major), 16.0
min (minor)]; [α]D24 = 13.2 (c = 1.02, CH2Cl2); IR (thin film):
1
1701 cm-1; H NMR (400 MHz, CDCl3, TMS): δ 7.46-7.40 (m,
2H), 7.35-7.29 (m, 2H), 4.25 (q, J = 7.6 Hz, 1H), 1.98 (s, 3H),
1.58 (d, J = 7.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.5,
143.8, 134.7, 133.2, 128.7, 128.6, 107.2, 50.4, 15.4, 12.5; (M +
H)+ HRMS m/z calcd for (C12H12ClO2)+: 223.0526; Found:
223.0521.
(R,Z)-4-(1-(4-Chlorophenyl)ethylidene)-3-methyloxetan-2-one
[(R,Z)-2h]: Following general procedure, propionyl chloride (0.65
mL, 7.35 mmol) in dichloromethane (2.0 mL) was added over 8
h to a solution of methyl 4-chlorophenylketene 1c (612 mg, 3.68
mmol), Hünig's base (1.28 mL, 7.35 mmol) and TMS-quinine
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