10.1002/ejoc.201800656
European Journal of Organic Chemistry
FULL PAPER
Acylation of Racemic Amines 1a and 1b with Racemic Acyl
Chlorides 2a-c. General Procedure: A solution of the appropriate acyl
chloride 2a, 2b, or 2c (0.5 mmol) in the appropriate solvent (5 mL) was
added to a solution of amine 1a or 1b (1 mmol) in the same solvent (5
mL) at +20 or –20 C. The reaction mixture was kept in a thermostat at a
given temperature for 6 h; then successively washed with 4 M HCl (2 × 4
mL), saturated aqueous NaCl (4 × 5 mL), 5% NaHCO3 (2 × 5 mL), and
water (2 × 5 mL). The organic layer was separated, dried over Na2SO4,
and evaporated under reduced pressure. The residue was analyzed by
GC (Shimadzu GC-2010), then recrystallized to yield the major (R*,S*)-
diastereomers of amides 3a-c and 4a-c.
(R*,S*)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(2-(4-methoxyphenoxy)-
propionyl)-2H-[1,4]benzoxazine ((R*,S*)-4c): Yield 109 mg (60%), white
solid, m.p. 105-107 °C (n-hexane-EtOAc). GC: (R,S)-4c = 29.1 min, (R,R)-4c
= 29.8 min, (R*,S*)-(R*,R*) 99.5:0.5. 1H NMR (500 MHz, DMSO-d6,
100 °C): = 7.53 (ddd, J = 9.3, 5.5, 2.5 Hz, 1 H, C5H benzoxazine), 6.78-
6.87 (m, 5 H, Ar acyl and C6H benzoxazine), 5.29 (q, J = 6.3 Hz, 1 H,
C2H acyl), 4.71 (qdd, J = 6.8, 2.6, 1.4 Hz, 1 H, C3H benzoxazine), 4.33
(dd, J = 11.0, 1.4 Hz, 1 H, C2HA benzoxazine), 4.06 (dd, J = 11.0, 2.6 Hz,
1 H, C2HB benzoxazine), 3.69 (s, 3 H, OMe), 1.49 (d, J = 6.3 Hz, 3 H, Me
acyl), 1.13 (d, J = 6.8 Hz, 3 H, Me benzoxazine) ppm. 13C NMR (125
MHz, DMSO-d6, 100 °C): = 168.61, 153.96, 150.21, 146.63 (dd, J
=242.5, 9.9 Hz), 138.61 (dd, J = 244.4, 15.3 Hz), 135.94 (dd, J = 10.0,
3.2 Hz), 120.83, 118.88 (dd, J = 8.0, 4.3 Hz), 116.43, 114.45, 106.37 (d,
J = 18.3 Hz), 71.79, 69.62, 55.10, 45.91, 16.46, 14.63 ppm. 19F NMR
(470 MHz, DMSO-d6, 100 °C): = 20.95-21.13 (m, 1 F, C7F), 2.11 (ddd,
J = 21.0, 7.9, 2.0 Hz, 1 F, C8F) ppm. Anal. calcd. for C19H19F2NO4: C,
62.81; H, 5.27; N, 3.85; F, 10.46. Found: C, 63.04; H, 5.17; N, 3.90; F
10.44.
(R*,S*)-3,4-Dihydro-3-methyl-N-(2-(4-nitrophenoxy)propionyl)-2H-
[1,4]benzoxazine ((R*,S*)-3b): Yield 104 mg (61%), white solid, m.p.
129-130 °C (n-hexane-EtOAc). GC: (R,S)-3b = 32.4 min, (R,R)-3b = 33.4
1
min, (R*,S*)-(R*,R*) 99.7:0.3. H NMR (500 MHz, DMSO-d6, 100 °C): =
8.13 (app. d, J = 9.2 Hz, 2 H, Ar acyl), 7.65-7.67 (m, 1 H, C5H
benzoxazine), 6.99-7.06 (m, 3 H, C7H benzoxazine and Ar acyl), 6.88 (dd,
J = 8.2, 1.1 Hz, 1 H, C8H benzoxazine), 6.83-6.86 (m, 1 H, C6H
benzoxazine), 5.62 (q, J = 6.3 Hz, 1 H, C2H acyl), 4.61-4.66 (m, 1 H, C3H
benzoxazine), 4.20 (dd, J = 11.0, 1.5 Hz, 1 H, C2HA benzoxazine), 4.08
(dd, J = 11.0, 2.7 Hz, 1 H, C2HB benzoxazine), 1.60 (d, J = 6.3 Hz, 3 H,
Me acyl), 1.16 (d, J = 6.7 Hz, 3 H, Me benzoxazine) ppm. 13C NMR (125
MHz, DMSO-d6, 100 °C): = 167.21, 161.56, 145.65, 141.21, 125.35,
125.10, 124.16, 122.68, 119.63, 115.95, 115.09, 71.58, 69.07, 45.13,
16.51, 14.82 ppm. Anal. calcd. for C18H18N2O5: C, 63.15; H, 5.30; N, 8.18.
Found: C, 63.04; H, 5.26; N, 8.06.
Kinetic Resolution of Racemic Acyl Chlorides 2a–c with (S)-Amines
1a,b. General Procedure: A solution of the appropriate acyl chloride (0.6
mmol) in toluene (2 mL) was added to a solution of (S)-amine 1a or 1b
(0.3 mmol) and PhNEt2 (44.8 mg, 0.3 mmol) in toluene (4 mL) at +20 C.
The reaction mixture was kept in a thermostat at +20 C for 24 h and
then evaporated to dryness under reduced pressure. The residue was
dissolved in MeCN (10 mL), then saturated aqueous Na2CO3 (10 mL)
was added. The reaction mixture was stirred for 1 h, after which MeCN
was removed by evaporation under reduced pressure. An aqueous
solution was extracted with CHCl3 (2 5 mL). The organic layers were
washed with 4 M HCl (2 4 mL), saturated aqueous NaCl (4 5 mL),
and water (2 5 mL). The organic layer was separated, dried over
Na2SO4, and evaporated under reduced pressure. The residue was
analyzed by GC.
(R*,S*)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(2-(4-nitrophenoxy)-
propionyl)-2H-[1,4]benzoxazine ((R*,S*)-4b): Yield 127 mg (67%), white
solid, m.p. 183-184 °C (n-hexane-EtOAc). GC: (R,S)-4b = 32.9 min, (R,R)-4b
= 33.9 min, (R*,S*)-(R*,R*) 98.4:1.6. 1H NMR (500 MHz, DMSO-d6,
100 °C): = 8.13-8.20 (m, 2 H, Ar acyl), 7.55 (ddd, J = 9.3, 5.5, 2.6 Hz, 1
H, C5H benzoxazine), 7.02-7.08 (m, 2 H, Ar acyl), 6.83 (app. dt, J = 9.8,
8.2 Hz, 1 H, C6H benzoxazine), 5.64 (q, J = 6.3 Hz, 1 H, C2H acyl), 4.66
(qdd, J = 6.8, 2.7, 1.5 Hz, 1 H, C3H benzoxazine), 4.37 (dd, J = 11.1, 1.5
Hz, 1 H, C2HA benzoxazine), 4.17 (dd, J = 11.1, 2.9 Hz, 1 H, C2HB
benzoxazine), 1.58 (d, J = 6.4 Hz, 3 H, Me acyl), 1.18 (d, J = 6.8 Hz, 3 H,
Me benzoxazine) ppm. 13C NMR (125 MHz, DMSO-d6, 100 °C): =
167.41, 161.41, 146.74 (dd, J =243.0, 10.1 Hz), 141.28, 138.63 (dd, J =
242.8, 17.3 Hz), 136.04 (dd, J = 10.2, 3.4 Hz), 125.15, 120.65, 118.85
(dd, J = 8.0, 4.3 Hz), 115.14, 106.49 (d, J = 18.3 Hz), 71.63, 69.59, 45.18,
16.24, 14.72 ppm. 19F NMR (470 MHz, DMSO-d6, 100 °C): = 21.27-
21.41 (m, 1 F, C7F), 2.31 (ddd, J = 20.9, 8.0, 1.6 Hz, 1 F, C8F) ppm. Anal.
calcd. for C18H16F2N2O5: C, 57.15; H, 4.26; N, 7.40; F, 10.04. Found: C,
56.94; H, 4.08; N, 7.30; F 9.77.
Alkaline aqueous solutions (after extraction with CHCl3) were combined,
acidified with 4 M HCl to pH 1–2, and extracted with CHCl3 (2 5 mL).
The organic layer was separated, washed with saturated aqueous NaCl
(2 5 mL), dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by flash column chromatography (n-hexane–
EtOAc as an eluent) and analyzed by chiral HPLC.
(S)-2-(4-Nitrophenoxy)propionic Acid (5b) obtained as result of KR of
acyl chloride 2b using amine (S)-1a. Yield 53 mg (83%), white solid, m.p.
87-89 °C. HPLC (Chiralcel OD-H, n-hexane-iPrOH-CF3COOH 20:1:0.02):
(R)-5b 23.4 min, (S)-5b 20.5 min; ee 88%. []D = −41.2 (c = 1.0 in EtOH)
(ref:[30] []D = +48.7 (c = 1.0 in EtOH), (R)-5b, ee 98%). 1H NMR (500
MHz, CDCl3): = 7.89-8.54 (br. s, 1 H, COOH, overlapped with Ar signal),
8.21 (app. d, J = 9.2 Hz, 2 H, Ar), 6.95 (app. d, J = 9.2 Hz, 2 H, Ar), 4.91
(q, J = 6.9 Hz, 1 H, C2H), 1.73 (d, J = 6.9 Hz, 3H, Me) ppm. 13C NMR
(125 MHz, CDCl3): = 18.24, 72.21, 114.92, 125.99, 142.27, 162.09,
176.43 ppm. Anal. calcd. for C9H9NO5: C, 51.19; H, 4.30; N, 6.63. Found:
C, 51.05; H, 4.09; N, 6.82.
(R*,S*)-3,4-Dihydro-3-methyl-N-(2-(4-methoxyphenoxy)propionyl)-2H-
[1,4]benzoxazine ((R*,S*)-3c): Yield 106 mg (65%), white solid, m.p. 87-
89 °C (n-hexane-EtOAc). GC: (R,S)-3c = 29.1 min, (R,R)-3c = 29.8 min,
1
(R*,S*)-(R*,R*) 99.3:0.7. H NMR (500 MHz, DMSO-d6, 100 °C): = 7.63
(app. d, J = 7.9 Hz, 2 H, C5H benzoxazine), 7.05 (ddd, J = 8.2, 7.2, 1.3
Hz, 1 H, C7H benzoxazine), 6.85-6.89 (m, 2 H, Ar acyl), 6.74-6.81 (m, 4
H, C6H, C8H benzoxazine and Ar acyl), 5.27 (q, J = 6.4 Hz, 1 H, C2H
acyl), 4.67 (qdd, J = 6.8, 2.5, 1.6 Hz, 1 H, C3H benzoxazine), 4.16 (dd, J
= 11.0, 1.6 Hz, 1 H, C2HA benzoxazine), 3.96 (dd, J = 11.0, 2.7 Hz, 1 H,
C2HB benzoxazine), 3.68 (s, 3 H, OMe), 1.51 (d, J = 6.4 Hz, 3 H, Me acyl),
1.11 (d, J = 6.8 Hz, 3 H, Me benzoxazine) ppm. 13C NMR (125 MHz,
DMSO-d6, 100 °C): = 168.43, 153.86, 150.36, 145.58, 125.12, 124.24,
122.87, 119.51, 116.40, 115.87, 114.42, 71.67, 69.07, 55.10, 44.80,
16.77, 14.74 ppm. Anal. calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28.
Found: C, 69.74; H, 6.30; N, 4.13.
(S)-2-(4-Methoxyphenoxy)propionic Acid (5c) obtained as result of KR
of acyl chloride 2c using amine (S)-1b. Yield 51 mg (87%), yellowish oil.
HPLC (Chiralpak AD, n-hexane–iPrOH–CF3COOH 20:1:0.02): (S)-5c
=
12.3 min, (R)-5c = 15.4 min; ee 71%. []D = −29.4 (c = 0.54 in EtOH)
(ref:[31] []D = −42.7 (c = 0.95 in EtOH). 1H NMR (400 MHz, CDCl3): =
8.00-11.50 (br. s, 1 H, COOH), 6.86 (app. dt, J = 9.3, 2.7 Hz, 2 H, Ar),
6.82 (app. dt, 2 H, J = 9.3, 2.7 Hz, Ar), 4.70 (q, J = 6.9 Hz, 1 H, C2H),
3.77 (s, 3 H, OMe), 1.63 (d, J = 6.9 Hz, 3 H, Me) ppm. 13C NMR (125
MHz, CDCl3): = 18.43, 55.64, 73.16, 114.75, 116.65, 151.23, 154.69,
+
177.93 ppm. HRMS (ESI): calcd. for C10H12NaO4 [M+Na]+ 219.0628;
found 219.0624.
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