SPECIAL TOPIC
Enantioselective α-Oxidation of Ketones
IR (neat): 1626 (s), 3288 (br) cm–1.
1181
MS: m/z = 453.1 [M + Na].
HRMS: m/z calcd for C19H27INaO3: 453.0897; found: 453.0911.
1H NMR (400 MHz, CDCl3): δ = 1.13 (d, J = 7.0 Hz, 3 H), 2.49 (s,
3 H), 3.10 (br, 1 H), 4.45–4.57 (m, 1 H), 5.07 (d, J = 2.9 Hz, 1 H),
5.91 (d, J = 8.0 Hz, 1 H), 7.07–7.13 (m, 1 H), 7.23–7.32 (m, 3 H),
7.34–7.39 (m, 2 H), 7.40–7.45 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 13.8, 29.4, 51.8, 75.7, 99.6, 125.2,
126.4 (2C), 127.6, 128.3, 128.4 (2C), 130.6, 141.2, 142.9, 143.8,
170.9.
(S)-2-Iodophenyl 1-Benzoylpyrrolidine-2-carboxylate (10)
N-Benzoyl-L-proline7 (1.0 g, 8.7 mmol), 2-iodophenol (0.84 g, 3.8
mmol), diisopropylcarbodiimide (0.47 mL, 3.0 mmol), and DMAP
(23 mg, 0.19 mmol) were dissolved in CH2Cl2 (3 mL) and stirred at
r.t. overnight. The reaction mixture was cooled to 0 °C and filtered
through Celite. The filtrate was washed with H2O (30 mL), sat. aq
NaHCO3 (20 mL) and cold 1N HCl (20 mL), then dried (MgSO4),
filtered and concentrated. Purification by flash chromatography
(silica gel; PE–EtOAc, 5:1) provided 10.
MS: m/z = 394.0 [M – 1].
N-[(1R,2S)-1-Hydroxy-1-phenylpropan-2-yl]-2-iodo-N,3-di-
methylbenzamide (13)
2-Iodo-3-methylbenzoic acid8 (0.5 g, 1.9 mmol) was dissolved in
CH2Cl2 (19 mL) at r.t. and oxalyl chloride (0.32 mL, 3.9 mmol) and
DMF (0.01 mL) were added sequentially. The reaction mixture was
stirred overnight then concentrated under vacuum. The residue was
dissolved in THF (10 mL) and added dropwise to a solution of
(1S,2S)-pseudoephedrine hydrochloride (313 mg, 1.6 mmol) and
Et3N (0.5 mL, 3.6 mmol) in THF (10 mL) at 0 °C. The mixture was
allowed to warm to r.t. overnight and then quenched with H2O (20
mL) and extracted with EtOAc (3 × 20 mL), dried (MgSO4), filtered
and concentrated. Purification by flash chromatography (silica gel;
PE–EtOAc, 1:1) provided 13 as four amide rotamers (A/B/C/D ratio
15:9:2:1 in DMSO).
Yield: 0.95 g (59%); white solid; mp 78–80 °C.
IR (neat): 1129 (s), 1410 (m), 1615 (m), 1774 (m) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.95–2.05 (m, 1 H), 2.17–2.27 (m,
1 H), 2.44–2.55 (m, 2 H), 3.58–3.65 (m, 1 H), 3.71–3.79 (m, 1 H),
4.91 (dd, J = 8.0, 6.2 Hz, 1 H), 6.98 (td, J = 7.8, 1.5 Hz, 1 H), 7.25–
7.29 (m, 1 H), 7.33–7.46 (m, 4 H), 7.57–7.62 (m, 2 H), 7.82 (dd,
J = 8.0, 1.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 23.9, 29.7, 50.4, 59.9, 90.1, 123.8,
127.7 (2C), 128.1, 128.7 (2C), 130.0, 130.7, 136.3, 139.6, 146.1,
170.2, 170.3.
MS: m/z = 444.0 [M + Na].
Yield: 280 mg (44%); white solid; mp 181–185 °C.
IR (neat): 1011 (m), 1402 (m), 1614 (s), 3380 (br) cm–1.
HRMS: m/z calcd for C18H16INNaO3: 444.0067; found: 444.0077.
(S)-Methyl 2-(2-Iodo-3-methylbenzamido)-3-methylbutanoate
(11)
1H NMR (500 MHz, DMSO-d6): δ (data for two major rotamers A
and B) = 1.00 (d, J = 6.8 Hz, 3 H, A), 1.05 (d, J = 6.9 Hz, 3 H, B),
2.39 (s, 3 H, A), 2.40 (s, 3 H, B), 2.64 (s, 3 H, B), 2.99 (s, 3 H, A),
3.38–3.46 (m, 1 H, A), 4.48 (dd, J = 8.2, 3.6 Hz, 1 H, A), 4.68 (dd,
J = 7.5, 4.6 Hz, 1 H, B), 4.84–4.92 (m, 1 H, B), 5.53 (d, J = 4.5 Hz,
1 H, B), 5.63 (d, J = 3.6 Hz, 1 H, A), 6.63–6.68 (m, 1 H, B), 6.77–
6.83 (m, 1 H, A), 7.09 (d, J = 6.7 Hz, 2 H, A), 7.21–7.45 (m, 7 H, B
and 5 H, A).
13C NMR (126 MHz, DMSO-d6): δ (data for two major rotamers A
and B) = 13.9B, 15.7A, 27.1A, 28.6B, 28.9A, 31.3B, 53.1B, 59.5A,
74.1B, 74.3A, 99.8B, 100.3A, 124.2B, 126.4A, 127.2B (2C), 127.3A
(2C), 127.6B, 127.9A, 128.2A, 128.4B (2C), 128.6A (2C), 129.0B,
129.5A, 129.5B, 142.0A, 142.3B, 143.8A, 143.9B, 144.7A, 145.0B,
170.8B, 171.4A.
2-Iodo-3-methylbenzoic acid8 (0.5 g, 1.9 mmol) was dissolved in
CH2Cl2 (19 mL) at r.t., and oxalyl chloride (0.32 mL, 3.8 mmol) and
DMF (0.01 mL) were added sequentially. The reaction mixture was
stirred overnight then concentrated under vacuum. The residue was
dissolved in CH2Cl2 (9.6 mL) and cooled to 0 °C. L-Valine methyl
ester hydrochloride (320 mg, 1.9 mmol) and Et3N (0.53 mL, 3.8
mmol) were added and the mixture was allowed to warm to r.t. over-
night. The reaction was quenched with H2O (20 mL) and extracted
with CH2Cl2 (3 × 20 mL). The organic layer was washed sequen-
tially with 10% aq. HCl and 5% aq. NaOH solutions, then dried
(MgSO4), filtered and concentrated. Purification by flash chroma-
tography (silica gel; PE–EtOAc, 5:1) provided 11.
Yield: 228 mg (32%); white solid ; mp 95–97 °C.
IR (neat): 1199 (s), 1533 (s), 1644 (s), 1740 (s), 3263 (br) cm–1.
MS: m/z = 432.0 [M + Na].
1H NMR (400 MHz, CDCl3): δ = 1.02 (d, J = 6.9 Hz, 3 H), 1.11 (d,
J = 6.8 Hz, 3 H), 2.28–2.41 (m, 1 H), 2.51 (s, 3 H), 3.80 (s, 3 H),
4.79 (dd, J = 8.8, 4.8 Hz, 1 H), 6.48 (d, J = 8.7 Hz, 1 H), 7.13–7.19
(m, 1 H), 7.26–7.33 (m, 2 H).
HRMS: m/z calcd for C18H20INNaO2: 432.0431; found: 432.0427.
N-[(1S,2S)-1-Hydroxy-1-phenylpropan-2-yl]-2-(2-iodophenyl)-
N-methylacetamide (14)
2-Iodophenylacetic acid (0.50 g, 1.9 mmol) was dissolved in
CH2Cl2 (10 mL) at r.t. and oxalyl chloride (0.32 mL, 3.9 mmol) and
DMF (0.01 mL) were added sequentially. The reaction mixture was
stirred overnight then concentrated under vacuum. The residue was
dissolved in THF (10 mL) and added dropwise to a solution of
(1S,2S)-pseudoephedrine hydrochloride (313 mg, 1.6 mmol) and
Et3N (0.5 mL, 3.6 mmol) in THF (10 mL) at 0 °C. The mixture was
allowed to warm to r.t. overnight and then quenched with H2O (20
mL) and extracted with EtOAc (3 × 20 mL), dried (MgSO4), filtered
and concentrated. Purification by flash chromatography (silica gel;
PE–EtOAc, 1:1) provided 14 as two amide rotamers (A/B ratio 3:1
in CDCl3).
13C NMR (100 MHz, CDCl3): δ = 18.2, 19.3, 29.4, 31.6, 52.4, 57.8,
99.3, 125.3, 128.3, 130.7, 143.0, 143.6, 170.2, 172.2.
MS: m/z = 398.0 [M + Na].
HRMS: m/z calcd for C14H18INNaO3: 398.0224; found: 398.0223.
N-[(1S,2S)-1-Hydroxy-1-phenylpropan-2-yl]-2-iodo-3-methyl-
benzamide (12)
2-Iodo-3-methylbenzoic acid8 (1 g, 3.8 mmol) was dissolved in
CH2Cl2 (38 mL) at r.t. and oxalyl chloride (0.65 mL, 7.6 mmol) and
DMF (0.01 mL) were added sequentially. The reaction mixture was
stirred overnight then concentrated under vacuum. The residue was
dissolved in CH2Cl2 (5 mL) and added dropwise to a solution of
(1R,2S)-norephedrine (578 mg, 3.8 mmol) and Et3N (0.53 mL, 3.8
mmol) in CH2Cl2 (5 mL) at 0 °C. The mixture was allowed to warm
to r.t. overnight and then quenched with H2O (30 mL) and extracted
with CH2Cl2 (3 × 20 mL), dried (MgSO4), filtered and concentrated.
Purification by flash chromatography (silica gel; PE–EtOAc, 1:1)
provided 12.
Yield: 546 mg (75%); pale-yellow gum.
IR (neat): 1012 (s), 1620 (s), 2925 (w), 3366 (br) cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.91 (d, J = 6.7 Hz, 3 H, B), 1.14
(d, J = 7.0 Hz, 3 H, A), 2.89 (s, 3 H, A), 2.97 (s, 3 H, B), 3.75–3.81
(m, 2 H, B, 2 H, A), 3.88–3.98 (m, 1 H, B), 4.45–4.57 (m, 1 H, A),
4.57 (d, J = 8.8 Hz, 1 H, B), 4.64 (d, J = 7.9 Hz, 1 H, A), 6.89–6.98
(m, 1 H, B, 1 H, A), 7.15–7.20 (m, 1 H, A), 7.23–7.40 (m, 7 H, B,
6 H, A), 7.80–7.86 (m, 1 H, A, 1 H, B).
Yield: 1.09 g (72%); white solid; mp 66–68 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1178–1182