Oxidation of Oxazolines and Thiazolines to Oxazoles and Thiazoles
J . Org. Chem., Vol. 61, No. 23, 1996 8213
Dip ep tid e of (S)-N-ter t-Bu tyloxyca r bon yl Va lin e-Th r e-
on in e. Prepared as described in the general procedure using
2.0 g (9.22 mmol) of (S)-(+)-N-(tert-butyloxycarbonyl)valine,
2.13 mL (19.4 mmol) N-methylmorpholine, 1.33 mL (10.1
mmol) of isobutyl chloroformate, and 1.71 g (10.1 mmol) of
L-threonine methyl ester and obtained in 93% yield (2.84 g)
as a colorless oil. Used without further purification for the
next step. IR (thin film, cm-1) 3328, 2964, 1747, 1663; 1H NMR
(CDCl3, 300 MHz) δ 0.90 (d, J ) 7.01 Hz, 3H), 1.19 (d, J )
6.21 Hz, 3H), 3.73 (s, 3H), 2.10 (m, 1H), 3.83-4.10 (m, 1H),
4.34-4.58 (m, 1H), 4.61 (m, 1H), 5.15-5.18 (m, 1H), 6.85 (br,
s, 1H).
Dip ep t id e of (S)-N-ter t-Bu t yloxyca r b on yl Ala n in e-
Ser in e. Prepared as described in the general procedure using
2.50 g (13.23 mmol) of (S)-(+)-N-(tert-butyloxycarbonyl)alanine,
2.51 mL (27.8 mmol) of Et3N, 1.89 mL (14.6 mmol) of isobutyl
chloroformate, and 2.26 g (14.6 mmol) of racemic serine methyl
ester hydrochloride and obtained in 96% yield (3.68 g) as a
colorless oil. Used without further purification for the next
step. IR (thin film, cm-1) 3343, 2983, 1739, 1661; 1H NMR
(CDCl3, 300 MHz) δ 1.23 (d, J ) 7.01 Hz, 3H), 1.31 (s, 9H),
3.68 (s, 3H), 3.71-3.92 (m, 2H), 4.10-4.23 (m, 2H), 4.56 (m,
1H), 5.60 (d, J ) 7.23 Hz, 1H), 7.34 (d, J ) 7.56 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 18.1, 27.9, 49.8, 52.2, 54.3, 62.2, 79.8,
155.4, 170.6, 173.2.
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zolin es
8 or 20 (e-l) fr om th e Dip ep tid es via Bu r gess r ea gen t.
2-[(S)-1-[N-(ter t-Bu toxycar bon yl)am in o]-2-m eth ylpr opyl]-
4-ca r bom eth oxyoxa zolin e, 20e. To a solution of the dipep-
tide derived from (S)-N-tert-butyloxycarbonyl valine-serine
(4.35 g, 13.7 mmol) in 90 mL of THF (0.15 M) was added 3.58
g (15.1 mmol) of Burgess reagent,9 and the contents were
heated to reflux for 1.5 h. The solvent was concentrated under
vacuum and the residue flash chromatographed on SiO2 using
hexane/ethyl acetate (70:30) to give 20e in 68% yield (4.08 g)
as a colorless oil. IR (thin film, cm-1) 3310, 2966, 1720, 1658;
1H NMR (CDCl3, 300 MHz) δ 0.93 (d, J ) 6.90 Hz, 3H), 0.97
(d, J ) 6.84 Hz, 3H), 1.38 (s, 9H), 2.13 (m, 1H), 3.69 (s, 3H),
4.23-4.30 (dd, J ) 3.10, 8.20 Hz, 1H), 4.75-4.78 (dd, J ) 1.43,
10.22 Hz, 1H), 4.88-4.94 (m, 2H), 5.23 (d, J ) 9.10 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 16.3, 16.7, 31.4, 52.1, 53.8, 71.0,
78.8, 79.2, 155.9, 170.7, 170.9.
2-[(S)-1-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-m eth ylp r o-
p yl]-5-m eth yl-4-ca r bom eth oxyoxa zolin e, 20h . Prepared
as described in the general procedure using 2.50 g (7.53 mmol)
dipeptide of (S)-N-tert-butyloxycarbonyl valine-threonine and
1.97 g (8.28 mmol) of Burgess reagent.9 Flash chromatography
on SiO2 using hexane/ethyl acetate (70:30) gave 1.49 g (63%
yield) of 20h as a colorless oil. IR (thin film, cm-1) 3300, 2964,-
1715, 1658; 1H NMR (CDCl3, 300 MHz) δ 0.91 (d, J ) 6.90
Hz, 3H), 0.96 (d, J ) 6.84 Hz, 3H), 1.24 (d, J ) 6.45 Hz, 3H),
1.39 (s, 9H), 2.11 (m, 1H), 3.70 (s, 3H), 4.26-4.30 (dd, J )
3.12, 8.16 Hz, 1H), 4.73-4.76 (dd, J ) 1.41, 10.14 Hz, 1H),
4.89-4.93 (m, 1H), 5.20 (d, J ) 9.09 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 16.1,16.9, 28.3, 31.4, 51.9, 53.6, 70.7, 78.3, 79.5,
155.6, 170.0, 170.1.
of Burgess reagent. Flash chromatography on SiO2 using
hexane/ethyl acetate (65:35) gave 2.10 g (64% yield) of 20f as
a colorless oil. IR (thin film, cm-1) 3320, 2958, 1705, 1608; 1H
NMR (CDCl3, 300 MHz) δ 1.34 (d, J ) 7.77 Hz, 3H), 1.38 (s,
9H), 3.73 (s, 3H), 4.38-4.55 (m, 2H), 4.68-4.74 (dd, J ) 7.83,
10.59 Hz, 1H), 5.16 (br,s, 1H); 13C NMR (CDCl3, 75 MHz) δ
19.4, 28.1, 44.6,52.9, 67.6, 70.1, 80.2, 154.8, 171.0, 171.2.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th ia zolin es
fr om th e Im in o Eth er s. To a solution of the imino ether
(1.0 equiv) in anhydrous ethanol (0.32 M) was added L-cystine
ethyl ester (1.1 equiv) and the resulting solution stirred at rt
for 18 h. The solvent was evaporated and the residue flash
chromatographed on SiO2 using hexane/ethyl acetate to give
the desired product.
2-[(S)-1-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2-m et h yl-
p r op yl]-4-ca r bet h oxy-(S)-2-t h ia zolin e, 20i. Prepared as
described in the general procedure using 2.17 g (8.89 mmol)
2(S)-[N-(tert-butyloxycarbonyl)amino]-3-methylbutanimino eth-
yl ether and 1.32 g (8.89 mmol) of L-cystine ethyl ester. Flash
chromatography on SiO2 using hexane/ethyl acetate (85:15)
gave 0.750 g (42% yield) of 20i as a colorless oil. [R]23 -64.3
D
(c 1.1, CHCl3); IR (thin film, cm-1) 3350, 1705, 1618; 1H NMR
(CDCl3, 300 MHz) δ 0.81 (d, J ) 6.78 Hz, 3H), 0.91 (d, J )
6.81 Hz, 3H), 1.20 (t, J ) 7.11 Hz, 3H), 1.35 (s, 9H), 2.03-
2.18 (m, 1H), 3.41-3.51 (m, 2H), 4.15 (q, J ) 7.11 Hz, 2H),
4.40 (m, 1H), 5.05 (t, J ) 8.10 Hz, 1H), 5.20 (d, J ) 9.06 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 16.4, 19.2, 28.1, 32.3,
35.6, 57.7, 61.5, 77.5, 79.4, 155.3, 170.4, 175.5.
2-[(S)-1-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2-p h en yl-
eth yl]-4-ca r beth oxy-(S)-2-th ia zolin e, 20j. Prepared as de-
scribed in the general procedure using 1.08 g (3.70 mmol) of
2(S)-[N-(tert-butyloxycarbonyl)amino]-3-methylbutanimino eth-
yl ether and 0.55 g (3.70 mmol) of L-cystine ethyl ester. Flash
chromatography on SiO2 using hexane/ethyl acetate (85:15)
gave 0.630 g (45% yield) of 20j as a colorless oil. [R]23 -49.1
D
(c 1.3, CHCl3); IR (thin film, cm-1) 3310, 2960, 1700, 1606; 1H
NMR (CDCl3, 300 MHz) δ 1.28 (t, J ) 7.08 Hz, 3H), 1.37 (s,
9H), 3.00-3.23 (m, 2H), 3.44-3.60 (m, 2H), 4.23 (q, J ) 7.05
Hz, 2H), 4.78-5.18 (m, 3H), 7.15-7.29 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 28.2, 35.4, 39.9, 53.9, 61.8, 78.0, 79.8,
126.8, 128.3, 129.6, 136.1, 154.4, 170.3, 175.9.
Oxa zolin e, 20l.16 To a solution of the amide (1.22 g, 2.94
mmol) in 30 mL of THF was added 0.804 g (3.23 mmol) of
Burgess reagent, and the contents were refluxed for 1.5 h. The
solvent was removed under vacuum to give the crude product.
Column chromatography on SiO2 using hexane/ethyl acetate
(7:3) gave 0.806 g (69% yield) of the desired oxazoline 20l, in
65-70% overall yield from the acid. IR (thin film, cm-1) 1730,
1
1632; H NMR (CDCl3, 300 MHz) δ 0.02 (d, J ) 4.5 Hz, 6H),
0.84 (s, 9H), 1.30 (s, 3H), 1.35 (s, 3H), 1.65-1.91 (m, 2H), 2.52-
2.55 (d, J )7.3 Hz, 1H), 3.48 (t, J ) 7.65, 1H), 3.80 (s, 3H),
4.00-4.05 (dd, J ) 5.94, 7.95 Hz, 1H), 4.18-4.23 (m, 2H),
4.31-4.37 (dd, J ) 8.79, 10.74 Hz, 1H), 4.46 (dd, J ) 8.01,
8.79 Hz, 1H), 4.69 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ -4.9,
-4.7, 17.9, 25.7, 25.8, 26.9, 35.8, 40.9, 52.6, 67.4, 68.1, 69.1,
69.8, 72.4, 108.6, 168.3, 171.5. Anal. Calcd for C19H35NO6Si:
C, 56.83; H, 8.78. Found C, 56.58; H, 8.71.
2-[(S)-1-[N-(ter t-Bu toxycar bon yl)am in o]-2-ph en yleth yl]-
4-ca r bom eth oxyoxa zolin e, 20g. Prepared as described in
the general procedure using 3.0 g (8.20 mmol) of dipeptide of
(S)-N-tert-butyloxycarbonyl phenylalanine-serine and 2.14 g
(9.02 mmol) of Burgess reagent.9 Flash chromatography on
SiO2 using hexane/ethyl acetate (75:25) gave 2.03 g (71% yield)
of 20g as a colorless oil. IR (thin film, cm-1) 3335, 2977, 1745,
1709; 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9H), 2.97-3.14
(m, 2H), 3.71 (s, 3H), 4.37-4.41 (m, 1H), 4.51-4.71 (m, 2H),
5.14 (d, J ) 7.68 Hz, 1H), 7.07-7.26 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 28.2, 38.8, 49.6, 52.6, 67.7, 69.9, 79.7, 126.7, 128.2,
129.3, 129.4, 129.5, 135.7, 154.8, 169.3, 170.8.
Syn th esis of Oxazoles Usin g NBS an d P er oxide. 4-Car -
bom eth oxy-2-p h en yl-2-oxa zole, 14a .19 To 4-carbomethoxy-
2-phenyl-2-oxazoline (0.30 g, 1.46 mmol) and benzoyl peroxide
(20 mg, 0.082 mmol) was added 10 mL of dry benzene (0.15
M) and the reaction mixture brought to gentle reflux for 15
min. To this was added NBS (0.311g, 1.75 mmol) and further
refluxed for 1.5 h. The flask was cooled, and the contents were
poured over crushed ice. The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (2 × 20 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated under vacuum to afford the crude oxazole, which was
purified by radial chromatography using hexane/ethyl acetate
(95:10) as eluent to afford 0.247 g (83% yield) of 14a as a
Oxa zolin e Azid e, 20k .1h 1H NMR (CDCl3, 300 MHz) δ 1.20
(d, J ) 7.0 Hz, 3H), 1.63-1.76 (m, 1H), 1.88-2.00 (m, 1H),
2.63-2.71 (m, 1H), 3.34 (t, J ) 6.93 Hz, 2H), 3.76 (s, 3H),4.34-
4.49 (ddd, J ) 7.47, 8.67, 16.23 Hz, 2H), 4.68-4.74 (m, 1H).
2-[(S)-1-[N-(ter t-Bu t oxyca r b on yl)a m in o]-2-m et h yl]-4-
ca r bom eth oxyoxa zolin e, 20f. Prepared as described in the
general procedure using 3.5 g (12.1 mmol) of dipeptide of (S)-
N-tert-butyloxycarbonyl alanine-serine and 3.15 g (13.3 mmol)
1
colorless oil. IR (thin film, cm-1) 1725, 1612, 1572; H NMR
(CDCI3, 300 MHz) δ 3.92 (s, 3H), 7.40-7.48 (m, 3H), 8.04 (m,
2H), 8.25 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 52.2, 126.3,
126.8, 128.8, 131.1, 134.3, 143.8, 161.7, 162.4; MS m/z 203
(M+).