Diastereoselective ritter reactions of chiral cyclic n-acyliminium ions: Synthesis of pyrido-and pyrrolo[2,3-d]oxazoles and 4-hydroxy-5-N- acylaminopyrrolidines and 5-hydroxy-6-N-acylaminopiperidines

Article abstract of DOI:10.1021/jo800007g

(Chemical Equation Presented) Pyrido- and pyrrolo[2,3-d]oxazoles can be conveniently prepared in high yield from the Ritter reaction of nitriles and in situ generated chiral cyclic N-acyliminium ions, cis-4-Hydroxy-5- acylaminopyrrolidines and cis-5-hydroxy-6-acylaminopiperidines can be readily obtained by acid hydrolysis of these bicyclic heterocyclic compounds, respectively.

Full text of DOI:10.1021/jo800007g

inhibition of tumor cell heparanase,6 heperan sulfate 2-O-
sulfotransferase,7 N-acetylhexosaminidases,8 influenza virus
neuraminidase,9 and glucosidases.10
Diastereoselective Ritter Reactions of Chiral
Cyclic N-Acyliminium Ions: Synthesis of Pyrido-
and Pyrrolo[2,3-d]oxazoles and
4-Hydroxy-5-N-acylaminopyrrolidines and
5-Hydroxy-6-N-acylaminopiperidines
Ian R. Morgan,† Arife Yazici,† Stephen G. Pyne,*,† and
Brian W. Skelton‡
School of Chemistry, UniVersity of Wollongong, Wollongong,
New South Wales, 2522, Australia, and Chemistry M313, School
of Biomedical, Biomolecular and Chemical Sciences, UniVersity
of Western Australia, Crawley, Western Australia 6009,
Australia
The incorporation of the 2-acylamino group in these mol-
ecules often requires a multistep sequence, and thus, a more
direct route would be desirable.8,11 We report here that these
types of substituted heterocycles can be conveniently prepared
in a highly diastereoselective manner from the Ritter reaction
of nitriles and chiral cyclic N-acyliminium ions generated in
situ from the (5S)-hydroxy-2-pyrrolidinone and (6S)-hydroxy-
2-piperidone derivatives 4/5 and 6, respectively.
spyne@uow.edu.au
ReceiVed January 1, 2008
Treatment of (4S)-412 in a solution of the nitriles 7a-c at rt
with BF3‚Et2O (3 equiv) for 16 h followed by a mild basic
workup (saturated aqueous NaHCO3 solution) and purification
by column chromatography resulted in formation of the pyrrolo-
[2,3-d]oxazoles 8a-c in excellent yields (86-93%, Scheme 1,
Table 1, entries 1-3). Treatment of (4S)-4 with the nitrile 7d
(3 equiv) at rt in nitromethane solution with BF3‚Et2O (3 equiv)
for 16 h resulted in formation of the pyrrolo[2,3-d]oxazole 8d
in 91% yield (Scheme 1, Table 1, entry 4). Interestingly,
treatment of the O-benzyl ether analogue of 4, (4S)-5,13 with
the nitriles 7b,c also resulted in formation of the pyrrolo[2,3-
d]oxazoles 8b,c in high yields (87% and 80%, respectively,
Table 1, entries 5 and 6). The corresponding N-benzylamides
10b,c were also isolated in yields of 77% and 63%, respectively
(Scheme 1).
Pyrido- and pyrrolo[2,3-d]oxazoles can be conveniently
prepared in high yield from the Ritter reaction of nitriles
and in situ generated chiral cyclic N-acyliminium ions. cis-
4-Hydroxy-5-acylaminopyrrolidines and cis-5-hydroxy-6-
acylaminopiperidines can be readily obtained by acid hy-
drolysis of these bicyclic heterocyclic compounds, respectively.
The 6-membered ring hemiaminal (5S)-6 (dr ) 3:1) was
prepared from the known N-PMB-(3S)-hydroxyglutarimide14,15
by NaBH4 reduction.16 The major trans isomer of (5S)-6 could
be selectively crystallized from the mixture and its structure
was estabilished by X-ray crystallographic analysis (Supporting
Information). Treatment of the diol (5S)-6 (dr ) 3:1) with the
The 2-acylaminopyrrolidine and -piperidine structural motif
is found in several biologically active natural and synthetic
products. For example, odorine 1,1 (+)-odorinol 2,1 and its
enantiomer (-)-odorinol2 and the aglains3 are 2-acylaminopy-
rrolidine alkaloids isolated from Aglaia odorata Lour. (+)-
Odorinol 2 showed significant inhibitory activity on P-388
lymphocytic leukemia cell growth.2 The naturally occurring
N-iminosugar, siastatin B 3, has neuraminidase and â-glucu-
ronidase inhibition activities,4 while related 2-acetamidopiperi-
dine derivatives show antimetastatic activity on tumor cells5 and
(6) Kawase, Y.; Takahashi, M.; Takatsu, T.; Arai, M.; Nakajima, M.;
Tanzawa, K. J. Antibiot. 1996, 49, 61-64.
(7) Brown, J. R.; Nishimura, Y.; Esko, J. D. Bioorg. Med. Chem. Lett.
2006, 16, 532-536.
(8) Knapp, S.; Yang, C.; Pabbaraja, S.; Rempel, B.; Reid, S.; Withers,
S. G. J. Org. Chem. 2005, 70, 7715-7720.
(9) Shitara, E.; Nishimura, Y.; Nerome, K.; Hiramoto, Y.; Takeuchi, T.
Org. Lett. 2000, 2, 3837-3840.
(10) Shitara, E.; Nishimura, Y.; Kojima, F.; Takeuchi, T. Bioorg. Med.
Chem. Lett. 1999, 7, 1241-1246.
† University of Wollongong.
‡ University of Western Australia.
(11) Babidge, P. J.; Massy-Westropp, R. A.; Pyne, S. G.; Shiengthong,
D.; Ungphakorn, A.; Veerachat, G. Aust. J. Chem. 1980, 33, 1841-1845.
(12) Prepared from the known (3S)-hydroxysuccinimide (Kocˇalka, P.;
Pohl, R.; Rejmam, D.; Rosenberg, I. Tetrahedron 2006, 62, 5763-5774)
by NaBH4 reduction.
(1) Shiengthong, D.; Ungphakorn, A.; Lewis, D. E.; Massy-Westropp,
R. A. Tetrahedron Lett. 1979, 24, 2247-2250.
(2) Hayashi, N.; Lee, K.-H.; Hall, I. H.; McPhail, A. T.; Huang, H.-C.
Phytochemistry 1982, 21, 2371-2373.
(3) Nugroho, B. W.; Edrada, R. A.; Wray, V.; Witte, L.; Bringmann,
G.; Gehling, M.; Proksch, P. Phytochemistry 1999, 51, 367-376.
(4) Nishimura, Y.; Satoh, T.; Adachi, H.; Kondo, S.; Takeuchi, T.;
Azetaka, M.; Fukuyasu, Iizuka, Y. J. Am. Chem. Soc. 1996, 118, 3051-
3052.
(13) Prepared according to Huang, P.-Q. Synlett 2006, 1133-1149.
(14) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003,
5, 1927-1929.
(15) Ruan, Y.-P.; Wei, B.-G.; Xu, X.-Q.; Liu, G.; Yu, D.-S.; Liu, L.-X.;
Huang, P.-Q. Chirality 2005, 17, 595-599.
(5) Nishimura, Y.; Satoh, T.; Adachi, H.; Kondo, S.; Takeuchi, T.;
Azetaka, M.; Fukuyasu, Iizuka, Y. J. Med. Chem. 1997, 40, 2626-2633.
(16) Morgan, I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409-
1419.
10.1021/jo800007g CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/29/2008
J. Org. Chem. 2008, 73, 2943-2946
2943

TABLE 1
SCHEME 2
entry
starting material
product (yield, %)
1
2
3
4
5
6
7
8
9
4
4
4
4
5
5
6
6
6
6
6
8a (93)
8b (90)
8c (86)
8d (91)a
8b (87)
8c (80)
9a (99)
9b (91)
9c (58)b
9d (79)a
9e (0)
10
11
a MeNO2 as solvent, 3 equiv of 7d. b Starting 6 was also isolated in 21%
recovered yield.
SCHEME 1
These reactions are notable for providing products with high
cis diastereoselectivities. Typically, the addition of nucleophiles
to the iminium ions generated in situ from 4-6 show modest
diastereoselectivities.13,17 To rationalize the high diastereose-
lectivities and the stereochemical outcomes of these reactions
we suggest that attack of the nitriles 7a-d on the intermediate
N-acyliminium ion A (Ritter reaction)18,19 is reversible and gives
a mixture of the Ritter intermediates B and C (Scheme 2).
Because of its cis stereochemistry, intermediate B more readily
cyclizes to the oxazolidine cationic intermediate D. Deproto-
nation or O-debenzylation of D gives the oxazolidine E. When
R1 in D is Bn, the benzyl cation that is formed undergoes a
nitriles 7a-d, under similar conditions to that of (4S)-4 (BF3‚
Et2O (5 equiv), rt for 16 h, and finally at reflux for 30 min to
3 h), resulted in formation of the corresponding pyrido[2,3-d]-
oxazoles 9a-d in good to excellent yields (Table 1, entries
7-10). The use of the less nucleophilic 4-nitrobenzonitrile (7e)
resulted in only recovered starting hemiaminal 6 (Table 1, entry
11).
(17) (a) Thaning, M.; Wistrand, L.-G. J. Org. Chem. 1990, 55, 1406-
1408. (b) Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico, C.; Villa, R.
Tetrahedron Lett. 1990, 31, 4949-4952. (c) Koot, W.-J.; van Ginkel, R.;
Kranenburg, M.; Hiemstra, H. Tetrahedron Lett. 1991, 32, 401-404. (d)
Pilli, R. A.; Russowsky, D. J. Org. Chem. 1996, 61, 3187-3190. (e)
Louwrier, S.; Ostendorf, M.; Boom, A.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1996, 52, 2603-2628. (f) Lennartz, M. L.; Sadakane, M.;
Steckhan, E. Tetrahedron 1999, 55, 14407-14420. (g) Lennartz, M.;
Steckham, E. Synlett 2000, 319-322. (h) Russowsky, D.; Petersen, R. Z.;
Godoi, M. N.; Pilli, R. A. Tetrahedron Lett. 2000, 41, 9939-9942. (i)
Klitzke, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605-5608. (j)
Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809-823.
(k) Washburn, D. G.; Heidebrecht, R. W.; Martin, S. F. Org. Lett. 2003, 5,
3523-3525. (l) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663-
1667. (m) Huang, P.-Q.; Lu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003,
5, 1927-1929. (n) Meng, W.-H.; Wu, T.-J.; Zhang, H.-K.; Huang, P.-Q.
Tetrahedron: Asymmetry 2004, 15, 3899-3910. (o) Chen, B.-F.; Tasi, M.-
R.; Yang, C.-Y.; Chang, J.-K.; Chang, N.-C. Tetrahedron 2004, 60, 10223-
10231. (p) Othman, R. B.; Bousquet, T.; Fousse, A.; Othman, M.; Dalla,
V. Org. Lett. 2005, 7, 2825-2828. (q) Othman, R. B.; Bousquet, T.;
Othman, M.; Dalla, V. Org. Lett. 2005, 7, 5335-5337. (r) Tranchant, M.-
J.; Moine, C.; Othman, R. B.; Bousquest, T.; Othman, M.; Dalla, V.
Tetrahedron Lett. 2006, 47, 4477-4480.
(18) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045-
4048. (b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048-4050.
(19) Ritter-like reactions using nitriles, and the related Holy reaction using
cyanamide, has been employed on sugar acetals and related compounds,
providing analogous bicyclic sugar oxazolines. See: (a) Gordon, D. M.;
Danishefsky, S. J. J. Org. Chem. 1991, 56, 3713-3715. (b) Blanco, J. L.
J.; Rubino, E. M.; Mellet, C. O.; Fernandez, J. M. G. Synlett, 2004, 2230-
2232. (c) Jenkinson, S. F.; Jones, N. A.; Moussa, A.; Stewart, A. J.; Heinz,
T.; Fleet, G. W. J. Tetrahedron Lett. 2007, 48, 4441-4444 and references
cited therein.
Acid hydrolysis of 8a,b with 6 N HCl/MeOH (1:1) at rt for
25 min provided the corresponding cis-hydroxyamides 11a,b,
respectively, in respective yields of 42% and 70%, Scheme 1.
This method was less efficient (35-30% yields) for the synthesis
of corresponding 6-membered ring analogues 12a,b from the
acid hydrolysis of 9a,b (Scheme 1). This hydrolysis method
also gave several other minor uncharaterizable products by TLC
analysis. A much improved yield of 67% for 12b was achieved
by hydrolysis using silica gel and CHCl3/H2O (100 : 1) at rt
for 16 h and then at reflux for 2 h. An analogus acid hydrolysis
(6 N HCl/MeOH (1:1) at rt) of the aromatic derivatives 8c,d or
9c,d gave only recovered starting material, whereas more forcing
conditions (50 °C) resulted in a complex mixture of products.
The stereochemistry of the products 11a and 11b was deter-
mined to be cis based on their the coupling constants J4,5, which
were 5.0 and 5.6 Hz, respectively. On related systems, J4,5 is
typically 0-2.5 Hz for the trans isomers and 6.0-7.5 Hz for
the corresponding cis isomers.17a,b The highly crystalline hy-
droxy amides 12a,b were shown to have also have the cis
stereochemistry from their single-crystal X-ray structural analy-
sis (Supporting Information).
2944 J. Org. Chem., Vol. 73, No. 7, 2008

SCHEME 3
2.03 (3H, s); δC 170.7, 168.8, 135.9, 128.7, 128.6, 127.7, 83.2,
74.48, 44.3, 37.5, 14.1; MS (EI) m/z 230 (M+•,100%); HRMS (EI)
calcd for C13H14N2O2 (M+•) 230.1055, found 230.1057.
(()-(5S,6S)-4-(4-Methoxybenzyl)-3a,4,7,7a-tetrahydro-2-iso-
propyloxazolo[4,5-b]pyridin-5(6H)-one (9b). To a suspension of
the diol 6 (150 mg, 0.597 mmol) in isobutyronitrile (10 mL) was
added BF3‚OEt2 (375 µL, 2.984 mmol), and the resulting homo-
geneous solution was stirred at rt for 16 h upon which TLC analysis
indicated an incomplete reaction so the solution was heated at reflux
for 30 min. The reaction was quenched at 0 °C with saturated
NaHCO3 (10 mL) and brine (50 mL) and then allowed to stir for
10 min. The resulting mixture was extracted with EtOAc (3 × 70
mL), dried, and concentrated in vacuo to yield the crude product.
Flash chromatography (Et2O, Rf ) 0.31) of the crude product
Ritter reaction with the nitriles 7b,c to give the N-benzyl amides
10b,c, respectively (Scheme 2). The optical rotations of
compounds 9a-d and 12a,b were notably small or essentially
zero, suggesting that 6 may have undergone racemization under
the reaction conditions. This was confirmed by converting 12b
to its (S)- or (R)-Mosher’s esters by treating samples of 12b
with (R)- or (S)-Mosher’s acid chloride, respectively. 1H NMR
analysis of these derivatives indicated essentially a 1:1 mixture
of diastereomers were produced.20 In contrast, the optical
rotations of compounds 8a-d and 11a,b were relatively large
yielded 9b (164 mg, 0.543 mmol, 91%) as a colorless oil: νmax
/
cm-1 2971, 1655, 1514, 1248, 752; δH 7.41 (2H, d, J ) 8.5 Hz),
6.85 (2H, d, J ) 8.5 Hz), 5.48 (1H, d, J ) 14.8 Hz), 5.31 (1H, d,
J ) 9.2 Hz), 4.68-4.72 (1H, m), 3.95 (1H, d, J ) 14.8 Hz), 3.79
(3H, s), 2.63 (1H, app sept, J ) 7.0 Hz) 2.39-2.46 (1H, m), 2.23-
2.30 (1H, m), 2.18 (1H, ddd, J ) 14.5, 6.4 and 3.0 Hz), 1.88 (1H,
app, tt, J ) 14.3 and 3.7 Hz), 1.21 (3H, t, J ) 7.0 Hz), 1.20 (3H,
t, J ) 7.0 Hz); δC 174.9, 171.2, 159.0, 129.6, 129.2, 114.0, 78.5,
74.9, 55.2, 46.5, 28.3, 27.1, 25.0, 19.6, 19.5; MS (EI) m/z 302 (M+)
100; HRMS (EI) calcd for C17H22N2O3 (M+) 302.1630, found
302.1623.
(()-N-((2R,3S)-1-Benzyl-3-hydroxy-5-oxopyrrolidin-2-yl)ac-
etamide (11a). To a solution of oxazoline 8a (0.020 g, 0.086 mmol)
in MeOH (1 mL) at rt was added dropwise 6 N HCl (1 mL). The
reaction mixture was stirred at rt for 25 min, concentrated in vacuo,
then diluted with water (5 mL) and basified with solid NaHCO3 to
pH 9. The aqueous layer was extracted with EtOAc (3 × 10 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The crude
product was purified by flash column chromatography (5% MeOH
in EtOAc as eluent) to give the title compound (0.009 g, 42%) as
a white solid: Rf 0.24 (5% MeOH in EtOAc); mp 190-193 °C;
[R]23D -160 (c 0.075 MeOH); νmax/cm-1 3318, 1577, 1653, 1541,
1446, 1434, 1378, 1275, 1157; δH (MeOH-d4) 7.31-7.24 (5H, m),
5.55 (1H, d, J ) 5.0 Hz), 4.57 (1H, d, J ) 15.0 Hz), 4.39 (1H, br
q, J ) 6.5 Hz), 4.23 (1H, d, J ) 15.0 Hz), 2.68 (1H, dd, J ) 6.5,
17.5 Hz), 2.46 (1H, dd, J ) 5.0, 17.5 Hz), 1.88 (3H, s); δC (MeOH-
d4) 174.9, 173.9, 138.2, 129.5, 129.1, 128.5, 67.6, 65.8, 45.0, 39.6,
22.6; MS (EI) m/z 248 (M+•, 45); HRMS (EI) calcd for C13H16N2O3
(M+•) 248.1160, found 248.1158.
1
in magnitude. H NMR analysis of the analogous Mosher’s
esters of 11b indicated high enantiomeric purity (95% ee). It
seems likely therefore that hemiaminal 6 undergoes ring-opening
to the corresponding R-hydroxy aldehyde-secondary amide
(PMBN(H)COCH2CH2CH(OH)CHO) which undergoes race-
mization, through a Lewis acid-catalyzed enolization process
of the R-hydroxy aldehyde moiety, prior to recyclization back
to 6 and then the subsequent Ritter reaction. This does not seem
to be a problem in the 5-membered ring series.
Under oxidative reaction conditions (MnO2, toluene at reflux),
the pyrido[2,3-d]oxazole 9c was converted to the oxazolo[4,5-
b]pyridin-5(4H)-one 13 in 62% yield (Scheme 3). The analogous
pyrrolo[2,3-d]oxazole 8c, however, failed to provide the cor-
responding oxidized product when exposed to the same reaction
conditions.
In conclusion, pyrido- and pyrrolo[2,3-d]oxazoles can be
conveniently prepared in high yield from the Ritter reaction of
nitriles and chiral cyclic N-acyliminium ions. cis-4-Hydroxy-
5-acylaminopyrrolidines and cis-5-hydroxy-6-acylaminopip-
eridines can be readily obtained by acid hydrolysis of these
bicyclic heterocyclic compounds, respectively. The compounds
derived from the 6-membered hemiaminal 6 are obtained in
racemic form.
(()-(5S,6S)-N-1-(4-Methoxybenzyl)-3-hydroxy-6-oxopiperidin-
2-yl)isobutyramide (12b). Method 1. To a solution of the
oxazoline 9b (92 mg, 0.304 mmol) in MeOH/H2O (10 mL of a 9:1
v/v mixture) was added three drops of concentrated hydrochloric
acid, and the solution was stirred at rt for 6 h. The volatiles were
removed in vacuo, and the residue was purified by column
chromatography [EtOAc to 4% MeOH/EtOAc (Rf ) 0.31)] to yield
12b (35 mg, 0.090 mmol, 30%) as a colorless solid.
Method 2. To a solution of the oxazoline 9b (75 mg, 0.248
mmol) in chloroform (20 mL) were added silica gel (2 g) and water
(200 µL), and the resulting suspension was stirred vigorously for
15 h. TLC analysis indicated only starting material so the reaction
was heated at reflux for 2 h. The reaction was cooled, and the
volatiles were removed in vacuo. The silica gel was filtered and
washed with EtOAc/MeOH (100 mL of a 2:1 v/v), and then the
volatiles were removed. Column chromatography of the crude
residue from the silica gel yielded 12b (53 mg, 0.165 mmol, 67%)
showing spectroscopic data consistent with the amide prepared from
method 1 above. The starting oxazoline 9b was also recovered (15
mg, 0.0496 mmol, 20%): mp 169-173 °C; νmax/cm-1 3288, 2966,
1652, 1615, 1541, 1513, 1468, 1244, 1176, 1033; δH 7.17 (2H, d,
J ) 8.6 Hz), 6.83 (2H, d, J ) 8.6 Hz), 6.37 (1H, d, J ) 8.8 Hz),
5.47 (1H, dd, J ) 8.8, 4.1 Hz), 4.84 (1H, d, J ) 14.6 Hz), 4.02
(1H, d, J ) 14.6 Hz), 4.00-4.03 (1H, m), 3.76 (3H, s), 3.19 (1H,
br s), 2.58 (1H, app dt, J ) 18.1 and 5.4 Hz), 2.40-2.50 (1H, m),
Experimental Section
General Procedures. Unless stated otherwise, CDCl3 was used
1
as a solvent for all H NMR (500 MHz) and 13C NMR (125 Mz)
measurements. All IR spectra were determined as neat samples.
All solutions were dried over anhydrous MgSO4. Petrol refers to
the hydrocarbon fraction of boiling point 40-60 °C.
(3aR,6aS)-4-Benzyl-2-methyl-6,6a-dihydro-3aH-pyrrolo[2,3-
d]oxazol-5(4H)-one (8a). To a solution of diol 4 (0.10 g, 0.483
mmol) in acetonitrile (3 mL) at 0 °C was added dropwise BF3‚
Et2O (0.192 g, 1.35 mmol). The reaction mixture was warmed to
rt and stirred for 16 h. Saturated NaHCO3 solution (10 mL) was
added, and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The combined extracts were dried, filtered, and concentrated
in vacuo. The crude product was purified by flash column
chromatography (EtOAc as eluent) to give the title compound (0.103
g, 93%) as a colorless waxy solid: Rf 0.22 (EtOAc); [R]23D + 21.0
(c 0.19, CHCl3); νmax/cm-11680, 1433, 1308, 1227, 1065, 1024;
δH 7.34-7.32 (5H, m, ArH), 5.38 (1H, d, J ) 7.5 Hz), 5.07 (1H,
d, J ) 14.5 Hz), 4.90 (1H, t, J ) 7.5 Hz), 4.02 (1H, d, J ) 14.5
Hz), 2.85 (1H, dd, J ) 7.5, 18.5 Hz), 2.69 (1H, d, J ) 18.5 Hz),
1
(20) The H NMR spectra of the (S)- or (R)-Mosher’s ester derivatives
of 12b both showed two sets of doublet peaks (1:1 ratio) for the benzylic
methylene signals CHACHBPMP (see the Supporting Information).
J. Org. Chem, Vol. 73, No. 7, 2008 2945

2.36 (1H, app sept, J ) 6.9 Hz), 1.85-1.95 (2H, m), 1.14 (3H, d,
J ) 6.9 Hz), 1.13 (3H, d, J ) 6.9 Hz); δC (MeOH-d4)174.9, 171.2,
158.9, 129.5, 129.2, 114.0, 78.5, 74.9, 55.2, 46.5, 28.3, 27.1, 25.0,
19.6, 19.5; MS (ESI-) m/z 319.2 (M - H)-, 100; HRMS (ESI+)
calcd for C17H25N2O4 (M + H)+ 321.1814, found 321.1821.
4-(4-Methoxybenzyl)-2-phenyloxazolo[4,5-b]pyridin-5(4H)-
one (13). To a solution of the oxazoline 9c (48 mg, 0.143 mmol)
in anhydrous toluene (10 mL) was added activated manganese(IV)
dioxide (146 mg of 85% activity, 1.43 mmol, 10 equiv), and the
suspension was heated at 100 °C for 16 h. TLC analysis indicated
an incomplete reaction so a further portion of manganese(IV)
dioxide (146 mg, 10 equiv) was added and the mixture then heated
at reflux for 4 h, whereupon TLC analysis showed complete
consumption of the oxazoline (the product is fluorescent and the
oxazoline is not). The reaction was filtered through a short plug of
silica (5 cm) and eluted with EtOAc, and the volatiles were removed
in vacuo. The crude product was purified by column chromatog-
raphy [10% EtOAc/petrol to 50% EtOAc/Petrol (Rf ) 0.29)]
yielding 13 (28.5 mg, 0.086 mmol, 62%) as a pale yellow solid:
mp 120-122 °C. δH 8.16 (2H, dd, J ) 7.5 and 1.5 Hz), 7.62 (1H,
d, J ) 9.5 Hz), 7.59 (2H, d, J ) 9.0 Hz), 7.50-7.56 (4H, m), 6.82
(2H, d, J ) 9.0 Hz), 6.44 (1H, d, J ) 9.5 Hz), 5.44 (2H, s) and
3.76 (3H, s); δC 163.1, 161.6, 159.2, 133.7, 133.1, 131.8, 130.7,
129.0, 128.8, 127.2, 126.4, 124.3, 116.6, 113.8, 55.2, 45.8; MS
(EI) m/z 332 (M+), 100; HRMS (EI) calcd for C20H16N2O3 (M+)
332.1160, found 332.1155.
Acknowledgment. We thank the Australian Research Coun-
cil and the University of Wollongong for financial support.
Supporting Information Available: Full experimental proce-
1
dures and characterization data as well as copies of the H NMR
and 13C NMR spectra of all new compounds. Crystal/refinement
data and ORTEP plots of compounds 6, 12a, and 12b (CCDC nos.
668234, 668235, and 668236). This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800007G
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