On the use of hydrogen peroxide in the hydrolysis of azido N-(arylacetyl)-2-oxazolidinone derivatives

Full text of DOI:10.1021/jo961637x

J . Org. Chem. 1996, 61, 9603-9604
9603
On th e Use of Hyd r ogen P er oxid e in th e
Hyd r olysis of Azid o
N-(Ar yla cetyl)-2-oxa zolid in on e Der iva tives
Anthony J . Pearson* and Penglie Zhang
Department of Chemistry, Case Western Reserve University,
Cleveland, Ohio 44106
Received August 23, 1996
In our continuing studies directed toward the synthesis
of vancomycin and related glycopeptide antibiotics, non-
proteinogenic amino acids are required as the subunits.
For this purpose, compounds 1a -d were synthesized
from commercially available materials via standard well-
established asymmetric azidation chemistry.1 Conver-
Evans and co-workers have reported1c uncharacterized
minor side reactions during hydrogen peroxide-mediated
hydrolysis of azido N-(phenylacetyl)oxazolidinones, which
they hint as being free radical in nature. To check
whether the side reaction leading to compound 3 is a free
radical-mediated process, we ran the reaction in THF as
received from Aldrich (containing 0.029% BHT), THF
distilled from LiAlH4, and THF distilled from Na/ben-
zophenone. The results were comparable. This “undes-
ired” reaction also did not depend on whether the reaction
was conducted under Ar atmosphere or open to the air.
On the basis of these observations, we do not believe that
free radical processes account for the formation of
compounds 3.
sion of these compounds to arylglycine and arylalanine
subunits for the aforementioned target molecules re-
quired hydrolytic removal of the chiral auxiliary. Com-
pound 1a was treated with 2 equiv of LiOH in the
presence of 6 equiv of H2O2, which has been reported as
a method of choice to minimize any racemization.1 After
TLC showed the hydrolysis was complete, Na2SO3 was
added to quench the reaction. The usual aqueous workup
gave a 9:1 mixture (91% total yield) of 2a and 3a , with
2a as the major component. Fischer esterification
(PTSA‚H2O/EtOH) provided 4a and 5a , which were
separated by flash chromatography. Compound 4a has
been used in the synthesis of 16-membered cyclic peptide
models for teicoplanin and ristocetin A.2
The minor formation of the side product 3a was not
cause for concern, but a more serious problem was
encountered with 1b as the substrate. Hydrolysis with
LiOH/H2O2 gave a 1:1 mixture of 2b and 3b, in a
combined yield of 87%. Esterification with PTSA‚H2O/
MeOH furnished 4b and 5b, chromatographic separation
of which, in a variety of solvent systems, failed. Simi-
larly, a 1:1 mixture of 2c and 3c (89% total) was obtained
when 1c was subjected to the same hydrolysis conditions.
Esterification gave 4c and 5c, chromatographic separa-
tion of which was achieved with 1:4 EtOAc/hexanes as
solvent. The structure of 5c was secured by comparing
its IR and 1H and 13C NMR spectra with a sample
prepared by standard methods.3
In the following proposed mechanism4 (Scheme 1)
compound 6 is believed to be the key intermediate, which
leads to the formation of 3 via a known hydrogen
peroxide-mediated oxidation.5 From this mechanism, one
can see that formation of 6 depends on the electronic
properties of the substituents on the neighboring aro-
matic ring. More oxidation product is obtained when the
aromatic ring is more electron deficient, which is consis-
tent with base-catalyzed tautomerization of the azido-
acyl derivative followed by addition of HOO-. The fact
that no keto acid derivative is observed during hydrolysis
in the absence of hydrogen peroxide indicates that HOO-
is indeed the nucleophile in this reaction (see next
paragraph). This mechanism is also supported by the
fact that the oxidation products are formed only in the
preparation of arylglycine derivatives, while 1d did not
give any “undesired” product 3d . In a related kinetic
study of oxidation of R-ketols by alkaline hydrogen
peroxide, aromatic ketols were found to react much faster
than aliphatic ketols.6
(3) 3-Chloro-4-hydroxybenzoic acid was treated with K2CO3 (3
equiv)/MeI (5 equiv) to give 3-chloro-4-methoxybenzoic acid methyl
ester (5c). 3c was also obtained as the side product from the oxidation
of 3-chloro-4-methoxybenzyl alcohol with PCC.
(4) Another plausible pathway leading to 6 is as follows:
(1) (a) Evans, D. A.; Britton, T. C. J . Am. Chem. Soc. 1987, 109,
6881. (b) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141. (c) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow,
R. L. J . Am. Chem. Soc. 1990, 112, 4011.
(2) (a) Pearson, A. J .; Lee, K. J . Org. Chem. 1995, 60, 7153. (b)
Pearson, A. J .; Bignan, G.; Zhang, P.; Chelliah, M. J . Org. Chem. 1996,
61, 3940.
(5) Oxidation of R-keto acids by alkaline hydrogen peroxide is a
known reaction: March, J . Advanced Organic Chemistry, 3rd ed.; J ohn
Wiley & Sons, Inc.: New York, 1985; p 1175.
S0022-3263(96)01637-4 CCC: $12.00 © 1996 American Chemical Society

9604 J . Org. Chem., Vol. 61, No. 26, 1996
Notes
160.3, 152.4, 136.5, 134.8, 129.4, 129.0, 128.6, 128.1, 127.6, 127.5,
107.0, 106.9, 102.4, 70.2, 66.4, 63.6, 55.7, 55.5, 37.6; HRMS calcd
for C26H24N4O5 472.1747, found 472.1728.
Sch em e 1
1c: obtained as a mixture of 92:8 diastereomers; yield 85%;
[R]23D -112.4 (c 1.1, CHCl3); Rf 0.53 (1:2 EtOAc/Hex); IR (CHCl3)
1
1782, 1710 cm-1; H NMR (CDCl3) 7.60-6.90 (m, 8H), 6.16 (s,
1H), 5.61 (d, 1H, J ) 7.2 Hz), 4.79 (dq, 1H, J ) 7.2, 6.6 Hz),
3.97 (s, 3H), 1.00 (d, 3H, J ) 6.6 Hz); 13C NMR (CDCl3) 168.8,
156.0, 152.1, 132.5, 130.2, 129.0, 128.8, 128.5, 126.0, 125.6, 123.3,
112.3, 79.4, 62.9, 56.2, 55.5, 14.5; HRMS calcd for C19H17ClN2O4
(M+ - N2) 372.0868, found 372.0869.
Gen er a l P r oced u r e for Hyd r olysis. 1. With H2O2. To a
solution of starting material 1 in THF-H2O (3:1) at 0 °C were
added 30% H2O2 (6 equiv) and LiOH (0.5 N, 2 equiv). After TLC
showed the reaction was complete (0.5-1 h), aqueous Na2SO3
(1.5 N, 10 equiv) was added and the solution was stirred for an
additional 15 min. After removing the volatiles, the aqueous
residue was extracted with CH2Cl2, then acidified with 1 N HCl
to pH 1-2, and extracted again with CH2Cl2. This second CH2-
Cl2 extract was dried over Na2SO4 and concentrated.
2. With ou t H2O2. To a solution of starting material 1 in
THF-H2O (3:1) at 0 °C was added LiOH (0.5 N, 2 equiv). After
TLC showed the reaction was complete (0.5-1 h), THF was
removed, and the aqueous residue was extracted with CH2Cl2,
acidified with 1 N HCl to pH 1-2, and extracted again with CH2-
Cl2. The second CH2Cl2 layer was dried over Na2SO4 and
concentrated.
On the basis of the supposition that hydrogen peroxide-
mediated scission of the azido intermediate was the major
cause of the side product formation, we chose to use LiOH
without H2O2 in the hydrolysis step. The experimental
results showed clean reactions (∼90% yield) with both
1b,c. The observation that hydrogen peroxide is neces-
sary for R-keto acid formation indicates that the mech-
anism of this reaction is different from the earlier
reported hydrolysis of related compounds.7 Now the
main concern was the extent of racemization, which was
checked by Mosher’s method after 4b,c were hydroge-
nated with H2/Pd-C (10%) in the presence of 5 N HCl.8
Mosher’s amide formation was performed under standard
conditions.9 For 4c, 1H and 19F NMR of the product
showed a ratio of 92:8, confirming that there was little
racemization, considering 1c was also a 92:8 mixture of
diastereomers. For 4b, a 97:3 diastereomeric mixture
was observed from NMR.
In conclusion, while LiOH/H2O2 has been recom-
mended for the hydrolysis of racemization-prone substi-
tuted oxazolidinones, problems that arise from oxidative
cleavage of azido-substituted derivatives make it less
attractive for the preparation of electron deficient arylg-
lycines. In those cases the use of standard LiOH-
mediated hydrolysis provides an efficient, racemization-
free alternative.
2b: yield 90% (without H2O2); 1H NMR (CDCl3) 8.92 (b, 1H),
7.40-7.20 (m, 5H), 6.62 (s, 1H), 6.54 (s, 2H), 5.00 (s, 2H), 4.93
(s, 1H), 3.75 (s, 3H).
1
2c: yield 89% (without H2O2); H NMR (CDCl3) 7.40 (d, 1H,
J ) 3.1 Hz), 7.24 (dd, 1H, J ) 8.5, 3.1 Hz), 6.91 (d, 1H, J ) 8.5
Hz), 4.95 (s, 1H), 3.87 (s, 3H).
Gen er a l P r oced u r e for Ester ifica tion . A solution of
starting material 2 and PTSA‚H2O (2 equiv) in dry CH3OH was
refluxed overnight. After cooling to rt, CH3OH was removed and
the residue was dissolved in CH2Cl2. The solution was washed
with saturated NaHCO3 and brine. The organic layer was dried
over Na2SO4 and concentrated. Flash chromatography with
EtOAc/Hex gave the pure ester.
4b: yield 97%; [R]23D +95.2 (c 3.5, CHCl3); Rf 0.50 (1:2 EtOAc/
Hex); IR (CHCl3) 1753 cm-1 1H NMR (CDCl3) 7.40-7.20 (m,
;
5H), 6.60-6.40 (m, 3H), 5.01 (s, 2H), 4.87 (s, 1H), 3.75 (s, 3H),
3.73 (s, 3H); 13C NMR (CDCl3) 169.3, 161.1, 160.3, 136.4, 135.7,
128.5, 128.0, 127.5, 106.3, 106.0, 101.9, 70.1, 65.2, 55.4, 52.9;
HRMS calcd for C17H17N3O4 327.1219, found 327.1224.
4c: yield 95%; [R]23 -99.4 (c 1.3, CHCl3); Rf 0.51 (1:2 EtOAc/
D
Hex); IR (CHCl3) 1747 cm-1; H NMR (CDCl3) 7.41 (d, 1H, J )
1
2.2 Hz), 7.25 (dd, 1H, J ) 8.4, 2.2 Hz), 6.94 (d, 1H, J ) 8.4 Hz),
4.92 (s, 1H), 3.91 (s, 3H), 3.77 (s, 3H); 13C NMR (CDCl3) 169.2,
155.7, 129.5, 127.0, 126.7, 123.0, 112.2, 64.2, 56.1, 53.0; HRMS
calcd for C10H10ClN3O3 255.0411, found 255.0401.
Exp er im en ta l Section
Gen er a l Meth od s. General methods used are as described
elsewhere.10
Gen er a l P r oced u r e for Mosh er ’s Am id e F or m a tion . A
suspension of ∼10 mg of Pd-C (10%) in 3 mL of THF was purged
with H2 for 30 min. To the suspension were added compound 4
(0.05 mmol) and 5 N HCl (3 equiv). After stirring under H2
atmosphere at rt for 3 h, the mixture was filtered through Celite
and the filtrate was evaporated to give a white solid, to which
were added 4 mL of CH2Cl2 and pyridine (150 µL). The solution
was cooled to 0 °C, and then (S)-(+)-MTPACl (1.4 equiv) was
added. After the mixture stirred at 0 °C for 30 min and at rt
overnight, CH2Cl2 was evaporated and the residue was dissolved
in 15 mL of EtOAc. The organic layer was washed with 1 N
NaHCO3, 1 N HCl, and brine and dried over MgSO4. The crude
product was obtained as an oil.
Gen er a l P r ep a r a tion of 1. To a -78 °C solution of the
N-(arylacetyl)oxazolidinone starting material in THF was added
KHMDS (0.5 M in toluene, 1.1 equiv). The mixture was stirred
at -78 °C for 20 min, a solution of trisyl azide (1.3 equiv) in
THF was then added via cannula. After 2 min, the reaction was
quenched with glacial acetic acid (3.5 equiv) and the mixture
was warmed to 35 °C immediately. The slurry was stirred for
an additional 3 h, diluted with CH2Cl2, and separated. The
organic layer was washed with brine and aqueous NaHCO3,
dried over Na2SO4, and concentrated. Flash chromatography
with EtOAc/Hex gave the desired compound (1a ,d have been
reported elsewhere2).
F r om 4b: yield 79%; 19F NMR (CDCl3) -69.2, -69.4 (3:97).
F r om 4c: yield 96%; 19F NMR (CDCl3) -69.3, -69.5 (92:8).
1b: yield 79%; [R]23D +169.3 (c 1.0, CHCl3); Rf 0.53 (1:2 EtOAc/
1
Hex); IR (CHCl3) 1796, 1711 cm-1; H NMR (CDCl3) 7.45-7.15
(m, 10H), 6.75-6.60 (m, 3H), 6.05 (s, 1H), 5.01 (s, 2H), 4.55 (m,
1H), 4.09 (m, 2H), 3.76 (s, 3H), 3.37 (dd, 1H, J ) 13.4, 2.9 Hz),
2.80 (dd, 1H, J ) 13.4, 9.9 Hz); 13C NMR (CDCl3) 169.1, 161.1,
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (GM 36925) is greatly
acknowledged. P. Zhang is grateful to M. Chelliah and
G. Bignan for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H and 19F NMR
spectra for compound series b and c (12 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(6) Ogata, Y.; Sawaki, Y.; Shiroyama, M. J . Org. Chem. 1977, 42,
4061.
(7) (a) Raap, R. Tetrahedron Lett. 1969, 40, 3493. (b) Manis, P. A.;
Rathke, M. W. J . Org. Chem. 1980, 45, 4952.
(8) Acidic conditions were found to be essential to suppress dechlo-
rination of the aromatic ring in the hydrogenation step; see also:
Pearson, A. J .; Zhang, P.; Lee, K. J . Org. Chem. 1996, 61, 6581.
(9) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512. Dale,
J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543.
(10) Pearson, A. J .; Lee, K. J . Org. Chem. 1994, 59, 225.
J O961637X