Synthesis of N-arylated oxazolidinones via a palladium catalyzed cross coupling reaction. Application to the synthesis of the antibacterial agent Dup-721

Article abstract of DOI:10.1016/S0040-4039(01)00559-7

A method for the intermolecular coupling of aryl bromides and oxazolidinones is described. Application to intermediates useful for the preparation of a known class of antibacterial agent and the synthesis of the known antibacterial oxazolidinone Dup-721 are described.

Full text of DOI:10.1016/S0040-4039(01)00559-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3681–3684
Synthesis of N-arylated oxazolidinones via a palladium catalyzed
cross coupling reaction. Application to the synthesis of the
antibacterial agent Dup-721
David J. Madar,* Hana Kopecka, Daisy Pireh, Jonathan Pease, Marina Pliushchev,
Richard J. Sciotti, Paul E. Wiedeman and Stevan W. Djuric
Infectious Disease and Process Chemistry Research, Abbott Laboratories, D-47N, Bldg AP 52N, 200 Abbott Park Rd,
Abbott Park, IL 60064-6217, USA
Received 28 February 2001; accepted 21 March 2001
Abstract—A method for the intermolecular coupling of aryl bromides and oxazolidinones is described. Application to intermedi-
ates useful for the preparation of a known class of antibacterial agent and the synthesis of the known antibacterial oxazolidinone
Dup-721 are described. © 2001 Elsevier Science Ltd. All rights reserved.
As part of a program directed at the identification of
novel antibacterial agents of the oxazolidinone class,1
we wanted to identify a highly convergent route with
which to access the key oxazolidinone pharmacophore
present in such key compounds as linezolid(ZYVOX)
and eperezolid. This emerging class of antibacterials
should prove useful for the treatment of resistant
Gram-positive organisms.
However, when these experimental conditions were uti-
lized on more demanding substrates such as 4-bromo-
acetophenone, 2-fluoro-4-bromobenzaldehyde and 4-
bromo-2-nitropyridine the reactions failed to give the
desired product.
This prompted a screen of a number of palladium
catalysts and phosphine ligands that were known to
work well for the coupling between aryl halides and
amines. After considerable experimentation, the use of
We considered that the methods previously described
by Buchwald and Hartwig for the coupling between
aryl halides and amines via palladium(0) catalysis might
well be translated to our case in hand.2–4 Although this
reaction had not been extended to cyclic carbamates, a
report by Shakespeare described the coupling of aryl
bromides with cyclic amides suggested that a similar
approach could be successful.5 Also, Hartwig has pub-
lished the union between aryl halides and tert-butyl
carbamate using sodium phenoxide as base.6 More
recently, Yin and Buchwald have described the cou-
pling of aryl halides and amides as well as one example
of an acyclic carbamate with an aryl bromide.7
O
O
F3C
Br
HN
O
2
F3C
N
O
Pd(OAc)2, DPPF
NaOtBu, toluene
120oC
1
3
75% yield
Scheme 1.
O
O
O
The first experiment was with (S)-(−)-4-benzyl-2-oxazo-
lidinone and 4-bromobenzotrifluoride under the condi-
tions described by Shakespeare (Scheme 1).5 This
reaction afforded the N-arylated product 3 in good
yield (75%).
Br
HN
O
N
O
3
O
Pd2dba3, BINAP
Cs2CO3, toluene
100oC
4
1
* Corresponding author.
Scheme 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00559-7

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D. J. Madar et al. / Tetrahedron Letters 42 (2001) 3681–3684
Pd2(dba)3 and BINAP with cesium carbonate as base
was found to work with the widest variety of aromatic
bromides. With 4-bromoacetophenone and (S)-(−)-4-
benzyl-2-oxazolidinone, 1, under our optimized condi-
tions, a 61% isolated yield of coupled product 4 was
obtained (Scheme 2).8
Danielmeier and Steckhan.9 This material was further
elaborated to three useful intermediate oxazolidinones,
6, 7, and 8 (Fig. 2).
Silylated oxazolidinone 6 was prepared by treatment of
alcohol 5 with TBDPS-Cl/imidazole in DMF (95%
yield). N-Phthalamide derivative 7 was synthesized by
the two step sequence of tosylation (TsCl, pyridine) and
displacement with potassium phthalamide (71% overall
yield). Protected amide 8 was prepared by the three step
sequence of nosylation (2-nitrobenzenesulfonate, pyri-
dine) displacement with 2,4-dimethoxybenzylamine in
acetonitrile, and acetylation with acetic anhydride in
pyridine (50% overall yield).
With a relatively optimized coupling protocol, attention
was turned to the synthesis of oxazolidinones which are
useful as antibacterial agents exemplified by Dup-721
(Fig. 1).
(S)-Hydroxymethyl-2-oxazolidinone, 5, was prepared
from
D
-malic acid in three steps by the method of
O
O
O
O
N
O
O
N
N
O
N
N
N
O
O
O
O
HO
O
F
F
NH
NH
NH
eperezolid
Dup-721
linezolid
Figure 1.
O
O
O
O
HN
O
HN
O O
O
HN
O
HN
O
N
N
OTBDPS
OH
8
5
6
7
O
O
O
Figure 2.
F
O
O
O
N
O
N
O
O
OHC
N
O
O2N
N
O
O
O
N
OTBDPS
N
10 77%
9 69%
11 72%
O
O
Cl
F
O
N
O
EtO2C
O
O
O
NC
N
O
O
O
O
N
N
13 69%
12 58%
O
O
O2N
H3CO2C
O2N
O
O
O
O
N
O
N
O
H3CO2C
O
N
N
15 15%
14 67%
O
O
O
N
O
Br
N
O
O
N
16 69%
O
Figure 3.

D. J. Madar et al. / Tetrahedron Letters 42 (2001) 3681–3684
3683
F
F
OHC
O
O
O
O
O
OHC
Br
N
O
N
HN
O
N
Pd2dba3, BINAP
Cs2CO3, toluene
O
O
O
17
18
100oC
81%
Scheme 3.
O
O
TFA/CH2Cl2
N
O
N
O
O
O
O
O
65%
O
NH
N
Dup-721
11
O
Scheme 4.
These intermediates were then coupled with various
aromatic bromides to provide useful intermediates for
antibacterials. Shown below are representative exam-
ples prepared. Each N-arylated compounds in Fig. 3
was prepared from the corresponding oxazolidinone
listed in Fig. 2 and the appropriate aryl bromide.10 The
coupling was found to be tolerant of a wide variety of
functional groups including nitro, aldehyde, nitrile,
esters and enolizable ketones and esters. The reaction
with electron rich aryl bromides is exceedingly slow as
to be impractical. Also, control experiments were con-
ducted in the absence of the palladium catalyst to
demonstrate the essential nature of Pd(0) catalysis for
this reaction. No product was formed after heating for
36 hours (example 9 and 11).
References
1. Brickner, S. J. Curr. Pharm. Des. 1996, 2, 175–194.
2. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125–146.
3. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 805–818.
4. Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–
2067.
5. Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035–
2038.
6. Hartwig, J. F.; Kawatsura, M.; Hauck, S. L.; Shaugh-
nessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999,
64, 5575–5580.
7. We became aware of this work while our studies were in
progress: Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2,
1101–1104.
8. This result stands in contrast to the results of Buchwald
who found that acyl-substituted aryl bromides gave com-
petitive ketone arylation when Xanthphos was used as
the ligand and therefore could not be used as substrates.
Reference 7 and Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370.
9. Danielmeier, K.; Steckhan, E. Tetrahedron: Asymmetry
1995, 6, 1181–1190.
Ureas can also be arylated under the same type of
conditions. Thus, when urea 1711 and 2-fluoro-4-bromo-
benzaldehyde were treated under our standard condi-
tions, the unsymmetrical cyclic urea 18 was prepared in
81% isolated yield. To our knowledge, this is the first
example of this type of bimolecular reaction with a urea
(Scheme 3).
As a final note, we established the application of this
chemistry to the known antibacterial compound Dup-
721. The amide of arylated oxazolidinone 11 was
deprotected with a 1:1 mixture of trifluoroacetic acid
and methylene chloride to provide Dup-721 (which was
identical in all respects with the literature values)12 in
65% isolated yield (Scheme 4).
10. A representative procedure for compound 10 (Fig. 3): To
a degassed suspension of oxazolidinone 7 (2.50 g, 10
mmol) in toluene (20 mL) in a resealable tube was added
2-fluoro-4-bromobenzaldehyde (2.03 g, 10.0 mmol),
BINAP (498 mg, 0.80 mmol), cesium carbonate (4.56 g,
14.0 mmol) and finally Pd2(dba)3 (366 mg, 0.40 mmol).
The reaction was resealed and heated at 100°C for 24 h.
The reaction mixture was then cooled and partitioned
between saturated ammonium chloride (200 mL) and
ethyl acetate (200 mL). The aqueous layer was back
extracted with ethyl acetate (2×200 mL). The combined
organic layers were dried over magnesium sulfate, filtered
and concentrated to a crude solid. Recrystallization from
In summary, the Buchwald/Hartwig palladium cou-
pling methodology has been extended to include the
reaction of aryl bromides with cyclic carbamates and
ureas. This chemistry provided very useful intermedi-
ates for the synthesis of potential antibacterials of the
oxazolidinone class and the biological data on those
derived compounds will be the subject of future
publications.
1
methylene chloride afforded 10 (2.85 g, 77%). H NMR:
| 10.27 (s, 1H), 7.88 (m, 3H), 7.75 (m, 2H), 7.63 (dd,

3684
D. J. Madar et al. / Tetrahedron Letters 42 (2001) 3681–3684
J=2.1, 12.6 Hz, 1H), 7.27 (dd, J=2.1, 12.6 Hz, 1H), 5.04
11. Urea 17 was formed in high yield from the displacement
of the tosylate derived from 5 with 2,4-dimethoxybenzyl-
amine in DMSO at 40°C, followed by treatment with
acetic anhydride/pyridine.
12. Wang, C.-L. J.; Gregory, W. A.; Wuonola, M. A. Tetra-
hedron 1989, 45, 1323–1326.
(m, 1H), 4.16 (m, 2H), 4.00 (m, 2H). MS ESI (+) 369 [M
+1]+.
This procedure has been run on a ‘process scale’ with 145
g of 7 in 64% yield.
DMF was a more convenient solvent for the reaction.
.