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,