3-Aryl-2-oxazolidinones through the palladium-catalyzed N-arylation of 2-oxazolidinones.

Article abstract of DOI:10.1021/ol016208m

[reaction: see text] 3-Aryl-2-oxazolidinones are obtained in good yields through the palladium-catalyzed N-arylation of 2-oxazolidinones with aryl bromides. The nature of aryl bromides, phosphine ligands, bases, and solvents strongly affects the reaction

Full text of DOI:10.1021/ol016208m

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2539-2541
3-Aryl-2-oxazolidinones through the
Palladium-Catalyzed N-Arylation of
2-Oxazolidinones
Sandro Cacchi,* Giancarlo Fabrizi, Antonella Goggiamani, and Giovanni Zappia
Dipartimento di Studi di Chimica e Tecnologia delle Sostanza Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy
sandro.cacchi@uniroma1.it
Received May 31, 2001
ABSTRACT
3-Aryl-2-oxazolidinones are obtained in good yields through the palladium-catalyzed N-arylation of 2-oxazolidinones with aryl bromides. The
nature of aryl bromides, phosphine ligands, bases, and solvents strongly affects the reaction outcome.
Substituted 3-aryl-2-oxazolidinones have recently attracted
much attention as pharmacologically active compounds. For
example, 5-acetamidomethyl-3-aryl-2-oxazolidinones1 have
been shown to exhibit a potent antibacterial activity, and
5-(hydroxymethyl)-3-(3-methyl phenyl)-2-oxazolidinone is
a drug used as an antidepressant.2 For this reason, a variety
of approaches to this class of compounds have been
described,1e,3 and some of them are based on palladium
catalysis.4 New and flexible synthetic protocols, however,
are highly desirable, especially when they accommodate
important functionalities and are broad in scope.
In our efforts aimed at the development of new syntheses
of heterocycles, we were interested in the preparation of
3-aryl-2-oxazolidinones and envisaged the palladium-
catalyzed carbon-nitrogen bond-forming reactions between
aryl halides and amines or amides5 as a viable route to this
(1) For some leading works in this area, see: (a) Tucker, J. A.; Allwine,
D. A.; Grega, K. C.; Barbachyn, M. R.; Klock, J. L.; Adamski, J. L.;
Brickener, S. J.; Hutchinson, D. K.; Ford, C. W.; Zurenko, G. E.; Conradi,
R. A.; Burton, P. S.; Jensen, R. M. J. Med. Chem. 1998, 41, 3727-3735.
(b) Grega, K. C.; Barbachyn, M. R.; Klock, J. L.; Adamski, J. L.; Brickener,
S. J.; Hutchinson, D. K.; Ford, C. W.; Zurenko, G. E.; Conradi, R. A.;
Burton, P. S.; Jensen, R. M. J. Med. Chem. 1998, 41, 3727-3735. (c) Genin,
M. J.; Hutchinson, D. K.; Allwine, D. A.; Hester, J. B.; Hemmert, D. E.;
Garmon, S. A.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.;
Stapert, D.; Yagi, B. H.; Friis, J. M.; Shobe, E. M.; Adams, W. J. J. Med.
Chem. 1998, 41, 5144-5147. (d) Gleave, D. M.; Brickner, S. J.; Manninen,
P. R.; Allwine, D. A.; Lovasz, K. D.; Rohrer, D. C.; Tucker, J. A.; Zurenko,
G. E.; Ford, C. W. Bioorg. Med. Chem. Lett. 1998, 8, 1231-1236. (e)
Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.;
Ulanowicz, D. A.; Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops,
D. S.; Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 673-679. (f)
Brickner, S. J. Curr. Pharm. Des. 1996, 2, 175-194. (g) Gleave, D. M.;
Brickner, S. J. J. Org. Chem. 1996, 61, 6470-6474. (h) Gante, J.; Juraszyk,
H.; Raddatz, P.; Wurzziger, H.; Bernotat-Danielowski, S.; Melzer, G.;
Rippmann, F. Bioorg. Med. Chem. Lett. 1996, 6, 2425-2430. (i) Barbachyn,
M. R.; Hutchinson, D. K.; Brickner, S. J.; Cynamon, M. H.; Kilburn, J. O.;
Klemens, S. P.; Glickman, S. E.; Grega, K. C.; Hendges, S. K.; Toops, D.
S.; Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 680-685. (l)
Ding, C. Z.; Silverman, R. B. J. Med. Chem. 1993, 36, 3606-3610. Park,
C.-O.; Brittelli, D. R.; Wang, C. L.-J.; Marsh, F. D.; Gregory, W. A.;
Wuonola, M. A.; McRipley, R. J.; Eberly, V. S.; Slee, A. M.; Forbes, M.
J. Med. Chem. 1992, 35, 1156-1165. (m) Gregory, W. A.; Brittell, D. R.;
Wang, C.-L. J.; Kezar, H. S., III; Carlson, R. K.; ParK, C.-H.; Corless, P.
F.; Miller, S. J.; Rajagopalan, P.; Wuonola, M. A.; McRipley, R. J.; Eberly,
V. S.; Slee, A. M.; Forbes, M. J. Med. Chem. 1990, 33, 2569-2578. (n)
Gregory, W. A.; Brittell, D. R.; Wang, C.-L. J.; Wuonola, M. A.; McRipley,
R. J.; Eustice, D. C.; Eberly, V. S.; Bartholomew, P. T.; Slee, A. M.; Forbes,
M. J. Med. Chem. 1989, 32, 1673-1681.
(2) The Merck Index, Monograph 9659, 12th Ed. on CD-ROM, Version
12:3a, Chapman & Hall/CRCnetBase, 2000. Moureau, F.; Wouters, J.;
Vercauteren, D. P.; Collin, S.; Evrard, G.; Durant, F.; Ducrey, F.; Koenig,
J. J.; Jarreau, F. X. Eur. J. Med. Chem. 1994, 29, 269-277. Moureau, F.;
Wouters, J.; Vercauteren, D. P.; Collin, S.; Evrard, G.; Durant, F.; Ducrey,
F.; Koenig, J. J.; Jarreau, F. X. Eur. J. Med. Chem. 1992, 27, 939-948.
Keane, P. E.; Kan, J. P.; Sontag, N.; Benedetti, M. S. J. Pharm. Pharmacol.
1979, 31 752-754.
(3) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem.. Int. Ed.
2000, 39, 625. Jegham, S.; Nedelec, A.; Burnier, Ph.; Guminski, Y.; Puech,
F.; Koenig, J. J.; George, P. Tetrahedron Lett. 1998, 39, 4453-4454. Schaus,
S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937-7940.
(4) Moreno-Manas, M.; Morral, L.; Pleixats, R.; Villarroya, S. Eur. J.
Org. Chem. 1999, 181-186. Larksarp, C.; Alper, H. J. Am. Chem. Soc.
1997, 119, 3709-3715. Trost, B.; Sudhakar, A. R. J. Am. Chem. Soc. 1988,
110, 7933-7935. Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett.
1988, 29, 99-102.
(5) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-
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Res. 1998, 31, 805-818. Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998,
37, 2046-2067.
10.1021/ol016208m CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/14/2001

class of compounds. Particularly, we thought that the
palladium-catalyzed N-arylation of the 2-oxazolidinone
nucleus (Scheme 1) might provide a convenient and useful
alternative to known methods.
reaction conditions (Table 1, entry 4). Electron-neutral and
slightly electron-rich aryl bromides failed to give the desired
products (Table 1, entries 6-8). Therefore, to extend the
methodology to a wider range of aryl bromides, m-bro-
moanisole was selected as the model system and the
influence of phosphine ligand, bases, and solvents on the
reaction outcome was briefly investigated.
Scheme 1 N-Arylation of 2-Oxazolidinones
Only minor amounts of 3f were formed by using a variety
of catalyst systems such as Pd(OAc)2/P(Cy)37b or Pd(OAc)2/
P(But)3 at 120 °C in the presence of lithium, sodium,
potassium carbonate, and bicarbonate bases, or NaOBut in
toluene, or Pd2(dba)3/dppf in the presence of NaOBut in
toluene. Even the use of Pd2(dba)3 with the chelating ligand
Xantphos7c,9 and Cs2CO3 in dioxane (conditions reported to
give excellent results with amides and carbamates)10 led to
the formation of 3f in trace amounts. Use of the same catalyst
system and base [Pd2(dba)3, Xantphos, Cs2CO3] but switching
to toluene as the solvent produced a significant improvement,
still unsatisfactory, however, from a synthetic point of
view: 3f was isolated in 38% yield.
Eventually, we were pleased to find that subjecting
m-bromoanisole to 2-oxazolidinone in the presence of Pd-
(OAc)2, Xantphos, and NaOBut, in toluene, at 120 °C for
16 h afforded 3f in 73% yield (15% at 100 °C). Substitution
of Pd(OAc)2 with Pd2(dba)3, keeping all other parameters
the same, produced a similar result (3f was isolated in 71%
yield). When the procedure11 was extended to include other
aryl bromides (Table 2), Pd(OAc)2 and Pd2(dba)3 gave similar
results in some cases (Table 2, entries 5 and 6), but in
general, the latter was found to give higher yields (Table 2,
entries 3 and 4, 9 and 10, 13 and 14). Consequently, Pd2-
(dba)3 was used as catalyst precursor.
Under these conditions [Pd2(dba)3, Xantphos, NaOBut,
toluene, 120 °C], a variety of neutral, slightly electron-rich,
and slightly electron-poor aryl bromides reacted satisfactorily.
Depending on the nature of the aryl bromide, minor amounts
of N-phenyl derivatives, most probably generated via phenyl
transfer from the ligand to the nitrogen atom,12 were isolated
(see, for example, Table 2, caption to entry 17). The presence
of substituents close to the carbon-bromo bond was found
to hamper the reaction (Table 2, compare entry 11 with
entries 12 and 13, and entry 4 with 15).
Here we report that such a process can be attained and
that its success depends on the appropriate selection of some
reaction parameters such as the nature of the catalyst system,
the base, and the solvent.
Initial attempts were based on the use of the same catalyst
system applied to the preparation of N-aryl lactams6 [Pd-
(OAc)2, dppf,7a NaOBut, toluene, 120 °C]. Under these
conditions, good results were obtained with aryl bromides
containing electron-withdrawing groups para to the bromo
group (Table 1, entries 1-3),8 though with p-bromobenzal-
Table 1. Pd(OAc)2/dppf-Catalyzed N-Arylation of
2-Oxazolidinone 1 (R1 ) R2 ) H)a
entry
aryl bromide 1
time (h)
yield (%), 3b
1
2
3
4
5
6
7
8
p-CN-C6H4-Br
p-NO2-C6H4-Br
p-MeCO-C6H4-Br
p-CHO-C6H4-Br
p-CHO-C6H4-Br
PhBr
24
5
3
5
5
16
16
16
75, a
80, b
71, c
45, d c
-
tr, e
d
m-MeO-C6H4-Br
p-But-C6H4-Br
9, f
tr, g
a Unless otherwise stated, reactions were performed in toluene at 120
°C using the following molar ratios: 1:2:Pd(OAc)2:dppf: NaOBut ) 1:1.5:
0.05:0.05:1.4. b Yields refer to single runs and are given for isolated
products. The compounds are 95-99% pure as judged by NMR and HPLC
analysis. c p-Bromobenzyl alcohol and tert-butyl p-bromobenzoate, very
likely generated via a Cannizzaro-type reaction, were isolated in 19% and
3% yield, respectively. d In the presence of Cs2CO3. p-Bromobenzaldehyde
was recovered in 51% yield.
With aryl bromides containing electron-withdrawing groups
para to the bromo group, the Pd(OAc)2/dppf combination
(9) Kranenburg, M.; van der Burgt, Y. E. M.; Kramer, P. C. J.; van
Leeuwen, W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081-3089.
dehyde only a moderate yield was attained most probably
because of the instability of the aldehyde group under the
(10) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104.
(11) Representative Procedure. A solution of Xantphos (21.7 mg, 0.037
mmol) and Pd2(dba)3 (17 mg, 0.19 mmol) in toluene (1 mL) was stirred
under argon at room temperature for 20 min. Then, m-bromoanisole (95
µL, 0.75 mmol), 2-oxazolidinone (71.3 mg, 1.1 mmol), NaOBut (100.9 mg,
1.4 mmol), and toluene (1 mL) were added. The reaction mixture was
refluxed at 120 °C for 16 h. After this time, the mixture was cooled, diluted
with ethyl acetate, and washed with water. The organic layer was dried
(Na2SO4) and concentrated under vacuum. The residue was purified by
chromatography on silica gel eluting with a n-hexane/ethyl acetate 70/30
(v/v) mixture to give 3f (103 mg, 71% yield).
(6) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035-2038.
(7) (a) dppf ) 1, 1′-bis(diphenylphosphino)ferrocene. (b) Cy ) cyclo-
hexyl. (c) 9,9-Dimethyl-4,6-bis(diphenylphosphino)xanthene.
(8) Representative Procedure. A solution of dppf (25.0 mg, 0.045
mmol) and Pd(OAc)2(8.4 mg, 0.019 mmol) in toluene (1 mL) was stirred
under argon at room temperature for 20 min. Then, p-bromoacetophenone
(150 mg, 0.75 mmol), 2-oxazolidinone (82 mg, 1.13 mmol), NaOBut (101.4
mg, 1.056 mmol), and toluene (2 mL) were added. The reaction mixture
was refluxed at 120 °C for 2 h. After this time, the mixture was cooled,
diluted with ethyl acetate, and washed with water. The organic layer was
dried (Na2SO4) and concentrated under vacuum. The residue was purified
by chromatography on silica gel eluting with a n-hexane/ethyl acetate 60/
40 (v/v) mixture to give 3c (109 mg, 71% yield).
(12) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 3694-
3703. Hermann, W. A.; Brossmer, C.; O¨ fele, K.; Beller, M.; Fischer, H. J.
Organomet. Chem. 1995, 491, C1-C4. Segelstein, B. E.; Butler, T. W.;
Chenard, B. L. J. Org. Chem. 1995, 60, 12-13. Kong, K.-C.; Cheng, C.-
H. J. Am. Chem. Soc. 1991, 113, 6313-6315.
2540
Org. Lett., Vol. 3, No. 16, 2001

the same reaction was carried out in the presence of Pd-
(OAc)2, dppf, and Cs2CO3 (Table 1, entry 5).
Table 2. Pd2(dba)3- or Pd(OAc)2/Xantphos-Catalyzed
N-Arylation of 2-Oxazolidinone 2 (R1 ) R2 ) H)a
Incidentally, it may be noted that subjection of p-
bromobenzaldehyde and [1,3]-oxazinan-2-one, the six-
membered ring analogue of 2-oxazolidinone, to these con-
ditions gave the corresponding N-aryl derivative in 87%
yield.
entry
aryl bromide 1
[Pd]
yield (%), 3b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
m-MeO-C6H4-Br
m-MeO-C6H4-Br
PhBr
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
73, f
71, f
55, e
63, e
We next turned our attention to the N-arylation of 4- and
5-substituted 2-oxazolidinones. Good results were usually
obtained both with substituents at C-4 (close to the nitrogen
nucleophile) and with substituents at C-5 (Table 3).
PhBr
m-CF3-C6H4-Br
m-CF3-C6H4-Br
p-F-C6H4-Br
85, h c,d
88, h c,e
53, ic,f
60, j
16, k
45, k
66, l
50, m
2, n
31, n
tr, o
48, p
49, gg
64, q
25, r h
60, r c,i
30, cl
40, cc,m
50, b
18, d n
79, d o,p
7, d o
m-F-C6H4-Br
m-CN-C6H4-Br
m-CN-C6H4-Br
2-bromo-naphthalene
1-bromo-naphthalene
9-bromo-anthracene
9-bromo-anthracene
o-Me-C6H4-Br
Table 3. Pd2(dba)3/Xantphos-Catalyzed N-Arylation of 4- or
5-Substituted 2-Oxazolidinones 2a
substituted
2-oxazolidinone 2
p-Me-C6H4-Br
entry
aryl bromide 1
R1
R2
yield (%), 3b
p-But-C6H4-Br
p-C6H4-C6H4-Br
m-MeCO-C6H4-Br
m-MeCO-C6H4-Br
p-MeCO-C6H4-Br
p-MeCO-C6H4-Br
p-NO2-C6H4-Br
p-CHO-C6H4-Br
p-CHO-C6H4-Br
p-CHO-C6H4-Br
1
2
3
4
5
6
7
8
9
p-CHO-C6H4-Br
m-MeO-C6H4-Br
p-Ph-C6H4-Br
p-CHO-C6H4-Br
m-MeO-C6H4-Br
p-Ph-C6H4-Br
p-CHO-C6H4-Br
m-MeO-C6H4-Br
p-Ph-C6H4-Br
p-CHO-C6H4-Br
m-MeO-C6H4-Br
p-Ph-C6H4-Br
PhCH2
PhCH2
PhCH2
iPrCH2
iPrCH2
iPrCH2
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
87, a a c
55, a b
89, a c
94, ba c
42, bb
64, bc
95, ca c
57, cb
50, cc
90, d a c
64, d b
62, d c
10
11
12
Me
Me
Me
a Unless otherwise stated, reactions were performed in toluene at 120
°C for 16 h using the following molar ratios: 1:2:[Pd]:Xantphos:NaOBut
) 1:1.1:0.05:0.05:1.4. b Yields refer to single runs and are given for isolated
products. The compounds are 95-99% pure as judged by NMR and HPLC
analysis. c A 1:2 ) 1:2 molar ratio was used. d Under standard conditions,
3h was isolated in 38% yield. e Under standard conditions, 3h was isolated
in 63% yield. f Under standard conditions, 3i was isolated in 17% yield.
g 3-Phenyl-2-oxazolidinone was isolated in 11% yield. h Oxazolidinone
derivatives with dimeric and trimeric N-aryl substituents were isolated in
24% and 6% yield, respectively. i The oxazolildinone derivative containing
a dimeric N-aryl substituent was isolated in 21% yield. l The oxazolildinone
derivative containing a dimeric N-aryl substituent was isolated in 19% yield.
m The oxazolildinone derivative containing a dimeric N-aryl substituent was
isolated in 8% yield. n For 1 h. o At 100 °C for 1 h. p In the presence of
Cs2CO3.
H
a
Unless otherwise stated, reactions were performed in toluene at 120
°C for 16 h using the following molar ratios: 1:2:Pd2(dba)3:Xantphos:
NaOBut ) 1:1.1:0.025:0.05:1.4. b Yields refer to single runs and are given
for isolated products. The compounds are 95-99% pure as judged by NMR
and HPLC analysis. c At 100 °C for 1 h in the presence of Cs2CO3.
In summary, we have developed a convenient and straight-
forward procedure for the preparation of 3-aryl-2-oxazoli-
dinones. With aryl bromides containing a para electron-
withdrawing substituent, good results were obtained in the
presence of Pd(OAc)2, dppf, and NaOBtt in toluene, whereas
neutral, slightly electron-rich, and slightly electron-poor aryl
bromides reacted satisfactorily by using Pd2(dba)3, Xantphos,
and NaOBut in toluene. With p-bromobenzaldehyde the best
result was obtained by using Pd2(dba)3, Xantphos, and Cs2-
CO3.
provides a better catalyst system (compare Table 1, entries
2-4 with Table 2, entries 21-24). Employing Pd2(dba)3 and
Xantphos did not produce comparable yields, even by
increasing the oxazolidinone to aryl bromide ratio (compare
Table 2, entries 21 and 22 with Table 1, entry 3). With
p-bromoacetophenone, as well as with m-bromoacetophe-
none, ketone arylation processes13 were observed in the
presence of the Pd2(dba)3/Xantphos catalyst system and
oxazolidinone derivatives bearing N-aryl substituents arylated
at the carbon R to the carbonyl group were isolated in
significant yield (Table 2, captions to entries 19-22).
p-Bromobenzaldehyde gave the best result using Pd2(dba)3,
Xantphos, and Cs2CO3 as the base (Table 2, entry 25).
Interestingly, no oxazolidinone derivative was isolated when
Acknowledgment. The authors are greatly indebted to
Consiglio Nazionale delle Ricerche (CNR) and to the
University “La Sapienza”, Rome, for financial support of
this research.
Supporting Information Available: Characterization
data for 3-aryl-2-oxazolidinones 3a-n, p-r, aa-dc and
4-(2-oxo-[1,3]oxazinan-3-yl)-benzaldehyde. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370. Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473-1478.
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Org. Lett., Vol. 3, No. 16, 2001
2541