Palladium-catalyzed synthesis of N-aryloxazolidinones from aryl chlorides

Article abstract of DOI:10.1021/ol034428p

(Matrix presented) An efficient method for intermolecular N-arylation of oxazolidinones using Pd₂dba₃ and various phosphine ligands in the presence of a weak base is reported. The conditions allow the use of cheaper aryl chlorides containing functionalities such as enolizable ketones, amides, etc., which would be incompatible with other coupling methods. The coupling reaction can be used to prepare enantiopure N-aryl β-amino alcohols. Depending on the stereoelectronic nature of the aryl chloride, careful choice of ligand was necessary for the success of these reactions.

Full text of DOI:10.1021/ol034428p

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2207-2210
Palladium-Catalyzed Synthesis of
N-Aryloxazolidinones from Aryl
Chlorides
Arun Ghosh,* Janice E. Sieser, Maxime Riou, Weiling Cai, and Luis Rivera-Ruiz
Process Research and DeVelopment, Pfizer Global Research and DeVelopment,
Eastern Point Road, P.O. Box 8013, Groton, Connecticut 06340-8013
arun_ghosh@groton.pfizer.com
Received March 11, 2003
ABSTRACT
An efficient method for intermolecular N-arylation of oxazolidinones using Pd2dba3 and various phosphine ligands in the presence of a weak
base is reported. The conditions allow the use of cheaper aryl chlorides containing functionalities such as enolizable ketones, amides, etc.,
which would be incompatible with other coupling methods. The coupling reaction can be used to prepare enantiopure N-aryl â-amino alcohols.
Depending on the stereoelectronic nature of the aryl chloride, careful choice of ligand was necessary for the success of these reactions.
Fatal infections with vancomycin-resistant enterococci (VRE)
among patients with compromised host defenses have
magnified the importance of new and improved antimicrobial
agents. N-Aryl oxazolidinones have recently attracted much
attention as a new class of synthetic antimicrobial agents1
effective against a number of Gram-positive bacteria and
have emerged as an approved therapeutic option for VRE.
Some N-aryl oxazolidinones have also been used as antide-
pressant agents,2 and a variety of elegant synthetic approaches
have been described in the literature.3 In a related project,
we needed to develop a method for efficient production of
N-aryl oxazolidinones on large scale. We envisioned that a
Pd-catalyzed C-N bond-forming process between aryl
halides and oxazolidinones would provide a convergent
access to such systems. Moreover, a wide number of
N-unsubstituted oxazolidinones are readily available in
enantiomerically pure form and can also be used as surrogates
to produce a diverse array of enantiopure â-amino alcohols
ready for further synthetic manipulation.
During the past few years, significant progress has been
made in the development of Pd-catalyzed cross-coupling of
(2) (a) Keane, P. E.; Kan, J. P.; Sontag, N.; Benedetti, M. S. J. Pharm.
Pharmacol. 1979, 31, 752-754. (b) 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. (c) 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. (d) Mai, A.;
Artico, M.; Esposito, M.; Sbardella, G.; Massa, S.; Befani, O.; Turini, P.;
Glovannini, V.; Mondovi, B. J. Med. Chem. 2002, 45, 1180-1183.
(3) (a) Trost, B.; Sudhakar, A. R. J. Am. Chem. Soc. 1988, 110, 7933-
7935. (b) Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988, 29,
99-102. (c) Schaus, S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37,
7937-7940. (d) Moreno-Manas, M.; Morral, L.; Pleixats, R.; Villarroya,
S. Eur. J. Org. Chem. 1999, 181-186. (e) Larksarp, C.; Alper, H. J. Am.
Chem. Soc. 1997, 119, 3709-3715. (f) Nicolaou, K. C.; Zhong, Y.-L.;
Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 625-628. (g) Jegham, S.;
Nedelec, A.; Burnier, Ph.; Guminski, Y.; Puech, F.; Koenig, J. J.; George,
P. Tetrahedron Lett. 1998, 39, 4453-4454.
(1) For a recent review, see: (a) Halle, E.; Majcher-Peszynska, J.;
Drewelow, B. Chemother. J. 2002, 11, 1-11. For some work in this area,
see: (b) 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. (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) Gleave, D. M.; Brickner, S. J.
J. Org. Chem. 1996, 61, 6470-6474.
10.1021/ol034428p CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/24/2003

Table 1. Optimization of Reaction Conditionsa
Scheme 1. N-Arylation of Oxazolidinone
entry
ligand
base
temp (°C)
conv (%)b
1
2
3
4
5
6
7
8
DPPF
DPEphos
BINAP
Xantphos
IPrHCl
tBu3P
DIphos
1
2
3
2
2
2
2
2
2
2
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
Cs2CO3
K3PO4
Cs2CO3
K3PO4
Cs2CO3
K3PO4
Cs2CO3
100
100
100
100
110
100
100
100
100
100
70
70
70
70
100
100
100
100
57
63
57
60
32
15
tr
amines and aryl halides.4 In particular, the ability to utilize
readily available and inexpensive aryl chlorides5 has further
enhanced the scope of the process in an industrial sense.
Efficient Pd-catalyzed N-arylation of amides or amide-type
nitrogens, on the other hand, has been less successful. The
scope of traditional Cu-catalyzed cross-couplings under
Ullmann/Goldberg-type conditions involving stoichiometric
copper reagents in a solvent with high dielectric constant
and high boiling point (e.g., collidine, DMF, pyridine) is also
limited.6
100c
100c
100c
49d
26d
19
9
10
11
12
13
14
15
16
17
18
33
63e
66e
61
72
Buchwald7 and Hartwig8 have independently demonstrated
the generality of Pd-catalyzed N-arylation involving amides
and have extended the chemistry to acyclic carbamates.9
Interestingly, the first example of intermolecular10 amidation
of an aryl bromide reported by Shakespeare described
superior reactivity of five-membered ring lactams compared
to four-, six-, or seven-membered congeners.11 Concurrent
with the studies described herein, two independent groups
reported that the above conditions were not suitable for
oxazolidinones, particularly with more demanding substrates,
and that improved conditions with wider applicability needed
to be developed.12 However, both groups used only reactive
aryl bromides as the coupling partners. To our knowledge,
efficient cross-coupling of aryl chlorides with oxazolidinones
a Unless otherwise stated, reactions were performed in toluene using the
following molar ratios: 4:5:[Pd]:ligand:base ) 1:1.1:0.04:0.08:1.4. b Judged
by NMR and HPLC analysis. c Isolated yields are 5-10% lower. d Used
THF as solvent. Most of the aryl halide (>90%) was recovered intact. e Used
dioxane as solvent.
has not been reported to date. In this paper, we describe that,
with proper choice of conditions, aryl chlorides can be used
successfully in the N-arylation of five-membered cyclic
carbamates.
Our initial attempts to effect N-arylation using aryl
chlorides met with limited success. However, an intensive
screening of a variety of ligands, Pd-ligand combinations,
and reaction variables using an electron-deficient aryl
chloride 4 and oxazolidinone 5 (Scheme 1) revealed several
interesting results (Table 1). With a few exceptions, Pd2-
(dba)3 proved to be superior to Pd(OAc)2 and was used as
the Pd source for comparison purposes.
(4) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (b)
Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-
Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (c) Yang, B. H.;
Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146. (d) Wolfe, J.
P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-1157. (e) Wolfe, J. P.;
Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000,
65, 1158-1174 and references therein.
(5) For recent reviews on chloroarene activation, see: (a) Grushin, V.
V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062. (b) Dai, C.; Fu, G. C. J.
Am. Chem. Soc. 2001, 123, 2719-2724 and references therein.
(6) Recently, improvements including use of truly catalytic copper salt
as well as significantly milder conditions have been described: (a) Klapars,
A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7727-7729. For an early report on intramolecular amidations under
relatively mild conditions, see: (b) Kametani, T.; Ohsawa, T.; Ihara, M.
Heterocycles 1980, 14, 277-280. For a review on Cu-catalyzed cross-
coupling reactions, see: (c) Lindley, J. Tetrahedron 1984, 40, 1435-1456.
(7) (a) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996,
21, 7525-7546. (b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-
37. (c) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104. (d) Yin,
J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-6048.
(8) Hartwig, J. F.; Kawatsura, M.; Hauck, S. L.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580.
Figure 1. Buchwald’s biaryl ligands used for optimization.
The Pd/chelating bis(phosphine)ligand combinations, in-
cluding DPPF, DPEphos, BINAP, or Xantphos,12a,13,14 as well
as several other ligands with Pd(OAc)2 or Pd2dba3, (Table
1, entries 1-7) were markedly slower compared to Buch-
wald’s biphenyl-derived ligands14 (Table 1, entries 8-10).
Notably, the Xantphos-derived catalyst system was found
recently to be the most generally effective catalyst for the
coupling of acyclic amides with activated (electron-deficient)
or electronically neutral aryl bromides.7c,d,13c
(9) (a) For a related process, see: Wang, Z.; Skerlj, R. T.; Bridger, G.
J. Tetrahedron Lett. 1999, 40, 3543-3546. (b) Arterburn, J. B.; Rao, K.
V.; Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351-1354.
(10) For intramolecular version, see: Wolfe, J. P.; Rennels, R. A.;
Buchwald, S. L. Tetrahedron 1996, 52, 7525-7546.
(11) (a) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035-2038.
Reference 7d also includes an example of oxazolidinone N-arylation.
(12) (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett.
2001, 3, 2539-2541. (b) Madar, D. J.; Kopecka, H.; Pireh, D.; Pease, J.;
Pliushchev, M.; Sciotti, R. J.; Wiedman, P. E.; Djuric, S. W. Tetrahedron
Lett. 2001, 42, 3681-3684.
2208
Org. Lett., Vol. 5, No. 13, 2003

An examination of bases, such as sodium carbonate,
potassium carbonate, cesium carbonate, potassium phosphate,
as well as tertiary and secondary amines, and alkoxides,
revealed the two most effective and functional group-
compatible15 bases to be cesium carbonate and potassium
phosphate. Although potassium phosphate showed a faster
reaction in ethereal solvents (e.g., THF or 1,4-dioxane; Table
1, entries 11, 12, 15, 16), this difference in reactivity was
less significant at slightly elevated temperature. Indeed, in
toluene, cesium carbonate gave consistently faster reactions
(Table 1, entries 13, 14, 17, 18) over a range of temperature
(70-115 °C) and proved to be crucial for a cleaner
conversion.
Table 2. Pd-Catalyzed N-Arylation of Oxazolidinonesa
As shown in Table 2, a variety of aryl chlorides can be
coupled to different substituted oxazolidinones.16,17 We found
that a combination of Pd2dba3 as the Pd(0) precursor and
Buchwald’s biaryl ligands (1-3, preferably 2) with Cs2CO3
as the base and toluene or 1,4-dioxane as the solvent provided
the most generally successful catalyst for the coupling of
oxazolidinone with activated (electron-deficient) aryl chlo-
rides. Electronically neutral or slightly electron-rich aryl
chlorides also reacted efficiently under these conditions
(Table 2, entries 2, 6-8, 9-11).
Aryl chlorides with electron-withdrawing groups para to
the chloro group reacted efficiently with a number of
oxazolidinones at temperatures from 100 to 115 °C using
Pd2dba3 as the Pd(0) precursor. N-Arylation involving aryl
chlorides that possess electron-donating substituents were
sluggish, as expected. Interestingly, Pd/BINAP systems
turned out to be superior in those cases compared to electron-
rich, bulky biaryl ligands 1-3 (data not shown). As
expected,18 aryl chlorides containing ortho substitutents are
particularly inert to this transformation. Attempts to increase
(13) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081-3089. For uses of
Xantphos in C-N bond-forming reactions, see: (b) Guari, Y.; van Es, D.
S.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Tetrahedron
Lett. 1999, 40, 3789-3790. (c) Wagaw, S.; Yang, B. H.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 10251-10263. (d) Harris, M. C.; Geis, O.;
Buchwald, S. L. J. Org. Chem. 1999, 64, 6019-6022. For a kinetic study
of Xantphos/Pd-catalyzed amine arylation reactions, see: (e) Guari, Y.; van
Strijdonck, G. P. F.; Boele, M. D. K.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Chem. Eur. J. 2001, 7, 475-482.
(14) DPPF ) 1,1-bis(diphenylphosphino)ferrocene, DPEphos ) bis(2-
diphenylphosphinophenyl)ether, BINAP ) 2,2-bis(diphenylphosphino)-1,1-
binaphthyl, Xantphos ) 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene.
(15) The alkoxide bases showed faster rates. However, lower yields were
observed as a result of hydrolytic decomposition of oxazolidinone, as well
as undesired N-arylation.
(16) Enantiopure oxazolidinones were used for this study. Comparison
of products from both antipodes by chiral HPLC (detailed in Supporting
Information) showed complete retention of stereochemistry. Preservation
of optical purity during Pd-catalyzed arylation of R-substituted amines has
been reported by others. See: Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818.
a Unless otherwise stated, reactions were performed in toluene using the
following molar ratios: 4:5:[Pd]:ligand:base ) 1:1.1:0.04:0.08:1.4. b Yields
refer to an average of two runs. The isolated compounds are 95-99% pure
as judged by NMR and HPLC analysis.
the catalyst loading in Pd/BINAP or Pd/Xantphos combina-
tions led to the formation of varying amounts of N-
phenyloxazolidinones, presumably via aryl group exchange
between the aryl-palladium complex and the phenyl ring
of the phosphine (LC and LC-MS analysis). However,
removal of these side products from the crude reaction
mixtures was straightforward with flash chromatography.
Cacchi’s N-arylation of oxazolidinones of aryl bromides
bearing a ketone functional group suffered from a competi-
(17) Typical Procedure. (Table 2, entry 2) An oven-dried tube was
charged with Pd2(dba)3 (45.6 mg, 0.05 mmol), ligand 2 (29.8 mg, 0.05
mmol), chlorobenzene (132 µL, 1.3 mmol), oxazolidinone (150 mg, 1.3
mmol), Cs2CO3 (590 mg, 1.82 mmol), and degassed toluene (1.5 mL). The
tube was evacuated and back-filled with nitrogen three times and then heated
at 115 °C with stirring for 18 h. The reaction mixture was allowed to cool
to room temperature, diluted with MTBE, and filtered through a pad of
Celite. The organic layer was washed with saturated NH4Cl, dried with
Na2SO4, and concentrated in vacuo. The crude residue was purified by
chromatography on silica gel using mixtures of ethyl acetate/hexanes as
the eluent to obtain pure product (81%).
(18) For similar reactivity of aryl bromides, see ref 12a.
Org. Lett., Vol. 5, No. 13, 2003
2209

transformation, the resulting N-aryloxazolidinones were
hydrolyzed using ethanolic NaOH to produce the corre-
sponding N-aryl â-amino alcohols (Table 3), which are
themselves of current interest.20
Table 3. Hydrolysis of N-Aryl Oxazolidinones to
N-Aryl-â-amino Alcohols
In summary, the first general intermolecular cross-coupling
between aryl chlorides and cyclic carbamates has been
developed by using a phosphine/Pd catalyst, Cs2CO3 as the
base, and toluene as the solvent. This N-arylation protocol
provides a reasonably broad substrate scope and good
functional group compatibility. Activated aryl halides that
bear electron-withdrawing groups at meta or para positions
efficiently underwent C-N bond formation with a variety
of oxazolidinones. Unactivated or deactivated aryl halides
also reacted with various amides under more carefully
controlled conditions.
Acknowledgment. We gratefully acknowledge Professors
D. Collum (Cornell) and S. Ley (Cambridge) for helpful
discussions and Drs. S. Gut, J. Ragan, and F. Urban for
insightful comments.
Supporting Information Available: General experimen-
tal details, synthetic procedures, and physical characterization
data for N-aryloxazolidinones (Table 2, entries 1-19, 22-
27). This material is available free of charge via the Internet
at http://pubs.acs.org.
OL034428P
tive ketone arylation process.19 Interestingly, such ketone
arylation processes were largely suppressed in our conditions
(Table 2, entries 19, 24-27). To extend the scope of this
(19) 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.
(20) Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703-3706.
2210
Org. Lett., Vol. 5, No. 13, 2003