Highly efficient CuI-catalyzed coupling of aryl bromides with oxazolidinones using Buchwald's protocol: a short route to linezolid and toloxatone.

Article abstract of DOI:10.1021/ol026902h

[reaction: see text] Coupling of a variety of substituted aryl bromides with oxazolidinones has been achieved using the Buchwald protocol for the amidation of aryl halides. This procedure is exemplified by the synthesis of two medicinally important molecules, linezolid and toloxatone.

Full text of DOI:10.1021/ol026902h

ORGANIC
LETTERS
2003
Vol. 5, No. 7
963-965
Highly Efficient CuI-Catalyzed Coupling
of Aryl Bromides with Oxazolidinones
Using Buchwald’s Protocol: A Short
Route to Linezolid and Toloxatone†
B. Mallesham, B. M. Rajesh, P. Rajamohan Reddy, D. Srinivas, and
Sanjay Trehan*
DiscoVery Research, Dr. Reddy’s Laboratories Limited, Bollaram Road,
Miyapur, Hyderabad-500 050, India
strehan@drreddys.com
Received September 14, 2002
ABSTRACT
Coupling of a variety of substituted aryl bromides with oxazolidinones has been achieved using the Buchwald protocol for the amidation of
aryl halides. This procedure is exemplified by the synthesis of two medicinally important molecules, linezolid and toloxatone.
N-Aryloxazolidinones constitute an important class of phar-
macologically active compounds. They exhibit selective and
reversible inhibition of monoamine oxidase A, an important
enzyme responsible for the degradation of various amine
neurotransmitters.1 Over the past decade, a new class of
antibacterial compounds have emerged with the same
template, and in general, they are referred to as oxazolidinone
antibiotics.2 They have potent activity against a variety of
Gram-positive bacterial pathogens including methicillin-
resistant Staphylococcus aureas (MRSA) and vancomycin-
resistant Enterococci (VRE). For these reasons, much atten-
tion has been given to the synthesis of these classes of com-
pounds. Any general method developed for the synthesis of
these compounds must ensure compatibility with the sub-
stitution on the aryl and oxazolidinone moieties (Figure 1).
† DRL publication No. 248.
(1) (a) 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. (b) 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.
Figure 1.
(2) (a) Selvakumar, N.; Srinivas, D.; Khera, M. K.; Kumar, M. S.;
Mamidi, N. V. S. R.; Sarnaik, H.; Chandrasekar, C.; Rao, B. S.; Raheem,
M. A.; Das, J.; Iqbal, J.; Rajagopalan, R. J. Med. Chem. 2002, 45, 3953-
3962 and references therein. (b) Park, C.-H.; 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. (c)
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. (d)
Kan, J. P., et al. Eur. J. Med. Chem. 1977, 12, 13. (e) Gregory, W. A.;
David R. Britelli, 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.
Most of the methods reported involve construction of the
oxazolidinone as the key step in the synthesis of 5-substituted
3-aryloxazolidinones.2,3 Recently, Pd-catalyzed coupling of
oxazolidinones with aryl bromides has been developed that
could be used for the synthesis of this class of compounds.4
(3) (a) Jegham, S.; Nedelec, A.; Burnier, Ph.; Guminski, Y.; Puech, F.;
Koenig, J. J.; George, P. Tetrahedron Lett. 1998, 4453-4454. (b) Schaus,
S. E.; Jacobsen, E. N. Tetrahedron Lett 1996, 7937-7940.
10.1021/ol026902h CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/04/2003

This work had the precedence in the pioneering work of
Buchwald and Hartwig.5 Recently, Buchwald reported a
landmark development in the Goldberg coupling reaction
using CuI (1-10 mol %) for the amidation of aryl halides.6
In the reaction, (()-trans-1,2-diaminocyclohexane was used
to solubilize CuI, and K3PO4 or K2CO3 was used as base.
The procedure, in addition to being cost-effective, could also
tolerate some functional groups that are otherwise problem-
atic in palladium-catalyzed coupling reactions.6 In this proce-
dure oxazolidinones were not evaluated for amidation of aryl
halides. Subsequently, it was shown that ethylenediamine
could be used instead of cyclohexanediamine.6b,7 Two exam-
ples were reported in which oxazolidinones were coupled
with aryl iodides using 10 mol % of CuI in only modest
yields.7 These results indicated the potential of CuI catalyzed
reaction for the synthesis of 3-aryl-2-oxazolidinones.
In a program intended toward developing a cost-effective
and direct method to this group of compounds in our lab-
oratory, we have worked on CuI-mediated coupling reactions,
and herein we disclose our efforts in this area. Initial attempts
were carried out for the coupling of bromobenzene and
oxazolidinone following Buchwald conditions using com-
mercially available CuI (10 mol %) and (()-trans-cyclo-
hexanediamine (10 mol %) with various bases such as K3PO4,
K2CO3, and Cs2CO3. Potassium carbonate gave product in
45% yield, and with the other two bases only a trace amount
of product was formed. After having failed to improve the
yield even after using CuI from three different commercial
sources, we have achieved a dramatic increase in the yield
(78%) by using recrystallized CuI.8 Subsequently, performing
the reaction using freshly distilled (()-trans-cyclohexanedi-
amine along with recrystallized CuI resulted in the product
in excellent isolated yield. After some experimentation, the
reaction conditions were optimized and it was found that 3
mol % CuI along with 10 mol % (()-trans-cyclohexanedi-
amine and 2 equiv of potassium carbonate in dioxane at 110
°C for 15 h gave product consistently in over 90% yield. To
generalize this procedure, various aryl bromides and oxazo-
lidinones were coupled, and the results are summarized in
Table 1.
Table 1. Coupling of Oxazolidinone with Various Aryl
Bromidesa
entry
aryl bromide
CuI (mol %)
% isolated yield
1
2
3
4
5
6
7
8
9
C6H5-Br
3
3
3
3
3
3
5
3
3
3
90
50
81
98
86
45
82
30
80
83
p-NO2-C6H4Br
p-CN-C6H4Br
p-COMe-C6H4Br
p-MeS-C6H4Br
p-MeO-C6H4Br
p-MeO-C6H4Br
p-CHO-C6H4Br
m-Me-C6H4Br
o-MeO-C6H4Br
10
a All reactions were carried out in dioxane at 110-120 °C (bath
temperature) under argon atmosphere.
To generalize the coupling reaction further, some substi-
tuted oxazolidinones were prepared from leucinol and phenyl
glycinol by treatment with diethyl carbonate. Additionally,
more relevant substituted oxazolidinones for the synthesis
of targeted molecules were prepared from racemic 5-(hy-
droxymethyl)-2-oxazolidinone (Scheme 1).2e,9 The alcohol
Scheme 1a
a Reagents: (a) CH3SO2Cl, Et3N, CH2Cl2, 0-25 °C, 1 h; (b)
potassium phthalimide, DMF, 70 °C, 4 h; (c) PPTS, dihydropyran,
CH2Cl2, 25 °C, 12 h.
The coupled product was obtained in high yield in most
of the cases except for the case where a strong electron-
donating group was present on the aromatic ring. In this
case, the yield was improved by using more CuI (5 mol %)
(Compare entries 6 and 7). The yield with the formyl group
on the aromatic ring resulted in product only in modest yield
(entry 8). It is important to note that the thiomethyl group
in the aromatic group was well tolerated in the reaction,
which can be troublesome in Pd catalyzed reactions (entry 5).
1 was protected with dihydropyran to give the compound
3.10 The alcohol 1 was also converted to compound 2 by a
two-step procedure involving mesylation followed by treat-
ment with potassium pthalimide. These substituted oxazo-
lidinones were also coupled with aryl halides and the results
are compiled in Table 2.
Substituted oxazolidinones also gave the coupled products
in excellent yields. Oxazolidinone with free hydroxyl group
could also be coupled with bromobenzene albeit in poor yield
(Table 2, entry 5). Even though oxazolidinone 2 was partially
(4) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001,
3, 2539-2541.
(5) (a) Hartwig J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (b)
Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-860. (c) Wolfe, J. P.; Wagaw,
S.; Marcoux J.-F.; Buchwald, S. L.; Acc. Chem. Res. 1998, 31, 805-818.
(6) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727-7729. (b) Klapars, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421-7428.
(7) Kang S.-K.; Kim, D.-H.; Park, J.-N. Synlett 2002, 427-430.
(8) CuI was crystallized using a procedure reported by Dieter. See:
Dieter, R. K.; Silks, L. A., III.; Fishpaugh, J. R.; Kastner, M. E. J. Am.
Chem. Soc. 1985, 107, 4679-4692.
(9) Leung, M.-K.; Lai, J.-L.; Lau, K.-H.; Yu, H.-H.; Hsiao, H.-J. J. Org.
Chem. 1996, 61, 4175-4179.
(10) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772-3773.
964
Org. Lett., Vol. 5, No. 7, 2003

Scheme 2a
a Reagents: (a) HONO, CuBr, 47% HBr; (b) CuI (5 mol %), (()-trans-1,2-diaminocyclohexane (10 mol %), dioxane, K2CO3, 110 °C,
15 h; (c) PPTS, EtOH, reflux,1 h; (d) CH3SO2Cl, Et3N, CH2Cl2, 0-25 °C, 1 h; (e) NaN3, DMF, 70 °C, 2 h; (f) CH3COSH, 25 °C, 15 h.
Scheme 3a
Table 2. Coupling of Various Substituted Oxazolidinones with
Aryl Bromides
a Reagents: (a) CuI (5 mol %), (()-trans-1,2-diaminocyclohex-
ane (10 mol %), K2CO3, dioxane, 110 °C, 15 h; (b) PPTS, EtOH,
reflux, 1 h.
linezolid using known procedures.2c Similarly, toloxatone2d
was prepared in two steps from 3 and 3-bromotoluene
(Scheme 3).
In conclusion, we have developed an efficient and high-
yielding CuI-mediated N arylation of oxazolidinones using
the Buchwald protocol. Various aryl bromides and substituted
oxazolidinones were used to evaluate the utility of this
procedure. The synthesis of linezolid and toloxatone has been
achieved using the method developed.
Acknowledgment. We are thankful to the Analytical
Research Department of Discovery Research, Dr. Reddy’s
Laboratories Ltd., for their support in carrying out this inves-
tigation. We are also indebted to Dr. R. Rajagopalan for his
encouragement.
Note Added after ASAP Posting. In the version posted
ASAP March 4, 2003, bonds were missing from the product
soluble under these reaction conditions, the coupled product
was still obtained in decent yield (Table 2, entry 6).
structures in entries 1, 6, and 7 of Table 2. The corrected
The utility of this protocol has been exemplified by the
version was posted March 6, 2003.
synthesis of linezolid and toloxatone (Figure 1) as shown in
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Schemes 2 and 3. The key step in the synthesis of linezolid
is the coupling of the aryl bromide 5, which was prepared
from known aniline2b 4 via a Sandmeyer reaction, with the
oxazolidinone 3. Deprotection of compound 6 using PPTS
in boiling ethanol gave alcohol 7,10 which was converted to
OL026902H
Org. Lett., Vol. 5, No. 7, 2003
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