CuI/N,N-dimethylglycine-catalyzed synthesis of N-aryloxazolidinones from aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2012.05.081

CuI/N,N-dimethylglycine catalyzed coupling of aryl bromides with substituted oxazolidinones took place at 120 °C in DMF, affording the corresponding N-arylation products with good to excellent yields. A number of functional groups, such as ketone, nitrile, nitro, methoxy, and hydroxyl were tolerated under these conditions, thereby allowing diversity synthesis of N-aryloxazolidinones.

Full text of DOI:10.1016/j.tetlet.2012.05.081

Tetrahedron Letters 53 (2012) 3981–3983
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuI/N,N-dimethylglycine-catalyzed synthesis of N-aryloxazolidinones from
aryl bromides
Jiaojiao Li a, Yihua Zhang a, , Yongwen Jiang b, Dawei Ma b,
⇑
⇑
a Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
CuI/N,N-dimethylglycine catalyzed coupling of aryl bromides with substituted oxazolidinones took place
at 120 °C in DMF, affording the corresponding N-arylation products with good to excellent yields. A num-
ber of functional groups, such as ketone, nitrile, nitro, methoxy, and hydroxyl were tolerated under these
conditions, thereby allowing diversity synthesis of N-aryloxazolidinones.
Received 7 April 2012
Revised 15 May 2012
Accepted 18 May 2012
Available online 26 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keyword:
Coupling
N-Aryloxazolidinone is an important structural motif for phar-
maceutical and medicinal utilization. Indeed, several clinically
used drugs bearing this moiety have been developed. For example,
Linezolid (1, Fig. 1)1 and Eperezolid (2)2 are two antibacterial drugs
that are effective against a number of gram-positive bacterial
pathogens including methicilin-resistant Staphylococcus aureas
(MRSA) and vancomycin-resistant Enterococci (VRE).3 Toloxatone
(3), a selective and reversible inhibitor of monoamine oxidase A,
has been approved for the treatment of depression.4
O
F
O
N
O
N
NHCOCH3
NHCOCH3
Linezolid (1)
O
F
O
O
N
N
N
HO
Owing to the importance of N-aryloxazolidinones in the phar-
maceutical field, much attention has been directed to the elabora-
tion of this class of compounds. Formation of oxazolidinones from
N-aryl aminoalcoholes is the most classical approach for assem-
bling N-aryloxazolidinones.3a In recent years, metal-catalyzed
cross coupling reactions of oxazolidinones with aryl halides, aryl
tosylates, or aryl sulfamates open a new avenue to access these
compounds. In 2001, Cacchi et al., reported that coupling of aryl
halides (both bromides and chlorides) with oxazolidinones could
be catalyzed by the combination of Pd2(dba)3 (or Pd(OAc)2) and
Xantphos.5 Soon after that, a Pfizer group described that a biaryl
phosphine ligand could more effectively affect the Pd2(dba)3-
catalyzed coupling of aryl chlorides with oxazolidinones.6 Quite
recently, Ni-catalyzed amination of aryl sulfamates7 and Pd-cata-
lyzed coupling of hetero-aromatic tosylates8 with oxazolidinones
were reported to be able to afford N-aryloxazolidinones with great
diversity.
Eperezolid (2)
O
H3C
O
N
OH
Toloxatone (3)
Figure 1. Structures of bioactive N-aryloxazolidinones.
utilized as the catalyst to promote the N-arylation of oxazolidinon-
es. The usefulness of this catalytic system was further demon-
strated by the synthesis of Toloxatone and Linezolid. Although
the reaction conditions are compatible with simple and some
substituted oxazolidinones, reaction of aryl bromides with steri-
cally hindered and hydroxymethyl-substituted oxazolidinones
gave the coupling product in low yields.9,10 Additionally, compar-
ing with other commonly used ligands, trans-1,2-diaminocyclo-
hexane is more expensive. To solve these problems, several
groups have explored alternative approaches by using different
copper sources and ligands.11 However, all these catalytic systems
were found to be effective only for aryl iodides.11
In 2003, Trehan and co-workers9 and Cacchi et al.,10 indepen-
dently described that CuI/trans-1,2-diaminocyclohexane could be
⇑
Corresponding authors.
E-mail addresses: zyhtgd@sohu.com (Y. Zhang), madw@mail.sioc.ac.cn (D. Ma).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.081

3982
J. Li et al. / Tetrahedron Letters 53 (2012) 3981–3983
Table 2
In the past decade, we have demonstrated that some amino
CuI/N,N-dimethylglycine-catalyzed synthesis of N-aryloxazolidinonesa
acids are useful ligands for promoting copper-catalyzed N-aryla-
tion of aryl and vinyl halides.12 In particular, we found that the
combination of CuI and N,N-dimethylglycine could catalyze cou-
pling of vinyl halides with oxazolidinones.13 As an extension of this
work, we recently discovered that N,N-dimethylglycine is an excel-
lent ligand for copper-catalyzed coupling of aryl bromides with
oxazolidinones. Under the action of this catalytic system, both ste-
rically hindered and hydroxymethyl-substituted oxazolidinones
could be used as the coupling partners, providing the correspond-
ing arylation products with good to excellent yields. Herein, we
wish to disclose our results.
We started our studies by conducting a coupling reaction of 4-
bromoanisole with oxazolidin-2-one using K2CO3 as a base. It was
found that under the catalysis of 5 mol % CuI and 10 mol % N,N-
dimethylglycine, this reaction completed at 120 °C after 24 h in
DMF to afford the desired product 6a in 88% yield (Table 1, entry
1). Changing solvent to dioxane gave a similar result (entry 2),
however, in DMSO only 68% yield was observed (entry 3). The
decreasing yields were also found when switching base to K3PO4
and Cs2CO3 (entries 4 and 5). Further attempts by changing the
copper salts to CuCl, CuBr, and Cu2O failed to give improved results
(entries 6–8). However, increasing the catalytic loading could give
the best yield even at 110 °C (entry 9). These results give alterna-
tive choices when prices of catalytic system and substrates are
considered. Without addition of N,N-dimethylglycine only 9% cou-
pling yield was observed (entry 10), indicating that the presence of
the ligand is essential for complete conversion.
Based on the above investigations, we further examined the
reaction scope by changing aryl bromides and substituted oxazo-
lidinones (Table 2). We were pleased to observe that a wide range
of N-aryloxazolidinones could be prepared with good to excellent
yields by using our catalytic system. Electron-rich aryl bromides
generally required longer reaction time than electron-deficient
ones (comparing entries 6 and 10, and 11 and 15). The coupling
reaction between 3-methylphenyl bromide and 5-(hydroxy-
methyl)oxazolidin-2-one also worked well, affording Toloxatone
(3) directly (entry 16). In contrast with CuI/trans-1,2-diamino-
cyclohexane catalyzed reaction,9,10 no O-arylation product was ob-
served under our reaction conditions. Similarly, 6q was obtained in
O
N
O
5 mol % CuI
O
O
10 mol % DMG
+
Br HN
K2CO3, DMF,120 ºC
R'
X
R'
X
R
6
R
4
5
DMG = N,N-dimethylglycine
Entry
Time (h)
24
Productb (yield)
O
O
N
1
2
3
4
5
6
7
8
9
6b (90%)
O
O
18
18
18
18
18
24
24
24
MeOC
N
6c (95%)
O
O
NC
N
6d (98%)
O
O
Cl
N
6e (88%)
MeOC
O
O
N
6f (91%)
NO2O
O
N
6g (79%)
O
O
MeS
N
6h (96%)
O
O
Me
Me
N
Table 1
Coupling of 4-bromoanisole with oxazolidin-2-one under different conditionsa
6i (68%)
O
N
O
O
[Cu]
O
O
N,N-dimethylglycine
MeO
MeO
Br
O
N
+ HN
base, solvent
6a
4a
5a
6j (72%)
O
OMe
Entry
[Cu]
Solvent
Base
Temp (°C)
Yieldb (%)
O
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
Cu2O
CuI
DMF
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
120
120
120
120
120
120
120
120
110
120
88
83
68
44
21
81
75
67
94c
9d
10
11
12
30
24
24
N
Dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
6k (84%)
O
O
O
MeOC
6l (90%)
N
10
CuI
O
a
Reaction conditions: 4-bromoanisole (1 mmol), oxazolidin-2-one (1.2 mmol),
copper salt (0.05 mmol), N,N-dimethylglycine (0.1 mmol), base (2 mmol), solvent
(0.5 mL), 24 h.
MeOC
6m (93%)
N
b
Isolated yield.
Ph
c
0.1 mmol of CuI and 0.2 mmol of N,N-dimethylglycine were used.
N,N-dimethyl-glycine was not added.
d

J. Li et al. / Tetrahedron Letters 53 (2012) 3981–3983
3983
Table 2 (continued)
Acknowledgments
Entry
Time (h)
24
Productb (yield)
The authors are grateful to the Ministry of Science and Technol-
ogy (Grant 2009ZX09501-00), the Chinese Academy of Sciences
and the National Natural Science Foundation of China (Grant
20632050 and 20921091) for their financial support.
O
O
NC
N
13
14
6n (97%)
Ph
Supplementary data
O
O
MeO
6o (92%)
N
50
50
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.081.
Ph
O
References and notes
O
MeO
6p (65%)
N
15
1. (a) 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.
Z.; Zurenko, G. E. J. Med. Chem. 1996, 39, 673; (b) Renslo, A. R.; Jaishankar, P.;
Venkatachalam, R.; Hackbarth, C.; Lopez, S.; Patel, D. V.; Gordeev, M. F. J. Med.
Chem. 2005, 48, 5009; (c) Tucker, J. A.; Allwine, D. A.; Grega, K. C.; Barbachyn,
M. R.; Klock, J. L.; Adamski, J. L.; Brickner, 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.
2. (a) Xu, G.; Zhou, Y.; Yang, C.; Xie, Y. Heteroat. Chem. 2008, 19, 316; (b) Lohray, B.
B.; Gandhi, N.; Srivastava, B. K.; Lohray, V. B. Bioorg. Med. Chem. Lett. 2006, 16,
3817; (c) McKee, E. E.; Ferguson, M.; Bentley, A. T.; Marks, T. A. Antimicrob.
Agents Chemother. 2006, 50, 2042.
3. (a) Gregory, W. A.; Brittelli, 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; (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.
4. (a) Mai, A.; Artico, M.; Esposito, M.; Sbardella, G.; Massa, S.; Befani, O.; Turini,
P.; Glovannini, V.; Mondovi, B. J. Med. Chem. 2002, 45, 1180; (b) Valente, S.;
Tomassi, S.; Tempera, G.; Saccoccio, S.; Agostinelli, E.; Mai, A. J. Med. Chem.
2011, 54, 8228; (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.
Me
O
O
O
16
17
18
24
30
18
24
N
OH
3 (72%)
F
O
O
N
N
OH
6q (72%)
O
N
O
N
6r (82%)
O
O
5. Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539.
6. Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz, L. Org. Lett. 2003, 5, 2207.
7. Ramgren, S. D.; Silberstein, A. L.; Yang, Y.; Garg, N. K. Angew. Chem., Int. Ed.
2011, 50, 2171.
19
N
S
6s (53%)
a
8. Mantel, M. L. H.; Lindhardt, A. T.; Lupp, D.; Skrydstrup, T. Chem. Eur. J. 2010, 16,
5437.
9. Mallesham, B.; Rajesh, B. M.; Reddy, P. R.; Srinivas, D.; Trehan, S. Org. Lett. 2003,
5, 963.
Reaction conditions: aryl bromide (1 mmol), substituted oxazolidin-2-one
(1.2 mmol), CuI (0.05 mmol), N,N-dimethylglycine (0.1 mmol), K2CO3 (2 mmol),
DMF (0.5 mL).
b
Isolated yield.
10. Cacchi, S.; Fabrizi, G.; Goggiamani, A. Heterocycles 2003, 61, 505.
11. (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10,
5607; (b) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609; (c) Mino, T.; Harada,
Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2008, 614; (d) Phillips, D. P.; Zhu,
X.-F.; Lau, T. L.; He, X.; Yang, K.; Liu, H. Tetrahedron Lett. 2009, 50, 7293; (e)
Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, P.;
Punniyamurthy, T. J. Org. Chem. 1971, 2009, 74; (f) Lin, B.; Liu, M.; Ye, Z.; Ding,
J.; Wu, H.; Cheng, J. Org. Biomol. Chem. 2009, 7, 869; (g) Jammi, S.;
Krishnamoorthy, S.; Saha, P.; Kundu, D. S.; Sakthivel, S.; Ali, M. A.; Paul, R.;
Punniyamurthy, T. Synlett 2009, 20, 3323; (h) Ali, M. A.; Saha, P.;
Punniyamurthy, T. Synthesis 2010, 6, 908.
72% yield, which could be used for assembling racemic Linezolid
(1). Additionally, two heteroaryl bromides were found to be appli-
cable, producing 6r and 6s, respectively (entries 18 and 19).
In conclusion, we have developed an efficient method for
assembling N-aryloxazolidinones, which relied on a CuI/N,N-dim-
ethylglycine-catalyzed coupling reaction of aryl bromides with
substituted oxazolidinones. The economical catalytic system used
here, together with good coupling yields and compatibility for a
variety of substrates will make this method very competitive in
the preparation of bioactive N-aryloxazolidinones.
12. Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
13. Pan, X.; Cai, Q.; Ma, D. Org. Lett. 1809, 2004, 6.