Oxazolidin-2-one-promoted CuI-catalyzed amidation of aryl halides and cyclization of o-halobenzanilides

Article abstract of DOI:10.1055/s-2008-1072764

Oxazolidin-2-one was found to be a versatile and efficient ligand for the CuI-catalyzed amidation of aryl halides and the cyclization of ortho-halobenzanilides. Notably, the less active halides could also be applied successfully in the synthesis of benzoxazoles and benzothiazoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072764

LETTER
1335
Oxazolidin-2-one-Promoted CuI-Catalyzed Amidation of Aryl Halides and
Cyclization of o-Halobenzanilides
C
–N
,
C–O,
C–S
C
e
oupling Re
a
n
ctions g Chang Ma, Xuan Zhen Jiang*
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, P. R. of China
Fax +86(571)87951611; E-mail: chejiang@zju.edu.cn
Received 13 January 2008
yl)ethane.16 However, the high cost and/or tedious
Abstract: Oxazolidin-2-one was found to be a versatile and effi-
cient ligand for the CuI-catalyzed amidation of aryl halides and the
cyclization of ortho-halobenzanilides. Notably, the less active ha-
lides could also be applied successfully in the synthesis of benzox-
azoles and benzothiazoles.
preparation of some ligands used in these important pro-
tocols are the major drawbacks. Hence, it is still essential
to search for other new, less costly and versatile ligands
for this copper-catalyzed protocol.
Key words: amidation, cyclizations, catalysis, ligand, coupling
In our latest work we turned our attention to the synthesis
of O–O type ligands and their use in copper-catalyzed C–
N coupling reactions.17 To extend the application of our
ligands, we tested the commonly used oxazolidin-2-one as
a C–N coupling partner. To our delight, the reactions af-
forded satisfactory results. In 2003, Buchwald reported
the copper-catalyzed amidation of halides.18 We noted
from the work that the access to a molecule containing the
oxazolidin-2-one unit is more efficient than others. Relat-
ed works also documented that the five-membered lac-
tams, used as C–N coupling substrates, displayed greater
efficiency than the four-, and six-membered lactams.3a
From these valuable clues, we speculated that oxazolidin-
2-one has the possibility to be applied as a potential
ligand. Through the systematic and rational design of ox-
azolidin-2-one-based structures, a series of derivatives
was synthesized (Figure 1).
The formation of C–N bond is of great importance in the
preparation of intermediates and target molecules in the
chemical, pharmaceutical, and materials industries.1 De-
spite significant improvements in the palladium-catalyzed
N-arylation of amines, some limitations still exist that pre-
vent these reactions from being employed to their full po-
tential.2 For examples, substantial structural variations
cannot be accommodated and certain functional groups
are found to be incompatible in some cases,3 the sterically
hindered phosphine ligands are not easily available, and
the palladium reagents have limited applications due to
their high cost and air sensitivity. Copper-catalyzed Ull-
mann reaction and the related Goldberg reaction were ap-
plied as alternative C–N bond-forming methodologies.4
Unfortunately, these methods also suffer from relatively
limited scope of substrates, high reaction temperature (up
to 210 °C), and the requirement of stoichiometric amounts
of copper reagents.
Initially, we tested the coupling reaction of pyrrolidin-2-
one (1a) with 1-bromo-4-methoxybenzene (2a) in the
presence of different copper salts and ligands, as well as
bases. Employing the trial and error approach, we were
pleased to find that the reaction of 1a with 2a in DMSO at
120 °C for 24 hours in the presence of CuI (10 mol%), L1
(20 mol%), and MeONa (1.5 equiv) occurred smoothly to
give the coupling product 1-(4-methoxyphenyl)pyrroli-
din-2-one (3a) in good yield (78%, Table 1, entry 1).
In recent years, the use of ligands to facilitate the copper-
catalyzed N-arylation of nucleophiles with aryl halides is
one of the active research areas in the formation of func-
tionalized nitrogen-containing structures. Several groups
have disclosed the use of different ligands, including ami-
no acids,5 diamines,6 diimines,7 aminoarenethiolate,8
phosphines,9 2-aminopyrimidine-4,6-diol,10 hydroxy-
quinoline,11 (S)-pyrrolidinylmethylimidazoles,12 4,7-
dimethoxy-1,10-phenanthroline,13 2-oxocyclohexanecar-
boxylate,14 benzotriazole,15 and 1,1,1-tri(hydroxymeth-
The following details were noteworthy. First, not all
ligands could be employed for the reaction. For examples,
L3 and L4 could not be applied as promoters in our cataly-
sis system (Table 1, entries 3 and 4), while the sterically
more hindered ligands L5, L6, and L7 afforded 3a in lower
S
S
O
H
N
H
N
H
N
O
HN
NH
HN
NH
HN
NH
S
O
O
S
S
O
O
O
S
S
O
O
L1
L2
L3
L4
L5
L6
L7
Figure 1
SYNLETT 2008, No. 9, pp 1335–1340
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072764; Art ID: W01208ST
© Georg Thieme Verlag Stuttgart · New York

1336
H. C. Ma, X. Z. Jiang
LETTER
Table 1 Copper-Catalyzed Amidation of 1-Bromo-4-methoxyben-
zene (2a) with Pyrrolidin-2-one (1a)a
product in good to excellent yields. 2-Bromopyridine (2d)
even displayed greater efficiency than iodobenzene (entry
4 vs. entry 2). As reported previously in the copper-cata-
lyzed N-arylation reactions, certain groups at the ortho
position of aryl halides had the ability to coordinate to
copper and promoted the Ullmann-type reaction.10 In our
reactions, we also found that the nitrogen atom in 2-bro-
mopyridine possessed the ability to promote the coupling
reactions (Table 2, entries 4, 7, and 17). Interestingly,
while pyrrolidin-2-one (1a) was an effective partner in all
cases (Table 2, entries 1–4), the analogous piperidin-2-
one (1g, n = 1) and azepan-2-one (1g, n = 2) were not re-
active (Table 2, entry 18), presumably due to their in-
creased steric hindrance and different pKa values in
DMSO.3a,18,19
O
O
Br
+
N
OMe
NH
MeO
3a
1a
2a
Entry Ligand [Cu]
Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)b
1
2
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
L1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl2
CuI
CuI
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
K2CO3
78
71
c
3
–
c
4
–
As for the amides 1b–1e, the N-arylation reactions were
conducted successfully in good to excellent yields
(Table 2, entries 5–15). Higher chemoselectivity was
found for 2-iodochlorobenzene, and only the iodide func-
tion was displaced in the reaction (Table 2, entries 13–
15). Competitive hydrolysis of the acetyl group in the
products 3j–3m led to low yields of the products in the
presence of MeONa (Table 2, entries 10–13). Such prob-
lems could be circumvented when K2CO3 was used as an
alternative, and the product yields were enhanced
(Table 2, entries 10–13). For substrate 1f, the reaction
provided N-arylation products, and no O-arylation prod-
ucts were found (Table 2, entries 16 and 17).20 It was also
noted that a small amount of water did not have any effect
on the reaction (Table 2, entry 16).
5
25
24
28
46
45
61
63
55
67
46
6
7
8
9
toluene
10
11
12
13
14
DMF–H2Od
DMSO
DMSO
DMSO
Cs2CO3
DMSO
During our investigation on the amidation of 1-chloro-2-
iodobenzene (Table 2, entries 14 and 15), further cycliza-
tion products, such as benzoxazoles and benzothiazoles,
were observed when the temperature was elevated to 150
°C for longer reaction time. We recognized the utility of
this protocol for the one-pot preparation of these hetero-
cyclic products. However, the yields were low; it was pos-
sible that the intermediates 3n and 3o were easily
a Reaction conditions: 1a (1.5 mmol), 2a (1.5 mmol), base (2.3
mmol), [Cu] (10 mol%), ligand (20 mol%), solvent (2 mL), 120 °C.
b GC yield.
c No reaction was detected.
d DMF (2 mL) and H2O (0.1 mL) as solvent.
yields (Table 1, entries 5–7). The best results were ob-
tained only when the ligands contained O or S atom locat-
ed in the lactam ring (Table 1, entries 1 and 2). hydrolyzed in the presence of NaOMe. Therefore we test-
Presumably, both L1 and L2 acted as tridentate O-, N-, and ed other bases for the cyclization reaction, and found that
S-donor ligands that might be more effective in stabilizing K2CO3 was more efficient than others.
or solubilizing the copper complex.16 In our case, ligand
Consequently, we employed this modified reaction condi-
tions to effect the intramolecular cyclization of o-halo-
benzanilides and the results were detailed in Table 3.
L1 was preferred due to its easy preparation and lower mo-
lecular weight. Secondly, the nature of solvent had notice-
able influence on the reaction. The polar solvent DMSO
Generally, the desired products could be obtained from
was more favorable than others (yield 78%, Table 1, entry
the cyclization reaction. For less active chlorides, higher
1). Thirdly, with regard to the efficiency of the base in the
temperature (up to 150 °C) and longer reaction time (72 h)
amidation reaction, MeONa was found to be highly effec-
were required in comparison with reactions involving bro-
tive (Table 1, entry 1). Finally, various copper salts such
mides and iodides. As expected, cyclizations to benzothi-
as CuI, CuBr, CuCl2 all afforded 3a in average to good
azole occurred more readily than those to benzoxazoles.
For example, N-(2-chlorophenyl)benzothioamide (4b)
gave the cyclized product 5b in 56% yield when the reac-
yields (Table 1, entries 1, 11 and 12).
The optimized reaction conditions, L1 (20 mol%), CuI (10
mol%), amide (1.5 mmol), halide (1.5 mmol), MeONa
(1.5 equiv, 2.3 mmol), in DMSO (2 mL) at 120 °C for 24
hours, were applied to the amidation of a number of func-
tion was conducted at 140 °C for 30 hours (Table 3, entry
2). However, N-(2-chlorophenyl)benzamide (4a) only
gave the benzoxazole analogue in 22% yield even the re-
tionalized halides. As can be seen from Table 2, a wide action was performed at 150 °C for three days (Table 3,
range of representative amides, including the cyclic entry 1). When we utilized the more reactive bromo- and
amides and arylides, could be arylated to give the desired iodo-substituted reactants, the cyclizations proceeded
Synlett 2008, No. 9, 1335–1340 © Thieme Stuttgart · New York

LETTER
C–N, C–O, C–S Coupling Reactions
1337
smoothly in good yields under milder reaction conditions. lobenzanilides. The newly developed catalyst system was
The rate of cyclization of the ortho-haloanilides followed also applicable to the less active chloro-substituted sub-
the order I >Br >Cl, and was consistent with the generally strates. We believe that the present catalyst system could
accepted reaction mechanism.17
provide an excellent complement to the Pd- or Cu-cata-
lyzed methods that have already been utilized in a number
of applications, and is of great importance to the research
and development in the pharmaceutical industry.
In summary, we have disclosed that oxazolidin-2-one
could act as a versatile and efficient ligand for the CuI-cat-
alyzed arylation of amides and the cyclization of o-ha-
Table 2 N-Arylation of Amidesa
O
O
NH2
NH2
O
O
NH
O
R
H
R
Ar
N
N
+
ArX
1a
1b
1c
O
O
N
O
NH
NH
NH2
1a–h
2a–g
3a–r
MeCONH2
1, 2
1d
1e
1f
1g
Entry Amide
Halide
Product Yield (%)b Entry Amide Halide
Product
Yield (%)b
O
H
N
Br
42
1
3a
3b
74
85
10
11
1d
1d
2b
2e
88c
N
OMe
O
MeO
1a
3j
2a
O
H
I
N
32
2
80c
N
O
MeO
1a
2b
3k
O
Br
H
N
45
3
3c
3d
3e
76
89
70
12
13
14
1d
1d
1b
2f
76c
N
O
1a
2c
3l
O
H
N
I
Br
32
4
78c
N
N
O
O
Cl
Cl
N
1a
1b
2g
2g
3m
2d
O
H
N
5
6
7
86
78
N
H
Cl
2b
3n
3o
3p
OMe
O
O
I
H
N
3f
85
80
15
16
1e
1f
2g
2b
N
H
MeO
O
N
Cl
O
1b
2e
87
1b
3g
N
H
N
81d
N
2d
Synlett 2008, No. 9, 1335–1340 © Thieme Stuttgart · New York

1338
H. C. Ma, X. Z. Jiang
LETTER
Table 2 N-Arylation of Amidesa (continued)
O
O
NH2
NH2
O
O
NH
O
O
R
H
R
Ar
N
N
+
ArX
1a
1b
1c
O
N
O
NH
NH
NH2
1a–h
2a–g
3a–r
MeCONH2
1, 2
1d
1e
1f
1g
Entry Amide
Halide
Product Yield (%)b Entry Amide Halide
Product
Yield (%)b
O
N
O
I
8
3h
3i
79
69
17
18
1f
2d
2b
93
N
N
N
H
2f
1b
3q
NH
9
1c
1g
no reaction
O
2b
a Reaction conditions: L1 (20 mol%), CuI (10 mol%), amide (1.5 mmol), halide (1.5 mmol), MeONa (1.5 equiv, 2.3 mmol), DMSO (2 mL),
120 °C, 24 h.
b Isolated yield.
c Reaction was performed with 2 equiv of K2CO3 instead.
d With DMSO (2 mL) and H2O (0.1 mL) as solvent.
Table 3 Synthesis of Substituted Benzoxazoles and Benzothiazolea
H
N
R
N
Y
X = Cl, Br, I
Y = O, S
R
Y
X
5a–f
4a–f
Entry
1
Reactant
Product
Conditions, Yieldb
H
N
O
X = Cl, 150 °C, 72 h, 22%
X = Br, 110 °C, 20 h, 67%
X = I, 90 °C, 6 h, 83%
N
O
X
5a
5b
5c
4a
4b
H
N
N
S
X = Cl, 140 °C, 30 h, 56%
X = Br, 110 °C, 18 h, 77%
X = I, 90 °C, 6 h, 83%
2
3
S
X
Cl
N
O
H
N
X = Br, 110 °C, 20 h, 64%
X = I, 90 °C, 6 h, 88%
Cl
O
X
4c
Synlett 2008, No. 9, 1335–1340 © Thieme Stuttgart · New York

LETTER
C–N, C–O, C–S Coupling Reactions
1339
Table 3 Synthesis of Substituted Benzoxazoles and Benzothiazolea (continued)
H
N
R
N
Y
X = Cl, Br, I
Y = O, S
R
Y
X
5a–f
4a–f
Entry
4
Reactant
Product
Conditions, Yieldb
Cl
N
S
H
X = Cl, 140 °C, 30 h, 70%
X = Br, 110 °C, 18 h, 84%
X = I, 90 °C, 6 h, 83%
N
Cl
S
O
S
X
5d
5e
5f
4d
4e
4f
Me
Me
N
O
H
N
X = Br, 110 °C, 20 h, 62%
X = I, 90 °C, 6 h, 80%
Me
Me
5
6
X
N
S
H
N
X = Cl, 140 °C, 30 h, 66%
X = Br, 110 °C, 18 h, 83%
X = I, 90 °C, 6 h, 87%
X
a Reaction conditions: L1 (20 mol%), CuI (10 mol%), ortho-halobenzanilides (1.5 mmol), and K2CO3 (2 equiv) as base.
b Isolated yield.
(3) (a) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035.
Acknowledgement
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We are grateful for the financial supported from the National Natu-
ral Science Foundation of China (No. 20376071). We also thank Dr.
Hanfeng Ding and Weijun Yao for fruitful discussions.
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H. C. Ma, X. Z. Jiang
LETTER
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(21) General Procedure for the Coupling of Halides with
Amides: To a solution of MeONa (2.3 mmol) in DMSO (2
mL) were added CuI (29 mg, 0.15 mmol) and L1 (26 mg, 0.3
mmol). After stirring the mixture at r.t. for 30 min, the halide
(1.5 mmol) and the amide (1.5 mmol) were added to the
flask, and the reaction mixture was stirred at 120 °C for
24 h. The mixture was cooled to r.t., H2O (10 mL) was
added, and the resulting suspension was extracted with
EtOAc (4 × 10 mL). The extracted layer was dried over
MgSO4, then concentrated, and purified by column
chromatography on silica gel to provide the desired
products.
(22) 3-(Pyridin-2-yl)quinazolin-4(3H)-one (3q): bright yellow
solid; mp 135–137 °C(uncorrected). IR (KBr): 3448, 2924,
1688, 1610, 1590, 1563, 1478, 1440, 1294, 1255, 774, 760
cm–1. 1H NMR (400 MHz, CDCl3): d = 8.65–8.66 (d, J = 4.4
Hz, 1 H), 8.57 (s, 1 H), 8.22–8.24 (d, J = 8.0 Hz, 1 H), 8.06–
8.08 (t, J = 7.2 Hz, 1 H), 7.83–7.91 (m, 2 H), 7.74–7.76 (d,
J = 8.0 Hz, 1 H), 7.54–7.63 (m, 2 H). 13C NMR (100 MHz,
CDCl3): d = 160.1, 149.9, 149.6, 147.8, 146.1, 138.9, 135.4,
128.0, 127.8, 126.9, 124.6, 122.6, 122.1. LRMS (EI, 20 eV):
m/z (%) = 223 (100) [M+]. Anal. Calcd for C13H9N3O: C,
69.95; H, 4.06; N, 18.82. Found: C, 69.46; H, 4.38; N, 18.65.
(19) (a) Valter, B.; Petrov, E. S.; Stehlicek, J.; Sebrenda, J.
Collect. Czech. Chem. Commun. 1985, 50, 834.
(b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
Synlett 2008, No. 9, 1335–1340 © Thieme Stuttgart · New York

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