Approach to highly functionalized oxazolones by a Pd-catalyzed cyclization of N-alkynyl tert-butyloxycarbamates

Article abstract of DOI:10.1016/j.tetlet.2012.04.074

A mild and operationally simple approach to highly functionalized oxazolones has been developed, which involves an intramolecular oxypalladation of N-alkynyl tert-butyloxycarbamates, followed by either protonolysis of the alkenyl C-Pd bond to afford 3,5-disubstituted oxazolones or allylation with allyl halides in the presence of Ag₂CO₃ to generate 3,4,5-trisubstituted oxazolones, respectively.

Full text of DOI:10.1016/j.tetlet.2012.04.074

Tetrahedron Letters 53 (2012) 3433–3436
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Approach to highly functionalized oxazolones by a Pd-catalyzed cyclization
of N-alkynyl tert-butyloxycarbamates
⇑
⇑
Zenghui Lu, Xiaowei Xu, Zhaozhen Yang, Lichun Kong , Gangguo Zhu
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and operationally simple approach to highly functionalized oxazolones has been developed, which
involves an intramolecular oxypalladation of N-alkynyl tert-butyloxycarbamates, followed by either
protonolysis of the alkenyl C–Pd bond to afford 3,5-disubstituted oxazolones or allylation with allyl
halides in the presence of Ag2CO3 to generate 3,4,5-trisubstituted oxazolones, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 March 2012
Revised 14 April 2012
Accepted 18 April 2012
Available online 24 April 2012
Keywords:
Oxazolones
N-Alkynyl tert-butyloxycarbamates
Palladium
Oxypalladation
Allyl halides
Oxazolones constitute
a
fundamentally important class of
wish to report here an operationally simple and efficient method
for the synthesis of highly functionalized oxazolones, including
3,5-disubstituted and 3,4,5-trisubstituted oxazolones.
heterocyclic compounds occurring in many natural products and
pharmacological active molecules. They are also one of the most
important building blocks in organic chemistry and have been fre-
quently used in a wide range of chemical transformations, such as
the cycloaddition reaction,1 radical reaction,2 Pauson–Khand
reaction,3 preparation of functionalized oxazolidinones4 and other
reactions. As such, the development of general and practical proce-
dure for the synthesis of oxazolones is highly desirable.
The traditional method utilizes Lewis acid or base-catalyzed
condensation of 1,2-aminoketones with carbonyl compounds.5
However, the harsh conditions, such as high temperature and toxic
carbonylation reagents, limit the application of this method. A
promising method for the synthesis of oxazolones came from the
groups of Hashmi6a and Gagosz,6b where they reported an approach
to 3,5-disubstituted oxazolones via a Au-catalyzed transformation
of N-alkynyl tert-butyloxycarbamates. More recently, Lautens and
co-workers described an elegant synthesis of 3,5-disubstituted
oxazolones by the Pd-catalyzed reaction of b,b-dibromoenamides.7
In contrast, the efficient synthesis of 3,4,5-trisubstituted oxazol-
ones, especially in a single chemical transformation, remains a
challenge.
Our investigation commenced with the exploration of the
reaction with N-alkynyl tert-butyloxycarbamate6,9 1a as the
Table 1
Screening of the reaction conditionsa
O
Boc
PdX2
O
Ph
N
Bn
N
solvent
Ph
Bn
1a
2a
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(OAc)2
/
Pd(MeCN)2Cl2
Pd(PhCN)2Cl2
PdCl2
THF
THF
THF
THF
THF
THF
THF
Dioxane
CH3CN
CH2Cl2
CH3OH
Toluene
HOAc
EtOAc
70
NR
77
75
72
69
79
54
48
47
38
50
35
84
PdBr2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Recently, we have started a project with the aim to develop new
synthetic useful reactions involving the Pd-catalyzed functionali-
zation of heteroatom-substituted acetylenes,8 such as haloalkynes,
ynol ethers and ynamides. Pursuing our interest in this line, we
a
Reaction conditions: 1a (0.25 mmol) and Pd catalyst (0.013 mmol) in 1 mL of
⇑
Corresponding authors. Tel.: +86 579 82283702; fax: +86 0579 82282610.
E-mail addresses: sky35@zjnu.cn (L. Kong), gangguo@zjnu.cn (G. Zhu).
solvent at 40 °C for 5–8 h.
Isolated yields.
b
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.074

3434
Z. Lu et al. / Tetrahedron Letters 53 (2012) 3433–3436
Table 2
catalyst is essential for the occurrence of this reaction (Table 1, en-
Synthesis of 3,5-disubstituted oxazolones 2a
try 2). Encouraged by this promising result, we then tested other
palladium sources for this transformation. Although most of the
palladium catalysts worked well for this reaction, Pd(CF3CO2)2
turned out to be the best choice (Table 1, entries 1–7). Afterward,
we decided to perform further optimization using Pd(CF3CO2)2 as
the catalyst. It was found that the solvent EtOAc was the optimal
one, producing 3,5-disubstituted oxazolone 2a in 84% yield (Table
1, entries 8–14). Therefore, further substrate screening were car-
ried out using 5 mol % of Pd(CF3CO2)2 at 40 °C with the use of
EtOAc as the solvent.10
As shown in Table 2, under the standard conditions, either aro-
matic or alkyl N-alkynyl tert-butyloxycarbamates afforded the de-
sired oxazolones 2 in moderate to excellent yields. For example,
substrate 1b resulted in the 3,5-disubstituted oxazolone 2b in
72% yield (Table 2, entry 2). The steric hindrance on the benzene
ring indeed has little influence on the reaction, for instance, yna-
mides 1c and 1d afforded the corresponding oxazolones 2c and
2d in comparable yields (Table 2, entries 3 and 4).
The reaction of aliphatic ynamides 1l and 1m proceeded
smoothly to give oxazolones 2l and 2m in good yields, while the
silylated substrate 1n was reluctant to participate in the reaction
under the optimal reaction conditions (Table 2, entries 12–14).
Furthermore, we briefly examined the effects of substituents on
the nitrogen atom of starting materials 1. For example, substrates
with an N-butyl group 1p and an N-Cy group 1q successfully pro-
duced the desired 3,5-disubstituted oxazolones 2p and 2q in
respective yields of 71% and 72% (Table 2, entries 16 and 17).
So far, we have implemented a mild protocol for the synthesis
of 3,5-disubstituted oxazolones. Clearly, the scope and synthetic
O
Boc
R2
Pd(CF3CO2)2
EtOAc, 40 °C
O
R1
N
N
R2
R1
1
2
Entry
1
R1
R2
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
84 (2a)
72 (2b)
80 (2c)
78 (2d)
83 (2e)
88 (2f)
78 (2g)
83 (2h)
80 (2i)
82 (2j)
75 (2k)
63 (2l)
70 (2m)
NR
4-F-C6H4
4-Cl-C6H4
2-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
4-Me-C6H4
4-t-Bu-C6H4
4-MeO-C6H4
3,4-MeO2-C6H3
2-Naphthyl
n-C8H17
TBSO(CH2)2
TES
Ph
Ph
Ph
77 (2o)
71 (2p)
72 (2q)
n-Bu
Cy
a
Under the optimal conditions.
Isolated yields.
b
substrate. To our delight, the oxazolone product 2a was isolated in
70% yield by treating 1a with 5 mol % of Pd(OAc)2 in THF at 40 °C
for 8 h (Table 1, entry 1). It is worth to mention that the palladium
Table 3
Synthesis of 3,4,5-trisubstituted oxazolones 4a
R1
Pd(MeCN)2Cl2
Ag2CO3, 25 °C
O
N
R2
Boc
R3
X
R1
N
+
O
R3
R2
3
1
4
Ph
4-F-C6H4
4-Cl-C6H4
O
N
O
O
N
O
N
O
O
O
Bn
Bn
Bn
84% (4c)
87% (4a)
90% (4b)
84% (4a)b
2-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
O
N
O
O
O
N
O
N
Bn
75% (4f)
2-Naphthyl
Bn
Bn
80% (4d)
80% (4e)
3,4-OMe2-C6H3
4-t-Bu-C6H4
O
O
N
O
O
O
O
N
N
Bn
78% (4g)
Bn
Bn
66% (4h)
72% (4i)
TBSO(CH2)2
Ph
Ph
O
O
N
O
O
N
O
O
N
Bn
82% (4j)
Bn
65% (4k)
Ph
77% (4l)
a
Reaction conditions: 1 (0.25 mmol), Pd(MeCN)2Cl2 (0.013 mmol), and Ag2CO3 (0.38 mmol) in 3 (5.0 mmol) at 25 °C for 2–
5 h.
b
Allyl bromide was used.

Z. Lu et al. / Tetrahedron Letters 53 (2012) 3433–3436
3435
utility of this protocol would be significantly enhanced if it enabled
the formation of 3,4,5-trisubstituted oxazolones. To this end, yna-
mide 1a was treated with 3 equiv of allyl chloride 3a as well as
1.5 equiv of K2CO3 and 5 mol % of Pd(MeCN)2Cl2 in EtOAc, and
the desired 3,4,5-trisubstituted oxazolone 4a was generated in
45% yield, together with the formation of 27% of 2a. After several
trials, 3,4,5-trisubstituted oxazolone 4a was still obtained in less
than 50% yield. We questioned that the neat reaction could in-
crease the concentration of allyl halides, thus favoring allylation
of the oxazolone–palladium intermediate (see the proposed
mechanism).
reaction conditions and operational simplicity. Further investiga-
tions on synthetic applications of this protocol are undergoing.
Acknowledgments
We acknowledge the National Natural Science Foundation of
China (Nos. 20902084 and 21172199) as well as the Analysis and
Testing Project of Zhejiang Province (2011C37051) for the financial
support of this work.
Supplementary data
To test this idea, substrate 1a was treated with 20 equiv of allyl
chloride 3a and 5 mol % of Pd(MeCN)2Cl2 using K2CO3 as a proton
scavenger at 25 °C. As expected, the yield of 3,4,5-trisubstituted
oxazolone 4a was enhanced to 72%, and only less than 10% of 2a
was observed. Encouraged by this result, we further screened the
base for this reaction. Pleasingly, the formation of the undesired
3,5-disubstituted oxazolone 2a was completely inhibited and the
3,4,5-trisubstituted oxazolone 4a was obtained in 87% yield when
1.5 equiv of Ag2CO3 was used.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
04.074.
References and notes
1. (a) Hashimoto, N.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1994, 35, 721; (b)
D’Andrea, S. V.; Freeman, J. P.; Szmuszkovicz, J. J. Org. Chem. 1990, 55, 4356.
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Tetrahedron Lett. 1996, 37, 8155.
With the optimal conditions in hand,11 we then investigated the
scope and limitations of this N-alkynyl tert-butyloxycarbamates–
allyl halides coupling reaction. In general, 3,4,5-trisubstituted oxa-
zolones bearing various functional groups, such as F-, Cl-, Br-, OMe-
substituted phenyl groups, were synthesized in good to excellent
yields (Table 3). For example, N-alkynyl tert-butyloxycarbamates
1b and 1c coupled smoothly with allyl chloride 3a to provide
3,4,5-trisubstituted oxazolones 4b and 4c in 90% and 84% yields,
respectively. Moreover, substituted allyl halide, 2-methyl-substi-
tuted allyl chloride (3b), for instance, led to the corresponding
3,4,5-trisubstituted oxazolone 4k in 65% yield.
A plausible mechanism is proposed in Scheme 1 to account for
this Pd-catalyzed transformation of N-alkynyl tert-butyloxycarba-
mates. The cationic palladium intermediate A, resulted from the
intramolecular oxypalladation of C–C triple bond,12 leads to an
oxazolone–palladium intermediate B by releasing of isobutylene
and proton, followed by protonolysis of the alkenyl13 C–Pd bond
to form 3,5-disubstituted oxazolones 2 and regenerate the palla-
dium catalyst (path a, Scheme 1). On the other hand, the palladium
species B reacts with allyl halides 3 in the presence of Ag2CO3 to
furnish an alkyl palladium intermediate C, which is subsequently
converted into 3,4,5-trisubstituted oxazolones via the b-Cl elimina-
tion14 reaction (path b, Scheme 1).
3. (a) Nomura, I.; Mukai, C. Org. Lett. 2002, 4, 4301; (b) Nomura, I.; Mukai, C. J. Org.
Chem. 2004, 69, 1803.
4. (a) Yonezawa, Y.; Shin, C.-G.; Ohtsu, A.; Yoshimura, J. Chem. Lett. 1982, 1171;
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5. For selected reports on the synthesis of oxazolones, see: (a) Lenz, G. R.;
Costanza, C. J. Org. Chem. 1988, 53, 1176; (b) Aichaoui, H.; Poupaert, J. H.;
Lesieur, D.; Henichart, J.-P. Tetrahedron 1991, 47, 6649; (c) Hamad, M. O.;
Kiptoo, P. K.; Stinchcomb, A. L.; Crooks, P. A. Bioorg. Med. Chem. 2006, 14, 7051;
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76, 6338; (f) Lu, Z.; Kong, W.; Yuan, Z.; Zhao, X.; Zhu, G. J. Org. Chem. 2011, 76,
8524.
9. For the preparation of N-alkynyl tert-butyloxycarbamate substrates, see: (a)
Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.;
Petersen, M. E.; Sagamanove, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006, 71,
4170; (b) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776; (c)
Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser, R. L. Tetrahedron
2006, 62, 3815; (d) Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62,
3823.
10. Representative procedure for the Pd-catalyzed synthesis of 3,5-disubstituted
oxazolones: To a solution of 1a (77 mg, 0.25 mmol) in 1 mL of EtOAc was
added Pd(CF3CO2)2 (4.3 mg, 0.013 mmol) at 40 °C. After stirring for 5 h, the
reaction mixture was concentrated and purified by column chromatography on
silica gel (hexanes/EtOAc = 6/1) to give 53 mg (yield: 84%) of 2a as a white
solid, mp: 148–150 °C. 1H NMR (CDCl3, 400 MHz): d 4.79 (s, 2H), 6.64 (s, 1H),
7.21–7.50 (m, 10H); 13C NMR (CDCl3, 100 MHz): d 47.9, 108.9, 122.9, 127.3,
128.0, 128.2, 128.5, 128.8, 129.1, 135.3, 139.3, 155.0; MS (EI, m/z): 251 (M+,
95), 207 (2), 160 (8), 132 (20), 105 (100).
To summarize, a practical dichotomy method for the effective
synthesis of 3,5-disubstituted and 3,4,5-trisubstituted oxazolones
has been developed by trapping the intermediate resulting from
oxypalladation of N-alkynyl tert-butyloxycarbamates with either
proton generated in situ or allyl halides. The notable features of
this reaction include its high efficiency in the formation of multi-
functional oxazolones in a single step, as well as its relatively mild
11. Representative procedure for the Pd-catalyzed synthesis of 3,4,5-trisubstituted
oxazolones: To a mixture of 1a (77 mg, 0.25 mmol) in allyl chloride (0.4 mL,
5.0 mmol) was added Pd(CH3CN)2Cl2 (3.5 mg, 0.013 mmol) and Ag2CO3
(105 mg, 0.38 mmol) at 25 °C. After stirring for 2 h, the reaction mixture was
quenched with water, extracted with EtOAc, dried over anhydrous Na2SO4 and
concentrated. Column chromatography on silica gel (hexanes/EtOAc = 8/1)
gave 63 mg (yield: 87%) of 4a as a yellow solid, mp: 78–80 °C. 1H NMR (CDCl3,
400 MHz): d 3.18–3.32 (m, 2H), 4.84 (s, 2H), 5.16 (d, J = 17.2 Hz, 1H), 5.22 (d,
J = 10.0 Hz, 1H), 5.79–5.86 (m, 1H), 7.27–7.39 (m, 8H), 7.47 (d, J = 7.6 Hz, 2H);
13C NMR (CDCl3, 100 MHz): d 27.4, 45.4, 117.8, 120.1, 125.0, 127.0, 127.9,
127.9, 128.0, 128.8, 129.0, 132.1, 135.7, 136.2, 155.4; MS (EI, m/z): 291 (M+,
R1
1
O
N
[Pd]+
4
O
O
[Pd]
R2
A
a
h
t
a
p
2
R1
[Pd]
R1
16), 141 (4), 128 (13), 105 (100); HRMS (EI) Calcd for
291.1259. Found 291.1258.
C
19H17NO2 (M+)
O
N
O
N
R2
path b
3, Ag2CO3
[Pd]
H+
+
O
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Cl
R2
B
C
Scheme 1. Proposed mechanism.

3436
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