Synthesis of oxazoles through Pd-catalyzed cycloisomerization-allylation of N-propargylamides with allyl carbonates

Article abstract of DOI:10.1016/j.tetlet.2010.01.018

In the presence of Pd₂(dba)₃-Cy₃P catalyst, IPr·HCl salt [IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], and Cs₂CO₃, N-propargylamides react with allyl carbonates to give 2,5-disubstituted o

Full text of DOI:10.1016/j.tetlet.2010.01.018

Tetrahedron Letters 51 (2010) 1471–1474
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Tetrahedron Letters
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Synthesis of oxazoles through Pd-catalyzed cycloisomerization–allylation
of N-propargylamides with allyl carbonates
*
*
Akio Saito , Koichi Iimura, Yuji Hanzawa
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of Pd2(dba)3-Cy3P catalyst, IPrÁHCl salt [IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene], and Cs2CO3, N-propargylamides react with allyl carbonates to give 2,5-disubstituted oxazoles
having homoallyl groups through the tandem cycloisomerization–allylation.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 18 December 2009
Revised 7 January 2010
Accepted 8 January 2010
Available online 18 January 2010
Transition metal-catalyzed cyclizations of alkynes containing
heteroatom nucleophiles are developing into one of the most
efficient strategies for the heterocyclic synthesis.1 In particular,
the Pd-catalyzed procedure provides us with a tandem approach
to the synthesis of functionalized heterocycles through the regio-
and stereoselective addition of a heteroatom to the triple bond
and the subsequent cross-coupling with organic halides and so
on.2 Although the incorporation of aryl, vinyl,3 and acyl4 groups
into heterocycles by such a methodology has been well studied,
the tandem procedures including an allylation process have been
less reported.5
lyl ethyl carbonate (1.2 equiv), and the results are shown in Table
1. At the outset, it turned out that monodentate ligands were
important for the formation of 2a (entries 1, 3–5), and the biden-
tate phosphine ligands such as BINAP, dppe, dppp, dppb, and dppf
did not give 2a (entry 2). Thus, in the presence of Pd2(dba)3, Cy3P,
and K2CO3 in refluxing MeCN, 1a was consumed within 20 h giving
rise to the oxazole 2a in 17% yield along with 3a in 60% yield (entry
5). The use of Cs2CO3 instead of K2CO3 increased the yield of 2a to
24% with suppressing the formation of 3a (entry 6).13 The additive
of imidazolium salt14 IPrÁHCl was effective in the reaction of 1a in
the presence of Pd2(dba)3 and Cs2CO3 in MeCN (entry 9), and the
combined usage of IPrÁHCl with Cy3P improved the yield of 2a up
to 46% (entry 10).15 Furthermore, by the dilution of the reaction
solution and increasing the amount of allyl ethyl carbonate
(3 equiv), 2a was obtained in 70% yield (entry 12).16 It should be
mentioned that the other solvents such as THF, DME, dioxane,
and DMF were inferior.
Oxazoles are important heterocyclic compounds due to wide-
spread application not only to biologically active compounds6,7
but also to synthetic intermediates.6 Thus, a novel and an efficient
procedure for the construction of oxazole nucleus has remained an
attractive goal,8 and some metal-catalyzed protocols from N-prop-
argylamides have been reported (Scheme 1).9–12 For example, a
tandem cycloisomerization–coupling reaction of propargylamides
with aryl iodides in the presence of Pd(0) catalyst is an effective ac-
cess to 2,5-disubstituted oxazoles having arylmethyl groups at 5-
position.9a The Pd(0)-catalyzed cycloisomerization–coupling reac-
tion with acyl chlorides9b and Pd(II)-catalyzed oxidative carbonyl-
ation in the presence of CO and MeOH9c lead to the incorporation
of acyl groups into the side chain. The preparation of 5-oxazolecar-
baldehydes by the oxidative Pd-catalyzed process10 and the forma-
tion of 5-methyl-oxazoles via the simple cycloisomerization
We next investigated the scope of propargylamides 1 and 5 in
the reaction with allyl ethyl carbonate by the present catalytic sys-
tems [Pd2(dba)3, Cy3P, IPrÁHCl, Cs2CO3/MeCN] (Table 2). As well as
the terminal alkyne 1a, inner alkynes 1b, 1d, and 1e successfully
R'
N
O
N
O
N
O
R'
O
O
R
R
R
Ar
11
R''
OMe
catalyzed by AuCl3 has been known. We herein describe the
new and useful incorporation procedure of unsaturated side chain
into the oxazoles from propargylamides and allyl carbonates cata-
lyzed by palladium complex.
Pd(0)
Ar-I
Pd(0)
R''COCl
Pd(II)
CO, MeOH
Our initial effort was focussed on the evaluation of palladium
catalytic systems for the reaction of N-propargylamide 1a with al-
H
N
R'
R'
R
AuCl3
Pd(II)
N
O
N
R
R
O
Oxidant
O
CHO
* Corresponding authors. Tel.: +81 (0) 42 721 1571; fax: +81 (0) 42 721 1569.
E-mail addresses: akio-sai@ac.shoyaku.ac.jp (A. Saito), hanzaway@ac.shoya
ku.ac.jp (Y. Hanzawa).
Scheme 1. Synthesis of oxazoles from N-propargylamides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.018

1472
A. Saito et al. / Tetrahedron Letters 51 (2010) 1471–1474
Table 1
Screening of catalytic system for the formation of 2a
EtO2CO
H
N
N
N
N
N
O
N
O
Pd2(dba)3 (2.5 mol%)
Ph
N
Cl
Cl
+
Ph
Ph
additive / MeCN
90°C, 20-24 h
O
N
N
IMes HCl
IPr HCl
Cl
1a
2a
3a
IAd HCl
Entry
Ligand (mol %)
Base (equiv)
Allyl carbonate (equiv)
MeCN (mL)
2aa (%)
3aa (%)
1aa (%)
1b
2
3
4
5
6
7
8
9
—
K2CO3 (5.0)
K2CO3 (5.0)
K2CO3 (5.0)
K2CO3 (5.0)
K2CO3 (5.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3.0
2
2
2
2
2
2
2
2
2
2
4
6
9
—
6
9
17
24
—
—
—
3
5
60
28
—
64
35
28
18
8
—
29
17
26
0
15
0
0
c
BINAP (10)
Ph3P (20)
(2-furyl)3P (20)
Cy3P (20)
Cy3P (20)
IAdÁHCl (6)
IMesÁHCl (6)
IPrÁHCl (6)
—
30
46
64
70
11
0
0
10
11
12
IPrÁHCl (6), Cy3P (10)
IPrÁHCl (6), Cy3P (10)
IPrÁHCl (6), Cy3P (10)
0
a
b
c
Yields were determined by 1H NMR analysis.
5 mol % Pd(Ph3P)4 was used instead of Pd2(dba)3.
N-allyl-N-(prop-2-ynyl)benzamide: 71%.
reacted with allyl ethyl carbonate to give the corresponding ally-
lated products 2 in good yields (entries 1, 2, 4, and 5). A similar
observation has been reported in the Pd-catalyzed reaction of
propargylamides with aryl iodides.9a It has been proposed that
the incorporation of aryl groups into the oxazoles proceeds via
the oxypalladation–reductive elimination domino mechanism.9a
Therefore, the present incorporation of allyl groups would consist
of the cyclization of propargylamides through the oxypalladation
caused by
p-allyl palladium complex, which was generated by pal-
ladium(0) and allyl ethyl carbonate, and the subsequent reductive
Table 2
Cycloisomerization–allylation of various propargylamides 1 or 5 with allyl ethyl carbonatea
H
H
N
N
O
N
O
N
O
Pd2(dba)3, IPr HCl
Cy3P, Cs 2CO3
Ph
N
R2
R2
Ph
R2
R1
EtO2CO
or
or
+
O
O
R1
MeCN, 90°C, 21 h
R1
R1
1
5
2 or 6
4
3 or 7
Entry
Substrate
Product
Yieldb (%)
1
2
3
1a: R1 = H
2a: R1 = H
2b: R1 = Et
70
32
0
(3a 8)
(3b 5)
(1c 44)
HN
Ph
N
O
1b: R1 = Et
1c: R1 = tBu
Ph
2c: R1 = tBu
O
R1
R1
4
5
1d: X = H
1e: X = MeO
2d: X = H
2e: X = MeO
62
60
(3d 11)
(3e 13)
HN
Ph
N
O
O
Ph
Ph
X
X
80
(2f 0)
HN
Ph
N
O
O
6
1f
4f
NO2
O2N
7
8
9
5a: X = MeO
5b: X = Me
5c: X = Cl
6a: X = MeO
6b: X = Me
6c: X = Cl
55
70
70
7
(7a 26)
(7b 12)
(7c 10)
(7d 31)
X
N
X
H
N
O
10
5d: X = NO2
6d: X = NO2
O

A. Saito et al. / Tetrahedron Letters 51 (2010) 1471–1474
1473
Table 2 (continued)
Entry
Substrate
Product
Yieldb (%)
(7e 10)
11
12
5e: X = O
5f: X = S
6e: X = O
6f: X = S
50
58
N
O
H
N
(7f trace)
X
X
O
H
N
Ph
N
O
Ph
Ph
13
5g
5h
6g
6h
67
22
(7g 29)
(7h 56)
O
O
H
N
Ph
N
O
14
a
Conditions for 1: Pd2(dba)3: 2.5 mol %, IPrÁHCl: 6 mol %, Cy3P: 10 mol %, Cs2CO3: 3 equiv, allyl ethyl carbonate: 3 equiv, MeCN: 6 mL. Conditions for 5: Pd2(dba)3: 5 mol %,
IPrÁHCl: 12 mol %, Cy3P: 20 mol %, Cs2CO3: 6 equiv, allyl ethyl carbonate: 6 equiv, MeCN: 6 mL.
b
Isolated yield.
the palladium-catalyzed cycloisomerization–allylation reaction of
propargylamide derivatives with allyl carbonates. The present pro-
cedure would raise new possibilities for the incorporation of allyl
groups into heterocycles. Synthetic applications and detailed
mechanistic studies of the present reaction are underway.
EtO2CO
N
O
N
O
Pd2(dba)3, IPr HCl, Cy3P
Ph
Ph
Cs2CO3 / MeCN
R
90ºC, 21 h
R
3a: R=H
3d: R=Ph
3f: R=p-NO2Ph
4a 0% (3a 96%)
4d 0% (3d 96%)
4f 83%
Acknowledgment
This work was supported by Grant-in-Aid for Young Scientists
(B), MEXT Japan (No. 21790024).
Scheme 2. Allylation of oxazole 3.
References and notes
elimination. In the case of 1f, diallylated 4f was observed in 80%
yield due to the high acidity of p-nitrobenzylic protons (entry 6).
Actually, the treatment of 3f with allyl ethyl carbonate under the
same conditions led to the formation of 4f (Scheme 2). In contrast
to 3f, methyl derivative 3a or benzyl derivative 3d did not bring
about the allylated 2a or 2d and the diallylated 4a or 4d. Thus,
the simply cyclized compound 3 would not be considered to take
part into the present formation of 2 from 1.
The reactions of 5a–h having a different acyl group yielded the
desirable oxazole compounds, albeit a slight increase in the
amount of Pd-catalyst (entries 7–14).
The present catalytic systems could be applied to the other allyl
carbonates in the reaction of 1a (Scheme 3). Thus, the reaction with
cinnamyl ethyl carbonate (R1 = H, R2 = Ph) afforded 8 in 89% yield
without a detection of the regioisomer and stereoisomer. On using
ethyl 1-phenylallyl carbonate (R1 = Ph, R2 = H), 8 was also obtained
in good yield. Furthermore, ethyl methallyl carbonate brought
about the corresponding oxazole 9.
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zole compounds possessing the unsaturated side chains through
Ph
H
Pd2(dba)3, IPr HCl
Cy3P, Cs 2CO3
Ph
Ph
N
N
R1=H, R2=Ph: 89% (+ 3a 9%)
R1=Ph, R2=H: 53% (+ 3a: 27%)
EtO2CO
R2
+
+
Ph
O
O
O
R1
MeCN, 90°C, 21 h
1a
8
H
N
Pd2(dba)3, IPr HCl
Cy3P, Cs 2CO3
N
Ph
(+ 3a 19%)
EtO2CO
O
MeCN, 90°C, 21 h
1a
9 66%
Scheme 3. Cycloisomerization-allylation of 1a with various allyl carbonate derivatives.

1474
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allyl-o-alkynyl-trifluoroacetanilide
intermediates,
N-allyl-N-(prop-2-
ynyl)benzamide was not converted into the oxazole 2a by the present
catalytic system. See, Ref. 5c.