Intermolecular coupling of alkynes, isocyanates, and acyl chlorides: an efficient method for the synthesis of 5-hydroxypyrrol-2(5H)-ones

Article abstract of DOI:10.1016/j.tetlet.2007.10.096

New insights into the reaction of diethylzirconocene with an alkyne, an isocyanate, and an acyl chloride in this order are reported. The products of 5-hydroxypyrrol-2(5H)-ones are obtained in good yields after hydrolysis. It is an efficient method for the synthesis of 5-hydroxypyrrol-2(5H)-ones.

Full text of DOI:10.1016/j.tetlet.2007.10.096

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Tetrahedron Letters 48 (2007) 9199–9202
Intermolecular coupling of alkynes, isocyanates, and acyl
chlorides: an efficient method for the synthesis of
5-hydroxypyrrol-2(5H)-ones
Ken-ichiro Kanno,a Shenyong Ren,a Yanzhong Li,a Kiyohiko Nakajimab and
Tamotsu Takahashia,*
aCatalysis Research Center and Graduate School of Pharmaceutical Sciences, Hokkaido University,
and SORST, Japan Science and Technology Corporation (JST), Kita-ku Sapporo 001-0021, Japan
bDepartment of Chemistry, Aichi University of Education, Igaya, Kariya, Aichi 448-8542, Japan
Received 24 August 2007; revised 11 October 2007; accepted 16 October 2007
Available online 24 October 2007
Abstract—New insights into the reaction of diethylzirconocene with an alkyne, an isocyanate, and an acyl chloride in this order are
reported. The products of 5-hydroxypyrrol-2(5H)-ones are obtained in good yields after hydrolysis. It is an efficient method for the
synthesis of 5-hydroxypyrrol-2(5H)-ones.
Ó 2007 Elsevier Ltd. All rights reserved.
5-Hydroxypyrrol-2(5H)-ones are a class of very attrac-
R1
R3
R2
O
tive heterocycles due to their wide range of interesting
biological activities.1,2 Within the last several decades,
5-hydroxypyrrol-2(5H)-ones have been evaluated for
antineoplastic activity in tumor cells of white mice.3 In
some cases, these functional 5-membered lactams have
shown antitumor activity.4 Many methods have been
developed to synthesize these useful functional hetero-
cycles. For example, oxidative bromination reaction of
nicotine,5 amination of the corresponding lactones,6
metal-catalyzed condensation–cyclization reaction of
acyl cyanides with 3-oxoamides,7 Ni-catalyzed cyana-
tion of a-ketoalkynes in H2O,8 halolactamization–
hydroxylation of 2,3-allenamides with CuX2,9 and regio-
selective reduction of 3-methoxymaleimides10 can give
5-hydroxypyrrol-2(5H)-one derivatives. However, develop-
ment of a highly efficient methodology for the synthesis
of 5-hydroxypyrrol-2(5H)-ones with diversity is still of
high interest.
R1
+
R2
O
N
C
HO
R4
+
O
N
R3
R4
Cl
1
Scheme 1.
zation of three different alkynes was achieved.11 Simi-
larly, selective synthesis of pyridine derivatives from
two alkynes and a nitrile was also possible with zir-
conocene complexes.12 Furthermore, the zirconium-
mediated reactions with isocyanates could produce
pyridone and cyclopentenone derivatives.12b,13,14 During
the course of our study on the chemistry of zirconocene-
mediated cycloaddition reaction, we envisioned that
5-hydroxypyrrol-2(5H)-ones may be synthesized by the
coupling reaction of an alkyne, an isocyanate, and an
acyl chloride (Scheme 1). Herein we would like to report
this reaction.15
So far, our group has developed zirconium-mediated
cycloaddition reactions of unsaturated compounds such
as alkynes, alkenes, nitriles, and isocyanates. In the case
of the benzene formation reaction, highly selective cycli-
A typical procedure for the synthesis of 5-hydroxy-
pyrrol-2(5H)-one from alkyne, isocyanate, and acyl
chloride is as follows (Scheme 2). Zirconacyclopentene
2 was prepared by the reaction of an alkyne with
Cp2ZrEt2 in THF at 0 °C.16 To the solution was added
*
Corresponding author. Tel.: +81 11 706 9149; fax: +81 11 706
9150; e-mail: tamotsu@cat.hokudai.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.096

9200
K. Kanno et al. / Tetrahedron Letters 48 (2007) 9199–9202
R1
N
R1
R2
O
1) R3NCO, 50 °C, 1 h
Cp2ZrEt2
R2
HO
R4
R1
R2
2) R4COCl, CuCl, rt, 3 h
Cp2Zr
THF, 0 °C, 3 h
3) H+
R3
2
1
Scheme 2. Synthesis of 5-hydroxypyrrol-2(5H)-ones.
1.2 equiv of an isocyanate, and the reaction mixture was
stirred for 1 h at 50 °C. Then CuCl and an acyl chloride
were added at room temperature, and the reaction mix-
ture was stirred for 3 h at the same temperature. After
usual work-up and purification by a silica gel column
chromatography, the corresponding 5-hydroxypyrrol-
2(5H)-one was obtained in high yield.
The results of the reactions with various substrates are
summarized in Table 1. The reaction using symmetrical
alkynes proceeded smoothly with aryl or aliphatic iso-
cyanates and acyl chlorides to afford the corresponding
5-hydroxypyrrol-2(5H)-ones in good yields (entries 1–6).
When unsymmetrical alkyne such as 1-trimethylsilyl-1-
propyne was employed, the corresponding products
Table 1. Formation of 5-hydroxypyrrol-2(5H)-one derivatives
Entry
Alkyne
Isocyanate
Acylchloride
PhCOCl
Product
Yielda (%)
90 (75)
Bu
Ph
Bu
O
1
PhNCO
Bu
Bu
1a
1b
1c
HO
N
Ph
Pr
Pr
O
Bu
2
3
PhNCO
BnNCO
BuCOCl
PhCOCl
71 (58)
68 (51)
Pr
Pr
Pr
Pr
HO
N
Ph
Pr
Pr
O
Ph
HO
N
Bn
Pr
Pr
t
-Bu
1d
1e
4
5
PhNCO
BuNCO
t-BuCOCl
75 (63)
57 (43)
Pr
Et
Pr
Et
HO
N
Ph
O
Et
Et
Ph
PhCOCl
HO
N
Bu
O
Ph
Ph
O
Ph
1f
6
7
BuNCO
PhNCO
PhCOCl
PhCOCl
77 (71)
56 (36)
Ph
Ph
HO
N
Bu
TMS
Me
O
Ph
1g
TMS
Me
HO
N
Ph
TMS
Me
O
Bu
1h
1i
8
9
PhNCO
TsNCO
BuCOCl
PhCOCl
68 (47)
81 (68)
TMS
TMS
Me
Me
HO
N
Ph
TMS
Me
O
Ph
HO
N
Ts
a NMR yields; isolated yields are given in parentheses.

K. Kanno et al. / Tetrahedron Letters 48 (2007) 9199–9202
9201
Table 2. Formation of hydroxypyrrolone 1b with a catalytic amount
of CuCl
Pr
Pr
O
Pr
Pr
1) Cp2ZtEt2
HO
Bu
+
2) CuCl, rt
3) H+
N
Ph
Ph NCO
O
1b
Bu
Cl
Entry
CuCl (equiv)
Time (h)
Yield of 1ba (%)
1
2
3
2
0.5
0.1
3
12
24
71
81
72
a NMR yield.
with a catalytic amount of CuCl. When the reaction was
carried out with 0.1 equiv of CuCl, product 1b was
obtained without significant loss of the yield. However,
it takes one day to complete the reaction.
Figure 1. Molecular structure of 1g.
were obtained as single isomers in high yields (entries 7–
9). The structure of silylated 5-hydroxypyrrol-2(5H)-one
1g was unambiguously confirmed by X-ray crystallogra-
phy (Fig. 1). Isocyanates with functional groups such as
benzyl and tosyl groups could also be used in the reac-
tion (entries 3 and 9) to form the desired products 1c
and 1i, respectively. Even with sterically congested piva-
loyl chloride, the corresponding tert-butylated com-
pound 1d was obtained without significant loss of the
yield (entry 4). However, the reaction with tert-butyl iso-
cyanate gave no desired product.
In summary, we developed the synthetic methodology of
5-hydroxypyrrol-2(5H)-ones 1 through an intermole-
cular coupling of alkynes, isocyanates, and acyl chlo-
rides mediated by zirconium and copper. This method
could be used for a variety of substrates and gave
a number of the derivatives of 1 in one-pot reaction
from the ordinary and commercially available starting
materials.
Supplementary data
In Scheme 3, a plausible reaction mechanism of the
5-hydroxypyrrol-2(5H)-one formation was proposed.
At the beginning, Cp2ZrEt2 reacts with an alkyne to
afford zirconacyclopentene 2. And an isocyanate reacts
with 2 to form either aza- or oxazirconacyclopentene 3
or 4, which we have already reported in the similar reac-
tions.13,14 Transmetalation of zirconacycle 3 or 4 to
CuCl gives 5 or 6, which reacts with an acyl chloride
to give 7 or 8 and releases CuCl. Finally, the intramole-
cular addition of the nitrogen atom to the carbonyl
group followed by hydrolysis affords the corresponding
5-hydroxypyrrol-2(5H)-one 1.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.10.096.
References and notes
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ˇ
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In fact, as shown in Table 2, the reaction also proceeded
´
´
´ˇ
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R1
O
R1
X
R1
R2
Y
R2
Y
R2
Cp2ZrEt2
Cl
- CuCl
R4
R3 NCO
CuCl
Cu
M
R1
R2
Cp2Zr
Cp2Zr
X
3: X = NR3, Y = O
4: X = O, Y = NR3
5: X = NR3, Y = O
6: X = O, Y = NR3
M = Cu or Cp2ZrCl
2
R4
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R4
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R1
R1
R2
O
R2
O
R2
R2
H+
R4
MO
R4
HO
O
O
or
M
O
O
R3
N
N
N
M
N
R3
R3
R3
7
8
9
1
Scheme 3. Mechanism of formation 5-hydroxypyrrol-2(5H)-ones.

9202
K. Kanno et al. / Tetrahedron Letters 48 (2007) 9199–9202
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