An efficient copper-mediated 1,3-Dipolar cycloaddition of pyrazolidinone-based dipoles to terminal alkynes to produce N/N-bicyclic pyrazolidinone derivatives

Article abstract of DOI:10.1246/cl.2010.1086

A simple dinuclear copper complex [Cu(μ-OH)(tmen)]₂Cl ₂ (tmen = N,N,N′,N′,-tetramethylethylenediamine) could act as an effective precatalyst for the 1,3-dipolar cycloaddition of pyrazolidinone-based dipoles to terminal alkynes to pro

Full text of DOI:10.1246/cl.2010.1086

doi:10.1246/cl.2010.1086
1086
Published on the web September 4, 2010
An Efficient Copper-mediated 1,3-Dipolar Cycloaddition of Pyrazolidinone-based Dipoles
to Terminal Alkynes to Produce N,N-Bicyclic Pyrazolidinone Derivatives
Takamichi Oishi, Kazuaki Yoshimura, Kazuya Yamaguchi, and Noritaka Mizuno*
Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656
(Received July 28, 2010; CL-100659; E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp)
A simple dinuclear copper complex [Cu(®-OH)(tmen)]2Cl2
(tmen = N,N,N¤,N¤-tetramethylethylenediamine) could act as
an effective precatalyst for the 1,3-dipolar cycloaddition of
pyrazolidinone-based dipoles to terminal alkynes to produce the
corresponding N,N-bicyclic pyrazolidinone derivatives.
Initially, the [Cu(®-OH)(tmen)]2Cl2-mediated 1,3-dipolar
cycloaddition of 1-benzylidene-3-oxo-1-pyrazolidinium-2-ide
(1a) to ethyl propiolate (2a) was carried out in various solvents
under Ar atmosphere (Table S1).7 A typical procedure for the
1,3-dipolar cycloaddition is as follows: Into a glass vial were
successively placed catalyst (typically 1 mol % Cu with respect to
a dipole), a pyrazolidinone-based dipole (0.5 mmol), an alkyne
(0.55 mmol), and a solvent (3 mL). Then, the resulting solution
was stirred at 60 °C under Ar atmosphere. The yields were
determined by 1H NMR analyses. The products could be isolated
by column chromatography on silica gel. Among the solvents
examined, non- and low-polar solvents such as chloroform and
toluene gave the corresponding N,N-bicyclic pyrazolidinone 3aa
in high yields. Polar tetrahydrofuran and acetonitrile gave 3aa in
moderate yields. On the other hand, protic and highly polar
solvents such as methanol and N,N-dimethylformamide were
poor likely because of the strong coordination to the active
site(s). The hydrolytic decomposition of 1a proceeded to some
extent (ca. 4%) when the reaction was carried out in water.
Under the conditions described in Table 1,12 the 1,3-dipolar
cycloaddition of 1a to 2a efficiently proceeded to give the
corresponding N,N-bicyclic pyrazolidinone 3aa in the presence
of [Cu(®-OH)(tmen)]2Cl2 (Entry 1).8 In this case, only the
single regioisomer 3aa could be obtained. The reaction hardly
proceeded in the absence of catalysts (Entry 9). The catalytic
activities of simple copper salts and complexes alone were lower
than that of [Cu(®-OH)(tmen)]2Cl2 (Entries 2-8).13 Therefore,
the dicopper core in [Cu(®-OH)(tmen)]2Cl2 plays an important
role in the present transformation.
1,3-Dipolar cycloaddition reactions are one of the most
powerful procedures for the synthesis of a variety of five-
membered heterocycles in a convergent manner.1 For example,
the groups of Sharpless2a and Meldal2b have independently
reported that the 1,3-dipolar cycloaddition of organic azides (as
dipoles) to alkynes (as dipolarophiles) can dramatically be
accelerated by the presence of copper (pre)catalysts and is totally
regioselective, affording the corresponding 1,4-disubstituted-
1,2,3-triazole derivatives (so-called “click reaction”). To date,
many efficient copper-based (pre)catalysts have been reported
for the click reaction.2-5
Very recently, we have also reported that the copper-
substituted silicotungstate with the diazido-bridged dicopper
core TBA4[£-H2SiW10O36{Cu2(®-1,1-N3)2}] (TBA = tetra-n-
butylammonium) could act as an efficient homogeneous pre-
catalyst with extremely high turnover frequency (TOF) and
turnover number (TON).5 The dicopper core plays an important
role for the click reaction: Initially, the alkyne homocoupling
efficiently proceeds via the Cu(II)-alkynyl intermediate {Cu2(®-
C¸CR)2}, followed by the formation of the corresponding diyne
(as a co-product) and truly active Cu(I) species.6 This means that
an alkyne itself can act as an efficient reducing reagent to
generate the catalytically active Cu(I) species in situ and no
additional reducing reagents are necessary in the case of
“dicopper complexes”.
Table 1. 1,3-Dipolar cycloaddition of 1a to 2a with various
copper-based catalystsa
On the basis of the above-mentioned results, we found that a
dinuclear copper complex [Cu(®-OH)(tmen)]2Cl2 could act as
an effective precatalyst for the click reaction (Figure S1).7 In
addition, we now found that the 1,3-dipolar cycloaddition of
pyrazolidinone-based dipoles (azomethine imides) to terminal
alkynes was efficiently promoted by [Cu(®-OH)(tmen)]2Cl2 and
the catalytic activity was superior to that of TBA4[£-H2-
SiW10O36{Cu2(®-1,1-N3)2}].8
In this paper, we mainly focused on the synthetic scope of
the [Cu(®-OH)(tmen)]2Cl2-mediated 1,3-dipolar cycloaddition
of pyrazolidinone-based dipoles to terminal alkynes. The N,N-
bicyclic pyrazolidinone derivatives produced by this reaction
have a variety of applications.9 However, only a few catalytic
systems, for example, CuI/Cy2NMe10a,10b and Cu(I)-exchanged
zeolites,10c have been reported until now. Although [Cu(®-
OH)(tmen)]2Cl2 has been utilized as a catalyst for various
functional group transformations,11 the [Cu(®-OH)(tmen)]2Cl2-
mediated 1,3-dipolar cycloaddition reactions have never been
reported.
O
O
N
N
N
N
catalyst
COOEt
COOEt
+
Ph
Ph
1a
2a
3aa
Entry
Catalyst
Yieldb/%
1
2
3
4
5
6
7
8
9
[Cu(®-OH)(tmen)]2Cl2
CuSO4¢5H2O
CuCl2¢2H2O
Cu(ClO4)2¢6H2O
Cu(OTf)2
49(98)c
2
4
3
3
4
11
19
3
CuCl
CuI
[Cu(CH3CN)4]PF6
None
aReaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), catalyst
(Cu: 1 mol % with respect to 1a), CD3CN (3 mL), 60 °C, 1.0 h,
Ar (1 atm). bDetermined by 1H NMR analysis. cThe result
obtained with CDCl3.
Chem. Lett. 2010, 39, 1086-1087
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1087
Table 2. Scope of the [Cu(®-OH)(tmen)]2Cl2-mediated 1,3-dipo-
lar cycloadditiona
suggesting that the addition of an alkyne (acetylide species)
mainly takes place anti to the methyl group in 1d
(Figure S2).7,10c
O
O
O
O
O
Cl
N
N
N
N
N
N
N
N
Notably, the catalyst amount could be much reduced; in a
5 mmol-scale 1,3-dipolar cycloaddition of 1a to 2a using only
2.5 ¯mol of [Cu(®-OH)(tmen)]2Cl2 (Cu: 0.1 mol %), the TOF
1a
1b
1f
1c
1d
O
O
O
N
N
¹1
N
N
(based on the initial rate) was 305 h and the TON reached up
N
N
to 860 (eq 1). These TOF and TON values were much higher
than those reported for copper-based systems so far; CuI/
Cy2NMe (TOF: 1.0 h¹1, TON: 20).10a,10b and Cu(I)-exchanged
zeolites (TOF: 4.5 h¹1, TON: 18).10c
1e
1g
O
O
O
O
O
O
S
O
O
2a
2b
2c
2d
2e
Entry Dipole Alkyne Product Time/h Yieldb/%
O
O
N
N
cat. (Cu: 0.1 mol%)
N
N
COOEt
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2a
2a
2a
2a
2a
2a
3aa
3ab
3ac
3ad
3ae
3ba
3ca
3dac
3ea
3fa
1.0
1.0
1.0
2.0
1.0
2.0
1.0
3.0
8.0
1.0
2.5
98
96
97
92
96
97
99
97
>99
89
ð1Þ
COOEt
+
Ph
CDCl3 (30 mL)
60°C, 6 h, Ar
Ph
3aa (86% yield)
1a (5.0 mmol) 2a (5.5 mmol)
TOF: 305 h−1, TON: 860
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
References and Notes
10
11
1
2
3
a) R. Huisgen, in 1,3-Dipolar Cycloaddition Chemistry, ed. by A.
Padwa, Wiley, New York, 1984, pp. 1-176. b) K. V. Gothelf,
K. A. Jørgensen, Chem. Rev. 1998, 98, 863.
1g
3ga
>99
aReaction conditions: Dipole (0.5 mmol), alkyne (0.55 mmol),
[Cu(®-OH)(tmen)]2Cl2 (Cu: 1 mol % with respect to dipoles),
CDCl3 (3 mL), 60 °C, Ar (1 atm). At the initial stage of the
reaction, the alkyne homocoupling proceeded to reduce Cu(II)
species in [Cu(®-OH)(tmen)]2Cl2 (¯0.9% with respect to
alkynes). bDetermined by 1H NMR analysis. csyn/anti = 90/10.
a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem., Int. Ed. 2002, 41, 2596. b) C. W. Tornøe, C.
Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057.
a) H. C. Kolb, K. B. Sharpless, Drug Discovery Today 2003, 8,
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Finn, J. Am. Chem. Soc. 2006, 128, 6056. c) P. Kele, G. Mezö, D.
Achatz, O. S. Wolfbeis, Angew. Chem., Int. Ed. 2009, 48, 344, and
references cited therein.
As mentioned above, the alkyne homocoupling efficiently
proceeded on the dicopper core in TBA4[£-H2SiW10O36{Cu2(®-
1,1-N3)2}].6 Similarly, it was confirmed by a separate experi-
ment that the alkyne homocoupling efficiently proceeded on the
dicopper core in [Cu(®-OH)(tmen)]2Cl2.6 An alkyne 2a (100
equivalents) was added to a chloroform solution of [Cu(®-
OH)(tmen)]2Cl2 (1.7 mM), and the resulting solution was heated
to 60 °C for 30 min under Ar atmosphere. Then, the UV-vis
spectrum was measured. By the treatment, the absorption band at
700 nm assignable to the d-d transition of the Cu(II) species
almost disappeared, and a new broad absorption band appeared
around 400-500 nm. The solid-state UV-vis spectrum of
[CuI(C¸CPh)]n shows a similar broad absorption band around
400-460 nm.4a Therefore, in the present [Cu(®-OH)(tmen)]2Cl2-
mediated 1,3-dipolar cycloaddition, it is likely that the Cu(I)-
acetylide species would be formed by the reaction of the in situ
generated Cu(I) species with an alkyne, followed by the reaction
with a pyrazolidinone-based dipole to form the corresponding
N,N-bicyclic pyrazolidinone.10
Finally, we turned out our attention to the synthetic scope of
the 1,3-dipolar cycloaddition. As shown in Table 2, various
kinds of pyrazolidinone derivatives and terminal alkynes with
electron-withdrawing groups could be used as dipoles and
dipolarophiles, respectively, to produce the corresponding N,N-
bicyclic pyrazolidinone derivatives in excellent yields. The 1,3-
dipolar cycloaddition of a dipole monomethyl-substituted at the
5-position (1d) to 2a showed a high syn-diastereoselectivity for
the methyl and phenyl groups of 3da (syn/anti = 90/10),
4
a) K. Yamaguchi, T. Oishi, T. Katayama, N. Mizuno, Chem.®Eur.
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Chem. Soc. 2008, 130, 15304.
5
6
7
8
K. Kamata, S. Yamaguchi, M. Kotani, K. Yamaguchi, N. Mizuno,
Angew. Chem., Int. Ed. 2008, 47, 2407.
Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
The reaction rate for the 1,3-dipolar cycloaddition of 1a to 2a with
¹1
[Cu(®-OH)(tmen)]2Cl2 was 6.9 mM min (in CDCl3) and ca. 1.9
times larger than that with TBA4[£-H2SiW10O36{Cu2(®-1,1-
¹1
N3)2}] (3.6 mM min (in CD3CN)).
9
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12 The solubilities of common copper salts in chloroform were low.
Although acetonitrile was not the best solvent for [Cu(®-
OH)(tmen)]2Cl2, the reactions were carried out in acetonitrile in
order to dissolve copper salts and complexes examined in Table 1.
13 It is known that bases and/or stabilizing ligands are required to
generate the acetylide species in the case of common copper salts.
Chem. Lett. 2010, 39, 1086-1087
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/