Development of a tailor-made bis(oxazolidine)pyridine-metal catalyst for the [3+2] cycloaddition of azomethine imines with propiolates

Article abstract of DOI:10.1039/c3cc44354j

A series of bis(oxazolidine)pyridine ligands (the PyBodines) were newly designed and synthesized for the development of a highly efficient, tailor-made catalyst for the [3+2] cycloaddition of azomethine imines with propiolates. The PyBodine(l-Ala)-Cu(OAc)₂ catalyst was selected on the basis of solid-phase catalysis/CD-HTS and exhibited high efficiency, producing the (R)-adducts with excellent enantioselectivity.

Full text of DOI:10.1039/c3cc44354j

Featuring research from the laboratory of Synthetic
Organic Chemistry (Prof. Takayoshi Arai), Department
of Chemistry, Graduate School of Science,
Chiba University, Japan
As featured in:
Tailor-made Bis(oxazolidine)pyridine-metal catalyst for the
asymmetric synthesis of pyrazolone heterocycles
Novel bis(oxazolidine)pyridine ligands (PyBodine) were developed
in a tailor-made manner for the [3+2] cycloaddition of azomethine
imines with propiolates. The PyBodine(L-Ala)-Cu(OAc)2 catalyst
was selected on the basis of solid-phase catalysis/CD-HTS and
exhibited high efficiency, producing the (R)-adduct with excellent
enantioselectivity.
See Takayoshi Arai et al.,
Chem. Commun., 2013, 49, 7776.
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Development of a tailor-made bis(oxazolidine)pyridine–
metal catalyst for the [3+2] cycloaddition of azomethine
imines with propiolates†
Cite this: Chem. Commun., 2013,
49, 7776
Received 10th June 2013,
Accepted 3rd July 2013
Takayoshi Arai,* Yuta Ogino and Toru Sato
DOI: 10.1039/c3cc44354j
www.rsc.org/chemcomm
A series of bis(oxazolidine)pyridine ligands (the PyBodines) were development of an asymmetric catalyst for the synthesis of
newly designed and synthesized for the development of a highly pyrazolone heterocycles via the [3+2]-cycloaddition of azo-
efficient, tailor-made catalyst for the [3+2] cycloaddition of azo- methine imines with propiolates is demonstrated using a new
methine imines with propiolates. The PyBodine(L-Ala)–Cu(OAc)2 family of bis(oxazolidine)pyridine–metal catalysts.
catalyst was selected on the basis of solid-phase catalysis/CD-HTS
The pyrazolone heterocycles are a family of unique five-
and exhibited high efficiency, producing the (R)-adducts with membered-ring lactams, each containing a N–N bond. These
excellent enantioselectivity.
compounds serve as a good example of highly functionalized,
complex molecules and have been applied to the development
Catalytic asymmetric synthesis is an important process in of fine chemicals with applications in dyes, textiles, photo-
chemistry for generating chiral molecules during the produc- graphy and cosmetics as well as pharmaceuticals.1 The [3+2]
tion of sophisticated and highly functionalized compounds cycloaddition of azomethine imines is advantageous for the
such as pharmaceuticals and agricultural chemicals. Although efficient construction of the core structure of the unique
the success of this process depends primarily on the develop- bicyclic pyrazolo[1,2-a]pyrazolone skeleton (Scheme 1).2
ment of efficient asymmetric catalysts, the enormous variety of
In 2003, Fu et al. succeeded in the first catalytic asymmetric
complicated organic reactions precludes the design of a single cyclization of azomethine imines with terminal alkynes, using a
universal catalyst capable of controlling every possible reaction phosphaferrocene–oxazoline–CuI catalyst.3 Following additional
with high activity and suitable stereoselectivity. In addition, the pioneering work by this group,4 several remarkable catalytic
development of appropriate catalysts for specific reactions, asymmetric [3+2] cyclizations employing azomethine imines
or for use with unique substrates, remains challenging even in were reported by Sibi,5 Maruoka,6 Suga7 and Chen.8 In addi-
modern chemistry, and is generally achievable only through signi- tion, Kobayashi et al. recently reported outstanding results for
ficant efforts. One means of shortening the time required to develop the synthesis of an unusual 5,7-disubstituted product via the
new catalysts is the high-throughput exploration of a variety of reverse regioselective cycloaddition of azomethine imines with
candidates using a tailor-made approach, whereby a catalytic terminal alkynes.9,10 Our group is also interested in the unique
compound is tuned to exhibit high efficiency for a specific reaction molecular framework of the pyrazolone heterocycles, and we
through diverse modifications (Fig. 1). Here, the tailor-made have previously reported preliminary results obtained using our
Fig. 1 A tailor-made approach for the development of new catalysts.
Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Inage,
Chiba 263-8522, Japan. E-mail: tarai@faculty.chiba-u.jp; Fax: +81-43-290-2889;
Tel: +81-43-290-2889
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data and 1H- and 13C-NMR spectra. See DOI: 10.1039/c3cc44354j
Scheme 1 Summary of our previous work on PyBidine (L1)–CuOAc catalyzed
[3+2] cycloaddition.
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specially designed bis(imidazolidine)pyridine (L1, PyBidine)11–
CuOAc catalyst. We determined that the [3+2] cycloaddition of
azomethine imines with electron-deficient terminal alkynes was
efficiently catalyzed by the chiral Pybidine–CuOAc complex, giving
bicyclic pyrazolo[1,2-a]pyrazolone derivatives with 74% ee.12
Although we have directed significant effort towards improving
the enantiomeric excess resulting from this [3+2] cycloaddition
by tuning the catalyst structure, it has been proven to be
difficult to structurally modify the L1 imidazolidine moiety,
since only limited numbers of commercially available chiral
diamines are available. It is, however, noteworthy that use of
the bis(imidazoline)pyridine (i.e. pybim; L2)13–CuOAc catalyst
resulted in only 35% ee under the same reaction conditions.
This result prompted us to select the saturated oxazolidine five
membered ring as a tunable imidazolidine analog, rather than
the oxazoline ring, which contains a C to N double bond.
Our purpose was therefore to employ oxazolidines, which
may be prepared using a variety of readily obtainable chiral
amino alcohols, to investigate a wide range of structural varia-
tions while keeping the saturated five membered ring similar to
imidazolidine. By analogy with the synthesis of PyBidine (L1),
a new family of bis(oxazolidine)pyridines, which we termed
PyBodines, were designed as structurally tunable ligands.14
Despite several reports to date concerning the successful syn-
thesis of oxazolidine-based chiral ligands,15 the stability of
PyBodine is obscure, and the stereochemistry and selectivity
of the newly formed stereogenic center at the C2 position on the
oxazolidine ring has to be confirmed before applying the ligand
to the formation of a catalyst. These PyBodine ligands were
readily obtained in good to quantitative yields via the simple
condensation of 2,6-pyridinedicarboxaldehyde with a series of
chiral amino alcohols derived from L-amino acid methyl esters,
as shown in Scheme 2.
Fig. 2 The 1H-NMR spectrum of PyBodine(Ala) in acetone-d6.
approach based on solid-phase catalysis/circular dichroism-high
throughput screening (CD-HTS).16 Using a polymer-supported
2,6-pyridinedicarboxaldehyde (see ESI† for preparation procedures),
18 different PyBodine–Cu complexes were synthesized from
combinations of six amino alcohols and three neutral copper
salts, which showed good catalyst activity in the previous
study12 (Scheme 3).
The most efficient catalyst was rapidly established using this
custom-made approach of the solid-phase catalysis/CD-HTS trials,
as presented in Fig. 3. It is evident that the use of PyBodine(Ala)–
Cu(OAc)2 resulted in the strongest CD signal. The negative CD
signal obtained at 254 nm suggests the selective formation of the
(R) isomer of 3a, whereas the use of PyBodine(Pro)–Cu(OAc)2
produced the largest positive signal, associated with the forma-
tion of (S)-3a.
Several of the bis(oxazolidine)pyridines we studied exhibited
reasonable stability over several months of storage under air.
More importantly, we determined that the stereogenic center at
the C2 position of the oxazolidine ring may be controlled with a
high degree of precision, as confirmed by the 1H-NMR spectrum
shown in Fig. 2. NOE experiments revealed that the (2S,4S)-
oxazolidine isomer was obtained, which differs from the stereo-
chemistry of the original (2R,4S)-PyBidine. The (2S,4S) isomer is
the most stable diastereomer since it allows the 2,4-diequatorial
orientation of substituent groups, while the stereochemistry of
the (2R,4S)-imidazolidine group in L1 occurs as the result of the
trans-substituent on the 5-membered ring.
Scheme 3 Preparation of polymer-supported PyBodine–Cu catalysts.
Based on the above study of the PyBodines, we attempted to
find the most efficient catalyst for the [3+2] cycloaddition of
azomethine imine with ethyl propiolate, utilizing a tailor-made
Scheme 2 Synthesis of PyBodines. The notations in parentheses indicate the
amino alcohol incorporated.
Fig. 3 Solid-phase catalysis/CD-HTS.
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Table 1 Optimization of reaction conditions for PyBodine(Ala or Pro)–Cu(OAc)2
Although we are still attempting to fully elucidate the
detailed mechanism of the PyBodine(Ala)–Cu(OAc)2-catalyzed
[3+2] cyclization, the results of prior work indicate that the
reaction proceeds via a Cu(I)–acetylide following the reduction
of the Cu(II) complex.17 A proposed model reaction which shows
how the use of PyBodine(Ala)–Cu(OAc)2 results in enantioface
selection to give the (R)-product is provided in the ESI.†
In conclusion, we have developed a series of bis(oxazolidine)-
pyridine ligands (the PyBodines) with applications in the [3+2] cyclo-
addition of azomethine imines with propiolates. The most efficient
catalyst, PyBodine(L-Ala)–Cu(OAc)2, was tailor-made for this reaction
using a screening process based on solid-phase catalysis/CD-HTS.
This work was supported by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology (Japan), and by the Workshop on Chirality in
Chiba University (WCCU).
catalyzed [3+2] cycloaddition in solution phase
Entry
PyBodine
Temp. (1C)
Time (h)
Yield (%)
ee (%)
1
2
Ala
Pro
Ala
Ala
Pro
Pro
rt
rt
À40
À40
À40
À40
0.5
0.5
50
28
47
99
99
50
99
88
99
82
55b
90
3
4a
5
94
76b
68b
6a
47
a
b
4A MS was added. (S)-3a was obtained.
Table 2 PyBodine(Ala)–Cu(OAc)2 catalyzed [3+2] cycloadditiona
Notes and references
Entry
R1
R2
Time (h)
Yield (%)
ee (%)
1 (a) T. Eicher and S. Hauptmann, The Chemistry of Heterocycles,
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1
2
3
4
5
6
7
Ph
Et
Et
Et
Et
Et
Et
Et
Me
tBu
Et
28
19
43
27
19
26
45
23
25
27
20
99
81
90
72
77
82
82
92
99
99
99
94
90
95
94
89
94
84
98
80
88
85
p-Me-C6H4
o-Me-C6H4
m-Cl-C6H4
p-F-C6H4
p-I-C6H4
p-MeO-C6H4
Ph
Ph
c-C6H11
iPr
¨
2 (a) S. Karlsson and H.-E. Hogberg, Org. Prep. Proced. Int., 2001, 33, 103;
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8
9b
10
11
Et
a
Absolute configuration of the products is presented by analogy from
the comparison of [a]D.3 b Reaction at À40 1C to room temperature.
The highly stereoselective construction of the PyBodine(Pro)
ligand was also confirmed using 1NMR spectroscopy (see ESI†).
Having identified the most efficient catalysts, their performance
under various reaction conditions was ascertained, as summarized
in Table 1. During simple application of the reaction conditions 11 (a) T. Arai, A. Mishiro, N. Yokoyama, K. Suzuki and H. Sato, J. Am.
Chem. Soc., 2010, 132, 5338; (b) T. Arai, A. Mishiro, E. Matsumura,
A. Awata and M. Shirasugi, Chem.–Eur. J., 2012, 18, 11219.
12 T. Arai and Y. Ogino, Molecules, 2012, 17, 6170.
examined in solid-phase catalysis at room temperature, the
solution phase catalysis using PyBodine(Ala)–Cu(OAc)2 gave
¨
(R)-3a in 99% yield with 82% ee (entry 1), while PyBodine(Pro)– 13 S. Bhor, G. Anilkumar, M. K. Tse, M. Klawonn, C. Dobler,
B. Bitterlich, A. Grotevendt and M. Beller, Org. Lett., 2005, 7, 3393.
14 E. T. J. Strong, S. A. Cardile, A. L. Brazeau, M. C. Jennings,
Cu(OAc)2 gave (S)-3a in 99% yield with 55% ee (entry 2). In the
case of the PyBodine(Ala)–Cu(OAc)2 catalyzed cycloaddition,
R. McDonald and N. D. Jones, Inorg. Chem., 2008, 47, 10575.
reducing the reaction temperature to À40 1C improved the 15 Representative examples of oxazolidine-consisting chiral ligands:
(a) H. Nakano, K. Osone, M. Takeshita, E. Kwon, C. Seki,
H. Matsuyama, N. Takano and Y. Kohari, Chem. Commun., 2010,
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enantioselectivity to 90% ee, although the yield was reduced to
50% even when the reaction was allowed to proceed for 50 h
(entry 3). It was, however, possible to improve the catalytic
activity by adding 4A MS, producing (R)-3a in 99% yield with
94% ee after 28 h (entry 4). When using PyBodine(Pro)–
Cu(OAc)2, the addition of 4A MS produces only minimal effect
(entries 5 and 6).
(c) S. Liu and C. Wolf, Org. Lett., 2007, 9, 2965; (d) C. Wolf and S. Liu,
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examined, generating the results summarized in Table 2.
Various azomethine arylimines were successfully converted to
the desired products in a highly enantioselective manner. Use
of azomethine cyclohexylimine resulted in the desired product
with 88% ee (entry 10) while the reaction of 1a with methyl
propiolate resulted in up to 98% ee (entry 8).
Ed., 2010, 49, 7895.
17 For a mechanism Cu(I)-catalyzed [3+2]-cycloaddition using Cu(II)
complexes, see (a) K. Kamata, S. Yamaguchi, M. Kotani, K. Yamaguchi
and N. Mizuno, Angew. Chem., Int. Ed., 2008, 47, 2407; (b) T. Oishi,
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c
7778 Chem. Commun., 2013, 49, 7776--7778
This journal is The Royal Society of Chemistry 2013