Asymmetric intramolecular [3 + 2] cycloaddition reactions of acylhydrazones/olefins using a chiral zirconium catalyst

Article abstract of DOI:10.1021/ja027681d

Catalytic asymmetric intramolecular [3 + 2] cycloaddition of hydrazone/olefins has been attained. In the presence of a chiral zirconium catalyst prepared from zirconium alkoxide and a BINOL derivative, the desired pyrazolidine derivatives were obtained in

Full text of DOI:10.1021/ja027681d

Published on Web 10/26/2002
Asymmetric Intramolecular [3 + 2] Cycloaddition Reactions of
Acylhydrazones/Olefins Using a Chiral Zirconium Catalyst
Shuj Kobayashi,* Haruka Shimizu, Yasuhiro Yamashita, Haruro Ishitani, and Jun Kobayashi
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 Japan
Received July 12, 2002
Scheme 1. Intramolecular [3 + 2] Cycloaddition of Hydrazones
The [3 + 2] cycloaddition reaction provides one of the most
efficient methods for constructing five-membered ring systems.1
Indeed, cycloadditions of 1,3-dipolars such as nitrones, nitrile
oxides, and so forth with olefins affording isoxazoline derivatives
have been well studied, and some highly enantioselective reactions
using catalytic amounts of chiral Lewis acids have been developed.2
On the other hand, cycloaddition of hydrazones such as 1,3-dipolars
with olefins is a useful reaction to afford pyrazolidine derivatives,
which can be easily converted to 1,3-diamines after N-N bond
cleavage. Chiral 1,3-diamines are versatile components not only
as chiral ligands in asymmetric catalysis but also as biologically
important compounds such as cisplatin derivatives.3 However, this
type of [3 + 2] cycloaddition has not been well developed
previously despite its potential usefulness. It was reported that
strongly acidic conditions4 or high temperature (thermal conditions)5
were required to achieve this cycloaddition, and no asymmetric
catalysis has been reported.
Table 1. Reaction Conditions Testeda
entry
Zr(OR)4b
BINOL/mol %
additive
yield/%
ee/%
In the course of our investigations to develop novel reactions
using hydrazones,6 we have found that Lewis acids such as Sc-
(OTf)3 and Zr(OTf)4 effectively catalyzed [3 + 2] cycloaddition
of acylhydrazones.7,8 As an extension of this finding, we undertook
a project to develop asymmetric intramolecular [3 + 2] cycload-
dition reactions using a chiral Lewis acid.
1
2
3
4
5
6
Zr(OtBu)4
Zr(OtBu)4
Zr(OtBu)4
Zr(OPr)4
Zr(OPr)4
Zr(OPr)4
2a/20
2b/20
2b/12
2b/12
2c/12
2d/12
-
-
35
86
92
9
75
93
PrOH c
-
-
82, 56d,86e
92, 93d,95e
86
99
92
96
PrOH c
a
In our initial investigation, we conducted an intramolecular
[3 + 2] cycloaddition reaction of 4-nitrobenzoylhydrazone (1a)
derived from 3-methylcitronellal as a model substrate in the
presence of a chiral zirconium/BINOL complex, which has been
shown to be an efficient catalyst for asymmetric Mannich-type
reactions,9 aza Diels-Alder reactions,10 Strecker reactions,11 allyl-
ation reactions of imines,12 Mukaiyama aldol reactions,13 and hetero
Diels-Alder reactions (Scheme 1).14 It was found that a chiral
zirconium catalyst prepared from Zr(OtBu)4 and (R)-3,3′-dibromo-
1,1′-bi-2-naphthol ((R)-3,3′-Br2BINOL, (R)-2b)9d gave a promising
result of affording the desired pyrazolidine derivative as a sole trans-
isomer in 86% yield with 75% ee (Table 1, entry 2). A zirconium
complex prepared from Zr(OtBu)4 and (R)-6,6′-Br2BINOL ((R)-
2a) resulted in a much lower yield and selectivity (entry 1). Addition
of propanol (PrOH) to this catalyst system led to dramatic
improvements in both the yield and selectivity (entry 3). When Zr-
(OPr)4-PrOH was used instead of Zr(OtBu)4 as a zirconium source,
almost the same result was obtained (entry 4). The selectivity was
slightly improved, but the reactivity decreased when toluene or
benzene was used as a solvent. The catalyst prepared from (R)-
3,3′-I2BINOL, ((R)-2c) showed similar high selectivity (entry 5).
Finally, it was found that a complex prepared from Zr(OPr)4-PrOH
and (R)-3,3′,6,6′-I4BINOL ((R)-2d), in which iodo groups were
introduced at the 6,6′-positions of (R)-3,3′-I2BINOL as electron-
The reactions were performed in CH2Cl2 at room temperature for 4-11
h, unless otherwise noted. b 10 mol %. c 50 mol %. d Benzene was used as
a solvent. e Toluene was used as a solvent.
Table 2. Asymmetric Intramolecular [3 + 2] Cycloaddition
Reactions of Hydrazones Using a Chiral Zirconium Catalysta
yield/%
(cis/trans)
ee/%
(trans)
entry
hydrazone
solvent, time
1
1a
1a
1a
1b
1c
1fd
1g
1h
CH2Cl2, 4.5 h
CH2Cl2, 12 h
benzene, 28 h
benzene-CH2Cl2, 64 h
CH2Cl2, 12 h
benzene, 1 h
99 (<1/>99)
87 (<1/>99)
70 (<1/>99)
62 (29/71)
91 (<1/>99)
57e (<1/>99)
38 (<1/>99)
73 (11/89)
96
90
95
92
97
72
81
90
2b
3b
4c
5c
6
7c,f
8c,g
benzene, 21 h
benzene, 1 h
a
Unless otherwise noted, the catalyst was prepared from Zr(OPr)4 (10
mol %), (R)-2d (12 mol %) and PrOH (50 mol %), and the asymmetric
reaction was performed at room temperature. In entries 5, 6, (R)-2c was
used instead of (R)-2d. b Catalyst (5 mol %). c Catalyst (20 mol %).
d Unpurified. e Yield was determined based on the starting material 4. f 40
°C. g 60 °C.
withdrawing groups,13b showed an excellent catalyst ability; the
cyclization occurred in 99% yield with excellent selectivity (96%
ee) (entry 6).
We then tested other substrates, and the results are summarized
in Table 2. In the reaction of 1a, 5 mol % of the zirconium catalyst
worked well, and a high yield and selectivity were obtained (entries
2, 3). On the other hand, the reaction of substrate 1b, which
* To whom correspondence should be addressed. E-mail: skobayas@
mol.f.u-tokyo.ac.jp.
9
13678
J. AM. CHEM. SOC. 2002, 124, 13678-13679
10.1021/ja027681d CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Correlation between the Chiral Substrate and the
Chiral Catalysts
In summary, we have demonstrated the first example of catalytic
asymmetric intramolecular [3 + 2] cycloaddition of hydrazones/
olefins. The cycloaddition proceeded in the presence of a chiral
zirconium complex as a catalyst under mild conditions. While the
adducts, chiral pyrazolidine derivatives, are a biologically interesting
class of compounds, the N-N bonds of the adducts have been
shown to be readily cleaved under reductive conditions to afford
chiral diamine derivatives.
Acknowledgment. This work was partially supported by
CREST and SORST, Japan Science Technology Corporation, and
a Grant-in-Aid for Scientific Research from Japan Society of the
Promotion of Sciences.
1
Supporting Information Available: Experimental details and H
and 13C NMR spectra of the products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 3. Transformation of the Products by N-N Bond
Cleavage
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