Zirconium-catalyzed enantioselective [3+2] cycloaddition of hydrazones to olefins leading to optically active pyrazolidine, pyrazoline, and 1,3-diamine derivatives

Article abstract of DOI:10.1021/ja049498l

Asymmetric [3+2] cycloaddition of hydrazones to external olefins has been successfully conducted in high yields with high enantioselectivities using a chiral zirconium catalyst. These reactions open ways to synthetically and biologically important pyrazoline, pyrazolidine, and 1,3-diamine derivatives. Further, several experiments suggested that the reactions proceeded via concerted pathways.

Full text of DOI:10.1021/ja049498l

Published on Web 08/19/2004
Zirconium-Catalyzed Enantioselective [3+2] Cycloaddition of
Hydrazones to Olefins Leading to Optically Active
Pyrazolidine, Pyrazoline, and 1,3-Diamine Derivatives
Yasuhiro Yamashita and Shuj Kobayashi*
Contribution from the Graduate School of Pharmaceutical Sciences,
The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received January 28, 2004; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Abstract: Asymmetric [3+2] cycloaddition of hydrazones to external olefins has been successfully conducted
in high yields with high enantioselectivities using a chiral zirconium catalyst. These reactions open ways to
synthetically and biologically important pyrazoline, pyrazolidine, and 1,3-diamine derivatives. Further, several
experiments suggested that the reactions proceeded via concerted pathways.
cycloaddition reactions4 of acylhydrazones with olefins proceed
smoothly under the influence of a catalytic amount of a Lewis
Introduction
Asymmetric [3+2] cycloaddition of 1,3-dipoles to olefins
provides powerful methods for the synthesis of various optically
active five-membered ring systems containing heteroatoms.
Recently, catalytic enantioselective versions of this reaction
using chiral Lewis acids have been studied, and several highly
stereoselective [3+2] cycloaddition reactions of nitrones, nitrile
oxides, and azomethine ylides, etc., leading to optically active
isoxazolidine, isoxazoline, and pyrrolidine derivatives, have been
reported.1 On the other hand, catalytic asymmetric [3+2]
cycloaddition of azomethine imines, diazoalkanes, and nitrile
imines, which affords optically active five-membered rings
containing two adjacent nitrogen atoms, has not been well
investigated despite the potential usefulness for synthesis of
many biologically active compounds, and only a few examples
of enantioselective synthesis have been reported.2 Kanemasa
et al. reported catalytic enantioselective cycloaddition of diaz-
oalkanes to electron-deficient olefins using Lewis-acid catalysts
modified by chiral DBFOX ligands.2a Fu et al. also reported
recently that fused azomethine imines reacted with terminal
alkynes in high enantioselectivity in the presence of a chiral
Cu(I) catalyst.2b
acid.5 Furthermore, asymmetric intramolecular [3+2] cyclo-
addition reactions of acylhydrazones using a chiral Lewis acid
have been disclosed recently.6 However, the substrates were
restricted, and the reactions were limited to only an intra-
molecular fashion. Herein, we report highly enantioselective
catalytic asymmetric intermolecular [3+2] cycloaddition of
hydrazones to olefins (Scheme 1). The synthesis of optically
active pyrazolidine, pyrazoline, and 1,3-diamine derivatives is
also described.
Results and Discussion
We initially investigated the cycloaddition of p-nitrobenzoyl-
hydrazone 1a of 3-phenylpropionaldehyde to ketene dimethyl
dithioacetal 2a (Table 1). The reaction proceeded in the presence
of a chiral zirconium catalyst prepared from zirconium pro-
poxide (Zr(OPr)4), (R)-3,3′,6,6′-I4BINOL (3a), and propanol
(PrOH) to afford the desired product in moderate yield with
moderate enantioselectivity (entry 1). When the reaction was
conducted using a catalyst prepared from (R)-3,3′-I2BINOL (3b),
the enantioselectivity was slightly improved (entry 2). The yield
and selectivity were slightly decreased when the catalyst was
prepared without PrOH (entry 3). Furthermore, the enantio-
Our group has been interested in an acylhydrazone as an imine
equivalent and revealed that benzoylhydrazones and its deriva-
tives reacted with several nucleophiles in the presence of a
Lewis-acid catalyst such as Sc(OTf)3 or a Lewis-base promoter.3
On the basis of these findings, we focused on the use of
acylhydrazones as general 1,3-dipolars and found that [3+2]
(4) Examples of [3+2] cycloaddition of hydrazones with olefins. Under acidic
conditions, see: (a) Hesse, K.-D. Liebigs Ann. Chem. 1970, 743, 50. (b)
Fevre, G. L.; Sinbandhit, S.; Hamelin, J. Tetrahedron 1979, 35, 1821. (c)
Fouchet, B.; Joucla, M.; Hamelin, J. Tetrahedron Lett. 1981, 22, 1333. (d)
Shimizu, T.; Hayashi, Y.; Ishikawa, S.; Teramura, K. Bull. Chem. Soc.
Jpn. 1982, 55, 2456. (e) Shimizu, T.; Hayashi, Y.; Miki, M.; Teramura K.
J. Org. Chem. 1987, 52, 2277. Under thermal conditions, see: (f) Grigg,
R.; Kemp, J.; Thompson, N. Tetrahedron Lett. 1978, 2827. (g) Grigg, R.;
Dowling, M.; Jordan, M. W.; Sridharan, V. Tetrahedron 1987, 43, 5873.
(h) Snider, B. B.; Conn, R. S. E.; Sealfon, S. J. Org. Chem. 1979, 44, 218.
(i) Fevre, G. L.; Hamelin, J. Tetrahedron Lett. 1979, 1757. (j) Ibrahim, Y.
A.; Abdou, S. E.; Selim, S. Heterocycles 1982, 19, 819. (k) Badawy, M.
A.; El-Bahaie, S. A.; Kadry, A. M.; Ibrahim, Y. A. Heterocycles 1988, 27,
7. (l) Khau, V. V.; Martinelli, M. J. Tetrahedron Lett. 1996, 37, 4323. (m)
Sun, B.; Adachi, K.; Noguchi, M. Tetrahedron 1996, 52, 901.
(1) Reviews: (a) ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, Chapter 3. (b) Gothelf, K. V.;
Jørgensen, K. A. Chem. ReV. 1998, 98, 863.
(2) (a) Kanemasa, S.; Kanai, K. J. Am. Chem. Soc. 2000, 122, 10710. (b)
Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778.
(3) (a) Oyamada, H.; Kobayashi, S. Synlett 1998, 249. (b) Kobayashi, S.;
Hasegawa, H.; Ishitani, H. Chem. Lett. 1998, 1131. (c) Kobayashi, S.;
Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124. 5640. (d) Kobayashi,
S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125,
6610. (e) Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 7768. See also: (f) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc.
1992, 114, 6266.
(5) Kobayashi, S.; Hirabayashi, R.; Shimizu, H.; Ishitani, H.; Yamashita, Y.
Tetrahedron Lett. 2003, 44, 3351.
(6) Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J. J.
Am. Chem. Soc. 2002, 124, 13678.
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J. AM. CHEM. SOC. 2004, 126, 11279-11282
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A R T I C L E S
Yamashita and Kobayashi
Scheme 1. Asymmetric Intermolecular [3+2] Cycloaddition of
Hydrazones to Olefins
Table 2. Asymmetric Intermolecular [3+2] Cycloaddition of
Hydrazones to 2aa
entry
R (1)
product
yield (%)b
ee (%)
1
2
PhCH2CH2 (1b)
(CH3)2CHCH2 (1c)
c-C6H11 (1d)
4ba
4ca
4da
4ea
4fa
87
84
74
79
60
90
77
97
98
95
97
96
97
97
3
4c
5c
6
CH3(CH2)4 (1e)
CH3(CH2)2 (1f)
PhCH2 (1g)
4ga
4ha
7c
tBuMe2SiOCH2CH2 (1h)
a The reaction was performed in toluene at 0 °C for 18 h in the presence
of a zirconium catalyst (10 mol %) prepared from Zr(OPr)4 (10 mol %),
(R)-3b (12 mol %), and PrOH (50 mol %). b Isolated yield. c Additional
PrOH was not used.
Table 1. Asymmetric Intermolecular [3+2] Cycloaddition of
Hydrazones to Ketene Dimethyl Dithioacetal 2aa
Table 3. Asymmetric Intermolecular [3+2] Cycloaddition of
Hydrazones to Vinyl Ethers 2b-ea
entry
hydrazone
2a (equiv)
(R)-3
yieldb (%)
ee (%)
ee (%)
(major/minor)
1
1a
1a
1a
1b
1b
1b
1.2
1.2
1.2
1.2
1.5
2.0
3a
3b
3b
3b
3b
3b
67
84
74
71
85
87
67
70
66
97
97
97
1
2
entry
R (1)
R (2)
product yield (%)b
drc
2
3c
4
1
2
3
4
5
6
7
PhCH2CH2 (1a)
PhCH2CH2 (1a)
PhCH2CH2 (1a)
PhCH2CH2 (1a)
(CH3)2CHCH2 (1i) OPr (2c)
c-C6H11 (1j)
OEt (2b)
OPr (2c)
5ab
5ac
94
95
90
38
86
95
65
84
70
52/48
54/46
81/19
76/24
58/42
67/33
59/41
68/32
50/50
92/98
92/98
87/93
92/92
99/99
92/99
93/96
84/98
42/81
OtBu (2d) 5ad
5
6
SEt (2e)
5ae
5ic
a The reaction was performed in toluene at 0 °C for 18 h in the presence
of a zirconium catalyst (10 mol %) prepared from Zr(OPr)4 (10 mol %),
(R)-3 (12 mol %), and PrOH (50 mol %). b Isolated yield. c Additional PrOH
(50 mol %) was not used.
OPr (2c)
OPr (2c)
OPr (2c)
OPr (2c)
5jc
CH3(CH2)4 (1k)
5kc
5lc
8d PhCH2 (1l)
9e Ph (1m)
5mc
a The reaction was performed in toluene at 0 °C for 18 h in the presence
of a zirconium catalyst (10 mL%) prepared from Zr(OPr)4 (10 mol %) and
(R)-3a (12 mol %). b Isolated yield. c Determined by 1H NMR analysis.
d The reaction was performed at 10 °C. e The reaction was performed at 20
°C for 24 h in the presence of a Zr catalyst prepared from Zr(OtBu)4 (20
mol %) and (R)-3c (24 mol %).
selectivity was dramatically improved to 97% when benzoyl-
hydrazone 1b was employed (entry 4). The amount of the ketene
dimethyl dithioacetal also affected the reactivity, and the yield
was improved to 87% by using 2 equiv of the ketene dimethyl
dithioacetal (entry 6).
suitable for the present reaction because of its low reactivity.
When a catalyst prepared from Zr(OPr)4 and 3,3′,6,6′-I4BINOL
was employed in the reaction of 1a with ethyl vinyl ether (2b)
or propyl vinyl ether (2c), the desired pyrazolidines were
obtained in high yields with high enantioselectivities, albeit with
moderate diastereoselectivities (Table 3, entries 1 and 2). The
reaction with a bulky vinyl ether, tert-butyl vinyl ether (2d),
showed a slightly higher diastereoselectivity, although enanti-
oselectivities of both diastereomers were somewhat lower (entry
3). Ethyl vinyl sulfide (2e) was found to be less reactive (entry
4). We then examined the reactions of other hydrazones with
2c. The hydrazones of R-branched and â-branched aliphatic
aldehydes also reacted with 2c smoothly to afford the corre-
sponding adducts in high yields with high enantioselectivities
(entries 5 and 6).7 Although diastereoselectivity was moderate,
it is noteworthy that both diastereomers showed excellent
enantioselectivity in most cases and that the lower diastereo-
selectivity was not a serious drawback from a synthetic point
of view (vide infra). In the reaction of 1m (aromatic hydrazone),
We then investigated the reactions of other hydrazones, and
the results are summarized in Table 2. In all cases, the
intermolecular [3+2] cycloadditions proceeded smoothly in the
presence of a catalytic amount of the chiral zirconium catalyst
to afford the desired pyrazolidine derivatives in high yields with
excellent ee’s. It is noted that hydrazones derived from a
â-branched aldehyde (entry 2), a sterically hindered aldehyde
(entry 3), an enolizable aldehyde (entry 6), and a functionalized
aldehyde (entry 7) reacted with the olefin without any side
reactions and that high levels of enantioselectivity were
achieved.7
We next studied the reactions with vinyl ethers as olefins.
The products expected are pyrazoridines containing a N,O-acetal
structure, which would be further modified by Lewis-acid-
mediated carbon-carbon bond formation. In preliminary in-
vestigations it was found that benzoylhydrazone 1b was not
(7) The absolute configuration of the cycloadduct 5nc was determined by
converting the product to MS-153. The absolute configuration of other
adducts was determined by analogy.
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11280 J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004

Zirconium-Catalyzed Enantioselective [3+2] Cycloaddition
Scheme 2. Transformation of the Productsa
A R T I C L E S
Scheme 3. Proposed Reaction Mechanisms
Scheme 4. Synthesis of ent MS-153a
a Reagents and conditions: (a) SmI2, THF-MeOH, -78 °C, 83%; (b)
LiAlH4, THF, reflux; (c) Ac2O, pyridine, rt, 95% (2 steps); (d) LiAlH4,
THF, -78 °C; (e) AcCl, pyridine, DMAP, CH2Cl2, rt, 76% (2 steps); (f)
Me3SiOTf, H2CdC(OSiMe3)SEt, CH3CN, 0 °C, 68% (dr ) 86:14).
a Reagents and conditions: (a) Zr(OPr)4 (20 mol %), (R)-3,3′-I2BINOL
(24 mol %), toluene, 10 °C, 48 h, 76%, dr ) 62/38, 84% ee (major)/97%
ee (minor); (b) LiAlH4, THF, -78 °C; (c) nicotinoyl chloride hydrochloride,
iPr2NEt, DMAP, rt, 68% (2 steps); (d) Raney-Ni (W-2), EtOH-acetate
buffer (pH ) 5.2) (2:1), rt, 29% (88% ee).
the desired cycloaddition product was obtained in good yield
but the stereoselectivities were a little lower (entry 9).
The products obtained were converted to several valuable
compounds (Scheme 2). Transformation of pyrazolidines to 1,3-
diamines is an important method to afford useful chelating
agents. The N-N bond of product 4ba was cleaved by SmI2 to
give N,S-acetal 6 in high yield as a diastereomer mixture.3b,f
This compound was converted to 1,3-diamine 7 by reduction
with LiAlH4 and acetylation in high yield. On the other hand,
product 5ac was converted to acetylated 2-pyrazoline 8 in good
yield with high optical purity (95% ee).8 This result indicates
that the starting diastereomers have the same absolute configu-
rations regarding the asymmetric centers derived from the
CdN double bonds of the hydrazones and that the moderate
diastereoselectivity obtained in the cycloaddition was not a
serious issue in further transformation of the product. Moreover,
5ac reacted with the silyl enol ether derived from S-ethyl
ethanethioate in the presence of trimethylsilyl triflate to afford
synthetically useful compound 9 in good yield with good
diastereoselectivity.9
In the current [3+2] cycloaddition of the hydrazones to
olefins, two reaction mechanisms are proposed (Scheme 3). One
is a stepwise pathway, nucleophilic addition to the imine moiety
and successive cyclization, and the other is a [3+2] concerted
pathway, simultaneous cyclization of a 1,3-dipole equivalent
with an olefin. In addition to the above information that both
diastereomers of the products have the same absolute configura-
tions at the carbon atoms connected to the R1 substituents, we
conducted several experiments to clarify the reaction mecha-
nism. When the reaction of hydrazone 1a with vinyl ether 2c
was carried out in toluene at 0 °C for 3 h using the standard
chiral zirconium catalyst (10 mol %) shown in Table 3, the
desired cycloaddition adduct (5ac) was obtained in 57% yield
with moderate diastereoselectivity (ds ) 54/46) and high
enantioselectivity (91% ee (major)/98% ee (minor)). These
selectivities are almost the same as those of the reaction for 18
h (Table 3, entry 2), suggesting that epimerization of the product
(having a N,O-acetal moiety) did not occur during the reaction
course. Further, we conducted several experiments in the
reaction of 1a with 2c by changing several reaction parameters
(temperature, ligands of the zirconium catalyst, loading amounts
of the catalyst). In these experiments, the diastereomer ratio
was 54/46-63/37 and the enantioselectivity was 91-93% ee
(major) and 96-98% ee (minor), showing that the ee’s of the
major and minor isomers are clearly different. This difference
is also observed in almost all entries in Table 3 (remarkably
observed in entry 9). If the reaction proceeded via the stepwise
pathway, the enantioselectivity of the major and minor diaster-
eomers might be the same, and therefore, the above results
suggest that the present reaction would proceed via the concerted
pathway. We also performed the reaction of hydrazone 1a with
2-methoxypropene as a representative of a 1-alkyl-substituted
vinyl ether, and it was revealed that the reaction proceeded
sluggishly under the standard reaction conditions. This result
also suggests that the reaction would proceed via the concerted
pathway, because an alkyl substituent at the 1-position of a vinyl
ether would increase the nucleophilic addition of the vinyl ether
to a hydrazone in the stepwise pathway but decrease the
reactivity in the concerted pathway due to the steric hindrance.
(8) This imine formation by removal of the acyl group using LiAlH4 is rare.
See: Biswas, K. M.; Mallik, H.; Halder, S. Monatsh. Chem. 1997, 128,
1283.
Finally, synthesis of a biologically important compound, MS-
153, and its derivatives was investigated (Scheme 4). MS-153
is a cerebroprotecting agent and is employed as a biological
(9) (a) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477. (b) Sugiura, M.;
Hagio, H.; Hirabayashi, R.; Kobayashi, S. Synlett 2001, 1225. (c) Sugiura,
M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001,
123, 12510.
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A R T I C L E S
Yamashita and Kobayashi
tool;10 however, its asymmetric synthesis has not hitherto been
reported. The [3+2] cycloaddition of hydrazone 1n to 2c
proceeded smoothly to afford pyrazolidine 5nc in good yield
with high enantioselectivity. The p-nitrobenzoyl group was
removed by reduction using LiAlH4 followed by nicotinoylation.
The adduct 10 thus obtained was a useful intermediate for the
synthesis of MS-153 derivatives. In fact, after removal of the
phenylthio group, ent MS-153 (11) was obtained with high
enantioselectivity.11
temperature, and propanol (0.2 mmol) in toluene (0.3 mL) was added.
The mixture was stirred for additional 0.5 h. The catalyst solution was
transferred to another vessel using toluene (0.5 mL), in which hydrazone
1b (0.40 mmol) was placed, and the mixture was stirred at 0 °C. Ketene
acetal 2a in toluene (0.5 mL) was then added to the suspension, and
the whole was stirred at the same temperature for 18 h. After water
was added to quench the reaction, the mixture was extracted three times
with CH2Cl2. The organic phases were combined and dried over
anhydrous Na2SO4. After filtration and concentration under reduced
pressure, the crude product was purified by column chromatography
(aluminum oxide) to afford the desired pyrazolidine derivative (4ba).
The optical purity of this adduct was determined by HPLC analysis
using a chiral column.
Experimental Procedures for Asymmetric Intermolecular [3+2]
Cycloaddition of p-Nitrobenzoylhydrazones to Vinyl Ethers 2b-d
Using a Chiral Zirconium Catalyst Prepared from (R)-3a. A typical
experimental procedure is described for the reaction of 1a with 2c. To
a suspension of (R)-3,3′,6,6′-I4BINOL (3a, 0.048 mmol) in toluene (0.3
mL) was added Zr(OPr)4 (0.040 mmol) in toluene (0.4 mL) at room
temperature. The mixture was stirred for 3 h at the same temperature.
The catalyst solution was transferred to another vessel using toluene
(0.8 mL), in which hydrazone 1a (0.40 mmol) was placed, and the
mixture was stirred at 0 °C. Vinyl ether 2c (4.0 mmol) in toluene (0.5
mL) was then added to the suspension, and the whole was stirred at
the same temperature for 18 h. After water was added to quench the
reaction, the mixture was extracted three times with CH2Cl2. The organic
phases were combined and dried over anhydrous Na2SO4. After filtration
and concentration under reduced pressure, the crude product was
purified by column chromatography (aluminum oxide) to afford the
desired pyrazolidine derivative (5ac). The diastereomer ratio was
determined by 1H NMR analysis, and the optical purity of this adduct
was determined by HPLC analysis using a chiral column.
Conclusion
In summary, we demonstrated that asymmetric [3+2] cy-
cloaddition of hydrazones to olefins successfully proceeds in
high yields with high enantioselectivities in the presence of a
chiral zirconium catalyst. This is the first example of catalytic
enantioselective [3+2] cycloaddition of hydrazones to external
olefins. These reactions open ways to synthetically and biologi-
cally important pyrazoline, pyrazolidine, and 1,3-diamine
derivatives. For the reaction mechanism, [3+2]-concerted
pathways have been proposed based on several experiments.
Further applications of these reactions to the synthesis of other
biologically important compounds are now in progress.
Experimental Section
Experimental Procedures for Asymmetric Intermolecular [3+2]
Cycloaddition of Benzoylhydrazones to Ketene Dimethyl Dithio-
acetal 2a Using a Chiral Zirconium Catalyst Prepared from (R)-
3b. A typical experimental procedure is described for the reaction of
1b with 2a. To a suspension of (R)-3,3′-I2BINOL (3b, 0.048 mmol) in
toluene (0.3 mL) was added Zr(OPr)4 (0.040 mmol) in toluene (0.4
mL) at room temperature. The mixture was stirred for 0.5 h at the same
Acknowledgment. This work was partially supported by
CREST, SORST, and ERATO, Japan Science Technology
Corporation, and a Grant-in-Aid for Scientific Research from
Japan Society of the Promotion of Sciences.
(10) (a) Kajiya, S.; Iizuka, H.; Okumura, K.; Fujiwara, J.; Ohto, N.; Kawazura,
H.; Takahashi, Y.; Shiga, Y. Eur. Pat. Appl. EP 373512 A1 19900620,
1990. (b) Kosuge, K.; Umemura, K.; Ohashi, K.; Nakashima, M. Jpn. J.
Pharmacol. 1995, 67, 277. (c) Umemura, K.; Gemba, T.; Mizuno, A.;
Nakashima, M. Stroke 1996, 27, 1624. (d) Kawazura, H.; Takahashi, Y.;
Shiga, Y.; Shimada, F.; Ohto, N.; Tamura, A. Jpn. J. Pharmacol. 1997,
73, 317. (e) Shimada, F.; Shiga, Y.; Morikawa, M.; Kawazura, H.;
Morikawa, O.; Matsuoka, T.; Nishizaki, T.; Saito, N. Eur. J. Pharmacol.
1999, 386, 263. (f) Abekawa, T.; Honda, M.; Ito, K.; Inoue, T.; Koyama,
T. Psychopharmacology 2002, 160, 122.
Supporting Information Available: Full experimental section
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) We thank Dr. K. Okumura (Mitsui Chemicals) for providing us with copies
of the NMR spectrum of MS-153.
JA049498L
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11282 J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004