Catalytic enantioselective 1,3-dipolar cycloadditions of alkyl diazoacetates with α,β-disubstituted acroleins

Article abstract of DOI:10.1039/b910321j

A catalytic route to highly functionalized chiral 2-pyrazolines by an asymmetric 1,3-dipolar cycloaddition reaction of ethyl diazoacetate with α-substituted and α,β-disubstituted acroleins has been developed; in the presence of chiral (S)-oxazaborolidiniu

Full text of DOI:10.1039/b910321j

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Catalytic enantioselective 1,3-dipolar cycloadditions of alkyl
diazoacetates with a,b-disubstituted acroleinswz
Lizhu Gao,a Geum-Sook Hwang,b Mi Young Leea and Do Hyun Ryu*a
Received (in Cambridge, UK) 27th May 2009, Accepted 10th July 2009
First published as an Advance Article on the web 31st July 2009
DOI: 10.1039/b910321j
A catalytic route to highly functionalized chiral 2-pyrazolines by
an asymmetric 1,3-dipolar cycloaddition reaction of ethyl
diazoacetate with a-substituted and a,b-disubstituted acroleins
has been developed; in the presence of chiral (S)-oxazaborolidinium
ion 1 as catalyst, the reaction proceeded with high to excellent
enantioselectivities (up to 99% ee).
Initially, the 1,3-dipolar cycloaddition reaction between
tert-butyl diazoacetate and methacrolein was examined in
the presence of 20 mol% oxazaborolidinium ion 1a, activated
by triflimide. When the reaction was carried out at ꢀ78 1C in
toluene, the desired cycloadduct, optically active 2-pyrazoline,
was formed in moderate yield and 82% ee. However, with
dichloromethane as the solvent, the desired cycloadduct was
obtained in an improved yield and enantioselectivity. Replacement
of the tert-butyl group of diazoacetate by the sterically less
hindered ethyl group under similar conditions produced the
desired product in 81% yield and 90% ee (Table 1, entry 3).
The same reaction with chiral catalyst 1a activated by triflic
acid provided the desired product in a better yield (88%) but
with reduced enantioselectivity (84% ee). We then investigated
the effect of changing the catalyst boracycle substituent, and
found that the best boron aryl substituent is phenyl (entries 5
Cycloaddition reactions of diazoalkanes with olefinic dipolaro-
philes have received considerable interest because the resulting
pyrazolines and pyrazoles can be converted into a variety of
nitrogen-containing molecules.1–5 Over the past decade, highly
diastereoselective variants of these reactions using different
chiral auxiliaries have been reported.2 In comparison, catalytic
asymmetric 1,3-dipolar cycloaddition reactions of diazoalkanes
with olefins have not been well explored to date.
The Kanemasa group reported the first enantioselective,
chiral Lewis acid-catalyzed cycloaddition of trimethylsilyldiazo-
methane to b-alkyl-substituted, a,b-unsaturated oxazolidinone
imides as a bidentate dipolarophile.3 The Maruoka group
developed an enantioselective cycloaddition between diazoacetates
and readily available a-substituted acroleins in the presence
of a chiral titanium BINOLate catalyst4 and extended this
methodology to a short synthesis of the alkaloid manzacidin
A. Recently, the Sibi group reported similar cycloaddition
reactions of diazoacetates to a,b-unsaturated pyrazolidinone
imides using Mg2+-based Lewis acid catalysts.5 However,
it is important to note that in these reported 1,3-dipolar
cycloadditions, the substrate scope was limited or fewer
atom-economical bidentate dipolarophiles were used.
and 6). Ar
= 3,5-dimethylphenyl (mexyl) as the aryl
substituent in 1c provided better enantioselectivity relative to
Ar = phenyl in 1b, which is consistent with the results from
previous studies (entry 6).
After determination of the most favorable parameters for
1,3-dipolar cycloadditions catalyzed by the cationic Lewis
acids 1, the scope of this methodology was studied with
various a-substituted acroleins using 1b and 1c as catalysts.
As shown in Table 2, excellent yields and enantioselectivities
were obtained with 2-ethyl, 2-isopropyl and 2-cyclohexyl
acroleins (Table 2, entries 2–5). In the case of 2-benzyl
acrolein, the use of the mexyl-substituted catalyst 1c improved
the ee of 3 to 91% (entry 7).
Attempts to expand the scope of the enantioselective
1,3-dipolar cycloaddition of ethyl diazoacetate with a,b-
disubstituted acroleins are illustrated in Table 3. When
Given the limited substrate scope and low efficiency in
enantioselective diazoacetate 1,3-dipolar cycloaddition, we
evaluated the chiral oxazaborolidinium ions 1 as Lewis acid
catalysts for these reactions (Scheme 1). Catalysts 1, generated
from the corresponding oxazaborolidines by protonation with
trifluoromethanesulfonimide (triflimide), behave as powerful
Lewis acids and have been proven to be effective catalysts for
enantioselective Diels–Alder reactions,6 cyanosilylations,7
Michael reactions8 and recently, three component coupling
reactions.9 In addition, there is much evidence for the formation
of complexes between catalysts 1 and aldehydes.6c,7a,10
a Department of Chemistry, Sungkyunkwan University,
Suwon 440-746, Korea. E-mail: dhryu@skku.edu;
Fax: 82 31 290 5976; Tel: 82 31 290 5931
b Korea Basic Science Institute and Graduate School of Analytical
Science and Technology, Chungnam National University, 5St,
Anam-Dong, Seongbuk-Gu, Seoul, 136-713, Korea
w Dedicated to Professor Sung Ho Kang on the occasion of his 60th
birthday.
Scheme 1 Enantioselective 1,3-dipolar cycloaddition of diazoacetates
with a,b-disubstituted acroleins.
z Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/b910321j
ꢁc
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Table 1 Enantioselective 1,3-dipolar cycloaddition between alkyl
diazoacetate and methacrolein catalyzed by 1a
Table 3 Enantioselective 1,3-dipolar cycloaddition between ethyl
diazoacetate and a,b-disubstituted acroleins catalyzed by 1ba
Entry
R
Catalyst
t/h
Yield (%)b
Ee (%)c
Entry
R1, R2
t/h
Yield (%)b
Ee (%)c
1d
2
t-Bu
t-Bu
Et
Et
Et
1a
1a
1a
1a
1b
1c
5
1
2
2
2
2
55
61
81
88
87
86
82
88
90
84
91
95
1d
2
3
4
5
6
7
8
–(CH2)4–
–(CH2)4–
–(CH2)3–
–(CH2)5–
Me, Me
Me, Et
1
1
0.5
0.5
1
1
1
1
31
75
73
70
93
90
70
81
92
92
97
85
90
85
92
99
3
4e
5
6
Et
a
All reactions were performed with methacrolein and alkyl diazo-
b
Ph, Me
Ph, Et
c
acetates (1.5 equiv.) at ꢀ78 1C. Isolated yield. Determined by
d
chiral HPLC analysis after reduction of the aldehyde. Toluene was
a
Unless indicated, all reactions were performed with a,b-substituted
e
used instead of dichloromethane as a solvent. TfOH was used
b
acroleins and ethyl diazoacetates (1.5 equiv.) at ꢀ93 1C. Isolated
c
yield. Determined by chiral HPLC analysis. Reaction was per-
d
instead of Tf2NH for the preparation of catalyst 1a.
formed at ꢀ78 1C with CH2Cl2 as the solvent.
cycloaddition between a diazoacetate and a,b-disubstituted
acroleins.
Table 2 Enantioselective 1,3-dipolar cycloaddition between ethyl
diazoacetate and a-substituted acroleins catalyzed by 1b and 1ca
The observed stereochemistry in the asymmetric reaction
using oxazaborolidinium ion catalysts 1 can be explained with
the transition state model shown in Fig. 1. The coordination
mode of the a,b-unsaturated aldehyde to 1 is the same as that
previously proposed in enantioselective Diels–Alder and
cyanosilylation reactions. This organized formyl C–Hꢂ ꢂ ꢂO
hydrogen-bonded complex can reduce the LUMO energy of
the a,b-unsaturated aldehyde. As shown in Fig. 1, the formyl
carbon is situated above the bulky phenyl group, which
effectively screens the rear face of the acrolein from attack
by ethyl diazoacetate. Thus, the endo mode of addition of the
1,3-dipole from the front face of the acrolein is favorable and
leads to the (4S,5R)-pyrazoline as the major enantiomer.
Due to the greater screening ability of the mexyl group,
catalyst 1c provided higher ee compared to catalyst 1b
(Table 2, entries 4–7).
Entry
R
t/h
Catalyst
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
Me
Et
i-Pr
C6H11
C6H11
PhCH2
PhCH2
2
1
1
1
1
0.5
0.5
1c
1b
1b
1b
1c
1b
1c
86
91
97
94
94
72
72
95d
91
92
85
92
76
91
a
All reactions were performed with a-substituted acrolein and ethyl
b
c
diazoacetates (1.5 equiv.) at ꢀ78 1C. Isolated yield. Determined by
d
chiral HPLC analysis. The absolute configuration was assigned as
(R)-enriched. For details see the ESI.
1-cyclohexenecarboxaldehyde was employed as the dipolarophile
at ꢀ78 1C in dichloromethane, a 31% yield of bicyclic
pyrazoline 4 was isolated with high enantioselectivity, along
with b-keto ester 5 (35%)11 (entry 1). Fortunately, the isolated
yield of 4 could be improved by performing reaction at –93 1C
using propionitrile as the solvent (entry 2). Under optimized
conditions, 1,3-dipolar cycloadditions of 1-cyclopentene or
1-cycloheptene carboxaldehyde provided the desired bicyclic
2-pyrazolines in good yields and with high enantioselectivities
(entries 3 and 4). Encouraged by the high enantioselectivity
observed in the 1,3-dipolar cycloaddition of ethyl diazoacetate
with cyclic a,b-substituted enals, we applied the same catalytic
conditions to acyclic a-alkyl or aryl-b-alkyl disubstituted
acroleins. Remarkably, good results were obtained with the
a,b-dimethyl acrolein and a-phenyl-b-ethyl acrolein (entries
5 and 8). To the best of our knowledge, these are the
first examples of a chiral Lewis acid-catalyzed 1,3-dipolar
Fig.
1
Transition state model for the asymmetric 1,3-dipolar
cycloaddition reaction between ethyl diazoacetate and a,b-disubstituted
acroleins.
ꢁc
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In summary, we have developed a highly enantioselective,
catalytic reaction between ethyl diazoacetate and a-substituted
or a,b-disubstituted acroleins, producing highly functionalized
chiral (5R)-pyrazolines in good yields with high enantio-
selectivities. The absolute configuration of the products could
be predicted by the transition state model in Fig. 1. We believe
that these results will be useful in the synthesis of various
optically active pyrazolines. Further optimization of this
catalytic asymmetric reaction and extension of the reaction
scope, as well as synthetic applications are in progress.
This work was supported by the Korea Research Foundation
Grants funded by the Korean Government (MEST)
(KRF-2008-005-J00701, KRF-2008-331-C00160), and by the
Korea Science and Engineering Foundation (KOSEF) grant
funded by the Korean government (MEST) (No. R01-2008-
000-11094-0).
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This journal is The Royal Society of Chemistry 2009
5462 | Chem. Commun., 2009, 5460–5462