Copper(II)-catalyzed exo and enantioselective cycloadditions of azomethine imines

Article abstract of DOI:10.1021/ol800904t

(Chemical Equation Presented) A strategy for exo and enantioselective 1,3-dipolar cycloaddition of azomethine imines to 2-acryloyl-3-pyrazolidinone is described. The corresponding cycloadducts are isolated with high diastereoselectivities (up to > 96:4 ex

Full text of DOI:10.1021/ol800904t

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2971-2974
Copper(II)-Catalyzed Exo and
Enantioselective Cycloadditions of
Azomethine Imines
Mukund P. Sibi,* Digamber Rane, Levi M. Stanley, and Takahiro Soeta
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
mukund.sibi@ndsu.edu
Received April 18, 2008
ABSTRACT
A strategy for exo and enantioselective 1,3-dipolar cycloaddition of azomethine imines to 2-acryloyl-3-pyrazolidinone is described. The
corresponding cycloadducts are isolated with high diastereoselectivities (up to >96:4 exo/endo) and enantioselectivities (up to 98% ee).
Catalytic, enantioselective cycloaddition of 1,3-dipoles to
olefins has become a premier method for the preparation of
optically active, five-membered nitrogen-containing hetero-
cycles.1 Advances in the fields of chiral Lewis acid catalysis
and organocatalysis have led to the development of highly
enantioselective cycloadditions of a variety of nitrogen-
containing 1,3-dipoles, including azomethine,2 nitrilium,3 and
diazonium betaines.4 To date, the azomethine betaines
represent the most thoroughly studied class of 1,3-dipoles
in enantioselective cycloadditions. Highly enantioselective
cycloadditions of nitrones, azomethine ylides, and azome-
thine imines have all been reported. A variety of azomethine
ylide cycloadditions with olefins have been developed to
access pyrrolidine derivatives as either the endo or exo
isomer with high diastereo- and enantioselectivity.5 Likewise,
endo and enantioselective cycloadditions of nitrones with
olefins are well established,2b,6 while endo and enantio-
selective cycloadditions of azomethine imines with electron-
(3) For enantioselective cycloaddition of nitrile oxides, see: (a) Sibi,
M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 5366. For
enantioselective cycloaddition of nitrile imines, see: (b) Sibi, M. P.; Stanley,
L. M.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 8276.
(1) For a comprehensive review of 1,3-dipolar cycloadditions, see: (a)
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John
Wiley and Sons: Hoboken, NJ, 2003. For a recent review on asymmetric
1,3-dipolar cycloadditions, see: (b) Pellissier, H. Tetrahedron 2007, 63,
3235.
(4) For enantioselective cycloadditions of diazoalkanes and diazoacetates,
see: (a) Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710. (b)
Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2174.
(c) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett. 2007, 9, 1553.
(5) For selected endo and enantioselective azomethine ylide cycload-
ditions, see: (a) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem.
Soc. 2007, 129, 750. (b) Zhang, X.; Wang, B.; Longmire, J. M. J. Am.
Chem. Soc. 2002, 124, 13400. For selected exo and enantioselective
azomethine ylide cycloadditions, see: (c) Yan, X.-X.; Peng, Q.; Zhang, Y.;
Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006,
45, 1979. (d) Llamas, T.; Arraya´s, R. G.; Carretero, J. C. Org. Lett. 2006,
8, 1795.
(2) For a highlight on enantioselective cycloadditions of azomethine
ylides, see: (a) Na´jera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005,
44, 6272. For selected recent examples of enantioselective cycloadditions
of nitrones, see: (b) Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett.
2006, 8, 3351. (c) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 11926. For selected recent examples of enantioselective
cycloadditions of azomethine imines, see: (d) Chen, W.; Du, W.; Duan,
Y.-Z.; Wu, Y.; Yang, S.-Y.; Chen, Y.-C. Angew. Chem., Int. Ed. 2007, 46,
7667. (e) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett. 2007, 9, 97. (f) Sua´rez,
A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11244. (g)
Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778.
(6) (a) Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am.
Chem. Soc. 1998, 120, 12355. (b) Kobayashi, S.; Kawamura, M. J. Am.
Chem. Soc. 1998, 120, 5840
.
10.1021/ol800904t CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

Scheme 1
.
Exo-Selective Cycloadditions of Azomethine
Table 1. Optimization of Chiral Lewis Acid-Catalyzed Exo- and
Enantioselective Cycloadditions of Azomethine Imine 1aa
Betaines with R,ꢀ-Unsaturated Pyrazolidinone Imides
deficient olefins have recently begun to appear in the
literature.2d,e However, reports of exo and enantioselective
cycloadditions of nitrones or azomethine imines are relatively
scarce.7,8 We and others have previously reported approaches
for exo and enantioselective cycloadditions of nitrones to
electron-deficient alkenes,7a–c but to date, none of these
methods have proven general for exo-selective cycloadditions
of both nitrones and azomethine imines. The lack of general
methods for exo-selective cycloadditions of azomethine
betaines led us to investigate whether our strategy for exo
and enantioselective cycloaddition of nitrones7a with R,ꢀ-
unsaturated pyrazolidinone imides (Scheme 1, eq 1) could
be applied to azomethine imine cycloadditions (eq 2).
We began by optimizing reaction conditions for the
cycloaddition of azomethine imine 2a with pyrazolidinone
acrylate 1a. The optimal chiral Lewis acid from our study
of exo-selective nitrone cycloadditions, Cu(OTf)2/bis(oxazo-
line) 5, was also an effective catalyst for exo-selective
azomethine imine cycloadditions. Cu(OTf)2/5-catalyzed cy-
cloaddition of 2a with 1a gave the cycloadducts 3a and 4a
in 81% yield as a 90:10 mixture of exo and endo isomers
(Table 1, entry 1).9 Furthermore, the desired exo cycloadduct
was formed with 98% enantiomeric excess. Chiral Lewis
acids prepared from additional bis(oxazoline) ligands and
Cu(OTf)2 were employed as catalysts in an attempt to
improve the diastereo- and/or enantioselectivity of the
cycloaddition (entries 2-4). When Cu(OTf)2/t-Bu-BOX 6
was used as the chiral Lewis acid, exo-3a was isolated in
excellent ee, but the ratio of 3a:4a was decreased to 83:17
(entry 2). The results of reactions employing Ph-BOX 7 and
Bn-BOX 8 as the chiral ligand were very similar. The exo/
endo ratio was 84:16 with both ligands, and cycloadduct 3a
was isolated in -82% ee with ligand 7 (entry 3) and -84%
ee with ligand 8 (entry 4).
Lewis
acid
CLA
yield
exo
entry
L* (mol %) (%)b exo/endoc
eed (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Mg(OTf)2
Zn(OTf)2
Ni(ClO4)2
Cu(OTf)2
Cu(OTf)2
5
6
7
8
5
5
5
5
5
30
30
30
30
30
30
30
20
10
81
85
88
75
38
84
80
83
90
90:10
83:17
84:16
84:16
4:96
33:67
7:93
89:11
88:12
98
-98
-82
-84
46 (47)e
60 (-59)e
55 (85)e
98
94
a For experimental details, see the Supporting Information. b Isolated
yields. c Determined by 1H NMR. d Determined by chiral HPLC. e Values
in parentheses are for the endo adduct.
led to endo-selective cycloadditions of azomethine imine 2a
(entries 5-7). The Mg(OTf)2/5- and Zn(OTf)2/5-catalyzed
cycloaddition gave endo-4a as the major diastereomer with
modest enantioselectivity (entries 3 and 4). However, the
Ni(ClO4)2/5-catalyzed cycloaddition was highly endo selec-
tive and gave endo-4a with good ee (entry 5). The results
for the Ni(II)-catalyzed reaction were not surprising given
the excellent endo selectivities and enantioselectivities
reported in Suga’s Ni(II)/binaphthyldiimine-catalyzed azome-
thine imine cycloadditions.2e The difference in the diaste-
reoselectivity between Cu(II)- and Ni(II)-catalyzed cycload-
ditions can be explained by alternate approach of the
azomethine imine depending on the metal geometry of the
chiral Lewis acid complex. The Cu(II)-catalyzed cycload-
ditions likely proceed through distorted square planar
complexes, which favor exo approach of 1a. On the other
hand, the Ni(II)-catalyzed cycloadditions likely proceed
through an octahedral complex, which leads to endo approach
of 1a.
The use of additional chiral Lewis acid complexes
prepared from ligand 5 and Mg(II), Zn(II), or Ni(II) salts
With a reasonable study of chiral Lewis acids in hand,
we chose Cu(OTf)2/5 as the optimal choice for further exo-
selective azomethine imine cycloadditions. Our next goal was
to lower the loading of Cu(OTf)2/5. We were quite pleased
to observe essentially no loss of diastereo- or enantioselec-
tivity when the catalyst loading was decreased to 20 mol %
(compare entry 8 with entry 1). Furthermore, the loading of
Cu(OTf)2/5 could be decreased to 10 mol % with minimal
impact on the exo- and enantioselectivity (compare entry 9
with entries 1 and 8).
(7) For exo and enantioselective nitrone cycloadditions, see: (a) Sibi,
M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 718. (b) Suga,
H.; Nakajima, T.; Itoh, K.; Kakehi, A. Org. Lett. 2005, 7, 1431. (c)
Desimoni, G.; Faita, G.; Mella, M. Boiocchi, M. Eur. J. Org. Chem. 2005,
1020
.
(8) For an example of exo and enantioselective azomethine imine
cycloaddition, see: Chen, W.; Yuan, X.-H.; Li, R.; Du, W.; Wu, Y.; Ding,
L.-S.; Chen, Y.-C. AdV. Synth. Catal. 2006, 348, 1818
.
(9) An analogous experiment to entry 1, Table 1, employing Cu(ClO4)2
as the Lewis acid led to 91% yield of 3a and 4a as a 90:10 exo/endo mixture
with 98% ee for the exo adduct 3a.
2972
Org. Lett., Vol. 10, No. 14, 2008

Table 2. Effect Pyrazolidinone N-1 Substitutiona
Table 3. Effect of Azomethine Imine C-5 Substitutiona
entry
SM
T (°C)
yieldb (%)
exo/endoc
exo eed (%)
4 Å yield
MS
exo
exo/endoc ee (%)d
entry dipole product
(%)b
1
1a
1b
1c
rt
40
rt
90
86
79
88:12
92:08
95:05
94
98
98
2e
3
1
2
3
4
5e
6
7
2a
2b
2c
2c
2c
2d
2d
3a
3d
3e
3e
3e
3f
yes
yes
yes
no
no
yes
no
90
79
69
33
75
77
65
88:12
>96:04
72:28
88:12
81:19
73:27
86:14
94
95
91
94
98
95
95
a For experimental details, see the Supporting Information. b Isolated
yields. c Determined by 1H NMR. d Determined by chiral HPLC. e Reaction
performed at 40 °C in sealed, heavy wall pressure vessel.
3f
Previously, our group has shown that the size of the
fluxional N-1 substituent in the pyrazolidinone auxiliary can
impact the level of enantioselectivity in Cu(II)-catalyzed
Diels-Alder10 and nitrone cycloadditions.7a We prepared
R,ꢀ-unsaturated pyrazolidinone imides 1b and 1c to test
whether a similar correlation between the size of the fluxional
group (R) and the enantioselectivity was present in azome-
thine imine cycloadditions (Table 2). Unfortunately, a clear
correlation between R group size and enantioselectivity was
not apparent. Both smaller and larger R groups led to
moderate improvement in enantioselectivity when compared
to the standard N-benzyl auxiliary (compare entries 2 and 3
with entry 1). The limited impact of the fluxional group size
likely occurs because the sterically bulky ligands, such as 5
and 6, override any participation by the fluxional R group
in face shielding of the dipolarophile.10b Given the modest
impact of the N-1 substituent, we chose to conduct breadth
and scope studies with 1a since its reactivity is greater than
1b and 1c.
Enantioselective 1,3-dipolar cycloadditions of pyrazolidi-
none-derived azomethine imines with electron-deficient alk-
enes are often limited to C-5 unsubstituted or in one case
C-5 dimethyl-substituted azomethine imines. Therefore, we
sought to expand the scope of C-5 substitution in exo-
selective cycloadditions of pyrazolidinone-derived azome-
thine imines (Table 3). As shown above, cycloaddition of
C-5 dimethyl-substituted 2a proceeds in high diastereo- and
enantioselectivity (entry 1).
a For experimental details, see the Supporting Information. b Isolated
yields. c Determined by 1H NMR. d Determined by chiral HPLC. e Reaction
performed at 40 °C in sealed, heavy wall pressure vessel.
2c with 1a in the absence of 4 Å MS led to significant
increase in the diastereomeric ratio (compare entry 4 with
entry 3). However, the reaction in the absence of 4 Å MS
was sluggish and the yield of the cycloadducts was low. A
compromise between reactivity and diastereoselectivity could
be achieved by performing the cycloaddition at 40 °C in the
absence of 4 Å MS. Under these reaction conditions, the
cycloadducts are isolated in 75% yield as an 81:19 mixture
of exo and endo isomers (exo ee ) 98%).
Two issues arise from the results of these experiments.
First, the enantioselectivity for the cycloaddition performed
at 40 °C is greater than that for the corresponding cycload-
ditions performed at room temperature (compare entry 5 with
entries 3 and 4). These results remain contrary to the trends
commonly observed in enantioselective catalysis but are not
unprecedented. We have reported similar increases in enan-
tioselectivitywithincreasingreactiontemperatureinMg(NTf2)2/
5-catalyzed cycloadditions of diazoacetates with R,ꢀ-
unsaturated pyrazolidinone imides.4c Second, the increase
in exo selectivity when 4 Å MS are excluded from the
reaction is not well understood at this time but is clearly
relevant since a similar trend is observed for cycloadditions
of azomethine imine 2d with and without 4 Å MS (compare
entries 6 and 7).11
When C-5-unsubstituted azomethine imine 2b was used
as the dipole, the cycloadducts were isolated as a >96:04
ratio of exo and endo isomers and the enantiomeric excess
for the desired exo adduct 3d was 95% (entry 2). Interest-
ingly, an increase in the steric volume of the C-5 substituents
in 2c relative to 2a (R ) Et for 2c, R ) Me for 2a) led to
a decrease in the exo/endo ratio (compare entry 3 with entry
1). We were quite surprised to find that the cycloaddition of
After demonstrating that good diastereo- and enantiose-
lectivities were possible from cycloadditions with both C-5-
substituted and unsubstitututed azomethine imines, we set
out to explore the scope of azomethine imines derived from
5,5-dimethylpyrazolidin-3-one and a variety of aldehydes
(Table 4). Cycloadditions of azomethine imines (2e and 2f)
derived from electron-rich aromatic aldehydes gave the
desired cycloadducts with high exo and enantioselectivities
(10) (a) Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am.
Chem. Soc. 2001, 123, 8444. (b) Sibi, M. P.; Stanley, L. M.; Nie, X.;
Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2007, 129,
395.
(11) The 4 Å MS lead to increased reactivity by preventing adventitious
water molecules from binding to the Lewis acid, the enhanced diastereo-
selectivity in the absence of 4 Å MS may result from cycloaddition onto a
chiral copper complex with a copper-bound water molecule.
Org. Lett., Vol. 10, No. 14, 2008
2973

Table 4. Survey of Additional Azomethine Iminesa
Scheme 2. Cycloadditions of Azomethine Imines with
Pyrazolidinone Crotonate 9
4 Å yieldb
exo
exo/endoc eed (%)
entry
R
product MS
(%)
1
2
Ph (2a)
3a
3g
3h
3i
yes
yes
yes
yes
yes
yes
no
90
81
83
83
82
80
81
89
81
74
72
88:12
96:04
91:09
93:07
92:08
82:18
87:13
94:06
79:21
93:07
88:12
94
98
98
98
98
93
96
98
93
93
78
pMeOC6H4 (2e)
pMeC6H4 (2f)
pBrC6H4 (2g)
pClC6H4 (2h)
pCNC6H4 (2i)
pCNC6H4 (2i)
oClC6H4 (2j)
oFC6H4 (2k)
oFC6H4 (2k)
ity was once again observed when the cycloaddition of 2k
with 1a was conducted in the absence of 4 Å MS (compare
entry 10 with entry entry 9, 93:07 vs 79:21 exo/endo).
Finally, we have demonstrated that an azomethine imine
derived from an aliphatic aldehyde can be used without a
significant loss of diasteroselectivity and a modest decrease
in enantioselectivity (entry 11).
We have made attempts to expand the scope of dipolaro-
philes in exo and enantioselective cycloadditions of azome-
thine imines. Specifically, we sought to apply this method-
ology to ꢀ-substituted R,ꢀ-unsaturated pyrazolidinone imides.
Unfortunately, the cycloaddition of azomethine imine 2a with
pyrazolidinone crotonate 9 does not proceed in the presence
of 100 mol % of Cu(OTf)2/5. Acceptable yields could be
achieved by using azomethine imine 2b as the dipole in
Cu(OTf)2/5-catalyzed cycloadditions with 9. The cycload-
dition yielded exo-10 as a single isomer in 77% yield with
67% ee. Further attempts to improve the enantioselectivity
by lowering the reaction temperature led to low yields of
10.
In conclusion, we have illustrated an efficient method for
exo and enantioselective cycloaddition of azomethine imines
with pyrazolidinone acrylates. Cycloadducts derived from a
variety of azomethine imines were prepared in good to high
yields with moderate to good exo selectivity and high
enantioselectivity. Furthermore, this methodology represents
the first general strategy for exo and enantioselective
cycloaddition of azomethine betaines that tolerates both
nitrones and azomethine imines as dipoles. At present, the
dipolarophile scope for this azomethine imine cycloaddition
methodology is limited, and work to address this limitation
is ongoing in our laboratory.
3
4
5
3j
6
3k
3k
3l
3m
3m
3n
7
8
yes
yes
no
9
10
11e i-Pr (2l)
yes
a For experimental details, see the Supporting Information. b Isolated
yields. c Determined by 1H NMR. d Determined by chiral HPLC. e 20 mol
% of Cu(OTf)2 and 22 mol % of 5 was used to prepare the catalyst.
(entries 2 and 3). Azomethine imines derived from p-
halogenated benzaldehydes were also well tolerated (entries
4 and 5). In fact, cycloadditions of 2g and 2h gave the desired
exo diastereomers in 98% ee and g92:08 exo/endo ratio. A
crystal structure was obtained for exo cycloadduct 3i (see
Table 4, entry 3). The absolute stereochemistry was found
to be (5S,6R).12 This observation is consistent with the
stereochemical model proposed for our previously published
exo and enantioselective nitrone cycloadditions.7a,13 Cy-
cloaddition of 1a with an azomethine imine 2i, which is
derived from an aldehyde bearing a strong electron-
withdrawing group in the para position, led to a slightly lower
exo/endo ratio and a modest decrease in enantioselectivity
(entry 6). However, the diastereomeric ratio and enantiomeric
excess could be improved from 82:18 to 87:13 and 93% ee
to 96% ee, respectively, when the reaction was run in the
absence of 4 Å MS (compare entry 7 with entry 6).
Azomethine imines derived from ortho-substituted ben-
zaldehydes are also competent dipoles. Cycloaddition of
o-chlorobenzaldehyde-derived 2j occurred with excellent exo
selectivity to give the desired exo cycloadduct 3l in 98% ee
(entry 8). The enantioselectivity remained high when o-
fluorobenzaldehyde-derived azomethine imine 2k was em-
ployed as the dipole, but the exo/endo ratio was moderate
(79:21, entry 9). A remarkable improvement in exo selectiv-
Acknowledgment. We thank the NSF (CHE-0316203 and
CHE-0719061) for financial support of this work.
Supporting Information Available: Experimental pro-
cedures, characterization data, CIF file, and proof of stere-
ochemistry. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) See the Supporting Information for details and a crystal structure
of 3i. NOE experiments demonstrated that the exo cycloadduct was the
major diastereomer.
(13) The opposite enantiomer of ligand 5 was used for the exo-selective
nitrone cycloadditions in reference 7a.
OL800904T
2974
Org. Lett., Vol. 10, No. 14, 2008