Enantioselective copper-catalyzed [3+3] cycloaddition of azomethine ylides with azomethine imines

Article abstract of DOI:10.1002/anie.201307317

The more dipoles, the merrier: An asymmetric [3+3] cycloaddition of azomethine ylides derived from imines 1 with azomethine imines 2 in the presence of a chiral ferrocenylphosphine-copper catalyst afforded highly functionalized heterocyclic products 3 in high yield with excellent enantio- and diastereoselectivity (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene). The 1,3-dipolar reaction partners can be readily prepared from aldehydes. Copyright

Full text of DOI:10.1002/anie.201307317

Angewandte
Chemie
DOI: 10.1002/anie.201307317
Asymmetric Catalysis
Enantioselective Copper-Catalyzed [3+3] Cycloaddition of
Azomethine Ylides with Azomethine Imines**
Hongchao Guo,* Honglei Liu, Fu-Lin Zhu, Risong Na, Hui Jiang, Yang Wu, Lei Zhang,
Zhen Li, Hao Yu, Bo Wang, Yumei Xiao, Xiang-Ping Hu,* and Min Wang
The 1,3-dipolar cycloaddition has been established as a reli-
able and powerful tool for the synthesis of heterocyclic
compounds from simple starting materials.[1] In particular, the
catalytic asymmetric 1,3-dipolar [3+2] cycloaddition of azo-
methine ylides with electron-deficient alkenes for the enan-
tioselective preparation of structurally diverse pyrrolidines is
probably one of the most studied asymmetric 1,3-dipolar
cycloaddition reactions (Scheme 1a),[2,3] and considerable
progress has been made since the pioneering contributions
from the research groups of Jørgensen[4] and Zhang.[5]
partner; other types of cycloaddition reactions (e.g., [3+3] or
[3+4] cycloaddition) with azomethine ylides as one of the
reaction partners have received little attention. Only recently,
a novel cycloaddition reaction, the catalytic enantioselective
[6+3] cycloaddition of azomethine ylides with fulvene to
provide stereochemically rich piperidine derivatives, was
developed independently by the research groups of Wald-
mann[6] and Wang[7] (Scheme 1b). At present, the develop-
ment of new and efficient catalytic enantioselective higher-
order cycloaddition reactions to access chiral six- and seven-
membered rings and even larger heterocycles constitutes an
important challenge. It was recently demonstrated that the
zwitterion (which could be considered as a dipole) formed by
the conjugate addition of a phosphine to an allenoate reacted
with another kind of dipole in the form of azomethine imines
in [3+2], [3+3], [4+3], and [3+2+3] cycloaddition reac-
tions.[8] Inspired by this study, we conceived that a metal-
catalyzed asymmetric cycloaddition of a dipole with a dipole
might be feasible. Such a reaction has never been explored in
the cycloaddition chemistry of azomethine ylides. We envis-
aged that azomethine imines, which have been used exten-
sively as 1,3-dipoles in various metal-catalyzed and organo-
catalytic cycloaddition reactions,[9] might serve as a three-
atom synthon in a metal-catalyzed cycloaddition of azome-
thine ylides and undergo [3+3] cycloaddition to give biolog-
ically important hexahydro-8H-pyrazolo[1,2-a][1,2,4]triazin-
8-one derivatives (Scheme 1c).[10] Herein, we report the first
asymmetric [3+3] cycloaddition of azomethine ylides with
azomethine imines under the catalysis of a copper complex
with a chiral ferrocenyl P,N ligand to provide 8-oxohexa-
hydro-6H-pyrazolo[1,2-a][1,2,4]triazine-3-carboxylate deriv-
atives with high diastereo- and enantioselectivities (Sche-
me 1c).
However, in the past decade, most studies on the cyclo-
addition chemistry of azomethine ylides have been focused on
the development of chiral catalysts for asymmetric [3+2]
cycloaddition with electron-deficient alkenes as the reaction
Scheme 1. Asymmetric cycloaddition reactions of azomethine ylides.
Both azomethine ylides and azomethine imines are
versatile 1,3-dipoles and can be prepared readily from
aldehydes. We began the study by examining the reaction
between the azomethine ylide precursor 1a and the azome-
thine imine 2a (Table 1) in the presence of different metals,
chiral ligands, and bases in several solvents. Numerous
combinations of various commonly used chiral ligands, such
as 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl (binap), seg-
phos, the Trost diphosphine, Fesulphos, Taniaphos, quinap,
box, phox, Fc-phox, bpe, and Duphos,[2h] metal salts, such as
AgI, CuI, CuII, ZnII, and CaII salts, bases, such as Et3N, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyr-
idine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO),
iPr2NEt, CsCO3, KOtBu, K2CO3, potassium hexamethyldi-
silazide (KHMDS), and LiOH, and solvents, such as THF,
CH2Cl2, and toluene, were tested. The target product in
[*] Prof. Dr. H. Guo, H. Liu, Dr. R. Na, H. Jiang, Y. Wu, L. Zhang, Z. Li,
H. Yu, B. Wang, Dr. Y. Xiao, Prof. Dr. M. Wang
Department of Applied Chemistry, China Agricultural University
2 West Yuanmingyuan Road, Beijing 100193 (China)
E-mail: hchguo@cau.edu.cn
F.-L. Zhu, Prof. Dr. X.-P. Hu
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
Dalian 116023 (China)
E-mail: xiangping@dicp.ac.cn
[**] This research was supported by the NSFC (21172253, 21372256),
NCET-11-0481, the National Scientific and Technology Supporting
Program of China (2011BAE06B05-5), the National S&T Pillar
Program of China (2012BAK25B03), and Nutrichem. X.-P.H. also
thanks the DICP for the financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307317.
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12641

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Scheme 1c was generally obtained in very poor yield with
very poor enantioselectivity. The combination binap/AgOAc/
DBU afforded the best results, but the highest yield and
ee value were only 30 and 33%, respectively.
Finally, we turned our attention to ferrocenyl P,N ligands,
which have been employed in asymmetric [3+2] cycloaddition
reactions of azomethine ylides with electron-deficient alke-
nes.[2h] The screening experiments conducted with these chiral
ligands are summarized in Table 1. To our delight, with
[Cu(CH3CN)4]ClO4 (10 mol%), L1, and dichloromethane as
(entries 1 and 2).[11] The relative and absolute configuration of
3aa was assigned by X-ray crystal-structure analysis of the
analogue 3al obtained from the annulation of 1a with the
azomethine imine 2l (Table 3)[12] and comparison of the
optical rotation of the two compounds and NMR spectro-
scopic data.
We first examined the scope of the reaction with respect to
the azomethine ylide substrate under the optimized reaction
conditions. A range of azomethine ylides derived from
precursors 1 were tested in the [3+3] cycloaddition with
azomethine imine 2a. These functionalized azomethine ylides
were converted efficiently into the corresponding products
3aa–ja in 71–89% yield with 83–96% ee (Table 2). Good
reactivity and stereoselectivity were observed for azomethine
Table 1: Study of the reaction conditions.[a]
Table 2: Copper-catalyzed [3+3] cycloaddition of azomethine ylides with
azomethine imine 2a.[a]
Entry
Ligand
T [8C]
Yield [%][b]
d.r.[c]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L1
L2
L2
25
25
25
25
25
0
0
À5
81
85
50
trace
70
81
85
78
>20:1
>20:1
>20:1
–
>20:1
>20:1
>20:1
>20:1
72
77
74
–
37
80
90
95
Entry
1
R1
3
Yield [%][b]
d.r.[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
C6H5
4-MeC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
4-CF3C6H4
2-naphthyl
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
78
71
76
81
81
86
75
82
89
72
>20:1
14:1
95
88
90
91
94
96
83
90
95
90
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
[a] Unless otherwise indicated, reactions were carried out with 1a
(0.3 mmol), 2a (0.33 mmol), [Cu(CH3CN)4]ClO4 (0.03 mmol), the ligand
(0.033 mmol), and DBU (0.033 mmol) in CH2Cl2 (3 mL) for 24 h.
[b] Yield of the isolated product after chromatographic purification.
[c] The diastereomeric ratio and ee value were determined by HPLC
analysis on a chiral stationary phase. The product is levorotatory.
10
1j
3ja
[a] Unless otherwise indicated, reactions were carried out with
1 (0.3 mmol), 2a (0.33 mmol), [Cu(CH3CN)4]ClO4 (0.03 mmol), L2
(0.033 mmol), and DBU (0.033 mmol) in CH2Cl2 (3 mL) at À58C for
24 h. [b] Yield of the isolated product. [c] The diastereomeric ratio and
ee value were determined by HPLC analysis on a chiral stationary phase.
The products are levorotatory. When there were more than two
diastereomers, the diastereomeric ratio given is the ratio of the amount
of the major diastereomer to the total amount of other diastereomers.
the solvent at 258C, the target product 3aa was obtained in
81% yield with 72% ee and excellent diastereoselectivity
(Table 1, entry 1). When ligand L2 was used, both the yield
and the enantioselectivity were improved somewhat (85%
yield, 77% ee; Table 1, entry 2). The catalyst generated from
ligand L3 promoted the cycloaddition with 74% ee but in
moderate 50% yield (Table 1, entry 3). When ligand L4 was
employed, little conversion was observed (Table 1, entry 4).
Interestingly, the Cu catalyst formed with the ferrocenyl P,O
ligand L5 also promoted the reaction to afford the target
product in 70% yield, albeit with moderate 37% ee (Table 1,
entry 5). With L1 or L2 as the chiral ligand, a further
improvement in enantioselectivity was achieved by lowering
the reaction temperature (Table 1, entries 6–8): With the Cu–
L1 catalyst at 08C in CH2Cl2, the [3+3] cycloadduct was
produced in 81% yield with 80% ee. However, when the Cu–
L2 catalyst (10 mol%) was used at 0 and À58C, the ee value of
the product increased markedly to 90 and 95%, respectively,
with no significant erosion of the yield (85 and 78%; Table 1,
entries 7 and 8) with respect to that of the reactions at 258C
ylides with either electron-donating or electron-withdrawing
groups on the benzene ring (Table 2, entries 1–9). In partic-
ular, the reaction of the azomethine ylide derived from the
precursor 1 f with a 4-chlorophenyl group produced the
bicyclic product 3 fa with the highest selectivity (96% ee) in
86% yield (Table 2, entry 6). The azomethine ylide bearing
a 2-naphthyl group also underwent the desired [3+3] cyclo-
addition with 2a to give the corresponding pyrazolo[1,2-
a][1,2,4]triazine derivative in 72% yield with 90% ee
(Table 2, entry 10). Unfortunately, azomethine ylides derived
from aliphatic aldehydes were not viable substrates. The
strong electron-donating effect of alkyl groups on azomethine
ylides might lead to a decrease in activity of the ylides in the
cycloaddition reaction.
Next, we investigated the reactivity of various azomethine
imines 2 with the azomethine ylide derived from precursor 1a
as the reaction partner. The enantiomer of ligand L2 was used
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Table 3: Copper-catalyzed [3+3] cycloaddition of azomethine ylide 1a
aliphatic azomethine ylides, azomethine imines derived from
aliphatic aldehydes were not viable substrates.
with azomethine imines.[a]
Under acidic conditions, a very interesting epimerization
of the products 3 occurred to give their diastereomers 4. For
example, when the product (+)-3aa was treated with acetic
acid (1 equiv) in dichloromethane for 6 h, its diastereomer
(+)-4aa was obtained in 95% yield with a certain loss of
optical purity (Scheme 2). The relative and absolute config-
uration of (+)-4aa was assigned by X-ray crystal-structure
Entry
2
R2
3
Yield [%][b]
d.r.[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
14
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
4-MeC6H4
4-MeOC6H4
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-CF3C6H4
4-CNC6H4
2-naphthyl
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
60
73
80
70
68
79
70
70
77
76
83
78
73
75
>20:1
>20:1
10:1
>20:1
>20:1
10:1
18:1
>20:1
2:1
>20:1
>20:1
>20:1
>20:1
>20:1
85
84
93
93
91
92
90
87
91
90
90
83
90
89
[a] Unless otherwise indicated, reactions were carried out with 1a
(0.3 mmol), 2 (0.33 mmol), [Cu(CH3CN)4]ClO4 (0.03 mmol), ent-L2
(0.033 mmol), and DBU (0.033 mmol) in CH2Cl2 (3 mL) for 24 h. For
entries 3, 6, 7, and 9–11, the reactions were performed at 08C for 18 h.
[b] Yield of the isolated product. [c] The diastereomeric ratio and ee value
were determined by HPLC analysis on a chiral stationary phase. The
products are dextrorotatory. When there were more than two diastereo-
mers, the diastereomeric ratio given is the ratio of the amount of the
major diastereomer to the total amount of other diastereomers. [d] DBU
(0.0225 mmol, 7.5 mol%) was used.
Scheme 2. Epimerization and synthetic elaboration of product 3aa.
analysis of the compound rac-4aa[13] and (+)-4aj formed by
the epimerization of the product (+)-3aj.[12] As compared
with the product (+)-3aa, the configuration at C1 has been
inverted in (+)-4aa, and the phenyl substituent at this carbon
atom occupies the axial position in the chair conformation.
The treatment of product (+)-3aa with LiBH4 in THF
afforded a bicyclic heterocyclic compound 5 with an interest-
ing structure in 31% yield. Unfortunately, although product 5
was formed as a single diastereomer, it was racemic.
In conclusion, we have developed a copper-catalyzed
highly diastereo- and enantioselective [3+3] cycloaddition of
azomethine ylides with azomethine imines in the presence of
ferrocenyl P,N chiral ligands. Since azomethine ylides, azo-
methine imines, and ferrocenyl P,N chiral ligands are highly
accessible compounds, the reaction provides concise and
expedient access to a variety of optically active hexahydro-
8H-pyrazolo[1,2-a][1,2,4]triazin-8-one derivatives with poten-
tial biological activity. The high efficiency observed in this
reaction suggests that more cycloaddition reactions of 1,3-
dipoles with 1,3-dipoles could be anticipated. Further explo-
ration of the reaction mechanism and expansion of the scope
of the reaction to include other kinds of azomethine ylide and
azomethine imine substrates are under way.
as the chiral ligand in the reactions. With the Cu–ent-L2
catalyst (10 mol%), a variety of azomethine imines 2b–o
smoothly underwent the cycloaddition to provide the corre-
sponding heterocyclic products 3 in 60–83% yield with 83–
93% ee (Table 3). In general, the azomethine imines with
electron-withdrawing groups on the benzene ring showed
better enantioselectivity than those with electron-donating
groups (Table 3, entries 1 and 2 versus entries 3–13). An ortho
substituent on the benzene ring had a negative effect on the
diastereoselectivity of the reaction (Table 3, entries 3, 6, and
9), probably as a result of the steric hindrance caused by three
contiguous functional groups, namely, the ester group, the
ortho-substituted phenyl group, and the pyrazolidin-3-one
ring. The 2-naphthaldehyde-derived azomethine imine 2o
was also a viable substrate and underwent an efficient [3+3]
cycloaddition with 1a to give the product 3ao in high yield
with good enantioselectivity (Table 3, entry 14). The X-ray
crystallographic structure of product 3al[12] showed that the
six-membered ring of the bicyclic structure adopts a chair
conformation, and that all substituents on the six-membered
ring occupy the five equatorial positions; this arrangement
enables the structure to be very stable. Unfortunately, like
Received: August 20, 2013
Published online: October 2, 2013
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Keywords: asymmetric catalysis · azomethine imines ·
azomethine ylides · copper · [3+3] cycloaddition
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7.5 mol% of DBU at À58C, the ee value of 3aa could be
increased to 98%.
[12] CCDC 951058 ((+)-3al), 951059 ((+)-4aj), 951060 ((+)-3ae),
and 951061 (racemic 4aa) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[13] A single crystal of (+)-4aa has not yet been obtained, although
the growth of a suitable crystal has been attempted under
various conditions.
[11] Ligand L2 with 98% ee was used. By further increasing the
optical purity of the chiral ligand, it might be possible to improve
the enantioselectivity of the reaction further. The use of
a reduced amount of DBU sometimes led to an improvement
in the enantioselectivity of the reaction. For example, with
Angew. Chem. Int. Ed. 2013, 52, 12641 –12645
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12645