N-heterocyclic carbene-catalyzed [3+4] cycloaddition and kinetic resolution of azomethine imines

Article abstract of DOI:10.1021/ja411110f

The first N-heterocyclic carbene (NHC)-catalyzed [3+4] cycloaddition of azomethine imines and enals is disclosed. Oxidative catalytic remote activation of enals affords 1,4-dipolarophile intermediates that react with 1,3-dipolar azomethine imines to gener

Full text of DOI:10.1021/ja411110f

Communication
pubs.acs.org/JACS
N‑Heterocyclic Carbene-Catalyzed [3+4] Cycloaddition and Kinetic
Resolution of Azomethine Imines
Ming Wang, Zhijian Huang, Jianfeng Xu, and Yonggui Robin Chi*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
dipolarophiles to react with azomethine imines for [3+2]
ABSTRACT: The first N-heterocyclic carbene (NHC)-
catalyzed [3+4] cycloaddition of azomethine imines and
enals is disclosed. Oxidative catalytic remote activation of
enals affords 1,4-dipolarophile intermediates that react
with 1,3-dipolar azomethine imines to generate dinitrogen-
fused seven-membered heterocyclic products with high
optical purities. Our approach also provides effective
kinetic resolution of azomethine imines, in which the
substrate chiral center that is remote from the NHC
catalyst can be well resolved.
cycloadditions under metal catalysis. The [3+3] cycloadditions
of azomethine imines have been reported by the Hayashi7 and
Toste groups8 using Pd and Au metal catalysis respectively.
Outside of transition metal catalysis,9 organocatalytic cyclo-
additions of azomethine imines have also been developed.
Chen and co-workers developed amine-catalyzed [3+2]
cycloadditions of azomethine imines with α,β-unsaturated
aldehydes and cyclic enones.10 Kwon and Guo et al. reported
a phosphine-catalyzed [3+2] annulation of azomethine imines
and allenoates.11 Scheidt described an N-heterocyclic carbene
(NHC)-catalyzed diastereoselective [3+3] cycloaddition of
azomethine imines 1 with enals.12 Recently, the Wang group
reported a Et3N-catalyzed [3+3] annulation of azomethine
imines and 3-isothiocyanatooxindoles.13
The above [3+2] and [3+3] cycloadditions afford five- and
six-membered dinitrogen-fused heterocyclic products and have
received considerable studies. The related [3+4] cycloadditions
of azomethine imines that can form seven-membered
dinitrogen-fused heterocyclic derivatives (Figure 1a), on the
other hand, are much less studied. Elegant relevant work in this
direction include Hayashi’s Pd-catalyzed decarboxylative
formation of 1,4-dipolarophile intermediates to react with 1,3-
dipolar nitrones.14 Kwon and Guo observed [3+4] cyclo-
addition adducts with impressive yet still low yields in their
phosphine organocatalysis approach.11,15 Here we disclose
NHC-catalyzed enantioselective and diastereoselective [3+4]
cycloaddition of azomethine imines with enals (Figure 1b).16
Oxidative γ-carbon activation of enals via NHC catalysis afford
vinyl enolates17 as the reactive 1,4-dipolarophile. Racemic
azomethine imine substrates (0% ee) are used and the seven-
membered [3+4] adducts are obtained with excellent
diastereoselectivity and over 90% ee. Using the same catalytic
approach, kinetic resolution of azomethine imine substrates is
also achieved.
yrazolones and the related dinitrogen-fused heterocyclic
P
derivatives have interesting medicinally significant bio-
logical activities.1 For example, seven-membered dinitrogen-
fused heterocyclic derivatives are promising candidates as
insecticides, acaricides, herbicides, and acetyl-CoA carboxylase
inhibitors (Figure 1a)2 Since the use of stable azomethine
Key results of condition searching and optimization are
summarized in Table 1. The reaction between azomethine
imine 1a (0.22 mmol) and enal 2a (0.1 mmol) was chosen as a
model reaction and quinone 418 was used as an oxidant. Studies
on NHC catalysts revealed that when triazolium-based catalyst
A19 with an N-phenyl substituent was used, the desired [3+4]
cycloaddition product 3a was formed, albeit with a very low
yield (entry 1). Additional studies found that a switch to the
corresponding N-mesityl-substituted triazolium catalyst B19 led
Figure 1. Bioactive dinitrogen-fused heterocycles and our organo-
catalytic preparation method.
imines (e.g., 1) as 1,3-dipolar reagents reported by Dorn and
Otto3 in 1968, cycloaddition reactions of azomethine imines 1
have become one of the most efficient strategies for the
construction of dinitrogen-fused heterocyclic derivatives. In
2003, Fu and co-workers developed an asymmetric Cu-
catalyzed [3+2] cycloaddition and kinetic resolution of
azomethine imines 1 with alkynes.4 In addition to alkynes,4,5
electron-deficient alkenes6 have also been found as effective
Received: November 6, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja411110f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Table 1. Condition Optimization
Chart 1. Substrates Scope
b
c
entry
conditions
yield 3a (%)
ee 3a (%)
1
2
3
4
5
6
7
A, Cs2CO3, THF, 12 h
B, Cs2CO3, THF, 12 h
C, Cs2CO3, THF, 72 h
D, Cs2CO3,THF, 72 h
D, K2CO3, THF, 72 h
D, K2CO3, CH2Cl2, 72 h
trace
38
−
−
−
93
96
92
94
trace
47
64
75
d
D, K2CO3, CH2Cl2/THF , 72 h
72
a
Reaction conditions: 1a (0.22 mmol), 2a (0.1 mmol), NHC D (0.02
mmol), 4 (0.12 mmol), base (0.05 mmol Cs2CO3 or 0.4 mmol
b
K2CO3), solvent (2 mL), 4 Å molecular sieves. Isolated yield based
c
on 2a after chromatography. Enantiomeric excess of 3a determined
via chiral phase HPLC analysis; absolute configuration of the major
enantiomer was assigned on the basis of X-ray structure of 3j21 (see
d
Chart 1 and SI). Ratio of CH2Cl2/THF = 1:1 v/v.
to 3a with encouraging 38% yield (entry 2). Chiral triazolium
precatalysts were then evaluated (entries 3 and 4) and the use
of indanol-derived catalyst D20 with an N-mesityl substituent
afforded 3a with 47% yield and 93% ee. A switch of base from
Cs2CO3 (0.5 equiv, entry 4) to K2CO3 (4.0 equiv, entry 5) led
to a better yield (64%) and comparable ee (96%). As a note,
using more than 0.5 equiv of Cs2CO3 or less than 4.0 equiv of
K2CO3 both led to lower yields. Solvent CH2Cl2 (entry 6) was
then found to perform better than THF (entry 5) with respect
to reaction yield. The 92% ee for reaction in CH2Cl2 (entry 6)
was slightly lower than that in THF (entry 5). At last we found
the use of CH2Cl2/THF solvent mixture could consistently
afford the cycloaddition product with good yield and excellent
ee (entry 7).
Examples of azomethine imines and enals that work
effectively under the optimal condition (Table 1, entry 7) are
illustrated in Chart 1. With 2a as the model enal substrate,
azomethine imines derived from (hetero)aryl aldehydes bearing
various substituents all worked well, affording the correspond-
ing [3+4] reaction adducts 3a−e with good yields, excellent dr’s
(>20:1 dr) and ee (86−96% ee). Azomethine imines derived
from various pyrazolidinones containing different aryl (3f−h)
and alkyl (3i) substituent at the 5-position also reacted well.
With respect to the enals, replacing the phenyl substituent of
enal 2a to various (hetero)aryl (3j−o) were all tolerated in this
reaction (>20:1 dr, 94−98% ee). When a vinyl substituent (3p)
was used instead of β-phenyl substituent, the enantioselectivity
was slightly decreased (84% ee) while maintaining a high
diastereoselectivity (>20:1).22
a
Reaction conditions as in Table 1, entry 7. Yields are isolated yields.
The ratio of 1 and 2 is 2.2:1 because the reactions selectively consume
half of 1.
imines using our organocatalytic [3+4] reaction strategy should
be feasible. In our early study (Table 1, entry 7) of reacting 0.22
mmol azomethine imine 1a with 0.1 mmol enal 2a, when the
cycloaddition product 3a (>20:1 dr, 94% ee) was obtained in
72% yield (yield based on enal 2a), the azomethine imine 1a
was recovered in 58% yield (yield based on 1a initially used)
The fact that optically pure [3+4] reaction products could be
obtained from racemic azomethine imine substrates (Table 1,
entry 7; Chart 1) reveals that the two enantiomers of
azomethine imines have different reactivities under asymmetric
NHC catalysis. Therefore, a kinetic resolution for azomethine
B
dx.doi.org/10.1021/ja411110f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
and 51% ee. Since optically enriched azomethine imines are
useful building blocks for a range of reactions,23 we decided to
optimize our conditions for their kinetic chiral resolutions.
Prior to our work, the only related study we can find in the
literature is Fu’s Cu-catalyzed [3+2] cycloaddition to resolve
azomethine imines with an S-factor of 15−96.4b In short, by
increasing the relative equivalents of enal (2a) (see SI for
details), a variety of azomethine imines could be resolved with
high selectivity factors (S = 60−339) and good yield and ee
(Table 2). It is worth noting that previously NHC organo-
Scheme 1. Postulated Reaction Pathway
a
Table 2. Kinetic Resolution of Azomethine Imines 1
(S)-1
3
b
c
c
d
entry
1
conv (%) yield (%) ee (%) yield (%) ee (%)
S
1
2
3
4
5
1a
1b
1d
1g
1i
49
44
50
49
35
38
40
39
42
51
93
73
96
91
53
41
37
44
40
26
96
93
96
93
99
168
60
Scheme 2. Transformation of Compound 3
194
88
339
a
Reaction conditions: (rac)-1 (0.1 mmol), 2a (0.12 mmol), NHC D
(0.02 mmol), 4 (0.12 mmol), K2CO3 (0.4 mmol), THF (2 mL), 4 Å
b
molecular sieves. Conversions of (rac)-1, conv = ee1/(ee1 + ee3).
c
Isolated yield based on 1 after chromatography; note maximum
d
possible yield of (S)-1) is 50%. S-factor = ln[(1 − conv)(1 − ee1)/
ln[(1 − conv)(1 + ee1)].
catalysis has mainly been used for the kinetic resolution of
alcohols and amines through the formation of esters and
amides, respectively.24 In those reported reactions, the alcohol/
amine reactive sites are close to the chiral NHC catalysts. In our
kinetic resolution of azomethine imines, the substrate reactive
sites are remote (multiple bonds away) from the NHC
catalysts. Our results suggest that resolving the remote chiral
centers via NHC organocatalysis can be developed as a useful
strategy for challenging substrates.
A postulated reaction pathway is illustrated in Scheme 1.
Reaction of enal 2a with NHC catalyst forms Breslow
intermediate I. Oxidation of the Breslow intermediate converts
I to a NHC-bound ester intermediate II. Base-mediated
deprotonation on the γ-carbon of the NHC-bound α,β-
unsaturated ester intermediate II successfully gives vinyl enolate
intermediate III.17 This vinyl enolate intermediate behaves as a
1,4-dipolarophile to react with azomethine imine 1a to
eventually form the formal [3+4] cycloaddition adduct 3a
with a regeneration of the NHC catalyst. The kinetic resolution
originates from the reactivity difference between the chiral vinyl
enolate intermediate III and the two enantiomers of the
azomethine imine substrate.
The synthetic transformations of the seven-membered [3+4]
cycloaddition adducts were then evaluated (Scheme 2). Under
a simple protocol of NaOH in methanol, opening of the seven-
membered lactam ring of 3a (or 3q) followed by an
intramolecular Michael addition gave a dinitrogen-fused five-
membered heterocyclic compound 5a (or 5q) bearing a
quaternary carbon center. No apparent erosion of product ee
occurred and 5a (or 5q21) was obtained with >20:1 dr and 93%
ee (or 98% ee). The unsaturated carbon−carbon double bond
in 3a could be selectively reduced under H2 with Pd/C catalyst
to give 6a with 92% yield, > 20:1 dr, and 94% ee.
In summary, we have developed a NHC-catalyzed highly
diastereoselective (>20:1 dr) and enantioselective (84−99%
ee) [3+4] cycloaddition of azomethine imines and enals. NHC-
catalyzed remote activation of enals under oxidative conditions
affords vinyl enolate intermediates as 1,4-dipolarophiles.
Racemic azomethine imines (0% ee) can be used as 1,3-dipolar
substrates to afford dinitrogen-fused seven-membered hetero-
cyclic compounds with high optical purities (up to 99% ee). In
this catalytic process, the NHC catalyst enables highly effective
kinetic resolution of azomethine imines (S-factor up to 339).
The fact that the substrate’s chiral center which is remote to the
NHC catalysts can be effective resolved is impressive. Further
exploration of NHC organocatalysis for unusual cycloadditions
and kinetic resolutions is under progress in our laboratory. In
particular, kinetic resolution of challenging substrates bearing
remote chiral centers is of our ongoing interest.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and CIF files. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
robinchi@ntu.edu.sg
Notes
The authors declare no competing financial interest.
C
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Journal of the American Chemical Society
Communication
Na, R.; Wang, B.; Liu, H.; Zhang, L.; Liu, J.; Wang, M.; Zhong, J.;
Kwon, O.; Guo, H. Adv. Synth. Catal. 2012, 354, 1023−1034.
(16) Enals were previoulsy used as 1,3-dipolar substates (via
homoenolate intermediates) in cylcoaddition reactions; for examples,
see: (a) Lv, H.; Jia, W.-Q.; Sun, L.-H.; Ye, S. Angew. Chem., Int. Ed.
2013, 52, 8607−8610. (b) Izquierdo, J.; Orue, A.; Scheidt, K. A. J. Am.
Chem. Soc. 2013, 135, 10634−10637.
ACKNOWLEDGMENTS
■
Generous financial support for this work is provided by
Singapore National Research Foundation, Singapore Economic
Development Board, GlaxoSmithKline, and Nanyang Techno-
logical University (NTU). We thank Dr. Y. Li and Dr. R.
Ganguly (NTU) for X-ray structure analysis.
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(a) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012, 134, 8810−
8813. (b) Chen, X.; Yang, S.; Song, B. A.; Chi, Y. R. Angew. Chem., Int.
Ed. 2013, 52, 11134−11137.
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dx.doi.org/10.1021/ja411110f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX