Catalytic enantioselective 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines with α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ja100787a

(Figure Presented) A yet-unexploited class of azomethine imines, C,N-cyclic azomethine imines, could be successfully employed in highly enantioselective 1,3-dipolar cycloaddition with enals catalyzed by titanium-BINOLate to give pharmaceutically attractive tetrahydroisoquinoline and piperidine motifs. Copyright

Full text of DOI:10.1021/ja100787a

Published on Web 03/03/2010
Catalytic Enantioselective 1,3-Dipolar Cycloaddition of C,N-Cyclic Azomethine
Imines with r,ꢀ-Unsaturated Aldehydes
Takuya Hashimoto, Yuko Maeda, Masato Omote, Hiroki Nakatsu, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received January 28, 2010; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Catalytic enantioselective 1,3-dipolar cycloaddition (1,3-DC) has
arguably been one of the most ideal synthetic methods for the
stereoselective construction of heterocycles with congested stereo-
genic centers and heterofunctionalized acyclic molecules produced
by the subsequent reductive ring opening of the resulting cycload-
ducts.1 Among the developments in this area, asymmetric 1,3-DC
of azomethine imines has recently emerged as a relatively new
field,2 with which chiral pyrazolidines could be synthesized.
Catalytic systems employing metallo- and organocatalysts have been
successfully developed, facilitating asymmetric 1,3-DC with a
variety of dipolarophiles. However, for the 1,3-dipole, use of bench
stable N,N′-cyclized azomethine imines i has been the only option
available,3 thus severely narrowing its synthetic utility (Figure 1).
performance of this reaction system allowed us to decrease the
catalyst loading to 3 mol % without affecting the yield or selectivity
(entry 6).
Table 1. Optimization of Reaction Conditionsa
yield
(%)b
entry
catalyst (mol %)
solvent
exo/endoc ee(%)d
1
2
3
4
(S)-BINOL (10) Ti(OiPr)4 (10)
(S)-BINOL (20) Ti(OiPr)4 (10)
CH2Cl2 92
89:11 60/-
CH2Cl2 94 >95:5
85
80
92
86
90
(S)-BINOL (20) O[Ti(OiPr)3]2 (10) CH2Cl2 83 >95:5
(S)-BINOL (20) Ti(OiPr)4 (10)
toluene 94 >95:5
toluene 95 >95:5
toluene 95 >95:5
5e (S)-BINOL (20) Ti(OiPr)4 (10)
6
(S)-BINOL (6) Ti(OiPr)4 (3)
a Performed with 1a (0.50 mmol) and crotonaldehyde (1.0 mmol).
b Isolated yield. c Determined by the 1H NMR of the crude mixture.
d Determined by chiral HPLC after reduction of 2a. e Performed at -20
°C.
Figure 1. Classification of Azomethine Imines.
With regard to other azomethine imines, acyclic ones ii are
known to exist as a hemiaminal form iii preferentially and have to
be generated under harsh azeotropic conditions intolerant to
asymmetric catalysis.4,5 In line with these two, C,N-cyclic azome-
thine imines iv can be considered a third class of azomethine imines,
though their property and synthetic utility have rarely been studied
in the past and remain elusive.
With this promising result in hand, we investigated the generality
of this unprecedented asymmetric 1,3-DC (Table 2). As for the
substitution pattern of the C,N-cyclic azomethine imines, 5-, 6-,
and 7-methyl substituents were all tolerated, furnishing the cy-
cloadducts in high yields and selectivities (entries 1-3). The only
exception was the incorporation of the 8-methyl substituent wherein
the reaction resulted in moderate enantio- and diastereoselectivity
(entry 4). C,N-Cyclic azomethine imines having an electron-
donating or -withdrawing group could be utilized as well (entries
5-7). The absolute stereochemistry was determined by X-ray
crystallographic analysis of 2h, by which the exoselective fashion
of this 1,3-DC was confirmed.11 The focus was then moved to the
examination of applicable R,ꢀ-unsaturated aldehydes. With regard
to the ꢀ-substituents, both a longer alkyl chain and an aromatic
group were tolerated (entries 8 and 9). Additionally, rather
unreactive R,ꢀ-disubstituted enals could also be utilized (entries
10 and 11). In the case of R,ꢀ-unsaturated aldehydes lacking a
ꢀ-substituent, almost equal amounts of two diastereomers were
obtained (entries 12 and 13), suggesting the importance of the steric
factor for the exoselectivity.
This study prompted us to develop structurally distinct C,N-cyclic
azomethine imines which are not fused to the aromatic ring (Table
3).12 In this regard, the hydrobromic acid salt of such azomethine
imines could be prepared as a bench stable precursor 3. However,
attempted isolation of the free azomethine imine 4 after the
treatment with a base failed due to the preferential formation of
the corresponding hemiaminal 5. To address this issue, we
implemented the in situ generation of 4 under the anhydrous reaction
condition,13 using 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as
We report herein the exploitation of yet-unexplored C,N-cyclic
azomethine imines in highly enantioselective asymmetric 1,3-DC
catalyzed by a titanium-BINOLate complex, which offers access
to pharmaceutically attractive chiral tetrahydroisoquinolines and
piperidines with a 1,3-diamine unit.6,7 During the course of this
study, we also uncovered a new protocol for using azomethine
imines which preferably exist as the hemiaminal form in the
identical catalysis.
At the beginning of this research, we were particularly intrigued
by the early report of Tamura et al. in 1973 wherein the benzene-
fused C,N-cyclic azomethine imine 1a was synthesized as a
metastable compound.8,9 Accordingly, we set out to evaluate the
viability of asymmetric 1,3-DC of C,N-cyclic azomethine imine
1a and crotonaldehyde by using titanium-BINOLate complexes
(Table 1) based on our related studies.10 Gratifyingly, 1,3-DC
proceeded smoothly in the presence of the 1:1 complex of Ti(OiPr)4
and (S)-BINOL as catalyst, giving the cycloadduct 2a in high yield
with moderate stereoselectivities. Examination of other titanium-
BINOLates and reaction conditions revealed the high efficiency of
the 2:1 (S)-BINOL/Ti(OiPr)4 complex using toluene as solvent at
0 °C, giving the cycloadduct in 94% yield with excellent enantio-
and diastereoselectivity (entries 2-5). Notably, the high catalytic
9
4076 J. AM. CHEM. SOC. 2010, 132, 4076–4077
10.1021/ja100787a  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Reductive Cleavage of the N-N Bond
a base compatible with a Lewis acid catalyst. As summarized in
Table 3, the reaction could be conducted under otherwise identical
conditions to give a couple of cycloadducts 6 (entries 1-4),14
although the use of R,ꢀ-disubstituted enals led to low conversion
(data not shown). In the case of ꢀ-unsubstituted enals, the reaction
predominantly gave the endo isomer with uniformly high enanti-
oselectivities (entries 5-9).
In summary, we successfully demonstrated that C,N-cyclic
azomethine imines can be utilized as a promising 1,3-dipole in
asymmetric 1,3-DC. As the synthetic utility of azomethine imines
has been moving beyond archetypal 1,3-DCs,15 uncovering a new
class of useful azomethine imines would also offer new opportuni-
ties in these growing fields.
Table 2. Asymmetric 1,3-DC of C,N-Cyclic Azomethine Iminesa
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the MEXT, Japan.
entry
R1
R2
R3
yield (%)b
exo/endoc
ee(%)d
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
8
9
10
11
12
13e
5-Me (1b)
6-Me (1c)
7-Me (1d)
8-Me (1e)
6-MeO (1f)
6-Br (1g)
7-Br (1h)
H (1a)
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Pr
85 (2b)
99 (2c)
93 (2d)
94 (2e)
96 (2f)
93 (2g)
92 (2h)
86 (2i)
94 (2j)
85 (2k)
93 (2l)
98 (2m)
97 (2n)
>95:5
>95:5
>95:5
84:16
>95:5
>95:5
>95:5
>95:5
>95:5
95:5
89
92
H
H
H
H
H
H
H
H
Me
92
62/22e
82
References
95
93
85
99
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Me
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88
-(CH2)3-
Me
H
92:8
50:50
61:39
89/86e
96/98e
62/74e
H
H
a Performed with
1 (0.50 mmol) and aldehyde (1.0 mmol).
c
b Combined yield of exo/endo isomers. Determined by the H NMR of
the crude mixture. d Determined by chiral HPLC after reduction of 2.
e Ee value of the endo isomer.
1
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Azomethine Iminesa
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entry
R4
R2
R3
yield (%)b
exo/endoc
ee (%)d
1
2
3
4
5
6
7
8
9
(CH2)4 (3a)
(CH2)3 (3b)
Me (3c)
(CH2)4 (3a)
(CH2)4 (3a)
Me (3c)
(CH2)4 (3a)
(CH2)3 (3b)
Me (3c)
H
H
H
H
Me
Me
H
H
H
Me
Me
Me
Pr
H
H
H
H
H
74 (6a)
64 (6b)
65 (6c)
36 (6d)
98e (6e)
99e (6f)
98e (6g)
97e (6h)
98e (6i)
81:19
77:23
88:12
67:33
22:78
11:89
15:85
13:87
7:93
90
86
76
(11) For details, see Supporting Information.
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75
96/97f
98/98f
83/96f
89/96f
75/97f
a Performed with 3 (0.25 mmol) and aldehyde (0.50 mmol). b Isolated
yield of the exo isomer. c Determined by the 1H NMR of the crude
mixture. d Determined by chiral HPLC after reduction of 6. e Combined
yield of the isomers. f Ee value of the endo isomer.
Finally, SmI2-mediated ring opening of the cycloadduct 2a′ was
implemented to furnish the tetrahydroisoquinoline 7 having a side
chain with three contiguous stereogenic centers (Scheme 1).
JA100787A
9
J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010 4077