Asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines: An umpolung strategy

Article abstract of DOI:10.1002/anie.201100331

Oompa loompa: The title reaction has been accomplished with high stereoselectivity by use of an axially chiral dicarboxylic acid (see scheme). Employment of vinylogous aza-enamines as novel dipolarophiles was also implemented to establish a new concept of the inverse-electron-demand umpolung 1,3-dipolar cycloaddition. Bz=benzoyl, EDG=electron-donating group. Copyright

Full text of DOI:10.1002/anie.201100331

DOI: 10.1002/anie.201100331
Organocatalysis
Asymmetric Inverse-Electron-Demand 1,3-Dipolar Cycloaddition of
C,N-Cyclic Azomethine Imines: An Umpolung Strategy**
Takuya Hashimoto, Masato Omote, and Keiji Maruoka*
The catalytic asymmetric 1,3-dipolar cycloaddition (1,3-DC)
has now become one of the most established methods for the
stereoselective synthesis of five-membered heterocycles
having contiguous stereogenic centers, concurrent with the
development of chiral Lewis acids and organocatalysts.[1] As a
reaction mode for 1,3-DCs, normal-electron-demand (NED)
1,3-DCs proceed by the interaction of a catalytically activated
LUMO of electron-deficient alkenes with the HOMO of the
1,3-dipoles; alternatively, the inverse-electron-demand (IED)
1,3-DCs are facilitated by the interaction of the LUMO of an
acid-activated 1,3-dipole and the HOMO of electron-rich
alkenes. Although synchronous development of both features
in the realm of asymmetric catalysis would be highly desirable
to produce a diverse array of cycloadducts, IED 1,3-DCs are
far less developed to date and remain a challenge in contrast
to the sophistication and diversification of their NED
counterparts.[2,3,5h–j,11a]
We recently succeeded in shedding light on the as of yet
unexplored utility of C,N-cyclic azomethine imines 1 in the
titanium/binolate catalyzed NED 1,3-DC using enals as
dipolarophiles (Scheme 1).[4,5] As the next step of the study,
we set out to investigate the asymmetric IED 1,3-DC of these
1,3-dipoles,[6] coupled with the fact that the related methods
for catalytic asymmetric di- and tetrahydroisoquinoline
syntheses by the nucleophilic addition to (dihydro)isoquino-
line derivatives are still far from established in terms of the
generality and selectivity.[7]
We report herein the investigation toward this end using
vinyl ether as a conventional electron-rich dipolarophile and
the axially chiral dicarboxylic acid originally developed in our
group as a chiral Brønsted acid catalyst,[8] which succeeded in
attaining a remarkably broad substrate scope to give a variety
of C1-chiral tetrahydroisoquinolines with excellent enantio-
selectivity irrespective of the position and electronic nature of
the substituents. In addition, unique Lewis acid catalyzed
functionalizations of the cycloadducts were disclosed in which
tetrahydroisoquinolines with additional chiral stereocenter at
the C1 side chain could be generated stereoselectively. This
accomplishment prompted us to introduce a new concept
called the IED umpolung 1,3-DC, which gives cycloadducts
regioisomeric to the products of the previously reported
titanium/binolate-catalyzed NED 1,3-DC starting from the
same enals. This tactic could be realized by the umpolung
nature of enals imposed by the formation of the correspond-
ing N,N-dialkylhydrazones,[9] also known as vinylogous aza-
enamines (Scheme 1).
A clue to the development of asymmetric IED 1,3-DCs of
C,N-cyclic azomethine imines with vinyl ether was provided
from our early observation that these 1,3-dipoles easily form
stable protonated salts in the presence of a hydrobromic
acid.[4] This fact naturally led us to the use of a chiral Brønsted
acid, which has recently emerged as a powerful tool for
numerous stereoselective organic transformations.[10,11] As we
have been intensively working on the development of axially
chiral dicarboxylic acids as a class of chiral Brønsted acid
catalysts, we commenced the study of the asymmetric IED
1,3-DC between C,N-cyclic azomethine imine 1a and tert-
butyl vinyl ether using the most general axially chiral
dicarboxylic acid (R)-3a that bears 2,6-Me2-4-tBu-C6H2
groups as key 3,3’ substituents. As anticipated, (R)-3a facili-
tated the reaction in CH2Cl2 at 08C to give the exo and
endo adducts in 78% and 18% yields, respectively, but the
enantioselectivities were disappointingly low (Table 1,
entry 1). Screening of a series of catalysts bearing different
aryl substituents resulted in unsatisfactory selectivities
(entries 2–4). A breakthrough came when we developed the
new catalyst (R)-3e having diphenylmethyl groups at the 3,3’-
positions, with which the cycloadduct was furnished with a
drastically improved enantioselectivity and exo/endo ratio
(entry 5). Replacement of the phenyl group by a 2-naphthyl
group further enhanced the enantioselectivity to 82%
(entry 6). Finally, by changing the solvent to CHCl3 and
lowering the reaction temperature to À308C, the exo-adduct
2a could be obtained exclusively in 98% yield and 95% ee
Scheme 1. Normal- and inverse-electron-demand 1,3-dipolar cycloaddi-
tions of C,N-cyclic azomethine imines. binol=2,2’-dihydroxy-1,1’-
binaphthyl, Bz=benzoyl.
[*] Dr. T. Hashimoto, M. Omote, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502, (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the MEXT (Japan). M.O. thanks the Research
Fellowships of JSPS for Young Scientists for support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100331.
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Table 1: Optimization of the reaction conditions.[a]
at À208C to afford exo-2i in 95% yield with 94% ee
(entry 8).[13]
With the successful implementation of highly enantiose-
lective IED 1,3-DCs of C,N-cyclic azomethine imines and
vinyl ether, we moved our focus to the use of a different type
of dipolarophile. Vinylogous aza-enamines 4 (Table 3) are a
Table 3: Asymmetric IED umpolung 1,3-DC with vinylogous aza-enam-
ines.[a]
Entry Catalyst Solvent T [8C] t [h] Yield [%][b]
ee [%][c]
exo endo exo endo
1
2
3
4
5
6
7
8
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3 f
(R)-3 f
(R)-3 f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
0
À20
0
À20
À20
À20
À20
À30
8
4
4
24
24
12
5
78
67
63
47
73
85
95
98
18
23
13
18
<5
11
1
44
18
32
67
82
92
95
14
32
49
Entry
R
R’
Yield [%][b]
exo/endo[c]
ee [%][d]
5
1
2
3
4
H
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
Me (4b)
97 (5a)
94 (5b)
4.4:1
3.9:1
6.7:1
4.0:1
3.2:1
3.8:1
2.8:1
3.0:1
1.0:2.4
90
83
95
90
65
91
84
92
68
n.d.[d]
31
5-Me
6-Me
7-Me
8-Me
6-Br
6-MeO
7-MeO2C
H
>99 (5c)
>99 (5d)
>99 (5e)
>99 (5 f)
96 (5g)
<5
<2
n.d.[d]
23
10
5[e]
6
[a] Reaction conditions: 1a (0.10 mmol) and tert-butyl vinyl ether
(0.30 mmol) in the presence of 5 mol% (R)-3 (0.005 mmol). [b] Yield
of isolated product. [c] Determined by HPLC on a chiral stationary phase.
[d] Not determined. Np=napthyl.
7[f]
8
>99 (5h)
>99 (5i)
9
[a] Reaction conditions: 1 (0.10 mmol) and 4 (0.30 mmol) in the
presence of 5 mol% (R)-3g (0.005 mmol) for 24–72 h. [b] Combined
yield of isomers. [c] Determined by 1H NMR analysis of the crude
reaction mixture. [d] The ee values of the exo isomer determined by HPLC
(entries 7 and 8).[12] It is also worth noting that these reactions
could be carried out without the exclusion of moisture and air.
With the optimized conditions in hand, the scope of this
asymmetric IED 1,3-DC was investigated as summarized in
Table 2. The substitution patterns of azomethine imines had
little impact on the yields or enantioselectivities, thereby
providing the exo adduct exclusively with ee values ranging
from 92 to 97% (entries 1–4). C,N-cyclic azomethine imines
bearing electron-withdrawing groups could be utilized as well
in good yields with rigorous stereoselectivities (entries 5–7).
As the azomethine imine with an electron-donating methoxy
group displayed lower reactivity, the reaction was conducted
on
a
chiral stationary phase. [e] Performed at À308C for 48 h.
[f] Performed at À208C for 48 h.
class of umpolung substrates prepared from the simple
condensation of N,N-dialkylhydrazine and enals. As a result
of the electron donation from the N,N-dialkylamino moiety,
they are known to exhibit a nucleophilic character at their
b position, and this property was recently exploited for the
first time in asymmetric catalysis by our group.[8f] Taking into
account their reversed polarity relative to the parent enals
and the electron richness of the alkene moiety, we envisaged
that their use as a dipolarophile in the IED 1,3-DC developed
herein would provide a logical and distinguished way to give
the regioisomeric cycloadduct relative to that obtained by the
titanium/binolate-catalyzed NED 1,3-DC of C,N-cyclic azo-
methine imines with enals (Scheme 1).[4,14]
Table 2: Asymmetric IED 1,3-DC with tert-butyl vinyl ether.[a]
As proof of this concept, we set out to examine this IED
umpolung 1,3-DC between azomethine imine 1a and the
acrolein-derived vinylogous aza-enamine 4a under identical
reaction conditions using (R)-3 f as the catalyst. The reaction
proceeded smoothly, giving the expected regioisomer 5a with
a 2.0:1 exo/endo ratio and moderate enantioselectivities
(78% ee and 23% ee, respectively). The stereoselectivity
could be improved using the additionally modified catalyst
(R)-3g having bis(9,9-dimethyl-2-fluorenyl)methyl groups
(see Table 1) at a lower temperature (Table 3, entry 1). C,N-
cyclic azomethine imines bearing a variety of substituent
patterns and electron-withdrawing and electron-donating
groups were all tolerated, giving the corresponding cyclo-
adducts in almost quantitative yields with modest exo selec-
Entry
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
5-Me (1b)
6-Me (1c)
7-Me (1d)
8-Me (1e)
6-Br (1 f)
7-Br (1g)
7-CO2Me (1h)
6-OMe (1i)
>99 (2b)
90 (2c)
98 (2d)
>99 (2e)
>99 (2 f)
94 (2g)
>99 (2h)
95 (2i)
97
95
94
92
95
92
93
94
7
8[d]
[a] Reaction conditions:
1 (0.10 mmol) and tert-butyl vinyl ether
(0.30 mmol) in the presence of 5 mol% (R)-3 f (0.005 mmol) for 7–
20 h. [b] Yield of the isolated exo isomer. [c] The ee value of the
exo isomer was determined by HPLC on a chiral stationary phase.
[d] Performed at À208C for 12 h.
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tivities and high enantioselectivities for these exo isomers
(entries 2–8).[15] The reaction also proceeded with a meth-
acrolein-derived a-substituted vinylogous aza-enamine, but
the endo isomer was generated preferentially with low
enantioselectivity (entry 9). At present, b-substituted vinyl-
ogous aza-enamines, such as the one derived from crotonal-
dehyde could not be applied because of the generation of
some isomers arising from the nucleophilic attack of the
vinylogous aza-enamine at the b position.
Keywords: Brønsted acids · carboxylic acid · cycloadditions ·
organocatalysis · umpolung
.
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In an attempt to demonstrate the synthetic utility of so-
obtained cycloadducts, we carried out Lewis acid catalyzed
cyanation and Mukaiyama-type addition of a ketene silyl
acetal to exo-2a in anticipation of the replacement of the tert-
butoxy group by these nucleophiles (Scheme 2). To our
surprise, the reactions proceeded such that the tert-butoxy
groups were retained in the products, thereby giving 6 and 7
with high diastereoselectivities. These results are in keeping
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Scheme 2. Synthetic application of the cycloadduct: a) BF3·Et2O
(1.5 equiv), TMSCN (2.0 equiv), CH2Cl2, À78 to 08C, 3 h; b) BF3·Et2O
=
(1.5 equiv), H2C C(OMe)OTBS (2.0 equiv), CH2Cl2, À78 to 08C, 3 h.
TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl.
As one typical application of the cycloadduct derived
from the IED umpolung 1,3-DC, the aza-enamine part of exo-
5 f was converted into nitrile 8 by magnesium monoperox-
yphthalate (MMPP) without deterioration of the stereochem-
ical integrity as shown in Scheme 3.[17]
Scheme 3. Conversion of the aza-enamine moiety into the nitrile.
In summary, we have developed an asymmetric IED 1,3-
DC of C,N-cyclic azomethine imines and vinyl ether catalyzed
by a newly developed axially chiral dicarboxylic acid having
diarylmethyl groups at the 3,3’-positions. Based on this
finding, the concept of IED umpolung 1,3-DC was introduced
as a strategy for switching the regioselectivity of the cyclo-
addition from that of the titanium/binolate-catalyzed NED
1,3-DC with enals by using vinylogous aza-enamines as
umpolung substrates.
[9] For reviews, see: a) R. Brehme, D. Enders, R. Fernandez, J. M.
Lassaletta, Eur. J. Org. Chem. 2007, 5629; b) R. Lazny, A.
Nodzewska, Chem. Rev. 2010, 110, 1386.
Received: January 14, 2011
Published online: March 7, 2011
Angew. Chem. Int. Ed. 2011, 50, 3489 –3492
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3491

Communications
[10] For authoritative reviews, see: a) T. Akiyama, Chem. Rev. 2007,
[14] Lewis acid catalyzed 1,3-DC of nitrones and methacrolein is a
rare example which can afford the regioisomeric cycloadducts
107, 5744; b) M. Terada, Synthesis 2010, 1929.
ˇ
[11] For other chiral Brønsted acid catalyzed 1,3-DCs, see: a) P. Jiao,
D. Nakashima, H. Yamamoto, Angew. Chem. 2008, 120, 2445;
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Zhang, L.-Z. Gong, J. Am. Chem. Soc. 2008, 130, 5652; c) W.-J.
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L. He, X.-H. Chen, J. Song, W.-J. Chen, L.-Z. Gong, Org. Lett.
2009, 11, 4946; e) X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao, L.-Z.
Gong, J. Am. Chem. Soc. 2009, 131, 13819.
[12] No isomerization of the exo and endo isomers was detected
under the reaction conditions. Treatment of the isolated
exo isomer with BF3·Et2O at room temperature led to immediate
isomerization into the endo isomer.
depending on the catalysts, see: a) A. Badoiu, G. Bernardinelli,
E. P. Kꢂndig, Synthesis 2010, 2207; b) T. Hashimoto, M. Omote,
T. Kano, K. Maruoka, Org. Lett. 2007, 9, 4805, and references
therein.
[15] The relative configuration was determined by X-ray crystallo-
graphic analysis of rac-5b. See the Supporting Information for
details.
[16] For the determination of the relative stereochemistry and
discussion on the plausible mechanism, see the Supporting
Information.
[17] R. Fernꢁndez, C. Gasch, J.-M. Lassaletta, J.-M. Llera, J.
Vꢁzquez, Tetrahedron Lett. 1993, 34, 141.
[13] The absolute stereochemistry was determined by X-ray crystal-
lographic analysis of 2 f. See the Supporting Information for
details.
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Angew. Chem. Int. Ed. 2011, 50, 3489 –3492