Enantioselective formal alkenylations of imines catalyzed by axially chiral dicarboxylic acid using vinylogous aza-enamines

Article abstract of DOI:10.1002/anie.201003600

(Figure Presented) In the zone: The use of vinylogous azaenamaines (hydrazones) as a source of an alkenyl group has been achieved (see scheme). Unmasking of the aza-enamine moiety opens up a novel approach for the preparation of chiral allylic amines bearing an electron-withdrawing alkene moiety functionalized at the electron-deficient β position.

Full text of DOI:10.1002/anie.201003600

Communications
DOI: 10.1002/anie.201003600
Organocatalysis
Enantioselective Formal Alkenylations of Imines Catalyzed by Axially
Chiral Dicarboxylic Acid Using Vinylogous Aza-Enamines**
Takuya Hashimoto, Hidenori Kimura, and Keiji Maruoka*
Catalytic asymmetric synthesis of chiral allylic amines has
been an extensively studied research field owing to their
remarkable synthetic versatility. In this context, catalytic
asymmetric alkenylation of imines, though considered to be
quite a straightforward process, has only recently become an
attractive option toward this end, following the prevalence of
asymmetric allylic amination.[1] The rapidly growing field of
organocatalysis has played a pivotal role in this latest
development as can be seen in the asymmetric Petasis
reaction,[2] which gives chiral allylic amines with an elec-
tron-rich alkene group being transferred from the corre-
sponding alkenyl boron species.[3–6] The organocatalytic aza-
Morita–Baylis–Hillman reaction, wherein a,b-unsaturated
carbonyl compounds formally act as an alkenyl anion at
their a position via a catalytically generated ionic intermedi-
ate, constitutes another important strategy to afford chiral
allylic amines with an electron-withdrawing alkene moiety.[7]
Vinylogous aza-enamines (hydrazones; Scheme 1),[8]
which can be easily prepared by the condensation of the
corresponding a,b-unsaturated aldehydes and N,N-dialkylhy-
drazines, are known to be a class of umpolung species.[9] These
species exhibit nucleophilic character at the C1 and C3-
positions (b position) as a result of the electron-donation
from the N,N-dialkylamino group.[10] Their reactions at C3
with highly electrophilic reagents have been sporadically
reported in the literature,[11,12] and its reaction mechanism is
understood to proceed via the initial formation of the ionic
intermediate and successive deprotonation to regenerate the
alkene moiety. Although this fundamental understanding
clearly implies the possibility of applying the catalytically
activated prochiral substrates as electrophile in the reaction
with vinylogous aza-enamines to formally realize asymmetric
alkenylations, there has been no example reported to date
realizing this appealing objective.[13]
Herein we report the exploitation of this intriguing but yet
unexplored property of vinylogous aza-enamines in axially
chiral dicarboxylic acid catalyzed formal alkenylation of
imines (vinylogous imino aza-enamine reaction), which is
distinctive in that the reaction system generates highly
enantioenriched chiral allylic amines while obviating the
need for any kind of metallic sources in the catalyst and
substrates. Furthermore, as an aza-enamines moiety can be
easily converted into a nitrile group by treatment with a
peracid, this is considered to be a facile method for the
asymmetric alkenylation with acrylonitrile and its analogues
at the intrinsically electron-deficient b-carbon atom realized
by the reactivity umpolung, thus this process is complemen-
tary to aza-Morita-Baylis–Hillman reactions.
In general, the main obstacle on the use of aza-enamines
in asymmetric catalysis lies in the difficulty to attain high
enantioselectivities despite some landmark endeavors.[14] In
this context, we have recently reported that axially chiral
dicarboxylic acid, originally developed in our research
group,[15] has a remarkable ability to achieve an excellent
level of enantioselectivities in the asymmetric addition of
formaldehyde- and arylaldehyde-derived aza-enamines to
various N-Boc imines (imino aza-enamine reaction).[14a,b,16]
Based on this study, we set out to examine the axially chiral
dicarboxylic acid catalyzed addition of the vinylogous aza-
enamine 2a (derived from acrolein) to benzaldehyde N-Boc
imine (Table 1, entry 1). In this preliminary study, it imme-
diately became obvious that the application of the reaction
conditions optimized in our previous study was completely
ineffective for this specific reaction system. The reaction was
very sluggish, and the alkenylation product was obtained in
less than 20% yield as an E/Z mixture. Even worse, almost no
asymmetric induction was observed for the major E isomer,
thus requiring the development of a completely new reaction
system.[17]
Scheme 1. Reaction mode of vinylogous aza-enamines.
[*] Dr. T. Hashimoto, H. Kimura, 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
Homepage: http://kuchem.kyoto-u.ac.jp/yugo/english/index.html
Among the various parameters to be modified, replace-
ment of the N-protecting group of the imine was found to
have a significant effect. Namely, subjection of benzaldehyde
N-benzoyl imine to the otherwise identical reaction condi-
tions furnished the desired product as a 2.3/1 mixture of E/
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003600.
6844
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Angew. Chem. Int. Ed. 2010, 49, 6844 –6847

Angewandte
Chemie
Table 1: Optimization of the reaction conditions.[a]
With the optimized conditions in hand, we moved our
attention to an investigation of applicable N-benzoyl imines
as summarized in Table 2. Regardless of the substitution
Table 2: Formal alkenylations of imines catalyzed by axially chiral
dicarboxylic acid using vinylogous aza-enamines.[a]
Entry
R
Cat.
Solvent
Yield [%][b]
E/Z[c]
ee [%][d]
(E/Z)
Entry
R1
R2
Yield [%][b]
E/Z[c]
ee [%][d]
(E/Z)
1
2
3
4
5
6
Boc
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
1a
1a
1b
1c
1c
1c
1c
1c
1c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
<20
62
65
77
67
n.d.
1:–
2.3:1
2.0:1
2.3:1
1.6:1
2.9:1
3.0:1
2.9:1
3.3:1
74:53
79:57
79:57
79:43
80:71
86:80
87:81
91:87
1
2
3
4
5
6
7
8
9
Ph
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
Me (2b)
iPr (2c)
87 (3a)
82 (3b)
81 (3c)
71 (3d)
79 (3e)
87 (3 f)
72 (3g)
83 (3h)
77 (3i)
3.3:1
3.8:1
2.3:1
3.9:1
3.2:1
4.1:1
3.0:1
1.2:1
91:87
92:90
90:90
93:93
90:90
93:88
90:87
90:63
89:71
4-tolyl
3-tolyl
2-tolyl
2-Np
4-ClC6H4
4-MeOC6H4
Ph
81
88
7[e]
8[f]
9[g]
63
87[h]
[a] Reactions were performed with the imine (0.10 mmol) and 2a
(0.12 mmol) in the presence of 5 mol% of (R)-1 (0.005 mmol).
[b] Combined yield of
spectroscopy of the crude mixture using an internal standard (nitro-
methane). [c] Determined by 1H NMR spectroscopy of the crude mixture.
[d] Determined by HPLC analysis using a chiral stationary phase.
[e] Performed at À208C. [f] Performed at À358C. [g] Performed at
À358C for 48 hours with 10 mol% of (R)-1c (0.010 mmol). [h] Yield of
isolated product. Boc=tert-butoxycarbonyl, Bz=benzoyl, M.S.=molec-
ualr sieves, n.d.=not determined.
Ph
1:5.1
[a] Reactions were performed with the imine (0.10 mmol) and
2
E
and Z isomers determined by 1H NMR
(0.12 mmol) in the presence of 10 mol% of (R)-1c (0.010 mmol).
[b] Combined yield of E and Z isomers. [c] Determined by 1H NMR
spectroscopy of the crude mixture. [d] Determined by HPLC analysis
using a chiral stationary phase. Np=naphthyl.
patterns of the aromatic ring, reactions proceeded without
difficulty and gave the products 3 in high yields as a mixture of
E/Z isomers in favor of the E isomer (Table 2, entries 2–4). In
these cases, the enantioselectivies of the E and Z isomers
were almost identical ranging from 90 to 93% ee. An N-
benzoyl imine compound bearing a 2-napthtyl group could be
employed as well, and gave the E isomer with 90% ee
(Table 2, entry 5). Use of imines bearing electron-withdraw-
ing and electron-donating functionalities was also tolerated
(Table 2, entries 6 and 7).
As for the substrate scope with regard to vinylogous aza-
enamines, attachment of a methyl group at the C2-position
(2b) resulted in the formation of an almost equal amount of
the E and Z isomers (Table 2, entry 8). Whereas the enantio-
meric excess of the E isomer remained high (90%), that of the
Z isomer was found to be modest. This tendency was further
strengthened when the more bulky 2-ispropyl-substituted
vinylogous aza-enamine 2c was used as substrate, giving the
Z isomer as a major product (E/Z = 1:5.1) with 71% ee
(Table 2, entry 9). These results imply that E and Z re-
gioisomers may possibly be generated via a different tran-
sition state, though further research is needed to elucidate this
discrepancy.
Z isomers in fairly good yield with a promising 74% ee for the
E isomer (Table 1, entry 2). Notably, no product arising from
the bond formation at the C1-position of the vinylogous aza-
enamine was detected, nor was an isomerization of the E and
Z isomers observed under the reaction conditions. To further
increase the selectivity, we then turned our attention to the
modification of the 3,3’-aryl groups of the catalyst. Replace-
ment of the 4-substituent of the aryl group by a methyl or a 1-
adamantyl (Ad) group led to substantial improvement of the
enantioselectivity (Table 1, entries 3 and 4). Because the
dicarboxylic acid (R)-1c bearing the 2,6-dimethyl-4-(1-ada-
mantyl)-phenyl group was found to have a broader generality
than (R)-1b in the successive study, (R)-1c was set as an
optimal catalyst. Additional optimization with regard to
solvents and temperatures led to the reaction conditions using
1,2-dichloroethane as the solvent at À358C (Table 1,
entries 5–8). Under these conditions, a drastic increase of
the enantioselectivity for the Z isomer was observed, thus
dissipating the selectivity gap between E and Z isomers.
Finally, we opted for an increase in catalyst loading to
10 mol%, in which the E and Z isomers could be isolated in
87% combined yield with 91% ee for the E isomer (87% ee
for the Z isomer; Table 1, entry 9). Notably, the isolated
Z isomer could be isomerized to the thermodynamically
favored E isomer (E/Z ratio = 13:1) without deterioration of
the enantioselectivity by treatment with acetic acid at room
temperature.[18]
On the other hand, introduction of a C3-substituent to
vinylogous aza-enamines generally led to a decrease of the
reactivity and the formation of two regioisomeric adducts,
probably owing to the steric hindrance at the C3-position. For
example, use of the crotonaldehyde-derived vinylogous aza-
enamine 4 under the identical reaction conditions furnished
the C3-adduct 5 in 12% yield with 77% ee as a single
Angew. Chem. Int. Ed. 2010, 49, 6844 –6847
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Communications
E isomer, concomitant with a considerable amount of the C1-
adduct 6 (34%; Scheme 2).
A unique and notable exception with regard to the
reaction of the C3-substituted vinylogous aza-enamines, is
property of the substituent also affected the regioselectivity
although the reaction proceeded in high yields and enantio-
selectivities (Table 3, entries 6 and 7).
Finally, synthetic application of thus obtained allylic
amine 3a was investigated as shown in Scheme 3. Trans-
Scheme 3. Preparation of chiral g-amino nitriles.
Scheme 2. Use of vinylogous aza-enamines substituted at the C3-
position.
formation of the aza-enamine moiety into the nitrile com-
pound could be facilitated by a conventional oxidation
procedure using MMPP (magnesium monoperoxyphthalate)
and gave the a,b-unsaturated g-amino nitrile 10 in 96% yield
without deterioration of the enantioselectivity.[19] By taking
advantage of the electron-withdrawing nature of the
unmasked alkene moiety, this material was then treated
with a Grignard reagent to give b-substituted g-amino nitrile
11. Consequently, addition of methyl magnesium iodide at
low temperature in toluene led to the formation of the desired
compound in 72% yield with moderate diastereoselectivity in
favor of the syn isomer.
the use of the vinylogous aza-enamine 7 derived from
cyclopentenecarbaldehyde (Table 3). In the reaction with
benzaldehyde N-benzoyl imine, the C3-adduct 8a was
Table 3: Use of cyclopentenecarbaldehyde-derived vinylogous aza-enam-
ines in axially chiral dicarboxylic acid catalysis.[a]
In conclusion, we have succeeded in the use of vinylogous
aza-enamines as a source of an alkenyl group in highly
enantioselective formal alkenylations of imines catalyzed by
axially chiral dicarboxylic acid. Owing to the ease of the
oxidative transformation of an aza-enamine moiety into a
nitrile compound, the synthetic method reported here offered
facile access to enantiomerically enriched g-amino a,b-
unsaturated nitriles, which in turn could be easily modified
to prepare the synthetically important chiral g-amino acids.
To the best of our knowledge, this study is the first example in
which the synthetic potential of vinylogous aza-enamine
could be actually demonstrated in asymmetric catalysis.
Exploration of the further application of vinylogous aza-
enamines in other asymmetric catalyses is currently underway
in our laboratory.
Entry
R
8/9[b]
Yield [%][b]
ee [%][d]
1
2
3
4
5
6
7
Ph
5.3:1
8.3:1
8.8:1
0.7:1
3.1:1
5.4:1
14:1
80 (8a)
79 (8b)
82 (8c)
39 (8d)
73 (8e)
77 (8 f)
72 (8g)
92
92
90
84
90
92
85
4-tolyl
3-tolyl
2-tolyl
2-Np
4-ClC6H4
4-MeOC6H4
[a] Reactions were performed with the imine (0.10 mmol) and
(0.12 mmol) in the presence of 10 mol% of (R)-1c (0.010 mmol).
[b] Determined by H NMR spectroscopy of the crude mixture. [c] Yield
of isolated product. [d] Determined by HPLC analysis using a chiral
stationary phase.
7
1
Received: July 3, 2010
Published online: August 16, 2010
Keywords: alkenylation · allyl amines · dicarboxylic acids ·
hydrazones · organocatalysis
obtained as a major regioisomer (5.3:1) in 80% yield of
isolated product with 92% ee (Table 3, entry 1). As this
reaction would be a distinguished organocatalytic method for
the asymmetric addition of the cycloalkenyl moiety to imines,
we then examined the substrate scope with respect to imine
compounds. In the reactions of tolualdehyde N-benzoyl
imines, 3- and 4-tolualdehyde-derived imines were success-
fully converted into the desired products with good regio- and
enantioselectivities (Table 3, entries 2 and 3), whereas attach-
ment of a substituent at the 2-position was found to be
detrimental for the regioselectivity (Table 3, entry 4). Use of
2-naphthaldehyde derived imine furnished the C3-adduct in
73% yield with 90% ee (Table 3, entry 5). The electronic
.
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Chemie
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