Trio catalysis merging enamine, br?nsted acid, and metal lewis acid catalysis: Asymmetric three-component aza-diels-alder reaction of substituted cinnamaldehydes, cyclic ketones, and arylamines

Article abstract of DOI:10.1002/chem.201406569

A trio catalyst system, composed of arylamine, BINOL-derived phosphoric acid, and Y(OTf)₃, enables the combination of enamine catalysis with both hard metal Lewis acid catalysis and Br?nsted acid catalysis for the first time. Using this catalyst system, a three-component aza-Diels-Alder reaction of substituted cinnamaldehyde, cyclic ketone, and arylamine is carried out with high chemo- and enantioselectivity, affording a series of optically active 1,4-dihydropyridine (DHP) derivatives are obtained in 91-99 % ee and 59-84 % yield. DHPs bearing a chiral quaternary carbon center are also obtained with good enantioselectivity and moderate yield (three examples). Preliminary mechanistic investigations have also been conducted.

Full text of DOI:10.1002/chem.201406569

DOI: 10.1002/chem.201406569
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&
Asymmetric Synthesis
Trio Catalysis Merging Enamine, Brønsted Acid, and Metal Lewis
Acid Catalysis: Asymmetric Three-Component Aza-Diels–Alder
Reaction of Substituted Cinnamaldehydes, Cyclic Ketones, and
Arylamines
Yongming Deng,[a] Siddhartha Kumar,[a] Kraig Wheeler,[b] and Hong Wang*[a]
Abstract: A trio catalyst system, composed of arylamine,
BINOL-derived phosphoric acid, and Y(OTf)3, enables the
combination of enamine catalysis with both hard metal
Lewis acid catalysis and Brønsted acid catalysis for the first
time. Using this catalyst system, a three-component aza-
Diels–Alder reaction of substituted cinnamaldehyde, cyclic
ketone, and arylamine is carried out with high chemo- and
enantioselectivity, affording a series of optically active 1,4-di-
hydropyridine (DHP) derivatives are obtained in 91–99% ee
and 59–84% yield. DHPs bearing a chiral quaternary carbon
center are also obtained with good enantioselectivity and
moderate yield (three examples). Preliminary mechanistic in-
vestigations have also been conducted.
Introduction
The combination of organocatalysis with metal catalysis has
emerged as a powerful tool to develop new reactions that
cannot be achieved by organocatalysis or metal catalysis inde-
pendently.[1] The major problem in merging amine organocata-
lysts with metal Lewis acid catalysts is that acid–base quench-
ing causes catalyst inactivation. An effective strategy to over-
come this problem is the incorporation of a soft metal Lewis
acid such as Pd0 or AgI with a hard aliphatic amine (Figure 1,
top). By using this strategy, very challenging asymmetric direct
alkylation reactions have been achieved[1g–q] and a number of
de novo reactions based on allylic alkylation have been develo-
ped.[1r–u] However, the combination of enamine catalysis with
hard metal Lewis acid has turned out to be very difficult, and
few organic reactions through cooperative enamine–hard
metal Lewis acid catalysis have been reported.[1–3] Nevertheless,
a large variety of electrophiles can be activated by hard metal
Lewis acids (Figure 1, top), so the development of new strat-
egies to overcome the acid–base self-quenching problem
could represent an important breakthrough in organic synthe-
sis and catalysis.
Figure 1. Top: Different reaction modes in cooperative enamine–metal Lewis
acid catalysis. Bottom: Trio catalysis incorporating enamine and binary acid
catalysis.
To extend the possibilities for catalytic organic reactions, our
group has been engaged in developing new strategies to
merge enamine catalysis with hard metal Lewis acid catal-
ysis.[1a–d,2,3] Very recently, our group introduced a new strategy,
namely soft–hard reversion, to solve the acid–base quenching
problem.[2] In this approach, arylamines replace the well-estab-
lished and generally used aliphatic amines in enamine cataly-
sis. We demonstrated that arylamine-based enamine catalysis
could be successfully combined with hard metal Lewis acid
catalysis. Herein, we further demonstrate enamine catalysis
merged with both hard metal Lewis acid catalysis and Brøn-
[a] Dr. Y. Deng, S. Kumar, Prof. H. Wang
Department of Chemistry and Biochemistry, Miami University
701 E High Street, Oxford, OH 45056 (USA)
E-mail: wangh3@miamioh.edu
[b] Prof. K. Wheeler
Department of Chemistry, Eastern Illinois University
600 Lincoln Ave., Charleston, IL 61920 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406569.
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sted acid catalysis, to give
a novel trio catalyst system com-
posed of an arylamine, Y(OTf)3,
and a BINOL-derived phosphoric
acid (Figure 1, bottom). By using
this trio catalyst system, a chal-
lenging three-component aza-
Diels–Alder reaction of substitut-
ed cinnamaldehydes, cyclic ke-
tones, and arylamines was devel-
oped with excellent chemo- and
enantioselectivity.
Scheme 1. Proposed three-component ADA reaction of substituted cinnamaldehyde, cyclic ketone, and arylamine
catalyzed by a trio catalytic system.
Screening of conditions
Results and Discussion
We first tested our investigation by using 2-methylcinnamalde-
Design of asymmetric three-component aza-Diels–Alder re-
action through trio catalysis
hyde 1a, cyclohexanone, and p-chloroaniline as substrates
(Table 1). To gain good understanding of the reaction, we ini-
tially used a solo acid catalyst. All of the chiral Brønsted acids
examined (Table 1, entries 1–5) gave the Mannich product as
the major product alongside the ADA product in low to mod-
erate yield (7–24%), indicating that the solo Brønsted acid
cannot promote the ADA reaction. These data are consistent
with those reported previously.[6] Notably, however, good enan-
tioselectivity (88% ee; Table 1, entry 5) was obtained with the
phosphoric acid TRIP (5b).
The catalytic activity of solo metal Lewis acids was also
tested. Most of the metal salts, including Zn(OTf)2, In(OTf)3,
Sm(OTf)3, and Yb(OTf)3, also afforded the Mannich product as
the major product (see the Supporting Information). Fortunate-
ly, when Y(OTf)3 or La(OTf)3 was used, the reaction pathway
switched, giving dominantly ADA product (see the Supporting
Information). However, the chemoselectivity of this reaction re-
mained low.
In the past several years we have developed several difficult
asymmetric organic transformations through combining en-
amine catalysis with hard metal Lewis acid catalysis.[2,3] Like
many other metal Lewis acid-catalyzed reactions, a substrate
with a chelating site, such as a-ketoesters, is generally required
to attain maximal activation of the electrophiles. To greatly
extend the scope of cooperative enamine–hard metal Lewis
acid catalysis, new strategies must be developed to activate
electrophiles without chelating sites, such as cinnamaldehydes.
We considered binary acid catalysis, in which a BINOL-derived
chiral phosphoric acid and a metal Lewis acid are synergistical-
ly incorporated.[4] The binary acid catalytic systems are de-
signed to attain mutually enhanced acidity/electrophilicity and,
very importantly, binary acid catalysts are able to provide extra
binding sites for substrates (Figure 1).We previously demon-
strated the good compatibility of arylamines with either hard
metal Lewis acids or phosphoric acids.[2] As such, binary acid
catalysis appears to be an ideal complementary strategy to be
integrated with enamine catalysis (Figure 1).
We then attempted binary acid catalyst systems (Table 1, en-
tries 7–15) in the hope of obtaining both enantioselectivity
and enhanced activity of the ADA reaction. It was encouraging
that the combination of a chiral phosphoric acid and a metal
Lewis acid led to changes in both chemoselectivity and/or
enantioselectivity as compared to the solo acid catalyst sys-
tems. These results indicate a possible interaction between the
phosphoric acid and the metal Lewis acid. The combination of
Y(OTf)3 with chiral phosphoric acids 5a and 5c gave decreased
chemoselectivity relative to solo Y(OTf)3 (Table 1, entry 6). The
use of the more sterically hindered phosphoric acid 5b along-
side Y(OTf)3 was more promising, affording slightly better che-
moselectivity than solo Y(OTf)3 (Table 1, entry 8) and very good
enantioselectivity (89% ee). These results suggest that a binary
acid catalytic system had likely formed between Y(OTf)3 and
5b. The best chemoselectivity (ADAP/MP ratio=1:0.1) was ob-
tained when 5b was combined with Yb(OTf)3 (Table 1,
entry 10), albeit with decreased enantioselectivity relative to
using 5b only (45 vs. 88% ee; Table 1, entry 5). It should be
noted that other metal Lewis acids examined with 5b (Table 1,
Despite significant advances in the development of asym-
metric hetero-Diels–Alder reaction of carbonyl compounds in
recent years, there has been little development of inverted-
electron-demand aza-Diels–Alder reactions involving enamines
as the dienophiles.[5] Cinnamaldehyde and its derivatives repre-
sent a diverse class of materials that are easily accessible. Acti-
vation of this class of compounds in different reactions would
lead to new atom-economy and convenient organic transfor-
mations. We were interested in developing an aza-Diels–Alder
reaction of cinnamaldehydes with cyclic ketones and aryl
amines using the proposed trio catalytic system. In the pro-
posed aza-Diels–Alder reaction (Scheme 1), the arylamine re-
versibly forms an enamine intermediate with the cyclic ketone
serving as the amine catalyst. At the same time, the arylamine
also reversibly forms a 1-azadiene with the cinnamaldehyde.
Nucleophilic attack of the enamine (dienophile) on the 1-aza-
diene affords the desired aza-Diels–Alder (ADA) products.
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Table 1. Catalyst screening for three-component ADA reaction of 1a, 2a, and 3a.
Entry
MLA (5 mol%)
BA (5 mol%)
ADAP/MP
ADAP yield [%][a]
ee [%][b]
1
2
3
4
5[c]
6
7
8
–
–
–
–
–
TFA
benzoic acid
(+) CSA
5a
5b
–
1:5.3
1:2.4
1:7.4
1:3.4
1:2.6
1:0.45
1:0.77
1:0.39
1:0.95
1:0.1
–
7
11
5
19
24
61
53
62
44
73
trace
59
61
29
–
–
0
21
88
–
18
89
35
45
55
77
64
74
–
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Yb(OTf)3
Zn(OTf)2
La(OTf)3
In(OTf)3
Sm(OTf)3
YCl3
5a
5b
5c
5b
5b
5b
5b
5b
5b
9
10
11
12
13
14
15
1:0.20
1:0.17
1:0.51
–
trace
All reactions were conducted using 1a (0.1 mmol) and p-chloroaniline (0.13 mmol) with cyclohexanone (0.05 mL) in THF (0.5 mL) at room temperature.
[a] Yields were determined by 1H NMR spectroscopic analysis of crude reaction mixtures; [b] ee values were determined by chiral HPLC analysis; [c] the re-
action was conducted for 72 h. See the Supporting Information for experimental details. MLA=metal Lewis acid; BA=Brønsted acid; ADAP=product of
ADA reaction; MP=product of Mannich reaction.
Table 2. Solvent screening for the three-component ADA reaction of 1a,
2a, and 3a.
entries 12–14) were also able to give the ADA product as the
major product with moderate enantioselectivities (45–77% ee).
We next conducted solvent screening to further improve the
chemoselectivity and enantioselectivity of the ADA reaction
(Table 2). We decided to choose the Y(OTf)3/5b binary acid
system for solvent screening, as Y(OTf)3/5b displayed the high-
est enantioselectivity (Table 1, entry 8). Dichloromethane (DCM)
and 1,2-dichloroethane (DCE) turned out to be the best sol-
vents, both leading to excellent chemoselectivity (ADAP/MP=
1:0.04 in both cases) and enantioselectivity (98% ee in both
cases; Table 2, entries 9 and 10).
Entry Solvent
ADAP/MP ADAP yield [%][a] ee [%][b] Time [h]
1
2
3
4
5
6
7
8
9
toluene
CH3CN
Neat
MeOH
1,4-dioxane
H2O
CHCl3
acetone
DCM
1:0.94
1:0.02
1:2.6
38
70
15
67
44
50
87
78
81
84
92
35
80
93
43
99
69
88
98
98
48
48
48
48
48
48
24
24
24
24
1:0.3
1:0.91
1:0.68
1:0.04
1:0.06
1:0.04
1:0.04
Reaction scope
Having established the feasibility of this trio catalytic system,
we explored the scope of this three-component ADA reaction
using the optimized conditions (Table 2, entry 10). The scope
of the three substrates (arylamines, 2-methylcinnamaldehydes,
and cyclic ketones) is summarized in Table 3. Both electron-rich
p-methoxyaniline (4b), and more electron-deficient arylamines,
including aniline (4c), p-chloroaniline (4a), m-chloroaniline
(4e), and p-bromoaniline (4d), reacted with 1a and cyclohexa-
none to produce the ADA products in high enantioselectivities,
good yields, and excellent chemoselectivities (Table 3, 4a–e).
2-Methylcinnamaldehydes with both electron-donating and
electron-withdrawing aromatic substituents at the b-position
10
DCE
All reactions were conducted using 1a (0.1 mmol) and p-chloroaniline
(0.13 mmol) with cyclohexanone (0.05 mL) in dry solvent (0.5 mL) at room
temperature. [a] Yields were determined by 1H NMR spectroscopic analysis
of crude reaction mixtures; [b] ee values were determined by chiral HPLC
analysis.
reacted smoothly with cyclohexanone and p-chloroaniline to
afford the ADA product in high to excellent enantioselectivities
(94-99% ee) and good yields (59–84%; 4 f–k). It is notable that
2-methylcinnamaldehyde with an electron-withdrawing aro-
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98% ee) and 4q (70% yield,
95% ee) in a reaction time of
30 h in both cases.
Table 3. Substrate scope of three-component ADA reaction of substituted cinnamaldehydes, cyclic ketones,
and arylamine.
DHPs bearing a chiral quater-
nary carbon center (Scheme 2,
4r–t) were also realized. Using
b-substituted enal 1h, the ADA
reaction of cyclopentanone, 1h
and p-chloroaniline was achiev-
ed in moderate yield (58%) with
high enantioselectivity (96%;
4t). The ADA reactions of cyclo-
hexanone, 1h, and arylamines,
however, only produced ADA
products (4r and 4s) in low
yields (32% in both cases) with
moderate
enantioselectivities
(4r: 80% ee; 4s: 77% ee). The
lower stability of these DHPs ac-
counts partially for the lower
yields as a result of decomposi-
tion of the compounds on the
silica column.
The absolute configuration of
4k was established as 4R by X-
ray crystallography of compound
6.[7] Compound 6 was prepared
from 4k by reduction with NaB-
H(OAc)3 (Scheme 3).
Study of the trio catalytic
system
This three-component-catalyzed
three-component reaction is
complicated in nature. It is possi-
ble that this reaction involves
one or more transition states. To
further elucidate this novel
system, we performed a ratio
study of 5b and Y(OTf)3
(Table 4). The ratio study sug-
gested that the most active
binary acid catalyst was formed
in a 1:1 molar ratio, in good
agreement with the study of Luo
et al.[4b–d,i] ESI-MS spectra (anionic
mode) of a solution containing
5b and Y(OTf)3 revealed one
All reactions were conducted using 1 (0.2 mmol) and arylamine (0.26 mmol) with cyclic ketone (0.2 mL) in dry
DCE (2.0 mL) at room temperature. Yields refer to products isolated by chromatography and ee values were de-
termined by chiral HPLC analysis; [a] 1.0 mmol dihydrothiopyran-4-one was used in the reaction; [b] 0.05 mL
tetrahydro-4H-pyran-4-one was used in the reaction.
matic substituent (NO2) exhibited higher activity in the ADA re-
action (4k; t=16 h, 84% yield, 98% ee).
dominant peak at m/z 1287, corresponding to TRIP·Y(OTf)3.
The mass spectrometric analysis further confirmed that the
5b/Y(OTf)3 complex was formed in a 1:1 molar ratio.
To better understand the roles that both the phosphoric
acid and Y(OTf)3 play, we treated the catalytic systems with
triethylamine (Scheme 4). When TRIP was mixed with triethyl-
amine in the absence of Y(OTf)3, no reaction occurred, indicat-
ing that the acid functionality of phosphoric acid was fully
Cyclopentanone and heteroatom-containing cyclic ketones
were also active for the ADA reaction (4l–q). The ADA reac-
tions of cyclopentanone, however, resulted in slightly lower
yields (4l–o; 60–68% yield, 91–98% ee) than those of cyclohex-
anone. Dihydrothiopyran-4-one and tetrahydro-4H-pyran-4-one
underwent ADA reactions smoothly, giving 4p (73% yield,
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Table 4. Ratio study of binary acid catalyst 5b/Y(OTf)3.
Entry Y(OTf)3
[mol%]
5b
[mol%]
ADAP/
MP
ADAP yield
[%][a]
ee
[%][b]
Time
[h]
1
2
3
4
5
5
–
2.5
5
10
–
5
5
5
5
1:1.21 21
1:0.45 47
1:0.11 72
1:0.04 84
1:0.21 62
–
99
98
98
70
48
48
48
24
24
All reactions were conducted using 1a (0.1 mmol) and p-chloroaniline
(0.13 mmol) with cyclohexanone (0.05 mL) in dry DCE (0.5 mL) at room tem-
perature. [a] Yields were determined by 1H NMR spectroscopic analysis of
crude reaction mixtures; [b] ee values were determined by chiral HPLC anal-
ysis.
Scheme 2. ADA reactions of b-substituted enal 1h.
acid.[2] We believe that the arylamines in this trio catalyst
system play the same role. To further investigate this, we set
up parallel reactions using preformed 1-azadiene and cyclohex-
anone, and studied the effect on the reaction with different
amines (Table 5). In the presence of a primary (aniline) or a sec-
ondary arylamine (indoline), the two-component reactions pro-
ceeded the fastest (Table 5, entries 1 and 5). Without the addi-
tion of an amine (Table 5, entry 6), reaction still occurred. This
was an expected result, because 1-azadiene easily decomposed
back to the corresponding aldehyde and amine (Table 5,
entry 7), converting the reaction into a three-component reac-
tion. In the presence of a tertiary arylamine (Table 5, entry 2),
the reaction was much slower than those with primary and
secondary arylamines. It was also slower than the reaction
without addition of an arylamine. It is likely that the tertiary
amine interferes with the catalytic system by reversibly com-
bining with the metal Lewis acid and/or the Brønsted acid.
These data are similar to those obtained in our previous
work,[2] suggesting that enamine catalysis is taking place. We
also attempted reactions with an aliphatic primary amine (hex-
ylamine) and an aliphatic secondary amine (pyrrolidine). As ex-
pected, these reactions did not give any product, confirming
once again that aliphatic amines (hard bases) are not compati-
ble with hard metal Lewis acids
Scheme 3. Reduction of 4k and crystal structure of compound 6.
quenched by the base; however, when Y(OTf)3 was added into
the system, quantitative ADA product was obtained, albeit in
a much longer reaction time (60 h) than the reaction without
triethylamine (24 h, Table 2, entry 10), indicating that the pres-
ence of the phosphoric acid significantly facilitates the reac-
tion.
We demonstrated in our previous work that arylamines can
serve as effective amine catalysts in enamine catalysis by com-
bining with either a strong metal Lewis acid or a Brønsted
and strong Brønsted acids.
Based on these data and the
results in previous work involv-
ing binary acid catalysis[4b–i] and
BINOL-derived phosphoric acid,[8]
we proposed a possible transi-
tion state for this transformation
(Figure 2). In this model, YIII coor-
dinates to one of the oxygen
atoms of phosphoric acid; the
nitrogen atom of (E)-1-azadiene
binds to YIII and thus is activat-
ed; the hydrogen of the enam-
Scheme 4. Three-component ADA reactions catalyzed by trio catalytic systems with triethylamine.
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carbon center at C4 were also obtained with moderate to high
enantioselectivities and moderate yields.
Table 5. Effect of amine on two-component ADA reaction.
The three-component catalytic system also allows combina-
tional flexibility of arylamine, metal Lewis acid, and chiral phos-
phoric acid, offering easily tunable catalytic activity. The trio
catalysis introduced herein provides a new tool in asymmetric
catalysis, in particular in the growing field of combining amine
organocatalysts with transition metal catalysts. We expect
broad applications of this new concept in the development of
new asymmetric organic transformations in the near future.
Entry
Amine (mol%)
aniline (130)
Time [h]
Conversion [%][a]
1
2
3
<18
19
20
100
69
0
N,N-dimethylaniline (130)
pyrrolidine (130)
4
hexylamine (130)
20
0
5
6
7[b]
indoline (130)
19
21
24
91
82
17
–
–
Experimental Section
General procedure for asymmetric three-component ADA reac-
tion: To a Schlenk tube charged with argon was added Y(OTf)3
(5.36 mg, 0.01 mmol, 5 mol%) and 5b (0.01 mmol, 5 mol%). Dis-
tilled anhydrous DCE (2 mL) was added to the mixture. After stir-
ring at room temperature for 2 h, aldehyde 1 (0.2 mmol, 1.0 equiv),
arylamine (0.26 mmol, 1.3 equiv), and cyclic ketone (0.2 mL,
1.93 mmol) were added under argon protection. The resulting solu-
tion was stirred at room temperature until the reaction was com-
pleted (monitored by TLC). The reaction mixture was filtered
through an aluminum oxide plug, and the filtrate was concentrat-
ed. The residue was purified by column chromatography on alumi-
num oxide (eluent=8:1 hexane/ethyl acetate) to give the pure
products 4.
All reactions were conducted using 7c (0.2 mmol) with cyclohexanone
(0.2 mL) in dry DCE (2 mL) at room temperature. [a] Conversions were de-
termined by 1H NMR spectroscopic analysis of crude reaction mixtures;
[b] no cyclohexanone was included in this reaction; the conversion is the
conversion of 7c to the corresponding aldehyde and arylamine.
Acknowledgements
Figure 2. Proposed transition state for ADA reaction.
This work was supported by the National Science Foundation
(Career award CHE-1056420 to H.W. and CHE-0722547 to K.W.).
gen bond with another oxygen of the phosphoric acid and ap-
proaches the 1-azadiene via an endo-selective mode; the bi-
naphthyl skeleton, possessing axial chirality, shields the Re face
of the 1-azadiene and the enamine attacks from the Si face.
The proton of the phosphoric acid is likely to participate
through hydrogen bonding to stabilize the enamine intermedi-
ate and transition state. This proposed transition state explains
well the observed phenomena. The absolute configuration of
the chiral Diels–Alder product derived from this model also
matches well with the X-ray crystal structure.
Keywords: asymmetric catalysis
heterocycles · multicomponent reactions · synthetic methods
· cooperative catalysis ·
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It is very challenging to develop multiple catalyst-mediated
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novel trio catalysis involving chiral phosphoric acid, hard metal
Lewis acid, and arylamine. This three-component catalytic
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first time and was used to effect a new asymmetric three-com-
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Received: December 19, 2014
Revised: March 17, 2015
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FULL PAPER
Once, twice, thrice a catalyst: A three-
component aza-Diels–Alder reaction of
substituted cinnamaldehydes, cyclic ke-
tones, and arylamines was developed
with high chemo- and enantioselectivi-
ties (up to 99% ee), by using trio cataly-
sis involving enamine, metal Lewis acid,
and Brønsted acid catalysts.
&
Asymmetric Synthesis
Y. Deng, S. Kumar, K. Wheeler, H. Wang*
&& – &&
Trio Catalysis Merging Enamine,
Brønsted Acid, and Metal Lewis Acid
Catalysis: Asymmetric Three-
Component Aza-Diels–Alder Reaction
of Substituted Cinnamaldehydes,
Cyclic Ketones, and Arylamines
&
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Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
8
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!