Asymmetric Catalytic Aza-Diels–Alder/Ring-Closing Cascade Reaction Forming Bicyclic Azaheterocycles by Trienamine Catalysis

Article abstract of DOI:10.1002/chem.201604310

An asymmetric catalytic aza-Diels–Alder/ring-closing cascade reaction between acylhydrazones and in situ formed trienamines is presented. The reaction proceeds through a formal aza-Diels–Alder cycloaddition, followed by a ring-closing reaction forming the hemiaminal ring leading to chiral bicyclic azaheterocycles in moderate to good yield (up to 71 %), good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). Furthermore, transformations are presented to show the potential application of the formed product.

Full text of DOI:10.1002/chem.201604310

A Journal of
Accepted Article
Title: Asymmetric Catalytic Aza-Diels-Alder/Ring-Closing Cascade
Reaction Forming Bicyclic Azaheterocycles via Trienamine
Catalysis
Authors: Karl Anker Jørgensen, Yang Li, Casper Barløse, Julie
Jørgensen, and Bjørn Dreiø Carlsen
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To be cited as: Chem. Eur. J. 10.1002/chem.201604310
Link to VoR: http://dx.doi.org/10.1002/chem.201604310
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COMMUNICATION
Asymmetric Catalytic Aza-Diels-Alder/Ring-Closing Cascade Re-
action Forming Bicyclic Azaheterocycles via Trienamine Cataly-
sis
Yang Li,[a] Casper Barløse,[a] Julie Jørgensen,[a] Bjørn Dreiø Carlsen,[a] and Karl Anker Jørgensen*[a]
Abstract: An asymmetric catalytic aza-Diels-Alder/ring-closing
cascade reaction between acylhydrazones and in-situ formed tri-
enamines is presented. The reaction proceeds through a formal aza-
Diels-Alder cycloaddition, followed by a ring-closing reaction forming
the hemiaminal ring leading to chiral bicyclic azaheterocycles in
moderate to good yield (up to 71%), good enantio- (up to 92% ee)
and diastereoselectivity (up to >20:1 dr). Furthermore, transfor-
mations are presented to show the potential application of the
formed product.
product and adding more molecular complexity to the product.
Nitrogen-containing heterocycles exist in many biologically ac-
tive compounds and natural products.[5] The synthesis and study
of these compounds have continuously been a challenging and
hot topic.[6] The structure of the bicyclic azaheterocycle generat-
ed from the present reaction (Scheme 1, bottom) is quite unique
and interesting.[7] It has potential as an isosteric skeleton of a
natural product (+)-lentiginosine,[8] and the drug Perindopril.[9]
Trienamine catalysis has been widely used as a strategy to
provide chiral cyclic compounds since this catalytic concept was
first established in 2011.[1] Trienamines formed by condensation
of an aminocatalyst and 2,4-dienals can react with a variety of
dienophiles through a Diels-Alder reaction.[2] In contrast to the
development of Diels-Alder reactions based on the trienamine
concept, the trienamine catalyzed hetero-Diels-Alder reactions
have been much less investigated. According to the best of our
knowledge, two examples known are outlined in Scheme 1 (an
example of inverse-electron-demand aza-Diels-Alder reaction of
2,5-dienones has also been developed).[3] The first one, is based
on the application of dithioester dienophiles leading to a thio-
Diels-Alder cycloaddition to generate useful chiral sulfur-
containing cycloadducts.[3a] The other example is from the Chen
group, who demonstrated that nitrogen-containing tricycles could
be constructed through an aza-Diels-Alder cycloaddition apply-
ing cyclic imines as the dienophile.[3b] It should also be men-
tioned that in the latter work aldimines and ketimines were also
investigated, but due to their low reactivity or instability, no good
reactivity was observed. Thus, it seems to be a challenge to
apply linear imines for the [4+2] cycloaddition with 2,4-dienals
via trienamine catalysis and we envisioned that applying acylhy-
drazones as dienophiles might be the solution to this challenge
(Scheme 1).
In the following, we will present a novel enantioselective het-
ero-Diels-Alder reaction of acylhydrazones with trienamines for
the formation of azaheterocycles. The reaction proceeds by a
formal aza-Diels-Alder cycloaddition, followed by a ring-closing
reaction forming the hemiaminal ring. Hydrazones have been
applied to construct azaheterocycles through cycloadditions and
it has been shown that the reaction takes place at the nitrogen-
carbon double bond of the hydrazone affording tetrahydro-
pyridine or δ-lactam rings.[4] In the present work, the second
ring-closing step is assumed to generates a more stable end-
Scheme 1. Trienamine catalysed hetero-Diels-Alder reactions.
The development of the reaction conditions started out with
the reaction of the 2,4-dienal 1a and hydrazone 2a in the pres-
ence of catalyst 3a in CHCl3 at 40 oC. The reaction only reached
66% conversion after 20 h and 4a was formed with an enanti-
oselectivity of 63% ee (Table 1, entry 1). By adding 0.5 eq. of
DABCO, the reaction proceeded faster with almost full conver-
sion, even though slightly lower enantioselectivity was obtained
(Table 1, entry 2). This might relevant to the base properties of
DABCO that it accelerates the condensation between the cata-
lyst and aldehyde by deprotonating the catalyst, and furnishes
the reactive trienamine by deprotonating the doubly unsaturated
iminium ion (from the condensation between the catalyst and
aldehyde) at -position. Moreover, it might also accelerate the
ring-closing step by deprotonating the nitrogen involved in the
second step.[10] Other solvents were tested with DABCO as an
additive, as it was shown that different solvents had an impact
on the reaction time and the enantioselectivity (Table 1, entries
3-6). Dichloromethane gave a fast reaction, but low enantiose-
lectivity (Table 1, entry 3). In tetrahydrofuran and toluene, the
reaction took longer time and we were pleased to find that high-
er enantioselectivities were obtained. In both solvents, the reac-
[a]
Y. Li, C. Barløse, J. Jørgensen, B. D. Carlsen, Prof. Dr. K. A.
Jørgensen
Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201604310
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tion reacted to full conversion in 48 h and gave 64% ee and 70%
ee, respectively (Table 1, entries 4,5). The reaction provided
even better enantioselectivity in mesitylene, but a much slower
reaction time was observed (Table 1, entry 6). Considering the
reaction efficiency, we focused on using toluene as the solvent.
Different catalysts were also tested (Table 1, entry 7-9). When
more bulky silyl protected diphenyl prolinol catalyst 3b and 3c
were employed, the reactions proceeded slower, and no better
enantioselectivities were obtained (Table 1, entry 7,8). Less
bulky catalyst 3d did not give any better result regarding to both
the reaction time and enantioselectivity (Table 1, entry 9). Fur-
thermore, various reaction conditions and additives were inves-
tigated, but no improvement in both reactivity and selectivity
were observed. Acidic additives slowed down the reaction at
mized reaction condition, product 4a was formed with better
enantioseletivity (72% ee), good diastereoselectivity and yield
(Table 1, entry 5; Table 2, 4a). 2,4-Dienal 1b gave similar yield
and higher enantioselectivity (92% ee) as seen in Table 2, 4b.
This gave us a hint that dienals with aromatic substitution at the
R2-position might result in better enantioselectivity, so several
aromatic 2,4-dienals were synthesized and tested. Phenyl and
para-halophenyl substituted 2,4-dienals gave quite consistent
enantioselectivities (>90% ee) and moderate yields of 4c-e.
Finally, a trimethyl-substituted 2,4-dienal was demonstrated to
react smoothly and the obtained yield and enantioselectivity of
4f is higher compared to 4a.[11]
Table 2. Scope of the trienamine catalysed hetero-Diels-Alder reactions.[a]
o
room temperature. Increasing the temperature to 40 C, acidic
additives or Lewis acids, led to a decomposition of the hydra-
zones. We then turned our attention to test other 2,3-dienals as
substrates. When applying 2,4-dienal 1b, a significantly higher
enantioselectivity was obtained. The reaction took 72 h and
gave product 4b in 91% ee (Table 1, entry 10). Lowering the
amount of DABCO to 20 mol% did not impact the results (Table
1, entry 11). These reaction conditions were used as standard
reaction condition for the scope of the reaction. It should be
noted that it is difficult to observe the diastereoisomer peaks
from the crude NMR, so we focused our attention on improving
the enantioselectivity.
Table 1. Screening and optimization of reaction conditions for the cascade
reaction.[a]
DABCO
(eq.)
Conv.
(%)[b]
ee
Entry
1
3
Solvent
T (h)
(%)[c]
1
2
a
a
a
a
a
a
a
a
a
b
b
a
a
a
a
a
a
b
c
d
a
a
no
CHCl3
CHCl3
20
20
66
63
60
50
64
70
80
55
47
46
91
91
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
>95
>95
>95
>95
>95
>95
90
3
CH2Cl2
THF
24
4
48
5
toluene
mesitylene
toluene
toluene
toluene
toluene
toluene
48
6
110
76
7
[a] All reactions were performed using 1 (0.2 mmol), 2 (0.1 mmol), 3a (0.02
mmol), DABCO (0.02 mmol) in 0.5 mL toluene. The reported yields are for
both diastereoisomers. The ee (major diastereoisomer) and dr values were
determined by chiral phase UPC2. [b] Additive DABCO (0.1 mmol) and H2O
(2.0 mmol) were used.
8
110
72
9
65
10
11
72
>95
>95
72
Next, different acylhydrazones 2 were evaluated. It was
found that the acylhydrazones with bromo or no substituent at
the R4-position were tolerated (4g-k). Combining δ-bromophenyl
dienal (1b) with ethyl and iso-propyl glyoxylate aldehyde derived
hydrazones, the products 4g and 4h were obtained in good yield
and enantioselectivity, 88% ee and 87% ee, respectively. When
the benzyl glyoxylate aldehyde derived hydrazone was reacted
with aldehyde 1b, a messy reaction was observed. Applying the
standard reaction system to obtain pure product 4i proved to be
difficult. In the early optimizing process, we observed that by
[a] All reactions were performed using 1a/1b (0.1 mmol), 2a (0.05 mmol), 3
(0.01 mmol), 0.25 mL solvent. [b] Conversion of limiting reagent was measured
by 1H NMR analysis of the crude reaction mixture. [c] The ee value was de-
termined by chiral phase UPC2.
With optimized reaction conditions in hand, a variety of 2,4-
dienals 1 and acylhydrazones 2 were tested to study the scope
of the reaction (Table 2). In general, good diastereomeric ratios
were obtained after purification. When the screening substrates
2,4-dienal 1a and acylhydrazone 2a were applied to the opti-
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adding water and more DABCO as additives could give a more
pure product, even though the selectivities dropped. In this case,
we applied the latter reaction conditions to this entry furnishing
the corresponding product 4i in 62% yield 6:1 dr and 87% ee.
The phenylglyoxal derived hydrazone reacted with aldehyde 1b
sluggishly; however, by applying a trimethyl substituted 2,4-
dienal, product 4j was obtained in good yield and enantioselec-
tivity as one diastereoisomer, while reaction of the dimethyl
substituted 2,4-dienal gave 4k in lower yield and enantioselectiv-
ity.
Having established the scope and better understanding of
this reaction, a series of transformations were carried out
(Scheme 3). A reduction was performed to 4a in one-pot fashion
giving product 5 in 53% overall yield. The obtained enantioselec-
tivity is consistent, while the diastereomeric ratio increased
compared to 4a. This indicates that the diastereoselectivity is
mainly generated through the ring-closing step.[15] Samarium(II)
iodide was applied to cleave the nitrogen-nitrogen bond. The
ring-opened product 6 was obtained in good yield and compara-
ble stereoselectivity along with the transesterification and the
reduction of nitro group. The obtained tetrahydropyridine motif is
similar to palustrine family,[16] such as (-)-methyl palustramate[17]
and (+)-cannabisativeine,[18] and this transformation provides a
synthetic strategy towards potential bioactive alkaloids candi-
dates of these natural products.
The absolute configuration of the bicyclic azaheterocycle 4k
was established by X-ray crystallography (Figure 1).[12] The
remaining configurations were assigned by analogy. It should be
noted that the nitrogen atoms are stereocenteres in the crystal
1
state. In the H NMR spectra of the products (CDCl3), broaden-
ing and unclear peaks were observed, indicating a low barrier of
inversion for the nitrogen-nitrogen bond.[13] This was also the
main reason for the difficulties to determine the diastereomeric
ratio directly by NMR spectroscopy.[14]
Figure 1. X-Ray structure of 4k.
The mechanism was expected to proceed by pathway (1)
in Scheme 2 which includes the lowest-energy trienamine inter-
mediate.[1] However, the product obtained by this pathway do
not provide the right stereochemistry. In order to form the correct
stereocenter at the C1-position, two possible trienamine inter-
mediate conformations are given in pathway (2), in which the
remote diene will react at the other face, relative to the face
reacting in pathway (1). The final step is the formation of the
hemiaminal.
Scheme 3. Synthetic transformations of 4a.
In summary, a novel aza-Diels-Alder/ring-closing cascade
reaction forming chiral bicyclic azaheterocycles via trienamine
catalysis is reported. Acylhydrazone was applied as dienophile
to undergo a cycloaddition with in situ formed trienamine from an
organocatalyst and 2,4-dienals, followed by a hemiaminal ring-
closing reaction, leading to the formation of bicyclic azahetero-
cycles in moderate to good yields (up to 71%) and stereoselec-
tivities (up to 92% ee and up to >20:1 dr). The formed bicyclic
azaheterocycles and their transformed nitrogen-containing prod-
uct, can be considered as isosteres or alkaloids of bioactive
natural compounds, and might be potentially useful. Finally, the
mechanism of the reaction has been discussed and it is postu-
lated that the trienamine intermediate reacts with another geom-
etry of the diene-part compared to what is usually observed.
Acknowledgements
This work was financially supported by Aarhus University and
the Carlsberg Foundation. Y.L. acknowledges the Chinese
Scholarship Council for a Ph.d. fellowship. Magnus E. Jensen is
acknowledged for performing X-ray analysis.
Scheme 2. Proposed of the reaction mechanism in which (a) gives the wrong
stereochemistry and (b) leads to the observed stereochemistry,
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Keywords: asymmetric catalysis • cycloaddition • heterocycles •
organocatalysis • synthetic methods
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[12] See Supporting Information for details about X-ray analysis (CCDC:
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Entry for the Table of Contents (Please choose one layout)
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Yang Li, Casper Barløse, Julie Jørgen-
sen, Bjørn Dreiø Carlsen, and Karl An-
ker Jørgensen*
Page No. – Page No.
Asymmetric Catalytic Aza-Diels-
Alder/Ring-Closing Cascade Reaction
Forming Bicyclic Azaheterocycles via
Trienamine Catalysis
A novel asymmetric catalytic aza-Diels-Alder/ring-closing cascade reaction between
acylhydrazones and in situ formed trienamines is presented. The reaction proceeds
through a formal aza-Diels-Alder cycloaddition, followed by a ring-closing reaction
forming the hemiaminal ring providing chiral bicyclic azaheterocycles.
This article is protected by copyright. All rights reserved.