Asymmetric formation of bridged benzoxazocines through an organocatalytic multicomponent dienamine-mediated one-pot cascade

Article abstract of DOI:10.1021/ol501882x

An organocatalytic one-pot cascade leading to the stereoselective formation of novel bridged benzoxazocines is presented. The developed methodology is based on the first example of a γ-selective-Mannich-initiated cascade reaction and allows for direct annulation of the bridged benzoxazocines by incorporation of various α,β-unsaturated aldehydes, electron-rich anilines, and electron-deficient salicylaldehydes. The synthetic applicability of the products is demonstrated by relevant transformations.

Full text of DOI:10.1021/ol501882x

Letter
pubs.acs.org/OrgLett
Asymmetric Formation of Bridged Benzoxazocines through an
Organocatalytic Multicomponent Dienamine-Mediated One-Pot
Cascade
Lars Krogager Ransborg,† Mette Overgaard,† Joanna Hejmanowska,‡ Sebastian Barfusser,†
̈
Karl Anker Jørgensen,*,† and Łukasz Albrecht*,‡
†Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
‡Institute of Organic Chemistry, Łod
́
z University of Technology, Zeromskiego 116, 90-924 Łod
́
z, Poland
́
̇
́
S
* Supporting Information
ABSTRACT: An organocatalytic one-pot cascade leading to the stereo-
selective formation of novel bridged benzoxazocines is presented. The
developed methodology is based on the first example of a γ-selective-
Mannich-initiated cascade reaction and allows for direct annulation of the
bridged benzoxazocines by incorporation of various α,β-unsaturated
aldehydes, electron-rich anilines, and electron-deficient salicylaldehydes.
The synthetic applicability of the products is demonstrated by relevant
transformations.
Scheme 1. Different Cascade Types in Dienamine-Mediated
Catalysis
esigning new reaction profiles dedicated toward the
Dsynthesis of privileged structural scaffolds constitutes an
important challenge in modern organic chemistry.1 In
particular, cascade reactivities, where more than one bond is
being formed in a reaction sequence without isolation of the
corresponding intermediates, have received increased attention
in the chemical community.2 Among such strategies,
enantioselective approaches employing chiral catalysts occupy
a prominent position.2
Recently, aminocatalysis, where simple primary or secondary
amines are used as chiral inductors and reaction rate enhancers,
emerged as a highly reliable tool in the field.3 The different
reaction profiles offered by aminocatalytic activation modes
make them particularly well-suited for applications in cascade
reactions. In particular, dienamine intermediates, offering the
possibility to introduce stereogenic centers up to five bonds
away from the chirality of the catalyst, have been employed in
various cascade reactions affording access to carbo- and
heterocyclic frameworks.4 Various dienamine-mediated remote
functionalization cascade reactivities are summarized in Scheme
1. Most of these reactions are induced by a γ-selective Michael
addition followed by cyclization in either the ipso-position
(cascade type I)5 or the β-position (cascade type II).6
Surprisingly, examples of double cyclizations occurring in
both β- and ipso-positions are much less common (cascade type
III).7 Furthermore, dienamine-mediated reactions initiated by
reactions other than Michael addition are rare and, to the best
of our knowledge, no γ-selective-Mannich-initiated cascade
reactivity has been reported.
Figure 1. Bridged benzoxazocine-privileged core structure.8,9
Interestingly, synthetic methods toward benzo[1,5]oxazocines
are rare and no enantioselective method for their preparation
exists in the literature.10
The tetrahydrobenzo[1,5]oxazocine framework constitutes
an important structural motif present in biologically active
molecules (Figure 1). Their inhibitory activity against hepatitis
C,8 as well as CNS and analgesic activity,9 is well recognized.
Received: June 30, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Herein, we report a novel multicomponent one-pot cascade
approach for the synthesis of enantiomerically enriched
methylene bridged benzo[1,5]oxazocines. It utilizes initial
condensation of the corresponding aniline with salicylaldehyde
followed by a dienamine-mediated γ-selective Mannich-initiated
cycloaddition. Subsequent cyclization via oxy-Michael addition
furnishes a benzo[1,5]oxazocine framework in an enantiose-
lective manner (Figure 2).
cascade, thereby negatively affecting the overall yield (entry 2).
In contrast, an electron-poor system allowed for a rapid
reaction, unfortunately in an uncatalyzed fashion (entry 3).
Gratifyingly, the improved diastereoselectivity observed could
be attributed to steric properties, as the application of a
disubstituted electron-rich aniline afforded the product in a
similar diastereomeric ratio and improved enantiomeric excess
(entry 4).
With the model substrate established, the optimization
studies were directed toward the reaction solvent (Table 1,
entries 5−8). The results obtained were not conclusive,
although the yield of the reaction became unsatisfying for
very polar solvents (entry 7). However, preliminary inves-
tigations had revealed that the use of toluene resulted in better
diastereocontrol for less optimal substrates, and it was therefore
chosen as the best suited solvent.
The application of additives in the reaction showed a
remarkable effect (Table 1, entries 8−11). Addition of ortho-
nitrobenzoic acid (o-NBA) resulted in complete product
decomposition (entry 9), while use of sodium acetate allowed
for a cleaner reaction, thereby improving the obtained yield
(entry 10). Interestingly, while other acetates afforded similar
results, the application of cesium acetate dramatically slowed
down the reaction (entry 11).
The use of other secondary aminocatalysts under the
optimized conditions did not improve the reaction outcome
(Table 1, entries 12, 13). Finally, cooling of the reaction
mixture resulted in a slower reaction with a lower yield and
only marginally improved enantioselectivity, and the reaction at
room temperature was therefore found to be preferable.
With the optimized reaction conditions in hand, the scope of
the reaction with regard to the aldehyde substrate was
investigated (Table 2).
Figure 2. Strategy for the multicomponent-one-pot cascade formation
of bridged benzoxazocines from simple starting materials.
Investigations were initiated using E-2-pentenal 4a and 3-
nitrosalicylaldehyde 1a as model substrates. Preliminary results
showed that imine formation, with an aniline 2a, and the
subsequent organocatalytic step could be performed in a one-
pot fashion, providing the envisioned bridged benzoxazocine 5
in reasonable yield, but with modest diastereoselectivity (Table
1, entry 1).
To investigate the substrate dependence, a range of anilines
was tested (Table 1, entries 2−4). Introduction of an electron-
donating para-methoxy substituent increased the rate of the
initial condensation, but slowed down the second step of the
Table 1. Optimization of Reaction Conditions for One-Pot
a
Formation of Asymmetric Bridged Benzoxazocines 5
Table 2. Aldehyde Scope for the Organocatalytic One-Pot
a
Formation of Optically Active Bridged Benzoxazocines 5
entry
R
product
yield [%]
dr
ee [%]
entry Ar (2)
solvent
additive
yield [%]
dr
6:1
ee [%]
1
2
3
4
5
6
7
Me
H
5a
5b
5c
5d
5e
5f
77
44
44
41
42
42
22
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
87
73
85
76
80
76
88
1
2a
2b
2c
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
toluene
toluene
toluene
toluene
Et2O
−
−
−
−
−
−
−
86
59
73
50
42
86
28
59
nd
77
16
78
73
63
81
82
0
2
5:1
Et
3
10:1
Pen
4
>20:1
>20:1
>20:1
>20:1
>20:1
nd
85
84
81
82
86
nd
87
82
80
81
89
E-Pent-2-enyl
CH2Ph
5
6
dioxane
CH3CN
CHCl3
toluene
toluene
toluene
toluene
toluene
toluene
OBn
5g
a
7
Reactions performed on 0.1 mmol scale (see Supporting Information
for detailed reaction conditions).
8
NaOAc
o-NBA
NaOAc
CsOAc
NaOAc
NaOAc
NaOAc
9
10
11
12
13
14
>20:1
>20:1
>20:1
>20:1
>20:1
Application of crotonaldehyde 4b afforded the product 5b,
with no substituent on the methylene bridge, in an acceptable
yield and enantiomeric excess (Table 2, entry 2). Notably, this
product can only be formed as one diastereomer, as the bridge
carbon atom is not a stereogenic center and a cis-relationship of
the two bridgehead hydrogens is imposed in the cyclization
step. The introduction of alkyl chains resulted in a decrease in
both yield and enantioselectivity, although the diastereocontrol
b
c
d
a
Reactions performed on 0.1 mmol scale (see Supporting Information
b
for detailed reaction conditions). Using a diphenyl catalyst (Ar1 =
Ph). Using TBS-protected catalyst. Reaction at 5 °C.
c
d
B
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Organic Letters
Letter
was still excellent (entries 3, 4). A similar result was observed
with the introduction of alkyl substituents containing functional
groups. Nonetheless, a double bond as well as a phenyl group
was successfully introduced, with no further negative effect on
the reaction outcome (entries 5, 6). Finally, a benzyl protected
alcohol was shown to be compatible with the reaction
conditions, allowing for the formation of product 5g, carrying
the alcohol directly on the methylene bridge, with excellent
stereoselectivity, albeit with an unsatisfying yield (entry 7).
Having established the scope of α,β-unsaturated aldehydes,
investigations on the use of other electron-deficient salicylalde-
hydes 1 and anilines 2 were initiated (Scheme 2).
polycyclic substituents allows for products 5l and 5m to be
formed with high diastereo- and enantioselectivity. Nonethe-
less, inclusion of an anthracyl system in 5m comes at the cost of
a low yield, which can possibly be attributed to the reduced
solubility of the in situ formed imine intermediate.
Interestingly, the incorporation of an ethynyl group results in
clean and near-quantitative formation of product 5n, with
similar stereoselectivity to other para-substituted systems. The
same trend was observed when a nitrile group was introduced
at the 3-position of the salicylaldehyde (compare products 5o
and 5p). The clean reactivity observed for application of para-
ethynyl aniline was the key to successfully obtaining ester-
substituted product 5q and 5-cyano substituted product 5r,
which were both isolated with a good yield and stereocontrol.
The incorporation of a trifluoromethyl group proved
challenging, and product 5s was obtained in a low yield with
a diastereomeric ratio lower than previously observed with 3,5-
dimethoxy aniline 2d, nonetheless with essentially preserved
enantioselectivity. A comparable diastereomeric ratio was
observed for 5-nitro substituted product 5t, which was isolated
in high yield and moderate enantiomeric excess. Double
substitution of the salicylaldehyde was successfully demon-
strated, allowing for the formation of products 5u and 5v with
good results. Finally, a bromine substituted naphthyl system 5w
was synthesized with a high yield and stereoselectivity.
To demonstrate the synthetic applicability of the formed
products 5, investigations on selective transformations were
initiated. The compatibility with palladium coupling reactions
was verified through a Sonogashira coupling of 5n to afford the
extensively conjugated product 7 in high yield, and with a
preserved diastereomeric ratio and enantioenrichment (Scheme
3).
a
Scheme 2. Salicylaldehyde and Aniline Scope
Scheme 3. Application of Bridged Benzoxazocine Product 5n
in a Sonogashira Coupling
Reduction of the enamine moiety was attempted under one-
pot conditions, applying sodium triacetoxyborohydride as the
reductant. The three-step one-pot cascade proceeded smoothly,
affording the desired product 8 in good yield and with excellent
stereoselectivity (Scheme 4).
a
Reactions performed on 0.1 mmol scale (see Supporting Information
for detailed reaction conditions). Enantiomeric excess reported for
major diastereomer.
Scheme 4. One-Pot Formation of Saturated Benzoxazocine 8
The use of unsubstituted aniline 2a afforded product 5h in
good yield and stereoselectivity. Similar results were obtained
through the application of less bulky para- and ortho-methoxy
anilines, yielding products 5i and 5j, where the former carries a
PMP-protecting group on the enamine nitrogen atom.
Application of ortho-thiomethyl aniline for the formation of
product 5k afforded comparable results to the oxygen
counterpart, albeit with increased yield. The introduction of
C
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Organic Letters
Letter
Based on the absolute configuration assignments established
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ASSOCIATED CONTENT
* Supporting Information
■
S
(9) Raj, K. R.; Harry, G. P. Beecham Group LTD, DE1908324-(A1),
19690911.
Detailed experimental procedures and compound character-
izations. This material is available free of charge via the Internet
at http://pubs.acs.org.
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(11) See Supporting Information for details. CCDC 1009470
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kaj@chem.au.dk.
*E-mail: lukasz.albrecht@p.lodz.pl.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was made possible by financial support from Aarhus
University, FNU and the Carlsberg Foundation. This project
was realized within the Homing Plus Programme (cofinanced
from European Union, Regional Development Fund) and
Kolumb Supporting Grant, both from the Foundation for
Polish Science. Thanks are expressed to Magnus E. Jensen and
Dr. Jacob Overgaard (Department of Chemistry, Aarhus
University) for performing X-ray analysis.
D
dx.doi.org/10.1021/ol501882x | Org. Lett. XXXX, XXX, XXX−XXX