Rawal's catalyst as an effective stimulant for the highly asymmetric Michael addition of β-keto esters to functionally rich nitro-olefins

Article abstract of DOI:10.1039/c5ob02178b

A general approach to asymmetric synthesis of highly substituted dihydroquinolines was achieved through neighboring ortho-amino group engaged sequential Michael/amination/dehydration reactions on (E)-2-(2-nitrovinyl)anilines with cyclic and acyclic β-keto esters in the presence of a catalytic amount of Rawal's quinidine-NH-benzyl squaramide followed by TFA.

Full text of DOI:10.1039/c5ob02178b

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Rawal's catalyst as an effective stimulant for the highly asymmetric
Michael addition of β-keto esters to functionally rich nitro-olefins†
A. Suresh Kumar, T. Prabhakar Reddy, R. Madhavachary, and Dhevalapally B. Ramachary*
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5
A general approach to asymmetric synthesis of highly substituted
to develop an efficient asymmetric protocol due to their many
9
dihydroquinolines was achieved through neighboring ortho- 50 applications.
amino group engaged sequential Michael/amination/dehydration
reactions on (E)-2-(2-nitrovinyl)anilines with cyclic and acyclic β-
keto esters in the presence of a catalytic amount of Rawal’s
quinidine-NH-benzyl squaramide followed by TFA.
1
0
Recently organocatalytic domino/cascade reactions have emerged
as powerful strategy for the complex molecular synthesis by
employing simple and readily available precursors in a simple
1
2
2
3
3
4
4
5
0
5
0
5
0
5
1
operational manner. In this scenario, one of the important protocol
for the C–C bond formation is asymmetric Michael reaction, which
2
has been extensively used in cascade reactions. Wherein, the
Michael reaction of β-keto esters to nitro-olefins is a fully atom-
economic transformation with prominent synthetic potential as the
3
resulting functional groups will be in high demand. To control the
reactivity and selectivity of this Michael reaction, in 2003
Takemoto and co-workers identified the bifunctional thiourea–
4
Figure 1 Biologically active molecules containing 1,4-dihydroquinoline.
tertiary amine as an efficient catalyst. A milestone report by
Rawal’s group showed that replacement of the thiourea function by
a squaramide catalyst as the hydrogen-bond donor allows a
dramatic decrease in the catalyst loading and also increase in the
Recently, we and Kim group independently reported the
asymmetric synthesis of 2,3,4-trisubstituted 1,4-dihydroquinolines
by the cascade Michael/amination/dehydration reaction of
aldehydes or ketones with (E)-2-(2-nitrovinyl)anilines through
5,6
reaction rate/selectivity. The pioneering work of Rawal’s and
other groups from the past few years has shown the importance of
10
5
6
6
7
7
5
0
5
0
5
enamine-catalysis with excellent selectivity. However, there is no
5,6
chiral hydrogen-bonding catalysis through squaramide catalyst.
suitable asymmetric method to synthesise highly functionalized
,4-dihydroquinolines in optically pure form from (E)-2-(2-
nitrovinyl)anilines with β-keto esters through enolate-catalysis. In
continuation of our research interest in this area, we envisaged
functionally rich (E)-2-(2-nitrovinyl)anilines and β-keto esters as
Nowadays, bio-mimetic one-pot synthesis of the highly
functionalized chiral Michael adducts for synthetic applications are
in high demand. Recently, we and others have reported the natural
products inspired dihydrocoumarins synthesis through a Michael
addition of 1,3-dicarbonyls to 2-(2-nitrovinyl)phenol and
1
11
the
potential
substrates
for
the
newly
designed
7
subsequent intramolecular hemiacetalization. In this reaction, the
Michael/amination/dehydration reaction sequence (Scheme 1).
To find the best catalytic conditions, we screened a number of
emerging hydrogen-bond-donating organocatalysts for the reaction
of N-Boc-(E)-2-(2-nitrovinyl)aniline 1a with 1.3 equiv. of ethyl 2-
oxocyclopentanecarboxylate 2a (Table 1). Reaction of 1a with 1.3
equiv. of 2a under 10 mol% of quinine-NH-thiourea 3a-catalysis in
toluene at 25 °C for 4 h furnished the 4aa in 70% yield with 58%
ee and >99% de (Table 1, entry 1). The same reaction in DCM for
4 h furnished the product 4aa with ee increased to 75% with 68%
yield and >99% de (Table 1, entry 2). Reaction under the
hydroquinine-NH-thiourea 3b-catalysis furnished 4aa with
increased yield (82%) and no change in ee and de (Table 1, entry
ortho-hydroxyl group participates as neighboring group both during
and after the reaction and makes this sequence as a powerful tool
among the existing annulation methods. With this inspiration,
herein we describe an unusual efficient neighboring ortho-amino
group engaged asymmetric organocatalytic sequential one-pot
reaction for the synthesis of drug-like chiral dihydroquinolines
from simple substrates and catalysts by using sequential
Michael/amination/dehydration reactions.
Hydroquinolines are versatile synthetic intermediates in organic
synthesis and also prevalent unit in biological and pharmaceutical
8
substances (Figure 1). Even though numerous synthetic methods
have been known for their synthesis, there is an urgent requirement
3
). With these moderate results, we moved to investigate this
reaction with other set of hydrogen-bond-donating catalysts 3c-e
based on the chiral squaramide derivatives discovered by Rawal’s
group. Recently Rawal’s squaramide catalysts have been found to
be more powerful hydrogen-bond-donating catalysts compared to
School of Chemistry, University of Hyderabad, Hyderabad-500 046,
India. E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
†
Electronic supplementary information (ESI) available: Experimental
1 13
procedures and analytical data ( H NMR, C NMR and HRMS) for all
new compounds. See DOI: 10.1039/xxxxxxxx
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their corresponding thiourea analogues in both catalytic activity and
selectivity. Therefore, herein we shown interest to investigate
a
5,6
Table 1 Reaction optimization.
8
0
Rawal’s catalysts 3c-e for the high asymmetric induction.
Scheme 1 Reaction design for the 1,4-dihydroquinoline synthesis.
Unfortunately, reaction of 1a with 2a under 5 mol% of quinine-
NH-squaramide 3c in DCM at 25 °C for 6 h gave the product 4aa
in 71% yield with poor ee (18%) and good de (Table 1, entry 4).
After this poor selectivity, we shown interest to investigate the
electronic and steric factors of N-aryl group in the squaramide
catalyst, we used quinine-NH-benzyl squaramide catalyst 3d for the
high selectivity. Surprisingly, the Michael reaction of 1a with 2a
under 5 mol% of 3d-catalysis furnished the product (-)-4aa in 71%
yield with 97% ee and >99% de within 5 h (Table 1, entry 5). This
result is indicating that the presence of benzyl group in the
squaramide catalyst has significant effect on the outcome of
selectivity. In a similar manner, the Michael reaction of 1a with 2a
under the 5 mol% of quinidine-NH-benzyl squaramide 3e-catalysis
furnished the opposite enantiomer (+)-4aa in 77% yield with 98%
ee and >99% de within 5 h (Table 1, entry 6). Whereas 10 mol% of
8
9
9
5
0
5
a
Unless otherwise mentioned, all reactions were carried out with 1 (0.2
b
mmol), 2 (0.26 mmol), catalyst 3 (5 mol%) in DCM (0.3 M) at rt. Yield
refers to the column purified product. Ee and de was determined by CSP
HPLC analysis. 10 mol% of catalyst 3 was used. Reaction performed
with 2 mol% of 3e.
c
d
e
1
1
1
1
1
1
20
With the optimized conditions in hand, the scope of the Rawal’s
quinidine-NH-benzyl squaramide 3e-catalyzed asymmetric Michael
reaction was investigated. A series of substituted N-Boc-(E)-2-(2-
nitrovinyl)anilines 1d-g were reacted with 1.3 equiv. of cyclic β-
keto esters 2a-f catalyzed by 5 mol% of 3e at 25 °C in DCM for 8-
25 96 h to furnish the highly substituted chiral Michael adducts 4db-af
in 40-95% yields with excellent ee’s and de’s (Table 2). Electronic
and steric nature of the N-Boc-(E)-2-(2-nitrovinyl)anilines were
investigated with β-keto ester 2b. Halogen substituted N-Boc-(E)-
3e-catalysis furnished the product (+)-4aa in 77% yield with
decreased ee of 83% (entry 7), which indicates that the catalyst
loading has a significant effect on the selectivity of the reaction.
00 Use of brine instead of DCM as solvent with 2 mol% of catalyst 3e
the aforesaid product was obtained in 48% yield with 91% ee and
2
-(2-nitrovinyl)anilines 1d-e reacted well with 2b and furnished the
1
1
1
1
30 products (+)-4db and (+)-4eb in excellent yields (90 and 95%) and
ee’s (99%) with good to moderate de’s (97 and 70%) within 8 h
respectively. Methyl substituted N-Boc-(E)-2-(2-nitrovinyl)anilines
>99% de in 16 h (Table 1, entry 8). To obtain the highest selectivity
of the product 4aa, we thought of using sterically hindered
isopropyl 2-oxocyclopentanecarboxylate 2b with 1a under 3d/3e-
05 catalysis. Surprisingly, the reaction of 1a with 2b under 5 mol% of
1
f-g gave the desired products (-)-4fb and (+)-4gb in moderate to
good yields (40 and 70%) with excellent ee’s (>99%) and moderate
35 de’s (47 and 88%) through 3e-catalysis for 96 and 72 h,
respectively. We also tested the other cyclic β-keto esters to
investigate the generality of this asymmetric reaction. Methyl 2-
oxocyclopentanecarboxylate 2c with 1a under the 3e-catalysis
furnished the product (-)-4ac in 81% yield with 94% ee and 95% de
40 within 8 h. Intriguingly, six-membered cyclic β-keto ester 2d gave
the product (+)-4ad only in 40% yield with 94% ee and 84% de for
3e-catalysis in DCM at RT for 6 h furnished the product (+)-4ab in
80% yield with >99% ee and de (Table 1, entry 10). Similar
reaction under 3d-catalysis furnished the opposite enantiomer (-)-
ab in 75% yield with >99% ee and de (Table 1, entry 11). To
4
10 further investigate the reaction conditions, we carried out the
Michael reactions of other N-protected-(E)-2-(2-nitrovinyl)anilines
1b/1c with 2b under 3d- or 3e-catalysis in DCM at RT. It has
9
6 h; but simple ethyl 2-oxocyclohexanecarboxylate 2d’ gave the
shown that other carbamate protecting groups (Cbz and CO Et)
2
Michael product (+)-4ad’ in 65% yield with >99% ee and >99% de
for within 40 h (Table 2). Heterocyclic β-keto ester 2e with 1a
45 under 3e-catalysis furnished the product (+)-4ae in 60% yield with
were tolerated and the desired products were obtained in moderate
15 yields (42−65%) with excellent ee’s (96 to >99%) and de’s (97 to
>99%) within 8 h (Table 1, entries 12-14). Finally we envisioned
>
99% ee and de for 24 h. In a similar manner, 2-
the optimized condition to be 25 °C in DCM under 5 mol% of
Rawal’s catalysts 3d or 3e to furnish the Michael adduct 4ab in 75-
acetylcyclopentanone 2f with 1a under 3e-catalysis furnished the
product (+)-4af in 62% yield with 94% ee and 79% de within 8 h.
80% yield with >99% ee and >99% de (Table 1, entry 10-11).
2
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It was observed that compared to five membered cyclic β-keto
2h-i with 1a under 3e-catalysis in DCM followed by TFA-
1
50 esters, six-membered cyclic β-keto esters gave the corresponding 170 mediated one-pot amination/dehydration reaction generated the
products in low yield. The structure and absolute stereochemistry of
the Michael products 4 were confirmed by NMR analysis and also
finally confirmed by X-ray structure analysis on (+)-4ae as shown
cyclised products (+)-5ah-ai in 68% and 65% yields with 98% and
99% ee, respectively (Table 3). Likewise, ethyl 3-oxopentanoate
and 3-oxohexanoate 2j-k generated the expected cyclised products
(+)-5aj and (+)-5ak in 65% and 60% yields with excellent ee’s
12
in Fig. S1 (Supporting Information-1).
a-e
a-c
Table 3 Reaction application.
Table 2 Reaction scope.
a
b
Yield refers to the column purified product. Ee and de were determined
c
d
by CSP HPLC analysis. Only Micheal product obtained. In parenthesis
values refers to minor ee. Reaction of (+)-4al with TFA gave ethyl 2-
e
a
b
Yield refers to the column purified product. Ee and de were determined
c
phenylquinoline-3-carboxylate in 65% yield (see SI).
by CSP HPLC analysis. In parenthesis values refers to minor ee.
1
1
1
75 (99% and 97%) after 36 h respectively (Table 3). In the case of
ethyl 3-oxo-3-phenylpropanoate 2l, the Michael product (+)-4al
was obtained in 79% yield with 90% ee and 55% de at 25 °C for 8
h; but when in-situ treatment of (+)-4al with TFA at 0-25 °C for 24
h furnished the unexpected by-product ethyl 2-phenylquinoline-3-
80 carboxylate in 65% yield may be due to the electronic/steric
hindrance of phenyl group (Table 3 and see Supporting
Information-I). Reaction of substituted N-Boc-(E)-2-(2-
nitrovinyl)anilines 1d-e with 2g under 3e-catalysis followed by in
situ treatment with TFA furnished the cyclised products (+)-5dg
85 and (+)-5eg in good yields (62 and 60%) with excellent ee’s (99
and 98%) at 25 °C for 12 h, respectively (Table 3). Surprisingly,
the reaction of methyl substituted N-Boc-(E)-2-(2-nitrovinyl)aniline
1g with 2g under 3e-catalysis followed by in situ treatment with
1
1
1
55
In order to expand the reaction scope, we explored the utilization
of different acyclic β-keto esters 2g-l. First the reaction of 1a with
.3 equiv. of ethyl acetoacetate 2g under the catalysis of 3e at 25 °C
for 8 h in DCM furnished the product 4ag in 76% yield with 1:1 dr.
1
For the clear understanding of selectivity and also for the HPLC
60 separation, we transformed the product 4ag in situ into easily
separable and also very important 1,4-dihydroquinoline (+)-5ag in
7
2% yield with 98% ee through TFA-mediated cascade
amination/dehydration in DCM at 0-25 °C for 6 h in one-pot
manner (Table 3). We further investigated the substrate scope for
65 Rawal’s quinidine-NH-benzyl squaramide 3e-catalyzed and TFA-
promoted asymmetric Michael/amination/dehydration reaction
sequence with 1a-g and 2h-l for the synthesis of chiral 1,4-
t
dihydroquinolines (Table 3). Methyl and butyl-3-oxobutanoates
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TFA furnished the only Michael product (+)-4gg in 76% yield with
90 94/99% ee and 1:1 dr at 25 °C for 48 h without cyclization may be
due to the steric hindrance of methyl groups (Table 3). After these 230 EMR/2015/000860]. ASK thanks University Grants Commission
This work was made possible by a grant from the Department of
Science and Technology (DST), SERB, New Delhi [Grant No.:
1
13
interesting results, TFA-mediated cascade amination/dehydration
protocol was applied to the many of Table 2 compounds in DCM at
(UGC)-Dr. D. S. Kothari Postdoctoral Fellowship (DSKPDF)
Scheme, New Delhi for his postdoctoral research fellowship. We
thank Dr P. Raghavaiah for his help in X-ray structural analysis.
0-25 °C; for within 1 h compounds were decomposed.
Notes and references
2
2
2
2
2
2
2
2
2
2
2
2
2
35
40
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60
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75
80
85
90
95
1
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Figure 2 Proposed transition state for the asymmetric Michael reactions.
8
1
87; (i) J. Yu, F. Shi and L. –Z. Gong, Acc. Chem. Res., 2011, 44,
156-1171; For selected papers on asymmetric organocatalytic
1
2
2
2
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95
With controlled experimental data in hand, herein we firmly
elucidate the mechanism of the asymmetric Michael reaction
through double hydrogen-bonding assembly by 3e-catalysis, and
propose that the reaction most likely proceeds via TS-1 mechanism
sequential one-pot reactions, see: (j) N. S. Chowdari, D. B.
Ramachary and C. F. Barbas III, Org. Lett., 2003, 5, 1685-1688; (k)
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323-5331; (l) J. W. Yang, M. T. Hechavarria Fonseca and B. List,
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00 (Figure 2). In the case of the addition of β-keto-esters 1 to
substituted 2-(2-nitrovinyl)anilines 2 via Rawal’s 3e-catalysis, we
can rationalize the observed stereochemistries through a favoured
double hydrogen-bonding assembly transition state where the less
hindered si-face of 2 approaches the si-face of the in situ generated
05 enol as shown in TS-1. Outcome of decent selectivity and reactivity
for the β-keto-ester 1 addition to the 2-(2-nitrovinyl)anilines 2
could be explained by soft involvement due to the steric hindrance
of neighboring group Ar-NHBoc as shown in Figure 2.
Fascinatingly, the Michael reaction of simple (E)-(2-
10 nitrovinyl)benzene 1h and N-Boc-(E)-3-(2-nitrovinyl)aniline 1i
with 2b via 3e-catalysis in DCM at 25 °C for 6 h furnished the
expected products (-)-4hb in 63% yield with 98% ee and >99% de;
and (-)-4ib in 71% yield with 99% ee and >99% de respectively as
shown in eq. (1). This result gives evident for the fact that there is
15 not much of neighboring ortho-amino group participation in the
reaction pre-transition state and also Rawal’s catalyst 3e is
sufficient enough to activating both the substrates in the pre-
transition state along with steric hindrance of neighboring group
Ar-NHBoc to control the selectivity.
4
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20
In summary, we have developed Rawal’s quinidine-NH-benzyl
squaramide 3e-catalyzed and TFA-promoted asymmetric sequential
Michael/amination/dehydration reaction of N-protected-(E)-2-(2-
nitrovinyl)anilines 1 with β-keto esters 2 for the synthesis of
enantioenriched and highly functionalized 1,4-dihydroquinolines.
3
2
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25 Further work is in progress to utilize 1,4-dihydroquinoline
derivatives for biological studies.
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Acknowledgements
4
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Graphical Abstract for Table of Contents:
Short Statement
A general approach to the asymmetric synthesis of highly substituted dihydroquinolines was achieved through neighboring ortho-amino
group engaged sequential Michael/amination/dehydration reactions on (E)-2-(2-nitrovinyl)anilines with cyclic and acyclic β-keto esters in the
4
05 presence of a catalytic amount of Rawal’s quinidine-NH-benzyl squaramide followed by TFA (see Scheme).
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