Convergent catalysis: Asymmetric synthesis of dihydroquinolines using a combined metal catalysis and organocatalysis approach

Article abstract of DOI:10.1021/cs401176s

A convergent catalysis approach has been developed. The combined metal-catalyzed and organocatalyzed cascade consists of two oxidations, an aza-Michael addition and an aldol condensation, and involves a multicatalysis approach to provide 1,2-dihydroquinolines in a highly enantioselective fashion.

Full text of DOI:10.1021/cs401176s

Research Article
pubs.acs.org/acscatalysis
Convergent Catalysis: Asymmetric Synthesis of Dihydroquinolines
Using a Combined Metal Catalysis and Organocatalysis Approach
Magnus Rueping,* Jeremy Dufour, and Lan Bui
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A convergent catalysis approach has been
developed. The combined metal-catalyzed and organocata-
lyzed cascade consists of two oxidations, an aza-Michael
addition and an aldol condensation, and involves a multi-
catalysis approach to provide 1,2-dihydroquinolines in a highly
enantioselective fashion.
KEYWORDS: domino reaction, diphenylprolinol ether, Michael reaction, TPAP oxidation, aldol reaction
onvergent synthesis1−4 is a versatile synthetic strategy that
proved its strong potential in the synthesis of a large
number of natural products and biologically active mole-
cules.5−10 In a convergent synthesis, fragments of the target
molecule are synthesized independently and assembled
together at various stages of the designed synthetic route to
achieve a high degree of productivity (Scheme 1a). Compared
convergent synthesis should bring significant additional benefits
in terms of yield as well as reaction time (Scheme 1c). Among
the well-established domino reactions, chiral secondary amine-
catalyzed27,28 enantioselective organocascades emerged as a
practical method for the functionalization of α,β-unsaturated
aldehydes via iminium/enamine (Im/En) activation. In our
previous investigations in the field of organocatalyzed cascade
reactions, we observed that traces of acid impurities present in
the α,β-unsaturated aldehydes are detrimental to the
enantioselectivity.29−31
To avoid extra purification steps, we anticipate that in situ
generation of the aldehydes by metal-catalyzed oxidation of
alcohols would be advantageous.32−48 Such an oxidative process
could extend the versatility of Im/En cascades, especially when
the aldehydes are unstable or difficult to access.49−53 So far, to
the best of our knowledge, there is no example in which both
substrates of an Im/En cascade are generated in situ. Hence, we
became interested in designing a novel convergent enantiose-
lective cascade that would allow simultaneous conversion of the
appropriate alcohols into the corresponding carbonyl com-
pounds, which would subsequently react together in a
secondary amine catalytic cycle.
C
Scheme 1. Schematic Representation for (a) Convergent
Synthesis, (b) Domino Reactions, and (c) Merged
Convergent Synthesis and Domino Reactions
to linear syntheses, convergent syntheses are usually more
efficient in terms of the amounts of starting materials required
and the number of reaction steps of the main route, being thus
preferred in the synthesis of complex molecules.1−10 One way
to further enhance the efficiency of a convergent synthesis is to
take advantage of domino, tandem, or sequential reactions and
incorporate them in a more elaborate convergent strategy.
Domino reactions11−26 have attracted an increasing level of
interest in organic synthesis because of their ability to create
numerous bonds, via one-pot multistep processes, starting from
simple, readily available materials (Scheme 1b). These atom-
economical reactions represent a powerful tool for accessing
complex structures with a great level of stereocontrol.
Furthermore, they avoid laborious protection/deprotection
steps as well as additional workup and purification strategies.
Hence, merging the concepts of domino reactions and
Following this idea, we turned our attention to the Michael/
intramolecular aldol reaction between α,β-unsaturated alde-
hydes and benzaldehydes. Indeed, these two starting materials
could in principle be generated in situ by oxidation of the
corresponding allylic and benzyl alcohols. Interestingly, in
recent years, several elegant secondary amine-catalyzed domino
hetero-Michael/aldol/dehydration reactions54 were applied to
the asymmetric preparation of valuable heterocycles such as
chromenes,53,55−59 thiochromenes,60−62 or 1,2-dihydroquino-
lines.63−65 We herein report an unprecedented convergent
oxidative iminium/enamine cascade between 2-amino benzyl
Received: July 27, 2013
Revised: February 1, 2014
Published: February 18, 2014
© 2014 American Chemical Society
1021
dx.doi.org/10.1021/cs401176s | ACS Catal. 2014, 4, 1021−1025

ACS Catalysis
Research Article
alcohols 1 and allylic alcohols 2 yielding 1,2-dihydroquinolines
3 (Scheme 2).63−73 This class of heterocycles remains highly
important as they are found in a number of natural and
synthetic active molecules.74
Table 1. Survey of the Reaction Conditions for the
Convergent Enantioselective Oxidative Cascade Reaction
Scheme 2. Double Oxidative Iminium/Enamine Cascade
Reaction
a
b
c
entry
solvent
CH2Cl2
catalyst
yield (%)
ee (%)
de
,
1
2
3
4
5
6
7
8
9
6a
6a
6a
6b
6c
6a
6a
6a
6a
47
62
72
73
<5
70
68
20
22
93
95
95
95
47
94
94
85
94
To our delight, during the initial investigations, we found
that the catalytic oxidative system tetrapropylammonium
perruthenate (TPAP),75 associated with the mild terminal
oxidant N-methylmorpholine N-oxide (NMO), could be
combined in one pot with secondary amine-type catalysts.76−81
Thus, the TPAP/NMO system became the oxidant of choice
for the convergent enantioselective domino process presented
here. Both allylic and benzyl alcohols could be oxidized at room
temperature under mild conditions, suitable for secondary
amine catalysis.
e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Cl(CH2)2Cl
CHCl3
f
CH3CN
THF
a
Reaction conditions: 2:1 ratio of 1a (2 equiv, 4 mmol) to 2a (1 equiv,
1 mmol), TPAP (7 mol %), NMO (3.5 equiv), 4 Å molecular sieves
As proposed in Scheme 3, initial oxidation of allylic alcohol 1
by the TPAP/NMO system provides the α,β-unsaturated
aldehyde 4, releasing N-methylmorpholine (NMM). The
aldehyde is then activated in the form of iminium ion A by
condensation with the diarylprolinol ether catalyst 6.82−84
Michael addition of 2-N-protected benzaldehyde 5, formed by
in situ oxidation of the corresponding 2-amino benzyl alcohol 2,
yields enamine B.85 Intramolecular aldol reaction followed by
dehydration leads to 1,2-dihydroquinoline 3 and the release of
catalyst 6.
To test the feasibility of our proposed enantioselective
oxidative cascade, we first reacted N-Cbz-2-aminobenzyl
alcohol 1a with 2 equiv of cinnamyl alcohol 2a, the TPAP (7
mol %)/NMO (3.5 equiv) system, and diarylprolinol TMS
ether catalyst 6a in CH2Cl2 at room temperature. After 48 h,
the desired 1,2-dihydroquinoline 3a was isolated in a promising
yield (47%) and with very good enantioselectivity [93%
enantiomeric excess (ee) (Table 1, entry 1)]. The absolute
configuration was assigned to be R by comparing the sign of the
(150 mg), and catalyst 6 (20 mol %) in solvent (2 mL) at room
b
temperature for 48 h. Yields after purification by column
c
chromatography. Determined by high-performance liquid chromatog-
d
e
raphy (HPLC). Without 4 Å molecular sieves. A 1:2 ratio of 1a (1
f
equiv) to 2a (2 equiv) was used. Reaction conducted for 120 h.
optical rotation of the product with that of the known
compound from the literature.63 Use of 4 Å molecular sieves
proved to be beneficial for the yield and slightly increased the
enantioselectivity (62% yield, 95% ee, entry 2). A reversal of the
reagent ratio and the use of 4 Å molecular sieves increased the
yield to 72% and produced an excellent enantioselectivity (95%
ee, entry 3). Molecular sieves, known to enhance the efficiency
of TPAP/NMO oxidations, probably promoted the elimination
step as well. When screening the catalysts, we observed that the
TES-protected catalyst 6b provided the desired product in a
similar good yield, whereas organocatalyst 6c was detrimental
to enantioselectivity (entries 4 and 5). The effect of the solvent
was subsequently evaluated with the initial catalyst 1a. As seen
Scheme 3. Proposed Mechanism of the Convergent Oxidative Iminium/Enamine Cascade
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in entries 3, 6, and 7, chlorinated solvents such as dichloro-
methane, 1,2-dichloroethane [Cl(CH2)2Cl], and chloroform
(CHCl3) gave similar good results, whereas acetonitrile showed
a poor efficiency and gave a lower enantioselectivity (entry 8).
A polar solvent such as THF was also detrimental to the
cascade reaction, and the desired product was isolated in 22%
yield, although with 94% ee (entry 9).
With the optimized conditions in hand (Table 1, entry 3),
the scope of the enantioselective oxidative cascade reaction was
investigated.86 The reaction between N-Cbz-protected amino
alcohol 1a and a variety of cinnamyl alcohols 2 afforded the
desired 1,2-dihydroquinolines 3 in a highly enantioselective
fashion (Table 2, entries 1−8).
(Ts) groups are also compatible with the reaction (entries 10−
12). N-Ts-protected amino alcohol 1c turned out to be of
interest as it allowed reaction with alkyl- and ester-substituted
allylic alcohols, otherwise unreactive with the N-Cbz-protected
substrate after 48 h (entries 13−16). Hence, (E)-crotyl alcohol
and (E)-hex-2-en-1-ol were subjected to the oxidative domino
process and afforded the corresponding 1,2-dihydroquinolines
in good yields with good enantioselectivities (entries 13 and
14). In general, reactions with alkyl-substituted substrates were
found to occur faster than with the corresponding aryl-
substituted derivatives. Interestingly, silyl-protected hydroxy-
methyl and ester groups were also tolerated in the reaction and
could be further functionalized, although the enantioselectivity
was lower than for the aryl-substituted allylic alcohols (entries
15 and 16, ee’s of 87 and 80%, respectively).
After varying the allylic alcohols 2 and the protecting group
of the 2-aminobenzyl alcohol 1, we evaluated the generality of
our cascade by modifying the substitution on the aromatic ring
of the latter. In this regard, several readily available Cbz-
protected substrates were subjected to the domino cascade with
cinnamyl alcohol 2a (Table 3). Substrates bearing an electron-
Table 2. Scope of the Convergent Enantioselective Oxidative
Cascade Reaction
a
b
c
Table 3. Extended Scope of the Convergent Enantioselective
Oxidative Cascade Reaction
entry
R1
R2
3
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Ac (1b)
Ts (1c)
Ph
3a
3b
3c
3d
3e
3f
72
81
79
71
69
84
73
51
47
64
76
85
73
63
61
61
95
95
95
92
94
95
96
90
93
95
98
91
90
86
87
80
4-NO2-C6H4
4-Br-C6H4
4-F-C6H4
4-Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
2-MeO-C6H4
2-thienyl
Ph
3g
3h
3i
d
9
ef
,
10
11
12
13
3j
f
Ph
3k
3l
f
Ts (1c)
4-MeO-C6H4
Me
g
fg
Ts (1c)
3m
3n
3o
3p
14 ,
Ts (1c)
n-Pr
g
15
Ts (1c)
TBSOCH2
CO2Et
f
16
Ts (1c)
a
Reaction conditions: 2:1 ratio of 1 (2 equiv) to 2 (1 equiv), TPAP (7
mol %), NMO (3.5 equiv), 4 Å molecular sieves, and catalyst 6a (20
mol %) in CH2Cl2 at room temperature for 48 h. See the Supporting
b
Information for details. Yields after purification by column
c
d
chromatography. Determined by HPLC. Reaction conducted for
e
f
a
120 h. Reaction conducted for 84 h. A 1:2 ratio of 1 (1 equiv) to 2 (2
Reaction conditions: 2:1 ratio of 1 (2 equiv) to 2 (1 equiv), TPAP (7
g
equiv) was used. Reaction conducted for 12 h.
mol %), NMO (3.5 equiv), 4 Å molecular sieves, and catalyst 6a (20
mol %) in CH2Cl2 at room temperature for 48 h. See the Supporting
b
Information for details. Yields after purification by column
chromatography. Determined by HPLC. Reaction conducted for
120 h.
A strong electron-withdrawing group such as a nitro group at
the para position was compatible in the domino process,
providing the product in 81% yield with excellent enantiose-
lectivity (95% ee, entry 2). Halo-containing allylic alcohols were
also subjected to this oxidative cascade, affording 4-bromo- and
4-fluorophenyl-substituted enantiopure products (entries 3 and
4). The electronic effect of the substituent was rather low as
electron-rich 4-methoxyphenyl and 4-methylphenyl groups also
displayed very good results in terms of yields and ee’s (entries 5
and 6). However, the position of the methoxy substituent on
the phenyl ring had an impact on the outcome of the reaction,
as revealed by the ortho-, meta-, and para-substituted substrates
(entries 6−8). Furthermore, the reaction tolerated a hetero-
aromatic 2-thienyl allylic alcohol, although a longer reaction
time was required (entry 9). With regard to the N-protecting
group, we found that in addition to Cbz, acetyl (Ac) and tosyl
c
d
donating group [4-methyl, 4-methoxy, or 4,5-(OCH2O)]
provided very good results in terms of yields and ee’s (entries
1−3). Halo-containing aminobenzyl alcohols were compatible
in this oxidative cascade, affording the desired products with
very high enantioselectivity (entries 4−6). We then tested the
effect of the substituent ortho to the amino function. Pleasingly,
ortho methyl functionality provided a good yield and an
excellent ee (entry 7). Interestingly, a naphthalene derivative
reacted smoothly to provide the corresponding product in
acceptable yield with an excellent enantioselectivity (99% ee,
entry 8).
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In conclusion, we have developed a new convergent catalysis
approach by combining two catalytic oxidative cycles in one pot
with iminium/enamine catalysis. The convergence of this
process is caused by the oxidation of two substrates, an allylic
alcohol and a 2-amino benzyl alcohol, by the substrate-selective
redox TPAP/NMO system. This catalytic oxidation, compatible
with diarylprolinolsilyl ether catalysis, allows the in situ
generation of two aldehydes that react subsequently in an
enantioselective Michael addition/intramolecular aldol/dehy-
dration pathway. The domino reaction proved to be very
efficient and general, affording a wide range of enantiopure N-
protected 1,2-dihydroquinolines under mild and operationally
simple conditions. This original process widens the scope of
secondary amine catalysis as alcohols can now be used as
starting materials instead of more sensitive aldehydes.
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ASSOCIATED CONTENT
* Supporting Information
General procedures, full characterization of the products, and
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
6329−6332.
■
S
(31) Rueping, M.; Merino, E.; Sugiono, E. Adv. Synth. Catal. 2008,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: magnus.rueping@rwth-aachen.de. Fax: +49 241
8092665.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We acknowledge the ERC for financial support.
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