A copper(II)-catalyzed, sequential Michael-aldol reaction for the preparation of 1,2-dihydroquinolines

Article abstract of DOI:10.1016/j.tetlet.2011.12.017

A copper(II)-catalyzed, sequential Michael addition-aldol condensation reaction of N-carboxybenzyl-protected aminobenzaldehyde with various α,β-unsaturated N-acyl pyrroles is described. Substrate scope was found to include both aryl and aliphatic N-acyl p

Full text of DOI:10.1016/j.tetlet.2011.12.017

Tetrahedron Letters 53 (2012) 833–836
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A copper(II)-catalyzed, sequential Michael–aldol reaction for the preparation
of 1,2-dihydroquinolines
Anna M. Wagner, Claire E. Knezevic, Jessica L. Wall, Victoria L. Sun, Joshua A. Buss, LeeAnn T. Allen,
⇑
Anna G. Wenzel
Keck Science Department, Claremont McKenna, Pitzer and Scripps Colleges, Claremont, CA 91711, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper(II)-catalyzed, sequential Michael addition-aldol condensation reaction of N-carboxybenzyl
Received 1 October 2011
Revised 3 December 2011
Accepted 5 December 2011
Available online 9 December 2011
-protected aminobenzaldehyde with various
a,b-unsaturated N-acyl pyrroles is described. Substrate
scope was found to include both aryl and aliphatic N-acyl pyrroles as the Michael acceptors, and isolated
product yields as high as 93% were observed. The use of acetonitrile as the reaction solvent proved to be
crucial for catalysis, both to function as a labile ligand for copper, as well as an agent to minimize hydro-
lytic catalyst poisoning.
Keywords:
Heterocycles
Ó 2011 Elsevier Ltd. All rights reserved.
Lewis acid catalysis
Michael–aldol reaction
Acetonitrile
Small-molecule synthesis
Introduction
afford the corresponding aldol condensation product. Operationally
simple, this strategy benefits from its modular design and the use of
1,2-Dihydroquinolines have received considerable attention
due to their proven biological activity against a wide range of phar-
maceutical targets.1 These compounds also have utility as versatile
synthons for a range of biologically active alkaloids.2 In addition to
medicinal applications, derivatives of these compounds can
function as pesticides,3 corrosion inhibitors,4 fabric dyes,5 and
components in photographic and digital recording devices.6 Due
to the importance of this compound class, the development of
inexpensive synthetic routes toward their preparation is of intrin-
sic value. To date, several methods for the construction of 1,2-dihy-
droquinoline rings have been reported,7–9 some of which are
enantioselective.8a–c,9a,b,10 These methods are limited to specific
substrate classes, however, and the lack of a general synthetic
methodology leaves considerable room for further reaction
development.
readily accessible starting materials. Previously reported Michael–
aldol reactions have achieved these types of products via the use
of strong magnesium bases,8f biphasic base catalysis,8e and iminium
ion catalysis.8a–d In these examples, the selection of an appropriate
amine protecting group for the 2-(aminophenyl)carbonyl com-
pound is important, as insufficient substitution at R1 can lead to
unfavorable side reactions, a feature that has previously proven
problematic.
Protecting the amine functionality as either a carbamate or sul-
fonamide is a simple strategy to eliminate these side reactions, and
this tactic was successfully employed by Wang and Hamada.8b,c
However, N-protection makes the amine considerably less nucleo-
philic, which results in the formidable synthetic challenge of suffi-
ciently activating the Michael acceptor to enable amine conjugate
addition. Herein, we report the use of copper(II) in acetonitrile as
Of the possible routes for the preparation of 1,2-dihydroquino-
lines, one reaction holds particular promise for further elaboration:
a sequential Michael addition-aldol condensation reaction for the
preparation of 1,2-dihydroquinoline-3-carboxylic acid derivatives
(Scheme 1).8 In the envisioned reaction, the nitrogen atom of a 2-
(aminophenyl)carbonyl compound attacks the b-position of an
Aldol Condensation
R2
O
O
O
R4
R2
NHR1
R4
+
N
R3
R3
a,b-unsaturated carbonyl compound (Michael acceptor) to generate
R1
the corresponding enolate, which can then react intramolecularly to
Michael Addition
⇑
Corresponding author. Tel.: +1 909 607 0912; fax: +1 909 621 8588.
E-mail address: awenzel@kecksci.claremont.edu (A.G. Wenzel).
Scheme 1. Sequential Michael–aldol reaction for the preparation of 1,2-dihydro-
quinoline-3-carboxylic acid derivatives.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.017

834
A. M. Wagner et al. / Tetrahedron Letters 53 (2012) 833–836
an effective catalyst for activating the Michael acceptor in such
reactions.
acetonitrile, no conversion to product was observed. Second, the
high polarity and hydrophilicity of acetonitrile may also play a role
in sequestering water away from the copper complex coordination
sphere. As 1 equiv of water is generated during the aldol condensa-
tion step of the Michael–aldol reaction, we investigated whether
water could promote catalyst decomposition. When 1 equiv of
water was added to the reaction mixture in acetonitrile, reaction
conversion was reduced from 38% to 13%. Accordingly, we ex-
pected that reaction performance could be improved and catalyst
decomposition circumvented by the addition of a suitable desic-
cant. Indeed, such an improvement was observed when 4 Å pow-
dered sieves were added to the In(OiPr)3-catalyzed reaction of 6a
with 1b (Table 1, entry 3). Unfortunately, the use of desiccants
(4 Å sieves, K2CO3, Na2SO4, barium hydroxide, etc.) in the
Cu(OTf)2-catalyzed reaction in acetonitrile had the opposite ef-
fect—conversion to product was reduced by ca. 30%.
The ability of acetonitrile to ameliorate the effects of water and
promote reactivity in copper(II)-catalyzed reactions has previously
been observed in polymerization reactions of 2,6-dimethylphe-
nol.17,18 Reedijk and coworkers reported a spectacular increase in
reaction rate and conversion when acetonitrile was employed as
the reaction solvent. As with the Michael–aldol reaction, water is a
co-product of this polymerization reaction, yet increasing the
amount of water by just 3% in acetonitrile led to a 75% drop in cata-
lyst activity.17 The hydrophilicity of acetonitrile plays a noticeable
role in minimizing catalyst decomposition in both reactions. Indeed,
this ‘acetonitrile effect’ was not as efficient with other nitriles. De-
creased catalyst performance was observed when propionitrile, a
less hydrophilic nitrile, was employed as the reaction solvent (Table
2).
Further reaction optimization was achieved via heating (82 °C
was optimal), coupled with a small increase in catalyst loading. In
the reaction of 6a with 1b in the presence of Cu(OTf)2 (15 mol %),
the Michael–aldol product was isolated in 81% yields after 24 h;
additional conversion (product yield 93%) was attained upon
extending reaction time to 48 h. Interestingly, conventional heat
proved to be more effective than microwave heating: when micro-
wave heat was employed in the reaction of 6a with 1b, yields no
higher than 57% could be attained. Despite this, broad substrate
scope for the N-acyl pyrrole used as the Michael acceptor was
observed, with both aromatic and aliphatic substrates being well-
tolerated (Table 3). In addition, both electron-deficient and
electron-rich aryl rings performed similarly (Table 3, entries 2–4).
One of the attractive features of this methodology was the tolerance
observed toward some Lewis basic substrates, enabling the
preparation of furyl- and thienyl-substituted dihydroquinolines.
However, one limitation that must be noted was observed when
the 3-quinolinyl-substituted Michael acceptor 6h was employed
(Table 3, entry 8). Instead of the typical brown color of these reac-
tions, a blue–green color was observed, and negligible conversion
to 9 occurred. Presumably, in this case, the strong donor properties
of the pyridyl ring have overridden the weak donor properties of
acetonitrile as a ligand for copper(II), leading to a breakdown of
the ‘acetonitrile effect’.
Results and discussion
The N-protected, 2-(aminophenyl)carbonyl compounds 1a–c11
were selected for investigation with a variety of Michael acceptors
(e.g., 2a–8a; Scheme 2). As the initial conjugate addition sequence
was anticipated to be the rate-limiting step of this reaction, our
lead discovery investigations focused primarily on the use of metal
sources known to catalyze Michael addition reactions,12 particu-
larly those involving the use of aza-nucleophiles.13 Chiral phospho-
ric acid catalyst 1014 was included in our studies to investigate the
possibility of Brønsted acid catalysis. Trifluoromethanesulfonic
acid (TfOH) was also tested to rule out the possibility of triflate
counterion catalysis when metal triflate salts were examined.
After extensive investigation, only three Michael acceptor/me-
tal source combinations were found to generate appreciable con-
version of starting material to 9 at room temperature (Table 1).
Of these, only Cu(OTf)2 in acetonitrile with the N-carboxybenzyl
(N-Cbz)-protected 1b and the
a,b-unsaturated N-acyl pyrrole 6a
demonstrated significant catalyst turnover. The absence of reactiv-
ity with TfOH and CuOTf indicate that this reaction is copper(II)
catalyzed. Interestingly, no reaction was observed with the phenyl
ketone 3a, although N-acyl pyrroles have been reported to display
similar properties as phenyl ketones.15 For example, in 2002, Wab-
nitz and Spencer reported the addition of benzyl carbamate to a,b-
unsaturated ketones in the presence of Cu(OTf)2 (10 mol %).16
When these conditions were adapted to the reactions of 3a or 6a
with benzyl carbamate, both Michael acceptors displayed compa-
rable reactivity. This indicates that the different reactivity of 3a
and 6a observed in the Michael–aldol reaction is due to prefer-
ences associated with the interaction between the Michael accep-
tors and 1b.
The electron-donating character of the solvent was found to
strongly correlate with reaction conversion (Table 2). For example,
the best results (38% conversion to 9) were observed when acetoni-
trile was used as the reaction solvent, whereas only 11% conversion
was observed with nitromethane, a poor donor solvent with a sim-
ilar dielectric constant to acetonitrile. However, solvent donicity is
not the sole determining factor: tetrahydrofuran and diethyl ether
were among the strongest donor solvents investigated, yet these
solvents resulted in lower yields relative to acetonitrile.
The benefits of acetonitrile in the copper(II) catalysis of the
Michael–aldol reaction appear to be twofold. First, acetonitrile is
likely serving as an effective ligand for copper, conveying unique
reactivity to the metal center. When alternative ligands, such
as BINOL and bisoxazolines, were introduced in the place of
O
O
O
catalyst
(10 mol%)
R
+
H
R
solvent
N
Ph
NHR'
1a: R' = Ts
1b: R' = Cbz
1c
Ph
23 oC, 24 h
R'
2-8
(1.5 equiv)
9
: R' = Boc
Conclusions
solventsinvestigated:
Michaelacceptors:
CH2Cl2, THF, or MeCN
2a: R = H
catalysts investigated:
Mg(OTf)2, In(OTf)3,
Copper(II) triflate combined with acetonitrile is a surprisingly
robust catalyst system, allowing for reactions to proceed despite
the generation of water as a reaction co-product. When applied
to the sequential Michael–aldol reaction of N-carboxybenzyl (N-
3a: R = Ph
SiPh3
O
4a: R = NMe(OMe)
O
S
t
5a: R = OBu
AlCl3,
TiCl4,
In(OiPr)3
InCl3
AgOTf
O
O
F3C
OH
P
6a: R = pyrrolyl
OH
O
(TfOH)
7a
: R = pyrrolidin-2-one ZnEt2,
8a: R = N-imidazolyl
Zn(OTf)2, Sc(OTf)3
Cbz)-protected aminobenzaldehyde with
a,b-unsaturated N-acyl
SiPh3
CuOTf,
Yb(OTf)3
pyrroles, the corresponding 1,2-dihydroquinoline-3-carboxylic
acid derivatives were prepared in high yields. The N-acyl pyrrole
moiety can be readily transformed into various functional groups,
10
Cu(OTf)2, CuCl2
Scheme 2. Lead discovery investigation of catalysts and Michael acceptors.

A. M. Wagner et al. / Tetrahedron Letters 53 (2012) 833–836
835
Table 1
Lead discovery investigation—conditions resulting in the formation of 9a
Entry
Amino aldehyde
Michael acceptor
Catalyst
Solvent
Conversion to 9b (%)
1
2
3
1b
1b
1b
2a
6a
6a
Cu(OTf)2
Cu(OTf)2
In(OiPr)3
MeCN
MeCN
THF
12
38
13 (20)c
a
b
c
Reactions were carried out with 0.66 mmol of 1b, 1.0 mmol of 2a or 6a and catalyst (10 mol %) in 1.0 mL of solvent.
Determined via GC relative to dodecane (0.2 equiv) as an internal standard and by 1H NMR.
Reaction run in the presence of 4 Å molecular sieves (80 mg).
Table 2
Effect of solvent on reaction performancea
Solvent
Dielectric constant19
(e; 20 °C)
Donor number20 (kcal mol-1
)
Conversion to 9b (%)
MeCN
37.5
35.9
26.5
9.1
7.6
4.3
14.1
2.7
16.1
0.0
20.0
19.2
0.1
38
11
25
—
26
17
—
MeNO2
Propionitrile
CH2Cl2
THF
Et2O
Toluene
2.4
a
Reactions were carried out with 0.66 mmol of 1b, 1.0 mmol of 6a and Cu(OTf)2 (10 mol %) in 1.0 mL of solvent.
b
Determined via GC relative to dodecane (0.2 equiv) as an internal standard and by 1H NMR.
Table 3
sional use of their NMR spectrometers. Dr. Mona Shahgholi at the
Caltech Mass Spectrometry Facility is gratefully acknowledged.
Reaction scopea
O
R
O
O
N
Cu(OTf)2 (15 mol%)
MeCN,82 o
+
Supplementary data
H
N
C
N
NHCbz
1b
R
Cbz
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.017.
6a-j
9
(1.5 equiv)
Entry
Michael acceptor
R
Yield of 9b (%)
References and notes
After 24 h
After 48 h
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6a
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6i
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