Sc(OTf)3-catalyzed three-component cyclization of arylamines, β,γ-unsaturated α-ketoesters, and 1,3-dicarbonyl compounds for the synthesis of highly substituted 1,4-dihydropyridines and tetrahydropyridines

Article abstract of DOI:10.1021/jo400578m

A Sc(OTf)₃-catalyzed three-component cyclization reaction of arylamines, β,γ-unsaturated α-ketoesters and 1,3-dicarbonyl compounds was developed to synthesize highly substituted 1,4-dihydropyridines and fused bicyclic tetrahydropyridines carrying a quaternary all-carbon center.

Full text of DOI:10.1021/jo400578m

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Note
Sc(OTf)3-Catalyzed Three-Component Cyclization of Arylamines, beta,
gamma-Unsaturated alpha-Ketoesters and 1,3-Dicarbonyl Compounds for The
Synthesis of highly Substituted 1,4-Dihydropyridines and Tetrahydropyridines
Lu Liu, Ryan Sarkisian, Yongming Deng, and Hong Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400578m • Publication Date (Web): 24 Apr 2013
Downloaded from http://pubs.acs.org on May 3, 2013
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Sc(OTf)3-Catalyzed Three-Component Cyclization of Arylamines, β, γ-Unsaturated
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α-Ketoesters and 1,3-Dicarbonyl Compounds for The Synthesis of Highly
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Substituted 1,4-Dihydropyridines and Tetrahydropyridines
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Lu Liu†, Ryan Sarkisian†, Yongming Deng,† and Hong Wang*†
†Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056,
United States
wangh3@miamioh.edu
Abstract: A Sc(OTf)3ꢀcatalyzed threeꢀcomponent cyclization reaction of arylamines, β,
γꢀunsaturated αꢀketoesters and 1,3ꢀdicarbonyl compounds was developed to synthesize
highly substituted 1,4ꢀdihydropyridines and fused bicyclic tetrahydropyridines carrying a
quaternary allꢀcarbon center.
Multicomponent reactions (MCRs) represent one of the most efficient and atomꢀ
economic means to build up structural complexity and diversity.1 The development of
new MCRs has remained an intense research interest in organic community. 1,3ꢀ
Dicarbonyl compounds and their derivatives can be easily tuned to serve as a nucleophile
and/or an electrophile. This feature along with their inherently densely installed
functional groups enable them an important class of versatile and efficient synthetic
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platforms in organic transformations. In recent years, the utilization of 1,3ꢀdicarbonyl
compounds in MCRs has come to more and more prevalent.2
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9
Sixꢀmembered nitrogenꢀcontaining heterocyclic compounds, such as dihydropyridines
(DHPs) and tetrahydropyridines (THPs), have been recognized as a class of highly
important molecular skeletons abundant in natural products, pharmaceuticals,
agrochemicals, and functional materials,3 and as key intermediates in the preparation of
nitrogenꢀcontaining alkaloids.4 Much effort has been devoted to the development of new
methodologies to access dihydropyridines (DHPs) and tetrahydropyridines (THPs).5
Among a number of methodologies developed to date, the Hantzsch reaction utilizing an
amine, an aldehyde, and two 1,3ꢀdicarbonyl compounds is a concise and conventional
approach to synthesize symmetrical 1,4ꢀDHPs.6 Unsymmetrical 1,4ꢀDHPs provide much
larger structural diversity, and are thus of a more biological and synthetic interest.
Although the synthesis of unsymmetrical 1,4ꢀDHPs has been achieved through the
Hantzschꢀlike reactions by using two different 1,3ꢀdicarbonyl compounds, these reactions
suffer from side reactions forming symmetrical 1,4ꢀDHPs, and are of limited substrate
scope.7 The development of new methodologies to access unsymmetrical 1,4ꢀDHPs has
attracted much attention in recent years.8,9 The multicomponent cyclization reaction
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employing a 1,3ꢀdicarbonyl compound, a
α, βꢀunsaturated aldehyde and an arylamine has
appeared to be an efficient method to access unsymmetrical 1,4ꢀDHPs,9 making an ideal
complement to the Hantzsch reaction (Scheme 1). However, this method is limited to
α,
β
ꢀunsaturated aldehydes, i.e. cinnamaldehyde. To our knowledge, enones have not been
utilized in this reaction. This is likely due to the general understanding of lower activity
of enones resulted from both electronic and stertic factors. In our recent effort to develop
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asymmetric azaꢀDielsꢀAlder reaction of cyclic ketones with unsaturated αꢀketo esters and
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arylamines,10 we found that, although the use of enone to form 1ꢀazadiene is often
coupled with slower rates of ketiminations resulting in extensive side reactions,11 the azaꢀ
DielsꢀAlder reaction of an in situ formed 1ꢀazadiene intermediate and a cyclic ketone is
efficient enough to dominate through the enamineꢀmetal Lewis acid cooperative catalysis,
leading to the formation of azaꢀDielsꢀAlder products in high yields. We envision a similar
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cyclization reaction of
β
ꢀketoesters using metal Lewis acid catalysis. Due to the ease of
ꢀketoester, we speculate
formation of both an enol and an enamine intermediate from a
β
that this reaction can occur either through an enol and/or enamine pathway (Scheme 1).
Herein, we report a Sc(OTf)3ꢀcatalyzed threeꢀcomponent cyclization of arylamines, β, γꢀ
unsaturated αꢀketoesters and 1,3ꢀdicarbonyl compounds to afford highly substituted
unsymmetrical 1,4ꢀDHPs and fused bicyclic tetrahydropyridines bearing a quaternary allꢀ
carbon center.
Scheme 1.
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Previous work
Ph
O
5
6
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8
O
O
EtO2C
Ref 9a-f
RNH2
+
+
Ph
H
OEt
aldehyde
N
R
H
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Proposed three-component cyclization reaction
Ph
O
O
O
Metal Lewis acid EtO2C
+
+
Ph
CO2Me
ketone
RNH2
OEt
N
R
CO2Me
- H2O or
- H2NR
- H2O
NHR
elimination
Ph
OH
O
Ph
cyclization
EtO2C
EtO2C
HO
OEt
or
or
NHR O
Ph
CO2Me
+
N
CO2Me
N
R
CO2Me
RHN
R
OEt
We initiated our investigation by examining the cyclization of 1,3ꢀdicarbonyl compounds
1a, β, γꢀunsaturated αꢀketoesters 2a and pꢀmethoxyaniline 3a in the presence of 10 mol%
Y(OTf)3 and Cu(OTf)2 in THF at room temperature (Table 1, entries 1ꢀ2). The desired
cyclization product 4a was isolated in 33% yield from the reaction catalyzed by Y(OTf)3.
When DCM was used as the solvent, the NMR yield of this reaction increased to 45%. To
further improve the yield, a representative selection of Lewis acids including Zn(OTf)2,
Ni(ClO4)2•6H2O, Yb(OTf)3, La(OTf)3 and Sc(OTf)3 were tested in DCM (Table 1, entries
3ꢀ8). Sc(OTf)3 showed the best activity for this cyclization reaction. Prolonged reaction
time only slightly increased the yield (Table 1, entry 9). Other solvents, such as methanol,
toluene, acetonitrile and 1,2ꢀdichloroethane (DCE) did not improve the yield (Table 1,
entries 10ꢀ15). During the investigation, we found that addition of some pyridineꢀbased
ligands helped improve the yield of the reaction (Table 1, entries 9, 16ꢀ18). This is likely
because of that the addition of these ligands helps enhance the stability of possible metal
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complex intermediates. Optimal conditions were obtained when 10 mol% of Sc(OTf)3
and 12 mol% of 1,10ꢀphenanthroline were used in DCM under argon at reflux, affording
4a in 92% isolated yield (Table 1, entry 20).
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Table 1. Condition Screening
Entrya Metal
Ligand
Solvent
THF
Time
36h
48h
36h
36h
36h
36h
36h
36h
48h
48h
48h
48h
48h
48h
Yieldb (%)
1
Y(OTf)3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
38 (33)
trace
45
2
Cu(OTf)2
Y(OTf)3
THF
3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeOH
DCE
4
Zn(OTf)2
Ni(ClO4)2•6H2O
Yb(OTf)3
La(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
35
5
19
6
33
7
37
8
57
9
61
10
11
12
13
14
45
48
toluene
CH3CN
THF
45
21
33
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Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
ꢀ
CH3Cl
DCM
DCM
48h
60
16
Pyridine
48h
48h
48h
18h
18h
65
4,4ꢀmethlyꢀ2,2ꢀ
bipyridne
17
65
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18
1,10ꢀPhenanthroline DCM
1,10ꢀPhenanthroline DCM
1,10ꢀPhenanthroline DCM
73
19c
20c,d
91
99 (92)
aUnless noted, reactions were carried out with 0.4 mmol of 1a, 0.24 mmol of 2a, 0.2
mmol of 3a and 10 mol% of catalyst in 2 ml of solvent. bNMR yield. The numbers in
parenthesis are isolated yields. Under reflux. The reaction was carried out under
argon. PMP = 4ꢀmethoxyphenyl.
c
d
Having obtained the optimized reaction conditions, we next investigated the scope of this
threeꢀcomponent cyclization reaction of β, γꢀunsaturated αꢀketoesters 2 with 1,3ꢀ
dicarbonyl compound 1a and amine 3a. The results are summarized in Table 2. Both
electronic and steric factors of the substituents on the aromatic ring of enones 2 had no
obvious effects on the yields of the reaction (entries 1ꢀ8). Introduction of an alkenyl
substituent at the γꢀposition of the β, γꢀunsaturated αꢀketoester (2j) was well tolerated,
affording the corresponding regioselective cycloadduct 4j in 76% yields (entry 9).
Table 2. Scope of β, γ-Unsaturated α-Ketoesters
Entrya
R1
R2
Time Yieldb (%)
2
4
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1
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9
C6H5
CH2C6H5
20h
14h
21h
18h
20h
22h
18h
23h
24h
90
90
79
87
83
93
92
94
76
2b
2c
2d
2e
2f
4b
4c
4d
4e
4f
C6H5
CH2(4ꢀNO2C6H4)
4ꢀMeC6H4
4ꢀClC6H4
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀMeOC6H4
2,6ꢀCl2C6H3
C6H5CH=CH
Me
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CH2C6H5
Me
CH2C6H5
Me
2g
2h
2i
4g
4h
4i
Me
Et
2j
4j
aUnder argon, reactions were carried out with 0.4 mmol of 1a, 0.24 mmol of 2, 0.2 mmol of 3a, 10
mol% of Sc(OTf)3 and 12 mol% of 1,10ꢀphenanthroline in 2 ml of DCM. bYield of the isolated
product. PMP = 4ꢀmethoxyphenyl.
We also investigated the scopes of the 1,3ꢀdicarbonyl compounds (1) and the arylamines
(3) for this transformation (Table 3). In general, the reaction of an arylamine with an
electronꢀdonating group at the paraꢀposition was faster than an arylamine having an
electronꢀwithdrawing group at the paraꢀposition (entries 1ꢀ7); the reactions of more
sterically hindered orthoꢀsubstituted anilines also proceeded smoothly to give the desired
1,4ꢀDHPs in high yields (entries 5ꢀ6). It is interesting to note that, when an orthoꢀ
substituted aniline was used, extra axial chirality was created in the resulting 1,4ꢀDHP
(4o and 4p) due to the restricted rotation of the neighboring groups (R1, R and CO2Me).
This structural feature can only be made possible when enones are used in the cyclization
reaction. Both
βꢀketo esters and βꢀdiketones turned out to be suitable substrates for this
cyclization reaction (entries 8ꢀ11).
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Table 3. Scope of Arylamines and 1,3-Dicarbonyl Compounds
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7
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9
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Entrya 1/R1/R2
R
Time
36h
72h
48h
24h
24h
40h
24h
20h
20h
48h
72h
Yieldb (%)
3
4
1
1a/Me/OEt
C6H5
83
3b
3c
3d
3e
3f
4k
4l
2
4ꢀClC6H4
4ꢀBrC6H4
3ꢀClC6H4
2ꢀClC6H4
2ꢀIC6H4
80
1a
3
74
1a
4m
4n
4o
4p
4q
4r
4s
4t
4
63
1a
5
85 (51:49)
1a
6
83 (54:46)
1a
3g
3h
3a
3a
3a
3a
7
3,4ꢀ(CH3O)2C6H3
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
65
88
95
78
74
1a
8
1b/Me/OMe
1c/Me/OtꢀBu
1d/Me/Me
1e/Ph/OEt
9
10
11
4u
aUnder argon, reactions were carried out with 0.4 mmol of 1, 0.24 mmol of 2h, 0.2 mmol of 3, 10
mol% of Sc(OTf)3 and 12 mol% of 1,10ꢀphenanthroline in 2 ml of DCM. bYield of the isolated
product; the numbers in parenthesis are the ratios of the two isomers. PMP = 4ꢀmethoxyphenyl.
We also investigated the cyclization reaction of 2ꢀsubstituted 1,3ꢀdicarbonyl compounds
with enone 2 and arylamines. The cyclization reaction of 2ꢀsubstituted 1,3ꢀdicarbonyl
compounds would create a new allꢀcarbon quaternary center, which is of much more
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challenge to synthesize. We chose methyl 2ꢀoxocyclohexanecarboxylate 1f and methyl 2ꢀ
oxocyclopentanecarboxylate 1g. 1f and 1g would lead to the formation of bicyclic fused
ring systems. As it turned out, both sixꢀmembered 1f and fiveꢀmembered 1g reacted
smoothly with enone 2 and amine 3 under optimized conditions to afford unsymmetrical
bicyclic ring fused tetrahydropyridines in moderate yields (Scheme 2).
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Scheme 2. Synthesis of Tetrahydropyridinesa
A preliminary experiment was carried out for an asymmetric version of this reaction. The
application of a chiral ligand, i.e. indanꢀPybox, only resulted in low enantioselectivity
(27% ee) of this reaction in moderate yield (44%) (Scheme 3).
Scheme 3. Preliminary Examination of An Enantioselective Variant
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In summary, we have developed a Sc(OTf)3ꢀcatalyzed threeꢀcomponent cyclization
reaction of arylamines, β, γꢀunsaturated αꢀketoesters and 1,3ꢀdicarbonyl compounds,
providing facile access to highly substituted dihydropyridines and tetrahydropyridines
which are not accessible using existing methods. It is notable that fused bicyclic
tetrahydropyridines bearing a quaternary allꢀcarbon center were readily formed using this
approach. This method is an ideal complement to the existing methods. The mild
conditions, readily available starting materials, and high yields make this protocol useful
in organic synthesis.
Experimental Section:
β
, γꢀUnsaturated αꢀketoesters were prepared according to literature reported
procedures.12 1H NMR and 13C NMR spectra were acquired at 500 MHz and 125 MHz in
CDCl3. Dichloromethane was distilled from CaH2 prior to use.
General Procedure: A mixture of Sc(OTf)3 (0.02 mmol) and 1,10ꢀphenanthroline
(0.024 mmol) was stirred at room temperature for 2 h in DCM (2 ml). The appropriate
1,3ꢀdicarbonyl compounds 1 (0.4 mmol), β, γꢀunsaturated αꢀketoesters 2 (0.24 mmol) and
amine 3 (0.2 mmol) were then added. The resulting mixture was stirred under reflux.
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After the reaction was completed, the reaction mixture was purified through column
chromatography (silica, eluent: mixture of hexane and ethyl acetate).
Acknowledgements. We thank Miami University and NSF CHEꢀ1056420 for financial
support.
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1
Supporting Information Available: H and 13C NMR spectra data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Germany, 2005.
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