Ruthenium-Porphyrin-Catalyzed [4 + 2] Cycloaddition of α,β-Unsaturated Imines and Aldehydes

Article abstract of DOI:10.1021/acs.orglett.5b02654

A new efficient synthetic route to unsymmetrically substituted dihydropyridine scaffolds via dehydrative [4 + 2] cycloaddition of N-tosylated α,β-unsaturated imines with aldehydes has been developed. This transformation is enabled by (i) the remarkable ca

Full text of DOI:10.1021/acs.orglett.5b02654

Letter
pubs.acs.org/OrgLett
Ruthenium-Porphyrin-Catalyzed [4 + 2] Cycloaddition of α,β-
Unsaturated Imines and Aldehydes
Kazuki Maeda, Takuma Terada, Takahiro Iwamoto, Takuya Kurahashi,* and Seijiro Matsubara*,†
†
†
†
,†,‡
†Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
‡JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
*
S Supporting Information
ABSTRACT: A new efficient synthetic route to unsymmetri-
cally substituted dihydropyridine scaffolds via dehydrative [4 +
2] cycloaddition of N-tosylated α,β-unsaturated imines with
aldehydes has been developed. This transformation is enabled
by (i) the remarkable catalytic ability of the cationic Ru(IV)
porphyrin complex to activate both the imino and carbonyl
groups and (ii) the hydrophobic nature of the porphyrin
ligand, which helps realize robust Lewis acidity in the
dehydrative cycloaddition.
4
n essential role in biological processes through NADH
(a)). However, the electron-donating groups on the nitrogen
A
regeneration is played by 1,4-dihydropyridine scaffolds.
Furthermore, they show specific and significant medicinal
properties, i.e., they function as L-type calcium channel
atoms, which are required to enhance the nucleophilicity of the
enamines, may induce oxidation of the resulting products to
form pyridine scaffolds. This phenomenon leads to poor
modifiability in the synthesis of structurally diverse dihydropyr-
idines.
1
blockers in the treatment of hypertension. Moreover, because
of their reducing nature, dihydropyridines have attracted
considerable attention as potential biomimetic reductants in
combination with organocatalysts. Following Hantzsch’s
report on the most convenient route to symmetrically
To solve the underlying problems in dihydropyridine
synthesis, we chose to design a new synthetic route to
unsymmetrically substituted dihydropyridines. We hypothe-
sized the following: N-tosylated α,β-unsaturated imines can be
used as nitrogen sources and electrophiles in the presence of
Lewis acid catalysts, so that dehydrative [4 + 2] cycloaddition
with aldehydes, which provide enol-type nucleophiles in situ,
affords the desired dihydropyridine. The resulting product
would be stable to undesired oxidation owing to the electron-
withdrawing tosyl groups. The imine used can be considered as
a reverse-electron-demanding nitrogen atom source component, as
opposed to the conventional approach (Scheme 1 (b)).
Furthermore, the tosyl groups can be removed under reductive
conditions, so that oxidation-sensitive unprotected dihydropyr-
idines can be obtained. Herein, we report that the
intermolecular reaction of α,β-unsaturated imines with
aldehydes affords dihydropyridines in a single step.
2
3
substituted dihydropyridines, the medicinal and synthetic
applications of these compounds have seen a notable increase.
However, for effective control of the chemical properties of
dihydropyridines, reliable synthetic routes to unsymmetrically
substituted or more complicatedly substituted dihydropyridines
must be designed. Several modifications of Hantzsch’s method
have been proposed for the synthesis of unsymmetrical
dihydropyridine derivatives via [3 + 3] cycloaddition of
electrophilic enals with nucleophilic enamines (Scheme 1
Scheme 1. Synthetic Routes to Dihydropyridine Derivatives
Porphyrins have emerged as useful ligands for transition-
metal catalysts in organic synthesis, when the use of other
5
ligands is infeasible. During the course of our recent study on
metalloporphyrin-catalyzed cycloaddition to afford various
heterocycles, we postulated that metalloporphyrins also catalyze
the cycloaddition of α,β-unsaturated imines with aldehydes to
afford dihydropyridines.
To prove our hypothesis, we examined the reaction with an
N-tosylated α,β-unsaturated imine 1a and a highly enolizable
Received: September 13, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02654
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Organic Letters
Letter
aldehyde 2a as model substrates (Table 1), using various
catalysts and solvents. In this reaction, we first chose the
unambiguously show that specific characteristic of the
porphyrin ligands is crucial to this reaction. The dicationic
6
catalyst did not bring about any change in the yield of 3aa
−
Table 1. Dehydrative [4 + 2] Cycloaddition of α,β-
Unsaturated Imines 1a and Aldehydes 2a
(entry 7). The ruthenium porphyrin catalyst possessing BF
4
a
−
instead of SbF , too, had no drastic effect on the reaction
entry 8). Eventually, ruthenium porphyrin with a OTf
6
−
(
counteranion, [RuCl(TDMPP)]OTf, was found to be the best
Lewis acid catalyst that gave the highest isolated yield, 79%
(
entry 9). Interestingly, ruthenium carbonyl porphyrins, which
are known to be efficient catalysts for the activation of various
14
heterocompounds, did not catalyze the reaction at all (entry
0). This result emphasized the importance of the cationic
1
feature of the catalyst for this catalysis.
The reaction mechanism proposed based on these
observations is outlined in Scheme 2. First, the N-tosylated
b
entry
catalyst
[Co(TPP)]SbF6
solvent
yield (%)
Scheme 2. Plausible Reaction Mechanism
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
17
24
44
62
<1
14
62
62
[Fe(TPP)]SbF6
c
[Co(TPP)]SbF +[Fe(TPP)]SbF
6
6
[RuCl(TDMPP)]SbF6
[Mn(TPP)]SbF6
[Cr(TPP)]SbF6
[Ru(TDMPP)](SbF6)2
[RuCl(TDMPP)]BF4
[RuCl(TDMPP)]OTf
Ru(CO) (TDMPP)
d
79
10
<1
a
Reactions were carried out using catalysts (2 mol %), 1a (0.6 mmol, 3
equiv), and 2a (0.2 mmol) in 2 mL of toluene (80 °C) for 3 h.
b
1
Determined by H NMR analysis using TCE (1,1,2,2-tetrachloro-
c
ethane) as internal standards. 1 mol % of each metal porphyrin
complex was used. Isolated yields. TDMPP: 5,10,15,20-tetrakis(2,6-
d
dimethylphenyl)porphyrinato. TPP: 5,10,15,20-tetraphenylporphyri-
nato.
cationic cobalt(III) porphyrin complex as the Lewis acid
catalyst. We have previously reported that such a catalyst
efficiently activates N-tosylated imines to undergo the aza-
7
Diels−Alder reaction with unactivated dienes; hence, we
believed that it might be a good catalyst for the present
unsaturated imine 1 is activated by the Ru porphyrin catalyst to
give the cationic intermediate A. In a parallel step, the catalyst
isomerizes aldehyde 2 to its enol form enol-2. We previously
reported that the cationic ruthenium porphyrin complex has a
cycloaddition as well. Indeed, the reaction of 1a and 2a in the
presence of [Co(TPP)]SbF (2 mol %) afforded the desired
6
8
product 3aa in 17% yield (entry 1). The reaction with
11
[
Fe(TPP)]SbF (2 mol %), which is an efficient catalyst for
unique property in which it enolizes carbonyl compounds;
6
9
aldehyde activation, also afforded the product in 24% yield
entry 2). The yield of 3aa improved to 44% when a
this feature might play a critical role in the present reaction.
The 1,4-addition of enol-2 to A affords B, followed by
intramolecular proton transfer to C. Sequential nucleophilic
attack of the nitrogen atom onto the activated carbonyl carbon
of intermediate C affords cyclic adduct D. Finally, elimination
of water from D gives the unsymmetrically substituted
dihydropyridine scaffolds. The water molecule coordinating
onto the Ru center is removed by the hydrophobic environ-
(
combination of [Co(TPP)]SbF (1 mol %) and [Fe(TPP)]-
6
SbF (1 mol %) was used as the catalyst (entry 3). This result
6
suggests that ability to activate both the imino group and the
aldehyde group is a requisite for the catalyst. Motivated by this
result, we next selected ruthenium porphyrins, which are well-
10
known to show remarkable reactivity, as catalysts for the
reaction. We also had previously demonstrated that cationic Ru
porphyrins are effective catalysts for carbonyl and N-tosylated
10,14f
ment of the porphyrin ligand,
catalyst and promoting the reaction.
thus regenerating the
1
1,12
imino activation.
In the present study, the cationic Ru(IV)
With the optimized reaction conditions in hand, we
investigated the effects of substituents on the N-tosylated α,β-
unsaturated imines (Figure 1). The reaction of 1b with 2a
afforded 3ba in good yield. Importantly, the sterically more
hindered o-methylphenyl group on the substrate 1c did not
affect the reactivity. The electron-donating methoxy group
(1d), as well as the electron-withdrawing trifluoromethyl,
fluoro, cyano, and nitro groups (1e, 1f, 1g, and 1h respectively),
were tolerated in this catalytic system. The substrate with a
heteroaryl group such as a thienyl group was transformed to
porphyrin catalyst [RuCl (TDMPP)]SbF6 afforded 3aa in
yields as high as 62% (entry 4). Other metal porphyrins such as
manganese(III) and chromium(III) porphyrins were unreactive
13
for the cycloaddition (entries 5, 6). Thus, Ru porphyrin
catalyst was identified as the best Lewis acid catalyst for the
cycloaddition. Notably, nonporphyrin-ligated acid catalysts
such as ruthenium chloride and iron chloride showed lower
catalytic activity than did the ruthenium porphyrin catalyst or
failed to catalyze the reaction (Table S1). These results
B
DOI: 10.1021/acs.orglett.5b02654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
introducing electron-withdrawing coordinating groups into the
alkyl chains. Introduction of mono- and diester groups at the γ-
positions of the aliphatic aldehydes with active α-protons failed
to promote the reaction and gave unidentifiable byproducts (2f,
15
2
g). This result urged us to test the reaction of a diester-
substituted aliphatic aldehyde without α-protons (2h). Indeed,
the reaction of 2h with 1a afforded the desired product 3ah
with the acceptable yield. In the same way, 4-methyl-4-
nitropentanal 2i was transformed to dihydropyridine 3ai in 63%
yield. These results suggest that aliphatic aldehydes can be used
with this catalytic system by effective introduction of the
appropriate functional groups into the alkyl chains.
To demonstrate the synthetic utility of the reaction, we
briefly examined the detosylation of the cycloadduct to prepare
an unprotected dihydropyridine. Indeed, detosylation was
16
accomplished by the use of samarium iodide as a reductant.
In summary, we have developed a novel synthetic route to
unsymmetrically substituted dihydropyridine derivatives via
dehydrative [4 + 2] cycloaddition of N-tosylated α,β-
unsaturated imines and aldehydes catalyzed by cationic Ru(IV)
porphyrin complexes. The proposed methodology was
employed for the successful synthesis of various N-tosylated
dihydropyridine derivatives with unprecedented substitution
patterns, and the cycloadducts could be converted to
nontosylated dihydropyridines by reduction with samarium
iodide. The proposed strategy is expected to pave the way for
the construction of structurally diverse dihydropyridines, which
cannot be prepared via conventional methods, and thus
contributes to the design of pharmaceuticals and reductants
for organic synthesis.
a
Figure 1. Cycloaddition of imines 1 and 2a. Reactions were carried
out using [RuCl(TDMPP)]OTf (2 mol %), 1 (0.6 mmol, 3 equiv),
b
and 2a (0.2 mmol) in 2 mL of toluene (80 °C) for 3 h. Isolated yields.
3
ia, although the yield was low (38%). When the unsaturated
ketimine 1j was used in the reaction, the trisubstituted
dihydropyridine 3ja was obtained in good yield.
Next, the reaction scope of the aldehydes was examined
Figure 2). Aryl acetaldehydes with electron-donating func-
(
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02654.
Experimental procedures, spectroscopic (FID), and
analytical data for new compounds (PDF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Additional files (ZIP)
AUTHOR INFORMATION
■
Corresponding Authors
Figure 2. Cycloaddition of 1a and aldehydes 2. aReactions were
carried out using [RuCl(TDMPP)]OTf (2 mol %), 1a (0.6 mmol, 3
*
E-mail: kurahashi.takuya.2c@kyoto-u.ac.jp.
*E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp.
b
equiv), and 2 (0.2 mmol) in 2 mL of toluene (80 °C) for 3 h. Isolated
c
1
yields. Determined by H NMR analysis using TCE as internal
standards.
Notes
The authors declare no competing financial interest.
tional groups reacted with the unsaturated imines to give the
desired products in satisfactory yields (2b,2c). Similarly, the
substrate with the electron-withdrawing moiety, p-chlorophe-
nylacetaldehyde 2d, was converted to 3ad in 66% yield. On the
other hand, aliphatic aldehydes such as 2e resulted in a very low
product yield of 30%. This low reactivity of the aliphatic
aldehyde was thought to be derived from its low enolizability
and weak coordinating ability toward the catalyst. Therefore,
we attempted to enhance the reactivity of aliphatic aldehydes by
ACKNOWLEDGMENTS
■
This work was aided by Advanced Catalytic Transformation
Program for Carbon Utilization (ACT-C) from Japan Science
and Technology Agency (JST) and a Grant-in-Aid for Scientific
Research (No. 15H03809 and 25105729; 23655035) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (Japan). T.K. also acknowledges the Asahi Glass
Foundation.
C
DOI: 10.1021/acs.orglett.5b02654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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D
DOI: 10.1021/acs.orglett.5b02654
Org. Lett. XXXX, XXX, XXX−XXX