Recyclable polymeric π-acid catalyst effective in aqueous and solvent-free inverse-electron-demand aza-Diels-Alder reactions

Article abstract of DOI:10.1055/s-2005-923608

A polymer-supported π-acid (poly-DCKA-1) was found to be a highly efficient and recyclable catalyst in two- and three-component inverse-electron-demand aza-Diels-Alder reactions at room temperature not only in water but also under solvent-free conditions.

Full text of DOI:10.1055/s-2005-923608

288
LETTER
Recyclable Polymeric p-Acid Catalyst Effective in Aqueous and Solvent-Free
Inverse-Electron-Demand Aza-Diels–Alder Reactions
A
a
pplications of
a
R
u
e
cyclable Po
k
lymeric
p
-A
i
cid
C
a
o
talyst Masaki,*a,b Tomoyasu Yamada,a Hyouei Kawai,a Akichika Itoh,a Yoshitsugu Arai,a Hiroshi Furukawab
Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan
b
Faculty of Pharmacy, Meijo University, Tempaku-ku, Nagoya 468-8503, Japan
Fax +81(52)8348090; E-mail: masakiy@ccmfs.meijo-u.ac.jp
Received 24 October 2005
in the presence of a variety of acid catalysts is a useful tool
for the synthesis of the tetrahydroquinoline skeleton,
which is a key structure in the biological activity of
various natural products and pharmaceutical agents.10
Although the IED-aza-Diels–Alder reactions producing
tetrahydroquinolines have been carried out in organic sol-
vents, recently the reaction was found to proceed in aque-
ous conditions using indium(III) chloride as a catalyst.11
Abstract: A polymer-supported p-acid (poly-DCKA-1) was found
to be a highly efficient and recyclable catalyst in two- and three-
component inverse-electron-demand aza-Diels–Alder reactions at
room temperature not only in water but also under solvent-free con-
ditions.
Key words: polymer, p-acid catalyst, aza-Diels–Alder reaction,
aqueous reaction, solvent-free reaction
During our work with poly-DCKA-1, we found it to be a
highly efficient and recyclable catalyst promoting aque-
ous Mannich-type reactions of various imines including
unstable imines prepared in situ from aromatic and ali-
phatic aldehydes.12 Encouraged by these results we have
examined aza-Diels–Alder reactions using poly-DCKA-
1. Here we report preliminary results on IED-aza-Diels–
Alder reactions catalyzed by poly-DCKA-1, which was
found to be a highly efficient catalyst for the two- and
three-component IED-Aza-Diels–Alder reaction at room
temperature not only in water but also under solvent-free
conditions, and the catalyst could be reused repeatedly
without appreciable loss of activity after a simple recov-
ery procedure.
Organic reactions in water1 and under solvent-free
conditions2 have recently been recognized as useful and
environmentally sustainable tools for synthesis. The de-
velopment of insoluble and highly efficient reagents3 has
recently attracted much attention from the points of view
of convenient manipulation and green chemistry.4 In this
context, polymeric modification of reagents, especially,
reaction promoters and catalysts effective in organic reac-
tions in water and in solvent-free reactions has shown
much promise.5
In our work on the development of dicyanoketene acetals
(DCKA) (Figure 1) as novel p-acid catalysts,6 we reported
that polymer-supported DCKA (poly-DCKA-1), prepared
by copolymerization of a DCKA bearing a styrene func-
tionality with ethyleneglycol dimethacrylate (EGDMA),
catalyzes reactions of acetals, monothioacetalization,7a,b
cyanation,7b,c and the Mukaiyama aldol reaction with
silicone nucleophiles,7b,c as well as Mannich-type reac-
tions of imines with silicone enolates in acetonitrile.7d The
polymer was also found to catalyze hydrolysis of acetals
and silyl ethers in an aqueous system.7e,f
Initially, dicyanoketene ethylene acetal (DCKEA),13
a
simple standard DCKA, was observed not to react with 1-
methoxy-3-trimethylsiloxy-1,3-diene (Danishefsky’s di-
ene),14 a highly reactive diene, at room temperature, after
a reaction time of 24 hours and the diene was recovered
quantitatively. It had been reported that tetracyanoethyl-
ene (TCNE) reacts vigorously with 1,3-butadiene to give
a cycloadduct.15
We examined the catalytic activity of DCKEA in the aza-
Diels–Alder reactions of N-benzylideneaniline (1) with
representative 1,3-dienes, Danishefsky’s diene (2), 2,3-
dimethyl-1,3-butadiene (3), and cyclopentadiene (4)
(Scheme 1). Although 0.2 equivalents of DCKEA cata-
lyzed the reaction with 2 in acetonitrile at room tempera-
ture to give 1,2-diphenyl-2,3-dihydropyridine-4-one (5)
in quantitative yield after 0.5 hours, DCKEA induced no
reaction with 3, and sluggishly promoted the reaction with
4 giving cyclopenta[c]quinoline (6) in 7% yield after 24
hours, without any trace of 2-azabicyclo[2.2.1]hepta-4-
ene (7), the other cycloadduct which could form with 1 as
the dienophile. The results, however, suggested that
DCKAs have the ability to catalyze IED-aza-Diels–Alder
reactions. Thus, the catalytic properties of DCKEA and
the polymer-supported DCKA (poly-DCKA-1) were
O
O
OR
OR
NC
NC
NC
NC
O
O
O
O
NC
NC
O
O
Dicyanoketene
ethyleneacetal
(DCKEA)
Dicyanoketene
acetal
poly-DCKA-1
(DCKA)
Figure 1 Dicyanoketene acetals (DCKA).
Aza-Diels–Alder reactions are a very important method
for the synthesis of nitrogen-containing heterocyclic com-
pounds.8 The inverse-electron-demand (IED) aza-Diels–
Alder reaction9 of N-arylimines and nucleophilic olefins
SYNLETT 2006, No. 2, pp 0288–0290
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923608; Art ID: U29305ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
2.
2
0
0
6

LETTER
Applications of a Recyclable Polymeric p-Acid Catalyst
289
assessed in the reaction of 1 and 2,3-dihydro-4H-pyran (8)
at room temperature in various solvents including water
and under solvent-free conditions17 to provide pyra-
no[3,2-c]quinoline derivatives [9a (syn) and 9b (anti)].16
The simple molecular catalyst DCKEA promoted the
reaction moderately well in acetonitrile with poor syn/anti
selectivity although the reaction proceeded sluggishly or
not at all in water and under solvent-free conditions
(Table 1, entries 2–6). On the contrary, higher efficiencies
were exhibited by poly-DCKA-1 in water and under
solvent-free conditions (Table 1, entries 7–10), and high
levels of syn/anti selectivity were observed for poly-
DCKA-1 compared with DCKEA. Organic solvents in-
cluding acetonitrile gave poor results providing low yields
of the cycloadducts (9a and 9b) (Table 1, entries 11–16).
OTMS
2 (1.2 equiv),
DCKEA (0.2 equiv)
MeO
Ph
Ph
N
CH3CN, r.t., 30 min
O
5 (95%)
3 (3 equiv),
DCKEA (0.2 equiv)
CH3CN, r.t., 24 h
Ph
N
no reaction
Ph
1
4 (3 equiv),
DCKEA (0.2 equiv)
CH3CN, r.t., 24 h
H
Ph
N
H
Ph
N
Ph
7 (not detected)
H
6 (17%)
Scheme 1 Reaction of benzylideneaniline with 1,3-dienes catalyzed
by DCKEA.
Poly-DCKA-1 as a catalyst worked well in the three-com-
ponent IED-aza-Diels–Alder reaction of benzaldehyde
(one equivalent), aniline (one equivalent), and 8 (six
equivalents) in water at room temperature as shown in
Table 2. Although a large excess of dienophile 8 (11
equivalents) was necessary, the reaction also proceeded
under solvent-free conditions.
Table 3 demonstrates that poly-DCKA-1 could be used
repeatedly without appreciable loss of catalytic activity in
the IED-aza-Diels–Alder reaction after the simple opera-
tion to recover the catalyst.18
Although the mechanism for the excellent polymer effect
observed in water is not clear, pores of the polymer cata-
lyst are supposed to offer local hydrophobic micro-
Table 1 IED-Aza-Diels–Alder Reaction of Benzylideneaniline and Dihydropyran Catalyzed by DCKAs
O
O
H
H
Ph
catalyst ( 0.2 equiv)
solvent, r.t., 24 h
N
+
+
H
Ph
H
Ph
O
Ph
N
H
N
H
8
1
9b (anti)
9a (syn)
Entry
1
Catalyst
8 (equiv)
6.0
1.5
6.0
13
Solvent
CH3CN
CH3CN
CH3CN
–
Yield (%)
syn/anti
–
–
–
2
DCKEA
29
44:56
3
DCKEA
43
52:48
4
DCKEA
Trace
–
5
DCKEA
1.5
6.0
1.5
6.0
6.0
13
H2O
Trace
–
6
DCKEA
H2O
8
–
7
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
poly-DCKA-1
CH3CN
CH3CN
H2O
5
–
8
19
75:25
84:16
81:19
70:30
–
9
71
10
11
12
13
14
15
16
–
66
6.0
6.0
6.0
6.0
6.0
6.0
Et2O
10
THF
6
Benzene
CH2Cl2
DMF
8
–
8
–
2
–
Acetone
Complex mixture
Synlett 2006, No. 2, 288–290 © Thieme Stuttgart · New York

290
Y. Masaki et al.
LETTER
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Table 2 Three-Component IED-Aza-Diels–Alder Reaction Cata-
lyzed by Poly-DCKA-1 in Water and under Solvent-Free Conditions
poly-DCKA-1
(0.2 equiv)
9a (syn)
+
PhCHO + PhNH2 + 8
H2O or no solvent
r.t., 24 h
9b (anti)
(1 equiv) (1 equiv)
Solvent
H2O
–
8 (equiv)
Yield (%)
9a/9b
6.0
11
73
61
85:15
84:16
Table 3 Application of Recycled Poly-DCKA-1
poly-DCKA-1
(0.2 equiv)
1 + 8 (6 equiv)
9a (syn) + 9b (anti)
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H2O, r.t., 24 h
Cycle
1st
2nd
74
3rd
Yield (%)
9a/9b
71
73
84:16
86:14
85:15
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environments of condensed areas for the active part of the
catalyst, DCKA portion. The microenvironment might
enhance the local concentration of the lipophilic substrate
by positive incorporation from the aqueous media through
a hydrophobic interaction of the substrate and the catalyst,
resulting in rate acceleration and higher syn/anti stereo-
selectivity.
In conclusion, a polymer-supported DCKA (poly-DCKA-
1) was found to be a proton-free, metal-free, and recycla-
ble catalyst for the IED-aza-Diels–Alder reaction at room
temperature in water and under solvent free conditions.
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Acknowledgment
This work was supported in part by a Grant-in-Aid from Japan
Society of the Promotion of Science to whom the authors are
grateful.
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References and Notes
(16) The 9a(syn)/9b(anti) ratio was determined by 1H NMR
analysis based on the following publication: Ma, Y.; Qian,
C.; Xie, M.; Sun, J. J. Org. Chem. 1999, 64, 6462.
(17) Typical Procedure To a mixture of benzylideneaniline (453
mg, 2.5 mmol) and poly-DCKA-1 (189 mg, 0.5 mmol equiv)
in H2O (5.0 mL), was added 3,4-dihydro-4H-pyran (1.26 g,
15 mmol) at r.t., and the mixture was stirred for 24 h. EtOAc
was added, the poly-DCKA-1 was removed by filtration, and
the filtrate was extracted with EtOAc. The organic layer was
washed with H2O, dried over anhyd MgSO4, and concen-
trated in vacuo to give the crude product, which was purified
by column chromatography on silica gel (hexane–EtOAc) to
give pure diastereoisomers 9a (404 mg, 60%) and 9b (64
mg, 11%).
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the reaction mixture followed by washing successively with
H2O and EtOAc, and drying in vacuo at r.t. for 4 h.
Synlett 2006, No. 2, 288–290 © Thieme Stuttgart · New York