Organocatalytic decarboxylative Doebner-Knoevenagel reactions between arylaldehydes and monoethyl malonate mediated by a bifunctional polymeric catalyst

Article abstract of DOI:10.1055/s-0030-1260808

A bifunctional polystyrene bearing both DMAP and piperidine groups has been prepared and used as an organocatalyst for decarboxylative Doebner-Knoevenagel reactions of arylaldehydes and monoethyl malonate. Isolated yields of the resulting cinnamates were very high, and in all cases only the E-isomer was detected. When a polystyrene catalyst functionalized with only DMAP or piperidine groups was used in these reactions, catalysis was much less efficient. Furthermore, catalysis using a combination of the monofunctional polymers was also less efficient than with the bifunctional polystyrene. Thus, it appears that there is a synergistic effect obtained by co-locating the two different catalytic amine groups on the same polymer backbone. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260808

LETTER
1723
Organocatalytic Decarboxylative Doebner–Knoevenagel Reactions between
Arylaldehydes and Monoethyl Malonate Mediated by a Bifunctional
Polymeric Catalyst
D
oebner–
i
noeve
n
nage
l
Reacti
n
ons between
i
Arylaldehyde
L
s
and
M
onoeth
u
yl
M
alonate, Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +85228571586; E-mail: phtoy@hku.hk
Received 13 March 2011
organocatalysts,10,11 and have recently described the use
of immobilized DMAP catalysts in Morita–Baylis–Hill-
man reactions12 and CO2 addition to epoxide processes.13
Furthermore, we have reported a bifunctional polymeric
Abstract: A bifunctional polystyrene bearing both DMAP and pip-
eridine groups has been prepared and used as an organocatalyst for
decarboxylative Doebner–Knoevenagel reactions of arylaldehydes
and monoethyl malonate. Isolated yields of the resulting cinnamates
were very high, and in all cases only the E-isomer was detected. phosphine-phenol organocatalyst for alkyne isomeriza-
tion reactions,14,15 and a related amine-phosphine bifunc-
When a polystyrene catalyst functionalized with only DMAP or pi-
peridine groups was used in these reactions, catalysis was much less
tional polymer-supported reagent for a wide range of
efficient. Furthermore, catalysis using a combination of the mono-
Wittig reactions.16 Thus, we wanted to see if our strategy
functional polymers was also less efficient than with the bifunction-
of immobilizing two different catalyst or reagent groups
al polystyrene. Thus, it appears that there is a synergistic effect
onto the same polystyrene17 backbone would be applica-
obtained by co-locating the two different catalytic amine groups on
ble for the generation of a bifunctional DMAP-piperidine
polymeric organocatalyst. Herein we report the synthesis
of such a polymer and its application in a series of Doeb-
ner–Knoevenagel reactions that result in the stereoselec-
tive synthesis of a range of (E)-cinnamates from the
corresponding arylaldehydes.
the same polymer backbone.
Key words: Doebner–Knoevenagel reaction, organocatalysis,
polystyrene, DMAP, cinnamates
The Doebner–Knoevenagel reaction is a venerable and
versatile process that has received renewed interest in re-
cent years.1 For example, when malonic acid is used as the
pronucleophile, it has been demonstrated to be useful for
the conversion of 2- or 4-hydroxyarylaldehydes into the
corresponding styrenes,2 and has been used in conjunction
with a hydroformylation reaction in a one-pot procedure
for stereoselectively synthesizing (E)-a,b-unsaturated
carboxylic acids.3 Alternatively, it has been demonstrated
by List and co-workers4 that monoesters of malonic acid5
can also be used in a variation of this reaction for the ste-
reoselective synthesis of (E)-cinnamates from arylalde-
hydes (Scheme 1).6–8 These later reactions are efficiently
catalyzed by a combination of piperidine and DMAP, and
thus this process represents an attractive organocatalytic
alternative to the Wittig reaction for cinnamate synthesis
since only CO2 and water are produced as byproducts
rather than Ph3PO.
Since it was reported that the combination of DMAP and
piperidine catalyzed the reaction between nonenolizable
arylaldehydes and monoethyl malonate to form the corre-
sponding (E)-cinnamates, we co-polymerized monomers
1
12 and 218 with styrene in a 1:1:10 ratio. After deprotec-
tion and basification of the resulting polymer 3, bearing
both electron-rich 4-dialkylaminopyridine and cyclic sec-
ondary amine groups, was obtained in moderate overall
yield (Scheme 2).18 It should be noted that styrene was in-
corporated into 3 so that it could be isolated as a dry, free-
flowing powder. When no styrene was used, the resulting
polymer was a tacky, amorphous material that was diffi-
cult to handle. For comparison, monofunctional polymers
4 and 5 were prepared similarly by the omission of 2 or 1,
respectively, from the polymerization reaction. The
monomer incorporation ratios of 3–5, and thus the loading
1
levels, were determined by H NMR analysis, and were
found to be similar to the theoretical values based on the
monomer input ratios. It should be noted that polymers 3–
5 were found to be soluble in DMF, and thus they could
function as homogeneous catalysts.
CO2Et
DMAP (10 mol%)
Ar
+
HO2C
CO2Et
Ar CHO
piperidine (10 mol%)
+ CO2 + H2O
Scheme 1 The Doebner–Knoevenagel reaction in cinnamate syn-
For the benchmark Doebner–Knoevenagel reaction used
to assess the utility of bifunctional catalyst 3, we arbitrari-
ly chose 4-methoxybenzldehyde (6a) as the reaction part-
ner with monoethyl malonate (7) to form cinnamate 8a,
using 5 mol% of the catalyst(s) (Table 1).18,19 As can be
seen from entries 1 and 2, when either monofunctional
polymeric catalyst 4 or 5, with only DMAP or piperidine
groups, respectively, was used (5 mol% in DMF at 50 °C)
only low yield of desired product 8a was obtained. This is
thesis
We have been interested in both the development of poly-
mers for use in organic synthesis9 and polymer-supported
SYNLETT 2011, No. 12, pp 1723–1726
x
x
.x
x
.2
0
1
1
Advanced online publication: 29.06.2011
DOI: 10.1055/s-0030-1260808; Art ID: W06811ST
© Georg Thieme Verlag Stuttgart · New York

1724
J. Lu, P. H. Toy
LETTER
n3
n2
n1
1. AIBN, PhMe, 85 °C, 24 h
n1
+ n2
+ n3
2. TFA, CH2Cl2
3. KOH aq
NMe
N
N
NMe
N
NBoc
NH
2
N
1
n1 n2 n3
n1
10.1
9.3
n2
1
1
n3
1.1
0
for 3
for 4
for 5
10
8
1
1
0
1
0
1
3:
4:
5:
8
7.6
0
1
Scheme 2 Synthesis of polymers 3–5
similar to what was previously reported.4 However, when other substrates, and required a longer time to proceed to
a combination of 4 and 5 were used together, the isolated completion (Table 2, entry 1). Of the other benzldehyde
yield of 8a was dramatically higher (Table 1, entry 3). derivaties 6c–p studied, only very sterically hindered 6o
Significantly, when bifunctional catalyst 3 was used to failed to react to completion, even after a prolonged reac-
catalyze the reaction, nearly quantitative yield of 8a was tion time (Table 2, entry 14), and it was clear that none of
obtained (Table 1, entry 4), which is the same result ob- the substitutents studied exerted either a strong activating
served when the combination of actual DMAP and piperi- or deactivating effect. We also examined heteroaromatic
dine was used (Table 1, entry 5). Thus, it appears that aldehyde substrates 6q–s and found that the correspond-
there is an advantage to using a single bifunctional poly- ing (E)-a,b-unsaturated esters 8q–s could also be obtained
mer over using a combination of monofunctional poly- in essentially quantitative yield (Table 2, entries 16–18).
mers, and that 3 is a good replacement for the pair of DMAP In all cases formation of products 8b–s was highly stereo-
and piperidine catalysts in decarboxylative Doebner– selective, and only the E-isomer was detected by 1H NMR
Knoevenagel reactions.
spectroscopy. Furthermore, isolation of pure 8b–s was
simplified by the polar and macromolecular nature of 3,
since it did not elute during chromatographic purification
of the desired product. Additionally, since only a small
quantity of solvent was used in these reactions, it too was
separated from the desired product directly by chromatog-
raphy. Thus, 3 appears to be a general catalyst for these
reactions, and its use as a replacement for DMAP and pi-
peridine is advantageous. Unfortunately, attempts to re-
cover and reuse 3 were not successful due to difficulty in
precipitating it from the reaction mixtures and obtaining it
in a pure state.
Table 1 Catalyst Screening for the Reaction between 6a and 7
CHO
MeO
CO2Et
6a
+
catalyst(s) (5 mol%)
DMF, 50 °C, 15 h
CO2Et
MeO
8a
CO2H
7
Entry
Catalyst(s)
Isolated yield of 8a (%)a E/Zb
In summary, we have developed a soluble, bifunctional
polystyrene DMAP-piperidine material that is effective as
a catalyst in decarboxylative Doebner–Knoevenagel con-
densation reactions between arylaldehydes and monoeth-
yl malonate which result in the stereoselective formation
of (E)-cinnamates that are easily isolated in nearly quanti-
tative yield. Control reactions indicate that the DMAP and
piperidine groups attached to the polymer cooperate to-
gether to more efficiently catalyze the reactions than when
only one of the functional groups is present, and that co-
locating the two catalyst groups on the same polymer
backbone enhances this synergy compared to when a
combination of two monofunctional polymers is used. To
our knowledge this is the first example of such an obser-
vation with organic polymers, and thus the performance
of 3 compared to the combination of 4 and 5 in other or-
ganocatalytic applications, as well as the activity of other
bifunctional polymeric organocatalysts, is currently under
1
2
3
4
5
4
10
21
78
97
97
>99:1
>99:1
>99:1
>99:1
>99:1
5
4 + 5
3
DMAP + piperidine
a Yield of reactions using 6a (0.5 mmol), 7 (0.75 mmol), and cata-
lyst(s) (0.025 mmol) at 50 °C in DMF (0.5 mL) for 15 h.
b Determined by 1H NMR analysis.
After demonstrating the utility of 3 for catalyzing the for-
mation of 8a, we then studied the scope of aryl aldehydes
applicable in this reaction (Table 2).20 When 6b, bearing
an electron-donating 4-hydroxy group, was used as the
starting material, the reaction was more sluggish than with
Synlett 2011, No. 12, 1723–1726 © Thieme Stuttgart · New York

LETTER
Doebner–Knoevenagel Reactions between Arylaldehydes and Monoethyl Malonate
1725
Table 2 Doebner–Knoevenagel Condensation Reactions Catalyzed
by 3 (continued)
investigation. The results of these studies will be reported
in due course.
CO2Et
3 (5 mol%)
CO2Et
Table 2 Doebner–Knoevenagel Condensation Reactions Catalyzed
by 3
+
Ar CHO
Ar
DMF, 50 °C, 15–18 h
CO2H
6b–s
8b–s
E/Z > 99:1
CO2Et
7
3 (5 mol%)
CO2Et
+
Ar CHO
Ar
Entry Aldehyde
Product
Isolated yield (%)a
99
DMF, 50 °C, 15–18 h
CO2H
6b–s
8b–s
E/Z > 99:1
7
CHO
O
Entry Aldehyde
Product
Isolated yield (%)a
91b
12
8m
8n
O
6m
CHO
CHO
1
8b
13
14
90
HO
6b
Br
6n
6o
CHO
Cl
2
8c
92
96
CHO
Cl
8o
59d
6c
CHO
3
4
8d
CHO
6d
6e
15
16
8p
8q
95
99
CHO
NC
6p
8e
96
CHO
N
CHO
6q
5
6
7
8
8f
8g
8h
8i
99
98
89c
89
CHO
CHO
S
Br
17
18
8r
8s
99
91
6f
6r
O
CHO
Cl
6g
6s
CHO
a Reactions using 6b–s (0.5 mmol), 7 (0.75 mmol), and 3 (0.025
mmol) at 50 °C in DMF (0.5 mL) for 15–18 h.
b This reaction required 62 h to complete.
OHC
6h
c Since 6h bears 2 aldehyde groups, 1.50 mmol of 7 and 0.05 mmol of
3 were used. The product obtained was the corresponding (E,E)-bis-
enoate.
CHO
d This reaction was stopped after 48 h.
O2N
6i
OMe
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
CHO
OMe
9
8j
85
MeO
Acknowledgement
6j
CHO
OMe
This research was supported financially by the University of Hong
Kong and the Research Grants Council of the Hong Kong S. A. R,
P. R. of China (Project No. HKU 704108P).
10
11
8k
8l
99
98
6k
CHO
References and Notes
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1948, 70, 2601. (e) Klein, J.; Bergmann, E. D. J. Am. Chem.
AcHN
6l
Synlett 2011, No. 12, 1723–1726 © Thieme Stuttgart · New York

1726
J. Lu, P. H. Toy
LETTER
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(19) Increasing the catalyst loading did not significantly affect
the isolated yield or stereoselectivity of the reaction.
(20) General Procedure for Doebner–Knoevenagel Reactions
Commercially available arylaldehydes 6a–s (0.5 mmol), 7
(0.75 mmol), and catalyst 3 (0.025 mmol) were dissolved in
DMF (0.5 mL). The mixture was stirred at 50 °C for 15–18
h, and then the reaction mixture was purified directly by
column chromatography (EtOAc–hexane) to afford the
desired product 8a–s. In all cases only the E-stereoisomer
was observed by 1H NMR spectroscopy.
Synlett 2011, No. 12, 1723–1726 © Thieme Stuttgart · New York

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