A catalytic approach to the base-promoted reaction of epoxides with activated methylenes

Article abstract of DOI:10.1016/j.tetlet.2010.01.055

This contribution reports the results obtained in the definition of a catalytic method for the nucleophilic ring opening of epoxides by activated methylenes promoted by a polymer-supported base. The attention has been focused on the use of polymer supported bases and the best results have been obtained by using 4-(dimethylamino)pyridine (PS-DMAP) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine both on polystyrene (PS-BEMP). Solvent-free conditions has been essential for reaching a sufficient reactivity to realize this process, in fact when a reaction medium is used, the processes are almost unfeasible.

Full text of DOI:10.1016/j.tetlet.2010.01.055

Tetrahedron Letters 51 (2010) 1566–1569
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A catalytic approach to the base-promoted reaction of epoxides
with activated methylenes
*
Tommaso Angelini, Francesco Fringuelli, Daniela Lanari, Ferdinando Pizzo , Luigi Vaccaro
Dipartimento di Chimica, Università di Perugia, Via Elce di Sotto, 8 I-06123 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
This contribution reports the results obtained in the definition of a catalytic method for the nucleophilic
ring opening of epoxides by activated methylenes promoted by a polymer-supported base. The attention
has been focused on the use of polymer supported bases and the best results have been obtained by using
4-(dimethylamino)pyridine (PS-DMAP) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-
1,3,2-diazaphosphorine both on polystyrene (PS-BEMP). Solvent-free conditions has been essential for
reaching a sufficient reactivity to realize this process, in fact when a reaction medium is used, the pro-
cesses are almost unfeasible.
Received 4 December 2009
Revised 13 January 2010
Accepted 15 January 2010
Available online 22 January 2010
Keywords:
Epoxides
1,3-Dicarbonyl compounds
Solid bases
Ó 2010 Elsevier Ltd. All rights reserved.
Solvent-free conditions (SolFCs)
1. Introduction
We have developed several protocols for both the preparation
and the ring opening of epoxides by heteroatomic nucleophiles
Organic bases are promising alternatives to metal-containing
catalysts for a wide range of reactions.1 In addition, they can be se-
curelyanchoredona solidsupport, solvingtheproblemoftheirrecov-
ery and reuse and simplifying product isolation and purification.2
Our research is currently focused on the use of solid-supported
catalysts3 and we have showed that the efficiency of a polystyrene-
supported basic or ionic catalyst is significantly improved under
solvent-free conditions (SolFCs). The absence of a reaction medium
is an effective strategy to regain the catalytic efficiency generally
lost when a catalyst is anchored on a solid support. In fact, it is
noteworthy that in several cases, the use of SolFC is necessary for
the success of the process that can be dramatically slow or practi-
cally unfeasible by using an organic solvent.3b,c,e Highlights of our
methodologies were chemical efficiency, simplified experimental
procedures, and the minimization of the amount of organic solvent
used which is employed only to facilitate the separation of the
product from the heterogeneous catalyst.3b–f
Epoxides are useful reagents in organic synthesis, they gener-
ally react stereospecifically with several nucleophiles giving
highly-functionalized molecules that can be further manipulated.
The nucleophilic ring-opening reactions of epoxides can be pro-
moted by either acidic or basic catalysts, and efficient nucleophiles
are heteroatomic reactants, such as water, alcohols, thiols, amines,
halides, or pseudohalides.4 In addition, they are easily prepared
from a variety of substrates.
such as azide, halides, amines, and thiols, proving that the use of
alternative reaction media such as water5 and SolFC6,3f,h is crucial
for improving the efficiency of these processes. In our previous
works, we have not applied our strategy to the reactions of epox-
ides with activated methylenes.
Organometallic reagents like alkyllithium and Grignard re-
agents are known to undergo addition reactions to simple epox-
ides, but these reactions are complicated by
a variety of
competing processes,7 such as deprotonation and disproportion,
often requiring harsh conditions and the use of additives such as
BF3 and copper salts.8
Activated methylenes, such as 1,3-dicarbonyl compounds, can
be easily deprotonated and alkylated and their reactions allow
the access to highly functionalized compounds to be used as versa-
tile intermediates to prepare complex molecules. Surprisingly,
there are few examples that report the reaction of carbon nucleo-
philes (malonate, cyanoacetate, and acetylacetate esters) with
epoxides. In this context, the reaction of styrene oxide with dialkyl
malonates to give
moted ring-opening reaction followed by a lactonization of the
resulting
-hydroxy ester has been reported.9 These reactions are
a,c-substituted c-lactones through a base-pro-
c
usually performed in refluxing ethanol, with an overstoichiometric
amount of base (NaOH or Na) giving moderate yields. The use of
other carbon nucleophiles such as 1,3-diketones like acetylacetone
or
a-substituted malonate esters has never been reported.
Although it has been reported that more reactive aziridines
smoothly react with activated methylenes in the presence of a cat-
alytic amount of 2-tert-butylimino-2-diethylamino-1,3-dimethyl-
* Corresponding author. Tel.: +39 075 5855546; fax: +39 075 5855560.
E-mail address: pizzo@unipg.it (F. Pizzo).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.055

T. Angelini et al. / Tetrahedron Letters 51 (2010) 1566–1569
1567
perhydro-1,3,2-diazaphosphorine (BEMP),10 to the best of our
knowledge there are no reports of base-catalyzed protocols for
the reaction of carbon nucleophiles with epoxides.
plete conversion of 1a after 18 h, probably because of its stronger
basicity.11 PS-DMAP revealed to be more active than PS-TBD, de-
spite DMAP being less basic than TBD, which is probably due to
its minor steric hindrance.
In the presence of toluene or acetonitrile as reaction medium,
PS-BEMP showed a reduced activity, but the products’ distribution
was not significantly influenced by the polarity of the medium (Ta-
ble 1, entries 5 and 6).
In this Letter, we present our results on the approach to a cata-
lytic procedure for the reaction of activated methylenes with epox-
ides. Following our current interest based on the use of solid-
supported catalysts under SolFC, we have compared the catalytic
efficiency of different polystyrene-supported bases in the ring-
opening reaction of epoxides 1a–h by acetylacetone (2), dimethyl-
malonate (5), dimethyl methylmalonate (7), and dimethyl bromo-
malonate (10) under SolFC. Activated methylenes such as 2, 7, and
10 have never been used before as nucleophiles in epoxide ring-
opening reactions.
According to our previous works, we have chosen as represen-
tative solid bases the polystyrene-supported 4-(dimethyl-
amino)pyridine (PS-DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(PS-TBD),3a–f and the very strong Schwesinger’s phosphazene base
2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-
diazaphosphorine (PS-BEMP).3b,11 For all these bases, the solid
polymeric support was 200–400 mesh polystyrene co-polymerized
with 2% of divinylbenzene.
The use of PS-BEMP was then extended to epoxides 1b–h. The
results are illustrated in Table 2.13
Under SolFC and with 5 mol % of PS-BEMP, at 80 °C, acetylace-
tone (2) was able to react only with activated epoxides such O-pro-
tected glycidols and chloromethyl epoxide (1a and 1d–g). Under
these reaction conditions, n-octene oxide (1c) did not yield any
product, while styrene oxide (1b) decomposed. Glycidols function-
alized with a leaving group such as 1h were known to react with
activated methylenes in the presence of a stoichiometric quantity
of base, giving a nucleophilic substitution followed by ring-open-
Table 2
As a weak nucleophilic base a solid source of fluoride, Amber-
PS-BEMP-catalyzed ring-opening reaction of epoxides 1a–h by acetylacetone (2)
under SolFC at 80 °C
lyst-F (Amb-F)3a,c,e,12 was chosen as supported organic base.
O
OH
-BEMP (5 mol%)
80 °C
O
O
PS
O
2. Results and discussion
O
O
+
+
O
O
R
R
R
3
4
1
2
We have initially studied the reaction between O-phenyl glyc-
idol (1a) and acetylacetone (2), in equimolar quantities, under sol-
vent-free conditions, at 80 °C, and in the presence of 5 mol % of PS-
BEMP, PS-DMAP, PS-TBD, or Amb-F (Table 1).
The epoxide 1a reacted exclusively at the b-position, but to-
gether with the expected c-hydroxydiketone product 3a, the 1,3-
dioxane 4a was also detected. The latter comes from the attack
of the harder oxygen of the acetylacetone anion and consequent
ring closure by intramolecular Michael addition (Fig. 1). The ring-
opening reaction was efficiently catalyzed by PS-DMAP, PS-TBD,
and PS-BEMP, (Table 1, entries 1, 2, and 4) while the mild, ionic
base Amb-F (Table 1, entry 3) was less active. The phosphazene
base PS-BEMP was the best catalyst for this reaction, giving com-
Entry
Epoxide
T (h)
Yielda (%)
92
3/4b
O
PhO
1
2
18
71/29
—
1a
O
24
48
—
—
Ph
1b
O
3
4
5
6
7
8
—
H13C6
1c
O
O
O
24
48
48
24
24
72
80
80
75
—
72/28
66/34
64/36
63/37
—
1d
Table 1
Ring opening of epoxide 1a with acetylacetone (2) under SolFC at 80 °C catalyzed by
organic supported bases
Ph
O
1e
-base
O
OH
O
O
O
O
O
(5 mol%)
O
O
PhO
PhO
O
PhO
O
+
+
O
80 °C
1f
O
4a
1a
3a
2
Cl
Entry
Medium
Base
T (h)
Conversiona (%)
3a/4a
1g
1
2
3
4
5
6
SolFC
SolFC
SolFC
SolFC
PhMe(0.5 M)
MeCN(0.5 M)
PS-DMAP
PS-TBD
Amb-F
PS-BEMP
PS-BEMP
PS-BEMP
24
24
24
18
24
24
92
86
54
>99
7
72/28
79/21
76/24
71/29
57/43
77/23
O
TsO
1h
a
13
Overall isolation yield of both 3 and 4.
Measured by NMR analyses.
b
a
The remaining material was unreacted 1a and 2; measured by NMR analyses.
O
O
O
O
O
H
O
O
PhO
PhO
O
PhO
O
1a
4a
Figure 1. Formation of 1,3-dioxane 4a.

1568
T. Angelini et al. / Tetrahedron Letters 51 (2010) 1566–1569
Table 3
To avoid the formation of the corresponding spiro product,
-substituted malonates 7 and 10 were considered. Initially, we
Ring opening of epoxide 1a with dimethyl malonate (5) under SolFC at 80 °C
catalyzed by organic supported bases
a
have studied the reaction between O-phenylglycidol (1a) and
dimethyl methylmalonate (7) under SolFC in the presence of PS-
DMAP or PS-BEMP (Table 4).
Surprisingly, PS-DMAP revealed to be an active catalyst, while
PS-BEMP showed no catalytic activity. This can be tentatively
explained by invoking steric factors considering the bulkiness of
PS-BEMP. PS-DMAP promoted this reaction under SolFC at 80 °C
to give a mixture of 8 and 9 that was first purified and treated with
-base
PS
O
O
O
O
(5 mol%)
OPh
PhO
O
+
O
O
O
PhO
80 °C, 24 h
O
6
1a
5
-Base
PS
Entry
Yield of 6 (%)
LiI in aqueous DMF to give pure a-lactone 9 as a mixture of diaste-
roisomer with an overall 44% yield.
1
2
3
4
PS-DMAP
PS-TBD
PS-BEMP
45
10
89
—
Under the same conditions, the reaction between O-phenylglyc-
idol (1a) and dimethyl bromomalonate (10) gave different results
(Table 5). Bromomalonate anion reacted with 10 and after subse-
quent elimination of HBr led to tetramethyl ethene–tetracarboxyl-
ate (12). Epoxide 1a under these conditions in the presence of HBr
gave the corresponding bromohydrine (11).
PS-BEMP in PhMe
ing reaction with the formation of the corresponding cyclopro-
panes.10a,14 In our case we did not observe any reaction.
The stronger base PS-BEMP was again the best catalyst for this
transformation, giving shorter reaction time, while yields were
similar to those obtained with PS-DMAP.
It was also found that O-phenyl glycidol (1a) reacted under Sol-
FC at 80 °C in 24 h with dimethyl malonate (5), in equimolar quan-
tities and in the presence of a supported base, giving spirolactone
6. These results are illustrated in Table 3.
3. Conclusions
According to the previous results, PS-BEMP was the best cata-
lyst, giving product 6 in 89% yield under SolFC, while in toluene
the reaction did not occur at all (Table 3, exp 3 vs 4). Again,
PS-DMAP was more active than PS-TBD to promote the ring-
opening reaction (Table 3, exp 1 vs 2). With the intention of iso-
In conclusion, we have investigated the nucleophilic ring open-
ing of epoxides by activated methylenes 2, 5, 7, and 10 under sol-
vent-free conditions by using polystyrene-supported bases as
catalysts and stoichiometric quantities of reagents. The best results
have been obtained by using 5 mol % of PS-BEMP or PS-DMAP.
Swelling problems, related to the access to reactive sites of the
polymer-supported catalysts, can be overcome under SolFC, where,
apparently, the reactants flow through the polymer network more
easily than in the presence of an additional reaction medium.
These results are promising and represent the first effort to define
lating the product
c-lactone coming from the attack of 5 to 1a
and consequent lactonization, various reaction conditions and
1a/5 ratios were tested but with no result. This outcome is prob-
ably due to the higher acidity of the c-lactone compared to that
of dimethyl malonate (5)15 that under reaction conditions is
promptly deprotonated reacting as soon as it is formed with an-
other molecule of 1a.
Table 4
Ring opening of epoxide 1a with dimethyl methylmalonate (7) under SolFC at 80 °C in the presence of organic supported bases
-base
PS
O
O
O
O
O
O
O
LiI, DMF aq.
Reflux
(5 mol%)
80°C
R
PhO
PhO
PhO
+
O
O
8, R= CO2Me
9, R= H
1a
9
7
-Base
PS
Entry
T (h)
Yield of 9a (%)
1
2
PS-DMAP
PS-BEMP
24
48
44
—
Table 5
Ring opening of epoxide 1a with dimethyl bromomalonate (10) under SolFC at 80 °C catalyzed by organic supported bases
-base
PS
OH
O
O
O
MeO2C
MeO2C
CO2Me
CO2Me
(5 mol%)
80 °C
PhO
Br
PhO
+
+
O
O
Br
1a
10
11
12
Yield of 11a (%)
Yield of 12b (%)
-Base
PS
Entry
T (h)
1
2
PS-DMAP
PS-BEMP
120
36
83
79
70
82
a
Isolation yield calculated on 1a.
Isolation yield calculated on 10.
b

T. Angelini et al. / Tetrahedron Letters 51 (2010) 1566–1569
1569
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Acknowledgments
We gratefully acknowledge the Ministero dell’Istruzione
dell’Università e della Ricerca (MIUR) and the Università degli Stu-
di di Perugia for financial support. We also wish to thank the Fond-
azione Cassa di Risparmio di Perugia for a post-doc grant.
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Supplementary data
Supplementary data (all the procedures and the spectroscopic
data for known (8, 11 and 12) and new compounds (3a, 3d–g,
4a, 4d–g and 6)) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2010.01.055.
10. Moss, T. A.; Alba, A.; Hepworth, D.; Dixon, D. J. Chem. Commun. 2008, 2474–
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