E-factor minimized protocols for the polystyryl-BEMP catalyzed conjugate additions of various nucleophiles to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1039/c1gc16088e

Efficient protocols for the addition of carbon-, sulphur- and nitrogen-nucleophiles to α,β-unsaturated carbonyl compounds catalyzed by PS-BEMP have been reported. The adoption of solvent-free conditions (SolFC) was crucial for improving the efficiency of all the processes, while by using an organic reaction medium poor results were obtained. Addition reactions were performed by using equimolar amounts of reagents, and the products were isolated by simple filtration with the minimal amount of organic solvent. This approach allowed the E-factor, a measure of the waste of a reaction, to be minimized. Further waste minimization (95.7% compared to batch protocol) has been accomplished by defining a larger scale continuous-flow protocol operating under SolFC.

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PAPER
E-factor minimized protocols for the polystyryl-BEMP catalyzed conjugate
additions of various nucleophiles to a,b-unsaturated carbonyl compounds†
Simona Bonollo, Daniela Lanari, Julie M. Longo and Luigi Vaccaro*
Received 1st September 2011, Accepted 4th October 2011
DOI: 10.1039/c1gc16088e
Efficient protocols for the addition of carbon-, sulphur- and nitrogen-nucleophiles to
a,b-unsaturated carbonyl compounds catalyzed by PS-BEMP have been reported. The adoption
of solvent-free conditions (SolFC) was crucial for improving the efficiency of all the processes,
while by using an organic reaction medium poor results were obtained. Addition reactions were
performed by using equimolar amounts of reagents, and the products were isolated by simple
filtration with the minimal amount of organic solvent. This approach allowed the E-factor, a
measure of the waste of a reaction, to be minimized. Further waste minimization (95.7%
compared to batch protocol) has been accomplished by defining a larger scale continuous-flow
protocol operating under SolFC.
catalysts, which are generally but not always,7c–e less efficient than
their non-supported counterparts. In the past, this group has
shown that polystyrene-supported 1,5,7-triazabicyclo[4.4.0]dec-
Introduction
The Michael addition is one of the more important carbon–
carbon bond forming reactions in organic chemistry.1 The aza-
5-ene (PS-TBD, 1b) is more effective under SolFC than in typical
and sulfa-Michael additions2 are equally important carbon-
organic solvents.5h,i Further efforts have been made to reduce the
nitrogen and carbon-sulfur bond forming reactions, respectively,
environmental impact of these processes by using an equimolar
which are key steps in the preparation of several intermediates.
ratio of reactants to reduce waste. This, in turn, helps to reduce
In general, these reactions must take place in either strongly
the E-factor of these addition reactions.
basic or strongly acidic conditions.
Recently, we have focused our work on the optimization of
synthetic procedures, including Michael additions, by employing
eco-friendly reaction protocols based on the use of water,3
In particular, our attention has been focused on 2-
tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-
diazaphosphorine supported on polystyrene (PS-BEMP, 1a)
(Fig. 1), a very strong base (MeCNpKa is 27.63) and a member of
solvent-free conditions (SolFC),4 and polymer-supported
the class of Schwesinger’s phosphazene bases that have proved to
organocatalysts.5 With our approach we have achieved efficient
be widely useful, uncharged auxiliary bases.8 By using a catalytic
waste minimization (E-factor minimization)6 by setting single-
amount of PS-BEMP, we have reported the nucleophilic addition
and multistep cyclic continuous-flow reactors.5a–d,f
of nitroalkanes to a,b-unsaturated carbonyl compounds5f and
The development of polymer-supported material as reagents
the addition of carbon nucleophiles5e and phenols5c to epoxides
or organocatalysts has greatly increased in recent years.7
under solvent-free conditions, in batch condition and also by
These supported catalysts are a more sustainable and chem-
using a cyclic continuous flow reactor.
ically efficient alternative to traditional basic catalysts used
In this paper, we present the application of our approach
in Michael additions because they are easily recoverable and
to the use of PS-BEMP as catalyst for the Michael and hetero-
recyclable.
Michael addition of a variety of nucleophiles to a,b-unsaturated
carbonyl compounds.
The use of SolFC together with polymer-supported organo-
catalysts has been shown to increase the effectiveness of the
Results and discussion
Laboratory of Green Synthetic Organic Chemistry, CEMIN -
Dipartimento di Chimica, Universita` di Perugia, Via Elce di Sotto, 8,
Perugia, Italia. E-mail: luigi@unipg.it; Fax: +39 075 5855560; Tel: +39
075 5855541
† Electronic supplementary information (ESI) available: Characteriza-
tion data and copies of the 1H and 13C NMR spectra for compounds 6,
9, 10, 15, 23, 25, 27a, 27b, 28a, 28b, 29. See DOI: 10.1039/c1gc16088e
Initially, the efficiency of PS-BEMP (1a) was compared to that
of PS-TBD (1b), JJ-TBD (1c), and PS-DMAP (1d) (Fig. 1) in
the reaction of equimolar amounts of benzylidene acetone (2a)
and dimethylmalonate (3a) under SolFC with 5 mol% of catalyst
(Table 1).
164 | Green Chem., 2012, 14, 164–169
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Table 1 Optimization of the base-catalyzed Michael addition of
dimethylmalonate (3a) to trans-4-phenyl-3-buten-2-one (2a)a
and equimolar amounts of reactants (for exceptions see entries
3,7 and 8). These conditions, together with the use of SolFC,
allowed us to define a simple and chemically efficient protocol
for minimizing the amount of waste and consequently the E-
factor of the processes (for calculation of E-factor see Electronic
Supplementary Information†).
Waste was further minimized through the work-up procedure
consisting of a simple filtration of the reaction mixture using the
minimum possible amount of solvent. In the case of the carbon
nucleophiles, the E-factor ranged from 5.9 to 12.1. When methy-
lacrylate (2c) was used in the reaction with dimethylmalonate
(3a) and ethylnitroacetate (3b) an additional bis-adduct product
was formed when the reactants were used in a one to one ratio
(37% and 20% respectively).
To suppress this side product, three equivalents of the
nucleophile were used, though for the production of 10, 12%
of the product was still the bis-adduct.
The two sulfur nucleophiles, benzenethiol (13a) and bu-
tanethiol (13b), were very reactive (Table 3). In all cases, the
reactions reached 100% conversion at 30 ◦C in a very short time
and the products 14–19 were isolated in yields ranging from
92–97%.
Entry
Catalyst
Solvent (M)
Conversion (%)b
1
2
3
4
5
6
7
8
9
PS-BEMP
PS-BEMP
PS-TBD
—
—
—
—
86
100 (97)c
2
54
0
10
9
2
JJ-TBD
PS-DMAP
PS-BEMP
PS-BEMP
PS-BEMP
PS-BEMP
—
CH3CN (0.5)
CH2Cl2 (0.5)
THF (0.5)
MeOH (0.5)
63
a Reaction conditions: 2a (1.0 mmol), 3a (1.0 mmol), catalyst (5 mol%),
30 ◦C. b Determined by GC analyses. c Reaction conducted at 60 ◦C;
isolated yield for 4 reported in parentheses.
These nucleophiles also required the least amount of catalyst
(0.5 mol%), except for the formation of 15 (Table 3, entry 2),
in which 2 mol% of PS-BEMP was used. The E-factor for the
formation of 14–19 ranged from 5.7–8.8.
The results of the Michael additions of nitrogen nucleophiles,
20a–c are shown in Table 4. Due to the low nucleophilicity of
these heterocycles, temperatures from 60 to 80 ◦C were generally
required, except in the formation of 27a and 27b in which the
temperature was kept at 30 ◦C (Table 4, entry 7). These reactions
also proceeded much more slowly than the sulfur nucleophiles,
with reaction times ranging from 24 to 120 h. The E-factor
ranged from 9.5 to 12.7.
Finally, the recovery of the catalyst was also considered. PS-
BEMP was able to be reused for five consecutive runs without
any decrease of its catalytic efficiency.
Fig. 1 Supported bases used in this study.
In addition, we have also set a continuous-flow procedure
for the reaction of 2c with 3c (Scheme 1) to show that by this
After 24 h at 30 ◦C, the reaction with PS-BEMP was at 86%
conversion (Table 1, entry 1), while other supported bases, PS-
TBD and PS-DMAP respectively, gave only traces of product 4
(Table 1, entries 3,5). JJ-TBD, a more efficient catalyst than PS-
TBD,5a allowed us to obtain product 4 with a 54% conversion
(Table 1, entry 4).
PS-BEMP was then tested in a variety of reaction media and
the best isolated yield was obtained under SolFC (Table 1, entries
1–2 vs. entries 6–9). Also, in the presence of dichloromethane,
which is reported to be the most appropriate swelling solvent for
polystyrene resins, an unsatisfactory result was obtained (Table
1, entry 7).
The applicability of this protocol was then tested in the
Michael addition of carbon (3a–c), sulfur (13a–b), and nitrogen
nucleophiles (20a–c) with three representative a,b-unsaturated
carbonyl compounds 2a–c.
Table 2 shows the results for the reactions of 2a–c with 3a–c.
As with the reaction of 2a with 3a, PS-BEMP proved to
be an effective catalyst for the Michael additions of the other
carbon nucleophiles furnishing products 4–12 in high yields
(85–97%). The reactions proceeded with 5 mol% of the catalyst
Scheme 1 Continuous-flow protocol for the representative reaction of
2c with 3c.
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Table 2 PS-BEMP catalyzed Michael addition of carbon nucleophiles 3a–c to a,b-unsaturated carbonyl compounds 2a–ca
Entry
1
A
NuH
T/◦C
t (h)
Product
Yield (%)b
97
E-factorc
5.9
2a
3a
60
24
2
2a
3b
60
120
95d
9.0
3e
4
2a
2b
3c
3a
80
30
48
24
90d
95
6.5
11.0
5
6
2b
2b
3b
3c
30
30
24
24
93d
94d
7.5
11.3
7f,g
2c
3a
30
72
85
10.1
8f,g
2c
2c
3b
3c
30
30
3.5
3
90
92
9.5
9
12.1
a Reaction conditions: acceptor (1.0 mmol), donor (1.0 mmol), catalyst (5 mol%). b Isolated yield of the pure products. c For calculation see
Electronic Supplementary Information.† d Diastereoisomeric mixture. e 20 mol% of catalyst were used. f 3 equiv. of nucleophiles were used. g Column
chromatography purification was necessary.
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Table 3 PS-BEMP catalyzed sulfa-Michael addition of thiols 13a–b to a,b-unsaturated carbonyl compounds 2a–ca
Entry
1
A
R3SH
t (h)
Product
Yield (%)b
97
E-Factorc
5.7
2a
13a
5
2d
2a
2b
13b
13a
1
5
95
92
6.4
7.6
3
4
2b
13b
3
96
8.0
5
6
2c
2c
13a
13b
2
1
96
93
7.6
8.8
a Reaction conditions: acceptor (1.0 mmol), donor (1.0 mmol), catalyst (0.5 mol%), 30 ◦C. b Isolated yield of the pure products. c For calculation see
Electronic Supplementary Information.† d 2 mol% of catalyst were used.
approach it is also possible to even further reduce the waste of
processes performed under SolFC. According to our previous
reports in this field, the reactor is also a very effective tool to
maintain the catalyst integrity (chemical and physical) and per-
form the process at large scale without further optimization.5a–d,f
The schematic representation of the reactor is depicted in
Scheme 1 (thermostated box is not showed for clarity).
The equimolar mixture (50 mmol) of 2c and 3c was charged
into a glass column functioning as a reservoir. The catalyst PS-
BEMP (5 mol%, 2.5 mmol of BEMP) was charged into a glass
column and the reaction mixture was continuously pumped
through it at 30 ◦C for 3.0 h (the time necessary for the complete
conversion to 12. At this point, the pump was left to run in
order to recover the reaction mixture into the reservoir. Then
MeOH was added (3 ¥ 2 mL) to wash the catalyst and to
isolate product 12 in 95% yield after removal of the solvent
under reduced pressure.
The same protocol was repeated for five consecutive runs
and the efficiency of the catalyst was unchanged. After 3 h
the conversion of 2c and 3c to 12 was always complete and
the final product was always recovered in very high yields
(93–95%).
The E-factor of the process in flow is 0.52 (see Electronic
Supplementary Information† for details) with a reduction of
95.7% compared to the 12.1 value obtained in the batch process
(Table 2, entry 9).
Conclusions
In conclusion, we have reported an efficient protocol for
the Michael addition of carbon-, sulphur- and nitrogen-
nucleophiles to a,b-unsaturated carbonyl compounds employ-
ing PS-BEMP as catalyst. Reactions were conducted under
SolFC with equimolar amounts of reagents and the products
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Table 4 PS-BEMP catalyzed aza-Michael addition of N-heterocycles 20a–c to a,b-unsaturated carbonyl compounds 2a–ca
Entry
1
A
NuH
T/◦C
t (h)
Product
Yield (%)b
90d
E-Factorc
9.5
2a
20a
60
120
2
2a
20b
80
24
75
11.2
3
4
2a
2b
20c
20a
60
80
24
24
72
12.2
12.1
92d
5
6
7
2b
2b
2c
20b
20c
20a
80
60
30
24
24
72
91
83
94d
10.9
12.7
12.4
8e
2c
2c
20b
20c
60
60
96
72
96
99
11.5
9.8
9f
a Reaction conditions: acceptor (1.0 mmol), donor (1.0 mmol), catalyst (5 mol%). b Isolated yield of the pure products. c For calculation see Electronic
Supplementary Information.† d Regioisomeric mixture. e 3 equiv. of acceptor were used. f 2 equiv. of acceptor were used.
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were isolated by simple filtration using the minimal amount of
organic solvent necessary for the workup. This approach allowed
us to reduce dramatically the reaction’s waste, thus minimizing
the E-factor. We have also defined a continuous-flow protocol for
the representative reactions of 2c with 3c operating under SolFC
on a 50 mmol scale. Under these conditions the same catalyst
can be used for at least 5 consecutive runs with no decrease of its
efficiency. E-factor has been reduced by 95.7%. This approach
has allowed the physical integrity of the catalyst to be conserved
and proves that continuous-flow reactors operating under SolFC
is a promising tool to reduce waste.
A. A. Narine, Synthesis, 2007, 959–980; (d) G. Bartoli, M. Bartolacci,
A. Giuliani, E. Marcantoni, M. Massaccesi and E. Torregiani, J. Org.
Chem., 2005, 70, 169–174.
3 As representative examples see: (a) S. Bonollo, D. Lanari, F. Pizzo
and L. Vaccaro, Org. Lett., 2011, 13, 2150–2152; (b) S. Bonollo, D.
Lanari and L. Vaccaro, Eur. J. Org. Chem., 2011, 2587–2598; (c) S.
Bonollo, D. Lanari, A. Marrocchi and L. Vaccaro, Curr. Org. Synth.,
2011, 8, 319–329.
4 As representative examples see: (a) D. Lanari, R. Ballini, A. Palmieri,
F. Pizzo and L. Vaccaro, Eur. J. Org. Chem., 2011, 2874–2884; (b) L.
Castrica, F. Fringuelli, F. Pizzo and L. Vaccaro, Lett. Org. Chem.,
2008, 5, 602–606; (c) F. Fringuelli, R. Girotti, F. Pizzo and L. Vaccaro,
Org. Lett., 2006, 8, 2487–2489.
5 (a) D. Lanari, R. Ballini, S. Bonollo, A. Palmieri, F. Pizzo and L.
Vaccaro, Green Chem., 2011, DOI: 10.1039/C1GC15790F; (b) S.
Bonollo, D. Lanari, T. Angelini, A. Marrocchi, F. Pizzo and L.
Vaccaro, J. Catal., 2011, DOI: 10.1016/j.jcat.2011.09.032; (c) A.
Zvagulis, S. Bonollo, D. Lanari, F. Pizzo and L. Vaccaro, Adv. Synth.
Catal., 2010, 352, 2489–2496; (d) F. Fringuelli, D. Lanari, F. Pizzo
and L. Vaccaro, Green Chem., 2010, 12, 1301–1305; (e) T. Angelini,
F. Fringuelli, D. Lanari and L. Vaccaro, Tetrahedron Lett., 2010,
51, 1566–1569; (f) R. Ballini, L. Barboni, L. Castrica, F. Fringuelli,
D. Lanari, F. Pizzo and L. Vaccaro, Adv. Synth. Catal., 2008, 350,
1218–1224; (g) F. Fringuelli, D. Lanari, F. Pizzo and L. Vaccaro,
Eur. J. Org. Chem., 2008, 3928–3932; (h) F. Fringuelli, F. Pizzo, C.
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2004, 2756–2757.
Experimental section
Compounds 4,9 5,10 7,9 8,10 11,11 12,12 14,13 16,14 17,15 18,16 19,17
21a–b,18 22,19 24a–b,20 26,21 are known compounds, compounds
10, 23, 27a–b, 28a, 29 have been already prepared but spec-
troscopic data have not been reported, while compounds 6,
9, 15, 25, 28b are new compounds. Characterization data (1H
NMR, 13C NMR, GC-EIMS, mp, and elemental analyses) for
compounds 6, 9, 10, 15, 23, 25, 27a, 27b, 28a, 28b, 29 are reported
in Electronic Supplementary Information (ESI).†
6 (a) R. A. Sheldon, Chem Ind. (London, U. K.), 1997, 12–15; (b) R.
A. Sheldon, Green Chem., 2007, 9, 1273–1283; (c) J. Auge´, Green
Chem., 2008, 10, 225–231; (d) R. A. Sheldon, Chem. Commun., 2008,
3352–3365.
Representative experimental procedure
In a screw capped vial equipped with a magnetic stirrer PS-
BEMP (0.048 g, 0.1 mmol, 2.1 mmol g-1), trans-4-phenyl-3-
buten-2-one (2a) (0.292 g, 2.0 mmol) and dimethylmalonate (3a)
(0.229 ml, 2.0 mmol) were consecutively added and the resulting
mixture was left under vigorous stirring at 60 ◦C. After 24 h,
methanol was added, the catalyst was recovered by filtration and
the organic solvent was evaporated under vacuum to give pure
dimethyl-2-(1¢-phenyl-3¢-oxo-butyl)malonate (4) as a colourless
oil (0.541 g, 97% yield).
7 (a) T. E. Kristensen and T. Hansen, Eur. J. Org. Chem., 2010, 3179–
3204; (b) J. Lu and P. H. Toy, Chem. Rev., 2009, 109, 815–838. For
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V. Luis, M. J. Vicent and J. A. Mayoral, React. & Funct. Polym.,
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Fraile, E. Garc´ıa-Verdugo, M. J. Gil, S. V. Luis, J. A. Mayoral, V.
Martinez-Merino and Z. Ochoa, Green Chem., 2011, 13, 983–990.
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This work was supported by the REU program of the Na-
tional Science Foundation under award number CHE-0755206.
Thanks to the American Chemical Society for coordinating the
IREU exchange program. We gratefully acknowledge the Min-
istero dell’Istruzione, dell’Universita` e della Ricerca (MIUR)
within the projects PRIN 2008 and “Firb-Futuro in Ricerca”
and the Universita` degli Studi di Perugia for financial support.
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