Green synthesis of 6-cyano-2,2-dimethyl-2-H-1-benzopyran and its subsequent enantioselective epoxidation

Article abstract of DOI:10.1016/j.molcata.2014.11.027

The clean synthesis of 6-cyano-2,2-dimethyl-2-H-1-benzopyran epoxide starting from 3-methyl-2-butenal is reported using recyclable catalysts. H₄PMo₁₁VO₄₀ (PMo₁₁V) and (PyH)₃HPMo₁₁VO₄₀ (Py₃-PMo₁₁V) Keggin-type heteropolyacids were used to synthesize 6-cyano-2,2-dimethyl-2-H-1-benzopyran in two steps with 35% yield. This is an alternative procedure to the traditional methodology with pyridine or picoline as catalyst, where 6-cyano-2,2-dimethyl-2-H-1-benzopyran is obtained by condensation of 4-cyanophenol with 1,1-diethoxy-3-methyl-2-butene. The 6-cyano-2,2-dimethyl-2-H-1-benzopyran epoxide was obtained using Jacobsen-type catalysts, and in situ generated dimethyldioxirane (DMD) as oxidizing agent, that in comparison to m-CPBA/4-NMO and NaOCl/4-PPNO did not degrade the catalyst. In presence of 4-phenylpyridine N-oxide (4-PPNO) at 4 °C, enantioselectivities of 87% for 3S,4S-epoxide and 68% for 3R,4R-epoxide were obtained with the S,S- and R,R-Jacobsen catalysts, respectively. Overall yield was approximately 17% for 3S,4S-epoxide.

Full text of DOI:10.1016/j.molcata.2014.11.027

Journal of Molecular Catalysis A: Chemical 398 (2015) 11–16
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Green synthesis of 6-cyano-2,2-dimethyl-2-H-1-benzopyran and its
subsequent enantioselective epoxidation
Gustavo Romanellia, Ángel Sathicqa, Patricia Vázqueza, Aída Villab, Edwin Alarcónb,
Edwing Grajalesb, Jairo Cubillosc,∗
a Centro de investigación y Desarrollo en Ciencias Aplicadas (CINDECA), Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de
La Plata, CONICET-CCT-La Plata 47 N◦ 2 57, La Plata B1900AJK, Argentina
b Environmental Catalysis Research Group Chemical Engineering Department, Universidad de Antioquia UdeA, Calle 70 No. 52–21, Medellín, Colombia
c Escuela de Ciencias Químicas, Facultad de Ciencias, Universidad Pedagógica y Tecnológica de Colombia UPTC, Avenida Central del Norte, vía Paipa, Tunja,
Boyacá, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
The clean synthesis of 6-cyano-2,2-dimethyl-2-H-1-benzopyran epoxide starting from 3-methyl-
2-butenal is reported using recyclable catalysts. H4PMo11VO40 (PMo11V) and (PyH)3HPMo11VO40
(Py3–PMo11V) Keggin-type heteropolyacids were used to synthesize 6-cyano-2,2-dimethyl-2-H-1-
benzopyran in two steps with 35% yield. This is an alternative procedure to the traditional
methodology with pyridine or picoline as catalyst, where 6-cyano-2,2-dimethyl-2-H-1-benzopyran is
obtained by condensation of 4-cyanophenol with 1,1-diethoxy-3-methyl-2-butene. The 6-cyano-2,2-
dimethyl-2-H-1-benzopyran epoxide was obtained using Jacobsen-type catalysts, and in situ generated
dimethyldioxirane (DMD) as oxidizing agent, that in comparison to m-CPBA/4-NMO and NaOCl/4-PPNO
did not degrade the catalyst. In presence of 4-phenylpyridine N-oxide (4-PPNO) at 4 ◦C, enantioselectiv-
ities of 87% for 3S,4S-epoxide and 68% for 3R,4R-epoxide were obtained with the S,S- and R,R-Jacobsen
catalysts, respectively. Overall yield was approximately 17% for 3S,4S-epoxide.
Received 2 September 2014
Received in revised form
26 November 2014
Accepted 27 November 2014
Available online 29 November 2014
Keywords:
Heteropolyacids
Jacobsen-type catalyst
Sustainable synthesis
6-Cyano-2,2-dimethyl-2-H-1-benzopyran
Chromene epoxide
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
such as, coumarins [4], flavones [5], chromones [6], and dihydropy-
rimidinones [7], may be good catalysts for the reaction.
As a result of their antidepressant, antihypertensive, and hypo-
glycemic activity, as well as other biological effects, the interest
in the synthesis of 2-H-1-benzopyrans (chromenes) has increased
in the last decades [1]. For example, the antihypertensive lev-
cromakalim, an airways-selective potassium channel activator
for asthma treatment [2], could be synthesized from 6-cyano-
2,2-dimethyl-2-H-1-benzopyran (denoted here as 6-CN-2,2-DMB)
through its chiral epoxide. The reported methods to obtain 6-CN-
2,2-DMB have some drawbacks such as, low yields, long reaction
times, and difficult work-up. Furthermore, the synthesis of ben-
zopyran precursor is catalyzed by pyridine or pyrrolidine, which are
toxic and cannot be recovered and reused [3]. Therefore, alternative
methods for the green synthesis of 2H-1-benzopyrans are needed.
In this context, heteropolyacids, which have been successfully eval-
uated and recovered for the sustainable synthesis of heterocycles
The synthesis of chiral chromene epoxides has typically been
carried out with the Jacobsen’s catalytic system, based on chi-
ral salen manganese(III) complexes under homogeneous reaction
conditions [8]. Due to the intrinsic advantages of heterogeneous
catalysis, i.e., easy catalyst separation and recycling as well as prod-
uct separation [9], some homogeneous chiral catalysts has been
used in a two-phase system or they have been anchoring on a
solid support. It is generally believed that the immobilization of
chiral salen manganese(III) complexes onto solid supports could
isolate the catalytically active intermediate species Mn(V)-oxo,
which might greatly reduce the formation of inactive ꢀ-oxo-
Mn(IV) dimers and increase catalyst stability [10]. Unfortunately,
in comparison with their homogeneous counterparts, the immobi-
lized complexes often exhibit poor activity, leaching of the active
species, or low accessibility to substrates [11]. These limitations
seem to be well assessed by using a high ordered short hexag-
onal channel mesoporous support, modified with a long chain
melamine–piperazine linker, which allows the immobilization of
a type of dimeric chiral Mn(III) salen complex by covalent bonds
[10]. As a second approach, the modification of the highly soluble
∗
Corresponding author. Fax: +57 87422174.
E-mail address: jairo.cubillos@uptc.edu.co (J. Cubillos).
http://dx.doi.org/10.1016/j.molcata.2014.11.027
1381-1169/© 2014 Elsevier B.V. All rights reserved.

12
G. Romanelli et al. / Journal of Molecular Catalysis A: Chemical 398 (2015) 11–16
Fig. 1. Synthetic route of 6-CN-2,2-DMB.
Jacobsen’s Mn(III) salen complex with trigol linker enables an easier
work-up to recover and recycle the homogeneous catalyst by pre-
cipitation with a suitable solvent [11]. Although these approaches
are appealing, the modification of the catalyst structure and/or the
need of adding new reactants often result in a reduction of activity
and selectivity.
The tendency of salen manganese(III) catalysts to undergo
oxidative degradation when sodium hypochlorite (NaOCl), m-
chloroperbenzoic acid (m-CPBA), sodium periodate (NaIO4), and
iodobenzene (PhIO) are used as oxidants, limits the successful recy-
cling of the immobilized catalyst [12]. Moreover, these oxidants are
either expensive or result in undesirable by-products. A convenient
and economical alternative could be the in situ generated dimethyl-
dioxirane (DMD) as oxidant, by the addition of KHSO5 and acetone,
along with Jacobsen-type catalysts, which facilitate product isola-
tion and catalyst recovery by lowering catalyst solubility during
the epoxidation reaction of cis-ethyl cinnamate [13] and limonene
[14]; the catalysts showed very good stability against oxidative
degradation.
were recorded on 200 MHz and 50 MHz Varian equipment, and
were measured in CDCl3 relative to TMS (0.00 ppm). The organic
phase was dried on anhydrous Na2SO4 and filtered for its analysis
by GC using a Shimadzu 2014 instrument. Reactions were moni-
tored by TLC. Melting points were measured in an open capillary
using a Büchi melting point apparatus and were uncorrected.
The products of 6-CN-2,2-DMB epoxidation were analyzed by
gas chromatography coupled with mass spectroscopy (GC–MS) in
an Agilent 7890A–5975C chromatograph equipped with a chiral
column (cyclodex-␤, 30 m × 0.25 mm × 0.25 ␮m). The identifica-
tion of (3S,4S)-6-CN-2,2-DMB oxide and (3R,4R)-6-CN-2,2-DMB
oxide was carried out by using the S,S- or R,R-Jacobsen catalyst in
dicloromethane with m-CPBA at 0 ◦C for 2 h and detected by GC–MS.
The activity and enantioselectivity (ee) of the catalysts were eval-
uated by comparison of chromatographic peak areas.
2.2. Catalyst preparation
The heteropolyacid H4PMo11VO40 (PMo11V) was prepared by
hydrothermal synthesis [15]. A stoichiometric mixture of 85 wt%
phosphoric acid (0.98 g, 0.01 mol), vanadium pentoxide (0.91 g,
0.005 mol), and molybdenum trioxide (14.4 g, 0.11 mol) was pre-
pared in distilled water (150 mL). The mixture was stirred for 3 h at
80 ◦C. After cooling down to 20 ◦C and removal of insoluble molyb-
dates and vanadates, the heteropolyacid solution was evaporated
and dried at 85 ◦C for 24 h, obtaining a deep orange solid.
The heteropolyacid Py3HPMo11VO40 (Py3–PMo11V) (mixed
proton–pyridinium salt, containing three pyridinium cations per
heteropolyanion) was prepared as follows: firstly, an ethanolic
solution of aniline (30 mmol) was added to an ethanolic solution
of PMo11V (10 mmol), and the mixture was stirred at 75 ◦C for 1.5 h
and concentrated; then, the precipitate was filtered, washed with
more ethanol, and dried at 20 ◦C under vacuum; finally, the result-
ing orange fine powder was dissolved in water for recrystallization
and further purification.
In this paper, a suitable synthesis of 6-cyano-2,2-dimethyl-
benzopyran (6-CN-2,2-DMB) and its subsequent enantioselective
epoxidation is reported. The methodology includes three steps
involving heteropolyacid and homogeneous Jacobsen catalysts:
(i) 1,1-diethoxy-3-methyl-2-butene is prepared starting from 3-
methyl-2-butenal using PMo11V heteropolyacid as catalyst, (ii) the
isolated substrate is condensed with 4-cyanophenol in the presence
of Py3–PMo11V to obtain 6-CN-2,2-DMB (Fig. 1), and (iii) 6-CN-2,2-
DMB is enantiomerically epoxidized using Jacobsen-type catalysts
and in situ generated DMD as oxidizing agents (Fig. 2). Work-up
to separate heteropolyacids is easily carried out, and the Jacobsen
catalyst is precipitated in the reaction media containing the in situ
DMD as oxidant.
2. Experimental
S,S-Jacobsen and R,R-Jacobsen catalysts were synthe-
sized as previously reported [16]. 3-tert-Butyl-2-hydroxy
benzaldehyde (3-TBHB) was allowed to react with (1S,2S)-(+)-1,2-
diaminocyclohexane and (1R,2R)-(−)-1,2-diaminocyclohexane,
respectively, in a 2:1 molar ratio. The obtained (S,S) and (R,R)
ligands were complexed with tetra-hydrated manganese(III)
acetate and an excess of LiCl to give S,S- and R,R-Jacobsen catalysts,
respectively.
2.1. Materials and methods
All reactive grade solvents and reagents were purchased from
Aldrich and Fluka, and were used without further purification.
H3PMo12O40 (PMo12) and H4SiMo12O40 (SiMo12) catalysts are also
commercial products. In the preparation of 6-CN-2,2-DMB, all
yields are referred to the isolated products after purification. Prod-
ucts were characterized by 1H NMR and 13C NMR; the NMR spectra
Fig. 2. Enantioselective epoxidation of 6-CN-2,2-DMB using Jacobsen catalyst (R,R and S,S optical configuration) and in situ generated DMD as oxidant.

G. Romanelli et al. / Journal of Molecular Catalysis A: Chemical 398 (2015) 11–16
13
2.3. Characterization methods
(1 M, 2 × 7 mL), NaOH (1 M, 2 × 7 mL), saturated solution of NaCl
(10 mL), H2O (10 mL), dried (anhydrous Na2SO4), and concentrated.
The crude product was crystallized from hexanes. The crystals were
recovered by filtration, washed with hexanes, and dried to give 35%
yield, mp 46–47 ◦C, lit1 47 ◦C. 1H NMR (200 MHz, CDCl3) ı = 7.36 (dd,
J = 8 Hz, J = 2 Hz, 1 H), 7.24 (d, J = 2 Hz, 1 H), 6.80 (d, J = 8 Hz, 1 H), 6.31
(d, J = 10 Hz, 1 H), 5.72 (d, J = 10 Hz, 1 H), and 1.46 (s, 6H). 13C NMR
(50 MHz, CDCl3) ı = 156.7, 133.3, 132.2, 130.2, 121.5, 120.6, 119.1,
117.2, 103.5, 77.8, and 28.2.
Complete characterization of the catalysts PMo11
V and
Py3–PMo11V was reported in a previous work [17,18]. Here, we
present some relevant analysis of the catalysts in order to verify
their characteristics. PMo11V and Py3–PMo11V were characterized
with a Philips 505 scanning electron microscope (SEM) using an
accelerating voltage of 15 eV solid. The catalysts were also ana-
lyzed by 31P MAS NMR in Varian Mercury Plus 300 equipment; the
measurements were carried out at room temperature using 85 wt%
H3PO4 as external reference. The FTIR spectra at room temperature
in the 400–4000 cm−1 range were obtained in a Thermo Nicolet
IR200 equipment diluting the solid samples in KBR. The acidity
of a suspension of the catalysts in acetonitrile was determined by
means of potentiometric titration in a Metrohm 794 Basic Titrino
apparatus with a double junction electrode using a solution of n-
butylamine in acetonitrile (0.025 N); this methodology allows the
evaluation of the total number of acid sites and their acid strength.
R,R- and S,S-Jacobsen catalysts were characterized as previ-
ously described [13]. FTIR spectra were recorded from KBR powder
(1 wt%) using a Nicolet Avatar 330 FTIR spectrophotometer, and
UV–vis spectra on a Lambda 4 PerkinElmer spectrophotometer
with an integrating sphere using BaSO4 as standard. TGA was per-
formed on a TGA 2950 Thermal Analyzer at a heating rate of 5 K/min
from 300 to 1073 K under flowing air (100 mL/min).
2.4.4. Enantioselective epoxidation of 6-CN-2,2-DMB
The enantioselective epoxidation of 6-CN-2,2-DMB was carried
out following the procedure reported elsewhere [13,14]. Briefly,
20 mol% of S,S or R,R catalyst with 6-CN-2,2-DMB (0.0625 mmol)
as substrate and 0.1875 mmol of KHSO5 (Oxone® dissolved in 4 mL
H2O) as oxygen source were used. The catalyst and 6-CN-2,2-DMB
were dissolved in acetone (4 mL), and the reaction was initiated
by the stepwise addition of an aqueous KHSO5 solution, whereas,
the pH value of the reaction mixture was monitored and adjusted
to 8.0–8.5 by slow addition of aqueous 5 wt% NaHCO3 solution,
under continuous stirring. After complete addition of the aqueous
KHSO5 solution, magnetic stirring was stopped and the obtained
solid (catalyst and inorganic salts) was recovered by simple fil-
tration, and it was washed with enough water. The obtained dark
brown residue (recovered catalyst) was dissolved in 4 mL of acetone
and reused in a further reaction. The liquid phase separated from
the reaction system was extracted with CH2Cl2, the aqueous phase
was discarded, and the organic phase was washed and dried with
anhydrous sodium sulfate. The obtained mixture was concentrated
under vacuum and the product was analyzed by GC–MS. The effect
of 4-phenylpyridine N-oxide (4-PPNO, 0.0125 mmol) as additive,
and the reaction temperature were also evaluated.
2.4. Catalytic experiments
2.4.1. Reaction analysis for optimizing the synthesis of
1,1-diethoxy-3-methyl-2-butene and 6-CN-2,2-DMB
1,1-Diethoxy-3-methyl-2-butene was obtained from triethyl
orthoformate (1 mmol), 3-methyl-2-butenal (1 mmol), and abso-
lute ethanol (0.3 mL) at 20 ◦C; 6-CN-2,2-DMB was synthesized
with 1,1-diethoxy-3-methyl-2-butene (1.7 mmol), 4-cyanophenol
(1.3 mmol), and xylene (2 mL). About 5 mg were collected from the
reaction at fixed time intervals; the sample was diluted with 1 mL
of acetone, filtered, and the filtrate was analyzed by GC (Shimadzu
2014, with a 30 m × 0.32 mm SPB-1 capillary column).
3. Results and discussion
3.1. Catalyst characterization
The synthesis and full characterization of the PMo11V and
Py3–PMo11V catalysts were reported in a previous work [17,18].
The SEM–EDAX analysis of heteropolyacid catalysts shows a homo-
geneous distribution of V, Mo, and P according to the expected
percent atomic ratios. 31P MAS NMR results of PMo11V show only
a wide dissymmetric line at −3.20 ppm, which has been related
with the substitution of one Mo6+ atom by one V5+ atom in the
Keggin structure [15]. The FTIR spectrum of PMoV shows the main
bands at 1061 cm−1 with a shoulder at 1081 (P–Oa), 960 (Mo–Od),
866 (Mo–Ob–Mo), and 776 (Mo–Oc–Mo) cm−1 [15]. The FTIR spec-
tra of pyridinium salt (Py3–PMo11V) showed four peaks assigned
to a heteropolyacid Keggin structure and a shift of the character-
istic bands for pyridinium ion from 1440 cm−1 and 1380 cm−1 to
1533 cm−1 and 1483 cm−1, respectively, in good agreement with
previous reports [19]. This behavior indicates that the pyridine
acts as counter-cation and it does not modify the Keggin units. X-
ray diffraction patterns for PMo11V and Py3–PMo11V are similar to
those of Keggin commercial PMo structure, showing seven main
diffraction peaks at 8.1◦, 8.9◦, 9.3◦, 27.8◦, 28.8◦, and 28.2◦ corre-
sponding to a triclinic symmetry [20,21]. In regards to the acidic
properties, the heteropolyacid is a Brönsted acid, and PMoV dis-
plays very strong acid sites at 20 ◦C with a maximum acid strength
corresponding to an initial electrode potential of 978 mV, higher
than that obtained for the V-free sample (600 mV) [15]. When PMoV
is transformed into the Py3–PMo catalyst, the number of sites and
their acid strength decrease (initial electrode potential = 365 mV).
Chiral salen ligand and Mn(III) salen complexes were identified
according to previously reported characterization methods [13,14].
2.4.2. General procedure for the synthesis of
1,1-diethoxy-3-methyl-2-butene
PMo11V was used as catalyst in this preparation. Triethyl
orthoformate (18 mmol), 3-methyl-2-butenal (18 mmol), and the
catalyst (PMo11V, 1 mmol%) were added to absolute ethanol (5 mL)
at 20 ◦C. The progress of the reaction was monitored by thin layer
chromatography (TLC) and gas chromatography (GC) analyses.
After stirring for 1 h, the excess of ethanol was removed by evapo-
ration, and the resulting mixture was treated with toluene (10 mL);
finally, the catalyst was recovered by centrifugation and washing
with toluene (5 mL). The organic phase was dried on anhydrous
Na2SO4, filtered and concentrated to obtain the crude acetal. The
acetal was isolated as a clear, colorless liquid by vacuum distilla-
tion (89% yield, 116–119 ◦C at 170 mm Hg, and 117.0–118.5 ◦C at
171–172 mm Hg).
2.4.3. General procedure for the synthesis of 6-CN-2,2-DMB
Py3–PMo11
V was used as catalyst for the preparation of
6-CN-2,2-DMB. 1,1-Diethoxy-3-methyl-2-butene (17 mmol), 4-
cyanophenol (13 mmol), and the catalyst (Py3–PMo11V, 1 mmol%)
were added to p-xylene (20 mL) as solvent at 20 ◦C. The progress of
the reaction was monitored by TLC and GC analysis. The reaction
mixture was heated and stirred at 120 ◦C. After 6 h, the reaction
mixture was cooled down to room temperature. The clear, yellow
solution was diluted with p-xylene (10 mL) and the catalyst was
recovered by centrifugation, washed with p-xylene (5 mL), dried
in vacuum, and reused. The organic phases were washed with HCl

14
G. Romanelli et al. / Journal of Molecular Catalysis A: Chemical 398 (2015) 11–16
found that PMo11V displays a number of acidic sites larger than
PMo12 support [22].
The most active catalyst (PMo11V) was used in the next exper-
iments. Table 1, entries 4–7, displays the effect of the amount
of catalyst on the yield of 1,1-diethoxy-3-methyl-2-butene in the
reaction. The reaction yield increased from 48% to 89% when the
amount of PMo11V increased from 0.1 to 1 mmol% (Table 1, entries
4 and 5); a further increase in the amount of PMo11V caused a
very slight increase in 1,1-diethoxy-3-methyl-2-butene yield (90%,
Table 1, entry 7). Thus, 1 mmol% of PMo11V is an appropriate
amount in this reaction.
The effect of reaction time on 1,1-diethoxy-3-methyl-2-butene
yield using PMo12V as catalyst, under the same reaction conditions,
is shown in Table 1, entries 4, 7, and 8. It can be observed that the
yield increased with the reaction time up to 1 h and then leveled
off.
The possibility of recycling the PMo11V was examined and no
appreciable loss of catalytic activity was observed after four cycles
(Table 1, entries 4, 10–12); product yields varied from 89% to 87%.
It is well known that the reaction of an aldehyde with two alco-
hol molecules in the presence of an acid catalyst results in the
formation of an acetal. Alternatively, an orthoester could be used
instead as a source of the alcohol; in fact, the orthoesters can be
considered as the ‘acetals of esters’ or the triesters of the unknown
‘orthoacids’—the hydrates of carboxylic acids. The orthoesters are
hydrolyzed by water to ester and two alcohol molecules, in the
presence of an acid catalyst; in our case, triethylortoformate would
be hydrolyzed by the Brönsted sites of the PMo11V heteropolyacid.
Then, the aldehyde (in our case, 3-methyl-2-butenal), would react
with ethanol to form the corresponding acetal; this reaction is also
catalyzed by the Brönsted acid sites of the heteropolyacids. A plau-
sible mechanism is attached as supplementary material. The results
show that the incorporation of V into the structure of PMo notably
increases the acidity and catalytic activity. In a preview work, using
potentiometric titration, we found that PMo11V presents a greater
number of acidic sites than PMo12 [22].
Fig. 3. FTIR spectra of the fresh S,S-Jacobsen catalyst and used once with different
oxidizing agents. (a) fresh catalyst, (b) DMD, (c) m-CPBA/4-NMO, and (d) NaOCl/4-
PPNO.
The main feature of the FTIR spectra of the chiral salen ligands is
the intense band at 1640 cm−1, assigned to C N stretching vibra-
tions (see Fig. 3) [14]. The coordination of the chiral salen ligand
to the manganese atom is indicated by a band typical of metallos-
alen complexes at ca. 1530 cm−1 (see Fig. 3) [14]. Two characteristic
bands of the C N absorption at 450 and 510 nm in the DR UV–vis
spectra of the complexes also indicate the binding of manganese to
the chiral salen ligand [14].
3.2. Catalytic activity
3.2.1. Synthesis of 1,1-diethoxy-3-methyl-2-butene
This section describes the preparation of 1,1-diethoxy-3-
methyl-2-butene in the presence of Keggin heteropolyacids
(PMo12, SiMo12, and PMo11V), as reusable catalyst, in a homoge-
neous system. 1,1-diethoxy-3-methyl-2-butene synthesis involv-
ing the reaction of 3-methyl-2-butenal with triethyl orthoformate
is illustrated in Fig. 1. The possible presence of non-catalytic effects
was assessed by studying the reaction in absence of catalyst, and
no appreciable formation of 1,1-diethoxy-3-methyl-2-butene was
detected (5%, Table 1, entry 1).
3.2.2. Synthesis of 6-cyano-2,2-dimethyl-benzopyran
(6-CN-2,2-DMB)
The 6-CN-2,2-DMB synthesis involving in the reaction of 1,1-
diethoxy-3-methyl-2-butene with 4-cyanophenol is illustrated in
Fig. 1. Traditionally, this reaction has been catalyzed by pyridine
or picoline in homogeneous medium [23]. Initially, the non-
catalytic reaction between 1,1-diethoxy-3-methyl-2-butene and
4-cyanophenol was examined, and it was not observed in the for-
mation of 6-CN-2,2-DMB (Table 2, entry 1). Similarly, using PMo12
and PMo11V, under the same reaction conditions, the reaction does
not take place (Table 2, entries 2 and 3). However, the use of
Py3–PMo11V led to a 35% yield of product under the same reac-
tion conditions (Table 2, entry 5). This finding could be related to
the mechanism originally proposed by North et al. [1], who indi-
cated that both acid and basic catalysts with an appropriate pH are
necessary to carry out this reaction [1]. In our case, we propose that
small amounts of non-protonated pyridine and free heteropolyacid
on the catalyst surface can replace the function of basic and acid
catalysts reported in a homogeneous medium (see Fig. 4). There-
fore, it can be concluded that the synthesized catalyst Py3–PMoV
possesses bifunctional properties.
The yields of 1,1-diethoxy-3-methyl-2-butene of 70, 68, and 89%
(selectivity 100%), were obtained with the three catalysts (PMo12
,
PW12, and PMo11V, respectively, entries 2–4 of Table 1). These
results show that the incorporation of V into the structure of PMo
notably increases the catalytic activity. In a previous work, we
Table 1
Synthesis of 1,1-diethoxy-3-methyl-2-butene.a
Entry
Catalyst
Catalyst (mmol%)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13b
None
PMo12
PW12
PMo11
PMo11V
PMo11
PMo11
PMo11
PMo11
PMo11
PMo11
PMo11
PMo11
–
1
1
1
0.1
0.5
2
1
1
1
1
1
1
3
1
1
1
1
1
1
0.5
2
1
1
1
1
5
70
68
89
48
75
90
77
88
88
88
87
89
V
V
V
V
V
V
V
V
V
The effect of reaction temperature was studied with the most
active catalyst (Py3–PMo11V), Table 2, entries 4, 6, and 7. It was
found that, at temperature of 120 ◦C, the reaction significantly takes
place.
The possibility of recycling the catalyst was also examined and
no appreciable loss of catalytic activity was observed after four
cycles (Table 2, entries 5, 9–11); product yield varied between 38
and 36%.
a
Reaction conditions: triethyl orthoformate (1 mmol), 3-methyl-2-butenal
(1 mmol), absolute ethanol (0.3 mL), and 20 ◦C. Entries 10–12 correspond to the first,
second, and third catalyst reuse.
b
Scaled until 10-fold.

G. Romanelli et al. / Journal of Molecular Catalysis A: Chemical 398 (2015) 11–16
15
Table 2
Preparation of 6-CN-2,2-DMB.a
Entry
Catalyst
Catalyst (mmol%)
Temp. (◦C)
Time (h)
Conv. (%)
Selectivity (%)
Yield (%)
1
2
3
4
5
6
7
8
9
None
PMo12
PMo11
Py3–PMo11
Py3–PMo11
Py3–PMo11
Py3–PMo11
Py3–PMo11
–
1
1
1
1
1
1
2
1
1
1
1
120
120
120
120
120
100
80
120
120
120
120
120
12
12
12
12
6
12
12
6
6
6
6
6
–
–
–
37
38
5
–
–
–
–
–
–
33
35
5
V
V
V
V
V
V
90
92
100
–
94
92
94
94
92
–
–
34
37
36
36
38
32
34
34
34
35
Py3–PMo11V
10
11
12b
Py3–PMo11
Py3–PMo11
Py3–PMo11
V
V
V
a
Reaction conditions: 1,1-Diethoxy-3-methyl-2-butene (1.7 mmol), 4-cyanophenol (1.3 mmol), xylene (2 mL), and 120 ◦C. Entries 9–11 correspond to the first, second,
and third catalyst reuse.
b
Scaled until 10-fold.
In order to assess the possible catalyst solubilization, additional
tests were performed. The Py3–PMo11V sample (ca. 20 mg) was
stirred in xylene (2 mL) for 12 h, filtered, and dried in vacuum till
constant weight. No mass loss was detected. Moreover, the refluxed
xylene was used as solvent for attempting the reaction without
adding the catalyst. After 6 h, formation of 6-CN-2,2-DMB was not
detected and the starting material was almost quantitatively recov-
ered.
3R,4R-epoxide). These results are equivalent to those obtained by
using Jacobsen-type catalysts with NaOCl/4-PPNO as oxidant [25].
However, in our methodology, the catalyst could be recovered and
recycled after its precipitation during the reaction. The catalyst
can be conveniently recovered by filtration, washed with water,
and then, dissolved in acetone to be reused. In fact, the recov-
ered S,S catalyst was used twice under similar reaction conditions,
Table 3, entry 7; the slight decrease in enantioselectivity (from
87% to 80%) was attributed to the physical loss of catalyst rather
than to its oxidative degradation; this was evidenced by conducting
epoxidation experiments using NaOCl/4-PPNO and m-CPBA/NMO
as oxidation systems. In general, the reaction with m-CPBA/NMO
as oxidant proceeded much faster than with NaOCl/4-PPNO and
gave higher ee values (75% against 38%). However, in both cases,
the initially dark brown catalyst was partially decolorized after the
reaction. Catalyst decolorization was much more severe with m-
CPBA/NMO than with NaOCl/4-PPNO. Therefore, as confirmed by
FTIR analysis (aromatic region) of the reused catalyst, the catalyst
was deactivated in the presence of these oxidation systems. In fact,
comparison of the FTIR spectrum of the recovered catalyst by vac-
uum distillation at 180 ◦C after reaction with m-CPBA/NMO and
NaOCl/4-PPNO as oxidizing agents, with that of the catalyst used
with in situ generated DMD as oxidant, revealed that the main bands
assigned to the Mn(III) salen complexes (1530 cm−1) do not appear
in the spectrum of the catalyst used with m-CPBA/NMO (Fig. 3).
The reported catalytic system is attractive because, it allows the
use of an alternative oxygen source under smooth conditions, thus,
3.2.3. Enantioselective epoxidation of 6-CN-2,2-DMB
The S,S and R,R complexes were used as catalysts in the enan-
tioselective epoxidation of 6-CN-2,2-DMB at room temperature.
Dimethyldioxirane, formed from the reaction between acetone and
KHSO5 (oxygen source) in a slightly basic medium, that acted as oxi-
dizing agent. The enantioselective epoxidation reaction is outlined
in Fig. 2, whereas, the catalytic results are summarized in Table 3. In
terms of high conversion and selectivity, a KHSO5/6-CN-2,2-DMB
molar ratio of six was appropriate. Complete conversion and 70%
of selectivity were obtained in absence of the catalyst, but no enan-
tioselectivity was achieved (Table 3, entry 1). On the other hand, the
presence of S,S-Jacobsen as catalyst resulted in an ee of 35% (Table 3,
entry 2), indicating that the catalyst promotes the chiral induc-
tion between its catalytically active form and the substrate. Also,
4-PPNO has a pronounced effect on the enantioselectivity (Table 3,
entry 3). It is known that in a biphasic reaction pyridine derivatives
play a dual role: (a) stabilizing the oxo-Mn(V) and (b) transporting
the oxidant into the organic phase [24]. As the reduction in tem-
perature resulted into an increase in chiral induction (Table 3, entry
4), further experiments were performed with 4-PPNO at a reaction
temperature of 4 ◦C, Table 3, entries 5 and 6. When S,S-Jacobsen
was used as catalyst, the enantioselectivity (87% for 3S,4S-epoxide)
was better than that obtained using the R,R catalyst (68% for
Table 3
Enantioselective epoxidation of 6-CN-2,2-DMB.a
Entry
Conversion (%)
Selectivity (%)
ee (%)
1b
2
100
100
96
100
97
100
100
95
70
60
65
62
60
60
62
60
0
35h
6h
3c
4d
5e
6f
7g
8j
7h
8h
68i
80h
85
a
Reaction conditions: 6-CN-2,2-DMB (0.0625 mmol), KHSO5 (0.375 mmol), ace-
tone (4 mL), S,S-Jacobsen (0.016 mmol), water (4 mL), and room temperature.
b
Without catalyst.
c
4-PPNO (0.0125 mmol).
d
4 ◦C.
e
4-PPNO (0.0125 mmol) and 4 ◦C.
f
R,R-Jacobsen instead of S,S-Jacobsen, using the same condition as in “e”.
Second reuse of S,S-Jacobsen under similar conditions to “e”.
Optical configuration 3S,4S.
Optical configuration 3R,4R.
g
h
i
j
Fig. 4. Possible substrate activation by Py3–PMoV catalyst.
Scaled until 2-fold.

16
G. Romanelli et al. / Journal of Molecular Catalysis A: Chemical 398 (2015) 11–16
avoiding catalyst oxidative degradation that results from utilizing
strong oxidizing agents. Furthermore, the easy recovery of the cata-
lyst from the reaction medium and their recycling is another strong
advantage of this catalytic process. Finally, some of the catalytic
reactions was carried out using large-scale amounts (see entries
13, 12, and 8 in Tables 1, 2, and 3, respectively); these results show
that the activity of the catalytic systems did not change signifi-
cantly, which demonstrates the potential application in industry of
entire process.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2014.11.027.
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Acknowledgements
The authors are grateful to CONICET, “Universidad Nacional de
La Plata”, “Universidad de Antioquia (UdeA)”, “Ministerio de Cien-
cia, Tecnología e Innovación Productiva de la República Argentina
(MINCYT)”, and “Instituto Colombiano para el Desarrollo de la
Ciencia y Tecnología, “Francisco José de Caldas”(COLCIENCIAS)” for
financial support of this work through the Scientific and Technolog-
ical Cooperation Programme, Project No. CO/08/13. GPR, PGV, and
AGS are members of CONICET. Financial support of Sustainability
Strategy 2013–2014 from UdeA is also acknowledged.