Efficient iron-catalyzed acetal formation from styrene derivatives

Full text of DOI:10.1002/cctc.201300270

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R. Ray, A. D. Chowdhury, G. K. Lahiri*
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Efficient Iron-Catalyzed Acetal
Formation from Styrene Derivatives
All green in one medium: FeSO4·7H2O
in combination with pyridine-2-carbox-
ylic acid and H2O2 in methanol can effi-
ciently catalyze the formation of aryl-
aldehyde dimethyl acetals from the
corresponding styrene derivatives.
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DOI: 10.1002/cctc.201300270
Efficient Iron-Catalyzed Acetal Formation from Styrene
Derivatives
Ritwika Ray, Abhishek Dutta Chowdhury, and Goutam Kumar Lahiri*[a]
Acetals have immense industrial significance as diesel additives
and polymeric materials and as flavoring agent in beverages,
cosmetics, and foods.[1] Acetalization is the most useful syn-
thetic technique in any targeted organic synthesis to protect
the aldehyde and ketone groups of various multifunctional or-
ganic molecules.[2] Acetals constitute a versatile class of organic
synthons and intermediates, as they can easily be converted
into other useful functional groups.[2,3] Moreover, acetals are
the common functional group in natural products such as (À)-
xylomollin, anthogorgiene D, allamcin, incargutine B, and so
on.[4] The enzyme glycosyltransferase catalyzes the formation
of acetals from hemiacetals during the formation of glycosidic
bonds in cellulose.[5] Furthermore, the influential role of acetals
in biological activities has recently been demonstrated.[5b]
ventional methods for acetal synthesis have initiated subse-
quent exploration into the development of alternative
methodologies.
In this regard, different environmentally friendly solid acids,
viz. sulfated zirconia (SZ) or titania, Pt–Mo/ZrO2, Ce/montmoril-
lonite, acidic zeolites, mesoporous silica, siliceous mesoporous
material, metal phosphates, and polyaniline, have been suc-
cessfully used in acetalization reactions.[8] In addition, various
metal–organic frameworks have been efficiently utilized re-
cently for the said acetalization process in
a methanol
medium.[9] Unfortunately, all of these methods involve costlier
aldehydes as substrates.[8,9]
Though styrene has emerged over the last decade as the
most attractive alternative option for either Markovnikov or
anti-Markovnikov acetal synthesis,[6,7] the direct transformation
of styrene into benzaldehyde dimethyl acetal is limited to only
one example through a noncatalytic approach.[10]
Herein, we demonstrate an efficient and direct catalytic
transformation of styrene derivatives into the corresponding
arylaldehyde dimethyl acetals under mild and benign reaction
conditions by using cheap and readily available FeSO4·7H2O as
the catalyst, pyridine-2-carboxylic acid (pic) as the co-ligand,
and H2O2 as the oxidant in methanol (Scheme 1). To the best
of our knowledge, the present report demonstrates, for the
Acetals are usually prepared either from aldehydes or ke-
tones by using protic or Lewis acid catalyst.[2] However, these
methods have several limitations, such as the use of corrosive
and costly reagents or additives, high temperature, inconven-
ient reaction conditions, a large amount of waste, and high
catalyst loading.[2,3,6] In this context, the ruthenium-catalyzed
direct transformation of alcohols into acetals is exciting, as it
avoids relatively costlier aldehyde and ketone substrates.[6b]
However, very recently alkenes were found to be useful and
cheaper alternative substrates for acetal formation under
either catalytic or noncatalytic conditions (Markovnikov or anti-
Markovnikov acetals).[6,7] Nevertheless, the use of costlier cata-
lytic systems and unwanted organic oxidants are among the
limitations of these processes.[6,7] Such limitations of the con-
Scheme 1. Catalytic transformation of styrene derivatives into benzaldehyde
dimethyl acetals (pic=pyridine-2-carboxylic acid).
first time, the direct catalytic transformation of styrene into
benzaldehyde dimethyl acetal.
In this context, we recently reported an iron-based catalytic
system [Fe(BF4)2·6H2O/dipic=pyridine-2,6-dicarboxylic acid/PhI-
(OAc)2/MeOH at 298 K] for the anti-Markovnikov dimethyl
acetal formation from styrene.[6a] The presence of the environ-
À
mentally hazardous counteranion BF4 and the use of an or-
ganic oxidant with unavoidable residue during the workup
process instantaneously prompted us to develop an environ-
mentally sustainable catalytic system, that is, the utilization of
H2O2 as a possible oxidant. Thus, various iron salts were
screened with different commercially available bi- and triden-
tate ligands during the initial optimization of the suitable reac-
tion conditions (Table S1, Supporting Information). In essence,
the in situ generated catalyst derived from FeSO4·7H2O (1) and
pic as the ligand in the presence of H2O2 as the oxidant in
[a] R. Ray, Dr. A. D. Chowdhury, Prof. G. K. Lahiri
Department of Chemistry
Indian Institute of Technology Bombay
Powai, Mumbai-400076 (India)
Fax: (+91)022-2572-3480
E-mail: lahiri@chem.iitb.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300270.
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MeOH as the solvent led to the selective formation of (dime-
thoxymethyl)benzene in 98% yield from styrene as the sub-
strate (Table S1, Entry 11; see the Supporting Information). The
pic ligand exhibited the best activity and selectivity of all the li-
gands tested with FeSO4·7H2O (1) as the catalyst under similar
oxidizing conditions (Table S1, Entries 11–17; see the Support-
ing Information). The electron-rich anionic pic ligand facilitates
the in situ formation of the active catalyst, that is, a high-
valent iron–oxo species that renders the best activity (vide
infra).
tals.[6a,11] It was observed that the yield of acetal significantly
decreased with the simultaneous presence of the correspond-
ing aldehyde in the absence of molecular sieves.[6a]
Another remarkable feature of this work is that it proceeds
in a highly chemoselective manner. The formyl group attached
to the ring in substrates such as 2o remained completely unaf-
fected under such oxidizing environment; neither acetalized
nor oxidized. Interestingly, substrates such as cinnamaldehyde
with a formyl group attached at the b-carbon atom failed to
undergo any reaction under the present reaction protocol.[6a]
However, treatment of benzaldehyde under identical reaction
conditions did not produce any (dimethoxymethyl)benzene,
which suggests that direct acetalization of styrene instead of
the aldehyde intermediate is the only possible pathway.
The optimized reaction conditions indeed allowed the oxida-
tion of a wide variety of styrene derivatives (i.e., 2a–s) to the
corresponding acetals (i.e., 3a–s) in reasonable to excellent
yield by using 1 (4 mol%), pic (4 mol%), H2O2 as the oxidant
(1.5 equiv.), and 3 ꢁ molecular sieves in methanol (Scheme 1,
Table 1) in air. The yield and selectivity of the said reaction
were not affected much if the reaction was performed under
an inert atmosphere. The addition of molecular sieves is essen-
tial to achieve complete conversion to the corresponding ace-
A tentative mechanistic route is shown in Scheme 2. The
active iron–oxo species incorporating two pic ligands, as re-
vealed by ESI(+)-MS (Figure S1, Supporting Information),[12] ef-
Table 1. Iron-catalyzed acetalization of styrene derivatives.[a]
Scheme 2. A tentative reaction pathway.
fects the acetalization of terminal alkenes to afford benzalde-
hyde dimethyl acetals, and the alkene is believed to attack the
iron–oxo species through a side-on approach. This is then fol-
lowed by nucleophilic attack of a methanol solvent molecule
at the Ca atom of styrene. Nucleophilic attack of a second mol-
ecule of methanol occurs at the Cb atom with simultaneous
cleavage of the CaÀCb bond of styrene and subsequent in situ
formation of formaldehyde through cleavage of the FeÀO
bond. The presence of water in the reaction medium (derived
from H2O2) might facilitate the C=C cleavage process.[13] More-
over, the Lewis acidity of the substrate (alkene)-bound high-
valent iron center might also play a critical role towards such
a selective solvent nucleophilic attack (SNA). The formation of
isomerized acetal product 3s from 1-phenylcyclohexene (2s)
implies the existence of a cationic intermediate instead of
a radical or metallaoxetene intermediate.[11a,d] Such a cationic
intermediate is expected to be linked to the iron–oxo species
through its Cb atom.[12c] Notably, similar facile enzymatic CaÀCb
bond cleavage of styrene was reported to be catalyzed by
myeloperoxidase (MPO) and Coprinus cinereus peroxidase (CiP),
for which high-valent iron–oxo functions as the active
species.[5a]
[a] Reaction conditions: catalyst
1 (4 mol%), pic (4 mol%), substrate
(1 mmol), 30% H2O2 (1.5 equiv.), MeOH (4 mL), 3 ꢁ molecular sieves, 608C,
1
12 h. Yields were determined by H NMR spectroscopy. Isolated yields are
given in parentheses. See the Supporting Information for details. [b] 5–
10% aldehyde was also observed. [c] Substrate: cis-b-methylstyrene.
[d] Substrate: trans-b-methylstyrene. [e] Small amount of the correspond-
ing anti-Markovnikov aldehyde was also associated. [f] GC yield. [g] Prod-
uct identified by HRMS (see the Supporting Information).
Comparison of the present results with those reported ear-
lier[6a] reveals the formation of two different classes of acetal
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passed through a silica gel column by using petroleum ether/ethyl
acetate as eluent to isolate the desired product. The products were
confirmed, and GC yields were calculated on the basis of calibra-
tion with authenticated products; GC–MS spectra were also com-
pared. All the acetals (except 3 s) reported in this work are previ-
ously reported in the literature (see the Supporting Information for
references).[S2–S12] All the reactions were performed thrice to estab-
lish reproducibility and reliability. Moreover, the products were iso-
lated in the respective cases to ensure the general applicability of
the said reaction protocol (see the Supporting Information for
details).
products. A set of control experiments with various oxidants
(Table S2, Supporting Information), but under identical reaction
conditions, that is, the use of 1 (4 mol%) and pic (4 mol%) at
608C, showed that H2O2 and PhI(OAc)2 afford (dimethoxyme-
thyl)benzene and (2,2-dimethoxyethyl)benzene as major prod-
ucts, respectively, from styrene. Notably, the other oxidants
produced acetal products in negligible yield under identical re-
action condition (Table S2, Supporting Information). The forma-
tion of two different classes of acetal products can thus be at-
tributed to the specific use of H2O2 in the present case instead
of PhI(OAc)2 as in the earlier report. Therefore, PhI(OAc)2 failed
to facilitate C=C bond cleavage under the present reaction
protocol and selectively yielded the anti-Markovnikov acetal
products. Moreover, the present catalytic reaction proceeds at
608C, whereas the reaction performed in the earlier work[6a]
was optimized at room temperature, and this makes the pro-
cess more energy demanding and thereby accounts for C=C
cleavage leading to the desired selectivity. The varying dentici-
ty of the coligands, pic and dipic in the present case and in
the earlier report,[6a] respectively, possibly suggests the involve-
ment of two structurally different active Fe=O species (A and
B; Figure S3, Supporting Information) as supported by their re-
spective ESI(+)-MS (Figures S1 and S2, Supporting Informa-
tion). Therefore, it is logical to believe that the choice of H2O2
(or H2O in H2O2) as the oxidant and the denticity of the coli-
gand influenced the C=C bond cleavage process, which led to
the formation of two distinctly diverse acetal products.
Acknowledgements
The financial support received from Department of Science and
technology (DST), University Grants Commission (UGC) (fellow-
ship to R.R.), and Council of Scientific and Industrial Research
(CSIR) (fellowship to A.D.C.), New Delhi, India, is gratefully
acknowledged.
Keywords: acetals · homogeneous catalysis · iron · oxidation ·
styrenes
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In conclusion, an efficient and selective iron-catalyzed oxida-
tion protocol for the conversion of styrene into dimethyl acetal
has been developed under mild and benign reaction condi-
tions. This provides an unprecedented account of the single-
step catalytic formation of dimethyl acetals from alkenes; the
only other reported system involves a multistep noncatalytic
process.[10] The present catalytic system operates well under
ambient reaction conditions with an abundant, cheap, and
benign iron catalyst that is currently being considered as an
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Experimental Section
General procedure
In a 25 mL Schlenk tube, FeSO4·7H2O (12 mg, 0.04 mmol), pyridine-
2-carboxylic acid (5.3 mg, 0.04 mmol), and crushed molecular
sieves (3 ꢁ, 200 mg) were taken up in methanol (3 mL). The mix-
ture was stirred for 5 min at room temperature, which resulted in
an orange–yellowish solution. The oxidant (1.5 equiv.) was then
added after evacuating and backfilling the flask three times with
air, and the resultant reaction mixture was stirred in air at room
temperature for 1 min. The solution immediately turned light
yellow. A solution of the corresponding styrene (1 mmol) in metha-
nol (1 mL) was then added, and the mixture was stirred at 608C for
12 h. The reaction mixture was neutralized by adding an aqueous
solution of 10% sodium bisulfite and subsequently extracted with
diethyl ether (3ꢂ10 mL). The combined organic layer was washed
with distilled water (3ꢂ10 mL), dried with MgSO4, and then con-
centrated under reduced pressure. The resultant material was then
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Received: April 9, 2013
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