A generalized approach for iron catalyzed chemo- and regioselective formation of anti-Markovnikov acetals from styrene derivatives

Article abstract of DOI:10.1039/c2cc17889c

Fe(BF₄)₂·6H₂O in the presence of pyridine-2,6-dicarboxylic acid and PhI(OAc)₂ can efficiently catalyze the formation of chemoselective dialkyl acetals from styrene derivatives with anti-Markovnikov regioselectivity in good to high yields under mild and benign reaction conditions.

Full text of DOI:10.1039/c2cc17889c

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COMMUNICATION
A generalized approach for iron catalyzed chemo- and regioselective
formation of anti-Markovnikov acetals from styrene derivativesw
Abhishek Dutta Chowdhury and Goutam Kumar Lahiri*
Received 17th December 2011, Accepted 9th February 2012
DOI: 10.1039/c2cc17889c
Fe(BF4)2ꢀ6H2O in the presence of pyridine-2,6-dicarboxylic acid
and PhI(OAc)2 can efficiently catalyze the formation of chemo-
selective dialkyl acetals from styrene derivatives with anti-
Markovnikov regioselectivity in good to high yields under mild
Scheme 1
and benign reaction conditions.
Acetalization is known to be the most popular and widely
employed synthetic route towards the protection of aldehydic
and ketonic functionalities during the manipulation of various
multifunctional organic molecules.1 Acetals can also be directly
converted to other useful functional groups and hence can serve
as an important intermediate in the course of organic synthesis.1,2
Furthermore, hemiacetal formation is the mechanism by which
pentoses and hexoses assume their cyclic forms. Additionally
acetals have immense industrial importance particularly due to
their potential utility as flavoring agent in distilled beverages,
diesel additives and in plastic materials.3
Most of the existing methods for the synthesis of acetals
involve the treatment of aldehydes or ketones by either a
protic1,4 or a Lewis acid1,5 catalyst. But these methods have
Scheme 2
severe limitations, such as use of corrosive and costly reagents or
product by palladium catalyzed Wacker type oxidation protocol
additives, halogenated solvents, high temperature, inconvenient
(Scheme 2).7 On the contrary, complete reversal of regioselectivity
reaction conditions, large waste and high catalyst loading. In
i.e. the formation of Markovnikov acetals has been demonstrated
this context the recent report of ruthenium catalyzed direct
recently by Sigman et al. during similar kind of Wacker type
transformation of alcohols to acetals is noteworthy as it avoids
the use of expensive aldehydes or ketones as substrate.6 Direct
oxidation of styrene derivatives but by using Pd[(ꢁ)-sparteine]Cl2
as a catalyst (Scheme 2).8a Here anti-Markovnikov acetals are
transformation of a cheaper terminal alkene to an acetal instead
also reported to form as a minor product from styrene
containing an electron withdrawing functional group.8a Ochiai
of using a costlier aldehyde or ketone as substrate is regarded as
a challenging task. We therefore report here the direct and highly
et al. have also shown the synthesis of anti-Markovnikov
efficient catalytic conversion of various styrene derivatives to the
dimethyl acetal, (2,2-dimethoxyethyl)benzene, from styrene
corresponding terminal or anti-Markovnikov acetals under mild
using [PhI(OH)(18Crown6)]BF4 as the reagent in methanolic
and environmentally benign reaction conditions using a cheap
medium.8b However, the general regio- and chemoselective
and readily available iron-based catalyst (Scheme 1).
catalytic formation of anti-Markovnikov acetals from styrene
Over the years styrene has emerged as an attractive alternative
derivatives under benign catalytic conditions has not been
substrate for acetal synthesis (Scheme 2). Hosokawa et al.
reported in the literature till date (Scheme 2).
reported for the first time that styrene can be directly oxidized
During initial optimization of suitable reaction conditions
to acetal with high regioselectivity for the anti-Markovnikov
different iron, ruthenium, copper and cobalt salts in the
presence of various commercially available bi- and tridentate
ligands have been screened in the presence of PhI(OAc)2 as an
oxidant in methanol (Table 1) using styrene as the model
substrate. However, only iron based precursors have been found
to deliver measurable activity and/or selectivity. Among them,
both Fe(BF4)2ꢀ6H2O (1) and Fe(ClO4)2ꢀ6H2O have shown almost
Department of Chemistry, Indian Institute of Technology Bombay,
Powai, Mumbai-400076, India. E-mail: lahiri@chem.iitb.ac.in;
Fax: +91-022-2572-3480
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, and additional tables and figures.
See DOI: 10.1039/c2cc17889c
c
3448 Chem. Commun., 2012, 48, 3448–3450
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Table 1 Catalytic acetalization of styrenea
Table 2 Iron catalyzed acetalization of styrene derivativesa
Entry
Catalystb
Conversion (%)
Yieldc (%)
1
2
3
4
5
6
7
8
RuCl3ꢀxH2O/dipic
RuCl3ꢀxH2O/trpy
RuCl3ꢀxH2O/dppf
Ru(acac)3/dipic
[Ru(p-cym)2Cl2]2/dipic
Ru(trpy)Cl3/dipic
Ru(CO)3(PPh3)3/dipic
Fe2O3/dipic
FeCl3ꢀ6H2O/dipic
FeCl3ꢀ6H2O/dppf
FeCl2/dipic
Fe(acac)3/dipic
Fe(OAc)2/dipic
o1
o1
o1
o1
3
0
0
0
0
0
0
0
3
25
1
31
5
43
92(89)d
51
44
12
47
21
o1
77, 94e
43
39
51
35
12
9
11
o1
10
52
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
11
60
12
61
97
61
56
19
Fe(BF4)2ꢀ6H2O (1)/dipic
Fe(BF4)2ꢀ6H2O/dppf
Fe(BF4)2ꢀ6H2O/en
Fe(BF4)2ꢀ6H2O/dppe
Fe(BF4)2ꢀ6H2O/pic
Fe(BF4)2ꢀ6H2O/trpy
Fe(BF4)2ꢀ6H2O
59
32
10
Fe(ClO4)2ꢀ6H2O/dipic
Fe(ClO4)2ꢀ6H2O/dppf
Cu(ClO4)2ꢀ6H2O/dipic
Cu(BF4)2ꢀ6H2O/dipic
CuSO4ꢀ5H2O/dipic
CoCl2ꢀ6H2O/dipic
Co(acac)2(H2O)2/dipic
81, 98e
56
58
65
44
40
35
a
Reaction conditions: 1 mol% catalyst, 1 mol% L, styrene, 1.5 equiv.
PhI(OAc)2 in 4 mL methanol, RT, 20 h. See the experimental part for the
details. b dipic = pyridine-2,6-dicarboxylic acid, trpy =2,20 : 60,200 -terpyri-
dine, dppf = 1,10-bis(diphenylphosphino) ferrocene, en = ethylenediamine,
dppe = 1,2-bis(diphenylphosphino)ethane, pic = pyridine-2-carboxylic
acid, acac = acetylacetonate, p-cym = p-cymene or 4-isopropyltoluene.
c
Determined by GC using n-dodecane as an internal standard.
Determined by 1H NMR with PhTMS as an internal standard.
d
e
Isolated yield is given in parentheses. 48 h.
similar efficiency but the latter requires longer reaction time to
achieve similar conversion (entries 14 and 21, Table 1). Thus, the
in situ generated catalyst derived from Fe(BF4)2ꢀ6H2O and dipic
ligand (dipic: pyridine-2,6-dicarboxylic acid) has led to significant
activity and resulted in (2,2-dimethoxyethyl)benzene in 92%
yield (entry 14, Table 1). A large variety of oxidants have also
been tested with the Fe(BF4)2ꢀ6H2O/dipic catalytic system and
significant activity and selectivity have only been achieved by
PhI(OAc)2 (Table S1, ESIw). Moreover, only dipic exhibits
excellent activity and selectivity over other ligands in the
presence of 1 and PhI(OAc)2 as oxidant (entries 14–20, Table 1).
In essence, only one combination along with Fe(BF4)2ꢀ6H2O (1)
extends promising activity in terms of both conversion and
selectivity under specified reaction conditions. Notably, ruthenium
precursors in combination with dipic failed to show any activity
and other copper and cobalt catalysts display poor activity and/or
selectivity with dipic under identical reaction conditions.
The optimized reaction conditions indeed allowed the
oxidation of a wide variety of styrene derivatives (2a–u) to
the corresponding anti-Markovnikov acetals (3a–u) using only
1 mol% 1, 1 mol% dipic, PhI(OAc)2 as oxidant (1.5 equiv.)
and 3 A molecular sieves in methanol under aerial atmosphere
(Table 2 and ESIw). The same reaction conditions but an inert
atmosphere do not alter the yield and selectivity at all. The effect
of molecular sieves (MS) is highly prominent in the present case
a
Reaction conditions: 1 mol% 1, 1 mol% dipic, substrate, 1.5 equiv.
PhI(OAc)2 in 4 mL methanol, RT, 20 h. Isolated yields are given. See
ESI for details. Yields based on 1H NMR with PhTMS as an
b
c
d
internal standard. Substrate: cis-b-methyl styrene. Substrate:
trans-b-methyl styrene. Isomerisation of unreacted substrate is not
observed. 2 equiv. of PhI(OAc)2.
e
f
to achieve complete conversion to the acetal (vide infra).
Similar role of MS has already been established earlier.8a,9
Interestingly, Markovnikov acetals are not formed by any
means from any styrene derivatives, 2a–u in the present case.
Excellent yields are obtained generally with styrene containing
an electron donating functionality whereas poor yield has been
observed with styrene having an electron withdrawing group.
A slightly larger amount of oxidant is required to achieve good
yield from the allylic derivatives.
The most remarkable feature of this work is that it proceeds
in a highly chemoselective manner. Substrates like 2o and 2p
having a formyl group on the ring and at the b-carbon,
respectively, remain completely unaffected after the reaction,
neither acetalized nor oxidized even under such an oxidizing
environment. Moreover, the change of solvent from methanol to
ethanol or ethylene glycol similarly gives anti-Markovnikov acetals
in good to reasonable yields (Table S2, ESIw). Unfortunately, poor
c
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The role of weakly ligating strong Lewis acid, BF4ꢁ, cannot
be excluded.12b Further mechanistic studies are underway.
In summary, an efficient and selective iron-catalyzed
oxidation of styrene to anti-Markovnikov acetal has exclusively
taken place in alcoholic medium under mild reaction conditions.
This provides an unprecedented account of anti-Markovnikov
acetal formation, where the only reported catalyst exhibits low
catalytic activity.7 The present catalytic system operates well
at room temperature with an abundant, cheap and benign
iron-catalyst which is currently considered an ideal option to
replace any precious metal in homogeneous catalysis.12b,c The
present report of iron-catalyzed chemo- and regioselective
direct acetalization of styrene to its anti-Markovnikov acetal
may extend an alternate route for targeted organic synthesis.
The financial support received from DST and CSIR (fellowship
to A.D.C.), New Delhi, India, is gratefully acknowledged.
Scheme 3
yield of anti-Markovnikov acetals is obtained from the long-chain
alcohol, 1-pentanol (entry 3, Table S2, ESIw).10a
Notes and references
The dehydrating agent (MS) plays an additional crucial role
here.9 In its absence the reaction is considerably slow and the
terminal aldehyde is also formed to a large extent.10b The time
monitored model reaction with styrene as a substrate reveals
the formation of a minute amount (r3%) of phenylacetaldehyde
during the reaction (Fig. S1, ESIw). However, direct acetalization
of phenylacetaldehyde produces only 38% (2,2-dimethoxyethyl)-
benzene which in effect suggests that the acetalization of styrene
instead of aldehyde is the highly favored pathway for the present
catalytic system. The existence of only phenylacetaldehyde and
complete absence of acetophenone and/or styrene oxide during
the course of the reaction provides the necessary justification
in favor of the observed exclusive regioselectivity towards anti-
Markovnikov acetals (Fig. S1, ESIw). It should be noted that
during other reported iron-catalyzed oxidation of a terminal
alkene, acetal products were not detected.11
1 (a) J. R. Hanson, Protecting Groups in Organic Synthesis, Black-
well Science, Inc, Malden, MA, 1st edn, 1999; (b) T. W. Greene and
P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley
and Sons, New York, 3rd edn, 1999; (c) P. J. Kocienski, Protecting
Groups, Georg Thieme, Stuttgart, 1st edn, 1994.
2 (a) T. Hosokawa and S.-I. Murahashi, Acc. Chem. Res., 1990,
23, 49; (b) E. Schnitz and I. Eichorn, The Chemistry of the Ether
Linkage, ed. S. Patai, Wiley, New York, 1967.
3 (a) H. Maarse, Volatile Compounds in Foods and Beverages, Marcel
Dekker Inc, New York, 1991; (b) P. H. R. Silva, V. L. C. Gonc¸ alves
and C. J. A. Mota, Bioresour. Technol., 2010, 101, 6225.
4 (a) T.-J. Lu, J.-F. Yang and L.-J. Sheu, J. Org. Chem., 1995,
60, 2931; (b) R. Gopinath, S. J. Haque and B. K. Patel, J. Org.
Chem., 2002, 67, 5842.
5 (a) S. Velusamy and T. Punniyamurthy, Tetrahedron Lett., 2004,
45, 4917; (b) N. M. Leonard, M. C. Oswald, D. A. Freiberg, B. A.
Nattier, R. C. Smith and R. S. Mohan, J. Org. Chem., 2002, 67, 5202.
6 C. Gunanathan, L. J. W. Shimon and D. Milstein, J. Am. Chem.
Soc., 2009, 131, 3146.
7 (a) T. Hosokawa, T. Ohta and S.-I. Murahashi, J. Chem. Soc.,
Chem. Commun., 1983, 848; (b) T. Hosokawa, T. Ohta,
S. Kanayama and S.-I. Murahashi, J. Org. Chem., 1987, 52, 1758.
8 (a) A. M. Balija, K. J. Stowers, M. J. Schultz and M. S. Sigman,
Org. Lett., 2006, 8, 1121; (b) M. Ochiai, K. Miyamoto, M. Shiro,
T. Ozawa and K. Yamaguchi, J. Am. Chem. Soc., 2003, 125, 13006.
9 B. A. Steinhoff, A. E. King and S. S. Stahl, J. Org. Chem., 2006,
71, 1861.
10 (a) Maximum upto 36% of yield can be achieved from 1-decene as
substrate; (b) In the absence of 3 A MS, yield of (2,2-dimethoxyethyl)-
benzene is only B63% whereas phenylacetaldehyde is B18% under
identical reaction conditions.
11 (a) G.-Q. Chen, Z.-J. Xu, C.-Y. Zhoub and C.-M. Che, Chem.
Commun., 2011, 47, 10963; (b) J. Picione, S. J. Mahmood, A. Gill,
M. Hilliard and M. M. Hossain, Tetrahedron Lett., 1998, 39, 2681;
(c) K. Suda, K. Baba, S. Nakajima and T. Takanami, Chem.
Commun., 2002, 2570.
A tentative mechanism is proposed in Scheme 3. The active
iron catalyst mediates the acetalization of a terminal alkene to
an anti-Markovnikov acetal, where the alkene approaches the
iron bound oxo-atom via a side on approach. It then under-
goes a [1,2] hydride shift followed by two consecutive solvent
(methanol) neucleophilic attacks at the b-carbon atom which
eventually leads to the formation of selective anti-Markovnikov
acetals. Lewis acidic feature of the substrate bound iron center may
facilitate the selective neucleophilic attack of the solvent, which in
turn governs the exclusive regio- and chemoselectivity. Since no
epoxide has been detected during the reaction, the possibility of the
well known E–I (tandem epoxidation–isomerization) mechanism
can therefore be completely ruled out in the present case.12a
Additionally, one model reaction with styrene oxide as a
substrate resulted in 1,2-dimethoxyphenylethane which indeed
rules out the alternate possibility of the formation of styrene
oxide as an intermediate as well as the E–I mechanism.
12 (a) J. Chen and C.-M. Che, Angew. Chem., Int. Ed., 2004, 43, 4950;
(b) G. Wienhofer, I. Sorribes, A. Boddien, F. Westerhaus,
¨
K. Junge, H. Junge, R. Llusar and M. Beller, J. Am. Chem. Soc.,
2011, 133, 12875; (c) S. Enthaler, K. Junge and M. Beller, Angew.
Chem., Int. Ed., 2008, 47, 3317.
c
3450 Chem. Commun., 2012, 48, 3448–3450
This journal is The Royal Society of Chemistry 2012