Metal-free, catalytic regioselective oxidative conversion of vinylarenes: A mild approach to phenylacetic acid derivatives

Article abstract of DOI:10.1039/c5ra25296b

A new synthetic approach towards the synthesis of phenylacetic acids from aromatic alkenes has been developed for the first time under mild conditions by employing non-toxic reagents such as molecular iodine and oxone. This metal-free catalytic regioselective oxygenation of vinylarenes proceeds via tandem iodofunctionalization/de-iodination induced rearrangement.

Full text of DOI:10.1039/c5ra25296b

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Metal-Free, Catalytic Regioselective Oxidative Conversion of
Vinylarenes: A Mild Approach to Phenylacetic Acid Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Srujana Kodumuri,a Swamy Peraka, a,b Naresh Mameda,a,b Durgaiah Chevella,a Rammurthy
Banothua,b and Narender Namaa,b
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new synthetic approach towards the synthesis of phenylacetic
acids from aromatic alkenes has been developed for the first time
under mild conditions by employing non-toxic reagents such as
molecular iodine and oxone. This metal-free catalytic
regioselective oxygenation of vinylarenes proceeds via tandem
iodofunctionalization/de-iodination induced rearrangement.
Figure 1. Representative biologically active compounds containing phenylacetic
The selective oxidation methods for the conversion of readily acid moieties.
available and cheap hydrocarbons towards value-added
oxygenated products as versatile building blocks or fine
chemicals under mild conditions have been found to be
indispensable tools in modern organic synthesis.1 In particular,
the regioselective catalytic oxidative functionalization of
carbon-carbon double bond of alkenes is of utmost importance
for the synthesis of a wide variety of organic products, because
they are manufactured on very large scales. For example, the
Pd(II)-catalyzed direct oxidation of olefins to methyl ketones
(Markovnikov products), usually known as the Tsuji–Wacker
oxidation, has found widespread applications in both academia
and industry.2 Nevertheless, the achievement of anti-
Markovnikov selectivity in the oxidation of alkenes is a difficult
process and has been listed as one of the top ten challenges to
be addressed by catalysis since 1993.3 Over the past few years,
considerable efforts have been made toward the historical
challenge of anti-Markovnikov functionalization of alkenes.4,5
However, the regioselective oxidation of aromatic alkenes has
not been reported so far for the synthesis of arylacetic acid
derivatives.
a) Carbonylation of benzyl halides/benzyl alcohols:
CO/Fe or Rh or Pd
OH
OH
Ar
X/OH
Ar
ref. 5-6
O
O
X = halogen
b) Carboxylation of benzyl halides:
CO2/Ni
Ar
Ar
X
ref. 7
X = halogen
c) Hydrocarboxylation of styrenes:
CO2/Zn or Ni or Fe
OH
OH
Ar
Ar
Ar
ref. 8
O
O
d) Reduction of mandelic acids:
H3PO3/NaI
OH
ref. 9
OH
Ar
O
e) Regioselective oxidative conversion of vinylarenes:
Phenylacetic acids are important class of compounds found
in many natural products and pharmaceuticals,6 which exhibit
significant biological activities including anti-inflammatory,
antifungal, antityrosinase, and antimicrobial activity. For
example, the nonsteroidal anti-inflammatory drugs, such as
Ibuprofen and Diclofenac contain a phenylacetic acid moiety
"I+" Catalyzed
OH
Ar
Ar
O
This work
Scheme 1. Different methods for the synthesis of phenylacetic acids.
in their structures (Fig. 1). The particular high importance
among these compounds made attentive the chemists to
develop an assortment of synthetic protocols for their
preparation. The conventional methods for the synthesis of
phenylacetic acids involve the carbonylation of benzyl
halides/benzyl alcohols using transition metal catalysts
a.I&PC Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007,
Telangana, India. E-mail: narendern33@yahoo.co.in; nama@iict.res.in
b.Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical
Technology, Hyderabad, Telangana, India.
Electronic Supplementary Information (ESI) available: Experimental procedures
and NMR spectra (1H and 13 C). See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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(Scheme 1a).7-8 In recent years, the carboxylation of benzyl
halides,9 hydrocarboxylation of alkenes10 and reduction of
mandelic acids11 have provided direct access to phenylacetic
acids (Scheme 1b-d). However, since most of these standard
protocols rely on the use of transition metals (in catalytic
amounts or in over stoichiometric amounts), costly and/or
corrosive reagents, harsher reaction conditions and sometimes
require prior synthesis of their precursors, there is still an
apparent need for methodology improvement with respect to
environmental and economic issues. Indeed, the metal-free
catalytic regioselective oxygenation of vinylarenes would
enable the ecologically and economically viable production of
arylacetic acid derivatives.
Table 1. Optimization study for metal-free catalytic conversion of styrene (1a) to
phenylacetic acid (2a).a,b
Entry
Solvent
Oxone
Time (h)
Yield
(%)
42
(equiv.)
1
2
H2O
2
2
3
4
CH3CN-H2O
63
(4:1)
3
4
DME-H2O (4:1)
CHCl3-H2O (4:1)
DCM-H2O (4:1)
CCl4-H2O (4:1)
DCE-H2O (4:1)
DME-H2O (1:4)
DME-H2O (4:1)
DME-H2O (4:1)
DME-H2O (4:1)
DME-H2O (4:1)
DME-H2O (4:1)
DME-H2O (4:1)
DME-H2O (4:1)
DME-H2O (4:1)
DME-H2O (4:1)
2
2
6
6
6
6
6
2
6
6
6
6
6
6
6
6
6
88
-
5
2
-
Over the past few years, the iodine catalysts have been
increasingly employing as environmentally benign and
promising alternatives to many transition metal catalysts used
in various carbon-carbon and carbon-hetero atom bond
formation reactions.5,12 Nonetheless, to the best of our
knowledge, these catalysts have never been utilized for the
regioselective oxygenation (in an anti-Markovnikov fashion) of
vinylarenes for the preparation of phenylacetic acid moieties.
Being interested in important biological activities of
phenylacetic acids, we, herein, report the first non-metal
catalyzed protocol for the synthesis of phenylacetic acid
derivatives from aromatic alkenes employing mild reagents
such as molecular iodine and oxone at room temperature.
We initiated our investigation by choosing styrene (1a) as
6
2
-
7
2
-
8
2
70
75
88
20
83
88
<5
-
9
1.5
3
10
11
12c
13d
14e
15f
16g
17h
0.5
2
2
2
2
2
-
2
-
a
Reaction conditions: Unless otherwise stated, styrene (1 mmol), I2 (10
mol %), oxone, solvent (5 mL). Isolated yields. c I2 (5 mol %). I2 (15 mol
%). e m-CPBA was used as an oxidant instead of oxone. f K2S2O8 was used as
b
d
model substrate, molecular iodine as the source of an oxidant instead of oxone. g aq.H2O2 was used as an oxidant instead of
oxone. h aq.TBHP was used as an oxidant instead of oxone.
electrophilic iodine and oxone as terminal oxidant. To our
delight, the reaction of 1a with iodine and oxone in aqueous
Highly activated styrenes 1e and 1f furnished the
media indeed occurred to give the desired phenylacetic acid
corresponding products 2e and 2f, respectively, in moderate
product 2a in 42% yield at room temperature (Table 1, entry
yields (Table 2, entries 5-6). Halo substituents at para position
1). In an attempt to improve the yield of 2a, various co-solvent
of styrenes including 1g-1i were efficiently oxidized to give the
systems (homogeneous and biphasic system) have been
corresponding products 2g-2i in 77-91% yields possibly due to
investigated and found that the combination of 1,2-
dimethoxyethane (DME) and water (4:1; 5 mL) is the best for
Table 2. Regioselective metal-free catalytic oxidative conversion of terminal aromatic
olefins.a,b
achieving the maximum yield (88%) of phenylacetic acid (2a
)
(Table 1, entries 2-8). Next, we screened the amount of
reagents (iodine and oxone) and other oxidants to further
enhance the reaction yield. But, either increasing or decreasing
the amounts of reagents or replacing the oxone with various
oxidants such as m-CPBA, K2S2O8, aq.H2O2 and aq.TBHP did not
improve the yield of the reaction (Table 1, entries 9-17).
Entry
Olefin
Time
(h)
6
Product
2
Yield
(%)
88
86
45
76
48
54
91
77
83
52
50
00
1
With the optimized reaction conditions in hand, we then
focused our attention on assessing the scope of the reaction
against a variety of alkenes (Table 2 and Table 3). As shown in
Table 2, all the terminal aromatic alkenes reacted smoothly to
afford moderate to excellent yields of the corresponding anti-
markovnikov products. Styrene (1a) produced the respective
acid 2a in high yield (88%). In order to determine the influence
of substitution on aromatic ring of styrene on the reaction
path with this reagent system, we considered the reaction
with different substitutions. The alkyl substituted styrenes 1b-
1d were successfully converted into the corresponding acids
2b-2d in 45-86% yields (Table 2, entries 2-4) and the lower
yield of 2,4-dimethyl styrene (1c) probably due to steric
hindrance of ortho substituted methyl group.
1
2
Ar = Ph; 1a
2a
2b
2c
Ar = 4-MeC6H4; 1b
Ar = 2,4-diMeC6H3; 1c
Ar = 4-t-BuC6H4; 1d
Ar = 4-MeOC6H4; 1e
Ar = 2-MeOC6H4; 1f
Ar = 4-FC6H4; 1g
Ar = 4-ClC6H4; 1h
Ar = 4-BrC6H4; 1i
Ar = 3-BrC6H4; 1j
Ar = 3-NO2C6H4; 1k
Ar = C5H5N; 1l
2.5
3
3
4
4
2d
2e
2f
5
2
6
3.5
4
7
2g
2h
2i
8
3
9
4
10
11
12
5
2j
24
24
2k
2l
a
Reaction conditions: substrate (1 mmol), I2 (10 mol %), oxone (2 mmol), DME-
H2O (4:1, 5 mL), RT. b Isolated yields.
2 | J. Name., 2012, 00, 1-3
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Table 3. Regioselective metal-free catalytic oxidative conversion of aromatic
(disubstituted) and aliphatic olefins.a,b
DME/Water (50 mL; 4:1)
I2 (0.507 g; 10 mol%)
OH
Ph
Ph
Oxone (24.590 g; 2 equiv.)
rt, 6 h
(A)
O
1a
2a
Entry
Olefin
Time
(h)
Product
Yield
(%)
2.258 g; yield: 83%
(2.083 g; 20 mmol)
1
2 or 2’
DME/Water (100 mL; 4:1)
I2 (1.142 g; 10 mol%)
1
2
3
3
76
80
1a
2a
(B)
Oxone (55.328 g; 2 equiv.)
rt, 6 h
5.202 g; yield: 85%
(4.686 g; 45 mmol)
DME/Water (150 mL; 4:1)
I2 (2.538 g; 10 mol%)
(C)
1a
2a
Oxone (122.952 g; 2 equiv.)
rt, 6 h
(10.414 g; 100 mmol)
11.696 g; yield: 86%
3
4
3
1
35
91
Scheme 2. Large-scale experiments for the synthesis of phenylacetic acid (2a) from
styrene (1a)
in Scheme 2, all the preparative-scale reactions proceed
smoothly with excellent yields.
OH
In order to establish the reaction pathway for the
formation of phenylacetic acids from aromatic olefins, we
performed several control experiments and are outlined in
5
1.5
63
OH
2q'
Scheme 3. The reaction of styrene
(1a) under optimal
conditions in the presence of a radical inhibitor, such as
6
7
1-octene (1r)
4
5
56
58
trans-2-octene (1s)
a
Reaction conditions: substrate (1 mmol), I2 (10 mol %), oxone (2 mmol), DME-
H2O (4:1, 5 mL), RT. b Isolated yields.
the inductive and resonance effect of halogen (F, Cl and Br)
groups (Table 2, entries7-9). However, the halo substituent, for
example bromo group, at meta position provided lesser yield
than that obtained for para position (Table 2, entry 10).
Similarly, styrene containing strong electron with-drawing
group i.e. 3-nitro styrene (1k) also yielded the corresponding
product 2k in 50% yield even after prolonged the reaction time
for 24 h (Table 2, entry 11). In contrast, the hetero aromatic
alkene i.e., 2-vinylpyridine (1l) did not react under optimized
conditions and the only starting material (100%) was
recovered after 24 h (Table 2, entry 12).
Scheme 3. Control experiments.
TEMPO (2,2,6,6-tetramethyl piperidine 1-oxy) had no
significant effect on the yield of the desired product (Scheme
3, eq. 1), indicating the absence of a radical mechanism. The
reaction in the absence of I2 and oxone did not occur to
provide the product 2a (Scheme 3, eq. 2). When the reaction
was performed without I2, the reaction failed to deliver the
desired product (Scheme 3, eq. 3). The product 2a was also not
formed in the absence of oxone (Scheme 3, eq. 4). These
results collectively indicated the importance of iodine catalyst
and oxidant in this reaction. When the co-iodo intermediate 3a
was subjected to the standard reaction conditions, the
formation of 2a was observed in 90% yield (Scheme 3, eq. 5).
Also, the reaction of 1a was investigated using 3a as the
catalyst instead of I2, and obtained the product 2a in 75% yield
(Scheme 3, eq. 6). These reactions indicating that 3a may be
Next, we investigated the efficiency of this method with a
few 1,1-disubstituted, internal and aliphatic olefins (Table 3).
The reactions of α- and β-substituted styrene derivatives 1m
-
1o under standard conditions provided the corresponding anti-
Markovnikov products 2m-2o in 35-80% yields (Table 3, entries
1-3). These results suggesting that the reactions of styrene
derivatives may involve the rearrangement of aryl group under
the standard conditions. However, the aliphatic alkenes (cyclic
and acyclic) 1p-1s yielded the corresponding vicinal diols 2p’
-
2s’ in 56-91% yields instead of desired anti-Markonikov
(rearranged) products 2p-2s (Table 3, entries 4-7).
To illustrate the practical utility of this protocol, we have
performed the large-scale reactions (20, 45 and 100 mmol
scale) of styrene (1a) under optimized conditions. As outlined
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the intermediate in the anti-Markovnikov selective oxidation We thank the CSIR Network project CSC-0125 for financial
process.
support. K.S. P.S. and B. R. acknowledge the UGC, India and
M.N. and C.D. acknowledge the CSIR, India for financial
support in the form of fellowships.
Notes and references
1
2
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Chem. Int. Ed., 2009, 48, 9034; (c) L. Hintermann, in:
Transition Metals for Organic Synthesis., (Eds.: M. Beller, C.
Bolm), Wiley-VCH, Weinheim, 2004, p 279; (d) J. Tsuji,
Palladium Reagents and Catalysts: New Perspectives for the
21st Century, 2nd edn., Wiley, 2004; (e) J. M. Takacs and X.-
T. Jiang, Curr. Org. Chem., 2003,
Nagashima and H. Nemoto, Org. Synth., 1990,
Tsuji, Synthesis., 1984, 369; (h) J. Smidt, W. Hafner, R. Jira, R.
Sieber, J. Sedlmeier and A. Sabel, Angew. Chem., 1962, 74
93; Angew. Chem. Int. Ed. Engl., 1962, , 80; (i) J. Smidt, W.
7, 369; (f) J. Tsuji, H.
7, 137; (g) J.
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Hafner, R. Jira, J. Sedlmeier, R. Sieber, R. Rüttinger, and H.
Kojer, Angew. Chem., 1959, 71, 176.
3
4
anti-Markovnikov selective functionalization of alkenes was
highlighted as a challenging task in catalysis two decades
ago: J. Haggin, Chem. Eng. News., 1993, 71, 23.
(a) M. Beller, J. Seayad, A. Tillack, and H. Jiao, Angew. Chem.,
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and N. Narender, Adv. Synth. Catal., 2015, 357, 1125; (c) P.
Swamy, M. Naresh, M. M. Reddy, K. Srujana, C. Durgaiah, S.
Scheme 4. Plausible mechanism for the I2/oxone mediated catalytic conversion
of vinylarenes to arylacetic acids.
Based on the above investigated results and literature
reports, a plausible mechanism is proposed and is outlined in
Scheme 4. Initially, the I2 reacts directly with an alkene
form a co-iodo intermediate (or reacts with oxone to form
transient HOI species,5c which readily reacts with
to form 3).
The de-iodination of via its oxidation to hypervalent iodine
intermediate followed by reductive elimination led to HOI
and a short lived phenonium ion intermediate C 5c
The
intermediate undergoes aryl group migration to form
corresponding aldehyde , which upon oxidation in presence
of oxone led to the desired arylacetic acid . The HOI
1 to
3
5
6
1
3
4
.
C
Prabhakar and N. Narender, RSC Adv., 2015, 5, 73732.
5
(a) L. Xu, N. Feng, J. Xue, P. Wu and X. Wei, Redai Yaredai
Zhiwu Xuebao., 2008, 16, 140; (b) Y.-J. Zhu, H.-T. Zhou, Y.-H.
Hu, J.-Y. Tang, M.-X. Su, Y.-J. Guo, Q.-X. Chen and B. Liu, Food
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Chem. Soc., 2011, 133, 11936; (d) J. J. Jackson, H. Kobayashi,
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J. Am. Chem. Soc., 2015, 137, 656.
2
generated in the first cycle continues the catalytic cycle until
the complete consumption of starting material into the
product.
Conclusions
7
(a) G. Tangw, B. Weinberger and H. des Abbayes,
Tetrahedron Lett., 1983, 24, 4005; (b) C.W. Kohlpaintner, M.
Beller, J. Mol. Catal. A: Chemical, 1997, 116, 259; (c) A.
In conclusion, we have developed the first non-metal
mediated catalytic protocol for the synthesis of phenylacetic
acid derivatives from readily available starting materials using
simple and non-toxic reagents such as molecular iodine and
oxone. This new metal-free catalytic approach offers several
advantages such as mild conditions, simple work up
procedures, use of eco-friendly and readily available reagents
and the exclusion of the need for transition metals. Moreover,
the scope and limitations of this process are demonstrated
with various terminal and internal alkenes. Furthermore, a
plausible mechanism also proposed for the formation of
phenylacetic acid derivatives from vinylarenes under metal-
free catalytic conditions.
Giroux, C. Nadeau and Y. Han, Tetrahedron Lett., 2000, 41
,
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10 (a) C. M. Williams, J. B. Johnson and T. Rovis, J. Am. Chem.
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Thomas, J. Am. Chem. Soc., 2012, 134, 11900.
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Larsen and J. A. Murry, J. Org. Chem., 2011, 76, 9519.
12 For a review, see: (a) P. Finkbeiner and B. J. Nachtsheim,
Synthesis, 2013, 979; For selected examples, see: (b) S. Tang,
Y. Wu, W. Liao, R. Bai, C. Liu and A. Lei, Chem. Commun.,
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Acknowledgements
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Yusubov and V. V. Zhdankin, Adv. Synth. Catal., 2014, 356
3336; (e) ref. 11.
,
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Metal-Free, Catalytic Regioselective Oxidative Conversion of Vinylarenes: A Mild
Approach to Phenylacetic Acid Derivatives
Srujana Kodumuri, Swamy Peraka, Naresh Mameda, Durgaiah Chevella, Rammurthy Banothu and
Narender Nama∗
A first metal-free catalytic approach for the synthesis of phenylacetic acid derivatives from aromatic
olefins is reported.