Palladium-catalyzed: Ortho -halogen-induced deoxygenative approach of alkyl aryl ketones to 2-vinylbenzoic acids

Article abstract of DOI:10.1039/d0cc02941f

The 2-vinylbenzoic acids have wide applications in the field of polymer chemistry and are key precursors for the synthesis of important bioactive molecules. Herein, an ortho-halogen-induced deoxygenative approach for the generation of 2-vinylbenzoic acids from alkyl aryl ketones by palladium catalysis is discovered and explored. This approach requires no base or stoichiometric additives and can be carried out through a simple one-step process. Furthermore, the present reaction is scalable up to one-gram scale. The commercially available palladium on carbon (5 wt%) was used as a heterogeneous catalyst and showed excellent recyclability (<5 times) without significant loss in catalytic activity. Pleasingly, under our optimized conditions, the alpha alkyl substituted 2-iodoacetophenones exhibit good diastereoselectivity and predominantly (E)-2-vinylbenzoic acids were obtained with good to excellent yields.

Full text of DOI:10.1039/d0cc02941f

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DOI: 10.1039/D0CC02941F
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Palladium-Catalyzed ortho-Halogen-Induced Deoxygenative
Approach of Alkyl Aryl Ketones to 2-Vinylbenzoic Acids
Shankar Ram,a,b Ajay Kumar Sharma,a,b Arvind Singh Chauhana,b and Dr. Pralay Dasa,b *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The 2-vinylbenzoic acids have wide applications in the field of motif in many natural products (Scheme 1).7 When preparing
polymer chemistry and key precursor in the synthesis of important second- generation catalysts, the 2-vinylbenzoic acids and its
bioactive
molecules.
Herein,
ortho-halogen-induced derivatives are also used as a chelating ligand to enhance the
deoxygenative approach of alkyl aryl ketones for the generation of catalytic activity and selectivity of the catalyst.8 Furthermore,
2-vinylbenzoic acids by palladium catalysis has discovered and the carboxylated styrenes have various applications in the
explored. This approach requires no base or stoichiometric polymer industry to synthesize new and advanced polymeric
additives and can carried out through a simple one-step process. materials.9 Carboxylated polymers exhibit superior physical
Furthermore, the present reaction is scalable up to one-gram and mechanical properties compared with non-carboxylated
scale. The commercially available palladium on carbon (5 wt %) polymers. Due to vast applications of functionalized styrenes,
was used as a heterogeneous catalyst and showed excellent particularly 2-vinylbenzoic acids, various synthetic methods
recyclability (<5 times) without significant loss in catalytic activity. have developed. The palladium-catalyzed cross-coupling
Pleasingly, under our optimized conditions, the alpha alkyl reactions10 are one of the common methods for the synthesis
substituted
2-iodoacetophenones
exhibits
good of functionalized styrene, by reacting aryl halides with a
diastereoselectivity and predominantly (E)-2-vinylbenzoic acids variety of reagents. For example, Heck,11 Hiyama12 and Still13
were obtained with good to excellent yields.
cross-coupling reactions have been widely used in synthetic
organic procedures. However, such coupling reactions use
either ethylene gas under high pressure or vinyl reagents
which can be toxic or produce toxic organometallic residues.14
The direct olefination of alcohols with sulphones is another
approach to synthesize substituted styrenes.15 Besides the
coupling reactions and olefination of alcohols, the direct
2-Vinylbenzoic acids are widely used as key building blocks for
the synthesis of bioactive molecules and drug candidates, for
instance inhibitors of non-peptidic HIV protease (HIV Pr),1
inhibitors of glutamate carboxypeptidase II (GCPII),2 anti-
inflammatory drugs,3 anti-depressant drugs,4 agonist estrogen
receptors,5 etc. These are also key precursors for the synthesis
of useful β- and γ- aldehyde intermediates, common building
blocks for the synthesis of various important chemical
substances.6 In addition, they are found as a core structural
conversion of
Previous Work:
a) Stephan, 2015 (Deoxygenation of aryl alkyl ketones)16
O
R
R1
Cat. B(C6F5)3
R
R1
OH
O
H2 (60 atm)
OH
O
R2 = CH2, CHCH3, C(CH3)2
O
O
O
b) Goossen, 2016 (C-H hydroarylation of alkynes)17
HO
O
R1
HO
R2
OH HO
R
R2
R
H
Cat. [Ru]
base
OH
Aigialomycin D
OMe
Scoparine A
O
+
zearalenone
COOH
COOH
R1
-CO2H as DG
Scheme 1. Selected examples of natural products
Our work:
O
X
R1
COOH
R1
Cat. [Pd(0)]
oxalic acid
R
R
X = -I, -Br
R1 = -H, alkyl
- ortho-halogen-induced deoxygenation
- Base and additive free
- Milder and scalable
aNatural Product Chemistry & Process Development Division, CSIR-Institute of
Himalayan Bioresource Technology, Palampur, 176061, H.P., India
bAcademy of Scientific & Innovative Research, CSIR-IHBT, Palampur (H.P.)
E-mail: pdas@ihbt.res.in;
Electronic Supplementary Information (ESI) available: General information,
optimization details, mechanistic investigation and characterization data for
synthesized compounds. See DOI: 10.1039/x0xx00000x
- Diastereoselective
- Commercially available and recyclable catalyst
Scheme 2. Synthesis of functionalized styrenes
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acetophenones into styrenes is an attractive approach in the lower efficiency as compared to Pd/C (Table 1S, entries 10-12).
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DOI: 10.1039/D0CC02941F
synthetic organic chemistry. There are very few reports The efficiency of reaction was decreased on decreasing the
available in the literatures on the direct conversion of catalyst loading (1 mol %), equivalency of oxalic acid (3),
acetophenones to styrenes (Scheme 2). Stephan and co- reaction temperature and time (Table 1S, entries 13-16). N-
workers reported the reductive deoxygenation of aryl ketones formylsaccharin also delivered the desired transformation
under hydrogen pressure in the presence of catalytic amount under our catalytic conditions with 70% yield of 2a (Table 1S,
of B(C6F5)3.16 However, this method is only applicable to aryl entry 17). When oxalic acid replaced with formic acid, the
alkyl ketones. Later on, Goossen and co-workers reported the desired product 2a formed in traces along with dehalogenated
carboxylate-directed C-H hydroarylation of internal alkynes product (Table 1S, entry 18). These experiments clearly
with benzoic acids catalyzed by [Ru(p-cym)I2]2 complex to indicated that the feasibility of reaction in the presence of
synthesized wide variety of 2-vinylbenzoic acids.17 Recently, oxalic acid.
Hou and co-workers also demonstrated the palladium (0) With the best reaction conditions in our hands, the
nanoparticles catalyzed long range isomerization of 2- investigation of the substrate scope for the developed reaction
alkenylbenzoic acid derivatives to 2-vinylbenzoic acids.18 In protocol was pursued (Table 1). o-Iodoacetophenones having a
literature, there are few reports available where 2- series of functional groups were well tolerated under present
haloacetophenones used as starting material under CO catalytic system and the desired products were isolated in
environment in the presence of transition metal (Ni and Pd) moderate to good yields (2a-2i, 56-90% yields). Unfortunately,
catalyst and base but Zhang et al reported that cyclic ester was the similar reaction condition was not effective in case of 2-
the end product of the reaction.19 Till date, there is no single bromoacetophenone, even the reaction allowed to proceed up
report available for the synthesis of 2-vinylbenzoic acids to 48 hrs. Interestingly, when 2-bromoacetophenone treated
directly from 2-halogen substituted alkyl aryl ketones in one- with Pd/C (3 mol %), oxalic acid and KI (3 equiv.) as additive at
step under base free conditions.
130 oC for 36 hrs, the reaction proceed smoothly and the
Recently, we have developed a protocol for the isoindolinones anticipated product (2a) was isolated in 65% yield. This
synthesis from 2-iodoacetophenones under polystyrene reaction clearly demonstrated the unique role of iodide group
supported palladium (Pd@PS) nanoparticles (NPs) catalyzed in the
conditions using oxalic acid as C1 source.21c Inspiring by the
unique behaviour of 2-haloacetophenone in our earlier
development, herein, we have reported an unprecedented
deoxygenative approach for 2-vinylbenzoic acids synthesis
from 2-halogen substituted alkyl aryl ketones under Pd/C
catalyzed conditions using oxalic acid as CO (g) surrogate. The
overall reactivity of alkyl aryl ketone was induced by its 2-
halogen atom under intermediate steps were further
supported by several cross control experiments.
Table 1. Substrate scope.a
O
Pd/C (2 mol%)
(COOH)2 (6 equiv.)
R2
R1
CH3
R2
R1
nCH3
n
X
COOH
DMF:xylene (3:1)
130 oC, 6 hrs
R3
R3
2
X = I, Br
1
n = 0,1,2,3
n = 0,1,2,3,4
CH3
COOH
H3C
COOH
93%
H3CO
COOH
84%
2a
2b,
2c,
Our preliminary studies were focused on the reactions of o-
iodoacetophenone (1a) with oxalic acid in the presence of
heterogeneous and homogeneous palladium catalysts (Table
1S, ESI). After careful evaluation of reaction parameters such
as palladium catalysts, solvent system, temperature and time,
the mixture containing Pd/C (2 mol %) and oxalic acid (6
equiv.) in DMF:xylene as a solvent at 130 oC facilitated the
desired transformation and the product 2-vinylbenzoic acid20
(2a) was obtained in 90% isolated yield (Table 1S, entry 8).
Plausibly, controlling experiments clearly demonstrated that
the crucial role of palladium catalyst as well as oxalic acid in
the desired transformation (Table 1S, entries 2 and 3). Various
single solvent systems were screened but no satisfactory
results were obtained (Table 1S, entries 4-7). As a single
solvent, although DMF was the best solvent but
dehalogenation of starting material decreases the yield of
desired product 2a. Therefore, we chose the mixed solvent
system DMF and xylene in 3:1, which reduces the
dehalogenated product. The polystyrene supported palladium
nanoparticles (Pd@PS) developed by our group also facilitated
the desired reaction and the product 2a was obtained in 60%
isolated yield (Table 1S, entry 9). We were also screened
different homogeneous palladium catalysts, but all resulted in
COOH
77%
X = I, 90%
X = Br, 65%c
CH3
2d,
H3CO
H3CO
F
COOH H3CO
65%
COOH
56%
COOH
2h,
79%
H3C
COOH
2f,
2g,
2e,
71%
CH3
CH3
CH3
Cl
COOH
67%
COOH
83%
H3C
2k,
E:Z = 23.2:1
COOH
87%
COOH
81%
E:Z = 8.7:1
2i,
2l,
2j,
E:Z = 10.8:1
CH3
CH3
COOH
COOH
74%
E:Z = 7.1:1
COOH
2n,
2m,
79%
2o,
traces*
E:Z = 8.4:1
a
Reaction condition: 2-iodoacetophenone (0.20 mmol), oxalic acid (1.22 mmol)
catalyst (2 mol%), DMF:xylene (1.5:0.5), 130 oC, 6 hrs. Isolated yield. 2-
Bromoacetophenone (0.25 mmol), oxalic acid (1.5 mmol), catalyst (3mol%), KI
(0.75 mmol), DMF:xylene (3:1), 130 oC, 36 hrs.* By-product 3-(propan-2-
ylidene)isobenzofuran-1(3H)-one was formed with a yield 75%.
b
c
deoxygenation of aryl ketones. Electron rich para substituted
2-iodoacetophenones were found to be reactive and the
desired products were obtained in good yields (2b and 2c). The
steric hindrance around the carbonyl group little bit affects
substrate reactivity and reduces the yield of targeted products
2 | J. Name., 2012, 00, 1-3
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(2d-2e). In case of 2-iodoacetophenones with methoxy group reactions.22 In order to check the possibility of in situ
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at 5-position, the formation of side product (2-acetyl benzoic hydrogenation and dehydration reactionDoOfI:a1c0e.1t0o3p9h/De0nCoCn0e2,9w41eF
acids) was observed and therefore, provided moderate yields carried out the reaction of 1-(2-iodophenyl)ethanol (5) under
of the desired product (2f-2g). Halogen (such as -Cl, -F) standard conditions. Unfortunately, we got only
substituted 2-iodoacetophenones were also tested and well dehalogenated product along with starting material 5. As
tolerated under the present reaction conditions, gave previously described, the reaction of 2-iodopropiophenone in
moderate to good yields of corresponding product (2h-2i). the presence of CO pressure and base under transition metal
After screening the variations on phenyl ring, we moved (Ni and Pd) catalyzed conditions, ended with 5-endocyclization
toward the alpha alkyl substituted 2-iodoacetophenones to product 3-ethylideneisobenzofuran-1-(3H)-one (6).19 In order
check the diastereoselectivity (E/Z) under our reaction to confirm the possibility of intermediacy of this cyclic product,
conditions.
Various
alpha
alkyl
substituted
2- we also performed a reaction of 3-ethylideneisobenzofuran-1-
iodoacetophenones were subjected under optimized (3H)-one (6) under standard conditions. In this case, we did
conditions. To our delight, thermodynamically more stable not get the desired product even in traces. Obviously, this
trans isomers (-E)21 were obtained in good yields ranging from experiment omitted the intermediate 6. After performing all
74 to 87% (Table 1, products 2j-2n). 4-Methyl substituted 2- possibilities of the reaction pathways and according to the
iodopropiophenone showed excellent reactivity and selectivity literature reports, we became unable to reach in any
as compared to un-substituted one (2j) and delivered the conclusion. It is then assumed that after the coupling of
desired product (2k) in 87% isolated yield. On increasing the carbonyl in the halogen position, intra-molecular shifting of
length of alkyl chain (C2 to C4) at alpha position to carbonyl, oxygen from –COCH3 to carbonyl group may be promoting by
slight decrease in the yield as well as diastereoselectivity was ortho-halogen and palladium complex. In order to meet our
observed (Table 1, products 2l-2n).
assumption, we replaced oxalic acid with N-formylsaccharin
which act as only CO source.23 Pleasingly, the formation of
desired product 2a was observed in 70% isolated yield
(Scheme 3, entry 6). The result of this experiment has
similarity with our assumption but not enough to validate our
mechanism. In this context, we had hardly tried to purchase O-
18 labelled acetophenone from available sources, but
unfortunately, we did not find this chemical. Then, we have
prepared partially O-18 labelled 4-methyl-2-iodoacetophenone
(Scheme 3, entry 7).24 We have performed the final reaction
with this substrate (7) under standard conditions.
Interestingly, we also found O-18 labelled final product in the
same way as in the starting material. On the basis of this
experiment and the findings, we can conclude that carboxylic
acid was produced through a deoxygenative approach. The
proposed mechanism and hypothesis of the deoxygenative
cycle is illustrated in the supporting details (Scheme S1).
To assess the scalability of the present protocol, the reaction
of 4-methoxy-2-iodoacetophenone (1e) was performed on 3.6
mol scale in a 20 mL PTFE lined hydrothermal autoclave
reactor using 0.036 mol of Pd/C (5 wt%) and 21.6 mol oxalic
acid (Scheme 4). To our delight, the reaction went smoothly
and the desired product (2e) was isolated in 61% yield (390
mg).
O
CH3
Standard conditions
1)
nr
nr
3
O
CH3
Standard conditions
2)
COOH
O
4
CH3
Standard conditions
I2 or KI (1 equiv.)
3)
4
+
COOH
COOH
OH
90%
4
nd
OH
CH3
I
Standard conditions
Standard conditions
CH3
4)
5)
5
+
5
O
COOH
COOH
6
nd
O
O
Pd/C (2mol%)
N-Formylsaccharine
CH3
I
6)
7)
DMF (anhydrous)
130 oC, 6 hrs
1a
2a 70%
O16/18
CH3
Standard conditions
H3C
COO16/18
H
H3C
I
O-16 (major)
O-18 (minor)
7
Partially O-18
labelled
Scheme 3: Control experiments
We had conducted a series of control experiments to
understand the mechanism of desired transformation (Scheme
3). The acetophenone (3) was found to be un-reactive under
standard conditions. This indicates that ortho-iodine group is
essential for the desired transformation. During the
optimization study, we received a small amount of 2-acetyl
benzoic acid that could be either intermediate or by-product
of the reaction. However, 2-acetyl benzoic acid (4) did not
provide the desired product under standard conditions, even
prolonger the reaction time from 6 hrs to 12 hrs. The 2-acetyl
benzoic acid (4) together with one equivalent of I2 or KI under
standard conditions was also unable to deliver the desired
transformation. That means, 2-acetyl benzoic acid was a by-
product of the reaction. In our previous reports, oxalic acid has
well known for the carboxylation, carbonylation and reduction
In conclusion, first time we have developed 2-halogen-induced
deoxygenative approach of alkyl aryl ketones for the synthesis
of 2-vinylbenzoic acids under Pd/C catalyzed conditions using
oxalic acid as C1 source. A variety of 2-iodoacetophenones
were attempted and yielded the corresponding products in
good to excellent yields. Interestingly, the high
diastereoselectivity (E/Z) was observed for alpha alkyl
substituted 2-iodoacetophenones and corresponding products
(E isomer) obtained in excellent to good yields. The present
methodology was also tested on a one-gram scale substrate
successfully. The catalyst exhibits excellent stability and can be
easily recycled more than five times without significant loss of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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F. Stelzer, and K. Mereiter, Organometallics, 2004, 23, 3622-
catalytic activity. On the basis of control experiments, we
conclude that 2-iodine is the key for the desired deoxygenative
transformation.
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3626.
DOI: 10.1039/D0CC02941F
9
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Scheme 4. Gram scales reaction for the synthesis of 5-methoxy-2-vinylbenzoic
acida
O
HO
O
O
Pd/C (1 mol%)
CH3
+
H3C
H3C
DMF:xylene (3:1)
130 oC, 6 hrs
O
COOH
O
I
OH
1e
( 1 g, 3.6 mmol)
2e
61% (390 mg)
10 A.S.K. Hashmi, C. Lothschutz, R. Dopp, M. Rudolph, T. D.
Ramamurthi, and F. Rominger, Angew. Chem. Int. Ed., 2009,
48, 8243-8246.
Conflicts of interest
“There are no conflicts to declare”.
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Acknowledgment
We are grateful to the Director, CSIR-IHBT Palampur (H.P.) for
providing necessary facilities during the course of the work; S.
Ram, A.K. Sharma and A. S. Chauhan thanks to CSIR and DST-
INSPIRE, New Delhi for awarding fellowships.
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DOI: 10.1039/D0CC02941F
The first report on palladium catalyzed ortho-halogen induced deoxygenative approach for 2-
vinylbenzoic acids synthesis from 2-haloaryl ketones is described.