Remote meta C-H bond functionalization of 2-phenethylsulphonic acid and 3-phenylpropanoic acid derivatives

Article abstract of DOI:10.1039/c6cc08302a

This discovery illustrates selective meta C-H bond activation from multiple non-equivalent C-H bonds present in medicinally relevant arylethanesulfonic acid and the 2-arylpropanoic acid moiety using weakly coordinating nitrile as a directing group. Transformation of the meta olefinated compounds to important organic molecules has been demonstrated. Efforts were made to obtain mechanistic detail of the meta C-H bond functionalization reaction.

Full text of DOI:10.1039/c6cc08302a

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Remote meta C–H Bond functionalization of 2-phenethylsulphonic
acid and 3-phenylpropanoic acid derivatives
Atanu Modak, Anirban Mondal, Rahul Watile, Semanti Mukherjee, Debabrata Maiti*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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intension to diversify the medicinally and biologically relevant 2-aryl
ethane acid (sulphonic and carboxylic acid) moieties. Both 2-
phenylethanesulfonic acid and 3-phenylpropanoic acid derivatives
compose the structural backbone of a number of drug molecule e.g.
This discovery illustrates selective meta C–H bond activation from
multiple inequivalent C–H bonds present in medicinally relevant
arylethanesulfonic acid and 2-arylpropanoic acid moiety using
weakly coordinating nitrile as a directing group. Transformation of
the meta olefinated compounds to important organic molecules
have been demonstrated. Efforts were made to obtain mechanistic
detail of the meta C–H bond functionalization reaction.
naratriptan, baclofen, etc.
On the other hand, 2-
phenylethanesulfonic acid can be used as important tool in complex
molecule synthesis utilizing its α-sulphonyl carbanion.7 In addition,
the use of easily accessible 2-cyanophenol as directing group and
smooth installation (and removal) procedure to the target molecule
has made this strategy simple and useful.
Transition-metal-catalyzed direct functionalization of unactivated C–
H bond prevailed as an indispensable approach in synthesizing
various complex molecules from simple forms in last few decades.1
Due to the ubiquitousness of the C–H moiety in target molecules, the
utility of C–H activation suffers from the selectivity issues. The
selectivity has been achieved by creating the accurate metal
proximity towards a particular C–H bond with the aid of a judiciously
designed directing group.2 The directed ortho C–H functionalization
was accomplished through a conformationally rigid five or six
membered metalacyclic pre-transition state which is kinetically or
thermodynamically stable.3
The ultimate challenge arises for
activating the C–H bonds further to ortho, due to the requirement of
high energy associated with more than seven membered
metalacyclic intermediate. In this regard, the directing group assisted
meta C–H activation was pioneered by Yu and co-workers4 where
they have introduced perfectly designed directing templates for
meta C–H activation through macrocyclic cyclophene-like pre-
transition state.5 In a complementary approach, the meta-selective
functionalization with the help of steric and electronic bias or
applying transient mediator was also addressed.6 Recently our group
reported, meta C–H functionalization of aryl acetic acid5f and aryl
methane sulphonic acid5c moiety through cyano moiety containing
11 membered metalacyclic intermediate. Notably, large metalacyclic
intermediate formation and thereby promoting desired level of
selectivity across wide variety of substrate remained a challenging
and exciting area of research.
Scheme 1 Schematic diagram of present work
Scheme 2 Medicinal significance of 2-aryl ethane acid moieties
In our initial investigation with 1a for establishing the optimized
reaction conditions, we tested various reaction parameters such as
Pd-catalysts, solvent, temperature, and oxidant. Observed H NMR
1
spectral data revealed that the combination of catalytic 10 mol%
Pd(OAc)2 and 20 mol% N-formyl glycine (For-Gly-OH) with 2 equiv.
AgOAc (as the oxidant) in HFIP solvent (60 °C, 24 h) can afford
alkenylated product 2a in 67% isolated yield. During our optimization
experiment, we envisioned that an optimum amount of oxidant (2
equiv of silver (II) salt) and olefin (2 equiv.) is crucial to get good
mono: di olefination ratio.8 We inspected different olefin partners
for meta olefination of 2-phenylethanesulfonic acid. A wide range of
Herein, we are disclosing the meta C–H functionalization of aryl
moiety through a 12 membered metalacyclic intermediate with the
aDepartment of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai
400076, India
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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olefins were coupled at the meta position of the 2-
phenylethanesulfonic acid. Appreciable meta selectivity with good
yields was obtained with α,β- unsaturated ester, ketone and amide
(2a, 2b, 2d, 2g-2l). To our delight, vinyl phosphonate ester and vinyl
sulphone resulted the meta olefinated product (2c, 2e and 2f,
respectively) with excellent positional selectivity. Acrylate with bulky
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DOI: 10.1039/C6CC08302A
bioactive molecule e.g. vitamin
E and testosterone were
incorporated at the meta C–H bond of the phenylethanesulfonic acid
regardless of their steric bias (2j and 2k, respectively). Subsequently,
we
explored
the
scope
with
various
substituted
phenylethanesulfonic acid moiety where we found that both
electronically deficient (2l and 2m) as well as electronically rich (2n
and 2o) arene moieties were tolerated with synthetically useful
selectivity and yields.
Scheme 4 Meta selective allylation of 2-phenylethanesulfonic acid
derivatives
To make further diversification of the 2-phenylethanesulfonic acid
moiety, we performed the sequential olefination of the mono meta
olefinated product as substrates. Sequential hetero di-olefination
was successfully conducted to result the meta di-olefinated product.
Scheme
5 Meta selective sequential hetero-diolefination of 2-
phenylethanesulfonic acid derivatives
Subsequently, we concentrated on optimizing the reaction condition
for selective mono meta olefination of 2-arylpropanoic acid (1a').
Previously Yu group have reported the meta C–H olefination of 2-
arylpropanoic acid derivatives.4a
Indeed this novel report
demonstrated the first directing group assisted meta
functionalization. Observed high di:mono olefination prompted us to
employ the present directing group for controlling the reactivity over
the two meta C–H bonds owing to the less statistical availability. We
optimized various reaction parameters to develop coupling reaction
with substrate (1a') and olefin. Analysis of 1H NMR spectra revealed
that the combination of catalytic 7 mol% Pd(OAc)2 and 21 mol% N-
acetyl glycine (Ac-Gly-OH) with 2 equiv. Ag2CO3 (as the oxidant) in
DCE and equivalent amount solvent (65 °C, 48 h) can afford
alkenylated product 2a in 68% isolated yield with good level of meta-
selectivity (19:1). Furthermore, this reaction condition allowed us to
carry out diversification of the remaining meta C–H bond in a
controlled fashion.
Scheme 3 Meta selective mono-olefination of 2-phenylethanesulfonic
acid derivatives
Intriguingly, due to preferential β-hydrogen elimination (Hb is
favoured over Ha) double bond isomerization was observed in the
olefination reaction with α,α-di-substituted α,β- unsaturated ketone
and ester.5c In case of 1-acetyl-1-cyclohexene as olefin partner, the
In order to probe the synthetic applicability of this protocol, we
meta selective allyl product was formed (3a). However with extensively surveyed the scope of olefin as well as 3-
phenylpropanoic acid derivatives for selective meta olefination.
Under the optimized condition, α,β-unsaturated esters and ketone
resulted the desired mono olefinated product in good yield with
excellent meta selectivity ( 5a-5c). A class of vinyl sulfone derivatives
methacrylate derivatives, mixture of allyl and styrenyl products were
isolated with 2:1 selectivity (3b and 3c).
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(5d-5f) and a vinyl phosphonate (5g) ester were successfully attached
to meta position of 1a’. In accordance with our previous result, we
have encountered complete switch towards meta selective allyl
product of phenylpropanoic acid (5h) with 1-acetyl-1-cyclohexene.
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DOI: 10.1039/C6CC08302A
Scheme 8 Deprotection of acid moieties and recovery of the
directing template
Scheme 9 Synthetic diversification of the meta olefinated moiety
Scheme 6 Meta selective mono olefination of 3-phenylpropanoic acid
derivatives
Scheme
7 Meta selective hetero- and homo-di-olefination of 3-
phenylpropanoic acid derivatives
Figure 1 Mass spectrometric studies of the reaction mixture
As expected, we were successful to explore the sequential hetero di-
olefination and homo di- olefination using mono olefinated 2-
arylpropanoic acid derivatives as substrate. These di-olefinated
products have great significance in organic synthesis and materials
chemistry.9
The deprotection and recovery of the directing template was
successfully carried out followed by a base mediated hydrolysis.
Efficiency of this meta-functionalization strategy was then tested to
synthesize synthetically useful organic moieties (scheme 9).
Applicability of this protocol was extended to employ mono
olefinated product as a starting material for the synthesis of other
important intermediate. After a successful hydrogenation of the
olefinic double bond, meta alkylated product was obtained. In
another diversification, bromination of the olefinic moieties
produced the 1,2-dibromo alkylated product, which may be further
utilized in late stage modification in synthetic organic chemistry.
To gain insights into the mechanistic complexity, we carried out the
mass spectrometric studies of the reaction mixture in absence of
olefin with stoichiometric combination on palladium acetate and the
ligand. A 12- membered cyclophane like palladacycle is intercepted
in the reaction mixture using both 1a and 1a’ as substrate (figure 1).
Though the ligand-metal and solvent (HFIP)-metal interaction could
not be detected from mass spectrometric experiment, the
essentiality of the ligand and solvent was probed in control
experiments. Furthermore, the kinetic study of the olefination
reaction of 2-phenylethanesulfonic acid moiety (1a) revealed the 1st
order dependency with respect to the substrate (1a) and zero order
dependency with respect to the olefin partner (figure 2). Such an
observation suggests that olefin is unlikely to be involved in the rate
limiting step.
Based on experimental observation and previous reports, a
plausible catalytic cycle was drawn. At first, the weak coordination of
palladium with the nitrile group brings the metal towards the close
proximity of the meta C–H. Then, the meta C–H bond is cleaved
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through concerted metalation deprotonation5a,4c resulting a 12
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Subsequently, olefin binding, 1,2-
DOI: 10.1039/C6CC08302A
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Scheme 10 Proposed catalytic cycle of meta olefination
In conclusion, we have developed a method for meta C–H olefination
of aryl moiety with 2-cyanophenol as directing template. The
selective mono as well as sequential di functionalization allowed the
structural diversification of the 2-aryl ethane acid moieties. The
mechanistic studies suggest the formation of 12-membered
palladacycle formation as key intermediate along with elucidating
role of various reagent under reaction condition.
Notes and references
This activity is supported by Science and Engineering Research Board, India
(No. SB/S5/GC-05/2013). Financial support received from CSIR (A. Modak) is
gratefully acknowledged.
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Table of Contents
This discovery illustrates selective meta C–H bond activation from
multiple inequivalent C–H bonds present in medicinally relevant
arylethanesulfonic acid and 2-arylpropanoic acid moiety using
weakly coordinating nitrile as a directing group. Transformation of
the meta olefinated compounds to important organic molecules
have been demonstrated. Efforts were made to obtain mechanistic
detail of the meta C–H bond functionalization reaction.
This journal is © The Royal Society of Chemistry 20xx
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