Palladium(II)-Catalyzed meta-C-H Olefination: Constructing Multisubstituted Arenes through Homo-Diolefination and Sequential Hetero-Diolefination

Article abstract of DOI:10.1002/anie.201503112

Divinylbenzene derivatives represent an important class of molecular building blocks in organic chemistry and materials science. Reported herein is the palladium-catalyzed synthesis of divinylbenzenes by meta-C-H olefination of sulfone-based arenes. Successful sequential olefinations in a position-selective manner provided a novel route for the synthesis of hetero-dialkenylated products, which are difficult to access using conventional methods. Additionally, 1,3,5-trialkenylated compounds can be generated upon successful removal of the directing group. Jockeying for position: Reported herein is the palladium-catalyzed synthesis of mono- and divinylbenzenes by meta-C-H olefination of benzyl sulfones. Successful sequential olefinations in a position-selective manner provided a novel route for the synthesis of hetero-dialkenylated products, which are difficult to access using conventional methods. DG=directing group.

Full text of DOI:10.1002/anie.201503112

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503112
German Edition: DOI: 10.1002/ange.201503112
À
C H Activation
À
Palladium(II)-Catalyzed meta-C H Olefination: Constructing
Multisubstituted Arenes through Homo-Diolefination and Sequential
Hetero-Diolefination**
Milan Bera, Arun Maji, Santosh K. Sahoo, and Debabrata Maiti*
Abstract: Divinylbenzene derivatives represent an important
class of molecular building blocks in organic chemistry and
materials science. Reported herein is the palladium-catalyzed
substrates, and that the flexible nature of the sulfonyl (SO2),
compared to carbonyl (CO) moiety, in the scaffold would
enhance the directing power of the nitrile (Scheme 1).[7] We
À
synthesis of divinylbenzenes by meta-C H olefination of
sulfone-based arenes. Successful sequential olefinations in
a position-selective manner provided a novel route for the
synthesis of hetero-dialkenylated products, which are difficult
to access using conventional methods. Additionally, 1,3,5-
trialkenylated compounds can be generated upon successful
removal of the directing group.
Scheme 1. Development of a new scaffold.
À
T
ransition-metal-catalyzed functionalization of arene C H
bonds has been extensively investigated over the last two
decades by using a variety of directing groups (DGs).[1] In the
C H activation realm, directing groups are almost universally
were particularly interested in the synthesis of di-alkenylated
benzylsulfonyl scaffolds because of the importance of dio-
lefinated compounds in organic synthesis and materials
chemistry.[8] However the second olefination reaction is
expected to be challenging since the electronic and steric
properties of mono-olefinated species is completely different
from those of the starting materials.[9] Such challenges were
overcome and we herein disclose an approach for meta-
selective homo-diolefination and sequential hetero-diolefina-
À
ortho-selective.[2] Compared to ortho-functionalization, the
related meta-selective reactions pose a significant challenge.
In this regard, examples of meta-selective functionalization
have only recently been reported and are based on steric and
electronic bias.[3] An alternate template-based approach,
initiated by the group of Yu[4] and subsequently extended by
Tan and co-workers[5] as well as our group,[6] demonstrated
meta-selective functionalization in the presence of a suitable
À
tion of C H bonds of sulfone-based arenes (Scheme 2).
[10]
À
À
directing group. These meta-selective C H functionalizations
are usually independent of the substitution pattern and
electronic nature of the substrate. Importantly, activation of
meta C H bonds hinges upon the combined use of a weakly
coordinating nitrile-based template with a protected amino-
acid ligand.
Although ortho-C H olefination of benzyl sulfonamides
and ortho-selective hetero-diolefinations have been docu-
mented,[9] meta-selective hetero-diolefination is yet to be
reported.
À
Initially, benzylsulfonyl ester derivatives were tested with
various of nitrile-based directing groups (Scheme 3; for
structures see Figure 1).[6,11] Upon optimization, 2-hydroxy-
benzonitrile successfully delivered the diolefination product
During our previous work on palladium-catalyzed meta-
C H olefination with arylacetic acid derived scaffolds,
[6]
À
a number of limitations were encountered: 1) unsuccessful
diolefination, 2) transesterification of the directing group
with the solvent hexafluoroisopropanol (HFIP), and 3) mod-
erate to good meta-selectivity. Some of these drawbacks
probably originate from the conformational and electronic
bias of arylacetic acid based substrates. We reasoned that
a more electron-withdrawing SO2 group may reduce electron
density at the ortho- and para-position of the sulfone-based
[*] Dr. M. Bera, A. Maji, Dr. S. K. Sahoo, Prof. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
E-mail: dmaiti@chem.iitb.ac.in
[**] This activity is supported by SERB, India (SB/S5/GC-05/2013).
Financial support was received from DST under the Fast Track
Scheme (M.B.), CSIR (A.M.), and IIT-B (S.S.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503112.
Scheme 2. Outline of this work.
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Scheme 3. Development of directing group. Yields and selectivities
1
determined by H NMR analysis of crude reaction mixture.
Scheme 5. Advantages of the present scaffold.
Figure 1. X-ray structures[15] of SM1, 1 f, and 4q.
in 88% yield and with high selectivity (meta/other > 20:1).
Further optimization of the reaction parameters delivered
two different catalytic conditions (A: with 10 mol% Pd in
dichloroethane solvent and B: with 2 mol% Pd in HFIP
solvent) for mono-olefination (Scheme 4).[11] The major
Scheme 4. Two protocols for mono-olefination. DCE=1,2-dichloro-
1
ethane. Yields and selectivities determined by H NMR analysis of the
crude reaction mixture.
advantages of the benzylsulfonate (our present scaffold) are
as follows (Scheme 5): 1) the directing group is commercially
available, simple, and has a low molecular weight. Notably,
the templates of both Yu and Tan are synthesized through
five- and four-step procedures, respectively; 2) in general,
selectivity is very high (even for unbiased substrates). In
a number of cases, exclusive mono-olefinated products were
obtained. 3) two different robust conditions were developed
for mono-olefination; 4) the SO2-X unit (DG) can be
Scheme 6. The meta-selective mono-olefination. Yields and selectivi-
ties determined by 1H NMR analysis of crude reaction mixture. See
Figure 1 for X-ray structure.
exclusively (1 f–h). Complete mono-selectivity was also
obtained with both the ortho-methyl- and ortho-chloro-
substituted benzylsulfonyl ester (1i–l) under the reaction
conditions A. The meta-chloro- and fluoro-substituted ben-
zylsulfonyl esters were olefinated selectively at the 5-position
with different olefins (1m–p). In addition, this protocol is
compatible with electron-donating and electron-withdrawing
para substituents such as methyl (1q and 1r), chloro (1s and
1t), and fluoro (1u–1w). All para-substituted benzylsulfonyl
esters produced 10–15% of the diolefination product along
with monoalkenylated products. The 2,6-difluoro sulfonyles-
converted into
a number of interesting groups (see
Schemes 11 and 12).
Different acrylates and a,b-unsaturated ketones produced
the desired mono-olefination products in moderate to good
yields (1a–e; Scheme 6) with excellent meta-selectivity (meta/
others > 20:1). Olefins with amide, phosphonate, and sulfone
moieties resulted in meta-selective mono-olefination products
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Scheme 7. Substrate scope with internal olefins. Yields and selectiv-
ities determined by 1H NMR analysis of crude reaction mixture.
ter was olefinated to exclusively afford the meta-selective
mono-olefinated products (1x and 1y).
Interestingly under the reaction conditions C (Scheme 7),
di-substituted trans-olefins (e.g. fumarate, crotonate, cinna-
mate, and cinnamaldehyde) were successfully employed.[12]
Notably, exclusive mono-selectivities were observed in all the
entries. Although, a mixture of E and Z isomers were
detected, the E isomer was generated as the major product
(2a–c and 2e). With a cis-olefin such as dimethyl maleate,
E isomers were formed exclusively (2d and 2 f). These
phenomena indicate that the stereoselectivity is thermody-
namic in origin.[13]
Similarly, reaction with methacrylate and cyclic trisubsti-
tuted olefins proceeded to provide meta-selective monoallyl
benzene derivatives in good yields under the reaction
conditions B (3a–c; Scheme 8). Formation of these allyl
benzene derivatives could be explained by the regioselective
b-Hb elimination rather than b-Ha elimination.[11,14] Unfortu-
nately this reaction is not compatible with electron-neutral or
electron-rich olefins such as substituted styrenes.
Scheme 9. Substrate scope for homo-diolefination. Yields and selectiv-
ities determined by 1H NMR analysis of crude reaction mixture. See
Figure 1 for X-ray structure.
The trisubstituted cyclic olefins also reacted well under the
reaction conditions C to afford the meta-selective diallylben-
zene derivatives in good yields (4p and 4q).
To obtain sequential olefination in a position-selective
manner, mono-olefinated products were utilized. With the
prefunctionalized olefinated product (Scheme 6), acrylates,
methylvinyl ketone, ethylvinyl ketone, vinylsulfone, vinyl
phosphonate, amide, and disubstituted olefins were incorpo-
rated at the remaining meta-position in an exclusive manner
with good to excellent yields under the reaction conditions C
(5a–p; Scheme 10). Hetero-diolefination reactions by
sequential addition of two different olefins in a one-pot
process gave the desired product (e.g., 5c, 58% and 5k, 52%)
along with formation of other mono-olefinated and homo-
diolefinated products.[11]
Scheme 8. Formation of meta-allyl benzene. Yields and selectivities
determined by H NMR analysis of crude reaction mixture.
The 2-hydroxybenzonitrile group is easily removed by
hydrolysis at room temperature by using KOH in methanol to
produce the meta-substituted diacid 6 in excellent yield
(Scheme 11).
1
We subsequently explored homo-diolefination at the
meta positions under the reaction conditions C (Scheme 9).
Different acrylates, a,b-unsaturated ketones, and disubsti-
tuted internal olefins produced dialkenylated products in
good yields (4a–g). Notably, chloro, fluoro, and methyl
benzylsulfonyl esters gave dialkenylated products (4h–o).
Additionally, the SO2-DG scaffold can be easily cleaved
by a modified Julia olefination. All mono-, di-, and hetero-
diolefinated products, 1a, 4a, and 5c were reacted with
benzaldehyde in presence of LDA at À788C to afford the
corresponding 1,3-divinyl and 1,3,5-trivinylbenzene deriva-
tives, 7, 8, and 9 in good yields (Scheme 12).
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Scheme 13. Proposed catalytic cycle.
make a 12-membered cyclophane-like pre-transition state
(A). Because of the high electrophilicity, the nitrile-bound
PdII center is likely to be reactive towards the meta-C H
bond. Formation of the mono-olefinated product E from B
À
Scheme 10. Sequential hetero-diolefination. Yields and selectivities
determined by H NMR analysis of crude reaction mixture.
1
À
will involve 1) C H activation, 2) olefin binding, 3) 1,2-
migratory insertion, and 4) b-hydride elimination.
In summary, we have developed complementary methods
for meta-selective mono-, di-, and sequential hetero-diolefi-
nations of sulfone-based arene motifs with a 2-hydroxyben-
zonitrile template. Substituents are tolerated at all positions
À
on the arene framework. The strategy for sequential meta-C
H olefination provides a novel route for the synthesis of meta-
selective bis(alken)ylated compounds having two different
olefins, compounds which are difficult to access using conven-
tional methods.
Scheme 11. Hydrolysis of directing group.
À
Keywords: C H activation · olefination · palladium · sulfur ·
synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8515–8519
Angew. Chem. 2015, 127, 8635–8639
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Received: April 5, 2015
Revised: April 29, 2015
Published online: June 9, 2015
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