Palladium-catalyzed aryl C-H olefination with unactivated, aliphatic alkenes

Article abstract of DOI:10.1021/ja5082734

Palladium-catalyzed coupling between aryl halides and alkenes (Mizoroki-Heck reaction) is one of the most popular reactions for synthesizing complex organic molecules. The limited availability, problematic synthesis, and higher cost of aryl halide precursors (or their equivalents) have encouraged exploration of direct olefination of aryl carbon-hydrogen (C-H) bonds (Fujiwara-Moritani reaction). Despite significant progress, the restricted substrate scope, in particular noncompliance of unactivated aliphatic olefins, has discouraged the use of this greener alternative. Overcoming this serious limitation, we report here a palladium-catalyzed chelation-assisted ortho C-H bond olefination of phenylacetic acid derivatives with unactivated, aliphatic alkenes in good to excellent yields with high regio- and stereoselectivities. The versatility of this operationally simple method has been demonstrated through drug diversification and sequential C-H olefination for synthesizing divinylbenzene derivatives.

Full text of DOI:10.1021/ja5082734

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Communication
Palladium Catalyzed Aryl C–H Olefination with Unactivated, Aliphatic Alkenes
Arghya Deb, Sukdev Bag, Rajesh Kancherla, and Debabrata Maiti
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja5082734 • Publication Date (Web): 04 Sep 2014
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Journal of the American Chemical Society
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Palladium Catalyzed Aryl C–H Olefination with Unactivated,
Aliphatic Alkenes
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Arghya Deb, Sukdev Bag, Rajesh Kancherla, Debabrata Maiti*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India
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Supporting Information
Despite significant efforts for alkenylation using palladium
catalysts, previous reports are limited to activated or elec-
tronically biased olefins like acrylates and styrenes.5-8 To
achieve terminal insertion, pre-installed coordinating
groups11 have been found to be promising for selective cases,
but are limited in application. Till date, unbiased alkenes
remain the most challenging partner for C–H olefination
reaction (Scheme 1).7, 9, 12 In addition, regioselectivity issues
due to lack of intrinsic biasness in aliphatic alkene and the
migration of C–C double bond along the aliphatic chain re-
main unsolved.6k, 8h
ABSTRACT: Palladium catalyzed coupling between aryl hal-
ides and alkenes (Mizoroki-Heck reaction) is one of the most
popular reactions for synthesizing complex organic mole-
cules. Limited availability, problematic synthesis and higher
cost of aryl halide precursors (or their equivalents) have en-
couraged exploration of direct olefination of aryl carbon-
hydrogen (C–H) bonds (Fujiwara-Moritani reaction). Despite
significant progress, restricted substrate scope in particular
noncompliance of unactivated aliphatic olefins restricted the
usage of this greener alternative. Overcoming this serious
limitation, we report here a palladium-catalyzed chelation-
assisted ortho-C–H bond olefination of phenyl acetic acid
derivatives with unactivated, aliphatic alkenes in good to
excellent yields with high regio- and stereoselectivities. The
versatility of this operationally simple method has been
demonstrated through drug diversification and sequential C–
H olefination for synthesizing divinyl benzene derivatives.
Me
O
Me
Me
Me
Me
S
COOH
COOH
COOH
MeO
Ibuprofen
Naproxen
Tiaprofenic acid
(antiarthritic drug)
(analgesic and antipyretic)
(antiinflammatory drug)
Me
O
O
Me
F
S
COOH
COOH
COOH
Me
Flurbiprofen
(antiarthritic drug)
Suprofen
(eyedrop)
Ketoprofen
(analgesic and antipyretic)
Unactivated carbon-hydrogen bonds (C–H) are present in
every naturally occurring organic molecules. Functionaliza-
tion of these C–H bonds is arguably of highest synthetic im-
portance. Due to the low reactivity, transition metal catalysts
have been extensively employed to convert them to carbon-
heteroatom and carbon-carbon (C–C) bonds of interest.1
Figure 1. Commercial drugs with aryl acetic acid motif
Here we report a palladium catalyzed chelation-assisted
C–H olefination reaction between unactivated, aliphatic ole-
fins and synthetically useful phenyl acetic acid substrates.
Notably, only activated olefins were used previously for oxi-
dative Heck coupling of phenyl acetic acids.8h The present
alkenylation reaction has remarkably broad substrate scope,
which is enabled by bidentate directing group along with the
use of racemic 1,1'-binaphthyl-2,2'-diamine (rac-BINAM) lig-
and to enhance the catalytic activity of active Pd(II) species.
The generality of this protocol is demonstrated here by pre-
paring an exemplary set of alkenylated compounds (45 ex-
amples), most of which represent new chemical entities. The
versatility of the protocol is shown by direct olefination of
commercial drugs (Figure 1) with aliphatic olefins.
Palladium catalyzed coupling between aryl halide and
alkene (Mizoroki-Heck reaction) has traditionally been used
for the C–C bond formation to synthesize arylated alkenes.2
Given the importance of this reaction, introduction of alkene
into arene C–H bond (Fujiwara-Moritani reaction) to prepare
the same carbogenic scaffolds offers even more powerful
strategy to access wide array of pharmaceutical precursors
and drug molecules.3 However, requirement of large excess
of the arene (often solvent amount) and/or the
regioselectivity issues has impeded the practicality of the
Fujiwara-Moritani reaction.
To address these issues,
Scheme 2. Alkenylation with 1-octene
directing group assisted C(aryl)–H olefination reactions are
adopted in recent years. The usual approach is to use σ-
chelating directing groups with a metal center,4-8 which will
lead to ortho selectivity through conformationally rigid 5-7
membered rings. Very recently meta-selective C(aryl)–H
bond activation and oxidative coupling with alkenes has also
been reported by palladium catalyst.10
CONHQ
CONHQ
10 mol% Pd(OAc)2
O
20 mol% rac-BINAM
Me
Me
1 equiv BQ, 2 equiv NaHCO3
4
N
4
H
O2, 1 mL DCE, 100 ºC, 24 h
major
minor
N
+
1
(1 equiv)
NH2
NH2
N
O
Me
HN
+
4
(2 equiv)
rac-BINAM
CONHQ
Scheme 1. Arene Ortho C–H Bond Olefination
DG
DG
Conventional monodentate directing groups are found to
be ineffective in palladium catalyzed C–H bond olefination
with unactivated, aliphatic alkenes.8 We reasoned that a
rigid coordination to palladium with a bidentate directing
groups13 and a six-membered palladacycle formation14 during
C–H olefination of arene will help incorporating unactivated
olefins as the coupling partner. Although benzoic or 3-
DG
DG
R
different directing
groups (DG)
R
R
N
O
this work
R = aliphatic
(unactivated olefins)
previous work
HN
DG =
R = EWG
(activated olefins)
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phenylpropionic acid derived 8-amino quinolinamide failed
desired product with different internal alkenes (e.g. (E)-hex-
2-ene, cyclohexene, 1H-indene etc.) as well as 1,1-
disubstituted alkenes (e.g. β-pinene).
Table 3. Scope with Substituted Phenylacetic Acids15
to provide expected olefination product,15 phenyl acetic acid
derivative (3a) gave the alkenylated product with 1-octene in
40% yield (linear/branched, 4:1) using silver acetate as co-
oxidant. In order to increase the yield and to reduce the
branched product, we thought to saturate the coordination
sites of palladium by incorporating auxiliary ligand.
Interestingly, rac-BINAM provided 90% GC yield with 8:1
selectivity for linear/branched olefinated product with 1-
octene (Scheme 2).
1
2
3
4
5
6
7
8
CONHQ
CONHQ
CONHQ
10 mol% Pd(OAc)2
20 mol% rac-BINAM
R
R
R
+
1 equiv BQ, 2 equiv NaHCO3
O2, 1 mL DCE, 100 ºC, 24 h
+
H
major
(isolated)
minor
(isolated)
1
2
5
(0.1 mmol)
(0.2 mmol)
CONHQ
5a, R = 4-NO2, 85% (9:1, E/Z, 5:1) 5e, R = 3,4-Cl, 49% (15:1)
9
5b, R = 4-Cl, 78% (10:1)
5c, R = 4-Ph, 67% (8:1)
5d, R = 4-F, 55% (8:1)
5f, R = 2-Me, 58% (7:1)
5g, R = 3-Cl, 80% (10:1)
5h, R = 3-CF3, 65% (15:1)
Me
Table 1. Scope with Unactivated Aliphatic Olefins15
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4
R
CONHQ
CONHQ
n
CONHQ
10 mol% Pd(OAc)2
20 mol% rac-BINAM
CONHQ
Me
CONHQ
CONHQ
Me
R
n R
+
H
2
Me
4
Me
n R
1 equiv BQ, 2 equiv NaHCO3
+
4
O2, 1 mL DCE, 100 ºC, 24 h
major
(isolated)
minor
(isolated)
1
4
Cl
(0.1 mmol) (0.2 mmol)
CONHQ
5i, 55% (12:1)
Me
5j, 65%, single isomer
5k, 68% (8:1)
3a, n = 4, 88% (8:1)
3b, n = 6, 85% (8:1)
3c, n = 8, 85% (9:1)
3d, n = 10, 84% (8:1)
3e, n = 12, 85% (8:1)
3f, n = 14, 86% (8:1)
Me
Me
n
CONHQ
CONHQ
Me
4
CONHQ
CONHQ
CONHQ
CONHQ
Me
5l, 50% (8:1)
5m, 62%, single isomer
(X-ray)
3i, 62% (12:1)
Me
3j, 50%, single isomer
3g, 75% (8:1)
3h, 78 % (10:1)
To obtain insights into the electronic and steric effect on
this direct oxidative coupling of C(aryl)–H bonds and olefins,
1-octene was reacted with functionalized phenylacetamide of
8-aminoquinoline under the optimized reaction conditions
(Table 3). Notably, meta substituted phenyl acetic acid
derivatives employed in this study gave alkenylated product
exclusively at the 6-position (5f-5h). Halogenated arenes
not only underwent coupling at the ortho position selectively
and efficiently (5b, and 5d-5g), but also did not suffer any
Heck coupling or protodehalogenation reactions. Although a
moderate yield of olefin insertion into 1-naphthylacetamide
was attained (5l and 5m), complete selectivity for 2-position
We first tested different alpha olefins (Table 1), which are
important starting materials for synthetic lubricants,
synthetic fatty acids, polymers and plasticizers. Irrespective
of the chain length of terminal aliphatic alkenes, excellent
isolated yields (84-88%, 3a-3f) were obtained with high
linear/branched selectivity.
With different vinyl
cycloalkanes, regioselectivity
(linear/branched) was
improved with increasing cycloalkane ring size (3g-3i). Such
observations may be attributed to the preferred migratory
insertion towards linear product formation with α-branched
olefins. Olefination product with vinyl cyclooctane was
characterized by X-ray crystallography (3i), which further
confirmed the trans-geometry of the desired product.15, 16
vs. 8-position was noteworthy.
Further no branched
alkenylated product was detected for this case. This
olefination reaction was also successfully extended to α-
substituted phenyl acetic acid substrate (5k). Selectively
linear olefinated product was also obtained for commercial
drugs (Figure 1), such as Ibuprofen (5j) and Naproxen (5n).
Therefore, in combination with previous Rh-catalyzed
method,7 this report demonstrated the use of a variety of
unactivated aliphatic olefins for the generation of valuable
linear alkenylated products.
Table 2. Scope with Functionalized Unactivated Alkenes
CONHQ
CONHQ
CONHQ
10 mol% Pd(OAc)2
20 mol% rac-BINAM
R
n R
+
H
2
n
n R
1 equiv BQ, 2 equiv NaHCO3
O2, 1 mL DCE, 100 ºC, 24 h
+
major
(isolated)
minor
1
4
(isolated)
(0.1 mmol) (0.2 mmol)
CONHQ
CONHQ
CONHQ
CONHQ
O
Br
7
5
In Tables 1-3, a variety of mono-alkenylated products
have been synthesized without any need for ortho- or meta-
substituent to prevent the bis-alkenylation. Encouraged by
these results, we thought to provide divinylbenzene
derivatives since they are widely used as building blocks in
synthetic chemistry and materials research.17 Traditionally
dihaloarenes were used (Mizoroki-Heck reaction) as the
precursor for these commonly occuring carbogenic motifs.18
In order to obtain sequential functionalization with
unactivated olefins by position selective manner, mono-
olefinated products have been utilized following the present
method. Second olefination reaction is expected to be
problematic since electronic and steric properties of mono
olefinated species will be completely different than the
4a, 72% (11:1)
4b, 63%, single isomer 4c, 65% (8:1)
4d, 65% (8:1)
CONHQ
CONHQ
CONHQ
CO2Me
CO2Me
OH
6
6
4e, 68% (10:1, E/Z - 5:1)
4f, 61%, single isomer
4g, 80%, single isomer
The scope of the position-selective alkenylation reaction
was further extended to various functionalized aliphatic
olefins (Table 2). Allyl benzene produced 72% yield (4a)
with 11:1 selectivity for linear/branched products.
An
unconjugated terminal alkene moiety can be incorporated in
arene (4b) from allyl bromide via a concerted elimination
upon insertion of alkene in the initially generated palladium-
aryl species. Arene C–H bond can be selectively reacted with
aliphatic alkene bearing bromo substituent (4c). An epoxy
(4d), an ester (4e) and a hydroxyl group (4f) containing
alkenylated products were isolated in synthetically useful
yields. Unfortunately, present strategy failed to provide
starting materials.8g
Further, the ability of the
monoalkenylated product to coordinate with the palladium
centers may hinder the catalyst to achieve the second
alkenylation.19
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Table 4. Synthesis of Bis-alkenylated Products
Scheme 3. Proposed Mechanism
O
1
2
3
4
5
6
7
8
O2 + H+ + e
CONHQ
CONHQ
10 mol% Pd(OAc)2
OH
HN
H
(A)
HOAc
20 mol% rac-BINAM
R
+
H2O
R1
R
N
HO
O
R1
1 equiv BQ, 2 equiv NaHCO3
O2, 1 mL DCE, 100 ºC, 24 h
(isolated)
Pd(OAc)2
reoxidation
5
2
6
(0.2 mmol)
(0.1 mmol)
L
R3
R2
CONHQ
CONHQ
O
Pd(0)
Me
Me
Me
4
4
N
!-hydride elimination
OAc
O
N
R2 = R3 = H, 6b, 68%, single isomer
R2 = R3 = Cl, 6c, 78%, single isomer
R2 = R3 = Br, 6d, 75%, single isomer
PdII
6a, 65% (8:1)
N
(B)
H
L
O
NH
N
PdII
O
9
N
L
CONHQ
CONHQ
O
(E)
R
10
11
12
13
14
15
16
17
18
19
20
21
22
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Me
C-H activation
N
R4
O
4
4
R
HOAc
Major
6e, 85%, single isomer
R4 = Me, 6f, 70%, single isomer
R4 = Ph, 6g, 81%, single isomer
CONHQ
1,2-migratory
insertion
N
O
CONHQ
L
(C)
olefin
N
N
Me
Me
Me
Me
N
coordination
R
O
NH
4
4
N
L
O
PdII
N
O
PdII
L
6h, 52% (10:1)
6i, 55% (8:1)
R
R
CONHQ
CONHQ
(F)
Minor
(D)
R
MeO
Sequential olefinated product (e.g. 6g, Scheme 4) can be
8
4
6
4
O
O
hydrogenated with Pd/C/H2. In this way, different long
chain alkyl groups can be incorporated to arene. The
resulting product may further be applied for iterative
olefination.8g Notably, the 8-aminoquinoline moiety can be
easily removed by acid catalyzed hydrolysis.15
6j, 48% (8:1; E/Z, 5:1b)
6k, 50% (14:1; E/Z, 5:1b)
CONHQ
CONHQ
Me
Me
Br
4
6
4
6l, 47%, single isomer
6m, 48% (10:1)
CONHQ
CONHQ
Scheme 4. Hydrogenation of Bis-olefinated Product
Me
CO2Me
Me
Me
Me
CO2Me
(X-ray)
6o, 72%, single isomer
4
CONHQ
5
CONHQ
CONHQ
6
6
Pd/C
H2
6n, 81% (10:1)
CO2H
CO2H
CO2Bn
Despite several potential challenges as outlined above,
(homo)di-alkenylated products20 were obtained with 1-
octene and styrene derivatives (Table 4, 6a-6d).
Subsequently, we focused on synthesizing differentially
6g
50 %
R
In summary, we have developed an effective method of
olefination for acetic acid derivatives by using palladium-
catalyzed chelation-assisted ortho-C–H bond functionaliza-
tion technique. The applicability of this present protocol was
also demonstarted by the sequential bis-olefination reaction.
Synthetic applications based on present strategy and detailed
mechanistic investigations are currently underway.
substituted diolefinated compounds.
Generation of
unsymmetrical diolefinated products (Table 4) indicated that
the present catalytic system is indeed very reactive and
effective for both mono- and di-olefination. With pre-
installed 1-octene olefinated product 3a, styrene, ethyl
acrylate and benzyl acrylate were incorporated (6e-6g, 70-
85% yields). A variety of alkenes including alpha olefin, α-
branched olefin, allyl benzene, aliphatic alkene possessing
bromo, ester and epoxy groups were reacted with 1-octene-
olefinated product 3a to produce unsymmetrical
divinylbenzene compounds (6h-6o, Table 4).
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
dmaiti@chem.iitb.ac.in
ACKNOWLEDGMENT
A stable six-membered palladacycle intermediate (C) was
This activity is supported by SERB, India (SB/S5/GC-05/2013).
Financial support received from CSIR-India (fellowship to A.D.),
UGC-India (S. B.) and DST-Fast Track Scheme (R. K.) are gratefully
acknowledged. Palladium catalysts were obtained as a gift from
Johnson Matthey Chemicals, MIDC Taloja, India.
proposed with chelating auxiliary 8-aminoquinoline through
position-selective C–H activation (Scheme 3).13,
Upon
14a
olefin coordination with C, intermediate D will be formed.
BINAM (L) is unlikely to bind to the palladium center
throughout the catalytic cycle in presence of strongly
coordinating substrates. Upon olefin binding in D, bidentate
BINAM may act as monodentate ligand in order to stabilize
complex D.21 Unlike activated or electronically biased
olefins, migratory insertion may occur to both sides of
aliphatic alkene. Nonetheless, linear olefinated product was
obtained in major quantity compared to branched product.
These unsymmetrical ratios of olefinated product are likely
due to the preferential attack by C–Pd bond to the less
hindered site of olefin. Depending on preference, two eight
membered cyclometallated intermediate (E or F) has been
proposed to form after 1,2-insertion. Finally the N–H bond
formation will generate Pd(0), which will be oxidized to
Pd(II) with the help of benzoquinone and oxygen.
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detected. We could not isolate these compounds in pure form. For all
other entries, we could not detect the diolefination product.
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(22) A stoichiometric reaction under the experimental condition was
carried out in the absence of alkene. The ESI-MS indicated formation
of intermediate C along with the features of C without BINAM. This Pd-
species (C) gave the desired product in 20% yield (Scheme 2) with 1-
octene along with five other inseparable mixtures of compounds.
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Unactivated alkenes
45 examples
Excellent regioselectivity
Sequential bisolefination
High yield
Drug diversification
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