Palladium-Catalyzed Synthesis of Tetrasubstituted Olefins by Triple Domino Process

Article abstract of DOI:10.1002/adsc.201700169

An efficient, highly regio- and stereoselective protocol for the synthesis of tetrasubstituted olefins was developed to take place by a palladium(0)-catalyzed triple domino process. It involves the formation of three new C?C bonds through double carbopalladation and C?H activation across 2-bromoaryl alkynyl biaryls/heteroaryls with norbornene. This method is practically simple with broad substrate scope and tolerates a wide range of substituents. The products bearing 9H-pyrrolo[1,2-a]indole motifs reveal intriguing solid state fluorescence properties and thus form a new class of aggregation induced emission (AIE) fluorophores. (Figure presented.).

Full text of DOI:10.1002/adsc.201700169

Title: Palladium-Catalyzed Synthesis of Tetrasubstituted Olefins by
Triple Domino Process
Authors: Kanagaraj Naveen, Savariyappan Albert Nikson, and
Paramasivan Thirumalai Perumal
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10.1002/adsc.201700169
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Synthesis of Tetrasubstituted Olefins by
Triple Domino Process
Kanagaraj Naveen,a Savariyappan Albert Nikson,a and Paramasivan Thirumalai
Perumala*
Organic & Bio-organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai-600020, India
E-mail: ptperumal@gmail.com.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
number of domino annulation transformations to
synthesize a highly complex carbo- and heterocyclic
scaffolds through C-H activation by using readily
available substrates.[8] Moreover, meta C-H activation
of arenes have also been achieved by employing
norbornene as a transient mediator using arene
containing directing groups.[9] Though the significant
progress has been achieved in C-H activation by use
of norbornene as a transient mediator, but it is
completely excluded at the end of the process after
construction of the desired molecule. A careful
literature survey revealed the existence of norbornene
insertion reactions with limited functional groups.[10]
For instance, Catellani et al described the synthesis of
norbornene inserted product through tandem Heck
reaction of 1-bromo-2-vinylbenzene with norbornene
(Scheme 1a).[11] However, there has been no
precedent on the norbornene insertion reaction with
alkynes. Application of this strategy to synthesize
tetrasubstituted olefins has remained unexplored to
the best of our knowledge.
Abstract. An efficient, highly regio- and stereoselective
protocol for the synthesis of tetrasubstituted olefins was
developed to take place by a palladium(0)-catalyzed triple
domino process. It involves the formation of three new C-C
bonds through double carbopalladation and C-H activation
across 2-bromoaryl alkynyl biaryls/heteroaryls with
norbornene. This method is practically simple with broad
substrate scope and tolerates a wide range of substituents.
The products bearing 9H-pyrrolo[1,2-a]indole motifs reveal
intriguing solid state fluorescence properties and thus form
a new class of aggregation induced emission (AIE)
fluorophores.
Keywords: domino reaction; carbopalladation; C-H
activation; palladium catalyst; tetrasubstituted olefin
The tetrasubstituted olefin scaffold is often found in
natural products and pharmaceuticals.[1] As a result,
much effort has been devoted to the development of
effective methods to prepare these compounds.[2]
Helical tetrasubstituted olefins have particularly
attracted great interest because of their applications in
light-driven molecular switches and molecular
motors.[3] One of the best approaches to access
tetrasubstituted olefins involves direct intermolecular
or intramolecular addition of an active arylpalladium
halide (Ar-Pd-X) intermediate across alkynes.[4] In
this sense, we have also reported Pd-catalyzed
annulation reactions, in which 2-bromo-N-
benzylpropargylamines were employed as building
blocks for the synthesis of
a
variety of
tetrasubstituted olefins.[5] Development of new
domino processes with efficient routes for the regio-
and stereoselective synthesis of highly congested
tetrasubstituted olefins still remains a challenging
problem in organic synthesis.[6]
Scheme 1. Domino strategy for the synthesis of
tetrasubstituted olefins.
The palladium/norbornene catalytic combination
was originally introduced by Catellani et al, which
allowed the activation of both ipso- and ortho-
positions of aryl halides resulted in the synthesis of
highly functionalized aryl compounds.[7] Based on
this methodology, Lautens and co-workers explored a
This prompted us to synthesis tetrasubstituted
olefins via one pot domino process by using
norbornene insertion followed by C-H activation
method. In addition to our continuous efforts on
palladium-catalyzed reactions, herein we describe the
1
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10.1002/adsc.201700169
Advanced Synthesis & Catalysis
successful execution of simple and efficient
palladium(0)-catalyzed triple domino process
consisting of double carbopalladation and C-H
activation of 2-bromoaryl alkynyl biaryls/heteroaryls
with norbornene for the construction of helical
tetrasubstituted olefins (Scheme 1b).
bromophenyl)ethynyl)-1,1'-biphenyl
1a
and
norbornene 2 as trial substrates to explore norbornene
insertion and C-H activation reaction by using 10
mol% of Pd(PPh3)4 and 3.0 equiv of K2CO3 in DMF
o
as solvent under N2 at 100 C. Under this condition,
the desired tetrasubstituted olefin 3a was isolated in
54% yield (table 1, entry 1). With this preliminary
result, various parameters were further investigated to
increase the yield of 3a as shown in table 1. However,
generation of in situ palladium(0) complex from
palladium(II) salts led to diminish the yield of desired
product 3a, even upon prolonged reaction time
(entries 2-3). Replacing Pd(PPh3)4 with Pd2(dba)3
catalyst, resulted in decreased yield of 3a (entry 4).
On the basis of the results obtained, we concluded
that Pd(PPh3)4 was beneficial to the domino reaction
to afford the desired product. Subsequently, other
solvents like toluene, CH3CN, DMSO and 1,4-
dioxane were screened (entries 5-8). Interestingly,
when acetonitrile was used as solvent, the yield
improved remarkably to 78% (entry 6) and further
enhancement in the yield (82%) was observed when
DMSO was used (entry 7). To our delight, the use of
1,4-dioxane as a solvent drastically amplified the
yield of the cyclized product 3a to 94% (entry 8).
From the above studies, we found that 1,4-dioxane as
a better solvent for this domino reaction. Instead of
K2CO3 different bases such as Cs2CO3, K3PO4,
Na2CO3 and Et3N were studied to assesss the
outcome of the reaction as shown in table 1 (entries
9-12). Ultimately, the structure of tetrasubstituted
olefin 3a was unambiguously confirmed by single
crystal X-ray analysis (figure 1).[12]
Table 1. Optimization of the reaction conditions.[a]
Entry Pd
catalyst
Base
(equiv)
Solvent Time
(mL)
Yield
(%)[c]
(h)[b]
4
1
Pd(PPh3)4 K2CO3
Pd(OAc)2 K2CO3
DMF
54
36
32
26
38
78
82
94
2[d]
3[d]
4[d]
5
DMF
DMF
DMF
24
24
24
PdCl2
K2CO3
K2CO3
Pd2(dba)3
Pd(PPh3)4 K2CO3
Pd(PPh3)4 K2CO3
Pd(PPh3)4 K2CO3
Pd(PPh3)4 K2CO3
Toluene 24
6
CH3CN
DMSO
4
6
3
7
8
1,4-
dioxane
9
Pd(PPh3)4 Cs2CO3 1,4-
dioxane
1,4-
dioxane
Pd(PPh3)4 Na2CO3 1,4-
dioxane
1,4-
dioxane
Reactions were carried out with 1a (0.30 mmol),
6
72
68
28
30
10
11
Pd(PPh3)4 K3PO4
6
24
24
Next, we examined the scope of this palladium(0)-
catalyzed triple domino reaction of norbornene
insertion and C-H activation by using a wide range of
2-bromoaryl alkynyl biaryl substrates (1b-k) with
norbornene under ideal reaction conditions. We found
that the reaction was very efficient and well tolerant
to both electron donating and electron withdrawing
groups affording helical tetrasubstituted olefins in
good to excellent yields (3b-k) as depicted in table 2.
If the R1 position bears methyl 1b and chloro 1c
substituents in the 2-bromoaryl ring, the substrates
were transformed into the desired products 3b and 3c
in good yields. Slightly increased yields were
obtained for compounds 3d and 3e, wherein R1 was
substituted by electron withdrawing groups such as
ester 1d and nitro 1e respectively. We noticed that
under the present condition, an excellent result were
produced for both electron releasing and withdrawing
groups present as substituents at R2 position (3f & 3g).
We also studied the effect of R3 substituents present
at the para-position of biaryl ring under optimized
conditions, a slightly lower yield was obtained when
compared to substitutions at R1 and R2 positions of
substrates (3h-j). We then investigated the
regioselectivity of this palladium(0)-catalyzed
domino reaction for chloro substitution at the meta
position in R3 of the biaryl substrate 1k afforded
approximately a 3.3:1 regiochemical mixture of 3k in
good yield.
12
Pd(PPh3)4 NEt3
[a]
norbornene 2 (1.5 equiv), Pd catalyst (10 mol %) and base
[b]
(3.0 equiv) in solvent (4 mL) at 100 °C under N2.
Reactions monitored based on complete consumption of 1a
[c]
[d]
by TLC. Yield of isolated product 3a.
20 mol % of
PPh3 was used.
Figure 1. ORTEP diagram of 3a.
Our investigation commenced with initially
designed reaction between 2-((2-
2
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10.1002/adsc.201700169
Advanced Synthesis & Catalysis
Table 2. Scope of 2-bromoaryl alkynyl biaryls with
in 90% yield. The thiophene containing
tetrasubstituted olefin compound 3m was synthesized
smoothly with 83% yield. We also carried out the
reaction of pyrrole containing substrates (1n-t)
bearing electron donating or withdrawing groups at
R1 and R2 positions with norbornene which again
ended up in good yields of the cyclized product (3n-t).
To demonstrate the present palladium(0)-catalyzed
double carbopalladation and C-H activation for its
working simplicity and practical utility, we carried
out the reaction in gram scale with 1q (1.0 g) under
similar conditions provided an encouraging result as
that of smaller scale trial for 3q (Scheme 2).
norbornene.[a]
Scheme 2. Gram scale synthesis of 3q.
We next examined the substrate 1u having two
possible C-H bond activation sites under the
described conditions (Scheme 3). Interestingly, the
substrate underwent smooth carbocyclization to
afford regioselectively the desired tetrasubstituted
olefin 3u in 90% yield, which was confirmed through
1H NMR analysis by the presence of a singlet at 6.33
ppm for isoated hydrogen in the ring. This result
depicts that the formation of six membered
coordination facilitates over seven membered
coordination in the indole ring during the C-H
activation step.
[a] Isolated yields based on 0.30 mmol of 1a-k after column
chromatography.
Table 3. Scope of 2-bromoaryl alkynyl heteroaryls with
norbornene.[a]
Scheme 3. Regioselective C-H activation of 1u.
[a]
Isolated yields based on 0.30 mmol of 1l-t after column
chromatography.
Scheme 4. Palladium(0)-catalyzed C-H activation of fused
nitrogen heterocycles 1v-w.
In order to expand the scope of palladium(0)-
catalyzed domino strategy, we further investigated
the norbornene insertion and C-H activation reaction
with heteroaryl rings instead of aryl rings under
similar reaction conditions. These transformations
also worked well and afforded the expected
heterocyclic fused tetrasubstituted olefin products in
good yield as shown in the table 3. We observed that
the substrate containing furyl 1l provided the
corresponding norbornene annulated olefin product 3l
We extended our interest to utilize this
palladium(0)-catalyzed C-H activation methodology
with fused nitrogen heterocyclic systems, as fused
nitrogen heterocycles display a wide range of
biological activities and show promising applications
in various fields of chemistry.[13] In the case of fused
nitrogen heterocyclic substrate with phenyl 1v and
3
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10.1002/adsc.201700169
Advanced Synthesis & Catalysis
thiophenyl 1w as substituents instead of biaryl under
established conditions, the reaction proceeded
smoothly and afforded the fused nitrogen based
tetrasubstituted olefin products (3v-w) in good yields
(Scheme 4).
tetrasubstituted olefin compound 3a is obtained via
reductive elimination from intermediate E through
direct C-H activation.
To gain more detailed evidence on the mechanism
of this catalytic reaction, we carried out an
intramolecular competition experiment between
compound 1a-D1 with 2 under optimal conditions
(Scheme 5). The product was isolated as a mixture of
3a and 3a-D1 in 90% yield and showed a kH/kD of 4.0.
The observed KIE value suggests that the C-H bond
cleavage occurs in the cyclometalation step D
(Scheme 6), favoring C-H activation and it might be
the product-determining step.[14]
Figure 2. a) Normalized absorption (dash line) and PL
(solid line) spectra of compound 3n in thin film. b)
Absorption spectra of 3n in CH3CN/H2O mixtures with
different water fractions. c) PL spectra of 3n in different
H2O/CH3CN (v/v) mixtures; Concentration 10 μM,
Excitation wavelength 420 nm. d) Plot of PL peak intensity
of 3n vs water fractions in H2O/CH3CN mixtures. I0 was
the PL intensity in pure CH3CN solution.
Scheme 5. Intramolecular kinetic isotope effect of 1a-D1.
Some of the isolated norbornene fused 9H-
pyrrolo[1,2-a]indole products are showing interesting
solid state fluorescence properties. To understand this
photophysical phenomenon, PL spectrum of 3n in
thin film showed absorption and emission maxima at
404 and 600 nm respectively (figure 2a). To
investigate the AIE nature of compound 3n in
different ratios of acetonitrile/water mixtures, the
absorption and emission spectra were measured
(figure 2b & 2c). In pure acetonitrile, the compound
3n does not show any characteristic emission in PL
spectra. However, the emission intensities remain
unchanged until the water fraction was added upto fw
≤ 70%. The emission intensities drastically increased
on further addition of water that is fw > 70%, as a
result of the formation of aggregates. The emission
was enhanced progressively with a gradual increase
in the water content up to fw = 90% of the aqueous
mixture. When we changed the water content (fw)
from 90 to 99 vol%, PL spectra revealed a decrease in
its emission intensity due to the change in the packing
order of the aggregates from crystalline state to an
amorphous form in the condensed phase (figure 2d).
This phenomenon may be aroused from the
restriction of intramolecular vibration (RIV) because
the molecule composed of two different parts,
methanofluorenylidene and pyrroloindole around the
C=C bond which make the molecule nonplanar and
adopts a twisted conformation.[16] The tractability of
the methanofluorenylidene part allows the molecule
to dynamically bend or vibrate in the solution state.
Scheme 6. Plausible mechanism for the cyclized product
3a.
Based on the result, a plausible mechanism for
palladium(0)-catalyzed domino carbopalladation and
C-H activation reaction of 1a is proposed in Scheme
6. The initial oxidative addition of palladium(0) to 2-
bromoaryl alkynyl biaryl 1a affords the
arylpalladiumbromide intermediate A, which
undergoes carbopalladation with norbornene 2 to give
cis-exo-arylnorbornylpalladium(II) intermediate B.[15]
At this stage, the intermediate B can either form
intermediates F or C by a C-H activation on aryl ring
or carbopalladation on the tethered alkyne
respectively. Presumably, the carbopalladation of
alkyne is much faster than the C-H activation from
intermediate B, thereby preventing the formation of
G from F. The intermediate B undergoes strong
coordination with hitched alkyne followed by 5-exo-
dig carbopalladation to produce vinylicpalladium(II)
species C. Intermediate C undergoes coordination
with neighboring aryl ring C-H bond leading to the
formation of intermediate D. Finally, the
4
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10.1002/adsc.201700169
Advanced Synthesis & Catalysis
References
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palladium(0)-catalyzed two component triple domino
process which allows the synthesis of helical
tetrasubstituted
olefins
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double
carbopalladation and C-H activation of 2-bromoaryl
alkynyl biaryls/heteroaryls with norbornene. The key
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vinylicpalladium(II) intermediate via 5-exo-dig
carbopalladation
of
cis-exo-
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Experimental Section
General Procedure for the Synthesis of 3
In a clean oven-dried 50 ml two-necked round-bottomed
flask charged with mixture of norbornene 2 (1.5 equiv.),
Pd(PPh3)4 (10 mol %) and K2CO3 (3.0 equiv.) a solution of
2-bromoaryl alkynyl biaryls/heteroaryls 1 (0.3 mmol) in
1,4-dioxane (4 mL) was added under a N2 atmosphere. The
resulting solution was stirred at 100 °C for 3h (monitored
by TLC). Upon completion, the reaction mass was cooled
to room temperature; ethyl acetate and water were added.
The organic layer was separated, dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The
crude material was purified by column chromatography
using silica gel to afford the product 3.
Acknowledgements
The author K.N. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, India for the research fellowship.
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