Synthesis of Tetrasubstituted Olefins by Palladium-Catalyzed Double Heck Cyclization of Bromoenynes

Article abstract of DOI:10.1002/ejoc.201301806

Palladium-catalyzed regio- and stereoselective synthesis of tetrasubstituted olefins incorporating an indene scaffold was developed through 6-exo-dig carbocyclization followed by Heck cyclization with anti β-hydrogen elimination. The starting materials for the domino reaction were designed through an A³-coupling reaction.

Full text of DOI:10.1002/ejoc.201301806

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301806
Synthesis of Tetrasubstituted Olefins by Palladium-Catalyzed Double Heck
Cyclization of Bromoenynes
Kanagaraj Naveen,[a] Doraiswamy Muralidharan,[a] and Paramasivan Thirumalai Perumal*[a]
Keywords: Palladium / Cyclization / Heck reaction / Elimination / Alkynes
Palladium-catalyzed regio- and stereoselective synthesis of
tetrasubstituted olefins incorporating an indene scaffold was
developed through 6-exo-dig carbocyclization followed by
Heck cyclization with anti β-hydrogen elimination. The start-
ing materials for the domino reaction were designed through
an A3-coupling reaction.
molecular carbopalladation followed by Heck cyclization
with anti β-hydrogen elimination of bromoenynes
(Scheme 1).
Introduction
The formation of multiple C–C bonds in a single syn-
thetic transformation is of current interest to chemists as a
means to build complex structural skeletons in an effective
manner.[1] Such a transformation leads to simple and easy
synthetic methodology. In particular, palladium-catalyzed
domino carbocyclization reactions proceed with excellent
selectivity and functional-group tolerance to construct com-
plex structures.[2] Such cyclization processes start with the
formation of an active organopalladium species by conven-
tional oxidative addition of an aryl halide, which involves
intramolecular carbopalladation with an alkyne unit to
form an intermediate species. This intermediate is utilized
in different ways in Heck reactions,[3] cross-coupling reac-
tions,[4] nucleophilic substitutions, and C–H bond acti-
vation reactions.[5]
Tetrasubstituted olefins with conjugated systems display
remarkable properties in electronic devices and materials
science. Tetrasubstituted, highly crowded olefins possess
molecular switching properties and have been used in mo-
lecular devices.[6] In this sense, we also reported the solid-
state fluorescence of xanthene-type tetrasubstituted olefins
prepared through palladium-catalyzed 6-exo-dig cyclization
followed by C–H bond activation.[7] Indene scaffolds are
found in many natural products that show important bio-
logical activities.[8] They have also been utilized in materials
science[9] and in transition-metal complexes as ligand pre-
cursors.[10] Herein, we describe the palladium-catalyzed re-
gio- and stereoselective synthesis of tetrasubstituted olefins
incorporating an indene scaffold through consecutive intra-
Scheme 1. Proposed scheme for the synthesis of tetrasubstituted
olefins.
Results and Discussion
The prerequisite bromoenyne starting materials were
synthesized by an A3 coupling reaction,[7] and the scope of
the reaction was studied by varying styryl alkynes 2 and
aldehydes 3 (Table 1). Initially, the A3 coupling reactions
were performed with different substituted aldehydes to pro-
vide the corresponding bromoenynes in good yields
(Table 1, 4a–f). Reaction of 9-ethyl-9H-carbazole-3-carbal-
dehyde led to 4g in moderate yield. Next, we investigated
the reaction of various styryl alkynes substituted with dif-
ferent functional groups, which afforded the products in
moderate to good yields (Table 1, 4h–k & 4o). The reactions
proceeded well for styryl alkynes substituted with biaryl
and heteroaryl rings (Table 1, 4l–n).
[a] Organic Chemistry Division, CSIR – Central Leather Research
Institute,
Adyar, Chennai 600020, India
E-mail: ptperumal@gmail.com
http://www.clri.org/WriteReadData/Biodata/PT_Permual_
Profile.html
With the designed starting materials in hand, we initiated
the domino Heck cyclization of bromoenyne 4a with
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301806.
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Palladium-Catalyzed Double Heck Cyclization of Bromoenynes
Table 1. Synthesis of bromoenyne derivatives 4a–o by A3 coupling.[a]
[a] Yield of isolated product after column chromatography.
Pd(OAc)2 (10 mol-%), PPh3 (20 mol-%), and K2CO3 mal reaction conditions for this domino cyclization. We op-
(5 equiv.) in DMF at 100 °C under a N2 atmosphere. We timized the reactions with various bases and solvents. De-
obtained desired cyclized product 5a in 58% yield (Table 2, creased yields were obtained upon changing the base to
entry 1). This positive result prompted us to screen the opti- Cs2CO3 and Et3N (Table 2, entries 2 & 3). Next, we investi-
Table 2. Optimization of the palladium-catalyzed reaction of bromoenyne 4a.[a]
Entry
Pd source (mol-%)
Ligand (mol-%)
Base (equiv.)
Solvent
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
–
K2CO3 (5)
Cs2CO3 (3)
Et3N (3)
DMF
DMF
DMF
6
2
8
58
38
30
72
40
28
trace
86
42
46
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K3PO4 (5)
DABCO (3)
1,4-dioxane
CH3CN
PhMe
5
13
10
12
3
12
12
10
THF[c]
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
10
11
–
–
–
trace
[a] Reactions were performed with 4a (0.3 mmol), Pd source, and base in solvent (4 mL) under an atmosphere of N2. [b] Yield of isolated
product after column chromatography. [c] Reaction was performed at 60 °C.
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K. Naveen, D. Muralidharan, P. T. Perumal
SHORT COMMUNICATION
gated the reaction with different solvents such as CH3CN, was found for chloro-substituted styryl 5j. A slightly higher
PhMe, and THF (Table 2, entries 5–7). Upon performing yield was obtained for 5k with a nitro-substituted styryl
the reaction with 1,4-dioxane as the solvent, the reaction ring. Under similar conditions, a styryl ring bearing a biaryl
proceeded smoothly to afford the product in 72% yield moiety led to product 5l in a moderate yield of 58%. We
(Table 2, entry 4). From the above observation, 1,4-dioxane further investigated the reaction with heteroaromatic rings,
was a better solvent for the cyclization reaction. We contin- that is, 3-furanyl 5m and 2-thiophenyl 5n, and obtained
ued further investigations with Pd(PPh3)4 (10 mol-%) and yields of 62 and 80%, respectively. The cyclized product was
K2CO3 (5 equiv.). Desired cyclized product 5a was isolated confirmed by analysis of 5e by 1H NMR and 13C NMR
in a high yield of 86%, and the reaction was complete in a spectroscopy. A singlet at δ = 7.01 ppm in the 1H NMR
short time period (Table 2, entry 8). Upon decreasing the spectrum corresponds to the isolated hydrogen atom pres-
catalyst loading, the yield of the cyclized product was re- ent on the indene core. The two signals for the acetylene
duced (Table 2, entry 9). With K3PO4, 1,4-diazabicy- carbon atoms at δ = 89.41 and 85.81 ppm disappeared in
clo[2.2.2]octane (DABCO), and Pd(PPh3)4, the yield was the 13C NMR spectrum. Further, the identity of cyclized
considerably reduced (Table 2, entries 10 & 11).
product 5e was also confirmed by high-resolution mass
We explored the palladium-catalyzed carbocyclization re- spectrometry (m/z = 554.2149 [M + H]+). Finally, the regio-
action with various substituted bromoenynes under the op- and stereoselective formation of 5e was unambiguously
timized reaction conditions of Pd(PPh3)4 (10 mol-%) and confirmed by single-crystal X-ray diffraction analysis[11]
K2CO3 (5 equiv.) in 1,4-dioxane at 100 °C under a N2 atmo- (Figure 1). The arylpalladium intermediate undergoes syn
sphere. The results are summarized in Table 3. Substrates insertion with the alkyne by 6-exo-dig carbocyclization to
4b and 4c with methoxy and nitro groups in the aromatic produce the E intermediate, which is further involved in the
ring attached to the propargylic unit underwent cyclization, reaction with an alkene to yield the single E isomer of
which resulted in products 5b and 5c in 72 and 76% yield, product 5e.
respectively. The substrate with an unsubstituted proparg-
The mechanism of formation 5 consists of the following
ylic position gave cyclized product 5d in moderate yield. successive steps (Scheme 2): Initial oxidative addition of 4
Heteroaromatic moieties present at the propargylic position with palladium provides active organopalladium intermedi-
were tolerated under the reaction conditions, and corre- ate A, which is involved in coordination with alkyne B to
sponding cyclized products 5e,f were obtained in good form intermediate C by intramolecular 6-exo-dig carbopal-
yields. Electron-donating groups present on the styryl ring ladation. Intermediate C undergoes Heck reaction with
afforded products 5h,i,o in moderate yields. A similar yield substituted alkene D, which results in the formation of syn
Table 3. Scope of the palladium-catalyzed cyclization reaction.[a]
[a] Yield of isolated product after column chromatography.
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Palladium-Catalyzed Double Heck Cyclization of Bromoenynes
Scheme 2. Plausible mechanism for the formation of cyclized product 5.
yields. This domino reaction is an example of anti β-hydro-
gen elimination. Further extension of this methodology to
synthesize complex heterocycles is underway.
Experimental Section
General Procedure for the Synthesis of 5a: A solution of bromo-
enyne 4a (0.3 mmol) in 1,4-dioxane (4 mL) was added to a mixture
of Pd(PPh3)4 (0.03 mmol, 10 mol-%) and K2CO3 (0.15 mmol) in a
clean, dry, two-necked round-bottomed flask under a N2 atmo-
sphere. The reaction mixture was stirred at 100 °C for 3 h. Then,
the reaction mixture was cooled to room temperature and ethyl
acetate (15 mL) and water (3ϫ 15 mL) were added. The organic
layer was separated, dried with anhydrous Na2SO4, and concen-
trated under reduced pressure. The crude material was purified by
column chromatography (silica gel, 5–40% petroleum ether/ethyl
acetate) to afford 5a.
Supporting Information (see footnote on the first page of this arti-
cle): General procedures and NMR spectra of all compounds.
Acknowledgments
Figure 1. ORTEP diagram of 5e.
K. N. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship. The authors thank
the SAIF, IITM, Chennai for single-crystal X-ray diffraction analy-
carbopalladium intermediate E. Product 5 is formed by anti
β-hydrogen elimination[12] of E. The catalytic cycle is regen-
sis.
erated by reductive elimination of HBr.
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In conclusion, we described the synthesis of tetrasubsti-
tuted olefins incorporating an indene scaffold through a
palladium-catalyzed multiple C–C bond-formation strategy.
This cyclization reaction tolerates many functional groups
in the substrate to afford the products in moderate to good
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SHORT COMMUNICATION
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Received: December 4, 2013
Published Online: January 23, 2014
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