Expeditious Synthesis of Functionalized 1-Arylcyclooctadienes via Palladium-Catalyzed Lithium Cross-Coupling

Article abstract of DOI:10.1002/adsc.201600887

The palladium-catalyzed direct cross-coupling of aryl bromides and (1Z,5Z)-cycloocta-1,5-dien-1-yllithium is described as an important method to synthesize 1-arylcyclooctadienes. The use of a well-established Pd₂dba₃/XPhos catalytic system affords the desired new compounds in good to excellent yields; the reaction proceeds at room temperature with both high efficiency and selectivity. Finally we found the best conditions to combine a suitable lithium-halogen exchange with a cross-coupling reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.201600887

UPDATES
DOI: 10.1002/adsc.201600887
Expeditious Synthesis of Functionalized 1-Arylcyclooctadienes
via Palladium-Catalyzed Lithium Cross-Coupling
Angela E. E. Wandlera and Stefan Brꢀsea,b,*
a
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax : (+49)-721-6084-8581; phone: (+49)-721-6084-2903; e-mail: braese@kit.edu
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344
b
Eggenstein-Leopoldshafen, Germany
Received: August 11, 2016; Revised: September 21, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600887.
Abstract: The palladium-catalyzed direct cross-cou-
pling of aryl bromides and (1Z,5Z)-cycloocta-1,5-
dien-1-yllithium is described as an important
method to synthesize 1-arylcyclooctadienes. The use
Noteworthy, Murahashi coupling can be used for
other organometallic reactions like polymerization of
(hetero)arylenes[6] or in cross-coupling reactions em-
ploying a silicon-based transfer agent.[7]
of
a
well-established Pd2dba3/XPhos catalytic
Anyway, the methodology is still limited due to the
high reactivity of lithium reagents. Thus an optimized
method, which could increase the scope of substrates
and functional groups, is needed.[8] However, there
are remarkable advantages to use organolithium re-
agents even on an industrial scale, as they are readily
accessible, versatile, and inexpensive.[3e]
system affords the desired new compounds in good
to excellent yields; the reaction proceeds at room
temperature with both high efficiency and selectivi-
ty. Finally we found the best conditions to combine
a suitable lithium-halogen exchange with a cross-
coupling reaction.
Recently, we reported the synthesis of monofunc-
tionalized cyclooctadiene (COD) ligands via Kumada
cross-coupling reactions and their application in the
synthesis of platinum complexes.[9] These results
sparked our interest to undertake further studies on
the design of new COD derivatives being suitable for
the syntheses of metal complexes.
Keywords: alkenes; aryl bromides; cross-coupling;
cyclooctadiene; lithiation; palladium
Palladium-catalyzed cross-coupling reactions of orga-
Herein, we present the syntheses of new 1-arylcy-
nolithium compounds are one of the most powerful clooctadienes through a direct cross-coupling of lithi-
reactions in the field of carbon-carbon coupling meth- ated COD with aryl bromides (Scheme 1).
ods.[1] At the early outset of cross-coupling reactions,
Murahashi and co-workers developed a palladium-
catalyzed coupling of alkenyl halides with alkyl, aryl,
and heterocyclic lithium reagents.[2] Thereafter the
method was further developed, but still with low fre-
Scheme 1. Palladium-catalyzed direct cross-coupling of lithi-
ated COD.
quency. This cross-coupling reaction experienced
a comeback by the group of Feringa as they used it
for a lot of different carbon-carbon bond forma-
tions.[1,3] During the last years, the use of vinyl halides
and triflates was explored with success, but the area
Our research began with the preparation of lithiat-
of lithium cross-coupling is still by far less investigat- ed COD. The first step is a selective dibromination
ed compared to other metals such as boron, tin or of one double bond followed by a dehydrobromina-
zinc. Recently, the method has been further extended tion to afford 1-bromo-1,5-cyclooctadiene (3)
by replacing palladium with other metals: Diverse (Scheme 2).[10] Afterwards, the bromide 3 was treated
carbon-carbon bond forming reactions via iron-cata- with tert-butyllithium [caution: this material is pyro-
lyzed,[4] and also nickel-catalyzed coupling reactions[5] phoric] to form the lithiated compound 4 in a lithium-
of organolithium compounds with aryl chlorides were halogen exchange reaction (Table 1).[11] This is the
reported.
most important step for isolating the cross-coupled
product in high yields.
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When ligands L1 and L3 were used, we observed
the desired product 6a in the same yields (entries 1
and 3). Remarkably, the yield increased significantly
with the use of XPhos L2. We observed 6a in a very
good yield after 1 h reaction time at room tempera-
ture (entry 2). Furthermore, the solvent used for the
lithium-bromide exchange is crucial for high reactivity
and selectivity. The use of diethyl ether gave rise to
the best result (entry 2). The stability and reactivity of
the organolithium species depends on the polarity
and the structure of the solvent.[13]
Scheme 2. Synthesis of 1-bromo-1,5-cyclooctadiene.
Table 1. Optimization of the reaction conditions.
The use of diethyl ether for the lithium-halogen ex-
change and an aromatic cosolvent, such as toluene,
proved to be the best choice for the reaction
(entry 2). Using the same solvent for the whole reac-
tion limited the solubility of the reagent and thus the
yield of the cross-coupled product (entry 5).
After having established Pd2(dba)3 in liaison with
XPhos as the best catalytic system for the cross-cou-
pling of 4 with 5a, we explored the scope of the reac-
tion with several aryl bromides, containing interesting
functional groups (Figure 1, 5a–5k) for the synthesis
of 1-arylcyclooctadienes (Table 2).
Nearly all products were obtained in high selectivi-
ty and in low (6h; 23%) to excellent yields (6c, 6e;
85%) at room temperature within a reaction time of
1 h. All COD derivatives were unknown in the litera-
ture, except for 6e.[9a] Exploring the limits of the
cross-coupling reaction, we used 1-bromo-3-ethynyl-
benzene 5h as an electrophile. Organolithium re-
agents are widely used as bases for deprotonation re-
actions on a variety of substrates.[14] In consequence,
we isolated the product 6h in lower yield (23%) but
surprisingly did not observe other side products. In
Entry[a] [Pd]
Ligand
Solvent[b] Yield [%]
1
2
3
4
5
Pd2(dba)3 L1, SPhos
Pd2(dba)3 L2, XPhos
Pd2(dba)3 L3, P(t-Bu)3 Et2O
Pd2(dba)3 L2, XPhos
Pd2(dba)3 L2, XPhos
Et2O
Et2O
56
74
56
24
33
THF
toluene
[a]
Conditions: To a solution of bromide 3 (1.50 equiv.) in di-
ethyl ether, t-BuLi (3.00 equiv.) [caution: this material is
pyrophoric] was added at À788C. After 30 min the mix-
ture was warmed to 08C and kept at this temperature.
Pd2(dba)3 and the ligand were dissolved in toluene and
the solution containing compound 4 was added over 1 h
at room temperature.
[b]
Only the solvent for the lithium-halogen exchange was
varied. dba=dibenzylideneacetone.
This protocol was examined with several solvents.
The well-established catalytic system of Pd2(dba)3
with different ligands is already successfully used for
cross-coupling reactions of organolithium reagents
with aryl bromides.[1,3a,b,d–f,8,12] Because of our high in-
terest in the syntheses of COD ligands,[9] we began to
examine the cross-coupling reaction with [(4-bromo-
phenyl)ethynyl]trimethylsilane (5a) as a functionalized
halide. The most effective catalytic system for this
Murahasi reaction has been searched for (Table 1, en-
tries 1–3).
Figure 1. Aryl bromides 5a–k employed in Table 2. All re-
agents are commercially available and were used without
further purification.
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Table 2. Substrate scope for the palladium-catalyzed cross-
coupling reaction of aryl bromides and (1Z,5Z)-cycloocta-
1,5-dien-1-yllithium.[a]
bromobenzene 5e. It is known that the oxidative addi-
tion step of the cross-coupling cycle is working very
well for aryl bromides and for aryl iodides. Neverthe-
less, aryl chlorides are not well tolerated. The aryl
chlorides have to be activated with an electron-with-
drawing group to isolate a cross-coupled product in
a much better yield as shown in the previous reaction
(Table 2, 6e).[15] Surprisingly, the yield of compound
6e, starting from the aryl iodide, was low. A homo-
coupled product of the lithium compound was not ob-
served: not for this reaction and also not for the other
reactions. A competing metal-halide exchange reac-
tion might have caused this outcome.
The development of versatile methods to access
functionalized COD derivatives remains challenging,
although interesting applications for the ligands have
been reported in the literature. Hayashi and co-work-
ers proposed their use as ligands for rhodium com-
plexes to catalyze 1,4-addition reactions.[16] Further-
more, COD derivatives were also used as ligands in
palladium-catalyzed carboalkoxylation reactions.[17]
The methodology was therefore extended in the
synthesis of a COD dimeric structure 6k. For this re-
action we used dibromobenzene as a coupling re-
agent, increased the amount of the catalytic system
Pd2(dba)3 (5 mol/%) XPhos (20 mol/%) and changed
the amount of compound 4 (4 equiv.) to furnish the
product 6k in good yield (57%).
In conclusion, we were able to synthesize 1-arylcy-
clooctadienes in high selectivity and good to excellent
yields. The reaction takes place under mild conditions
at room temperature within 1 h. Additionally, COD
dimeric structures were unknown to literature up to
now and are easily accessible via this method.
Experimental Section
[a]
Conditions: COD-Li 4 (1.5 equiv.) was added (1 h, sy-
General Method: Direct Catalytic Cross-Coupling of
Lithiocyclooctadiene
ringe pump) to a solution of aryl bromide 5 (1.0 equiv.)
and catalyst in toluene. Isolated yields after column chro-
matography.
The reaction was also performed with the aryl chloride
(yield: 9%) and the aryl iodide (yield: 17%).
a) Lithiation of (1E,5Z)-1-bromocycloocta-1,5-diene: To
a solution of the bromide (1.50 equiv.) in anhydrous diethyl
ether, t-BuLi (3.00 equiv.) [caution: this material is pyro-
phoric] was added dropwise at À788C under an argon at-
mosphere. After 30 min of stirring at À788C, the reaction
mixture was warmed to 08C. The temperature was main-
[b]
[c]
4.0 equiv. COD-Li.
comparison to the synthesis of compound 6a, we have tained at 08C for 30 min. The organolithium compound was
used in solution without further purification in the next step.
b) Palladium-catalyzed cross-coupling reaction: In a dry
Schlenk flask, Pd2(dba)3 (2.5 mol%) and XPhos (10 mol%)
were dissolved in dry toluene and the solution was stirred
under an inert atmosphere at room temperature for 5 min.
The substrate (1.00 equiv.) was added and the solution
stirred at the indicated temperature. The previously pre-
pared lithium reagent was slowly added over 1 h via syringe
pump. Afterwards, the reaction was quenched with a saturat-
ed aqueous solution of NH4Cl and the mixture was extract-
shown that the use of protected terminal alkynes in-
creases the yield of the corresponding COD deriva-
tive. More challenging aryl bromides like 1-bromo-4-
methoxybenzene 5i and 4-bromo-N,N-diphenylaniline
5j could be successfully employed for the synthesis of
compound 6i and 6j in very good yields under mild
conditions.
The cross-coupling reaction of COD-Li 4 was also
carried out with iodobenzene (yield: 17%) and chlor-
obenzene (yield: 9%) but in lower yields compared to ed with Et2O. The organic phases were combined and dried
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over anhydrous Na2SO4. The solvent was removed under re-
duced pressure and the crude product was purified by
column chromatography.
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Acknowledgements
We thank the TRR 88 (3MET) for funding.
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Expeditious Synthesis of Functionalized 1-
Arylcyclooctadienes via Palladium-Catalyzed Lithium
Cross-Coupling
5
Adv. Synth. Catal. 2016, 358, 1 – 5
Angela E. E. Wandler, Stefan Brꢀse*
Adv. Synth. Catal. 0000, 000, 0 – 0
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