Cross-coupling knows no limits: Assessing the synthetic potential of the palladium-catalysed cross-coupling of organolithiums

Full text of DOI:10.1002/cctc.201402886

DOI: 10.1002/cctc.201402886
Highlights
Cross-Coupling Knows No Limits: Assessing the Synthetic
Potential of the Palladium-Catalysed Cross-Coupling of
Organolithiums
James D. Firth and Peter O’Brien*[a]
The use of palladium-catalysed cross-coupling methods for the
formation of carbonÀcarbon bonds has become a cornerstone
of modern synthetic chemistry,[1] allowing the selective synthe-
sis of numerous drugs[2] and natural products.[3] A suite of nu-
cleophilic organometallic coupling partners can now be de-
ployed for cross-coupling with aryl/vinyl halides and triflates,
including organozinc, organotin, organoboron, organosilicon
Scheme 1. Cross-coupling between aryl bromides and alkyllithiums.
and organomagnesium reagents. Pioneering work on the palla-
dium-catalysed cross-coupling of vinyl halides and organolithi-
um reagents was reported by Murahashi et al.[4] Not surprising-
ly, owing to the relatively high reactivity and low stability of
the organolithium coupling partners, few examples of such
chemistry exist.[5] However, in 2013 and 2014, the Feringa
group published a series of papers in which organolithium re-
agents were shown to be compatible, versatile and very useful
cross-coupling partners.[6–10] This highlight focuses on the syn-
thetic scope and limitations of Feringa’s methodology.[11]
In ground-breaking work in 2013, Feringa and co-workers
detailed a fast and highly selective palladium-catalysed cou-
pling of alkyl-, aryl- and heteroaryllithium reagents with aryl
bromides.[6] Fine-tuning of the palladium catalyst complex fa-
cilitated fast transmetalation and reductive elimination, thus
preventing b-hydride elimination. As a result, cross-coupled
products were formed in high yields with minimal formation of
dehalogenated, homo-coupled or isomerised products. In the
presence of 5 mol% Pd[P(tBu)3]2, commercially available alkyl-
lithiums (e.g., nBuLi, nHexLi, MeLi, Me3SiCH2Li and iPrLi) were
coupled with aryl bromides bearing halide, hydroxyl, acetal or
ester functionalities at room temperature within 1 h. For exam-
ple, products 1–4 were isolated in 84–92% yields (Scheme 1).
Vinyl bromides were also shown to be viable coupling part-
ners.
the aggregation state and reactivity of the organolithium re-
agents.
It was also shown that biaryl formation from aryllithiums
and aryl bromides could be achieved through in situ genera-
tion of a catalyst derived from [Pd2(dba)3] (dba=dibenzyli-
deneacetone) and P(tBu)3. Under these conditions, a range of
biaryls was produced, including 5–9 (71–89% yield, Scheme 2).
Notably, biaryl 6 was isolated in 93% yield on a 1 g scale by
Scheme 2. Cross-coupling between aryl bromides and (hetero)aryllithiums.
using only 1 mol% of the catalyst. Products 5 and 6 were
formed by using commercially available PhLi. In contrast, bi-
aryls 7–9 were generated by using organolithium reagents that
were pre-formed by bromine–lithium exchange (for 7) and di-
rected (ortho)lithiation (for 8 and 9), showing that these ap-
proaches are also compatible with the cross-coupling protocol.
The biaryl coupling methodology was subsequently developed
to utilise the cheaper aryl chlorides by modification of the cat-
alyst system to [Pd2(dba)3]/XPhos (XPhos=2-dicyclohexylphos-
phino-2’,4’,6’-triisopropylbiphenyl) or Pd-PEPPSI-IPent.[7] For ex-
ample, biaryl 6 was formed in 94% yield from the aryl chloride
by using Pd-PEPPSI-IPent at 408C with a 3.5 h reaction time.
Recently, the Feringa group further developed this chemistry
to include the use of aryl triflates in coupling reactions with
In the optimisation studies, unwanted lithium–halogen ex-
change resulted in the formation of dehalogenated and homo-
coupled products. The prevention of lithium–halogen ex-
change between the organolithium and the aryl bromide was
key to the success of the methodology. This was achieved
through the slow addition (over 1 h) of the organolithium re-
agent and the selection of toluene as solvent, which controlled
[a] Dr. J. D. Firth, Prof. P. O’Brien
Department of Chemistry, University of York
Heslington, York YO10 5DD (UK)
E-mail: peter.obrien@york.ac.uk
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Highlights
Scheme 3. Cross-coupling of aryl and vinyl triflates and organolithiums.
DavePhos=2-Dicyclohexylphosphino-2’-(N,N-dimethylamino)biphenyl.
SPhos=2-Dicyclohexylphosphino-2’,6’-dimethoxybiphenyl.
alkyl- and (hetero)aryllithiums.[8] Catalyst optimisation
[2.5 mol% [Pd2(dba)3] and 10 mol% DavePhos led to a wide
range of products from cross-coupling between aryl triflates
and organolithiums. Examples include the preparation of 10
and 11 (Scheme 3). Vinyl triflate 12 readily underwent cross-
coupling in the presence of 2.5 mol% [Pd2(dba)3] and 10 mol%
SPhos to give substituted cyclohexenes 13 and 14 (Scheme 3).
These examples with triflates represent an important develop-
ment because they can be easily formed from the correspond-
ing phenols and enolates, and they offer a viable alternative to
the use of aryl halides.
Scheme 5. Synthesis of hindered biaryl compounds.
sised in high yield at room temperature in short times (1–4 h,
Scheme 5). Importantly, the high reactivity of the organolithi-
um reagents facilitated rapid transmetalation, thus enabling an
efficient route to hindered tetra-ortho biaryls to be developed.
One advantage of using organolithiums to synthesise hindered
biaryls is that the ortho-substituted organolithiums can be pre-
pared by halogen–lithium exchange or direct (ortho)lithiation.
Additionally, functional groups that are often poorly tolerated
in other cross-coupling methods (e.g., the methoxy group)
confer an advantage in this approach by stabilising the orga-
nolithium reagent.
Feringa and co-workers also applied their organolithium
cross-coupling methodology to the palladium-catalysed cross
coupling of aryl and vinyl bromides with secondary alkyl orga-
nolithium reagents.[9] The desired reductive elimination was rel-
atively fast compared with undesired b-hydride elimination in
the majority of cases, leading to a wide range of products. For
example, 15–18 were isolated in 55–91% yield without isomer-
ization of the secondary alkyl group (Scheme 4). The ability to
cross-couple lithiated fluorene, to give 17, is significant be-
cause polyfluorenes find widespread use in organic optoelec-
tronics.
The methodology developed and exemplified by Feringa
and co-workers has several potential advantages over the use
of traditional organometallic coupling partners. The high reac-
tivity of organolithiums allows mild conditions for cross-cou-
pling to be employed (ambient temperature, 1–4 h). Addition-
ally, little waste is generated in comparison with other palladi-
um-catalysed cross-coupling methods (LiX is the only stoichio-
metric waste product and no additional base is required). Fur-
thermore, the organolithium reagents used are often cheap
and commercially available. Finally, although the use of orga-
noboron/organotin reagents can be highly successful, these re-
agents often require an additional step to prepare, typically
from an organolithium reagent.
There are, however, some issues with using this new meth-
odology in synthesis. For example, the high reactivity of the or-
ganolithiums results in a need for the cumbersome slow addi-
tion of the organolithium reagents and optimisation of cata-
lyst/solvent for each reaction type is required. Additionally,
there is a poor functional-group tolerance; for example, use of
1-bromo-2-methoxybenzene as a coupling partner results
mainly in the homo-coupled biaryl owing to bromine–lithium
exchange, facilitated by the Lewis basic ether.[9]
Scheme 4. Cross-coupling of secondary alkyl organolithiums with aryl and
vinyl bromides.
Finally, the Feringa group has advanced the cross-coupling
methodology to allow the synthesis of tri- and tetra-substitut-
ed ortho-biaryl compounds under mild conditions.[10] This is
often a highly challenging transformation. By using Pd-PEPPSI-
IPent (5 mol%), hindered biaryls, such as 19–22, were synthe-
To highlight and showcase the synthetic potential afforded
by this methodology, two synthetic sequences are presented
in Scheme 6. Starting from 23, the bromide can be selectively
cross-coupled with PhLi by using [Pd2(dba)3]/P(tBu)3 to give 24
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Highlights
more functionalised organolithium reagents, such as chiral or-
ganolithiums derived from saturated heterocycles.[12]
Keywords: cross-coupling · organolithiums · organometallics ·
palladium · synthetic methods
[1] C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus,
Angew. Chem. Int. Ed. 2012, 51, 5062–5085; Angew. Chem. 2012, 124,
5150–5174.
[2] J. Magano, J. R. Dunetz, Chem. Rev. 2011, 111, 2177–2250.
[3] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005, 44,
4442–4489; Angew. Chem. 2005, 117, 4516–4563.
Scheme 6. Synthetic potential of the new cross-coupling methodology.
[4] S. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, K. Kondo, J. Org.
Chem. 1979, 44, 2408–2417.
[5] A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi, J.-i. Yoshida, Angew.
Chem. Int. Ed. 2010, 49, 7543–7547; Angew. Chem. 2010, 122, 7705–
7709.
[6] M. Giannerini, M. FaÇanꢁs-Mastral, B. L. Feringa, Nat. Chem. 2013, 5,
667–672.
[7] V. Hornillos, M. Giannerini, C. Vila, M. FaÇanꢁs-Mastral, B. L. Feringa, Org.
Lett. 2013, 15, 5114–5117.
[8] C. Vila, V. Hornillos, M. Giannerini, M. FaÇanꢁs-Mastral, B. L. Feringa,
Chem. Eur. J. 2014, 20, 13078–13083.
[9] C. Vila, M. Giannerini, V. Hornillos, M. Fananas-Mastral, B. L. Feringa,
Chem. Sci. 2014, 5, 1361–1367.
[10] M. Giannerini, V. Hornillos, C. Vila, M. FaÇanꢁs-Mastral, B. L. Feringa,
Angew. Chem. Int. Ed. 2013, 52, 13329–13333; Angew. Chem. 2013, 125,
13571–13575.
[11] For a related highlight article, which focuses on the mechanistic aspects
of this reaction, see: V. Pace, R. Luisi, ChemCatChem 2014, 6, 1516.
[12] a) G. Barker, J. L. McGrath, A. Klapars, D. Stead, G. Zhou, K. R. Campos, P.
O’Brien, J. Org. Chem. 2011, 76, 5936; b) N. S. Sheikh, D. Leonori, G.
Barker, J. D. Firth, K. R. Campos, P. O’Brien, I. Coldham, J. Am. Chem. Soc.
2012, 134, 5300.
(87% yield). Use of Pd-PEPPSI-IPent and increasing the temper-
ature enabled the chloride to react with lithiated furan to give
25 in 90% yield. In a different two-stage strategy, the coupling
of styrene 26, iPrLi and an aryl bromide can be brought about
to give 28. The reaction proceeds by carbolithiation of styrene
26 with iPrLi to give organolithium 27, which was then cross-
coupled by using Pd[P(tBu)3]2 to give 28 in 54% yield.
In summary, palladium-catalysed cross-coupling of (hetero-
aryl)- and alkyllithium reagents with a range of coupling part-
ners has much synthetic potential. The methodology has al-
ready been widely exemplified and, owing to its complementa-
ry nature with other palladium-catalysed cross coupling reac-
tions, could become very useful to synthetic chemists. Bro-
mine–lithium exchange, directed (ortho)lithiation and
carbolithiation have all been shown to be compatible with the
new methodology. We eagerly await the next developments in
this area from the Feringa group and elsewhere. Indeed, a po-
tential avenue for exploration could involve the use of even
Received: November 4, 2014
Published online on && &&, 0000
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HIGHLIGHTS
J. D. Firth, P. O’Brien*
Organolithiums have passed the test!
Previously considered too reactive and
unstable, organolithiums have been
tamed and can now participate success-
fully in palladium-catalysed cross-cou-
pling with aryl/vinyl bromides and trif-
lates.
&& – &&
Cross-Coupling Knows No Limits:
Assessing the Synthetic Potential of
the Palladium-Catalysed Cross-
Coupling of Organolithiums
&
ChemCatChem 0000, 00, 0 – 0
www.chemcatchem.org
4
ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!