Communication
Abstract: A palladium-catalysed cross-coupling of organo-
lithium reagents with aryl and vinyl triflates is presented.
The reaction proceeds at 50 or 708C with short reaction
times, and the corresponding products are obtained with
moderate to high yields, with a variety of alkyl and
(hetero)aryl lithium reagents.
Figure 1. Palladium-catalysed cross-coupling with organolithium reagents.
to aryl chlorides again featuring excellent selectivities and high
yields (Figure 1).[15]
The development of new methodologies for transition-metal-
catalysed cross-coupling reactions has attracted the attention
of the chemistry community for the past 40 years.[1] In this con-
text, palladium-mediated CÀC bond formations, have played
a crucial role, and methodologies involving palladium catalysis
for cross-coupling have been shown to be particularly effec-
tive. As a consequence, palladium-catalysed cross-coupling has
found widespread application in the industrial manufacturing
of pharmaceuticals, fine chemicals and materials in the last de-
cades.[2] In particular, the synthesis of biaryls is of great interest,
because of the important role of this privileged structure in
functional materials and biologically active compounds, as well
as their application in ligand design for asymmetric catalysis.[3]
There are several well established methods for palladium-cata-
lysed cross-coupling using different organometallic partners in-
cluding organomagnesium (Kumada coupling),[4] organotin
(Stille coupling),[5] organozinc (Negishi coupling),[6] organobor-
on (Suzuki–Miyaura coupling)[7] and organosilicon (Hiyama-
Denmark coupling).[8] Murahashi pioneered the use of organo-
lithium[9] reagents in cross-coupling, but until recently organo-
lithium compounds have been rarely applied as organometallic
partners.[10,11] However, organolithium reagents represent an
attractive alternative in virtue of their widespread use in organ-
ic synthesis, easy preparation, versatility and low costs.[12]
Moreover, boron, tin, zinc or silicon reagents are frequently
prepared from the corresponding lithium reagents,[13] so the
direct use of organolithium compounds would eliminate addi-
tional transformation and purification processes. Furthermore,
organolithium reagents are readily prepared by direct metalla-
tion or halogen–lithium exchange.
The use of aryl and vinyl triflates in palladium-catalysed
cross-coupling reactions is particularly attractive due to the
fact that they are readily available from phenols and carbonyl
enolates.[16] The use of triflates offers a viable alternative in
cross-coupling reactions as phenolic hydroxyl and carbonyl
moieties are common organic functional groups and the syn-
thesis of non-commercially available aryl halides might involve
harsh reaction conditions and multiple steps.[17] In this context,
palladium-mediated cross-coupling of organometallic reagents
with organic triflates[18–20] is highly valuable and several meth-
ods based on palladium have been developed. Herein, we
present, to the best of our knowledge, the first direct cross-
coupling of alkyl and (hetero)aryl organolithium reagents with
aryl and vinyl triflates showing short reaction times and good
yields.[21]
The reaction between 2-naphthyl trifluoromethanesulfonate
(1a) and nBuLi was chosen as a model reaction for optimisa-
tion of the reaction conditions. We started our study by apply-
ing the optimised conditions for the cross-coupling of organo-
lithium reagents with aryl bromides,[14a] in which [Pd(PtBu3)2]
was used as a catalyst (Table 1, entry 1) at room temperature;
almost no conversion to the alkylated product 2a was ob-
served. A variety of phosphine ligands were subsequently
tested using nBuLi and 5 mol% of Pd catalyst at room temper-
ature.[22] The best conversions were obtained with Xphos and
JohnPhos (entries 3 and 4, respectively), but selectivity for 2a
was still not satisfactory, and a considerable amount of naph-
thalene (3) was formed, probably due to b-hydride elimination
of the Pd–alkyl intermediate followed by dissociation. An in-
crease of the temperature to 508C led to full conversion in all
cases (entries 7 to 12). The best conversion to the cross-cou-
pling product 2-butylnaphthalene (2a) (81%) was observed
when DavePhos was used as a ligand (entry 12). The use of
catalysts based on N-heterocyclic ligands, such Pd-PEPPSI-
IPent[23] (entry 6), didn’t afford satisfactory results, and al-
though with [Pd(PPh3)4] at 508C (entry 9) full conversion was
achieved, only 49% of the desired product 2a was obtained.
Once we optimized the reaction conditions (508C, 5 mol%
Pd catalyst, L=DavePhos, 72% isolated yield) for the cross-
coupling, we set out to investigate the scope of this process
using various alkyllithium reagents and aryl triflates (Table 2).
The reaction of MeLi with 2-naphthyl trifluoromethanesulfo-
nate and with 3,5-dimethoxyphenyl trifluoromethanesulfonate
proceeds with excellent yields affording the corresponding al-
kylated products 2b (93%) and 2e (88%), respectively. Com-
plete selectivity was observed for the alkylated product, and
the reduced arene was not found, probably due to the fact
Recently, our group reported the direct cross-coupling of or-
ganolithium reagents with aryl and alkenyl bromides.[14] The
fine-tuning of the catalyst and the reaction conditions (apolar
solvent and slow addition of the organolithium reagent) allows
the reaction to take place with high selectivity, under mild con-
ditions and in short times, avoiding side reactions, such as lithi-
um–halogen exchange or homocoupling reactions. Further-
more, we extended the cross-coupling of aryllithium reagents
[a] Dr. C. Vila, Dr. V. Hornillos, M. Giannerini, Dr. M. FaÇanꢀs-Mastral,
Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4278
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404398.
Chem. Eur. J. 2014, 20, 13078 – 13083
13079
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