Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-Coupling of Organolithium Reagents

Article abstract of DOI:10.1002/anie.201700417

The discovery of an ultrafast cross-coupling of alkyl- and aryllithium reagents with a range of aryl bromides is presented. The essential role of molecular oxygen to form the active palladium catalyst was established; palladium nanoparticles that are highly active in cross-coupling reactions with reaction times ranging from 5 s to 5 min are thus generated in situ. High selectivities were observed for a range of heterocycles and functional groups as well as for an expanded scope of organolithium reagents. The applicability of this method was showcased by the synthesis of the [¹¹C]-labeled PET tracer celecoxib.

Full text of DOI:10.1002/anie.201700417

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700417
German Edition: DOI: 10.1002/ange.201700417
Cross-Coupling Very Important Paper
Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-
Coupling of Organolithium Reagents
Dorus Heijnen+, Filippo Tosi+, Carlos Vila, Marc C. A. Stuart, Philip H. Elsinga,
Wiktor Szymanski, and Ben L. Feringa*
Abstract: The discovery of an ultrafast cross-coupling of alkyl-
and aryllithium reagents with a range of aryl bromides is
presented. The essential role of molecular oxygen to form the
active palladium catalyst was established; palladium nano-
particles that are highly active in cross-coupling reactions with
reaction times ranging from 5 s to 5 min are thus generated
in situ. High selectivities were observed for a range of hetero-
cycles and functional groups as well as for an expanded scope
of organolithium reagents. The applicability of this method was
showcased by the synthesis of the [11C]-labeled PET tracer
celecoxib.
lighter and less toxic stoichiometric waste (LiX). Reactions
with excellent chemoselectivity were initially achieved by
slow addition of the highly reactive lithium reagent.[2]
Typically, commercially available unaltered complexes were
employed, including Pd/PEPPSI, Pd(PtBu3)2 (C1), or Pd/dba/
XPhos, which are also prominent catalysts in closely related
transformations, such as Negishi or Suzuki cross-coupling
reactions.[3]
We envisioned that the exceptional reactivity and versa-
tility of organolithium reagents could be taken advantage of
in developing a fast cross-coupling that proceeds under
ambient conditions, especially in light of the major current
interest and important advances in fast cross-coupling reac-
tions under mild conditions.[4] To the best of our knowledge,
the very recently published procedure by the group of
Schoenebeck, based on the use of Grignard and organozinc
reagents (Figure 1), stands out in terms of short reaction
times.[5]
T
ransition-metal-catalyzed cross-couplings of organometal-
lic reagents have found widespread application in the syn-
thesis of pharmaceutical products and organic materials,
including the formation of important functionalized hetero-
cycles.[1] Despite their prominent role in the modern synthetic
repertoire, it remains of considerable interest to shorten
reaction times, apply milder conditions, use less expensive
starting materials, reduce catalyst loadings and trace residual
metals in the desired product, and to minimize the amount of
toxic waste. We have recently reported the direct cross-
coupling of alkyl-, alkenyl-, and aryllithium reagents with
a wide range of (pseudo)halogenated aryl and alkenyl
electrophiles catalyzed by either palladium or nickel com-
plexes.[2] These organolithium-based methods typically show
cross-coupling with enhanced speed (< 1 h), operate at mild
temperatures (in most cases room temperature), and produce
Figure 1. Recent fast cross-coupling reactions.
[*] D. Heijnen,[+] F. Tosi,[+] Dr. C. Vila, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry
Herein, we present the discovery of an ultrafast cross-
coupling with organolithium reagents. In stark contrast to the
common practice of rigorously excluding oxygen when work-
ing with such extremely reactive organometallic reagents, we
have found that molecular oxygen is essential to form the
University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
E-mail: B.L.Feringa@rug.nl
Dr. M. C. A. Stuart
Groningen Biomolecular Sciences and Biotechnology Institute
University of Groningen
À
active catalyst. Under our conditions, rapid C C bond
Nijenborgh 7, 9747 AG Groningen (The Netherlands)
formation occurs within seconds to minutes at room temper-
ature while catalyst speciation studies point to the involve-
ment of 2–3 nm large Pd nanoparticles. Using this new
procedure, chemoselective cross-coupling reactions with
organolithium reagents now include an expanded range of
heterocycles, functional groups, and organolithium com-
pounds. Furthermore, it provides a versatile method for
Prof. Dr. P. H. Elsinga
Department of Nuclear Medicine and Molecular Imaging
University of Groningen, University Medical Center Groningen
Hanzeplein 1, 9713 GZ Groningen (The Netherlands)
Dr. W. Szymanski
Department of Radiology
University of Groningen, University Medical Center Groningen
Hanzeplein 1, 9713 GZ Groningen (The Netherlands)
isotope labeling, that is, for introducing CD3 labels and short-
11
lived 11C radioisotopes (t = ( C) = 20.3 min) for PET imaging.
[+] These authors contributed equally to this work.
1
2
In preliminary experiments, we used the cross-coupling of
methyllithium and 1-bromonaphthalene in the presence of
Pd(PtBu3)2 (C1, 5 mol%) at room temperature to test
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201700417.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 1: Fast cross-coupling of (hetero)aryl bromides with organolithium
whether very short reaction times with full conversion would
be possible (Scheme 1). Under presumably identical condi-
tions, we were puzzled to observe greatly varying results.
reagents.[a]
Scheme 1. Optimization of the fast cross-coupling.
After eliminating many potential causes (variations in the
concentration of the reagents, light, temperature, the pres-
ence of salts, water, or trace metal impurities), we established
that minute traces of air were essential for catalyst activation.
Samples briefly purged with dry oxygen prior to MeLi
addition always gave complete and chemoselective conver-
sion into 1-methylnaphthalene. The lack of reactivity
observed after adding degassed water or when employing
strictly oxygen-free conditions supported the notion that the
presence of oxygen greatly enhanced the catalytic activity of
the system.
Under the optimized conditions, an extended range of
organolithium and aryl bromide reagents, compared to our
previously reported method,[2] underwent highly selective
coupling, providing excellent yields in 2–5 min at room
temperature (Table 1). Substrates from the naphthalene
(2a–3 f) and anthracene families (4a) gave good yields with
near-perfect selectivity when coupled with a variety of
commercially available organolithium reagents. Gratifyingly,
identical results were achieved with both electron-poor and
electron-rich substrates (5a–8a). Unwanted side reactions
À
were suppressed with near-perfect selectivity for C Br over
À
C Cl in aromatic and aliphatic substrates with competitive
coupling possibilities (9a–11a), while aryl bromides 12a–15a,
including CF3-substituted analogue 16a, gave selectivities
similar to those of the naphthalene substrates.[6] Remarkably,
the fast coupling of RLi can even be used when an epoxide
functional group is present at a temperature as low as À108C,
where the expected epoxide ring opening by the organo-
lithium reagent is effectively suppressed, to provide the
desired coupling product 17a. Importantly, alcohols 18a–20a,
including an unprotected phenol, provided the corresponding
products in good yields. Novel substrates were also found
amongst heterocycles 21a–26a.
[a] Reaction conditions: 0.6 mmol substrate in 4 mL toluene, 5 mol%
catalyst, 4 mL oxygen, 1.5 equiv (0.9 mmol) organolithium reagent. All
reactions were carried out at room temperature. Yields of isolated
products after column chromatography are given unless noted other-
wise. [b] Reaction performed at 08C. [c] Performed with 2.5 equiv of the
organolithium reagent at 408C. [d] Conversion determined by GCMS
analysis. [e] Reaction performed with 1 equiv of nBuLi at À108C.
[f] Reaction performed with 2.5 equiv of the organolithium reagent.
The direct lithiation of inexpensive, commercially avail-
able ferrocene is well described in the literature,[7] and the
corresponding nucleophile provides an alternative to the less
available and costly boron or halide derivatives to yield 27a
and 28a. Finally, aryllithium reagents synthesized via lithium–
halogen exchange (e.g., 3-anisyllithium) also proved to be
suitable coupling partners, providing biaryl 29a.
The reaction time of the coupling between nBuLi and
1-bromonaphthalene could be reduced to just 5 s at room
temperature with 5 mol% of the precatalyst, giving full
conversion and a turnover frequency of 14 ꢀ 103 hÀ1 (Table 2,
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 2: Variation of the catalyst loading.[a]
place.[13] Given the fast cross-coupling and the lack of any
reaction between C1 or C1ox and the electrophile, we next
tested whether the organolithium reagent initiates the
catalytic cycle by generation of the active Pd species. Upon
stoichiometric addition of nBuLi to a [D8]toluene solution of
C1ox, some of the Pd species were reduced to form again
catalytically inactive C1 (31P NMR analysis; see the Support-
ing Information), and stoichiometry indicates the formation
of another Pd0 species, presumably the active catalyst (see
below). Important information came from independent
experiments with the bridged dinuclear PdI complex C2
(Scheme 1), which is also a catalyst precursor in our cross-
coupling. Oxidation of C2 occurs within seconds at room
temperature, although we found that the product C2ox arising
from this reaction was not consistent with the one described in
the literature (see the Supporting Information).[14] Both C2
and C2ox gave full conversion in cross-couplings with RLi
reagents. The oxidation of C2 and subsequent reduction of
C2ox by nBuLi was studied in detail by 31P NMR spectroscopy
(Figure 2), showing, much to our surprise, partial formation of
mononuclear complex C1, which we knew to be catalytically
inactive.
Entry
C1 [mol%]
Addition time
Conversion
1
5
5 s
full
full
full
40%
full
full
2
3
4
0.5
2 min
10 min
10 min
30 min
30 min
0.05
0.025
0.025
0.05
5
6[b]
[a] All experiments were conducted at room temperature in toluene
(0.15m initial substrate concentration); entries 1 and 2 were conducted
on 0.3 mmol scale, entries 3–6 on 12 mmol (2.5 g) scale. Conversions
were determined by GCMS analysis. [b] 4-Bromoanisole was used as the
substrate.
entry 1), provided that an excess of oxygen was present with
respect to Pd complex C1. With a catalyst loading of 0.05%,
we were able to fully convert 1 on gram scale in just 10 min.
On the other hand, by reducing the rate of addition of nBuLi,
we were able to use a catalyst loading as low as 0.025 mol%
(entry 2–5). A slightly higher catalyst loading was necessary
for the coupling of 4-bromoanisole (entry 6).
Focusing on the crucial role of molecular oxygen, we
observed that the catalyst solution turned red upon purging
with O2, suggesting that Pd(PtBu3)2 (C1) was converted into
the active catalyst. Many d10 metal complexes are known to
rapidly interact with O2 to form stable h2-peroxo complexes;
however, C1 has not been reported as one of them.[8] The
reason for its stability towards O2 was attributed to the
extreme bulkiness of the ligands, which shield the Pd and
hence hamper its oxidation. Therefore, the sterically hindered
C1 complex needs prolonged oxygen exposure at room
temperature to ensure complete oxidation. To investigate
whether known peroxo complexes could be excluded as
possible catalysts, we tested the h2-peroxo derivatives of
Pd(PCy3)2 and Pd(PPh3)2,[5] which did not show any catalytic
Figure 2. 31P NMR spectra of C2 in [D8]toluene (a), after O2 exposur-
e (b,c), and nBuLi addition (d).
The lithium reagent promotes reduction from PdI to Pd0
and the formation of both Pd(PtBu3)2 (C1) and apparently
ligand-free Pd0, which becomes evident from the observed
stoichiometry (NMR analysis, see the Supporting Informa-
tion) of the complexes and ligands (Scheme 2).
1
activity (see the Supporting Information). Extensive H and
31P NMR studies with catalytically inactive C1 prior to and
after exposure to oxygen revealed the formation of free PtBu3
(see the Supporting Information), phosphine oxides, and (yet
unidentified) oxidized Pd species (C1ox) upon reaction with
O2.[9,10]
The hypothesis that the monoligated [Pd(PtBu3)] com-
plex, arising from dissociation of one phosphine from the
starting complex, acted as the active catalyst was excluded on
the basis of the lack of reactivity with aryl chlorides and
inhibition experiments by adding an excess of PtBu3 (up to
10 equiv, see the Supporting Information), which had no
effect on the outcome of the cross-coupling, suggesting
a different active species.[5,11,12]
Scheme 2. Reduction of C2 with RLi.
Following the cross-coupling reaction of 4-bromoanisole
by NMR spectroscopy, we also observed the in situ formation
of the bridged complex C2 from C1ox after RLi addition (in
accordance with previous observations by Schoenebeck using
Grignard reagents),[5] for which we suggest the stoichiometry
shown in Scheme 3.
The combined results of the RLi addition experiments
with C1ox, C2, and C2ox, which clearly showed reduction in all
cases, led to the hypothesis that a common active species, that
We were able to isolate the oxidized form (C1ox) of C1 by
washing the residue of the oxidation step with acetonitrile
(see the Supporting Information). Addition of 4-bromoani-
sole to C1ox at room temperature showed no change at all by
NMR analysis, which led to the conclusion that up until the
addition of the organolithium reagent, no reaction is taking
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
the isolated nanoparticles were successful, strongly support-
ing the involvement of PdNPs as the active catalyst.
Based on the experimental data, the catalyst activation
pathway shown in Scheme 4 is proposed. PdNPs are known to
be formed from PdII sources under reductive conditions.[16] In
Scheme 3. Schematic in situ formation of C2 from C1ox.
is, Pd nanoparticles (PdNPs), are formed in situ. TEM
measurements were carried out to investigate the presence
of nanoparticles in samples of C1 and C1ox prior to RLi
addition, but in neither case, any PdNPs were observed.
Studying the effect of the addition of the lithium reagent to
C1ox, we clearly observed PdNPs with dimensions of 2–3 nm
(Figure 3).
Scheme 4. Proposed catalyst activation pathway.
our system, O2 reacts first with the Pd0 complex, thereby
oxidizing it to C1ox (Scheme 4a), which is then in situ reduced
to highly active Pd0 nanoparticles by means of the organo-
lithium reagent, either directly (b) or via C2/C2ox (c–f; for
details, see the Supporting Information). The striking differ-
ence of the novel catalytic system presented here, compared
to other PdNP-catalyzed cross-coupling reactions,[17] is the
ultrafast cross-coupling of organolithium reagents, which can
be explained by the in situ formation of numerous small (2–
3 nm) Pd nanoparticles.
The benefits of the ultrafast coupling presented here can
best be exploited in reactions where time restrictions are
crucial. Therefore, we focused on the cross-coupling of
11
11
[1,18,19]
1
[ C]methyllithium (t = ( C) = 20 min) for PET labeling.
2
Such a method would be complementary to the more often
used electrophilic quenching of a nucleophilic drug precursor
with [11C]iodomethane. The presence of several nucleophilic
sites in specific precursors often results in undesired (over-
alkylated) side products. We selected the synthesis of
[11C]celecoxib to illustrate the usefulness of our method
(Scheme 5).[20,21]
Figure 3. TEM image and corresponding EDX spectrum of the PdNPs.
Initially, we explored the reaction of commercially
available MeLi and celecoxib precursor 30. Having isolated
the target 31 in excellent yield (91%), we used in situ
generated MeLi, prepared from MeI in both a stoichiometric
and a substoichiometric (0.1 equiv) ratio with respect to
nBuLi.[18] Gratifyingly, we were able to isolate the corre-
In a highly informative set of experiments, under opti-
mized cross-coupling conditions and with all previously
mentioned precatalysts (C1ox, C2, and C2ox), samples were
taken both during and at the end of the reaction, and analyzed
by TEM for the in situ formation of nanoparticles (Figure 3
and the Supporting Information). We were pleased to see the
formation of nanoparticles in all cases where product was
formed. Energy-dispersive X-ray analysis (EDX)[15] revealed
the elemental compositions of the samples, and clearly
showed an increase in the Pd/P ratio with respect to catalyti-
cally inactive complexes, supporting the formation of PdNPs
(see the Supporting Information). Isolation of these nano-
particles was successful by centrifugation and repeated
washing with toluene, and the absence of homogeneous Pd
1
complexes was confirmed by H and 31P NMR spectroscopy.
Fast cross-coupling reactions of organolithium reagents with
Scheme 5. Synthesis of radiolabeled celecoxib.
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
sponding product by preparative HPLC in good yield (85%)
pean Marie Curie Fellowship (FP7-PEOPLE-2011-IEF-
with respect to the MeI starting material.
300826).
With a representative result for the radiolabeling based on
the use of substoichiometric MeI in hand, the synthesis of
[11C]celecoxib (31*; coupling time 2 min, total preparation
time including HPLC purification < 15 min) was pursued.
The final decay-corrected radiochemical yield for 31* was
found to be 65% (average of three runs).
Conflict of interest
The authors declare no conflict of interest.
For further applications in isotope labeling, we considered
the direct incorporation of the CD3 moiety into organic
compounds. The use of deuterated MeI is desirable from
a cost perspective, and its use with a range of electrophiles has
recently been shown by Hu and co-workers.[22] As the
reported procedure requires a large excess of costly CD3I
(3.5 equiv), we anticipated that our method using in situ
Keywords: cross-coupling · isotope labeling · nanoparticles ·
organolithium regents · palladium
[1] a) 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; b) G. C. Fortman, S. P. Nolan,
Chem. Soc. Rev. 2011, 40, 5151 – 5169; c) E. I. Negishi, Angew.
Chem. Int. Ed. 2011, 50, 6738 – 6764; Angew. Chem. 2011, 123,
6870 – 6897; d) V. L. Andersen, H. D. Hansen, M. M. Herth,
G. M. Knudsen, J. L. Kristensen, Bioorg. Med. Chem. Lett. 2014,
24, 2408 – 2411; e) H. G. Lee, P. J. Milner, M. S. Placzek, S. L.
Buchwald, J. M. Hooker, J. Am. Chem. Soc. 2015, 137, 648 – 651;
f) A. M. Echavarren, D. J. Cꢁrdenas in Metal Catalyzed Cross-
Coupling Reactions, Wiley-VCH, Weinheim, 2004, pp. 1 – 40;
g) Thomas J. Colacot in New Trends in Cross-Coupling, The
Royal Society Of Chemistry, London, 2015.
generated CD3Li could provide
a viable alternative
(Scheme 6). As we had converted MeI into MeLi using
[2] a) M. Giannerini, M. FaÇanꢁs-Mastral, B. L. Feringa, Nat. Chem.
2013, 5, 667 – 672; b) D. Heijnen, V. Hornillos, B. P. Corbet, M.
Giannerini, B. L. Feringa, Org. Lett. 2015, 17, 2262 – 2265; c) V.
Hornillos, M. Giannerini, C. Vila, M. FaÇanꢁs-Mastral, B. L.
Feringa, Chem. Sci. 2015, 6, 1394 – 1398; d) D. Heijnen, J.
Gualtierotti, V. Hornillos, B. L. Feringa, Chem. Eur. J. 2016, 22,
3991 – 3995; e) V. Hornillos, M. Giannerini, C. Vila, M. FaÇanꢁs-
Mastral, B. L. Feringa, Org. Lett. 2013, 15, 5114 – 5117; f) E. B.
Pinxterhuis, M. Giannerini, V. Hornillos, B. L. Feringa, Nat.
Commun. 2016, 7, 11698; g) C. Vila, V. Hornillos, M. Giannerini,
M. FaÇanꢁs-Mastral, B. L. Feringa, Chem. Eur. J. 2014, 20,
13078 – 13083.
[3] a) S. C¸ alimsiz, M. Sayah, D. Mallik, M. G. Organ, Angew. Chem.
Int. Ed. 2010, 49, 2014 – 2017; Angew. Chem. 2010, 122, 2058 –
2061; b) A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000,
122, 4020 – 4028; c) A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed.
1998, 37, 3387 – 3388; Angew. Chem. 1998, 110, 3586—3587.
[4] a) B. C. Ranu, R. Dey, K. Chattopadhyay, Tetrahedron Lett.
2008, 49, 3430 – 3432; b) B. Mu, J. Li, Z. Han, Y. Wu, J.
Organomet. Chem. 2012, 700, 117 – 124; c) C. Mateos, J. A.
Rincon, B. Martin-Hidalgo, J. Villanueva, Tetrahedron Lett.
2014, 55, 3701 – 3705; d) A. Deangelis, D. H. Wang, S. L.
Buchwald, Angew. Chem. Int. Ed. 2013, 52, 3434 – 3437;
Angew. Chem. 2013, 125, 3518 – 3521; e) Y. Zhang, T. Rovis, J.
Am. Chem. Soc. 2004, 126, 15964 – 15965; f) C. Liu, W. Yang,
Chem. Commun. 2009, 6267 – 6269; g) G. Manolikakes, P.
Knochel, Angew. Chem. Int. Ed. 2009, 48, 205 – 209; Angew.
Chem. 2009, 121, 211 – 215; h) M. Kienle, P. Knochel, Org. Lett.
2010, 12, 2702 – 2705; i) S. Handa, J. D. Smith, M. S. Hageman,
M. Gonzalez, B. H. Lipshutz, ACS Catal. 2016, 6, 8179 – 8183.
[5] a) M. Aufiero, T. Scattolin, F. Proutiere, F. Schoenebeck,
Organometallics 2015, 34, 5191 – 5195; b) I. Kalvet, G. Magnin,
F. Schoenebeck, Angew. Chem. Int. Ed. 2017, 56, 1581 – 1585;
Angew. Chem. 2017, 129, 1603 – 1607.
Scheme 6. Cross-coupling of [D3]-MeLi.
nBuLi (see above), and successfully applied it in cross-
coupling also with the 11C analogue, an identical experimental
setup for CD3I was used. Much to our surprise, no CD3
incorporation was observed in the cross-coupling reaction
and in an electrophilic quench with benzaldehyde.[23,24]
Switching to tBuLi gave the desired reagent CD3Li, which
readily coupled with 2-bromonaphthalene to provide [D3]-2a
in 65% yield, establishing a new method for the incorporation
of the CD3 moiety.
In conclusion, a novel procedure for the rapid palladium-
catalyzed coupling of alkyl- and aryllithium reagents has been
developed, with a crucial role for O2 in generating the active
catalyst. Systematic studies towards the active catalyst species
revealed the formation of palladium nanoparticles for all
three active precatalysts upon addition of the organolithium
reagent, which facilitates rapid cross-couplings with a range of
aryl bromides at room temperature. The application of this
novel method was showcased in the coupling of
[11C]methyllithium in less than two minutes with a decay-
corrected yield of 65% as a key step in the synthesis of the
PET tracer celecoxib.
Acknowledgements
B.L.F. acknowledges financial support from The Netherlands
Organisation for Scientific Research, the European Research
Council (ERC Advanced Grant 227897), the Royal Nether-
land Academy of Arts and Sciences (KNAW), and the
Ministry of Education, Culture and Science (Gravitation
program 024.601035). C.V. was supported by an Intra-Euro-
[6] Compound 16a was not isolated owing to its volatility but
GCMS analysis of the crude reaction mixture showed full
conversion into the desired product.
[7] H. B. K. F. Rebiere, O. Samuel, Tetrahedron Lett. 1990, 31,
3121 – 3124.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
[8] a) K. Itami, T. Kamei, J. I. Yoshida, J. Am. Chem. Soc. 2003, 125,
14670 – 14671; b) T. Yoshida, S. Otsuka, J. Am. Chem. Soc. 1977,
99, 2134 – 2140.
[9] Attempts to reverse the process and deactivate the oxygenated
complex by means of degassing the reaction (freeze–pump–thaw
and argon purging) were not fruitful. Prolonged heating of the
oxygenated complex did not influence its properties, suggesting
that the process is irreversible.
[10] A. G. Sergeev, H. Neumann, A. Spannenberg, M. Beller,
Organometallics 2010, 29, 3368 – 3373.
[11] Z. L. Niemeyer, A. Milo, D. P. Hickey, M. S. Sigman, Nat. Chem.
2016, 8, 610 – 617.
[17] P. Taladriz-Blanco, P. Hervꢃs, J. Pꢃrez-Juste, Top. Catal. 2013, 56,
1154 – 1170.
[18] a) S. Reiffers, W. Vaalburg, T. Wiegman, H. Wynberg, M. G.
Woldring, Int. J. Appl. Radiat. Isot. 1980, 31, 535 – 539; b) P. J. H.
Scott, Angew. Chem. Int. Ed. 2009, 48, 6001 – 6004; Angew.
Chem. 2009, 121, 6115 – 6118.
[19] To the best or our knowledge, [11C]methyllithium has not been
used in a cross-coupling reaction.
[20] One of the simplest labeling options is to utilize [11C]-MeI as the
electrophile; however, it has also previously been converted into
an organometallic reagent in the form of a Stille, Grignard, or
Suzuki reagent.
[12] The formation of [Pd(PtBu3)] is often used to explain high
reactivity with aryl chlorides at room temperature, which is not
the case for our system; see: M. T. Reetz, E. Westermann,
Angew. Chem. Int. Ed. 2000, 39, 165 – 168; Angew. Chem. 2000,
112, 170 – 173 and Ref. [5] and [11].
[13] M. Yamashita, J. F. Hartwig, J. Am. Chem. Soc. 2004, 126, 5344 –
5345.
[14] V. Durꢂ-Vilꢂ, D. M. P. Mingos, R. Vilar, A. J. P. White, D. J.
Williams, Chem. Commun. 2000, 1525 – 1526.
[21] M. Suzuki, H. Doi, H. Koyama, Z. Zhang, T. Hosoya, H. Onoe,
Y. Watanabe, Chem. Rec. 2014, 14, 516 – 541.
[22] L. Hu, X. Liu, X. Liao, Angew. Chem. Int. Ed. 2016, 55, 9743 –
9747; Angew. Chem. 2016, 128, 9895 – 9899.
[23] As the organolithium reagent was fully consumed before any
transformation could take place and only starting material was
observed, we assumed that the difference in aggregation state of
CD3Li caused a rapid substitution with the formed n-iodobutane.
[24] T. Holm, J. Organomet. Chem. 1996, 506, 37 – 40.
[15] D. E. Newbury in Characterization of Materials, Wiley, New
York, 2002.
[16] D. Astruc, F. Lu, J. R. Aranzaes, Angew. Chem. Int. Ed. 2005, 44,
7852 – 7872; Angew. Chem. 2005, 117, 8062 – 8083.
Manuscript received: January 13, 2017
Final Article published: && &&, &&&&
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Cross-Coupling
D. Heijnen, F. Tosi, C. Vila,
M. C. A. Stuart, P. H. Elsinga,
W. Szymanski,
B. L. Feringa*
&&&& — &&&&
No oxygen, no coupling: Molecular
oxygen was shown to be crucial for the
fast palladium-catalyzed cross-coupling
of organolithium reagents developed
herein. Reactions times down to 5 s
provide a novel procedure for the prepa-
ration of radiolabeled compounds.
Oxygen Activated, Palladium
Nanoparticle Catalyzed, Ultrafast Cross-
Coupling of Organolithium Reagents
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!