Water and Sodium Chloride: Essential Ingredients for Robust and Fast Pd-Catalysed Cross-Coupling Reactions between Organolithium Reagents and (Hetero)aryl Halides

Article abstract of DOI:10.1002/anie.201812537

Direct palladium-catalysed cross-couplings between organolithium reagents and (hetero)aryl halides (Br, Cl) proceed fast, cleanly and selectively at room temperature in air, with water as the only reaction medium and in the presence of NaCl as a cheap additive. Under optimised reaction conditions, a water-accelerated catalysis is responsible for furnishing C(sp³)–C(sp²), C(sp²)–C(sp²), and C(sp)–C(sp²) cross-coupled products, in competition with protonolysis, within a reaction time of 20 s, in yields of up to 99 %, and in the absence of undesired dehalogenated/homocoupling side products even when challenging secondary organolithiums serve as the starting material. It is worth noting that the proposed protocol is scalable and the catalyst and water can easily and successfully be recycled up to 10 times, with an E-factor as low as 7.35.

Full text of DOI:10.1002/anie.201812537

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Accepted Article
Title: Water and Sodium Chloride: Essential Ingredients for Robust
and Fast Pd-catalysed Cross-Coupling Reactions between
Organolithiums and (Hetero)aryl halides
Authors: Giuseppe Dilauro, Andrea Francesca Quivelli, Paola Vitale,
Vito Capriati, and Filippo Perna
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812537
Angew. Chem. 10.1002/ange.201812537
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10.1002/anie.201812537
Angewandte Chemie International Edition
COMMUNICATION
Water and Sodium Chloride: Essential Ingredients for Robust and
Fast Pd-catalysed Cross-Coupling Reactions between
Organolithiums and (Hetero)aryl halides
Giuseppe Dilauro, Andrea Francesca Quivelli, Paola Vitale, Vito Capriati,* and Filippo Maria Perna
Dedication ((optional))
Abstract: Direct palladium-catalysed cross-couplings between
organolithiums and (hetero)aryl halides (Br, Cl) proceed fast, cleanly
and selectively at room temperature in air, with water as the only
reaction medium and in the presence of NaCl as a cheap additive.
Under optimised reaction conditions, a water-accelerated catalysis is
responsible for furnishing Csp3–Csp2, Csp2–Csp2, and Csp–Csp2
cross-coupled products, competitively with protonolysis, within a 20 s
reaction time, in yields of up to 99%, and in the absence of
undesired dehalogenated/homocoupling side-products even if it
starts from challenging secondary organolithiums. It is worth noting
that the proposed protocol is scalable and the catalyst and water can
easily and successfully be recycled up to 10 times, with an E-factor
as low as 7.35.
the slow addition of a (diluted) solution of the organolithium
reagent to the reaction mixture.[5a–g] Rapid cross-couplings of
organolithiums with a range of aryl bromides were also achieved
in toluene at room temperature (RT) by purging the mixture with
pure oxygen, which favoured the in situ generation of active
palladium nanoparticles (Scheme 1a).[5h]
The use of highly polar organometallic compounds of s-
block elements in environmentally benign, bio-inspired protic
solvents (water, glycerol, the so-called deep eutectic solvents,
DESs) represents one of the most formidable challenges in the
field of organometallics.[6] Recent years, however, have
witnessed the flourishing of greener and selective polar
organometallic and catalytic methodologies truly compatible with
nature-based solvents like DESs[7] and water.[8]
Selective formation of carbon-carbon bonds via transition metal-
catalysed cross-coupling reactions had revolutionised the field of
organometallic chemistry in the 70s, leading to three Nobel
Prizes shared by nine individuals during the period 2001–2010.[1]
The straightforward conversion of readily available organolithium
compounds into cross-coupling products has long represented a
challenge because of the high reactivity of these organometallic
reagents.[2] The direct metal-catalysed stereospecific synthesis
of olefins from vinyl halides and alkyllithiums was first reported in
1975 by Murahashi: inert atmosphere, long reaction time, toxic
and volatile organic compounds (VOCs) (benzene), and Pd(0)
compounds used in stoichiometric amount were strictly
required.[3] It was not until 2010 that Yoshida and co-workers
documented the first integrated Br-Li exchange of aryl bromides
with n-BuLi with a selective, faster Muharashi coupling with other
We herein disclose that Pd-catalysed direct cross-coupling
reactions can be efficiently and cleanly realized by a fast
addition of organolithium compounds to a variety of (hetero)aryl
halides (Br, Cl) by working under “on water” conditions and in
the presence of NaCl as an additive, with the expected adducts
being isolated in good to excellent yields (up to 98%) and with a
broad substrate scope (Scheme 1b). It is to be noted that these
processes (a) are run at RT and under air, and (b) end within 20
s.
Previous work:
Feringa (2013–2017) (Ref. 5)
Pd or Ni complex
RT to 70 °C, (O2)
X
R
RLi
+
(a)
Het
Het
slow addition
toluene
or minimum solvent
X = Br, Cl, OTf
This work:
aryl bromides (and then with vinyl halides) in
microreactor.[4]
a flow
Pd complex
RT, under air, 20 s
X
R
RLi
+
(b)
Het
Het
H2O, NaCl
The Muharashi coupling has been recently revisited by
Feringa and co-workers who reported optimised protocols for
performing direct cross-coupling of alkyl-, alkenyl-, and
(hetero)aryllithium reagents with a variety of aryl and alkenyl
(pseudo)halides as electrophilic partners catalysed by either
palladium or nickel complexes.[5] To avoid the notorious lithium-
halogen exchange and homocoupling side reactions, the key
factors were (a) the use of a non-polar solvent (toluene) or
fast addition
X = Br, Cl
Scheme 1. Direct cross-coupling reactions between organolithiums and
(hetero)aryl halides (a) in toluene or minimum solvent, (b) “on water”, in the
presence of NaCl, at RT and under air.
As a part of our program that is aimed at exploring the
boundaries of metal-,[7e–h,8h] organo-,[9a,b] and bio-catalysis[9c,d]
when using unconventional solvents, we became initially eager
to investigate the usefulness of DESs[10] as sustainable reaction
solventless conditions in combination with
a Pd-catalyst
containing bulky electron rich ligands [e.g., Pd/P(t-Bu3)3], and (b)
media
organolithiums and aryl halides.
We decided to study the Csp3–Csp2 cross-coupling
reaction between n-BuLi (2.0 in cyclohexane) and 1-
for
direct
cross-coupling
reactions
between
M
[*]
Dr. G. Dilauro, Dr. A. Francesca Quivelli, Dr. P. Vitale, Prof. V.
Capriati, Dr. F. M. Perna
bromonaphthalene 1a (0.2 mmol) as a model system for the
preparation of adduct 2aa using Pd[P(t-Bu)3]2 (5 mol%) as a
catalyst. Unsatisfactory results in terms of conversion and/or
selectivity were obtained in DESs formed between choline
chloride (ChCl) and urea or glycerol (Gly) even with an excess of
n-BuLi (3 equiv) (Table 1, entries 1,2). However, the only side
product isolated was the dehalogenated naphthalene 3aa,
Dipartimento di Farmacia–Scienze del Farmaco
Università di Bari “A. Moro”, Consorzio C.I.N.M.P.I.S.
Via E. Orabona 4, I-70125 Bari (Italy)
E-mail: vito.capriati@uniba.it
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812537
Angewandte Chemie International Edition
COMMUNICATION
presumably arising from a competing β-hydride elimination/olefin
dissociation pathway rather than from a Br-Li exchange as in the
absence of the Pd-catalyst, only the starting aryl bromide was
quantitatively recovered.[5d] Upon changing the hydrogen bond
donor to ethylene glycol (EG), oxalic acid (OxA), L-lactic acid
(LA) or malic acid (MA), the ratio 2aa:3aa could only be
improved up to 2:1 (Table 1, entries 3–6). In all cases studied, n-
BuLi was rapidly added in one portion to the mixture of catalyst
and 1a, which were pre-mixed for 10 min. During this time, the
catalyst slowly changed its colour from yellow to dark orange. A
turn of the catalyst (Pd[P(t-Bu)3]2) solution in toluene to red was
similarly observed by Feringa upon purging the mixture with
molecular oxygen. This was attributed to the formation of an
active form of the catalyst.[5h]
There is nowadays an increasing interest in developing
coupling reactions using more environmentally friendly solvents.
For instance, as for palladium-catalysed transformations, water
has been shown to boost catalysis by promoting the migratory
insertion and by accelerating the often rate-determining
oxidative addition step and the displacement of labile ligands.[11]
Thus, we switched to water as the solvent. When n-BuLi (3
equiv) was rapidly added in one portion to a suspension of 1a
(0.2 mmol) and Pd-catalyst in deionized water (1 mL, pH 6.0)
under air with vigorous stirring at RT to generate an emulsion
(vortex), an almost 1:1 mixture of 2aa and 3aa was isolated, but
with a quantitative conversion (Table 1, entry 7). This time, by
lowering the pH to 2.0 with HCl, a 2:1 mixture in favour of 2aa
was obtained, the overall conversion yield being 92% (Table 1,
entry 8). However, when H2SO4 was used in place of HCl (pH =
2) the formation of 2aa was suppressed dramatically (15% yield)
(Table 1, entry 9). Thus, when using water, we anticipated that
the chloride ion would play a key role in favouring the cross-
coupling reaction.
A detailed mechanistic rationalization of the beneficial
effect of halide ions on palladium catalysis has been provided by
Bäckvall, Amatore, Jutand, and others.[12a–e] In particular,
detailed DFT calculations and theoretical analysis performed by
Shaik and co-workers have shown that an “apparently
innocuous additive” such as a chloride ion may have a strong
impact on the catalytic cycle triggered by a Pd(0)L2 (L =
phosphine) complex by forming an anionic complex while
keeping a small P–Pd–P angle, which is a prerequisite for a low
activation barrier to oxidative addition[12d] Recently, the formation
and the role played by Pd0 and PdII ate complexes in cross-
coupling reactions have been thoroughly investigated by
Koszinowski and co-workers via spectroscopic/spectrometric
studies.[12f,g] By running the on-water coupling reaction in the
presence of 3 equiv of either LiCl or the cheapest NaCl as an
additive, adduct 2aa formed in 98% yield as a sole product
(Table 1, entries 10,11). To our delight, the effectiveness of such
a cross-coupling was still maintained (2aa: 98%) with 1.1 equiv
n-BuLi, 1 equiv NaCl, and at a loading of the catalyst as low as
2.5 mol% (Table 1, entry 12). Most importantly, it took only 20 s
at RT to achieve full conversion with a turnover frequency of
14.54 × 103 h–1 (see Supporting Information). By decreasing the
amount of NaCl up to 10 mol%, however, the 2aa:3aa ratio
became 70:15 (85% conversion). Thus, working under
heterogeneous conditions, the concentration of NaCl solution is
important. Notably, the rate of addition of the organolithium
reagent was also of utmost importance; the yield of 2aa dropped
considerably to 45% when n-BuLi (1.1 equiv) was added
dropwise to the reaction mixture (Table 1, entry 13) (see
Supplementary Movies). Finally, we also ascertained that the
presence of dissolved oxygen in water was crucial to speed up
the reaction most probably by generating an active form of the
catalyst.[5h] Indeed, when water was first deoxygenated with the
freeze-pump-thaw cycling technique and argon purging, 2aa
could be isolated in 32% yield (Table 1, entry 14).
Table 1. Pd-catalysed cross-coupling of 1-bromonaphthalene 1a with n-BuLi
in different solvents, at RT, and under air.[a]
Br
3
Pd[P(t-Bu)3]2 (x mol%)
+
+
n-BuLi
solvent, additive
RT, under air
(2.0 M)
1a
Solvent
2aa
3aa
Entry
Additive
Conv. (%)
2aa:3aa[b]
1
urea/Gly[c,d]
–
–
–
–
–
–
12
3:9
2
ChCl/Gly[c,d]
EG/ChCl[c,d]
89
20:69
3
Full
82
54:46
4
OxA/ChCl[c,d]
LA/ChCl[c,d]
53:29
5
90
55:35
6
MA/ChCl[c,d]
H2O (pH 6)[c,d]
H2O (HCl, pH 2)[c,d]
60
60:30
7
Full
92
55:45
8
–
61:31
9
H2O (H2SO4, pH 2)[c,d]
H2O (pH 6)[c,d]
H2O (pH 6)[c,d]
H2O (pH 6)[g,h]
H2O (pH 6)[g,h,i]
H2O (pH 6)[g,h,k]
MeOH[g,h]
–
15
>98:<2[e]
>98:<2[f]
>98:<2[f]
>98:<2[f]
>98:<2[j]
>98:<2[l]
<2:>98[f]
10
11
12
13
14
15
LiCl (3 equiv)
NaCl (3 equiv)
NaCl (1 equiv)
NaCl (1 equiv)
NaCl (1 equiv)
NaCl (1 equiv)
Full
Full
Full
45
32
Full
[a] Reaction conditions: 1.0 g DES or 1 mL deionized H2O per 0.2 mmol of 1a;
Gly/ChCl (2:1, mol mol–1); urea/ChCl (2:1, mol mol–1); EG/ChCl (3:1, mol mol–
1); OxA/ChCl (3:1, mol mol–1); LA/ChCl (3:1, mol mol–1); MA/ChCl (1:1, mol
mol–1). To a pre-mixed (10 min) suspension of aryl bromide 1a and the Pd-
catalyst in DES or H2O, n-BuLi was quickly added at RT and under air;
reaction time: 20 s. [b] Ratio determined by 1H NMR analysis of the crude
reaction mixture in the presence of the internal standard CH2Br2. [c] n-BuLi: 3
equiv. [d] Pd-catalyst: 5 mol%. [e] 15% isolated yield. [f] 98% isolated yield. [g]
n-BuLi: 1.1 equiv. [h] Pd-catalyst: 2.5 mol%. [i] n-BuLi was added in 10 min at
RT and under air. [j] 45% isolated yield. [k] The mixture was deoxygenated,
and the reaction was run under argon. [l] 32% isolated yield.
Upon replacing water with MeOH, only the dehalogenated
product 3aa was quantitatively recovered (Table 1, entry 15).
The latter reasonably formed further to
a fast β-hydride
elimination process as no reaction was observed in this solvent
in the absence of the Pd-catalyst. Further screening of catalysts
were unsuccessful (see Supporting Information).
With these optimised conditions in place, we evaluated the
reaction scope by reacting a variety of (hetero)aryl halides (1)
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10.1002/anie.201812537
Angewandte Chemie International Edition
COMMUNICATION
with
organolithium
reagents
(Table
2).
Using
1-
afford the expected adducts 2ia, 2ja–2je, 2ka–2kc, 2la, 2ma,
2na, 2oa, 2pa, 2qa, and 2ra in 61–98% yield. 2-Bromofluorene
(1s) and 2-bromonaphthalene (1t) also served as competent
reaction partners, delivering products 2sa, 2sb, 2ta and 2tb in
78–93% yield. Under the above conditions, cross-couplings with
aryl chlorides proceeded smoothly only in the presence of
electron-withdrawing groups (1u), although in moderate yields
(2ua, 2ub: 41–53%), whereas functional group tolerance could
not be extended to carbonyl derivatives, nitrile, carboxylic acid
and ester moieties. The coupling between 1.1 equiv of n-
BuMgCl or (allyl)MgCl or i-PrMgCl·LiCl with 1a proved to be
ineffective. The catalyst and water could be recycled easily. As
for the synthesis of 2aa (Table 1, entry 12), once the stirring was
stopped after the 20 s reaction time, VOCs introduced with n-
BuLi were removed under reduced pressure, leaving the product
2aa inside the reaction mixture. Then, upon addition of new,
fresh reagents, the catalyst and water could be successfully re-
used for further reaction runs. The catalyst retained optimum
activity over ten cycles, the overall yield of product 2aa being
97% (357 mg by adding 0.2 mmol substrate each cycle). The
associated E-factor for the recycling process was 7.35 (see
Supporting Information for details). Finally, we have also carried
bromonaphthalene 1a as our standard, commercially available
aliphatic and aromatic organolithium reagents, ranging from
MeLi to EtLi, HexylLi, s-BuLi, i-PrLi PhLi and Me3SiCH2Li led the
desired coupling products 2ab–2ah with high selectivities and
satisfactory yields (70–98%). Of note, it was reported that, when
working under solventless conditions, secondary alkyllithiums
such as i-PrLi and s-BuLi were found to only give
dehalogenation products.[5g] The Csp-Csp2 coupling between 1a
and (phenylethynyl)lithium (2.2 equiv) also provided the
expected adduct 2ai, albeit in 17% yield. Unsubstituted aryl
bromides (1b) or decorated with an electron-donating group
(MeO) at the ortho- (1c) or para-position (1d) provided adducts
2ba, 2ca, 2cb, and 2da–2df in 70–90% yield. Aryl bromides
bearing electron-withdrawing groups at the meta- and para-
positions, such as chlorine (1e,f) and the trifluoromethyl group
(1g) also effectively participated in the process, delivering
adducts 2ea, 2fa, 2fb, and 2ga–2gd in very good yields (77–
98%). The presence of a fluorine atom (1h) was equally
tolerated and produced valuable products 2ha–2hd at excellent
yields of 80–98%. Assorted aryl derivatives with “neutral”
substituents (methyl, ethyl, benzyl) (1i–k), a tertiary amino group
(1l), an acetal moiety (1m), electron-rich [3-bromothiophene (1n), out a gram scale coupling of 1a (4.83 mmol, 1 g) with n-BuLi
5-bromo-N-methylindole (1o)] and electron-deficient [2-
bromopyridine (1p), 4-bromisoquinoline (1q), 2-bromoquinoline
(1r)] heterocycles could be efficiently cross-coupled as well to
(1.1. equiv) in 5 mL water. The reaction proceeded uneventfully
at room temperature in air and resulted in the formation of 2aa in
99% (883 mg) isolated yield.
Table 2. Pd-catalysed cross-coupling between (hetero)aryl halides 1 and organolithium reagents on water, at RT and under air.[a]
Pd[P(t-Bu)3]2
RT, under air, 20 s
1a: 1-Bromonaphthalene; 1b: C6H5Br; 1c: 2-MeOC6H4Br; 1d: 4-MeOC6H4Br; 1e: 3-ClC6H4Br; 1f: 4-ClC6H4Br;
X
R
1g: 3-CF3C6H4Br; 1h: 4-FC6H4Br; 1i: 4-MeC6H4Br; 1j: 2-EtC6H4Br; 1k: 4-C6H5CH2C6H4Br; 1l: 4-Me2NC6H4Br;
1m: 2-(4-Bromophenyl)-1,3-dioxolane; 1n: 3-Bromothiophene; 1o: 5-Bromo-N-methylindole; 1p: 2-Bromopyridine;
1q: 4-Bromoisoquinoline; 1r: 2-Bromoquinoline; 1s: 2-Bromofluorene; 1t: 2-Bromonaphthalene; 1u: 4-CF3C6H4Cl
+
Het
RLi
Het
H2O, NaCl
1
2
Ph
Me3Si
Ph
OMe
OMe
Ph
Me
4
Et
3
3
[b]
2ab: MeLi, 85% 2ac: EtLi, 70% 2ad: HexylLi, 82% 2ae: s-BuLi, 98% 2af: i-PrLi, 72% 2ag: PhLi, 86% 2ah: Me3SiCH3Li, 98%[b]
PhC CLi
Cl
2ai:
, 17% 2ba: n-BuLi, 90% 2ca: n-BuLi, 70% 2cb: PhLi, 75%
F3C
Cl
F3C
4
4
MeO
Me
Cl
Ph
MeO
MeO
MeO
MeO
Ph MeO
Ph
3
3
3
2da: MeLi, 70% 2db: HexylLi, 82% 2dc: s-BuLi, 80% 2dd: n-BuLi, 85% 2de: PhLi, 80% 2df: i-PrLi, 74% 2ea: n-BuLi, 78% 2fa: n-BuLi, 86% 2fb: PhLi, 98% 2ga: PhLi, 77% 2gb: HexylLi, 94%
F3C
F3C
Me
F
F
Ph
Ph
F
Et
F
Me
3
3
3
3
2gc: s-BuLi, 80% 2gd: n-BuLi, 81% 2ha: EtLi, 80% 2hb: s-BuLi, 94% 2hc: n-BuLi, 90% 2hd: PhLi, 98% 2ia: n-BuLi, 75% 2ja: MeLi, 70% 2jb: s-BuLi, 98% 2jc: n-BuLi, 98% 2jd: PhLi, 98%
Ph
3
3
O
O
Ph
Ph
Ph
4
Me2N
N
Me
3
3
N
3
S
N
Ph
2je: HexylLi, 94% 2ka: n-BuLi, 88%[b] 2kb: s-BuLi, 81%[b] 2kc: EtLi, 86%[b] 2la: n-BuLi, 61%[b] 2ma: n-BuLi, 84%[b] 2na: n-BuLi, 75% 2oa: n-BuLi, 72% 2pa: PhLi, 90% 2qa: PhLi, 75%
SiMe3
3
4
4
F3C
F3C
3
3
N
3
2ra: n-BuLi, 68% 2sa: n-BuLi, 86%[b] 2sb: Me3SiCH3Li, 78%[b] 2ta: n-BuLi, 93% 2tb: HexylLi, 91% 2ua: n-BuLi, 53% 2ub: n-BuLi, 41%
[a] Isolated yield; 0.2 mmol 1 in 1 mL deionized water (pH 6.0), 1 equiv. NaCl, 1.1 equiv RLi, 2.5 mol% Pd-catalyst. [b] 2.2 equiv RLi.
To summarize, a practical and scalable protocol for performing
Acknowledgements
direct and fast (20 s reaction time) Pd-catalysed Csp3–Csp2,
Csp2–Csp2, and Csp–Csp2 cross-coupling reactions between
organolithiums and a variety of (hetero)aryl halides, at RT and
under air, and using bulk water as a non-innocent reaction
medium and NaCl as a cheap additive, has been developed.
Efforts towards improving functional group tolerance are
underway and will be reported in due course.
Interuniversity Consortium C.I.N.M.P.I.S., and the University of
Bari (code: capriati005057Prin15) are gratefully acknowledged
for supporting this work. The authors are also indebted to
Albermarle for the generous gift of organolithium reagents.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812537
Angewandte Chemie International Edition
COMMUNICATION
S. M. García, D. Tagarelli, P. Vitale, F. M. Perna, V. Capriati,
ChemSusChem 2018, 11, 3495; h) L. Cicco, N. Ríos-Lombardía, M. J.
Rodríguez-Álvarez, F. Moris, F. M. Perna, V. Capriati, J. García-Álvarez,
J. González-Sabín, Green Chem. 2018, 20, 3468; i) M. J. Rodríguez-
Álvarez, J. García-Álvarez, M. Uzelac, M. Fairley, C. T. O’Hara, E.
Hevia, Chem. Eur. J. 2018, 24, 1720; j) B. Saavedra, J. M. Pérez, M. J.
Rodríguez-Álvarez, J. García-Álvarez, D. J. Ramón, Green Chem.
2018, 20, 2151.
Keywords: organolithium compounds • cross-coupling reactions
• water chemistry • deep eutectic solvents • sustainable
chemistry
[1]
[2]
J. A. Gladysz, M. Bochmann, D. L. Lichtenberger, L. S. Liebeskind, T. J.
Marks, D. A. Sweigart, Organometallics 2010, 29, 5737.
H. J. Reich, Chem. Rev. 2013, 113, 7130; b) V. Capriati, F. M. Perna, A.
Salomone, Dalton Trans. 2014, 43, 14204; c) M. Shimizu, in Lithium
Compounds in Organic Synthesis – From Fundamentals to Applications
(Eds.: R. Luisi, V. Capriati), Wiley-VCH, Weinheim, 2014, ch. 6, p. 463.
a) M. Yamamura, I. Moritani, S. Murahashi, J. Organomet. Chem. 1975,
91, C39; b) S. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, K.
Kondo, J. Org. Chem. 1979, 44, 2408.
[8]
a) A. Krasovskiy, C. Duplais, B. H. Lipshutz, J. Am. Chem. Soc. 2009,
131, 15592; b) N. A. Isley, F. Gallou, B. H. Lipshutz, J. Am. Chem. Soc.
2013, 135, 17707; c) B. H. Lipshutz, S. Ghorai, Green Chem. 2014, 16,
3660; d) F. Zhou, C.-J. Li, Nat. Commun. 2014, 5, 4524; e) A.
Bhattacharjya, P. Klumphu, B. H. Lipshutz, Nat. Commun. 2015, 6,
7401; f) S. Handa, Y. Wang, F. Gallou, B. H. Lipshutz, Science 2015,
349, 1087; g) L. Cicco, S. Sblendorio, R. Mansueto, F. M. Perna, A.
Salomone, S. Florio, V. Capriati, Chem. Sci. 2016, 7, 1192; h) G.
Dilauro, M. Dell’Aera, P. Vitale, V. Capriati, F. M. Perna, Angew. Chem.
Int. Ed. 2017, 56, 10200; Angew. Chem. 2017, 129, 10334; for reviews:
i) A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725; j) R. N. Butler, A.
G. Coyne, Chem. Rev. 2010, 110, 6302; k) R. N. Butler, A. G. Coyne,
Org. Biom. Chem. 2016, 14, 9945; l) F. Zhou, C.-J. Li, Chem. Sci. 2018,
DOI: 10.1039/C8SC04271C.
[3]
[4]
a) A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi, J. Yoshida, Angew.
Chem. Int. Ed. 2010, 49, 7543; Angew. Chem. 2010, 122, 7705; b) A.
Nagaki, Y. Moriwaki, S. Haraki, A. Kenmoku, N. Takabayashi, A,
Hayashi, J. Joshida, Chem. Asian J. 2012, 7, 1061.
[5]
Selected publications: a) M. Giannerini, M. Fañanás-Mastral, B. L.
Feringa, Nat. Chem. 2013, 5, 667; b) V. Hornillos, M. Giannerini, C. Vila,
M. Fañanás-Mastral, B. L. Feringa, Org. Lett. 2013, 15, 5114; c) M.
Giannerini, V. Hornillos, C. Vila, M. Fañanás-Mastral, B. L. Feringa,
Angew. Chem. Int. Ed. 2013, 52, 13329; Angew. Chem. 2013, 125,
13571; d) C. Vila, M. Giannerini, V. Hornillos, M. Fañanás-Mastral, B. L.
Feringa, Chem. Sci. 2014, 5, 1361; e) V. Hornillos, M. Giannerini, C.
Vila, M. Fañanás-Mastral, B. L. Feringa, Chem. Sci. 2015, 6, 1394; f) D.
Heijnen, J. P. Gualtierotti, V. Hornillos, B. L. Feringa, Chem. Eur. J.
2016, 22, 3991; g) E. B. Pinxterhuis, M. Giannerini, V. Hornillos, B. L.
Feringa, Nat. Commun. 2016, 7, 11698; h) D. Heijnen, F. Tosi, C. Vila,
M. C. A. Stuart, P. H. Elsinga, W. Szymanski, B. L. Feringa, Angew.
Chem. Int. Ed. 2017, 56, 3354; Angew. Chem. 2017, 129, 3402; for
reviews, see: i) V. Pace, R. Luisi, ChemCatChem 2014, 6, 1516; j) J. D.
Firth, P. O’Brien, ChemCatChem 2015, 7, 395.
[9]
a) E. Massolo, S. Palmieri, M. Benaglia, V. Capriati, F. M. Perna, Green
Chem. 2016, 18, 792; b) D. Brenna, E. Massolo, A. Puglisi, S. Rossi, G.
Celentano, M. Benaglia, V. Capriati, Beilstein J. Org. Chem. 2016, 12,
2620; c) P. Vitale, V. M. Abbinante, F. M. Perna, A. Salomone, C.
Cardellichio, V. Capriati, Adv. Synth. Catal. 2017, 359, 1049; d) P.
Vitale, F. M. Perna, G. Agrimi, I. Pisano, F. Mirizzi, R. V. Capobianco, V.
Capriati, Catalysts 2018, 8, 55.
[10] For selected reviews, see: a) Q. Zhang, K. de Oliveira Vigier, S. Royer,
F. Jérôme, Chem. Soc. Rev. 2012, 41, 7108; b) M. Francisco, A. van
den Bruinhorst, M. C. Kroon, Angew. Chem. Int. Ed. 2013, 52, 3074;
Angew. Chem. 2013, 125, 3152; c) E. L. Smith, A. P. Abbott, K. S.
Ryder, Chem. Rev. 2014, 114, 11060; d) D. A. Alonso, A. Baeza, R.
Chinchilla, G. Guillena, I. M. Pastor, D. J. Ramón, Eur. J. Org. Chem.
2016, 612.
[6]
[7]
For recent review/concept articles dealing with the chemistry of polar
organometallics in unconventional reaction media, see: a) J. García-
Álvarez, E. Hevia, V. Capriati, Eur. J. Org. Chem. 2015, 6779; b) J.
García-Álvarez, E. Hevia, V. Capriati, Chem. Eur. J. 2018, 24, 14854.
a) C. Vidal, J. García-Álvarez, A. Hernán-Gómez, A. R. Kennedy, E.
Hevia, Angew. Chem. Int. Ed. 2014, 53, 5969; Angew. Chem. 2014,
126, 6079; b) V. Mallardo, R. Rizzi, F. C. Sassone, R. Mansueto, F. M.
Perna, A. Salomone, V. Capriati, Chem. Commun. 2014, 50, 8655; c) F.
C. Sassone, F. M. Perna, A. Salomone, S. Florio, V. Capriati, Chem.
Commun. 2015, 51, 9459; d) C. Vidal, J. García-Álvarez, A. Hernán-
Gómez, A. R. Kennedy, E. Hevia, Angew. Chem. Int. Ed. 2016, 55,
16145; Angew. Chem. 2016, 128, 16379; e) L. Cicco, M. J. Rodríguez-
Álvarez, F. M. Perna, J. García-Álvarez, V. Capriati, Green Chem. 2017,
19, 3069; f) F. Messa, S. Perrone, M. Capua, F. Tolomeo, L. Troisi, V.
Capriati, A. Salomone, Chem. Commun. 2018, 54, 8100; g) G. Dilauro,
[11] a) A. S. Dallas, K. V. Gothelf, J. Org. Chem. 2005, 70, 3321; b) F.
Christoffel, T. R. Ward, Catal. Lett. 2018, 148, 489.
[12] a) J. E. Bäckvall, B. Åkermark, S. O. Ljunggrgren, J. Am. Chem. Soc.
1979, 101, 2411; b) C. Amatore, A. Jutand, Acc. Chem. Res. 2000, 33,
314; c) X. Lu, Topics in Catalysis 2005, 35, 73; d) S. Kozuch, C.
Amatore, A. Jutand, S. Shaik, Organometallics 2005, 24, 2319; e) C.
Amatore, A. Jutand, G. Le Duc, Angew. Chem. Int. Ed. 2012, 51, 1379;
Angew. Chem. 2012, 124, 1408; f) K. Böck, J. E. Feil, K. Karaghiosoff,
K. Koszinowski, Chem. Eur. J. 2015, 21, 5548; g) M. Kolter, K. Böck, K.
Karaghiosoff, K. Koszinowski, Angew. Chem. Int. Ed. 2017, 56, 13244;
Angew. Chem. 2017, 129, 13427.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812537
Angewandte Chemie International Edition
COMMUNICATION
Water chemistry
Layout 1:
COMMUNICATION
Salt water heals everything! Water
with added NaCl was a very effective
reaction medium for performing direct
and fast (within 20 s) Pd-catalysed
cross-coupling reactions between
Giuseppe Dilauro, Andrea Quivelli,
Paola Vitale, Vito Capriati*, and Filippo
Maria Perna
Page No. – Page No.
organolithiums and
(hetero)aryl halides,
temperature and under air. Catalyst
and water recyclability and reusability
were added advantages of the
proposed protocol.
a
variety of
at room
Water
and
Sodium
Chloride:
Essential Ingredients for Robust and
Fast Pd-catalysed Cross-Coupling
Reactions between Organolithiums
and (Hetero)aryl halides
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
Page No. – Page No.
((Insert TOC Graphic here))
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.