Angewandte
Communications
Chemie
micellar conditions.[9c] All of these products could not be
be improved in DES from 65 to 78%. As testified by the
prepared by subjecting n-BuLi, in place of 2a, to the Pd-
catalyzed cross-coupling reactions “on water”, as reported.[12g]
Different (hetero)aromatics, like 1-bromonaphtalene (1o),
ethyl 5-bromobenzofuran-2-carboxylate (1p), 3-bromoquino-
line (1q) and 2-bromo-5-chlorothiophene (1r), proved to be
competent partners as well, and were efficiently cross-
coupled with 2a, delivering the corresponding educts 17–20
in a 65–98% yield. On the other hand, the aryl bromides with
an increased hydrophilicity bearing a free carboxy, an amino,
or an hydroxyl group on the aromatic ring, reacted poorly
(1s,t) (21,22: 10–30% yield), or did not react at all (1u,v) with
2a. The same also held for 6-bromonicotinaldehyde (1w),
which was quantitatively recovered at the end of the process,
whereas 5-bromopyrimidine (1x) furnished the educt 26 in
a 30% yield. However, when the reaction was alternatively
carried out in the eutectic mixture ChCl/urea (1:2 molmolÀ1)
at 608C in air, under heterogeneous conditions, all of the
desired products 21–26 could be isolated in a 35–78% yield.
Phenolic derivative 24 has been shown to exhibit significant
cytotoxic activity against two human oral cancer cell lines
(SCC-40 and SCC-29B).[17] By transferring these conditions to
some representative substrates (1c, 1 f, 1j, 1k, and 1m), which
had been previously reacted “on water”, the expected educts
5, 8, 12, 13, and 15 were produced in almost similar yields (72–
90%). Likewise, HexylZnCl (2b), MeZnCl (2c),
Me3SiCH2ZnCl (2d), (4-cyanobutyl)ZnBr (2e), and (4-
ethoxy-4-oxobutyl)ZnBr (2 f) underwent a smooth cross-
coupling reaction “on water”, with functionalized (hetero)-
aryl bromides 1a, 1c, 1g–1i, 1q, and 1y to afford the desired
products 27–41 in a 30–98% yield. Of note, the yields of
compounds 36–40 could be improved considerably from 30–
82% to 72–90% by alternatively working in the ChCl/urea
eutectic mixture.
The secondary alkyl organometallic compounds are
known to undergo cross-coupling with the aryl bromides to
give mixtures of linear and branched products because of
a competitive b-hydride-elimination pathway.[18] Lipshutz and
co-workers detected by NMR no undesired linear products in
the crude reaction mixture by promoting the Pd-catalyzed
coupling between secondary alkyl bromides and aryl halides
in the presence of Zn/TMEDA under micellar conditions.[9c]
To our delight, the effectiveness of such “on water” coupling
reactions was still maintained when using secondary alkylzinc
halides in the absence of additional ligands. Indeed, both i-
PrZnCl (2g) and s-BuZnCl (2h) effectively participated in
the process with 1a, 1c, 1h, and 1j, delivering the educts 42–
47 in very good yields (87–98%). Conjugated nitro-substi-
tuted aryl bromides, like 1l and 1z, and the bromoindole 1aa,
were also good substrates, affording the educts 48–50,
respectively, in a 65–87% yield. It is worth noting that the
conjugate addition to the activated alkene moiety of 1z did
not compete, in contrast to what was observed when using
lithium tetraorganozincates.[19] No cross-coupling was
observed when 3-bromophenol (1v) or the electron-rich 4-
bromoaniline derivative 1ab were reacted with 2h “on
water”. Remarkably, upon switching to the eutectic mixture
ChCl/urea, the desired products 51,52 could be isolated in
a 66–73% yield. The yield of the nitro derivative 48 could also
recent literature, although sharing some physicochemical
properties (e.g., a strong H-bonded network), water and DES
have been proven to be not on the same ground as far as the
reactivity of the organometallic compounds is concer-
ned.[5b,f,12g,20] Thus, they can advantageously and complemen-
tarily be used in organometallic chemistry. Finally, the C(sp2)-
C(sp2) coupling between PhZnCl (2i) and 1a, 1g, 1i, 1q, and
1r also proceeded uneventfully, providing the expected educts
53–57 in a 67–78% yield under the “on water” conditions.
Compounds 53, 56, 57 were also prepared in a 75–80% yield
in ChCl/urea. On the other hand, the electron-poor 2-
pyridylZnBr (2j) resulted a sluggish coupling partner as it
provided in the reaction with 1a the educt 58 in a yield not
higher than 35% in DES.
Both the Pd-catalyst and the DES ChCl/urea or water
could easily be recycled. The cross-coupling of bromoarene
1a with organozinc 2a was chosen as a model reaction, since it
provided educt 3 in 91–98% yield. As for catalyst/DES
recycling, upon completion of the first coupling, the in-flask
extraction with CPME afforded 3 (91% yield, number of
recycles = 0), but it left the Pd catalyst in the eutectic mixture.
Then, upon adding new, fresh reagents (1a and 2a), the
catalyst and DES could be successfully re-used for further
reaction runs. The catalyst remained active for over 7 cycles,
albeit with a drop in the chemical yield of 3 of up to 29% at
the end of the 7th cycle. The strategy for recycling catalyst/
water consisted in removing, after each run, VOCs introduced
with organozinc 2a under reduced pressure, and in adjusting
the pH value of the resulting mixture at about 6 by using
concentrated HCl, leaving the product 3 inside it. The catalyst
retained good catalytic activity over four cycles, and the
overall yield of product 3 was 86% (see ESI for details).
In conclusion, we have shown that the Pd-catalyzed
Negishi coupling of (hetero)aryl bromides with organozinc
halides can be accomplished with a wide substrate scope and
with very good reaction yields (up to 98%), by using bulk
water in the presence of NaCl, or alternatively the environ-
mentally friendly eutectic mixture of ChCl/urea. These
reactions are scalable, and they proceed under remarkably
mild conditions (RTor 608C), with short reaction times (20 s)
in air, in the absence of additional ligands, and with an easy
recycling of both the DES or water and the catalyst. This
simple novel protocol complements the traditional and recent
approaches to perform Negishi coupling, thereby reinforcing
the argument that notoriously moisture-sensitive organome-
tallic reagents can be used under aerobic conditions in protic
bio-based solvents like DESs or water.
Acknowledgements
This work was carried out under the framework of the
National PRIN project “Unlocking Sustainable Technologies
Through
Nature-Inspired
Solvents”
(Code:
2017A5HXFC_002) and it was financially supported by
MUR, and the University of Bari. The authors are also
indebted to Albermarle and to Zeon Europe GmbH for the
generous gift of the organozinc reagents and of a sample of
Angew. Chem. Int. Ed. 2021, 60, 10632 –10636
ꢀ 2021 Wiley-VCH GmbH