A Zinc Catalyzed C(sp3)?C(sp2) Suzuki–Miyaura Cross-Coupling Reaction Mediated by Aryl-Zincates

Article abstract of DOI:10.1002/chem.201704170

The Suzuki–Miyaura (SM) reaction is one of the most important methods for C?C bond formation in chemical synthesis. In this communication, we show for the first time that the low toxicity, inexpensive element zinc is able to catalyze SM reactions. The cross-coupling of benzyl bromides with aryl borates is catalyzed by ZnBr₂, in a process that is free from added ligand, and is compatible with a range of functionalized benzyl bromides and arylboronic acid pinacol esters. Initial mechanistic investigations indicate that the selective in situ formation of triaryl zincates is crucial to promote selective cross-coupling reactivity, which is facilitated by employing an arylborate of optimal nucleophilicity.

Full text of DOI:10.1002/chem.201704170

A Journal of
Accepted Article
Title: A Zinc Catalyzed C(sp3)-C(sp2) Suzuki-Miyaura Cross-Coupling
Reaction Mediated by Aryl-Zincates
Authors: Michael Ingleson, Richard Procter, Jay Dunsford, Richard
Layfield, Philip Rushworth, and David Hulcoop
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To be cited as: Chem. Eur. J. 10.1002/chem.201704170
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A Zinc Catalyzed C(sp3)-C(sp2) Suzuki-Miyaura Cross-Coupling
Reaction Mediated by Aryl-Zincates
Richard J. Procter[a], Jay J. Dunsford[a], Philip J. Rushworth[b], David G. Hulcoop[b], Richard A. Layfield[a]
and Michael J. Ingleson[a]*
Abstract: The Suzuki-Miyaura (SM) reaction is one of the most
important methods for C-C bond formation in chemical synthesis. In
this communication, we show for the first time that the low toxicity,
inexpensive element zinc is able to catalyze SM reactions. The cross
coupling of benzyl bromides with aryl-borates is catalyzed by ZnBr2,
in a process free from added ligand, and that is compatible with a
range of functionalized benzyl bromides and aryl boronic acid
pinacol esters. Initial mechanistic investigations indicate that the
selective in-situ formation of triaryl zincates is crucial to promote
selective cross-coupling reactivity, which is facilitated by employing
an arylborate of optimal nucleophilicity.
The selective formation of carbon-carbon bonds is arguably the
most important transformation in synthetic chemistry. Among the
most widely used C-C bond forming reactions is the Suzuki-
Miyaura (SM) cross coupling reaction,[1,2] which is even utilized
on large scale in industry.[3] This powerful method couples a
Scheme 1. Zinc compounds in “catalyst-free” coupling reactions.
boron based organic nucleophile with an organic electrophile,
typically catalyzed by Pd or Ni compounds.[4] Recently, catalysts
based on other metals, particularly less toxic metals (relative to
Pd/Ni),[5] e.g. copper[6] and iron (which has the lowest toxicity
use stoichiometric (or super-stoichiometric) quantities of zinc
rating),[7] that offer alternative reactivity profiles, and/or reduced
reagents. The use of sub-stoichiometric zinc compounds in C-C
coupling is extremely rare, with the only example, to the best of
costs, have gained increasing attention. However, zinc catalyzed
our knowledge, being the coupling of alkyl Grignard reagents
SM reactions are, to the best of our knowledge, unknown. This
with α - hydroxy ester triflates catalyzed by ZnCl2 (Scheme
1c).[13] We sought to develop a catalytic in zinc cross coupling
is despite the attractive features of zinc which include: (i) low
toxicity (in contrast to Ni compounds, zinc has the same toxicity
rating as iron),[5] and (ii) relatively high abundance, thus zinc
reaction that uses aryl boron nucleophiles. This requires an
compounds are inexpensive and have low supply risk.[8]
arylborate able to convert zinc halide by-products from cross
coupling back to arylzinc species that are effective for cross
The use of stoichiometric organozinc reagents in coupling
coupling with organic electrophiles. Herein we realize this goal
Negishi reaction.[9] More recently, stoichiometric organozinc
using readily accessible arylborate nucleophiles derived from
reactions is well established, particularly the Pd catalyzed
aryl boronic acid pinacol esters, with ZnBr2 proving an effective
require transition metal catalysts.[10] Of specific relevance to this
catalyst for coupling these arylborates with benzyl halides.
reagents have been used in coupling reactions that do not
While neutral aryl-boranes exchange aryl for alkyl on
reaction with dialkylzinc reagents,[14,15] in order to transmetallate
the presence of excess Et2Zn (Scheme 1a). The proposed
work is the coupling of arylboronic acids with benzylbromides in
to zinc halides more strongly nucleophilic aryl-boranes are
mechanism involves a zinc cation activating benzyl bromides for
required.[16,17] Attempts using aryl boronic esters activated by
alkoxides led to transfer of the alkoxide group to zinc in
preference to the aryl group (see Figure S2). In contrast, the
lithium borate, 1a (Scheme 2), selectively and rapidly (< 30 min
for complete consumption of 1a) transfers an aryl group to zinc
dihalides (halide = Br or Cl) in ether solvents, as indicated by the
formation of tert-butylboronic acid pinacol ester (tBuBPin) by
NMR spectroscopy (no PhBPin is observed precluding Zn-tBu
formation). An alternative pathway, rapid alkyl transfer from 1a
to form Zn-Bu species followed by rapid reaction of these with
ArylBPin to form Aryl-Zn species is precluded based on the slow
reaction between ZnEt2 and ArylBpin (< 5 % aryl transfer after
30 mins).
SN2 substitution.[11] Diaryl zinc species have also been reacted
with alkyl halides (including benzylic) to form C(sp2)–C(sp3)
bonds in the abscence of a catalyst, provided the reaction was
carried out in weakly-coordinating aromatic solvents
(Scheme1b).[12] These recent developments, while notable, all
[a]
[b]
R. J. Procter, Dr. J. J. Dunsford, Prof. Dr. R. A. Layfield, Dr. M. J .
Ingleson
School of Chemistry, The University of Manchester, Manchester
M13 9PL, U.K.
michael.ingleson@manchester.ac.uk
Dr. P. J. Rushworth, Dr. D. G. Hulcoop
Research and Development, GlaxoSmithKline, Gunnelswood Road,
Stevenage SG1 2NY, U.K.
With an effective boron to ZnX2 transmetallating agent in
hand the transmetallation from boron to zinc in arene solvents
was attempted, but it did not proceed significantly being
hindered by the low solubility of the aryl borate reagent and zinc
halides. Arene solvents were essential in previous work coupling
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/....
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10.1002/chem.201704170
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stoichiometric Ar2Zn with alkyl halides, whereas in ether solvents
coupling was effectively quenched.[12] By performing the
transmetallation in cyclopentyl methyl ether (CPME) and then
replacing CPME with benzene, the arylzinc product reacted with
3-methoxybenzyl bromide (2a) to generate the desired product
(3a) within 1 h at 20oC. Subsequently, we found that using 10
mol% of zinc dihalide both steps can be performed in CPME,
with heating enabling the cross coupling step (Scheme 2), albeit
with a lower hetero:homo coupling ratio. In contrast, using
ArylBPin / ZnEt2 mixtures with 2a as the electrophile led to
minimal C(sp2)-C(sp3) cross coupling after 18 h at 60oC.
Table 1. Optimization and impurity catalysis controls
Entry
Solvent
THF
T
catalyst
3b
/ %a
4b
/ %a
/ °C
(x mol%)
1
2
60
75
ZnBr2 (10)
ZnBr2 (10)
47
70
3
3
Benzene :
THF 10:1
3
4
Dioxane
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
60
60
80
60
60
60
60
60
60
60
ZnBr2 (10)
ZnBr2 (10)
86
90
87
0
1
1
5
ZnBr2 (10)
3
6
No catalyst
CuBr (13)
16
26
27
8
7
45
26
84
93
<1
47
Scheme 2. Transmetallation followed by cross-coupling
8
NiBr2(PPh3)2 (3)
FeBr2 (11)
9
The transmetallation and cross-coupling steps in ether
solvents was optimized using 4-fluorobenzyl bromide, 2b
(enabling quantitative in-situ analysis by 19F NMR spectroscopy).
This revealed that lower temperatures and other ether solvents
resulted in high selectivity for heterocoupling (see Table 1). It is
noteworthy that successful cross coupling was observed using
dioxane as the solvent (entry 3), whereas ZnPh2 effectively does
not undergo cross coupling with benzylbromides in dioxane even
at 60 °C over 18 h.[11] While highly selective cross coupling was
observed in dioxane and 2-MeTHF, 2-MeTHF was utilized for
this study due to its superior safety profile. Control reactions
were performed next to examine the possibility of trace metal
catalysis.[18] ZnBr2 obtained from multiple sources and of
different purity (including 99.999% purity) produced similar
coupling outcomes. When the reaction is performed without
ZnBr2 no 3b is formed, with only minor homocoupling (4b)
observed (entry 6). Catalysis by trace copper or nickel impurities
is disfavored on the basis of lower hetero- : homo-coupling
selectivity (entries 7 and 8). FeBr2 was examined and significant
heterocoupling was observed (entry 9). However, FeBr2 is
precluded as a “trace metal catalyst” in this chemistry due to
significant reactivity differences compared to ZnBr2 (e.g. FeBr2 is
an effective catalyst for heterocoupling using 1a and
arylGrignard reagents, whereas ZnBr2 does not couple
arylGrignard reagents with benzylbromides, see SI for further
10
11
12b
Pd(PPh3)4 (3)
MgBr2 (10)
ZnBr2 (10)
2
12
<1
aBy 19F NMR spectroscopy and GCMS. busing Li[nBuB(Pin)Ph], 5, instead of
1a.
Optimization of the boron nucleophile also was explored
and while the nbutyl congener of tbutyl borate 1a, i.e.
Li[nBuB(Pin)Ph], 5, cleanly formed 3b the reaction was slower
than that using 1a (entry 12). In contrast, using the alternative
phenyl source Na[BPh4] led to minimal conversion to 3b after 18
h (< 15 % 3b, see SI). Finally, 1.5 eq. of 1a was found to be
optimal (lower equivalents of 1a did not lead to full consumption
of the electrophile).
This zinc catalyzed cross-coupling was compatible with
electron withdrawing and electron donating groups (Table 2). It
was also tolerant of halide, CF3, OCF3, alkyl, ether, thioether and
heteroaryl groups with excellent heterocoupling selectivity
throughout. Electron withdrawing groups on the arylborate, e.g.
p-(OCF3), are compatible but result in a slower reaction (only
30 % heterocoupling after 24 h), so need longer reaction times.
While ketone and aldehyde functional groups proved to be
incompatible, esters and acetals were both amenable. Benzyl
chlorides reacted slower than the analogous bromides, as did 2o
benzyl electrophiles, however, both are also viable substrates if
longer reaction times are used. Bromodiphenylmethane and
methylallyl bromide were also effectively cross-coupled,
however, octylbromide and cycloheptylbromide were not
amenable. The formation of 3o was highly selective (> 95 %)
with minimal products from cine or tele substitution observed,
discussion).
A Pd catalyst also gave high heterocoupling
selectivity (entry 10). However, in the coupling of 4-
bromobenzylbromide (an electrophile containing both an aryl C-
Br and benzylic C-Br bond) with 1a, ZnBr2 selectively couples
through the benzylic carbon. In contrast, under identical
conditions Pd(PPh3)4 cross-couples through both the C(sp2)-Br
and the C(sp3)-Br, thus precluding Pd impurities as the catalyst
in this protocol (see SI). Finally, under these conditions MgBr2
led to no heterocoupling (entry 11). These results strongly
support a zinc catalyzed cross coupling between 1a and 2b.
indicating
an
organometallic
ipso
coupling
process
dominates.[10g] The observed scope is consistent with an SN2
mechanism and the minor amounts of homocoupling observed
(< 5 %) is attributed to a zinc free reaction based on Table 1
entry 6. Radical scavengers such as 9,10-dihydroanthracene
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(used in zinc mediated radical borylations),[19] and styrene (a
scavenger used in radical reactions involving arylborates)[20] did
not inhibit heterocoupling.
To determine if an aryl group can be transferred from 1a to a
diarylzinc species, equimolar ZnPh2 and 1a were reacted. This
resulted in slow (at 20oC) transfer to form [ZnPh3]- (with a
diagnostic δ13C = 168.8 for the ipso Cphenyl in 2-MeTHF)[24] and
tBuBpin. At 60°C approximately 2 h were required for formation
of [ZnPh3]- from ZnPh2 and 1a. Li[ZnPh3], synthesized from
ZnPh2 and one eq. of PhLi has a closely comparable δ13Cipso for
the Zn-Ph moiety (169.5 ppm in 2-MeTHF). Transmetallation still
proceeds in the presence of LiBr, for example using a 1:2
mixture of ZnPh2 : LiBr 35 % aryl transfer from 1a to zinc occurs
after 1 h at 60oC, thus aryl transfer to {[PhxZnBry]-}n species does
occur. Li[ZnPh3] only interacts weakly with 1 eq. of LiBr (as
indicated by very minor changes in the 1H and 13C NMR
resonances, max ∆δ = 0.02 ppm, addition of a second eq. of LiBr
results in no observable ∆δ). As [Ar4Zn]2- are documented,[24,25]
attempts to form [Ph4Zn]2- using 1a were explored. However, the
addition of 1a to [Ph3Zn]- (made in-situ) did not lead to any
observable aryl transfer (by NMR spectroscopy) disfavoring
formation of [Ph4Zn]2- under these conditions. In our hands
attempts to crystallise these zincates failed, nevertheless, the
above reactions indicate that a major Zn species present during
catalysis is [ZnPh3]-. However, [PhxZnBry]n- (x+y = 3 or 4, n = 1
or 2, y≥1) will also be present and presumably will increase in
concentration as catalysis proceeds due to the formation of LiBr
as a by-product from cross coupling. It is notable that 1a / ZnX2
does not produce any observable [Ph4Zn]2- in contrast to using
PhLi, thereby using borate 1a allows [Ar3Zn]- to be selectively
accessed without any dianioic zincate formation.[24] It is also
notable that Na[BPh4] gives drastically different transmetallation
outcomes to 1a, as it does not transfer an aryl to ZnPh2 in 2-
MeTHF (at 20oC or 60oC), and thus does not produce any
observable [Ph3Zn]-. A relative nucleophilicity scale in 2-MeTHF
for these nucleophiles is shown in Scheme 4, with 1a uniquely
positioned between the monoanionic triaryl and dianionic
tetraaryl zincates.
Table 2. Substrate scope for the zinc catalyzed C(sp3)-C(sp2) coupling
aWith benzyl chloride. b72 hours.
With a closed shell mechanism favored and neutral di
arylzinc reagents precluded as the active species (as ZnPh2 and
2a do not cross-couple in dioxane)[11] the formation of anionic
arylzincates from 1a was explored in 2-MeTHF. Anionic zincates
are more nucleophilic than Ar2Zn species and are often more
effective in the transfer of aryl groups to electrophiles,[21] e.g.
[tBu2PhZn]Li cleanly arylates MeI.[22] To assess for zincate
formation two eq. of 1a were reacted with ZnBr2 at 20oC, which
in
<
10 mins had completely formed tBuBPin (by NMR
spectroscopy) indicating transfer of two eq. of phenyl to zinc.
The likely composition of the ensuing zincate species will
predominantly be of the form {[PhxZnBry]-}n (x+y = 3 n = 1 or
higher aggregates), although only a single set of 1H and 13C
phenyl resonances were observed which is consistent with rapid
exchange on the NMR timescale (as is the case throughout
these experiments).[23] The zincate assignment is supported by
significant changes in the 1H and 13C{1H} NMR spectra on
addition of one eq. of LiBr to ZnPh2, whereas a second eq. of
LiBr results in only very minor chemical shift changes (indicating
minimal formation of [PhxZnBry]2- (x+y = 4) species).
Scheme 4: Relative aryl nucleophilicity (in 2-MeTHF)
The stoichiometric coupling reactivity of various zincates with
2b was assessed to identify if any lead to heterocoupling. In
each case benzylbromide 2b was combined with a zincate
mixture containing a specific ratio, e.g. ZnPhyBrx, generated by
combining ZnPh2 (or ZnBr2) with PhLi (or 1a) and LiBr. On
combining [ZnPh4]2- (formed from PhLi and ZnPh2)[24] and 2b in
2-MeTHF, 2b was consumed within 20 min at 25oC. However,
this led exclusively to homocoupled product 4b (Table 3, entry 1).
Therefore for selective heterocoupling [Ar4Zn]2- species have to
be avoided, presumably as these are more reducing thus lead to
single electron transfer reactivity. In contrast, [ZnPh3]- (made
from PhLi and ZnPh2) on combination with 2b led to
predominantly heterocoupling (entry 2). Repeating in the
presence of LiBr also led to formation of [ZnPh3]- (by comparable
δ13C for the ipso Cphenyl, entry 4) and a comparable coupling
Scheme 3. Reaction outcomes between 1a and ZnBr2
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and further investigations into the detailed mechanism and
scope of the reaction are ongoing.
Table 3. Zincate reactivity with 2b
Acknowledgements
13C
Temp
/ °C
We acknowledge the ERC (Grant Number 305868) the EPSRC
and GSK for financial support (Case award to RJP). Additional
research data supporting this publication are available as
Supporting Information accompanying this publication.
δ
Entry
x Ph
y Br
3b / %a
4b / %a
(ipso)
1
2
4
3
3
3
2
1
0
0
0
2
2
3
171.4
169.5
168.8
169.4
160.4
158.7
25b
60
60
60
60
60
0
59
69
63
3
100
11
9
3c
4
Conflict of Interest
11
10
0
The authors declare no conflict of interest.
5
6
0
Keywords: cross coupling • alkylation • transmetallation • boron
aYields by 19F NMR spectroscopy and GC-MS, mass balance where
• zincate
appropriate is unreacted 2b. b 20 min c = from ZnPh2 and borate 1a
outcome. Notably, a 1:1 mixture of 1a:ZnPh2 (post heating at
60oC for 18 h) when reacted with 2b produced predominantly 3b,
with a slightly improved hetero:homo coupling ratio (entry 3 vs 2,
[1] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
[2] N. Schneider, D. M. Lowe, R. A. Sayle, M. A. Tarselli, G. A. Landrum, J.
Med. Chem. 2016, 59, 4385.
t
[3] D. Blakemore, in Synthetic Methods in Drug Discovery, Chpt. 1. (Ed. T. J.
Colacot) The Royal Society of Chemistry 2016.
or 4), suggesting that BuBPin may subtly effects the catalytic
process and thus the overall selectivity. A number of mixed
zincates, [PhxZnBry]n- (with δ13C resonances supporting Zn-Br
moieties),[26] were reacted with 2b with reactivity slow at 60 °C
and giving more 4b than 3b (entry 5) or no reaction observed at
all (entry 6). Therefore the triarylzincates appear essential for
leading to significant heterocoupling. This is consistent with the
increased efficacy of 1.5 eq. of 1a relative to 1.1 eq. in the
catalysis as otherwise low activity bromide-zincates will
dominate as the reaction progresses.
[4] (a) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417. (b)
F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270. (c) S. Z. Tasker, E. A.
Standley, T. F. Jamison, Nature 2014, 509, 299. (d) N. Hazari, P. R. Melvin,
M. M. Beromi, Nat. Rev. Chem. 2017, doi:10.1038/s41570-017-0025 (and
references therein).
[5] See the European Medicines Agency ICH guideline Q3D on elemental
impurities (June 2016). Ref: EMA/CHMP/ICH/353369/2013.
[6] For select Cu catalysed C(sp3)-C(sp2) Suzuki-Miyaura coupling reactions
see: (a) C.-T. Yang, Z.-Q. Zhang, Y.-C. Liu, L. Liu, Angew. Chem. Int. Ed.
2011, 50, 3904. (b) Y.-Y. Sun, J. Yi, X. Lu, Z.-Q. Zhang, B. Xiao, Y. Fu,
Chem. Commun. 2014, 50, 11060. (c) P. Basnet, S. Thapa, D. A. Dickie, R.
Giri, Chem Commun. 2016, 52, 11072. For C(sp2)-C(sp2) see (d) Y. Zhou,
W. You, K. B. Smith, M. K. Brown, Angew. Chem. Int. Ed. 2014, 53, 3475
and references therein.
[7] For select Fe catalysed C(sp2)-C(sp3) Suzuki-Miyaura coupling reactions
see: (a) T. Hatakeyama, T. Hashimoto, Y. Kondo, Y. Fujiwara, H. Seike, H.
Takaya, Y. Tamada, T. Ono, M. Nakamura, J. Am. Chem. Soc. 2010, 132,
10674. (b) R. B. Bedford, P. B. Brenner, E. Carter, T. W. Carvell, P. M.
Cogswell, T. Gallagher, J. N. Harvey, D. M. Murphy, E. C. Neeve, J. Nunn,
D. R. Pye, Chem. Eur. J. 2014, 20, 7935. (c) T. Hashimoto, T. Hatakeyama,
M. Nakamura, J. Org. Chem., 2012, 77, 1168. For C(sp3)-C(sp3) see: (d) T.
Hatakeyama, T. Hashimoto, K. K. A. D. S. Kathriarachchi, T. Zenmyo, H.
Seike, M. Nakamura, Angew. Chem. Int. Ed. 2012, 51, 8834. For a recent
overview see: R. B. Bedford, Acc. Chem. Res., 2015, 48, 1485.
Previously, zinc Lewis acids were proposed to activate
benzylbromides by coordination to bromide and thus facilitate
SN2 substitution by arylborates or zincates.[11] To assess if Lewis
acids are present during catalysis, Et3PO was added (using the
conditions from Table 1 entry 4) after 3 h. The 31P{1H} NMR
spectrum showed a downfield shift of 12.44 ppm compared to
free Et3PO, confirming Lewis acidic species are present.
However, this may well be due to lithium Lewis acids as a similar
(∆δ = 13.98 ppm) downfield shift was observed on addition of
Et3PO to LiBr in 2-MeTHF. Furthermore, a 2:1 mixture of
ZnPh2:1a was heated in 2-MeTHF until 1a was consumed,
targeting a 1:1 mixture of Lewis acidic ZnPh2(solvent)n and
zincate [ZnPh3]-. To this mixture was added 2b with heating to
60oC for 1 h leading to poor coupling selectivity (3b:4b of 2.8 : 1).
Therefore under these conditions zinc Lewis acid mediated
[8]
British
http://www.bgs.ac.uk/mineralsuk/statistics/riskList.html
[9] E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821.
Geological
Survey
2015
Risk
List,
coupling is disfavored and
a mechanism involving SN2
[10] For metal catalyst free cross-coupling type reactions using stoichiometric
organozinc reagents: (a) S. Lemaire, I. N. Houpis, T. Xiao, J. Li, E. Digard,
C. Gozlan, R. Liu, A. Gavryushin, C. Diène, Y. Wang, V. Farina, P. Knochel,
Org. Lett. 2012, 14, 1480. (b) H. Minami, X. Wang, C. Wang, M. Uchiyama,
Eur. J. Org. Chem., 2013, 7891. (c) E. Shirakawa, F. Tamakuni, E. Kusana,
N. Uchiyama, W. Konagaya, R. Watabe, T. Hayashi, Angew. Chem. Int. Ed.
2014, 53, 521. (d) P. Quinio, D. S. Roman, T. León, S. William, K.
Karaghiosoff, P. Knochel, Org. Lett. 2015, 17, 4396. (e) K. Okura, E.
Shirakawa, Eur. J. Org. Chem. 2016, 3043. (f) M. Ellwart, I. S. Makarov, F.
Achrainer, H. Zipse, P. Knochel, Angew. Chem. Int. Ed. 2016, 55, 10502.
(g) S. Barroso, S. Lemaire, V. Farina, A. K. Steib, R. Blanc, P. Knochel, J.
Org. Chem. 2016, 81, 2804.
substitution by a triarylzincate is preferred, possibly involving
substrate activation by Li+ salts.
In conclusion, benzyl halides can be coupled with aryl
borates using ZnBr2 as catalyst. To the best of our knowledge
this is the first zinc catalyzed Suzuki – Miyaura reaction. Initial
studies indicate a SN2 mechanism with triarylzincates the key
nucleophiles. Our findings represent an advance in the
development of less toxic, base-metal cross-coupling catalysts
as alternatives to established methodologies using noble metals,
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[11] R. B. Bedford, N. J. Gower, M. F. Haddow, J. N. Harvey, J. Nunn, R. A.
Okopie, R. F. Sankey, Angew. Chem. Int. Ed. 2012, 51, 5435.
[12] J. J. Dunsford, E. R. Clark, M. J. Ingleson, Angew. Chem. Int. Ed. 2015,
54, 5688.
[13] (a) C. Studte, B. Breit, Angew. Chem. Int. Ed. 2008, 47, 5451. (b) G. J.
Brand, C. Studte, B. Breit, B. Org. Lett. 2009, 11, 4668.
[14] M. Srebnik, Tetrahedron Lett. 1991, 32, 2449.
[15] C. Bolm, J. Rudolph, J. Am. Chem. Soc. 2002, 124, 14850.
[16] R. B. Bedford, P. B. Brenner, E. Carter, J. Clifton, P. M. Cogswell, N. J.
Gower, M. F. Haddow, J. N. Harvey, J. A. Kehl, D. M. Murphy, E. C. Neeve,
M. L. Neidig, J. Nunn, B. E. R. Snyder, J. Taylor, Organometallics 2014, 33,
5767.
[17] J. J. Dunsford, E. R. Clark, M. J. Ingleson, Dalton Trans. 2015, 44, 20577.
[18] I. Thomé, A. Nijs, C. Bolm, Chem. Soc. Rev. 2012, 41, 979.
[19] S. K. Bose, K. Fucke, L. Liu, P. G. Steel, T. B. Marder, Angew. Chem. Int.
Ed. 2014, 53, 1799.
[20] C. Sandford, R. Rasappan, V. K. Aggarwal, J. Am. Chem. Soc. 2015, 137,
10100.
[21] For a review see: (a) F. Mongin, A. Harrison-Marchand, Chem. Rev. 2013,
113, 7563. For the reactivity of zincates with Pd see: (b) L. C. McCann, M.
G. Organ, Angew. Chem. Int. Ed. 2014, 53, 4386. (c) T. D. Bluemke, W.
Clegg, P. Garcia-Alvarez, A. R. Kennedy, K. Koszinowski, M. D. McCall, L.
Russo, E. Hevia, Chem. Sci., 2014, 5, 3552.
[22] Y. Kondo, M. Fujinami, M. Uchiyama, T. Sakamoto, J. Chem. Soc. Perkin
Trans. 1, 1997, 799.
[23] A. J. Roberts, A. R. Kennedy, R. McLellan, S. D. Robertson, E. Hevia, Eur.
J. Inorg. Chem. 2016, 55, 4752.
[24] A. Hernán-Gómez, E. Herd, M. Uzelac, T. Cadenbach, A. R. Kennedy, I.
Borilovic, G. Aromı, E. Hevia, Organometallics 2015, 34, 2614.
́
[25] W. Clegg, B. Conway, E. Hevia, M. D. McCall, L. Russo, R. E. Mulvey, J.
Am. Chem. Soc. 2009, 131, 2375.
[26] L. Jin, C. Liu, J. Liu, F. Hu, Y. Lan, A. S. Batsanov, J. A. K. Howard, T. B.
Marder, A. Lei, J. Am. Chem. Soc., 2009, 131, 16656
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10.1002/chem.201704170
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R. J. Procter, J. J. Dunsford, P. J.
Rushworth, D. G. Hulcoop, R. A.
Layfield and M. J. Ingleson*
Page No. – Page No.
A Zinc Catalyzed C(sp3)-C(sp2)
Suzuki-Miyaura Cross-Coupling
Reaction Mediated by Aryl-Zincates
The cross coupling of benzyl bromides with aryl-borates is catalyzed by ZnBr2, in a
process that is compatible with a range of functionalized benzyl bromides and aryl
boronic acid pinacol esters. Mechanistic investigations indicate that the in-situ
formation of triaryl zincates is crucial to promote selective cross-coupling reactivity,
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