Mechanochemical Activation of Zinc and Application to Negishi Cross-Coupling

Article abstract of DOI:10.1002/anie.201806480

A form independent activation of zinc, concomitant generation of organozinc species and engagement in a Negishi cross-coupling reaction via mechanochemical methods is reported. The reported method exhibits a broad substrate scope for both C(sp³)–C(sp²) and C(sp²)–C(sp²) couplings and is tolerant to many important functional groups. The method may offer broad reaching opportunities for the in situ generation organometallic compounds from base metals and their concomitant engagement in synthetic reactions via mechanochemical methods.

Full text of DOI:10.1002/anie.201806480

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Mechanochemical Activation of Zinc and Application to Negishi
Cross-Coupling
Authors: Qun Cao, Joseph L. Howard, Emilie Wheatley, and Duncan L.
Browne
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806480
Angew. Chem. 10.1002/ange.201806480
Link to VoR: http://dx.doi.org/10.1002/anie.201806480
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10.1002/anie.201806480
Angewandte Chemie International Edition
COMMUNICATION
Mechanochemical Activation of Zinc and Application to Negishi
Cross-Coupling
Qun Cao[a], Joseph L. Howard[a], Emilie Wheatley[a] and Duncan L. Browne*[a]
Abstract:
A
form independent activation of zinc, concomitant
reaching opportunities for the in situ generation and use of
organometallic compounds in synthesis from their base metals.
The late-stage modification of organic materials by metal
mediated carbon-carbon bond formation is a ubiquitous strategy
for the discovery of new or improved chemicals in many sectors.4
Key to the adoption of any developed late-stage technique is the
breadth of substrate scope and application, in this regard,
organozinc species are privileged compounds representing a
class of organometallic reagents with excellent functional group
compatibility. Unlike boronic acids, esters and boronates,
organozinc reagents are not widely available commercially and
must be prepared at the point of use. Owing to this limitation, the
Negishi cross-coupling reaction is under-utilised.5 This problem is
further compounded by the tedious preparation of organozinc
species, which can be achieved by several methods (Scheme 1).
generation of organozinc species and engagement in a Negishi cross-
coupling reaction via mechanochemical methods is reported. The
reported method exhibits a broad substrate scope for both Csp3-Csp2
and Csp2-Csp2 couplings and is tolerant to many important functional
groups. The method may offer broad reaching opportunities for the in
situ generation organometallic compounds from base metals and their
concomitant engagement in synthetic reactions via mechanochemical
methods.
The controlled and selective synthesis of carbon based molecules
is a critical endeavor that is key to the discovery of new medicines,
crop protection agents, flavors and fragrances as well as many
more materials with great importance to human quality of life.
Whilst synthetic chemistry as a discipline has a good grasp on
making molecules succumb to synthesis, focus in the modern era
is centered upon achieving sustainable synthesis through
reduced numbers of reaction steps, reduced quantities of waste
and milder reaction conditions.1 Many of these facets can be
achieved by exploring reaction technologies such as photo- or
electrochemistry which are complementary to traditional methods
and allow controlled access to reaction manifolds that were
previously unobtainable. Recently, we and others have been
exploring mechanochemistry as a method to complement the
synthetic toolkit.2 The method of solid state grinding or milling
using electronically-powered devices; mills, is attractive as it a)
negates the requirement for bulk solvent use during the reaction
step and b) provides a reproducible and sustainable energy input
in comparison to a human operated mortar and pestle. Indeed,
Metallation of C-H bonds can be achieved through
transmetallation method, whereby direct deprotonation or
directed-ortho-metallation with organomagnesium or
a
organolithium provides the initial metalation and is followed by
transmetallation to a zinc (II) species (A, Scheme 1).6 Indeed,
such an approach often leads to a loss of the broad functional
group tolerance afforded by organozinc reagents because they
[A] metallation of C-H bonds
- metallation followed by transmetallation - Zn(II)
R1
M
ZnX2
M = Mg or Li
[M]
ZnX
ZnX
H
R
R
R
functional group tolerance
determined by R1-M
R1
H
MX
- direct zincation - Zn(II)
TMPZnCl.LiCl or TMP2Zn
H
R
R
the
crystal
engineering
and
metal-organic-framework
[B] metallation of C-X bonds
communities are far ahead in exploring the potential of this
technique, and have uncovered a wealth of opportunities,
including reduced reaction times, increased ‘space-time yields’,
new polymorphic forms, liquid assisted grinding and the use of
grinding auxiliaries or ‘glidants’.3 As applied to organic synthesis
there are already several examples of reduced reaction times,
altered chemo-selectivity and the ability to synthesise products
that were previously unobtainable.2a However, when and how
these observations will arise is currently not predictable. Herein
we report on the use of mechanochemistry as a technique to
enable the form independent preparation of organozinc species,
from the base metal zinc, and their engagement in
mechanochemical Negishi cross-coupling reactions. The method
is operationally simple and requires no use of inert gases but is
instead conducted in air. The reported method offers broad
- metal/halogen exchange - Zn(II)
M = Mg or Li
R1
M
ZnX2
[M]
ZnX
ZnX
X
functional group tolerance
determined by R1-M
R
R
R
R
R1
X
MX
- direct zincation - Zn(0)
Zn
activated zinc needed
free from ZnO
X
R
[C] generation of activated zinc
- reduction of Zn(II) to Zn(0)*
X
Li, napthalene
R
Zn*
Reike zinc
ZnX
ZnCl2
R
- chemical removal of ZnO layer to generate Zn(0)*
BrCH2CH2Br, TMSCl
physical form of zinc
critical to success:
X
X
ZnX LiCl
R
R
R
R
Zn dust, LiCl, 30-60 oC, THF
dust
granules
flakes
mesh
foil
shot
I2 (5 mol%), DMA, 80 o
Zn dust
C
mossy
wires
powder
ZnX
sheet
[a]
Q. Cao, J. L. Howard, E. Wheatley, Dr. D. L. Browne
School of Chemistry
[D] this work - in situ mechanochemical generation of activated zinc
- form independant activation, concomitant oxidative insertion and subsequent reaction
Cardiff University
Main Building, Park Place, Cardiff CF10 3EQ
E-mail: dlbrowne@cardiff.ac.uk
Supporting information for this article is given via a link at the end of
the document. Information about the data underpinning the results
presented here, including how to access them, can be found in the
Cardiff University data catalogue
[mixer mill]
[mixer mill]
X
Ar
ZnX
R
R
R
catalyst
Ar [X]
Zn
at http://doi.org/10.17035/d.2018.0052918729.
Scheme 1 Formation of Organozinc reagents
This article is protected by copyright. All rights reserved.

10.1002/anie.201806480
Angewandte Chemie International Edition
COMMUNICATION
have been prepared via more reactive organometallic species.
Knochel and coworkers realized a solution to this through direct
zincation of C-H bonds using zinc-amide bases.7
organozinc reagents directly, the subsequent Negishi coupling
was investigated in a one-pot fashion.13 Initial reaction conditions
used bromobenzene as the coupling partner and the Pd-PEPPSI
family of catalysts, which have been reported to possess high
stabilities and exhibit good reactivity for the Negishi coupling.14
Tetrabutylammonium salts were explored as additives for the
mechanochemical Negishi coupling reaction (Scheme 3, entries
3-5), with tetrabutylammonium bromide (TBAB) providing the best
result with a 70% yield.15 A range of polar aprotic additives were
also investigated in the first step, this confirmed DMA as the most
effective, with DMF and NMP performing similarly.
An alternative tactic involves the metalation of C-X bonds (B,
Scheme 1), a strategy where metal-halogen exchange is
particularly popular, but again such an approach leads to a loss
of the broad functional group tolerance afforded by organozinc
reagents.8 More attractively, for C-X bonds, is the direct oxidative
insertion of Zn(0) from an activated zinc metal. Indeed, highly
reactive Rieke zinc can be formed by the reduction of ZnCl2 using
alkali metals and naphthalene, and will undergo oxidative addition
with an alkyl or aryl halide to generate the desired organozinc
species (C, Scheme 1).9 A complementary, and more popular
approach to generate activated zinc metal is to remove zinc oxide
from the metal surface by chemical reaction or entrainment,
typically achieved using chemical additives such as TMSCl, 1,2-
dibromoethane, bromine or iodine.10,11 All of the methods
described for preparing activated zinc require an inert atmosphere,
and those derived form zinc metal are highly dependent on the
physical form of zinc used, with multiple different forms of zinc
commercially available (Scheme 2, and photograph in ESI). We
have identified mechanical activation, by ball-milling, as a general
technique that could simplify and enable organometallic chemistry
by obviating the need for strictly dry solvents and specific base
metal forms whilst providing greater reproducibility in the
generation of these important materials.10k With regards to zinc
chemistry we sought to probe this hypothesis and develop a
method to generate and subsequently use organozinc reagents
(D, Scheme 1). Studies commenced by treating ethyl-4-
bromobutanoate to grinding in the presence of granular zinc (20-
30 mesh). Optimized conditions consisted of milling with 1.1
equivalents of zinc for 4 hours with 1.5 equivalents of DMA which
afforded 76% yield of the dehalogenated, ethylbutanoate (3) after
an acidic quench of the jar contents.17,12 These conditions were
then applied to a further 11 commercially available zinc forms
(Scheme 2). Notably, these forms vary in their particle size, and
consequently both their surface area to volume ratios and zinc
oxide to zinc metal ratio. There appears to be a general trend that
the forms with a lower surface area to volume ratio perform better,
likely attributable to the increased amount of inactive zinc oxide in
the forms with higher surface area to volume ratios. For example,
puriss, shot and mossy perform better than powder, flake and dust.
Having established the conditions required to generate
Step 1
O
O
Zn (20-30 mesh granular) (1.1 equiv)
Br
BrZn
OEt
Br
OEt
additive 1
mixer mill, 30 Hz, 4 h
1
2
Step 2
2
Pd-PEPPSI-IPr(BIAN) [1 mol%]
O
+
4
OEt
additive 2
mixer mill, 30 Hz, 4 h
5
Conv. [wrt%4][a]
Entry
additive 1 [equivs]
additive 2 [equivs]
Yield [%5][a]
59
1
2
DMA (1.5)
-
-
75
49
82
57
17
2
27
DMA (1.5)
TBAB (1.0)
TBACl (1.0)
TBAI (1.0)
TBAB (1.0)
TBAB (1.0)
TBAB (1.0)
TBAB (1.0)
TBAB (1.0)
TBAB (0.25)
TBAB (0.5)
TBAB (1.5)
TBAB (1.5)
TBAB (1.5)
70
3
DMA (1.5)
DMA (1.5)
DMA (1.5)
NMI (1.5)
Dioxane (1.5)
THF (1.5)
NMP (1.5)
DMF (1.5)
DMA (1.5)
DMA (1.5)
DMA (1.5)
DMA (1.5)
DMA (1.5)
15
4
13
5
2
6
39
7
69
82
81
82
78
86
0
47
8
69
9
69
10
11
12
13[b]
14[c]
15
61
67
0
0
0
77 (74)[d]
98
catalyst screen
R
R
R
R
N
N
N
N
R
R
R
R
R
R
MeO
OMe
N
N
Cl Pd Cl
Cl Pd Cl
R
R
N
N
Cl Pd Cl
N
Cl
Cl
Cl
6; R = i-Pr
Pd-PEPPSI-iPr
7; R = i-Pent
8; R = CH(Ph)2
Pd-PEPPSI-iPr*(OMe)
9; R = i-Pr
Pd-PEPPSI-iPr(BIAN)
Pd-PEPPSI-iPent
Conditions as entry 13 but 0.5 mol% catalyst
Entry
Catalyst
Conv. [wrt%4][a]
Yield [%5][a]
O
O
O
H+
16
17
18
19
Pd-PEPPSI-iPr
Pd-PEPPSI-iPr(BIAN)
Pd-PEPPSI-iPr*(OMe)
Pd-PEPPSI-iPent
40
68
26
78
38
64
25
76
Zn (1.1 equiv)
OEt
OEt
OEt
mixer mill, 30 Hz
4 h, DMA (1.5 equiv)
2 mmol
H
Br
ZnBr
3
1
2
Entry
Zn [form]
Hydrolysis Yield [%3][a]
Reaction conditions: Step 1: ethyl 4-bromobutanoate (2 mmol), 20-30 mesh Zn granular
(2.2 mmol), additive 1 as specified, mixer mill, 30 Hz, 4 hours; Step 2: bromobenzene (1
mmol), Pd-PEPPSI-IPr(BIAN)(1 mol%), additive 2 as specified, mixer mill, 30 Hz, 4 hours.
[a] Conversion and yield determined by GC using trifluorotoluene as internal standard.
[b] Zinc omitted from reaction [c] Pd catalyst omitted from reaction [d] Isolated yield.
1
2
3
4
5
6
7
8
9
zinc granular 20-30 mesh
zinc granular 20 mesh
zinc foil, thickness 0.25 mm 99.9%
zinc dust < 10 mm
76
73
72
65
82
82
63
74
61
84
79
69
zinc puriss, ACS reagent > 99.9%
zinc shot, 10 mm (dia), 2 mm (thick), 99.99%
zinc flake, ~ 325 mesh, 99.9%
zinc wire (0.04 in) dia. 99.95%
zinc powder 6 ~ 9 micro 97.5%
zinc, metal (powder)
Scheme 3 Optimization of one-jar, two-step reaction
10
11
12
zinc 99+% mossy
zinc foil, 0.38 mm
[a] Hydrolysis yield were determined by GC using trifluorotoluene as internal standard
[b] Yield of ethyl 4-iodobutanoate was determined by GC after iodometric titration
Scheme 2 Mechanochemical preparation of organozinc reagents.
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10.1002/anie.201806480
Angewandte Chemie International Edition
COMMUNICATION
Increasing the quantity of TBAB to 1.5 equivalents further
improved the yield to 77% (GC) corresponding to a 74% isolated
yield (Scheme 3, entry 15). Notably, omission of zinc (Scheme 3,
entry 13) or omission of palladium catalyst (Scheme 3, entry 14)
from the reaction resulted in none of the desired product
suggesting an innocent role of the grinding vessels and media.16
Finally a screen of four different Pd-PEPPSI catalysts was
undertaken, with Pd-PEPPSI-iPent determined to be the most
effective catalyst under these milling conditions (Scheme 3, Entry
17). With established conditions for the mechanochemical in situ
synthesis of an organozinc species and subsequent Negishi
coupling in a one-pot two-step manner in hand, the applicability
of these conditions to a range of different substrates was explored
(Scheme 4). Initially, formation of organozincs from sp3 hybridized
organobromides and subsequent coupling with sp2 hybridized C-
X coupling partners was investigated. It was found that chloro-,
bromo- and iodoarenes were successfully transformed in good
yields. The excellent functional group tolerance exhibited by
organozinc reagents is demonstrated, with molecules containing
esters, nitriles and ketones achieving high yields. Structures
primed for further derivatization were also synthesized, such as
boronate deriative 14, which could potentially undergo
subsequent Suzuki-Miyaura coupling. Orthogonal coupling, with
selectivity between the C-Br and C-OTs was also demonstrated
through the preparation of tosylate 12. Secondary organozinc
reagents were formed and reacted successfully, as exemplified
by preparation of the cyclohexyl derivatives 15 and 17. Electron-
rich aromatics also participated in the reaction process to furnish
dimethoxy derivative 21 and thiofuran compound 22, albeit in
moderate yields. The possibility of sp2-sp2 coupling was
investigated under similar conditions (Scheme 4).17 With these
conditions a number of biaryl products were successfully
synthesized in good yields. Sterically demanding ortho-
substituted bromoaryls were also competent coupling partners
(31, 35 and 39). Thiophenes (33, 34 and 40) and a pyridine (41)
R
R
Step 1
N
N
1. add reagents to milling jar
2. screw jar closed (finger tight)
3. press play
Br
R
R
alkyl
Zn (20-30 mesh granular)
Cl Pd Cl
ZnBr
Ar
N
alkyl/aryl
alkyl/aryl
or
mixer mill, 30 Hz
[1 mol%]
Cl
Step 2
Ar [X]
4 h, DMA (1.5 equiv)
I
Catalyst
R = i-Pent
Pd-PEPPSI-iPent
[CAS: 1158652-41-5]
1. open jar from Step 1
2. add catalyst and reagents
3. screw jar closed (finger tight)
4. press play
aryl
mixer mill, 30 Hz, 4 h, TBAB
Step 1 - mechanochemical organozinc preparation
Step 2 - mechanochemical Negishi coupling
mechanochemical sp3-sp2 Negishi coupling (1.1 equiv zinc)
OTs
EtO2C
CN
CO2Et
CN
F
BPin
10; 90% [X = Cl]
94% [X = Br]
93% [X = I]
11; 89% [X = Br]
92% [X = I]
12; 95% [X = Br]
13; 88% [X = Br]
14; 63% [X = I]
5; 74% [X = Br]
CN
Cl
Cl
F
F
O
CO2Et
CN
15; 46% [X = Br]
O
CN
17; 72% [X = Br]
CN
16; 54%[a] [X = Br]
19; 82%[b] [X = Br]
20; 47% [X = Br]
18; 77% [X = Br]
Cl
OMe
EtO2C
S
CO2Et
CO2Et
OMe
CN
23; 55%[b] [X = Br]
21; 33% [X = Br]
22; 42% [X = Br]
24; 51% [X = Br]
25; 92% [X = Br]
mechanochemical sp2-sp2 Negishi coupling (2.5 equiv zinc)
O
CN
F
SMe
CO2Et
F
OMe
CN
CO2Et
S
EtO2C
29; 57%[a] [X = Br]
MeO
MeO
NC
32; 51%[a] [X = Br]
33; 72% [X = Br]
28; 42% [X = Br]
27; 98% [X = Br]
26; 79% [X = Cl]
30; 71% [X = Br]
31; 61% [X = Br]
95% [X = Br]
87% [X = I]
CN
CO2Et
CO2Et
CN
CO2Et
CN
CO2Et
N
S
S
OMe
Cl
F
Cl
MeO
NC
34; 85% [X = Br]
35; 45% [X = Br]
36; 63% [X = Br]
37; 62% [X = Br]
38; 90% [X = Br]
39; 71% [X = Br]
40; 86% [X = Br]
41; 97% [X = Br]
[a] 6 h required for step 1; organozinc generation, [b] 3 mmol R1-Br, 3.3 mmol Zn was used for step 1; organozinc generation
Scheme 4 Scope of the mechanochemical Negishi reaction
This article is protected by copyright. All rights reserved.

10.1002/anie.201806480
Angewandte Chemie International Edition
COMMUNICATION
derivative were also prepared, highlighting the applicability of this
method to synthesize substituted heterocycles.
generous support. We thank the Cardiff Catalysis Institute for
providing access to the GC equipment used in this study and in
particularly the expert technical support from Dr Greg Shaw.
Encouraged by the success of this one-pot two step procedure,
we sought to push this methodology further and explore a one-
pot, one step protocol, whereby the organozinc reagent would be
generated and consumed through palladium catalysis all within
the same reaction jar. To bias the system against complex
mixtures, we took advantage of the fact that alkyl organozincs
form more readily than aryl organozinc species.18 Thus dosing
both alkyl and aryl halide coupling partners with zinc, DMA and
Pd-PEPPSI-iPent into the grinding jar along with the grinding ball
and grinding for 8 hours afforded the desired sp3 – sp2 bond
formation (Scheme 5). Excellent yields were obtained for the three
examples explored, demonstrating the ability to perform Negishi
coupling without directly handling organozinc reagents. Moreover,
this has been demonstrated with three different forms of zinc; 20-
30 mesh granular, powder and puriss, all of which lead to the
desired products in excellent yields.
Keywords: ball milling • mechanochemistry • solventless
reactions • organozinc • organometallic
[1]
[2]
For some recent reflections on the discipline of Organic Synthesis see:
P.S. Baran, J. Am. Chem. Soc. 2018, 140, 4751; and the collection of
papers that make up ‘Rosarium Philosophorum – Organic Synthesis’ in
Isr. J. Chem. 2018, 58, 1.
For some recent reviews on mechanochemistry see: a) J. L. Howard, Q.
Cao, D. L. Browne, Chem. Sci. 2018, 9, 3080; b) J. Andersen, J. Mack,
Green Chem. 2018, 20, 1435; c) T. Friščić, I. Halasz, V. Štrukil, M.
Eckert-Maksić, R. E. Dinnebier, ACS Cent. Sci. 2017, 3, 13; d) J. G.
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S. Vyle, P. F. Conlon, M. A. Gîlea, Y. Liang, Beilstein J. Org. Chem. 2018,
14, 955; f) T.-X. Métro, J. Martinez, F. Lamaty, ACS Sustainable Chem.
Eng. 2017, 5, 9599.
[3]
S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić,; F.
Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini,
A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed, D. C. Waddell,
Chem. Soc. Rev. 2012, 41, 413.
R
R
N
N
R
R
Cl Pd Cl
Br
Ar
N
alkyl
[4]
[5]
For an inciteful industrial perspective on late-stage functionalization see:
T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal; S. W. Krska, Chem.
Soc. Rev. 2016, 45, 546.
alkyl
Ar Br
[1 mol%]
Cl
Zn (form), DMA
mixer mill, 30 Hz, 8 h
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3215; b) C. I. Stathakis, S. Bernhardt, V. Quint, P. Knochel, Angew.
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2 Steps in 1 operation - generate & consume organo-zinc
1. add reagents to milling jar
2. screw jar closed (finger tight)
3. press play
EtO2C
CO2Et
CN
5;
10;
11;
78% [powder]
80% [20-30 Granular]
79% [puriss]
74% [powder]
76% [20-30 Granular]
84% [puriss]
96% [powder]
85% [20-30 Granular]
99% [puriss]
[6]
[7]
Scheme 5 One-pot, one-step Negishi reaction
In summary, we have developed a novel method for the synthesis
and subsequent reaction of organozinc species under
mechanochemical conditions, without the need to use inert
atmosphere techniques or dry solvents. Organozincs can be
generated from an alkyl halide irrespective of the physical form of
commercially available zinc metal. A coupling partner could then
be added to the reaction mixture along with a palladium catalyst
and TBAB to perform the Negishi reaction in a one-pot, two-step
process. Most excitingly, these conditions were successfully
modified to realize the direct generation and consumption of
organozinc reagents through a one-pot Negishi coupling process
for the synthesis Csp3 – Csp2 bonds thusrendering it more
operationally simplistic than current procedures.19 The application
of this technique to the generation and use of other organometallic
species is currently underway in our laboratories.
[8]
[9]
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3999; b) C. E. Tucker, T. N. Majid, P. Knochel, J. Am. Chem. Soc., 1992,
114, 3983; c) F. M, Piller, A. Metzger, M. A. Schade, B. A. Haag, A.
Gavryushin, P. Knochel, Chem. Eur. J., 2009, 15, 7192.
a) R. D. Rieke, S. J. Uhm, P. M. Hudnall, J. Chem. Soc., Chem. Commun.
1973, 269b. b) R. D. Rieke, P. T.-J. Li, T. P. Burns, S. T. Uhm, J. Org.
Chem. 1981, 46, 4323; c) L. Zhu, R. M. Wehmeyer, R. D. Rieke, J. Org.
Chem., 1991, 56, 1445; d) A. Guijarro, D. M. Rosenberg, R. D. Rieke, J.
Am. Chem. Soc. 1999, 121, 4155; e) R. D. Rieke, M. V. Hanson, J. D.
Brown, Q. J. Niu, J. Org. Chem. 1996, 61, 2726; f) M. V. Hanson, R. D.
Rieke, J. Am. Chem. Soc. 1995, 117, 10775.
[10] For some examples of preparing activated zinc using chemical additives
see: a) P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem.
1988, 53, 2390; b) S. C. Berk, P. Knochel, M. C. P. Yeh, J. Org. Chem.
1988, 53, 5789; c) P. Knochel, J. F. Normant, Tetrahedron Lett. 1984, 25,
1475; d) J. K. Gawroński, Tetrahedron Lett., 1984, 25, 2605; e) G. Picotin,
P. Miginiac, J. Org. Chem. 1987, 52, 4796; f) R. Ikegami, A. Koresawa,
T. Shibata, K. Takagi, J. Org. Chem., 2003, 68, 2195; g) M. S. Newman,
J. Am. Chem. Soc. 1942, 64, 2131; h) A. K. Bose, K. Gupta, M. S.
Acknowledgements
D.L.B is grateful to the EPSRC for a First Grant (D.L.B.
EP/P002951/1), CRD for a studentship award to J.L.H., the
EPSRC U.K. National Mass Spectrometry Facility at Swansea
University and the School of Chemistry at Cardiff University for
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Manhas, J. Chem. Soc., Chem. Commun. 1984, 86; i) S. Huo, Org. Lett.
2003, 5, 423; j) M. Kimura, M. Seki, Tetrahedron Lett., 2004, 45, 1635.
For an example of preparing activated zinc using a mortar and pestle
see: k) K. Tanaka, S. Kishigami, F. Toda, J. Org. Chem., 1991, 56, 4333.
[11] a) C. Jubert,; P. Knochel, J. Org. Chem. 1992, 57, 5425; b) A. Krasovskiy,
V. Malakhov, A. Gavryushin, P. Knochel, Angew. Chem. Int. Ed. 2006,
45, 6040; Angew. Chem., 2006, 118, 6186; c) H. Ren, G. Dunet, P. Mayer,
P. Knochel, J. Am. Chem. Soc. 2007, 129, 5376; d) A. Metzger, M. A.
Schade, P. Knochel, Org. Lett. 2008, 10, 1107.
[15] Organ and co-workers investigated the effect of salt additives on Negishi
coupling reactions and found that the addition of salts, e.g. lithium or
tertrabutyl ammonium, could facilitate the formation of higher-order
zincates, which are more active transmetallating agents for Negishi
coupling. TBAB (tetrabutylammonium bromide) was chosen as salt
additive in preference to hydroscopic lithium salts. For the effect of salts
as additives on palladium catalyzed Negishi coupling see: a) G. T.
Achonduh, N. Hadei, C. Valente, S. Avola, C. J. O'Brien, M. G. Organ,
Chem. Commun. 2010, 46, 4109; b) H. N. Hunter, N. Hadei, V. Blagojevic,
P. Patschinski, G. T. Achonduh, S. Avola, D. K. Bohme, M. G. Organ,
Chem. Eur. J., 2011, 17, 7845; c) L. C. McCann, H. N. Hunter, J. A. C.
Clyburne, M. G. Organ, Angew. Chem. Int. Ed. 2012, 51, 7024; Angew.
Chem., 2012, 124, 7130; d) L. C. McCann, M. G. Organ, Angew. Chem.
Int. Ed. 2014, 53, 4386; Angew. Chem., 2014, 126, 4475.
[12] The exact identity of the formed organozinc species has not been
confirmed, however, given the ease of handling and low exotherms upon
quenching (such as those studied and shown in Scheme 2 and Table S2)
we suspect that the materials are monoalkylzinc halides rather than
dialkylzinc species.
[13] For some previous examples of 1-pot, multi-step mechanochemical
reactions see: a) J. L. Howard, W. Nicholson, Y. Sagatov, D. L. Browne,
Beilstein J. Org. Chem, 2017, 13, 1950; b) M. Tyagi, D. Khurana, K. P.
R. Kartha, Carbohydr. Res. 2013, 379, ꢀ55; c) J. G. Hernández, I. S.
Butler, T. Friščić, Chem. Sci., 2014, 5, 3576; d) L. Konnert, M. Dimassi,
L. Gonnet, F. Lamaty, J. Martinez, E.ꢀColacino, RSC Adv. 2016, 6,
36978; e) Y.Zhao, S. V. Rocha, T. M. Swager, J. Am. Chem. Soc. 2016,
138, 13834.
[16] For a recent example of non-innocent balls (SUS304) see: Y. Sawama,
N. Yasukawa, K. Ban, R. Goto, M. Niikawa, Y. Monguchi, M. Itoh, H.
Sajiki, Org. Lett. 2018, 20, 2892.
[17] See supporting information for further information on reaction
optimisation and preparing organozinc species.
[18] A. Guijarro, D. M. Rosenberg, R. D. Rieke, J. Am. Chem. Soc. 1999, 121,
4155.
[19] You may find mills in laboratories concerned with formulation science,
forensic science, geology, earth science and food science – there is likely
to be access to a mill already in your institute, company or university.
[14] For pioneering developments of the Pd-PEPPSI catalyst series see: a)
E. A. B. Kantchev, C. J. O'Brien, M. G. Organ, Angew. Chem. Int. Ed.
2007, 46, 2768; Angew. Chem., 2007, 119, 2824; b) C. Valente, S.
Calimsiz, K. H. Hoi, D. Mallik, M. Sayah, M. G. Organ, Angew. Chem. Int.
Ed. 2012, 51, 3314; Angew. Chem., 2012, 124, 3370; c) C. Valente, M.
E. Belowich, N. Hadei, M. G. Organ, Eur. J. Org. Chem., 2010, 23, 4343;
d) S. Calimsiz, M. Sayah, D. Mallik, M. G. Organ, Angew. Chem. Int. Ed.
2010, 49, 2014; Angew. Chem., 2010, 122, 2058.
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COMMUNICATION
form independant mechanochemical generation of organozinc reagents
A form independent
activation of zinc,
Q. Cao, J. L. Howard, E.
Wheatley, D. L. Browne*
[mixer mill]
[mixer mill]
X
Ar
ZnX
R
concomitant generation of
organozinc species and
engagement in a Negishi
cross-coupling reaction via
mechanochemical methods
is reported. The reported
method exhibits a broad
substrate scope for both
Csp3-Csp2 and Csp2-Csp2
couplings.
R
R
catalyst
Ar [X]
Zn (form)
Page No. – Page No.
Form Independent
Mechanochemical
Activation of Zinc and
Application to Negishi
Cross-Coupling
[20 examples, sp3-sp2]
[18 examples, sp2-sp2]
dust
granules
flakes
foil
shot
mossy
wires
powder
mesh
[make & use in one-pot also possible]
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