Alkali Metal Effects in Trans-Metal-Trapping (TMT): Comparing LiTMP with NaTMP in Cooperative MTMP/Ga(CH2SiMe3)3 Metalation Reactions

Article abstract of DOI:10.1055/s-0037-1611646

Stepwise metalation and trapping, so called trans-metal-trapping (TMT), of anisole is studied using LiTMP as base and Ga(CH₂ SiMe₃)₃ as trap. The isolated 'trapped' intermediate is also assessed in C-C bond forming reactions, highlighting the inherent advantages and remaining challenges of this system. The same base trap mixture is found to metallate N-Me bonds of the diamines TMEDA and PMDETA. Comparative studies replacing LiTMP by NaTMP have found significant alkali metal effects on the extent of both base-trap cocomplexation and onward reactivities of TMT products.

Full text of DOI:10.1055/s-0037-1611646

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
feature
A
en
R. McLellan et al.
Feature
Synthesis
Alkali Metal Effects in Trans-Metal-Trapping (TMT): Comparing
LiTMP with NaTMP in Cooperative MTMP/Ga(CH2SiMe3)3 Meta-
lation Reactions
Ross McLellan
Me
M
TMP(H)
OMe
O
OMe
Marina Uzelac
Trans-Metal-
Trapping
R
I
Ga
H
Leonie J. Bole
I2
R
R
Jose María Gil-Negrete
David R. Armstrong
Alan R. Kennedy
TMP/ Ga R
M
3
Electrophilic
Quenching
55–74%
OMe
M = Li, 1%
M = Na, 65%
Metalation
TMP (M = Li, Na)
Alkali-Metal
Effect
M
Robert E. Mulvey*
0
0
0
0-
0
0
0
2-1
0
1
5-2
5
6
4
M
5–20%
Eva Hevia*
0
0
0
0-
0
0
0
2-3
9
9
8-7
5
0
6
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde,
Glasgow G1 1XL, UK
r.e.mulvey@strath.ac.uk
eva.hevia@strath.ac.uk
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Received: 30.11.2018
Accepted: 05.12.2018
Published online: 15.01.2019
DOI: 10.1055/s-0037-1611646; Art ID: ss-2018-z0802-fa
use bimetallic systems containing two metals of different
polarity within the same molecule. These systems can be
shown to behave in concert, resulting in higher selectivity
and in many cases using ambient reaction conditions
during metalation. Important examples of bimetallic for-
mulations used in deprotonation reactions are the classic
Lochmann–Schlosser superbases,3 Knochel’s turbo Hauser
reagents,4 and Uchiyama and Mongin’s TMP zincates.5 This
bimetallic approach, combining an alkali metal with a less
electropositive metal (e.g., Mg or Zn) into an ‘ate’ complex
has been termed alkali-metal-mediated metalation and, a
series of reactivity and structural studies have demonstrat-
ed that the high reactivity of the alkali metal can be har-
nessed by the less polar metal, while retaining the advan-
tages of selectivity that the non-alkali metal provides, thus
representing a ‘best of both worlds’ scenario.6 Recently we
have shown in our Strathclyde research groups that such
prodigious metal···metal cooperative effects can, in certain
cases work in sequence in a process that has been coined
trans-metal-trapping (TMT).7 A general depiction of TMT is
given in Scheme 1, and describes a process reliant upon the
stepwise reactivity of the two metal organic reagents with
the aromatic substrate. Deprotonation of the substrate with
a lithium amide base exists in a pKa dependent equilibrium
that typically lies towards the lithium amide and unreacted
aromatic substrate, meaning that when used in isolation, a
stoichiometric amount of lithium amide only delivers ca.
<10% of product, when intercepted with an electrophile
such as iodine.
License terms:
Abstract Stepwise metalation and trapping, so called trans-metal-
trapping (TMT), of anisole is studied using LiTMP as base and Ga(CH2-
SiMe3)3 as trap. The isolated ‘trapped’ intermediate is also assessed in
C–C bond forming reactions, highlighting the inherent advantages and
remaining challenges of this system. The same base trap mixture is
found to metallate N–Me bonds of the diamines TMEDA and PMDETA.
Comparative studies replacing LiTMP by NaTMP have found significant
alkali metal effects on the extent of both base-trap cocomplexation and
onward reactivities of TMT products.
Key words metalation, gallium trans-metal-trapping, carbanions, co-
operative effects, lithium, sodium
Deprotonative metalation (C–H to C–M exchange) of
aryl and heteroaryl substrates is a widely successful tool,
utilised in the construction of important organic molecules,
usually producing organometallic intermediates primed for
onward reactivity. Longstanding reagents of choice in this
context are alkyllithiums and lithium amides.1 Synthetic
drawbacks to these metalation transformations are com-
monly, poor functional group tolerance (at convenient tem-
peratures) and selectivity, necessitating cryogenic reaction
conditions to prevent unwanted side reactions or decompo-
sition of the lithiated species. One solution to these limita-
tions is to employ metal salts such as MgCl2 or ZnCl2·2LiCl
as in situ trapping agents during LiTMP metalations of
arenes and N-heterocycles in THF, in reactions that have
been performed under continuous flow conditions (TMP =
2,2,6,6,-tetramethylpiperidide).2 A second approach is to
However, in the presence of the Lewis acidic carbophilic
trap, the lithiated intermediate can be readily intercepted,
resulting in a so called crossover bimetallic complex that
stops short of full transmetalation, where separated lithium
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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Biographical Sketches
Ross McLellan received his M.Chem. de-
gree in chemistry from Heriot-Watt Uni-
versity in 2007. He obtained his Ph.D.
degree from the same institution in
2011 under the supervision of Professor
Alan Welch. His first postdoctoral posi-
tion with Dr Scott Dalgarno focussed on
the controlled formation and magnetism
of 3d/4f polynuclear metal clusters in
collaboration with Professor Euan
Brechin. He is currently a postdoctoral
research fellow at the University of
Strathclyde, where he is interested in de-
veloping main group systems and inves-
tigating their use in catalysis.
Marina Uzelac obtained her B.Sc. and
M.Sci. in chemistry from the University
of Zagreb, Croatia. She then moved to
the UK, to carry out her Ph.D. studies at
the University of Strathclyde under the
supervision of Professor Eva Hevia devel-
oping new gallium-mediated transfor-
mations for C–H functionalisation and
small molecule activation processes. She
graduated in 2016 and then took up a
postdoctoral position working in a col-
laborative project with Professors Robert
Mulvey and Eva Hevia exploiting multi-
component s-block metal reagents in
deprotonative metalation and C–C bond
forming processes. In 2018 Marina
joined the group of Professor Michael J.
Ingleson working on the development of
new organozinc catalysts with applica-
tion in bond forming processes.
Leonie J. Bole obtained her undergradu-
ate degree in 2016 from the University
of Strathclyde completing her M.Sc. on
inverse crown chemistry under the su-
pervision of Dr Charles T. O’Hara. She is
currently working towards her Ph.D. in
main group organometallic chemistry
with Prof. Eva Hevia and Dr Charles T.
O’Hara at the University of Strathclyde.
Jose María Gil-Negrete obtained both
his B.Sc. and M.Sc. from the University of
A Coruña, Spain. Since 2014 he is pursu-
ing a Ph.D. under the direction of Profes-
sors Luis Sarandeses and Jose Pérez
Sestelo, also at the University of
A
Maria was a visiting researcher in the
University of Strathclyde, Glasgow, with-
in the group of Professor Eva Hevia.
Coruña. His research is focussed on the
development of new applications for in-
dium organometallics in organic synthe-
sis. During the summer of 2017, Jose
David Armstrong was born in the
North-East of England in County Durham
and educated at Newcastle University for
both his B.Sc. and Ph.D. degrees. The lat-
ter was carried out under the supervision
of Peter Perkins and was a theoretical in-
vestigation of Group III compounds. Ap-
pointed at the University of Strathclyde
in 1970 as a lecturer and subsequently
promoted to a senior lectureship, he cur-
rently holds an emeritus position. David
has been performing theoretical calcula-
tions for about 50 years, publishing over
two hundred research papers with his
most recent work focussing on different
aspects of polar organometallic chemis-
try.
Alan Kennedy was awarded both B.Sc.
and Ph.D. (K. Muir and R. Cross) degrees
in chemistry by the University of
Glasgow (1986–1993). He has worked at
the University of Strathclyde since 1994
and is a crystallographer specialising in
structure-property relationships in small
molecules, notably pharmaceuticals, co-
lourants, and metal complexes. He has
published over 550 career papers.
Robert Mulvey was born in Glasgow
(Scotland) in 1959 and did his B.Sc. and
Ph.D. (R. Snaith) at the University of
Strathclyde (1977–1984). Following two
years postdoctoral research at the Uni-
versity of Durham (K. Wade), he re-
turned to Strathclyde in 1986 as a Royal
Society Research Fellow, and was pro-
moted to Professor in 1995. His research
has mainly focused on alkali, alkali-earth,
and early p-block metals with emphasis
on synergistic effects in bimetallic sys-
tems. Prof. Mulvey has received many
distinguished prizes including the RSC
Meldola Medal, RSC Main Group Element
Award, Royal Society Wolfson Research
Merit Award, Royal Society Leverhulme
Trust Senior Research Fellowship, GDCh
Arfvedson Schlenk Prize, and a Humboldt
Research Award. A Fellow of both the
Royal Society of Edinburgh and Royal So-
ciety of Chemistry, he has published ap-
proaching 300 papers.
Eva Hevia received her M.Sci. degree in
chemistry from the Universidad de Ovie-
do (Spain) in 1998. She obtained her
Ph.D. degree from the same institution
in 2002 under the supervision of Profes-
sor Victor Riera and Dr Julio Perez. Next
she was awarded a Marie Curie Fellow-
ship held at the University of Strathclyde
under the direction of Prof. Robert Mul-
vey. In 2006 she took up a Royal Society
University Research Fellowship at the
University of Strathclyde where she is
currently a Professor of Inorganic Chem-
istry. Her research interests include s-
block metal-mediated transformations
ticles and her research has been
recognised with several awards including
the Royal Society of Chemistry (RSC)
Harrison-Meldola Prize (2009), SRUK
Emerging Investigator Awards (2016),
and, most recently, the RSC Corday-
Morgan Prize (2017). In 2018 Eva was
elected as Fellow of the Royal Society of
Edinburgh.
with
a particular emphasis on green
chemistry and catalysis. She has pub-
lished over 120 peer-reviewed journal ar-
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inertness towards co-complexation with LiTMP, and there-
fore our first step was to establish whether GaR3 is bulky
enough to compromise its ability to form a weakly basic,
coordinatively saturated ate complex with LiTMP. Such sep-
aration of the organometallic reagents appears a prerequi-
site for an effective TMT process, and this is underlined by
the fact that LiTMP/iBu2AlTMP mixtures are better TMT
agents than LiTMP/iBu3Al mixtures, which form the alumi-
nate LiAl(TMP)(iBu)3 in a complicated equilibrium mixture
of five compounds.7a Thus a comparison of the 1H NMR
spectra (Figure 1) of an equimolar mixture of LiTMP and
GaR3 and those of the individual components reveals that
the two TMT reagents remain separate in benzene-d6 solu-
tion. The lack of co-complexation is best deduced by the in-
formative singlet at δ = 0.13 which corresponds to coinci-
dentally overlapping CH2 and CH3 resonances of the CH2-
SiMe3 group on gallium.10 Furthermore, resonances for both
tetrameric and trimeric forms of LiTMP are present and
identical to those previously reported.11
Trans-Metal Trapping (TMT)
FG
FG
Li
H
+ TMP(H)
LiTMP +
MR2X metal
trap
MR2X metal
trap
No reaction
FG
Li
MR2X
FG
–LiX
MR2
Bimetallic crossover
complex
Full transmetalation
Scheme 1 Description of trans-metal-trapping using LiTMP as base,
and comparison with conventional transmetalation
and non-lithium metal products would form. A key aspect
of this chemistry proven with lithium is that the base and
the trap do not combine to form a bimetallic complex that
would be inert towards the substrate. Functioning only on
emergence of the deprotonated substrate (carbanion), the
trap inserts into the Li–C bond and drives the equilibrium
towards the desired metallated substrate.
In this article we present a deeper understanding of key
mechanistic insights of trans-metal-trapping (TMT), by
combining structural, reactivity, and theoretical studies,
using anisole, a classical substrate in directed ortho-metala-
tion, as a case study. A key feature of our exploratory stud-
ies of TMT is the stepwise reactivity exhibited by the two
organometallic constituents. In this respect the bulky
tris(trimethylsilylmethyl)gallium has been demonstrated
as an excellent trap for diazine and fluoroaromatic anions,
that when metallated by conventional bases are prone to
rapid decomposition.8 Therefore this study aims to high-
light the benefits of LiTMP/Ga(CH2SiMe3)3 in metalation.
From a synthetic perspective, liquid Ga(CH2SiMe3)3 (hereaf-
ter GaR3) possesses good hydrocarbon solubility (similar to
iBu2AlTMP another successful trapping agent)7 giving it a
decided advantage over salt traps (e.g., MgCl2, ZnCl2),9
which generally need the use of ethereal solvents (usually
THF) and often require low temperatures to avoid compet-
ing salt metathesis reactions. More importantly, gallium is
characterised by strong carbophilicity and is therefore well
equipped to sedate ultra-sensitive anions post metalation
with LiTMP. This fact is well illustrated in our comparative
studies into the metalation of fluoroarenes, where it was
shown that the resultant gallium TMT product had far su-
perior stability against decomposition (via benzyne forma-
tion) than the aluminium counterpart.8b The poor stability
may also be attributed to the fluorophilicity of aluminium
meaning that aluminium traps may in general be incompat-
ible with fluorinated substrates. Apart from these intrinsic
properties of GaR3, a key specification of the trapping re-
agent, as demonstrated with iBu2AlTMP previously,7 is its
Figure 1 Comparative 1H NMR spectra of free GaR3 (bottom), free LiT-
MP (middle), and a mixture of GaR3 and LiTMP (top) in C6D6
To further understand the ability (or lack thereof) to co-
complexation we elected to perform some DFT studies, in
order to determine energetics of such a process, forming a
hypothetical lithium gallate I. In the optimised geometry of
I the metals are connected by a TMP bridge and an alkyl
bridge with another two monosilyl groups terminally
bonded to the gallium atom. GaR3 was modelled as a mono-
mer according to its known structure in the solid state,12
while LiTMP was modelled as a monomer, and a trimer and
tetramer which are the two known aggregates of this com-
pound in non-polar solvents.11 Co-complexation between
monomeric LiTMP is energetically favoured (–17.1 kcal
mol–1), which is unsurprising given the high energy of mo-
nomeric LiTMP (Table 1). Crucially, co-complexation of both
trimeric and tetrameric LiTMP with GaR3 are energetically
disfavoured (+9.0 kcal mol–1), and in line with the finding
from the solution studies.
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Table 1 Comparison of DFT-Computed Relative Energies of Co-com-
plexation of LiTMP and GaR3
n
ΔE Co-complexation (kcal mol–1
)
1
3
4
–17.1
+9.0
+9.0
Next we determined to ascertain the effect of Lewis do-
nor ligands on the TMT process. In particular PMDETA
(N,N,N′,N′′N′′-pentamethyldiethylenetriamine) has been
crucial in facilitating the crystallisation of TMT products,8
which is important since structural data of these complexes
provide valuable information on the modus operandi of
metalation. Reaction between PMDETA, LiTMP, and
GaR3 at room temperature in hexane for one hour lead to
the isolation and structural characterization of
[Li{Me2NCH2CH2N(Me)CH2CH2N(Me)CH2}(TMP)GaR2] (1).
The molecular structure of 1 (Figure 2, top) reveals that PM-
DETA has been metallated at a terminal NCH3 group. The
lithium atom reveals a contacted ion pair arrangement
where the two metal centres connect through two anions,
namely a TMP bridge and an ambidentate NCH2 fragment of
the metallated PMDETA.
Interestingly, that a TMP anion is retained in the struc-
ture might suggest that it is GaR3 that deprotonated the
substrate as the structure incorporates a TMP anion and
only two monosilyl groups on gallium. However GaR3 on its
own is not a sufficiently strong base to metallate PMDETA,
therefore the α-deprotonation is based on the stepwise co-
operation between LiTMP and GaR3. LiTMP deprotonates
the triamine followed by the fast trans-metal-trapping pro-
cess with GaR3 yielding a proposed intermediate A (Scheme
2) where concomitantly produced TMPH helps to fill the co-
ordination sphere of lithium and is thus in close proximity
to GaR3. The sterically encumbered intermediate and en-
hanced acidity of coordinated TMPH makes it possible for
the otherwise inert gallium alkyl to react affording 1 and
Me4Si.
Figure 2 Molecular structure of 1 with 30% probability displacement
ellipsoids (top); all hydrogen atoms except those on metallated CH2
group of PMDETA have been omitted for clarity. Molecular structure of
2 with 30% probability displacement ellipsoids (bottom); all hydrogen
atoms except those on metallated CH2 group of TMEDA have been
omitted for clarity.
intermediate A
N
N
N
N
N
N
Li
ii) alkyl basicity
Li
i) amide basicity
CH2
Ga
N
N
N
CH2
Ga
+ TMPH H2C
SiMe3
– Me4Si
N
R
R
GaR3 + LiTMP
R
R
1
Scheme 2 Proposed reaction sequence for the surprising formation of 1
addition, it was found that the bulkiness of a reagent such
as GaR3 precludes chelation and instead, it acts as a bridging
ligand as observed in the crystal structure of R3Ga–TMEDA–
GaR3,13 Further, to an extent, experimental support for the
proposed pathway came from the addition of a similar, but
smaller Lewis donor TMEDA to the mixture of LiTMP and
GaR3 from which we were able to isolate crystals of [(TME-
DA)Li{Me2NCH2CH2N(Me)CH2}GaR3] (2) (Figure 2, bottom).
The molecular structure of 2 has a contacted ion pair struc-
ture with three alkyl groups on gallium and no TMP anion
incorporation, reminiscent of the proposed intermediate A.
Here, due to the smaller size of the diamine, N4-tetracoordi-
nated lithium is capped with two molecules of TMEDA one
of which is metallated and the other one is neutral, com-
pleting the coordination sphere and avoiding the close
Although we have no direct evidence for the proposed
mechanism, it is supported indirectly by the notion that tri-
organogallium reagents cannot deprotonate coordinating
additives such as PMDETA or TMEDA as C–H bonds adjacent
to N centres in tertiary amines are only weakly acidic. In
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proximity of TMPH and GaR3, which would induce alkyl ba-
sicity. Confident that LiTMP and GaR3 indeed remain sepa-
rate in non-coordinating solvent, yet cooperate in metala-
tion reactions we next tested this mixture as a TMT reagent
using anisole as a benchmark molecule in directed ortho-
metalation. Thus, to a hexane suspension of equimolar
amounts of GaR3 and LiTMP at room temperature, a molar
equivalent of anisole was added to give a light yellow sus-
pension. After stirring the mixture for one hour, an equiva-
lent of PMDETA was added and the solution placed at –33 °C
affording a crop of colourless crystals of [(PMDETA)Li(o-
C6H4OMe)GaR3] (3) in 55% isolated yield (Scheme 3).
Figure 3 Molecular structure of 3 with 30% probability displacement
ellipsoids; all hydrogen atoms have been omitted for clarity
N
OMe
N
Li
OMe
N
i) hexane, rt, 1 h
GaR3
+ TMPH
GaR3 + LiTMP
+
[Na{Me2NCH2CH2N(Me)CH2CH2N(Me)CH2}(TMP)GaR2] (4)
(Figure 4, top) is directly analogous to that of the lithium
gallate 1. Anticipating that since metalation occurs in this
instance, then GaR3 and NaTMP remain as separate entities
in solution, GaR3 was added to NaTMP in a J. Young’s NMR
tube in C6D6, causing dissolution of the normally insoluble
NaTMP. The 1H NMR spectrum after 15 minutes revealed, in
contrast to the case with LiTMP, that the characteristic reso-
nance of GaR3 was absent, indicating the surprising forma-
tion of a co-complex, albeit the resonances are broad and
indicative of either a mixture of compounds or a system un-
dergoing a degree of exchange. This reaction mixture was
probed further by adding anisole directly and reaction
monitoring revealed a small amount of metalation along-
side the signals of coordinated anisole (Figure 5). Further
ii) PMDETA (1 equiv)
3
Scheme 3 Synthesis of [(PMDETA)Li(o-C6H4OMe)Ga(CH2SiMe3)3] (3)
The structure of 3 (Figure 3) revealed the formation of a
mixed-metal lithium gallate with the metal centres con-
nected by an ambidentate ortho-metallated anisole frag-
ment giving rise to a contacted ion-pair structure. The or-
tho carbon of the metallated anisole fragment bonds to gal-
lium forming a new Ga–C bond (Ga–C13 2.0501(15) Å). The
distorted tetrahedral lithium is fully solvated by the triden-
tate PMDETA as well as from the oxygen atom of anisole. In
these studies we have demonstrated that LiTMP and GaR3
are a highly efficient combination of base and trap, to selec-
tively metallate useful aromatic molecules, illustrated by
the potency of LiTMP as a base and of GaR3 in being able to
stabilise the newly formed organic carbanions. Probing the
synthetic utility of 3, I2 was added as an electrophilic source
in an effort to prepare 2-iodoanisole. Interestingly, only a
trace amount of ca. 1% of the quenched product was ob-
tained, presumably reflecting the high stability of the
metallated C–Ga bond. Thus, this TMT system is excellent in
the stabilisation of incipient carbanions albeit the stability
likely inhibits the downstream utility in simple electrophil-
ic quenching studies.
Underscoring the utility of this metal pairing, we next
investigated an analogous system using NaTMP in place of
LiTMP, rationalising that the larger alkali metal may be bet-
ter equipped to form a complex with GaR3, hence limiting
the ability of the system to promote TMT. Firstly a control
reaction between NaTMP and anisole in hexane at room
temperature, followed by a standard iodine quench in THF
afforded only ca. 20% of 2-iodoanisole. A second control re-
action of the in situ GaR3/NaTMP mixture with PMDETA re-
veals metalation of a methyl group of the Lewis donor after
structural characterisation. The structure of this product
1
monitoring by H NMR details that additional metalation
does not occur over an 18 hour window at room tempera-
ture. Repeating the reaction in a Schlenk flask at room tem-
perature in hexane followed by addition of TMEDA after
two hours stirring, and placing at 4 °C, resulted in a crop of
crystals that were characterised X-ray diffraction as
[(TMEDA)Na(o-C6H4OMe)GaR3] (5, 17%) (Figure 4, bottom),
a sodium analogue of 3. This result is surprising since reac-
tion of the suggested sodium gallate with anisole would
likely possess insufficient basicity to promote metalation,
comparable with the LiTMP/iBuAl3 mixture that forms a
lithium aluminate that lacks the intrinsic basicity to pro-
mote C–H bond cleavage.7a Thus we attribute the reactivity
as the result of unrestricted NaTMP that had not yet formed
a complex with GaR3, in accordance with the busier 1H NMR
spectrum recorded after 15 minutes. Probing the co-com-
plex formation further, an equimolar mixture of NaTMP
and GaR3 in C6D6 was monitored by 1H NMR until the spec-
tra ceased evolving. At this point (3 days) anisole was added
and the resulting spectrum detailed that metalation does
not occur, giving further evidence to our original hypothe-
sis and emphasizing the importance of the lithium reagent
in preventing co-complexation and therefore subdued reac-
tivity (Figure 5).
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NMR tube in C6D6 for 15 minutes was followed by addition
of NaTMP. At this point trans-metal-trapped anisole
1
[(TMP(H)Na(o-C6H4OMe)GaR3] (6) was observed in the H
NMR spectrum in 74% yield against hexamethylbenzene
(C6Me6) as internal standard (Scheme 4). Addition of TME-
DA to this mixture affords a spectrum reminiscent of 5.
N
OMe
Na
N
Na
i) GaR3, NaTMP
ii) TMEDA
i) GaR3,15 min
ii) NaTMP
OMe
N
MeO
H
GaR3
GaR3
C6D6, rt
hexane, rt
5, 17%
Order of addition crucial
6, 74%
Scheme 4 The effect of addition order in TMT using GaR3/NaTMP sys-
tem. GaR3 and NaTMP form complex limiting TMT to give 5 (left). Pre-
reaction of GaR3 with anisole enhances yield of 6 (right).
Repeating this reaction in a Schlenk flask and conduct-
ing an electrophilic quench with iodine resulted in forma-
tion of 2-iodoanisole in 65% yield. That sodium gallate 5 af-
fords 2-iodoanisole in reasonable yields after an electro-
philic quench is itself surprising since the analogous
reaction with 3 only affords trace amounts of products. This
clear alkali metal effect, with the sodium gallate exhibiting
far superior onward reactivity than the lithium counterpart
suggests that when paired with the appropriate secondary
metal, gallium–carbon bond functionalisation can be facile.
Finally, while we have demonstrated that the GaR3
trans-metal-trapping system is highly efficient in stabilis-
ing emergent carbanions, post metalation with LiTMP, tak-
ing this trans-metal-trapping to the next level, that is, using
the complexes in further C-element bond formation, re-
mains to be realised as a routine procedure. The challenge is
that since the trap must be a strong Lewis acidic carbophilic
metal complex, logically that will produce a strong metal–
carbon bond that may not be easily broken by an electro-
phile. Standard electrophilic quenching strategies using ei-
ther iodine, or N-bromosuccinimide proved to be unsuc-
cessful, resulting in essentially hydrolysed material after re-
action and aqueous workup. This is rather unsurprising
given the robust nature of the Ga–C bonds formed using the
LiTMP GaR3 system. Thus, we turned attention to C–C bond
formation via palladium-catalysed cross-coupling proto-
cols. A reaction between 3, 4-bromobenzonitrile, and
Pd(PPh3)4 in THF at 80 °C for 16 hours was performed. After
a standard organic workup, the cross-coupled product 2′-
methoxybiphenyl-4-carbonitrile (7) was isolated in 73%
yield. However the reaction yield was not reproducible
(typically yields varied in the range 50–70% on repeated
runs), and variable amounts of 4-[(trimethylsilyl)meth-
yl]benzonitrile were obtained, indicating that under these
conditions the reaction evidenced poor selectivity. Using a
different organic electrophile, benzoyl chloride, under the
same conditions resulted in a moderate 62% yield of 2-ben-
zoylanisole (8) (Scheme 5).
Figure 4 Molecular structure of 4 with 30% probability displacement
ellipsoids (top); all hydrogen atoms have been omitted for clarity except
for those on the metallated CH2 group of PMDETA. Molecular structure
of 5 with 30% probability displacement ellipsoids (bottom); all hydro-
gen atoms have been omitted for clarity.
Figure 5 Comparative NMR spectra illustrating that as co-complex for-
mation progresses in time the extent of metalation decreases
Lastly we sought to investigate whether the order of ad-
dition would prejudice the reaction in favour of the metal-
lated (trapped) product, rationalising that pre-complex-
ation of anisole with Lewis acidic GaR3 would compromise
the moderately slow complexation of GaR3 with NaTMP and
hence result in enhanced yields of metallated products. In
this case reaction between GaR3 and anisole in a J. Young’s
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

G
R. McLellan et al.
Feature
Synthesis
O
N
N
CN
N
Li
OMe
O
O
O
Cl
Br
CN
GaR3
Pd(PPh3)4 (5 mol%)
THF, 16 h 80 °C
Pd(PPh3)4 (5 mol%)
THF, 16 h 80 °C
7
3
8
Scheme 5 Palladium-mediated C–C bond formation from 3, using 4-bromobenzonitrile or benzoyl chloride, affording 2′-methoxybiphenyl-4-carboni-
trile or 2-benzoylanisole, respectively
Rationalising that under the reasonably harsh reaction
conditions required to promote cross-coupling, competing
reaction of a CH2SiMe3 occurs, we decided to perform one
more reaction between the homoleptic lithium gallate
LiGaR4, and 4-iodoacetophenone. Once more the cross-cou-
pled product was formed in a moderate 62% yield against a
ferrocene internal standard. Thus while we demonstrate a
rare example of gallium-based cross-coupling,8b,14 conclu-
sions can be drawn. A major facet of the trans-metal-trap-
ping strategy is the stabilisation of incipient carbanions by
forming strong C–Ga bonds. This however, as one would ex-
pect, appears to be problematic, from the standpoint of fac-
ile onward reactivity. Thus, this case study clearly suggests
a way forward for trans-metal-trapping. Finding new pair-
ings of base and trapping agent that do not co-complex in
the mild conditions used in reaction is the first goal since
the lack of co-complexation promotes higher yielding pro-
cesses. The choice of trap should also fulfil two require-
ments: (i) the atom should be able to form strong enough
M–C bonds to stabilise the frequently sensitive metalation
anions; (ii) the resulting M–C bonds should also be labile
enough to promote straightforward reactivity into more
complicated and synthetically useful bis-aryl or heteroaryl
molecules. Moreover, despite the fact that the LiTMP/GaR3
system is a superior base/trap pairing, the NaTMP/GaR3 sys-
tem is more predisposed to favour onward Ga–C functional-
isation. Replacing lithium by sodium as the pre-eminent
metallating agent would be attractive from a sustainability
viewpoint given their comparative earth abundance. Future
work will determine whether this alkali metal effect is due
primarily to sodium versus lithium or whether the different
coordination spheres involved (e.g., TMEDA versus PMDE-
TA) influences the remarkable difference in iodination effi-
ciency. Current work in our laboratories is focussed on
meeting these goals by incorporating the crucial elements
into new trans-metal-trapping systems.
priate) from the appropriate drying agent prior to use. LiTMP11 and
Ga(CH2SiMe3)3 were prepared as previously described or by slight
15
variations thereof. NMR Spectroscopy: NMR spectra were recorded on
a Bruker AV3 or AV 400 MHz spectrometer operating at 400.13 MHz
for 1H, 376.46 MHz for 7Li and 100.62 MHz for 13C. All 13C spectra were
proton decoupled. 1H and 13C NMR spectra were referenced against
the appropriate solvent signal. 7Li NMR spectra were referenced
against LiCl in D2O at δ = 0.00. X-ray Crystallography: Crystallographic
data were collected on Oxford Diffraction instruments with Mo Kα
radiation (λ = 0.71073 Å) or Cu Kα radiation (λ = 1.54184 Å). Struc-
tures were solved using SHELXS16a or OLEX2,16b while refinement was
carried out on F2 against all independent reflections by the full matrix
least-squares method using the SHELXL programs or by the Gauss-
Newton algorithm using OLEX2. All non-hydrogen atoms were re-
fined using anisotropic thermal parameters. Selected crystallographic
details and refinement details are provided in Table S1. CCDC
1880970–1880974 contains the supplementary crystallographic data
for these structures. These data can be obtained free of charge from
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures. DFT computational studies17 em-
ploying the B3LYP method18,19 and the 6-311G(d,p) basis set.20
[(PMDETA)Li(o-C6H4OMe)Ga(CH2SiMe3)3] (3)
To a suspension of LiTMP (0.074 g, 0.5 mmol) and Ga(CH2SiMe3)3
(0.165 g, 0.5 mmol) in hexane (10 mL), an equivalent of anisole (0.054
g, 54 μL, 0.5 mmol) was added at r.t. As soon as anisole was added, a
yellow fine suspension was formed which persisted during stirring
for 1 hour at r.t. PMDETA (0.11 mL, 0.5 mmol) was added, the solvent
was exchanged in vacuo for toluene and the yellow solution placed in
freezer to obtain 3 (0.17 g, 55%) as colourless crystals suitable for X-
ray diffraction analysis.
1H NMR (400.13 MHz, 298 K, THF-d8): δ = 7.44 (d, 1 H, Ar-H), 6.78 (t, 1
H, Ar-H), 6.53 (t, 1 H, p-CH), 6.40 (d, 1 H, Ar-H), 6.40 (d, 1 H, Ar-H),
3.59 (s, 3 H, OCH3), 2.47 (m, 4 H, NCH2CH2N), 2.37 (m, 4 H,
NCH2CH2N), 2.26 (s, 3 H, NCH3), 2.20 [s, 12 H, N(CH3)2], –0.19 [s, 27 H,
Si(CH3)3], –0.85 (s, 6 H, CH2SiMe3).
13C NMR (100.62 MHz, 298 K, THF-d8): δ = 166.7 (Ar-C), 155.2 (C-Ga),
138.8 (Ar-C), 125.0 (Ar-C), 120.9 (Ar-C), 119.4 (Ar-C), 107.5 (Ar-C),
58.5 (PMDETA), 56.2 (PMDETA), 54.3 (OCH3), 46.0 (PMDETA), 43.7
(PMDETA), 3.9 [Si(CH3)3], 0.5 (CH2SiMe3).
7Li NMR (376.46 MHz, 298 K, THF-d8): δ = 0.14.
Anal. Calcd for C28H63GaLiN3OSi3: C, 54.35; H, 10.26; N, 6.79. Found: C,
54.95; H, 9.94; N, 7.55.
All reactions and manipulations were conducted under a protective
argon atmosphere using either standard Schlenk techniques or an
MBraun glove box fitted with a gas purification and recirculation unit.
NMR experiments were conducted in J. Young’s tubes oven dried and
flushed with argon prior to use. Hexane, toluene, and THF were dried
by heating to reflux over sodium benzophenone ketyl and then dis-
tilled under N2 prior to use. All other reagents were purchased com-
mercially from Sigma-Aldrich and dried via distillation (where appro-
[(TMEDA)Na(o-C6H4OMe)Ga(CH2SiMe3)3] (5)
In a Schlenk flask, Ga(CH2SiMe3)3 (0.33 g, 1 mmol) and NaTMP (0.163
g, 1 mmol) were suspended in hexane and stirred at r.t. for 1 h. To this
mixture, one equivalent of anisole (0.11 mL, 1 mmol) was added, re-
taining the white suspension, and stirred at r.t. for a further 2 h. Upon
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
R. McLellan et al.
Feature
Synthesis
addition of TMEDA (0.21 mL, 1 mmol), a colourless solution was ob-
tained which, with slow cooling to 4 °C, produced a crop of colourless
crystals of 5 (98 mg, 17%).
[t, 4 H, β-TMP(H)], 1.05 [s, 12 H, CH3 of TMP(H)], 0.25 [s, 28 H, Si(CH3)3
+ TMP(H)], –0.59 (s, 6 H, CH2SiMe3).
1H NMR (400.13 MHz, 298 K, C6D6): δ = 8.00 (dd, 1 H, Ar-H), 7.09 (td, 1
H, Ar-H), 7.04 (td, 1 H, Ar-H), 6.56 (dd, 1 H, Ar-H), 6.40, 3.46 (s, 3 H,
OCH3), 1.59 [s, 12 H, N(CH3)2], 1.54 (s, 4 H, NCH2CH2N), 0.33 [s, 27 H,
Si(CH3)3], –0.51 (s, 6 H, CH2SiMe3).
13C NMR (100.62 MHz, 298 K, C6D6): δ = 165.1 (Ar-C), 149.7 (C-Ga),
141.4 (Ar-C), 127.9 (Ar-C), 123.0 (Ar-C), 112.2 (Ar-C), 56.9 (OCH3), 56.5
(TMEDA), 45.1 (TMEDA), 3.6 [Si(CH3)3], –0.7 (CH2SiMe3).
NMR Study: Synthesis of [(PMDETA)Li(o-C6H4OMe)Ga(CH2SiMe3)3]
(3)
In a J. Young’s NMR tube, equimolar amounts of Ga(CH2SiMe3)3 (83
mg, 0.25 mmol) and LiTMP (36 mg, 0.25 mmol) were combined in
C6D6 (0.5 mL) resulting in a white suspension. Addition of anisole (27
μL, 0.25 mmol) was then performed and allowed to react for 1 h at r.t.
with a white suspension persisting. Dissolution was achieved by the
addition of PMDETA (53 μL, 0.25 mmol) to afford a yellow solution;
compound 3 was obtained in 75% yield (1H NMR with C6Me6 as inter-
nal standard).
2′-Methoxybiphenyl-4-carbonitrile (7)
To a solution of 3 (200 mg, 0.323 mmol) in THF (8 mL) were added 4-
bromobenzonitrile (59 mg, 0.323 mmol) and Pd(PPh3)4 (18 mg 5
mol%). The mixture was then stirred at reflux temperature for 16 h.
After removal of all volatiles in vacuo, the residue was extracted with
Et2O (20 mL), then washed with H2O (2 × 10 mL) and brine (2 × 10
mL). The organic phase was then dried (MgSO4) and concentrated.
Column chromatography (silica gel, hexane/EtOAc 95:5–90:10) af-
forded 7 (49 mg, 0.24 mmol, 73%) as a colourless oil; Rf = 0.45. 1H and
13C NMR spectra are in agreement with those previously published.21
1H NMR (400.13 MHz, 298 K, C6D6): δ = 8.19 (d, 1 H, Ar-H), 7.06 (t, 1 H,
Ar-H), 7.02 (dt, 1 H, p-CH), 6.31 (d, 1 H, Ar-H), 3.44 (s, 3 H, OCH3), 2.03
(s, 3 H, NCH3), 1.83 (m, 4 H, NCH2CH2N), 1.75 (m, 4 H, NCH2CH2N),
1.57 [s, 12 H, N(CH3)2], 0.32 [s, 27 H, Si(CH3)3], –0.34 (s, 6 H,
CH2SiMe3).
13C NMR (100.62 MHz, 298 K, C6D6): δ = 164.6 (Ar-C), 142.6 (Ar-C),
131.7 (C-Ga), 124.3 (Ar-C), 125.9 (Ar-C), 116.5 (Ar-C), 62.7 (OCH3),
57.2 (PMDETA), 53.5 (PMDETA), 45.6 (PMDETA), 44.5 (PMDETA), 4.1
[Si(CH3)3], 1.5 (CH2SiMe3).
7Li NMR (376.46 MHz, 298 K, C6D6): δ = 0.10.
2-Benzoylanisole (8)
To a solution of 3 (200 mg, 0.323 mmol) in THF (8 mL) were added
Pd(PPh3)4 (18 mg, 5 mol%) followed by benzoyl chloride (0.037 mL,
0.323 mmol) via syringe. The mixture was then stirred at reflux tem-
perature for 16 h. After removal of all volatiles in vacuo, the residue
was extracted with Et2O (20 mL), then washed with H2O (2 × 10 mL)
and brine (2 × 10 mL). The organic phase was then dried (MgSO4) and
concentrated. Column chromatography (silica gel, hexane/EtOAc
95:5–90:10) afforded 8 (43 mg, 0.20 mmol, 62%) as a colourless solid;
Rf = 0.35. 1H and 13C NMR spectra are in agreement with those previ-
ously published.22
Metalation of Anisole followed by Electrophilic Quenching Using
I2: NaTMP + Anisole
In a Schlenk flask, NaTMP (0.163 g, 1 mmol) was suspended in hexane
(10 mL) at r.t. To this, anisole (0.11 mL, 1 mmol) was added affording a
white suspension, and the mixture was stirred at r.t. for 2 h. In a sepa-
rate Schlenk tube, a solution of I2 (6 mmol) was prepared in THF (10
mL). Both Schlenk tubes were then cooled to –78 °C in an acetone/dry
ice bath and stirred for 20 min until completely cooled. Then, the
I2/THF solution was syphoned into the mixture at –78 °C and allowed
to slowly warm up to r.t. over 16 h. Workup of the mixture was
achieved by addition of sat. aq Na2S2O3 solution until bleaching oc-
curred (approx. 20 mL), followed by addition of sat. aq NH4Cl (10 mL).
The mixture was then extracted with EtOAc (3 × 10 mL) and the com-
bined organic layers were washed with brine (10 mL), dried (MgSO4),
and filtered. All organic solvents were then removed under reduced
pressure to give a brown solid; 2-iodoanisole was obtained in 20%
yield (NMR using C6Me6 a internal standard in CDCl3). Spectroscopic
values obtained are in good agreement with those previously report-
ed in the literature.23
NMR Study: Synthesis of [(TMP(H)Na(o-C6H4OMe)GaR3] (6)
In a J. Young’s NMR tube, Ga(CH2SiMe3)3 (83 mg, 0.25 mmol) and
anisole (27 μL, 0.25 mmol) were combined together in C6D6 solvent
affording a colourless solution. 1H NMR analysis confirmed no reac-
tivity had occurred between these two species. To this mixture,
NaTMP (41 mg, 0.25 mmol) was added and upon dissolution gave a
colourless solution. Analysis by 1H NMR spectroscopy indicated meta-
lation of anisole had occurred in 74% yield (using C6Me6 as an internal
standard) to give 6. [Note: TMP(H) resonances are lower frequency by
~0.3 ppm than ‘free’ TMP(H); we propose this is due to coordination
of TMP(H) to Na in the absence of any other donor molecules.) Finally,
addition of TMEDA (38 μL, 0.25 mmol) resulted in its coordination to
the sodium centre and release of TMP(H) (confirmed by 1H NMR).
Metalation of Anisole followed by Electrophilic Quenching Using
I2: LiTMP (or NaTMP) + GaR3 + Anisole
In a Schlenk flask, LiTMP (0.146 g, 1 mmol) and Ga(CH2SiMe3)3 (0.33
g, 1 mmol) were suspended in hexane (10 mL) at r.t. To this, anisole
(0.11 mL, 1 mmol) was added retaining a white suspension, and the
mixture was stirred at r.t. for 2 h [for NaTMP (0.163 g, 1 mmol) reac-
tion, the order of addition was reversed so that NaTMP was added
last]. In a separate Schlenk tube, a solution of I2 (6 mmol) was pre-
pared in THF (10 mL). Both flasks were then cooled to –78 °C in an
acetone/dry ice bath and stirred for 20 min until completely cooled.
Then, the I2/THF solution was syphoned into the mixture at –78 °C
and allowed to slowly warm up to r.t. overnight (approx. 16 h in to-
tal). Workup of the mixture was achieved by addition of sat. aq
Na2S2O3 solution until bleaching occurred (approx. 20 mL), followed
by addition of sat. aq NH4Cl (10 mL). The mixture was then extracted
with EtOAc (3 × 10 mL) and the combined organic layers were washed
with brine (10 mL), dried (MgSO4), and filtered. All organic solvents
[(TMP(H)Na(o-C6H4OMe)GaR3] (6)
1H NMR (400.13 MHz, 298 K, C6D6): δ = 7.97 (dd, 1 H, Ar-H), 7.09 (m, 1
H, Ar-H), 7.02 (td, 1 H, p-CH), 6.61 (d, 1 H, Ar-H), 3.46 (s, 3 H, OCH3),
2.08 (s, C6Me6), 1.28 [m, 2 H, γ-TMP(H)], 0.92 [t, 4 H, β-TMP(H)], 0.70
[s, 12 H, CH3 of TMP(H)], 0.26 [s, 28 H, Si(CH3)3 + TMP(H)], –0.57 (s, 6
H, CH2SiMe3).
Post-TMEDA Addition:
1H NMR (400.13 MHz, 298 K, C6D6): δ = 7.90 (dd, 1 H, Ar-H), 7.06 (m, 1
H, Ar-H), 6.98 (td, 1 H, p-CH), 6.58 (d, 1 H, Ar-H), 3.48 (s, 3 H, OCH3),
2.08 (s, C6Me6), 1.65 (m, 16 H, TMEDA), 1.53 [m, 2 H, γ-TMP(H)], 1.24
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

I
R. McLellan et al.
Feature
Synthesis
were then removed under reduced pressure to give a brown solid. The
yield of 2-iodoanisole was 65% (using NaTMP) and 1.5% (LiTMP) (NMR
using C6Me6 as internal standard in CDCl3). NMR data are in agree-
ment with those previously published for 2-iodoanisole.23
Kienle, M.; Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 7256.
(g) Garcia-Álvarez, J.; Kennedy, A. R.; Klett, J.; Mulvey, R. E.
Angew. Chem. Int. Ed. 2007, 46, 1105. (h) Blair, V. L.; Clegg, W.;
Conway, B.; Hevia, E.; Kennedy, A. R.; Klett, J.; Mulvey, R. E.;
Russo, L. Chem. Eur. J. 2008, 14, 65. (i) Wunderlich, S. H.;
Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 9717. (j) Alborés, P.;
Carrella, L. M.; Clegg, W.; García-Álvarez, P.; Kennedy, A. R.;
Klett, J.; Mulvey, R. E.; Rentschler, E.; Russo, L. Angew. Chem. Int.
Ed. 2009, 48, 3317. (k) Nagaradja, E.; Chevallier, F.; Roisnel, T.;
Jouikov, V.; Mongin, F. Tetrahedron 2012, 68, 3063. (l) Bedford,
R. B.; Brenner, P. B.; Carter, E.; Cogswell, P. M.; Haddow, M. F.;
Harvey, J. N.; Murphy, D. M.; Nunn, J.; Woodall, C. H. Angew.
Chem. Int. Ed. 2014, 53, 1804. (m) Martínez-Martínez, A. J.;
Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T. Science (Washington,
D. C.) 2014, 346, 834.
Funding Information
We thank the European Research Council (ERC StG, MixMetApps) and
the EPSRC (EP/N011384/1) for their generous sponsorship of this re-
search.
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Supporting Information
Supporting information for this article is available online at
(7) (a) Armstrong, D. R.; Crosbie, E.; Hevia, E.; Mulvey, R. E.;
Ramsay, D. L.; Robertson, S. D. Chem. Sci. 2014, 5, 3031.
(b) Uzelac, M.; Kennedy, A. R.; Hevia, E. Inorg. Chem. 2017, 56,
8615. (c) Uzelac, M.; Mulvey, R. E. Chem. Eur. J. 2018, 24, 7786.
(8) (a) Uzelac, M.; Kennedy, A. R.; Hevia, E.; Mulvey, R. E. Angew.
Chem. Int. Ed. 2016, 55, 13147. (b) McLellan, R.; Uzelac, M.;
Kennedy, A. R.; Hevia, E.; Mulvey, R. E. Angew. Chem. Int. Ed.
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(9) Frischmuth, A.; Fernández, M.; Barl, N. M.; Achrainer, F.; Zipse,
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Chem. Int. Ed. 2014, 53, 7928.
(10) Armstrong, D. R.; Brammer, E.; Cadenbach, T.; Hevia, E.;
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(11) Hevia, E.; Kennedy, A. R.; Mulvey, R. E.; Ramsay, D. L.;
Robertson, S. D. Chem. Eur. J. 2013, 19, 14069.
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P.; Okuda, J. Eur. J. Inorg. Chem. 2007, 665.
(13) Hallock, R. B.; Hunter, W. E.; Atwood, J. L.; Beachley, O. T. Jr.
Organometallics 1985, 4, 547.
https://doi.org/10.1055/s-0037-1611646.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I