Magnesium-mediated arylation of amines via C-F bond activation of fluoroarenes

Article abstract of DOI:10.1039/c9cc01670h

A series of new Mg(ii) amides featuring a bulky β-diketiminate backstop ligand, has been synthesised. These complexes are demonstrated to be excellent sources of nucleophilic amides that can participate in rapid C-F activation of several fluoroarenes at room temperature or using microwave assistance, leading to the installment of synthetically important C-N bonds via nucleophilic substitution.

Full text of DOI:10.1039/c9cc01670h

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DOI: 10.1039/C9CC01670H
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Magnesium-Mediated Arylation of Amines via C-F Bond Activation
of Fluoroarenes
Leonie J. Bole, Laia Davin, Alan R. Kennedy, Ross McLellan and Eva Hevia*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A series of new Mg(II) amides featuring a bulky -diketiminate amines via C-F bond cleavage. Thus, Diness has recently
backstop ligand, has been synthesised. These complexes are reported arylation of several amines by reaction with
demonstrated to be excellent sources of nucleophilic amides that fluoroarenes in the presence of LiHMDS as an early main group
can participate in rapid C-F activation of several fluoroarenes at alternative to transition metal catalysed Ullman and Buchwald-
room temperature or using microwave assistance, leading to the Hartwig couplings, although high temperatures (100oC) are
installment of synthetically important C-N bonds via nucleophilic required.7 Other Group one examples using such as BuLi, LiH or
KOtBu have also been described8 although selectivity control
has proved challenging due to the high basicity of the group 1
metal reagent. Notably, harsh reaction conditions are employed
(high T, long reaction times, excess of metal reagent) and very
limited tangible information is available regarding the nature of
the organometallic intermediates involved. In parallel to these
studies, it has been shown that other main group metals such
as Al, Pb and Sn can facilitate the transformation of C-F bonds
into C-NR2 (R= Me, Et). 9
substitution.
Fluorinated aromatic molecules are essential building blocks in
medicinal chemistry, where it has been estimated that 20% of
new drugs contain at least one C-F bond in their structure.1
Given the rarity of naturally occurring fluorinated organic
molecules, the regioselective functionalisation of fluorinated
building blocks is of importance synthetically to expand the pool
of fluoro organic molecules.2 Metallation is a powerful and
productive tool used in this regard,3 but despite the advantages
and renowned activity of the ubiquitous organolithium
reagents, such metallations are often impaired by poor
selectivity and unwanted side reactions.3a C-F bond activation is
a much rarer route to fluorinated organic molecules and is
dominated by precious transition metal complexes, wherein
careful complex construction is usually required to favour C-F
over competing C-H activation.4 The use of main group
complexes in C-F activation is starting to motor, accelerated in
part by the aspiration to turn towards more sustainable
chemical transformations. It has recently been reported that
low valent Mg(I), Al(I) and Si(II) complexes can regioselectively
promote oxidative addition of fluoroarene C–F bonds.5
Moreover, Grignard reagents, traditionally poor metallating
reagents can participate in C-C coupling reactions via
nucleophilic substitution although in most cases the presence
of a directing group is required.6 Nucleophilic aromatic
substitution has also shown promise in accessing arylated
Scheme 1. Contrasting reactivity of -diketiminate stabilised magnesium complexes
towards ppf: (a) deprotonative metallation vs C-F bond activation.
Recently we reported the synthesis and applications of specially
designed
[(DippNacnac)Mg(TMP)]
tetramethylpiperidide; DippNacnac = Ar*NC(Me)CHC(Me)NAr*;
Ar*
2,6-iPr2-C6H3) and [(DippNacnac)Mg(nBu)·THF] (2).10
Combining a sterically controlling -diketiminate ligand with a

-diketiminate stabilized mononuclear Mg systems
(1) (TMP=2,2,6,6-
=

kinetically-activated basic TMP amide, 1 has emerged as a
regioselective base capable of promoting the room tem-
perature direct Mg–H exchange of a range of challenging N-
heterocyclic substrates and fluoroarenes such as ppf [= 2-(2,4-
difluorophenyl)pyridine] (Scheme 1a).10a Contrastingly,
replacing TMP by a butyl group switches on an alternative
reaction pathway, affording the relevant C-F bond activation
L. J. Bole, Dr L. Davin, Dr A. R. Kennedy, Dr R. McLellan, Prof. E. Hevia
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde
Glasgow, G1 1XL (UK)
E-mail: eva.hevia@strath.ac.uk
† Supporting information for this article is given via a link at the end of the document.
This journal is © The Royal Society of Chemistry 20xx
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-diketiminate ligand acts as (Table 1). In all cases the reaction occurs with formation of a
product (Scheme 1b).10b While the
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a spectator in these reactions, it plays a mandatory role large amount of white precipitate, whichDhOaIs: 1b0e.1e0n39i/dCe9nCtCif0i1e6d70aHs
facilitating stabilization of the newly formed sensitive anion in C-F activation coproduct [{(DippNacnac)MgF}2.2THF] (8)12 which
the metallation reactions as well as generating a unique can also be seen in small amounts in the 19F NMR spectrum of
coordination environment for Mg, enabling substrate the reaction crudes at -189 ppm.
coordination which favours nucleophilic addition/substitution Illustrating the potent nucleophilic power of these magnesium
besides controlling the regioselectivity of the Mg for hydrogen systems, the mild reaction conditions (rt, 10 min) sit in sharp
exchange reactions.10
contrast with those recently reported for the lithium-mediated
Expanding the synthetic potential of

-diketiminate stabilised amination of 2(2-fluorophenyl)pyridine with secondary amines,
magnesium complexes, here we present their first applications that not only require high temperatures and long reaction times
towards promoting regioselective amination of fluoroarenes to (110oC, 12h), but also a large excess of amine and lithium
access a range of N-aryl tertiary amines.
hydride.8c Remarkably, in all cases selective C-F bond activation
To begin we elected to prepare a series of new complexes is observed suppressing completely the competitive
containing a nucleophilic (and less basic than benchmark 1) deprotonative metallation of the substrate, a selectivity
magnesium amide functionality by the amine exchange reaction problem which has previously noted when using polar group 1
of 1 with aliphatic amines, nBu2NH, piperidine or morpholine in organometallics.7,8b Additionally, while amination of 2-
THF at room temperature, which resulted in rapid halopyridines has been extensively studied using transition
deprotonation of the respective amine. In all cases we were metal catalysis (e.g., using Pd, Ni, Cu or Cr),13 or by substitution
able to structurally characterise the new magnesium amides reactions using highly basic lithium amides, investigations of
[(DippNacnac)Mg(NnBu2).THF] (3), [(DippNacnac)Mg(NC5H10)]2 (4) magnesium systems have been scarce. A notable exception is
and [(DippNacnac)Mg(NC4H8O).THF] (5), albeit the data quality of the work of Knochel on amination of pyridine-2-sulfonyl
5 is poor and only suitable for general connectivity (see SI). The chloride with mixed-metal amides NR2MgCl.LiCl.14
molecular structures of 3 and 5 are monomeric with Mg
surrounded by 3 N atoms and an O atom of THF. In contrast, 4 Table 1 Reactions of
-diketiminate magnesium amides 3-6 with ppf
surprisingly displays a dimeric rearrangement (Fig. 1), despite and 2-fluoropyridine.[a][b]
piperidine having a nearly identical steric profile to morpholine,
which is reminiscent to that described by Hill for the pyrrolidide
adduct [(DippNacnac)Mg(NC4H8)]2 (6).11
Figure 1 Molecular structures of 3 (left) and 4 (right). Hydrogen atoms are omitted
for clarity and thermal ellipsoids are rendered at 30% probability. Dipp
substituents drawn as transparent for clarity.
[a] Reactions carried out using 0.25 mml of ppf or 2-F-pyridine, 0.25 mmol of relevant
Mg amide complex in 0.5 mL of D8-THF. See ESI for experimental details. [b] Yields
determined by 1H NMR using 15 or 20 mol% FeCp2 as an internal standard.
Furthermore, in situ studies have revealed that arylamides 7a-d
can be formed in similar yields using a one pot approach by
reacting the relevant amine with ppf in the presence of
equimolar amounts of TMP-base 1 (Scheme 2). Despite the fact
that 1 has proved to readily deprotonate this substrate at its C3
position on the fluorinated ring (Scheme 1a),10b formation of the
relevant amide complex 3-6 is preferred, switching on the C-F
bond activation reaction pathway.
1
Interestingly, H DOSY NMR studies of 4 and 6 revealed that in
d8-thf solution, both species also exhibit monomeric
arrangements as those seen in crystalline 3 and 5. With these
potentially nucleophilic sources of amides in hand, we next
assessed their suitability for C-F activation using ppf and 2-
fluoropyridine as model substrates.
A
series of reactions between 3-6 with 2-(2,4-
difluorophenyl)pyridine or 2-fluoropyridine were conducted in
J. Young’s NMR tubes at room temperature in d8-THF (Table 1).
Monitoring these reactions by 1H and 19F NMR revealed in each
case, quantitative conversion (for ppf) or (ca. 80% for 2-
fluoropyridine) to the desired tertiary amine, resulting from a
regioselective C-N bond forming/C-F bond cleavage process
Scheme 2. One-pot arylation of amides with ppf using TMP-amido magnesium complex
1.
2 | J. Name., 2012, 00, 1-3
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At this point it is evident that sufficiently nucleophilic
COMMUNICATION
ligand, confirming that a coordination adduct exisVtisewinArstiocleluOtniolinne

-
diketiminate magnesium amides, that are monomeric in (see ESI). A related pyridine coordinaDtiOoIn: 10a.1d0d3u9/cCt9ChCa0s16a7l0sHo
solution are excellent in promoting C-F activation, thus we structurally characterised by Hill.15 This scenario, predisposes
decided to test the generality of the reaction using the less ppf for addition of the amide group to the aryl group generating
nucleophilic amines diphenylamine and aromatic N-heterocycle a new C-N bond (see II in Scheme 3) which is followed by the
benzotriazole. Reaction of 1 with both amines resulted in elimination of the highly insoluble fluoride complex 8,
isolation as off-white crystalline solids in each case, furnishing amination products 7a-d. A similar pyridyl-directed
corresponding
to
[(DippNacnac)Mg(NPh2)]
(9)
and amination can be envisaged in forming 7e-h.
[(DippNacnac)Mg(N3C6H4)]2 (10), in 61 and 55% isolated yields
(see ESI for details). X-ray crystallographic studies revealed a
monomeric structure for 9; whereas 10 is a dimer, where the
benzotriazolyl anions connect the Mg centres through their
N=N junction, giving rise to a six-membered {MgNCMgNC} ring,
with each Mg clamped by a
-diketiminate ligand (Fig. 2).
Reflecting the lower basicity and higher degree of electronic
delocalization on the amido N groups, in both complexes the
geometry around this N atom in both complexes is trigonal
planar (sum of the angles around Namide is 359.77 and 360.1o for
9 and 10 respectively).
Scheme 3. Proposed reaction sequence for magnesium-mediated C-F bond amination of
ppf. by 3-6.
We next pondered if this approach could be extended to other
1
fluoroarenes without a pyridyl directing group. H and 19F NMR
monitoring of the reaction of piperidide complex 4 with
perfluoroarene C6F6 showed no C-F bond activation at room
temperature. By heating at 70oC over 40h, the 19F spectrum of
the reaction mixture showed formation of a new product which
exhibiting three resonances in a 2:2:1 ratio -151.2, -164.7 and -
165.2 ppm consistent with the activation of one C-F bond in C6F6
Figure 2 Molecular structures of
9 (left) and 10 (right). Hydrogen atoms are
omitted for clarity and thermal ellipsoids are rendered at 30% probability. Dipp to form 2,3,4,5,6-pentafluoro-Npiperidide (10a), along with a
substituents drawn as transparent for clarity.
resonance at -189 ppm which can be assigned to fluoride
Reactivity studies of 9 and 10 with equimolar amounts of
ppf show that at room temperature neither of these amido
complexes can promote the C-F bond activation reaction. For
9, by increasing the temperature of the reaction to 70oC for 11h
tertiary amine 7e was formed in a 75% yield (see ESI) whereas
in the case of 10 even after 14h at this 110oC no reaction was
observed. Revealing a close structure/reactivity interplay, these
magnesium-mediated amine arylation processes seem to be
limited to aliphatic amines, whereas aromatic ones formed
more resonance stabilized magnesium intermediates which
react sluggishly with the fluoroarene.
A proposed rationale for how these transition-metal free C-F
bond cleavage/C-N bond forming processes may occur is
depicted in Scheme 3. First the substrate (as illustrated with ppf
in Scheme 3) may coordinate to Mg via the pyridyl N, placing
the ortho-C-F bond of the aryl group, pre-activated by the
pyridyl substituent, in close proximity to the reactive
magnesium amide bond (intermediate I in Scheme 3). While I
cannot be detected when ppf is reacted with Mg amides 3-6 as
the reaction occurs almost instantaneously, using less
complex 8. Disappointingly, despite the harsh reaction
conditions the conversion observed for 11a was 26%.
In an attempt to optimise the reaction conditions, we decided
to probe microwave radiation which is known to accelerate
reaction rates using milder conditions, affording in some cases
higher yields with a greater control of the selectivity than that
produced by conventional heating.16 Pleasingly, reaction of 1,
piperidine and hexafluorobenzene in THF in a microwave vial
(125 ⁰C, 20 minutes) afforded 11a in a yield of 80% (Table 2).
This approach can also be extended to morpholine and
pyrrolidine affording 11b and 11c in 78 and 87% yield
respectively. On the other hand using primary amine aniline or
dibutylamine the yields noticeably dropped (34 and 18%
respectively, 11d-e in Table 2); whereas diphenylamine and
benzotriazole fail to react with C6F6. Extending this reactivity to
octafluorotoluene revealed that efficient and selective C-F
activation in just one hour at room temperature in THF
affording arylation products 11f-11i in excellent yields ranging
from 99-85% (Table 2). When the reaction of 4 was attempted
with less activated fluorobenzene (MW, 125oC, 60 min) only
modest conversions to the activation product 11j were
obtained (20%), however it is important to note that no other
reactions were observed (i.e. deprotonative metalation) (see SI
nucleophilic diphenylamide
9
it can be detected
spectroscopically. DOSY NMR studies of this proposed
intermediate showed that resonances corresponding to ppf,
and the amide diffuse together with those of the DippNacnac
for details). These results demonstrate the ability of
-
This journal is © The Royal Society of Chemistry 20xx
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diketiminate stabilised magnesium amides to promote C-F
activation of perfluoroarenes via the installation of synthetically
relevant C-N bonds. For these reactions where the substrate
lacks of a pyridyl directing group, approximation of the
fluoroarene to the magnesium amide complex can be envisaged
to occur by the formation of Mg..F-C interactions which could
then facilitate the nucleophilic attack. The key role of these
interactions has been elegantly demonstrated by Crimmin for
the addition of fluoroarenes and fluoroalkanes to low oxidation
state Mg-Mg complexes.17
Notes and references
Keywords: magnesium • amides • fluoroarenes • C-F bond
activation •C-N bond formation • C-F bond activation •β-
diketiminate
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DOI: 10.1039/C9CC01670H
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Table 2 C-F activation of non-directed fluoroarenes
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[a] Reactions were carried out in a microwave reactor on a 1 mmol (0.5 M) scale in THF
solvent at 125 oC for 20 min. Yields calculated against 10 mol% FeCp2 as an internal
standard. 11a-11c purified and isolated by column chromatography. Isolated yields
shown in brackets [b] Reaction time was extended to 1h. [c] Yields correspond to
reactions carried out in a Schlenk flask for 1 h at room temperature in THF solvent. NMR
yields determined against 10 mol% FeCp2 as an internal standard. Isolated yields shown
in brackets.
In summary, pushing forward the synthetic utility of
-
diketiminate stabilised magnesium complexes, by synthesizing
and structurally defining a range of nucleophilic amide complex,
a new method for arylating amines via C-F bond activation of
fluoroarenes is presented. Nucleophilic substitution is facile at
room temperature when assisted by a pyridyl directing group or
using perfluorinated octafluorotoluene; whereas for
hexafluorobenzene, microwave assistance is required.
Structural insights on how the reactivity profiles of these
magnesium species can be finely tuned have also been unveiled.
We thank the European Research Council (ERC StG,
MixMetApps) and the EPSRC (EP/N011384/1) for their generous
sponsorship of this research. We also thank Prof. Robert E.
Mulvey and Dr. Charles T. O’Hara for insightful discussions. Data
supporting this research are openly available from
www.datasettbc.com.
Conflicts of interest
There are no conflicts to declare.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC01670H
Ar*
Ar*
N
Mg
N
THF
N
Mg
N
Ar*
Y
Y
N
Ar*
NR2
+
NHR2
Z
X
NR2
via monomeric
Mg amide
Z
X
F
RT, 10 min
X-ray/ DOSY NMR
Text for TOC
Exploiting the high nucleophilic power of structurally defined β-diketiminate
stabilised magnesium amides, a new method for amine arylation via rapid C-F
bond activation of fluoroarenes is introduced.