Buttressing Effect as a Key Design Principle towards Highly Efficient Palladium/N-Heterocyclic Carbene Buchwald–Hartwig Amination Catalysts

Article abstract of DOI:10.1002/chem.201702859

The backbone substitution of the standard 1,3-bis(2,6-diisopropylphenyl)-2H-imidazol-2-ylidene (IPr) ligand by dimethylamino groups was previously shown to induce a dramatic improvement in the catalytic efficiency of the corresponding Pd–PEPPSI (pyridine-enhanced pre-catalyst preparation, stabilization, and initiation) pre-catalysts in N-arylation reactions. Herein, a thorough structure/activity study towards rationalizing this beneficial effect has been described. In addition to the previously reported IPr (Formula presented.) and IPr (Formula presented.) ligands, the new IPr (Formula presented.) and IPr (Formula presented.) ligands, which bear one bulkier diisopropylamino group and a combination of dimethylamino and chloro substituents, respectively, have been designed and analyzed in the study. The influence of the backbone substitution was found to be steric in origin and is related to the well-known buttressing effect encountered in arene chemistry. The usefulness and versatility of this approach was demonstrated through the development of a highly efficient catalytic system for the challenging arylation of bulky α,α,α-trisubstituted primary amines. The optimized system based on the [PdCl(η³-cinnamyl)(IPr (Formula presented.))] or [PdCl(η³-cinnamyl)(IPr (Formula presented.))] pre-catalysts operates under unprecedented mild conditions (catalyst loadings: 0.5–2 mol %, reaction temperatures: 40–60 °C) with a wide substrate scope.

Full text of DOI:10.1002/chem.201702859

A Journal of
Accepted Article
Title: Buttressing effect as key design principle towards highly efficient
palladium/N-heterocyclic carbene Buchwald-Hartwig amination
catalysts
Authors: Yin Zhang, Guy Lavigne, Noël Lugan, and Vincent César
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10.1002/chem.201702859
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Buttressing effect as key design principle towards highly efficient
palladium/N-heterocyclic carbene Buchwald-Hartwig amination
catalysts
Yin Zhang,[a] Guy Lavigne†,[a] Noël Lugan,[a] Vincent César*,[a]
Abstract: The backbone substitution of the standard 1,3-bis(2,6-
diisopropylphenyl)-2H-imidazol-2-ylidene (IPr) ligand by
to provide highly stable and active Pd-NHC catalysts thanks to
their strong -electronic donation and good steric protection.[7]
Another beneficial advantage of NHCs resides in the high
synthetic flexibility of their precursors, offering in fine a wide scope
of stereoelectronic properties for the corresponding ligands.[8]
During the last decade, collective efforts have been directed
towards the improvement of Pd-NHC based catalytic systems in
terms of efficiency, scope and practicability. From the benchmark
1,3-bis(2,6-diisopropylphenyl)-2H-imidazol-2-ylidene ligand (IPr),
which led to the best catalytic outcome among the classical
NHCs,[9] excellent results have been obtained upon formal
replacement of the 2,6-diisopropylphenyl (Dipp) nitrogen
substituents by bulkier aryl groups bearing extended ortho
substituents such as 3-pentyl (leading to the IPent ligand),[10] 4-
heptyl (IHept ligand),[11] 5-nonyl (INon ligand)[11] or diphenylmethyl
groups (IPr* ligand) (Fig. 1).[12] The development of these NHCs
was based on the concept of “flexible steric bulk”, first introduced
by Glorius, according to which the bulky NHC ligand efficiently
stabilizes the reactive, mono-coordinated, low-valent active
species [Pd0(NHC)] and facilitates the reductive elimination step,
while its flexibility allows its adjustment to the incoming
substrates.[13] In parallel, we and others have investigated the
direct modification of the heterocyclic skeleton of the IPr ligand
and have shown that backbone substitution has eventually a
beneficial effect on the catalytic efficiency of the resulting Pd-
catalysts.[14,15] The improvement was particularly impressive
dimethylamino groups was previously shown to induce a dramatic
improvement of the catalytic efficiency of the corresponding Pd-
PEPPSI pre-catalysts in N-arylation reaction.
A
thorough
structure/activity study aiming at rationalizing this beneficial effect is
now described. In addition to the previously reported IPrNMe and
2
IPr(NMe ) ligands, the new IPrNiPr and IPr(NMe ,Cl) ligands bearing
respectively, one bulkier diisopropylamino group and a combination
of dimethylamino and chloro substituents, have been designed and
included in the study. It is shown that the influence of the backbone-
substitution is actually steric in origin and is related to the well-known
buttressing effect encountered in arene chemistry. The usefulness
and versatility of this approach are demonstrated through the
development of a highly efficient catalytic system for the challenging
arylation of bulky -trisubstituted primary amines. The optimized
2
2
2
2
3
system based on the [PdCl(3-cinnamyl)(IPr(NMe ) )] or [PdCl( -
2
2
cinnamyl)(IPrNiPr )] pre-catalysts operates under unprecedented mild
2
conditions (catalyst loadings: 0.5-2 mol%, reaction temperatures: 40-
60°C) and over a large substrate scope.
Introduction
The palladium-catalyzed amination of aryl halides has become a
valuable and powerful tool for the construction of carbon-nitrogen
(C-N) bonds to access anilines, a common structure found in
natural compounds, drug agents, fine chemicals and other
complex molecules.[1,2] The broad success of this catalysis has
greatly benefited from i) the development of well-defined, easy to
handle pre-catalysts able to readily liberate the mono-ligated
palladium(0) active species into the catalytic cycle,[3] and
especially from ii) the advent of specially designed classes of
ligands, enabling the C-N coupling in high levels of efficiency and
selectivity. In that prospect, and apart bulky monodentate and
electron-rich tertiary phosphines,[4] N-heterocyclic carbenes
(NHCs)[5,6] have been increasingly employed as ancillary ligands
when substituting the 4/5 positions of the imidazolyl ring with one
(IPrNMe
)
and especially with two dimethylamino groups
2
(IPr(NMe2)2).[14a-b] In our first report, we concluded that this observed
booster effect could be seen as the result of a synergism between
steric and electronic effects since the incorporation of the NMe2
groups led to a sequential increase of both the electronic donation
and steric bulkiness of the correspondi ng NHC. In the meantime,
Organ and co-workers developed a wide variety of Pd-PEPPSI-
NHC pre-catalysts,[16] some of the NHCs exhibiting backbone
modification, and showed in particular that pre-catalysts based on
the dichloro-substituted IPentCl or IHeptCl supporting ligands
greatly outperform their respective IPent-and IHept-based
standard analogues.[17,18] In these studies, the improvement of the
pre-catalysts efficiency was essentially ascribed to steric effects,
while electronic effects were judged as being rather
unimportant.[17b,c]
2
2
[a]
Dr Y. Zhang, Dr G. Lavigne, Dr N. Lugan, Dr V. César
LCC-CNRS, Université de Toulouse, INPT, UPS, Toulouse, France
Fax: (+)33 (0) 5 61 55 30 03
E-mail: vincent.cesar@lcc-toulouse.fr
Deceased on 23 April 2015
†
Supporting information for this article is given via a link at the end of
the document
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Synthesis of the new NHCs and palladium PEPPSI pre-
catalysts
The 4-(diisopropylamino)imidazolium triflates 3a-bNiPr were
2
prepared following the same strategy than the one we previously
developed for the 4-(dimethylamino) imidazolium triflates 3a-
[14a]
bNMe
.
The two-step sequence consists in an alkylation of the
2
formamidine 1a-b with N,N-diisopropyl-2-chloroacetamide
followed by a selective activation of the amide function of the
intermediate 2a-b by triflic anhydride leading to an intramolecular
cyclization (Scheme 1). Whereas the first step proceeded in high
yield (95-99%), the second cyclisation step was less efficient as
compared to the dimethylamino derivatives, probably due to a
higher steric congestion of the heterocycle. The corresponding
Pd-PEPPSI-IPrNiPr complex 5NiPr was obtained in four steps
2
2
through the classical route we described in our previous
communication.[14a] Complex 5NiPr was fully characterized by the
2
usual spectroscopic methods supplemented by a single-crystal X-
Ray diffraction study (Figure 2).
Figure 1. Context and principle of the present work.
In this context, we became interested in getting a deeper
understanding of the structural features at play in our systems and,
eventually, in establishing the “key design principle” on which
optimization of Pd-NHC catalysts through backbone
functionalization may be based. To this end, our strategy relied
on further derivatizing our first two amino-substituted NHC ligands
IPrNMe2 and IPr(NMe2)2 into two complementary directions: i) a formal
substitution of the dimethylamino (NMe2) group by the bulkier
diisopropylamino (NiPr2) group in order to increase steric
shielding and conversely, ii) a formal replacement of one of the
dimethylamino groups by an electron-withdrawing chlorine atom
in order to diminish the electronic donicity.
Through the present work, we shall demonstrate that the
observed beneficial influence of the substitution of the
imidazolylidene ring on the catalytic activity in Pd-catalyzed
amination mainly arises from steric effects prompting us to
i
2
2
Scheme 1. Synthesis of the imidazolium salts 2a-bN Pr , and 2a-b(NMe ,Cl) and of
i
2
2
,Cl)
the corresponding Pd-PEPPSI complexes 3N Pr , and 3(NMe
(Mes = 2,4,6-
formalize it as
a buttressing effect, which is classically
trimethylphenyl, Dipp = 2,6-diisopropylphenyl).
encountered in aryl chemistry. Exploiting this concept allowed to
develop a highly efficient Pd-NHC catalytic system for the
challenging arylation of bulky primary amines.
We next turned our attention to the synthesis of the imidazolium
salts 3a-b(NMe ,Cl) through direct oxidative chlorination of the
2
corresponding imidazolium salts 3a-bNMe on the imidazolyl C5
2
Results and Discussion
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position (Scheme 1). We were encouraged in this direction by our
previous demonstration of such a reactivity trend in related NHCs
having a functionalized heterocyclic backbone.[19] Whereas no
this study. In a first set of experiments, the amination of 4-
chloroanisole by morpholine (0.5 mol% catalyst, 1.1 eq. KOtBu,
DME, 25°C) was monitored against reaction time. The resulting
reactivity profiles are displayed in Figure 3. In order to exclude
potential experimental bias resulting from the variable hydrolysis
level of the KOtBu base, the latter was strictly purified to remove
any traces of KOH and tBuOH, and then stored and weighed in a
glove box. It is worth noting that this protocol drastically increases
the catalytic efficiencies of all the pre-catalysts, including those of
reaction occurred when mixing the imidazolium triflates 3a-bNMe
2
with a small excess (1.2 equiv) of N-chlorosuccinimide (NCS) in
CH2Cl2 at room temperature, we were pleased to observe the
complete disappearance of the signal corresponding to the C5-
proton of the imidazolium ring in the 1H NMR spectrum after only
30 minutes when carrying out the reaction in CHCl3. This
dichotomy in reactivity could be ascribed to the more acidic
character of chloroform, which should assist this transformation.
5NMe and 5(NMe ) we investigated previously.[14a] As a matter of
2
2 2
example, pre-catalyst 5(NMe ) led to full conversion in 10 minutes
2 2
The pure imidazolium triflates 3a-b(NMe ,Cl) were obtained in 47-
using the new protocol, to be compared to 2 hours using the
2
65% yields after a simple column chromatography and/or
previous one. Analysis of the kinetic curves indicates that the
recrystallization. The molecular structure of 3b(NMe ,Cl) was further
three pre-catalysts 5(NMe ) , 5(NMe ,Cl), and 5NiPr exhibit about the
same activity, while the IPent-derived complex 6 is a little less
efficient. Conversely, the reaction did not reach completion after
2
2 2
2
2
confirmed by an X-Ray diffraction analysis (Figure S1, supporting
information). Such a reactivity is unique as previous procedures
for the halogenation of imidazolium rings all proceeded in three
steps involving the generation of the free imidazol-2-ylidene, its
reaction with an oxidizing reagent, and a final reprotonation.
Besides, strict anhydrous and inert reaction conditions are also
required limiting the practicability and generality of the previous
procedure.[20] Moreover, we could also capitalized on the peculiar
reactivity of the 4-(dimethylamino)imidazol-2-ylidene core to
Cl
2 hours when using pre-catalysts 5NMe , 5, and 5
.
2
2
directly derivatize the Pd-PEPPSI-IPrNMe complex 5NMe into its
2
2
chloro-derivative Pd-PEPPSI-IPr(NMe ,Cl), 5(NMe ,Cl), in a very good
yield (85%) (Scheme 1). This strategy turned out to be very
advantageous for a rapid optimization of the catalytic system
2
2
thanks to the late point of divergence.[19c-d,21] Complex 5(NMe ,Cl)
2
was fully characterized and its molecular structure was
unambiguously confirmed by an X-Ray diffraction analysis (Figure
2).
Figure 3. Reactivity profiles of the amination of 4-chloroanisole with morpholine
using Pd-PEPPSI-NHC pre-catalysts 5XY and 6. Conversions were determined
by GC analysis using dodecane as internal standard. Reactions were performed
in duplicate. DME = 1,2-dimethoxyethane.
i
2
2
,Cl)
Figure 2. Molecular structures of 5N Pr (left) and 5(NMe
(right), thermal
ellipsoids set at the 30% probability level. H-atoms have been omitted for clarity.
We then decided to further explore the effect of the imidazolyl-
backbone substitution in the challenging amination of the more
sterically hindered 2-chloroanisole with morpholine under the
same reaction conditions as above (Figure 4). The kinetic profiles
revealed exactly the same trend as for 4-chloroanisole and is
Comparison of the catalytic activities of Pd-PEPPSI-NHC pre-
catalysts
The catalytic efficiencies of the newly synthesized IPr-derived
palladium PEPPSI pre-catalysts 5NiPr and 5(NMe ,Cl) were then
2
2
even accentuated. Indeed, complex 5(NMe ) shows the best
2 2
evaluated in relation to those of our previously reported pre-
efficiency with 91% conversion in 5 min, and full conversion after
less than 1 hour, at 25°C. This result advantageously compares
with the most active system known to date based on the
catalysts 5NMe and 5(NMe ) , of the standard Pd-PEPPSI-IPr pre-
2
2 2
catalyst 5, and of the dichloro-substituted 5Cl . For comparative
2
purposes, the Pd-PEPPSI-IPent complex 6 was also included in
[PdCl(cin)(SIPr)] pre-catalyst (cin
=
3-cinnamyl).[15a] Pre-
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catalysts 5NMe , and 5 are much less efficient showing 34%, and
literature data,[8b-c] and because the electronic properties are
similarly influenced by the backbone substitution in IMes and IPr
2
15% conversion, respectively, after 2 hours, while 5Cl is basically
inactive. Again, the pre-catalyst 5NiPr showing 90% conversion
after 2 hours, is found to be much more efficient than its
dimethylamino analogue 5NMe , indicating that the increase of the
2
ligands series. In supplement to the rhodium complexes 8NMe and
2
2
8(NMe ) we already described,[14a] the new complex 8NiPr was
2 2
2
2
synthesized in two steps from [RhCl(COD)]2 and the
2
steric hindrance of the amino substituent has a significant effect
on the catalytic outcome of the amination reactions. Likewise, the
corresponding imidazolium salt 3aNiPr to give first the
intermediate complex [RhCl(COD)(IMesNiPr2)] 7NiPr that was
2
chloro-amino-substituted 5(NMe ,Cl) exhibits about the same activity
converted to the carbonyl complex 8NiPr in a subsequent
2
2
as 5(NMe ) suggesting also that the replacement of one of the
carbonylation step (73% overall yield) (Scheme 2, left side).
Taking again advantage of the specific reactivity of the enamine-
type heterocyclic backbone of coordinated IMesNMe2, complex
2 2
NMe2 group in IPr(NMe2)2 by a chlorine atom has only a small effect
in these two model catalyses. On the overall, the analysis of the
two reactivity profiles allows classifying the various NHC ligands
we considered into three categories according to the catalytic
efficiency of the resulting pre-catalysts. The first category is
8NMe was readily derivatized into 8(NMe ,Cl) upon reaction with NCS
2
2
in CHCl3 (Scheme 2, left side).
composed of the most efficient IPr(NMe2)2, IPr(NMe ,Cl) and IPrNiPr
2
2
ligands, the third one includes the low efficiency IPr, IPrCl and
IPrNMe2 ligands, and the second one consisting of the IPent ligand
only, its efficiency being in between.
2
i
2
Scheme 2. Synthesis of the new rhodium-carbonyl complexes 8N Pr and
2
8(NMe ,Cl) and selenoureas 9XY
.
The -acidity of the series of NHC ligands we considered was next
evaluated against the chemical shifts of the 77Se nuclei in the
seleno adducts IMesXY-Se, the latter values offering a reliable
scale of the π-acidity of NHCs.[23] Here, the new selenoureas 9NMe
,
2
NiPr
9(NMe ) , and 9
were readily synthesized upon reaction of the
2 2
2
corresponding carbenes with elemental selenium, while 9(NMe , Cl)
2
was obtained upon derivatisation of 9NMe by reaction with NCS
2
(Scheme 2, right side).
Figure 4. Reactivity profiles of the amination of 2-chloroanisole with morpholine
using Pd-PEPPSI-NHC pre-catalysts 5XY and 6. Conversions were determined
by GC analysis using dodecane as internal standard. Reactions were performed
in duplicate. DME = 1,2-dimethoxyethane.
Finally, the steric properties of the ligands in complexes Pd-
PEPPSI-NHC 5XY and 6 were quantified by calculating the percent
buried volume (%Vbur) using the geometry resulting from single
crystal X-ray diffraction analyses.[24] Data for complexes 5NMe and
2
5(NMe ) were retrieved from our previous publication,[14a] while
2 2
Rationalization of the catalytic efficiency in terms of
stereoelectronic effects: buttressing effect in N-heterocyclic
carbenes
those of complexes 5 and 6 were recovered from the CCDC
database.[25] Finally, for the fate of comparison, we determined
the solid-state structure of complex 5Cl , which had not been
2
In order to investigate structure/activity trends, we then turned our
attention to the in-depth characterization of stereoelectronic
properties of the whole series of NHC ligands we had in hands.
The overall electronic donicity of the NHC ligands were first
reported before.(Figure S2).
The stereoelectronic parameters of backbone-substituted IPrXY
thus determined, along with those of IPent, are gathered in Table
1.
av
quantified by recording the average IR stretching frequency CO
of the carbonyl ligands in complexes [RhCl(CO)2(IMesXY)] 8XY
,
which is correlated to the Tolman Electronic Parameter (TEP)
value of the ligand by a well-established linear correlation.[8b,c-22]
The IMes platform was chosen here for comparison purposes with
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conclude that the beneficial effect observed with amino-
substituted IPr ligands is steric in origin and that electronic effects
are much less important. This is particularly clear when
Table 1. Stereoelectronic parameters of backbone-substituted IPrXY and
IPent.
av
Entry
NHC
CO of
8XY
TEP
value
(cm-1)[b]
(77Se)
in 9XY
(ppm)[c]
%Vbur
(%)
(from
5XY)
considering the catalytic activity of pre-catalyst 5(NMe ,Cl), which is
2
about the same as the of 5(NMe ) , while IPr(NMe ,Cl) is much less
2
2 2
(cm-1)[a]
electron-donating than IPr(NMe2)2. Conversely, the carbenes IPrNiPr
and IPrNMe exhibit about the same electron donating properties,
2
2
1
2
3
IMes/IPr
2037.6
2035.8
2034.0
2050.3
2048.8
2047.4
27[d]
32
34.3
39.7
2
2
but 5NiPr greatly surpasses 5NMe in terms of efficiency in
amination catalysis. At that point, we could not totally figure the
exact, precise effect the backbone substituents had on the
catalytic activity of the resulting complexes since the %Vbur is a
global steric descriptor, and the %Vbur for the four amino-
substituted IPr ligands we considered are very close and should
actually be considered as identical within the experimental errors.
Opportunely, in 2016 Cavallo and co-workers put the new
SambVca2 web application at disposal of the research
community.[29] The implementation of the X-Ray structures of
complexes 5, 5XY, and 6 into this application gave access to the
three-dimensional topographical map of our complexes. The
shape of the catalytic pocket defined by the ancillary NHC ligand
could then be analyzed in details. By choosing the right
coordinates, the coordination sphere around Pd was divided into
four quadrants and the steric shielding provided by the NHC
(IMes/IPr)NMe2
(IMes/IPr)(NMe2)2
26
40.2/
38.7
4
5
6
7
(IMes/IPr)NiPr2
(IMes/IPr)(NMe2,Cl)
(IMes/IPr)Cl2
IPent
2035.0
2038.0
2042.5
-
2048.2
2050.6
2054.2
2049.3[e]
36
40.6
39.8
34.2
38.3
68
174[f]
101[d]
[a] IR spectra recorded in CH2Cl2; [b] TEP values calculated using the
av
equation TEP = 0.8001 CO + 420.0 cm-1; [c] NMR spectra recorded in
CDCl3; [d] from reference 23b; [e] from reference 26; [f] Value obtained from
IPrCl2, from reference 23b.
ligands in each of them was calculated separately. The Ccarbene
-
Pd bond was chosen as the z axis and the imidazolylidene plane
constituted the (xz) plane. With this cutting, each quadrant is
occupied by one of the four ortho substitutents of the N-aryl
groups of the NHC ligand (iPr group for complexes 5XY and 3-
pentyl group for complex 6) (Figure 5).
Several features can be drawn from a detailed analysis of these
data. First, the 77Se chemical shifts of the amino-substituted NHC-
(NMe )
2 2
Se adducts 9NMe , 9
and 9NiPr do not really differ from the
2
2
one of the unsubstituted derivative 9, highlighting that the grafting
of an amino group onto the imidazolyl skeleton has only little effect,
if any, on the -acidity of the corresponding NHC (entries 1-4). In
other words, the amino groups interact at best weakly with the -
system of the imidazol-2-ylidene. This corroborates our recent
work on amino/ammonio-substituted imidazol-2-ylidenes and is in
agreement with previous DFT calculations by Huber and Weiss
on related systems.[27,28] Comparison of the TEP values confirms
our working hypothesis as a size increase of the amino group
does not affect the electron donicity of the mono-substituted
NHCs (compare 8NMe vs. 8NiPr , entries 2 and 4), whereas the
2
2
formal substitution of a dimethylamino group in 8(NMe ) by a
2 2
chloride led to a diminished electronic donation of the chloro-
amino-substituted NHC in 8(NMe ,Cl) (entries 3 and 5). Interestingly,
2
the TEP value of the latter NHC is about the same as the
unsubstituted standard IMes ligand. Yet the %Vbur of IPr(NMe ,Cl)
2
ligand in 5(NMe ,Cl) (entry 5) is much higher than the one of standard
2
IPr in 5 (entry 1), and is similar to the one of IPr(NMe ) in 5(NMe )
(entry 3). Actually, it appears that the substitution of the
heterocyclic backbone by at least one amino group leads to a
strong increase of the %Vbur from 34.3% in 5 (entry 1) to values
2 2
2 2
(NMe )
NiPr
around 40% in 5NMe , 5
, 5
, and 5(NMe ,Cl) (entries 2-5). As
2
2 2
2
2
expected, the substitution of the heterocycle by two chlorine
atoms gives access to a poorer electron donating NHC, but this
has virtually no effect on the steric shielding of the IPrCl2 ligand in
complex 5Cl compared to 5.
2
Figure 5. Steric map views of the Pd-PEPPSI-NHC complexes 5XY and 6. For
unsymmetrically substituted complexes, the amino group was placed arbitrarily
as the X substituent and was thus on the right of the steric map. 1 and 2
Correlating the stereoelectronic properties of the NHCs with the
catalytic activity of the corresponding pre-catalysts 5XY allows to
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represent the dihedral angles between the imidazolyl and aryl planes. Values in
corners are the %Vbur of the NHC ligand in the corresponding quadrant.
provide a rationalization of the beneficial effect that previous
NHC-backbone substitution had in the Buchwald-Hartwig
amination reaction.[15,17]
In general, except for complex 5Cl , two diametrically opposed
2
quadrants are sterically crowded, whereas the other two are
relatively unhindered. Noteworthy, the most hindered quadrant is
always on the same side as the amino group on the heterocyclic
backbone (on the right side of the steric map), confirming that the
NMe2 and the NiPr2 groups clearly push one of the ortho-iPr
groups of the Dipp aryl groups in direction of the reactive catalytic
site. This is done through a twist of the aryl group around the N-
CDipp bond illustrated by the dihedral angles 1 and 2, which
largely deviate from 90°. They also exert a repulsion directly on
the isopropyl group and force the latter to interact more tightly with
the palladium center. Such an additional repulsion is clear in
complex 5NMe , in which the more steric quadrant is on the NMe2
2
side (North-East quadrant: 53.8%), whereas the dihedral angle 1
= 72.67° is more acute than 2 = 75.32°. On the overall, the %Vbur
values in the bulky quadrants and the asymmetry level between
the four quadrants are positively correlated with the respective
catalytic activities of the pre-catalysts 5XY. For example, the most
(NMe ,Cl)
active catalysts 5(NMe ) , 5
,
and 5NiPr are the most
2 2
2
2
dissymmetric and exhibit the most highly congested quadrants.
Interestingly, complex 5(NMe ) is represented by two independent
2 2
conformers in the crystal lattice with conformer A being more
Scheme 3. Buttressing effect in carbene chemistry (A) and in NHC-Pd catalysis
(B).
crowded than conformer B, thus indicating that the bulky IPr(NMe )
2 2
ligand nevertheless possesses some degree of flexibility.
Concerning the mechanism of the amination reactions, the
dependence of the catalytic efficiency against the steric properties
of the NHC ligands would support a catalytic cycle in which the
rate limiting step is the reductive elimination step. Indeed, it is well
accepted that the latter is facilitated by the increase of the
bulkiness of the supporting ligand, while the oxidative addition
step and the coordination-deprotonation of the amine are much
less affected by the steric hindrance.
We attribute the beneficial influence of the carbenic heterocycle
decoration to a buttressing effect of the amino groups. The
concept of buttressing effect was first introduced to rationalize
some long range interactions between substituents in aryl
chemistry: the effect of a substituent in ortho position of a defined
functional group is strengthened by the presence of another more
distant group, usually on the meta position.[30] This effect can
influence the conformational dynamic, the thermodynamic
properties such as acidity and basicity, or the reactivity of the
functional group.[31] Tomioka introduced this concept in reactive
triplet carbene chemistry, where the meta alkyl substituent R
forces the methyl group of the OMe substituent to be out the plane
of the aryl group and thus to interact more efficiently with the
carbene center in a C-H bond insertion reaction (Scheme 3A).[32]
Here, the amino groups on the 4 and/or 5 position of the imidazolyl
ring forces the twist of the 2,6-diisopropylphenyl groups around
the N-C bond from the orthogonal starting conformation, which
induces a more closely interaction of the iPr groups with the active
coordination sphere (Scheme 3B). We thus propose that the key
design principle in the backbone decoration of our NHCs for Pd-
catalyzed amination reaction rests on the buttressing effect of the
amino substituents. As an extension, this study would also
Implementation of buttressing effect in Pd-catalyzed
arylation of bulky primary amines
In order to further illustrate the usefulness and versatility of this
approach, we devised developing a challenging amination
reaction with our ligand set and we focused on the arylation of
very hindered -trisubstituted primary amines. Despite the
broad interest of incorporating bulky alkyl groups in compounds
of pharmaceutical interest,[33] the Buchwald-Hartwig amination
reaction using bulky primary amines such as tert-butylamine or 1-
adamantyl amine had been barely studied. The catalytic systems
that have been disclosed generally suffer from quite high catalyst
loading (1-5 mol%), high reaction temperatures (100-120°C), and
the scope was often restricted to one or two examples.[34,35] Still,
in 2015, Buchwald and co-workers reported a very efficient
phosphine-based catalytic system operating under relatively mild
conditions (0.5-2 mol% of catalyst, NaOtBu as base, reaction
temperature: 80-120°C) and exhibiting a very wide substrate
scope.[37]
The highly challenging coupling between 2-chloroanisole and tert-
butylamine - never reported to date - was chosen as model
reaction. Potassium tert-butoxide and DME were selected as
base and solvent, respectively, and we decided to operate at the
quite low temperature of 60°C to have the reaction conditions as
mild as possible (Table 2). In an initial screening, the efficiencies
NiPr
of pre-catalysts 5(NMe ) , 5
, and 5(NMe ,Cl), which were the most
2 2
2
2
active pre-catalysts in the previous study (Figures 3 and 4), were
evaluated. Disappointingly, the best conversion we got was 30%
(NMe )
2 2
only after 4 h using 5NiPr , whereas pre-catalysts 5
and
2
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5(NMe ,Cl) were almost inactive under these conditions (Table 2,
in analytically pure form and the molecular structures of 11NMe
2
2
and 11(NMe ,Cl) were confirmed by X-Ray diffraction analysis
2
entries 1-3).
(Figures S3 and S4 in the ESI).
Table 2. Screening of pre-catalysts 5XY, 11XY and 12 and reaction conditions
for the arylation of tert-butyl amine with 2-chloroanisole.[a]
Entry
1
Pd cat.
T (°C)
60
time (h)
GC conv. (%)[b]
2 2
)
5(NMe
4
4
4
1
2
4
4
3
3
3
3
5
2
2
5NiPr
60
30
2
,Cl)
3
5(NMe
60
traces
100
95
Scheme 4. Synthesis of the new [PdCl(cin)(IPrXY)] pre-catalysts 11XY
.
2 2
)
4
11(NMe
60
Gratifyingly, complexes 11(NMe ) and 11NiPr were found to be
2
11NiPr
60
2 2
2
5
highly efficient in the model reaction. Full conversion is observed
2
,Cl)
6
11(NMe
60
15
NiPr
after 1 hour at 60°C for 11(NMe ) while complex 11
leads to 95%
2 2
2
conversion after 2 hours (Table 2, entries 4-5). Surprisingly,
2
7
11NMe
60
84
complex 11(NMe ,Cl) gives 15% conversion only under the same
2
0 (5)[c]
97
conditions (entry 6). We tentatively assigned this discrepancy to
8
11
60
a low stability of the catalyst in this case. Pre-catalyst 11NMe
2
2 2
)
11(NMe
40
bearing the less bulky IPrNMe ligand is a little less efficient with
9
2
84% conversion after 4 hours, while the standard pre-catalyst
[PdCl(cin)(IPr)] (11) leads to almost no conversion (entries 7-8).
Strikingly, the catalysis could even be carried out at 40°C with pre-
2
10
11
11NiPr
40
87
12[d]
40
88
catalysts 11(NMe ) and 11NiPr with only a slight alteration of the
2 2
2
conversion (97% using 11(NMe ) and 87% using 11NiPr after 3
hours, entries 9-10). Eventually, under the same reaction
conditions, the complex [PdCl(cin)(IPent)] (12) exhibits about the
2 2
2
[a] Reaction conditions: 2-chloroanisole (1.0 mmol), tert-butylamine (1.1
mmol), Pd cat. (0.5 mol%), KOtBu (1.1 mmol), DME (1.0 mL). [b] Calibrated
GC conversions were reported using dodecane as the internal standard and
were averaged over two runs. [c] Conversion in parentheses after 24 h of
reaction. [d] 12 = PdCl(cin)(IPent).
same activity as complex 11NiPr (entry 11).
2
With the fully optimized catalytic conditions in hand, the substrate
scope was next investigated with respect to the nature of the bulky
amine and of the stereoelectronic properties of the (hetero)aryl
chloride partner (Scheme 5). Under these mild reactions
We assigned this lack of activity to a sluggish activation of the pre-
catalysts to form the [Pd0(NHC)] active species. Indeed, the Pd-
PEPPSI-NHC type catalysts are known to be readily reduced to
Pd0 species when using morpholine and KOtBu through
displacement of the pyridine by morpholine, deprotonation to
generate an amido-complex, -hydrogen elimination, and
reductive elimination of HCl from [(NHC)PdClH] species.[10b,38]
Here, tert-butylamine does not possess -hydrogens, which
severely hinders the activation pathway. We thus reasoned that a
pre-catalyst known to be more readily activated by a base would
circumvent this issue. As the [PdCl(cin)(NHC)] complexes, first
disclosed by Nolan,[15a] were proved to be readily activated by
bases such as KOtBu through a nucleophilic attack of the latter
on the cinnamyl ligand, we synthesized the series of pre-catalysts
conditions, pre-catalyst 11(NMe ) is highly efficient for the coupling
2 2
of tert-butylamine or 1-adamantylamine with a wide range of ortho,
meta or para substituted aryl chlorides, eventually possessing
strongly deactivating methoxy groups, as well as with heteroaryl
and naphthyl derivatives, to afford the coupling products 10a-i in
excellent yields and short reaction time. Although a slightly higher
reaction temperature (60°C) is required in certain cases for
achieving good conversions when using adamantyl amine (10g-
i), the conditions employed here generally remain much milder
than the ones previously reported in literature.[34-37] These
encouraging results prompted us to further explore the possibility
to couple even more sterically hindered amines such as tert-amyl
amine, tert-octyl amine, and trityl amine, which appeared to be
suitable substrates in Pd-catalyzed amination only recently.[37] For
(NMe )
2 2
NiPr
2
11NMe , 11
, and 11
by reacting the in situ generated free
2
these amines, the temperature of 60°C was found necessary to
NHC with [PdCl(cin)]2 (Scheme 4). In addition, using our
good conversion. Interestingly, complex 11NiPr
2
chlorination strategy, 11(NMe ,Cl) was obtained in high yield by
achieve
a
2
performed systematically better than 11(NMe ) for coupling t-amyl
2 2
reacting 11NMe with NCS in CHCl3. All complexes were obtained
2
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amine and t-octyl amines. For instance, full conversion is
trisubstituted primary amines using aryl chlorides as electrophilic
partners.
observed for the coupling of 2-chloroanisole and t-octyl amine
with 11NiPr after 4 hours at 60°C to afford 10k, while a 84%
2
conversion only is obtained when using 11(NMe ) . The higher
2 2
flexibility of IPrNiPr ligand compared to IPr(NMe ) may be a
reasonable explanation for this trend, allowing the ligand to better
accommodate the very high steric hindrance of the amine
substrate. A variety of challenging (hetero)aryl chlorides can also
be successfully engaged in this reaction to afford the coupling
2
2 2
products 10j-o and 10q using 0.5 mol% of 11NiPr . An increase of
2
the catalyst loading to 1 mol% and reaction time to 18 h are
needed to produce 10p albeit in an excellent 99% isolated yield.
Strikingly, using 1 mol% of catalyst 11(NMe ) , trityl amine can even
2 2
be successfully coupled with 4-chloro and 2-chloroanisole to give
10r-s in 82%, and 83% yields, respectively. Coupling of the latter
with 3-chloropyridine is a little less efficient but 10t is nevertheless
obtained in 54% yield. Turning now our attention to the di-ortho
substituted aryl chlorides, we found that 2-chloroxylene can be
readily coupled with adamantyl amine, t-amyl amine and t-octyl
amine to give anilines 10u-w using 1 mol% of 11(NMe ) (2 mol%
2 2
for 10w) at 60°C for a longer but still acceptable time of 14-18 h.
Under the same reaction conditions, complex 11NiPr is much less
2
efficient and we explain this fact by a lower catalyst stability.
Finally, 2,6-dimethoxyphenyl chloride is a suitable substrate
producing anilines 10x-y in good yields.
Conclusions
Prompted by the huge impact of the Pd-catalyzed arylative
amination in synthetic chemistry, the quest of improved Pd-NHC
catalysts has been the subject of intense research over the last
decade and major breakthroughs have often been attained by
advances in ligand design. While earlier successful developments
mainly relied on the modification of the N-aryl groups, the recent
years have seen the advent of a complementary strategy based
on the direct decoration of the carbenic heterocycle. We have now
demonstrated in the case of amino and chloro substituted IPr
derivatives that the beneficial effect of the substitution observed
in catalysis can be correlated to the stereoelectronic features of
the ligand. In particular, the amino groups, and to a lower extent
the chloro substituents, exert a steric constrain on the Dipp arms
forcing them to be twisted and to interact more strongly with the
coordination sphere during the catalytic process. This relay
ensured by the N-Dipp groups is very similar to the well-known
buttressing effect occurring in aromatic compounds. This
buttressing effect thus appears as the key leading principle in the
optimization of NHC ligands by substitution of their heterocyclic
backbones and would serve as a rationalizing frame for the
observed beneficial influence of the NHC-backbone decoration.
Thanks to the non-spherical tridimensional structure of the amino
groups NR2, which can accommodate several conformations, this
steric effect does not rigidify too much the system and some
flexibility degree remains present, the latter being necessary for a
better catalyst efficiency. We further validated the potential of our
ligand design strategy by implementing a proper ligand set in the
challenging arylation of highly sterically hindered -
Scheme 5. Scope of the Pd-catalyzed arylation of bulky primary amines using
pre-catalysts 11(NMe or 11N Pr2 , yields refer to the average of isolated yields of
two runs after column chromatography. Reaction conditions: aryl chloride (1.0
mmol), amine (1.1 mmol), KOtBu (1.1 mmol), DME (1.0 mL).
2 2
)
i
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couple a large variety of aryl chlorides and bulky primary amines.
We are currently working on the extension of this ligand design
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Acknowledgements
This work was supported by the “Centre National de la Recherche
Scientifique” (CNRS). We are grateful to the China Scholarship
Council for providing a PhD grant to Yin Zhang. Dr Christian Bijani
(LCC-CNRS) is warmly acknowledged for his help with the 77Se
NMR.
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Keywords: N-heterocyclic carbenes • ligand design • palladium
• catalysis • C-N bond • primary amines
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10.1002/chem.201702859
Chemistry - A European Journal
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Buttressed IPr ligand: Through a
complete structure/activity study, the
dramatic improvement of Pd-NHC
catalysts induced by the direct
introduction of amino substituents
onto the imidazolyl backbone of IPr is
shown to be steric in origin, and is the
result of the twisting of the N-aryl
groups induced by the bulky backbone
substituents. The implementation of
the strategy in the challenging
Yin Zhang, Guy Lavigne, Noël Lugan,
Vinecnt César*
Page No. – Page No.
Buttressing effect as key design
principle towards highly efficient
palladium/N-heterocyclic carbene
Buchwald-Hartwig amination
catalysts
arylation of -trisubstituted
primary amines is also reported.
This article is protected by copyright. All rights reserved.