Daniel Perdomo Uruburu.

1
Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Sede Bogotá, 111321 Bogotá, Colom-
bia. Email: dperdomou@unal.edu.co
ABSTRACT: Buchwald−Hartwig reaction is an amination catalyzed by palladium, this reaction it is one of the most used in the
pharmaceutical industry because change the way to synthesizing aromatics amines and allows the carbon-nitrogen coupling. The
reaction was reported 25 years ago by the simultaneous works of Buchwald and Hartwig, in this text the idea is to give the reader a
general outlook of this amination and the useful applications in the industry and academy. Also, it will be explained the catalytic
cycle with PdL2, the scope of the reaction, the different catalytic systems published and the activity, efficiency and selectivity of they.
Finally, it will be proposing a catalytic system based in the knowledge of organometallic chemistry and the information consulted.

Introduction
The report and discovery of this reaction had the origin in early
reports by Migita in 1983 about the palladium-catalyzed cou-
pling of aryl bromides and tin amides. In 1994 two independent
reports appeared, one by the Hartwig group, who examined the
reaction intermediates and catalytic species of this reaction 3,
and the other, by the Buchwald group, who described an im-
proved method to avoid the isolation of toxic and sensitive tin
amides. A year later, both Buchwald and Hartwig reported pro-
tocols for what is now the prototypical C−N coupling reaction
of an amine with an aryl halide using a palladium catalyst and
a hindered base (Equation 1). After these initial reports, the re-
action quickly took off and was adopted in a variety of academic
and industrial settings for synthesis .1 Even that Migita was the
first person who report the reaction, Buchwald and Hartwig
were who study the reaction in a deep way.
Equation 1: General equation reported by Hartwig in 1994.
Aromatic amines are essential because they are building blocks
for many chemical reactions like: electrophilic aromatic substi-
tution, diazonium salts coupling and derivatization of aromatic
compounds with the diazonium salt or to be employed like a
base.2 The aromatic amines also have interesting application in
pharmaceutics and agrochemical industry.3-4-5 In general 40%
of syntenic medicines have anilines groups (Figure 1) and about
10% of total medicines are synthetized employing Buch-
wald−Hartwig coupling.4
Figure 1: Occurrence of a functional group in the IBEX data-
base (6.2M records of pharmaceutical drug discovery patents
and journals) versus those found in the Dictionary of Natural
Products (0.23M records). Where indicated, a nonspecific R
group represents a free site at any position. As an example, THP
would include any pyranose derivative found in the DNP. 15
Also, it is interesting to consider about how it could be the clas-
sical way of the synthetic route to produce an aromatic amine,
there are many ways but the process is long and the scope of the
methods is poor without consider the limited functional group
tolerance. Clear examples of the ways to synthetize aromatic
amines is the nucleophilic aromatic substitution but in this case,
it will be necessary to have a aryl halide with electron-with-
drawing groups to activate the process1,2; by the other hand we
can think in a multiple step process starting with a nitration of
benzene, after that it would be necessary a reduction step using
Fe, HCl or H2, Ni to finish with a alkylation in the nitrogen.
Other method to consider is the Ullmann-type couplings can re-
quire up to stoichiometric amounts of copper, elevated temper-
atures, and display competing biaryl formation (Figure 2).1-6-2
Buchwald−Hartwig reaction is now observed as a extremally
useful tool in the organic chemist’s synthesis toolbox for the
biter scope and times of reaction. Unfortunately, this process is
yet to approach generality and the goal of being able to couple
any nitrogen nucleophile with any aryl or heteroaryl halide is
far from be finish.8

Figure 2: The general Strategies for the Synthesis of Aromatic
Amines. 1-2
Now, if we think about, what kinds of metals catalyst could cat-
alyze this cycle PdL2 is the most extensively employed because
of the grate tolerance to functional groups, like radicals or elec-
trophiles;18 That’s why in the text we will study the catalytic
cycle with this catalyst. But it is important to remember that it
is not the only one. Other catalyst exists but they are not so ex-
tended, for example the NHC-ligated Ni(I) Complexes that gain
popularity in recent years.9 Considering the cupper that can be
used to generate aromatic amines but the mechanism is an Ul-
man coupling that is different to the Buchwald-Hartwig cou-
pling. 6
Finally, the main objective of the manuscript is that the reader
understands all the catalytic cycle, the importance of it and the
general importance of the selection of each of the elements in
the reactions the ligands, the base, the solvent and the metals.
Results
In general, Hartwig describe the catalytic process textually in
this way: Aryl halide addition to tri-o-tolylphosphine palladium
(0) gives dimeric, rather than monomeric, aryl bromide com-
plexes. These compounds are cleaved in the presence of amine
to form monometallic aryl halide complexes possessing one
phosphine and one amine ligand. The enhanced acidity of the
amine when coordinated to palladium allows these compounds
to be deprotonated with LiN(SiMe3)2. The resulting amido com-
plexes undergo rapid reductive elimination of arylamine at
room temperature to produce tri-o-tolylphosphineligated
L2Pd(0). This addition of aryl bromide to L2Pd, coordination
and deprotonation of secondary amine, and reductive elimina-
tion of tertiary arylamine provides an efficient catalytic route to
arylamines in the absence of tin reagents (Figure 2).10
Figure 3: Mechanism of the Palladium Catalyzed C−N Cross-Cou-
pling Reaction.1-10 I: Oxidative addition of the aryl halide into
Pd(0) species I, after the formation of complex II the amine Coor-
dination form the complex III, and this significantly increases the
acidity of ammine, allowing its deprotonation by a hindered base
such as tBuONa or LiHMDS forming the complex IV, which its
transformed by a reductive elimination to give the arylated amine
product and the regeneration of the catalyst.
Its important to remember that the previously description it’s
just a summary of the catalytic cycle because the kinds of lig-
ands, the base, the metal and the solvent play an important task
in the reaction, and also generate intermediaries that are not vis-
ible in the general mechanism nut those in the figure 3 can be
insulated.
According to the previous paragraph, a good question is: What
is the main role of the base in the mechanism? Because is easy
to see from pKa values that the amine can be deprotonated by
commonly used bases like alkoxides only if the amine has al-
ready been activated by coordination to the metal. However, it
is not known whether the base always has to coordinate first like
the recent evidence shows (Figure 4), 8 or whether an external
base can deprotonate the amine in a coordinatively saturated
square planar palladium complex. The details of this part of the
catalytic cycle is important because you can expect which bases
can be competent in the overall reaction without generation in-
terference with the solvent, also the base is important in the
scope of reaction and performanse.8-10-18 Also the solvent is im-
portant because the intermediaries have charge.
Figure 4: Pd (II) section of the reaction in benzene with t-BuO−
as the base.8
Overall is obviously to see that in the theorical calculations of
Sunesson et al.8, the coordination of the base to Pd complex is
energetically favorable because the free energy shows that the
process take place in a spontaneous way. It is also imperative to
consider that if the base had to coordinate, the compound 10
will have 18e-. So, if it was true, the stability of this step of the
catalytic cycle could be prove by a calorimetric study of this
step. Also, it would be too much relevant that the catalyst in the
first stage have just 12e-.8-13

Now it’s the time to consider the role of the ligands in the reac-
tion; the ligands are a fundamental protagonist because the cat-
alyst loadings, and times of reaction depend of the nature of the
ligand, today an important goal to address such substrate com-
binations to lower catalyst loadings, and to reduce the time of
reaction.14 also the kind of ligand make the conditions favorable
to synthetize specific types of aromatic amines in an acceptable
conditions; an example of this is the case of (1)BrettPhos and
(2)RuPhos. Buchwald published a user’s guide of the numerous
biaryl phosphine ligands developed by his group and their pre-
ferred applications in order to aid selection of reaction condi-
tions and further optimization.14 (figure 5)
Figure 7: Ructions condition to synthetize secondary aromatic
amines using BrettPhose as ligand.14
In addition it is important to know that the ligand can be a bi-
dentate ligand that favor a planar square, that make easiest the
action of the base. 18
As an additional note, it is important to understand that this re-
action is not very used with ammonia because the N-H bond is
strong enough to make the complex stable. Industrially the NH3
is used but with extremely high temperatures and pressures.
This is one of the main goals in the development of this reac-
tion.18

Finally, it is necessary to consider what kind of metal catalyst

can carry out this reaction, Takahiro et al. write about a Ni(I)
catalyst that comes from a Ni(III)-Ni(I) compound for a Buch-
wald−Hartwig reaction (Figure 8).8 in this case the complex
Figure 5: Ligands and precatalysts used in these studies for Pd- that carry out the reaction with base have 15e-. So, it the base
catalyzed C–N bond formation (1 are used with primary amines, 2 is coordinate the total electrons would be 17 e- and the geometry
are used for secondary amines).14 it is not conserved but the compound has a maximum of 4 spices
in coordination. But the catalyst has less efficient.
So, a case of the importance of the ligand in a procedure is given
in figure 6 and 7, because the condition to carry out a reaction
depend of the ligand that is in use. Figure 6 have the case of
tertiary amines that could be synthetize using RuPhos but the
condition is not favorable if the used phosphine is BrettPhose.
Contrary to the figure 6 the figure 7 illustrate favorable process
using BrettPhose as a ligand generating secondary amines. But
today is possible to synthetize aromatic amines without support-
ing ligands, it is a not extended technic. 16

Figure 8: Mechanism of the Ni (I) Catalyzed C−N Cross-Coupling

Reaction.15

Considering the entering manuscript, we can propose the Pt like

Figure 6: Ructions condition to synthetize tertiary aromatic
amines using RuPhos as ligand.14
a good candidate for this catalytic cycle because it belongs to
ten group of the transition metals the same as Ni and Pd. Also
is probable that because the Pt is a soft acid, it could have a poor
interaction with the amine and the base. We can suppose that
there is high steric impediment so we could synthetize just
smaller aromatic amines if the metal is Pt (0). The catalyst will
be no so effective in a general way but it will be to much selec-
tive if we want to catalyze the formation of aromatic amines in
a complex mixture with small phosphine as ligands or no one
considering the recent advances16. In general, the best option is
to use the Pd (0) catalyst, but Pt (0) could have some interesting
applications. Probably the catalytic mechanism is the same as
the palladium catalyst with the same number of electrons be-
cause of the most common oxidation states of the Pd and Pt.17
Conclusion
The study shows for this catalytic cycle that the ligand, the base,
and the metal are crucial in the performance of C-N coupling,
and in an overall way the best metals to carry out the reaction is
the Pd(0), even tough if we had a mixture, a Ni(I) or Pt(0) cata-
lyst could be better options because they have more selectivity.
It is also important to remember that the Buchwald-Hartwig re-
action is a great and important tool in organic synthesis most if
we consider that today the Buchwald-Hartwig reaction also can
be performance directed toward photocatalytic strategies, nota-
bly allowing reactions to be conducted at room tempera-
ture15,and without supporting ligand16. Finally, the good yield
of the reactions makes the reaction an excellent strategy in phar-
maceutical industry because the extended activity of aromatic
amines. 4-6
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