2,6-Bis(diphenylphosphino)pyridine: A simple ligand showing high performance in palladium-catalyzed CN coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2014.06.020

The use of commercially available 2,6-bis(diphenylphosphino)pyridine as a ligand in conjunction with K₂CO₃, DMAc and TBAB is an effective method for the palladium-catalyzed CN coupling of a variety of aryl halides with anilines, N-heterocyclic aromatic amines, and a cyclic secondary amine. The reactions proceed in good to excellent yield (up to 98%) while the loading of Pd(OAc)₂ was as low as 0.025 mol %.

Full text of DOI:10.1016/j.tetlet.2014.06.020

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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2,6-Bis(diphenylphosphino)pyridine: a simple ligand showing high
performance in palladium-catalyzed CAN coupling reactions
a
a
b
a,
⇑
Shirin Nadri , Ezzat Rafiee , Sirous Jamali , Mohammad Joshaghani
a
Faculty of Chemistry, Razi University, Kermanshah 67149, Iran
Chemistry Department, Sharif University of Technology, PO Box 11155-3615, Tehran, Iran
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of commercially available 2,6-bis(diphenylphosphino)pyridine as a ligand in conjunction with
CO , DMAc and TBAB is an effective method for the palladium-catalyzed CAN coupling of a variety
of aryl halides with anilines, N-heterocyclic aromatic amines, and a cyclic secondary amine. The reactions
proceed in good to excellent yield (up to 98%) while the loading of Pd(OAc) was as low as 0.025 mol %.
Received 26 March 2014
Revised 12 May 2014
Accepted 5 June 2014
Available online xxxx
K
2
3
2
Ó 2014 Published by Elsevier Ltd.
Keywords:
Palladium
Phosphine ligand
Buchwald–Hartwig reaction
CAN Coupling
To date, many different strategies have been reported for the
synthesis of aryl amines. Despite the potential utility of classical
methods such as nucleophilic substitution, reductive amination,
The juxtaposition of a pyridine and two phosphine moieties,
presenting a P–N–P framework, in a 2,6-relationship of the type
1
2
shown in Figure 1, has found considerable attention in the field
and Ullmann-type amination,3 several have one or more certain
drawbacks including harsh reaction conditions, low functional
group compatibility, and the necessity of using excess reagents
or catalyst. On account of its high tolerance to different functional
groups and mild reaction conditions, Pd-catalyzed amination has
been the subject of extensive study since the pioneering works
of Buchwald and Hartwig5 (Scheme 1), and have found
widespread application in the synthesis of pharmaceuticals and
of organometallic chemistry.
8–10
Within this family of ligands,
P) py (1), is more rigid
2,6-bis(diphenylphosphino)pyridine (Ph
2
2
than other examples (2–4) due to the absence of the methylene
groups connecting the phosphorus atoms and the pyridine ring.
In recent work, we reported our results concerning the utility of
2 2
(Ph P)
py in Heck coupling reactions of various aryl halides.11 Con-
4
sidering the importance of the Buchwald–Hartwig type amination
reaction in organic synthesis, and in continuation of our studies on
6
,7
11–19
fine chemicals.
Pd-catalyzed carbon–carbon coupling reactions,
in this Letter
Several modifications have been reported including variation of
the ligands, palladium source, solvent, and bases in order to per-
form the coupling reaction more efficiently. It is well known that
a careful selection of the ligand in terms of its electronic and steric
characteristics is extremely crucial in various Pd-catalyzed CAC and
C-heteroatom bond-forming reactions. As a result, numerous
efforts have been dedicated to the search for more efficient and
versatile ligands for expanding the applications of Pd-catalyzed
reactions. Phosphines are among the most utilized ligands in
transition metal complex catalyzed reactions since their electronic
we report a series of experiments on the carbon–nitrogen coupling
reaction using (Ph P) py as a supporting ligand.
Using ligand 1, we initially conducted the reaction between bro-
mobenzene and aniline following a reported procedure using
2
2
0.025 mol % of Pd(OAc)
vent, sodium carbonate (K
nium bromide (TBAB) as the additive.
2
, N,N-dimethylacetamide (DMAc) as the sol-
2
CO ) as the base, and tetrabutylammo-
3
1
1,20
The reaction proceeded
successfully to afford diphenylamine in 94% yield after one hour.
This result was encouraging, and we evaluated the efficiency of
the Pd(OAc) /(Ph P) py system with other substrates. We began
2 2 2
(
r
-donating ability with
p
-accepting capacity) and steric charac-
by examining the aryl bromide partner (Table 1, entries 1–8). The
desired products were obtained in good to excellent yields within
teristics can be easily varied by introducing different substituents.
1
–3 h without obvious discrimination of the electronic nature of
the benzene substituents. However, 1-bromo-4-nitrobenzene gave
a yield of 74% after five hours, probably due to a competitive
dehalogenation reaction which has been reported in the literature
⇑
Corresponding author. Tel./fax: +98 831 4274559.
E-mail address: mjoshaghani@razi.ac.ir (M. Joshaghani).
http://dx.doi.org/10.1016/j.tetlet.2014.06.020
040-4039/Ó 2014 Published by Elsevier Ltd.
0
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2
S. Nadri et al. / Tetrahedron Letters xxx (2014) xxx–xxx
R1
Pd cat.
ligand
R
1
seems that the presence of the S-atom polarizes the aromatic ring,
thereby making it prone to oxidative addition.
Ar-X
+
HN
Ar
N
base
Sterically hindered 1-bromonaphthalene could also be coupled
in good yield in a relatively short reaction time (Table 1, entry 8).
The coupling between 4-bromobenzonitrile and aniline did not
take place under our conditions (Table 1, entry 6). This result
was very similar to that of Hong’s group for their cobalt-containing
R2
R2
X= I, Br, Cl, OTf
1
2
R , R = H, aryl, alkyl
Scheme 1. Palladium-catalyzed Buchwald–Hartwig reaction.
2
3,24
P,N-ligand.
They came to the supposition that the poor reactiv-
ity of cyano-substituted bromobenzene might be due to the cyano
group coordinating with Pd, therefore interfering with the catalytic
role of the Pd species.
t
PPh
N
2
PPh
2
P( Bu)
2
P(Cy)
2
2
N
N
N
2 2 2
The performance of the Pd(OAc) /(Ph P) py system was further
evaluated with other substituted anilines (Table 1, entries 9–13).
Coupling of benzylamine with bromobenzene worked well,
providing the expected product in 98% yield (Table 1, entry 9).
Steric hindrance had an effect upon the rate of the reactions. For
example, 4-ethylaniline reacted with bromobenzene within one
hour to give the desired product in 98% yield (entry 10). However
the reaction with 2-ethylaniline occurred over six hours producing
the product in 80% yield (Table 1, entry 11).
t
PPh
2
PPh
2
P( Bu)
2
P(Cy)
1
2
3
4
Figure 1. Examples of 2,6-disubstituted phosphine-pyridine ligands.
to occur when using aryl halides bearing electron-withdrawing
2
1,22
substituents
(Table 1, entry 7). The reaction with 3-bromothio-
phene was successfully achieved (entry 5), providing a useful way
for the introduction of an amino group on the thiophene ring. It
Encouraged by these positive results, we proceeded to
investigate the CAN coupling between aniline and chlorobenzene,
Table 1
Palladium-catalyzed amination of aryl halidesa
R1
R2
R1
R2
H
N
Pd(OAc)
2 2 2
/ (Ph P) py
Br(Cl)
+
H2N
K
2
CO , DMAc,TBAB, 135 °C
3
Entry
1
Aryl halide
Amine
Product
Time (h)
Yield (%)
94
TONb
4760
H
N
Br
NH
1
2
2
H
3
C
3
H C
NH2
2
H
N
83
3320
Br
H
N
3
4
5
6
7
MeO
Br
Br
NH
NH
NH
NH
NH
2
2
2
2
2
MeO
4
3
1
5
5
76
3040
3200
3200
—
H
H
3
C
H
3
C
N
80
H
Br
N
80
S
S
H
NC
Br
Br
NC
N
No reaction
74
H
O
2
N
O2N
N
2960
Br
Br
NH2
8
9
2
1
72
98
2880
3920
H
N
NH2
NH
H
1
1
0
1
Br
Br
NH
2
N
1
6
98
80
3920
3200
NH2
H
N
NH
2
H
N
Br
Br
1
2
2
81
3240
NO
2
O N
2
NH2
1
1
3
4
3
3
97
88
3880
3520
H
N
H
N
Cl
NH
2
a
Reaction conditions: aryl halide (4 mmol), amine (4 mmol), K
TON = mol product/mol catalyst.
2 3 2 2 2
CO (4 mmol), Pd(OAc) (0.025 mol %), (Ph P) py (0.05 mol %), TBAB (3 mmol), DMAc (4 mL), 135 °C.
b
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S. Nadri et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2
a
CAN coupling of various aminopyridines with bromobenzene
Pd(OAc)
2
(
Ph p) py
2
2
Br + (H)N-Heterocycle
N-Heterocycle
K
2
3
CO , DMAc
TBAB, 135 °C
Entry
1
Amine
Time (h)
4
Yield (%)
91
TONb
3640
H
N
N
2
NH2
NO
N
2
3
2
4
94
3760
-
2
H3C
N
Scheme 2. Two possible pathways for the reaction between 4-bromoaniline and
bromobenzene.
No reaction
H2N
N
Pd(OAc)2
4
5
H N
CH3
4
1
No reaction
78
-
2
(Ph
2 2
P) py
H
2
N
Br + H N
H N
NH
2
2
2-(Aminomethyl)pyridine
3120
K CO , DMAc
2
3
TBAB, 135 °C
a
Reaction conditions: bromobenzene (4 mmol), amine (4 mmol),
K
2
CO
3
(
(
4 mmol), Pd(OAc) (0.025 mol %), (Ph P) py (0.05 mol %), TBAB (3 mmol), DMAc
2
2
2
Scheme 3. CAN coupling between 4-bromoaniline and aniline.
4 mL), 135 °C.
b
TON = mol product/mol catalyst.
which is known to be less reactive than the bromo analogue due to
the stronger CACl bond, which delays the oxidative addition to the
Pd(0) species. Fortunately, the coupling was satisfactory with a low
4
-Aminopyridine and 2-amino-3-nitropyridine reacted effi-
ciently to give excellent yields of products (Table 2, entries 1 and
). 2-Amino-6-methylpyridine was unreactive under similar reac-
loading of only 0.025 mol % of Pd(OAc)
product after three hours (Table 1, entry 14).
-Bromoaniline is an interesting test substrate, because it con-
2
to give an 88% yield of
2
4
tion conditions (Table 2, entry 3). At first glance, this result may be
attributed to the steric hindrance present in the substrate, but since
our effort employing 2-amino-5-methylpyridine was not successful
tains two functional groups, both susceptible to coupling reactions.
In fact, there are two pathways for the conversion of 4-bromoani-
line that involve the NH group for construction of a CAN bond
2
through the Buchwald–Hartwig reaction, or the Br group to form
a CAC bond through an Ullmann-type reaction as illustrated in
Scheme 2.
(
Table 2, entry 4), we are inclined to assume that the electronic effect
of the methyl group is mostly responsible for the decreased catalytic
activity. We found that our system could also catalyze the arylation
of 2-(aminomethyl)pyridine (Table 2, entry 5).
We considered morpholine as a suitable candidate for further
evaluation of the influence of ligand 1 on the CAN coupling of a
cyclic secondary amine. The results are summarized in Table 3.
In order to identify which reaction was preferred, we reacted
4
-bromoaniline and bromobenzene using our conditions, which
gave a mixture of amination product and biphenyl derivative in
0% and 30% yield, respectively. This demonstrates clearly that the
7
amination reaction is much faster than the Ullmann coupling. The
Ullmann reaction mechanism involves consecutive oxidative
addition of the aryl halide to Pd(0) and Pd(II) species, respectively.
Table 3
a
CAN coupling of morpholine with aryl bromides
2
The electron-donating ability of the NH group may slow the second
oxidative addition step in the catalytic cycle and allow amination to
dominate. The application of a 2-fold excess of bromobenzene ver-
sus 4-bromoaniline had no effect on the selectivity for the Ullmann
reaction and the product ratio remained constant as before, (70:30).
However, with prolonged time (17 h) a di-coupled amination prod-
uct was obtained.
Pd(OAc)2
(Ph P) py
2
2
R
Br + H
N
O
R
N
O
K CO , DMAc
2
3
TBAB, 135 °C
It is important to note that there is another route for the conver-
sion of 4-bromoaniline based on CAN coupling of 4-bromoaniline
and aniline as shown in Scheme 3. In this reaction 4-bromoaniline
acts as an electrophile and adds oxidatively to the Pd(0) center.
Unfortunately, the reactivity toward aliphatic amines such as
n-butylamine and isopropylamine, which was observed by
Entry
1
Aryl halide
Time (h)
3
Yield (%)
TONb
3680
Br
92
90
64
70
2
3
4
H C
Br
Br
Br
3
4
3
3600
2560
2800
3
2
5,26
others,
was not achieved with our catalyst system (data not
shown), presumably due to the volatility of these substrates under
the employed high temperature conditions.
OHC
MeO
N-heterocyclic aromatic amines, especially aminopyridines,
occupy important roles in chemistry, being a key structural feature
of many natural products, and are present in several classes of
pharmaceutical drugs. Thus, we explored further the scope of
ligand 1 in the amination of heterocyclic substrates and the results
are shown in Table 2.
a
Reaction conditions: aryl bromide (4 mmol), morpholine (4 mmol),
4 mmol), Pd(OAc) (0.025 mol %), (Ph P) py (0.05 mol %), TBAB (3 mmol), DMAc
(4 mL), 135 °C.
2 3
K CO
(
2
2
2
b
TON = mol product/mol catalyst.
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4
S. Nadri et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Our catalytic system showed good activity for the arylation of
morpholine. However, in the cases of 4-bromobenzaldehyde and
10. Gibson, D. H.; Pariya, Ch.; Mashuta, M. S. Organometallics 2004, 23, 2510–2513.
1
1
1
1
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4
-bromoanisole an unidentified product was also observed.
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3. Joshaghani, M.; Daryanavard, M.; Rafiee, E.; Xiao, J.; Baillie, C. Tetrahedron Lett.
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aryl halides with anilines, N-heterocyclic aromatic amines and a
cyclic secondary amine. Good to high yields of products were
obtained with excellent functional group tolerance.
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20. Typical experimental procedure for the Buchwald–Hartwig reaction: A round-
bottomed flask was charged with bromobenzene (4 mmol), aniline (4 mmol),
Acknowledgment
1
4
The authors thank Razi University Research Council for support
of this work.
TBAB (3 mmol), and K
2 3
CO (4 mmol) under a dry nitrogen atmosphere. A
solution of (Ph P) py (0.05 mol % in 2 mL of DMAc) and a solution of palladium
2
2
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