Buchwald-Hartwig amination of aryl chlorides catalyzed by easily accessible benzimidazolyl phosphine-Pd complexes

Article abstract of DOI:10.1055/s-0031-1290666

This study describes the efficacy of benzimidazolyl phosphine ligands, which are easily synthesized from inexpensive and commercially available o-phenylenediamine, 2-bormobenzoic acid, and chlorophosphines, in the Buchwald-Hartwig amination of aryl chlorides. Primary and secondary aromatic/aliphatic amines are effective substrates in this catalytic system. Functional groups such as keto and esters are also compatible. The catalyst loading can be reduced to 0.1 mol% Pd. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290666

LETTER
1181
Buchwald–Hartwig Amination of Aryl Chlorides Catalyzed by Easily
Accessible Benzimidazolyl Phosphine-Pd Complexes
B
uchwald–Hartw
i
i
g Amin
n
ation Ho Chung, Chau Ming So,* Shun Man Wong, Chi Him Luk, Zhongyuan Zhou, Chak Po Lau, Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong
Fax +852(2364)9932; E-mail: bccmso@inet.polyu.edu.hk; E-mail: bcfyk@inet.polyu.edu.hk
Received 28 December 2011
activity in various cross-coupling reactions of aryl halides
and, especially, aryl chlorides (Figure 1).11
Abstract: This study describes the efficacy of benzimidazolyl
phosphine ligands, which are easily synthesized from inexpensive
and commercially available o-phenylenediamine, 2-bormobenzoic
acid, and chlorophosphines, in the Buchwald–Hartwig amination of
aryl chlorides. Primary and secondary aromatic/aliphatic amines are
effective substrates in this catalytic system. Functional groups such
as keto and esters are also compatible. The catalyst loading can be
reduced to 0.1 mol% Pd.
Phosphine ligands that possess a potentially hemilabile
coordinating group have been studied in the past decade.12
In 1999, Guram, Bei and co-workers reported a prelimi-
nary study of P,N-type ligands (Figure 2) for amination
reactions of aryl chlorides.13 Although these P,N-type
ligands only showed low to moderate activity, they dem-
onstrated the possibility of using P,N-type ligands in am-
ination reactions. Recently, Stradiotto and co-workers
reported a series of highly effective DalPhos P,N-ligands
for amination reactions (Figure 2).14
Key words: palladium, cross-coupling, amination, aryl chlorides,
phosphine
Buchwald–Hartwig amination is one of the most powerful
tools available for constructing aromatic carbon–nitrogen
bonds in synthetic organic chemistry.1 This method has
been widely used in the synthesis of pharmaceutically
useful intermediates and biologically active compounds
and materials.1 Since the first catalytic amination protocol
was discovered,2 efforts toward increasing the reaction ef-
ficacy have been actively pursued.3 Recently, aryl iodides
and bromides were reported to be successfully converted
into the corresponding aryl amines by employing simple
copper4 or iron salts5 with various ligands as catalysts.
However, the use of easily available and inexpensive aryl
chlorides still requires a highly active palladium catalyst
for the amination reactions. For cross-coupling processes,
it has been recognized that the efficiency is significantly
affected by the structure of the ligand. Therefore, flexible
modifications that result in ligands with appropriate ster-
ic/electronic nature are crucial in dealing with problemat-
ic and specific substrates in this area. The advancement of
some notable ligands such as t-Bu3P,6 Bellers’s PAP,7
Buchwald’s biaryl-phosphines,8 Hartwig’s Q-Phos,9 and
Verkade’s amino-phosphine10 provide excellent catalytic
O
NMe2
Me
N
PCy2
NMe2
Me
PCy2
N
O
PAd2
PAd2
Mor-DalPhos
Me-DalPhos
Figure 2 Recently developed P,N-ligands for amination reactions
Although a variety of ligands have been developed, the
rapid assembly of structurally diverse ligand scaffolds
through simple synthetic methods is still important for the
development of versatile catalysts for widespread applica-
tions of coupling reactions. In a continuation of our inter-
est in developing heterocyclic phosphine ligands,15 we
herein report our exploration of a benzimidazole-derived
phosphine that contains attractive features of a resourceful
ligand: (i) a tunable 2-phenylbenzimidazole skeleton pro-
viding potential diversification; (ii) a hemilabile chelating
Fu group
Buchwald group
Hartwig group
Pt-Bu2
Beller group
Verkade
group
R'
R
PCy2
N
R
N
Fe
PCy2
N
P
Ph
Ph
Ph
Ph
Pt-Bu3
R
N
R
R
Ph
Q-Phos
N
PAP
Figure 1 Some recently developed effective phosphine ligands
SYNLETT 2012, 23, 1181–1186
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 26.04.2012
DOI: 10.1055/s-0031-1290666; Art ID: W81211ST
© Georg Thieme Verlag Stuttgart · New York

1182
K. H. Chung et al.
LETTER
group that can provide weak coordinating properties for To test the effectiveness of the benzimidazole-derived
dynamic interaction of metal centers that could increase ligands, 4-chlorotoluene with N-methylaniline were used
catalyst longevity, and (iii) a tunable phosphino group on as model substrates. A catalyst loading of 0.5 mol% Pd
the aryl ring that could provide electron density and po- was initially applied in probing the ligand efficacy
tential electronic fine-tuning.
(Table 1).
With the benzimidazolyl ligands L1–L3 in hand, a survey
of Pd sources was subsequently started using toluene as
O
H
NH2
N
PPA
HO
+
Table 1 Investigations on the Effectiveness of the Benzimidazolyl
N
NH2
Br
Phosphine Ligands in the Amination of Aryl Chloridesa
70%
Br
Cl
NaH, THF, Me2SO4
R2P
N
Me
N
Me
N
n-BuLi, ClPR2
Ph
Me
+
Pd-L
Me
N
N
N
N
base, solvent
Me
Me
H
R2P
Br
Me
L1–L3
75%
N
Ph
L1, R = Ph, 80%
L2, R = Cy, 70%
L3, R = i-Pr, 83%
Entry Pd source
Pd (%) Base
Solvent Yield (%)b
Scheme 1 Synthetic pathway to benzimidazolyl phosphine ligands
1c
2c
3c
4c
5d
6e
7
Pd(OAc)2
Pd(dba)2
Pd2(dba)3
0.5
0.5
0.5
t-BuONa toluene 84
t-BuONa toluene 86
t-BuONa toluene 99
t-BuONa toluene 84
t-BuONa toluene 62
t-BuONa toluene 92
t-BuONa toluene 96
t-BuONa toluene 83
t-BuONa toluene 94
t-BuONa dioxane 93
t-BuONa toluene 74
t-BuONa dioxane 66
t-BuONa p-xylene 67
The ligand precursor of these heterocyclic phosphine
ligands was efficiently obtained through simple conden-
sation between commercially available and inexpensive
o-phenylenediamine and 2-bromobenzoic acid in the
presence of polyphosphoric acid.16 Notably, a practical
scale-up synthesis of up to 100 mmol was possible with-
out difficulties in either synthetic or purification process-
es. The methylated ligand precursors were then lithiated
by treatment with n-BuLi and trapped with ClPR2, afford-
ing the corresponding benzimidazolyl phosphines in good
to excellence yields (Scheme 1). L2 was recrystallized
from ethyl acetate and was subjected to an X-ray diffrac-
tion study (Figure 3).17 It is worth noting that this class of
ligand exhibits high air-stability in both solid and solution
states.18
PdCl2(MeCN)2 0.5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
0.5
0.5
0.5
0.2
0.2
0.2
0.1
0.1
0.1
0.1
0.2
0.1
0.1
0.2
0.2
8
9
10
11
12
13
14
15
16
17
18f
19g
K3PO4
K3PO4
Cs2CO3
K2CO3
toluene 65
toluene 85
toluene 34
toluene
4
1
t-BuONa toluene
t-BuONa toluene 81
a Reaction conditions: Pd, ligand L2, Pd/L ratio1:4, ArCl (1.0 mmol),
N-methylaniline (1.5 mmol), base (2.5 mmol), solvent (3.0 mL), 20 h,
135 °C under nitrogen.
b Calibrated GC yields were calculated using dodecane as the internal
Figure 3 ORTEP representation of benzimidazolyl phosphine li-
gand L2 (30% probability ellipsoids). Hydrogen atoms have been
omitted for clarity. Selected bond distances (Å) and angles (deg):
P(1)–C(13), 1.8536(14); P(1)–C(20), 1.8597(15); P(1)–C(14),
1.8583(15); C(13)–P(1)–C(14), 101.22(6); C(13)–P(1)–C(20),
102.88(7); C(14)–P(1)–C(20), 104.06(7).
standard.
c Pd/L ratio 1:2.
d Pd/L ratio 1:1.
e Pd/L ratio 1:3.
f Ligand = L1.
g Ligand = L3.
Synlett 2012, 23, 1181–1186
© Thieme Stuttgart · New York

LETTER
Buchwald–Hartwig Amination
1183
the solvent and t-BuONa as the base. Use of Pd2(dba)3 also effective in this system. Ligand L1, with a diphe-
gave the best result among Pd(OAc)2, Pd(dba)2 and nylphosphino moiety, provided trace amounts of substrate
PdCl2(MeCN)2 (Table 1, entries 1–4), and a metal/ligand conversion, whereas the dicyclohexylphosphino ana-
ratio of 1:4 provided the highest yield (Table 1, entries 1 logue, L2, showed the best performance (Table 1, entries
and 5–7). These conditions were then chosen for further 9, 18, and 19). Ligand L3, bearing a diisopropylphosphino
screening. Among the commonly used organic solvents moiety, gave a lower catalytic activity in the amination re-
examined, toluene gave the best result (Table 1, entries 9– action.
13). Several bases were examined in the presence of
ligand L2, and t-BuONa was found to be the base of
choice in this catalytic system (Table 1, entries 11 and 14–
17). It is worth noting that the weaker base K3PO4 was
were effective substrates that gave the corresponding
We first employed the preliminary optimized reaction
conditions for the amination of aryl chlorides with aro-
matic amines (Table 2).19 Aniline and N-methylaniline
Table 2 Palladium-Catalyzed Amination of ArCl with Aromatic Aminesa
Cy2P
N
R2
Pd-L2 (0.2–0.5 mol%)
R1
+
R1
HN
R2
N
t-BuONa, toluene
135 °C
R3
N
R3
Me
L2
Cl
Entry
1
ArCl
Amine
Product
Pd (mol%)
0.2
Time (h)
20
Yield (%)b
99
Me
Me
H
H
N
H
N
H
Cl
Me
Me
2
3
4
5
0.2
0.2
0.2
0.5
20
20
20
24
90
99
90
90
N
N
Me
Me
Cl
Me
Me
Me
N
H
H2N
Cl
Me
Me
Me
MeO
MeO
Me
Me
H2N
N
H
Me
Me
Cl
Me
Me
N
H
Cl
H2N
Me
Me
MeO
MeO
6
7
0.2
0.2
20
20
99
94
N
HN
Cl
Me
Me
N
HN
Cl
a Reaction conditions: ArCl (1.0 mmol), amine (1.5 mmol), t-BuONa (2.5 mmol), Pd2(dba)3/L2 = 1:4, toluene (3.0 mL), 135 °C under nitrogen.
b Isolated yield.
© Thieme Stuttgart · New York
Synlett 2012, 23, 1181–1186

1184
K. H. Chung et al.
LETTER
O
products in excellent yields (Table 2, entries 1 and 2). A
sterically hindered amine was also found to be a suitable
coupling partner in this C–N bond formation, generating
the tri-ortho-substituted product (Table 2, entry 3). Ami-
nation of a deactivated aryl chloride did not diminish the
desired product yields when compared with amination of
neutral aryl chloride (Table 2, entry 4). Furthermore, a
fused cyclic amine also coupled well with chloroarenes
(Table 2, entries 6 and 7).
O
Me
Me
O
Pd (0.2 mol%)/L2
toluene (3 mL)
N
Me
K3PO4, 135 °C, 20 h
Cl
Cl
93%
74%
Me
O
N
N
H
Me
OMe
OMe
We than examined the reactivity of the Pd-L2 system to-
wards the amination of aryl chlorides with cyclic and ali-
phatic amines (Table 3). Morpholine and piperidine
showed excellent reactivity in the amination reaction
(Table 3, entries 1–3). An acyclic secondary amine such
as dihexylamine was also compatible with this system
(Table 3, entry 4).
Scheme 2 Palladium-catalyzed amination of functionalized aryl
chloride
one of the important applications of amination reactions is
to synthesize pharmaceutically useful intermediates that
usually contain reactive functional groups. In this system,
using K3PO4 as base, reactive functional groups such as
keto and ester moieties were also compatible and the de-
sired products were obtained in good yield (Scheme 2).
The coupling of heteroaryl chlorides was also studied.
The results showed that 2-chloropyridine was an effective
substrate for the amination reaction (Table 4). Under 0.5
mol% Pd loading, cyclic, aromatic and aliphatic amines
were transformed into the corresponding coupled prod-
ucts in excellent yields. In the absence of the Pd2(dba)3, no
coupling product between 2-chloropyridine and dibenzyl-
amine was observed (Table 4, entries 5 and 6).
In conclusion, we have developed a series of efficient ben-
zimidazolyl phosphine ligands that can be used in aromat-
ic C–N bond-forming reactions. These ligands can be
easily accessible on large scales using inexpensive and
commercially available starting materials. Palladium
complexes derived from these ligands provide highly ac-
tive catalysts for amination of aryl chlorides with aromatic
Functional group compatibility is one of the major con-
cerns for the effectiveness of an amination system since
Table 3 Palladium-Catalyzed Amination of ArCl with Aliphatic Aminesa
Cy2P
N
R2
R3
Pd-L2 (0.2–0.5%)
R1
R1
+
HN
R2
t-BuONa, toluene
135 °C, 20 h
N
N
R3
Me
L2
Cl
Entry
1
ArCl
Amine
Product
Pd (mol%)
0.2
Yield (%)b
89
Me
Me
Me
Me
Me
HN
O
O
N
N
N
O
O
Cl
Cl
Cl
Cl
Me
Me
2
3
4
0.2
0.5
0.5
86
80
73
HN
HN
Hex
Hex
HN
Me
N
Hex
Hex
a Reaction conditions: ArCl (1.0 mmol), amine (1.5 mmol), t-BuONa (2.5 mmol), Pd2(dba)3/L2 = 1:4, toluene (3.0 mL), 20 h, 135 °C under
nitrogen.
b Isolated yield.
Synlett 2012, 23, 1181–1186
© Thieme Stuttgart · New York

LETTER
Buchwald–Hartwig Amination
1185
Table 4 Palladium-Catalyzed Amination of Heteroaryl Chloridesa
Cy2P
N
N
R2
R3
Pd-L2 (0.2–0.5%)
R1
+
R1
HN
R2
N
t-BuONa, toluene
135 °C
N
R3
Me
L2
Cl
Entry
1
ArCl
Amine
Product
Pd (mol%)
Time (h)
20
Yield (%)b
92
N
N
N
0.2
0.2
HN
H
O
N
O
Cl
Cl
Me
N
Me
N
N
2
20
99
Ph
N
Ph
N
N
N
N
3
0.5
0.5
0.5
0.5
24
24
24
24
98
95
0
N
N
N
N
N
N
N
N
H
H
H
H
Ph
Bn
Cl
Cl
Cl
Cl
Ph
Bn
N
N
4
Bn
Bn
Bn
Bn
5c
6d
Bn
Bn
Bn
Bn
N
0
Bn
Bn
Me
N
7
0.5
24
97
N
HN
Cl
a Reaction conditions: ArCl (1.0 mmol), amine (1.5 mmol), t-BuONa (2.5 mmol), Pd2(dba)3/L2 = 1:4, toluene (3.0 mL), 20 h, 135 °C under
nitrogen.
b Isolated yield.
c Without Pd2(dba)3 and L2.
d Without Pd2(dba)3.
and aliphatic amines. Functional groups such as keto and
ester moieties are compatible with the use of K3PO4 as
base. In view of the simplicity of the ligand synthesis, we
anticipate that further diversification of the ligand scaf-
fold will be attainable.
References and Notes
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A.; Diedrich, F., Eds.; Wiley-VCH: Weinheim,
2004. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int.
Ed. 2008, 47, 6338. (c) Corbet, J.-P.; Mignani, G. Chem.
Rev. 2006, 106, 2651. (d) Schlummer, B.; Scholz, U. Adv.
Synth. Catal. 2004, 346, 1599. (e) King, A. O.; Yasuda, N.
In Organometallics in Process Chemistry; Larsen, R. D.,
Ed.; Springer: Berlin, Heidelberg, 2004, 205–246; and
references therein. (f) Lawrence, S. A. Amines, Synthesis,
Properties, and Application; Cambridge University Press:
Cambridge, 2004. (g) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131.
(2) For an early report on catalytic amination, see: (a) Kosugi,
M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.
For early reports on Buchwald–Hartwig amination, see:
(b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem. Int. Ed. Engl. 1995, 34, 1348. (c) Louie, J.; Hartwig,
J. F. Tetrahedron Lett. 1995, 36, 3609.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the Research Grants Council of Hong Kong (CERG:
PolyU5005/07P), PolyU Internal Competitive Research Grant (A-
PG13) and SKL of Chirosciences for financial support. We are also
grateful to Prof. Albert S. C. Chan’s research group (PolyU Hong
Kong) for sharing of GC instruments.
(3) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top.
© Thieme Stuttgart · New York
Synlett 2012, 23, 1181–1186

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K. H. Chung et al.
LETTER
Curr. Chem. 2002, 219, 131. (b) Hartwig, J. F. In
(14) (a) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto,
M. Angew. Chem. Int. Ed. 2010, 49, 4071. (b) Lundgren, R.
J.; Stradiotto, M. Angew. Chem. Int. Ed. 2010, 49, 8686.
(c) Lundgren, R. J.; Sappong-Kumankumah, A.; Stradiotto,
M. Chem. Eur. J. 2010, 16, 1983.
(15) For indolyl scaffold ligands, see: (a) So, C. M.; Lau, C. P.;
Kwong, F. Y. Org. Lett. 2007, 9, 2795. (b) So, C. M.;
Yeung, C. H.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2008,
73, 7803. (c) So, C. M.; Lau, C. P.; Zhou, Z.; Kwong, F. Y.
Angew. Chem. Int. Ed. 2008, 47, 6402. (d) Chung, K. H.;
So, C. M.; Wong, S. M.; Luk, C. H.; Zhou, Z.; Lau, C. P.;
Kwong, F. Y. Chem. Commun. 2012, 48, 1967.
(16) According to the list price from Aldrich (21-2-2011), o-
phenylenediamine costs 0.18 USD/G and 2-bromobenzoic
acid costs 0.88 USD/G.
(17) CCDC-865333 contains the supplementary crystallographic
data for L2. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002. (c) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A.;
Diederich, F., Eds.; John Wiley & Sons: Weinheim, 2004.
(4) For selected examples of copper-catalyzed amination, see:
(a) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2008,
47, 3096. (b) Xu, H.; Wolf, C. Chem. Commun. 2009, 1715.
(c) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
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J. Org. Chem. 2005, 70, 5164. (e) Rout, L.; Jammi, S.;
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E.; de Vries, J. D.; van Klink, G. P. M.; van Koten, G.
Tetrahedron Lett. 2007, 48, 7366. (g) Chang, J. W. W.; Xu,
X.; Chan, P. W. H. Tetrahedron Lett. 2007, 48, 245.
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(5) (a) Correa, A.; Bolm, C. Angew. Chem. Int. Ed. 2007, 46,
8862. (b) Correa, A.; Bolm, C. Chem. Eur. J. 2008, 14,
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391. (d) Buchwald, S. L.; Bolm, C. Angew. Chem. Int. Ed.
2009, 48, 5586.
(6) For selected amination references, see: (a) Nishiyama, M.;
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617.
(b) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
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1555.
(7) (a) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.;
Riermeier, T.; Monsees, A.; Dingerdissen, U.; Beller, M.
Chem. Eur. J. 2004, 10, 2983. (b) Zapf, A.; Beller, M.
Chem. Commun. 2005, 431.
(8) For a selected amination reference, see: (a) Wolfe, J. P.;
Tomori, H. J.; Sadighi, P.; Yin, J.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1158. (b) For recent review, see: Surry,
D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
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www.ccdc.cam.ac.uk/data_request/cif.
(18) There was no detectable phosphine oxide signal of L2 in the
31P NMR spectrum when the solid form of the ligand was
allowed to stand under air for one month.
(19) Palladium-Catalyzed Amination of Aryl Chlorides;
General Procedure: A stock solution of [Pd2 (dba)3] (0.023
g, 0.10 mmol) and ligand L (Pd/L = 1:4) were loaded into a
reaction tube equipped with a Teflon-coated magnetic stir
bar. The tube was evacuated and flushed with nitrogen (3
cycles). A stock solution was prepared by adding freshly
distilled toluene (5.0 mL). Bases (2.5 mmol) were loaded
into an array of Schlenk tubes. The tubes were evacuated and
flushed with nitrogen (3 cycles). Aryl chlorides (1.0 mmol),
amines (1.5 mmol) and the stock solution (0.1 mol% Pd per
0.5 mL stock solution) were loaded into the tubes. Toluene
was then added to give a total volume of 3.0 mL in each tube.
The solutions were stirred at room temperature for several
minutes and then placed into a preheated oil bath (135 °C)
for the time period indicated in the Tables. After completion
of reaction as judged by GC analysis, the reaction tube was
allowed to cool to room temperature and the reaction was
quenched with water and diluted with EtOAc. The organic
layer was separated and the aqueous layer was washed with
EtOAc. The combined organic layer was dried, filtered and
concentrated under reduced pressure and the crude products
were purified by flash column chromatography on silica gel
(230–400 mesh) to afford the desired product.
4-Methyl-N-phenylaniline (Table 2, entry 1): 1H NMR
(400 MHz, CDCl3): d = 2.50 (s, 3 H), 5.70 (s, 1 H), 7.05–
7.09 (m, 1 H), 7.16–7.19 (m, 4 H), 7.26–7.30 (m, 2 H), 7.40–
7.46 (m, 2 H); 13C NMR (100 MHz, CDCl3): d = 20.6, 116.8,
118.8, 120.1, 129.2, 129.7, 130.7, 140.2, 143.9; MS (EI):
m/z (%) = 183.1 (100) [M]+, 167.1 (20), 91.0(14), 77.1 (10).
Synlett 2012, 23, 1181–1186
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