Coupling of ortho-substituted aryl chlorides with bulky amides

Article abstract of DOI:10.1039/c1cc14844c

Voluminous amides were coupled with deactivated, sterically hindered aryl chlorides in excellent yields providing products, which have not been efficiently accessible by transition metal catalysis so far. Application of an unsymmetric bisphosphine ligand was critical for the high catalytic activity.

Full text of DOI:10.1039/c1cc14844c

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COMMUNICATION
Coupling of ortho-substituted aryl chlorides with bulky amidesw
a
b
a
¨
Florian C. Falk, Roland Frohlich and Jan Paradies*
Received 5th August 2011, Accepted 1st September 2011
DOI: 10.1039/c1cc14844c
Voluminous amides were coupled with deactivated, sterically
hindered aryl chlorides in excellent yields providing products,
which have not been efficiently accessible by transition metal
catalysis so far. Application of an unsymmetric bisphosphine
ligand was critical for the high catalytic activity.
Nitrogen containing heterocycles are ubiquitous structural
elements in molecule design for medicine, life science and crop
protection, ensuring a constant demand for efficient syntheses.1
The amination and the amidation of sp2-hybridized halides are
some of the most powerful methodologies for the introduction
of nitrogen into complex molecules.2 This can be achieved by
transition metal catalysts, which exhibit high functional group
tolerance, allowing the elegant assembly of complex molecules.3
Very efficient catalysts have been reported, which depend on
the nature of the halide (or pseudo-halide, e.g. triflate) for the
C–N bond formation.2b,4 Buchwald has demonstrated that
carefully designed monodentate biaryl phosphine ligands
are exceptionally potent to promote the coupling of mainly
meta- and para-substituted aryl chlorides with amides.3a,4c,5c,5e
Additionally, only few examples are described for the coupling
of deactivated aryl chlorides with bulky amides.5b,6 A copper
mediated amidation of aryl chlorides with bulky amides was
described providing the product in medium yield.6b However,
here, we present a catalytic system, which is exceptionally potent
for the coupling of ortho- and ortho,ortho-disubstituted aryl
chlorides with sterically challenging amides accessing highly
encumbered C–N bond formation products in excellent yields.
Bisphosphines display remarkable features in palladium
mediated amidations:5 First, the binding mode of the amidate
ligand can be modulated (k1 versus k2).5e,5f,5g Second, unsym-
metrically substituted bisphosphines can increase the rate of
reductive elimination.5d,5h These two criteria were consulted
for the synthesis of a novel bisphosphine embedded in the highly
rigid [2.2]paracyclophane scaffold.7 A new flexible high yielding
synthesis towards pseudo-geminally substituted bisphosphine
Scheme 1 Synthesis of GemPhos derivatives 1 and 6.8
derivatives, GemPhos, was developed (Scheme 1). The synthesis
of GemPhos derivatives commences from racemic 4-[2.2]para-
cyclophanyl-diphenylphosphine oxide7g,9 (2, Scheme 1), which
underwent electrophilic bromination regiospecifically in 81%
yield. The pseudo-geminal substitution pattern in 3 was
unambiguously established by NMR spectroscopy (31P NMR
d = 27.9 ppm) and crystal structure analysis.8 Reduction of
3 was achieved by stepwise conversion first to the sulfide
5 (31P NMR d = 41.1 ppm) followed by sulfur metathesis
with triethoxy phosphite11 furnishing the phosphine 4 (31P NMR
d = ꢀ9.7 ppm) in 61% over two steps (Scheme 1).10 The
bromophosphine 4 was converted either into the symmetrical
bisphosphine 6 (Ph2-GemPhos, 87% yield) or into the racemic,
unsymmetrical bisphosphine 1 (PhCy-GemPhos, 72% yield)
by metallation and treatment with the corresponding chloro-
phosphine. This high yielding synthesis (44% 1, 53% 6 over four
steps) required only one chromatographic purification (last step)
and can be performed on a gram scale. The structural and
electronic features of these extraordinary ligands were analyzed
by NMR, IR spectroscopy and single crystal structure analysis
(see ESIw).8 The two bisphosphines were subjected to coordination
to palladium(II). The dicationic square planar Pd-complexes
were unambiguously characterized by NMR spectroscopy and
X-ray crystal structure analysis8 confirming the exclusive cis-
coordinating nature of 1 and 6. The efficiency of the bisphos-
phine ligands was first investigated in the palladium catalyzed
C–N bond formation reaction of 4-chlorotoluene (7a) and
benzamide (8a). The palladium species, which was obtained
from the reaction of symmetrical bisphosphine 6 with all
palladium sources, furnished ineffective catalysts. In contrast,
the palladium complexes generated by the reaction of 1
a Institute of Organic Chemistry, Karlsruhe Institute of Technology,
Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany.
E-mail: jan.paradies@kit.edu; Fax: +49 721 608 5637;
Tel: +49 721 608 5344
b Institute of Organic Chemistry, University of Munster,
¨
Corrensstrasse 40, D-48149 Munster, Germany.
¨
E-mail: frohlic@uni-muenster.de; Fax: +49 251 83 39772;
Tel: +49 251 83 33293
w Electronic supplementary information (ESI) available. CCDC
816638–816643. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc14844c
c
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Chem. Commun., 2011, 47, 11095–11097 11095

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Table 1 Amidation of aryl chlorides
microwave reactors.12,13 Heating of 7a, 8a in a CEM micro-
wave reactor with 2 mol% of activated catalyst/1 to 150 1C for
5 h furnished product 9aa in 99% yield (Table 1, entry 1).
Subsequently, the scope for the coupling of aryl chlorides with
a number of challenging amides using both conventional
heating and microwave irradiation was explored (Table 1).
Generally the reactions were promoted by the catalyst system
Pd(OAc)2/1/H2O and furnished the products in good to
excellent yields under both conventional heating and microwave
irradiation. Coupling of deactivated 7b with the bulky amide
8b proceeded in 72% yield (entry 2, lit. 15%14). This obser-
vation encouraged us to investigate the amidation of sterically
demanding coupling partners (entries 3 to 13). Indeed, the
amidation of 2-chlorotoluene (7c) with 8a afforded the C–N
coupling product 9ca in quantitative yield (entry 3, 99%, lit.
93%15). In particular, the poorly nucleophilic sulfone amide 8c
is a very challenging substrate for the amidation and has
not yet been successfully applied in the C–N bond formation
of ortho-substituted aryl chlorides. The amidation of 7c pro-
ceeded smoothly with sulfone amide 8c in 78% and 76% yields
(entry 4). Even lithium hexamethyldisilazide (8d, LHMDS,
entry 5) as an ammonia surrogate was successfully applied in the
literature, unprecedented amidation of ortho-substituted 7c.15
The resulting aniline 9cd was obtained in 43% and 47%
yields.z Secondly, we investigated the influence of the nature of
the ortho-substituents on the amidation reaction (entries 6 to 9).
Electron withdrawing (7d), electron donating (7e and 7f) and aryl
groups (7g) are all well tolerated in combination with synthe-
tically important nitrogen nucleophiles. The corresponding
products 9 (entries 6 to 9, 9ef 99%, lit. 10%16) were obtained
in excellent yields. Even the combination of the highly electron-
rich and sterically encumbered chloroarene 7f with a weak nucleo-
phile serendipitously furnished the aryl lactam 9fg in quantitative
yield. To our knowledge the amidation of the corresponding
biaryl chlorides (e.g. 7g) has not been reported yet.17 The reaction
of 7g with acetamide 8h furnished acetyl protected biaryl amine
9gh in 99% yield and represents a significant development in the
catalytic amidation of aryl chlorides. The efficient amidation of
ortho,ortho-disubstituted aryl chlorides has not been reported so
far.16,18 The application of our catalytic system to the reaction of
7h with 8a furnished the amidation product in excellent yield
(entry 10, 96% yield). Alkyl groups in the ortho position of the
amides 8i–8k increase the steric bulk making these substrates
challenging coupling partners in the amidation of 7h. Electron
deficient (8i) and electron rich amides (8j) were applied in the
amidation of the sterically encumbered aryl chloride 7h (entries 11
and 12) furnishing the products 9hi and 9hj in high yields. The
most bulky amide for the coupling with 7j is the ortho,meta-
substituted 8k. The coupling furnished the tetra-substituted,
highly sterically restricted amide 9hk in 81% yield under both
conventional heating and microwave irradiation demonstrating
the scope for the developed system.
Yield/%a
b
mWc
Entry ArCl
1
Amide
Product
93
58
99
72
2
3
4
5
6
99
78
99
76
HN(SiMe3)2 8d
47 43d
94
99
99
92
99
94
7
8
9
99
99
10
11
96
72
94
71
12
87
81
89
81
13
a
b
Yield of product after column chromatography. Conventional
equiv. ArCl, equiv. amide, 2–4 mol% Pd(OAc)2,
heating:
1
1
6–12 mol% 1, 4–16 mol% H2O, 1.5 equiv. Cs2CO3, 125 1C to
c
150 1C, 18–24 h, 1 M in 1,4-dioxane. Microwave irradiation: 1 equiv.
ArCl, 1 equiv. amide, 2–4 mol% Pd(OAc)2, 6–12 mol% 1, 4–16 mol%
H2O, 1.5 equiv. Cs2CO3, 125 1C to 150 1C, 5 h, 1 M in 1,4-dioxane;
(see ESIw for details; mW = microwave irradiation). Lower yield due
to its high vapour pressure.
d
with the palladium sources proved as highly active catalysts.
The pre-formation of the catalyst according to a protocol by
Buchwald5c and the application of 1,4-dioxane as solvent were
critical for the efficient amidation of 7a. The product N-4-toloyl
benzamide (9aa) was obtained in high yield (93%) after
stirring at 110 1C for 18 h. A commonly applied technique
for a fast synthesis of amides and/or peptides employs
In order to determine whether the reactivity is a result of a
possible monoligated phosphine–palladium complex we con-
ducted NMR experiments (0.1 mmol scale). The incubation of
Pd(OAc)2, three equivalents of 1 and one equivalent of water
furnished the palladium(0) bisphosphine complex (A) (Scheme 2,
for 31P{1H} NMR spectra see ESIw). The 31P{1H} NMR spectrum
exhibits four resonances, which were assigned to monooxidized
c
11096 Chem. Commun., 2011, 47, 11095–11097
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In summary, the high yielding amidation of bulky, deactivated
aryl chlorides with sterically encumbered amides was developed,
providing substrates, which include ubiquitous N-protective
groups (Ac, Boc, sulfone) and Evans-auxiliaries. The application
of a rigid, unsymmetrical substituted bisphosphine was critical for
the efficiency of the process. Mechanistic studies concentrating on
the unusual activity of the bisphosphine/Pd complex are currently
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11095–11097 11097