A diaminochlorophosphine for palladium-catalyzed arylations of amines and ketones

Article abstract of DOI:10.1002/anie.200602222

(Chemical Equation Presented) Sterically hindered substituents on a secondary chlorophosphine 1 prevent formation of a diaminooxophosphine, and thereby allow for highly efficient arylation reactions of amines and α-C-H acidic ketones with (hetero)aryl chlorides.

Full text of DOI:10.1002/anie.200602222

Angewandte
Chemie
ꢀ
C N Coupling
Initial experiments were directed at probing the reactivity
of various diaminochlorophosphines with respect to salt
elimination with NaOtBu (Scheme 1). While diaminochloro-
phosphine 1 was quantitatively converted to daop 2 within
two hours, no reaction occurred when using bulky chloride
3[17] under otherwise identical reaction conditions.
DOI: 10.1002/anie.200602222
A Diaminochlorophosphine for Palladium-
Catalyzed Arylations of Amines and Ketones**
Lutz Ackermann,* Julia H. Spatz, Christian J. Gschrei,
Robert Born, and Andreas Althammer
Palladium-catalyzed amination reactions of aryl halides are
ꢀ
indispensable tools for the synthesis of compounds with N
C(sp2) linkages.[1–4] Iodides and electronically activated bro-
mides can be successfully transformed by employing simple
palladium salts. Aryl chlorides, however, are arguably the
most useful single class of substrates because of their lower
cost and the wider diversity of available compounds. The
conversion of aryl chlorides usually requires recently devel-
oped stabilizing ligands.[5] The ligand design has been focused
predominantly on electron-rich tertiary phosphines.[6,7] Owing
to their electron-rich nature tertiary phosphines and their
transition-metal complexes are often prone to oxidation. An
alternative approach makes use of complexes derived from
air-stable secondary phosphine oxides.[8] However, applica-
tions of these catalysts to more challenging substrates, such as
ortho-substituted aryl chlorides or acyclic alkyl amines,[9,10]
have so far not been reported.[11]
Scheme 1. Salt elimination from diaminochlorophosphines with
NaOtBu.
The catalytic activity of sterically congested 3 was tested
in the amination of electronically deactivated aryl chloride 5a
(Table 1). A palladium complex of 3 (Table 1, entry 3) proved
Table 1: Ligand studies for the amination of aryl chloride 5a.[a]
Recently, we described the diaminooxophosphine (daop)
ligand 2, which allowed for palladium-catalyzed amination
reactions of electronically deactivated aryl chlorides.[12,13]
During studies on the in situ generation of daop ligand 2
through salt elimination from the corresponding chlorophos-
phine 1,[14] we observed an initial oxidative addition of
chloride 1 to a low-valent palladium species, thereby giving
rise to a phosphenium cation.[12] Phosphenium cations are
isolobal to N-heterocyclic singlet carbenes,[15,16] which are
frequently employed in transition-metal catalysis.[7] There-
fore, we wondered if a catalyst with a superior reactivity
profile could be developed by preventing salt elimination and
daop formation. Herein, we present a sterically hindered
diaminochlorophosphine as ligand for efficient arylation
Entry
[Pd(dba)2][b]
(mol%)
L (mol%)
Yield [%][c]
1
2
3
4
5
6
7
5.0
5.0
5.0
1.0
1.0
0.5
5.0
1 (10.0)
2 (10.0)
3 (10.0)
3 (1.0)
3 (2.0)
3 (1.0)
63
62
98
32
93
86
31
4 (10.0)
[a] Reaction conditions: 5a (1.0 mmol), 6a (1.2 mmol), NaOtBu
(1.3 mmol), toluene (3.0 mL), 1058C, 17 h. [b] dba=dibenzylideneace-
tone. [c] Yield of isolated product.
ꢀ
reactions of amines and a-C H acidic ketones with ample
scope.
more active than the ones generated from either chlorophos-
phine 1 or daop 2[12] (Table 1, entries 1 and 2). The superior
catalytic performance allowed for a significant reduction of
catalyst loading (Table 1, entries 5 and 6), with an optimal
palladium/ligand ratio of 1:2 (Table 1, entries 4 and 5).
Importantly, a complex derived from the corresponding
daop 4 displayed a considerably reduced efficacy (Table 1,
entry 7). These experiments highlight a different working
mode for sterically hindered ligand 3, when compared with
the one observed for preligand 1.[18]
Subsequently, the scope of the amination reaction with
aryl chlorides was studied, with particular emphasis on more
demanding substrate combinations (Table 2). Sterically hin-
dered aniline derivatives were efficiently converted (Table 2,
entries 1, 2, 5, 8, 9, and 13). Furthermore, high yields of
isolated product were obtained using electron-rich, thereby
electronically deactivated, aryl chlorides and bromides, even
[*] Dr. L. Ackermann, Dipl.-Chem. J. H. Spatz, Dipl.-Chem. C. J. Gschrei,
Dipl.-Chem. R. Born, Dipl.-Chem. A. Althammer
Department Chemie und Biochemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77425
E-mail: lutz.ackermann@cup.uni-muenchen.de
Homepage: http://www.cup.uni-muenchen.de/oc/ackermann/
[**] Support by the DFG (Emmy Noether-Programm), the Fonds der
Chemischen Industrie, Professor Paul Knochel, and the Ludwig-
Maximilians-Universität is gratefully acknowledged. We thank Salt-
igo GmbH (Leverkusen) for the generous gift of chemicals.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 7627 –7630
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7627

Communications
Table 2: Amination reactions with challenging substrates.[a]
Entry
1
Chloride
Amine
Product
Yield [%][b]
97
Entry
8
Chloride
Amine
Product
Yield [%][b]
98
5b
6b
7b[c]
5e
6b
7i[c]
2
3
97
93
9
87
94
5c
6b
7c[c]
10a
6b
7j[c]
10
5d
5d
5e
6c
6d
6e
7d
7e
5e
5e
5e
6 f
6g
6h
7k
4
5
96
91
11
12
85
80
7l
7 f[d]
7m
6
93
88
13
14
85
91
5e
5e
6c
6d
7g
7h
5 f
6b
7n[c]
7
5b
6i
7o
[a] Reaction conditions: 5 (1.0 mmol), 6 (1.2 mmol), NaOtBu (1.3 mmol), [Pd(dba)2] (5.0 mol%), 3 (10.0 mol%), toluene (3.0 mL), 1058C, 2–21 h.
[b] Yield of isolated product. [c] Mes=2,4,6-Me3C6H2 . [d] Ar=2,6-(iPr)2C6H3 .
when bearing ortho substituents (Table 2, entries 3–12). Thus,
tetra-ortho-substituted diaryl amines were prepared in high
yields (Table 2, entries 5, 8, and 9). Acyclic alkyl amines are
difficult substrates, as the palladium amide complexes derived
thereof easily undergo b-hydride elimination.[3] Nonetheless,
the catalyst formed from bulky 3 performed well in arylation
reactions of alkyl amines (Table 2, entries 10–12). Also the
synthesis of a heteroaromatic species or of a tertiary amine
proceeded well (Table 2, entries 13, and 14, respectively).
Among representative secondary chlorophosphines, steri-
cally hindered diaminochlorophosphine 3 exhibited superior
catalytic performance in the a-arylation[19] of ketone 8a with
aryl chloride 5a (Table 3, entry 1, and the Supporting
Information).
A palladium complex that was generated from ligand 3
proved applicable to the a-arylation employing iodides,
bromides, and chlorides (Table 3, entries 1–3). With respect
to aryl chlorides, electronically deactivated electrophiles were
efficiently converted, thus giving rise to the corresponding
ketones with high yields of isolated product (Table 3,
entries 4–11).
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Angew. Chem. Int. Ed. 2006, 45, 7627 –7630

Angewandte
Chemie
Table 3: Scope of the a-arylation usingelectron-rich chlorides. [a]
Entry
1
R1
Halide
Product
Yield [%][b]
90
Entry
7
R1
Halide
Product
Yield [%][b]
89
H
OMe
8a
5a
8c
5g
9e
2
3
4
H
98
96
92
8
F
80
78
75
8a
10b
11a
9a
8b
5h
5h
9 f
H
9
OMe
8a
8c
9g
F
10
H
8b
5c
9b
8a
5i
9h
5
6
OMe
90
90
11
OMe
87
8c
5c
9c
8c
5i
9i
F
8b
5g
9d
[a] Reaction conditions: 8 (1.2 mmol), 5 (1.0 mmol), NaOtBu (1.3 mmol), [Pd(dba)2] (2.0 mol%), 3 (4.0 mol%), toluene (2.5 mL), 1058C, 24 h.
[b] Yield of isolated product.
toluene (3.0 mL) was stirred for 10 min at room temperature under
N2. NaOtBu (125 mg, 1.30 mmol), 6a (103 mg, 1.18 mmol), and 5a
(147 mg, 1.03 mmol) were added, and the resulting mixture was
stirred at 1058C for 17 h. Et2O (50 mL) and brine (50 mL) were added
to the cooled reaction mixture. The separated aqueous phase was
extracted with Et2O (3 ” 50 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The remaining residue
was purified by column chromatography on silica gel (n-pentane/
Et2O, 5 :1!4:1) to yield 7a as an orange solid (199 mg, 98%).
In summary, we have demonstrated that sterically hin-
dered substituents on the nitrogen atoms of secondary
chlorophosphines prevent formation of diaminooxophos-
phines and thereby facilitate efficient palladium-catalyzed
ꢀ
arylation reactions of amines and a-C H acidic ketones with
ample scope.
Experimental Section
Representative procedure for the palladium-catalyzed amination of
aryl chlorides (Table 1, entry 3): A solution of [Pd(dba)2] (29 mg,
0.05 mmol, 5.0 mol%) and 3 (44 mg, 0.10 mmol, 10.0 mol%) in
Received: June 2, 2006
Revised: July 25, 2006
Published online: October 17, 2006
Angew. Chem. Int. Ed. 2006, 45, 7627 –7630
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7629

Communications
ꢀ
Keywords: arylation · C N coupling· cross-coupling·
palladium · phosphane ligands
.
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