Modular diamino- and dioxophosphine oxides and chlorides as ligands for transition-metal-catalyzed C-C and C-N couplings with aryl chlorides

Article abstract of DOI:10.1002/anie.200462371

(Chemical Equation Presented) Air-stable diamino- and dioxophosphine oxides were used as ligands in palladium-catalyzed Suzuki reactions of aryl chlorides. Additionally, a diaminophosphine chloride was applied to palladium- and nickel-catalyzed C-C and C-N bond-forming reactions.

Full text of DOI:10.1002/anie.200462371

Communications
Catalyzed Cross-Couplings
Modular Diamino- and Dioxophosphine Oxides
and Chlorides as Ligands for Transition-Metal-
ꢀ
ꢀ
Catalyzed C C and C N Couplings with Aryl
Chlorides**
Lutz Ackermann* and Robert Born
Transition-metal-catalyzed cross-coupling reactions[1] such as
the Suzuki coupling[2] and the Buchwald–Hartwig amination[3]
provide reliable tools in synthetic organic chemistry. Aryl
iodides and activated aryl bromides can be transformed
successfully using simple palladium salts. In contrast, analo-
gous reactions of the more readily available aryl chlorides
require recently developed stabilizing ligands.[4] While the
ligand design focused primarily on electron-rich alkyl-sub-
stituted tertiary phosphines,[1,4,5] Li presented an alternative
strategy that employs alkyl-substituted secondary phosphine
oxides.[6,7] Their synthesis generally relies on the use of the
corresponding metalated species,[6,8] thereby limiting the
flexibility of this approach. On the other hand, heteroatom-
substituted phosphine oxides are easily accessible from
diamines, diols, and amino alcohols.[9,10] Hence, we wondered
if phosphine oxides derived from diamines or diols could be
utilized as ligands for the cross-coupling of aryl chlorides.[11,12]
Herein, we present the first use of inexpensive air-stable
diaminophosphine oxides in palladium-catalyzed Suzuki-type
reactions of aryl chlorides. Furthermore, unprecedented
applications of a diaminophosphine chloride[13] to palladium-
ꢀ
ꢀ
and nickel-catalyzed C C and C N bond-forming reactions
are reported.
We synthesized three sterically encumbered, air-stable
phosphine oxides 3 directly from PCl3 and the corresponding
diamine in a one-pot procedure (Scheme 1). The reactivity of
[*] Dr. L. Ackermann, R. Born
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Department Chemie und Biochemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77425
E-mail: lutz.ackermann@cup.uni-muenchen.de
[**] We thank Prof. Paul Knochel, the DFG (Emmy Noether-Programm),
and the Ludwig-Maximilians-Universitꢀt for support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Synthesis of novel diaminophosphine oxides 3.
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DOI: 10.1002/anie.200462371
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Angewandte
Chemie
Table 2: Scope of the Suzuki cross-coupling reaction employing phosphine oxide 3c.[a]
the complexes generated from dia-
minophosphine oxides 3a–c as well
as from taddol derivative 3d was
probed in the palladium-catalyzed
Suzuki reaction of 4-chlorobenzo-
trifluoride (4a) with phenylboronic
acid (5a) (Table 1). Preliminary
experiments showed THF and
KOtBu to be the best solvent and
bases, respectively, when the di(i-
sopropyl)phenyl-substituted ligand
3a was used. Although the reaction
proceeded well at ambient temper-
ature (entry 2), quantitative con-
version of aryl chloride 4a was
achieved only with 5 mol% of the
palladium catalyst (entries 3 and
4). Changing the substituents on
nitrogen to mesityl groups resulted
in decreased conversion (entry 5).
A significant improvement of cata-
lytic performance was accom-
plished with the sterically hindered
ligand 3c (entry 6) or the taddol
derivative 3d (entry 7).
Entry
Aryl
chloride
Boronic
acid
Product
Yield [%][b]
1
2
75
78
3
4
5
70
93
95
6
81
The optimized catalyst system
facilitated the efficient conversion
of a representative set of electron-
rich aryl chlorides (Table 2). In
addition, the catalyst enabled the
synthesis of ortho-substituted biar-
yls (entries 3–5) and the function-
alization of heteroaromatic aryl
chlorides (entries 8 and 9) with
good to excellent yields of isolated
product.
7
8
70
88
9
94
[a] Reaction conditions: 4 (1.00 mmol), 5 (1.50 mmol), KOtBu (3.00 mmol), [Pd(dba)2] (2 mol%), 3c
(4 mol%), THF (5 mL). [b] Yield of isolated product.
Application of diaminophos-
phine oxide 3c to palladium-cata-
lyzed Buchwald–Hartwig amination reactions led to unsat-
isfactory results, yielding predominantly the corresponding
Table 1: Air-stable phosphine oxides 3 in Suzuki cross-coupling reac-
hydrodehalogenated arenes. However, during studies
directed towards an in situ preparation of ligands we found
that a complex generated from phosphine chloride 2c and
[Pd(dba)2][14] resulted in efficient amination of aryl chlorides
(Table 3). The protocol is applicable to various amines 7
(entries 1–4 and 12) and diversely substituted aryl chlorides 4
(entries 1 and 5–8), including deactivated 4-chloroanisole
(4h) (entry 8). Analogous aryl bromides 4m and 4n were
converted quantitatively but provided only slightly improved
yields of isolated product due to reduction of the aryl halide
(entries 10 and 11). It is worth noting that the use of chloride
2c enabled efficient conversion of deactivated chloroanisole
4h in a representative set of palladium- and nickel-catalyzed
reactions such as Suzuki reaction (entry 14), Buchwald
tions.[a]
Entry
Ligand
[Pd(dba)]2 [mol%]
t [h]
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
–
2.0
5.0
5.0
2.0
5.0
2.0
2.0
12
14
2
18
16
3
60
20
60
60
60
60
60
<2
83
97
3a
3a
3a
3b
3c
3d
68
(12)[c]
94
arylation of ketone
8 (entry 16), and nickel-catalyzed
11
92
Kumada cross-coupling with Grignard reagent 9 (entry 17).
While pyridine 6i was obtained in excellent yield (entry 15),
the synthesis of tetra-ortho-substituted biaryls was not
viable.[5a,15]
[a] Reaction conditions: 4a (1.00 mmol), 5a (1.50 mmol), KOtBu
(3.00 mmol), [Pd(dba)2]/3=1:2, THF (5 mL); dba=dibenzylideneace-
tone. [b] Yield of isolated product. [c] Determined by GC analysis.
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Communications
Table 3: Transition-metal-catalyzed coupling reactions of aryl chlorides 4 using phosphine chloride 2c (see Scheme 1; R=tBu).[a]
Entry Aryl halide
1
Pronucleophile t [h] Product
Yield [%][b] Entry Aryl halide
Pronucleophile t [h] Product
Yield [%][b]
83
3
82
81
10
11
1
2
3
4
3
1
20
15
68
PhNHMe 7c
Ph2NH 7d
2
80
59
12
13
62[d]
89
12
5
6
5
81
75
14
15
20
2
62
91
16
7
5
81
16
17
24
60
64
8
9
6
8
63
PhMgCl 9
24
62[c]
[a] General reaction conditions: Amination: 4 (1.00 mmol), 7 (1.20 mmol), NaOtBu (1.30 mmol), [Pd(dba)2] (5 mol%), 2c (10 mol%), toluene (2.5 mL), 1058C.
Ketone arylation: 4 (1.00 mmol), 8 (1.20 mmol), NaOtBu (1.30 mmol), [Pd(dba)2] (2 mol%), 2c (4 mol%), toluene (2.5 mL), 1058C. Kumada reaction: 4 (1.00 mmol),
9 (1.50 mmol), [Ni(acac)2] (3 mol%), 2c (3 mol%) in THF (5 mL), 208C. Suzuki reaction: 4 (1.00 mmol), 5 (1.50 mmol), KOtBu (3.00 mmol), [Pd(dba)2] (5 mol%), 2c
(10 mol%), THF (5 mL), 608C. [b] Yield of isolated product. [c] Using 12 (10 mol%) instead of 2c. [d] Conversion, determined by GC analysis.
NMR studies directed towards elucidating the catalystꢀs
mode of action in amination reactions were performed.
Addition of phosphine chloride 2c to a solution of [Pd(dba)2]
in toluene gave rise to a compound displaying a singlet low-
field resonance at d = 308.7 ppm in the 31P NMR spectrum,
suggesting the formation of a phosphenium species.[14] Upon
addition of an excess NaOtBu to this mixture, phosphine 12
(d = 110.3 ppm) was formed along with a
exhibited catalytic activity comparable to that observed with
2c/[Pd(dba)2] (Table 3, entries 8 and 9). To the best of our
knowledge, this is an unprecedented example for the use of a
highly modular, diaminooxophosphine (daop) ligand in
palladium-catalyzed amination reactions of deactivated aryl
chlorides.[11]
In summary, we have presented the use of air-stable
diamino- and dioxophosphine oxides as ligands in palladium-
catalyzed Suzuki reactions of aryl chlorides. The unprece-
dented use of a diaminophosphine chloride as a ligand
compound exhibiting a resonance at d =
115.2 ppm, which was also selectively
ꢀ
ꢀ
generated by reaction of phosphine 12
with [Pd(dba)2].
In the amination reaction of aryl
chloride 4h the system 12/[Pd(dba)2]
precursor in palladium- and nickel-catalyzed C C and C N
bond-forming reactions of aryl chlorides has also been
demonstrated. Further studies are directed towards an
improvement of the present systems.
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Chemie
Hamada, J. Am. Chem. Soc. 2004, 126, 3690 – 3691; b) X. Linghu,
J. R. Potnick, J. S. Johnson, J. Am. Chem. Soc. 2004, 126, 3070 –
3071.
Experimental Section
Representative procedure for palladium-catalyzed amination using
phosphine chloride 2c (Table 3, entry 8): A solution of [Pd(dba)2]
(29 mg, 0.05 mmol, 5 mol%) and phosphine chloride 2c (23 mg,
0.10 mmol, 10 mol%) in toluene (2.5 mL) was stirred for 10 min at
ambient temperature under N2. NaOtBu (125 mg, 1.3 mmol), mor-
pholine (7a) (105 mg, 1.2 mmol), and 4-chloroanisole (4h) (142 mg,
1.00 mmol) were added, and the resulting mixture was stirred at
1058C for 6 h. Et2O (50 mL) and brine (50 mL) were added to the
cold reaction mixture. The separated aqueous phase was extracted
with Et2O (2 ꢁ 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,
4:1!2:1) to yield 10h as a white solid (121 mg, 63%).
[11] Verkade recently disclosed successful palladium-catalyzed cross-
coupling reactions of aryl chlorides using a triaminophosphine
with a bicyclic framework: a) J. You, J. G. Verkade, Angew.
Chem. 2003, 115, 5205 – 5207; Angew. Chem. Int. Ed. 2003, 42,
5051 – 5053; b) J. G. Verkade, Top. Curr. Chem. 2003, 233, 1 – 44;
c) for a discussion of the s-donor abilities of diamino phosphines,
see: M. L. Clarke, D. L. Cole-Hamilton, A. M. Z. Slawin, J. D.
Woollins, Chem. Commun. 2000, 2065 – 2066.
[12] For a single account on the use in palladium-catalyzed cross-
coupling reactions on aryl bromides, see: R. B. Bedford, S. L.
Hazelwood, M. E. Limmert, J. M. Brown, S. Ramdeehul, A. R.
Cowley, S. J. Coles, M. B. Hursthouse, Organometallics 2003, 22,
1364 – 1371.
[13] Recently, a patent was filed describing the use of a dialkyl-
substituted phosphine chloride in amination and Suzuki reac-
tions: G. Y. Li, US patent application 20040147392, July 29,
2004.
[14] a) An example of oxidative addition of a chlorodiazaphospho-
lene to yield a phosphenium complex: D. Gudat, A. Haghverdi,
M. Nieger, J. Organomet. Chem. 2001, 617–618, 383 – 394; See,
also: b) H. Nakazawa, Adv. Organomet. Chem. 2004, 50, 107 –
143; c) D. Gudat, Coord. Chem. Rev. 1997, 163, 71 – 106.
[15] G. Altenhoff, R. Goddard, C. W. Lehmann, F. Glorius, J. Am.
Chem. Soc. 2004, 126, 15195 – 15201, and references therein.
Received: October 20, 2004
Published online: March 16, 2005
Keywords: cross-coupling · nickel · P ligands · palladium ·
.
phosphorus trichloride
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