AlAr3(THF): Highly efficient reagents for cross-couplings with aryl bromides and chlorides catalyzed by the economic palladium complex of PCy3

Article abstract of DOI:10.1039/b707703c

Novel and highly efficient cross couplings of aryl bromides and chlorides with AlAr₃(THF) (Ar = Ph, 2,4,6-Me₃C₆H ₂, 2-naphthyl or 4-Me₃SiC₆H₄) catalyzed by the economic palladium catalyst of PCy₃ are reported without the use of a base and under mild reaction conditions at room temperature or temperatures ≤60°C even for couplings of bulky aryl halides and the Al(2,4,6-Me₃C₆H₂)₃(THF) reagent. The Royal Society of Chemistry.

Full text of DOI:10.1039/b707703c

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AlAr (THF): highly efficient reagents for cross-couplings with aryl
3
bromides and chlorides catalyzed by the economic palladium complex of
PCy3{
a
Shih-Lun Ku, Xin-Ping Hui, Chien-An Chen, Yi-Ying Kuo and Han-Mou Gau*
b
a
a
a
Received (in Cambridge, UK) 22nd May 2007, Accepted 29th June 2007
First published as an Advance Article on the web 18th July 2007
DOI: 10.1039/b707703c
Novel and highly efficient cross couplings of aryl bromides and
chlorides with AlAr (THF) (Ar Ph, 2,4,6-Me
-naphthyl or 4-Me SiC ) catalyzed by the economic
Pd(OAc)
less electron-rich PPh
achieved in CH Cl (entry 4) and DME (entry 10).
2
is a better catalytic system than the Pd complex of the
(Table 1). The best yields of 99% were
3
=
3
C
6
H
2
,
3
2
3
6
H
4
2
2
palladium catalyst of PCy are reported without the use of a
3
base and under mild reaction conditions at room temperature
ð1Þ
or temperatures ¡60 uC even for couplings of bulky aryl
halides and the Al(2,4,6-Me
3
C
6
H
2
)
3
(THF) reagent.
Generalities of the Pd/PCy
3
catalytic system were then studied
on a variety of aryl bromides in DME with results listed in Table 2.
The catalytic system works excellently to aryl bromides bearing
either electron-donating substituents or an electron-withdrawing
substituent. For examples, yields of coupling products ranged from
83 to 95% (entries 1–5) for electron-rich substrates such as
1
Since the discovery of cross-coupling reactions in the early 1970s,
2
a tremendous amount of catalytic systems using organoborons,
3
4
organotins, organosilicons, organozincs or organozirconiums,
5
6
7
and organomagnesiums as coupling reagents have been devel-
oped. Nowadays, cross couplings of organic halides are one of the
8
most powerful synthetic techniques applied to material, medic-
4-methoxybromobenzene,
4-tert-butylbromobenzene,
4-bro-
mothioanisole, p-bromotoluene and 3,5-dimethylbromobenzene.
For aryl bromides bearing an electron-withdrawing substituent
such as 4-fluorobromobenzene, the coupling product was obtained
in 93% yield (entry 6). However, a lower 65% yield (entry 7) was
obtained for 4-nitrobromobenzene probably due to a higher
affinity of the nitro group toward the aluminium reagent which
retards access of the substrate to the catalytic metal centre. For
sterically hindered 2-methoxybromobenzene and 2,4-dimethylbro-
mobenzene, coupling products were obtained in 92 and 93% yields
(entries 8 and 9). The system works well also to the most sterically
hindered 2,6-dimethylbromobenzene to afford the product in a
satisfactory 70% yield (entry 10). Coupling reactions of aryl
chlorides bearing either an electron-donating or an electron-
withdrawing substituent were also investigated and a higher
reaction temperature at 60 uC and a prolonged reaction time of
12 h are required to furnish products in ¢91% yields (entries 11–
9
10
inal, and other chemistry. Earlier systems worked well for
substrates of organic iodides, bromides and triflates. However,
recent developments of cross coupling reactions focus on using the
1
1
cheap but the more inert organic chlorides as substrates and on
1
2
developing catalytic systems for the formation of C–O and C–N
1
3
bonds. It is established that catalytic systems of bulky and
electron-rich phosphoranes and carbenes are effective for couplings
of organic chlorides. In contrast, coupling reactions employing
1
4
organoaluminium reagents are rare. For aryl–alkyl coupling
1
5
employing alkylaluminium reagents, severe reaction conditions
1
6
are required for coupling of aryl chlorides. Organoaluminiums
are more reactive than organoboron, organosilicon and organo-
zinc reagents and are expected to facilitate coupling reactions of
the inert organic chlorides.
We here report novel and highly efficient cross couplings of aryl
bromides and chlorides with the easily prepared arylaluminium
14). Nevertheless, AlPh (THF) is a superior reagent for aryl–aryl
3
reagents, AlAr (THF) (Ar = Ph, 2,4,6-Me
3
3
C
6
H
2
, 2-naphthyl or
17
4
-Me SiC H ). In this study, the cheapest and commercial
3
Table 1 Couplings of 4-methoxybromobenzene with AlPh
catalyzed by palladium complexes of phosphine
3
(THF)
6
4
a
3 3
available PPh and PCy were selected as the ligands. Reaction
b
Yield (%)
conditions (eqn (1)) were optimized on the 4-methoxybromoben-
zene which is a sluggish substrate in many coupling systems. To
our surprise, the reactions proceed at room temperature without
the addition of a base which is an essential ingredient in coupling
Entry
L
Solvent
1
2
3
4
5
6
7
8
9
10
a
PPh
3
Toluene
Toluene
CH Cl
41
55
28
99
65
9
16
41
82
99
PCy
PPh3
PCy
PPh
PCy
PPh
PCy
PPh
PCy
-Methoxybromobenzene : AlPh
3
2
2
2
2
reactions. It is found that PCy
3
at 2 mol% along with 1 mol%
3
CH
Cl
3
THF
THF
DMF
DMF
DME
DME
3
a
Department of Chemistry, National Chung Hsing University, Taichung,
402, Taiwan. E-mail: hmgau@dragon.nchu.edu.tw;
Fax: (+)886-4-22862547; Tel: (+)886-4-22878615
3
3
3
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, 730000, China
3
4
3
(THF) : Pd(OAc)
2
: ligand =
1
H
{
Electronic supplementary information (ESI) available: Yields and
b
1
.0 : 1.3 : 0.010 : 0.020 mmol; solvent, 4 mL. Yields are based on
H NMR spectra.
13
and C NMR data and spectra of coupling products. See DOI: 10.1039/
b707703c
1
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Chem. Commun., 2007, 3847–3849 | 3847

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Table 2 Couplings of aryl bromides and chlorides with AlPh
3
(THF)
Table 3 Couplings of aryl bromides with AlAr
3
(THF) catalyzed by
a,b
a,b
catalyzed by the Pd(OAc) /PCy
2
3
catalytic system
the Pd(OAc)
2
3
/PCy system
c
Yield (%)
Entry
1
Substrate
T/uC
t/h
Yield (%)
91
Entry
Substrate
T/uC
t/h
d,e
1
rt
3
25
4
—
—
5
d,f
2
2
rt
3
95
25
25
40
40
40
60
4
4
8
4
5
5
d
3
3
4
rt
rt
3
3
93
83
d
4
83
90
94
92
5
6
7
5
rt
3
95
6
7
8
rt
rt
rt
3
3
3
91
65
92
8
60
60
5
5
96
92
9
9
rt
rt
3
3
94
70
g,h
1
1
0
60
60
5
5
93
85
10
g,i
1
a
1
1
1
2
60
60
12
12
91
94
Preheating AlAr
3 2 3
(THF) : Pd(OAc) : PCy (0.0125 : 0.0050 :
b
0
Al(2,4,6-Me
0
preheating the catalytic system.
.010 mmol) in toluene at 100 uC for
1
h.
Substrate:
= 0.50 : 0.65 : 0.0050 :
3
C
.01 mmol; solvent, toluene (4 mL). Isolated yields. Without
6
H
2
)
3
(THF) : Pd(OAc)
2
: PCy
3
c
d
e
f
In DME.
(THF) : Pd(OAc)
In THF.
= 1.0 :
SiC H .
6 4
g
4
.3 : 0.010 : 0.020 mmol. Ar = 2-naphthyl. Ar = 4-Me
-methylbromobenzene : AlAr
3
2
: PCy
3
h
i
1
3
1
1
3
4
60
60
12
12
93
95
hindered Al(2,4,6-Me
Table 3, entry 5). The above result strongly suggests that the
formation of the active Pd(0) species is a rate determining step for
reactions using the bulkiest Al(2,4,6-Me (THF) reagent. To
support the argument, reaction of Pd(OAc) , PCy and Al(2,4,6-
3 6 2 3
C H ) (THF) reagent in 90% yield in 4 h
(
a
3 2 3
ArX : AlPh (THF) : Pd(OAc) : PCy = 1.0 : 1.3 : 0.010 :
b
.020 mmol; solvent, DME (4 mL). Products are purified by
0
3 6 2 3
C H )
column chromatography and isolated yields are reported as average
values of two runs of reactions.
2
3
Me C H ) (THF) in a ratio of 1 : 2 : 2.5 was carried out at 100 uC
3
6
2 3
in toluene for 1 h and the self-coupling 2,29,4,49,6,69-hexamethyl-
biphenyl was obtained in 94% yield (eqn (2)), suggesting the
formation of the Pd(0) species. Results in entries 6–9 were obtained
employing the preheated catalytic system. For 4-fluorobromoben-
zene, the coupling product was obtained in 94% yield at 40 uC in
5 h (entry 6). For aryl bromides with an ortho-substituent, a higher
reaction temperature at 60 uC is required to give products in
¢92% yields (entries 7–9). The higher reaction temperature
required for the ortho-substituted aryl bromides suggests that
the transmetallation step is also slower for the hindered Al(2,4,6-
3
coupling reactions in terms of the Pd/PCy catalytic system. For
couplings of aryl chlorides with arylboron or aryltin reagents,
longer reaction times, higher reaction temperatures, and/or higher
catalyst loading were required to afford products in satisfactory
1
8
yields.
Cross couplings of 4-methoxybromobenzene with the bulky
Al(2,4,6-Me (THF) reagent were subsequently examined. It
3 6 2 3
C H )
is surprisingly found that coupling reactions did not take place at
all at 25 uC in 4 h in DME and THF (Table 3, entries 1 and 2). In
toluene, the product was obtained in a yield of 5%. However, the
product was obtained in 83% yield when the reaction time was
Me
bromobenzene with two other arylaluminium reagents of
Al(2-naphthyl) (THF) and Al(4-Me SiC (THF) were con-
C H ) (THF) reagent. In this study, couplings of 4-methyl-
3 6 2 3
extended to 8 h at 40 uC. If 1 mol% Pd(OAc)
.5 mol% Al(2,4,6-Me (THF) were preheated in toluene at
00 uC for 1 h, the resulting solution catalyzed the coupling
reaction of 4-methoxybromobenzene and the most sterically
2
, 2 mol% PCy
3
and
3
3
H )
6 4 3
2
3
C
6
H
2
)
3
ducted using the preheated systems to afford 2-p-tolylnaphthalene
in 93% yield (entry 10) and 4-trimethylsilyl-49-methylbiphenyl in
85% yield (entry 11).
1
3
848 | Chem. Commun., 2007, 3847–3849
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3
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2
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Chem. Commun., 2007, 3847–3849 | 3849