Cross-coupling of aryl halides and triflates with intramolecularly stabilized group 13-metal alkylating reagents in the presence of mixed-metal catalysts

Article abstract of DOI:10.1055/s-2003-36833

In the presence of tertiary phosphines, the palladium-containing mixed-metal complexes [(CO)₄Fe(μ-PPh₂)Pd(μ-Cl)]₂(1) and [(CO)₃Co]₂(μ-CO)Pd[μ-(Ph₂PCH ₂)₂] (2) catalyze the cross-coupling of aryl triflates and halides (including chlorides) with intramolecularly stabilized dialkylaluminum, -gallium and -indium reagents 3-8. The reactions are high yielding, and homocoupling and hydrodehalogenation processes are minimal even when the alkyl moieties of the alkylating reagents contain β-hydrogen atoms. As the components of the mixed-metal complexes are either poor catalysts, or completely inactive, the high catalytic activity of 1 and 2 is attributed to synergism between the different metal nuclei of the catalysts.

Full text of DOI:10.1055/s-2003-36833

302
PAPER
Cross-Coupling of Aryl Halides and Triflates with Intramolecularly Stabilized
Group 13-Metal Alkylating Reagents in the Presence of Mixed-Metal Catalysts
C
ross-Coupling of Ary
a
l
Halides an
r
d
T
rifla
g
tes
w
ith
D
ial
a
kylmeta
l
R
r
eagents ita Shenglof,a Dmitri Gelman,a Bernd Heymer,b Herbert Schumann,b Gary A. Molander,c Jochanan Blum*a
a
b
c
Department of Organic Chemistry, Hebrew University, Jerusalem 91904, Israel
Fax +972(2)6513832; E-mail: jblum@chem.ch.huji.ac.il
Institut für Chemie, Technische Universität, 10623 Berlin, Germany
Fax +49(30)31422168; E-mail: schumann@chem.tu-berlin.de
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323 USA
Fax +1(215)5737165; E-mail: gmolandr@sas.upenn.edu
Received 7 November 2002
as
[1,3-bis(diisopropylphosphino)propane]palladium,
Abstract: In the presence of tertiary phosphines, the palladium-
containing mixed-metal complexes [(CO)4Fe( -PPh2)Pd( -Cl)]2
(1) and [(CO)3Co]2( -CO)Pd[ -(Ph2PCH2)2] (2) catalyze the cross-
coupling of aryl triflates and halides (including chlorides) with in-
[Pd(dippp)2]6 and some Ni(II) compounds.7,8 Both types
of catalysts have, however, several shortcomings: Pd(dip-
pp)2 and its analogs are highly air sensitive and do not ac-
tramolecularly stabilized dialkylaluminum, -gallium and -indium tivate electron-neutral aryl bromides and iodides.6 Cross-
reagents 3–8. The reactions are high yielding, and homocoupling
couplings in the presence of the conventional nickel-phos-
and hydrodehalogenation processes are minimal even when the
phine complexes promote in many cases hydrogenolysis
alkyl moieties of the alkylating reagents contain -hydrogen atoms.
rather than alkylation of the ring-bound chlorine atoms,7
As the components of the mixed-metal complexes are either poor
and reactions by phosphine-free nickel catalysts are often
catalysts, or completely inactive, the high catalytic activity of 1 and
2 is attributed to synergism between the different metal nuclei of the
associated with undesired homo-couplings.8 Therefore,
we found it imperative to search further for new cross-
coupling catalysts that have on the one hand a wide range
of activity and on the other hand, do not promote unde-
sired hydrogenolysis and homocoupling processes.
catalysts.
Key words: aryl halides, cross-coupling, group 13-metal complex-
es, mixed-metal catalysts
In this paper we report the application of two palladium-
containing mixed-metal complexes, (2Fe-Pd)octacarbon-
yl[ -(di- -chlorodipalladio)bis( -diphenylphosphino)]-
diiron (1)9 and (Co-Co)(2Co-Pd)[ -carbonylhexacarbon-
yl[[1,2-ethanediylbis[diphenylphosphine]-P,P ]palladi-
um]dicobalt] (2)10,11 (Figure 1) as catalysts for efficient
and selective cross-coupling of haloarenes (including
chloroarenes) and triflates with stabilized group 13-metal
alkylating reagents. Typically, when a solution of 0.75
mmol of 1-bromonaphthalene in anhydrous benzene is
In the course of our studies on cross-coupling processes,
we have shown that intramolecularly stabilized alumi-
num, gallium and indium alkylating reagents of general
formula [R2MX(CH2)2Y]n (M = Al, Ga, In; R = alkyl, ar-
yl; X = O, CH2; Y = OMe, NMe2 and n = 1, 2) cross-alky-
late aryl iodides, bromides and triflates in the presence of
either PdCl2(PPh3)2 or Pd(PPh3)4.1–4 These palladium
complexes, however, do not activate electron-neutral aryl
chlorides which are favored substrates in industrial pro-
cesses. Neither do the various catalysts designed in recent
years for chloroarene activation in the Suzuki and Stille
reactions listed in reference,5 promote efficient cross-cou-
pling of aromatic chlorides with stabilized group 13-metal
alkylating reagents. The only catalysts that we found of
significant utility for activation of aryl chlorides in our
processes are electron-rich palladium complexes such
cross-methylated
with
1.5
mmol
of
[Me2AlOCH2CH2NMe2]2 (3) (Figure 2) at 78 °C in the
presence of 0.037 mmol of 1 for 30 min followed by
quenching with 5% hydrochloric acid, 80% of 1-methyl-
naphthalene is isolated. Further examples of 1- and 2-cat-
alyzed cross-alkylation experiments illustrated in
Scheme 1 are summarized in Tables 1 and 2.
Figure 1 Structures of catalysts 1 and 2
Synthesis 2003, No. 2, Print: 31 01 03.
Art Id.1437-210X,E;2003,0,02,0302,0306,ftx,en;Z14202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Cross-Coupling of Aryl Halides and Triflates with Dialkylmetal Reagents
303
Scheme 1 M: Al, Ga, In; L: chelating ligand; L : ligand residue af-
ter hydrolysis; X: halogen or triflate group; R: alkyl group of
reagents 3–8
Table 1 indicates that both complexes 1 and 2 catalyze, in
the presence of a tertiary phosphine at 78 °C, the cross-
coupling of naphthyl bromides and triflates with alumi-
num, gallium and indium alkylating agents 3–8. Except
for two cases described in entries 8 and 10 of Table 1, in
which some hydrodehalogenation of the substrate oc-
curred, neither homocoupling, nor other side-reactions
were found to take place. Best results were obtained when
Figure 2 Structures of dialkylaluminum, -gallium and -indium
complexes 3–8 used in this study
the mixed metal catalysts were supported with a five-fold PPh3 was replaced by P(t-Bu)3. This applied also to
molar ratio of PPh3. Electron-neutral naphthyl chlorides chlorobenzene derivatives with electron-donating substit-
usually gave unsatisfactory results under these conditions. uents (see, e.g. Table 2, entry 7). Although P(t-Bu)3 is a
The chloroarenes, however, reacted smoothly when the highly versatile co-catalyst in palladium-promoted Stille,
reaction temperature was increased to 110–120 °C and the Suzuki, Heck, Negishi and Sonogashira couplings,12 this
Table 1 Cross-Alkylation of Some Naphthyl Halides and Triflates with 3–8 (Figure 2) in the Presence of Catalyst 1 or 2a
Entry
Substrate
Alkylating
Reagent
Catalyst
Reaction
Time (h)
Reaction
Temp (°C)
Product Yield
(%)b
Yield (%)
1
2
1-C10H7Clc
1-C10H7Clc
1-C10H7Clc
2-C10H7Clc
1-C10H7Br
1-C10H7Brc
1-C10H7Br
1-C10H7Br
1-C10H7Br
1-C10H7Br
1-C10H7Br
1-C10H7Br
1-C10H7OTf
1-C10H7OTf
2-C10H7OTf
1-C10H7OTf
2-C10H7OTf
3
3
3
3
3
3
4
4
5
6
7
8
3
3
3
4
4
1
2
2
2
1
2
1
2
1
1
1
1
1
2
1
1
1
2.5
20
1
120d
78
1-C10H7Me
1-C10H7Me
1-C10H7Me
2-C10H7Me
1-C10H7Me
1-C10H7Me
1-C10H7Et
1-C10H7Et
1-C10H7i-Bu
1-C10H7Et
1-C10H7Et
1-C10H7Me
1-C10H7Me
1-C10H7Me
1-C10H7Me
1-C10H7Et
2-C10H7Et
24
15
85
85
99
89
99
78e
4
3
120
120
78
4
2.5
0.5
2
5
6
78
7
8
78
8
8
78
9
4
78
10
11
12
13
14
15
16
17
16
8
78
51e
99
22
98
8
78
4
78
1
78
1
78
1
78
97
98
98
2
78
1
78
a Reaction conditions: 0.75 mmol substrate, 1.5 mequiv alkylating reagent, 0.037 mequiv catalyst, 0.15 mmol PPh3 (when either naphthyl bro-
mides or triflates were used) and an amount of benzene to obtain a 0.05 M solution of the substrate.
b The yields were determined by GC and are average of at least two experiments that did not differ by more than 5%. The missing percentage
reflect usually on the unreacted substrate.
c P(t-Bu)3 was used instead of PPh3.
d No reaction took place at 78 °C.
e Occasionally contaminated with varying amounts (4–20%) of naphthalene.
Synthesis 2003, No. 2, 302–306 ISSN 0039-7881 © Thieme Stuttgart · New York

304
M. Shenglof et al.
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Table 2 Cross-Alkylation of Some Activated Aryl Halides and Triflates with Stabilized Group 13-Metal Reagents in the Presence of Catalyst
1 or 2a
Entry
Substrate
Alkylating
Reagent
Catalyst
Reaction
Time (h)
Reaction
Temp (°C)
Product
Yield (%)b
1
2
FC6H3-2,4-(NO2)2
4-ClC6H4NO2
4-BrC6H4NO2
4-IC6H4NO2
3
3
3
3
3
3
3
3
3
4
4
5
5
6
6
6
7
8
8
8
1
1
1
1
1
2
2
2
1
1
2
1
1
1
1
1
1
1
1
1
20
20
2.5
0.5
20
2.5
1
78
78
78
78
78
120
120
120
78
78
78
78
78
78
78
78
78
78
78
78
MeC6H3-2,4-(NO2)2
4-MeC6H4NO2
4-MeC6H4NO2
4-MeC6H4NO2
4-MeC6H4CF3
4-MeC6H4CN
98
64
96
96
66
95
95
90
61
88
76
7
3
4
5
4-ClC6H4CF3
4-ClC6H4CNc
4-ClC6H4OMec
6
7
4-MeC6H4OMe
4-MeC6H4Cl
c
8
1,4-C6H4Cl2
2.5
1.5
1.5
1.5
20
20
20
20
16
20
20
20
20
9
4-TfOC6H4Br
4-MeC6H4Br
10
11
12
13
14
15
16
17
18
19
20
4-TfOC6H4NO2
4-TfOC6H4NO2
4-ClC6H4NO2
4-EtC6H4NO2
4-EtC6H4NO2
4-i-BuC6H4NO2
i-BuC6H3-2,4-(NO2)2
4-EtC6H4NO2
ClC6H3-2,4-(NO 2)2
4-ClC6H4NO2
30
21
53
38
97
39
86
36
4-BrC6H4NO2
4-EtC6H4NO2
ClC6H3-2,4-(NO 2)2
4-ClC6H4NO2
EtC6H3-2,4-(NO2)2
4-EtC6H4NO2
4-ClC6H4NO2
4-MeC6H4NO2
MeC6H3-2,4-(NO2)2
4-MeC6H4NO2
ClC6H3-2,4-(NO 2)2
4-BrC6H4NO2
a Experimental conditions as in Table 1.
b The yields were determined by GC. The missing percentage reflects on the unreacted starting material.
c P(t-Bu)3 was used.
phosphine has proven unsatisfactory, in our earlier stud- cross-couplings catalyzed by electron-rich palladium cat-
ies, in palladium-assisted cross-alkylation with group 13- alysts,6 the gallium reagent with the dimethylaminoetha-
metal reagents.6 When either catalyst 1 or 2 was employed nolato-stabilizing ligand, 6, is more efficient than reagent
in the latter cross-couplings, the nature of the added phos- 8 with the nitrogen-deficient methoxyethanolato groups.
phine had a significant effect on the efficiency of the cat-
alyst. For example, the cross-coupling of 1-
bromonaphthalene with 3 in the presence of 2 and added
P(4-MeC6H4)3, PPh3, P(4-ClC6H4)3, or P(t-Bu)3 gave after
Similar features of the cross-couplings with reagents 3–8
were observed also with the aryl halide and triflate deriv-
atives listed in Table 2. In none of these experiments have
undesired side products been detected. Table 2 indicates
2 hours under the conditions of Tables 1, 23%, 29%, 31%
that the mixed-metal complexes promote, apart from aryl
and 89% of 1-methylnaphthalene, respectively.
chlorides, bromides and triflates, also iodo- and fluoroare-
Although 1- and 2-halonaphthalenes differ in their steric nes activated by electron attracting groups (see entries 1
constraints, there is no significant difference in their abil- and 4). 4-Bromophenyl triflate undergoes selective cross-
ity to cross-couple with the alkylating agents. The reac- coupling via the triflate, rather than the bromo function
tions depend, however, strongly on the structure of the (entry 9).
alkylating reagent. Thus, reagent 5 with bulky i-Bu groups
Although the neutral aryl chlorides cross-couple very
reacts much slower than the less hindered reagents 3 and
slowly or not at all at 78 °C by catalysts 1 and 2 in the
4 (cf., e.g. entries 5, 7 and 9 in Table 1). In contrast to
presence of PPh3, their nitro derivatives react at reason-
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Cross-Coupling of Aryl Halides and Triflates with Dialkylmetal Reagents
305
13C NMR (50.32 MHz, (toluene-d8): = 4.22 (GaCH2CH3), 11.06
(GaCH2CH3), 44.83 (NCH3), 58.87 (NCH2), 61.37 (OCH2).
able rates. The reaction rates increase further when a sec-
ond nitro group is introduced into the substrate molecules
(compare e.g., entries 12, 14, 18 with entries 13, 16 and EIMS (70 eV, 30 °C): m/z (%) = 215/217 [M+, 1], 186/188 [(M –
C2H5)+, 100], 127/129 {[Ga(C2H5)2]+, 9}, 88 [(C4H10NO)+, 44], 69/
19, respectively, in Table 2).
71 (Ga+, 9), 58 (C8H8N+, 64).
We attribute the high activity and selectivity of 1 and 2 in
the cross-coupling to synergism between the metal nuclei
in the catalysts. Control experiments with 1-chloronaph-
Anal. Calcd for C16H40Ga2N2O2: C, 44.49; H, 9.33; N, 6.49; Ga,
32.28. Found: C, 44.39; H, 9.15, N, 6.79, Ga, 32.34.
thalene and 3 in which the mixed metal catalyst 1 and 2
were replaced by their starting materials, i.e., by
Fe(CO)4(HPPh2) and [Pd( -C3H5)( -Cl)]2, and by
Na[Co(CO)4] and PdCl2(Ph2PCH2CH2PPh2), respective-
ly, revealed that the mononuclear iron and cobalt compo-
nents are completely inactive, and the palladium
complexes [together with P(t-Bu)3] give under the condi-
tions of Table 1 much lower yields of 1-methylnaphtha-
lene than catalysts 1 and 2. Typically, the reaction of 1-
chloronaphthalene and 3 proceeded in the presence of 2 at
120 °C six times faster (initial rates) than in the presence
of the cobalt-free PdCl2(Ph2PCH2CH2PPh2). We recall
that synergistic effects have already been observed in 1
during the selective isomerization and carbonylation of
oct-1-ene,13 and in 2 during selective homologation of
methanol.10,14
Bis{ -[2-(dimethylaminoethanolato-N,O:O]}tetraethyldiindi-
um (7)
The preparation of this compound has been reported, but the mole-
cule has only been partly characterized.18 It has now been obtained
in 92% yield from 2-dimethylaminoethanol and triethylindium by
the same manner described for the synthesis of 6; mp 69–71 °C
[Lit.18 mp 62–64.5 °C].
1H NMR (300 MHz, benzene-d6): = 0.47 (q, 8 H, J = 9 Hz,
InCH2CH3), 1.25 (t, 12 H, J = 9Hz, InCH2CH3), 2.25 (s, 12 H,
NCH3), 2.35 (t, 4 H, J = 6 Hz, NCH2), 3.71 (t, 4 H, J = 6 Hz, OCH2).
13C NMR (benzene-d6): = 6.11 (InCH2CH3), 13.11 (InCH2CH3),
44.81 (NCH3), 59.59 (NCH2), 63.42 (OCH2).
EIMS (70 eV, 56 °C): m/z (%) 493 [(M – C2H5)+, 100], 435
+
+
(C10H25In2N2O2 , 10), 434 (C10H24In2N2O2 , 8), 406
+
(C10H20In2N2O2 , 21), 262 (C8H21InNO+, 6), 232 (C6H15InNO+, 80),
204 (C5H13InO+, 26),
Anal. Calcd for C16H40In2N2O2: C, 36.80; H, 7.72; N, 5.37. Found:
C, 36.93; H, 7.47; N, 5.30.
In conclusion, the Pd-Fe and Pd-Co mixed-metal com-
plexes 1 and 2 proved to be the best catalysts among those
studied so far for cross-coupling of aryl halides with in-
tramolecularly stabilized group 13-metal alkylating re-
agents 3–8. These catalysts activate the various halides
and pseudo-halides, including chlorides and fluorides,
and apart from a few isolated cases they promote neither
undesired homocoupling nor hydrodehalogenation pro-
cesses. The performances of 1 and 2 are quite similar in
most cases although 1 seems to be a somewhat more po-
tent chloro-arene activation catalyst than 2 at 120 °C, and
a better catalyst for cross-coupling of aryl bromides and
triflates at 78 °C. On the other hand, 2 activates unsubsti-
tuted aryl chlorides already at 78 °C while 1 is inactive at
this temperature.
Cross-Alkylation of Aryl Halides and Triflates; General Proce-
dure
A solution of the alkylating reagent (1.5 mmol), the aromatic sub-
strate (0.75 mmol), the catalyst (0.0375 mequiv) and an appropriate
tertiary phosphine (0.15 mmol) in anhyd benzene (15 mL) was
placed in a preheated thick walled glass tube. The reaction vessel
was sealed under N2 and heated with the aid of a thermostated oil
bath at the required temperature for the desired length of time. After
cooling to r.t., the reaction mixture was diluted with Et2O and treat-
ed with an excess of 5% aq HCl. Phase separation, extraction of the
products from the aqueous layer with an appropriate solvent, and
purification of the extracts by column chromatography, and/or fil-
tration through a millipore filter, gave products that were character-
ized by comparison of their IR, NMR and GC-MS with those of
authentic samples. In some cases, where the desired reaction tem-
perature was 78 °C, the reactions were conducted in an open system
in boiling benzene. The results proved to be practically identical to
those of the experiments carried out in the sealed glass tubes.
(2Fe-Pd) Octacarbonyl[ -(di- -chlorodipalladio)bis( -diphenyl-
phosphino)]diiron (1),9 (Co-Co)(2-Co-Pd)[ -carbonylhexacarbon-
yl[[1,2-ethanediylbis[diphenylphosphine]-P,P ]palladium]di-
cobalt] (2),10 bis{ -[2-(dimethylamino)ethanolato-N,O:O]}tetram-
Acknowledgment
ethyldialuminum
(3),15
bis{ -[2-(dimethylamino)ethanolato-
N,O:O]}tetraethyldialuminum (4),16 bis{ -[2-(dimethylamino)eth-
anolato-N,O:O]}tetra(2-methylpropyl)dialuminum (5),16 and bis[ -
(2-methyoxyethanolato-O1:O1,O2)]tetramethyldigallium (8)17 were
prepared according to literature procedures.
We thank the United States-Israel Binational Science Foundation
(BSF, grant No. 2000013) and the Exchange Program between the
Hebrew University of Jerusalem and the Technische Universität,
Berlin for financial support of this study.
Bis{ -[2-(dimethylaminoethanolato-N,O:O]}tetraethyldigalli-
um (6)
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Synthesis 2003, No. 2, 302–306 ISSN 0039-7881 © Thieme Stuttgart · New York