Palladium-Catalyzed Methylation of Aryl and Vinyl Halides by Stabilized Methylaluminum and Methylgallium Complexes

Article abstract of DOI:10.1021/jo970822n

The intramolecularly stabilized mono- and dialkylaluminum complexes 1a, 2, 3, 4a, 5a, 5c, 6a, 6c, 7, 8, and 9 in the presence of palladium catalysts, cross-alkylate aryl, vinyl, and benzyl bromides and iodides under mild standard laboratory conditions. Aryl bromides with carbonyl substituents or benzylic halides are converted partially into dialkyl compounds. Under similar conditions, the analogous stabilized dimethylgallium complexes 1b, 4b, 5b, 6b, and 10 methylate aryl and vinyl bromides and iodides in a highly selective manner. Substituted bromobenzenes XC₆H₄Br, where X = CHO, COPh, CO₂Et, CN, NO₂, Cl, CH₂Br, or CH=CHCOPh, are methylated by the organogallium reagents usually only at the aromatic ring halogen atom to give substituted toluenes as single products. The methylation rates were shown to depend on the nature of the chelating ligands, on the solvent, and on the type of palladium catalyst employed.

Full text of DOI:10.1021/jo970822n

J . Org. Chem. 1997, 62, 8681-8686
8681
P a lla d iu m -Ca ta lyzed Meth yla tion of Ar yl a n d Vin yl Ha lid es by
Sta bilized Meth yla lu m in u m a n d Meth ylga lliu m Com p lexes
J ochanan Blum,* Dmitri Gelman, Wae¨l Baidossi, Eduard Shakh, Ayelet Rosenfeld, and
Zeev Aizenshtat
Department of Organic Chemistry, The Hebrew University, J erusalem 91904, Israel
Birgit C. Wassermann, Michael Frick, Bernd Heymer, Stefan Schutte, Sonja Wernik, and
Herbert Schumann*
Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t, 10623 Berlin, Germany
Received May 7, 1997X
The intramolecularly stabilized mono- and dialkylaluminum complexes 1a , 2, 3, 4a , 5a , 5c, 6a , 6c,
7, 8, and 9 in the presence of palladium catalysts, cross-alkylate aryl, vinyl, and benzyl bromides
and iodides under mild standard laboratory conditions. Aryl bromides with carbonyl substituents
or benzylic halides are converted partially into dialkyl compounds. Under similar conditions, the
analogous stabilized dimethylgallium complexes 1b, 4b, 5b, 6b, and 10 methylate aryl and vinyl
bromides and iodides in a highly selective manner. Substituted bromobenzenes XC6H4Br, where
X ) CHO, COPh, CO2Et, CN, NO2, Cl, CH2Br, or CHdCHCOPh, are methylated by the
organogallium reagents usually only at the aromatic ring halogen atom to give substituted toluenes
as single products. The methylation rates were shown to depend on the nature of the chelating
ligands, on the solvent, and on the type of palladium catalyst employed.
In tr od u ction
aluminum compounds do alkylate aryl and vinyl bro-
mides and iodides in the presence of palladium catalysts
(eq 1) and that the analogous stabilized gallium com-
plexes cross-alkylate these halides in a highly selective
manner.
Although palladium-catalyzed cross-alkylation of aryl
and alkenyl halides and pseudohalogenides can be car-
ried out with the aid of a variety of metal and metallo-
idalkyls,1 only a few examples for such alkylations by
trialkylaluminum reagents have been reported.2 The fact
that just a very small number of scientists have inves-
tigated these reactions is probably associated with the
pyrophoric nature of these alkylating agents. Recently,3
we have demonstrated that the air sensitivity of the
trialkylaluminum compounds can be reduced by replace-
ment of one alkyl group of R3Al by a chelating ligand L
and that the resulting dialkyl complexes (R2AlL)n, where
n ) 1 or 2, efficiently alkylate ketones, aldehydes, and
activated CdC in aromatic solvents under standard
laboratory conditions. However, in contrast to some
conventional metal alkyls, the aluminum complexes were
found neither to alkylate aryl and aroyl chlorides nor to
affect any other types of halides under our reaction
conditions. In this paper we report that the stabilized
RX (1) [Pd], (2) R′ AlL8 RR′ + AlCl2X + L′
(1)
2
(3) aq HCl
R ) aryl, vinyl, benzyl
R′ ) alkyl
X ) Br, I
L ) chelating ligand
L′ ) lignad residue after hydrolysis
Resu lts a n d Discu ssion
[(3-Dimethylamino)propyl]dimethylaluminum (1a)4 (ob-
tained from Me2AlCl and Me2N(CH2)3Li5) which served
in our previous work as the standard methylation agent
for transformation of ketones and aldehydes to the
respective methyl carbinols3 has been employed also in
the present research. When, for example, a solution of
1 mmol of 1-bromonaphthalene and 2 × 10-2 mmol of
PdCl2(PPh3)2 in dry benzene was heated at 50-85 °C
under N2 for 30 min, followed by treatment with 0.505
mmol of 1a in the same solvent at 80-90 °C for 12 h
and quenching with cold 2% aqueous hydrochloric acid,
98% of 1-methylnaphthalene was obtained. Although
both methyl groups in 1a were shown to take part in the
alkylation process (vide infra), the reaction time could
be reduced to 2 h if the molar ratio aluminum complex:
bromide was further increased to 1:1. Under similar ex-
perimental conditions a variety of other aryl bromides
and iodides could be converted into the respective meth-
ylated products. Some representative results are sum-
marized in Table 1 (experiments 1-10). It has been
shown that the methylation of dihalides proceeds step-
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) See, e.g.: (a) Farina, V. In Comprehensive Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Hegedus, L.
S., Eds.; Elsevier: Oxford, U.K., 1995; Vol. 12, Chapter 3.4. (b) Trost,
B. M.; Fleming, I.; Pattenden, G., Eds. Comprehensive Organic
Synthesis; Pergamon Press: Oxford, U.K., 1991; Vol. 3, Chapters 2.1-
2.5 and references therein.
(2) (a) Baba, S.; Negishi, E. J . Am. Chem. Soc. 1976, 98, 6729. (b)
Negishi, E.; Okukado, N.; King, A. O.; von Horn, D. E.; Spiegel, B. I.
J . Am. Chem. Soc. 1978, 100, 2254. (c) Zhumagaliev, S.; Yagudeev, T.
A.; Nurgalieva, A. N.; Sarbaev, T. G.; Godovikov, N. N. Zh. Obsch.
Khim. 1979, 49, 2290. (d) Takai, K.; Oshima, K.; Nozaki, H. Tetrahe-
dron Lett. 1980, 253. (e) Matsushita, H.; Negishi, E. J . Am. Chem.
Soc. 1981, 103, 2882. (f) Negishi, E.; Chatterjee, S.; Matsushita, H.
Tetrahedron Lett. 1981, 22, 3735. (g) Negishi, E.; Luo, F.-T.; Frisbee,
R.; Matsushita, H. Hetrocycles 1982, 18, 117. (h) Negishi, E.; Mat-
sushita, H. Org. Synth. 1984, 62, 31. (i) Ohta, A.; Inoue, A.; Watanabe,
T. Heterocycles 1984, 22, 2317. (j) Crisp, G. T.; Papadopoulos, S. Aust.
J . Chem. 1989, 42, 279. (k) Hirota, K.; Isobe, Y.; Maki, Y. J . Chem.
Soc., Perkin Trans. 1 1989, 1165. (l) Hirota, K.; Kitade, Y.; Kanbe, Y.;
Maki, Y. J . Org. Chem. 1992, 57, 5268. (m) Qingleo, L.; Mangalagiu,
I.; Benneche, T.; Undheim, K. Proc. 8th IUPAC OMCOS Symp., Santa
Barbara, CA, Aug 1995; p 159.
(4) Schumann, H.; Frick, M.; Heymer, B.; Girgsdies, F. J . Orga-
nomet. Chem. 1996, 512, 117 and references therein.
(5) Thiele, K. H.; Langguth, E.; Mu¨ller, G. E. Z. Anorg. Allg. Chem.
1980, 462, 152.
(3) Baidossi, W.; Rosenfeld, A.; Wassermann, B. C.; Schutte, S.;
Schumann, H.; Blum, J . Synthesis 1996, 1127.
S0022-3263(97)00822-0 CCC: $14.00 © 1997 American Chemical Society

8682 J . Org. Chem., Vol. 62, No. 25, 1997
Blum et al.
Ta ble 1. P a lla d iu m -Ca ta lyzed Meth yla tion of Rep r esen ta tive Ar yl, Ben zyl, a n d Vin yl Br om id es a n d Iod id es by 1a a
expt
substrate
bromobenzene
time, hb
products (yield, %)
1
2
3
4
5
6
7
8
1
12
8
toluene (97)
toluene (91)
iodobenzene
1-bromonaphthalene
2-bromonaphthalene
9-bromoanthracene
2-iodobromobenzene
1,8-diiodonaphthalene
1-methylnaphthalene (98)
2-methylnaphthalene (98)
2
9-methylanthracene (92)6
o-xylene (80), 2-bromotoluene (13)
3
1,8-dimethylnaphthalene (84),7 1-iodo-8-methylnaphthalene (7),8
1-iodonaphthalene (0.5), 1-methylnaphthalene (0.5)
2,2′-dimethyl-1,1′-biphenyl (99)9
8
9
2,2′-diiodo-1,1′-biphenyl
bis(2-iodophenyl)methane
3,4-dibromothiophene
benzyl bromide
9-bromo-9-phenylfluorene
(1-naphthyl)phenylbromomethane
(E)-â-bromostyrene
6.5
6
3
bis(2-methylphenyl)methane (87)10
3-bromo-4-methyltiophene (76),11 3,4-dimethylthiophene (14)12
ethylbenzene (99)
10
11
12
13
14
15
16
3
12
6c
5
8
2
9-methyl-9-phenylfluorene (100)13
R-(1-naphthyl)ethylbenzene (60)14
(E)-1-phenyl-1-propene (97)
(Z)-R-bromostilbene
2-bromoindene
(Z)-R-methylstilbene (96)
2-methylindene (88),15 indene (<1), 2,3-dimethylindene (<1)16
Standard reaction conditions: 1 mmol of halide, 2 × 10-2 mmol of PdCl2(PPh3)2, in 4 mL of benzene at 50 °C for 30 min; addition of
a
0.505 mmol of 1a in 3 mL of the same solvent at 80 °C, N2 or Ar atmosphere. The time does not include the initial heating at 50 °C.c A
b
longer reaction period resulted in the formation of substantial amounts of side products.
Ta ble 2. P a lla d iu m -Ca ta lyzed Meth yla tion of Som e F u n ction a lized Ar yl Br om id es by 1a a
expt
substrate
time, hb
products (yield, %)
1
2
3
4
5
6
7
8
9
4-Br C6H4CHOb
4-Br C6H4COPh
2-Br C6H4CO2Et
3-Br C6H4CO2Et
8
19
12
12
12
8
3
8
3
4-MeC6H4CHO (62), 4-MeC6H4CH2OH (18), 4-MeC6H4CO2H (18)
4-MeC6H4C(Me)(Ph)OH (17), 4-MeC6H4COPh (3)
2-MeC6H4CO2Et (13), C6H5CO2Et (18)
3-MeC6H4CO2Et (40), C6H5CO2Et (6)
4-MeC6H4CO2Et (75), C6H5CO2Et (10)
4-MeC6H4CN (81)
4-Br C6H4CO2Et
4-Br C6H4CNb
4-Br C6H4CH2Brb
4-Br C6H4CHdCHCOPhb
2-Br C6H4CtCC6H4-2-Br
4-MeC6H4Et (16)c
4-MeC6H5CHdCHCOPh (85)
2-MeC6H4CtCC6H4-2-Me (96)17
Standard reaction conditions: 1 mmol of bromide in 4 mL of benzene, 2 × 10-2 mmol of PdCl2(PPh3)2, in 4 mL of benzene; heating
a
for 30 min at 80 °C; addition of 0.505 mmol of 1a in 3 mL of the same solvent at 85 °C. Substrate:1a :catalyst ) 50:50:1. c Contaminated
with ca. 80% of a variety of bi- and polyphenyl and bi- and polybenzyl derivatives.
b
wise, i.e., the starting materials are converted initially
into the monomethylated products which give dimethy-
larenes in the second step. Thus, when the dimethylated
products start to accumulate, most of the starting diha-
lides have already been consumed.
Cannizzaro-like reaction (cf. ref 3). Comparison of ex-
periments 3 and 4 in Table 1 and experiments 3-5 in
Table 2 indicates that the methylation processes are
affected by steric constraints.
Stabilized alkylaluminum complexes other than 1a
could also be used successfully in the palladium-catalyzed
cross-alkylation reactions. The dialkyl complexes 2, 3,
4a , 5a , 5c, 6a , 6c, 7, and 8, as well as the monomethyl
compound 9 (Chart 1), have been prepared from R3Al,
R2AlCl, RAlCl2, or AlCl3 by the general routes used
previously in our and other laboratories.4,18,19 The vari-
Experiments 11-13 indicate that primary benzyl
bromides react in a similar fashion. The secondary
bromide (1-naphthyl)phenylbromomethane gives however
only 60% of the R-(1-naphthyl)ethylbenzene together with
undesired side products.
Vinyl bromides could also be methylated by 1a in high
yields. Under the conditions of Table 1, the reactions
proceeded with retention of configuration (see experi-
ments 14 and 15). However, when an equimolar rather
than a catalytic amount of the palladium complex had
been employed, some Z-E isomerization of the double
bond took place. Excess of the palladium compound led
also to some hydrogenolysis of the halogen atoms by
which nonmethylated hydrocarbons were formed.
Since 1a affects also carbonyl groups,3 we have inves-
tigated the behavior of the methylation agent toward
substituted aryl bromides with vulnerable functional
groups (see Table 2). Usually, though not always, both
the aromatic halogen and the second function underwent
methylation. When only one function had been meth-
ylated it was usually the aromatic ring bromide. An
exception was 4-bromobenzyl bromide (Table 2, experi-
ment 7) which gave, in addition to a poor yield of
p-methylethylbenzene, a variety of coupling compounds
including bromobibenzyl derivatives. The methylation
of the bromobenzaldehyde by the basic reagent (experi-
ment 1) was found to be accompanied by products of a
(6) Krollpfeiffer, F.; Branscheid, F. Ber. 1923, 56, 1617.
(7) Ried, W.; Boden, H. Chem. Ber. 1958, 91, 1354.
(8) Experimental data: separated from the reaction mixture by a 2
m long GC column packed with 10% OV-101 on Chromosorb W; pale
yellow semisolid; 300-MHz 1H NMR (CDCl3) δ 3.20 (s, 3), 7.37 (dd, 1,
J 6,7 ) 5 Hz, J 5,7 ) 1.5 Hz), 7.26-7.38 (m, 2), 7.70 (dd, 1, J 5,6 ) 9 Hz,
J 5,7 ) 1.5 Hz), 7.79 (dd, 1, J 2,4 ) 1 Hz, J 3,4 ) 9 Hz), 8.29 (dd, 1, J 2,3
)
7 Hz, J 2,4 ) 1 Hz); GC-MS (70 eV), 150°) m/z (rel intensity) 268 (M•+),
100), 141 (C11H9+, 43), 139 (C11H7+, 12), 115 (C9H7+, 18). Anal. Calcd
for C11H9I: C, 49.28; H, 3.38. Found: C, 49.09; H, 3.20.
(9) Ullmann, F.; Meyer, G. M.; Lo¨wenthal, O.; Gilli, E. Liebigs Ann.
Chem. 1904, 332, 38.
(10) Glaser, F.; Dahmen, H. Chem. Ztg. 1957, 81, 822.
(11) Gronowitz, S.; Moses, P.; Håkansson, R. Arkiv Kemi 1960-1,
16, 267.
(12) J anda, M.; Srogl, J .; Stibor, I.; Nemec, M.; Vopatrna´, P.
Synthesis 1972, 545.
(13) Dice, J . R.; Watkins, E.; Schumann, H. L. J . Am. Chem. Soc.
1950, 72, 1738.
(14) Brown, B. R.; Hammick, D. L. J . Chem. Soc. 1948, 1395.
(15) Parham, W. E.; Wright, C. D. J . Org. Chem. 1957, 22, 1473.
(16) Cologne, J .; Weinstein, G. Bull. Chem. Soc. Fr. 1951, 961.
(17) Colman, G. H.; Holst, W. H.; Maxwell, R. D. J . Am. Chem. Soc.
1936, 58, 2310.
(18) Schumann, H.; Hartmann, U.; Wassermann, W.; J ust, O.;
Dietrich, A.; Pohl, L.; Hostalek, M.; Lokai, M. Chem. Ber. 1991, 124,
1113.

Pd-Catalyzed Alkylation of Aryl and Vinyl Halides
J . Org. Chem., Vol. 62, No. 25, 1997 8683
Ta ble 3. Dep en d en ce of th e In itia l Ra te of Meth yla tion
of 1-Br om on a p h th a len e by 5a on th e Na tu r e of th e
P a lla d iu m Ca ta lysta
Ch a r t 1
palladium
catalyst
palladium
catalyst
rel rate
rel rate
Pd(PPh3)4
PdCl2(PPh3)2
[NH4]2[PdCl4]
1.00
0.93
0.40
PdCl2
Pd(CN)2
Pd(OAc)2
0.15
0.03
0.02
a
Reaction conditions: 1 mmol of substrate, 2 × 10-2 mmol of
palladium compound in 4 mL of benzene for 30 min at 88 °C in a
sealed ampule; then addition of 0.252 mmol of 5a in 3 mL of
benzene at the same temperature.
Ta ble 4. Dep en d en ce of th e In itia l Ra te of Meth yla tion
of 1-Br om on a p h th a len e by 5a on th e Na tu r e of th e
Rea ction Med iu m a
solvent
benzene
toluene
heptanes
chlorobenzene
cyclohexane
rel rate
solvent
rel rate
0.26
0.15
0.12
0.11
negligible
1.00
0.80
0.74
0.71
0.50
ether
chloroform
1,2-dichloroethane
tetrahydrofuran
dimethyl sulfoxide
a
Reaction conditions as in Table 3 except that the catalyst was
PdCl2(PPh3)2 and that instead of benzene various dried solvents
were used.
of the higher dialkylaluminum complexes into ethylene-
aluminum complexes and molecular hydrogen or by their
transformation to aluminum hydrides.21 Since dissocia-
tion of the dimethylaluminum complexes is less common,
dehalogenation in 1a -mediated reactions has been ob-
served only in a few cases (see Table 2, experiments 3-5).
The cross-alkylation could be catalyzed by several
different palladium compounds. The results of a set of
comparative experiments using 5a as methylating agent
are summarized in Table 3. Similar relative rates were
observed when dimeric 5a was replaced by monomeric
1a . In addition to the palladium catalysts listed in Table
3, we were able to use a sample of 10% Pd/C (that had
been purchased from Industrie Engelhard, Rome) for 1a -
mediated methylation of 9-bromoanthracene and (Z)-R-
bromostilbene under the conditions of Table 1. Both the
rate and the selectivity were found to be lower than those
in experiments with the homogeneous palladium cata-
lysts. The bromoarene gave after 12 h 9-methylan-
thracene in 61% yield, and the stilbene derivative formed
a mixture of 53% of (Z)- and 7% of (E)-R-methylstilbene.
This discrepancy could be eliminated by pretreatment of
the palladium with 2-3 equiv of PPh3. Under such
conditions (Z)-R-bromostilbene afforded exclusively the
(Z)-product in 95% yield. When, however, these experi-
ments were repeated with three other brands of Pd/C,
no methylation whatsoever took place (even upon in-
creasing the temperature to 155 °C or increasing the
amount of the supported palladium).
ous aluminum alkoxide derivatives were shown by mass
spectral and by X-ray diffraction analyses to exist as
dimers, while all the oxygen-deficient complexes proved
to be monomers20 The efficiencies of the stabilized
dimethylaluminum complexes were found to vary sig-
nificantly and to depend in the first place on the
structural features of the chelating ligands (vide infra).
There has also been observed a substantial difference in
activity between the dimethyl- and the diethylaluminum
compounds. In general, the stabilized methylaluminum
complexes reacted faster than the ethyl analogues and
gave in most cases clean methylated products in high
yields. The ethylating agents 6c and 7 formed consider-
able amounts of ethyl-free parent compounds, in addition
to the expected products. For example, upon interaction
of 6c with 9-bromoanthracene for 12 h under our stan-
dard conditions, 80% of 9-ethylanthracene and 9% of
anthracene were obtained. Similarly 7 and 1-bromonaph-
thalene gave after 24 h a mixture of 61% of 1-ethylnaph-
thalene, 19% of naphthalene, and 17% of unreacted
starting material. The formation of the dehalogenated
arenes can be rationalized either by thermal dissociation
The methylations proved to take place in a variety of
solvents. The rate was found, however, to depend
strongly on the nature of the media. The efficiency of
methylation of 1-bromonaphthalene by 5a in some com-
mon solvents is listed in Table 4. Noncoordinating
aromatic solvents were shown to be the most effective
ones.
Trimethylgallium could be stabilized by the same
method as the corresponding aluminum compounds.4
Complexes 1b, 4b, 5b, 6b, and 10 have been prepared
(19) Mu¨ller, J .; Englert, U. Chem. Ber. 1995, 128, 493.
(20) X-ray diffraction analyses of the alkylaluminum and -gallium
complexes that have not been described previously will be published
in a separate paper.
(21) Cf. Eisch, J . J . In Comprehensive Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. N., Eds.; Pergamon Press:
Oxford, U.K.; 1982; Vol. 1, pp 608-609 and references therein.

8684 J . Org. Chem., Vol. 62, No. 25, 1997
Blum et al.
Ta ble 5. P a lla d iu m -Ca ta lyzed Meth yla tion of Ar yl a n d Vin yl Br om id es by Tw o Sta bilized Dim eth ylga lliu m Com p lexesa
gallium
complex
expt
substrate
time, hb
products (yield, %)
1
2
3
4
5
6
7
8
bromobenzene
bromobenzene
4-bromotoluene
4-bromoanisole
1-bromonaphthalene
1-bromonaphthalene
(Z)-R-bromostilbene
(Z)-R-bromostilbene
1b
5b
1b
1b
1b
5b
1b
5b
7
12
3c
3d
15
17
3
toluene (100)
toluene (90)
p-xylene (48)
4-methoxytoluene (31), 4,4′-dimethoxy-1,1′-biphenyl (5)
1-methylnaphthalene (99)
1-methylnaphthalene (95), naphthalene (3)
(Z)-R-methylstilbene (89), (E)-R-methylstilbene (6)
(Z)-R-methylstilbene (100)
12
a
Reaction conditions: 1 mmol of halide, 2 × 10-2 mmol of PdCl2(PPh3)2 in 4 mL of benzene; heating for 30 min at 80 °C; addition of
b
0.505 mmolar equiv of the gallium complex in 3 mL of benzene and heating at the same temperature. At 100% conversion, except when
stated otherwise. c At 49% conversion. At 40% conversion.
d
Ta ble 6. Rela tive In itia l Ra tes of Meth yla tion of
1-Br om on a p h th a len e by Va r iou s Sta bilized Alu m in u m
a n d Ga lliu m Com p lexes in th e P r esen ce of P d Cl2(P P h 3)2
u n d er Com p a r a ble Con d ition sa
bromo groups. Representative gallium-mediated meth-
ylation experiments of such functionalized aryl bromides
are summarized in Table 7. To the best of our knowledge,
no other current methylating agent affects aromatic
bromine atoms in such high selectivity. Both the elec-
tronic and the steric structure of the second substituent
on the aryl halide affect the rate but have little influence
on the nature of the products. In no case did the side
products (usually coupling compounds of the starting
material) exceed 5%.
methylating
agent
rel
methylating
agent
rel
initial rate
initial rate
5a
5c
2
3
8
1.00
0.87
0.80
0.70
0.56
0.47
0.35
4b
1b
5b
10
9
0.30
0.20
0.04
0.04
0.03
0.03
<0.01
4a
1a
6a
6b
Under the conditions for methylation of ketones and
aldehydes by 1a , benzoyl chloride could not be alkylated.3
Instead, the acid chloride and the chelating ligand
residue formed undesired benzoyl derivatives. When,
however, the reactions were performed in the presence
of catalytic amounts of PdCl2(PPh3)2, moderate yields of
acetophenone were formed along with decomposition
products of the chelating ligands. For example, reaction
of 1 mmol of PhCOCl in benzene with 2 × 10-2 mmol of
the palladium complex for 30 min at 80 °C, followed by
heating for 12 h with either 5a or 5b, afforded 29% of
the expected acetophenone and 57% of PhCO2(CH2)2OMe.
Both the methylations by the aluminum and the
gallium complexes must be preceded by interaction of the
substrate and the palladium catalyst. Experiments in
which the alkylating agent was either heated first with
the organic halide or added right from the beginning to
the reaction mixture gave unsatisfactory results. In some
such cases none of the expected products was formed, at
all. Thus, it seems to us that the reaction mechanism of
the methylation of vinyl bromides (which differs from
that of the Heck reaction23) consists of the steps shown
in Scheme 1. It is thus reasonable that the first step in
the methylation of vinyl bromides is the formation of a
Pd(0) η2-complex of the olefin.23d This complex is likely
to undergo intramolecular oxidative addition to form a
η1-Pd(II) alkenyl complex. Thereafter, exchange of the
palladium-bound bromine with one methyl group of the
methylating agent takes place. The catalytic cycle is
completed by reductive elimination, by which the meth-
ylated product and the starting Pd(0) catalyst are formed.
The methylation of the aryl halides (shown in Scheme
2) is assumed to take place by a similar route, except
that the addition of the substrate to the Pd(0) catalyst
directly forms an η1-Pd(II) compound rather than an η2-
or η6-palladium intermediate. If a π-bound complex were
formed in this stage, one would expect partial scrambling
a
Reaction conditions: 1 mmol of halide, 2 × 10-2 mmol
PdCl2(PPh3)2; heating in a sealed ampule in 4 mL of benzene for
30 min at 88 °C; then addition of 0.505 mmolar equiv of the
alkylating agent in 3 mL of the same solvent; heating at 88 °C.
in the framework of this study, and their capability to
act as methylating agents has been investigated. It was
found that unlike the analogous aluminum complexes3
they neither alkylate carbonyl functions nor activated
double bonds. They do, however, react smoothly with
aryl and alkenyl (but not benzyl) bromides and iodides.
Some representative examples are listed in Table 5. The
table indicates that 1b and 5b differ slightly in their
activity and selectivity and that the rates are somewhat
slower than those recorded with the aluminum complex
1a .
In fact, we have compared the methylation potencies
of the various aluminum and gallium compounds for
1-bromonaphthalene under comparable conditions and
found that several gallium complexes are even superior
to some dialkylaluminum compounds. The figures given
in Table 6 reveal that while the best aluminum methyl-
ating agent is 5a having an -O(CH2)2OMe chelating
ligand, the preferred gallium complex is bis[µ-[2-(dimeth-
ylamino)ethanolato]tetramethyldigallium (4b). It seems
that one of the factors, though not the only one, that
affects the methylation is steric hindrance. The guaiacol
derivatives 6a and 6b are the slowest methylating agents
among those studied. Since kinetic measurements re-
vealed that the transfer of the first methyl group of the
alkylating agents to the substrate is faster than the
second one, we found it useful to employ at least
equivalent quantities of the aluminum or gallium com-
plexes and the substrate when rapid methylation is
required. The monomethylaluminum complex 9 with two
chelating (CH2)3NMe groups reacts of course much slower
than 1a in which two active methyl groups exist.
Since, in contrast to the aluminum complexes, the
gallium compounds do not methylate carbonyl as well as
some other vulnerable functions, we were able to selec-
tively substitute the bromine atoms of aryl bromides that
have carbonyl, cyano, nitro, chloro,22 and even benzylic
(22) A method for activation of aromatic chlorine atoms by our
alkylating agents will be reported in a separate paper.
(23) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Heck, R. F.
Palladium Reagents in Organic Synthesis; Academic Press: New York,
1985. (c) Heck, R. F. In Comprehensive Organic Chemistry; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 4, pp
833-863. (d) Carbi, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.

Pd-Catalyzed Alkylation of Aryl and Vinyl Halides
J . Org. Chem., Vol. 62, No. 25, 1997 8685
Ta ble 7. Selective Meth yla tion of Ar yl Br om id es w ith Vu ln er a ble Su bstitu en ts by Sta bilized Dim eth ylga lliu m
Com p lexes u n d er Com p a r a ble Con d ition sa
expt
substrate
gallium complex
products (yield, %)b
1
2
3
4
5
6
7
8
9
4-BrC6H4CHO
4-BrC6H4COPh
4-BrC6H4CHdCHCOPh
4-BrC6H4CO2Et
4-BrC6H4CN
2-BrC6H4NO2
4-BrC6H4NO2
4-BrC6H4Cl
4-BrC6H4CH2Br
1b
5b
1b
1b
1b
1b
1b
1b
1b
4-MeC6H4CHO (95)
4-MeC6H4COPh (100)
4-MeC6H4CHdCHCOPh (30)
4-MeC6H4CO2Et (98)
4-MeC6H4CN (82)
2-MeC6H4NO2 (48)
4-MeC6H4NO2 (61)
4-MeC6H4Cl (70), (4-MeC6H4)2 (5)
4-MeC6H4CH2Br (30)
a
Reaction conditions: 1 mmol of substrate, 2 × 10-2 mmol of PdCl2(PPh3)2, in 4 mL of benzene; heating at 85 °C for 30 min; addition
b
of 1.1 mmol of 1b or 0.505 mmol of 5b of the gallium complex in 3 mL of benzene; heating at 85 °C for 3 h. In no case, except in expt
8, has more than 2% side product been obtained. The missing percentage reflexes on the unreacted starting material.
bis[µ-[2-(dimethylamino)ethanolato-N,O:O]]tetramethyldialu-
minum (4a ),28 bis[µ-[2-(dimethylamino)ethanolato-N,O:O]]tet-
ramethyldigallium (4b),29 bis[µ-(2-methoxyethanolato-O1:O1,
O2)]tetramethyldialuminum (5a)30,31 bis[µ-(2-methoxyethanolato-
O1:O1,O2)]tatramethyldigallium (5b ),4 bis[µ-(3-methoxy-2-
propanolato-O2:O2,O3)]tetramethyldialuminum (5c),4 bis[µ-(2-
methoxyphenolato-O1:O1,O2)]tetramethyldialuminum (6a ),4,32
bis[µ-(2-methoxyphenolato-O1:O1,O2)]tetramethyldigallium
(6b),4,32 bis[µ-(2-methoxyphenolato-O1:O1,O2)]tetraethyldialu-
minum (6c),32 and bis[µ-[(2-methoxyphenyl)methanolato-O1:
O1,O2]]tetramethyldialuminum (8)4 have been prepared as
described previously.
Sch em e 1
[8-(Dim eth yla m in o)n a p h th a len -1-yl-C,N]d im eth yla lu -
m in u m (3). To a stirred suspension of 16.3 g (64.9 mmol) of
[8-(dimethylamino)naphthyl]lithium etherate33 in 180 mL of
Et2O was added slowly under exclusion of air 7.00 g (64.9
mmol) of Me2AlCl at -78 °C. After 60 min at this temperature
the reaction mixture was allowed to warm to room tempera-
ture and stirred for further 18 h. Subsequently, the clear
solution was decanted from the LiCl and the solvent was
removed in vacuo. The residue was crystallized from a 2:5
mixture of toluene/hexane affording 9.4 g (64%) of 3 as
colorless crystals: mp 62 °C; 200-MHz 1H NMR (C6H6) δ -0.31
(s, 6), 2.18 (s, 6), 6.68 (dd, 1, J 5,7 ) 1 Hz, J 6,7 ) 7.5 Hz), 7.13
(dd, 1, J 5,6 ) 8.2 Hz, J 6,7 ) 7.5 Hz), 7.48 (dd, 1, J 2,3 ) 6.3 Hz,
J 3,4 ) 8.2 Hz), 7.57 (dd, 1, J 5,6 ) 8.2 Hz, J 5,7 ) 1 Hz), 7.64 (dd,
1, J 2,4 ) 1.3 Hz, J 3,4 ) 8.2 Hz), 8.03 (dd, 1, J 2,3 ) 6.3 Hz, J 2,4
) 1.3 Hz); 50-MHz 13C{1H} NMR (C6H6) δ -8.9, 48.8, 114.6,
124.7, 126.0, 127.8, 128.0, 128.3, 133.7, 134.6, 137.3, 151.2;
104-MHz 27Al{1H} NMR (C6H6) δ -180; EIMS (70 eV, 77 °C)
Sch em e 2
m/z (rel intensity) 227 (M•+, 1, 212 [(M - Me)+, 100], 197 [(M
- 2 Me)•+, 64], 154 (C11H8N+, 7), 127 (C10H7+, 5), 57 (AlMe2
,
+
2). Anal. Calcd for C14H15AlN: mol wt 227; C, 73.98; H, 7.98;
N, 6.16. Found: mol wt (cryoscopy in C6H6) 207; C, 74.41; H,
7.94; N, 6.54.
of the methyl group in the product. Thus, both 1- and
2-bromonaphthalene should have formed mixtures of 1-
and 2-methylnaphthalene, which was not the case.
In conclusion, we find the various intramolecularly
stabilized dimethyl- and diethylaluminum complexes to
be efficient reagents for palladium-catalyzed alkylation
of aryl, benzyl, and vinyl bromides and iodides that
operate in aromatic solvents under standard laboratory
conditions. The analogous dimethylgallium compounds
are of particular utility for selective methylation of
aromatic bromides and iodides that have vulnerable
functions that do not withstand other common organo-
metallic alkylating agents.
Bis[µ-(3-m eth oxy-3-m eth ylbu ta n ola to-O1:O1,O2)]tetr a -
eth yld ia lu m in u m (7). To a solution of 11.4 g (0.1 mol) of
Et3Al in 100 mL of pentane was added dropwise under Ar at
-30 °C 118.g (0.1 mol) of freshly distilled 3-methoxy-3-
methylbutanol. During the addition, a violent evolution of gas
was observed. The resulting white suspension was stirred for
an additional 2 h at -30 °C and afterwards allowed to warm
to room temperature. After the solution was stirred for a
further 12 h the solvent was removed in vacuo. The clear
(25) Pohl, L.; Hostalek, M.; Schumann, H.; Hartmann, U.; Wasser-
mann, W.; Brauers, A.; Regel, G. K.; Hoevel, R.; Balk, P.; Scholz, F. J .
Cryst. Growth 1991, 107, 309.
(26) Schumann, H.; Hartmann, U.; Dietrich, A.; Pickardt, J . Angew.
Chem., Int. Ed. Engl. 1988, 27, 1077.
(27) Schumann, H.; Hartmann, U.; Wassermann, W. Polyhedron
1990, 9, 353.
(28) Beachley, O. T., J r.; Racette, K. C. Inorg. Chem. 1976, 15, 2110.
(29) Rettig, S. J .; Storr, A.; Trotter, J . Can. J . Chem. 1975, 53, 58.
(30) Lehmkuhl, H.; Scha¨fer, R. Liebigs Ann. Chem. 1967, 705, 23.
(31) Benn, R.; Rufinska, A.; Lehmkuhl, H.; J anssen, E.; Kru¨ger, C.
Angew. Chem., Int. Ed. Engl. 1983, 22, 779.
Exp er im en ta l Section
[3-(Dimethylamino)propyl-C,N]dimethylaluminum (1a ),24,25
[3-(dimethylamino)propyl-C,N]dimethylgallium (1b ),24-27 [2-
[(dimethylamino)methyl]phenyl-C,N]dimethylaluminum (2),19
(24) Erdmann, D.; Van Ghemen, M. E.; Pohl, L.; Schumann, H.;
Hartmann, U.; Wassermann, W.; Heyen, M.; J urgensen, H. (Merck
Patent G.m.b.H.) Ger. Offfen. DE 3,631,469 (March 17, 1988) [Chem.
Abstr. 1988, 109, 43200x].
(32) Hendershot, D. G.; Barber, M.; Kumar, R.; Oliver, J . P.
Organometallics 1991, 10, 3302.
(33) J astrzebski, J . T. B. H.; Knaap, C. T.; van Koten, G. J .
Organomet. Chem. 1983, 255, 287.

8686 J . Org. Chem., Vol. 62, No. 25, 1997
Blum et al.
2
1
liquid residue was distilled to give 15.2 g (75%) of 7 as a
colorless oil: bp 98-100 °C (0.1 mbar); 200-MHz 1H NMR
(C6H6) δ 0.20 (m, 4), 0.87 (s, 3), 1.02 (s, 3), 1.36 (m, 6), 1.69
(m, 1), 2.02 (m, 1), 2.93 (s, 3), 3.83 (m, 1), 4.08 (m, 1); 50-MHz
13C{1H} NMR (C6H6) δ -0.2, 9.6, 24.4, 24.8, 43.5, 43.9, 49.0,
59.3, 60.3, 73.3, 74.8; EIMS (70 eV, 77 °C) m/z (rel intensity)
) 12.7 Hz), 28.9 (d, J P,C ) 5.6 Hz), 32.3 (d, J P,C ) 4.6 Hz);
81-MHz 31P{1H} NMR (C6H6) δ 20.33; EIMS (70 eV, 40 °C),
m/z (rel intensity) 273/271 [(M - Me)+, 100], 217/215 (C18H19
-
GaP+, 18), 161/159 (C4H11GaP•+, 27), 101/99 (C2H5Ga+, 16),
69/71 (Ga•+, 12), 57 (C4H9+, 18). Anal. Calcd for C13H30GaP:
mol wt 287; C, 54.39; H, 10.53; Ga, 24.29. Found: mol wt
(cryoscopy in C6H6) 281; C, 4.49; H, 10.59; Ga, 24.18.
Gen er a l P r oced u r e for th e Alk yla tion of Ar yl, Ben zyl,
a n d Vin yl Ha lid es. Typically, a solution of 1 mmol of the
substrate and 2 × 10-2 mmol of the palladium catalyst in 4
mL of dry solvent is heated at 50-90 °C under N2 in a reaction
vessel for 30 min. When the solvent is benzene, a sealed
pressure tube is used. To this solution is added 0.505 mmol
of monomeric or 0.252 mmol of dimeric stabilized alkylalumi-
num or gallium complex in 3 mL of the same solvent, and the
heating is continued at 70-90 °C for the required length of
time. The cooled mixture is treated with excessive dilute (2-
10%) hydrochloric acid. Phase separation and extraction of
the product from the aqueous layer by an appropriate solvent
are followed by concentration of the combined organic solutions
and purification by column chromatography. All known
products have been characterized by comparison with authen-
tic samples obtained either from commercial sources or by the
synthetic routes described in the literature cited in Tables 1
and 2.
404 (M•+, 1), 375 [(M - Et)+, 33], 317 [(M - 3Et)+, 4], 307
+
(C14H33Al2O3+, 7), 287 (C14H33Al2O2+, 25), 259 (C11H25Al2O3
,
100), 245 (C10H23Al2O3+, 58), 202 (C10H23AlO2+, 2), 173
(C8H18AlO2•+, 25), 117 (C6H13O2+, 17), 85 (C4H10Al+, 10). Anal.
Calcd for C20H46Al2O4: C, 59.38; H, 11.46. Found: C, 59.03;
H, 11.28.
Bis[3-(dim eth ylam in o)pr opyl-C,N]m eth ylalu m in u m (9).
To a stirred solution of 6.23 g (46.7 mmol) of AlCl3 in 200 mL
of Et2O was added dropwise under Ar at -78 °C 4.32 (46.7
mmol) of Me2AlCl. The suspension was allowed to warm
slowly, refluxed for 1 h, and stirred for another 15 h at room
temperature. The resulting solution was added dropwise to a
stirred suspension of 17.4 g (0.187 m) of [3-(dimethylamino)-
propyl]lithium5 in 500 mL of pentane at -78 °C. The reaction
mixture was warmed to room temperature, stirred for 15 h,
and filtered, and the filtrate was concentrated under reduced
pressure. Distillation gave 15.0 g (75%) of 9 as a colorless oil:
bp 60 °C (0.02 mbar); 200-MHz 1H NMR (C6H6) δ -0.67 (s, 3),
0.02 (m, 4), 1.73 (m, 4), 191 (s, 12), 204, (m, 4); 50-MHz 13C{1H}
NMR (C6H6) δ -8.8, -3.8, 22.5, 45.6, 62.5; 104-MHz 27Al{1H}
NMR (C6H6) δ 138; EIMS (70 eV, 80 °C) m/z (rel intensity)
214 (M•+, 3), 199 [(M - Me)+, 42], 128 (C6H14AlN+, 100), 86
(C5H12N+, 20), 58 (C3H8N+, 25). Anal. Calcd for C11H27AlN2:
C, 61.64; H, 12.70; N, 13.07. Found: C, 61.24; H, 12.63; N,
12.88.
Slow alkylation reactions could be enhanced by doubling the
amount of the alkylating agent. When low-boiling products
had been expected, the reactions were conducted in deuterated
solvents (usually benzene-d6) and the reaction mixtures ana-
lyzed by NMR prior to their isolation. Kinetic measurements
were performed in reaction vessels equipped with sampling
devices which were heated with the aid of oil baths that could
be adjusted to (0.2 °C within the range of the desired
temperature. Samples were withdrawn from the reaction
mixture each 2-10 min and worked up as described above, in
a specially designed microapparatus. The final organic solu-
tions were analyzed by gas chromatography (OV-17 on Chro-
mosorb W).
[3-[Bis(1,1-d im et h ylet h yl)p h osp h in o]p r op yl-C,P ]d i-
m eth ylga lliu m (10). To a suspension of the Grignard
reagent, prepared from 5.57 g (25.0 mmol) of 1-chloro-3-[bis-
(1,1-dimethylethyl)phosphino]propane and 0.68 g (28.0 mmol)
of Mg turnings in 30 mL of Et2O, was added dropwise under
exclusion of air a solution of 3.38 g (25.0 mmol) of Me2GaCl in
30 mL of the same solvent. After the mixture was stirred for
an additional 12 h at room temperature, the solvent was
removed in vacuo, and 50 mL of pentane was added to the
residue. The solution was filtered, and the filtrate was
concentrated in vacuo to give 6.03 g (84%) of 10 as colorless
crystals: mp (sealed capilary) >150 °C (dec); 200-MHz 1H
Ack n ow led gm en t. We are grateful to the Exchange
Program between the Technical University of Berlin and
the Hebrew University of J erusalem for the interest in
this research. H.S. also thanks the Fonds der Chemis-
chen Industrie and the Deutsche Forschungsgemein-
schaft for financial support of this study.
3
NMR (C6H6) δ 0.10 (d, 6, J P,H ) 5.2 Hz), 0.58-0.69 (m, 2),
3
0.90 (d, 18, J P,H ) 14.8 Hz), 1.14-1.26 (m, 2), 1.85-2.06 (m,
2
2); 50-MHz 13C{1H} NMR (C6H6) δ -4.7 (d, J P,C ) 10.5 Hz),
15.1 (d, 2J P,C ) 29.9 Hz), 22.3 (d, 2J P,C ) 15.5 Hz), 26.2 (d, 1J P,C
J O970822N