574
J. Blum et al.
PAPER
Unlike the reaction of 4-(NO2)C6H3-1,2-Cl2 with 8 in the The rate of ethylation was found to be slower than that of
presence of either catalyst 1 or 4 (Table 1, Entry 20 and the corresponding methylation reaction, and in the case of
Table 2, Entry 16), the dichloride 1,4-C6H4Cl2 undergoes 1-chloronaphthalene led to the formation of some methyl-
bis-methylation with 8 in the presence of the electron-rich free naphthalene as side product.5 The preferred alkyla-
3 or 5 to give chlorine-free p-xylene. Catalyst 4 proved to tion of aryl chlorides over that of aryl bromides (except
be inactive in this reaction. However, when 4-chlorotolu- with 4-bromochlorobenzene) catalyzed by the electron-
ene rather than p-dichlorobenzene is used as starting ma- rich complexes 3-5 is surprising, in view of the fact that
terial, 4 readily catalyzes its transformation to p-xylene complex 4 oxidatively adds to Ar-Br faster than to Ar-
(Table 2, Entries 21, 22). 4-Bromochlorobenzene reacts in Cl.12 Indeed, the reaction of BrC6H4-4-CH2C6H4-4’-Cl
the presence of 4 and 5 (but not in the presence of 3) to with an equimolar amount of complex 4 leads exclusively
give solely 4-ClC6H4Me (Entries 19, 20). This observa- to the C-Br oxidative addition product,13 in contrast to the
tion is unexpected in the light of the finding that 4 cata- result of catalytic methylation of this compound (Table 2,
lyzes the methylation of unsubstituted aryl chlorides but Entry 37). Thus, we believe that the expected mechanism
not the analogous aryl bromides (vide infra).
involving C-X oxidative addition to 3-5 followed by
alkylation of the resulting palladium complex is unlikely
in this case. It is possible that the alkylation agent reacts
with the Pd(0) complex to generate an anionic palladium
complex which activates the chloroarene. Further studies
aimed at mechanistic clarification are in progress.
Chlorobenzene and 1-chloronaphthalene undergo smooth
alkylation. An example in which chlorobenzene yields
72% of toluene (together with 28% of unreacted starting
material) after 48h at 90°C is illustrated in Scheme 3. Fur-
ther experiments with chlorobenzene and 1-chloronaph-
thalene are listed in Table 2 (Entries 23-34). Experiments
26-29 (Entries 26-29) demonstrate that in analogy to the
methylation of nitrated aryl chlorides, the ratio sub-
Catalysts 3, 4 and 5 were prepared from [(2-methylallyl)PdCl]2 and
the appropriate phosphines.5 The aluminium and gallium derived
strate:alkylating agent strongly effects the reaction rate. alkylating agents 6-13 were synthesized as described previously.2
Although many non-activated aryl chlorides are alkylated
in the presence of 4, the analogous bromine compounds
are usually not affected. All attempts to methylate bro-
mobenzene, 4-bromoanisole, ethyl 4-bromobenzoate and
Alkylation of Aryl Chlorides; Genereal Procedure
A solution of the substrate (1 mmol) and the palladium catalyst
(0.02 mmol) in anhyd benzene (2 mL) or toluene was heated at 90°C
in a pressure tube under exclusion of air for 15 min. To this mixture
1- and 2-bromonaphthalene by complexes 6-9 in the
was added the appropriate amount of the alkylating agent (indicated
presence of 4, gave under our standard experimental con-
ditions, at most 2% of methylated products. The bromides
were hardly affected even when the temperature was in-
creased to 130°C. The palladium catalysts 3 and 5 promot-
ed however, slow methylation of some aryl bromides as
demonstrated in entries 35 and 36 of Table 2. Only in two
cases did we observe significant activation of aryl bro-
mides by 4: (i) in the cross methylation of 2,4-
(NO2)2C6H3Br (Table 2, Entry 10) and (ii) in the transfor-
mation of 4-ClC6H4Br to 4-chlorotoluene (Table 2, Entry
19) (vide supra). On the other hand, 4-catalyzed methyla-
tion of BrC6H4-4-CH2C6H4-4’-Cl11 took place preferen-
tially on the chlorine atom. Attempts to alkylate a mixture
of 1 mmol of C6H5Cl and 1 mmol of C6H5Br in the pres-
ence of 2 equivalents of 8 by 4 under the conditions of Ta-
ble 2, affected solely the chlorobenzene (35% of toluene
was obtained after 22 h) while the bromobenzene re-
mained completely unreacted.
in Tables 1 and 2) in the same solvent (1 mL). The heating was con-
tinued for the length of time indicated in the Tables. The cooled
mixture was treated with an excess of aq 2% HCl. Phase separation
and extraction of the product from the aqueous layer by an appro-
priate organic solvent, were followed by concentration of the organ-
ic extracts and purification of the product by column
chromatography. The products were characterized either by direct
comparison with authentic samples, or analyzed by IR, GC/MS, 1H
and 13C NMR spectroscopy.
Acknowledgement
We thank the Israel Science Foundation (administered by the Israel
Academy for Sciences and Humanities), and the Exchange Program
between the Hebrew University of Jerusalem and the Technical
University of Berlin for financial support of this study.
Refernces
(1) Baidossi, W.; Rosenfeld, A.; Wassermann, B.C.; Schutte, S.;
Schumann, H.; Blum, J. Synthesis 1996, 1127.
(2) Blum, J.; Gelman, D.; Baidossi, W.; Shakh, E.; Rosenfeld, A.;
Aizenshtat, Z.; Wassermann, B.C.; Frick, M.; Heymer, B.;
Schutte, S.; Wernik, S.; Schumann, H. J. Org. Chem. 1997,
62, 8681.
(3) (a) Blum, J.; Gelman, D.; Aizenshtat, Z.; Wernik, S.;
Schumann, H. Tetrahedron Lett. 1998, 39, 5611.
(b) Katz, J.A.; Schutte, S.; Michman, M.; Schumann, H.;
Blum, J., unpublished results.
Scheme 3
(4) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1655.
(5) See e.g., Grushin, V.; Alper, H. Chem. Rev. 1994, 94, 1047,
and references cited therein.
(6) Ben-David, Y.; Portnoy, M.; Milstein, D. J. Am. Chem. Soc.
1989, 111, 8742.
The ethylation reagent 13 was shown to alkylate both
NO2-activated aryl chlorides in the presence of catalyst 1
(Table 1, Entry 18 and Table 2, Entry 4), as well as the
non-activated 1-chloronaphthalene (Table 2, Entry 34).
Synthesis 2000, No. 4, 571–575 ISSN 0039-7881 © Thieme Stuttgart · New York