Iron-catalyzed homocoupling of bromide compounds

Article abstract of DOI:10.1021/jo060673l

The homocoupling of bromide compounds was successfully performed in one pot by a combination of metallic magnesium and a catalytic amount of iron salts. The binary catalytic system differentiates itself from other homocoupling reactions catalyzed by iron salts in that it requires neither the in situ preparation of Grignard reagent nor the addition of a 1,2-dihalogen compound as an oxidant. Various aromatic and alkyl bromides underwent the homocoupling smoothly affording the corresponding symmetrical hydrocarbon compounds in moderate to excellent yields.

Full text of DOI:10.1021/jo060673l

Iron-Catalyzed Homocoupling of Bromide
Compounds
as the catalysts mainly because of their wide applicable scope
and excellent compatibility with many functional groups.3
However, these catalysts generally involved eco-disadvantageous
ligands such as phosphine compounds so as to catalyze the
coupling reaction effectively. Furthermore, most of these
catalysts are expensive and/or sensitive to oxygen and moisture.
Therefore, the development of a more efficient synthetic
methodology to form carbon-carbon bond catalyzed with
readily available, stable, and safe catalysts is still in demand.
Since the pioneering work of Kochi in 1975, iron salts have
,
†
‡
,†
Xiaoliang Xu,* Dongping Cheng, and Wen Pei*
College of Chemical Engineering and Materials and College of
Pharmaceutical Science, Zhejiang UniVersity of Technology,
Hangzhou 310014, People’s Republic of China
pei_wen58@hotmail.com.
emerged as a powerful and alternative catalyst used in the homo-
ReceiVed March 29, 2006
or cross-coupling of halogen compounds and Grignard reagents.4
Correspondingly, a large number of documents can be found
concerning iron salts-catalyzed coupling reactions and their high
catalytic efficiency, cheapness, and environmental friendliness
5
,6
made them quite impressive. Recently, Hayashi and Cahiez
group reported the homocoupling of aryl Grignard reagents
catalyzed by iron trichloride in the presence of 1,2-dihalogen
7
ethane. Although their methods are better for the synthesis of
The homocoupling of bromide compounds was successfully
performed in one pot by a combination of metallic magne-
sium and a catalytic amount of iron salts. The binary catalytic
system differentiates itself from other homocoupling reac-
tions catalyzed by iron salts in that it requires neither the in
situ preparation of Grignard reagent nor the addition of a
symmetrical biaryls, there were three obvious drawbacks: (1)
the procedure required sequential procedures; namely, Grignard
reagents had to be prepared in situ before the homocoupling
reaction began, (2) almost stiochiometric toxic 1,2-dihalogen
ethane was used as the oxidant, and (3) no examples of
alkylbromides coupling were given. Herein we wish to report
a more convenient alternative method for the synthesis of several
kinds of symmetrical hydrocarbons catalyzed by a combination
of iron salts and metallic magnesium in one pot.
1,2-dihalogen compound as an oxidant. Various aromatic and
alkyl bromides underwent the homocoupling smoothly af-
fording the corresponding symmetrical hydrocarbon com-
pounds in moderate to excellent yields.
(2) (a) Handbook of Combinatorial Chemistry: Drugs, Catalysts, Materi-
als; Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim,
Germany, 2002. (b) Beller, M.; Zapf, A.; M a¨ gerlein, W. Chem. Eng.
Technol. 2001, 24, 575.
Transition metal-catalyzed coupling reactions of halogen
compounds to form carbon-carbon bonds are among the most
(3) (a) Handbook of Organopalladium Chemistry for Organic Synthesis;
1
powerful methods in organic synthesis. In a few decades, this
Negishi, E., Ed.; Wiley: New York, 2002. (b) Tsuji, J. Palladium Reagents
and Catalysts: InnoVations in Organic Synthesis; Wiley: New York, 1996.
(c) Trost, B. M.; Verhoeven, T. R. In ComprehensiVe Organometallic
Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon:
Oxford, U.K., 1982; Vol. 8, p 799.
methodology evolved into a general tool for the preparation of
fine chemicals, materials, and pharmaceutically active com-
pounds both in the laboratory and on the industrial scale, and it
is widely appreciated in the context of parallel synthesis and
combinational chemistry.2 Although a variety of metallic
reagents can be applied in this coupling reaction, the field is
largely dominated by the use of palladium and nickel complexes
(4) (a) Kochi, J. K. J. Organomet. Chem. 2002, 653, 11. (b) Smith, R.
S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502. (c) Neumann, S. M.; Kochi,
J. K. J. Org. Chem. 1975, 40, 599. (d) Kochi, J. K. Acc. Chem. Res. 1974,
7, 351. (f) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487. (g)
Tamura, M.; Kochi, J. K. Bull. Chem. Soc. Jpn. 1971, 44, 3063. (h) Tamura,
M.; Kochi, J. K. Synthesis 1971, 303.
†
College of Chemical Engineering and Materials.
College of Pharmaceutical Science.
(5) Recent reviews: (a) F u¨ rstner, A.; Martin, R. Chem. Lett. 2005, 34,
624. (b) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081. (c)
Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217.
(6) (a) Bica, K.; Gaertner, P. Org. Lett. 2006, 8, 733. (b) Bedford, B.
R.; Betham, M.; Bruce, W. D.; Danopoulos, A. A.; Frost, M. R.; Hird, M.
J. Org. Chem. 2006, 71, 1104. (c) Bedford, B. R.; Bruce, W. D.; Frost, M.
R.; Hird, M. Chem. Commun. 2005, 4161. (d) Bedford, B. R.; Bruce, W.
D.; Frost, M. R.; Goodby, W. J.; Hird, M. Chem. Commun. 2004, 2822. (e)
Martin, R.; F u¨ rstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955. (f) Nagano,
T.; Hayashi, T. Org. Lett. 2004, 6, 1297. (g) F u¨ rstner, A.; Leitner, A. Angew.
Chem., Int. Ed. 2003, 42, 308. (h) F u¨ rstner, A.; De Souza, D.; Parra-Rapado,
L.; Jensen, J. T. Angew. Chem., Int. Ed. 2003, 42, 5358. (i) Nakamura, M.;
Matsuo, K.; Inoue, T.; Nakamura, E. Org. Lett. 2003, 5, 1373. (j) F u¨ rstner,
A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609. (k) F u¨ rstner, A.;
Leitner, A.; M e´ ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856.
(l) Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi,
A. Angew. Chem., Int. Ed. 2001, 40, 621. (m) Nakamura, M.; Hirai, A.;
Nakamura, E. J. Am. Chem. Soc. 2000, 122, 978. (n) Cahiez, G.; Avedissian,
H.; Synthesis 1998, 1199. (o) Yanagisawa, A.; Nomura, N.; Yamamoto, H.
Tetrahedron 1994, 50, 6017. (p) Yanagisawa, A.; Nomura, N.; Yamamoto,
H. Synlett 1991, 513.
‡
(
1) For cross-coupling, see (a) Cross-Coupling Reactions. A Practical
Guide; Miyaura, N., Ed.; Topics in Current Chemistry; Springer: Berlin,
002; Vol. 219. (b) Palladium in Heterocyclic Chemistry: A Guide for the
Synthetic Chemist; Li, J. J., Gribble, G. W., Eds.; Elsevier: Oxford, U.K.,
000. (c) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (d) Duncton,
2
2
M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235. (e)
Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, Germany, 1998. (f) Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1. (g) Rossi, R.; Carpita, A.; Bellina,
F. Org. Prep. Proced. Int. 1995, 27, 127. (h) Snieckus, V. Pure Appl. Chem.
994, 66, 2155. (i) Knight, D. W. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 3, p
81. (j) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (k) Negishi,
E. Acc. Chem. Res. 1982, 15, 340. (l) Kumada, M. Pure Appl. Chem. 1980,
2, 669. For self-coupling, see (a) Bringmann, G.; Walter, R.; Weirich, R.
Angew. Chem., Int. Ed. Engl. 1990, 29, 977. (b) Sainsbury, M. Tetrahedron
1
4
5
1
980, 36, 3327. (c) Fanta, P. E. Chem. ReV. 1946, 38, 139; 1964, 64, 613;
Synthesis 1974, 9. (d) Goshaev, M.; Otroshchenko, O. S.; Sadykov, A. S.
Russ. Chem. Soc. ReV. 1972, 41, 1046. (e) Posner, G. H. An Introduction
to Synthesis Using Organocopper Reagents; John Wiley: New York, 1980.
(7) (a) Nagano, T.; Hayashi, T. Org. Lett. 2005, 7, 491. (b) Cahiez, G.;
Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005, 7, 1943.
(
f) Nelson, T. D.; Meyers, A. I. J. Org. Chem. 1994, 59, 2655.
1
0.1021/jo060673l CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/28/2006
J. Org. Chem. 2006, 71, 6637-6639
6637

TABLE 2. Catalytic Fe(acac)3 or Fe(DBM)3/Mg Catalyzed the
Homocoupling of Bromide Compoundsa
The catalytic effect of iron, vanadium, and titanium salts on
the homocoupling reaction of 4-bromotoluene was investi-
gated in the presence of metallic magnesium (eq 1 and Table
1). It was found that no desired product was obtained with
TABLE 1. The Effect of Iron, Vanadium, or Titanium Salts on the
a
Homocoupling of 4-Bromotoluene
entry
metallic salt
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF-ether
THF-toluene
ether-toluene
ether
time (min)
yield (%)b
0
1
2
3
4
5
6
7
8
9
60
30
30
30
30
30
30
30
30
60
60
120
120
c
3% TiCl4
5% VCl3
3% VCl3
4% VO(acac)2
5% FeCl3
65
62
67
73
d
78
81
85
88
75
2% FeCl3
d
2% Fe(acac)3
2% Fe(DBM)3
2% Fe(DBM)3
2% Fe(DBM)3
2% Fe(DBM)3
2% Fe(DBM)3
e
f
1
1
1
1
0
1
2
3
g
68
45
h
56
a
4-Bromotoluene, 1 mmol; metallic salt, see the table; metallic Mg
turnings, 2 mmol; anhydrous THF, 4 mL; vigorously stirring; room
b
c
temperature. Isolated yields. An amount of 15% 4-methylphenol was
d
e
f
obtained. Acac ) acetyl acetone. DBM ) dibenzoyl methane. A total
of 3 mL of THF and 0.5 mL of ether. A total of 3 mL of THF and 0.5
mL of toluene. A total of 3 mL of ether and 0.5 mL of toluene.
g
h
metallic magnesium in the absence of catalysts (entry 1). When
a catalytic amount of TiCl4, VCl3, or VO(acac)2 was added
together with 2 mmol of Mg in THF, the desirable biaryl was
obtained but in moderate yield (entries 3, 4, and 5). Better re-
sults came from the use of iron salts as the catalysts. For
example, 5% and 2% of iron trichloride catalysis gave the biaryl
in 78% and 81% isolated yield, respectively (entries 6 and 7).
Compared with iron trichloride, Fe(acac)3 and Fe(DBM)3 gave
more satisfactory results (entries 8 and 9). Several cosol-
vents, such as THF-ether, THF-toluene, and ether-toluene
were further surveyed for the Fe(DBM)3-catalyzed coupling
reaction, but no improvement was observed (entries 10-12).
Use of ether as a solvent resulted in lower yield also (entry
a
Bromide compounds, 1 mmol; Fe(acac)3 or Fe(DBM)3, 2 mmol %;
metallic Mg turnings, 2 mmol; anhydrous THF, 4 mL; vigorously stirring;
room temperature. b Isolated yields. c Acac ) acetyl acetonate. DBM )
dibenzoyl methane. e Reaction was carried out with 40 mmol metallic Mg
turnings, 0.4 mmol Fe(DBM)3, 20 mmol 4-bromotoluene, 60 mL anhydrous
THF.
d
1
3). Considering that iron trichloride is moisture sensitive, we
symmetrical hydrocarbons in moderate to excellent yields
(except entry 13). Aromatic bromides substituted with electro-
donating groups such as methyl, methoxy, and N, N-dimethyl
can be efficiently converted into the corresponding biaryls
2a,c,d,g (entries 1, 2, 4, 5, and 8). Heteroaryl bromides such as
2-bromothiophene and â-bromonaphthalene also work well as
the coupling substrates (entries 6 and 7). It is noteworthy that
the present reaction system is tolerant of a strong electro-
withdrawing group such as trifluoromethyl, and the desired
products 2h and 2i were obtained in good yields; reductive
cleavge of fluoro-carbon in the trifluoromethyl group was not
observed (entries 9 and 10). Interestingly, aliphatic bromides
can also undergo the self-coupling reaction though with good
to reasonable yields. Benzyl bromide afforded 2j in 79% yield
finally chose Fe(acac)3 or Fe(DBM)3 as the catalyst and THF
as the solvent.
From Table 1, the combination of Fe(acac)3 or Fe(DBM)3
and Mg was found to be a more efficient catalytic system to
catalyze the homocoupling of 4-bromotoluene in THF; although
the effect of several cosolvents, titanium, and vanadium salts
was tried. To explore the scope of this catalytic coupling system,
more bromide compounds were used as the substrates (eq 2
and Table 2). It should be noted that the catalytic homocoupling
reaction proceeded successfully in the absence of 1,2-dichlo-
roethane, therefore providing an extremely preferable way for
the synthesis of symmetrical hydrocarbon.
(
entry 11); cyclohexyl bromide afforded the 2k in moderate
yields (entry 12); and 1-bromohexane gave the dodecane 2l in
low yield (entry 13), which may result from the rapid â-hydro
elimination as a side reaction. The present homocoupling can
be readily scaled up to the reaction of 20 mmol of 4-bromo-
toluene using 1 mol % of the Fe(DBM)3 catalyst, which gave
83% yield of 2a (entry 14). Unfortunately, no desired product
A variety of bromide compounds underwent the homocou-
pling reactions with the catalytic Fe(acac)3 or Fe(DBM)3/Mg
system in THF at room temperature to give the corresponding
6
638 J. Org. Chem., Vol. 71, No. 17, 2006

was obtained using chlorobenzene as the substrate under this
reaction condition.
In conclusion, an efficient homocoupling reaction of bromide
compounds is reported with a combination of the catalytic
system Fe(acac)3 or Fe(DBM)3 and Mg in the absence of a 1,2-
dihalogen ethane. The described here is environmentally friendly
and has large-scale synthetic potential.
According to the reported literatures concerning iron salts
catalysis,6 a possible mechanism is postulated as follows (eq
,7
3
and 4): Iron acetylacetonate was first reduced by metallic
magnesium and/or Grignard reagent to form a low valent
8
activated iron A. Then this species reacts with Grignard reagent
Experimental Section
to generate an iron intermediate B, which gives a little amount
of RH or R-R. B is inserted into bromide compounds to form
an iron and magnesium complex C which, if alkyl substituted,
may undergo â-hydrogen elimination to give ethylene com-
9
A general procedure for the homocoupling coupling induced by
the catalytic system Fe(acac)
dried two-necked round-bottom flask with a suspension of 2 mmol
48 mg) of magnesium turnings and 0.02 mmol Fe(acac) (7.0 mg)
3
/Mg is as follows: To a 10 mL flame-
(
3
1
0
pounds or else react with Grignard reagent to give dialkyl or
diaryl substituted intermediate D. Reductive elimination of the
homocoupling product regenerates catalytically active species
B. Although more detailed investigation should be carried out
for the mechanism of the catalytic homocoupling reaction, it
can be postulated that a low-valent iron species generated by
treatment with Mg or Grignard reagent is involved in the
in 3 mL of anhydrous THF was added 1 mmol bromide compounds
under the atmosphere of argon. The mixture was stirred at room
temperature for the time indicated in Table 2. Then a little amount
of silica gel (300-400 mesh) was added, and the resulting mixture
evaporated to dryness. Purification was done by column chroma-
tography on silica gel (300-400 mesh) with hexane as eluent to
give the pure homocoupling products 2.
1
1
catalytic cycle.
Supporting Information Available: Experimental procedures,
compound characterization data for selected compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO060673L
(
8) B o¨ nnemann, H.; Bogdanovi c´ , B.; Brinkmann, R.; Spliethoff, B.; He,
D. W. J. Organomet. Chem. 1993, 451 (1-2), 23.
9) According to Prof. H. B. Kagan’s report, anhydrous THF can act as
a proton source. (a) Kagan, H. B.; Namy, J. L.; Girard, P. Tetrahedron
981, 37 (Suppl 1), 175. (b) Kagan, H. B. New. J. Chem. 1990, 14, 453.
(
1
(10) Bogdanovi c´ , B.; Schwickardi, M. Angew. Chem., Int. 2000, 39, 4610.
(11) The 2% Fe(DBM)3-catalyzed coupling reaction of phenylbromide
magnesium reagent with bromobenzene in a ratio of 1:1 was investigated.
It gave the biphenyl in 73% yield.
J. Org. Chem, Vol. 71, No. 17, 2006 6639