Iron and copper salts in the synthesis of benzo[b]furans

Article abstract of DOI:10.1002/adsc.201000269

Intramolecular C-O bond forming reactions of aryl 2-bromobenzyl ketones lead to benzo[b]furans. The cyclizations can be catalyzed by 10 mol% of iron trichloride (of 98% or of 99.995% purity) or sub-mol% quantities of copper(II) chloride (of 99.995% purity

Full text of DOI:10.1002/adsc.201000269

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DOI: 10.1002/adsc.201000269
Iron and Copper Salts in the Synthesis of Benzo[b]furans
Julien Bonnamour,a Marꢀa Piedrafita,a,b and Carsten Bolma,*
a
Institute for Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax : (+49)-241-8092-391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
On leave from: Instituto de Quꢀmica Organometꢁlica Enrique Moles, Unidad Asociada al C.S.I.C., Universidad de
b
Oviedo, Julian Claverꢀa 8, 33006 Oviedo, Spain
Received: April 6, 2010; Revised: May 28, 2010; Published online: June 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000269.
À
Abstract: Intramolecular C O bond forming reac-
tions of aryl 2-bromobenzyl ketones lead to ben-
zo[b]furans. The cyclizations can be catalyzed by
10 mol% of iron trichloride (of 98% or of 99.995%
purity) or sub-mol% quantities of copper(II) chlo-
ride (of 99.995% purity).
cross-couplings in the presence of catalytic amounts
of FeCl3 have been studied.[18] Recent results revealed
that parts per million (ppm) quantities of copper
(present in the iron salt) can influence such reac-
tions.[19,20] Because our previous studies had included
À
the synthesis of benzoxazoles by intramolecular C O
cross-coupling,[18d] we decided to focus our attention
on a related ring closure reaction and to investigate
the catalytic effects of iron and copper salts in intra-
molecular cyclizations of aryl 2-bromobenzyl ketones
to give 2-arylbenzo[b]furans.
Keywords: benzofurans; copper; cross-coupling;
iron
Atom absorption spectroscopy (AAS) of a sample
of FeCl3 (98% from Merck) (Table 1) showed the
Benzo[b]furans are widely distributed in nature,[1] and presence of nickel (190 ppm), palladium (13.2 ppm),
many derivatives, in particular, 2-aryl-substituted copper (344 ppm) and manganese (1720 ppm). This
ones, exhibit biological activities.[2–7] Consequently, finding prompted us to verify the importance of each
various synthetic approaches towards benzo[b]furans of these metals in a given test reaction.
have been developed,[8] including, for example, elec-
trophilic cyclizations of the corresponding alkynyl- or
Using
2-(2-bromophenyl)-1-(4-methoxyphenyl)-
AHCTUNGTRENNUNG
o-alkenylphenols.[9] Many of those processes are palla- the FeCl3 described above in combination with
dium-[10] or copper-catalyzed.[11] Furthermore, metal- 20 mol%
of
2,2,7,7-tetramethylhepta-2,5-dione
free reactions, such as cycloadditions starting from (TMHD) and an excess of Cs2CO3 (2 equiv.) in DMF
ortho-silylaryl triflates[12] or reactions between arynes at 1208C for 24 h afforded the 2-arylbenzo[b]furan 2a
and iodonium ylides[13] have been applied. Recently,
Kim and co-workers reported low temperature boron
Table 1. Effects of metal dichlorides in cyclizations of 1a.
trichloride-mediated cyclodehydrations for the syn-
thesis of 3-arylbenzo[b]furan derivatives.[14] Finding
an effective protocol that involves low cost materials
and mild reaction conditions is a prevailing and scien-
tifically interesting challenge.
Iron catalysts show promising properties in many
synthetically valuable transformations,[15] and iron is
Entry
Metal
ppm
Mol%
Yield [%][a]
generally regarded to be a cheap, benign and non-
toxic metal.[16] Recently, Zhao and Li used iron tri-
chloride in oxidative syntheses of functionalized ben-
zo[b]furans,[17] but the required large quantity of the
metal salt (2.5 equiv.) or the presence of strong oxi-
dants renders these aromatic ring closures by intramo-
1
2
3
4
5
6
FeCl3 (98%)
–
CuCl2
MnCl2·4H2O
PdCl2
NiCl2·6H2O
10
–
0.0088
0.0510
0.0002
0.0053
79
8
60
8
8
8
–
344
1720
13.2
190
À
lecular C O bond formations synthetically less attrac-
tive. In our group, various C S, C N, C O and C C
[a]
À
À
À
À
Yield of the isolated product after flash chromatography.
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Julien Bonnamour et al.
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in 79% yield (Table 1, entry 1).[22] In the absence of
Finally, important experiments were performed
the metal salt, 2a was obtained in only 8% yield indi- without added copper. There, the product was ob-
cating the positive effect of the metal salt. Next, all tained in only 8% yield, when 0.0088 mol% of FeCl3
metals found by AAS were applied in their respective was applied (Table 2, entry 9). However, using
quantities. Considering that they were present in a 10 mol% of FeCl3 (with a purity of 99.995%) led to
sample of FeCl3 (an oxidant and chlorinating agent) 79% of 2a (entry 10), which clearly indicated a cata-
the corresponding chloride salts in oxidation state 2+ lytic effect of FeCl3 at high catalyst loading.
were applied. With the exception of CuCl2 none of
Next, the substrate scope was evaluated. Consider-
the other metal salts showed any effect. Noteworthy, ing that the highest yield of 2a was obtained in the
even with only 344 ppm of copper salt (corresponding catalysis with the standard FeCl3 obtained from
to 0.0088 mol%) the product was obtained in 60% Merck (98% purity; Table 1, entry 1) and knowing
yield (Table 1, entry 3).
the impact of the metal contaminants in this sample,
Apparently, copper showed a very high activity in this salt was selected for subsequent studies. As
this intramolecular C O bond formation. In order to before, TMHD served as ligand,[22] and 10 mol% of
À
elucidate its role further, the effects of mixtures of FeCl3 was applied. In order to avoid formation of cy-
high purity iron trichloride and copper dichloride clized products by uncatalyzed intramolecular nucleo-
(both from Aldrich with purities of 99.995%) on cycli- philic substitution the reaction temperature was kept
zations of 1a to give 2-(p-methoxyphenyl)benzo[b]fur- at 1208C.[23]
an (2a) were tested. The results are summarized in
Table 2.
Good yields (up to 87%) were obtained in cata-
lyzed O-arylations of substrates with electron-donat-
The intramolecular ring closure of 1a with 10 mol% ing groups in the para position of the carbonyl-substi-
of FeCl3 and 0.0088 mol% of CuCl2 gave 2a in 79% tuted arene (Table 3, entries 1–5). An electron-with-
yield (Table 2, entry 1), which mirrored the earlier drawing chloro group hampered the cyclizations and
result with FeCl3 (from Merck having a purity of the yield of the resulting benzo[b]furan 2f was only
98%). When the loading of FeCl3 was lowered to 0.1 25% (entry 6). Steric hinderance appeared to support
and 0.0088 mol% (at a constant CuCl2 amount of the reactions as indicated by the cyclization of mesi-
0.0088 mol%), the yield of 2a decreased to 68% and tyl-substituted 1e, which gave the corresponding prod-
65%, respectively (entries 2 and 3). By a stepwise uct 2e in 89% yield (entry 5). 2,3-Disubstituted ben-
increase of the amount of CuCl2 (in the absence of zo[b]furans 2g and 2h were obtained from cyclic ke-
iron) from 0.0088 to 0.05 mol% a yield of 79% for 2a tones 1g and 1h in 33% and 76% yield, respectively
could finally be reached (entries 4–8). A comparison (entries 7 and 8). Also, aryl benzyl ketones with me-
of all results obtained in catalyses with 0.0088 mol% thoxy substituents para to the bromo group in the
of CuCl2 (entries 1–4) revealed the predominant benzyl fragment (1k–n) cyclized to the corresponding
effect of the copper salt. However, at high catalyst benzo[b]furans, but generally the yields were lower
loading FeCl3 showed an impact. While in the absence compared to the ones observed in reactions with the
of the iron salt 2a was obtained in 60% yield related unsubstituted educts (Table 3, entries 11–14).
(entry 4), it increased to 79% upon addition of
10 mol% of FeCl3 (entry 1).
Knowing that the FeCl3 applied in the substrate
scope screening had a purity of 98% and that it con-
tained ca. 0.0088 mol% of copper, all experiments
were repeated under identical conditions using as cat-
alyst the appropriate amount of CuCl2 (with a purity
of 99.995% obtained from Aldrich) instead of FeCl3.
These results are also shown in Table 3.
In general, the same trend was observed with re-
spect to the substitution pattern. In all cases, product
formation occurred, but the yields were significantly
lower than in the reactions catalyzed by the iron salt.
The best results were achieved in cyclizations of com-
pounds 1b and 1e, which afforded the corresponding
benzo[b]furans in yields of 67% and 69%, respective-
ly (Table 3, entries 2 and 5).
In summary, we have demonstrated that benzo[b]-
furans can be obtained by metal-catalyzed cyclizations
starting from appropriately substituted aryl 2-bromo-
benzyl ketones. The reactions proceed well in the
presence of 10 mol% of FeCl3 having a purity of 98%.
Although generally lower yields are observed, CuCl2
Table 2. Effect of FeCl3/CuCl2 mixtures on the synthesis of
2a starting from 1a.
[a]
[a]
Entry Mol% of FeCl3
Mol% of CuCl2
Yield [%][b]
1
2
3
4
5
6
7
8
10
0.1
0.0088
0
0
0
0
0
0.0088
0.0088
0.0088
0.0088
0.02
0.03
0.04
0.05
0
79
68
65
60
63
67
77
79
8
9
0.0088
10
10[c]
0
79
[a]
With a purity of 99.995% (Aldrich).
Yield of the isolated product after flash chromatography.
Using a stock solution of FeCl3 in DMF.
[b]
[c]
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Iron and Copper Salts in the Synthesis of Benzo[b]furans
Table 3. Substrate scope in the benzo[b]furan syntheses.
Entry
1
Substrate
Product
Yield [%][a]
79 (60)
2
3
72 (67)
59 (50)
4
54 (42)
5
6
7
87 (69)
25 (16)
33 (30)
8
76 (60)
9
75 (45)
81 (36)
47 (42)
10
11
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Julien Bonnamour et al.
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Table 3. (Continued)
Entry
Substrate
Product
Yield [%][a]
30 (10)
12
13
36 (31)
66 (59)
14
[a]
Yield of the isolated product after flash chromatography; in parentheses, results from experiments performed with 0.0088
mol% of CuCl2 (99.995%; Aldrich).
(with a purity of 99.995%) shows a remarkable activi- spectroscopy. M.P. also thanks the MICINN-fondo social Eu-
ropeo for a predoctoral FPU fellowship.
ty, and even 0.0088 mol% of this salt are sufficient to
provide products with up to 69% yield. Further inves-
tigations to study these effects are in progress in our
laboratories.
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charged with the 2-(2-bromophenyl) ketone (1.0 equiv.,
0.32 mmol), Cs2CO3 (2.0 equiv., 0.64 mmol) and FeCl3
(0.1 equiv, 0.03 mmol). The aperture of the tube was then
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