Palladium-catalyzed direct C-4 arylation of 2,5-disubstituted furans with aryl bromides

Article abstract of DOI:10.1002/adsc.200800410

A simple and atom-economic procedure for the selective C-4 arylation of 2,5-disubstituted furans via C-H bond activation using electron-deficient aryl bromides is reported. Only 0.5 mol% of the commercially available dimeric (allene)palladium chloride, [Pd(C₃H₅)Cl]₂, was employed as catalyst. This environmentally attractive procedure has been found to be tolerant to a variety of functional groups on the aryl bromide such as carbonyl, nitrile, nitro, fluoro, ester or trifluoromethyl.

Full text of DOI:10.1002/adsc.200800410

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DOI: 10.1002/adsc.200800410
Palladium-Catalyzed Direct C-4 Arylation of 2,5-Disubstituted
Furans with Aryl Bromides
Aditya L. Gottumukkalaa and Henri Douceta,*
a
Institut Sciences Chimiques de Rennes,UMR 6226 CNRS-UniversitØ de Rennes “Catalyse et Organometalliques”,
Campus de Beaulieu, 35042 Rennes, France
Fax : (+33)-(0)2-2323-6939; phone: (+33)-(0)2-23-23-63-84; e-mail: henri.doucet@univ-rennes1.fr
Received: July 1, 2008; Published online: October 2, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800410.
Abstract: A simple and atom-economic procedure
However, these protocols are multi-step approaches,
resulting in relatively low overall yields, with the for-
mation of considerably large amount of waste prod-
ucts.
for the selective C-4 arylation of 2,5-disubstituted
À
furans via C H bond activation using electron-defi-
cient aryl bromides is reported. Only 0.5 mol% of
the commercially available dimeric (allene)palla-
The direct coupling of furans with aryl halides via
À
dium chloride, [Pd
A
C H activation/functionalization would provide a
alyst. This environmentally attractive procedure has
been found to be tolerant to a variety of functional
groups on the aryl bromide such as carbonyl, nitrile,
nitro, fluoro, ester or trifluoromethyl.
cost-effective and environmentally attractive proce-
dure for the preparation of arylfurans. The C-2 or C-5
selective arylation of heteroaromatics including
À
furans via a palladium-catalyzed C H bond activation
has been largely described in recent years.[9] On the
other hand, the selective C-3 or C-4 arylation of
furans using such a reaction has attracted less atten-
tion. Some examples of regioselective intramolecular
cyclization of furan derivatives have been reported.[10]
The perarylation of furans or diarylation of benzofur-
an has also been described.[11] However, to the best of
À
Keywords: aryl bromides; atom-economy; C H
bond activation; furans; palladium
Substituted furans continue to attract the attention of our knowledge, the selective C-3 or C-4 arylation of
À
synthetic organic chemists, due to their inherent bio- furans via a palladium-catalyzed bimolecular C H
logical activity as evidenced by a number of recent re- bond activation reaction has not been reported. Thus,
views and communications.[1–3] Conventional methods it would be useful to develop a simple procedure al-
for the synthesis of arylfurans include metal-catalyzed lowing the direct arylation of furans to obtain 3- or 4-
cross-coupling reactions such as Suzuki,[4] Stille[5] or arylated furans in a regioselective manner.
Negishi[6] type reactions, which permit the coupling or
We initially directed our efforts towards palladium-
aryl halides with organometallic derivatives of furans. catalyzed direct arylation of the symmetrically substi-
Nevertheless, these procedures require the appropri- tuted 2,5-dimethylfuran with aryl bromides
ate functionalization of one or both the coupling part- (Scheme 1, Table 1). The reaction was found to pro-
ners. Moreover, they produce stoichiometric amounts duce 1a–3a, with moderate yields using only 0.5
of metallic salts as by-products.
Among the various arylfurans, C-4 arylated carbon-
ylfurans are of particular interest as they form a key
structural unit of several natural products. Classical
methods for their synthesis are based on regioselec-
tive Vilsmeier formylation, of pre-arylated furans.[7]
Alternatively, metal-mediated cyclizations of pre-
grafted propargyl alcohols to form the substituted ar-
ylfurans have also been reported.[8] Other methods in-
clude the bromination of 2,5-disubstituted furans, fol-
lowed by bromide-lithium exchange and arylation.[2b] Scheme 1.
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Table 1. Pd-catalyzed direct arylation of 2,5-dimethylfuran
Table 2. Arylation of 2-acetyl-5-methylfuran, optimization of
(Scheme 1).[a]
the reaction conditions (Scheme 2).[a]
Entry Aryl bromide
Major product
Yield
[%]
Entry Solvent Base
Catalyst
(OAc)2
Conv. Ratio [%]
[%]
4a/4b/4c
1
2
3
4
5
DMAc KOAc Pd
DMAc KF Pd(OAc)2
DMAc Cs2CO3 Pd(OAc)2
DMAc Na2CO3 Pd(OAc)2
DMAc K2CO3 Pd(OAc)2
3PO4 Pd(OAc)2
(OAc)2
KOAc Pd(OAc)2
(OAc)2
KOAc Pd(OAc)2
DMAc KOAc Pd(OAc)2/
DPPB
DMAc KOAc Pd(OAc)2/
DPPE
DMAc KOAc Pd(OAc)2/
PPh3
G
82
55
54
75
11
61
18
5
67/33/0
39/39/12
0/42/58
21/27/52
0/14/86
0/20/80
nd
AHCTREUNG
AHCTREUNG
AHCTREUNG
AHCTREUNG
1
2
1a
2a
3a
52
36
46
6DMAc
7
8
9
10
11
K
ACHTREUNG
Xylene KOAc PdACHTREUNG
DMF
DME KOAc Pd
NMP
R
U
ACHTREUNG
AHCTREUNG
nd
3
25
88
100
71/29/0
59/32/9
51/40/9[b]
[a]
Reaction conditions: [PdACTHER(UGN C3H5)Cl]2 (0.5 mol%), aryl bro-
12
13
N
100
100
54/35/11[b]
57/38/5[c]
mide (0.5 mmol), 2,5-dimethylfuran (1.5 mmol), KOAc
(1 mmol), DMAc (3 mL), 1208C, 12 h, isolated yields.
AHCTREUNG
mol% of [PdACHTREUNG(C3H5)Cl]2 as catalyst, in the presence of
14
15
DMAc KOAc [Pd
DMAc KOAc [PdAHCTREUNG
E
87/13/0[d]
71/26/3[b]
KOAc as base, DMAc as solvent, at 1208C for 12 h.
Despite the use of an excess of 2,5-dimethylfuran
(3 equiv.), the formation of relatively large quantities
of diarylated products 1b–3b, was also observed. In
addition, the formation of homocoupling products of
the aryl bromides was inevitable, lowering the yields.
The highest yield (52%) was observed using 4-bromo-
benzonitrile (Table 1, entry 1). 4-Bromoacetophenone
and methyl 4-bromobenzoate resulted in moderate
yields of 36and 4%6 of
(Table 1, entries 2 and 3).
Then, we studied the regioselectivity of this aryla-
tion reaction using non-symmetrically 2,5-disubstitut-
ed furans. When using 2-acetyl-5-methylfuran and
DPPB
(C3H5)Cl]2/ 100
PPh3
16DMAc KOAc [Pd
C
49/40/11[c]
[a]
Reaction conditions: PdACHTREUNG
AHCTREUNG
(0.5 mmol), 2-acetyl-5-methylfuran (1 mmol), base
(1 mmol), solvent (3 mL), 12 h, conversions and ratios of
4a/4b/4c determined by GC and NMR.
1 mol% of diphosphine ligand.
2 mol% of PPh3.
Isolated yield of 4a: 63%.
[b]
[c]
[d]
2a and 3a, respectively
KOAc as base, we generally observed a regioselective the reaction of 2-acetyl-5-methylfuran with 4-bromo-
coupling in favour of the 4-arylated compound 4a acetophenone, as the model reaction (Scheme 2). Ini-
(Scheme 2). This regioselectivity suggests that the co- tially, a series of bases was screened to determine
ordination of the metal species to the carbonyl group their influence on the selectivity employing PdACHTREUNG(OAc)2
of the furan is not an essential step of the catalytic (1 mol%) as catalyst, DMAc as the solvent, at 1208C,
cycle. In the course of this reaction, the formation of for 12 h. Bases exhibit a considerable difference of ef-
products 4b and 4c was also observed. We observed ficiency and selectivity for this reaction (Table 2, en-
that the ratio of products 4a/4b/4c strongly depends tries 1–6). The best results for C-4 arylation were ob-
on the reaction conditions and catalyst (Scheme 2, tained using KOAc. In addition to the high conver-
Table 2). In order to control the regioselectivity of sion of the aryl bromide, a selectivity of 67% in
this coupling, we performed a series of experiments favour of 4a was observed (Table 2, entry 1). Bases
using various solvents, bases and catalysts. We chose such as KF or Na2CO3 led to almost equimolar mix-
tures of 4a and 4b together with diarylated product
4c. On the other hand, Cs2CO3, K2CO3 or K3PO4 gave
only C-3 arylation and diarylated products 4b and 4c.
This dramatic switch in selectivity might come from
different mechanisms. The presence of NaOAc should
lead to the formation of ionic Pd+ AcOÀ complexes,
whereas Cs2CO3, K2CO3 might stabilize neutral PdX
species. The ionic Pd+ AcOÀ complexes should favour
an electrophilic aromatic substitution mechanism and
the PdX species a Heck-type reaction.[9a] Next, we ex-
Scheme 2.
amined the influence of the solvent. The non-polar
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Palladium-Catalyzed Direct C-4 Arylation of 2,5-Disubstituted Furans
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Scheme 3.
solvent xylene gave only traces of expected product phine, exhibit the highest selectivity (87%) towards
(Table 2, entry 7). Among the polar solvents, the use the desired product 4a (Table 2, entry 14). Lower se-
of DME or DMF resulted in low conversion (Table 2, lectivities were obtained in the presence of phosphine
entries 8 and 9). DMAc and NMP showed nearly ligands (Table 2, entries 11–13 and 15, 16).
equal conversions of the starting material (Table 2,
Then, we explored the scope and limitations of this
entries 1 and 10). However, DMAc gave a higher se- reaction using various aryl bromides and 2-carbonyl-
lectivity in 4a and was employed for further optimiza- 5-methylfurans (Scheme 3), using these optimized
tion. The selectivity of the reaction was also largely coupling conditions, ([Pd
dependent on the catalyst (Table 2, entries 11–16). We 1208C for 12 h). The results are summarized in the
observed that [Pd(C3H5)Cl]2, in the absence of phos- Table 3. 2-Formyl-5-methylfuran was coupled selec-
ACHTRE(UNG C3H5)Cl]2, KOAc, DMAc at
AHCTREUNG
Table 3. 4-Arylation of 2-carbonyl-5-methylfurans with aryl bromides (Scheme 3).[a]
Entry
Furan derivative
Aryl bromide
Product
Yield [%]
48
1
5
2
3
4
5
6
7
8
6
54
76
36
72
52
56
53
2185
7
8
9
10
11
12
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Aditya L. Gottumukkala and Henri Doucet
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Table 3. (Continued)
Entry
Furan derivative
Aryl bromide
Product
Yield [%]
65
9
13
10
14
46
11
12
traces
63
15
16
17
18
19
20
13
14
15
16
17
38
65
58
58
67
18
21
61
[a]
Reaction conditions: [PdACHTRE(UGN C3H5)Cl]2 (0.5 mol%), aryl bromide (0.5 mmol), furan derivative (1 mmol), KOAc (1 mmol),
DMAc (3 mL), 1208C, 12 h, isolated yields.
tively to 4-bromobenzonitrile and 4-bromobenzalde- 9 and 13, respectively (Table 3, entries 3, 5 and 9).
hyde to form 5 and 6 in 48 and 54% yields, respective- With these substrates, the reaction proceeded cleanly.
ly (Table 3, entries 1 and 2). The reactions of 2-acetyl- Using 4-bromonitrobenzene, 4-(trifluoromethyl)bro-
5-methylfuran with electron-deficient aryl bromides mobenzene, 4-bromopropiophenone or 3,5-bis(tri-
also proceeded conveniently in most cases. Good re- fluoromethyl)bromobenzene, 10–12 and 14 were ob-
gioselectivities and yields were observed using 4-bro- tained in 46-56% yields (Table 3, entries 6–8 and 10).
mobenzonitrile, 4-bromofluorobenzene or 4-bromo- On the other hand, the use of 4-bromotoluene result-
benzaldehyde, resulting in 76, 72 and 65% yields of 7, ed in only traces of the expected product (Table 3,
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Palladium-Catalyzed Direct C-4 Arylation of 2,5-Disubstituted Furans
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4-(2,5-Dimethylfuran-3-yl)benzonitrile (1a): The reaction
of 4-bromobenzonitrile (0.091 g, 0.5 mmol), 2,5-dimethylfur-
an (0.144 g, 1.5 mmol) and KOAc (0.098 g, 1 mmol) with
entry 11). This demonstrates that the electron density
on the aryl bromide drastically affects the reaction.
1-(5-Methylfuran-2-yl)propan-1-one was also found
to be a suitable reactant (Table 3, entries 12–18). A
relatively high yield of 63% was observed in the pres-
ence 4-bromobenzonitrile (Table 3, entry 12). Similar
yields (58–67%) were observed in the presence of
methyl 4-bromobenzoate, 4-(trifluoromethyl)bromo-
benzene, 4-bromobenzaldehyde, 3-bromobenzonitrile
or 3,5-bis(trifluoromethyl)bromobenzene (Table 3, en-
tries 14–18). A relatively lower yield of the 38% was
obtained using 4-bromoacetophenone due to the for-
mation of unidentified side-products (Table 3,
entry 13).
[PdACHTRE(UNG C3H5)Cl]2 (0.9 mg, 0.0025 mmol) affords the correspond-
ing product 3a; yield: 0.051 g (52%). 1H NMR (200 MHz,
CDCl3): d=2.32 (s, 3H), 2.45 (s, 3H), 6.15 (s, 1H), 7.47 (d,
J=8.2 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d=13.3, 13.4, 106.3, 109.3, 119.2, 120.2,
127.6, 132.4, 139.4, 147.4, 150.6; anal. calcd. for C13H11NO:
C 79.16, H 5.62; found: C 78.97, H 5.82.
Compound 1b was also isolated in low yield. 1H NMR
(200 MHz, CDCl3): d=2.37 (s, 6H), 7.13 (d, J=8.4 Hz, 4H),
7.59 (d, J=8.4 Hz, 4H).
1-[4-(5-Acetyl-2-methylfuran-3-yl)phenyl]ethanone (4a):
The reaction of 4-bromoacetophenone (0.100 g, 0.5 mmol),
2-acetyl-5-methylfuran (0.124 g, 1 mmol) and KOAc
In summary, we report herein an atom-economic
method for the selective C-4 arylation of 2,5-disubsti-
tuted furans. No prior preparation of an organometal-
lic derivative is required, reducing the number of re-
quired steps to obtain these compounds. An electron-
withdrawing substituent on the furan seems to favour
the reaction. This procedure has proved to be tolerant
to a variety of functional groups on the aryl bromide
such as ester, formyl, acetyl, nitrile, nitro, fluoro or
trifluoromethyl. Moreover, it is economically and en-
vironmentally attractive as the only by-products are
AcOH/KBr instead of metallic salts using classical
coupling procedures.
(0.098 g, 1 mmol) with [PdACTHER(UGN C3H5)Cl]2 (0.9 mg, 0.0025 mmol)
affords the corresponding product 4a; yield: 0.076g (63%).
1H NMR (200 MHz, CDCl3): d=2.51 (s, 3H), 2.59 (s, 3H),
2.66 (s, 3H), 7.35 (s, 1H), 7.51 (d, J=8.1 Hz, 2H), 8.04 (d,
J=8.1 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=13.8, 25.8,
26.6, 118.5, 123.2, 127.5, 128.9, 135.7, 137.2, 150.8, 154.0,
186.2, 197.4; anal. calcd. for C15H14O3: C 74.36, H 5.82;
found: C 74.21, H 5.68.
Compounds 4b and 4c were also isolated in low yields.
1H NMR (4b, 200 MHz, CDCl3): d=2.46(s, 3H), 2.48 (s,
3H), 2.65 (s, 3H), 6.35 (s, 1H), 7.74 (d, J=8.1 Hz, 2H), 8.00
(d, J=8.1 Hz, 2H); 1H NMR (4c, 200 MHz, CDCl3): d=
2.44–2.65 (m, 12H), 7.35–7.55 (m, 4H), 7.90–8.10 (m, 4H).
Supporting Information
Additional experimental procedures and spectral data are
available as Supporting Information.
Experimental Section
General Remarks
All chemical reactants and metal complexes were obtained
from commerical sources and used without further purifica-
tion. DMAc analytical grade (99%) was not distilled before
use. KOAc (99+%) was employed. All reactions were run
under argon using vacuum lines in Schlenk tubes and oven-
Acknowledgements
A. G. is grateful to EGIDE for a grant. We thank the Centre
National de la Recherche Scientifique and “Rennes Metro-
pole” for providing financial support.
1
dried glassware. H (200 MHz) and 13C (50 MHz, unless spe-
cifically mentioned) NMR spectra were recorded in CDCl3
solutions. Chemical shifts (d) are reported in ppm relative
to CDCl3. Flash chromatographies were performed on silica
gel (230–400 mesh).
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