A new route to 3-acyl-2-aminobenzofurans: Palladium-catalysed cycloisomerisation of 2-(cyanomethyl)phenyl esters

Article abstract of DOI:10.1039/b904127c

Treatment of 2-(cyanomethyl)phenyl esters with a catalytic amount of Pd(OAc)₂, PCy₃, and Zn afforded 3-acyl-2-aminobenzofuran derivatives in good to excellent yields, which can be used as building blocks for the synthesis of benzofur

Full text of DOI:10.1039/b904127c

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A new route to 3-acyl-2-aminobenzofurans: palladium-catalysed
cycloisomerisation of 2-(cyanomethyl)phenyl estersw
Masahito Murai, Koji Miki and Kouichi Ohe*
Received (in Cambridge, UK) 27th February 2009, Accepted 7th April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b904127c
Treatment of 2-(cyanomethyl)phenyl esters with a catalytic
amount of Pd(OAc)2, PCy3, and Zn afforded 3-acyl-2-amino-
benzofuran derivatives in good to excellent yields, which can be
used as building blocks for the synthesis of benzofuran fused
heterocycles.
of 1a in the presence of Pd(OAc)2 (10 mol%) and P(t-Bu)3
(20 mol%) in DMF at 100 1C, we isolated 3-acyl-2-amino-
benzofuran (27%)13 instead of the expected N-acyl-2-amino-
benzofuran 3a (eqn (1)).
Transition metal-catalysed addition reactions to nitriles have
received considerable attention as a potential tool for the
synthesis of amines and amides.1–4 We recently reported the
copper-catalysed pyrrolinone synthesis from carbonyl-ene-
nitriles and nucleophiles, in which hydration of a cyano moiety
followed by dehydrative cyclisation (cycloisomerisation)
produced 2-aza-2,4-cyclopentadienone as an intermediate.5
Although several transition metal-catalysed cycloisomerisation
of alkynes leading to heterocycles have been well-investigated,6
counterparts of nitriles are limited and still remain challenging.7
Here we report a novel palladium-catalysed cycloisomerisation
of 2-(cyanomethyl)phenyl esters 1 involving cleavage of an
acyl–oxygen bond and a unique intramolecular oxyacylation
to a cyano moiety, which leads to the formation of 3-acyl-2-
aminobenzofurans 2 (Scheme 1).
ð1Þ
This interesting result stimulated us to optimise conditions
for the cycloisomerisation of 1a (Table 1). Several phosphines
including PCy3, PCy2Ph, and 1,10-bis(diphenylphosphino)-
ferrocene (dppf) were also effective (Table 1, entries 1–3),
whereas PPh3 was found to be ineffective for the reaction
(Table 1, entry 4). Other palladium compounds including
PdCl2 and Pd2(dba)3 did not catalyse the reaction, even when
PCy3 was used as a ligand (data not shown in Table 1). On
the other hand, the use of Ni(cod)2 (10 mol%) and PCy3
(20 mol%) produced a yield of 2a comparable to that of the
combination of Pd(OAc)2 and PCy3 (Table 1, entry 5). Since
Pd(PCy3)2 might be considered the active catalyst for the
present reaction, we next examined the reaction in the presence
of Pd(PCy3)2. To our delight, the yield of 2a increased to 62%
yield (Table 1, entry 6). Furthermore, it was revealed that
the addition of Zn(OAc)2 to the Pd(PCy3)2 system was
effective in facilitating the reaction to give 2a in 96% yield
(Table 1, entry 7). We also found that the reaction proceeded
smoothly using the combined catalyst system of inexpensive
Pd(OAc)2–PCy3–Zn to furnish 2a in 98% yield (Table 1,
entry 8).14 The solvent DMF was found to give the best
results, whereas DMSO, toluene, and dioxane decreased the
yield of 2a.
Scheme 1 Transition metal-catalysed cycloisomerisation.
Although 2-aminobenzofurans are an important class of
heterocyclic compounds, they are difficult to work with because
of their instability.8 However, it is well known that substitution at
the 3-position as well as N-acylation, remarkably increases the
stability of otherwise unstable 2-aminobenzofurans.9,10 We
hypothesized that intramolecular oxyacylation of 1 via cleavage
of the acyl–oxygen bond followed by prototropic isomerisation
of a cyclic N-acylimino ether would give rise to a series of stable
N-acyl-2-aminobenzofurans.11 We first examined the reaction
of 2-(cyanomethyl)phenyl 4-trifluoromethylbenzoate 1a, which
contains an acyl–oxygen bond prone to cleavage by low-valent
transition metals because of activation by the electron-
withdrawing CF3 group.12 When we carried out the reaction
With the optimal reaction conditions (Pd(OAc)2, PCy3, and
Zn powder) established, we next examined the reactions of
2-(cyanomethyl)phenyl esters 1 containing various carboxylates.
The results are summarised in Table 2. All reactions were
conducted in the presence of 4 A molecular sieves (MS4A) to
avoid competitive hydrolysis of 1 to 2-(cyanomethyl)phenol.
Reactions of 1b–d with the halogen at either the ortho or
para position occurred smoothly and gave good yields of
3-acyl-2-aminobenzofurans 2b–d (Table 2, entries 1–3).
The cycloisomerisation described here is applicable to
esters having either moderately electron-withdrawing or
electron-donating substituents (Table 2, entries 4–8).
Surprisingly, 2-(cyanomethyl)phenyl acetate 1j also afforded
Department of Energy Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Kyoto 615-8510, Japan.
E-mail: ohe@scl.kyoto-u.ac.jp; Fax: +81 75-383-2499;
Tel: +81 75-383-2495
w Electronic supplementary information (ESI) available: Additional
experimental details and 1H and 13C spectra of selected compounds.
CCDC 722188. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b904127c
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Table 1 Optimization of cycloisomerisation of 1aa
Conversion
(%)
Yield
(%)b
Entry
[M]–ligand–additive
1
Pd(OAc)2–PCy3
Pd(OAc)2–PCy2Ph
Pd(OAc)2–dppf
Pd(OAc)2–PPh3
Ni(cod)2–PCy3
Pd(PCy3)2
Pd(PCy3)2–Zn(OAc)2
Pd(OAc)2–PCy3–Zn
54
53
78
79
68
68
100
100
36
31
32
0
32
62
96
98
2
3c
4
5
6
7d
8e
a
Reaction conditions: 1a (0.40 mmol), [M] (0.040 mmol), ligand
(0.080 mmol) in DMF (2.0 mL) was stirred at 100 1C for 15 h.
Scheme 2 Crossover experiment.
b
c
Isolated yields. Dppf (10 mol%) was used. d Zn(OAc)2 (0.040 mmol)
e
was used. Zinc powder (0.040 mmol) was used.
Table 2 Palladium-catalysed cycloisomerisation of 2-(cyanomethyl)-
phenyl esters 1a
Scheme 3 Plausible reaction mechanism.
Yield
(%)b
Entry
R
Time/h
Product
Zn(OAc)2, which is generated from the reaction of Pd(OAc)2
with zinc, might accelerate the oxidative cleavage of an
acyl–oxygen bond forming an intermediate A by coordination
to the carbonyl group.17 In the next step, oxypalladation
of a cyano moiety followed by prototropic isomerisation gives
the intermediate B. Subsequent s–p isomerisation of an
azaallyl–palladium, and reductive elimination at the 3-position
of the benzofuran, yields 3-acyl-2-aminobenzofuran 2, and
regenerates the catalyst.18,19
1
2
3
4
5
6
7
8
9
4-FC6H4
4-ClC6H4
2-ClC6H4
2-Naph
Ph
4-MeC6H4
4-MeOC6H4
4-Me2NC6H4
Me
1b
1c
1d
1e
1f
1g
1h
1i
24
24
24
24
72
72
72
96
72
60
24
2b
2c
2d
2e
2f
2g
2h
2i
74
79
91
89
68
71
64
68
57
50
68
1j
1k
1l
2j
2k
2l
10
11
H
OEt
Since 3-acyl-2-aminobenzofurans have both an amino
and a carbonyl group, they are considered key building
blocks for the synthesis of benzofuran fused heterocycles.
Elbfluorene 7, which is a CDK (cyclin-dependent-kinase)
inhibitor is a logical target for the application of 3-acyl-2-
aminobenzofuran.20 A synthesis of elbfluorene 8 has been
accomplished via 6 steps involving the palladium-catalysed
cycloisomerisation of 1n and the subsequent annulation
(Scheme 4).
a
Reaction conditions: 1 (0.40 mmol), Pd(OAc)2 (0.040 mmol), PCy3
(0.080 mmol), Zn powder (0.040 mmol) and MS4A (40 mg) in DMF
b
(2.0 mL) at 100 1C. Isolated yields.
3-acetyl-2-aminobenzofuran 2j in 57% yield (Table 2, entry 9).
Furthermore, the substrate scope could be expanded to formate
1k and carbonate 1l, giving 2-amino-3-formylbenzofuran 2k
and 2-amino-3-ethoxycarbonylbenzofuran 2l in 50% and 68%
yields, respectively (Table 2, entries 10 and 11).
In conclusion, we have developed a unique palladium-
catalysed cycloisomerisation of 2-(cyanomethyl)phenyl esters.
The reaction provides a new route to 3-acyl-2-aminobenzo-
furans, which are rather inaccessible substituted heterocyclic
structures. Furthermore, 3-acyl-2-aminobenzofurans are
applicable to the synthesis of biologically active nitrogen-
containing heterocycles as demonstrated by the synthesis
of elbfluorene. Further mechanistic investigations and
studies on synthetic applications are now in progress in our
laboratory.
To gain an insight into the reaction mechanism, a crossover
experiment was carried out (Scheme 2). Palladium-catalysed
cycloisomerisation of a mixture of equimolar amounts of
esters 1b and 1m yielded only two types of 3-acyl-2-
aminobenzofurans, 2b and 2m without any crossover
products. This result clearly shows that the present cyclo-
isomerisation reaction proceeds in an intramolecular fashion.
Although the details of the process remains unknown, we
propose the following mechanism for the reaction involving
oxidative cleavage of an acyl–oxygen bond with the low-valent
palladium species (Scheme 3).12,15 The oxidative cleavage
of an acyl–oxygen bond with transition metals is known
to be difficult to achieve, except in the case of esters
activated by electron-withdrawing groups12 and esters having
2-pyridylmethyl as a directing group.16 In the present reaction
This work was financially supported by a Grant-in-Aid for
Scientific Research (B) (Grant No. 19350093) from the Japan
Society for the Promotion of Science (JSPS). M. M. thanks the
JSPS Research Fellowships for Young Scientists. We would
like to thank Dr Tetsuaki Fujihara for his help with the X-ray
crystallographic analysis.
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Scheme 4 Reagents and conditions: (a) Pd(OAc)2, PCy3, Zn powder,
MS4A, DMF, 100 1C, 9 h, 78%; (b) diketene, TMSCl, MeCN, 50 1C,
18 h; (c) NaOMe, MeOH, rt, 8 h; (d) Tf2O, pyridine, CH2Cl2, ꢁ78 1C
B rt, 2 h, 56% (3 steps); (e) HCl, THF, 50 1C, 8 h, 78%; (f) Et3SiH,
Pd(OAc)2, dppf, DMF, 70 1C, 3 h, 96%. MOM = methoxymethyl.
13 The structure of 2a was unambiguously determined by X-ray
crystallography. See ESIw.
14 Neither Zn(OAc)2 nor zinc catalysed the reaction at all in the
Notes and references
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This journal is The Royal Society of Chemistry 2009
3468 | Chem. Commun., 2009, 3466–3468