Direct preparation of benzofurans from O-arylhydroxylamines

Article abstract of DOI:10.1055/s-0029-1218273

Reaction of O-arylhydroxylamine hydrochlorides with either cyclic or acyclic ketones in the presence of methanesulfonic acid leads directly to the benzofuran derivative via a proposed one-pot condensation-rearrangement- cyclisation reaction sequence in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218273

LETTER
3003
Direct Preparation of Benzofurans from O-Arylhydroxylamines
Benzofuran
S
y
a
nthesis nny Contiero, Kevin M. Jones, Edward A. Matts, Achim Porzelle, Nicholas C. O. Tomkinson*
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20874030; E-mail: tomkinsonnc@cardiff.ac.uk
Received 4 August 2009
R1
O
R1
Abstract: Reaction of O-arylhydroxylamine hydrochlorides with
R2
either cyclic or acyclic ketones in the presence of methanesulfonic
acid leads directly to the benzofuran derivative via a proposed one-
pot condensation–rearrangement–cyclisation reaction sequence in
good to excellent yields.
R2
TFAT, DMAP
CH2Cl2, 0 °C
N
N
COCF3
O
1
2
Key words: benzofuran, hydroxylamine, sigmatropic rearrange-
ment
[3,3] then
ring closure
O
TFAT:
O
O
S
F3C
O
CF3
R1
The benzofuran nucleus represents an important pharma-
cophore embedded within the structure of a range of nat-
ural and synthetic compounds which display a broad
range of biological activities.1 This has rendered benzo-
furans important synthetic targets.2 An overview of cur-
rent methods available for the preparation of benzofurans
has recently been reported3 which reveals the range of in-
novative disconnection strategies to access this hetero-
cyclic motif. This number of methods highlights the
significance of the scaffold as a synthetic target.
DMAP:
Me2N
R2
O
N
3
Scheme 1 Reaction of O-aryl oxime ethers 1 with TFAT and DMAP
Within this report we show that reaction of O-arylhydro-
xylamine hydrochloride salts 5–7 with cyclic or acyclic
ketones in the presence of methanesulfonic acid provides
a convenient and direct method for the preparation benzo-
furan derivatives. This allows access to benzofurans under
mild reaction conditions without the need for initial oxime
formation or trifluoroacetylation of the hydroxylamine
nitrogen.
Of the methods available to prepare benzofurans one of
the most synthetically accessible involves [3,3]-sigmatro-
pic rearrangement of preformed O-aryl oxime ethers 1
promoted by Brønsted or Lewis acids.4 More recently,
Naito and co-workers have shown this reaction can also
be triggered by N-trifluoroacetylation of the oxime ether
1 with trifluoroacetyl triflate (TFAT) providing access to
benzofurans 3 (Scheme 1).5 Within this report it was
shown that treatment of O-aryl oxime ether 1 with trifluo-
roacetic acid did not lead to the benzofuran 3 (at room
temperature) and it was concluded that N-acylation was
the crucial step for [3,3]-sigmatropic rearrangement.
Our investigations began with the preparation of O-aryl-
hydroxylamine salts 5–7. Two synthetic routes have re-
cently been reported for the preparation of this class of
compound. The first involves the O-arylation of N-hy-
droxyphthalimide 4 followed by deprotection and salt for-
mation.10 The second involves a copper-catalysed O-
arylation of benzaldehyde oxime.11 In our hands, the
Sharpless method proved to be higher yielding and more
amenable to scale-up. We therefore adopted this method
for the preparation of 5–7 which were used within this in-
vestigation (Scheme 2). It is noteworthy that this method
of O-arylation has been shown to be effective for a variety
of different arylboronic acids other than those adopted
within the current work; therefore, the methodology de-
scribed within this communication should be applicable to
other O-arylhydroxylamine substrates.
Over recent years we have prepared a variety of hydroxyl-
amine reagents6 for the a-oxygenation of carbonyl
compounds7 and the functionalisation of aromatic rings8
via a proposed [3,3]-sigmatropic rearrangement strategy.
We were intrigued whether this approach to bond con-
struction was also applicable to C–C bond formation
through the use of O-arylhydroxylamine reagents such
that suitable conditions could be found to directly convert
a ketone to the corresponding benzofuran. Success of this
strategy would require discovery of acidic reaction condi-
tions that could trigger the rearrangement of intermediate
oxime ethers analogous to 1 in a similar manner to the
well-established Fischer indole synthesis.9
O
1. ArB(OH2), CuCl,
O
4 Å MS, DCE, Py
H2N
N
OH
2. NH2NH2•H2O, MeOH, CH2Cl2
3. HCl, Et2O
•HCl
R
O
4
5 R = H (21%)
6 R = Me (30%)
7 R = Br (28%)
SYNLETT 2009, No. 18, pp 3003–3006
Advanced online publication: 23.10.2009
x
x
.x
x
.2
0
0
9
DOI: 10.1055/s-0029-1218273; Art ID: D20909ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Preparation of O-arylhydroxylamine hydrochlorides

3004
F. Contiero et al.
LETTER
Selected results for the optimisation of reaction conditions substrates 15–17 were also effective within the transfor-
are outlined in Table 1. In agreement with previous find- mation giving the benzofurans 24–26 in good to excellent
ings, reaction of O-phenylhydroxylamine hydrochloride 5 yield (51–95%). Although far from an exhaustive list of
(1 equiv) with cyclohexanone 7 (1 equiv) at room temper- possible carbonyl substrates, the standard reaction condi-
ature failed to produce any of the benzofuran (entry 1). tions adopted in the majority of these transformations [60
Encouragingly, warming the reaction mixture to 60 °C °C, 2 h, THF, MeSO3H (2 equiv)] suggest that specific op-
provided some benzofuran (25%; entry 2). Crucial to op- timisation will provide an efficient and direct means to ac-
timising the desired benzofuran synthesis was the addition cess a diverse array of benzofuran products.
of a co-acid. After much experimentation, methanesulfon-
O
O
ic acid emerged as the acid of choice (entries 3 and 4). Op-
5, MeSO3H
timal reaction conditions involved reaction of 5 (1 equiv)
with 7 (1 equiv) at 60 °C (oil bath temperature) in THF for
two hours, the benzofuran 8 being isolated in a pleasing
THF, 60 °C, 2 h
7
8 (70%)
70% yield after purification by column chromatography
O
O
(entry 4).12
5, MeSO3H
THF, 60 °C, 2 h
Table 1 Optimisation of Benzofuran Synthesisa
S
S
9
18 (62%)
O
O
O
co-acid
H2N
O
O
+
5, MeSO3H
THF, Δ
•HCl
THF, 60 °C, 2 h
O
7
5
Co-acid (equiv)
none
8
O
10
19 (48%)
Entry
Time (h)
Temp (°C) Yield (%)b
O
O
5, MeSO3H
1
2
3
4
2
2
1
2
r.t.
60
60
60
–
THF, 60 °C, 2 h
none
25
42
70
11
20 (29%)
MeSO3H (1.5)
MeSO3H (2.0)
O
O
5, MeSO3H
a All reactions performed at 0.5 M concentration in THF with 1 equiv-
alent of cyclohexanone 7 and 1 equivalent of O-phenylhydroxylamine
hydrochloride 5.
THF, 60 °C, 2 h
t-Bu
t-Bu
12
b Isolated yield of 8.
21 (70%)
O
O
5, MeSO3H
Having found efficient conditions for the transformation a
series of alternative cyclic and acyclic ketone substrates
were examined to discover some of the scope and limita-
tions of the process (Scheme 3). Use of heteroatom-
substituted cyclic ketones 9 and 10 provided simple ac-
cess to the interesting heterocycles 18 (62%) and 19
(48%) under the standard reaction conditions. In line with
the proposed formation of an intermediate imine the reac-
tion appears to be influenced by sterics, with the tetra-
methyl-substituted cyclohexanone 11 leading to a
substantially reduced yield of the benzofuran 20 (29%)
under standard conditions, however, the product could
easily be isolated analytically pure after chromatography.
Moving the steric bulk away from the carbonyl group with
4-tert-butylcyclohexanone (12) restored the reaction effi-
ciency (21; 70%). Use of the nonsymmetrical 2-methylcy-
clohexanone (13) resulted in selective enamine formation
at the secondary centre to give benzofuran 22 (41%). The
acidic reaction conditions necessary for the transforma-
tion will obviously restrict functional group tolerance of
the overall transformation. Interestingly, reaction of the
ketal containing substrate 14 allowed formation of the
nonsymmetrical dibenzofuran 23 (47%) when reacted for
an extended period of time (24 h). Along with the cyclic
ketones discussed above, aliphatic and aromatic acyclic
THF, 60 °C, 3 h
13
22 (41%)
O
O
5, MeSO3H
THF, 60 °C, 24 h
O
O
HO
14
23 (47%)
O
5, MeSO3H
O
THF, 60 °C, 2 h
15
24 (51%)
O
O
5, MeSO3H
Ph
THF, 60 °C, 24 h
16
25 (95%)
O
O
5, MeSO3H
4-BrC6H4
THF, 60 °C, 4 h
Br
17
26 (79%)
Scheme 3 Alternative ketone substrates 9–17
Synlett 2009, No. 18, 3003–3006 © Thieme Stuttgart · New York

LETTER
Benzofuran Synthesis
3005
Examination of the alternative hydroxylamine salts 6 and and by heating the reaction system in the presence of a
7 showed a similar reactivity profile with both cyclic and suitable co-acid reagents such as trifluoroacetyl triflate
acyclic ketones allowing access to the corresponding ben- and 4-(N,N-dimethylamino)pyridine can be avoided.
zofuran derivatives 27–30 (70–84%; Scheme 4).
O
Acknowledgement
O
6, MeSO3H
The authors thank the EPSRC Mass Spectrometry Service, Swansea
for high-resolution spectra.
THF, 60 °C, 2 h
7
27 (84%)
O
References and Notes
O
6, MeSO3H
Ph
(1) (a) d’Ischia, M.; Napolitano, A.; Pezella, A. In
Comprehensive Heterocyclic Chemistry III, Vol. 2;
Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.;
Pergamon Press: London, 2008, 353. (b) Keay, B. A.;
Hopkins, J. M. In Comprehensive Heterocyclic Chemistry
III, Vol. 2; Ramsden, C. A.; Scriven, E. F. V.; Taylor,
R. J. K., Eds.; Pergamon Press: London, 2008, 571.
(2) For reviews dealing with benzofuran synthesis, see:
(a) Hou, X.-L.; Yang, Z.; Wong, H. N. C. Prog. Heterocycl.
Chem. 2002, 14, 139. (b) Gilchrist, T. L. J. Chem. Soc.,
Perkin Trans. 1 2001, 2491. (c) Horton, D. A.; Bourne,
G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
(d) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive
Heterocyclic Chemistry, Vol. 4; Katritzky, A. R.; Rees,
C. W., Eds.; Pergamon Press: New York, 1984, 657.
(3) Miyata, O.; Takeda, N.; Naito, T. Heterocycles 2009, 78,
843.
THF, 60 °C, 24 h
16
28 (73%)
O
O
7, MeSO3H
THF, 60 °C, 2 h
Br
7
29 (76%)
O
O
7, MeSO3H
4-BrC6H4
Br
THF, 60 °C, 4 h
Br
17
30 (70%)
Scheme 4 Alternative hydroxylamine salts 6 and 7
(4) (a) Sheradsky, T. Tetrahedron Lett. 1966, 5225.
(b) Kaminsky, D.; Shavel, J. Jr.; Meltzer, R. I. Tetrahedron
Lett. 1967, 859. (c) Mooradian, A.; Dupont, P. E.
Tetrahedron Lett. 1967, 2867. (d) Alemagna, A.; Baldoli,
C.; Del Buttero, P.; Licandro, E.; Maiorana, S. J. Chem.
Soc., Chem. Commun. 1985, 417. (e) Guzzo, P. R.; Buckle,
R. N.; Chou, M.; Dinn, S. R.; Flaugh, M. E.; Kiefer, A. D.
Jr.; Ryter, K. T.; Sampognaro, A. J.; Tregay, S. W.; Xu,
Y.-C. J. Org. Chem. 2003, 68, 770.
A plausible mechanistic pathway for the transformation is
outlined in Scheme 5. Condensation of the salt 5 with cy-
clohexanone (7) should lead to the protonated enamine 31
which can then undergo a [3,3]-sigmatropic rearrange-
ment under the acidic reaction conditions. Rearomatisa-
tion and intramolecular cyclisation followed by
elimination of ammonia would then provide the observed
product 8.
(5) Norihiko, T.; Miyata, O.; Naito, T. Eur. J. Org. Chem. 2007,
1491.
O
O
(6) For example, see: (a) Jones, K. L.; Porzelle, A.; Hall, A.;
Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett. 2008, 10,
797. (b) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O.
Org. Lett. 2009, 11, 233. (c) Porzelle, A.; Woodrow, M. D.;
Tomkinson, N. C. O. Synlett 2009, 798.
5, MeSO3H
THF, 60 °C, 2 h
8
7
(7) (a) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.;
Jones, T. C.; Killeen, N. M.; Taylor, P. H.; Thomas, S. P.;
Tomkinson, N. C. O. Org. Lett. 2005, 7, 5729. (b) Beshara,
C. S.; Hall, A.; Jenkins, R. L.; Jones, T. C.; Parry, R. T.;
Thomas, S. P.; Tomkinson, N. C. O. Chem. Commun. 2005,
1478. (c) Hall, A.; Jones, K. L.; Jones, T. C.; Killeen, N. M.;
Porzig, R.; Taylor, P. H.; Yau, S. C.; Tomkinson, N. C. O.
Synlett 2006, 3435. (d) Hall, A.; Huguet, E. P.; Jones, K. L.;
Jones, T. C.; Killeen, N. M.; Yau, S. C.; Tomkinson, N. C.
O. Synlett 2007, 293. (e) Jones, T. C.; Tomkinson, N. C. O.
Org. Synth. 2007, 84, 233. (f) Knowles, D. A.; Mathews,
C. J.; Tomkinson, N. C. O. Synlett 2008, 2769.
– H2O
– NH3
H
O
O
O
H2N
H
N
NH2
H
H
H
31
32
33
Scheme 5 Proposed mechanistic pathway
(8) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Eur. J.
In conclusion, we have described a simple method for the
direct formation of benzofurans from O-arylhydroxyl-
amine hydrochlorides and cyclic or acyclic ketones. The
reaction proceeds without the need for purification of sol-
vents or the exclusion of moisture and air, greatly adding
to the practicality of the method. Specific advantages over
existing literature methods include the fact that isolation
of the intermediate O-aryl oxime ether is not necessary
Org. Chem. 2008, 5135.
(9) For a review of the Fischer indole reaction, see: (a)Hughes,
D. L. Org. Prep. Proced. Int. 1993, 25, 607. (b) Humphrey,
G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(10) Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett.
2001, 3, 139.
(11) Nonappa, D. P.; Pandurangan, K.; Maitra, U.; Wailes, S.
Org. Lett. 2007, 9, 2767.
Synlett 2009, No. 18, 3003–3006 © Thieme Stuttgart · New York

3006
F. Contiero et al.
LETTER
(12) Typical Experimental Procedure; 1,2,3,4-
light yellow oil. 1H NMR (400 MHz, CDCl3): d = 7.28–7.32
(m, 2 H), 7.06–7.12 (m, 2 H), 2.62–2.66 (m, 2 H), 2.50–2.54
(m, 2 H), 1.80–1.86 (m, 2 H), 1.71–1.78 (m, 2 H). 13C NMR
(62.5 MHz, CDCl3): d = 154.4, 154.0, 128.9, 123.0, 122.1,
118.4, 112.9, 110.8, 23.5, 23.0, 22.7, 20.5. LRMS (EI+):
m/z = 172.1 [M]+. HRMS (MALDI): m/z [M]+ calcd for
C12H12O: 172.0883; found: 172.0880.
Tetrahydrodibenzofuran (8):13 O-Phenylhydroxylamine
hydrochloride (0.146 g, 1 mmol) was dissolved in THF (2
mL) and warmed to 60 °C. After 5 min methanesulfonic acid
(0.150 g, 2 mmol) and cyclohexanone (0.100 g, 1 mmol)
were added and the reaction was monitored by TLC. On
completion, the solvent was removed under reduced
pressure. Purification by column chromatography (PE–
EtOAc, 20:1) gave the title compound 8 (0.121 g, 70%) as a
(13) Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2004, 6,
4755.
Synlett 2009, No. 18, 3003–3006 © Thieme Stuttgart · New York

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