Iridium(III)-catalyzed tandem Claisen rearrangement-intramolecular hydroaryloxylation of aryl allyl ethers to form dihydrobenzofurans

Article abstract of DOI:10.1016/j.tetlet.2005.01.006

Iridium(III)-catalyzed tandem Claisen rearrangement and intramolecular hydroaryloxylation of ally aryl ethers is described, which provides a mild method to prepare dihydrobenzofurans.

Full text of DOI:10.1016/j.tetlet.2005.01.006

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1237–1239
Iridium(III)-catalyzed tandem Claisen
rearrangement–intramolecular hydroaryloxylation of aryl
allyl ethers to form dihydrobenzofurans
Virginia H. Grantꢀ and Bing Liu*
Chemical Development, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA
Received 3 December 2004; revised 23 December 2004; accepted 5 January2005
Available online 18 January2005
Abstract—Iridium(III)-catalyzed tandem Claisen rearrangement and intramolecular hydroaryloxylation of ally aryl ethers is
described, which provides a mild method to prepare dihydrobenzofurans.
Ó 2005 Elsevier Ltd. All rights reserved.
Table 1. Results of catalyst screening for Claisen hydroaryloxylation
of 1
The Claisen rearrangement is a classic reaction for car-
bon–carbon formation in organic synthesis.1 Although
the reaction is traditionallyperformed under thermal
conditions, there is considerable current interest in cata-
cat. (5 mol%)
additive (10 mol%)
lysis of the Claisen rearrangement by metal catalysts un-
der mild conditions.2 The Claisen rearrangement of allyl
aryl ethers has been achieved efficiently with stoichio-
metric amount of Lewis acids3,4 and substoichiometric
amount of metal catalysts such as Yb(OTf)3,5 Sc(OTf)3
in ionic liquid,6 and Mo(CO)6.7 We are interested in
the metal catalyzed tandem Claisen rearrangement and
hydroaryloxylation of allyl aryl ethers as a general meth-
od to make dihydrobenzofurans.6,7 Herein we report
our results from a thorough screen, which identified
IrCl3/AgOTf as an efficient catalyst for the tandem Cla-
isen rearrangement cyclization of allyl aryl ethers to
form dihydrobenzofurans.
ClCH2CH2Cl,
60 °C, 24 h
OH
O
O
1
2
3
a
EntrystCataly
Additive
Yield
(%)
1
RuCl3
None
AgOTf
None
0
43
0
2
RuCl3
PtCl2
PtCl2
PtCl4
3
4
AgOTf
AgOTf
Ph3P
11
12
0
5
6
PtCl2(CH2@CH2)
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
IrCl3
7
None
AgOTf
None
44
20
0
8
9
10
11
12
13
14
15
16
AgOTf
None
22
0
Transition metal complexes, known to either promote
Claisen rearrangement2 or facilitate the intramolecular
hydroalkoxylation of hydroxy-olefins,8 were included
in the screen. Table 1 summarized the results from the
screening study. With the exception of Cu(OTf)2, none
of these metal catalysts examined proved effective for
the conversion of phenyl allyl ether to dihydrofurans at
AgOTf
None
25
0
IrCl3
PdCl2(CH3CN)2
None
AgOTf
None
AgOTf
65
0
0
a The reaction was performed at 0.5 M of 1 in 1,2-dichloroethane at
60 °C for 24 h.
Keywords: Iridium(III) chloride; Claisen rearrangement; Hydroaryl-
oxylation; Dihydrobenzofuran.
60 °C. PdCl2(CH3CN)2 afforded undesired products,
mainlyphenol from cleavage of allly phenly ether.
Sc(OTf)3 as well as Yb(OTf)3 promoted onlythe Claisen
rearrangement of allyl phenyl ether to 2-allylphenol (2)
but not the subsequent cyclization to dihydrofuran.
*
Corresponding author. Tel.: +1 919 483 8165; fax: +1 919 315
8735; e-mail: bing.b.liu@gsk.com
ꢀ Current address: Department of Chemistry, Vanderbilt University,
Nashville, TN 37235, USA.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.006

1238
V. H. Grant, B. Liu / Tetrahedron Letters 46 (2005) 1237–1239
The platinum based system, [PtCl2(CH2@CH2)]2/PPh3,
successful for the intramolecular hydroalkoxylation of
hydroxy-olefins failed to facilitate the formation of
dihydrofuran from either 1 or 2-allylphenol.8 In order
to increase the electrophilicityat the metal centers, we
attempted to add silver salts to the reaction mixture.9
It was found that the addition of AgOTf promoted
the formation of dihydrofuran 3 except in the case of
Cu(OTf)2, where the yield of the desired product 3 de-
creased upon the addition of AgOTf due to the forma-
tion of multiple undesired products. To our delight, the
combination of IrCl3/AgOTf afforded 3 in 65% yield.10
Interestingly, neither IrCl3 nor AgOTf individuallywas
able to promote the formation of dihydrofuran 3 from
allyl phenyl ether. It was found that AgOTf was some-
what effective to catalyze the formation of dihydrofuran
from 2-allylphenol, albeit only in 11% yield.11 These
results suggest that a more reactive iridium catalyst is
generated in situ upon the addition of AgOTf.
The tandem Claisen hydroaryloxylation was next ex-
plored on a range of allyl aryl ethers to probe the scope
of this cascade process (Table 2). This method was
applicable to substrates with functional groups such as
methoxy, methylenedioxy, and chloro. All substituents
gave moderate to good yields, although it should be
noted that the conversion of 12 to hydrobenzofuran 13
was slightlysluggish. The reaction was also observed
tolerant of substitution at the internal olefinic position.
In the case of 1,1-disubstituted olefin 14, the reaction
was facile and nearlycomplete in three hours. The tan-
dem Claisen cyclization reaction appeared to be sensi-
tive to terminal olefinic disubstitution. For example,
phenyl prenyl ether 16 failed to produce dihydrofuran
17, giving phenol as the major product. Iridium-cata-
lyzed tandem Claisen hydroaryloxylation was also amen-
able to the formation of fused cyclic ether such as 19,
albeit in a lower yield due to the competing ether cleav-
age. Allyl 1-naphthyl ether also underwent the iridium-
catalyzed tandem process to afford dihydrofuran 21 in
63% yield.
Table 2. Iridium catalyzed Claisen hydroaryloxylation of aryl ethers
a
EntrySubstrate
Product
(%)
1
O
O
4
5 (70%)
2
In summary, we have developed a tandem Claisen
hydroaryloxylation of ally aryl ethers using IrCl3/
AgOTf catalyst. A variety of dihydrobenzofurans are
accessible through this protocol under mild conditions.
Our future efforts are directed to expand this protocol
into tandem amino-Claisen cyclization for the indoline
synthesis.
O
O
6
7 (75%)
MeO
MeO
3
O
O
8
9 (76%)
O
O
O
O
4
O
O
Supplementary data
10
11 (72%)
Cl
Cl
Supplementarydata associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.01.006. The 1H NMR and 13C NMR data for
dihydrofurans is available online with the paper in
ScienceDirect.
5b
6c
7
O
O
12
13 (59%)
O
O
15 (80%)
14
References and notes
1. Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
2. Hiersemann, M.; Abraham, L. Eur. J. Org. Chem. 2002,
1461.
3. Maruoka, K.; Sato, J.; Banno, H.; Yamamoto, H.
Tetrahedron Lett. 1990, 31, 377, and references cited
therein.
4. Wipf, P.; Ribe, S. Org. Lett. 2001, 3, 1503.
5. Sharma, G. V. M.; Ilangovan, A.; Sreenivas, P.; Maha-
lingam, A. K. Synlett 2000, 615.
O
O
O
17 (0)
16
8
O
18
19 (50%)
6. Zulfiqar, F.; Kitazume, T. Green Chem. 2000, 2, 296.
7. Bernard, A. M.; Cocco, M. T.; Onnis, V.; Piras, P. P.
Synthesis 1997, 41, and references cited therein.
8. Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 9536.
9. Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6,
581.
10. A typical experiment was as follows: A mixture containing
allyl phenyl ether (1.34 g, 10 mmol), IrCl3 (0.15 g,
9
O
O
20
21 (63%)
a All reactions were performed with 5 mol % of IrCl3 and 10 mol % of
AgOTf in ClCH2CH2Cl (0.5 M) at 60 °C for 24 h, unless otherwise
noted.
b Performed at 60 °C for 36 h.
c Performed at 60 °C for 4 h.

V. H. Grant, B. Liu / Tetrahedron Letters 46 (2005) 1237–1239
1239
0.5 mmol), AgOTf (0.26 g, 1 mmol), and 1,2-dichloro-
ethane (20 mL) was heated under nitrogen at 60 °C for
24 h. After removal of solvents, the residue was purified by
silica gel column chromatography(hexane/dichloro-
methane = 9/1) to afford dihydrobenzofuran 3 (0.87 g,
65%) as a colorless oil. IR (neat, cmÀ1) 1479, 1463, 1228,
746. H NMR (CDCl3, 400 MHz): d 7.15 (d, J = 7.3 Hz,
1H), 7.10 (t, J = 7.8 Hz, 1H), 6.82 (t, J = 7.3 Hz, 1H), 6.76
(d, J = 7.8 Hz, 1H), 4.87–4.96 (m, 1H), 3.30 (dd, J = 15.4
and 8.8 Hz, 1H), 2.82 (dd, J = 15.4 and 7.7 Hz, 1H), 1.47
(d, J = 6.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d 22.0,
37.4, 79.7, 109.5, 120.4, 125.2, 127.2, 128.2, 159.7. Anal.
Calcd for C9H10O: C, 80.56; H, 7.51. Found: C, 80.32; H,
7.29. All products were successfullycharacterized using
1H NMR, 13C NMR, and elemental analysis.
1
11. For a RuCl3ÆxH2O catalyzed cyclization of 2-allylphenol,
see: Hori, K.; Kitagawa, H.; Miyoshi, A.; Ohta, T.;
Furukawa, I. Chem. Lett. 1998, 1083.