Gold-catalyzed cyclizations of (o-alkynyl)phenoxyacrylates with external nucleophiles: Regio-and stereoselective synthesis of functionalized benzo[b]oxepines

Article abstract of DOI:10.1021/ol302252h

A catalytic approach to benzo[b]oxepines with high stereoselectivity by Au-catalyzed cyclization of (o-alkynyl)phenoxyacrylates with various nucleophiles under mild reaction conditions has been developed. Notably, the use of vinyl ether instead of alcohol could afford the same benzoxepines. The reaction may proceed by Au-catalyzed oligomerization of vinyl ether to release the alcohol, which then reacts with (o-alkynyl)phenoxyacrylates to furnish the benzoxepines.

Full text of DOI:10.1021/ol302252h

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4742–4745
Gold-Catalyzed Cyclizations of
(o‑Alkynyl)phenoxyacrylates with
External Nucleophiles: Regio- and
Stereoselective Synthesis of
Functionalized Benzo[b]oxepines
Jun Liu and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
People’s Republic of China
yhliu@mail.sioc.ac.cn
Received July 16, 2012
ABSTRACT
A catalytic approach to benzo[b]oxepines with high stereoselectivity by Au-catalyzed cyclization of (o-alkynyl)phenoxyacrylates with various
nucleophiles under mild reaction conditions has been developed. Notably, the use of vinyl ether instead of alcohol could afford the same
benzoxepines. The reaction may proceed by Au-catalyzed oligomerization of vinyl ether to release the alcohol, which then reacts with
(o-alkynyl)phenoxyacrylates to furnish the benzoxepines.
The development of efficient methodologies for the
construction of medium-sized rings remains a very impor-
tant challenge in organic synthesis.1 Benzo[b]oxepines are
common seven-membered structural motifs found in many
natural products,2 biologically active substances,3 and
natural herbicides.4 Therefore, considerable attention has
been paid to the synthesis of functionalized benzo[b]-
oxepines. Particularly, attractive strategies are based on
transition-metal-catalyzed transformations, such as Rh-
catalyzed intramolecular olefin hydroacylations,5 Os-
catalyzed hydroxylation of aromatic alkynols,6 Pd-
catalyzed [5 þ 2] annulation of 2-acylmethoxyarylboronic
acids7 with allenoates7a or alkynes,7b Pd-catalyzed seq-
uential alkylationꢀalkenylation reactions,8 Au-catalyzed
heterocyclization/PetasisꢀFerrier rearrangement,9 etc.
(1) For reviews on medium-sized rings in natural products, see:
(a) Shiina, I. Chem. Rev. 2007, 107, 239. (b) Yet, L. Chem. Rev. 2000,
100, 2963.
(2) For examples, see: (a) Bruder, M.; Haseler, P. L.; Muscarella, M.;
Lewis, W.; Moody, C. J. J. Org. Chem. 2010, 75, 353. (b) Macias, F. A.;
Molinillo, J. M. G.; Varela, R. M.; Torres, A.; Fronczek, F. R. J. Org.
Chem. 1994, 59, 8261. (c) Engler, M.; Anke, T.; Sterner, O. J. J. Antibiot.
1997, 50, 330. (d) Engler, M.; Anke, T.; Sterner, O. J.; Brandt, U. J.
J. Antibiot. 1997, 50, 325. (e) Asakawa, Y.; Hashimoto, T.; Takikawa,
K.; Tori, M.; Ogawa, S. Phytochemistry 1991, 30, 235. (f) Kim, S.; Su, B.-
N.; Riswan, S.; Kardono, L. B. S.; Afriastini, J. J.; Gallucci, J. C.; Chai,
H.; Farnsworth, N. R.; Cordell, G. A.; Swanson, S. M.; Kinghorn, A. D.
Tetrahedron Lett. 2005, 46, 9021. (g) Kashima, K.; Sano, K.; Yun, Y. S.;
Ina, H.; Kunugi, A.; Inoue, H. Chem. Pharm. Bull. 2010, 58, 191.
(3) Wijnberg, J. B. P. A.; van Veldhuizen, A.; Swarts, H. J.; Frankland,
J. C.; Field, J. A. Tetrahedron Lett. 1999, 40, 5767.
(5) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc.
2009, 131, 6932.
ꢀ
(6) Varela-Fernandez, A.; Garcıa-Yebra, C.; Varela, J. A.; Esteruelas,
ꢀ
M. A.; Saa, C. Angew. Chem., Int. Ed. 2010, 49, 4278.
(7) (a) Yu, X.; Lu, X. J. Org. Chem. 2011, 76, 6350. (b) Liu, G.; Lu, X.
Adv. Synth. Catal. 2007, 349, 2247.
(8) Lautens, M.; Paquin, J. -F.; Piguel, S. J. Org. Chem. 2002, 67,
3972.
(9) Sze, E. M. L.; Rao, W.; Koh, M. J.; Chan., P. W. H. Chem.;Eur.
J. 2011, 17, 1437.
(4) Vyvyan, J. R.; Looper, R. E. Tetrahedron Lett. 2000, 41, 1151.
r
10.1021/ol302252h
Published on Web 09/04/2012
2012 American Chemical Society

Although much progress has been achieved, the reactions
involving a stereoselective process is quite rare. Recently,
we have developed several Au-catalyzed highly efficient
methodologies for the construction of seven-membered
carbo- or heterocycles such as Au-catalyzed Friedelꢀ
Crafts/hydroarylations10 or tandem annulations leading
to dihydrocyclohepta[b]indoles,11 ring-opening cycloami-
nation of aziridine-ynes leading to 3-benzo[d]azepines.12
These results encouraged further exploration of the syn-
thetic routes to benzo[b]oxepines. We hypothesized that the
Au-catalyzed cyclization of (o-alkynyl)phenoxyacrylates
with nucleophiles might offer an opportunity for the syn-
thesis of benzoxepines. Here, we report our success in Au-
catalyzed cyclization of (o-alkynyl)phenoxyacrylates as-
sisted by external oxygen or nitrogen nucleophiles. The
reaction provides a highly regio- and stereoselective route
to benzo[b]oxepines and its analogues under mild reaction
conditions (Scheme 1).
Table 1. Optimization Studies for the Formation of
Benzo[b]oxepine 3a
BuOH
time yield of yield of
entry (equiv)
catalyst
solvent
(h)
2a (%)a 3a (%)a
1
2
3
4
5
6
7
8
2
Ph3PAuNTf2 DCE
Ph3PAuNTf2 DCE
Ph3PAuNTf2 DCE
Ph3PAuNTf2 DCM
Ph3PAuNTf2 THF
Ph3PAuNTf2 toluene
10
18
8
ꢀ
92
5
43
ꢀ
49b
83
1.1
2
25
2
ꢀ
79
2
21
ꢀ
62b,c
42d
66b
72
2
7
2
Ph3PAuOTf
DCE
19
19
ꢀ
2
Ph3PAuSbF6 DCE
ꢀ
a Isolated yield. b Containing some amounts of byproducts. c Reflux.
d 80 °C, 38% of 1a was recovered.
Scheme 1a
alkynylphenoxyacrylates. The results are summarized in
Figure 1. The reactions accommodate a wide range of
substituents on the alkyne terminus, since aryl, hetero-
aryl, and alkyl groups are all suitable for this cyclization
reaction, and in all cases, benzo[b]oxepines 3 were obtained
in high yields as a single diastereomer. The functionalities
such as ꢀMeO, ꢀCl, ꢀCF3, and p-CO2Et on the terminal
aryl rings were well tolerated during the reaction. Gener-
ally, substrates containing electron-withdrawing groups
required longer reaction times (compare 3cꢀe with 3b).
Alkyne 1f with a sterically demanding 1-naphthyl group
cyclized smoothly to generate 3f in 78% yield. A thienyl
group was also compatible, furnishing 3g in 79% yield.
n-Butyl or cyclopropyl substituted (o-alkynyl)phenoxy-
acrylate could be readily converted to 3h and 3i in 87ꢀ
89% yields. Substitution with ꢀMe or ꢀCl groups on the
parent phenyl ring also worked efficiently to give 3j and 3k
in 89% and 79% yields, respectively. A conformationally
restricted (E)-methyl 3-(1-(alkynyl)naphthalen-2-yloxy)-
acrylate 1l provided 3l in 79% yield. Interestingly, when a
nitrogen-tethered acrylate was subjected to the reaction
conditions, 2,3-dihydrobenzo[b]azepine 4 was obtained in
92% yield as a single diastereomer. Therefore the present
reaction could be extended to the efficient synthesis of
various aza-heterocycles by simply changing the hetero-
atom linkers. The structures of these benzoxepine derivatives
were unambiguously confirmed by X-ray crystallographic
analysis of 3d, 3g, and 4.13
a X = O, NTs; NuH = ROH, TMSN3.
The requisite substrates of (E)-2-alkynylphenoxyacry-
lates 1 could be easily synthesized through base-promoted
addition reactions of the corresponding 2-alkynylphenols
to methyl propiolate. To our delight, the reaction of (E)-
methyl 3-(2-(phenylethynyl)phenoxy)acrylate 1a with 2.0
equiv of n-BuOH catalyzed by 5 mol % of PPh3AuNTf2
cleanly delivered the desired 2,3-dihydrobenzo[b]oxepine
3a in high yield (92%) (Table 1, entry 1). The result in-
dicates that an endo-dig cyclization takes place preferen-
tially rather than the exo-dig mode. High stereoselectivity
is also noted, as only trans-3a was obtained. Increasing the
amount of n-BuOH to 5.0 equiv, however, was found to
result in the formation of 2-phenylbenzofuran 2a in 43%
yield. In this case, 3a could be isolated in ca. 49% yield;
however, it contained some byproducts, which could not
be separated by column chromatography. One byproduct
was assigned to be (E)-methyl 3-butoxyacrylate as com-
pared with the NMR spectra of an authentic sample.
Decreasing the amount of n-BuOH to 1.1 equiv afforded
a lower yield (83%) (entry 3). Solvents such as DCM,
THF, and toluene gave 3a in lower yields (entries 4ꢀ6).
Changing the counteranion of the Au catalyst to OTfꢀ or
SbF6ꢀ led to 3a in 66ꢀ72% yields (entries 7ꢀ8).
Next, we investigated the scope of nucleophiles (Table 2).
It was found that, in addition to n-butanol, a variety of
alcohols could be used as effective nucleophiles for this
reaction. Treatment of 1a with simple alcohols such as
methanol or ethanol afforded the corresponding benzox-
epine products 3m and 3n in 83ꢀ84% yields (Table 2,
With the optimized reaction conditions in hand, we next
examined the scope of differently substituted (E)-2-
(10) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351,
1517.
(11) Xie, X.; Du, X.; Chen, Y.; Liu, Y. J. Org. Chem. 2011, 76, 9175.
(12) Du, X.; Yang, S.; Yang, J.; Liu, Y. Chem.;Eur. J. 2011, 17,
4981.
(13) See Supporting Information.
Org. Lett., Vol. 14, No. 18, 2012
4743

entries 1 and 2). A bulky alcohol such as t-BuOH afforded
a moderate yield of 3o, possible due to the strong steric
effects (entry 3). Functional alcohols such as benzyl
alcohol, allylic alcohol, or phenol underwent the cycliza-
tion reaction smoothly to generate the desired 3pꢀ3r in
82ꢀ89% yields (entries 4ꢀ6). In the case of 3r, the use of
JohnphosAuSbF6(MeCN) (catalyst A) as the catalyst is
required to achieve a better yield. Furthermore, a nitro-
gen nucleophile such as TMSN3 could also be successfully
employed for this cyclization, and the corresponding N3-
substituted benzoxepine 3s was obtained in 85% yield
(entry 7).
Table 2. Gold-Catalyzed Cyclization of 1a with Various
Nucleophiles
Electron-rich alkenes such as vinyl ethers are usually
utilized as dipolarophiles in metal-catalyzed cycloaddition
reactions.14 Unexpectedly, here we found that when vinyl
ethers were employed instead of alcohols, the same ben-
zoxepines 3 could also be obtained. For example, treat-
ment of 1a with 5 mol % PPh3AuNTf2 and 5 equiv of
n-butyl vinyl ether in DCE yielded trans-3a in 94% yield
after 7 h at rt (Table 3, entry 1). As shown in Table 3, the
reactions using vinyl ethers as components worked effi-
ciently with a wide range of substrates, and good to
excellent yieldswereobtainedinmostcases. Tounderstand
themechanism, we treatedn-butylvinyl etherwith1 mol %
PPh3AuNTf2 in DCE at rt. Vinyl ether was completely
consumed after 1 h, and oligomerized products were
formed, which was confirmed by NMR and ESI-MS
examination.15,16 Addition of phenoxyacrylate 1a to the
above reaction mixture also produced benzoxepine pro-
duct 3a in high yield. The result suggested that vinyl ether
a Isolated yield. b 5 mol % of catalyst A was used instead of
Ph3PAuNTf2.
might notreact with1adirectlybut servedasa precursor. It
is likely that n-BuOH was released during the oligomeriza-
tion process, which then acts as a nucleophile to react with
(o-alkynyl)phenoxyacrylates.15 It is noted that there is no
report for the oligomerization of vinyl ethers in Au- or Pt-
catalyzed reactions employing vinyl ethers.14aꢀl
To understand the stereochemical course of this reac-
tion, we also prepared cis-phenoxyacylate 5. It was found
(14) For Au: (a) Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 12638. (b) Li, G.; Huang, X.; Zhang, L. J. Am.
Chem. Soc. 2008, 130, 6944. (c) Jadhav, A. M.; Bhunia, S.; Liao, H.-Y.;
Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 1769. (d) Teng, T.-M.; Das, A.;
Huple, D. B.; Liu, R.-S. J. Am. Chem. Soc. 2010, 132, 12565. (e) Teng, T.-
M.; Liu, R.-S. J. Am. Chem. Soc. 2010, 132, 9298. (f) Garayalde, D.;
€
Kruger, K.; Nevado, C. Angew. Chem., Int. Ed. 2011, 50, 911. For Pt:
(g) Kusama, H.; Ishida, K.; Funami, H.; Iwasawa., N. Angew. Chem.,
Int. Ed. 2008, 47, 4903. (h) Kusama, H.; Funami, H.; Iwasawa, N.
Synthesis 2007, 2014. (i) Saito, K.; Sogou, H.; Suga, T.; Kusama, H.;
Iwasawa, N. J. Am. Chem. Soc. 2011, 133, 689. (j) Kusama, H.; Funami,
H.; Takaya, J.; Iwasawa, N. Org. Lett. 2004, 6, 605. (k) Kusama, H.;
Miyashita, Y.; Takaya, J.; Iwasawa, N. Org. Lett. 2006, 8, 289. (l) Ishida,
K.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842. For W:
(m) Iwasawa, N.; Shido, M.; Maeyama, K.; Kusama, H. J. Am. Chem. Soc.
2000, 122, 10226. (n) Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem.
Soc. 2001, 123, 5814. (o) Kusama, H.; Funami, H.; Shido, M.; Hara, Y.;
Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2005, 127, 2709. (p) Kusama,
H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 11592.
ꢀ
ꢀ
(15) See: Keki, S.; Nagy, M.; Deak, G.; Zsuga, M. J. Phys. Chem. B
Figure 1. Au-catalyzed formation of benzo[b]oxepine or -[b]-
azepine derivatives. All yields are isolated yields. Unless noted,
all the reactions were carried out at rt using 2.0 equiv of n-BuOH
and 5 mol % PPh3AuNTf2 in DCE. a50 °C, 10 mol % PPh3AuNTf2
was used. b1.1 equiv of n-BuOH was used.
2001, 105, 9896.
(16) For Au-catalyzed polymerization of styrenes, see: Urbano, J.;
ꢀ
Hormigo, A. J.; de Fremont, P.; Nolan, S. P.; Dıaz-Requejo, M. M.;
ꢀ
Perez, P. J. Chem. Commun. 2008, 759. For Au-catalyzed polymeriza-
tion of cyclopentadienes, see: Sanguramath, R. A.; Patra, S. K.; Green,
M.; Russell, C. A. Chem. Commun. 2012, 1060.
4744
Org. Lett., Vol. 14, No. 18, 2012

Table 3. Gold-Catalyzed Formation of Benzo[b]oxepines 3 via
the Reactions with Vinyl Ethers
Scheme 2
time
(h)
yield
(%)a
entry
R1
R2
product
Scheme 3
1
Ph
1a
1b
1c
1d
1e
1f
nBu
nBu
nBu
nBu
nBu
nBu
nBu
nBu
nBu
Et
7
3a
3b
3c
3d
3e
3f
94
93
93
86
99
98
82
77
87
88
2
p-MeOC6H4
p-ClC6H4
p-CF3C6H4
p-CO2EtC6H4
1-naphthyl
2-thienyl
nBu
3.5
22
20
6
3
4b
5b
6
7
7
1g
1h
1i
3
3g
3h
3i
8
6
9
cyclopropyl
Ph
3
10
11
1a
1n
7
3n
c
H
nBu
8
ꢀ
a Isolated yields. b 50 °C. 10 mol % of PPh3AuNTf2 was used. c 44%
of 1n was recovered.
may be explained by competitive addition of ROH to the
alkene moiety promoted by gold19 followed by decomposi-
tion to give (o-alkynyl)phenol, which cyclizes in the pre-
sence of a gold catalyst to afford benzofuran 2.20
that the use of n-BuOH failed to produce the desired
product. The major product was benzofuran 2a in the
presence of 5 mol % PPh3AuNTf2 in DCE, while the reac-
tion became complicated when catalyst A was used as a
catalyst. In contrast, 5 reacted with n-butyl vinyl ether
smoothly in the presence of 5 mol % catalyst A at 80 °C to
give 6 in 90% yield as a single cis-diastereomer (Scheme 2).
The 1H NMR of 6 shows the value of the coupling constant
of the methine protons is as small as 1.6 Hz, while this value is
5.6 Hz in trans-3a. The above results indicated that the (E)-or
(Z)-geometry of the starting acrylates reflects the stereochem-
istry of the benzoxepine products during the reaction.
A possible reaction mechanism for the present reactions
with alcohols is shown in Scheme 3. Activation of the triple
bond in enyne type substrate 1 by gold(I) triggers the intra-
molecular attack of the alkene and leads to the stereo-
selective formation of a cyclopropyl gold carbene inter-
mediate 8.17 A subsequent regio- and stereoselective attack
of the nucleophile on the cyclopropyl ring in 8 gives the
vinyl gold species 10,18 which then undergoes protodeme-
talation to deliver the trans-benzoxepine 3. In the presence
of a large excess amount of alcohol, benzofuran 2 was
observed as a byproduct. The formation of benzofuran
In summary, we have developed a new catalytic ap-
proach to benzo[b]oxepines with high stereoselectivity
through gold-catalyzed cyclization of (o-alkynyl)phenoxy-
acrylates with various nucleophiles under mild reaction con-
ditions. Notably, vinyl ether could also be used to afford the
same benzoxepines. The reaction may proceed by gold-
catalyzed oligomerization of vinyl ether to release the alcohol,
which then reacts with (o-alkynyl)phenoxyacrylates to fur-
nish the benzoxepines. Clarification of the reaction mechan-
ism and further application of this chemistry are in progress.
Acknowledgment. We thank the National Natural
Science Foundation of China (Grant Nos. 21125210,
21121062), Chinese Academy of Science and the Major
State Basic Research Development Program (Grant No.
2011CB808700) for financial support.
Note Added after ASAP Publication. Errors in Tables 1
and 3 were corrected September 5, 2012.
Supporting Information Available. Experimental details,
spectroscopic characterization of all new compounds, and
X-ray crystallography of 3d, 3g, and 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
ꢀ
ꢀ~
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^
Chem. Rev. 2008, 108, 3326. (b) Michelet, V.; Toullec, P. Y.; Genet, J.-P.
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S. A. Adv. Synth. Catal. 2006, 348, 2271.
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(19) For Au-catalyzed addition of alcohols to alkenes, see: (a) Hirai,
T.; Hamasaki, A.; Nakamuru, A.; Tokunaga, M. Org. Lett. 2009, 11,
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Martınez, A.; Garcıa-Garcıa, P.; Fernandez-Rodrıguez, M. A.; Rodrıguez,
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Cardenas, D. J.; Echavarren, A. M. Chem.;Eur. J. 2003, 9, 2627. (d)
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~
~
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Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.; Cardenas,
D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402. (e) Genin,
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^
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4745