Gold-catalyzed tandem intramolecular heterocyclization/petasis-ferrier rearrangement of 2-(Prop-2-ynyloxy)benzaldehydes as an expedient route to benzo[b]oxepin-3(2a H)-ones

Article abstract of DOI:10.1002/chem.201003096

The golden ring: A synthetic approach to benzo[b]oxepin-3(2a H)-ones by heterocyclization/Petasis-Ferrier rearrangement of 2-(prop-2-ynyloxy) benzaldehydes is reported. Uniquely, the ring formation was found to only proceed efficiently in the presence of

Full text of DOI:10.1002/chem.201003096

COMMUNICATION
DOI: 10.1002/chem.201003096
Gold-Catalyzed Tandem Intramolecular Heterocyclization/Petasis–Ferrier
Rearrangement of 2-(Prop-2-ynyloxy)benzaldehydes as an Expedient Route
to Benzo[b]oxepin-3ACHTNUTGRNEUNG(2H)-ones
Ella Min Ling Sze, Weidong Rao, Ming Joo Koh, and Philip Wai Hong Chan*[a]
Partially or fully hydrogenated benzo[b]oxepines are
common ring motifs found in many pharmaceutically inter-
esting and potentially bioactive natural compounds.[1–7] Rep-
resentative examples range from the structurally simple and
bioactive heliannuol A,[2] pterulone,[3] and radulanin A[4] to
the architecturally challenging compounds edulisone A[5]
and ovafolinin B.[6] For this reason, the establishment of new
synthetic methods to construct this biologically important
class of compounds has received an immense amount of at-
tention.[1–7] The synthetic strategies toward functionalized
benzo[b]oxepines can be divided into two groups: manipula-
tion of a pre-existing oxygen-containing cyclic core or as-
sembly from acyclic precursors. Despite the advances made
through both these approaches, the development of new
synthetic methods to prepare this class of oxygen heterocy-
cles from readily available substrates and catalysts with se-
lective control of substitution patterns under mild and op-
erationally simplistic conditions remains desirable.
sis,[10–11] we reasoned that a strategy that made use of O-
propargylated salicylaldehydes in the presence of a Lewis
acid gold catalyst would hold promise as a new method for
benzo[b]oxepin-3ACTHNUTRGNEUNG(2H)-one synthesis. As part of an ongoing
program exploring the scope of gold catalysis in heterocyclic
synthesis,[9] our discovery that AuI complex 3 can effect
tandem intramolecular heterocyclization/Petasis–Ferrier re-
arrangement[12] of 2-(prop-2-ynyloxy)benzaldehydes is re-
ported herein (Scheme 1). This process provides a conven-
The emergence of gold complexes as powerful and versa-
ꢀ
tile Lewis acid catalysts that can mediate a plethora of C X
(X=C, N, O, S) bond formations has been well documented
in recent years.[8–10] Among this myriad of works, one nota-
ble innovation has been the formation of carbocycles and
heterocycles from cyclization of a carbonyl compound teth-
ered to an alkyne in the presence of a gold catalyst.[8,10] For
example, Yamamoto and Jin recently reported an efficient
synthetic route to fused tri- and tetracyclic enones based on
the AuCl3/AgSbF6-catalyzed tandem heteroenyne metathe-
sis/Nazarov cyclization of 1,3-enynyl ketones.[10b] On the
basis of this and other previous studies on carbonyl metathe-
Scheme 1. Gold(I)-catalyzed synthesis of benzo[b]oxepin-3ACHTUNGTRENNUNG(2H)-ones
from 2-(prop-2-ynyloxy)benzaldehydes. R1 =H, alkyl, aryl, halide, or
NO2; R2, R3 =H or alkyl.
ient synthetic route to benzo[b]oxepin-3ACTHUNRTGNEUNG(2H)-ones in 21–
99% yield for a wide variety of substrates under mild and
operationally simplistic conditions that did not require the
exclusion of air or moisture. A study that delineates the in-
fluence on reactivity of a substituent at the ortho position to
the ethereal moiety on the salicylaldehyde is also presented.
To the best of our knowledge, synthetic methods involving
metal-mediated cyclizations of propargylic aldehydes of type
1 have thus far been reported to typically give the benzopyr-
an product.[13]
[a] E. M. L. Sze, Dr. W. Rao, M. J. Koh, Prof. Dr. P. W. H. Chan
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax : (+65)6791-1961
We began by examining the cyclization of 1a by a variety
of Lewis and Brønsted acids to establish the optimal reac-
tion conditions (Table 1 and Table S1 in the Supporting In-
E-mail: waihong@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003096.
Chem. Eur. J. 2011, 17, 1437 – 1441
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1437

Table 1. Optimization of the reaction conditions.[a]
or near quantitative recovery of the starting material was
found. Importantly, the contrasting catalytic activity ob-
served for the reaction mediated by pTsOH·H2O also
proved that the cationic AuI complex is the catalytic species
(see Table S1 in the Supporting Information). In our hands,
only the analogous reactions of 1a mediated by 3 in MeNO2
or catalyzed by Ph3PAuCl/AgSbF6 afforded 2a in high yields
(90–92%, Table 1, entry 9 and Table S1 in the Supporting
Information). On the basis of the above results, reaction of
1a in the presence of 3 (5 mol%) and BnOH (1.2 equiv) in
CH2Cl2 at room temperature for 1 h and then pTsOH·H2O
(20 mol%) at 408C for 6 h under atmospheric conditions
provided the optimal conditions.
BnOH [equiv]
Solvent
Time[b] [h]
Yield [%][c]
1
2
2
1.2
1
2
2
–
–
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeNO2
1,4-dioxane
THF
1/6
1/6
1/6
1/6
6/6
1/6
1/6
1/–
24/6
5/–
5/–
2/6
91
99
97
77
2[d]
3[d]
4[d]
5[d,e]
6[f]
7
76
24[g]
37
8[h]
9
10
11
12
–
[i]
With the optimum conditions in hand, we next turned our
attention to exploring the scope of the present procedure
for a series of 2-(prop-2-ynyloxy)benzaldehydes and the re-
sults are summarized in Table 2. These experiments showed
90
[i]
2
2
2
–
–
[i]
PhMe
65
[a] All reactions were performed with a 20:1 ratio of 1a/catalyst at room
temperature followed by addition of pTsOH·H2O (20 mol%) at 408C.
[b] The first value indicates the initial reaction time and the second value
indicates the reaction time after the addition of pTsOH·H2O. [c] Isolated
yield. [d] Reaction conducted under atmospheric conditions. [e] Reaction
conducted with 3 (1 mol%). [f] Reaction conducted without pTsOH·H2O.
[g] Side product 4 was obtained in 71% yield. [h] Reaction conducted
Table 2. Tandem intramolecular heterocyclization/Petasis–Ferrier rear-
rangement of 1b–t catalyzed by 3.[a]
Substrate
Product
R
Yield [%][b]
1
2
3
I
Cl
F
tBu
NO2
Br
Cl
F
93
98
88
66
99
99
80
61
70
58
1
with CaSO4 (50 mg). [i] No reaction based on H NMR spectroscopic and
TLC analyses of the crude mixture.
4[c]
5[d]
6
7
8
9
10
11[e]
12[f]
formation). This study initially revealed that 1a treated with
3 (5 mol%) and benzyl alcohol (BnOH, 2 equiv) in CH2Cl2
at room temperature for 1 h followed by para-toluenesulfon-
ic acid (pTsOH·H2O, 20 mol%) at 408C for 6 h gave 2a in
91% yield (Table 1, entry 1). The structure of the benzo-
tBu
Ph
OMe 53
Me
52
ACHTUNGTRENNUNG[b]oxepin-3ACHTUNGTRENNUNG
(2H)-one product was determined by 1H NMR
13[f]
21
spectroscopy measurements and X-ray crystallographic anal-
ysis (see Figure S45 in the Supporting Information).[14] Our
studies subsequently showed that when the reaction was re-
peated under atmospheric conditions a further increase of
8% in product yield was achieved (Table 1, entry 2). A com-
parable increase in product yield was found when the
amount of BnOH was decreased from 2 to 1.2 equiv under
these latter conditions (Table 1, entry 3). However, lower
product yields (77 and 76%) were obtained when the cata-
lyst loading of 3 was reduced to 1 mol% or the amount of
BnOH was further decreased to 1 equiv (Table 1, entries 4
and 5). Removing pTsOH·H2O or BnOH from the reaction,
on the other hand, was found to lead to a marked decrease
in product yields as well as the isolation of 4[15] as a byprod-
uct in 71% yield in the absence of the Brønsted acid
(Table 1, entries 6 and 7). The introduction of CaSO4 to
remove water from the reaction was also found to have a
detrimental effect with no product detected by either TLC
14
15
Me
H
32
29
16[g]
17[c]
36
41
18[h]
62
58
19[h]
1
or H NMR spectroscopic analyses and recovery of the sub-
[a] All reactions were performed with a 20:1 ratio of 1/3 and BnOH
(1.2 equiv) at room temperature for 1 h followed by pTsOH·H2O
(20 mol%) at 408C for 6 h under atmospheric conditions. [b] Isolated
yield. [c] Reaction time of the first step=24 h. [d] Reaction time of the
first step=2 h. [e] Reaction time of the first step=1.5 h. [f] Reaction
time of the first step=5 h. [g] Reaction time of the first step=10 h.
[h] Reaction carried out in (CH2Cl)2 at 808C for 2 h.
strate in near quantitative yield (Table 1, entry 8). Similarly,
a one-step reaction at 408C for 6 h in other solvent systems
or Lewis and Brønsted acid catalysts did not improve the re-
sults (Table 1, entries 10–12 and Table S1 in the Supporting
Information). In these reactions, either lower product yields
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Heterocyclization of Benzaldehydes to Benzo[b]oxepines
COMMUNICATION
that with 3 as catalyst, salicylaldehydes 1b–t underwent the
heterocyclization/Petasis–Ferrier rearrangement process and
gave the corresponding benzo[b]oxepin-3ACTHUNRTGNEUNG(2H)-ones in 21–
99% yield. Notably, these cyclizations also demonstrated
that both the electronic and steric nature of the substrate
was found to play a pivotal role on reactivity. We found that
starting materials containing an electron-withdrawing group,
as in 1b–d and 1 f–i (Table 2, entries 1–3 and 5–8), required
shorter reaction times and afforded higher product yields
than their counterparts with an electron-donating group at
the same position (1e and 1j–m Table 2, entries 4 and 9–12).
Moreover, steric factors become more important and a dra-
matic enhancement in reactivity could be observed in sub-
strates in which R¼H at the position ortho to the ethereal
moiety (Table 2, entries 1–12) compared with substrates that
were unsubstituted at this position as in 1n–p (Table 2, en-
tries 13–15). In these reactions, the corresponding products
2b–m were received in 52–99% yield whereas 2n–p were af-
forded in 21–32% yield. In addition, the size and thus spa-
tial volume occupied by the ortho substituent was found to
contribute to the enhanced reactivity. An inspection of en-
tries 5–12 in Table 2 shows a gradual decrease in product
yields or that a longer reaction time is needed as the size of
the ortho substituent decreases on going from 1 f!1g!
1h!1i and 1j!1k!1l!1m, respectively. Similarly, a
moderate product yield was obtained when the conforma-
tionally restricted 2-naphthaldehyde adduct 1q was subject-
ed to the standard conditions (Table 2, entry 16). In addi-
tion, reactions of 1r, 1s, and 1t, which contain either a
methyl group at the propargylic carbon center or a pendant
internal alkyne moiety, were initially found to give low
product yields (21–28%) under the standard conditions. Ef-
ficient transformation to the products in 41–62% yield was
only achieved when these cyclizations were repeated at a re-
action temperature of 808C (Table 2, entries 17–19).
Scheme 2. Tandem intramolecular heterocyclization/Petasis–Ferrier rear-
rangement of 18O-labeled 1a catalyzed by 3.
catalytic activity was observed when the reaction was con-
ducted in the absence of BnOH and near quantitative recov-
ery of 1a was achieved when the reaction was repeated
under inert conditions (Table 1, entries 6 and 7). Added to
this was the higher product yields obtained and the shorter
reaction times required for the cyclization of substrates with
a
pendant electron-withdrawing group (Table 2), which
would be consistent with typical reactivities found in a hemi-
acetal-forming step.
Although highly speculative, the above results lead us to
tentatively propose the mechanism depicted in Scheme 3 for
the reaction of 1a. This could involve formation of the hem-
The competitive formation of 4 for the cyclization of 1a
in the absence of pTsOH·H2O mentioned earlier (Table 1,
entry 6) led us to speculate on the possible involvement of
this compound as an intermediate in the reaction. Although
not isolated, a side product similar to 4, which was observed
by TLC analysis in all the reactions described in Table 2 and
disappeared on addition of the Brønsted acid, provides addi-
tional support to this hypothesis.[16]
The beneficial effect of adding BnOH prompted us to
also consider a reaction involving an intermediate that con-
tains a hemiacetal moiety, particularly given the presence of
the Lewis acid. To support this hypothesis as well as to gain
a better understanding of the reaction mechanism, we con-
ducted an 18O-labeling experiment. Treating a solution of 1a
with an 18O content of 50% in CH2Cl2 with 3 (5 mol%)
under the conditions shown in Scheme 2 gave 2a in 51%
yield and with an 18O content of 43% incorporated at the
ketone moiety, as determined by HRMS analysis of the
crude mixture (see the Supporting Information for details).
It is worth noting that the possible involvement of a hemi-
acetal intermediate in the catalytic cycle is also evident in a
number of experiments examined in this work. First, lower
Scheme 3. Tentative mechanism for the tandem intramolecular heterocyc-
lization/Petasis–Ferrier rearrangement of 1a catalyzed by 3.
iacetal A resulting from a nucleophilic addition of BnOH to
the carbonyl moiety of the propargylic aldehyde in the pres-
ence of the Lewis acid. It is possible that activation of the
alkyne bond of this newly formed hemiacetal intermediate
due to coordination to the alkynophilic gold catalyst triggers
7-exo-dig intramolecular cyclization and formation of the
benzo[e]ACTHNUTRGNE[UNG 1,4]dioxepine-substituted vinyl gold species B. Sub-
sequent Petasis–Ferrier rearrangement[12] involving cyclore-
version to give the enolic gold adduct C followed by intra-
molecular cyclization would provide the aurated benzo[-
b]oxepin-3ACTHNUGTRNEUNG(2H)-one complex D. A final debenzoxylative
deauration or protodeauration followed by debenzoxylation
step would then deliver 2a. The competitive formation of 4
supports the fact that the latter of these two possible deaur-
ative processes is the more likely or facile path given our
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1439

P. W. H. Chan et al.
earlier studies showing that the role of pTsOH·H2O was
solely confined to promoting debenzoxylation and regenera-
tion of the alcohol. We surmise the remarkable enhance-
ment in reactivity (noted in Table 2 for substrates such as
1a), which increases as the size of the ortho substituent in-
creases, could be due the preferred conformation shown in
Scheme 3. In doing so, unfavorable steric interactions be-
tween the alkyne and the bulkier of the two ortho groups in
the substrate can be kept to a minimum. It is possible that
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Experimental Section
BnOH (0.36 mmol) was added to an open round-bottomed flask contain-
ing 1 (0.3 mmol) and 3 (15 mmol) in CH2Cl2 (3 mL). The reaction mixture
was then stirred at room temperature until complete consumption of the
starting material, based on TLC analysis. At this point, pTsOH·H2O
(0.06 mmol) was added to the reaction mixture, which was then heated at
408C for 6 h. On cooling to room temperature, the solvent was removed
under reduced pressure. The resulting crude mixture was purified by
flash column chromatography on silica gel (eluent: n-hexane/EtOAc
(9:1)) to give benzo[b]oxepin-3ACTHNUTRGNEU(GN 2H)-one.
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Acknowledgements
This work is supported by a College of Science Start-Up Grant from Na-
nyang Technological University (NTU) and Science and Engineering Re-
search Council Grant (0921010053) from A*STAR, Singapore. An Un-
dergraduate Research Experience on Campus stipend (to M.J.K.) from
NTU is also gratefully acknowledged.
Keywords: aldehydes · cyclization · gold · homogeneous
catalysis · steric hindrance
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Heterocyclization of Benzaldehydes to Benzo[b]oxepines
COMMUNICATION
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[14] CCDC-792236 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[15] CCDC-792237 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[16] The possible involvement of 4 as an intermediate in the reaction
was further supported by the following control experiment: Treat-
ment of 4 with of pTsOH·H2O (20 mol%) in CH2Cl2 at 408C for 6 h
afforded 2a in 99% yield.
[11] For leading examples of carbonyl metathesis mediated by other
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Received: October 17, 2010
Published online: January 12, 2011
Chem. Eur. J. 2011, 17, 1437 – 1441
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