Ligand- and Br?nsted acid/base-switchable reaction pathways in gold(i)-catalyzed cycloisomerizations of allenoic acids

Article abstract of DOI:10.1039/c4ob02640c

Gold-promoted cyclizations of 2,2-diaryl substituted γ-allenoic acids were found to give three isomeric lactone products, each of which could be obtained selectively by exploiting Br?nsted acid/base and ligand effects. Simple 5-exo-trig cyclization products were favored by strong donor ligands or base additives, whereas weak donor ligands and a Br?nsted acid additive gave isomeric enelactones resulting from double bond migration. Further optimization afforded a class of medicinally relevant bridged tricyclic lactones via a tandem hydroacyloxylation/hydroarylation process. Kinetic studies and control experiments indicated that the initial 5-exo-trig cyclization product serves as a branch point for further isomerization to the other lactone products via cooperative gold(i)/Br?nsted acid catalysis. This journal is

Full text of DOI:10.1039/c4ob02640c

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Ligand- and Brønsted acid/base-switchable
reaction pathways in gold(I)-catalyzed
cycloisomerizations of allenoic acids†
Cite this: Org. Biomol. Chem., 2015,
13, 3936
Sachin Handa,a Sri S. Subramanium,a Aaron A. Ruch,a,b Joseph M. Tanskic and
LeGrande M. Slaughter*a,b
Gold-promoted cyclizations of 2,2-diaryl substituted γ-allenoic acids were found to give three isomeric
lactone products, each of which could be obtained selectively by exploiting Brønsted acid/base and
ligand effects. Simple 5-exo-trig cyclization products were favored by strong donor ligands or base addi-
tives, whereas weak donor ligands and a Brønsted acid additive gave isomeric enelactones resulting from
double bond migration. Further optimization afforded a class of medicinally relevant bridged tricyclic lac-
tones via a tandem hydroacyloxylation/hydroarylation process. Kinetic studies and control experiments
indicated that the initial 5-exo-trig cyclization product serves as a branch point for further isomerization
to the other lactone products via cooperative gold(I)/Brønsted acid catalysis.
Received 20th December 2014,
Accepted 13th February 2015
DOI: 10.1039/c4ob02640c
www.rsc.org/obc
latter can involve cascade reactions, in which gold-catalyzed
steps are followed by Brønsted acid catalysis,9 or may result
Introduction
Gold(I) complexes catalyze a diverse array of transformations from AuI-assisted Brønsted acid catalysis.10 Brønsted acid can
initiated by π-electrophilic activation of alkynes, allenes, and also serve to generate active gold(I) species when basic anionic
alkenes toward attack by heteroatom or carbon-based nucleo- ligands are present.11 It is important to identify and control
philes.1 Although applications of gold catalysis in the synthesis these various Brønsted acid effects on gold catalysis in order to
of complex natural products have begun to appear,2 wider maximize catalyst efficiency and to enable optimization of
adoption may be hindered by the mechanistic intricacy of potentially competing reaction pathways.
these processes, which limits predictive ability.3,4 Gold-
Gold-catalyzed cycloisomerizations of alkynes12 and allenes13,14
mediated reactions can often evolve along divergent mechanis- containing pendent carboxylic acids as internal nucleophiles
tic pathways that are sensitive to ligand effects, substrate struc- have been relatively little investigated15 in comparison to
ture, or reaction conditions.5 Furthermore, there is much related intramolecular hydrofunctionalizations involving
evidence that Brønsted acid—either deliberately introduced or amines and alcohols.16 In particular, only three limited
generated in situ from the nucleophile—can significantly affect reports of gold-catalyzed hydroacyloxylations of allenoic acids
the outcomes of gold-catalyzed transformations.6 Several appeared prior to our study, each of them utilizing the same
reports have indicated enhanced rates and/or yields in gold- single substrate, which contains an unsubstituted –CH2CH2–
catalyzed reactions with added Brønsted acid, presumably due linkage between the allene and the carboxylic acid.13,17 In
to accelerated protodeauration.7 In other cases, added one study, bimetallic diphosphine gold(I)/chiral silver phos-
Brønsted acid changes the reaction stereoselectivity8 or opens phate catalyst systems were employed to achieve varying
new reaction pathways that do not occur with gold alone. The degrees of enantioselectivity.13a,18 More recently, it was
reported that chiral silver(I) phosphate salts alone are effective
catalysts for cyclizations of four γ-allenoic acids bearing
geminal diphenyl groups adjacent to the carboxylic acid,
even at room temperature.15d In these prior reports, only the
γ-lactones resulting from simple 5-exo-trig cyclization were
observed.
With a goal of developing modular routes to lactones that
could form the cores of medicinally relevant organic mole-
cules,19 we examined gold-catalyzed cycloisomerizations of 2,2-
diaryl allenoic acids using an expanded series from this known
aDepartment of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078,
USA
bDepartment of Chemistry, University of North Texas, 1155 Union Circle #305070,
Denton, Texas 76203, USA. E-mail: legrande@unt.edu
cDepartment of Chemistry, Vassar College, Poughkeepsie, New York 12604, USA
†Electronic supplementary information (ESI) available: Synthetic procedures for
allenoic acid substrates; crystal data for compounds 2a, 4a, and 9; kinetic plots;
copies of 1H and 13C NMR spectra. CCDC 997310–997312. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4ob02640c
3936 | Org. Biomol. Chem., 2015, 13, 3936–3949
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substrate class.15d,20,21 A special goal was to identify and opti-
mize any products resulting from alternative reaction path-
ways. A few reports have shown that different cyclization
products can be obtained in some types of intramolecular
allene hydrofunctionalizations upon changing the catalytic
metal.22 We hypothesized that ligand effects could be utilized
to achieve similar results with allenoic acids, given literature
precedent for ligand control of regioselectivities in some
related gold-catalyzed cycloisomerizations of functionalized
alkynes5a–c,23 and allenes24 involving internal nucleophiles
other than carboxylic acids. During these studies, we found
that gold-catalyzed cyclizations of several 2,2-diaryl-substituted
γ-allenoic acids lead to three isomeric lactone products, each
of which can be selected by exploiting Brønsted acid/base
effects in combination with ligand effects. One product is a
tricyclic δ-lactone resulting from an unprecedented tandem
hydroacyloxylation/hydroarylation process. Evidence of co-
operativity between AuI and Brønsted acid has been found in two
of the catalytic reaction pathways.
Table 1 Ligand and counterion effects on product distribution in cata-
lytic cycloisomerizations of allenoic acid 1aa
Yield 2ab Yield 3ab Yield 4ac
Entry
L
X−
t (h) (%)
(%)
(%)
1d
2d
3d
4d
5d
6e
PPh3
SbF6−
SbF6−
SbF6−
SbF6−
4.0
5.0
6.0
3.0
4.0
4.0
6.0
4.5
67
58
83
88
2
<2
10
92
40
—
29
31
7
<2
70
63
60
5
—
—
—
—
20
30
12
0
−
5
6
7
P(OPh)3 SbF6−
P(OPh)3 SbF6
P(OPh)3 OTf−
7e
8e
P(OPh)3 NTf2
− f
9e
P(OPh)3 BArF − g 7.0
45
50
0
45
4
10e
P(OPh)3 BF4
3.5
−
Results and discussion
During an initial screen of in situ-generated cationic AuI com-
plexes bearing common ancillary ligands in the catalytic
cycloisomerization of known 2,2-diphenyl γ-allenoic acid sub-
strate 1a,15d two additional products were observed alongside
the expected 5-exo-trig cyclization product 2a (Table 1). Cata-
lysts containing PPh3 or CyJohnPhos (5) afforded 2a as the
major product, along with ∼30% yields of the double bond iso-
merized enelactone 3a (entries 1,2), which has not been pre-
viously reported. Switching to the more strongly donating
N-heterocyclic carbene ligands IMes (6) and SIMes (7) nearly
eliminated the isomerized product and provided improved
yields of 2a (entries 3,4). The structure of 2a was confirmed by
X-ray diffraction analysis,† and the structure of 3a was
assigned on the basis of 1H–13C 2D NMR correlation spec-
troscopy (HMQC and HMBC; see the ESI†).
a Reaction conditions: 1a (0.30 mmol), LAuCl (5 mol%), AgX (5 mol%),
solvent (2.0 mL). b 2a and 3a obtained as an inseparable mixture; ratio
1
determined by H NMR. c Isolated yield. d In CH2Cl2 at 45 °C. e In DCE
at 65 °C. f LiNTf2 was used. g BArF − = tetrakis[3,5-bis(trifluoromethyl)-
4
phenyl]borate.
Fig. 1 X-ray crystal structure of 4a with 50% probability ellipsoids. A
second, crystallographically independent molecule with a nearly identi-
cal conformation is also present in the asymmetric unit.
When poorly donating P(OPh)3 was used as a ligand, for-
mation of 2a was substantially reduced, and a third product
was observed in addition to 3a (Table 1, entry 5). The H NMR
1
spectrum of this compound showed an absence of olefinic
protons, and X-ray crystallography revealed it to be tricyclic
δ-lactone 4a (Fig. 1),† which arises from an apparent tandem (entry 10), so the combination of (PhO)3PAuCl (8) and AgBF4
hydroacyloxylation/hydroarylation process. Although several was selected for further optimization.
metal-catalyzed tandem reactions that combine heteroatom
Given the acidic functional group of allenoic acid 1a, we
addition to a carbon–carbon π-bond with hydroarylation have hypothesized that protons might play an important role in the
been reported,25 such reactions have rarely afforded bridged reaction pathways leading to 3a and 4a. Therefore, we exam-
ring structures,25e,f and there are no examples involving car- ined the effects of co-catalytic amounts of Brønsted base
boxylic acid nucleophiles.26,27 Furthermore, the tricyclic (NEt3) or Brønsted acid (p-toluene sulfonic acid hydrate,
lactone core of 4a is found in the bioactive natural product car- TsOH·H2O) on the product distribution (Table 2). Addition of
nosol,28 suggesting that this tandem cyclization process could 5 mol% NEt3 completely suppressed the formation of 3a and
have value in medicinal chemistry.29 A screen of silver salt acti- 4a and afforded near quantitative yields of 2a (Table 2, entry
vators (entries 6–10) revealed that replacing the SbF6− counter- 1), although higher amounts of base resulted in a lower yield
−
ion with BF4 increased the yield of 4a to 45% at 65 °C (entry 2). By contrast, increasing amounts of TsOH·H2O led to
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Table 2 Brønsted acid/base effects on product distribution in catalytic
cycloisomerizations of allenoic acid 1aa
Yield 2ab Yield 3ab Yield 4ac
Entry Additive
t (h) (%)
(%)
(%)
1d
2d
3f
4f
5f
NEt3 (5 mol%)e
3.0
8.0
4.0
95
65
86
61
—
—
—
7
31
93
—
—
—
—
—
NEt3 (20 mol%)e
TsOH·H2O (5 mol%)
TsOH·H2O (20 mol%) 4.0
TsOH·H2O (20 mol%) 24
a Reaction conditions: 1a (0.30 mmol), (PhO)3PAuCl (5 mol%), AgBF4
(5 mol%), solvent (2.0 mL), 45 °C. b 2a and 3a obtained as an
inseparable mixture; ratio determined by 1H NMR. c Isolated yield.
d In CH2Cl2. e NEt3 added as a 1.0 M stock solution in DCE. f In DCE.
correspondingly higher quantities of isomerized enelactone 3a
(entries 3,4) while still disfavoring formation of 4a. With
20 mol% TsOH·H2O and 5 mol% 8/AgBF4 at extended reaction
times, 3a was obtained exclusively in 93% yield (entry 5).
In order to gain further insights into the effects of Brønsted
acid and base additives on gold-catalyzed cycloisomerizations
of 1a, the rates of these reactions were studied under various
conditions (Table 3). For these experiments, a pre-activated cat-
ionic gold catalyst, nominally formulated as [(PhO)3PAu]BF4
(u[Au]),30 was generated in situ by treating 8 with AgBF4 in
DCE, followed by filtration of residual silver salts to preclude
any background catalysis by AgI.15d Monitoring of reaction pro-
ducts over time by 1H NMR spectroscopy revealed complete
conversion of 1a to 2a within 2 min at 45 °C in the presence of
Fig. 2 Product concentrations versus time for the catalytic cycloiso-
merization of 1a with 5 mol% cationic [Au] plus 20 mol% TsOH·H2O:
(a) first five minutes; (b) over 24 h.
5 mol% [Au], either with or without 20 mol% TsOH·H2O
added. Subsequently, 2a was transformed into 3a at a signifi-
cantly faster rate [0.39(6) mM min−1] with 5 mol% gold catalyst
plus 20 mol% TsOH·H2O than with gold catalyst alone [0.04(5)
mM min−1] (Table 3, entries 1,2).31 Fig. 2 illustrates the rapid
initial formation of 2a, followed by slow isomerization to 3a,
for the reaction involving gold catalyst plus added TsOH·H2O.
A control experiment with 20 mol% TsOH·H2O in the absence
of [Au] (Table 3, entry 3) showed that purely acid-catalyzed for-
mation of 2a (60 min for completion) and 3a [0.20(1) mM
min−1] also occurs, but at significantly slower rates. In
addition, isolation of products from the Brønsted acid-cata-
lyzed reaction (20 mol% TsOH·H2O), using conditions identi-
cal to those used for the gold-catalyzed reactions listed in
Table 2, revealed incomplete conversion to 3a even after 24 h
(14% and 80% respective yields of 2a and 3a). Addition of NEt3
to the cationic [Au] catalyst slowed the formation of 2a con-
siderably but led to no observable 3a (entry 4), consistent with
the clean formation of 2a achieved with added NEt3 in the
optimization studies (Table 2).
Table 3 Measured initial rates of formation of 2a and 3a, starting from
1aa
Initial rate
of formation
(mM min−1
)
An additional concern was the possible role of silver in
these catalytic processes, given that cycloisomerizations of 1a
and three similar allenoic acids were reported to be facile with
AgI phosphate salts as catalysts.15d An experiment utilizing
5 mol% [Au] catalyst and 20 mol% TsOH, but without removal
of the AgCl formed upon catalyst pre-activation (Table 3,
entry 5), revealed a somewhat higher rate for formation of 3a
[0.51(8) mM min−1] compared with the corresponding reaction
in which AgCl was filtered off (Table 3, entry 2). Thus, back-
ground catalysis by heterogeneous silver salt apparently con-
tributes to, but does not dominate, the isomerization pathway
leading to 3a. AgBF4 alone (5 mol%, entry 6) catalyzed the
Entry
Au catalystb
Additive
2a
3ac
1
2
3
4
5
5 mol% [Au]
5 mol% [Au]
—
5 mol% [Au]
5 mol% 8
None
>100d
>100d
11.4(7)
17.5(2)
>100d
0.04(5)
0.39(6)
0.20(1)
—
TsOHe (20 mol%)
TsOHe (20 mol%)
NEt3 (5 mol%)
TsOHe (20 mol%),
AgBF4 (5 mol%)f
AgBF4 (5 mol%)
0.51(8)
6
—
6.6(2)
—
a Reaction conditions: 1a (0.30 mmol), DCE (1.5 mL), 45 °C.
b Preactivated gold catalyst [Au] was prepared by reaction of 8 with
AgBF4, followed by removal of AgCl by filtration. c Rate measurement
began after formation of 2a was complete. d Formation of 2a was
complete within 2 min. e TsOH·H2O used. f AgCl was not filtered off.
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Table 4 Measured initial rates of formation of 3a, starting from 2aa
Initial rate of
3a formation
Entry
Au catalystb
Additive
(mM min−1
)
1
2
3
4
5 mol% [Au]
—
5 mol% [Au]
—
TsOH (20 mol%)
TsOH (20 mol%)
none
TsOH (20 mol%), AgBF4
(5 mol%)
0.88(2)
0.26(1)
0.002(1)
0.23(1)
a Reaction conditions: DCE, 2a (0.18 M), 45 °C. b Preactivated gold
catalyst [Au] was prepared by reaction of 8 with AgBF4, followed by
removal of AgCl by filtration.
cyclization of 1a to 2a more slowly than 20 mol% Brønsted
acid (entry 3) and did not catalyze further isomerization to 3a.
Given the apparent intermediacy of 2a in the formation of
3a from 1a, further kinetic studies examined the rate of iso-
merization of purified 2a to 3a under catalytic conditions
(Table 4). Conversion of 2a to 3a occurred at a relatively fast
rate with 5 mol% cationic [Au] plus 20 mol% TsOH [0.88(2)
mM min−1] (entry 1), whereas the Brønsted acid-catalyzed
reaction with 20 mol% TsOH alone was substantially slower
[0.26(1) mM min−1] (entry 2). The higher rate for formation of 3a
from 2a (Table 4, entry 1) versus 1a (Table 3, entry 2) under the
same conditions was postulated to reflect partial catalyst de-
activation or decomposition in the reaction starting from 1a.
With 5 mol% [Au] and no added acid, the transformation of 2a
to 3a barely occurred (entry 3), affording less than a 3% yield
of 3a after 24 h. These experiments suggest a mechanistic
scenario in which cooperative gold/Brønsted acid catalysis is
required for efficient formation of 3a, subsequent to the initial
cycloisomerization of 1a to 2a. Notably, the TsOH-catalyzed
isomerization of 2a to 3a was not faster in the presence of
AgBF4 (entry 4), indicating that this type of cooperativity appar-
ently does not extend to homogeneous AgI catalysts.
Scheme 1 Selective catalytic 5-exo-trig cyclizations of allenoic acids
1a–k to enelactones 2a–k.
The ability to select competing pathways to two isomeric
lactone products by addition of simple acid/base additives is
notable, given that only nonisomerized enelactones such as 2a
were obtained in previous studies of metal-catalyzed γ-allenoic
acid cyclizations.13a–c,15d,32 Double bond isomerizations have
been previously reported to occur in conjunction with AuI-pro-
moted nucleophilic additions to alkenes,33 dienes,10a and
alkynes,34 but cooperativity between gold and Brønsted acid in
these reactions has only rarely been investigated.10a These
observations enabled us to formulate general conditions for
the selective synthesis of either nonisomerized or double bond
Scheme 2 Selective catalytic synthesis of double-bond isomerized
enelactones 3a–i,k. a 20 mol% TsOH·H2O. b 5 mol% TsOH·H2O.
isomerized enelactones, in synthetically useful yields, for a isomerization process (2a–k, Scheme 1). Addition of 20 mol%
family of allenoic acids containing differently sized carbocycles TsOH·H2O (5 mol% was sufficient for cyclopentylidene sub-
at the allene terminus and/or chlorine- or oxygen-substituted strates 1b,e,g,i) facilitated selective formation of the isomer-
2-aryl groups (Schemes 1 and 2). Enelactones of type 2 were ized analogues of type 3, although extended reaction times of
cleanly obtained by adding 5 mol% NEt3 to the 8/AgBF4 12 h were needed to obtain optimal yields (3a–i and 3k,
catalyst system, which effectively suppressed the double-bond Scheme 2). Substrate 1j (R = Me, Ar = Ph) did not afford a
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Table 5 Isomerizations of 1a and 2a with catalytic Brønsted acida
Yield 2ac
(%)
Yield 3ac
(%)
Yield 4ad
(%)
Scheme 3 Gold-catalyzed isomerization of 2a at 75 °C, showing iso-
lated yields. No 2a was recovered; the remaining mass balance reflects Entry
sm
HAb
decomposition to unidentifiable material.
1
2
3
4
5
6
7
8
9
2a
1a
2a
1a
2a
1a
1a
1a
1a
1a
2a
TsOH·H2O
HBF4(aq)e
HBF4(aq)e
—
63
56f
—
—
—
—
—
—
—
—
91
26
34
84
81
85
86
91
—
—
—
—
—
—
9
11
—
—
—
52
37
59
g
HBF4·OEt2 g
double bond isomerized product of type 3 due to the lack of a
HBF4·OEt2
ring that could host a thermodynamically favored internal
alkene. Notably, products 2 and 3 could not be chromato-
graphically separated for substrates 1a–i,k, reinforcing the
importance of selective catalytic routes to the two distinct
isomers.
TfOH (1 mol%)
TfOH (5 mol%)
TfOH (10 mol%)
TfOH (20 mol%)
TfOH (50 mol%)
TfOH (20 mol%)
10
11
As no products of hydroarylation without lactonization were
observed with 1a, we hypothesized that the formation of tri-
cyclic lactone 4a might occur via the intermediacy of hydroacyl-
oxylation products 2a and/or 3a. Subjecting a purified sample
of enelactone 2a to the preactivated [Au] catalyst at an elevated
temperature of 75 °C in DCE for 16 h afforded a substantial
amount of 4a (29% isolated yield), in addition to a 55% yield
of 3a (Scheme 3). Submission of 3a to the same catalytic con-
ditions resulted in no detectable formation of 4a; 1H NMR ana-
lysis of the product mixture indicated 88% recovery of
unreacted 3a, with only a trace (<1%) of 2a present. Thus, 4a is
likely formed via the intermediacy of 2a.
Although the transformation of 2a into 4a represents a
formal alkene hydroarylation, it seems unlikely that this
occurs via AuI-based carbophilic activation of the carbon–
carbon double bond toward arene attack, given the geometric
constraints imposed by the five-membered lactone ring of 2a
and the scant literature precedent for such a reaction.35 Gold-
catalyzed additions of arenes to nonconjugated alkenes are
rare and mostly limited to examples involving electron-rich
aromatic rings.36 Furthermore, a closely related tricyclic ether
was reported to form upon heating an analogous allenol with
20 mol% TsOH·H2O or TfOH,37 suggesting that Brønsted acid
catalysis may also be important in the formation of 4a.38
Therefore, we examined reactions of 1a and 2a with catalytic
amounts of Brønsted acids at 75 °C (Table 5). No formation of
4a was observed with either TsOH·H2O or aqueous HBF4, and
conversion to 3a was not complete with the latter (entries 1–3).
However, HBF4·OEt2 led to small amounts of 4a (entries 4,5),
and 4a was the only product obtained when the stronger
Brønsted acid TfOH was employed, although yields were still Entry
a Reaction conditions: 1a or 2a (0.30 mmol), DCE (2.0 mL), 75 °C, 16 h.
b 20 mol% HA, except as noted. c 2a and 3a obtained as an inseparable
mixture; ratio determined by 1H NMR. d Isolated yield. e 48 wt% HBF4.
f Unreacted 2a recovered. g 51–57 wt% HBF4.
Because efficient formation of 4a under purely Brønsted
acid catalysis was elusive, we developed an alternative AuI-pro-
moted procedure involving an initial low-temperature incu-
bation period followed by heating at 75 °C. A −20 °C
incubation temperature proved optimal (Table 6). We postulate
that the low temperature step suppresses catalyst deactivation
processes while allowing buildup of a small steady-state con-
centration of strong Brønsted acid, equivalent to unsolvated
HBF4 (pKa ∼ −10.3 in DCE39). TfOH is a reasonable surrogate
for this putative Brønsted acid given its similarly low pKa in
DCE (∼−11.4).39 Notably, a 20 mol% loading of TfOH was
found to be optimal with no gold catalyst present (Table 5,
Table 6 Optimization of gold-promoted formation of tricyclic lactone 4aa
Incubation
temp (° C)
Yield 2a
(%)
Yield 3ab
(%)
Yield 4ab
(%)
modest (entries 9,11). The similar yields of 4a obtained from
both 1a and 2a using 20 mol% HBF4·OEt2 (entries 4,5) or
TfOH (entries 9,11) as the catalyst further support the interme-
diacy of 2a in this reaction. These results lead to the con-
clusion that a very strong Brønsted acid, at least as strong as
[HOEt2]+ (pKa ≤ −3.6), is required to achieve formation of 4a.
1
2
3
25 °C
0 °C
−20 °C
—
—
—
80
60
18
12
37
80
a Reaction conditions: 5 mol% cationic [Au] (prepared in situ from 8 +
AgBF4 followed by filtration), 1a (0.30 mmol), DCE (2.0 mL). b Isolated
yield.
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Scheme 5 Double hydroarylation of allenoic acid 1k.
Scheme 4 Synthesis of tandem hydroacyloxylation/hydroarylation pro-
ducts 4: Optimized conditions versus TfOH-catalyzed conditions.
a 5 mol% cationic [Au], DCE, 2–8 h at −20 °C, then 3–7 h at 75 °C.
b 20 mol% TfOH, DCE, 75 °C, 16 h. c NMR yield; inseparable mixture with
2f (2%) and 3f (93%). d No 4g obtained.
Fig. 3 X-ray crystal structure of 9 with 50% probability ellipsoids. The
phenyl group (C17–C22) is disordered, with only the major orientation
shown.
entries 6–10), whereas the maximum Brønsted acid con-
centration that can be formed in the incubation phase of the
gold-promoted process is 5 mol%. The improved yields of 4a
Fig. 3).† Although similar double intramolecular hydroaryla-
tions of allenes have been reported using Bi(OTf)3 as a cata-
obtained under the latter conditions, despite the lower concen- lyst,40 we are not aware of any precedent for this
tration of Brønsted acid, suggest that the optimal reaction con-
ditions involve cooperative gold/Brønsted acid catalysis rather
than purely Brønsted acid catalysis that is initiated by gold.38
The optimized protocol (Method A, Scheme 4) afforded
good yields of tricyclic lactones from allenoic acids 1a–c,
transformation involving transition metal catalysts. The tetra-
cyclic core of 9 is found in a class of bioactive terpenoid
quinone methides,41 highlighting the potential synthetic value
of this cycloisomerization.
To account for the combined effects of ligand and Brønsted
demonstrating that the gold/Brønsted acid-catalyzed tandem acid in allenoic acid cyclizations, we propose the mechanistic
process is potentially generalizable, at least with unsubstituted
phenyl groups present. However, substrates with an inflexible
scenario depicted in Scheme 6. Lactone 2 is generated rapidly
from 1 by a gold-mediated oxygen addition/protodeauration
xanthene moiety in place of 2,2-diaryl substituents (1h,i) were sequence (Path A) and remains as the major product in the
unable to undergo hydroarylation, and most others with func-
absence of a suitably activating ligand and/or added proton
tionalized aryls (1d–g) gave only varying amounts of 3 but no
source. Isomerization of 2 to 3 occurs via carbocation for-
isolable 4 under these conditions, suggesting high sensitivity mation and H+ elimination, following attack on the alkene by
Brønsted acid or electrophilic [L-Au]+ (Path B).42 The synergis-
to the aryl group substitution pattern in this transformation.
An alternative, gold-free protocol using 20 mol% TfOH as the
tic effect of TsOH with gold on the rate of isomerization to 3
catalyst (Method B) provided substantially poorer yields of 4 in may result from Lewis acid activation of the Brønsted acid,10
accelerated protodeauration with higher H+ concentration, or
most cases (4a–4c, Scheme 4). However, this method gave isol-
able tricyclic lactone in two cases in which the gold-based
both. With sufficiently strong Brønsted acid present (pKa
≤
system was ineffective (4f, 4g), albeit in modest yields, indicat- −3.6), protonation of the lactone can compete kinetically with
ing that the simple Brønsted acid catalyst is complementary to
the gold-based system for some substrate types.
alkene activation, shifting the reaction manifold toward
tandem hydroacyloxylation/hydroarylation (Path C). A plausible
Whereas hydroarylation is accompanied by oxygen addition mechanism43 involves elimination from the protonated
lactone44 to yield a diene, which in turn is protonated or
in the formation of tricyclic lactones 4a–c,f,g, the behavior of
unsymmetrically substituted allenoic acid 1k shows that the
aurated to yield an allylic carbocation that can undergo attack
hydroacyloxylation step can be bypassed when suitably located by an aryl group.45 Further reaction of H+ or LAu+ with the
resonance donor groups are present. Under conditions that
gave 4 with other allenoic acids, 1k yielded a tetracyclic acid 9
resulting 1,4-dihydronaphthalene derivative, followed by a 1,2-
hydride shift and attack of oxygen on the tertiary carbocation,
resulting from an apparent double hydroarylation occurring in furnishes the tricyclic lactone product 4. The increased electro-
philicity of AuI resulting from weak ligand donicity is important
tandem with double bond isomerization (Scheme 5 and
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Scheme 7 Possible mechanisms for the formation of 9 (Ar’ = 3-MeO-
C6H4).
pathways leading to products 2–4 (Scheme 7). The reaction
could begin with acid-promoted ring opening of the intermedi-
ate lactone 2k in a mechanism similar to Path C (a, Scheme 7),
but with the resulting diene undergoing protonation/auration
at the less substituted end. This would give a different allyl
cation that could undergo attack by the 3-methoxylphenyl
group to yield a five-membered ring. Alternatively, 2k could
revert to 1k upon heating (b, Scheme 7), followed by either
gold-mediated 5-exo-trig hydroarylation or protonation at the
central allene carbon and aryl attack at the resulting allylic
cation. Either mechanistic pathway (a or b) would be followed
by proton- or gold-mediated isomerization of the remaining
carbon–carbon double bond (similarly to Path B) and a second
hydroarylation to complete the tetracyclic structure. Although
these mechanistic pathways are speculative, they both account
for the formation of a five-membered carbocycle in 9, in con-
trast to the six-membered ring resulting from hydroarylation
in tricyclic lactones 4. The presence of a resonance donor
methoxy group at the aryl 3-position is of 1k is clearly impor-
tant in promoting the initial 5-exo-trig hydroarylation, given
that similar reactivity was not observed for 1f and 1g, which
contain donor groups at the 4-position.
Scheme 6 Mechanistic rationale for competing reaction pathways of
allenoic acids.
in both Paths B and C, manifesting the isolobal relationship
of LAu+ to H+.46 However, an additional role of P(OPh)3 in pro-
moting Path C is evidently to slow the protodeauration of the
organogold species formed upon initial cyclization of 1a,47
thereby leading to a controlled buildup of very strong Brønsted
acid (equivalent to unsolvated HBF4) that is a key cocatalyst in
this reaction pathway. Added NEt3 suppresses Paths B and C
due to the key role of protons in both mechanisms.
Path C differs from the mechanism proposed for a similar
acid-catalyzed isomerization of a γ-allenol, in which the inter-
mediacy of the 5-exo-trig cyclization product was not con-
sidered.37 We cannot rule out an alternative mechanism in
which the initial cyclization product 2 reverts to allenoic acid 1
at elevated temperature, followed by gold-promoted 6-endo-dig
hydroarylation, H+ attack at the remaining double bond, and
trapping of the resulting carbocation by the carboxylic acid.
However, this would involve a typically disfavored initial attack
at the central allene carbon,16a and no evidence for reversibil-
ity in the conversion of 1 to 2 has been observed.48 In addition,
the presence of a bulky L-Au group as “E” in the proposed
Conclusions
allylic
cation
intermediate
preceding
hydroarylation
(Scheme 6) could explain the failure of the larger aryl groups
in substrates 1f and 1g to yield tricyclic lactones under gold-
promoted conditions (Method A, Scheme 4), despite giving
modest yields of the hydroarylation products under purely
Brønsted acid catalysis (Method B).
To explain the formation of the unexpected double hydro-
arylation product 9 with substrate 1k (Scheme 5), we postulate
two mechanistic scenarios that share some features with the
In summary, ligand and Brønsted acid/base effects can be
exploited in concert to selectively switch between three iso-
meric products in AuI-catalyzed cyclizations of 2,2-diaryl alle-
noic acids, albeit with limited substrate scope in the case of
the tandem hydroacyloxylation/hydroarylation process. The
kinetically favored enelactone product 2 serves as a divergence
point for distinct mechanistic pathways leading to either
alkene isomerization product 3 or bridged tricyclic lactone 4,
3942 | Org. Biomol. Chem., 2015, 13, 3936–3949
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via cooperative gold/Brønsted acid catalyzed processes that are with a septum cap and placed in a pre-heated aluminum block
dependent on the strength of the Brønsted acid. The first two heater, and the reaction mixture was stirred at 45 °C for 12 h.
reactions provide alkene-appended lactones that could be ela- After complete consumption of starting material as monitored
borated into more complex structures, while the third pathway by TLC, the reaction mixture was diluted with 10.0 mL of
opens access to medicinally relevant bridged polycyclic lac- CH2Cl2 and washed with 10.0 mL of water. The organic layer
tones. These results reinforce previously accumulated was separated and dried over anhydrous sodium sulfate. The
evidence6–11 suggesting that Brønsted acid/base effects should solvent was evaporated under reduced pressure to obtain the
be carefully examined in order to maximize the efficiency and crude product, which was purified by flash chromatography on
product structural diversity of gold-catalyzed organic reactions. silica.
Synthesis of tricyclic lactones 4a–d and tetracyclic acid 9
(Method A). In a nitrogen glovebox, precatalyst 8 (5 mol% rela-
tive to 1) and AgBF4 (5 mol%) were added to 2.0 mL of dry
Experimental section
DCE in a 4 mL reaction vial. The precatalyst mixture was
General experimental details
stirred for 30 min at 25 °C, and the AgCl precipitate was then
All manipulations were carried out under nitrogen in dried,
distilled solvents unless otherwise noted. Diethyl ether, THF,
and hexanes were purified by distillation from sodium benzo-
phenone ketyl. Dichloromethane and DCE were washed with a
sequence of concentrated H2SO4, deionized water, 5% Na2CO3
and deionized water, followed by pre-drying over anhydrous
CaCl2, and were then refluxed over and distilled from P2O5
under nitrogen. Pyridine and NEt3 were dried over activated
4 Å molecular sieves and then distilled, degassed, and stored
over dried 4 Å sieves under nitrogen. Au(PPh3)Cl,49 Au(CyJohn-
Phos)Cl [Au(5)Cl],49 and Au[P(OPh)3]Cl (8)50 were synthesized
by a reported procedure51 starting from Au(THT)Cl.52 Au(IMes)-
removed by three successive filtrations through celite. The fil-
trate was placed in a fresh 4 mL reaction vial, and the substrate
(1a–c,1k; 100 mg) was introduced. The vial was sealed with a
septum cap, and several layers of PTFE tape were wrapped
around the cap seal for protection. The reaction mixture was
stirred at −20 °C (dry ice/CCl4 bath) under rigorously dry con-
ditions until the starting material had been consumed as
monitored by TLC (2–8 h). The reaction mixture was then
heated at 75 °C for an additional 3–7 h. The reaction mixture
was cooled to room temperature and loaded directly onto a
silica pad for column chromatographic purification.
Brønsted acid-catalyzed synthesis of tricyclic lactones 4f,g
(Method B). Reaction setup followed Method A, but with no
pre-activation step and no −20 °C incubation period. After
addition of TfOH (20 mol%) to a preheated (75 °C) solution of
substrate, the reaction mixture was heated with stirring for
16 h, followed by workup.
Cl [Au(6)Cl],53 Au(SIMes)Cl [Au(7)Cl],53 and AgBArF 54 were
4
prepared by literature procedures. All gold complexes were ulti-
mately derived from chloroauric acid (99.9%, 49% Au) pur-
chased from Strem. AgBF4 (99%), AgSbF6 (98%), and HBF4(aq.)
(48 wt%) were purchased from Strem. HBF4·Et2O (51–57 wt%)
was purchased from Aldrich. p-TsOH·H2O (99%) and TfOH
(99%) were purchased from Acros. Allenoic acid substrates
were synthesized by literature procedures (1a,1j)15d,22b or by
modifications thereof (see the ESI† for details).20,21
Kinetic procedures
Typical kinetic procedure with allenoic acid 1a. Substrate 1a
(100 mg, 0.30 mmol), TsOH·H2O (11.5 mg, 0.060 mmol) and
mesitylene (4.0 μL; NMR internal standard) were added to a
Optimized catalytic procedures
Synthesis of nonisomerized enelactones 2a–k. In a nitrogen 4 mL reaction vial, which was closed with a septum screw-cap.
glovebox, allenoic acid substrate (1a–k, 100 mg) was added to A catalyst stock solution was prepared by mixing 8 (33 mg,
2.0 mL dry CH2Cl2 in a 4 mL reaction vial. Precatalyst (PhO)3- 0.060 mmol) and AgBF4 (11.5 mg, 0.060 mmol) in 1.5 mL of
PAuCl 8 (5 mol%), AgBF4 (5 mol%) and NEt3 (5 mol%, as a dry DCE, stirring for 15 min, and filtering three times through
1.0 M stock solution in DCE) were then introduced. The vial was celite to remove the AgCl precipitate. The filtrate was diluted to
sealed with a septum cap and placed in a pre-heated alumi- a volume of 2.0 mL. A 0.5 mL aliquot of this solution was syr-
num block heater, and the reaction mixture was stirred at inged into the vial containing the substrate, followed by
45 °C for 2 h. After complete consumption of starting material 1.0 mL of pre-heated (45 °C) DCE, and the vial was placed in a
as monitored by TLC, the reaction mixture was diluted with pre-heated aluminum block reactor with magnetic stirring. At
10.0 mL of CH2Cl2 and washed with 10.0 mL of water. The periodic intervals, 20 μL aliquots were withdrawn and added to
organic layer was separated and dried over anhydrous sodium 0.60 mL of a CDCl3 solution containing methylisocyanide55
sulfate. The solvent was evaporated under reduced pressure to (25 mM), in order to deactivate the gold catalyst. Reaction ali-
obtain the crude product, which was purified by flash chrom- quots were stored at −4 °C until analysis. Product concen-
atography on silica.
trations were determined by 1H NMR integration of product
Synthesis of isomerized enelactones 3a–i. In a nitrogen resonances versus mesitylene. The catalyst deactivation pro-
glovebox, substrate (1a–i, 100 mg) was added to 2.0 mL dry cedure was verified by adding fresh substrate 1a to a deacti-
CH2Cl2 in a 4 mL reaction vial. Precatalyst 8 (5 mol% relative vated aliquot containing product 2a in 0.25 mM MeNC–CDCl3.
to 1), AgBF4 (5 mol%) and TsOH·H2O (5 mol% for 3b,3e,3g,3i; After 12 h at 25 °C, no change in the concentration of 2a and
20 mol% for others) were then introduced. The vial was sealed no formation of 3a were observed.
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Substrate 1a is only partially soluble in DCE, but dissolu- 1750 (s), 1640 (w) cm−1. HRMS (ESI-orbitrap, [C23H22Cl2O2
tion occurred concomitant with its conversion to 2a. In cases Na]+) calc. 423.0894, found m/z 423.0898.
in which the rates were slow enough to be measured, the 3,3-Bis(4-chlorophenyl)-5-(cyclopentylidenemethyl)dihydro-
+
appearance of 2a followed pseudo zero-order kinetics, consist- furan-2(3H)-one (2e).56 Rf 0.55 (1 : 4 diethyl ether–hexanes);
ent with a constant equilibrium concentration of 1a in solu- white solid, m.p. = 103–104 °C, yield 68 mg (68%). 1H NMR
tion. Kinetic plots for formation of 3a were consistent with (400 MHz, CDCl3): δ 7.37–7.21 (m, 8H), 5.38–5.34 (m, 1H),
reactions that are pseudo first-order in 2a (see the ESI† for 4.95–4.89 (m, 1H), 3.00 (dd, J = 13.0, 5.2 Hz, 1H), 2.64 (dd, J =
plots). Initial rates were determined by least-squares fitting of 13.2, 10.4 Hz, 1H), 2.39–2.26 (m, 3H), 2.24–2.15 (m, 1H),
product concentration versus time plots over the linear region, 1.72–1.54 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 176.6,
with uncertainties reported at the 95% confidence level.
153.2, 140.4, 138.2, 134.2, 133.6, 129.4, 129.2, 128.8, 128.8,
Typical kinetic procedure with enelactone 2a. Enelactone 2a 117.0, 75.8, 57.5, 44.0, 34.2, 29.4, 26.3, 26.0. IR (neat): ν 2977
(60 mg, 0.18 mmol), TsOH·H2O (7.0 mg, 0.036 mmol) and (w), 2922 (w), 1909 (w), 1752 (s), 1647 (w) cm−1. HRMS
mesitylene (2.5 μL; NMR internal standard) were added to a (ESI-orbitrap, [C22H20Cl2O2 + Na]+) calc. 409.0738, found m/z
4 mL reaction vial, which was closed with a septum screw-cap. 409.0736.
A catalyst stock solution was prepared by mixing 8 (19.5 mg,
5-(Cyclohexylidenemethyl)-3,3-bis(2,3-dihydrobenzofuran-5-
0.036 mmol) and AgBF4 (7.0 mg, 0.036 mmol) in 1.5 mL of dry yl)dihydrofuran-2(3H)-one (2f). Rf 0.45 (3 : 7 ethyl acetate–
DCE, stirring for 15 min, and filtering three times through hexanes); viscous yellow oil, yield 64 mg (64%). 1H NMR
celite to remove the AgCl precipitate. The filtrate was diluted to (400 MHz, CDCl3): δ 7.20 (s, 1H), 7.14 (s, 1H), 7.13 (dd, J = 8.4,
a total volume of 2.0 mL. A 0.5 mL aliquot of this solution was 2.4 Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H), 6.77 (d, J = 8.4 Hz,
syringed into the vial containing the substrate, followed by 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.39–5.35 (m, 1H), 4.95–4.88
0.5 mL of pre-heated (45 °C) DCE, and the vial was placed in a (m, 1H), 4.56 (quintet, J = 8.8 Hz, 4H), 3.17 (dt, J = 13.6, 8.8 Hz,
pre-heated aluminum block reactor with magnetic stirring. 4H), 2.98 (dd, J = 13.0, 5.2 Hz, 1H), 2.60 (dd, J = 12.4, 10.8 Hz,
Data collection and analysis were performed as in kinetic 1H), 2.39–2.28 (m, 3H), 2.26–2.15 (m, 1H), 1.72–1.58 (m, 6H).
experiments with 1a.
13C NMR (101 MHz, CDCl3): δ 178.2, 159.7, 159.2, 148.5, 135.0,
132.0, 128.1, 127.3, 126.9, 124.8, 124.5, 119.1, 109.3, 108.8,
73.4, 75.6, 71.7, 71.6, 57.6, 45.4, 37.1, 29.9, 29.9, 29.7, 28.4,
27.4, 26.6. IR (neat): ν 2948 (w), 2763 (w), 1755 (s), 1685 (w),
Product characterization
5-(Cyclohexylidenemethyl)-3,3-diphenyldihydrofuran-2(3H)- 1616 (m) cm−1. HRMS (ESI-orbitrap, [C27H28O4 + Na]+) calc.
one (2a). Rf 0.50 (1 : 9 acetone–hexanes); colourless viscous oil, 439.1885, found m/z 439.1886.
1
yield 95 mg (95%). H and 13C NMR data were in agreement
5-(Cyclopentylidenemethyl)-3,3-bis(2,3-dihydrobenzofuran-
5-yl)dihydrofuran-2(3H)-one (2g). Rf 0.40 (3 : 7 ethyl acetate–
with published values.15d
5-(Cyclopentylidenemethyl)-3,3-diphenyldihydrofuran-2(3H)- hexanes); white solid, m.p. 154–155 °C, yield 60 mg (60%).
one (2b). Rf 0.52 (1 : 4 diethyl ether–hexanes); white solid, 1H NMR (400 MHz, CDCl3): δ 7.22 (s, 1H), 7.14–7.12 (m, 2H),
yield 75 mg (75%). 1H and 13C NMR data were in agreement 6.98 (dd, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4 Hz, 1H), 6.69 (dd, J =
with published values.15d
8.4 Hz, 1H), 5.39–5.36 (m, 1H), 4.95–4.89 (m, 1H), 4.58 (t, J =
5-(Cycloheptylidenemethyl)-3,3-diphenyldihydrofuran-2(3H)- 8.8, Hz, 2H), 4.54 (t, J = 8.8, Hz, 2H),3.19 (t, J = 8.8, Hz, 2H),
one (2c). Rf 0.49 (1 : 4 diethyl ether–hexanes); white solid, 3.15 (t, J = 8.8, Hz, 2H), 2.98 (dd, J = 12.8, 4.8 Hz, 1H), 2.60 (dd,
m.p. = 111–112 °C, yield 82 mg (82%). 1H NMR (400 MHz, J = 12.8, 4.8 Hz, 1H), 2.39–2.28 (m, 3H), 2.26–2.15 (m, 1H),
CDCl3): δ 7.43–7.36 (m, 4H), 7.34–7.29 (m, 5H), 7.28–7.22 1.72–1.58 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 178.2, 159.7,
(m, 1H), 5.28 (dt, J = 8.8, 1.2 Hz, 1H), 5.06 (ddd, J = 9.6, 8.4, 159.2, 152.4, 135.1, 132.0, 128.1, 127.4, 127.4, 126.9, 124.8,
5.2, 1H), 3.07 (dd, J = 13.0, 5.2 Hz, 1H), 2.69 (dd, J = 13.2, 124.5, 117.6, 109.3, 108.8, 75.7, 75.6, 71.7, 57.5, 44.9, 34.1,
10.4 Hz, 1H), 2.36–2.20 (m, 4H), 1.63–1.46 (m, 8H). 13C NMR 29.9, 29.9, 29.4, 26.3, 26.0. IR (neat): ν 3050 (w), 2967 (m), 2929
(101 MHz, CDCl3): δ 177.4, 150.4, 142.4, 139.9, 129.1, 128.5, (w), 1917 (w), 1755 (s), 1567 (m) cm−1. HRMS (ESI-orbitrap,
127.9, 127.8, 127.5, 127.3, 122.3, 73.8, 58.4, 44.5, 37.9, 30.6, [C26H26O4 + Na]+) calc. 425.1729, found m/z 425.1729.
29.7, 29.1, 28.7, 27.3. IR (neat): ν 2970 (w), 2918 (w), 1901 (w),
1757 (s), 1647 (w) cm−1. HRMS (ESI-orbitrap, [C24H26O2 + H]+) xanthen]-2-one (2h).56 Rf 0.55 (3 : 7 ethyl acetate–hexanes);
calc. 347.2011, found m/z 347.2016.
viscous yellow oil, yield 80 mg (80%). 1H NMR (400 MHz,
5-(Cyclohexylidenemethyl)-4,5-dihydro-2H-spiro[furan-3,9′-
3,3-Bis(4-chlorophenyl)-5-(cyclohexylidenemethyl)dihydro- CDCl3): δ 7.35–7.12 (m, 8H), 5.44 (ddd, J = 10.0, 8.4, 6.0 Hz,
furan-2(3H)-one (2d). Rf 0.57 (1 : 4 diethyl ether–hexanes); 1H), 5.25 (d, J = 8.4 Hz, 1H), 2.72 (dd, J = 13.6, 6.4 Hz, 1H),
viscous yellow oil, yield 73 mg (73%). 1H NMR (400 MHz, 2.31–2.12 (m, 4H), 2.26 (dd, J = 13.6, 10.0 Hz, 1H), 1.64–1.48
CDCl3): δ 7.36–7.20 (m, 8H), 5.17 (d, J = 8.4 Hz, 1H), 5.05 (ddd, (m, 6H). 13C NMR (101 MHz, CDCl3): δ 177.3, 151.7, 151.0,
J = 10.4, 8.4, 4.8 Hz, 1H), 2.95 (dd, J = 13.2, 4.8 Hz, 1H), 2.63 148.8, 129.3, 129.0, 127.5, 125.9, 124.3, 124.1, 123.7, 122.9,
(dd, J = 13.2, 10.4 Hz, 1H), 2.20–2.03 (m, 4H), 1.59–1.48 (m, 119.0, 117.6, 116.7, 73.8, 50.8, 50.3, 37.1, 29.8, 28.4, 28.0, 26.6.
6H). 13C NMR (101 MHz, CDCl3): δ 176.6, 149.3, 140.3, 138.2, IR (neat): ν 2955 (w), 2769 (w), 1909 (w), 1751 (s), 1685 (w),
134.2, 133.6, 129.4, 129.2, 128.8, 128.7, 118.4, 73.4, 57.5, 44.4, 1616 (m) cm−1. HRMS (ESI-orbitrap, [C23H22O3 + Na]+) calc.
37.1, 29.7, 28.3, 27.9, 26.5. IR (neat): ν 2979 (w), 2926 (w), 1908 (w), 369.1467, found m/z 369.1465.
3944 | Org. Biomol. Chem., 2015, 13, 3936–3949
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5-(Cyclopentylidenemethyl)-4,5-dihydro-2H-spiro[furan-3,9′-
5-(Cyclopent-1-en-1-ylmethyl)-3,3-diphenyldihydrofuran-2-
xanthen]-2-one (2i).56 Rf 0.49 (3 : 7 ethyl acetate–hexanes); (3H)-one (3b). Rf 0.52 (1 : 4 diethyl ether–hexanes); viscous
white solid, m.p. = 150–151 °C, yield 78 mg (78%). 1H NMR yellow oil, yield 70 mg (70%). 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3): δ 7.35–7.26 (m, 3H), 7.23 (dd, J = 3.2, δ 7.42–7.34 (m, 4H), 7.34–7.22 (m, 6H), 5.51–5.49 (m, 1H),
1.2 Hz, 1H), 7.21–7.20 (m, 1H), 7.18–7.12 (m, 3H), 5.44–5.40 4.55–4.48 (m, 1H), 3.07 (dd, J = 13.2, 5.2 Hz, 1H), 2.64 (dd, J =
(m, 1H), 5.32–5.26 (m, 1H), 2.74 (dd, J = 13.2, 6.0 Hz, 1H), 14.8, 6.4 Hz, 1H), 2.63 (dd, J = 13.2, 10.4 Hz, 1H), 2.46 (dd, J =
2.48–2.19 (m, 4H), 2.26 (dd, J = 13.6, 10.0 Hz, 1H), 1.78–1.59 14.8, 6.4 Hz, 1H), 2.35–2.26 (m, 4H), 1.92–1.84 (m, 2H).
(m, 4H). 13C NMR (101 MHz, CDCl3): δ 177.3, 152.9, 151.7, 13C NMR (101 MHz, CDCl3): δ 177.1, 142.3, 140.0, 138.8, 129.0,
151.0, 129.3, 129.0, 127.4, 125.9, 124.3, 124.1, 123.7, 122.9, 128.4, 127.8, 127.8, 127.6, 127.4, 127.2, 76.0, 58.2, 43.7, 36.8,
117.6, 117.6, 116.7, 76.2, 50.2, 34.2, 29.4, 26.4, 26.0. IR (neat): 35.7, 32.6, 23.5. IR (neat): ν 2929 (s), 2862 (m), 1953 (w), 1748
ν 3055 (w), 2969 (m), 2922 (w), 1913 (w), 1755 (s), 1599 (m) cm−1
.
(s), 1608 (w) cm−1. HRMS (ESI-orbitrap, [C22H22O2 + H]+) calc.
HRMS (ESI-orbitrap, [C22H20O3 + Na]+) calc. 355.1310, found m/z 319.1698, found m/z 319.1697.
355.1316.
5-(Cyclohept-1-en-1-ylmethyl)-3,3-diphenyldihydrofuran-2-
5-(2-Methylprop-1-en-1-yl)-3,3-diphenyldihydrofuran-2(3H)- (3H)-one (3c). Rf 0.49 (1 : 4 diethyl ether–hexanes); white
1
one (2j). Rf 0.55 (1 : 4 diethyl ether–hexanes); colourless oil, solid, m.p. = 95–96 °C, yield 78 mg (78%). H NMR (400 MHz,
yield 85 mg (85%). 1H and 13C NMR data were in agreement CDCl3): δ 7.41–7.32 (m, 4H), 7.32–7.22 (m, 6H), 5.67 (t, J = 6.4
with published values.15d
Hz, 1H), 4.48–4.41 (m, 1H), 3.02 (dd, J = 13.0, 5.2 Hz, 1H), 2.61
5-(Cyclohexylidenemethyl)-3-(3-methoxyphenyl)-3-phenyldi- (dd, J = 13.2, 10.4 Hz, 1H), 2.55 (d, J = 14, 6.8 Hz, 1H), 2.30
hydrofuran-2(3H)-one (2k). Rf 0.48 (1 : 4 diethyl ether– (d, J = 14, 6.8 Hz, 1H), 2.15–2.07 (m, 4H), 1.73 (quintet, J = 6.0
hexanes); white solid, m.p. = 110–114 °C, yield 83 mg (83%). Hz, 2H), 1.52–1.48 (m, 4H). 13C NMR (101 MHz, CDCl3):
Mixture of two diastereomers (1 : 1 ratio by 1H NMR); not δ 177.3, 142.5, 140.0, 139.1, 130.6, 129.0, 128.5, 127.9, 127.8,
separable by TLC. 1H NMR (400 MHz, CDCl3; proton count 127.5, 127.3, 73.8, 58.2, 45.6, 43.7, 33.2, 32.5, 28.5, 27.1, 26.7.
reflects both diastereomers): δ 7.41 (dd, J = 8.4, 1.2 Hz, 2H, IR (neat): ν 2926 (s), 2857 (m), 1952 (w), 1750 (s), 1602 (w)
both diastereomers), 7.34 (td, J = 6.8, 2.0 Hz, 2H, both diaster- cm−1. HRMS (ESI-orbitrap, [C24H26O2 + H]+ calc. 347.2011,
eomers), 7.33–7.27 (m, 6H, both diastereomers), 7.25–7.20 (m, found m/z 347.2015.
2H, both diastereomers), 7.02 (dd, J = 7.6, 1.2 Hz, 1H, one dia-
3,3-Bis(4-chlorophenyl)-5-(cyclohex-1-en-1-ylmethyl)dihydro-
stereomer), 6.95 (t, J = 2.5 Hz, 1H, one diastereomer), furan-2(3H)-one (3d). Rf 0.54 (1 : 4 diethyl ether–hexanes);
6.91–6.90 (m, 1H, one diastereomer), 6.89–6.84 (m, 2H, both viscous yellow oil, yield 71 mg (71%). 1H NMR (400 MHz,
diastereomers), 6.77 (dd, J = 8.0, 2.4 Hz, 1H, one diastereo- CDCl3): δ 7.36–7.32 (m, 2H), 7.30–7.27 (m, 4H), 7.25–7.22
mer), 5.21 (d, J = 8.4 Hz, 1H, one diastereomer), 5.21 (d, J = (m, 2H), 5.54–5.51 (m, 1H), 4.47–4.40 (m, 1H), 2.95 (dd, J =
8.4 Hz, 1H, one diastereomer), 5.13–5.05 (m, 2H, both diaster- 12.8, 4.8 Hz, 1H), 2.56 (dd, J = 13.2, 10.4 Hz, 1H), 2.48 (dd,
eomers), 3.78 (s, 3H, one diastereomer), 3.75 (s, 3H, one dia- J = 14.4, 6.4 Hz, 1H), 2.26 (dd, J = 14.4, 5.6 Hz, 1H), and
stereomer), 3.05 (dd, J = 4.8, 3.2 Hz, 1H, one diastereomer), 2.00–1.92 (m, 4H), 1.64–1.51 (m, 4H). 13C NMR (101 MHz,
3.01 (dd, J = 4.8, 3.2 Hz, 1H, one diastereomer), 2.69 (dd, J = CDCl3): δ 176.5, 140.4, 138.2, 134.1, 133.6, 132.5, 129.3, 129.2,
10.4, 5.6 Hz, 1H, one diastereomer), 2.65 (dd, J = 10.4, 5.6 Hz, 128.8, 128.8, 125.5, 76.2, 57.3, 43.5, 43.4, 29.0, 25.4, 22.9, 22.3.
1H, one diastereomer), 2.28–2.06 (m, 8H, both diastereomers), IR (neat): ν 2926 (s), 1899 (w), 1759 (s), 1593 (m) cm−1. HRMS
1.61–1.49 (m, 12H, both diastereomers). 13C NMR (101 MHz, (ESI-orbitrap, [C23H22Cl2O2 + Na]+) calc. 423.0894, found m/z
CDCl3): δ 177.3, 177.2, 160.1, 159.6, 148.7, 148.7, 143.9, 142.3, 423.0890.
141.4, 139.8, 130.0, 129.4, 129.1, 128.5, 127.8, 127.8, 127.5,
3,3-Bis(4-chlorophenyl)-5-(cyclopent-1-en-1-ylmethyl)dihydro-
127.3, 120.2, 119.8, 119.0, 114.4, 113.9, 113.0, 112.4, 73.5, 73.4, furan-2(3H)-one (3e). Rf 0.55 (1 : 4 diethyl ether–hexanes);
58.4, 58.4, 55.4, 55.4, 44.8, 44.8, 37.1, 29.8, 29.7, 28.4, 27.9, white solid, m.p. = 96–97 °C, yield 63 mg (63%). 1H NMR
26.6. HRMS (ESI-orbitrap, [C24H26O3 + Na]+) calc. 385.1780, (400 MHz, CDCl3): δ 7.34 (dt, J = 8.8, 2.0 Hz, 2H), 7.30–7.26
found m/z 385.1777.
(m, 4H), 7.23 (dt, J = 8.8, 2.0 Hz, 2H), 5.48 (br. s, 1H), 4.51–4.44
5-(Cyclohex-1-en-1-ylmethyl)-3,3-diphenyldihydrofuran-2(3H)- (m, 1H), 2.97 (dd, J = 13.2, 4.8 Hz, 1H), 2.63 (dd, J = 15.0,
one (3a). To obtain optimal yields, a reaction time of 24 h and 7.2 Hz, 1H), 2.56 (dd, J = 13.2, 10.4 Hz, 1H), 2.44 (dd, J = 15.0,
20 mol% TsOH were used. Rf 0.50 (1 : 9 acetone–hexanes); 5.6 Hz, 1H), 2.34–2.24 (m, 4H), 1.87 (quintet, J = 7.2 Hz, 2H).
viscous yellow oil, yield 93 mg (93%). 1H NMR (400 MHz, 13C NMR (101 MHz, CDCl3): δ 176.4, 140.4, 138.5, 138.3, 134.2,
CDCl3): δ 7.39–7.34 (m, 4H), 7.33–7.27 (m, 5H), 7.26–7.20 133.7, 129.4, 129.2, 128.8, 128.0, 76.1, 57.3, 43.5, 36.7, 35.7,
(m, 1H), 5.52–5.51 (m, 1H), 4.49–4.42 (m, 1H), 3.01 (dd, J = 12.8, 32.6, 23.5. IR (neat): ν 2929 (s), 2851 (m), 1901 (w), 1761 (s),
4.8 Hz, 1H), 2.59 (dd, J = 13.2, 10.4 Hz, 1H), 2.47 (dd, J = 14.4, 1593 (m) cm−1. HRMS (ESI-orbitrap, [C22H20Cl2O2 + Na]+) calc.
6.4 Hz, 1H), 2.26 (dd, J = 14.4, 6.4 Hz, 1H), 1.99–1.92 (m, 4H), 409.0738, found m/z 409.0737.
1.63–1.50 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 177.3, 142.4,
5-(Cyclohex-1-en-1-ylmethyl)-3,3-bis(2,3-dihydrobenzofuran-
140.0, 132.7, 129.0, 128.5, 127.8, 127.8, 127.5, 127.3, 125.2, 76.2, 5-yl)dihydrofuran-2(3H)-one (3f). Rf 0.49 (3 : 7 ethyl acetate–
58.2, 43.7, 43.6, 29.0, 25.4, 22.9, 22.3. IR (neat): ν 2923 (s), hexanes); viscous yellow oil, yield 60 mg (60%). 1H NMR
2857 (m), 1951 (w), 1755 (s), 1609 (w) cm−1. HRMS (ESI-orbitrap, (400 MHz, CDCl3): δ 7.19–7.13 (m, 2H), 7.10 (dd, J = 8.4,
[C23H24O2 + Na]+) calc. 355.1674, found m/z 355.1670.
1.2 Hz, 1H), 6.97 (dd, J = 8.4, 1.2 Hz, 1H), 6.77 (d, J = 6.8, Hz,
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1H), 6.72 (d, J = 15.6, 1H), 5.52 (br. s, 1H), 4.56 (dt, J = 14.0, viscous oil, yield 41 mg (41%). Mixture of two diastereomers
8.8 Hz, 4H), 4.47–4.40 (m, 1H), 3.17 (dd, J = 13.2, 8.8 Hz, 4H), (1 : 1 ratio by 1H NMR); not separable by TLC. 1H NMR
2.93 (dd, J = 13.0, 5.2 Hz, 1H), 2.51 (dd, J = 12.8, 10.0 Hz, 1H), (400 MHz, CDCl3; proton count reflects both diastereomers):
2.47 (dd, J = 15.0, 6.8 Hz, 1H), 2.25 (dd, J = 14.2, 5.8 Hz, 1H), δ 7.37–7.21 (m, 5H, both diastereomers), 6.99 (dd, J = 8.0,
2.03–1.94 (m, 4H), 1.66–1.53 (m, 4H). 13C NMR (101 MHz, 1.6 Hz, 1H, one diastereomer), 6.93 (t, J = 2.4 Hz, 1H, one dia-
CDCl3): δ 178.2, 159.7, 159.3, 135.2, 132.9, 132.1, 129.4, 128.8, stereomer), 6.90–6.86(m, 2H, both diastereomers), 6.85 (d, J =
128.1, 127.4, 127.0, 125.2, 124.8, 124.5, 109.3, 108.9, 76.2, 71.7, 2.4 Hz, 1H, one diastereomer), 6.83 (d, J = 2.8 Hz, 1H, one
71.6, 57.4, 44.5, 43.7, 29.9, 29.1, 25.4, 23.0, 22.4. IR (neat): diastereomer), 6.80 (d, J = 2.8 Hz, 1H, one diastereomer), 6.78
ν 3058 (w), 2962 (m), 2922 (w), 1901 (w), 1758 (s), 1598 (m) (d, J = 2.4 Hz, 1H, one diastereomer), 5.52 (s, 1H, both diaster-
cm−1. HRMS (ESI-orbitrap, [C27H28O4 + Na]+) calc. 439.1885, eomers), 4.51 (m, 1H, both diastereomers), 3.77 (s, 3H, one
found m/z 439.1883.
diastereomer), 3.75 (s, 3H, one diastereomer), 3.04 (m, 1H,
5-(Cyclopent-1-en-1-ylmethyl)-3,3-bis(2,3-dihydrobenzofuran- both diastereomers), 2.62 (m, 1H, both diastereomers), 2.50
5-yl)dihydrofuran-2(3H)-one (3g). Rf 0.40 (3 : 7 ethyl acetate– (dd, 14, 7.2 Hz, 1H both diastereomers), 2.28 (dd, J = 14,
hexanes); viscous yellow oil, yield 61 mg (61%). 1H NMR 5.6 Hz, 1H, both diastereomers), 1.99 (m, 8H, both diastereo-
(400 MHz, CDCl3): δ 7.19–7.18 (m, 1H), 7.14–7.13 (m, 1H), 7.10 mers), 1.64 (m, 12H, both diastereomers). 13C NMR (125 MHz,
(dd, J = 8.4, 2.0 Hz, 1H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 6.75 (d, CDCl3): δ 177.3, 177.2, 160.1, 159.6, 144.0, 142.3, 141.3, 139.8,
J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.49–5.47 (m, 1H), 4.57 132.7, 130.0, 129.5, 129.0, 128.5, 127.8, 127.5, 127.3, 125.3,
(t, J = 8.8, Hz, 2H), 4.54 (t, J = 8.8, Hz, 2H), 4.51–4.44 (m, 1H), 125.2, 120.3, 119.8, 114.4, 113.9, 112.9, 112.2, 76.3, 76.2, 58.2,
3.18 (t, J = 8.8, Hz, 2H), 3.16 (t, J = 8.8, Hz, 2H), 2.96 (dd, J = 58.1, 55.4, 47.4, 43.8, 43.6, 29.1, 25.4, 22.9, 22.3. HRMS (ESI-
13.2, 4.8 Hz, 1H), 2.62 (dd, J = 14.8, 6.0 Hz, 1H), 2.52 (dd, orbitrap, [C24H26O3 + H]+) calc. 363.1960, found m/z 363.1945.
J = 13.2, 10.4 Hz, 1H), 2.43 (dd, J = 14.8, 6.0 Hz, 1H), 2.33–2.25
1-Cyclohexyl-4-phenyl-1,2,3,4-tetrahydro-1,4-(epoxymethano)-
(m, 4H), 1.87 (quintet, J = 8.0 Hz, 2H). 13C NMR (101 MHz, naphthalen-9-one (4a). Method A; reaction time 7.5 h at
CDCl3): δ 178.2, 159.7, 159.2, 152.4, 135.1, 132.0, 128.1, 127.4, −20 °C, then 6 h at 75 °C. Rf 0.58 (1 : 4 acetone–hexanes);
127.4, 126.9, 124.8, 124.5, 117.6, 109.3, 108.4, 75.7, 71.7, 71.6, white solid, m.p. = 232–233 °C, yield 80 mg (80%). 1H NMR
57.5, 44.9, 34.1, 29.9, 29.9, 29.4, 26.4, and 26.0. IR (neat): (400 MHz, CDCl3): δ 7.52–7.47 (m, 4H), 7.46–7.41 (m, 1H), 7.40
ν 3051 (w), 2967 (m), 2926 (w), 1934 (w), 1757 (s), 1567 (m) (d, J = 8.8 Hz, 1H), 7.29 (dt, J = 7.5, 1.2 Hz, 1H), 7.17 (dt, J =
cm−1. HRMS (ESI-orbitrap, [C26H26O4 + Na]+) calc. 425.1729, 7.68, 1.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 2.55–2.47 (m, 2H),
found m/z 425.1731.
2.42–2.35 (m, 1H), 2.21–2.14 (m, 2H), 2.11–2.05 (m, 1H),
5-(Cyclohex-1-en-1-ylmethyl)-4,5-dihydro-2H-spiro[furan-3,9′- 1.98–1.89 (m, 2H), 1.82–1.77 (m, 1H), 1.69 (t, J = 10.4 Hz, 1H),
xanthen]-2-one (3h). Rf 0.50 (3 : 7 ethyl acetate–hexanes); 1.62–1.49 (m, 2H), 1.47–1.38 (m, 2H), 1.36–1.28 (m, 1H).
viscous yellow oil, yield 78 mg (78%). 1H NMR (400 MHz, 13C NMR (101 MHz, CDCl3): δ 174.4, 141.9, 138.7, 135.7, 129.7,
DMSO-d6): δ 7.41–7.27 (m, 4H), 7.23–7.17 (m, 4H), 5.59 (br s, 128.3, 128.1, 128.0, 126.9, 124.4, 122.3, 85.4, 53.2, 28.8, 27.5,
1H), 5.06–4.99 (m, 1H), 2.80 (dd, J = 13.6, 7.2 Hz, 1H), 2.53 (dd, 27.0, 26.8, 26.8, 26.5. IR (neat): ν 2933 (m), 2851 (m), 1952 (w),
J = 13.6, 7.2 Hz, 1H), 2.40 (dd, J = 14.0, 5.2 Hz, 1H), 2.33 (dd, 1737 (s), 1600 (w) cm−1. HRMS (ESI-orbitrap, [C23H24O2 + H]+)
J = 14.0, 10.0 Hz, 1H), 2.05–1.94 (m, 4H), 1.62–1.50 (m, 4H). calc. 333.1855, found m/z 333.1851.
13C NMR (101 MHz, DMSO-d6): δ 176.8, 150.4, 149.4, 132.8,
1-Cyclopentyl-4-phenyl-1,2,3,4-tetrahydro-1,4-(epoxymethano)-
129.4, 129.2, 127.8, 126.4, 124.4, 124.3, 124.1, 123.0, 122.4, naphthalen-9-one (4b). Method A; reaction time 5 h at −20 °C,
116.9, 116.3, 76.5, 48.6, 48.0, 43.2, 28.3, 24.7, 22.4, 21.8. IR then 7 h at 75 °C. Rf 0.35 (1 : 4 diethyl ether–hexanes); white
(neat): ν 2973 (w), 2934 (m), 2859 (w), 1902 (w), 1767 (s), 1493 solid, m.p. = 231–234 °C (decomp), yield 71 mg (71%).
(m) cm−1
369.1467, found m/z 369.1451.
.
HRMS (ESI-orbitrap, [C23H22O3
+
Na]+) calc. 1H NMR (400 MHz, CDCl3): δ 7.52–7.40 (m, 6H),7.29 (td, J =
15.2, 1.2 Hz, 1H), 7.18 (td, J = 15.2, 1.2 Hz, 1H), 6.64 (dd,
5-(Cyclopent-1-en-1-ylmethyl)-4,5-dihydro-2H-spiro[furan- J = 7.6, 0.8 Hz, 1H), 2.91 (quintet, J = 8.8 Hz, 1H), 2.57–2.43
3,9′-xanthen]-2-one (3i). Rf 0.49 (3 : 7 ethyl acetate–hexanes); (m, 2H), 2.20–2.14 (m, 1H), 2.13–1.96 (m, 2H), 1.90–1.79
viscous yellow oil, yield 72 mg (72%). 1H NMR (400 MHz, (m, 3H), 1.77–1.68 (m, 3H), 1.67–1.58 (m, 1H). 13C NMR
CDCl3): δ 7.34–7.28 (m, 2H), 7.22–7.11 (m, 6H), 5.51 (br. s, 1H), (101 MHz, CDCl3): δ 174.6, 141.5, 139.6, 135.8, 129.7, 128.3,
4.88–4.80 (m, 1H), 2.73 (dd, J = 14.2, 6.0 Hz, 1H), 2.71 (dd, J = 128.2, 128.0, 127.0, 124.2, 122.3, 85.7, 53.5, 42.2, 30.5, 27.9,
13.4, 6.4 Hz, 1H), 2.50 (dd, J = 14.0, 6.4 Hz, 1H), 2.31 (t, J = 27.9, 27.3, 26.6, 26.3. IR (neat): ν 2951 (w), 2865 (w), 1739 (s),
7.6 Hz, 4H), 2.23 (dd, J = 13.2, 10.0 Hz, 1H), 1.92–1.84 (m, 2H). 1601 (w), 1477 (m) cm−1. HRMS (ESI-orbitrap, [C22H22O2 + H]+)
13C NMR (101 MHz, CDCl3): δ 177.2, 151.6, 150.8, 138.4, 129.3, calc. 319.1698, found m/z 319.1697.
129.0, 128.2, 127.4, 125.8, 124.3, 124.1, 123.6, 122.8, 117.6,
116.8, 76.5, 50.0, 49.9, 37.3, 35.8, 32.6, 23.5. IR (neat): ν 3057 naphthalen-9-one (4c). Method A; reaction time 3 h at −20 °C,
(w), 2969 (m), 2920 (w), 1904 (w), 1750 (s), 1561 (m) cm−1
then 5 h at 75 °C. Rf 0.37 (1 : 4 diethyl ether–hexanes); white
HRMS (ESI-orbitrap, [C22H20O3 + Na]+) calc. 355.1310, found solid, m.p. = 218–219 °C, yield 83 mg (83%). 1H NMR
m/z 355.1318. (400 MHz, CDCl3): δ 7.51–7.40 (m, 5H), 7.38–7.26 (m, 2H), 7.18
1-Cycloheptyl-4-phenyl-1,2,3,4-tetrahydro-1,4-(epoxymethano)-
.
5-(Cyclohex-1-en-1-ylmethyl)-3-(3-methoxyphenyl)-3-phenyl- (t, J = 7.6 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 2.58–2.50 (m, 3H),
dihydrofuran-2(3H)-one (3k). Rf 0.48 (1 : 4 diethyl ether–hexanes); 2.22–1.56 (m, 14H). 13C NMR (101 MHz, CDCl3): δ 174.5, 141.9,
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139.5, 135.7, 129.7, 128.3, 128.1, 128.0, 126.9, 124.4, 122.1, laboratory oversight, and Prof. Jimmie Weaver (OSU) for
87.3, 53.2, 40.7, 29.2, 29,2, 28.1, 27.7, 27.2. IR (neat): ν 3042 helpful discussions.
(w), 2946 (w), 1864 (w), 1739 (s), 1610 (w), 1486 (m) cm−1
.
HRMS (ESI-orbitrap [C24H26O2 + H]+) calc. 347.2011, found m/z
347.1991.
Notes and references
9-Cyclohexyl-6-(2,3-dihydrobenzofuran-5-yl)-1,2,6,7,8,9-hexa-
hydro-9,6-(epoxymethano)naphtho[2,1-b]furan-11-one (4f). Method
B. Rf 0.42 (2 : 8 ethyl acetate–hexanes); viscous yellow oil, yield
1 (a) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180;
(b) A. Fürstner and P. W. Davies, Angew. Chem., Int. Ed.,
2007, 46, 3410; (c) Z. Li, C. Brouwer and C. He, Chem. Rev.,
2008, 108, 3239; (d) N. D. Shapiro and F. D. Toste, Synlett,
2010, 675; (e) Modern Gold Catalyzed Synthesis, ed. A. S. K.
Hashmi and F. D. Toste, Wiley-VCH, Weinheim, 2012.
2 (a) A. S. K. Hashmi and M. Rudolph, Chem. Soc. Rev., 2008,
37, 1766; (b) M. Rudolph and A. S. K. Hashmi, Chem. Soc.
Rev., 2012, 41, 2448; (c) A. Fürstner, Acc. Chem. Res., 2014,
47, 925.
1
54 mg (54%). H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 7.25
(d, J = 8 Hz, 2H), 6.76 (d, J = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H),
4.59–4.54 (m, 4H), 3.25–3.18 (m, 4H), 2.73–2.70 (m, 1H),
2.21–2.14 (m, 2H), 2.09–1.98 (m, 3H), 1.67–1.66 (m, 1H),
1.66–1.63 (m, 1H), 1.44–1.35 (m, 1H), 1.44–1.24 (m, 3H),
1.12–1.03 (m, 2H), 0.88–0.81 (m, 1H). 13C NMR (101 MHz,
CDCl3): δ 178.6, 159.2, 158.8, 133.7 (2C), 130.6 (2C), 126.9 (2C),
124.0, 109.0 (2C), 84.3, 71.4, 56.9, 53.0, 52.0, 36.0, 32.0, 30.3,
30.0, 29.9, 26.8, 23.8, 21.0. IR (neat): ν 2932 (m), 2857 (m),
1762 (s), 1614 (w), 1492 (m), 1235 (m) cm−1. HRMS (ESI-
orbitrap, [C27H28O4 + Na]+) calc. 439.1885, found m/z 439.1874.
9-Cyclopentyl-6-(2,3-dihydrobenzofuran-5-yl)-1,2,6,7,8,9-hexa-
hydro-9,6-(epoxymethano)naphtho[2,1-b]furan-11-one (4g). Method
B. Rf 0.45 (2 : 8 ethyl acetate–hexanes); viscous yellow oil, yield
3 C. Obradors and A. M. Echavarren, Chem. Commun., 2014,
50, 16.
4 For an example of a mechanistically intricate, but neverthe-
less highly predicable gold-catalyzed reaction, see the fura-
nyne cycloisomerization: (a) A. S. K. Hashmi, T. M. Frost
and J. W. Bats, J. Am. Chem. Soc., 2000, 122, 11553;
(b) A. S. K. Hashmi, M. Rudolph, H.-U. Siehl, M. Tanaka,
J. W. Bats and W. Frey, Chem. – Eur. J., 2008, 14, 3703.
Alternative reaction pathways in furanyne cycloisomeriza-
tions have also been identified: (c) A. S. K. Hashmi, Pure
Appl. Chem., 2010, 82, 1517.
5 (a) C. Nieto-Oberhuber, M. P. Muñoz, E. Buñuel,
C. Nevado, D. J. Cárdenas and A. M. Echavarren, Angew.
Chem., Int. Ed., 2004, 43, 2402; (b) C. Nieto-Oberhuber,
S. López, M. P. Muñoz, D. J. Cárdenas, E. Buñuel,
C. Nevado and A. M. Echavarren, Angew. Chem., Int. Ed.,
2005, 44, 6146; (c) C. H. M. Amijs, V. López-Carrillo,
1
31 mg (31%). H NMR (400 MHz, CDCl3): δ 7.61 (s, 1H), 7.31
(s, 1H), 7.04 (d, J = 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 6.71 (d, J =
8 Hz, 1H), 4.60–4.54 (m, 4H), 3.26–3.18 (m, 4H), 2.83–2.79
(m, 1H), 2.45 (t, J = 8 Hz, 2H), 2.13–1.26 (m, 9H), 0.88–0.81
(m, 1H). 13C NMR (101 MHz, CDCl3): δ 177.8, 159.2, 159.1,
134.2, 131.6, 128.4, 127.4, 127.2, 126.9, 124.6, 124.1, 109.0,
108.9, 96.0, 76.8, 71.5, 58.0, 56.6, 48.8, 38.4, 34.2, 30.4, 30.0,
30.0, 28.2, 22.4. IR (neat): ν 2926 (m), 2855 (m), 1762 (s),
1616 (w), 1491 (m), 1231 (m) cm−1. HRMS (ESI-orbitrap,
[C26H26O4 + Na]+) calc. 425.1729, found m/z 425.1719.
2-Methoxy-4-phenyl-4,5,5a,6,6a,7,8,9,10,10a-decahydroace-
phenanthrylene-4-carboxylic acid (9). Method A; reaction
time 4 h at −20 °C, then 4.5 h at 75 °C. Rf 0.49 (3 : 4 diethyl
ether–hexanes); white solid, m.p. = 292–295 °C (decomp), yield
M.
Raducan,
P.
Pérez-Galán,
C.
Ferrer
and
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1
80 mg (80%). H NMR (400 MHz, CDCl3): δ 7.32–7.22 (m, 5H),
7.11 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 3.82 (s, 3H),
2.91–2.85 (m, 1H), 2.83–2.76 (m, 1H), 2.64–2.54 (m, 2H),
2.29–2.26 (m, 1H), 2.04–2.01 (m, 1H), 1.93–1.87 (m, 1H),
1.70–1.63 (m, 2H), 1.52–1.39 (m, 3H), 1.38–1.25 (m, 3H).
13C NMR (101 MHz, CDCl3): δ 178.9, 159.9, 142.0, 141.2, 138.8,
136.8, 128.5, 127.4, 127.3, 111.4, 109.0, 63.5, 55.8, 48.4, 38.5,
36.2, 34.1, 33.2, 28.8, 28.2, 25.9, 22.4. IR (neat): ν 3282 (br),
2928 (m), 2957 (m), 1710 (m) cm−1. HRMS (ESI-orbitrap,
[C24H26O3 + H]+) calc. 363.1960, found m/z 363.1957.
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Acknowledgements
This work was initiated under support from the U.S. National
Science Foundation (CHE-1214066 and CHE-1360610) and
continued with funding from the Oklahoma Center for the
Advancement of Science & Technology (HR12–171). We thank
Doug Powell (Univ. of Oklahoma) for assistance with the X-ray
structure of 9, Prof. Frank D. Blum (OSU) for assistance with
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Organic & Biomolecular Chemistry
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