Gold(I)-Catalyzed Cycloisomerization-Dimerization Cascade of Benzene-Tethered 1,6-Enynes

Article abstract of DOI:10.1021/acs.joc.7b01273

An unprecedented stereoselective domino reaction of 1,6-enynes with an aryl ring at C3-C4 in the presence of gold(I) catalysts at low temperature is described. This process involves a novel 5-exo-dig cycloisomerization-dimerization sequence to afford formal Diels-Alder adducts that undergo a smooth gold-catalyzed double bond migration at room temperature. In addition, the first examples of the gold mesoionic carbene mediated [2+2+2] cycloaddition of these enynes with benzaldehyde are reported.

Full text of DOI:10.1021/acs.joc.7b01273

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Article
Gold(I)-Catalyzed Cycloisomerization-Dimerization
Cascade of Benzene-Tethered 1,6-Enynes
Mónica Álvarez-Pérez, Maria Frutos Pastor, Alma Viso, Roberto Fernández de la Pradilla,
Maria C. De La Torre, Miguel A. Sierra, Heinz Gornitzka, and Catherine Hemmert
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01273 • Publication Date (Web): 26 Jun 2017
Downloaded from http://pubs.acs.org on June 27, 2017
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Gold(I)-Catalyzed Cycloisomerization-Dimerization Cascade of
Benzene-Tethered 1,6-Enynes
Mónica Álvarez-Pérez,† María Frutos,†§ Alma Viso,*,†§ Roberto Fernández de la Pradilla,†§ María C. de
la Torre,*,†§ Miguel A. Sierra,*,║§ Heinz Gornitzka,^ and Catherine Hemmert.^
‡
‡
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†Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas (IQOG-
║
CSIC), Juan de la Cierva 3, 28006-Madrid, Spain. Departamento de Química Orgánica I, Facultad de
§
Química, Universidad Complutense, 28040-Madrid, Spain. Centro de Innovación en Química
Avanzada (ORFEO-CINQA), Facultad de Química, Universidad Complutense, 28040-Madrid, Spain.
^CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, F-31077
Toulouse Cedex 4, France. ‡Université de Toulouse, UPS, INPT, F-31077 Toulouse Cedex 4, France.
TABLE OF CONTENTS GRAPHIC
R1
Au catalyst
rt
R1
69-90%
2
3
6
R1
H
H
Au catalyst
H
_10 - 0 ºC
84-91%
R1
R1
1
R1 = H, MeO
Ph
Au catalyst
PhCHO
70-72%
R1
O
ABSTRACT: An unprecedented stereoselective domino reaction of 1,6-enynes with an aryl ring at C3-
C4 in the presence of gold(I) catalysts at low temperature is described. This process involves a novel 5-
exo-dig cycloisomerization-dimerization sequence to afford formal Diels-Alder adducts that undergo a
smooth gold-catalyzed double bond migration at room temperature. In addition, the first examples of
the gold mesoionic carbene mediated [2+2+2] cycloaddition of these enynes with benzaldehyde are
reported.
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INTRODUCTION
The highly versatile reactivity of 1,6-enynes in the presence of gold(I) catalysts is well established.1
The cycloisomerization of these enynes is particularly useful due to the broad array of products
potentially accessible via the different intermediates that are currently accepted depending on the
reaction conditions and the gold catalysts used. Thus, 1,6-enynes I undergo cycloisomerizations to
form cyclopropyl metal carbene intermediates II (5-exo-dig) and/or III (6-endo-dig) (Scheme 1),2
which evolve through skeletal rearrangements by single cleavage to afford dienes IV if external
nucleophiles are absent.3 In the presence of nucleophiles, they give rise to substituted exocyclic alkenes
V.4 Alternatively, intermediates III may lead to fused cyclopropanes VI or to methylenecyclohexenes
VII.3 Furthermore, gold(I) catalysis encompasses a high potential for the construction of complex
target compounds in a domino fashion by trapping intra- or intermolecularly the carbene intermediates
with suitable functional groups, producing a rapid increment of molecular complexity in a single
operation. In this regard, alkenes can act as partners in cyclopropanations,5 and carbonyl derivatives
may lead to cycloadducts of strikingly different structures depending upon the substitution of the
alkene moiety of the enynes.6 We have recently disclosed the straightforward synthesis of gold
mesoionic carbenes with a chiral sulfoxide group at C4 and we have begun exploring their catalytic
activity in the cycloisomerization of 1,6-enynes. These sulfinyl gold carbenes displayed a good
catalytic profile in selected examples producing 1,3-dienes in good yields and with high 5-exo
regioselectivity that appears to be related to the steric bulk of the N1-substituent of the catalyst.7
Seeking to broaden the scope of the process we examined the reactivity of 1,6-enynes with an aromatic
tether such as 1-(ethynyl)-2-(3-mehylbut-2-enyl)benzene 1a that provided a dimeric fluorene-like
structure assigned as 2a (Table 1, Figure 1). This unprecedented serendipitous finding along with the
presence of fluorene-like skeletons in natural products8 prompted us to study the process in some depth
and the results are disclosed herein.
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Scheme 1. Rationale for Cycloisomerization of 1,6-Enynes.
R
LAu
Z
IV
R
Z
H
NuH
Z
H
H
R
II
V
H
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Nu
AuL
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I
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III
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RESULTS AND DISCUSSION
Upon examining the reaction of 1-(ethynyl)-2-(3-methylbut-2-enyl)benzene (1a) with catalyst SS-L1-
AuCl (Table 1) and NaBArF (3 mol% each) in CH2Cl2 at rt (1 h), we obtained an excellent yield (90%)
of an unexpected product 2a (Table 1) that had spectral features (NMR, MS) that were clearly different
from those reported for the expected diene 4a.9 Careful examination of the data for 2a suggested a
“dimeric” structure like the one shown in Table 1 and this was then rigorously established by X-ray
diffraction analysis (Figure 1).
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Table 1. Cycloisomerization-Dimerization Cascade of 1-(Ethynyl)-2-(3-methylbut-2-enyl)benzene
1a under Gold(I) Catalysis.
2a
catalyst/additivea
+
H
CH2Cl2, 1 h
H
1a
3a
O
+
S
ClAu
N
N
N
SS-L1-AuCl
Ph
RS-L1-AuCl
4a
Product ratiob (yield %)
Entry Substrate
Conditionsa
2a
93 (90)
91 (81)
--
3a
4a 1a
1
1a
1a
1a
3a
3 mol% SS-L1-AuCl/NaBArF, rt
3 mol% RS-L1-AuCl/NaBArF, rt
3 mol% SS-L1-AuCl/NaBArF, -10 ºC
3 mol% RS-L1-AuCl/NaBArF, rt
7
--
--
--
--
--
--
--
--
--
--
2
9
100 (91)
--
3
4
100 (93)
25
75
5
4a
3 mol% RS-L1-AuCl/NaBArF, rt
(88) c
6
7
4a
1a
1a
1a
1a
1a
1a
1a
1 equiv NaBArF, rt d
3 mol% NaBArF, rt
25 mol% NaBArF, rt e
--
100 (79)
--
2
--
--
--
14
--
98
8
--
--
13 73
9
3 mol% SS-L1-AuCl, rt
6
94
--
10
11
12
13
5 mol% Ph3PAuCl/NaBArF, rt
5 mol% Ph3PAuCl/AgSbF6, rt
10 mol% AgSbF6, rt
--
20
80
100 (90)
(38) f
--
3 mol% Ph3PAuCl/AgSbF6, 0 ºC
86 (84)
14
--
a In all cases, the additive was employed in equimolar amount to the gold(I) catalyst. b Measured by
1H NMR of the crude. Unoptimized yields in parentheses. Yield of the combined dimerization.
c
d
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NaBArF was added in 4 portions at 1 h intervals to produce 3a cleanly; the reaction was allowed to
e
continue for an additional hour (5 h total) to afford pure 3a in high yield after chromatography.
Addition of increasing amounts of NaBArF to this mixture up to 1 equiv led to a 60% yield of 3a after
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2 h. f TLC and 1H NMR analyses showed a complex mixture and substantial decomposition.
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Figure 1. X-Ray structure of 2a.
A more detailed examination of the original experiment revealed minor amounts of a related product
3a in the crude reaction mixture (Table 1, entry 1). In an effort to clarify the structure of 3a, the process
was tested with diastereomeric catalyst RS-L1-AuCl that afforded comparable results (Table 1, entry 2).
Fortunately, careful control of the reaction temperature (-10 ºC) led to very clean crude reaction
mixtures with catalyst SS-L1-AuCl (Table 1, entry 3) that produced 3a as a single isomer and in
excellent yields (91%). At this stage, a detailed spectroscopic study of 3a, including 2D NMR
experiments, strongly supported the proposed structure that may be described as the cycloadduct of a
formal Diels-Alder regio- and stereoselective “dimerization” of 3-indenyl diene 4a.
To gain insight into these processes, we examined the stability of 3a to a hypothetical gold-catalyzed
isomerization at rt to afford 2a and indeed submitting pure 3a to the catalytic reaction conditions at rt
gave an excellent yield of 2a (Table 1, entry 4). This isomerization appears to require gold catalysis
since 3a was stable in the presence of stoichiometric NaBArF (see below entry 6). On the other hand,
the treatment of indenyl diene 4a, prepared as described in the literature,10 under the reaction
conditions produced a 25:75 mixture of cycloadducts 2a:3a (Table 1, entry 5). To assess the effect of
NaBArF on the cycloaddition, diene 4a was treated with increasing amounts of NaBArF up to
stoichiometric, and monitored by 1H NMR, to yield cycloadduct 3a (79%, Table 1, entry 6). In view of
this unexpected and high-yielding NaBArF catalyzed cycloaddition we examined the stability of enyne
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1a with 3% NaBArF that afforded mainly starting material and just 2% ratio (1H NMR) of indenyl
diene 4a (Table 1, entry 7). Interestingly, addition of increasing amounts of NaBArF and monitoring by
1H NMR revealed measurable increasing amounts of diene 4a and cycloadduct 3a (Table 1, entry 8)
that ultimately led to clean conversion to 3a (60%) upon addition of a full equivalent of NaBArF. Thus,
it appears that NaBArF is not just an adequate promoter of the cyclocondensation of diene 4a to
cycloadduct 3a, but remarkably, it is also possible to trigger the full cycloisomerization-cycloaddition
cascade from enyne 1a. These results are likely to follow a different reaction pathway than upon gold(I)
catalysis. As a final control experiment, enyne 1a was treated with 3 mol% of catalyst SS-L1-AuCl, in
the absence of NaBArF, to produce a 94:6 mixture of starting material 1a and diene 4a (Table 1, entry
9).
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At this stage, we decided to examine the behavior of Ph3PAuCl, a gold(I) complex commonly used in
catalysis, in the cycloisomerization-dimerization cascade of enyne 1a and the results obtained are
summarized in Table 1, entries 10-13. Activation with NaBArF resulted in a 20:80 mixture of dimer 3a
and diene 4a (Table 1, entry 10). In contrast, activation with AgSbF6 led to a good conversion and yield
of isomerized dimer 2a (Table 1, entry 11). The use of 5 mol% AgSbF6 essentially led to recovery of
starting material and 10 mol% AgSbF6 was required to promote some reaction affording a complex
mixture of side products and a low yield of 2a (38%, Table 1, entry 12). Finally, reducing the catalyst
load in cold CH2Cl2 (3%, 0 ºC) gave rise to a good yield of dimer 3a, along with some diene 4a (Table
1, entry 13).
It is worth noting that, from a qualitative standpoint, our carbene catalysts led to slightly faster and
cleaner reactions than Ph3PAuCl. Furthermore, the possibility of having achieved asymmetric induction
in the cycloaddition to either 3a or 2a with our enantiopure carbene catalysts led us to evaluate the
optical purity of these cycloadducts. This was carried out by chiral HPLC and, to our dismay, the
cycloadducts resulted to be virtually racemic in all cases (see Supporting Information for details).
At this point we decided to briefly survey the scope of the process by introducing substituents at the
aryl moiety of the 1,6-enynes, as well as by varying the substitution of the alkene fragment and the
results obtained are summarized in Table 2. Thus, substrate 1b, with a MeO group at the para position
to the allyl residue, gave good yields of cycloadducts 2b (69%) and 3b (87%) upon treatment with our
carbene catalyst at different temperatures (Table 2, entries 1 and 2). In contrast, regioisomeric substrate
1c, at low temperature afforded a 27:73 mixture of 2c and 3c, suggesting a more facile isomerization in
this case. Treatment of this mixture with the carbene catalyst at rt gave an excellent yield of 2c (Table
2, entries 3 and 4).
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Table 2. Cycloisomerization-Dimerization Cascade under Gold(I) Catalysis. Scope of the Process.
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Entry Substrate
Conditionsa
Product (yield %)b [ratio]c
2b (69)
1
2
3
4
5
1b
1b
SS-L1-AuCl/NaBArF, rt
SS-L1-AuCl/NaBArF, -10 ºC
SS-L1-AuCl/NaBArF, -10 ºC
SS-L1-AuCl/NaBArF, rt
Ph3PAuCl/AgSbF6, rt
3b (87)
1c
2c+3c [27:73]c
2c+3c
1d
2c (98)
5 (63)
6
1e
SS-L1-AuCl/NaBArF, rt
Ph3PAuCl/AgSbF6, rt
2e/3e (74) [50:50]b
2e/3e (73) [72:28]b
3e (48)d
7
8
1e
1e
SS-L1-AuCl/NaBArF, -10 ºC
a
A 3 mol % of gold(I) catalyst and additive was used except for entry 5 where 5% of each was
employed. The reactions have not been optimized. b Yields in parentheses. c Isomeric ratios in brackets
1
d
determined by H NMR of the crude. A 13% of isomeric 1,5-enyne, (E)-1-(ethynyl)-2-(but-1-
enyl)benzene, contained in the batch of starting material was recovered unaltered.
The effect of a disubstituted terminal alkene was examined next and substrate 1d, upon treatment with
Ph3PAuCl/AgSbF6, gave a fair yield of naphthalene derivative 5 (Table 2, entry 5), with identical
spectral data to that reported in the literature.11 Finally, treatment of crotyl derivative 1e (5:1, E/Z
mixture) either with our gold carbene or with Ph3PAuCl/AgSbF6 at rt, produced variable mixtures of
cycloadducts 2e:3e, depending upon the catalyst/additive used (Table 2, entries 6 and 7). Isomerized
adduct 2e was isolated as a single isomer by careful chromatography of these mixtures. In contrast, our
carbene at low temperature gave a fair yield of 3e, as a single isomer after chromatography, along with
a less polar fraction that contained unreacted conjugated 1,5-enyne (13%) present in this batch of
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starting material and a cycloisomerization derived indenyl diene of Z geometry, (Z)-3-(prop-1-enyl)-
1H-indene, that appears to be quite unreactive under these conditions.
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7
8
9
While 1,6-enynes bearing an aryl ring at C3-C4 are suitable substrates for [2+2+1] annulations with
N-hydroxyanilines12 and for [2+2+3] cycloadditions with nitrones,13 to the best of our knowledge, the
related [2+2+2] cycloadditions with aldehydes remain elusive, in sharp contrast with the structurally
related 1,7-enynes.6d In fact, it has been mentioned that these 1,6-enynes gave only cycloisomerization
instead of cycloaddition to benzaldehyde under certain gold-catalyzed conditions.6d This prompted us
to carry out exploratory experiments on these reactions and the results obtained are summarized in
Table 3.
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After some experimentation, we found that slow addition of a solution of enyne 1a to a solution of
our catalyst, NaBArF and 5 equiv of PhCHO, afforded oxacycle 6a as a single isomer in 70% yield
(Table 3, entry 1). In this manner, formation of homocycloaddition derived products (2a, 3a) and diene
4a was minimized. Switching the gold(I) source to Ph3PAuCl, (Table 3, entry 2) under identical
reaction conditions led to poor yields of a separable 60:40 mixture of 6a and diastereomer 7a, along
with substantial amounts of diene 4a and a small amount of 3a (50% and 8% conversion, respectively).
Finally, substrate 1b, with a MeO group para to the allyl moiety gave rise to oxacycle 6b as a single
isomer in 72% yield under catalysis by our gold carbene (Table 3, entry 3). The structure and relative
stereochemistry of compounds 6 was determined by detailed examination of their spectral data
including 2D NMR experiments that indicated a trans relationship for the key proton atoms (H1 and
H9a). The optical purity of these products was evaluated by chiral HPLC that indicated that they were
also racemic (see Supporting Information).
Table 3. Cycloisomerization-Cross-Cycloaddition Cascade of 1,6-Enynes with Benzaldehyde
under Gold(I) Catalysis.
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Entry 1
R1
Catalyst
Product (yield%)b [dr]c
3
4
5
6
6
7
4a
3a
1
1a
1a
H
H
SS-L1-AuCl
Ph3PAuCl
6a (70)
--
--
50 d
--
8d
2
6a (21) 7a (13)
7
8
[60:40]
9
3
1b MeO
SS-L1-AuCl
6b (72)
--
--
--
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a
Enyne 1 was added with a syringe pump (1 mL/h). The best yields were accomplished with 5
equiv of PhCHO. In all cases, the additive was employed in equimolar amount to the gold(I) catalyst. b
c
1
d
yields in parentheses. Diastereoisomeric ratio as determined by H NMR of the crude mixture. An
additional 50% conversion to 4a and 8% conversion to 3a was shown by the 1H NMR spectrum of the
crude.
A rationale to account for the formation and stereochemistry of benzaldehyde cycloadducts 6 is
shown in Scheme 2. A gold containing cationic species 9 formed by the accepted Au(I) cyclization of
enyne 1a through intermediate 8 is trapped by the aldehyde to form intermediate Au(I) species 11 and
12. These species evolve to products 6 (from 11) and 7 (from 12) by cationic cyclization and
deauration. Since the use of Ph3PAuCl to promote the cyclization leads to a 60:40 mixture of syn-anti
isomers 6 and 7 in low yield, the complete diastereoselectivity and enhanced yield found with our
sulfinyl gold carbene catalyst may be related with the sulfinyl moiety participating in the stabilization
of intermediate 11 to produce syn-isomer 6. This hypothesis requires that the cyclization of 9 and the
aldehyde through chair-like transition state 106d has to be reversible (Scheme 2).14 A similar stabilizing
effect of a cationic species by the sulfoxide moiety of catalyst SS-L1-AuCl, which determines in those
cases the reactivity or inertia of the catalyst has been reported recently by us.7 At this point we do not
have a full understanding of the nature of this stabilizing interaction.
Scheme 2. Plausible Reaction Pathway for the Gold(I) Catalyzed Reaction of 1a with PhCHO.
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H
2
3
LAu
d+
LAu
d+
LAu
O
4
5
1a
Ph
PhCHO
H
6
7
8
9
10
8
9
H
H
10
11
12
13
14
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18
19
20
LAu
LAu
O
O
+
O
Ph
Ph
H
Ph
H
H
6a
11
12
To clarify the reaction pathway of the cyclodimerization process, a crossover cycloisomerization-
dimerization experiment using a 50:50 mixture of 1a and 1b as starting material in the presence of SS-
L1-AuCl was carried out (Scheme 3). The resulting reaction mixture contained (1H NMR) an
equimolecular mixture of the four possible different cycloadducts (2a:2b:2ab:2ba), arising from “self-
condensation” 2a and 2b, and from “cross-condensation” 2ab and 2ba. It can be concluded that no
substrate discrimination occurs during the cyclization process.
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Scheme 3. Crossover in Cycloisomerization-Dimerization of 1a and 1b.
2a
2b
(21%)
(18%) +
OMe
3 mol% SS-L1-AuCl/NaBArF
CH2Cl2, 1 h, rt
1a : 1b
50 : 50
2ab (21%)
+
MeO
2ba
(20%)
In parallel to the mechanism depicted in Scheme 2, cyclization-deauration of intermediate 9 should
form 3-indenyl diene 4a (Scheme 4). Intermediate 9 reacts with diene 4a to produce a cyclized cation
14 through transition state 13. The reaction product 3a is formed from 14 following a pathway
analogous to the one depicted for aldehydes in Scheme 2. Allylic isomerization produced the
conjugated olefin 2a. It should be noted that formation of compound 3a is a formal Diels-Alder
reaction of indene 4a that did not take place in the absence of Au(I) except for stoichiometric amounts
of NaBArF (Table 1, entry 8). To rule out a possible Au(I) catalyzed Diels-Alder reaction, highly
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reactive dienophiles like methyl 3-methyl-2-butenoate and N-phenylmaleimide were added to the
reaction mixture. Diels-Alder adducts arising from diene 4a were not formed leading instead to
variable mixtures of 2a, 3a, and 4a. Other less reactive dienophiles in “normal” (1-hexene, 2-methyl-1-
phenyl-1-propene, phenylacetylene, 2,3-dimethyl-1,3-butadiene) or “inverse” Diels-Alder reaction
(ethyl vinyl ether) produced analogous results. Therefore, formation of compounds 3 parallels the
reaction of species 9 with aldehydes. This species may be formed directly from enyne 1a or from
indene 4a by Au(I) cycloreversion (Table 1, entry 5). Finally, regarding the NaBArF promoted
cycloisomerization-dimerization of enyne 1a (Table 1, entries 7 and 8), we have observed a similar
effect in the Nicholas reaction promoted by a Au(I) species.15 It is tempting to speculate that, at least
the self-cycloaddition of indenyl diene 4a, is facilitated by some anionic acceleration due to the mildly
basic NaBArF,16 though, extensive experimentation is needed to propose a reasonable reaction pathway
for these reactions.
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Scheme 4. Plausible Reaction Pathway for the Gold(I) Catalyzed Cycloisomerization-
Dimerization of 1a.
CONCLUSION
In summary, an unprecedented and facile gold(I) catalyzed cycloisomerization-dimerization cascade
of 1,6-enynes with a benzene tether at C3-C4 has been reported. The scope of this serendipitous finding
regarding the enyne substrates and the gold catalyst sources has been explored briefly and an
interesting NaBArF catalyzed cycloisomerization-dimerization process has been unveiled in this study.
In addition, these 1,6-enynes appear to be adequate substrates for a gold(I) carbene catalyzed process
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with benzaldehyde resulting in a highly diastereoselective [2+2+2] cycloaddition that had not been
previously reported in the literature. The presence of the sulfinyl ligand clearly influences the
selectivity of the cyclization with benzaldehyde.
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EXPERIMENTAL SECTION
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General synthetic methods.
Reagents and solvents were handled using standard syringe techniques. Anhydrous solvents were
purified by filtration on a solvent purification system (SPS). Crude products were purified by flash
chromatography on 230-400 mesh silica gel with distilled solvents. H and 13C NMR spectra were
recorded at 300, 400 or 500 MHz (1H NMR) and at 100 or 126 MHz (13C NMR) using CDCl3 and d3-
MeCN at 298K, unless otherwise stated. Chemical shifts are given in ppm. Only the characteristic
peaks in the infrared spectra (n max) are quoted. Optical rotations were measured with a 100 mm path
cell, at 20 ºC and using a sodium lamp. High resolution mass spectra (HRMS) were recorded using an
accurate mass QTOF spectrometer. HRMS MALDI/TOF spectra were recorded in TOF/TOF
spectrometer in positive mode of detection using dithranol as matrix.
1
Analytical chiral HPLC was performed with detection at 254 nm using a Chiralcel OD-H column.
Enynes 113 and catalysts SS-L1-AuCl and RS-L1-AuCl7 were synthesized as previously described.
4a8 and 511 have been previously reported and only their 1H NMR is given.
General procedure for the [2+2+2] cycloisomerization-dimerization cascades.
A mixture of the gold(I) catalyst and the activating agent (3-5% mol of each one) in 1 mL anhydrous
CH2Cl2 was prepared in a 2-necked round bottom flask under argon. A solution of the enyne (1 equiv,
0.10-0.17 mmol) in 1 mL anhydrous CH2Cl2 was then added in one portion, at rt (for 2) or at -10 ºC
(for 3). The reaction was monitored by TLC to assess the consumption of starting material and diene
1
and by H NMR to assess the 2:3 ratio. The reaction was filtered through a short pad of celite with
hexane or pentane and purified by flash chromatography on silica gelafter removal of solvents.
2-(1H-Inden-3-yl)-1,1,3,3-tetramethyl-2,3,4,9-tetrahydro-1H-fluorene (2a). Following the general
protocol, enyne 1a (19.3 mg, 0.113 mmol), SS-L1-AuCl (1.90 mg, 3.4 µmol, 3 mol%) and NaBArF
(3.01 mg, 3.4 µmol, 3 mol%) were mixed in 2 mL of CH2Cl2 under argon. After purification, 17.4 mg
of 2a (0.051 mmol, 90%) was obtained (Table 1, entry 1). Alternatively, reaction of RS-L1-AuCl (2.80
mg, 5.0 µmol, 3 mol%), NaBArF (4.40 mg, 5.0 µmol, 3 mol%) and enyne 1a (28.4 mg, 0.167 mmol) in
2 mL of CH2Cl2 gave 23.0 mg of 2a (0.068 mmol, 81%) after purification (Table 1, entry 2). Starting
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from 3a (32.6 mg, 0.096 mmol), SS-L1-AuCl (1.60 mg, 2.9 µmol, 3 mol%) and NaBArF (2.55 mg, 2.9
µmol, 3 mol%) in 2 mL CH2Cl2, 30.3 mg of 2a (0.089 mmol, 93%) was obtained (Table 1, entry 4).
Using Ph3PAuCl (3.2 mg, 6.4 µmol, 5 mol%), AgSbF6 (2.2 mg, 6.4 µmol, 5 mol%) and enyne 1a (28.4
mg, 0.167 mmol) in 2 mL of CH2Cl2, 19.7 mg of 2a (0.057 mmol, 90%) were isolated (Table 1, entry
11).
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Data for 2a: crystalline solid. Mp 108-110 ºC. Rf 0.18 (Hex). 1H NMR (400 MHz, CDCl3) δ 7.37 (m,
3H), 7.15 (m, 5H), 6.34 (s, 1H), 3.38 (s, 2H), 3.32 (s, 2H), 3.02 (s, 1H), 2.37 (br s, 2H), 1.23 (s, 3H),
1.09 (s, 3H), 1.01 (s, 3H), 0.84 (s, 3H). C{1H}NMR, HSQC, HMBC (100 MHz, CDCl3) δ 148.9,
13
148.6, 146.4, 143.3, 143.2, 143.1, 133.4 (C), 130.4, 126.3, 126.1, 124.5, 124.1, 123.7, 123.6, 119.2,
118.1, 51.7 (CH), 39.1, 38.5 (CH2), 37.5 (C), 36.5 (CH2), 35.1 (C), 32.4, 31.2, 25.2, 24.1 (CH3). IR
(KBr): 3042, 2960, 2888, 1629, 1605, 1470, 1458, 1393, 1380, 1362, 1260, 1210, 1019, 972, 778, 756,
719 cm-1. HRMS (ESI) m/z Calcd for C26H28 [M]+: 340.2186; Found 340.2185. Elemental analysis
calcd for C26H28: C, 91.71; H, 8.29; found: 91.65; H, 8.52. [ ]D25 ~ 0 (c = 1.0, CHCl3).
a
6-Methoxy-2-(5-methoxy-1H-inden-3-yl)-1,1,3,3-tetramethyl-2,3,4,9-tetrahydro-1H-fluorene
(2b).
Following the general protocol, SS-L1-AuCl (1.73 mg, 3.1 µmol, 3 mol%), NaBArF (2.75 mg, 3.1
µmol, 3 mol%) and enyne 1b (20.7 mg, 0.103 mmol) were mixed in 2 mL of CH2Cl2 to give 14.4 mg
of 2b (0.036 mmol, 69%) after purification (Hex:CH2Cl2) (Table 2, entry 1).
Data for 2b: crystalline solid. Mp 113-115 ºC. Rf 0.18 (Hex:CH2Cl2, 1:1). 1H NMR, COSY, NOESY
(400 MHz, CDCl3) d 7.30 (d, J = 8.1 Hz, 1H, H7’), 7.24 (d, J = 8.1 Hz, 1H, H8), 6.89 (d, J = 2.0 Hz,
1H, H4’), 6.76 (d, J = 2.2 Hz, 1H, H5), 6.70 (dd, J = 8.1, 2.0 Hz, 1H, H6’), 6.65 (dd, J = 8.1, 2.2 Hz,
1H, H7), 6.38 (s, 1H, H2’), 3.79 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.34 (s, 2H, H1’), 3.29 (s, 2H, H9),
2.95 (s, 1H, H2), 2.35 (s, 2H, H4), 1.23 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.86 (s, 3H). 13C{1H}NMR,
HSQC, HMBC (100 MHz, CDCl3) d 159.2, 159.0, 150.5, 150.2, 147.9, 143.0, 135.5, 135.3, 133.3 (C),
131.9 (C2’), 123.93, 123.89, 109.7 (2), 105.7, 104.2 (CH), 55.7 (2 CH3), 51.8 (CH, C2), 39.1 (C4),
37.8 (CH2, C1’), 37.6 (C), 35.8 (CH2, C9), 35.1 (C), 32.5, 31.2, 25.2, 24.1 (CH3). IR (KBr): 2958,
2885, 1618, 1607, 1475, 1362, 1286, 1214, 1160, 1032, 798 cm-1. HRMS (ESI) m/z Calcd for
C28H33O2 [M+H]+ 401.2475; Found 401.2493.
7-Methoxy-2-(6-methoxy-1H-inden-3-yl)-1,1,3,3-tetramethyl-2,3,4,9-tetrahydro-1H-fluorene
(2c).
Following the general protocol, SS-L1-AuCl (1.86 mg, 3.3 µmol, 3 mol%) was dissolved in CH2Cl2
under argon at -10 ºC. NaBArF (2.96 mg, 3.3 µmol, 3 mol%) and 1c (22.3 mg, 0.111 mmol) in 1 mL
CH2Cl2 were subsequently added. After 1h, the reaction was filtered through celite using hexane and
1
analyzed by H NMR, which indicated a 2c:3c 27:73 ratio (Table 2, entry 3). This mixture was
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redissolved in 1 mL of CH2Cl2 and added onto a mixture of SS-L1-AuCl (1.86 mg, 3.3 µmol, 3 mol%)
and NaBArF (2.96 mg, 3.3 µmol, 3 mol%) in 1 mL CH2Cl2 at rt. After 1h, filtration through celite
(hexane) and flash chromatography (Hex:CH2Cl2), 22.2 mg of 2c (0.055 mmol, 98 %) were obtained
(Table 2, entry 4).
Data for 2c: crystalline solid. Mp 162-164 ºC. Rf 0.17 (Hex:CH2Cl2, 3:2). 1H NMR, COSY, NOESY
(400 MHz, CDCl3) d 7.23 (d, J = 8.3 Hz, 1H, H4’), 7.07 (d, J = 8.3 Hz, 1H, H5), 7.03 (d, J = 1.8 Hz,
1H, H7’), 7.00 (d, J = 2.3 Hz, 1H, H8), 6.80 (d, J = 8.3 Hz, 2H, H6+H5’), 6.21 (s, 1H, H2’), 3.78 (s,
6H, 2OMe), 3.37 (s, 2H, H1’), 3.32 (s, 2H, H9), 2.96 (s, 1H, H2), 2.34 (s, 2H, H4), 1.23 (s, 3H), 1.10
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(s, 3H), 1.02 (s, 3H), 0.86 (s, 3H). C{1H}NMR, HSQC, HMBC (100 MHz, CDCl3) d 157.8, 157.6,
146.3, 145.04, 145.01, 142.7, 142.3, 139.7, 132.8 (C), 128.1 (C2’), 119.5, 118.2, 111.6, 111.5, 110.8,
110.2 (CH), 55.9, 55.7 (CH3), 51.9 (CH, C2), 39.2 (CH2, C4), 38.4 (CH2, C1’), 37.4 (C), 36.5 (CH2,
C9), 35.1 (C), 32.4, 31.2, 25.1, 24.1 (CH3). IR (KBr): 2960, 2925, 2875, 1608, 1595, 1482, 1467, 1381,
1283, 1240, 1225, 1121, 1027, 853, 815, 803 cm-1. HRMS (ESI) m/z Calcd for C28H33O2 [M+H]+
401.2475; Found 401.2475. Elemental analysis calcd for C28H32O2: C, 83.96; H, 8.05; found: 83.64;
H, 8.35.
(1RS,2SR,3RS)-2-(1H-Inden-3-yl)-1,3-dimethyl-2,3,4,9-tetrahydro-1H-fluorene (2e). Following the
general protocol, SS-L1-AuCl (2.29 mg, 4.1 µmol, 3 mol%), NaBArF (3.64 mg, 4.1 µmol, 3 mol%) and
enyne 1e (21.4 mg, 0.137 mmol) in 2 mL of CH2Cl2 were mixed at rt. After 1h and filtration through
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celite, H NMR indicated a 50:50 mixture of 2e:3e (Table 2, entry 6). Purification (hexane) gave 16.0
mg of the mixture of products (0.051 mmol, 74%). Alternatively, Ph3PAuCl (2.24 mg, 4.4 µmol, 3
mol%), AgSbF6 (1.5 mg, 4.4 µmol, 3 mol%) and enyne 1e (21.0 mg, 0.134 mmol) were mixed in 2 mL
1
of CH2Cl2 and protected from light. Analysis by H NMR after 1h and filtration through celite
indicated a 72:28 mixture of 2e:3e (Table 2, entry 7). Purification (hexane) gave 15.3 mg of combined
products (0.049 mmol, 73%). After a second careful chromatography pure 2e (5 mg) was isolated for
characterization.
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Data for 2e: colorless oil. Rf 0.17 (Hex). H NMR, COSY (500 MHz, CDCl3) d 7.50 (d, J = 7.3 Hz,
1H), 7.47 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.24–7.32 (m, 3H), 7.21 (t, J = 7.3 Hz, 1H),
7.15 (t, J = 7.3 Hz, 1H), 6.30 (t, J = 1.9 Hz, 1H, H2’), 3.46–3.38 (m, 3H, H1’ + H9a), 3.25 (d, J = 22.1
Hz, 1H, H9b), 3.00 (br s, 1H, H1), 2.73 (d, J = 15.7 Hz, 1H, H4a), 2.39 (t, J = 10.2 Hz, 1H, H2), 2.28–
1
2.42 (br s, 1H, H3), 2.18 (m, 1H, H4b), 1.07 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H). H
Homodecoupling (500 MHz, 318 K): JH1-H2= 8.4, JH2-H3= 10.8 Hz. NOESY 2D (400 MHz, 328 K):
13
correlation peaks between H2-Me1, H2-Me3, H1-H3, H2’-H3. C{1H}NMR, HSQC, HMBC (100
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MHz, CDCl3, 328 K) d 147.4 (br), 146.0, 145.4, 145.2, 143.4, 135.7 (C), 129.6 (br, C2’), 126.4, 126.0,
124.7, 124.1, 124.1, 123.6, 120.2, 118.1, 50.9 (br, CH, C2), 38.7 (C9), 37.9 (CH2, C1’), 37.1 (br, C1),
33.8 (br, CH, C3), 32.0 (CH2, C4), 20.7, 19.6 (CH3). IR (film): 3019, 2955, 2924, 2854, 1742, 1683,
1457, 1377, 1261, 1154, 968, 769, 719 cm-1. HRMS (MALDI/TOF) m/z Calcd for C24H23 [M+H]+
311.1799; Found 311.1785.
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(2SR,9aSR)-2-(1H-Inden-3-yl)-1,1,3,3-tetramethyl-2,3,9,9a-tetrahydro-1H-fluorene (3a). Following the
general protocol at -10 ºC, SS-L1-AuCl (1.95 mg, 3.5 µmol, 3 mol%), NaBArF (3.09 mg, 3.5 µmol, 3
mol%) and 1a (19.8 mg, 0.116 mmol) in 2 mL of CH2Cl2 yielded after purification (Hex) 18.0 mg of
3a (0.053 mmol, 91%), (Table 1, entry 3). Alternatively, reaction of 4a (10.2 mg, 0.060 mmol) with
NaBArF (53 mg, 0.060 mmol, 1 equiv) in 1 mL anhydrous CH2Cl2 afforded 8.17 mg (0.024 mmol,
79%) of 3a (Table 1, entry 6). Also, reaction of 1a (22.3 mg, 0.131 mmol) with NaBArF (116 mg,
0.060 mmol, 1 equiv) in 2 mL of CH2Cl2 afforded after 2 h 13.4 mg (0.039 mmol, 60%) of 3a (Table 1,
entry 7+8).
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Data for 3a: crystalline solid. Mp 133-135 ºC. Rf 0.17 (Hex). H NMR, COSY, NOESY (500 MHz,
CDCl3) d 7.52–7.42 (m, 3H), 7.32 (t, J = 7.5 Hz, 1H), 7.29–7.26 (m, 1H), 7.24–7.16 (m, 3H), 6.49 (t, J
= 2.0 Hz, 1H, H2’), 5.96 (d, J = 2.5 Hz, 1H, H4), 3.48 (dd, J = 4.1, 1.9 Hz, 2H, H1’), 3.08 (s, 1H, H2),
3.02–2.91 (m, 2H, H9a + H9a), 2.83 (dd, J = 14.4, 7.3 Hz, 1H, H9b), 1.20 (s, 3H), 1.08 (s, 3H), 1.00
(s, 3H), 0.81 (s, 3H). 1H NMR, COSY, NOESY (500 MHz, d3-MeCN) d 7.53–7.48 (m, 2H), 7.48–7.43
(m, 1H), 7.33–7.24 (m, 2H), 7.23–7.15 (m, 3H), 6.54 (t, J = 2.3 Hz, 1H, H2’), 6.01 (d, J = 2.9 Hz, 1H,
H4), 3.48 (s, 2H, H1’), 3.14 (s, 1H, H2), 3.02 (td, J = 8.6, 2.9 Hz, 1H, H9a), 2.95 (dd, J = 15.8, 8.9 Hz,
1H, H9a), 2.80 (dd, J = 15.8, 8.5 Hz, 1H, H9b), 1.20 (s, 3H), 1.06 (s, 3H), 0.95 (s, 3H), 0.78 (s, 3H).
NOESY 2D (500 MHz, d3-MeCN): correlation peaks between H2-H9a, H2-Me (0.78), H9a-Me (0.78).
13C{1H}NMR, HSQC, HMBC (126 MHz, CDCl3) d 149.0, 144.7, 143.3, 142.6, 141.2, 139.1 (C),
130.8 (C2’), 127.9 (C4), 127.7, 126.6, 126.1, 125.4, 124.4, 123.6, 120.3, 119.2, 53.7 (C9a), 52.8 (CH,
C2), 38.6 (CH2, C1’), 37.33, 37.25 (C), 33.0 (CH3), 32.2 (CH2, C9), 28.1, 26.7, 17.6 (CH3).
13C{1H}NMR, HSQC, HMBC (126 MHz, d3-MeCN) d 149.9, 145.6, 144.3, 143.1, 141.9 140.2 (C),
132.3 (C2’), 128.7, 128.4 (C4), 127.5, 126.9, 126.3, 125.3, 124.6, 121.0, 120.0, 54.1 (C9a), 53.2 (CH,
C2), 39.1 (CH2, C1’), 37.9, 37.8 (C), 32.9 (CH3), 32.6 (CH2, C9), 28.1, 27.0, 17.8 (CH3). IR (KBr):
2952, 2877, 1604, 1461, 1362, 1166, 975, 860, 755 cm-1. HRMS (ESI) m/z Calcd for C26H29 [M+H]+
341.2264; Found 341.2269. Elemental analysis calcd for C26H28: C, 91.71; H, 8.29; found: 91.81; H,
8.60. [ ]D25 ~ 0 (c = 0.64, CHCl3).
a
(2SR,9aSR)-6-Methoxy-2-(5-methoxy-1H-inden-3-yl)-1,1,3,3-tetramethyl-2,3,9,9a-tetrahydro-1H-
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fluorene (3b). Following the general protocol, SS-L1-AuCl (1.85 mg, 3.3 µmol, 3 mol%), NaBArF
(2.93 mg, 3.3 µmol, 3 mol%) and enyne 1b (22.1 mg, 0.110 mmol) were mixed in 2 mL of CH2Cl2
under argon at -10 ºC. After purification (Hex:CH2Cl2), 19.3 mg of 3b (0.048 mmol, 87%) was
isolated (Table 2, entry 2).
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Data for 3b: crystalline solid. Mp 152-154 ºC. Rf 0.23 (Hex:CH2Cl2, 3:2). 1H NMR, COSY, NOESY
(400 MHz, CDCl3) d 7.31 (d, J = 8.1 Hz, 1H, H7’), 7.09 (d, J = 8.2 Hz, 1H, H8), 6.92 (s, 2H, H5 +
H4’), 6.71 (m, 2H, H7 + H6’), 6.44 (s, 1H, H2’), 5.86 (d, J = 2.8 Hz, 1H, H4), 3.77 (s, 6H, 2OMe),
3.35 (s, 2H, H1’), 2.96–2.88 (m, 2H, H9a + H2), 2.81 (dd, J = 15.4, 8.7 Hz, 1H, H9a), 2.68 (dd, J =
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15.3, 8.3 Hz, 1H, H9b), 1.12 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.74 (s, 3H). C{1H}NMR, HSQC,
HMBC (126 MHz, CDCl3) d 159.1, 159.0, 150.7, 142.5, 142.4, 139.4, 136.9, 135.5 (C), 132.4 (C2’),
127.9 (C4), 126.0, 123.9, 115.0, 109.6, 105.7, 104.5 (CH), 55.7, 55.6 (CH3), 54.3 (C9a), 53.0 (CH, C2),
37.9 (CH2, C1’), 37.4, 37.3 (C), 33.0 (CH3), 31.4 (CH2, C9), 28.1, 26.8, 17.5 (CH3). IR (KBr): 2954,
2832, 1607, 1487, 1475, 1362, 1288, 1217, 1158, 1034, 841 cm-1. HRMS (ESI) m/z Calcd for
C28H33O2 [M+H]+ 401.2475; Found 401.2493. Elemental analysis calcd for C28H32O2: C, 83.96; H,
8.05; found: 83.82; H, 8.08.
(2SR,9aSR)-7-Methoxy-2-(6-methoxy-1H-inden-3-yl)-1,1,3,3-tetramethyl-2,3,9,9a-tetrahydro-1H-
fluorene (3c). Following the general protocol, SS-L1-AuCl (1.86 mg, 3.3 µmol, 3 mol%), NaBArF
(2.96 mg, 3.3 µmol, 3 mol%) and enyne 1c (22.3 mg, 0.111 mmol) reacted in 2 mL of CH2Cl2 at -10
ºC. Purification (Hex:CH2Cl2) gave 6.9 mg of 3c (0.017 mmol, 30%), which readily isomerized to a
27:73 mixture of 2c:3c (Table 2, entry 3).
Partial data for 3c from a 27:73 2c:3c mixture: Rf 0.18 (Hex:CH2Cl2, 3:2). 1H NMR, COSY, NOESY
(400 MHz, CDCl3) d 7.30 (d, J = 8.3 Hz, 1H, H4’ or H5), 7.23 (d, J = 8.3 Hz, 1H, H5 or H4’), 7.02 (d,
J = 2.3 Hz, 1H, H7’ or H8), 6.79 (dd, J = 8.3, 2.3 Hz, 1H, H5’ or H6), 6.74 (s, 1H, H8 or H7’), 6.71
(dd, J = 8.4, 2.1 Hz, 1H, H6 or H5’), 6.25 (s, 1H, H2’), 5.73 (d, J = 2.8 Hz, 1H, H4), 3.77 (s, 3H,
OMe), 3.75 (s, 3H, OMe), 3.37 (s, 2H, H1’), 2.92 (s, 1H, H2), 2.92–2.68 (m, 3H, H9a + H9a+ H9b),
1.10 (s, 3H), 0.99 (s, 3H), 0.91 (s, 3H), 0.73 (s, 3H). 13C{1H}NMR, HSQC, HMBC (100 MHz, CDCl3)
d 159.9, 157.8, 146.3, 145.0, 142.4, 142.2, 138.5, 134.2 (C), 128.5 (C2’), 125.9 (C4), 121.1, 119.5,
113.2, 111.6, 110.3, 110.2 (CH), 55.7, 55.6 (CH3), 54.1 (C9a), 53.0 (CH, C2), 38.5 (CH2, C1’), 37.4,
37.2 (C), 33.1 (CH3), 32.4 (CH2, C9), 28.2, 26.9, 17.5 (CH3). IR (film): 2926, 2855, 1741, 1683, 1482,
1466, 1381, 1289, 1244, 1226, 1141, 1111, 1033, 840, 805 cm-1. HRMS (ESI) m/z Calcd for C28H33O2
[M+H]+ 401.2475; Found 401.2475.
(1SR,2SR,3RS,9aSR)-2-(1H-Inden-3-yl)-1,3-dimethyl-2,3,9,9a-tetrahydro-1H-fluorene (3e). Following
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the general protocol, SS-L1-AuCl (2.31 mg, 4.1 µmol, 3 mol%), NaBArF (3.67 mg, 4.1 µmol, 3 mol%)
and enyne 1e (24.8 mg, 87% purity, 0.138 mmol) in 2 mL of CH2Cl2 were mixed at -10 ºC. Filtration
through celite and purification (hexane) gave 8.90 mg of 3e (0.029 mmol, 48%) and 2.81 mg of
unaltered 1,5 enyne (E)-1-(ethynyl)-2-(but-1-enyl)benzene (0.018 mmol, 13%) (Table 2, entry 8).
Data for 3e: colorless oil. Rf 0.19 (Hex). 1H NMR, COSY, NOESY (500 MHz, CDCl3) d 7.49 (dd, J =
7.1, 3.8 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.25–7.10 (m, 3H), 6.17–6.12 (m,
1H, H2’), 6.13 (t, J = 3.3 Hz, 1H, H4), 3.35–3.30 (m, 2H, H1’), 3.02–2.92 (m, 1H, H9a), 2.86 (s, 1H,
H2), 2.82–2.77 (m, 2H, H9), 2.77–2.70 (m, 1H, H3), 2.38–2.30 (m, 1H, H1), 1.29 (d, J = 7.6 Hz, 3H),
1.09 (d, J = 7.2 Hz, 3H). NOESY 2D (500 MHz, CDCl3): correlation peaks between H2’-H3, H3-H4.
13C{1H}NMR, HSQC, HMBC (126 MHz, CDCl3) d 149.3, 145.3, 145.2, 144.8, 141.2, 140.2 (C),
128.1 (C2’), 127.6, 126.5, 126.1, 125.4, 124.6, 124.1, 121.0 (C4), 120.2, 119.1, 45.8 (C2), 39.7 (CH,
C9a), 37.9 (CH2, C1’), 34.3 (CH, C3), 33.2 (CH2, C9), 31.6 (CH, C1), 23.8, 16.7 (CH3). IR (film):
3018, 2957, 2926, 2872, 1742, 1668, 1605, 1462, 1377, 1255, 1153, 1021, 969, 771, 754, 724 cm-1.
HRMS (MALDI/TOF) m/z Calcd for C24H23 [M+H]+ 311.1799; Found 311.1784.
3-(2-Methylprop-1-en-1-yl)-1H-indene (4a).8 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 7.3 Hz, 1H),
7.40 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.21 (td, J = 7.3, 1.3 Hz, 1H), 6.34 (s, 1H), 6.19 (m,
1H), 3.46 (s, 2H), 1.97 (s, 3H), 1.91 (s, 3H). HRMS (ESI) m/z Calcd for C13H15 [M+H]+ 171.1168;
Found 171.1170.
1,3-Dimethylnaphthalene (5).11 Following the general protocol, AgSbF6 (5.73 mg, 16.7 µmol, 5 mol%),
Ph3PAuCl (8.25 mg, 16.7 µmol, 5 mol%) and enyne 1d (52.1 mg, 0.334 mmol) were mixed in 5.2 mL
of CH2Cl2 and protected from light. After filtration through celite and purification (Hex), 33.0 mg of 5
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(0.212 mmol, 63%) were obtained. H NMR (300 MHz, CDCl3) δ 7.99–7.90 (m, 1H), 7.80–7.72 (m,
1H), 7.51–7.39 (m, 3H), 7.18 (s, 1H), 2.67 (s, 3H), 2.48 (s, 3H). MS (EI) m/z 156 (M+, 100), 141 (92),
128 (14), 115 (18).
Procedure for the cross cascade between 1a and 1b. Following the general protocol, to a mixture of
SS-L1-AuCl (3.11 mg, 5.6 µmol, 3 mol%) and NaBArF (4.94 mg, 5.6 µmol, 3 mol%) in 1.7 mL of
CH2Cl2 was added a solution of 1a (16.3 mg, 96 µmol, 0.53 equiv) and 1b (18.3 mg, 91 µmol, 0.50
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equiv) in 1.7 mL of CH2Cl2. After 1h, analysis by H NMR of the reaction crude indicated an
equimolar mixture of 2a:2b:2ab:2ba. Purification (Hex:CH2Cl2) gave 5.7 mg of 2a (0.017 mmol,
18%), 7.2 mg of 2ab (0.019 mmol, 21%), 6.7 mg of 2ba (0.018 mmol, 20%) and 7.4 mg of 2b (0.019
mmol, 21%).
Data for 2-(5-methoxy-1H-inden-3-yl)-1,1,3,3-tetramethyl-2,3,4,9-tetrahydro-1H-fluorene (2ab):
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colorless oil. Rf 0.39 (Hex:CH2Cl2, 2:1). H NMR, COSY (500 MHz, CDCl3) δ 7.44 (d, J = 7.3 Hz,
1H), 7.37 (d, J = 8.1 Hz, 1H, H7’), 7.30 (t, J = 7.3 Hz, 1H), 7.25 (d, J = 6.1 Hz, 1H), 7.17 (td, J = 7.3,
1.2 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H, H4’), 6.77 (dd, J = 8.1, 2.3 Hz, 1H, H6’), 6.45 (t, J = 1.8 Hz, 1H,
H2’), 3.84 (s, 3H, OMe), 3.41 (s, 4H, H9+H1’), 3.02 (s, 1H, H2), 2.47 (dt, J = 16.6, 2.1 Hz, 1H, H4),
2.41 (dt, J = 16.6, 3.3 Hz, 1H, H4), 1.30 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H), 0.93 (s, 3H). 13C{1H}NMR,
HSQC, HMBC (126 MHz, CDCl3) δ 158.9, 150.53, 148.6, 146.4, 143.2, 143.0, 135.5, 133.4 (C),
131.94 (C2’), 126.3, 124.1, 123.9 (C7’), 123.6, 118.1, 109.7 (C6’), 105.6 (CH, C4’), 55.7 (CH3), 51.8
(C2), 39.1 (CH2), 37.8 (CH2), 37.5 (C), 36.5 (CH2), 35.1 (C), 32.5, 31.2, 25.2, 24.1 (CH3). IR (film):
3046, 2961, 2888, 2833, 1618, 1607, 1573, 1472, 1396, 1381, 1363, 1289, 1265, 1217, 1180, 1166,
1147, 1052, 1033, 798, 759, 739, 722, 705 cm-1. HRMS (ESI) m/z Calcd for C27H31O [M+H]+:
371.2369; Found 371.2363.
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Data for 2-(1H-inden-3-yl)-6-methoxy-1,1,3,3-tetramethyl-2,3,4,9-tetrahydro-1H-fluorene (2ba):
colorless oil. Rf 0.35 (Hex:CH2Cl2, 2:1). 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 7.3 Hz, 1H), 7.41
(d, J = 7.6 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.1 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H, H5), 6.72
(dd, J = 8.0, 2.4 Hz, 1H, H7), 6.42 (t, J = 2.0 Hz, 1H, H2’), 3.86 (s, 3H, OMe), 3.46 (s, 2H, H1’), 3.35
(t, J = 2.4 Hz, 2H, H9), 3.09 (s, 1H, H2), 2.41 (s, 2H, H4), 1.30 (s, 3H), 1.16 (s, 3H), 1.09 (s, 3H), 0.91
(s, 3H). 13C{1H}NMR, HSQC, HMBC (126 MHz, CDCl3) δ 159.2, 150.2, 148.9, 147.9, 143.3, 143.2,
135.3, 133.3 (C), 130.4 (C2’), 126.1, 124.5, 123.9, 123.7, 119.2, 109.7 (C7), 104.2 (C5), 55.7 (CH3),
51.7 (CH, C2), 39.1 (CH2, C1’), 38.6 (CH2), 37.6 (C), 35.8 (CH2), 35.1 (C), 32.4, 31.2, 25.2, 24.1
(CH3). IR (film): 2962, 2887, 2833, 1618, 1607, 1574, 1475, 1381, 1287, 1265, 1214, 1163, 1033, 910,
858, 782, 760, 738, 722, 705 cm-1. HRMS (ESI) m/z Calcd for C27H31O [M+H]+: 371.2369; Found
371.2381.
General procedure for the [2+2+2] cycloisomerization-cross-cyclization cascades.
A mixture of the gold(I) catalyst (3% mol), the activating agent (3% mol) and benzaldehyde (5 equiv)
in 1 mL of anhydrous CH2Cl2 was prepared in a 2-necked round bottom flask under argon at rt. A
0.08–0.12 M solution of the enyne in anhydrous CH2Cl2 (1 equiv, 0.12 mmol) was slowly added (1
mL/h) by a syringe pump. After completion of the addition, the crude was filtered through a short pad
of celite and purified by flash chromatography on silica gel.
(1SR,9aSR)-3,3-Dimethyl-1-phenyl-1,3,9,9a-tetrahydroindeno[2,1-c]pyran (6a). Following the general
protocol, 1a (19.2 mg, 0.113 mmol) in 1 mL of CH2Cl2 was slowly added (1 mL/h) to a mixture of SS-
L1-AuCl (1.89 mg, 3.4 µmol, 3 mol%), NaBArF (3.00 mg, 3.4 µmol, 3 mol%) and benzaldehyde (57.4
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µL, 0.56 mmol, 5 equiv) in CH2Cl2. Purification (Hex:CH2Cl2) afforded 21.9 mg of 6a (0.079 mmol,
70%) and 3.1 mg 3a (0.009 mmol, 16%) (Table 3, entry 1).
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Data for 6a: crystalline solid. Mp 64-66 ºC. Rf 0.23 (Hex:CH2Cl2,10:1). H NMR, COSY, NOESY
(500 MHz, CDCl3) d 7.48–7.41 (m, 3H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.24–7.16
(m, 3H), 5.96 (d, J = 2.8 Hz, 1H, H4), 4.48 (d, J = 9.5 Hz, 1H, H1), 3.09 (dddd, J = 9.5, 8.7, 8.6, 2.8
Hz, 1H, H9a), 2.78 (dd, J = 15.7, 8.6 Hz, 1H, H9a), 2.64 (dd, J = 15.7, 8.7 Hz, 1H, H9b), 1.48 (s, 3H),
1.41 (s, 3H). NOESY 2D (400 MHz): correlation peaks between H9a-H9, H1-H-9, H1-Me, H1-ArH.
13C{1H}NMR, HSQC, HMBC (126 MHz, CDCl3) d 144.5, 141.7, 140.9, 140.4 (C), 128.7 (Ph-2Cmeta),
128.3, 128.0, 127.1 (Ph-2Cortho), 126.9, 125.3, 124.3 (C4), 120.7, 77.6 (CH, C1), 74.6 (C), 46.7 (CH,
C9a), 33.9 (CH2, C9), 29.9, 27.2 (CH3). IR (KBr): 3034, 2970, 2923, 1604, 1462, 1358, 1230, 1157,
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1039, 750, 701 cm . HRMS (ESI) m/z Calcd for C20H21O [M+H] 277.1587; Found 277.1594. [ ]D
~ 0 (c = 1.0, CHCl3).
(1SR,9aRS)-3,3-Dimethyl-1-phenyl-1,3,9,9a-tetrahydroindeno[2,1-c]pyran (7a). Following the general
protocol enyne 1a (20.7 mg, 0.122 mmol), Ph3PAuCl (1.80 mg, 3.7 µmol, 3 mol%), NaBArF (3.24 mg,
3.7 µmol, 3 mol%) and benzaldehyde (18.6 µL, 0.183 mmol, 1.5 equiv) in 2 mL of CH2Cl2 gave after
purification (Hex:EtOAc, 99:1) 7.1 mg of 6a (0.026 mmol, 21%) and 4.4 mg of 7a (0.016 mmol, 13%)
(Table 3, entry 2). 4a (50%) and 3a (8%) were also identified in the reaction mixture by 1H NMR.
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Data for 7a: crystalline solid. Mp 75-77 ºC. Rf 0.09 (Hex:EtOAc, 99:1). H NMR, COSY, NOESY
(500 MHz, CDCl3) d 7.49 (d, J = 6.8 Hz, 1H), 7.28 (dd, J = 7.8, 1.9 Hz, 2H, Ph-Hortho), 7.25–7.16 (m,
6H), 6.12 (d, J = 3.3 Hz, 1H, H4), 5.37 (d, J = 7.3 Hz, 1H, H1), 3.50 (dddd, J = 9.3, 8.2, 7.3, 3.3 Hz,
1H, H9a), 2.92 (dd, J = 16.2, 9.3 Hz, 1H, H9a), 2.62 (dd, J = 16.2, 8.2 Hz, 1H, H9b), 1.41 (s, 3H), 1.08
(s, 3H). NOESY 2D (400 MHz): correlation peaks between H9a-H9, H1-H-9a, H1-Me, H1-ArH.
13C{1H}NMR, HSQC, HMBC (126 MHz, CDCl3) d 144.5, 140.8, 140.1, 139.8 (C), 128.9 (Ph-2Cortho),
128.5, 128.2 (Ph-2Cmeta), 127.5, 125.7, 124.4, 124.3 (C4), 120.7, 75.8 (CH, C1), 72.5 (C), 41.2 (CH,
C9a), 34.4 (CH2, C9), 29.5, 29.2 (CH3). IR (KBr): 3018, 2961, 1602, 1461, 1356, 1269, 1155, 1032,
754, 700 cm-1. MS (EI) m/z 276 (M+, 6), 261 (75), 170 (100), 155 (81).
(1SR,9aSR)-6-Methoxy-3,3-dimethyl-1-phenyl-1,3,9,9a-tetrahydroindeno[2,1-c]pyran (6b). Following
the general protocol enyne 1b (22.7 mg, 0.113 mmol), SS-L1-AuCl (1.90 mg, 3.4 µmol, 3 mol%),
NaBArF (3.01 mg, 3.4 µmol, 3 mol%) and benzaldehyde (57.7 µL, 0.57 mmol, 5 equiv) in 2 mL of
CH2Cl2 gave after purification (Hex:CH2Cl2) 24.8 mg of 6b (0.081 mmol, 72%) and 3.3 mg 3b (0.008
mmol, 14%) (Table 3, entry 3).
Data for 6b: colorless oil. Rf 0.18 (Hex: CH2Cl2, 1:1). 1H NMR, COSY, NOESY (500 MHz, CDCl3) d
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7.45 (d, J = 7.3 Hz, 2H, Hortho), 7.38 (t, J = 7.3 Hz, 2H, Hmeta), 7.30 (t, J = 7.3 Hz, 1H, Hpara), 7.09 (d, J
= 8.2 Hz, 1H, H8), 6.95 (d, J = 2.5 Hz, 1H, H5), 6.76 (dd, J = 8.2, 2.5 Hz, 1H, H7), 5.94 (d, J = 2.9 Hz,
1H, H4), 4.47 (d, J = 9.5 Hz, 1H, H1), 3.82 (s, 3H), 3.10 (dddd, J = 9.5, 8.6, 8.5, 2.9 Hz, 1H, H9a),
2.71 (dd, J = 15.3, 8.6 Hz, 1H, H9a), 2.57 (dd, J = 15.3, 8.5 Hz, 1H, H9b), 1.48 (s, 3H), 1.40 (s, 3H).
NOESY 2D (400 MHz): correlation peaks between H9a-H9, H1-H-9, H1-Me, H1-ArH. 13C{1H}NMR,
HSQC, HMBC (126 MHz, CDCl3) d 159.2, 141.7 (2C), 141.1, 136.7 (C), 128.7 (Ph-Cmeta), 128.0 (Ph-
2Cpara), 127.1 (Ph-2Cortho), 125.9 (C8), 124.3 (C4), 115.2 (C7), 105.1 (C5), 77.5 (CH, C1), 74.6 (C),
55.7 (CH3), 47.4 (CH, C9a), 33.1 (CH2, C9), 29.9, 27.2 (CH3). IR (film): 2969, 2932, 2855, 1679,
1610, 1487, 1466, 1454, 1358, 1328, 1285, 1238, 1176, 1147, 1032, 840, 745, 700 cm-1. HRMS (ESI)
m/z Calcd for C21H23O2 [M+H]+ 307.1698; Found 307.1750.
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Crystal data:
Data were collected at low temperature using oil-coated shock-cooled crystals on a Bruker-AXS APEX
II diffractometer with MoKa radiation (λ = 0.71073 Å). The structure was solved by direct methods17
and all non hydrogen atoms were refined anisotropically using the least-squares method on F2.18
Crystal data for 2a: Crystals were obtained by slow evaporation of a concentrated solution of
compound 2a in hexanes. C26H28, Mr = 340.48, crystal dimensions 0.4 x 0.3 x 0.3 mm3, monoclinic,
P21/c, a = 8.125(1) Å, b = 21.014(2) Å, c = 11.266(2) Å, β = 99.032(3)°, cell volume = 1899.6(3) Å3, Z
= 4, ρcalcd = 1.191 Mg/m3, µ = 0.067 mm–1, T = 100(2) K, 2θmax = 52.7°, 31344 reflections collected,
3861 independent, Rint = 0.1211, R1 = 0.0496 and wR2 = 0.1002 for I > 2σ(I), R1 = 0.0961 and wR2 =
0.1174 for all data, residual electron density = 0.244eA–3.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
* Miguel A. Sierra, sierraor@ucm.es
* María C. de la Torre, mc.delatorre@csic.es
* Alma Viso, almaviso@iqog.csic.es
ORCID
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Miguel A. Sierra, 0000-0002-3360-7795
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María C. de la Torre, 0000-0002-7310-8202
Alma Viso, 0000-0003-2622-4777
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Roberto Fernández de la Pradilla, 0000-0002-6633-8499
Mónica Álvarez-Pérez 0000-0001-8305-8694
María Frutos, 0000-0003-4700-874X
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Heinz Gornitzka, 0000-0002-8838-5907
Catherine Hemmert, 0000-0002-8122-5177
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Support for this work under grants (CTQ2013-46459-C2-01-P to MAS, CTQ2013-46459-C2-02-P to
MCT, CTQ2014-51912-REDC Programa Redes Consolider) from the MINECO (Spain) is gratefully
acknowledged. Prof. R. Martínez-Álvarez (UCM) is acknowledged by his help in recording the
MALDI spectra.
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Copies of 1D and 2D NMR spectra of compounds 2, 3, 6 and 7 and 1H NMR of 4a and 5 and HPLC
profiles for 3a and 6a. Thermal ellipsoid plot for the crystal structure of 2a.
REFERENCES
(1) (a) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028–9072. (b) Obradors, C.; Echavarren,
A. M. Acc. Chem. Res. 2014, 47, 902–912.
(2) (a) Nieto-Oberhuber, C.; López, S.; Jiménez-Núñez, E.; Echavarren, A. M. Chem. Eur. J. 2006,
12, 5916–5923. (b) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350. (c)
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