Gold(i)-catalyzed diastereoselective synthesis of 1-α-oxybenzyl-1: H -indenes

Article abstract of DOI:10.1039/c8ob00406d

The gold(i)-catalyzed oxycyclization of β-aryl monosubstituted o-(alkynyl)styrenes gives rise to 1-α-methoxy or 1-α-hydroxybenzyl-1H-indenes in a diastereospecific way. In contrast to β,β-disubstituted o-(alkynyl)styrenes, the stereochemical outcome of this process, diastereospecific reaction supports the higher contribution of a gold intermediate with a cyclopropylcarbene-like character.

Full text of DOI:10.1039/c8ob00406d

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C8OB00406D
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Gold(I)‐catalyzed diastereoselective synthesis of 1‐‐oxybenzyl‐
1H‐indenes†
Received 00th January 20xx,
Accepted 00th January 20xx
Cintia Virumbrales, Samuel Suárez‐Pantiga, Marta Solas, Manuel A. Fernández‐Rodríguez and
Roberto Sanz*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The gold(I)‐catalyzed oxycyclization of ‐aryl monosubstituted o‐ catalysis.11 Using these
,‐disubstituted o‐(alkynyl)styrenes,
(alkynyl)styrenes gives rise to 1‐‐methoxy or 1‐‐hydroxybenzyl‐ and external oxygen nucleophiles, we have been able to
1H‐indenes in a diastereospecific way. In contrast with ,‐ prepare 1‐alkoxy‐ or 1‐hydroxy‐dialkylmethyl‐1H‐indenes.
disubstitued o‐(alkynyl)styrenes, the stereochemical outcome of However, when these starting materials possess two different
the process, diastereospecific reactions, supports the higher groups at the
‐position the stereoselectivity of the cyclization
contribution of a gold intermediate with cyclopropylcarbene‐like had not been properly established in our previous work, and
character.
we assumed that the oxycyclization was not stereospecific
likely due to a high contribution of a gold‐stabilized
homoallylic carbocation species as intermediate (Scheme 1a).8c
At this point, we decided to explore the gold‐catalyzed
Gold‐catalyzed cycloisomerization reactions of 1,n‐enynes
have received a good deal of attention in the last years
providing versatile routes to interesting carbocyclic structures
not easily prepared by classical methods.1 In this context, 1,5‐
enyne cycloisomerizations involving almost always 5‐endo‐dig
cyclizations2 have been less developed, despite their synthetic
usefulness for the preparation of interesting cyclopentene
derivatives.3 In this field, our group and others have been
specially interested in the study of the reactivity of o‐
(alkynyl)styrenes,4 as a particular type of 1,3‐dien‐5‐ynes.5
Although most of the previously reported cycloisomerizations
of o‐(alkynyl)styrenes led to naphthalene derivatives through
formal 6‐endo cyclizations,6 considering Gagosz and co‐
workers´ report about the synthesis of cyclopentenes through
5‐endo alkoxycyclization of 3‐acetoxy‐1,5‐enynes,7 we first
demonstrated that the corresponding 5‐endo cyclization
pathway could be induced by a proper selection of the olefin
nucleophilic additions to
‐aryl‐monosubstituted o‐
(alkynyl)styrenes.12 In this case two major issues, regio‐ and
stereoselectivity, should be addressed. Firstly, for the initial
substitution pattern. We found that
,‐disubstituted o‐
(alkynyl)styrenes undergo selectively 5‐endo cyclizations, using
cationic gold complexes bearing triphenyl phosphine as ligand
both in the presence or absence of silver salts.8 In this way,
indene derivatives, which are privileged scaffolds mainly due
to their applications in materials science and as ligands for
metallic catalysts,9 are easily accessed from simple starting
materials.10 After our seminal work, different authors have
reported related 5‐endo cyclizations of
,‐disubstituted o‐
(alkynyl)styrenes under gold‐ and other transition metal‐
Área de Química Orgánica, Departamento de Química, Facultad de Ciencias,
Universidad de Burgos, Pza. Misael Bañuelos s/n, 09001 Burgos, Spain.
E‐mail: rsd@ubu.es
† Electronic Supplementary Information (ESI) available: Experimental details,
characterization data, NMR spectra of all products. CCDC 1585617 for 3i. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x
Scheme 1 Gold(I)‐catalyzed alkoxycyclization of ,‐disubstituted o‐(alkynyl)styrenes
(previous work) and ‐monosubstituted o‐(alkynyl)styrenes (this work).
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olefin attack, triggered by the gold‐activation of the alkyne, a halved without a serious impact on the reaction outcome
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regioisomeric 6‐endo cyclization could be competitive with the (entry 8), supporting its remarkably hiDgOhI:a1c0t.1iv0i3t9y/Cf8oOrBa00w40id6De
previously reported 5‐endo as the positive charge would be variety of Au‐catalyzed transformations that had been
located at secondary carbons in the carbocationic‐like elegantly shown by Gagosz and co‐workers.14 A brief silver salt
intermediate for both types of ring closures (Scheme 1b). screening showed no beneficial silver effect or improvement
Secondly, the stereochemical outcome of these reactions, i.e. for this process (entries 911). Remarkably, in all the tests only
stereospecific or non‐stereospecific nature of the process, one diastereoisomer of indene 2a was observed in the 1H NMR
could contribute to shed light about the controversial of the crude reaction mixture, whose stereochemistry was
character of the involved gold intermediates, which could be initially assigned based on previous literature reports.7a
also influenced by the nature of the ligands on the gold
catalyst.13 Herein, we want to report our results about the complexes with highly electron‐donating ligands, such as
nucleophilic additions to ‐aryl‐monosubstituted o‐ NHCs, enhance the carbene‐like character of the gold
(alkynyl)styrenes under gold‐catalysis, which take place intermediates in cyclizations of 1,5‐enynes.13 Considering this
selectively through 5‐endo cyclizations and in
fact in the context of the ligand effects in gold catalysis,15
diastereospecific manner leading to new family of these preliminary results seem to support that the reactions of
these ‐aryl monosubstituted o‐(alkynyl)styrenes would take
‐phenyl o‐ place through an intermediate that requires a higher
Echavarren and co‐workers had established that gold

a
a
functionalized indene derivatives (Scheme 1c).

1
To perform our goal, we selected (E)‐

(alkynyl)styrene 1a as model substrate and treated it with an retrodonation of gold to stabilize the initially generated
excess of MeOH in CH2Cl2 under the catalysis of a selection of carbocation and so, they proceed more efficiently with
gold complexes (Table 1). In a first attempt, 1a was treated complexes bearing donor ligands.
with Ph3PAuNTf2 and after 1 h we observed the partial but
stereospecific formation of 1‐ ‐methoxybenzyl‐1H‐indene 2a proceeded to evaluate the behaviour of a series of
(entry 1). A similar result was obtained when using the (alkynyl)styrenes . As shown in Table 2, the transformation
catalytic system Ph3PAuCl/AgSbF6 that we had previously used was suitable for a variety of starting substrates 1a‐e bearing
for the methoxycyclization of ‐disubstituted o‐ different substituents at the triple bond, including
(alkynyl)styrenes (entry 2). A slightly better result was (hetero)aromatic, alkyl, alkenyl, and arylthio groups (entries
displayed by gold catalyst bearing a phosphite ligand (entry 3), 7). Interestingly, starting from geometrically pure E‐isomers
whereas complete conversions were obtained when gold of the o‐(alkynyl)styrenes 1a‐e the corresponding
complexes with bulky biarylphosphines as ligands were methoxybenzyl indenes 2a‐e were obtained in high yields, and
employed (entries 4 6). However, the best yield was obtained as single diastereoisomers in all the cases, showing the
With the optimized reaction conditions in hand, we


‐aryl o‐
1
,
1

,

using the NHC‐gold(I) complex IPrAuNTf2, possessing the potential of this reaction as a wide variety of groups are
weakly coordinating counteranion Tf2N and a highly electron‐ allowed to be present in the starting alkyne. In addition, we
donating ligand (entry 7). Moreover, the catalyst load could be have also checked that the stereoinformation of the alkene is
finely transferred to the final cyclizated product, as using 1a as
Table 1 Effect of the gold catalyst on the methoxycyclization of (E)‐‐phenyl o‐
a ca. 1/1 mixture of geometrical isomers led to the
corresponding indene 2a as ca. 1/1 mixture of
diastereoisomers (entry 2). Moreover, using (Z)‐1b as starting
material the other diastereoisomer of 2b diast‐2b) was
(alkynyl)styrene 1aa
a
(
selectively formed (entries 3 vs. 4), thus proving the
stereospecificity of the reaction. Regarding the aryl substituent
at the ‐position of the olefin, p‐tolyl‐ as well as 1‐naphthyl‐
Entry Catalyst
Conversion (%)b
76
66
97
100
100
100
100
100
100
100
100
Yield (%)c
51
54
65
76
62
84
89
84
63
79
86
substituted o‐(alkynyl)styrenes 1f‐i behaved the same way as
parent 1a providing high yields of the corresponding indene
derivatives 2f‐i and with complete control of the
stereochemical outcome of the reactions determined by the
1
Ph3PAuNTf2
2
3
4
Ph3PAuCl/AgSbF6
[(3,5‐t‐Bu)2C6H3O3]3AuCl/AgNTf2
XPhosAuNTf2
stereochemistry of the starting enyne (entries
Moreover, substrates bearing functionalized aryl groups, such
as 1j and 1k also methoxycyclized leading to the
corresponding indenes 2j and 2k in good yields and in a
diastereospecific manner (entries 12 13). Interestingly, with o‐
811).
5
6
BrettPhosAuNTf2
JohnPhosAuNTf2
IPrAuNTf2
7
,
8d
9
IPrAuNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgSbF6
IPrAuCl/AgBF4

10
11
(alkynyl)styrene 1k possessing a butyl group as alkyne
substituent the methoxycyclization of the E‐isomer was found
to be slower than the Z‐isomer leading, in the first case, to
competitive addition of methanol to the triple bond (entry 13).
Finally, o‐(alkynyl)styrenes 1l and 1m, functionalized with an
a Reactions conducted using 0.1 mmol of 1a in CH2Cl2 (0.8 mL). b Determined by
1H NMR analysis of the crude reaction mixture. Determined by 1H NMR using
c
CH2Br2 as internal standard. When the NMR yield is significantly lower than the
conversion several unidentified products were observed. Carried out with 2.5
mol% of catalyst.
d
electron‐rich 4‐methoxyphenyl group at the ‐position, were
2 | J. Name., 2012, 00, 1‐3
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hydroxycyclization under the standard conditions, resulting in
Table
2
Gold‐catalyzed methoxycyclization of ‐aryl o‐(alkynyl)styrenes 1.
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3
iDnOhI:i1g0h.10y3ie9/ldCs8OaBn0d04i0n6Da
Diastereospecific synthesis of 1‐methoxybenzyl‐1H‐indenes 2a
formation of the expected alcohols
stereospecific manner. As established above, the nucleophilic
addition of water to (E)‐1a afforded one diastereoisomer of 3a
whereas starting from a mixture of geometrical isomers of 1a
led to hydroxyindene derivative 3a as mixture of
,
a
diastereoisomers (entries 1 vs. 2). A similar result was
observed for o‐(alkynyl)styrene 1b bearing a butyl group as
substituent of the triple bond (entries 3 vs. 4). Starting enynes
1c‐e, possessing different groups at the triple bond, also
efficiently underwent the hydroxycyclization reaction giving
rise to the corresponding alcohols as single diastereoisomers
although with 1e no complete conversion was achieved under
Entry 1
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R
Ph
Ph
E/Z
>20/1 2a
1/1 2a
>20/1 2b
<1/20 diast‐2b >20/1 87
2
d.r.b
>20/1 93
1/1 86
>20/1 91
Yield (%)c
1
2
3
4
5d
6
7
8
9
1a
1a
1b
1b
1c
1d
1e
1f
n‐Bu
n‐Bu
c‐C6H9
3‐Thf
SPh
Ph
n‐Bu
Ph
n‐Bu
Ph
e
>20/1 2c
>20/1 2d
>20/1 2e
>20/1 2f
>20/1 2g
>20/1 2h
>20/1 2i
>20/1 2j
>20/1 82
>20/1 87
>20/1 90
>20/1 86
>20/1 75
>20/1 88
>20/1 91
>20/1 85
these conditions (entries 5
(alkynyl)styrenes , bearing different aryl groups at the
position of the olefin, 1h,i,l,m also provided access to the
corresponding 1‐( ‐hydroxybenzyl)indenes in good yields
(entries 8 11), although with butyl‐substituted starting o‐
7). In addition, selected starting o‐
1
‐
4‐MeC6H4
4‐MeC6H4
1‐naphthyl
1‐naphthyl
4‐ClC6H4
4‐ClC6H4
4‐MeOC6H4
4‐MeOC6H4
1g
10 1h
11 1i
12 1j
13g 1k
14 1l
15 1l

3

(alkynyl)styrene 1i complete conversion was again not
achieved (entry 9). Analogous to what was observed in its
methoxyclization, when o‐(alkynyl)styrene 1l, bearing an
electron‐rich 4‐methoxyphenyl group as aryl substituent of the
alkene, was used as starting material the diastereospecificity
was practically lost and the corresponding hydroxyindene
derivative 3l was obtained as a mixture of diastereoisomers
(entry 10). Moreover, in order to unambiguously establish the
relative stereochemistry of the diastereoisomer generated in
these gold‐catalyzed methoxy‐ and hydroxycyclizations of o‐
n‐Bu
Ph
Ph
<1/20 diast‐2k >20/1 88
>20/1 2l
16/1
1/5
9/1
86
83
70
1/8
9/1
2l
2m
16 1m 4‐MeOC6H4
n‐Bu
a Reactions conducted using 0.3 mmol of o‐(alkynyl)styrene derivative 1 in CH2Cl2
(1 mL) at RT. Determined by 1H NMR analysis of the crude reaction mixture.
b
c
d
e
Isolated yield of product based on starting material 1. Reaction time = 48 h.
Cyclohexen‐1‐yl. f 3‐Thienyl. g Reaction time = 4 h. When the reaction was carried
out with (E)‐1k sub‐products derived from competitive attack of MeOH to the
triple bond were also formed, although 2k was also formed with d.r. > 20/1.
(alkynyl)styrenes 1, the structure of 3i was further assigned by
X‐ray analysis.18
subjected to the standard conditions giving rise to the
methoxy‐functionalized indene derivatives 2l and 2m in high
Having determined that the methoxycyclization reaction of
‐aryl o‐(alkynyl)styrenes is stereospecific, i.e. the
yields (entries 14
minor loss of the stereospecificity (entries 14

16). The reactions of 1l take place with a
15), likely due to

1

stereoinformation is completely transferred in most of the
a competitive contribution of the carbocationic like‐character
of the gold intermediate considering the ability of the 4‐
methoxyphenyl group to stabilize carbocations at the benzylic
position. A similar observation had been reported by
Echavarren et al. in the alkoxycyclization of 1,6‐enynes.16
As we had previously demonstrated that water could also
be a useful nucleophile for the hydroxycyclization reactions of
Table 3 Gold‐catalyzed hydroxycyclization of ‐aryl o‐(alkynyl)styrenes 1. Synthesis of
1‐(1‐hydroxybenyl)‐1H‐indenes 3a
,
‐disubstituted o‐(alkynyl)styrenes,8c we decided to check if
Entry
1d
2
3
4
5
6
7
8
1
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R
Ph
Ph
E/Z
>20/1 3a
1/1 3a
>20/1 3b
1/1 3b
>20/1 3c
>20/1 3d
>20/1 3e
>20/1 3h
>20/1 3i
>20/1 3l
>20/1 3m
3
d.r.b Yield (%)c
>20/1 76
1/1 76
>20/1 77
1/1 72
>20/1 70
>20/1 75
>20/1 60g
>20/1 79
>20/1 53h
3.5/1 65
>20/1 63
this process also works with ‐aryl o‐(alkynyl)styrenes 1. After
1a
1a
1b
1b
1c
1d
1e
1h
1i
some experimentation with model 1a we found that the use of
a mixture of CH2Cl2 and dioxane as solvent allows external
water to participate in the cyclization leading to the formation
n‐Bu
n‐Bu
c‐C6H9
3‐Thf
SPh
Ph
n‐Bu
Ph
n‐Bu
e
of 1‐(‐hydroxybenzyl)‐1H‐indene 3a that was obtained in
good yield and as a single diastereoisomer (Table 3, entry 1).
Remarkably, in the optimization study for this process we
observed no hydroxycyclization for 1a in the presence of
Ph3PAuNTf2 or (PhO)3PAuCl/AgSbF6 as catalysts,17 showing
again the superior activity of the gold complex bearing the
1‐naphthyl
1‐naphthyl
4‐MeOC6H4
4‐MeOC6H4
9
10
11
1l
1m
NHC ligand for the cyclizations of
(alkynyl)styrenes. Taking into account the potential synthetic
interest of 1‐( ‐hydroxybenzyl)‐1H‐indenes for further
transformations, we decided to prepare variety of
hydroxycyclizated products . A selection of starting (E)‐
o‐(alkynyl)styrenes efficiently underwent
‐monosubstituted o‐
a
Reactions conducted using 0.3 mmol of o‐(alkynyl)styrene derivative 1 in a 1:1
mixture of CH2Cl2 and 1,4‐dioxane (1.6 mL) at rt. Determined by 1H NMR
analysis of the crude reaction mixture. Isolated yield of product based on
starting material 1. Reaction time = 4 h. Cyclohexen‐1‐yl. 3‐Thienyl. ~80%
conversion. ~65% conversion despite an additional load of 2.5 mol % of the
b

c
a
d
e
f
g
3

‐aryl
h
1
the
catalyst was added.
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cases from the alkene to the final indene, we wondered if this
fact is also true for ‐disubstituted o‐(alkynyl)styrenes as it
had not been properly established in our previous reports
(Table 4).8c When (Z)‐
‐methyl‐ ‐phenyl o‐(alkynyl)styrene 4a
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DOI: 10.1039/C8OB00406D

,

4


was used as starting enyne the corresponding
methoxycyclizated indene 5a was obtained as a single
diastereoisomer, under the same conditions described for
1
(entry 1). Moreover, almost the same result was obtained
using gold complexes bearing Ph3P as ligand in the presence or
absence of silver salts (entries 23). In this case, the similar
reactivity of substrate 4a in the presence of the gold catalyst,
bearing both the NHC and the phosphine ligands, is not
surprising due to the higher nucleophilic nature of the
trisubstituted alkene that would contribute to stabilize the
carbocationic‐like character of the intermediate. However,
submission of o‐(alkynyl)styrene 4b, with an ethyl substituent
Scheme 2 Mechanistic proposal
catalyzed enyne cyclizations,13 a likely mechanism to account
for the observed stereoselectivity issues is outlined in Scheme
2. An initial activation of the alkyne through coordination of
cationic gold(I) triggers the attack of the olefin moiety through
a 5‐endo cyclization to give intermediate cyclopropyl carbene
instead of a methyl one at the
‐position, to the same
conditions resulted in an almost complete loss of
stereospecificity (entry 4). Intrigued by this result, other o‐
A
, which has an alkenylgold carbocation mesomeric form A´
Whereas attack of the O‐nucleophile to would ensure a
stereospecific process leading to the vinyl gold species that
would be subsequently protodemetalated to afford the
functionalized indenes and , the competitive contribution of
.
A
(alkynyl)styrenes
4 with different substituents at the ‐
B
positions were also tested. With 4c, bearing a propyl group as
R substituent, the corresponding methoxycyclizated product
5c was obtained as a mixture of diastereoisomers clearly
different from the mixture of geometrical isomers of the
starting material (entry 5). A similar behaviour was observed
for substrates 4d (Ar = 4‐FC6H4, R = Et), 4e (Ar = 4‐MeOC6H4, R
2
3
A´ to the intermediate gold complex structure would lead to a
partial loss of the stereoinformation from the configurationally
defined alkene. When this stereoinformation is totally
transferred to the final indene it seems to indicate a greater,
or almost exclusive, contribution of the cyclopropyl gold
= Me), and 4f (Ar = 4‐MeOC6H4, R = Et) (entries 6
results seem to indicate that when starting from
disubstituted o‐(alkynyl)styrenes possessing a more
8). These
,‐
carbene
A, as well as its configurational stability. However,
4,
when the final functionalized indene derivative is obtained as a
mixture of diastereoisomers in spite of starting from only one
geometrical isomer of the alkene, as it is the case with most of
the ,‐disubstituted o‐(alkynyl)styrenes 4, it seems to point
out that a competitive contribution of the carbocationic
nucleophilic trisubstituted alkene, their methoxycyclization
reactions are not completely stereospecific in all cases, with
variable degrees of stereoinformation loss that could also be
influenced by steric hindrance issues.
By analogy with our previously reported mechanistic
intermediate A´ is occurring, likely due to the higher
proposal for the methoxycyclization of
,‐disubstituted o‐
(alkynyl)styrenes8c and on the basis of other known gold‐
stabilization of the positive charge at the
substrate caused by its tertiary nature. In agreement with
Echavarren´s and Gagosz´s proposals,7,13 our results with
‐carbon of the
Table 4 Gold‐catalyzed methoxycyclization of ,‐disubstituted o‐(alkynyl)styrenes 4a

‐
monosubstituted o‐(alkynyl)styrenes support that the
intermediates in these Au‐catalyzed cyclizations are gold‐
stabilized homoallylic carbocations and not open carbocations,
and are probably better represented as cyclopropyl gold
carbenes instead of simple carbocations.19 In addition, the
rapid and stereospecific attack of the nucleophile to
Entry
1
4
Ar
Ph
Ph
Ph
Ph
Ph
R
E/Z
5
d.r.b
>20/1
16/1
16/1
3/1
3/1
5/1
13/1
8/1
Yield (%)c
4a
4a
4a
4b
4c
4d
4e
4f
Me
Me
Me
Et
n‐Pr
Et
<1/20
<1/20
<1/20
17/1
8/1
1/15
<1/20
1/18
5a
5a
5a
5b
5c
5d
5e
5f
87
89
86
78
61
60
88
90
configurationally stable cyclopropyl gold carbene
A accounts
2d
3e
4
for the relative stereochemistry of the obtained indene
derivatives. For substrates 4b‐f, as well as with 1l, in which the
reactions are not completely stereospecific, the bond rotation
of the carbocationic intermediate should be faster than the
attack of the methanol, likely due to the higher weakeness of
the cleaved bond in these cases. The stereospecific reaction of
4a shows that the homoallylic stabilization of the carbocation
is significant even for a substrate in which the positive charge
is highly stabilized by methyl and phenyl groups.
5f
6
7
8
4‐FC6H4
4‐MeOC6H4
4‐MeOC6H4
Me
Et
a Reactions conducted using 0.3 mmol of o‐(alkynyl)styrene derivative 4 in CH2Cl2
(2 mL) at rt. Determined by 1H NMR analysis of the crude reaction mixture.
b
c
d
Isolated yield of product based on starting material 4. Carried out with
Ph3PAuNTf2 as catalyst. e Carried out with Ph3PAuCl/AgSbF6 as catalytic system. f
Carried out with an additional load of 2.5 mol % of catalyst and one hour more.
Conclusions
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(a) T. Shibata, Y. Ueno and K. Kanda, Synlett, 2006, 411. For
In conclusion, we have reported the gold(I)‐catalyzed
methoxy‐ and hydroxy‐cyclizations of ‐aryl‐monosubstituted
o‐(alkynyl)styrenes that take place in regio‐ and
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related processes catalyzed by other tDraOnI:s1i0ti.o10n3‐9m/Ce8taOlB00406D
complexes, see: (b) J. W. Dankwardt, Tetrahedron Lett.,
2001, 42, 5809; (c) V. Mamane, P. Hannen and A. Fürstner,
Chem. Eur. J., 2004, 10, 4556.

a
stereospecific way leading to interesting functionalized indene
derivatives in high yields and as single diastereoisomers. The
obtained results support that the intermediates in these gold‐
catalyzed cyclizations are better described as cyclopropyl gold
carbenes in which the positive charge is significantly stabilized
homoallylically. Further attack of the external nucleophile to
these intermediates is faster than the competitive rotation
around the weakest bond of the cyclopropyl ring. Only with
highly activated and/or sterically‐encumbered substrates,
which place the positive charge in a tertiary carbon, the
cyclizations are not completely stereospecific.
7
8
(a) A. K. Buzas, F. M. Istrate and F. Gagosz, Angew. Chem.,
Int. Ed., 2007, 46, 1141; (b) S. Böhringer and F. Gagosz, Adv.
Synth. Catal., 2008, 350, 2617.
(a) A. Martínez, P. García‐García, M. A. Fernández‐Rodríguez,
F. Rodríguez and R. Sanz, Angew. Chem., Int. Ed., 2010, 49
,
4633; (b) P. García‐García, M. A. Rashid, A. M. Sanjúan, M. A.
Fernández‐Rodríguez and R. Sanz, Org. Lett., 2012, 14, 4778;
(c) A. M. Sanjuán, M. A. Rashid, P. García‐García, A. Martínez‐
Cuezva, M. A. Fernández‐Rodríguez, F. Rodríguez and R.
Sanz, Chem. Eur. J., 2015, 21, 3042; (d) A. M. Sanjuán, C.
Virumbrales, P. García‐García, M. A. Fernández‐Rodríguez
and R. Sanz, Org. Lett., 2016, 18, 1072. For related
halocyclization reactions of these substrates, see: (e) R. Sanz,
A. Martínez, P. García‐García, M. A. Fernández‐Rodríguez, M.
A. Rashid and F. Rodríguez, Chem. Commun., 2010, 46, 7427;
(f) P. García‐García, A. M. Sanjuán, M. A. Rashid, A. Martínez‐
Cuezva, M. A. Fernández‐Rodríguez, F. Rodríguez and R.
Sanz, J. Org. Chem., 2017, 82, 1155.
See, for instance: (a) M. Enders and R. W. Baker, Curr. Org.
Chem., 2006, 10, 937; (b) J.‐i. Nishida, S. Tsukaguchi and Y.
Yamashita, Chem. Eur. J., 2012, 18, 8964.
Conflicts of interest
There are no conflicts to declare.
9
Acknowledgements
We gratefully acknowledge Ministerio de Economía
Competitividad (MINECO) and FEDER (CTQ2016‐75023‐C2‐1‐
P), and Junta de Castilla y León and FEDER (BU076U16) for
financial support. C.V. thanks Universidad de Burgos for a
predoctoral contract. S.S.‐P. thanks Junta de Castilla y León
and FEDER for a postdoctoral contract.
y
10 For reviews for the synthesis of indenes, see: (a) G. Qiu and
J. Wu, Synlett, 2014, 25, 2703; (b) B. Gabriele,R. Mancuso
and L. Veltri, Chem. Eur. J., 2016, 22, 5056. For selected
recent reports, see: (c) A. Preinfalk, A. Misale and N.
Maulide, Chem. Eur. J., 2016, 22, 14471; (d) B. Ma, Z. Wu, B.
Huang, L. Liu and J. Zhang, Chem. Commun., 2016, 52, 9351.
(e) R. Barroso, M. Paraja, M.‐P. Cabal and C. Valdés, Org.
Lett., 2017, 19, 4086.
11 See, for instance: (a) D. Vasu, H.‐H. Hung, S. Bhunia, S. A.
Gawade, A. Das and R.‐S. Liu, Angew. Chem., Int. Ed., 2011,
50, 6911; (b) C.‐H. Chen, Y.‐C. Tsai and R.‐S. Liu, Angew.
Chem., Int. Ed., 2013, 52, 4599; (c) M.‐C. P. Yeh, C.‐J. Liang,
Notes and references
1
For selected reviews, see: (a) A. S. K. Hashmi, Pure Appl.
Chem., 2010, 82, 1517; (b) C. Obradors and A. M. Echavarren,
Acc. Chem. Res., 2014, 47, 902; (c) R. Dorel and A. M.
Echavarren, Chem. Rev., 2015, 115, 9028.
H.‐F. Chen and Y.‐T. Weng, Adv. Synth. Catal., 2015, 357
,
3242; (d) W. Fang, Y. Wei and M. Shi, Chem. Commun., 2017,
53, 11666.
12 Only particular examples for the alkoxycyclization of ‐
2
We have classified all the cyclization reactions along the
manuscript only considering the evolution of the triple bond
of the enyne, although the more accurate way to name
these electrophilic promoted cyclizations attending to the
Baldwin´s classification should reflect the ring closure to
monosubstituted o‐(alkynyl)styrenes, such as enol ethers,
had been previously reported: (a) Y. Liu, J. Guo, Y. Liu, X.
Wang, Y. Wang, X. Jia, G. Wei, L. Chen, J. Xiao and M. Cheng,
Chem. Commun., 2014, 50, 6243; (b) J. Wang, K. Huang, L.
Liu, W. Chang and J. Li, Tetrahedron Lett., 2015, 56, 2659.
13 (a) V. López‐Carrillo, N. Huguet, A. Mosquera and A. M.
Echavarren, Chem. Eur. J., 2011, 17, 10972. For a similar
discussion with 1,6‐enynes, see: (b) P. Pérez‐Galán, N. J. A.
Martin, A. G. Campaña, D. J. Cárdenas and A. M. Echavarren,
both ‐bonds (5‐exo‐trig/5‐endo‐dig in these cases). See, for
example: (a) R. K. Mohamed, S. Mondal, K. Jorner, T. Faria
Delgado, H. Ottoson and I. V. Alabugin, J. Am. Chem. Soc.,
2015, 137, 15441. For a recent review on the Baldwin rules,
see: (b) K. Gilmore, R. K. Mohamen and I. V. Alabugin, WIREs
Comput. Mol. Sci., 2016, 6, 487.
Chem. Asian J., 2011, 6, 482; (c) R. Dorel and A. M.
Echavarren, J. Org. Chem., 2015, 80, 7321.
3
4
(a) M. R. Luzung, J. P. Markham and F. D. Toste, J. Am. Chem.
Soc., 2004, 126, 10858; (b) L. Zhang and S. A. Kozmin, J. Am.
Chem. Soc., 2004, 126, 11806; (c) F. Gagosz, Org. Lett., 2005,
14 L. Ricard and F. Gagosz, Organometallics, 2007, 26, 4704.
15 For selected recent examples, see: (a) R. E. Ebule, D.
Malhotra, G. B. Hammond and B. Xu, Adv. Synth. Catal.,
2016, 358, 1478; (b) D. Ding, T. Mou, M. Feng and X. Jiang, J.
Am. Chem. Soc., 2016, 138, 5218.
16 E. Jiménez‐Núñez, C. K. Claverie, C. Bour, D. J. Cárdenas and
A. M. Echavarren, Angew. Chem., Int. Ed., 2008, 47, 7892.
17 See ESI for further details.
18 CCDC 1585617 (3i) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
19 For recent reviews about the nature of cationic
intermediates relevant to Au‐catalyzed enyne cyclizations,
see: (a) Y. Wang, M. E. Muratore and A. M. Echavarren,
7
, 4129.
For other reactions of o‐(alkynyl)styrenes leading to indene
derivatives see, for instance: (a) Ru‐catalyzed: R. J.
Madhushsaw, C.‐Y. Lo, C.‐W. Hwang, M.‐D. Su, H.‐C. Shen, S.
Pal, I. R. Shaikh and R.‐S. Liu, J. Am. Chem. Soc., 2004, 126
,
15560; (b) Radical‐mediated: S. Mondal, R. K. Mohamed, M.
Manoharan, H. Phan and I. V. Alabugin, Org. Lett., 2013, 15
,
5650; (c) Al‐promoted: H. Kinoshita, N. Hirai and K. Miura, J.
Org. Chem., 2014, 79, 8171; (d) FLP‐catalyzed: S. Tamke, Z.‐
W. Qu, N. A. Sitte, U. Flörke, S. Grimme and J. Paradies,
Angew. Chem., Int. Ed., 2016, 55, 4336.
E. Aguilar, R. Sanz, M. A. Fernández‐Rodríguez and P. García‐
García, Chem. Rev., 2016, 116, 8256.
5
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Chem. Eur. J., 2015, 21, 7332; (b) R. J. Harris and R. A.
Widenhoefer, Chem. Soc. Rev., 2016, 45, 4533.
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