Formal [4 + 1] Cycloadditions of β,β-Diaryl-Substituted ortho-(Alkynyl)styrenes through Gold(I)-Catalyzed Cycloisomerization Reactions

Article abstract of DOI:10.1021/acs.orglett.6b00191

Gold(I)-catalyzed cycloisomerization of β,β-diaryl-o-(alkynyl)styrenes at 80 °C selectively yields dihydroindeno[2,1-a]indenes in a transformation that encompasses a formal [4 + 1] cycloaddition and takes place through a cascade 5-endo-cyclization-diene a

Full text of DOI:10.1021/acs.orglett.6b00191

Letter
pubs.acs.org/OrgLett
Formal [4 + 1] Cycloadditions of β,β-Diaryl-Substituted ortho-
(Alkynyl)styrenes through Gold(I)-Catalyzed Cycloisomerization
Reactions
Ana M. Sanjuan, Cintia Virumbrales, Patricia García-García,† Manuel A. Fernandez-Rodríguez,
́
́
and Roberto Sanz*
́
Area de Química Organ
́
ica, Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Banuelos s/n,
̃
09001-Burgos, Spain
S
* Supporting Information
ABSTRACT: Gold(I)-catalyzed cycloisomerization of β,β-diaryl-o-(alkynyl)-
styrenes at 80 °C selectively yields dihydroindeno[2,1-a]indenes in a
transformation that encompasses a formal [4 + 1] cycloaddition and takes
place through a cascade 5-endo-cyclization−diene activation−iso-Nazarov
cyclization. In addition, by performing the reaction at 0 °C, the same
substrates exclusively give rise to benzofulvene derivatives, which have also been shown to be intermediates in the formation of
the tetracyclics.
Scheme 1. Previous Work and Proposed Study
old(I) catalysis is currently well established as a powerful
Gtool for the straightforward construction of complex
molecules from readily available starting materials.1 Intense
research on this topic during the past decade has demonstrated
the unique ability of gold(I) complexes to selectively activate
triple bonds toward the attack of a wide range of different
nucleophiles.2 In particular, the cycloisomerization of enynes
has attracted great interest, and its usefulness has been
demonstrated in the construction of intricate carbocyclic
skeletons not easily accessible by other methodologies, through
the development of diverse cascade processes.3
In this context, we became interested in gold(I)-catalyzed
cycloisomerizations of conjugated dienynes,4 with particular
attention to o-(alkynyl)styrenes.5 Thus, we described an
enantioselective synthesis of indenes by gold(I)-catalyzed
cycloisomerization of o-(alkynyl)styrenes (Scheme 1, eq 1).5a
Moreover, we found that when an o-(alkynyl)styrene having a
secondary alkyl group at the β-position of the styrene moiety is
used as starting material, a formal [3 + 3] cycloaddition occurs,
involving the aromatic group initially bonded to the triple bond
and finally giving rise to dihydrobenzo[a]fluorenes (Scheme 1,
eq 2).5b In both cases, the reaction is proposed to proceed
through a common carbocationic intermediate, which can be
also described as a cyclopropyl gold carbene-like intermediate,6
generated by a 5-endo nucleophilic attack of the olefin to the
gold-activated alkyne. This gold intermediate evolves through a
proton elimination in the first case and through a more
complex cascade process in the second one. Taking these
results into account, we wondered about the outcome of the
reaction under gold(I) catalysis of β,β-diaryl-o-(alkynyl)-
styrenes, for which none of the previously described pathways
is available (Scheme 1, eq 3).
to dihydroindeno[2,1-a]indenes by a formal [4 + 1] cyclo-
addition process.
To start our investigations, we selected β,β-diphenyl-o-(p-
tolylethynyl)styrene 1a as model substrate and performed its
reaction with AuPPh3NTf2 as catalyst in DCM as the solvent at
room temperature (Scheme 2). Under these conditions and not
surprisingly, benzofulvene 2a was obtained as a major product,
presumably coming from the elimination of the only proton
available in intermediate Ia. More interestingly, a minor
product 3a was also formed which presented a tetracyclic
skeleton coming from a formal [4 + 1] cycloaddition involving
Herein we report the gold(I)-catalyzed cycloisomerization of
β,β-diaryl-o-(alkynyl)styrenes through a cascade process leading
Received: January 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preliminary Result
Scheme 4. Proposed Mechanism
the double bond, one of the phenyl rings, and the external
carbon of the alkyne.7 The structure of 3a was confirmed by X-
ray diffraction analysis.8
With the aim of increasing the selectivity of the process, we
screened several parameters. Different gold catalysts with
ligands of diverse nature lead in all cases to mixtures of
products (2a, 3a, and others) in variable amounts.9 Gratifyingly,
selective reactions could be achieved by controlling the reaction
temperature (Scheme 3). Thus, performing the reaction at 0 °C
Scheme 3. Effect of the Temperature in the Selectivity
could be understood as an iso-Nazarov cyclization or an
intramolecular Friedel−Crafts reaction. Moreover, formation of
minor amounts of 4a could be explained by nucleophilic attack
of the aromatic ring initially bonded to the triple bond either in
intermediate Ia followed by alkene isomerization (via b) or,
alternatively, from intermediate IIb. The transformation of 2a
into 3a and 4a could also be catalyzed by another Lewis or
Brønsted acid, as shown in Scheme 3, presumably through an
analogous mechanism.11
Besides the mechanistic interest for the developed
procedures, the relevance of the molecules obtained should
be noted. Thus, benzofulvene derivatives are present in
biologically and pharmaceutically active molecules as well as
in molecular materials.12 On the other hand, little is known
about the possible applications of dihydroindeno[2,1-a]-
indenes, which is not surprising considering the lack of efficient
methodologies for their synthesis to date.13 In contrast,
structurally related dibenzopentalenes have been extensively
studied and shown as promising substrates for material
science.14
With these considerations in mind, the scope of these new
transformations was examined. First, we checked the generality
of the encountered methodology for the synthesis of
benzofulvenes by performing the gold(I)-catalyzed reaction of
a series of o-(alkynyl)styrenes at 0 °C (Table 1). Pleasantly, this
transformation provided benzofulvenes 2 in high yields for
most of the o-(alkynyl)styrenes tested, including those with
electron-rich and -poor aromatic, heteroaromatic, and aliphatic
groups initially bonded to the triple bond.
allowed for the selective synthesis of benzofulvene 2a, which
could be isolated in 75% yield. Moreover, we were pleased to
find that by merely increasing the reaction temperature to 80
°C dihydroindeno[2,1-a]indene 3a was exclusively formed in
excellent yield. These results, apart from setting useful synthetic
conditions, suggest that 2a could be an intermediate in the
formation of 3a. In fact, isolated 2a could be transformed in 3a
by heating it in the presence of the gold catalyst, a silver salt, or
a Brønsted acid, thus confirming our hypothesis. Trace
amounts of isomeric tetracyclic compound 4a were also formed
in these essays.
With these results in hand, we propose the following
mechanism that accounts for all the previously discussed
observations (Scheme 4). The reaction would start with the
coordination of the gold catalyst to the triple bond followed by
intramolecular formal 5-endo attack of the olefin generating
carbocationic intermediate Ia (that could also be represented
by resonance structure Ib), analogously to what was previously
proposed for other o-(alkynyl)styrenes.5 Then, proton
elimination followed by protodemetalation would lead to
benzofulvene 2a and regenerate the gold catalyst (via a). Under
appropriate reaction conditions, the diene moiety in 2a could
be activated by coordination of the gold catalyst,10 leading to an
allylic carbocation species II. This is trapped by one of the
aromatic rings bonded to the olefin yielding 3a in a process that
Once we had demonstrated the generality of the synthesis of
benzofulvenes 2, we focused on analyzing the scope of the
gold(I)-catalyzed formal [4 + 1] cycloaddition of o-(alkynyl)-
styrenes to produce dihydro[2,1-a]indenes having a quaternaty
center at the ring junction.
First, we selected o-(alkynyl)styrenes 1a−j having two
identical aryl groups as substituents of the olefin, and we
B
DOI: 10.1021/acs.orglett.6b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Synthesis of Benzofulvenes 2
Table 3. Synthesis of Dihydroindenes 3k−n from o-
(Alkynyl)styrenes 1k−n Bearing Different Aryl Substituents
b
entry
1
Ar
R
2
yield (%)
b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
Ph
2a
2b
2c
2d
2e
2f
79
91
76
95
69
82
91
76
yield
a
entry
1
Ar1
Ar2
product
ratio
(%)
4-MeOC6H4
3-FC6H4
3-Th
1
2
3
4
1k
1l
4-ClC6H4 Ph
3k + 3k′
3l + 3l′
3m + 3m′
3n
10:1
12:1
10:1
−
73
86
74
82
4-FC6H4
Ph
4-MeOC6H4
4-MeOC6H4
1m
1n
c-C3H5
Ph
3,4,5-(MeO)3
C6H2
1g
1h
4-MeC6H4
4-MeC6H4
4-MeC6H4
n-Bu
2g
2h
a
Determined by 1H NMR analysis of the crude reaction mixture.
Yield of isolated mixture of products 3 and 3′ referred to starting o-
b
a
Reaction conditions: 1 (0.2 mmol), AuPPh3NTf2 (3 mol %), CH2Cl2
(0.8 mL), 0 °C, 3−4 h. Yield of isolated product referred to starting
product 1.
b
(alkynyl)styrene 1.
Finally, we wondered if o-(alkynyl)styrenes 5 having an alkyl
and an aryl group as β-substituents of the olefin would allow
the preparation of dihydroindeno[2,1-a]indenes 6 with an alkyl
substituent at position 10. Although first assays provided only
indenes 7 even when the reaction was heated to 80 °C,5a we
determined that the formal [4 + 1] cycloadduct 6a could be
prepared with moderate yield in one step using a Brønsted acid
as an additive (Scheme 5). However, if the alkyne substituent is
not aromatic, such as in 5b, the second cyclization is disfavored
and only the corresponding indene 7b is obtained.
were pleased to find that all of them provided the
corresponding [4 + 1] cycloaducts 3a−j in high to excellent
yields (Table 2). Dihydroindeno[2,1-a]indenes having as a
a
Table 2. Synthesis of Dihydroindenes 3
b
Scheme 5. [4 + 1] Formal Cycloaddition of β-Alkyl, β-Aryl-
Substituted o-(Alkynyl)styrene 5a
entry
1
Ar
R
3
yield (%)
1
2
3
4
5
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
Ph
3a
3b
3c
3d
3e
3f
96
75
76
80
74
84
86
81
78
80
4-MeOC6H4
3-FC6H4
3-Th
c
6
c-C3H5
7
8
9
1g
1h
1i
4-MeC6H4
4-MeC6H4
Ph
4-MeC6H4
n-Bu
3g
3h
3i
n-Bu
d
10
1j
Ph
(CH2)3CN
3j
a
Reaction conditions: 1 (0.2 mmol), AuPPh3NTf2 (3 mol %), DCE
b
(0.8 mL), 80 °C, 2−3 h. Yield of isolated product referred to starting
product 1. Reaction time: 15 h. Carried out in the presence of
c
d
additional DNBSA (10 mol %).
In summary, we have shown that β,β-diaryl-o-(alkynyl)-
styrenes cycloisomerize under gold(I) catalysis giving rise
selectively to benzofulvenes at 0 °C and to dihydroindeno[2,1-
a]indenes at 80 °C. The formation of these tetracycles implies a
formal [4 + 1] cycloaddition and proceeds through a cascade 5-
endo-cyclization−diene activation−iso-Nazarov (Friedel−
Crafts) cyclization. These compounds were obtained with
high yields and with a variety of substituents, including a
quaternary center at the ring junction and aryl or alkyl groups at
the C-10 position. These results further demonstrate the
usefulness of gold(I)-catalyzed cycloisomerizations of o-
(alkynyl)styrene derivatives in the selective synthesis of
polycyclic compounds.
substituent of the quaternary center electron-rich (entries 1, 3,
and 7) and electron-poor aromatic (entry 4), heteroaromatic
(entry 5), and aliphatic groups (entries 6 and 8−10), including
cyclic (entry 6) and functionalized ones (entry 10), could be
efficiently synthesized using this methodology.15
Next, we decided to check the reactivity of o-(alkynyl)-
styrenes 1k−n, having two different aryl groups in the olefin, in
order to explore the selectivity of the formal [4 + 1]
cycloaddition.16 Gratifyingly, we found that all reactions were
highly selective, yielding as the major product the one coming
from the nucleophilic attack of the more electron-rich aryl
group, as expected (Table 3). Noteworthy, complete selectivity
was achieved when o-(alkynyl)styrene 1n, having a highly
electron-rich group, was used as starting material. Nevertheless,
even substrates with less prominent electronic differences (Ph
vs 4-ClC6H4 or Ph vs 4-MeOC6H4) lead to notable high
selectivities (∼10:1).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00191.
C
DOI: 10.1021/acs.orglett.6b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Full experimental procedures, characterization data, and
Letter
(7) For a recent revision on gold-catalyzed cycloaddition reactions:
Muratore, M. E.; Homs, A.; Obradors, C.; Echavarren, A. M. Chem. -
Asian J. 2014, 9, 3066−3082.
copies of NMR spectra (PDF)
(8) CCDC-1429680 contains the supplementary crystallographic
data for 3a. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
AUTHOR INFORMATION
■
Corresponding Author
(9) See Supporting Information for complete details.
*E-mail: rsd@ubu.es.
(10) For a previous example of activation of conjugated dienes by
gold(I) catalysts, see: Kanno, O.; Kuriyama, W.; Wang, Z. J.; Toste, F.
D. Angew. Chem., Int. Ed. 2011, 50, 9919−9922.
(11) (a) Zhang, X.; Teo, W. T.; Rao, W.; Ma, D.-L.; Leung, C.-H.;
Chan, P. W. H. Tetrahedron Lett. 2014, 55, 3881−3884. (b) Strom, K.
R.; Impastato, A. C.; Moy, K. J.; Landreth, A. J.; Snyder, J. K. Org. Lett.
2015, 17, 2126−2129.
Present Address
†
́
́
Departamento de Quımica Organ
́
ica y Quımica Inorgan
́
ica,
Universidad de Alcala,
́
28871 Alcala
́
de Henares, Madrid, Spain
Notes
The authors declare no competing financial interest.
(12) For selected examples of synthesis of benzofulvenes, see:
(a) Dyker, G.; Borowski, S.; Henkel, G.; Kellner, A.; Dix, I.; Jones, P.
G. Tetrahedron Lett. 2000, 41, 8259−8262. (b) Chen, W.; Cao, J.;
Huang, X. Org. Lett. 2008, 10, 5537−5540. (c) Ye, S.; Yang, X.; Wu, J.
Chem. Commun. 2010, 46, 2950−2952. (d) Li, D.-Y.; Wei, Y.; Shi, M.
Chem. - Eur. J. 2013, 19, 15682−15688. (e) Martinelli, C.; Cardone,
A.; Pinto, V.; Talamo, M. M.; D’arienzo, M. L.; Mesto, E.; Schingaro,
E.; Scordari, F.; Naso, F.; Musio, R.; Farinola, G. M. Org. Lett. 2014,
16, 3424−3427. (f) Xiao, Q.; Zhu, H.; Li, G.; Chen, Z. Adv. Synth.
ACKNOWLEDGMENTS
■
We are grateful to the Junta de Castilla y Leon
́
(BU237U13)
́
and Ministerio de Economıa y Competitividad (MINECO) and
FEDER (CTQ2013-48937-C2-1-P) for financial support.
́
́
(Consejerıa
A.M.S. and C.V. thank Junta de Castilla y Leon
de Educacion) and Fondo Social Europeo and Universidad de
Burgos, respectively, for predoctoral contracts. P. G.-G. thanks
MINECO for a “Ramon y Cajal” contract.
́
́
Catal. 2014, 356, 3809−3815. (g) Alvarez, E.; Nieto Faza, O.; Silva
Lopez, C.; Fernandez-Rodríguez, M. A.; Sanz, R. Chem. - Eur. J. 2015,
21, 12889−12893.
́
́
́
(13) Only a few particular examples of dihydroindeno[2,1-a]indenes
having a quaternary center at the ring junction have been described in
the literature, and they were generally obtained by low yielding
procedures: (a) Ten Hoeve, W.; Wynberg, H. J. Org. Chem. 1980, 45,
2930−2937. (b) Shim, S. C.; Chae, J. S.; Choi, J. H. J. Org. Chem.
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DOI: 10.1021/acs.orglett.6b00191
Org. Lett. XXXX, XXX, XXX−XXX