Gold(I)-catalyzed 6-endo hydroxycyclization of 7-substituted-1,6-enynes

Article abstract of DOI:10.3762/bjoc.9.263

The cyclization of o-(alkynyl)-3-(methylbut-2-enyl)benzenes, 1,6-enynes having a condensed aromatic ring at C3-C4 positions, has been studied under the catalysis of cationic gold(I) complexes. The selective 6-endo-dig mode of cyclization observed for the

Full text of DOI:10.3762/bjoc.9.263

Gold(I)-catalyzed 6-endo hydroxycyclization of
7-substituted-1,6-enynes
Ana M. Sanjuán, Alberto Martínez, Patricia García-García,
Manuel A. Fernández-Rodríguez and Roberto Sanz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2242–2249.
Área de Química Orgánica, Departamento de Química, Facultad de
Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n, 09001
Burgos, Spain
doi:10.3762/bjoc.9.263
Received: 29 June 2013
Accepted: 08 October 2013
Published: 29 October 2013
Email:
Roberto Sanz* - rsd@ubu.es
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
* Corresponding author
Keywords:
Guest Editor: F. D. Toste
catalysis; dihydronaphthalenes; gold; gold catalysis;
hydroxycyclization; selectivity
© 2013 Sanjuán et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The cyclization of o-(alkynyl)-3-(methylbut-2-enyl)benzenes, 1,6-enynes having a condensed aromatic ring at C3–C4 positions, has
been studied under the catalysis of cationic gold(I) complexes. The selective 6-endo-dig mode of cyclization observed for the
7-substituted substrates in the presence of water or methanol giving rise to hydroxy(methoxy)-functionalized dihydronaphthalene
derivatives is highly remarkable in the context of the observed reaction pathways for the cycloisomerizations of 1,6-enynes bearing
a trisubstituted olefin.
Introduction
The cycloisomerization reactions of enynes catalyzed by gold alkoxy(hydroxy)cyclization IV [15-17] (Scheme 1). The less
complexes are a powerful tool for accessing complex products common 6-endo cyclization via metal carbenes V was also
from rather simple starting materials under soft and straightfor- observed in particular cases affording methylenecyclohexene
ward conditions [1-4]. In this context, 1,6-enynes have been derivatives like VI [14]. On the other hand, 1,6-enynes VII,
extensively studied, mainly by Echavarren and co-workers, as bearing an aryl substituent at the alkyne, undergo a formal
substrates in the identification of new reactivities catalyzed by intramolecular [4 + 2] cycloaddition through an initial 5-exo
gold and other transition metal complexes [5-13]. Cyclopropyl cyclization followed by a Friedel–Crafts-type reaction to cyclo-
metal carbenes II are usually formed by exo-dig processes from penta[b]naphthalenes VIII or, alternatively, a 6-endo cycliza-
enynes I bearing a terminal alkyne, which in the absence of tion to bicyclo[4.1.0]hept-4-enes like IX [18,19] (Scheme 1). In
external nucleophiles undergo skeletal rearrangements to afford the case that MeOH is present a 5-exo methoxycyclization is
products such as III (single cleavage) [14]. However, reactions observed, e.g., in the formation of X resembling the behaviour
of II with alcohols or water give the corresponding products of of I [16,20]. In addition, the gold-catalyzed reaction of 7-phe-
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Beilstein J. Org. Chem. 2013, 9, 2242–2249.
Scheme 2: Cyclization of o-(alkynyl)-(3-methylbut-2-enyl)benzenes 1.
Previous work and proposed pathways.
Scheme 1: Gold(I)-catalyzed reactions of 1,6-enynes.
tures highlighting both the carbocation or carbenoid nature of
this intermediate (Scheme 2).
nyl-1,6-enynes with a terminal double bond gives rise to bi-
cyclo[3.2.0]heptene derivatives [19,21].
Results and Discussion
As established in Scheme 2, we were intrigued by the possi-
Despite the numerous studies about the metal-catalyzed trans- bility that o-(alkynyl)-(3-methylbut-2-enyl)benzenes 1 could
formations of 1,6-enynes, o-(alkynyl)-(3-methylbut-2- undergo a 6-endo-dig cyclization in the presence of cationic
enyl)benzenes 1 that are also 1,6-enynes bearing an attached gold(I) complexes instead of the usually more favoured 5-exo-
aryl ring at the C3–C4 positions, have been scarcely studied. dig pathway. So, we initially prepared a variety of these
Only Liu and co-workers have reported the behaviour of o-disubstituted benzene derivatives 1 by two approaches (see
terminal substrates 1 (R = H) under ruthenium catalysis, which Supporting Information File 1) (Scheme 3). First, o-(bromo)-3-
afford the corresponding metathesis-type product XI [22] (methylbut-2-enyl)benzene was prepared by the reaction of
(Scheme 2). More recently, the same authors have described the commercially available 2-methyl-1-propenylmagnesium bro-
gold-catalyzed [2 + 2 + 3] cycloaddition reaction of these com-
pounds with nitrones giving rise to functionalized 1,2-
oxazepane derivatives XIII. This cascade process takes place
through the interception of the 1,4-dipole equivalent XII gener-
ated by an initial 5-exo cyclization, although with some gold
catalysts minor amounts of XI were also obtained [23]
(Scheme 2). Following our interest in the development of new
gold-catalyzed reactions [24-31], in this context we thought that
it could be interesting to study if the cyclization of easily avail-
able compounds 1 bearing an internal acetylene moiety would
take place through an initial 5-exo cyclization that in the case of
aryl-substituted enynes (R = Ar) would give rise to a formal [4
+ 2] cycloaddition product XIV [18,19], or alternatively,
through a relatively less common 6-endo-dig pathway via gold
Scheme 3: Synthesis of o-(alkynyl)-(3-methylbut-2-enyl)benzenes 1.
species XV, which could be represented as two resonance struc-
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Beilstein J. Org. Chem. 2013, 9, 2242–2249.
mide with 2-bromobenzyl bromide in the presence of CuI and Prompted by this result and taking into account the reported
2,2’-bipyridyl [32]. This aryl bromide could be coupled with results about the 5-endo hydroxy- and alkoxycyclization of 1,5-
selected terminal alkynes by using cesium carbonate as a base enynes [36], as well as our recent report about the alkoxycy-
and PdCl2(MeCN)2/XPhos as a catalytic system [33]. Alter- clization of 1,3-dien-5-ynes [31], we wondered if the presence
natively, several o-(alkynyl)bromobenzenes [34] could be trans- of an external protic nucleophile, such as methanol or water,
formed into the corresponding derivatives 1 by bromine–lithium could have an important influence on controlling the selectivity
exchange and further treatment with 3,3-dimethylallyl bromide of the reaction. Encouragingly, when we treated model sub-
in the presence of TMEDA [23].
strate 1a with (Ph3P)AuNTf2 in a 10:1 mixture of CH2Cl2 and
MeOH as the solvent, the methoxyalkyl-substituted derivative
We selected 1-(2-(2-(3-methylbut-2-enyl)phenyl)ethynyl)- 6a was obtained as the major product along with minor amounts
benzene (1a) as model substrate for the initial experiments of 3a (ca. 6:1 ratio) (Scheme 5) [37]. Moreover, the use of H2O
(Scheme 4). Its reaction with (Ph3P)AuNTf2, reported by (20 equiv) also led to a high yield of the hydroxyalkyl-substi-
Gagosz and co-workers as a very active catalyst for the cycloi- tuted dihydronaphthalene derivative 7a, whose structure was
somerization of closely related 7-aryl-1,6-enynes [35], gave rise further confirmed by X-ray analysis [38]. In both cases the high
to a ca. 3:1 mixture of dihydronaphthalene derivative 2a and selectivity (>5:1) of these reactions for the 6-endo-type cycliza-
tetracyclic compound 3a along with some other unidentified tion should be noted and only minor amounts (10–15%) of 3a
minor products. The two major products resulted to be insepa- were also formed.
rable by column chromatography and were isolated in 68%
overall yield. It is remarkable that compound 2a, derived from a
6-endo cyclization and further proton elimination from inter-
mediate resonance structures 4a and 4a’, is generated in prefer-
ence to 3a which would be the expected product derived from a
formal [4 + 2] cycloaddition initiated by a 5-exo cyclization fol-
lowed by a Friedel–Crafts-type process in intermediate 5a or
5a’, as described by Echavarren and co-workers [18,19].
Scheme 5: Initial experiments and proof of concept.
Due to the unexpected 6-endo-favored pathway found for sub-
strate 1a [39], we attempted to further improve this selectivity
in the hydroxycyclization process (Table 1). Switching the
ligand from Ph3P to XPhos or N-heterocyclic carbene (IPr)
slightly decreases the selectivity for the 6-endo cyclization (Ta-
ble 1, entry 1 vs entries 2 and 3). However, when the cationic
gold complex (JohnPhos)(NCMe)AuSbF6, developed by
Echavarren and co-workers [40], was employed as a catalyst a
moderate increase in the ratio of 7a vs 3a was observed
(Table 1, entry 4). Both cationic gold complexes (Ph3P)AuNTf2
and (JohnPhos)(NCMe)AuSbF6 gave rise to a similar yield of
isolated alcohol 7a. Changing the solvent from CH2Cl2 to a
mixture containing other more polar solvent such as acetone or
dioxane (Table 1, entries 5 and 6) did not have a significant
influence on the selectivity but led to the formation of minor
amounts of alcohol 8a, derived from a 5-exo hydroxycycliza-
tion reaction. With a 1:1 mixture of CH2Cl2/dioxane the effect
of the selected catalytic systems was checked (Table 1, entries
7–10). We found that the use of JohnPhos as a ligand and SbF6
as a counter ion (Table 1, entries 9 and 10) resulted in a slightly
Scheme 4: Gold(I)-catalyzed cycloisomerization of 1a.
better selectivity, although trace amounts of alcohol 8a were
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Beilstein J. Org. Chem. 2013, 9, 2242–2249.
Table 1: Effect of the catalyst and reaction conditions on the hydroxycyclization of 1a. 6-Endo vs 5-exo cyclization.a
Ratiob
6-endo/5-exo
Entry
Catalyst
Solvent
Yield (%)c
1
2
(Ph3P)AuNTf2
XPhosAuNTf2e
CH2Cl2
5:1d
3:1d
4:1d
6:1d
4.5:1h
5:1h
3:1h
3:1h
7:1h
7:1h
76
—
—
77
—
75i
—
—
77i
—
CH2Cl2
3
IPrAuCl/AgSbF6f
CH2Cl2
4
(JohnPhos)(NCMe)AuSbF6g
(Ph3P)AuNTf2
CH2Cl2
5
CH2Cl2/Me2CO (1:1)
CH2Cl2/dioxane (1:1)
CH2Cl2/dioxane (1:1)
CH2Cl2/dioxane (1:1)
CH2Cl2/dioxane (1:1)
CH2Cl2/dioxane (1:1)
6
(Ph3P)AuNTf2
7
XPhosAuNTf2e
8
JohnPhosAuNTf2g
(JohnPhos)(NCMe)AuSbF6g
JohnPhosAuCl/AgSbF6g
9
10
aReactions were carried out by treatment of 1a (0.1 mmol) with H2O (2.2 mmol, 0.04 mL) in 0.4 mL of solvent until complete consumption of the
starting material, as judged by GC–MS and/or TLC analysis (overnight). bDetermined by 1H NMR analysis of the crude reaction mixture. cIsolated
yield of 7a. dThe 5-exo pathway gives rise to 3a. eXPhos = 2-dicyclohexylphosphino-2’,4’,6’-tri-isopropylbiphenyl. fIPr = 1,3-bis-(2,6-di-isopropylphen-
yl)imidazol-2-ylidene. gJohnPhos = 2-(di-tert-butylphosphino)biphenyl. hA mixture of 3a and 8a was obtained through the 5-exo pathway. iApproxi-
mately 5% of 8a was also isolated.
also generated, which make the isolation of 7a more difficult. mation of the corresponding products 3 or 8, derived from an
Overall, we concluded that both commercially available gold initial 5-exo cyclization, becomes more competitive (Table 2,
complexes (Ph3P)AuNTf2 and (JohnPhos)(NCMe)AuSbF6 lead entries 4 and 5). Then, we turned our attention to alkyl-substi-
to comparable good results in the 6-endo hydroxycyclization of tuted alkynes (Table 2, entries 8 and 9), which could not
1a. The type of products derived from the 5-exo pathway (3a undergo the formal [4 + 2] cycloaddition leading to 3. In these
and 8a) depends on the solvent: in CH2Cl2 3a is mainly cases, and after some optimization studies, we surprisingly
obtained, whereas the alcohol 8a appears when a more polar found that the solvent has an important role on the selectivity of
mixture of solvents was used.
the cyclization. When a 1:1 mixture of CH2Cl2/dioxane was
used the 5-exo hydroxycyclization that gives rise to alcohols 8
Once we have selected the best conditions to favor the 6-endo was competitive with the 6-endo process (3:1 for 1h and 1.7:1
hydroxycyclization reaction, a selection of substrates 1a–k, for 1i), allowing the isolation of the corresponding methylenein-
bearing different groups at the triple bond, were reacted under dene derivatives 8h and 8i in 21% and 30% yield, respectively
the established conditions (Table 2). When aromatic or alkenyl [41]. Gratifyingly, we found that when the same reactions were
groups are present as the substituents of the alkyne (Table 2, performed in CH2Cl2 the 6-endo cyclization was completely
entries 1–7) the 6-endo cyclization takes place in selective or selective leading to the corresponding alcohols 7 in high yields
almost exclusively fashion allowing the isolation of 2-(1,2- (Table 2, entries 8 and 9). On the other hand, the reaction of
dihydro-3-substituted naphthalen-2-yl)propan-2-ol derivatives 7 trimethylsilyl-substituted enyne 1j did not proceed at all
in usually high yields. Interestingly, we have also observed that (Table 2, entry 10), whereas the presence of a phenylthio group
when starting with enynes possessing an electron-rich aromatic as an R substituent mainly afforded the corresponding 6-endo
ring or an alkenyl group at the C7-position of the 1,6-enyne the product 7k although the reaction was significantly slower (Ta-
cyclization results almost completely selective via the 6-endo ble 2, entry 11). As expected [10-12] the terminal enyne 1l (R =
mode (Table 2, entries 2,3 and entries 6,7). However, in the H) underwent exclusively the 5-exo cyclization leading to the
case of halogen-containing aromatic substituents at C7 the for- corresponding alcohol 8l in 55% yield (Table 2, entry 12).
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Beilstein J. Org. Chem. 2013, 9, 2242–2249.
Table 2: Synthesis of 2-(1,2-dihydro-3-substituted-naphthalen-2-yl)propan-2-ol derivatives 7 by gold-catalyzed 6-endo hydroxycyclization of
enynes 1.a
Entry
Starting material
R
Product
Yield (%)b
1
2
1a
1b
1c
1d
1e
1f
Ph
4-MeOC6H4
2,4,5-(Me)3C6H2
3-ClC6H4
2,4-(F)2C6H3
thiophen-3-yl
c-C6H9
7a
7b
7c
7d
7e
7f
77 (12)c
80
3
71
4
63 (22)d
75e
82
5
6
7
1g
1h
1i
7g
7h
7i
79
8f
9
c-C3H5
77
n-Bu
82
10
11h
12
1j
SiMe3
—
7k
8l
—g
1k
1l
SPh
60
H
55
aReactions were carried out by treatment of 1 (0.3 mmol) with H2O (22 equiv, 0.12 mL) in 1.2 mL of solvent until complete consumption of the starting
material, as judged by GC–MS and/or TLC analysis (overnight). bIsolated yield of compounds 7 after column chromatography. cYield of 3a which
could not be isolated in pure form. dIsolated yield of 3d which was obtained as a mixture of regioisomers with respect to the chlorine atom position.
eIsolated along with ≈10% of 8e. ≈10% of 2e is also observed. fCarried out with (Ph3P)AuNTf2. Slightly lower yield (ca. 5%) was obtained with (John-
Phos)(NCMe)AuSbF6. gStarting material was recovered. hReaction time: 48 h.
At this point we wondered if the cyclization would be diastereo- (see Supporting Information File 1). First, the hydroxycycliza-
selective, so we prepared enynes 1m by reacting tion of 1m, as a pure E isomer, under the previously established
2-(phenylethynyl)phenyllithium with geranyl bromide and 1n conditions afforded the dihydronaphthalene derivative 7m as a
by two Wittig reactions from 2’-(phenylethynyl)acetophenone single isomer (Scheme 6), whose relative configuration was
Scheme 6: Gold(I)-catalyzed hydroxycyclization of enynes 1m,n.
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Beilstein J. Org. Chem. 2013, 9, 2242–2249.
assigned by analogy with previously related results reported by
Gagosz and co-workers [37]. On the other hand, the reaction of
1n afforded a ca. 2.5:1 mixture of alcohol 7n [42] and the tetra-
cyclic product 3n, derived from an initial 5-exo cyclization and
subsequent Friedel–Crafts reaction (Scheme 6). Both com-
pounds were isolated as single stereoisomers with a high overall
yield [43]. In this case, the 5-exo pathway was more competi-
tive compared to the result of model substrate 1a, probably due
to the Thorpe–Ingold-type effect caused by the methyl group at
the allylic position. To account for the stereoselectivity of these
reactions we proposed the generation of a stabilized
gold–carbenoid intermediate such as A that undergoes stereose-
lective attack by water (Scheme 6).
Scheme 8: Labelling experiment and proposed mechanism.
Furthermore, we have also carried out the methoxycyclization
of selected 1,6-enynes 1 by their treatment with catalytic
amounts of (JohnPhos)(NCMe)AuSbF6 in a 30:1 mixture of the observed reaction topologies in the gold-catalyzed cycloiso-
CH2Cl2 and MeOH as the solvent (Scheme 7) [44]. The corres- merization of these substrates. The new oxygen-functionalized
ponding methoxy-functionalized dihydronaphthalene deriva- dihydronaphthalene derivatives have been synthesized in high
tives 6 were obtained in high yields although the corresponding yields.
minor isomer derived from a 5-exo cyclization could not be sep-
arated in the case of 6a and 6h.
Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. Copies of 1H NMR and 13C NMR spectra for
new compounds.
Supporting Information File 1
Experimental and analytical data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-263-S1.pdf]
Supporting Information File 2
NMR spectra.
Scheme 7: Gold(I)-catalyzed methoxycyclization of selected 1,6-
enynes 1 [45].
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-263-S2.pdf]
Finally, to support the proposed intermediacy of gold–carbenoid
intermediate 4 or 4’ (Scheme 4), we treated enyne 1b with D2O
instead of water and under the same catalytic conditions we Acknowledgements
observed the exclusive formation of the deuterated compound We gratefully acknowledge the Ministerio de Ciencia e
[D]-7b in 75% yield (>90% deuterium incorporation at C4). Innovación (MICINN) and FEDER (CTQ2010-15358) for
The generation of that compound could be explained by financial support. A. M. S. thanks the Junta de Castilla y León
deuterodemetallation of the vinylgold species B generated by an (Consejería de Educación) and the Fondo Social Europeo for a
attack of the nucleophile on intermediate 4b or 4b’ (Scheme 8).
PIRTU contract. P. G.-G. and M. A. F.-R. thank MICINN for
“Juan de la Cierva” and “Ramón y Cajal” contracts.
Conclusion
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42.Isolated with trace amounts of 8n.
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Beilstein J. Org. Chem. 2013, 9, 2242–2249.
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