Gold(I)-catalyzed tandem cyclization-selective migration reaction of 1,3-dien-5-ynes: Regioselective synthesis of highly substituted benzenes

Article abstract of DOI:10.1021/ol202129n

Highly substituted benzene derivatives have been easily prepared in a regioselective way from readily available 1,3-hexadien-5-ynes through a gold(I)-catalyzed tandem reaction. The process involves an initial cyclization followed by a selective Wagner-Meerwein shift in which the migration preference seems to be determined by the ability to stabilize a positive charge.

Full text of DOI:10.1021/ol202129n

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4970–4973
Gold(I)-Catalyzed Tandem
CyclizationꢀSelective Migration Reaction
of 1,3-Dien-5-ynes: Regioselective
Synthesis of Highly Substituted Benzenes
ꢀ
Patricia Garcıa-Garcıa, Alberto Martınez, Ana M. Sanjuan,
´
Manuel A. Fernandez-Rodrıguez, and Roberto Sanz*
´
´
ꢀ
´
ꢀ
´
Area de Quımica Organica, Departamento de Quımica, Facultad de Ciencias,
Universidad de Burgos, Pza. Misael Banuelos s/n, 09001-Burgos, Spain
ꢀ
´
~
rsd@ubu.es
Received August 5, 2011
ABSTRACT
Highly substituted benzene derivatives have been easily prepared in a regioselective way from readily available 1,3-hexadien-5-ynes through a
gold(I)-catalyzed tandem reaction. The process involves an initial cyclization followed by a selective WagnerꢀMeerwein shift in which the
migration preference seems to be determined by the ability to stabilize a positive charge.
The transition-metal-catalyzed enyne cycloisomeriza-
tion has become in the past decade a powerful strategy
for the synthesis of functionalized cyclic structures.1 In
particular, gold complexes have shown a great ability to
promote a wide variety of synthetically and mechanisti-
cally interesting transformations of polyunsaturated
systems.2 In this regard, we have recently reported a
gold-catalyzed cycloisomerization of o-alkynylstyrenes
that provides an easy enantioselective access to the indene
skeleton (eq 1).3 In this context, and in continuation of our
ongoing work in gold-catalyzed transformations,4 we be-
came interested in the potential of related 1,3-dien-5-ynes 1
as precursors for gold(I)-catalyzed cycloisomerizations
(eq 2).5 If a reaction pathway analogous to that observed
for o-alkynylstyrenes took place, highly substituted cyclo-
pentadienes would be obtained. However, the fact that the
central double bond is now not forming part of an
aromatic ring could obviously play a definitive role in the
reactivity giving rise to a completely different outcome.6
(1) Selected recent revisions on transition-metal-catalyzed cycloi-
^
somerization reactions: (a) Michelet, V.; Toullec, P. Y.; Genet, J.-P.
ꢀ
ꢀ~
Angew. Chem., Int. Ed. 2008, 47, 4268–4315. (b) Jimenez-Nunez, E.;
Echavarren, A. Chem. Rev. 2008, 108, 3326–3350.
€
(2) Selected recent revisions on gold catalysis: (a) Furstner, A. Chem.
Soc. Rev. 2009, 38, 3208–3221. (b) Shapiro, N. D.; Toste, F. D. Synlett
2010, 675–691. (c) Das, A.; Sohel, S. M. A.; Liu, R.-S. Org. Biomol.
Chem. 2010, 8, 960–979. (d) Hashmi, A. S. K. Angew. Chem., Int. Ed.
2010, 49, 5232–5241. (e) Krause, N.; Winter, C. Chem. Rev. 2011, 111,
1994–2009. (f) Nolan, S. P. Acc. Chem. Res. 2011, 44, 91–100.
ꢀ
(3) Martı
Rodrıguez, F.; Sanz, R. Angew. Chem., Int. Ed. 2010, 49, 4633–4637.
(4) (a) Sanz, R.; Miguel, D.; Rodrıguez, F. Angew. Chem., Int. Ed.
2008, 47, 7354–7357. (b) Sanz, R.; Miguel, D.; Gohain, M.; Garcıa-
guez, M. A.; Gonzalez-Perez, A.; Nieto-
Faza, O.; de Lera, A. R.; Rodrıguez, F. Chem.;Eur. J. 2010, 16
´
nez, A.; Garcıa-Garcıa, P.; Fernandez-Rodrıguez, M. A.;
´
´
´
´
´
´
Whereas the thermal cycloaromatization of 1,3-hexa-
dien-5-ynes to benzene derivatives (the “dihydro variant”
of the Bergman cyclization also known as Hopf cyclization)
ꢀ
Garcıa, P.; Fernandez-Rodrı
´ ´
ꢀ
ꢀ
´
9818–9828.
r
10.1021/ol202129n
Published on Web 08/25/2011
2011 American Chemical Society

usually proceeds at >200 °C,7 their transition-metal-
catalyzed cycloisomerization reactions have been scarcely
explored. Some of the few reported examples are related to
the ruthenium-catalyzed cycloaromatization of 1,3-dien-5-
ynes having a terminal alkyne, which take place via
vinylidene intermediates.8 With 1-substituted 1,3-dien-5-
ynes, Liu et al. have observed different reaction pathways
depending on the substitution of the external olefin that
mainly involve a [1,7]-hydrogen shift.9 More recently, a
mild gold-catalyzed cycloaromatization of related 2,4-
dien-6-yne carboxylic acids has also been described.10
Herein, we report a novel gold-catalyzed cycloaromatiza-
tion of simple 1,3-dien-5-ynes 1 that takes place with a
concurrent selective migration reaction.
To our aim, we initially selected 1-(2-methylprop-1-
enyl)-2-(2-phenylethynyl)-cyclohexene 1a as a model
substrate.11 Although decomposition occurred when
AgSbF6 or PtCl2 were used as catalysts, we were delighted
to find that its reaction in dichloromethane at rt in the
presence of catalytic amounts of Ph3PAuNTf212 gives rise
to 1,2,3,4-tetrahydronaphthalene derivative 2a as a single
product that could be isolated in good yield (Scheme 1).
The structure of 2a was determined by NMR experiments
and confirmed by X-ray diffraction analysis.13
related o-alkynylstyrenes (eq 1).3 Moreover, although a
cycloaromatization has taken place, as it had been earlier
reported for analogous substrates using alternative
catalysts,8,9 the topology of the substituents in the final
product notably differs from that described so far, thus
accounting for a distinct reaction mechanism. More inter-
estingly, it is worth pointing out that in this transformation
one of the methyl groups initially bonded to the terminal
olefin has formally migrated to an adjacent carbon in the
final product.14 A mechanism that could account for this
cyclizationꢀmigration sequence is depicted in Scheme 2.
The reaction would start with the coordination of the gold
complex tothe triple bond of the starting dienyne 1atogive
intermediate 3. An intramolecular nucleophilic attack of
the terminal olefin would lead to intermediate 4. This
intermediate could be represented as the contribution of
several resonance structures (40, 400, ...), delocalizing the
positive charge along different positions of the molecule.
Migration of one of the methyl groups in 4 would afford
intermediate 5. This migration could be explained either
from 400, which would imply the transformation of a
secondary carbocation into a more stable tertiary one
(WagnerꢀMeerwein rearrangement), or from 40 with a
simultaneous opening of the cyclopropane ring. Finally,
intermediate 5 would eliminate a proton to deliver aryl-
gold compound 6 that after protodeauration affords the
final product 2a.
Scheme 1. Initial Experiment: Cycloaromatization of 1a to
Tetrahydronaphthalene 2a
Scheme 2. Proposed Mechanism for the Formation of 2a from
1a: Tandem CyclizationꢀMigration Reaction
The observed reaction pathway is clearly different from
that previously observed in the cycloisomerization of
(5) For recent examples of Au-catalyzed cycloisomerizations of
related 1,5-enynes, see: (a) Buzas, A. K.; Istrate, F. M.; Gagosz, F.
Angew. Chem., Int. Ed. 2007, 46, 1141–1144. (b) Kirsch, S. F.; Binder,
ꢁ
J. T.; Crone, B.; Duschek, A.; Haug, T. T.; Liebert, C.; Menz, H. Angew.
Chem., Int. Ed. 2007, 46, 2310–2313. (c) Horino, Y.; Yamamoto, T.;
Ueda, K.; Kuroda, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131
2809–2811.
(6) For an interesting example of selectivity switch by a small
modification of the substrate, see: (a) Hashmi, A. S. K.; Rudolph, M.;
ꢀ
Huck, J.; Frey, W.; Bats, J. W.; Hamzic, M. Angew. Chem., Int. Ed. 2009,
48, 5848–5852.
(7) (a) Hopf, H.; Musso, H. Angew. Chem., Int. Ed. 1969, 8, 680.
(b) For a review, see: Zimmermann, G. Eur. J. Org. Chem. 2001, 457–471.
(8) (a) Merlic, C. A.; Pauly, M. E. J. Am. Chem. Soc. 1996, 118,
11319–11320. (b) Lian, J.-J.; Odedra, A.; Wu, C.-J.; Liu, R.-S. J. Am.
Chem. Soc. 2005, 127, 4186–4187.
Noteworthy, in our previously reported cycloisomeriza-
tion of related o-alkynylstyrenes we proposed a similar
initial cyclization step, followed by a proton elimination
from the corresponding intermediates analogous to 4 or 40,
to explain the observed formation of indene derivatives.3
Nevertheless, in the reaction of 1,3-dien-5-yne 1a the
proposed alternative reaction pathway via 40 or 400 could
(9) Lian, J.-J.; Lin, C.-C.; Chang, H. K.; Chen, P.-C.; Liu, R.-S.
J. Am. Chem. Soc. 2006, 128, 9661–9667.
ꢀ
(10) Garcıa-Garcıa, P.; Fernandez-Rodrıguez, M. A.; Aguilar, E.
´ ´ ´
Angew. Chem., Int. Ed. 2009, 48, 5534–5537.
(11) For the preparation of starting dienynes 1, 7, and 9, see
Supporting Information.
ꢀ
(12) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7
4133–4136.
(14) (a) For a review on 1,2-alkyl migrations in reactions catalyzed by
π-acids, see: Crone, B.; Kirsch, S. F. Chem.;Eur. J. 2008, 14, 3514–
3522. (b) For a review on Cu-, Ag-, and Au-catalyzed migratory
cycloisomerizations, see: Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Aldrichimica Acta 2010, 43, 37–46.
(13) CCDC 827051 (2a) 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.
Org. Lett., Vol. 13, No. 18, 2011
4971

behighlyfavored becausenow itinvolves anaromatization
step, which is most probably the driving force of the whole
process. It is also worth noting that whereas most of the
reported 1,2-alkyl shifts in cascade Au-catalyzed reactions
involve migration to an adjacent metal carbenoid center or
a pinacol-type rearrangement,14a few examples have been
described involving alternative pathways.15
Table 1. Scope of the Gold-Catalyzed Rearrangement of
1,1-Dimethyl-1,3-hexadien-5-ynes 1a
Considering the novelty and interest of this transforma-
tion, as well as its potential application as a method for
the regioselective synthesis of useful penta-substituted
benzenes,16 we decided to optimize the reaction conditions
and test its scope. After checking several gold complexes,17
wefound out thatthe bestconditionsconsisted inthe use of
5 mol % of XphosAuNTf2 (XPhos = 2-dicyclohexylpho-
sphino-20,40,60-triisopropylbiphenyl) in CH2Cl2 as solvent
at rt, which allowed the formation of 2a in 87% yield in a
short reaction time of <15 min. Under these optimized
conditions a series of 1,3-dien-5-ynes 1 were reacted, and
the results are shown in Table 1.18
Gratifyingly, the cyclizationꢀmigration sequence takes
place in good yields for 1,3-dien-5-ynes 1aꢀg bearing
different substituents at the terminal position of the triple
bond, including aromatic, heteroaromatic, alkenyl, cyclic,
and functionalized alkyl, as well as heteroatomic, groups
(Table 1, entries 1ꢀ6).19 Moreover, regarding the substi-
tuent at the central double bond of the dienyne (R1, R2),
the reaction tolerates both cyclic (entries 1ꢀ7) and linear
(entry 8) aliphatic groups, as well as aromatic substituents
(entries 9ꢀ10),20 although a decrease in yield is observed
when two aromatic substituents are present (entry 11).21
Next, taking into account the proposed mechanism that
includes a migration step, we considered that dienynes 7
yield
(%)b
entry
1
R1
R2
R3
2
1
1a
1b
1c
1d
1e
1f
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
Ph
2a
2b
2c
2d
2e
2f
87
2c
3
3-Th
c-C6H9
c-C3H5
(CH2)3CN
SPh
85
85
4
74
5
55
6
83
7
1g
1h
1i
ꢀCH2O(CH2)2ꢀ
Ph
2g
2h
2i
76
8
Et
Et
Ph
86
9
ꢀ(CH2)2(o-C6H4)ꢀ
Ph
74d
75d
50e
10
11
1j
Me
Ph
Ph
Ph
Ph
2j
1k
Ph
2k
a Reactions stirred at rt for 30 min (complete consumption of the
starting material was checked by GC-MS analysis). b Yield of isolated
product based on the corresponding starting dienyne 1. c Using
Ph3PAuNTf2 as catalyst. d 10% of an isomeric side product was also
isolated; see ref 20. e Lower yield was mostly due to decomposition under
the reaction conditions. 3-Th = 3-thienyl, c-C6H9 = cyclohexenyl, c-
C3H5 = cyclopropyl.
bearing a cyclic group at the terminal position of the olefin
could be of great interest, because if they react in the same
way as dienynes 1 their transformation would imply a ring
expansion.22 Therefore, we submitted several dienynes
7aꢀe to the optimized reaction conditions and were de-
lighted to find that, although some side reactions were
observed for particular substrates, tricyclic compounds 8,
analogous to 2, could be isolated in moderate to high yields
(Table 2). Notably, not only five-membered rings were
expanded to six-membered rings but also the more challen-
ging expansion from a six-membered ring to a seven-
membered ring was efficiently achieved, in a reaction that
is compatible with different selected substituents in both
the central olefin and the terminal position of the triple bond.
Finally, to check the selectivity of the migration step, we
faced the reaction of dienynes 9, which have two different
substituents in the terminal position of the olefin, and
therefore two groups that could potentially migrate (Table
3).23 Pleasantly, a selective migration occurs in all cases, as
determined by 1H NMR of the crude product.24 From the
(15) (a) Dudnik, A. S.; Schwier, T.; Gevorgyan, V. Org. Lett. 2008,
ꢀ
10, 1465–1468. (b) Suarez-Pantinga, S.; Palomas, D.; Rubio, E.;
ꢀ
Gonzalez, J. M. Angew. Chem., Int. Ed. 2009, 48, 7857–7861. (c) Davies,
P. W.; Martin, N. Org. Lett. 2009, 11, 2293–2296. (d) Li, W.; Li, Y.;
Zhang, J. Chem.;Eur. J. 2010, 16, 6447–6450.
(16) For transition-metal-catalyzed approaches to polysubstituted
benzenes, see: (a) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901–
2915. For recent examples of nonmetal-catalyzed syntheses of poly-
functionalized benzenes from 1,3-hexadien-5-ynes, see: (b) Matsumoto,
S.; Takase, K.; Ogura, K. J. Org. Chem. 2008, 73, 1726–1731. (c) Zhou,
H.; Xing, Y.; Yao, J.; Chen, J. Org. Lett. 2010, 12, 3674–3677. For other
gold-catalyzed syntheses of benzene rings, see: (d) Hashmi, A. S. K.;
Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553–11554. (e)
Dankwardt, J. W. Tetrahedron Lett. 2001, 42, 5809–5812. (f) Shibata, T.;
Ueno, Y.; Kanda, K. Synlett 2006, 411–414. (g) Hashmi, A. S. K.;
Rudolph, M.; Siehl, H.-U.; Tanaka, M.; Bats, J. W.; Frey, W. Chem.;
Eur. J. 2008, 14, 3703–3708.
(17) See Supporting Information for details.
(18) 1 mol % of XPhosAuNTf2 was sufficient to cyclize model
substrate 1a (84% yield). However, no complete conversions were
observed for some other substrates when using 1 mol % of catalyst.
(19) The corresponding terminal alkyne decomposed under the
reaction conditions.
(20) For dienynes 1i and 1j an isomer of the expected product was
also isolated in ∼10% yield.
(23) Selected examples of gold-catalyzed selective migrations: (a)
Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 5195–
5197. (b) Hashmi, A. S. K.; Yang, W.; Rominger, F. Angew. Chem., Int.
Ed. 2011, 50, 5762–5765. See also ref 15. For Ru-catalyzed 1,2-halo and
aryl shifts in the cycloisomerization of terminal o-(ethynyl)styrenes, see:
(c) Shen, H.-C.; Pal, S.; Lian, J.-J.; Liu, R.-S. J. Am. Chem. Soc. 2003,
125, 15762–15763. See, also: Madhushaw, R. J.; Lo, C.-Y.; Hwang,
C.-W.; Su, M.-D.; Shen, H.-C.; Pal, S.; Shaikh, I. R.; Liu, R.-S. J. Am.
Chem. Soc. 2004, 126, 15560–15565.
(21) For dienynes 1j and 1k it was observed that only the geometrical
isomer with the stereochemistry shown in Table 1 (entries 10ꢀ11)
reacted under the standard reaction conditions.
(22) Selected examples of gold-catalyzed ring expansions: (a) Gorin,
D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260–
ꢀ
ꢀ~
11261. (b) Jimenez-Nunez, E.; Claverie, C. K.; Nieto-Oberhauer, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5452–5455. (c) Lee,
J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912–914. (d) Li,
C. W.; Pati, K.; Lin, G.-Y.; Sohel, S. M. A.; Hung, H.-H.; Liu, R.-S.
Angew. Chem., Int. Ed. 2010, 49, 9891–9894.
(24) It was initially checked that both the E and Z isomers of the
starting materials 9 showed analogous reactivity, and therefore, reac-
tions were usually performed with a mixture of isomers.
4972
Org. Lett., Vol. 13, No. 18, 2011

Table 2. Tricyclic Compounds 8 by Gold-Catalyzed Cycloaro-
matizationꢀRing Expansion Sequence of Dienynes 7a
Table 3. Tetrahydronaphthalene Derivatives 10 by Gold-Cata-
lyzed Tandem CyclizationꢀSelective Migration Reactions of
Dienynes 9a
entry
7
R
X
n
8
yield (%)b
entry
9b
R1
Et
R2
R3
Ph
X
10
yield (%)c
1
7a
7b
7c
7d
7e
Ph
CH2
O
1
1
2
2
2
8a
8b
8c
8d
8e
62
60
80
81
76
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9f
Me
Me
Et
CH2
CH2
CH2
CH2
CH2
O
10a
10b
10c
10d
10e
10f
75
79
78
72
40
62
64
2
Ph
3c
4
Ph
CH2
CH2
O
Ph
Ph
i-Pr
H
Ph
Ph
c-C6H9
Ph
Ph
Ph
Me
Ph
Ph
5
Ph
a Reactions stirred at rt for 30 min (complete consumption of the
starting material was checked by GC-MS analysis). b Yield of isolated
product based on the corresponding starting dienyne 7. c Reaction
performed with Ph3PAuNTf2 as catalyst.
Et
3-Th
3-Th
9g
i-Pr
O
10g
a Reactions stirred at rt for 30 min (complete consumption of the
starting material was checked by GC-MS analysis). b Starting dienynes 9
were used as a mixture of geometrical isomers. c Yield of isolatedproduct
based on the corresponding starting dienyne 9.
results (Table 3) we can determine the following migration
aptitude order: ethyl migration selectively takes place over
methyl migration (entry 1); for substrates bearing both an
aliphatic and aromatic substituent, migration of the aro-
matic ring is preferred over methyl and ethyl migration
(entries 2ꢀ3), whereas the isopropyl group selectively
migrates over the phenyl group (entry 4).25 Finally, in
product 10e (entry 5), which was obtained in moderate
yield due to decomposition of the starting material under
the reaction conditions,26 formal migration of the hydro-
gen can be observed, although in this case the reaction
could also be explained through a direct proton elimina-
tion from a 400 type intermediate (Scheme 2). Therefore, the
migration aptitudeof the differentsubstituentsturns out to
bei-Pr > Ph > Et > Me,27 resembling thegeneralorder of
likelihood of migration for the BaeyerꢀVilliger oxidation,
and showing that the major factor in determining which
group migrates seems to be the ability to accommodate
partial positive charge. These results also demonstrate the
compatibility of the reaction with the presence of an
aromatic group in the terminal position of the olefin. In
this sense, the high versatility of the reported transforma-
tion that allows variability in all the possible positions of
the starting dienyne, together with the complete selectivity
of the migration step, makes this reaction a useful meth-
odology for the regioselective synthesis of pentasubstituted
benzenes with up to five different substituents, as illu-
strated with examples 10f,g (Table 3, entries 6ꢀ7).
In conclusion, we have discovered that 1,1-disubsti-
tuted-1,3-hexadien-5-ynes react under gold-catalyzed con-
ditions through an unprecedented tandem cyclizationꢀ
migration sequence. Moreover, when two different groups
can participate in the WagnerꢀMeerwein shift a complete
selectivity was observed, which very roughly follows the
order in which the groups are able to stabilize a positive
charge. Further studies to prove the mechanism of this
transformation and to extend its scope are currently in
progress in our laboratory.
Acknowledgment. We are grateful to the Ministerio de
ꢀ
Ciencia e Innovacion (MICINN) and FEDER (CTQ2010-
15358 and CTQ2009-09949/BQU) and Junta de Castilla y
ꢀ
Leon (BU021A09 and GR-172) for financial suport. A.M.
S. thanks Junta de Castilla y Leon for a predoctoral
ꢀ
fellowship. P.G.-G. and M.A.F.-R. thank MICINN for
ꢀ
“Juan de la Cierva” and “Ramon y Cajal” contracts. This
paper is dedicated to Prof. Dr. Francisco J. Arnaiz on the
ꢀ
occasion of his 65th birthday.
Supporting Information Available. Experimental pro-
cedures, characterization data for all new compounds,
1
and crystallographic data (CIF). Copies of H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(25) The structure of the final products was determined based on
NOESY experiments. See Supporting Information for details.
(26) A dienyne bearing only one methyl group at the terminal
position of the olefin did not react under the reaction conditions and
decomposed upon heating to 80 °C in DCE in the presence of Xpho-
sAuNTf2 (5 mol %).
(27) An alternative mechanism involving skeletal rearrangements
previous to the migration step, which could imply a reversed migratory
aptitude, cannot be completely ruled out at this point.
Org. Lett., Vol. 13, No. 18, 2011
4973