Gold(I)-catalyzed intramolecular [4+2] cycloadditions of arylalkynes or 1,3-enynes with alkenes: Scope and mechanism

Article abstract of DOI:10.1021/ja075794x

The cyclizations of enynes substituted at the alkyne gives products of formal [4+2] cyclization with Au(I) catalysts. 1,8-Dien-3-ynes cyclize by a 5-exo-dig pathway to form hydrindanes. 1,6-Enynes with an aryl ring at the alkyne give 2,3,9,9a-tetrahydro-1

Full text of DOI:10.1021/ja075794x

Published on Web 12/13/2007
Gold(I)-Catalyzed Intramolecular [4+2] Cycloadditions of
Arylalkynes or 1,3-Enynes with Alkenes: Scope and
Mechanism
Cristina Nieto-Oberhuber,†,‡ Patricia Pe´rez-Gala´n,† Elena Herrero-Go´mez,†
Thorsten Lauterbach,† Cristina Rodr´ıguez,† Salome´ Lo´pez,† Christophe Bour,†
Antonio Rosello´n,† Diego J. Ca´rdenas,‡ and Antonio M. Echavarren*,†,‡
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16, 43007 Tarragona,
Spain and Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
Received August 8, 2007; E-mail: aechavarren@iciq.es
Abstract: The cyclizations of enynes substituted at the alkyne gives products of formal [4+2] cyclization
with Au(I) catalysts. 1,8-Dien-3-ynes cyclize by a 5-exo-dig pathway to form hydrindanes. 1,6-Enynes with
an aryl ring at the alkyne give 2,3,9,9a-tetrahydro-1H-cyclopenta[b]naphthalenes by a 5-exo-dig cyclization
followed by a Friedel-Crafts-type ring expansion. A 6-endo-dig cyclization is also observed in some cases
as a minor process, although in a few cases, this is the major cyclization pathway. In addition to cationic
gold complexes bearing bulky biphenyl phosphines, a gold complex with tris(2,6-di-tert-butylphenyl)phosphite
is exceptionally reactive as a catalyst for this reaction. This cyclization can also be carried out very efficiently
with heating under microwave irradiation. DFT calculations support a stepwise mechanism for the
cycloaddition by the initial formation of an anti-cyclopropyl gold(I)-carbene, followed by its opening to form
a carbocation stabilized by a π interaction with the aryl ring, which undergoes a Friedel-Crafts-type reaction.
Scheme 1
Introduction
Enynes I react via the 5-exo-dig pathway with electrophilic
transition metal complexes or halides MXn acting as catalysts
to give a variety of cycloisomerization and addition derivatives
via cyclopropyl metal carbenes II intermediates (Scheme 1).1,2
Thus, reaction with nucleophiles R′OH (alcohols or water)1,2
or electron-rich aromatic systems3,4 gives products of type III,
whereas in the absence of nucleophiles, dienes IV or, less
commonly, cyclobutenes V can be obtained.1,5,6 In addition to
the nucleophilic attack at intermediates II to give products III,
certain carbon nucleophiles also react at the carbene carbon4 in
a process that is similar to the intermolecular cyclopropanation
with alkenes catalyzed by gold(I).7 Similar pathways take place
in the gold(I)-cyclization of 1,5-8 and 1,7-enynes.9
For some of these transformations, cationic complexes
generated by chloride abstraction from [AuCl(PPh3)] have
proven to be very reactive catalysts.10 However, enynes bearing
† Institute of Chemical Research of Catalonia (ICIQ).
‡ Universidad Auto´noma de Madrid.
(1) Reviews: (a) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-
1382. (b) Echavarren, A. M.; Nevado, C. Chem. Soc. ReV. 2004, 33, 431-
436. (c) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006,
45, 7896-7936. (d) Zhang, L.; Sunm, J.; Kozmin, S. A. AdV. Synth. Catal.
2006, 348, 2271-2296. (e) Hashmi, A. S. K.; Hutchings, G. J. Angew.
Chem., Int. Ed. 2006, 45, 7896-7936. (f) Jime´nez-Nu´n˜ez, E.; Echavarren,
A. M. Chem. Commun. 2007, 333-346. (g) Fu¨rstner, A.; Davies, P. W.
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9
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J. AM. CHEM. SOC. 2008, 130, 269-279
269

A R T I C L E S
Scheme 2
Nieto-Oberhuber et al.
Figure 1.
electrophilicity and react with 1,6-enynes to form intermediates
II that are less prone to undergo skeletal rearrangement, which
allows their intermolecular trapping by alkenes to form cyclo-
propanes.7 Recently, we have prepared new gold(I) complex 5
bearing tris(2,6-di-tert-butylphenyl)phosphite as a bulky ligand,
whose cationic derivative formed in situ by chloride abstraction
with AgSbF6 is the most electrophilic Au(I) catalyst that we
have tested thus far in reactions with substituted enynes (Figure
1).7
Cationic complexes formed in situ from 1a-d catalyze the
formal [4+2] cycloaddition of substituted dienynes 6 and
arylenynes 9 under mild conditions (Scheme 2).12 In contrast,
the thermal intramolecular [4+2] cycloaddition of dienynes
of type 6 has been described to proceed at temperatures as
high as 600 °C,18 although milder conditions (heating at 110-
250 °C) are required for the intramolecular reaction of conju-
gated enynes with ynamines.19 Reaction of substrates 9 to give
10 is of particular interest as pycnantuquinones A (11a) and B
(11b)20 have the carbon skeleton of tricyclic compounds 10.
These quinones have been isolated from an African tree and
display antihyperglycemic activity in mice.20 Recently, pyc-
nantuquinone C (11c), a new member of this family, has been
isolated from an alga.21 Products somewhat related to 10 have
been obtained by Grigg et al. by palladium-catalyzed intermo-
lecular [2+2+2] cycloaddition reaction of enynes with aryl or
vinyl halides22 and by Ohno et al. by intramolecular Pd-catalyzed
tandem cyclization of bromoenynes.23 A different type of
cyclization, in which the phenyl group participates in the
process, has been observed in the gold-catalyzed cycloisomer-
ization of allenynes.24
substituted alkynes, in particular those with an aryl group, are
quite reluctant to undergo cycloisomerization and alkoxycy-
clization reactions.2d,10a We decided to prepare new gold(I)
complexes bearing bulky, biphenyl-based phosphines 1a-d,
which have been shown by Buchwald et al. to be excellent
ligands for Pd-catalyzed reactions.11 Indeed, upon being mixed
with Ag(I) salts, complexes 1a-d lead to very active catalysts.12
More convenient are cationic complexes 2a-b and 3,6b which
are stable crystalline solids that can be handled under ordinary
conditions, yet are very reactive as catalysts in a variety of
transformations.13,14,15 The structures of 1a-d, 2a-b, and 3 have
been confirmed by X-ray crystallography.16 Gold complexes
with N-heterocyclic ligands have also been prepared.12,17 These
complexes bearing these highly donating ligands are of moderate
(6) (a) Nieto-Oberhuber, C.; Lo´pez, S.; Mun˜oz, M. P.; Ca´rdenas, D. J.; Bun˜uel,
E.; Nevado, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2005, 44, 6146-
6148. (b) Nieto-Oberhuber, C.; Lo´pez, S.; Jime´nez-Nu´n˜ez, E.; Echavarren,
A. M. Chem. Eur. J. 2006, 11, 5916-5923. (c) Ferrer, C.; Raducan, M.;
Nevado, C.; Claverie, C. K.; Echavarren, A. M. Tetrahedron 2007, 63,
6306-6316. (d) Cabello, N.; Jime´nez-Nu´n˜ez, E.; Bun˜uel, E.; Ca´rdenas,
D.; Echavarren, A. M. Eur. J. Org. Chem. 2007, 4217-4223.
(7) Lo´pez, S.; Herrero-Go´mez, E.; Pe´rez-Gala´n, P.; Nieto-Oberhuber, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 6029-6032.
(8) Buzas, A. K.; Istrate, F. M.; Gagosz, F. Angew. Chem., Int. Ed. 2007, 46,
1141-1144.
(9) Cabello, N.; Rodr´ıguez, C.; Echavarren, A. M. Synlett 2007, 1753-1758.
(10) (a) Nieto-Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.; Ca´rdenas,
D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402-2406.
(b) Nieto-Oberhuber, C.; Mun˜oz, M. P.; Lo´pez, S.; Jime´nez-Nu´n˜ez, E.;
Nevado, C.; Herrero-Go´mez, E.; Raducan, M.; Echavarren, A. M. Chem.
Eur. J. 2006, 11, 1677-1693.
Here, we describe the scope and limitations of the gold-
catalyzed [4+2] cycloaddition reaction. For this reaction, we
have found that in addition to 1a-d and 2a-b, precatalyst 5 is
exceptionally reactive. This cyclization is also substantially
(11) (a) Kaye, S.; Fox, J. M.; Hicks, F. A.; Buchwald, S. L. AdV. Synth. Catal.
2001, 343, 789-794. (b) Walker, S. D.; Border, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871-1876. (c) Strieter,
E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
13978-13980. (d) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685-4696. (e) Barder, T. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 5096-5101.
(12) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005,
127, 6178-6179.
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2005, 24, 2411-2418.
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J. Am. Chem. Soc. 1996, 118, 4218-4219.
(19) (a) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776-
5777. (b) See also: Danheiser, R. L.; Gould, A. E.; Ferna´ndez de la Pradilla,
R.; Helgason, A. L. J. Org. Chem. 1994, 59, 5514-5515.
(20) Fort, D. M. et al. J. Org. Chem. 2000, 65, 6534-6539.
(21) Laird, D. W.; Poole, R.; Wikstro¨m, M.; van Altena, I. A. J. Nat. Prod.
2007, 70, 671-674.
(22) Brown, S.; Clarkson, S.; Grigg, R.; Sridharan, V. Tetrahedron Lett. 1993,
34, 157-160.
(23) (a) Ohno, H.; Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem., Int.
Ed. 2005, 44, 5103-5106. (b) Related cyclization of allenenes with aryl
halides: Ohno, H.; Miyaura, K.; Takeoka, Y.; Tanaka, T. Angew. Chem.,
Int. Ed. 2003, 42, 2647-2650.
(13) Nieto-Oberhuber, C.; Lo´pez, S.; Mun˜oz, M. P.; Jime´nez-Nu´n˜ez, E.; Bun˜uel,
E.; Ca´rdenas, D. J.; Echavarren, A. M. Chem. Eur. J. 2006, 11, 1694-
1702.
(14) Jime´nez-Nu´n˜ez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A.
M. Angew. Chem., Int. Ed. 2006, 45, 5451-5455.
(15) (a) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105-
1109. (b) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem. Eur. J.
2007, 13, 1358-1373.
(16) Herrero-Go´mez, E.; Nieto-Oberhuber, C.; Lo´pez, S.; Benet-Buchholz, J.;
Echavarren, A. M. Angew. Chem. Int. Ed. 2006, 45, 5455-5459.
9
270 J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008

Gold(I)-Catalyzed Intramolecular [4+2] Cycloadditions
A R T I C L E S
accelerated by heating the reactions in CH2Cl2 under microwave
irradiation. We also report a DFT theoretical study on the
mechanism of the reaction of arylenynes 9 that indicates that
the [4+2] cycloaddition is a stepwise process, which occurs by
opening of the initial cyclopropyl gold(I) carbenes to form a
carbocation that undergoes a Friedel-Crafts-type reaction.
Cycloaddition of Arylenynes. We examined in detail the
reaction of arylenyne 9a with different Au(I) catalysts (2 mol
%) as well as with PtCl2 (Table 2). Although the cycloaddition
proceeded well with [AuCl(PPh3)]/AgSbF6, it was considerably
faster with catalysts generated from complex 1a or with 2a
(Table 2, entries 1-3). Among the assayed solvents, the best
results were obtained in CH2Cl2 (Table 2, entry 3). Slower
reactions were obtained in other solvents, whereas in acetonitrile,
the reaction did not proceed (Table 2, entries 4-9). The cationic
catalyst generated from complex 5 provided 10a in quantitative
yield (Table 2, entry 10), whereas PtCl2 was inefficient under
these conditions (Table 2, entry 11). The reaction can also be
carried under microwave heating (Table 2, entries 1-16).26 The
best results were obtained in CH2Cl2 or 1,2-dichoroethane, in
which the cyclization of 9a could be carried out cleanly in only
1 min at 50 °C with 2a (Table 2, entries 12 and 13) or in 30 s
with 5 and AgSbF6 (Table 2, entry 16). Gas chromatography
and 1H NMR analysis show exceptionally clean reaction
mixtures in these cycloadditions.
Experimental Results
Cycloaddition of Dienynes. 1,8-Dien-3-yne 6a reacts by a
5-exo-dig pathway25 to give hydrindane 7a with 1a/AgSbF6 as
the catalyst (Table 1, entry 1). Similarly, 6b gives 7b along
with regioisomeric diene 8 as a minor compound (Table 1, entry
2). The same ratio of 7b and 8 (∼5:1) was obtained by using
other Au(I) catalysts. Dienynes 6c and 6d also provided
hydrindanes 7c and 7d, respectively (Table 1, entries 3-9).
Diene 7d was obtained as a single diastereoisomer, whose
configuration was determined by NOESY. Hydrindanes 7c and
7d were obtained in short times and in good yields with 2a
under microwave heating (Table 1, entries 4, 7, and 9; see
below) or with 5/AgSbF6 at room temperature (Table 1, entries
5 and 8).
Table 1. Au(I)-Catalyzed Cyclization of 1,8-Dien-3-ynes 7a-d [Z )
C(CO2Me)2]a
Table 2. Cyclization of Arylenyne 9a
entry
[M] (mol %)
solvent
conditionsa
time
yield (%)
1
2
3
4
5
6
7
8
9
[AuCl(PPh3)]/AgSbF6 (2) CH2Cl2
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
12 h
2 h
83
1a /AgSbF6 (2)
2a (2)
CH2Cl2
CH2Cl2
acetone
toluene
DMF
MeNO2
Et2O
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
DCE
85
2 h
83
2a (2)
6 h
81
2a (2)
20 h
20 h
5 h
27
2a (2)
25
2a (2)
77
2a (2)
20 h
20 h
2 h
24 h
1 min
78
2a (2)
< 2
10 5/AgSbF6 (2)
11 PtCl2 (5)
12 2a (2)
99
< 2
93b
92b
74b
16b
95b
13 2a (2)
1 min
1 min
1 min
14 2a (2)
acetone
toluene
CH2Cl2
15 2a (2)
16 5/AgSbF6 (2)
0.5 min
a A ) room temperature. B ) microwave heating, 50 °C. b Yield
determined by GC.
Substituted arylenynes 9b-d reacted with catalysts 1a-d to
give 2,3,9,9a-tetrahydro-1H-cyclopenta[b]naphthalenes 10b-d
stereospecifically (Table 3). Thus, E/Z diastereomers 9b and
9c provided tricyclic compounds 10b and 10c, respectively
(Table 3, entries 1-6), as a result of retention of the alkene
configuration. Retention of configuration was also observed in
the cyclization of trans-cinammyl derivative 9d (Table 3, entries
7-10). In the cycloadditions of 9b and 9d, substantial rate
accelerations were observed using complex 5 as the precatalyst
(Table 3, entries 5 and 11). In the presence of water, enyne 9b
also provided alcohol 13 (Table 3, entry 9), the product of an
endo-hydroxycyclization.2b This cyclization was more efficiently
carried out under microwave heating (Table 3, entry 10). In
a Reactions carried out at room temperature in CH2Cl2 with 2 mol %
catalyst. b Reaction under microwave heating in CH2Cl2 at 80 °C with 2
mol % catalyst.
When the reaction of dienyne 6a was carried out in MeOH
as solvent with catalyst 1a/AgSbF6, compound 12 (eq 1) was
obtained as a result of a 5-exo-dig methoxycyclization2,6b via
an intermediate of type II (Scheme 1).
(24) Lemie`re, G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; de Kozak, A.; Aubert,
C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 7596-
7599.
(25) For the involvement of intermediates of type VI: (a) Trost, B. M.; Hashmi,
A. S. K. Angew. Chem., Int. Ed. 1993, 32, 1085-1087. (b) Trost, B. M.;
Hashmi, A. S. K. J. Am. Chem. Soc. 1994, 116, 2183-2184.
(26) See the Supporting Information for additional data.
9
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A R T I C L E S
Nieto-Oberhuber et al.
contrast to the efficient cyclization of 9d, phenylenyne 9e failed
to cyclize with Au(I) catalysts (Table 3, entry 12). Tosylamide
9f also failed to afford a [4+2] cycloaddition product and led
instead to azabicyclo[4.1.0]hept-4-ene 14f with catalyst 2a
(Table 3, entry 13), the product of an endo-cyclization.10b Ether
9g also failed to give a [4+2] cycloaddition product (Table 3,
entry 14). The lack of reactivity of 9e-g can be attributed to
the electron-withdrawing effect of the groups at the tether, which
presumably disfavor formation of the initial Au(I)-alkyne
complex.
4). Interestingly, in the case of 9h, in addition to 10h,
cycloadduct 15h was also obtained as a minor product (Table
4, entries 1-3). Product 15h is the result of an initial 6-endo-
dig cyclization.27 Although the cyclization of 9h was accelerated
by microwave heating, the 10h/15h ratio was identical to that
obtained at room temperature (Table 4, entry 3). As before, faster
reactions at room temperature were observed using 5 as the
precatalyst (Table 4, entries 6, 8, and 11). Tricyclic compound
10k was obtained as single stereoisomer. The structure of
cycloadduct 10i has been confirmed by X-ray crystallography.28
Table 3. Au(I)-Catalyzed Cyclization of Arylenynes 9b-d (E )
Table 4. Au(I)-Catalyzed Cyclization of Arylenynes 9h-k (E )
CO2Me)a
CO2Me)a
a Reactions run with 2 mol % catalyst in CH2Cl2 at room temperature.
b Reaction under microwave heating at 80 °C with 2 mol % catalyst in
CH2Cl2.
Substrates with meta substituents 9l-o gave, as expected,
mixtures of regioisomeric cycloadducts (Table 5). Thus, in the
case of 9l, four products were obtained with 2a or 5/AgSbF6
with catalysts at room temperature (Table 5, entries 1 and 3).
However, under microwave heating with catalyst 2a, substrate
9l afforded only compounds 10l and 10′l (Table 5, entry 2).
Nitrile derivative 9m reacted more sluggishly than 9l to give a
1:1 mixture of regioisomers 10m/10′m in 52% yield using 2a
(5 mol %) as catalyst (Table 5, entry 4). In the reaction of 9n
carried out for 3 h, 2,3,9,9a-tetrahydro-1H-fluorenes 15n and
15′n were also formed in low yields (Table 5, entry 7). These
compounds could not be obtained pure. The result with substrate
9o is noteworthy as, although the reaction with 2a at room
temperature led to a mixture of four products, reaction under
microwave heating with 2a or with 5/AgSbF6 at room-
temperature gave 15′′o as single regioisomer in excellent yield
a Reaction run with 2 mol % catalyst in CH2Cl2 at room temperature.
b Reaction in acetone at room temperature with 5% mol catalyst. c Reaction
under microwave heating at 80 °C with 2 mol % catalyst in CH2Cl2.
The cycloaddition tolerates a variety of para substituents at
the aryl ring. Thus, substrates 9h-i with methoxy, nitro, and
cyano groups reacted efficiently to give products 10h-i (Table
9
272 J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008

Gold(I)-Catalyzed Intramolecular [4+2] Cycloadditions
A R T I C L E S
(Table 5, entries 8-10). Product 15′′o is the result of an initial
endo-dig cyclization followed by the isomerization of the alkene
to the internal position.
6). These cyclohexadienes arise by a 6-endo cyclization followed
by cyclopropane opening followed by 1,2-H migration (see
below).
Table 6. Au(I)-Catalyzed Cyclization of Arylenynes 9p-r (E )
Table 5. Au(I)-Catalyzed Cyclization of Arylenynes 9l-o (E )
CO2Me)a
CO2Me)a
a Reactions run with 2 mol % catalyst in CH2Cl2 at room temperature.
b Reaction under microwave heating at 80 °C with 2 mol % catalyst in
CH2Cl2.
Reaction of enyne 9s bearing an ortho-nitro group gave
exclusively benzo[c]isoxazole (anthranil) derivative 18 in 90%
yield, instead of the expected cycloadduct as a result of a
preferred attack of the nitro group at the alkyne (eq 2). Related
anthranils have been obtained by Asao and Yamamoto in the
cyclization of o-(alkynyl)nitrobenzenes catalyzed by AuBr3.29
a Reaction run using 2 mol % catalyst in CH2Cl2 at room temperature.
b Reaction under microwave heating at 80 °C with 2 mol % catalyst in
CH2Cl2. c Reaction run using 5 mol % catalyst. d Reaction in the presence
of 4 Å molecular sieves.
Alternatively, aryl enynes 9p-r with ortho substituents gave
products 10p-r, respectively (Table 6). The structure of
cycloadduct 10q was confirmed by X-ray crystallography. In
the reactions of 9p and 9r, cyclohexadienes 16p and 16r were
also obtained as minor compounds (Table 6, entries 1-4, and
As models for the synthesis of the pycnanthuquinones 11a-
c, we assayed the cycloadditions of arylenynes 9t-y (Scheme
3). The reaction of 9t with catalyst 2a (5 mol %) gave a 10:1
(27) Interestingly, this was the major pathway in the Pt(II)-catalyzed cycload-
dition of arylalkynes with enesulfonamides or enamides: Harrison, T. J.;
Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367-370.
9
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Nieto-Oberhuber et al.
mixture of 10t and tetrahydro-1H-fluorene 15t, which could not
be obtained pure. The presence of excess silver salt led to poor
results. Thus, a less clean reaction was observed with 2a and
AgSbF6 (3 mol % each), which led to ∼ 3:1 ratio of 10t and
15t and the formation of several uncharacterized byproducts.
The reaction of 9u proceeded with many Au(I) catalyst, although
the isolated yields were low. After much experimentation, a
35% yield of 10u was achieved using catalyst 2a. Substrates
9v-y also react with catalyst 2a to give tricyclic compounds
10v-y. It is interesting to note that these cyclizations proceed
smoothly with substrates that do not benefit from the effect of
gem-substitution (Thorpe-Ingold effect) from substituents at
the tether.
terminal position with groups capable of stabilizing the develop-
ing positive charge (eq 3). Using precatalyst 5 substrates 9ab
and 9ac led to complex mixtures or variables, probably due to
the relatively high reactivity of the resulting cyclobutenes in
the presence of Au(I) and/or Ag(I). Cyclobutenes related to 17
had been obtained by Trost et al. using palladacyclopentadienes
as catalysts5a,b and, more recently, by Fu¨rstner et al. by using
Pt(II) as catalyst under a CO atmosphere.30
Scheme 3
We also examined the cycloaddition of arylalkynes with
enolethers (Scheme 5). Substrates 9ad-af reacted with the gold-
(I) catalyst generated from 5 to give cyclopenta[b]naphthalenes
18ad-af in remarkably fast reactions (2-10 min). The resulting
products result from a [4+2] cycloaddition followed by elimina-
tion of MeOH. Alternatively, when the reaction of 9af was
performed in MeOH, dimethyl acetal 19 was obtained in 80%
yield, as a result of trapping of the initial intermediate of the
cycloaddition process (see below).2b
Scheme 5
Tetracyclic compound 10z was obtained in excellent yield
with 5/AgSbF6 in 30 min from 1-naphthyl derivative 9z (Scheme
4). The same yield was realized using 2a as catalyst, but the
reaction required 12 h at room temperature. No cycloadduct
could be obtained from substrate 9aa, in which the reactive
position of the naphthalene (C-2) has been blocked with a
methyl group.
Scheme 4
The cyclization of 1,7-enynes 20a-c was also examined
(Scheme 6). In contrast to the behavior of 1,7-enynes unsub-
stituted at the alkyne, which suffer single cleavage skeletal
rearrangement,9 these substrates led to [4+2] cycloadditions.
Thus, cyclization of 20a afforded the expected tricycle 21a along
with fluorene derivative 22 as a minor product. Reaction of 20b
proceed uneventfully to provide 21b, whereas diol 20c gave
23, in which one of the primary alcohols has been added to the
Enynes 9ab and 9ac gave cyclobutenes 17ab and 17ac under
these conditions, which suggests that the [4+2] cycloaddition
only proceeds with substrates bearing alkenes substituted at the
(28) See Supporting Information.
(29) Asao, N.; Sato, K.; Yamamoto, Y. Tetrahedron Lett. 2003, 44, 5675-
5677.
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Gold(I)-Catalyzed Intramolecular [4+2] Cycloadditions
A R T I C L E S
alkene in a subsequent reaction catalyzed by Au(I) or H+. The
relative configuration of 23 was assigned on the basis of NOESY
experiments in CDCl3 and benzene-d6.
Scheme 7
Scheme 6
8-11 take into account the solvent effect for CH2Cl2 by means
of polarized continuum model.33
Gold(I)-complex of hept-6-en-1-ynylbenzene (VIIIa) react
through TSVIIIa-IXa to give anti-cyclopropylgold(I) carbene IXa
(Scheme 8) in an exothermic transformation (∆G ) -10.5
kcal‚mol-1). The second step of the cycloaddition proceeded
by opening of the cyclopropane to give Wheland intermediate
Xa via transition state TSIXa-Xa, in which the incipient primary
carbocation is stabilized in a π-interaction with the aryl ring.
Although moderately exothermic (∆G ) -6.2 kcal‚mol-1), the
activation energy (∆Gq ) 21.8 kcal‚mol-1) is higher than that
required for the skeletal rearrangement pathway to give XIa
(∆Gq ) 12.3 kcal‚mol-1), which is the intermediate in the
double cleavage rearrangement of complex VIIIa.6 This activa-
tion energy is similar (∆Gq ) 14.2 kcal‚mol-1) than that
required in the same step of the double cleavage rearrangement
of 1-octen-6-yne,6a which shows that methyl and phenyl groups
have similar effects on this reaction.
Finally, we also tried the cyclization of diaryldiyne 24 with
catalyst 2a (eq 4). The reaction proceeded in 12 h at room
temperature to give adduct 25 in 95% yield, the product of an
endo cyclization process. No reaction was observed with
similar diynes that were arylated only at one of the alkynes. As
part of a broader study on this cyclization carried out by the
group of Liu,31,32 compound 25 was also obtained in the reaction
of 24 with [AuCl(PPh3)]/AgSbF6 (room temperature, 12 h,
81%).
We also examined the evolution of gold(I)-complex VIIIa
by an endocyclic pathway via intermediate XIIa (Scheme 9).
In this case, the activation energy to reach TSVIIIa-XIIa is lower
than that for the exocyclic pathway. Although a Friedel-Crafts-
type process could also be found from endo cyclopropyl gold-
(I) carbene XIIa to give XIIIa via TSXIIa-XIIIa, the activation
energy for his process is much higher than that required for the
formation of bicyclo[3.2.0]heptyl carbocation XIVa. Therefore,
for model complex VIIIa, the more favorable pathways would
be the skeletal rearrangement via XIa (Scheme 8) or formation
of a bicyclo[3.2.0]hept-6-ene via XIVa. This is consistent with
the experimental results shown in eq 3 for 9ab.
Mechanistic Discussion. The cyclization of dienynes 6
presumably proceeds through intermediates such as VI, which
undergo ring expansion in a process that is reminiscent of the
Nazarov cyclization to form allyl cation VII (Scheme 7). This
is followed by loss of a proton followed by proto-demetalation
to give dienes 7a-d and 8. Regioselective proton loss occurs
under kinetic control, as products 7a-b (see Table 1) are 2.5-
3.5 kcal‚mol-1 less stable than dienes like 8 (PM3 calculations).
Formation of intermediate VI in the cyclization is supported
by the isolation of adduct of exo-dig methoxycyclization 12 form
6a (eq 1). The stereochemistry shown in the cyclization of VI
to VII is consistent with the isolation of 7d as a single isomer
in the cyclization of 6d (Table 1).
For the cyclization of VIIIb, anti-cyclopropyl gold(I)-carbene
IXb is formed in an almost thermoneutral process (Scheme 10).
This system corresponds to the Au(I) complex of substrate 9x
(Scheme 3). Interestingly, IXb opens to form IX′b, an aryl-
stabilized π-cation complex (Scheme 10b). The transition state
connecting intermediates IXb and IX′b was not located. It is
important to stress that intermediates IXb and IX′b are both
stationary points in the reaction coordinate with different bond
lengths and angles and not canonical forms, although the
difference in energy is small. At the B3LYP/6-31G(d) (C, H,
In order to understand the different behavior observed in the
cycloadditions of arylalkynes with alkenes depending on the
substitution at the alkene, we performed DFT calculations on
model gold(I)-complexes VIIIa-b. Results shown in Schemes
P), LANL2DZ (Au) level, ∆G was found to be 3.6 kcal‚mol-1
,
(30) Fu¨rstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127, 8244-
8245.
whereas at a higher level (B3LYP/ 6-311+G(d,p) (C,H,P)
LANL2DZ (Au)) the energies are more similar (∆G ) 2.0 kcal‚
(31) Lian, J.-J.; Chen, P.-C.; Lin, Y.-P.; Ting, H.-C.; Liu, R. S. J. Am. Chem.
Soc. 2006, 128, 11372-11373.
(32) Different structures were assigned by Shibata et al. in the gold(I)-catalyzed
cyclization of diaryldiynes of type 24: Shibata, T.; Fujiwara, R.; Takano,
D. Synlett 2005, 2062-2066.
(33) Gas phase DFT calculations and additional details are provided as part of
the Supporting Information.
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A R T I C L E S
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Scheme 8. Reaction Pathway and Energies for the Exo-cycloaddition of VIIIa to Wheland Intermediate Xa or Double Cleavage Skeletal
Rearrangement Gold(I) Carbene XIaa
a Calculations at the B3LYP/6-31G(d) (C, H, P), LANL2DZ (Au) level (+ZPE-corrected electronic energies are given in Kcal‚mol-1; ∆G in brackets),
including solvent effect for CH2Cl2.
Scheme 9. Reaction Pathway and Energies for the Endo-cycloaddition of VIIIa to Wheland Intermediate XIIIa or Cyclobutene Precursor
XIVaa
a Calculations at the B3LYP/6-31G(d) (C, H, P), LANL2DZ (Au) level (+ZPE-corrected electronic energies are given in Kcal‚mol-1; ∆G in brackets),
including solvent effect for CH2Cl2.
mol). The second step of the cycloaddition takes place to give
Wheland intermediate Xb with low activation energy in an
exothermic process via TSIX′b-Xb. The stepwise nature of this
cycloaddition is further supported by the isolation of 19 in the
reaction of 9af carried out in MeOH (Scheme 5).
The skeletal rearrangement via TSIXb-XIb and XIb requires
a relatively high activation energy. Interestingly, in contrast to
that found for XIVb, DFT calculations show that the skeletal
rearrangement for the dimethyl substituted 1,6-enyne would
proceed by a single cleavage mechanism.5,6 The barrier for this
single cleavage rearrangement is higher that that calculated for
(E)-6-octen-1-yne (∆G ) 9.1 Kcal‚mol-1),6a which is probably
due to the stabilizing effect of the phenyl group on the carbene
in IXb.
A similar pathway is probably followed in the cyclizations
of 1,7-enynes 20a-c shown in Scheme 6. Formation of fluorene
derivative 22 as a minor product can be explained by a 1,2-
hydrogen shift of a six-membered ring analogue of cation of
IX′b followed by a Friedel-Crafts cyclization.
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Gold(I)-Catalyzed Intramolecular [4+2] Cycloadditions
A R T I C L E S
Scheme 10. Reaction Pathway and Energies for the Exo-cycloaddition of VIIIb to Wheland Intermediate XIIIb and Selected Distances for
TSIX′b-Xb, IXb, and IX′ba
a Calculations at the B3LYP/6-31G(d) (C, H, P), LANL2DZ (Au) level (+ZPE-corrected electronic energies are given in Kcal‚mol-1; ∆G in brackets),
including solvent effect for CH2Cl2.
Scheme 11. Reaction Pathway and Energies for the Endo-cycloaddition of VIIIb to Wheland Intermediate XIIIb or Cyclobutene Precursor
XIVba
a Calculations at the B3LYP/6-31G(d) (C, H, P), LANL2DZ (Au) level (+ZPE-corrected electronic energies are given in Kcal‚mol-1; ∆G in brackets),
including solvent effect for CH2Cl2.
In the alternative cyclization of VIIIb by the endocyclic
pathway, we found intermediate XII′b preceding formation of
cyclopropyl gold(I) carbene XIIb, although the transition state
connecting these two intermediates could not be found (Scheme
11). Intermediate XIIb then evolves by a Friedel-Crafts-type
process via TSXIIb-XIIIb to form XIIIb. The alternative formation
of bicyclo[3.2.0]heptyl carbocation XIVb via TSXIIIb-XIVb
proceeds with a much higher activation energy. Cyclohexadienes
16p and 16r (Table 6) are presumably formed by a 1,2-H shift
from intermediates XII′b.
Although the pathway shown in Scheme 9 for the opening
of XIIa to form bicyclo[3.2.0]heptyl carbocation XIVa provides
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J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008 277

A R T I C L E S
Nieto-Oberhuber et al.
Scheme 12. Alternative Reaction Pathway and Energies for the Reaction of VIIIa to Cyclobutene Precursor XIVa via IXca
a Calculations at the B3LYP/6-31G(d) (C, H, P), LANL2DZ (Au) Level (+ZPE-corrected electronic energies are given in Kcal‚mol-1; ∆G in brackets),
including solvent effect for CH2Cl2.
Scheme 13. Two Pathways for the Formation of
a reasonable pathway for the formation of cyclobutenes 17ab
6-Phenylbicyclo[3.2.0]hept-6-ene (XVa) from VIIIaa
and 17ac (eq 3), we found an alternative pathway after
examining the reactivity of syn-cyclopropyl gold(I) carbene IXc
(Scheme 12). The direct formation of this intermediate from
VIIIa is unlikely, as the activation energy is almost twice as
large as that required for the formation of anti-cyclopropyl gold-
(I) carbene IXa. However, rotation around the cyclopropane-
carbene bond is a facile process in this case (∆Gq ) 8.6
kcal‚mol-1), which actually favors formation of syn-IXc. The
same activation energy was found in the gas-phase calcula-
tions.33 This is in sharp contrast with that previously found for
the corresponding cyclopropyl gold(I) carbene formed from (E)-
oct-6-en-1-yne, for which an activation of 24.7 kcal‚mol-1 (gas
phase) was found, favoring the anti-cyclopropyl carbene by 4.6
kcal‚mol-1 6a
. The low rotational barrier can be attributed to the
a Energies correspond to ∆Gq and ∆G (boldface) in Kcal‚mol-1.
conjugation of the cyclopropane with the phenyl ring in
33
TSIXa-IXc
.
the electrophilic aromatic substitution, which explains the
relative insensitivity to the presence of electron-withdrawing
substituents at the para position (see Table 4).
In order to further confirm this mechanism we performed
the reaction of 9a-d5 with catalyst 2a in CH2Cl2. As expected,
the deuterium that is lost from the aryl ends up at the
positioninitially activated by gold (see Xb in Scheme 10) leading
to 10a-d5 (66% deuterium content at the alkene) (eq 5).
syn-Cyclopropyl carbene IXc then opens to form XIVa with
an activation energy of 11.9 kcal‚mol-1 (Scheme 12). These
results indicate for the formation of XIVa from VIIIa the anti-
to syn-isomerization pathway might compete with the opening
of XIIa (Scheme 13). Benzylic carbocation XIVa presumably
undergoes a proton-elimination, followed by the protonolysis
of the C-Au bond to form XVa.
Overall, according to the DFT calculations, the mechanism
of the [4+2] cycloaddition of arylenynes proceeds via VIIIb-
Xb, followed by aromatization to form alkenyl gold intermediate
XVI, which undergoes proto-demetalation to form XVII
(Scheme 14). For systems related to model VIIIb (i.e., substrate
9x coordinated to Au(PH3)+), the rate determining step is the
attack of the alkene to the alkyne coordinated to Au(I) and not
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Gold(I)-Catalyzed Intramolecular [4+2] Cycloadditions
A R T I C L E S
Scheme 14. Mechanism for the [4+2] Cycloaddition of
assayed for this type of cyclizations and allows to obtain
complex systems at room temperature in short reactions times.
The intramolecular [4+2] cycloadditions of arylalkynes with
alkenes proceeds stepwise by the initial formation of a anti-
cyclopropyl gold(I)-carbene, followed by its opening to form a
carbocation stabilized by a π interaction with the aryl ring and
a Friedel-Crafts-type reaction. Aryl substituents stabilize
intermediate gold carbenes, which results in higher barriers for
their skeletal rearrangement and lower ones for their anti to syn
isomerization. This cycloaddition tolerates a variety of functional
groups at the aryl, including electron-releasing (OMe) and
electron-withdrawing (CN, NO2) substituents at ortho, meta, and
para positions. The reaction can also be extended to 1,7-enynes
and also proceeds satisfactorily in the absence gem-dialkyl effect
at the tether between the allyl and propargyl chains. Progress
toward the synthesis of the pycnanthuquinones by using this
cycloaddition is underway.
Arylenynes.
We also monitored by 1H NMR the cyclization of enyne 9a
catalyzed by complex 2a between 282 and 305.5 K. The reaction
followed pseudo-first-order kinetics, with ∆Gq ) 22.4 ( 0.5
kcal‚mol-1, ∆Hq ) 12.6 ( 0.1 kcal‚mol-1, ∆Sq ) -33.1 (
0.5 cal‚K-1‚mol-1. The activation enthalpy is higher than that
determined in the skeletal rearrangement for an enyne without
the phenyl substituent at the alkyne,10a which is consistent with
the lower reactivity of 1,6-enynes substituted with an aryl at
the alkyne in metal-catalyzed reactions.2d
Acknowledgment. This work was supported by the MEC
(Projects CTQ2004-02869, CTQ2007-60745/BQU, Consolider
Ingenio 2010, Grant CSD2006-0003, predoctoral fellowships
to C.N.-O., P.P.-G., E.H.-G., Juan de la Cierva postdoctoral
contract to T.L., postdoctoral fellowship to C.B., and Torres
Quevedo postdoctoral contracts to S. L. and A. R.), Farmiva
(postdoctoral fellowship to C. R.), the AGAUR (2005 SGR
00993), and the ICIQ Foundation. We thank Dr. J. Benet-
Buchholz and E. Escudero-Ada´n (X-ray diffraction unit, ICIQ)
for the structures of 5, 10i, and 10q and Elo´ısa Jime´nez-Nu´n˜ez
for obtaining crystals of 5 suitable for X-ray diffraction.
Conclusions
We have found novel reactivity of alkenyl- and aryl-
substituted 1,6-enynes by using highly alkynophilic Au(I)
complexes with biphenyl phosphines or a bulky phosphite as
ligands. While thermal intramolecular [4+2] cycloadditions
(dehydro-Diels-Alder reactions) of enynes with alkenes only
take place at high temperatures, these transformations proceed
with cationic Au(I) catalysts under mild conditions to provide
bi- or tricyclic ring systems. In particular, the cationic Au(I)
complex generated from complex 5 is the most active catalyst
Supporting Information Available: Additional data on reac-
tions under microwave irradiation, characterization data, X-ray
diffraction data, additional computational data, Cartesian coor-
dinates, and absolute energies. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA075794X
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J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008 279