The role of cyclobutenes in gold(I)-catalysed skeletal rearrangement of 1,6-enynes

Article abstract of DOI:10.1039/c2ob25419k

1,6-Enynes with electron-donating substituents at the alkyne undergo gold(i)-catalysed single cleavage skeletal rearrangement, whereas substrates with electron-withdrawing substituents evolve selectively to double cleavage rearrangement. Theoretical calcu

Full text of DOI:10.1039/c2ob25419k

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PAPER
The role of cyclobutenes in gold(I)-catalysed skeletal rearrangement
of 1,6-enynes†‡
Ana Escribano-Cuesta,a Patricia Pérez-Galán,a Elena Herrero-Gómez,a Masaki Sekine,a
Ataualpa A. C. Braga,a Feliu Maserasa,b and Antonio M. Echavarren*a,c
Received 27th February 2012, Accepted 2nd May 2012
DOI: 10.1039/c2ob25419k
1,6-Enynes with electron-donating substituents at the alkyne undergo gold(I)-catalysed single cleavage
skeletal rearrangement, whereas substrates with electron-withdrawing substituents evolve selectively to
double cleavage rearrangement. Theoretical calculations provide a qualitative rationale for these effects,
and suggest that bicyclo[3.2.0]hept-5-enes are involved as intermediates. We provide the first X-ray
structural evidence for the formation of a product of this class in a cycloisomerisation of a 1,6-enyne.
Introduction
1,n-Enynes (n = 5–7) give rise to a series of fascinating skeletal
rearrangements in the presence of gold(I) and other electrophilic
metals as catalysts.1–8 For gold(I), the rearrangement was pro-
posed to be initiated by the activation of the alkyne in complexes
1 to form intermediates 2, with highly distorted structures that
are intermediate between cyclopropyl gold carbenes and gold-
stabilized homoallylic carbocations.2,9 These intermediates
evolve to form two main types of dienes 3 (single exo-cleavage)
and 4 (double exo-cleavage) (Scheme 1).2,9–20 The involvement
of intermediates 2 in skeletal rearrangements and other processes
has been supported by different trapping experiments.6,11,21,22
The initial step in the gold23 or platinum catalysed24 cyclisation
of furanynes also proceeds by intermediates related to 2.
A third type of product 5 (single endo-cleavage) was discov-
ered using cationic gold(I) catalysts.19,25 Products of type 5 were
later found in reactions catalysed by InCl3,12e,f Fe(III),3b or
Ru(II).26 In the single cleavage rearrangement, the alkene
configuration of the starting enyne is preserved using gold(I) and
other metal catalysts.1,25 However, in cases where the alkene is
substituted with strongly electron-donating groups, we have
found that cationic gold(I) catalysts lead selectively to
cis-configured products starting both from cis- or trans-enynes.27
Scheme 1 Main reaction pathways for the gold(I)-catalyzed cyclo-
isomerization of 1,6-enynes.
The double exo-cleavage skeletal rearrangement leads to dienes
4 with predominant1,10,11,25 or exclusive Z28 configuration
via rearranged carbenes 6.9
Based on theoretical calculations on a 1,6-enyne model
system bearing a trans-disubstituted alkene (1, Z = CH2, R =
Me, R′ = H), we proposed that the skeletal rearrangement to
form single exo-cleavage products 3 can occur directly, by-
passing involvement of bicyclo[3.2.0] hept-5-enes 7.9 These pro-
ducts could arise by expansion of syn-cyclopropyl gold(I)
carbene intermediates.9 Cyclobutenes of type 7 have been
obtained in metal-catalyzed reactions of 1,7-,12d,13,19,29 and 1,8-
enynes.30 Additionally, the endo-cyclization pathway via inter-
mediates 8 can lead to regioisomeric cyclobutenes 9 or bicyclo-
[4.1.0]hept-2-ene derivatives 10.5,31,32 Cyclobutenes 9 were also
formed using palladium10a,b or platinum catalysts.33
aInstitute of Chemical Research of Catalonia (ICIQ), Av. Països
Catalans 16, 43007 Tarragona, Spain. E-mail: aechavarren@iciq.es
bDepartament de Química, Universitat Autónoma, de Barcelona, 08193
Bellaterra, Spain
cDepartament de Química Analítica i Química Orgànica, Universitat
Rovira i Virgili, C/Marcelli Domingo s/n, 43007 Tarragona, Spain
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: Experimental
results, computational and X-ray crystallographic data. CCDC 867857
(2,4-dinitrophenylhydrazone of 43b). For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c2ob25419k
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.

Table 1 Gold(I)-catalyzed skeletal rearrangement of 1,6-enynes 14a–j
leading to single cleavage (15), double cleavage (16) rearrangement and
cyclobutenes 17a
Scheme 2 Gold(I)-catalysed cycloisomerisation of 11.35
Entry
14
X
M
15 (%)
16 (%)
17 (%)
In the case of 1,6-enynes, it has been argued that the for-
mation of bicyclo[3.2.0] hept-5-enes 7 would be very unlikely
due to their highly strained trans-cycloheptene structure, a
species that is not stable at room temperature.10d,34 However, a
compound of this type was reported in the gold(I)-catalysed reac-
tion of 1,6-enyne 11 that leads to a 1 : 1 mixture of endo-type
cycloisomerization product 12 and cyclobutene 13
(Scheme 2).35,36
We have obtained the first X-ray structural evidence for the
formation of a product of type 7 with a bicyclic skeleton
embedded in a trans-cycloheptene. One important aspect that
has not been addressed yet is the control of the single vs. double
selectivity in the skeletal rearrangement of 1,n-enynes. Here we
report the first examples in which the single vs. double skeletal
rearrangement is controlled by the nature of the substituents at
the alkyne. We also report a more comprehensive mechanistic
study on the skeletal rearrangement of 1,6- and 1,7-enynes
which concludes that cyclobutenes can indeed be intermediates
in some of the rearrangements.
1
2
3
4
5
6
7
8
a
b
b
b
b
c
d
e
f
g
h
i
j
j
H
A
A
B
C
D
A
A
A
A
A
A
A
A
B
C
PtCl4
73
78
—
—
96
70
63
45
55
30
20
11
—
—
—
96
3
2
23
10
—
—
—
0
25
38
40
—
—
—
—
—
—
0
p-MeO
p-MeO
p-MeO
p-MeO
m-MeO
p-AcO
p-BzO
Cl
COMe
CF3
CN
NO2
NO2
—
—
—
2
—
—
—
40
65
70
93
90
10
0
9
10
11
12
13
14
15
16
j
j
NO2
NO2
a Reactions carried out in CH2Cl2 with 5 mol% catalyst at 80 °C under
microwave irradiation for 10–60 min.
Results and discussion
Scheme 3 Single- and double-cleavage rearrangement of 14g-13C.
Skeletal rearrangement of 1,6-enynes
First we studied the rearrangement of 7-aryl-1,6-enynes 14a–j
with gold and platinum catalysts (Table 1). Due to the poor reac-
tivity of enynes bearing terminal unsubstituted alkenes in metal-
catalysed cycloisomerisations, the reactions were carried out by
heating at 80 °C under microwave irradiation. Interestingly,
single- or double-cleavage was observed as a function of the sub-
stituents at the aryl group. Parent enyne 14a (X = H) leads to
single cleavage product 15a as the major product, along with
cyclobutene 17a, using gold(I) cationic catalyst A5a (Table 1,
entry 1). Similar results were obtained with substrates bearing
p-MeO and m-MeO groups using catalyst A (Table 1, entries 2
and 6). No reaction was observed using gold(I) complexes B and
C6b (Table 1, entries 3 and 4), whereas platinacycle D led to
diene 15b in excellent yield (Table 1, entry 5). Reaction of
enynes 14d–f led to single cleavage products 15d–f
accompanied by cyclobutenes 17d–f (Table 1, entries 7–9). In
contrast, enynes 14g–j bearing strongly withdrawing groups
p-COMe, p-CF3, p-CN, and p-NO2 led preferentially or exclu-
sively to double cleavage dienes 16g–j (Table 1, entries 10–15).
Surprisingly, in the case of 1,6-enyne 14j, PtCl4 as catalyst led
exclusively to single cleavage diene 15j in excellent yield
(Table 1, entry 17). This total inversion of the selectivity
confirms that platinum and gold behave differently in the skeletal
rearrangement of enynes.25
To prove that the products formed in these rearrangements cor-
respond to single and double cleavage, we repeated the result of
entry 10 in Table 1 using 14g-13C labelled with 13C at the ter-
minal alkene carbon (Scheme 3). Under these conditions, single
cleavage 15g-13C and double cleavage 16g-13C dienes were
obtained.
A DFT study (B3LYP, 6-31G(d) (C, P, N, H) and LANL2DZ
(Au)) was carried out on 1,6-enyne-gold(I) complexes 18a–c
(L PMe3) in order to explain the observed selectivity
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2012

Scheme 5 Gold(I)-catalyzed single-cleavage rearrangement of 1,7-
enynes.
Table 3 Gold(I)-catalyzed rearrangement of 1,7-enyne 27a
Scheme 4 Main reaction pathways for the cycloisomerization of 18a–c.
Table 2 Relative energies of stationary points of Scheme 4a
Entry
[Au]
Yield (%)
E/Z ratio
1
2
3
A
B
C
92
96
82
1 : 1.5
1 : 4
1.3 : 1
a Reactions carried out in CH2Cl2 with 5 mol% catalyst at 23 °C for 1 h.
The starting enyne 27 was a 2.5 : 1 mixture of E and Z isomers.
H
p-MeO
p-NO2
TS18–19
19
TS19–20
20
TS18–21
21
TS21–23
TS18–22
22
16.04
−0.84
11.92
−4.37
23.87
0.51
9.00
17.41
0.85
17.71
−2.30
13.10
−8.86
27.77
−4.57
11.08
17.73
3.27
13.61
−1.39
8.79
−0.86
23.16
−0.49
6.77
via TS22–23b was also lower (15.06 kcal mol−1) than that
required for the anti-5-exo pathway.
While the energies of the transition states leading to the
6-endo-dig and syn-5-exo-dig pathways are quite similar for the
three enyne-gold(I) complexes 18a–c, substituents at the aryl
cause a more significant effect on the transition states TS18–19 in
the anti-5-exo-dig pathway.
16.93
0.18
TS22–23
23
TS23–24
24
14.41
−10.82
18.01
−22.80
13.47
−11.31
18.21
−21.92
16.01
−10.75
16.77
−25.92
a Relative free energies (kcal mol−1) including solvation effects in
dichloromethane. DFT calculations B3LYP, 6-31G(d) (H, C, N, O, P)
and LANL2DZ (Au).
Skeletal rearrangement of 1,7-enynes
Cationic gold(I) complexes are the best catalysts for the skeletal
rearrangement of 1,7-enynes 25 to form single cleavage
1,6-dienes 26 (Scheme 5).38 Additional examples have been reported
12d,18,39,40
with Ru(II),12a Pt(II),12b,e Pt(IV),10a Ir(I),12c GaCl3
InCl312f catalysts.
and
(Scheme 4). Three possible reaction pathways were considered:
anti-5-exo-dig, syn-5-exo-dig, and 6-endo-dig cyclization. This
study completes related work using more simple PH3 as the
model phosphine, in which we found that the syn-5-exo-dig
pathway followed by cyclopropane expansion competes with the
6-endo-dig pathway for the formation of intermediates of type
23a–c.5b
According to the calculations, the syn-5-exo-dig pathway pro-
ceeding through TS18–21 does not compete in any of the three
cases considered (Table 2). For the parent (18a) and the p-nitro-
substituted (18c) systems, calculations show that the anti-5-exo-dig
pathway through TS19–20 to form carbene 20a, precursor of
double exo-cleavage rearranged product 16, is the most favour-
able. On the other hand, although very similar energies of acti-
vation were calculated for the anti-5-exo-dig and 6-endo-dig
cyclizations in the case of the enyne with an electron-donating
OMe substituent in the aromatic ring, according to the potential
energies,37 the 6-endo-dig cyclization would be the most
favourable reaction pathway for this system (14.00 vs.
16.19 kcal mol−1). The potential energy for the formation of 23b
Interestingly, 1,7-enyne 27 (2.5 : 1 mixture of E and Z
isomers) with an electron-rich group at the alkene terminus gives
mixtures of diene 28 enriched in the Z stereoisomer (Table 3).
The origin of this cis-selectivity, which is more significant with
the most electrophilic gold(I) catalyst B (Table 3, entry 2), is still
unclear although is related to that we found before for
1,6-enynes with electron-donating substituents at the alkene.27
In contrast with the exclusive formation of single cleavage
rearrangement dienes 26 and 28, the reaction of enyne 29 with a
disubstituted alkyne using catalyst gold(I) A at room temperature
gave only diene 30 by double cleavage rearrangement
(Scheme 6). Less reactive substrates 31a–b reacted at 80 °C to
give cyclobutenes 32a–b, which do not undergo conrotatory ring
opening under these conditions.
Preliminary studies were performed using [Au(PH3)]+. In this
case, a bifurcation on the reaction pathway was found depending
on the conformation of the newly-formed six-membered ring
(namely, two pseudo-chair and a boat type conformation).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.

Table 4 Activation parameters for the [2 + 2] cycloaddition of
1,8-enyne 38a
[Au]
ΔG‡
ΔH‡
ΔS‡
A
C
21.2 4.4
19.2 4.8
6.3 0.4
11.3 0.3
−46.4 4.0
−26.5 4.5
Scheme 6 Cycloisomerisation of 1,7-enynes 29 and 31a–b.
a (ΔG298‡ and ΔH‡ in kcal mol−1 and ΔS‡ in cal K−1 mol−1).
Table 5 Activation parameters for the skeletal rearrangement of
1,6-enyne 40a
[Au]
ΔG‡
ΔH‡
ΔS‡
A9
C
E
21.7 1.1
19.9 2.1
19.3 1.5
3.7 0.3
13.1 0.5
11.1 0.3
−60.6 4.0
−22.8 2.1
27.5 1.4
Scheme 7 Mechanism for the single- and double-cleavage rearrange-
ment of 1,7-enynes.
However, when the rearrangement was computed using [Au-
(PMe3)]+, the reaction takes place in all cases through a pseudo-
chair conformation. The reaction pathway is slightly different for
the gold(I) complexes of (E)-non-1-en-7-yne (33a) and (E)-oct-
1-en-7-yne (33b) (Scheme 7). In the first case, formation of
single cleavage rearranged dienes proceeds through cyclopropyl
carbene 34a that gives rise to 36 through a shallow potential
surface in which bicyclo[4.2.0]octane 35 is an intermediate. In
contrast, intermediate 37, the precursor for double-cleavage
diene, was formed directly via the opening of the cyclopropyl
carbene intermediate 34b.
a (ΔG298‡ and ΔH‡ in kcal mol−1 and ΔS‡ in cal K−1 mol−1).
the reaction with catalyst A, which is similar to those determined
for the skeletal rearrangement of 1,6-enyne 40 and its cyclohexyl
analogue using the same catalyst.9 We repeated the experiments
with 1,6-enyne 40 using gold(I) catalysts C and E with more
donating NHC ligands (Table 5). Again, although the free ener-
gies of activation are almost the same with the three catalysts,
the activation enthalpies with C and E are higher and the entropic
terms lower than those with phosphine gold(I) complex A.
As previously suggested,9 these experimental activation para-
Formation of strained cyclobutenes
Cyclobutenes are the products in the intermolecular reaction
between alkenes and terminal alkynes in the presence of a cat-
ionic gold(I) catalyst.41 To determine the activation energies
required for the [2 + 2] cycloaddition between alkynes and
alkenes in gold(I)-catalysed reactions, we decided to study the
cycloisomerisation of 1,8-enyne 38, which was reported to give
stable cyclobutene 39.30 The kinetics of this reaction were
studied using catalysts A and C. The reaction showed pseudo-
first order behaviour between −58 and −28 °C, which allowed
us to determine the thermodynamic parameters shown in
Table 4.
meters probably correspond to
a rate-determining ligand
exchange that is outside of the catalytic cycle, in which the
diene- or cyclobutene-gold(I) complex equilibrates with the start-
ing enyne. This reasoning is supported by the observation of a
low enthalpy of activation (5 kcal mol−1) and large negative
entropic term (−33 eu) in the intermolecular isobutylene
exchange processes of a [o-biphenylP(t-Bu)2]Au complex,
which occur by an associative mechanism.42
Although we had never before detected bicyclo[3.2.0]hept-5-
enes of type 7 in the skeletal rearrangement and related reactions
of many 1,6-enynes,2,5,6,9,19 when substrates 42a–b were
allowed to react in the presence of catalyst E, bicyclo[3.2.0]hept-
5-ene derivatives 43a–b were isolated in good yields
(Scheme 8). The bicyclo[3.2.0]hept-5-ene structure of 43b was
Interestingly, although very similar free energies of activation
were obtained, the enthalpies and entropies of activation were
very different for the reactions with catalysts A or C. Particularly
interesting is the large and negative activation entropy found for
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2012

Scheme 9 Proposed mechanism for the cycloisomerisation of
1,6-enynes 42a–b.
Table 6 Calculated energies for the conrotatory opening of bicyclo-
[3.2.0]hept-5-enes (48) and bicyclo[4.2.0]oct-6-enes (50)a
Scheme 8 Cycloisomerisation of 1,6-enynes 42a–b.
Entry
n
R1
R2
ΔG‡
ΔG
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
2
2
2
2
H
H
Me
Ph
Ph
H
H
33.38
23.90
39.88
25.20
41.06
30.52
29.51
31.64
31.06
30.18
−14.67
−26.89
−5.35
Me
Me
H
Me
H
Me
Me
H
−16.40
−1.74
−13.60
−16.79
−9.84
H
Me
Ph
Ph
−7.46
10
Me
−9.29
a Free energies (kcal mol−1). DFT calculations B3LYP, 6-31G(d) (H, C).
Fig. 1 X-Ray crystal structure for the 2,4-dinitrophenylhydrazone of
bicyclo[3.2.0]hept-5-ene derivative 43b.
cyclobutene opening.37 In the case of 7-phenylbicyclo[4.2.0]oct-
6-enes (Table 6, entry 9) that barrier was found to be
5.9 kcal mol−1 higher, in agreement with the isolation of deriva-
tives 32a–b in the cycloisomerisation of 1,7-enynes 31a–b
(Scheme 6). Finally, the conrotatory opening of 6,7,7-trimethyl-
bicyclo[3.2.0]hept-5-ene was calculated to be more difficult
(ΔG‡ = 39.88 kcal mol−1) (Table 6, entry 3), which is consistent
with the isolation of bicyclo[3.2.0]hept-5-ene derivatives 43a–b.
definitively confirmed by X-ray diffraction of its crystalline
2,4-dinitrophenylhydrazone (Fig. 1).43
Lower yields or complex reaction mixtures were obtained in
the presence of other gold(I) catalysts. However, using platinum(II)-
catalyst D, 42a led to 1,4-diene 44. We19b and others44 have
obtained related products, which result via the opening of inter-
mediate 2 to form carbocationic species that evolve by proton
loss to give products of formal Alder-type cycloisomerization. In
this case, an intermediate like 46 might be involved as an inter-
mediate by an intramolecular attack of the carbonyl group to
cyclopropyl carbene 45.45 Proton loss from 46 or 57 would give
44, whereas cyclobutene formation might occur by direct ring
expansion from 45 (Scheme 9).
The computed free energies of activation for the thermal con-
rotatory opening of a series of bicyclo[3.2.0]hept-5-enes (48)
and bicyclo[4.2.0]oct-6-enes (50) to form dienes 49 and 51,
respectively, range between 24 and 41 kcal mol−1, with entropic
terms that are almost negligible (Table 6).37 For 6-phenylbicyclo-
[3.2.0]hept-5-ene, the barrier is 25.20 kcal mol−1 (Table 6, entry
4), slightly lower than that calculated for the opening of the cor-
responding gold(I) complex 23a (28.83 kcal mol−1). In general,
coordination to gold(I) was calculated to increase the barrier for
Conclusions
The mechanistic scenario for the cycloisomerisation of
1,n-enynes is rather complex, with several competing pathways
whose relative rates depend highly on the substitution pattern of
the starting substrates. Here we have found the first examples in
which the single vs. double skeletal rearrangement is controlled
by the substituents at the alkyne, which has been rationalized
theoretically. In this study, we propose that products of single
cleavage rearrangement can be formed via the opening of the
gold(I) complexes of bicyclo[3.2.0]hept-5-enes. We also report
the first theoretical study of the skeletal rearrangement of
1,7-enynes. Finally, we have obtained for the first time X-ray
structural evidence for the formation of a strained bicyclo[3.2.0]-
hept-5-enes, which has a bicyclic skeleton embedded in a trans-
cycloheptene.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.

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29 (a) A. Fürstner, A. Schlecker and C. W. Lehmann, Chem. Commun.,
2007, 4277–4279; (b) G. B. Bajracharya, I. Nakamura and Y. Yamamoto,
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We thank the MICINN (CTQ2010-16088/BQU, Consolider
Ingenio 2010, Grant CSD2006-0003 and FPI predoctoral fellow-
ship to P. P.-G.), the MEC (FPU predoctoral fellowships to
A. E.-C. and E. H.-G.), the AGAUR (2009SGR47), Dr
E. Escudero-Adán (ICIQ X-Ray Diffraction unit), and the ICIQ
Foundation for financial support. We also thank Dr Dominic
Janssen, and Dr Noemí Cabello for additional experiments on
the skeletal rearrangement of 1,7- and 1,8-enynes.
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Org. Biomol. Chem.
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43 The asymmetric unit is made up of two molecules. One molecule presents
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.