Intermolecular gold-catalyzed cycloaddition of alkynes with oxoalkenes

Article abstract of DOI:10.1002/chem.201300131

As good as gold: Gold(I) catalyzes a new intermolecular reaction of terminal alkynes with functionalized alkenes that gives 8-oxabicyclo[3.2.1]oct- 3-enes by a [2+2+2] cycloaddition process in which two C-C bonds and one C-O bond are formed (see scheme). Copyright

Full text of DOI:10.1002/chem.201300131

COMMUNICATION
DOI: 10.1002/chem.201300131
Intermolecular Gold-Catalyzed Cycloaddition of Alkynes with Oxoalkenes
Carla Obradors[a] and Antonio M. Echavarren*[a, b]
Gold(I) catalysts selectively activate alkynes in polyfunc-
tional substrates, which triggers a wide variety of cycliza-
tions.[1] We developed a tandem process for the simultane-
structural motif present in natural products[12] and other bio-
logically relevant compounds.[13] In addition to the major cy-
cloaddition pathway, we have also identified a competitive
process leading to the formation of 2-(arylethynyl)tetrahy-
drofurans. We also report a detailed mechanistic study that
explains the formation of both product types by activation
of the alkyne by gold(I), whereas the oxoalkenes can com-
petitively be activated by the strong Brønsted acid generat-
ed in situ.
À
À
ous formation of two C C bonds and one C O bond by a
gold(I)-catalyzed [2+2+2] alkyne/alkene/carbonyl cycload-
dition of 1,6-enynes bearing a carbonyl group (Scheme 1).[2]
We first examined the cycloaddition between phenylacet-
AHCTUNGTREGyNNNU lene and 5-methylhex-5-en-2-one (5a). No cycloaddition
was observed using AuCl or complex D (Table 1, entries 1
Table 1. Optimization of the gold(I)-catalyzed intermolecular cycloaddi-
tion of alkynes with oxoalkenes (see the Supporting Information).[a]
Scheme 1. Intramolecular gold(I)-catalyzed [2+2+2] alkyne/alkene/car-
bonyl cycloaddition of 1,6-enynes.
Entry
Catalyst
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
AuCl
A
B
C
D
E
E
E
E
F
23
23
23
23
23
23
50
50
80
50
50
–
15
15
25
–
39
67
46
43
63
57
As has been demonstrated in many gold(I)-catalyzed reac-
tions of enynes,[1,3] this cycloaddition is stereospecific. This is
best illustrated in the cyclization of substrates 1 to form in-
termediates 2, which were later transformed into oxatricyclic
sesquiterpenes (+)-orientalol F (3)[4] and (À)-englerin A
(4).[5,6] Cationic gold(I) complexes also catalyze the cyclo-
8[c]
9
10
11
ACHTUNGTRENNUNG
isomerization of oxo-1,5-enynes[7] as well as the addition of
carbonyl compounds to 1,n-enynes.[8]
G
[a] Reaction conditions: 3 mol% catalyst, c=0.5m, 2–5:1 phenylacet-
ylene/5a, 24 h. [b] Determined by 1H NMR spectroscopy by using 1,4-di-
acetylbenzene as internal standard. [c] c=1m.
In contrast to the large number of gold-catalyzed intramo-
lecular cycloisomerization reactions developed over the last
decade,[1] the development of gold(I)-catalyzed intermolecu-
lar reactions of alkynes with alkenes has been much more
challenging.[9–11] Herein, we report the intermolecular cyclo-
addition reaction of terminal alkynes with 5-oxoalkenes that
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
leads to the formation of 8-oxabicycloACTHNUTRGNEUNG[3.2.1]oct-3-enes, a
[a] C. Obradors, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢀsos Catalans 16, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
[b] Prof. A. M. Echavarren
Departament de Quꢁmica Analꢁtica i Quꢁmica Orgꢂnica
Universitat Rovira i Virgili, C/Marcel·li Domingo s/n
43007 Tarragona (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300131.
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and 5), whereas other cationic gold(I) complexes A–C and
E–G led to 1,5-dimethyl-3-phenyl-8-oxabicyclo[3.2.1]oct-3-
AHCTUNGTRENNUNG
ene (6a) in low to moderate yields. As we observed before
in the intermolecular reaction of alkynes with alkenes,[9] in-
creasing the steric bulkiness of the ligand in the gold(I)
complex led to a significant improvement in the cycloaddi-
tion reaction. The best results were obtained using cationic
tBuXPhos–gold(I) catalyst E in 1,2-dichloroethane (DCE)
at 508C for 24 h (Table 1, entry 7),[14] whereas related cation-
ic complexes [(tBuBrettPhos)Au
ACHTUNGTREN(NGNU MeCN)]SbF6 (F) and
[(Me4tBuXPhos)Au
ACHTUNGTRENNUNG
lower yields (Table 1, entries 10 and 11).
The cycloaddition reaction proceeds in a general manner
with aryl acetylenes substituted at ortho, meta, or para posi-
tions and oxoalkenes 5a–f to form cycloadducts 6a–y in
moderate to excellent yields (Table 2). Aryl acetylenes with
Figure 1. X-ray crystal structure of cycloadduct 6p. ORTEP plot (50%
thermal ellipsoids).
Table 2. Scope of the intermolecular gold(I)-catalyzed [2+2+2] cycload-
dition of alkynes with oxoalkenes.
a 2 mmol scale without observing a drop in the yield (see
the Supporting Information). (3-Thienyl)acetylene also re-
acted with oxoalkene 5a to furnish product 6t (Table 2,
entry 20). Reaction of aldehyde 5e led to cycloadduct 6x in
low yield owing to the lower nucleophilicity of the carbonyl
moiety (Table 2, entry 23). Substrate 5 f led stereoselectively
to 6y in moderate yield with a tricyclic skeleton (Table 2,
entry 24). Alkyl-substituted alkynes and oxoalkenes with
monosubstituted alkenes failed to form oxabicyclic products.
DFT calculations (M06 functional) revealed a stepwise
Entry
R1
R2
R3
Yield [%]
1
2
3
4
5
6
7
8
Ph
Ph
p-Tol
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Ph
Me
Me
Me
Ph
Me
Ph
Me
Ph
Me
Me
Ph
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
6a (68)[a]
6b (68)
6c (55)
6d (43)
6e (68)
6 f (65)
6g (55)[a]
6h (61)
6i (49)[a]
6j (70)
6k (70)
6l (49)[a]
6m (59)
6n (55)[a]
6o (60)
6p (65)
6q (91)
6r (41)
6s (62)
6t (40)
À
À
formation of the C C and C O bonds (Scheme 2). The nu-
p-MeOC6H4
p-FC6H4
p-FC6H4
p-ClC6H4
p-ClC6H4
p-BrC6H4
p-BrC6H4
m-Tol
m-FC6H4
m-FC6H4
m-ClC6H4
m-ClC6H4
m-HOC6H4
m-MeOC6H4
o-MeC6H4
2-naphthyl
3-thienyl
Ph
cleophilic attack of alkene 5a to complex I is the rate-deter-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
6u (87)
6v (54)
6x (16)
Ph
Ph
tBu
H
Scheme 2. Catalytic cycle for the intermolecular gold(I)-catalyzed
[2+2+2] cycloaddition of alkynes with oxoalkenes based on DFT calcula-
tions (M06, 6-31G(d) (C, H, P, O) and SDD (Au), CH2Cl2).
24
Ph
[a] 2,2,5-Trimethyl-5-(arylethynyl)tetrahydrofurans
side products in 26–42% yields.
7
were obtained as
mining step with free activation energy of 15.9 kcalmolÀ1
(see the Supporting Information for additional computation-
al details). This process occurs both regio- and stereoselec-
tively and forms intermediate II with a highly unsymmetri-
electron-donating and -withdrawing substituents react simi-
larly. The reaction tolerates a free phenol to form 8-
À
oxabicyclo
[3.2.1]oct-3-ene (6p; Table 2, entry 16), the struc-
cal cyclopropyl gold(I) carbene structure (new C C bond
lengths of 1.58 and 1.73 ꢄ). Regioselective attack of the car-
ture of which was confirmed by X-ray diffraction
(Figure 1).[17] In addition, the reaction can be carried out on
bonyl group at the most substituted position through TSII–III
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Cycloaddition of Alkynes with Oxoalkenes
COMMUNICATION
then leads to oxonium cation
III, which undergoes a Prins re-
action to close a seven-mem-
bered ring leading to benzylic
cation IV and, finally, to 6a by
metal elimination and ligand
exchange between
V
and
phenyl acetylene.[18,19]
Reaction of oxoalkene 5g
with phenylacetylene led to 8-
cyclobutene
product,
8
as the major
along with 6z
(Scheme 3). Cyclobutene 8 is
formed by ring expansion of in-
termediate II’ to form VI. The
alternative opening of II’ to
form six-membered ring oxoni-
um cation III’ was not ob-
served.
Scheme 4. Isotopic labeling experiment and mechanistic proposal for the
formation of 2,2,5-trimethyl-5-(arylethynyl)tetrahydrofurans.
Tetrahydrofurans 7 were also
observed as side products in
some of the cycloaddition reac-
tions. Reaction of deuterated p-
bromophenylacetylene with 5a
led to [D]6i and [D3]7a, which
demonstrates that the tetrahy-
tion of 9 releases Brønsted acid HSbF6. Digold complexes
similar to 9 have been isolated recently and their role in cat-
alysis has been discussed.[20,21,23–26]
drofurans are formed by
a
proton-catalyzed process, pre-
sumably via oxonium cation
VII in equilibrium with 5a, 5a’,
and VII’, followed by the nucle-
ophilic attack of alkynyl gold
species
VIII
or
IX
(Scheme 4).[20–24]
Performing the reaction at
À788C allowed monogold spe-
cies I to be observed spectro-
scopically.[23,24] However, at
room temperature, over the whole process, a single signal at
d=65.22 ppm was observed by 31P NMR spectroscopy corre-
sponding to digold complex 9 (=IX, L=tBuXPhos), which
was characterized by X-ray diffraction (Figure 2).[18] Forma-
Figure 2. X-ray crystal structure of digold complex 9 (=IX; L=tBuX-
Phos). ORTEP plot (50% thermal ellipsoids).
We decided to probe whether complex 9 was actively in-
volved in the catalytic cycle. Our results indicate that this
digold complex acts as a dead end, sequestering most of the
active gold(I), since no reaction was observed between 5a
and 9 under stoichiometric conditions (Table 3, entry 1).
Furthermore, under catalytic conditions using 2.5 mol% of
9, only 9% of 6a was obtained after 19 h at 508C. Neverthe-
less, when HSbF6 was added substoichiometrically, the equi-
librium was re-established to allow the formation of the re-
active species I and then, the reaction proceeded to give
product 6a with slightly lower yield (Table 3, entry 4). No
Scheme 3. Intermolecular gold(I)-catalyzed reaction of phenylacetylene
with oxoalkene 5g.
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A. M. Echavarren and C. Obradors
Table 3. Test of the catalytic activity of complex 9.
Table 4. Synthesis of arylethynyltetrahydrofurans 7.[a]
Entry
9
Alkyne/
alkene
Additive
Yield
[%][a]
Entry
Ar
Additive[b]
Product
Yield [%]
[mol%]
1
2
3
4
5
6
7
8
9
p-BrC6H4
p-BrC6H4
Ph
–
TsOH
–
TsOH
–
TsOH
–
TsOH
–
7a
7a
7b
7b
7c
7c
7d
7d
7e
7e
32
50
14
50
26
48
31
47
42
57
1
100
2.5
2.5
2.5
0:1
3.5:1
1:2
–
–
–
–
9
8
2[b]
3[c]
4
Ph
5:1[d]
HSbF6·6H2O
(2.5 mol%)
HSbF6·6H2O
(2.5 mol%)
50 (45)[e]
p-ClC6H4
p-ClC6H4
m-FC6H4
m-FC6H4
m-ClC6H4
m-ClC6H4
5
–
5:1
–
1
[a] Determined by H NMR spectroscopy using 1,4-diacetylbenzene as in-
ternal standard. [b] Dimerization of the alkyne detected.[27] [c] Reaction
time of 4 d. [d] Proportion of alkyne increased to account for the compet-
itive hydration. [e] Isolated yield.
10
TsOH
[a] Traces of oxabicycles 6 were also formed in entries 2, 4, 6, 8, and 10.
[b] 10 mol%.
reaction was observed with HSbF6 in the absence of gold
complex (Table 3, entry 5). The same behavior was observed
in the reaction between oxoalkene 5g and phenylacetylene
to form 8 and 6z using 9 as the gold source (see the Sup-
porting Information).
Acknowledgements
We thank the MICINN (CTQ2010-16088/BQU), the MEC (FPU fellow-
ship to C.O.), the AGAUR (2009 SGR 47), and the ICIQ Foundation for
financial support. We also thank the ICIQ X-ray diffraction unit for the
structures of 6p and 9.
Computationally, the free activation energy for the key
attack of oxoalkene 5a to the phenylacetylene moiety of a
model of 9 (=IX, Ar=Ph, L=PMe3) is 10 kcalmolÀ1 higher
than that corresponding to the first step (I to II) in
Scheme 2 (also see the Supporting Information). Therefore,
these results suggest that digold complex 9 acts as an un-
reactive resting state outside the catalytic cycle, which
lowers the concentration of the active species [LAuL’]+ and
explains the rather long reaction times.
We reasoned that it would be possible to improve the for-
mation of the arylethynyltetrahydrofurans 7, which can be
valuable synthetic intermediates,[28] by performing the reac-
tion in the presence of a strong Brønsted acid. Indeed, tetra-
hydrofurans 7a–e were obtained in 47–57% yield by per-
forming the reaction with E and TsOH as catalysts (en-
tries 2, 4, 6, 8, and 10, Table 4).
Keywords: alkynes
calculations · gold · homogeneous catalysis
· cycloaddition · density functional
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In summary, we have developed a new intermolecular
gold(I)-catalyzed reaction of terminal alkynes with function-
alized alkenes that leads to 8-oxabicycloACTHNUTRGNEUNG[3.2.1]oct-3-enes by
À
a [2+2+2] cycloaddition process in which two C C bonds
À
and one C O bond are formed. Our experimental and theo-
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main catalytic cycle in the intermolecular cycloaddition of
alkynes with functionalized alkenes. Our efforts are now fo-
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catalyzed reactions based on these results.
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Cycloaddition of Alkynes with Oxoalkenes
COMMUNICATION
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Chem. Int. Ed. 2011, 50, 3236–3239; c) Y. Wang, K. Ji, S. Lan, L.
Zhang, Angew. Chem. Int. Ed. 2012, 51, 1915–1918.
[17] CCDC-913001 (6p) and CCDC-913002 (9) contain the supplementa-
ry 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.
[18] A gold- or platinum-catalyzed tandem cycloisomerization/Prins-type
cyclization in which the Prins reaction is proton-catalyzed: J. Bar-
luenga, A. Diꢅguez, A. Fernµndez, F. Rodrꢁguez, F. J. FaÇanµs,
Angew. Chem. 2006, 118, 2145–2147; Angew. Chem. Int. Ed. 2006,
45, 2091–2093.
[19] The alternative activation of the alkene by gold(I) to form a five-
membered ring oxonium cation, followed by attack of the alkyne
and ring closure in a stepwise 4C+2C cycloaddition process is less
likely, because treatment of 5a with catalyst E (5 mol%) in 1,2-di-
[28] D. S. B. Daniels, A. L. Thompson, E. A. Anderson, Angew. Chem.
2011, 123, 11708–11712; Angew. Chem. Int. Ed. 2011, 50, 11506–
11510.
Received: January 14, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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A. M. Echavarren and C. Obradors
Cycloaddition
C. Obradors,
A. M. Echavarren* ........... &&&& — &&&&
As good as gold: Gold(I) catalyzes a
new intermolecular reaction of termi-
nal alkynes with functionalized alkenes
by a [2+2+2] cycloaddition process in
Intermolecular Gold-Catalyzed Cyclo-
addition of Alkynes with Oxoalkenes
À
À
which two C C bonds and one C O
bond are formed (see scheme).
that gives 8-oxabicycloACTHNUGTRNEUNG[3.2.1]oct-3-enes
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www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!