Gold-catalyzed cyclizations of 1,6-diynes

Article abstract of DOI:10.1021/ol900681b

New gold-catalyzed cyclization reactions of 1,6-diynes (2,2- dipropargylmalonates) are reported. Symmetrically (Me, Et) and unsymmetrically disubstituted (Me, Et, Ph) 1,6-diynes provided stereoselectively the Z-cyclopentylidene derivatives in 31-60% and 4

Full text of DOI:10.1021/ol900681b

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2449-2452
Gold-Catalyzed Cyclizations of
1,6-Diynes
Christian Sperger and Anne Fiksdahl*
Department of Chemistry, Norwegian UniVersity of Science and Technology,
NO-7491 Trondheim, Norway
anne.fiksdahl@chem.ntnu.no
Received April 2, 2009
ABSTRACT
New gold-catalyzed cyclization reactions of 1,6-diynes (2,2-dipropargylmalonates) are reported. Symmetrically (Me, Et) and unsymmetrically
disubstituted (Me, Et, Ph) 1,6-diynes provided stereoselectively the Z-cyclopentylidene derivatives in 31-60% and 49-83% yield, respectively.
High regioselectivity (97:3) was obtained for the cyclization of Me/Ph-substituted 1,6-diynes. A monosubstituted terminal diyne afforded a
cyclopentene derivative (2-acetyl-3-alkylcyclopent-2-ene-1,1-dicarboxylate, 43%), while the diterminal 1,6-diyne (2,2-di(prop-2-ynyl)malonate)
produced a cyclohexenone derivative (3-methyl-5-oxocyclohex-3-ene-1,1-dicarboxylate, 61%). Plausible reaction mechanisms are proposed for
the formation of the products.
After being neglected by organic chemists for a long time,
gold catalysis of organic reactions has become a rapidly
expanding field in very recent years.1 The high oxidation
potential of gold(I) to gold(III) allows most gold(I) catalyzed
reactions to proceed without air exclusion.2 Gold catalysts
are exceptionally alkynophilic, but less oxophilic than other
common Lewis acids. Thus, oxygen, water or alcohols are
often well tolerated in contrast to reactions with most air
and moisture sensitive Lewis acids or transition metal
complexes. Due to the high affinity of gold complexes toward
double and triple bonds, gold catalysis can afford highly
selective reactions and give access to complex molecules.3-6
Gold catalysts interact with π-systems to activate multiple
bonds for nucleophilic attack.7,8 A number of cyclization and
cycloaddition reactions have been shown to take place in
the presence of different gold catalysts, mainly with phos-
phine ligands.2 In particular, gold-catalyzed cycloisomeri-
sation of enynes has been extensively studied, involving
selective alkyne activation by gold.5,9,10 Such reactions often
involve complex intermediates to afford a manifold of
products.1,2 The addition of alcohols to alkynes in the
presence of mercury(II) salts is a well-known old reaction.11
However, alkynes have successfully been used as substrates
for gold catalysis. Hydration of alkynes to form the respective
ketones by catalysis with an active cationic gold-phosphine
species has been demonstrated.12 In recent years, the gold(I)-
mediated activation of alkynes toward addition of alcohols
or water in the presence of acids has been investigated,
mainly providing the acetal product.13 The acetals were in a
(1) Hashmi, A. S. Chem. ReV. 2007, 107, 3180.
(2) Shen, H. C. Tetrahedron 2008, 64, 7847.
(8) Kovcs, G.; Ujaque, G.; Lleds, A. J. Am. Chem. Soc. 2008, 130, 853.
(3) Lo´pez, S.; Herrero-Go´mez, E.; Pe´rez-Gala´n, P.; Nieto-Oberhuber,
(9) Buzas, A. K.; Istrate, F. M.; Gagosz, F. Angew. Chem., Int. Ed. 2007,
C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 6029
(4) Schelwies, M.; Dempwolff, A. L.; Rominger, F.; Helmchen, G.
Angew. Chem., Int. Ed. 2007, 46, 5598
(5) Lee, S. I.; Kim, S. M.; Choi, M. R.; Kim, S. Y.; Chung, Y. K. J.
Org. Chem. 2006, 9366
(6) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 18002
.
45, 1141
.
(10) Witham, C. A.; Mauleo´n, P.; Shapiro, N. D.; Sherry, B. D.; Toste,
.
F. D. J. Am. Chem. Soc. 2007, 129, 5838.
(11) Reichert, J. S.; Bailey, J. H.; Niewland, J. A. J. Am. Chem. Soc.
1923, 45, 1553.
.
(12) Teles, H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998,
37, 1415.
.
(7) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, 4,
(13) Mizushima, E.; Sato, K.; Hayashi, T.; Tanakaq, M. Angew. Chem.,
Int. Ed. 2002, 41, 4563.
333
.
10.1021/ol900681b CCC: $40.75
Published on Web 05/04/2009
 2009 American Chemical Society

rapid equilibrium with their corresponding enol ethers and
the product distribution was influenced by the substituents.
In case of unsymmetrical substituted alkynes the addition
took place at the less sterically hindered position. On the
other hand, terminal alkynes were attacked exclusively at
the higher substituted carbon.
Table 1. Gold-Catalyzed Cyclizations of 1,6-Diynes
The low yields, high temperatures and often harsh acidic
conditions previously applied for the toxic mercury(II) or
gold-catalyzed hydration of alkynes encouraged us to
investigate less vigorous conditions for the hydration of
alkynes catalyzed by gold(I) complexes. It has been shown
that the catalytic activity of gold complexes is strongly
dependent on the counterion.8 In case of a strong interaction
entry
time ratioa
yieldb
(substrate) R1 R2
AuCl(L)
[h]
4′/4′′ (4′+4′′)/5 [%]
-
of the counterion with the gold metal center (e.g., Cl
,
-
CF3COO-), no or a low reactivity of the gold catalyst was
1 (3a)
2 (3a)
3 (3a)
4 (3a)
5 (3a)
6 (3a)
7 (3b)
8 (3b)
9 (3b)
10 (3c)
11 (3c)
12 (3d)
13 (3d)
14 (3e)
Me Me AuCl(PEt3)
Me Me AuCl(IMes)
Me Me AuCl(PEt3)c
Me Me AuCl(PEt3)d
3
60/0
60/0
-
3
observed. Replacing these ions by a less nucleophilic anion
-
-
-
-
-
-
-
5
24
52/0
0
-
(e.g., SbF -, BF4 ) by adding an appropriate silver salt
6
Me Me AuCl(IMes)d 24
0
increases the catalytic activity.
e
Me Me
Et Et AuCl(PEt3)
24
3
0
f
Our introductory experiment demonstrated the hydration
of the terminal phenylacetylene (1) in the presence of 2.5
mol % chloro(triethylphosphine)gold(I) and 3.0 mol %
AgSbF6 in pure methanol at room temperature. Subsequent
acidic work up and flash chromatography provided acetophe-
none (2, 63%), formed by hydrolysis of the acetal intermedi-
ate (Scheme 1).
Et Et AuCl(IMes)g 21
h
Et Et AuCl(PEt3)i
Me Et AuCl(PEt3)
Me Et AuCl(IMes)
Me Ph AuCl(PEt3)
Me Ph AuCl(IMes)
Et Ph AuCl(IMes)
3.5
5
31/43
60j/22
83j,k/0
49j/0
69/31
48/52
95/5
97/3
91/9
3
3
3
56j,k/0
3
64j,k/0
a According to GC after work up. b Isolated yield. c Reaction was
performed in MeOH/H2O ) 95/5. d Without AgSbF6. e With 3.0 mol %
AgSbF6. f Traces according to GC. g With 3.0 or 5.0 mol % AgSbF6.
h Conversion (5%) according to 1H NMR. i With 5 mol % AuCl(PEt3) and
7.5 mol % AgSbF6. j Isolated as a mixture. k For characterization pure
samples were obtained.
Scheme 1. Hydration of Phenylacetylene (1)
These results emphasize the importance of the anion
exchange to obtain catalytic activity.
Significantly lower reactivity was observed by replacing
the two methylsubstituents of 3a by two ethyl groups. In
contrast to the cyclization of 3a, the transformation of 3b
showed no or minor conversion into 4b in the presence of
2.5 mol % [AuCl(PEt3)] and 3.0 mol % AgSbF6 (entry 7) or
2.5 mol % AuCl(IMes) and either 3.0 or 5.0 mol % AgSbF6
(entry 8). Both the expected cyclopentane derivative 4b
(31%) and the dihydrated diketo-product 5b (43%) were
observed by using 5.0 mol % of the gold-phosphine catalyst
and 7.5 mol % of the silver salt (entry 9).
Cyclisation of unsymmetrically disubstituted 1,6-diynes
wouldgiverisetotwopossibleregioisomers.Themethyl-ethyl
disubstituted diyne 3c afforded the regioisomers 4′c and 4′′c
in 60% total yield in addition to the dihydrated diketo-product
5c (22%) by gold(I)-phosphine catalysis (entry 10). Despite
the small difference between the methyl and ethyl substituent,
the formation of the acetyl substituted product 4′c was
favored (69/31). Gold(I)-NHC catalysis afforded enhanced
yield (83%), but an approximately 1:1 mixture of the two
regioisomers 4′c and 4′′c was observed (entry 11). The
dihydrated diketoproduct 5c was not obtained.
To the best of our knowledge, there are no reports on gold-
catalyzed hydrations of diynes. When an analogous gold-
catalyzed reaction was carried out with symmetrically
substituted 1,6-diynes, different and new products were
formed (Table 1). Dimethylpropargylmalonate 3a underwent
a cyclization reaction in the presence of 2.5 mol %
[AuCl(PEt3)] and 3.0 mol % AgSbF6, providing a cyclopen-
tylidene derivative 4a (60%, Table 1, entry 1). The corre-
sponding diketone 5a formed by double hydration of the
diyne 3a was not detected. Replacing the phosphine ligand
by an N-heterocyclic carbene (NHC) ligand (IMes ) 1,3-
bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene) provided un-
changed yield of the desired product 4a (entry 2). A solvent
consisting of a mixture of methanol and water (95/5) afforded
comparable results (52% yield, entry 3).
In additional experiments we investigated the catalytic
activity of the AuCl(PEt3) and AuCl(IMes) complexes in the
absence of the silver salt (entries 4 and 5). As expected, no
reaction took place in the presence of 2.5 mol % of these
gold catalysts. To exclude the possibility of a silver catalyzed
cyclization reaction, diyne 3a was treated with 3.0 mol %
AgSbF6 in methanol (entry 6). According to GC, only starting
material 3a was present in the reaction mixture after 24 h.
In general, the introduction of a phenyl group afforded
high regioselectivities (entries 12-14). Independent of
neither applying gold(I)-phosphine/-NHC complexes nor the
nature of the other alkyne substituent (R1 ) Me, Et), the
benzylidenecyclopentane products 4′d,e were preferentially
2450
Org. Lett., Vol. 11, No. 11, 2009

formed (49-69%), consisting of 91-97% of the regioisomer
mixture. The diketo products 5d,e were not detected in any
of the reactions.
bonds (i) followed by a nucleophilic addition of deuterated
methanol (ii). An intermediate alkylenol ether is formed by
replacing the gold by a deuterium and the active gold
complex is regenerated (iii). Activation of the second triple
bond by coordination to the gold complex (iv) and subse-
quent cyclization, caused by acetal formation by addition of
a second deuterated methanol molecule (v), leads to the
steroselective formation of a Z-cyclopentylidene gold inter-
mediate. Gold-deuterium exchange (vi) regenerates the active
cationic gold complex and releases a dimethoxyacetal. Acidic
workup provided finally 4a-e.
Only one stereoisomer of products 4a-e was observed.
NOESY-NMR experiments of compounds 4a and 4′e
indicated a Z-configuration of the exocyclic cyclopentylidene
double bond. In both cases, a strong NOE correlation
between the exocyclic alkene proton and the H-5 proton as
well as between the H-3 proton and, respectively the vinylic
methylprotons (4a) or the ortho-phenylprotons (4′e), were
observed (Table 1). The absence of corresponding NOE
interactions between the H-5 proton and the vinylic methyl-
(4a) or phenyl group (4′e) as well as between the H-3 proton
and the vinylic proton supported the same conclusion.
In contrast to the formation of the stable cyclopentylidene
4a, a reaction of diyne 3a in the presence of a ruthenium
catalyst has previously been reported to provide an R,ꢀ-
unsaturated cyclopentene product 6.14,15 In the present work
we have obtained the cyclopentene derivative 6 by isomer-
ization of 4a by treatment with neutral Al2O3 (Scheme 2).16
The deuteration experiment supported this mechanism,
1
since, according to H NMR spectroscopy, complete deu-
teration of both the 3- and 5-positions of d-4a was observed.
Additionally, approximately 50% deuterium incorporation
of the acetylmethyl moiety was observed, rationalized by
acetal-enol ether equilibrium of the intermediates.
The lower reactivity of the diethylsubstituted diyne 3b to
undergo cyclization (Table 1, entries 4-6) may be explained
by the sterical hindrance appearing by approaching the two
ethyl groups in order to undergo cyclization in step v). The
regioselectivity in the cyclization of diynes 3c-e would be
dependent on stereochemical as well as electronic effects.
The observed favored formation of products 4′c-e may be
controlled by the preference of the active cationic gold
complex, acting as a Lewis acid, initially to activate the
alkyne with the higher electron density. Alternatively,
different electrophilic character of the two possible gold-
alkyne complexes would favor nucleophilic addition at the
more electrophilic alkyne.17 The results revealed that the
phenylsubstituted alkyne moiety of the Me/Ph or Et/Ph
substituted 1,6-diynes (3d,e) is less favored for nucleophilic
attack, as shown by the nearly entire formation of 4′d,e.
Terminal 1,6-diynes did not follow the same reaction
pathway, since two different cyclic products, respectively 7
and 9, were formed when mono- and diterminal diynes 3f
and 3g underwent gold-catalyzed cyclizations (Table 2).
Scheme 2. Isomerisation of 4a
On the basis of general mechanistic knowledge on the
addition of alcohols to alkynes13 and a cyclization reaction
of 3a performed in d4-methanol (Scheme 3), a general
Scheme 3
.
Proposed Mechanism for Gold Catalyzed
Cyclizations
Table 2. Reaction of Terminal Alkynes
entry substrate
AuCl(L)
t [°C] time [h] prod. yielda [%]
1
2
3
4
5
3f
3f
3f
3g
3g
AuCl(PEt3)
AuCl(PEt3)b
AuCl(IMes)
AuCl(PEt3)
AuCl(IMes)
rt
28
8
7
7
9
9
53
43
30
61
19
60
60
35
60
24
18
16.5
18
a Isolated yield. b With 3.0 mol % AuCl(PEt3) and 3.5 mol % AgSbF6.
reaction mechanism is proposed for the formation of the
cyclopentylidenes 4a-e from 1,6-diynes 3a-e. The active
cationic gold complex initially coordinates to one of the triple
At lower concentration and temperature a selective hydra-
tion of the terminal acetylene moiety of 3f took place and
Org. Lett., Vol. 11, No. 11, 2009
2451

only ketone 8 (53%) was isolated (Table 2, entry 1). Higher
temperature was required for the cyclization of diyne 3f into
a cyclopentene product 7 by gold-phosphine (43%) or gold-
NHC (30%) catalysis (entries 2-3).
The formation of product 7 may be rationalized by a
nucleophilic attack of methanol to the gold activated terminal
alkyne to form an enol ether that may undergo isomerization
into the higher substituted enol ether via an acetal (Scheme
4). A second methanol attack enables cyclization by acetal
cyclization and acidic workup (Table 2, entry 4). Application
of the gold-NHC system at elevated temperature gave lower
yield (19%, entry 5). A mechanism similar to the formation
of 7 may be proposed (Scheme 3), initiated by enol ether/
acetal formation. A comparable mechanism for the formation
of cyclohexene 9 has recently been reported.18 However, the
previous MeAuPPh3 catalyzed reaction only took place under
acidic conditions in the presence of water at 70 °C.
In conclusion, a new gold-catalyzed cyclization reaction
of disubstituted 1,6-diynes has been developed, providing
Z-cyclopentylidene derivatives. Mono- and diterminal 1,6-
diynes afforded R,ꢀ-unsaturated cyclopentene and cyclohex-
enone products. Plausible reaction mechanisms are proposed
for the formation of the products. Further investigations on
gold-catalyzed cyclization reactions of diynes including
modified substrates, new gold complexes and further mecha-
nistical studies are in progress.
Scheme 4. Proposed Mechanisms for Cyclization of Diyne 3f
Supporting Information Available: Full experimental
details, characterization for all compounds 3e, 4a, 4b, 5b,
1
4′c, 4′′c, 5c, 4′d, 4′′d, 4′e, 4′′e, 6, 7, 8, 9 and copies of H,
13C and NOESY NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL900681B
formation and attack at the gold activated alkyl-alkyne. Final
acidic hydrolysis and isomerization provides product 7. A
deuteration experiment supported this mechanism, since full
incorporation of deuteration had taken place in the 4-position
and, respectively, 50-60% in the acetylmethyl-position,
according to H NMR spectroscopy.
Cyclisation of the diterminal diyne 3g afforded the
cyclohexenone product 9 (61%) by gold-phosphine catalyzed
(14) Gonzlez-Rodrguez, C.; Varela, J. A.; Castedo, L.; Sa, C. J. Am.
Chem. Soc. 2007, 129, 12916–12917.
(15) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516–
11517.
(16) Hudlicky, T.; Srnak, T. Tetrahedon Lett. 1981, 22, 2251–2254.
(17) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008, 108,
3351.
1
(18) Zhang, C.; Cui, D.-M.; Yao, L.-Y.; Wang, B.-S.; Hu, Y.-Z.;
Hayashi, T. J. Org. Chem. 2008, 73, 7811.
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Org. Lett., Vol. 11, No. 11, 2009