Gold-catalyzed regioselective dimerization of aliphatic terminal alkynes

Article abstract of DOI:10.1055/s-0031-1289567

A gold-catalyzed regioselective homodimerization of -aliphatic terminal alkynes is described. Bulky and less Lewis acidic t-BuXPhosAuNTf₂ is the preferred catalyst, and the additive, anhydrous NaOAc, substantially facilitates the reaction. Geor

Full text of DOI:10.1055/s-0031-1289567

54
CLUSTER
Gold-Catalyzed Regioselective Dimerization of Aliphatic Terminal Alkynes
G
old-Catalyze
h
dAlkyne
D
i
e
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
Fax +1(805)8934120; E-mail: zhang@chem.ucsb.edu
Received 7 September 2011
catalysts are more stable upon heating and therefore capa-
ble of promoting the dimerization. These catalysts in-
Abstract: A gold-catalyzed regioselective homodimerization of
aliphatic terminal alkynes is described. Bulky and less Lewis acidic
t-BuXPhosAuNTf2 is the preferred catalyst, and the additive, anhy-
drous NaOAc, substantially facilitates the reaction.
13
cluded IPrAuNTf2
(Figure 1, Table 1, entry 2),
14
BrettPhosAuNTf2
(Table 1, entry 3), and t-
BuXPhosAuNTf2 (Table 1, entry 4). Among them, t-
BuXPhosAuNTf2 was the most effective. However, cata-
lyst decomposition still occurred, and the overall yields
were low. We reasoned that the addition of a base might
make the gold catalyst more stable and moreover facilitate
the formation of alkynylgold intermediates of type B.
Consequently, various bases (2 equiv) were tested. While
stronger bases such as Na2CO3 (Table 1, entry 5) and
Cs2CO3 (Table 1, entry 6) were proven deleterious,
NaHCO3 (Table 1, entry 7) was surprisingly effectively in
facilitating the reaction. Anhydrous NaOAc proved to be
even better, and the isolated yield was 83% (Table 1, entry 8).
Importantly, the branched ‘head-to-tail’ dimer 4a was
formed with high selectivity over the linear Z-enyne 5a,
formed via a ‘head-to-head’ dimerization. We were curi-
ous whether soluble acetate would perform the same feat.
To our surprise, no reaction was observed with either two
equivalents or 6 mol% of Me4N+OAc–. It is most likely
that soluble OAc– reacted with the gold catalyst to form t-
BuXPhosAuOAc, which is not catalytically active. 2-Bro-
mopyridine (pKa of its conjugated acid = 0.7115), a soluble
base but less basic than AcO– (pKa of AcOH = 4.76),
could promote the reaction but to a less extent (Table 1,
entry 11). 1,2-Dichloroethane was an inferior solvent for
this reaction (Table 1, entry 12). Control experiments
(Table 1, entries 13 and 14) established the indispensable
role of the gold catalyst in this reaction as neither its ab-
sence nor substituting it with AgNTf2 led to any observ-
able reaction.
Key words: gold, dimerization, regioselectivity, terminal alkynes,
enynes
Dimerization of terminal alkynes provides a rapid and
atom-economic access to synthetically versatile enynes1
and can be promoted by an amazingly broad range of met-
als including various transition metals such as Ni,2 Y,3
Ru,4 Rh,5 Pd,6 Ir,7 lanthalides,8 and actinides9 and main-
group metals.10 Three enyne isomers, Z-linear, E-linear,
and branched (gem) can be obtained with various levels of
regio- and/or stereoselectivities following either a ‘head-
to-head’ or a ‘head-to-tail’ union.
Albeit recent rapid development in homogeneous gold ca-
talysis,11 there are still many well-established reactions,
including dimerization of terminal alkynes, that have not
succumbed to gold catalysis. As a part of our general in-
terest in discovering new gold chemistry and probing po-
tential unique reactivities of gold catalysts, we decided to
study dimerization of terminal alkynes using soluble gold
catalysts. Since gold complexes can readily activate
alkynes toward nucleophilic attacks and alkynylgolds are
known to be nucleophilic,12 we anticipated, as shown in
Scheme 1, that the alkynylgold B, formed from the termi-
nal alkyne–gold complex A, might act as the nucleophile
to attack its precursor, thereby affording enynes 1 and 2
upon subsequent protodeauration. Interestingly, two dif-
ferent gold complexes would be involved in the key C–C
bond-formation step. Good ratio of 1/2 was anticipated as
a Markovnikov-type anti addition to the terminal C–C tri-
ple bond should be preferred. Herein, we disclose our pre-
liminary results.
The optimized reaction conditions were then applied to
the reaction scope study. As shown in Table 2, aliphatic
terminal alkynes such as 1-dodecyne (Table 2, entry 1),
cyclohexylacetylene (Table 2, entry 2), and cyclopentyl-
acetylene (Table 2, entry 3) were all amenable to the
We began with screening different gold catalysts and re-
action conditions for the dimerization of ethereal alkyne
3a. After some preliminary studies with different solvents
at various reaction temperatures, it was found that the re-
action was best conducted in refluxing toluene. Gold com-
plexes that are prone to thermal decomposition such as
Ph3PAuNTf2 (Table 1, entry 1) was totally ineffective due
to gold precipitation. Bulky and less Lewis acidic gold
AuL
+
LAu+
H+
R
AuL
R
+
R
R
A
B
AuL
R
H+
R
R
R
R
R
+
AuL
AuL
R
R
1
2
C
D
SYNLETT 2012, 23, 54–56
x
x
.x
x
.2
0
1
1
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289567; Art ID: Y04411ST
© Georg Thieme Verlag Stuttgart · New York
Scheme
alkynes
1
Proposed gold-catalyzed dimerization of terminal

CLUSTER
Gold-Catalyzed Alkyne Dimerization
55
Table 1 Reaction Optimizationa
be readily incorporated into aliphatic terminal alkynes
without compromising much of the reaction efficiency.
To our surprise, phenylacetylene was a poor substrate, and
only 8% of the dimer product was formed after 24 hours;
moreover, 2-methylbut-3-yn-1-ene was not a suitable sub-
strate (Table 2, entry 9). Extension of this chemistry to
heterodimerization led to mixtures of four branched enyne
products with low overall yields.
BnO
3
3 OBn
OBn
4a
+
Au catalyst (5 mol%)
BnO
anhydrous toluene
OBn
3
reflux, 24 h
3a
3
3
Table 2 Reaction Scope of Homodimerizationa
5a
R
t-BuXPhosAuNTf2 (5 mol%)
R
R
Entry Catalyst
Additiveb
Yield
(%)c
Ratioof
R
+
NaOAc (2 equiv)
toluene, reflux, 24 h
4a/5ad
R
3
4
5
1
2
Ph3PAuNTf2
–
–
–
Entry
R
4
Yield of
Ratioof
IPrAuNTf2
–
20
22
28
15
–
4.5:1
14:1
10:1
19:1
–
4 (%)b
4/5c
3
BrettPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
t-BuXPhosAuNTf2
–
–
1
n-decyl
4b
4c
4d
4e
4f
72
69
85
61
61
78
81
8
14:1
13:1
25:1
12:1
11:1
10:1
11:1
12:1
–
4
–
2
cyclohexyl
cyclopentyl
5
Na2CO3
Cs2CO3
NaHCO3
NaOAc
3d
4d
5
6
Ph
S
7
68
83e
–
5:1
14:1
–
PhCH2CH2
8
6
4g
4h
4i
PhthN
9
Me4N+OAc–
Me4N+OAc–f
2-BrPy
7
AcO
10
11
12g
13
14
–
–
8
Ph
39
22
–
>20:1
18:1
–
9
2-propenyl
4j
–
NaOAc
a Reaction run in Schlenk tubes under nitrogen; [alkyne] = 0.1 M.
b Isolated yield and containing small amount of inseparable 5.
c Determined by crude 1H NMR.
NaOAc
d Reaction time: 48 h; catalyst loading: 10 mol%.
AgNTf2
NaOAc
–
–
a Reaction run in Schlenk tubes under nitrogen; [alkyne] = 0.1 M.
b Conditions: 2 equiv.
The reaction mechanism is likely following what we orig-
inally conceived in Scheme 1. The role of NaOAc is
worth further commenting. It should facilitate the forma-
tion of B by deprotonation of complex A or trapping the
released proton; AcOH thus formed should be capable of
protodeauration under the elevated temperature in the
final step. The gold complex thus generated is t-BuXPhos-
AuOAc instead of t-BuXPhosAuNTf2. However, it is
likely that this inactive complex can be returned to its ac-
tive form by switching counteranion with the in situ gen-
erated NaNTf2, driven by the formation of crystalline and
barely soluble NaOAc. On the contrary, when
Me4N+OAc– was used, such a driving force was missing,
and all the gold catalyst was in its inactive t-BuXPhos-
AuOAc form.
c NMR yield using diethyl phthalate as the internal reference.
d Ratio determined by crude 1H NMR.
e Isolated yield.
f Conditions: 6 mol% instead.
g DCE as the reaction solvent.
iPr
iPr
tBu
tBu
P
N
N
iPr
Au
iPr
OMe
Cy
Au
iPr
NTf2
iPr
NTf2
Cy
P
MeO
iPr
iPr
iPr
t-BuXPhosAuNTf2
Au
NTf2
IPrAuNTf2
iPr
BrettPhosAuNTf2
In conclusion, a gold-catalyzed homodimerization of ali-
phatic terminal alkynes has been developed. The branched
‘head-to-tail’ enyne isomers are formed in mostly good
yields and with excellent selectivities over the linear iso-
mers. NaOAc was found to be effective as an additive in
facilitating the reaction. The likely reaction mechanism
entails a key C–C bond-formation step involving two dif-
ferent gold species.
Figure 1
dimerization, yielding the branched isomer (i.e., 4) in
mostly good yields. Several functional groups such as sul-
fide, phenyl, imide, and ester (Table 2, entries 4–7) could
© Thieme Stuttgart · New York
Synlett 2012, 23, 54–56

56
S. Sun et al.
CLUSTER
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Acknowledgment
The authors are grateful for the generous financial support by NIH
(R01 GM084254) and UCSB. L.Z. is a Sloan Fellow.
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Synlett 2012, 23, 54–56
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