Ethynyl benziodoxolones for the direct alkynylation of heterocycles: Structural requirement, improved procedure for pyrroles, and insights into the mechanism

Article abstract of DOI:10.1002/chem.201200200

This report describes a full study of the gold-catalyzed direct alkynylation of indoles, pyrroles, and thiophenes using alkynyl hypervalent iodine reagents, especially the study of the structural requirements of alkynyl benziodoxolones for an efficient acetylene transfer to heterocycles. An improved procedure for the alkynylation of pyrroles using pyridine as additive is also reported. Nineteen alkynyl benziodoxol(on)es were synthesized and evaluated in the direct alkynylation of indoles and/or thiophenes. Bulky silyl groups as acetylene substituents were optimal. Nevertheless, transfer of aromatic acetylenes to thiophene was achieved for the first time. An accelerating effect of a methyl substituent in both the 3-and 6-position of triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) on the reaction rate was observed. Competitive experiments between substrates of different nucleophilicity, deuterium labeling experiments, as well as the regioselectivity observed are all in agreement with electrophilic aromatic substitution. Gold(III) 2-pyridinecarboxylate dichloride was also an efficient catalyst for the reaction. Investigations indicated that gold(III) could be eventually reduced to gold(I) during the process. As a result of these investigations, a π activation or an oxidative mechanism are most probable for the alkynylation reaction.

Full text of DOI:10.1002/chem.201200200

FULL PAPER
DOI: 10.1002/chem.201200200
Ethynyl Benziodoxolones for the Direct Alkynylation of Heterocycles:
Structural Requirement, Improved Procedure for Pyrroles, and Insights into
the Mechanism
Jonathan P. Brand, Clara Chevalley, Rosario Scopelliti, and Jꢀrꢁme Waser*[a]
Abstract: This report describes a full
study of the gold-catalyzed direct alky-
nylation of indoles, pyrroles, and thio-
phenes using alkynyl hypervalent
iodine reagents, especially the study of
the structural requirements of alkynyl
benziodoxolones for an efficient acety-
lene transfer to heterocycles. An im-
proved procedure for the alkynylation
of pyrroles using pyridine as additive is
also reported. Nineteen alkynyl benz-
groups as acetylene substituents were
optimal. Nevertheless, transfer of aro-
matic acetylenes to thiophene was ach-
ieved for the first time. An accelerating
effect of a methyl substituent in both
the 3- and 6-position of triisopropylsil-
ACHUTNGRENyNUG lACTHNGUTRENNUeG thynyl-1,2-benziodoxol-3(1H)-one
(TIPS-EBX) on the reaction rate was
observed. Competitive experiments be-
tween substrates of different nucleophi-
licity, deuterium labeling experiments,
as well as the regioselectivity observed
are all in agreement with electrophilic
aromatic substitution. GoldACHTNUTRGNE(NUG III) 2-pyri-
dinecarboxylate dichloride was also an
efficient catalyst for the reaction. In-
vestigations indicated that goldACHTUNGTRENNUNG(III)
could be eventually reduced to gold(I)
during the process. As a result of these
investigations, a p activation or an oxi-
dative mechanism are most probable
for the alkynylation reaction.
Keywords: alkynylation
· gold ·
ACHTUNGTRENNUNGiodoxol(on)es were synthesized and
evaluated in the direct alkynylation of
indoles and/or thiophenes. Bulky silyl
heterocyclic compounds · iodine ·
reactivity
À
Introduction
methods to access heteroaryl acetylenes through C H bond
alkynylation would be highly desirable.
A
Numerous strategies for aryl–aryl bond formation directly
synthesis, both as synthetic intermediates and targets.[1] The
unique reactivity of acetylenes allows a wide range of syn-
thetic modifications through nucleophilic addition, cycload-
dition, cycloisomerisation, reduction, oxidation, and cross-
coupling. In addition, heteroaryl acetylenes find application
in the material sciences. Both oligomeric[2] and polymeric[3]
heteroaryl acetylenes can be used as molecular wires, liquid
crystals, sensors, and have many other important applica-
tions.
from unactivated C H bonds have been developed. In
[6]
À
contrast, catalytic direct alkynylation methods were scarce
up to 2009.[7] In 2002, Yamaguchi et al. first reported the
ortho alkynylation of phenols and anilines using GaCl3 and
chloroacetylenes.[8] In 2007, Gevorgyan and co-workers de-
veloped the first palladium-catalyzed direct alkynylation of
N-heterocycles using bromoacetylenes.[9] However, since
2009, the situation has radically changed[10] and alkynylation
of azoles,[11] electron-rich aromatics[12,13] and pentafluoro-
Two of the most frequently used methods for alkyne syn-
thesis are triple bond formation from carbonyl compounds[4]
and acetylene transfer using cross-coupling reactions such as
the Sonogashira reaction.[5] Despite the widespread use of
these reactions, both need pre-functionalization of the
arenes[11d,14] have subsequently been reported. Nevertheless,
ACHTUNGTRENNUNG
there still exists a paucity of general methods that can be ap-
plied to a range of different classes of aryl substrates. Most
of the strategies are based on the use of halogenoacetylenes
(mostly bromoacetylenes). Additionally, there are a few ex-
amples of reactions using directly terminal acetylenes but
these processes have usually a limited scope.[11d,12c,d,14] In
order to develop more efficient and general methodologies,
we decided to focus on more reactive alkynyl iodonium
salts, which were studied intensively 20 to 30 years ago.[15]
Due to the excellent leaving group ability of PhI, alkynyl io-
donium salts proved to be strongly electrophilic and reacted
with keto esters, cuprates and heteroatom nucleophiles.
However, alkynyliodonium salts were never used for the al-
kynylation of nucleophilic (hetero)aromatics.
heteroACHTUNGTRENNUNGcyclic ring, which could be challenging in complex
structures where achieving high chemo- and regioselectivity
is difficult. Furthermore, the number of linear steps required
to reach the target is also increased. As a result, more direct
[a] J. P. Brand, C. Chevalley, Dr. R. Scopelliti, Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
In 2009, we reported the first example of the use of a hy-
pervalent iodine reagent for the gold-catalyzed direct alky-
nylation of indoles and pyrroles (Scheme 1).[13a] Classical al-
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Results and Discussion
Improved procedure for pyrrole alkynylation: In our previ-
ous work in the AuCl-catalyzed alkynylation of indoles and
pyrroles, yields were usually lower for the latter (48–
79%).[13a] In particular, for applications in the functionaliza-
tion of more complex valuable pyrroles, a more efficient
protocol would be highly desirable. Pyrroles are very elec-
tron-rich heterocycles, and are sensitive to strong Lewis and
Brønsted acids. We hypothesized that a competitive degra-
dation of pyrroles by traces of HCl generated from AuCl
during the reaction was at the origin of the lower yields ob-
served. The mild base pyridine was consequently added to
quench adventitious acid in the reaction mixture. In fact, the
addition of 1.2 equivalents of pyridine led to a significant in-
crease in product yields (Table 1). The yield of the C2 alky-
Scheme 1. Direct alkynylation of indoles and pyrroles.
kynyl iodonium salts derived from iodobenzene were not
successful in this transformation, and we introduced triiso-
propylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX,
1) as an efficient acetylene transfer reagent.[16,17] In the case
of indoles, the process showed good to excellent yields, high
C3 regioselectivity, a broad functional group tolerance and
afforded easily deprotectable silyl acetylenes. For pyrroles,
C2-alkynylated products were obtained in moderate to good
yields. Importantly, this report was the first example of the
combination of gold and hypervalent iodine for direct alky-
nylation.[18]
Table 1. Improved alkynylation of pyrroles.
Building upon this work, we later reported the first direct
alkynylation of thiophenes using TIPS-EBX (1)
(Scheme 2).[13b] Primary investigation using the conditions
Entry
1[b]
Product
Yield [%][a]
71–17 (48–25)
2
3
81 (58)
84 (60)
Scheme 2. Direct alkynylation of thiophenes.
4
56[c]
for indole alkynylation afforded only low yields. This is in
accordance with the lower nucleophilicity of thiophene. Fine
tuning of reaction conditions was not successful to improve
the yields, but the discovery of a cooperative effect between
the gold catalyst and a Brønsted acid (trifluoroacetic acid
(TFA)) allowed the direct alkynylation of a broad range of
thiophenes in 48–83% yield. The reaction was applied to
a wide range of building blocks for material sciences.
5
6
73 (59)
97
7
83 (48)
[a] Reaction conditions: pyrrole
2
(0.20 mmol), TIPS-EBX (1)
Herein, we would like to report a further expansion of
our work, including 1) Improved conditions for the alkynyla-
tion of pyrroles, resulting in enhanced yields (from 48–79%
to 56–97%); 2) The first in depth studies of the influence of
the reagent structure on reaction rate and efficiency. In the
course of these studies, many unprecedented benziodoxo-
lone reagents were synthesized and their structures studied
by X-ray crystallography. Several reagents with reactivity su-
perior to TIPS-EBX were discovered, and 3) Finally, further
investigations toward the elucidation of the reaction mecha-
nism are reported, including qualitative structure–reactivity
relationships, kinetic isotope effects, intermediate-trapping
experiments, and studies on AuIII versus AuI catalysis.
(0.24 mmol), pyridine (0.24 mmol) and AuCl (0.01 mmol) in Et2O (4 mL)
at 238C under air for 12–15 h. Isolated product yields after column chro-
matography. Yields without addition of pyridine are given in parenthesis.
[b] Yields based on TIPS-EBX (1) with three equivalents of N-methyl-
pyrrole (2a). [c] 15% of bis-alkynylated product was isolated. 73% yield
of bis-alkynylated product could be obtained when three equivalents of
TIPS-EBX (1) were used.
nylation of N-methylpyrrole (2a) was increased from 48 to
71% (entry 1, Table 1). Interestingly, the C2/C3 selectivity
was increased from 1.9:1 to 4.2:1. The yield with 2-ethyl
(2b) and 2-phenyl (2c) pyrrole were enhanced from 58 and
60%, to 81 and 84%, respectively (entries 2–3, Table 1). Of
note, the alkynylation of 2,4-dimethylpyrrole (2d) did not
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Direct Alkynylation of Heterocycles
FULL PAPER
only afford 56% of monoalkynylated product but also 15%
of bis alkynylation product (entry 4, Table 1). In this case,
73% yield of the bis-alkynylated product was obtained
using three equivalents of TIPS-EBX (1).
pyridine followed by a basic work-up to remove iodobenzoic
acid were crucial to obtain reproducible yield and purity.
2,5-Disubstituted pyrroles were also efficiently alkynylat-
ed (entries 5 and 6, Table 1). A nearly quantitative transfor-
mation was obtained with 1,2,5-trimethylpyrrole (2 f;
entry 6, Table 1). In our previous work, trisubstituted pyr-
role 2g was a particularly challenging substrate and the de-
sired product was obtained only in 48% yield, probably due
to the three electron-donating substituents on the heterocy-
cle. In the presence of pyridine, however, the alkynylation
product was obtained in 83% yield (entry 7, Table 1), which
is very promising for the use of the method for especially
challenging electron-rich pyrroles. Our original motivation
for the use of pyridine was its basic properties. However,
pyridine is also a potential ligand for gold. To distinguish be-
tween these two possible effects, we then examined di-tert-
butylpyridine as additive. To our surprise, no increase in
yield was observed. This result might indicate that pyridine
is acting as a ligand and not as a base, and the lower yields
obtained in the absence of pyridine was due to a higher
Lewis acidity of the gold catalyst.
For both indoles and thiophenes, TIPS-EBX (1) had
proven a superior alkynylation reagent over TMS-EBX
(5a). To better quantify the importance of steric bulk on the
silicon atom, further silylated EBX reagents of increasing
size were synthesized (Scheme 3). A first difference was al-
Scheme 3. Synthesis of silylethynyl benziodoxolones.
Synthesis and study of alkynyl benziodoxolones: Essential
for the success of the alkynylation reaction was the replace-
ment of established alkynyliodonium salts by EBX-type re-
agents. In fact, in presence of Au catalysts, alkynyliodonium
salts only yielded diyne products, and the desired alkynyla-
tion was not observed. When considering the key role of the
reagent structure, we decided to realize a more precise
structure–reactivity relationship study of the alkynyl benz-
ready apparent during the preparation of the reagents: the
Zhdankin protocol worked well for sterically hindered silyl
groups, but a problem with yield reproducibility was ob-
served for smaller protecting groups, especially TMS. We
then discovered that partial decomposition of the reagent
often occurred upon treatment with pyridine. A milder neu-
tralization using sodium bicarbonate led to a more reprodu-
cible synthesis of the desired reagents.
A
All new reagents were first tested in the alkynylation of
indole (6) (Scheme 4). Reagents with bulky silyl groups such
ACHTUNGTRENNUNG
agents. We were also motivated by the recent report of Fujii
and Ohno on the favorable effect of a nitro group para to
the iodine in a Cu-catalyzed annulation reaction,[19] and
wanted to see if such an effect would also be observed in
Au-catalyzed reactions. A second important objective of this
work was to examine if the method could also be extended
to the transfer of alkynes without a silyl protecting group. In
this context, the goal was to examine the potential of the re-
agents in a broad sense, and not yet to develop truly effi-
cient processes.
Scheme 4. Alkynylation of indole (6) using silylethynyl benziodoxolones.
Alkynyl benziodoxolones were first reported and structur-
ally characterized by Ochiai and co-workers in 1991.[20] In
1996, Zhdankin and co-workers published an improved syn-
thesis of this class of reagents and also synthesized silyl al-
kynyl benziodoxolones, including TIPS-EBX (1) for the first
time.[17] Nevertheless, these compounds did not find applica-
tion in organic synthesis despite the utility of the parent al-
kynyliodonium salts. We optimized the synthesis of TIPS-
EBX (1) to afford the reagent in 86% yield on a 30 g scale
without column chromatography from iodosyl benzoic acid
(4) [Eq. (1)]. On a large scale, acidic work-up to remove
as SiMe2tBu (5c) and SiPh2tBu (5d) gave similar results as
TIPS-EBX (1). However, both TMS-EBX (5a) and
SiEt3EBX (5b) gave poor results in Et2O (as well as low re-
producibility for TMS-EBX (5a)). Due to their low solubili-
ty, the reaction was carried out in CH3CN. TMS-EBX (5a)
still did not afford any product, whereas the SiEt3 reagent
5b afforded 57% of the alkynylated product.
To investigate the reason for the low yield obtained for
small groups, we investigated the stability of the catalyst in
the presence of TMS-EBX (5a). When TIPS-EBX (1) and
indole (6) were added to a premixed solution of AuCl and
TMS-EBX (5a), a low yield was obtained (8%). On the
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J. Waser et al.
contrary, premixing of TIPS-EBX (1) and AuCl did not lead
to a decrease of yield. This result may indicate the degrada-
tion of AuCl by TMS-EBX (5a).
When TMS-EBX (5a) was used for the alkynylation of 2-
hexylthiophene (8), only traces of product were observed
(Scheme 5). In contrast to what had been observed for
Scheme 6. Alkynylation of indoles using phenyl and alkyl ethynyl benzio-
doxolones.
this yield is still low, it constituted the first example of the
transfer of alkyl acetylene by using gold catalysis.
In the case of 2-hexyl-thiophene (8), aromatic EBX re-
agents afforded products in moderate yields (Table 2, en-
Scheme 5. Alkynylation of 2-hexylthiophene (8) using silylethynyl ben-
ziodoxolones. Hex=Hexyl.
Table 2. Alkynylation of 2-hexylthiophene (8) using phenyl and alkyl
ethynyl benziodoxolones.
indole alkynylation, no TMS-EBX (5a) was remaining. This
result is probably due to the degradation of the reagent
under acidic conditions. A steady improvement of the yield
was observed by increasing the size of the silyl group (SiEt3,
SiMe2tBu and SiPh2tBu). Importantly, whereas the triisopro-
pylsilyl product was difficult to separate from the starting
material, the tert-butyldiphenylsilyl group allowed an easier
separation.
The high efficiency observed for the transfer of silyl acety-
lenes is important for practical applications, as easy depro-
tection of the products gave access to terminal acetylenes,
which can then be further functionalized. Nevertheless, the
transfer of aryl and alkyl acetylenes directly would allow
a more convergent synthesis of complex compounds. For
this reason, we decided to investigate acetylene transfer
using aryl and alkyl EBX reagents.
Entry
Product
Yield
[%][a]
1
2
23
27
3
4
5
35
n.r.[b]
36
Again, the use of NaHCO3 instead of pyridine for neutral-
ization and benziodoxole ring closure led to a reproducible
synthesis of Ph-EBX (5e) in 46% yield. To examine steric
and electronic effects on the aryl acetylene, the synthesis of
mesitylene, para-nitrobenzene and para-methoxybenzene re-
agents was then attempted. None of these reagents have
been previously reported. Mesitylene (5 f) and para-nitro-
phenyl EBX (5g) were obtained in moderate yields (30 and
59%, respectively). Unfortunately, no product was obtained
for para-methoxybenzene due to the fast degradation of the
product under the reaction conditions. In addition to aro-
matic groups, alkyl acetylenes were also investigated. Grati-
fyingly, the conditions developed for Ph-EBX (5e) proved
to be efficient for the very sensitive nBu-EBX (5h) (28%
yield). In contrast to other reagents, this product was not pu-
rified by recrystallization but by flash chromatography. tBu-
EBX (5i) was synthesized using the procedure reported by
Zhdankin and co-workers.[17]
[a] Reaction conditions:
AuCl (5 mol%), TFA (0.48 mmol, 0.2m), RT, 14–36 h. Isolated product
yield after column chromatography. [b] n.r.: no reaction. Hex=Hexyl.
8
(0.40 mmol), benziodoxolone (0.48 mmol),
tries 1–3). These results are promising, and future work will
be directed towards the optimization of this highly conver-
gent synthesis of arylated alkynyl thiophenes. Alternatively,
arylacetylenes can also be obtained in higher yields from the
TIPS-acetylene products in a one-pot deprotection-Sonoga-
shira sequence.[21] nBu-EBX (5h) was unsuccessful for the
alkynylation of thiophene (Table 2, entry 4), but tBu-EBX
(5i) gave 36% yield (entry 5).
The difference in reactivity of aromatic alkynyl benz-
AHCTUNGTREGiNNUN odoxolones between indoles and thiophenes was intriguing,
because generally indoles were the most reactive substrates
in our methodology. We wondered if the relative success ob-
tained with 2-hexylthiophene (8) was due to the presence of
TFA. In fact, when indole (6) was submitted to thiophene
alkynylation conditions with Ph-EBX (5e), a mixture of C2
and C3 alkynylated indoles 12 was observed by 1H NMR
spectroscopy in only 5 min (Scheme 7). Unfortunately, sig-
When Ph- (5e) and nBu- (5h) EBX were submitted to
the reaction conditions with indole (6), only traces of prod-
uct were obtained (Scheme 6). In the case of tBu-EBX, the
alkynylated product was obtained in 25% yield. Although
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Direct Alkynylation of Heterocycles
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Scheme 7. Alkynylation of indole (6) using ethynyl benziodoxolones and
TFA.
nificant batch to batch variations in both yield (33 to 47%)
and regioselectivity (C2/C3 60 to 100%) were observed.
To investigate whether this lower regioselectivity was due
to the reaction conditions or the structure of the reagent, we
used TIPS-EBX (1) with indole (6) under the same condi-
tions. In this case however, substitution at position 3 only
was obtained in 29% yield. The lower yields obtained with
indole (6) in presence of acids can be rationalized by the
higher acid-sensitivity of this electron-rich heterocycle. The
change of regioselectivity with Ph-EBX (5e) is more intrigu-
ing, and perhaps indicates a change of mechanism depen-
Scheme 8. Synthesis of analogues of TIPS-EBX (1).
A
Under standard reaction conditions with indole (6), all
substituted benziodoxolones gave the product in yields com-
parable to TIPS-EBX (1) (86%, entries 1–7, Table 3). Inter-
estingly, bis CF3 benziodoxole 15g afforded a mixture of the
C3-alkynylated (43%) and C2-alkynylated (15%) products
(Table 3, entry 8). Protonated benziodoxolone 15h did not
form any product and degradation of indole (6) was ob-
served (Table 3, entry 9). Dimethyl benziodoxole 17 only af-
forded traces of product (Table 3, entry 10). This result
showed the highly different properties of compounds 1, 15g
and 17. The reaction was consequently only minimally influ-
ent clearly showed the superiority of bulky silyl groups. It
can be hypothesized that the improved solubility and stabili-
ty of bulky silyl EBX reagents can explain their higher effi-
ciency in the alkynylation of heterocycles. Furthermore, the
À
more electron-rich C Si bonds could also play a role to ex-
plain the exceptional reactivity of these reagents. Prelimina-
ry results were also obtained for the transfer of aryl acety-
lenes in the case of 2-hexylthiophene (8), but further im-
provement is required in this case.
The influence of substituents on the benziodoxolone aro-
matic ring was then investigated to increase the reactivity of
TIPS-EBX (1). A range of EBX reagents bearing electron-
donating or electron-withdrawing groups as well as bistri-
fluoromethyl-substituted benziodoxole 15g were synthesized
in moderate to good yields using Zhdankin procedure
(Scheme 8).[17] In addition, a protonated benziodoxolone
15h was also synthesized using a known method.[17]
Table 3. Alkynylation of indole (6) using analogues of TIPS-EBX (1).
Togni reported the efficiency of dimethyl benziodoxole
structure in CF3 transfer.[22] In contrast to bistrifluorometh-
yl-substituted benziodoxole, alkynyl dimethyl benziodoxole
17 has never been synthesized. Unfortunately, no product
was obtained when Zhdankinꢂs method was used. However,
we discovered that the addition of lithiated triisopropylsilyl-
Entry
Benziodoxol(on)e
Yield
[%][a]
1
2
3
4
5
6
7
8
1
85
83
84
84
81
80
77
15a
15b
15c
15d
15e
15 f
15g
15h
17
ACHTUNGTRENNUNGacetylene to benziodoxole 16 activated by TMSOTf led to
17 in 86% of yield [Eq. (2)]. 17 represents a highly interest-
ing new electrophilic acetylene due to the higher trans effect
present in dimethyl benziodoxole.[23]
43 (15)[b]
0
traces
9
10
[a] Reaction conditions: indole
6
(0.10 mmol), benziodoxol(on)e
(0.12 mmol), and AuCl (0.01 mmol) in a 0.025m solution of undecylcya-
nide in CH3CN (2 mL) at 238C under air for 14 h. GC/MS yield using un-
decylcyanide as internal reference. [b] C2-alkynylation product.
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J. Waser et al.
enced by substitution on the benzene ring, but the carbonyl
group was an essential component of the reagent for an effi-
cient alkynylation.
Mechanistic investigations: The reactivity and properties of
both gold and hypervalent iodine have recently attracted
broad interest. Gold complexes have been first established
as excellent catalysts for the activation of p systems.[24] More
recently, other types of reactions involving changes in the
oxidation state of the gold catalyst have also incited a strong
interest in the scientific community.[25] Conversely, hyperva-
lent iodine reagents are involved in oxidative and atom
transfer processes, which have been proposed to proceed
either through two electrons or SET mechanisms.[26,27] Based
only on these results in the literature, several pathways are
possible for the Au-catalyzed alkynylation reaction. The
three main mechanisms envisaged are the p activation
Scheme 11. Lewis acid activation mechanism
mechanism
(Scheme 9),
the
AuI/AuIII
mechanism
(Scheme 10), and the Lewis acid activation of the benz-
ACHTUNGTRENiNGNU odoxolone, which can be followed either by a SET mecha-
nism or by a direct attack on the iodine (Scheme 11).
The first step of the p activation mechanism involves co-
ordination of the triple bond by gold chloride, which leads
to an increased electrophilicity (Scheme 9).[24] A Friedel–
Craft-type reaction of indole (6) at the most electrophilic
b position of the alkynyl benziodoxolone would then be in
accordance with the inherent reactivity of alkynyl iodonium
ions.[28] This step is expected to follow an electrophilic aro-
matic substitution mechanism. The vinyl gold intermediate
B can then undergo an a elimination to generate a carbene,
which then rearranges to form the triple bond (Fritsch–But-
tenberg–Wiechell-type rearrangement).
An alternative mechanism involves an oxidative addition
III
À
of gold in the C I bond to form the Au intermediate A
(Scheme 10).[25,29] The highly electrophilic gold
(III) species
can then undergo indole auration through electrophilic aro-
matic substitution. A reductive elimination then affords al-
kynylated indole 7e.
AuCl could also act as a Lewis acid and increase the elec-
trophilicity of the iodine atom (Scheme 11).[22] The activated
hypervalent iodine A can then form a charge transfer com-
plex B with the electron-rich heterocycle. According to
Kita,[26c] a single electron transfer can occur to form C,
which can then either directly rearrange to 7e through
Scheme 9. p Activation mechanism.
alkyne transfer (path a) or form the iodineACTHNUTRGNE(NUG III) intermediate
D and give 7e by a subsequent ligand coupling (path b). A
direct nucleophilic attack of indole (6) on A can also gener-
ate D through a two electron transfer (path c).
In the three mechanisms, an attack of unactivated indole
(6) as nucleophile has been proposed. Another possible al-
ternative would be the nucleophilic activation of indole (6)
by auration on the three position.[30] The formed Au com-
plex would then act as nucleophile instead of indole (6) in
the described catalytic cycles.
Unfortunately, the study of the mechanism of the gold-
catalyzed alkynylation with TIPS-EBX (1) is made more dif-
ficult by the characteristics of the reaction. First, reproduci-
ble kinetics measurements are very difficult due to the het-
Scheme 10. Oxidative mechanism.
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Direct Alkynylation of Heterocycles
FULL PAPER
erogenous nature of gold chloride. Second, electron-rich li-
gands like phosphines or carbenes inhibit the reaction, even
if the more reactive cationic gold complexes are used. In
our previous communication, we used only simple triphenyl-
phosphine cationic complexes, but when the screen was ex-
tended to other ligands recently introduced in gold catalysis,
no better results were obtained.[31] This is a major drawback
for mechanistic investigations, because well-defined metal
complexes would potentially allow the characterization of
reactive intermediates, which is particularly challenging for
gold species. In fact, vinyl gold species could be recently iso-
lated, but this was only possible using N-heterocyclic car-
bene ligands or phosphines.[32] Furthermore, phosphine
NMR spectroscopy is a valuable tool for studying the struc-
ture and oxidation state of metal complexes. Consequently,
mostly indirect evidence had to be used to better understand
the reaction.
In this section, we will first present further experiments
which indicated that a Lewis Acid or a SET mechanism was
less probable. To further investigate the mechanism, we de-
cided then to concentrate our efforts on semi-quantitative
competitive experiments to gain a better insight into the ki-
netics of the reaction. Furthermore, the fact that AuIII was
also a catalyst for the reaction was highly interesting, as it
could be better rationalized by a p activation mechanism:
we consequently decided to investigate AuIII catalysts in
more detail.
SET and Lewis acid mechanisms: Single-electron-transfer
pathways are less likely for two reasons. First, the high elec-
trophilic aromatic substitution regioselectivity observed with
indoles would not be in agreement with SET processes, for
which C2 substitution would be expected.[26c] The case is less
clear for thiophenes, as in this case both electrophilic aro-
matic substitutions and SET processes give C2 functionali-
zation. Second, no formation of heterocyclic dimers was ob-
served, which is a frequent process for heterocyclic radical
cations.[26c] Furthermore, the reaction was also done in the
presence of one equivalent of TMSN3 which has been dem-
onstrated to react rapidly with indole or thiophene radical
cations.[26b] For both indole (6) and 2-hexylthiophene (8), no
addition of azide on the heterocycle was observed. Howev-
er, it is difficult to exclude the presence of a tight radical
pair, which would react too rapidly to be trapped. Direct
attack on iodine, Lewis acid-catalyzed or not, also appeared
less probable for us, although it is often proposed for tri-
fluoromethylation using benziodoxolone reagents.[22] In fact,
no alkynylation was observed for indole (6) and/or 2-hex-
ylthiophene (8) in an extended screening of Lewis and
Brønsted acids including HCl, TsOH, TFA, FeCl3, AlCl3,
Prior to describing new experiments, it is important here
to briefly summarize the knowledge gathered through our
previous work on the alkynylation of indoles and thio-
ACHTUNGTRENNUNG
phenes:[13a,b]
1) The alkynylation method showed a regioselectivity con-
sistent with an electrophilic aromatic substitution (C3 of
indole, C2 of pyrrole and thiophene).
2) AuCl was always the best catalyst, but with indole mod-
erate yields could also be obtained with AuCl3.[33]
3) An isolated gold thiophene complex did not react with
TIPS-EBX (1). Protonated benziodoxole 15h was also
not able to transfer an acetylene to 2-hexylthiophene (8).
4) Reaction with a 13C-labeled EBX reagent 19 showed that
no silicium shift occurred during the reaction [Eq. (3)].
Ochiai reported that the addition of a-ketoester nucleo-
phile on alkynyliodonium proceeds via carbene forma-
tion followed by 1,2-shift of the best migrating group,[28]
often silicium or hydrogen. As a result, addition of
indole (6) in a position followed by TIPS 1,2 shift can be
ruled out. On the other hand, a 1,2-shift of indole cannot
be excluded as aromatic groups are known to be prone
to this type of rearrangement.
ZnACTHUGNTREN(NNGU OTf)2, YbACHTNURTGENG(NUN OTf)3, and InACHTNUGTREN(UNNG OTf)3. The unique reactivity of
AuCl would be very difficult to explain, as simple Lewis and
Brønsted acids should be even more efficient to promote
the reaction. In addition, control experiments at high tem-
perature without the gold catalyst did not afford any prod-
uct, although this has been observed for arylation reactions
using iodonium salts.[34] A first important conclusion of
these mechanistic studies is consequently that an activation
À
of the I O bond followed by reaction on iodine is not prob-
able. Consequently, the Au-catalyzed alkynylation reaction
seems to be mechanistically distinct from other reactions
using benziodoxolone reagents, in particular trifluorometh-
AHCTUNGTRENNyGUN lation.
Competitive experiments: As complete kinetic studies were
difficult because of the heterogenous nature of AuCl, we
then turned to competitive experiments to gain a semi-quan-
titative insight into the reaction rate. The alkynylation was
carried out with mixtures of indole (6) (N=5.55), 5-cyanoin-
dole (21) (N=2.83) and 5-methoxyindole (23) (N=6.22), as
the nucleophilicity of these substrates has been described
quantitatively (Scheme 12).[35] The reactivity pattern ob-
served is correlated with the nucleophilicity according to the
Mayrꢂs scale, as the ratio of products was 3.0:1 between
The regioselectivity results obtained are in agreement
with what would be expected for an electrophilic aromatic
substitution. Nevertheless in this study we discovered that
the regioselectivity for the alkynylation of indole was depen-
dent on the structure of the reagent (benziodoxole vs. ben-
ziodoxolone), which seemed to indicate that several mecha-
nisms could be possible. On the other hand, substitution of
the benzene ring of the reagents showed surprisingly little
effect on the yield.
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J. Waser et al.
AuIII catalysis: At this point, we decided to re-investigate
AuIII catalysts for the reaction, as we hoped it could help us
exclude a mechanism involving redox catalysis. In particular,
we found that gold 2-pyridinecarboxylate dichloride (26)
was a good catalyst for the alkynylation of indole (6)
[Eq. (5)]. Furthermore, this catalyst is much better defined
Scheme 12. Competitive experiments with indoles.
than AuCl and clear solutions were obtained during the re-
action. Despite the fact that we cannot be sure that both re-
actions have the same mechanism, this cleaner reaction pro-
file motivated us to compare the reactivity of the different
synthesized alkynyl benziodoxolones (Figure 1). In particu-
lar, substitution on the benzyl ring of the EBX reagents had
led to no changes in yield. By studying the full profile of the
reaction instead of just the yield, we hoped to be able to
detect subtle effects that we had missed in the preparative
reactions.
indole (6) and 5-cyanoindole (21), and 3.7:1 between 5-
methACHTUNGTRENNUNGoxyindole (23) and 5-cyanoindole (21), respectively. Al-
though the differences of reactivity are lower than in Mayrꢂs
model reaction for the reaction of nucleophile with an elec-
trophile, this result certainly confirms that an electrophilic
attack on the indole is part of the rate determining step of
the reaction. This result is in agreement with the high regio-
selectivity observed for the most electron-rich position of
the functionalized heterocycles.
A qualitative determination of a potential kinetic isotope
effect was then achieved by reaction of 37% deuterated
indole 25 with 0.6 equivalents of TIPS-EBX (1) [Eq. (4)].
When 25 was submitted to the reaction conditions, a slight
enrichment in deuterium was observed. However, perform-
ing the reaction in the absence of TIPS-EBX (1) showed
a significant loss of deuterium even without reaction,
making interpretation of this result impossible (not shown).
We hypothesized that this outcome could be due to traces of
acid or reversible auration of indole 25. Based on our previ-
ous results, we repeated these reactions in the presence of
pyridine. In this case, the same deuterium enrichment was
observed both with and without TIPS-EBX (1). Although
the reason for this effect is not clear, the same result ob-
tained in both cases demonstrated that there is no signifi-
cant kinetic deuterium effect in the alkynylation reaction
À
itself. Consequently, it appears that cleavage of the C H
bond is not occurring during the rate-limiting step. This
would be in agreement with a rate-limiting electrophilic
attack on the indole, followed by a fast proton transfer and
re-aromatization. In the case of thiophene, as it is not possi-
ble to slow down proton–deuterium exchange by the addi-
tion of pyridine, no conclusive results could be obtained.
Figure 1. Kinetic profile for the alkynylation of indole (6) using triiso-
propyl ethynyl benziodoxolones.
5-MethylTIPS-EBX (15a) and 4,5-dimethoxyTIPS-EBX
(15d) gave similar kinetics as TIPS-EBX (1).[36] In contrast,
5-fluoro (15b) and 5-nitroTIPS-EBX (15c) have higher ini-
tial rates, even if they gave slightly lower final yields
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Direct Alkynylation of Heterocycles
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(Figure 1). Interestingly, 3-methylTIPS-EBX (15e) and 6-
methylTIPS-EBX (15 f) led to the highest reaction rates.
The observed kinetics are difficult to explain: an acceler-
ating effect of the para electron-withdrawing group would
be in accordance with a rate-limiting step involving electro-
philic attack of the reagent (p activation mechanism,
Scheme 9). However, the effect is weak, and could eventual-
ly also be explained by a ligand effect during the auration
step in the oxidative mechanism (Scheme 10). The even
stronger effect observed by the introduction of a methyl
group in 3 or 6 positions is startling. To better understand
the reactivity, we decided to analyze the structure of the re-
agents by X-ray crystallography. First, high-quality crystals
of TIPS-EBX (1) were obtained by recrystalization from
CH3CN. In accordance with previously published X-ray
structures of alkynyl benziodoxolones,[17,20] the T-shape of
the hypervalent iodine was confirmed. Furthermore, the
alkyne is nearly in the same plane as the benziodoxolone
(torsion angle C8-I1-C7-C6: À8.338; Figure 2).
be expected, and consequently a more reactive reagent.[37] 6-
MethylTIPSEBX (15 f), however, displayed a nearly perfect-
ly planar structure (torsion angle C8-I1-C7-C6: À0.728)
(Figure 4). In this case, the accelerating effect is more diffi-
Figure 4. X-ray structure of 6-methylTIPS-EBX (15 f). Selected bond
À
À
lengths [ꢃ] and angles [8]: C8 I1: 2.0733(12), I1 O1: 2.3088(9); C8-I1-
C7: 91.58(5), C8-I1-C7-C6: À0.72(10).
cult to rationalize. Nevertheless, it is interesting to observe
À
that the I1 O1 bond is shorter than in TIPS-EBX (1)
À
(2.3088 vs. 2.3379 ꢃ) and the C8 I1 bond longer (2.0733 vs.
2.0539 ꢃ), which could tentatively be used to rationalize the
different reactivity of this reagent.
With the more reactive reagent 15 f, a higher yield was
obtained both for indole 27 and pyrrole 28 (Figure 5).
Figure 2. X-ray structure of TIPS-EBX (1). Selected bond lengths [ꢃ]
À
À
and angles [8]: C8 I1: 2.0539(19), I1 O1: 2.3379(13); C8-I1-C7: 91.37(7),
C8-I1-C7-C6: À8.33(16).
The structure of TIPS-EBX (1) was then compared with
the two methyl-substituted reagents 15e and 15 f. In the
case of 3-methylTIPS-EBX (15e), the steric bulk of the
methyl group forces the alkyne substituent outside the plane
of the ring (torsion angle C8-I1-C7-C6: 34.68) (Figure 3). In
this case, a weaker 3-center-4-electron hypervalent bond can
Figure 5. Improved yield using 6-methylTIPS-EBX (15 f).
The fact that goldACTHNUTRGNEUNG(III) is active for the reaction is mecha-
nistically highly interesting. It seems to indicate that a p ac-
tivation mechanism is more probable. Nevertheless, in situ
reduction of AuIII to AuI can be envisaged.[38] When TIPS-
EBX (1) was mixed with a stoichiometric amount of AuCl,
the reagent was transformed into iodobenzoic acid (18) and
bisalkyne 29 [Eq. (6)].
On the contrary, when complex 26 was used, no reaction
was observed [Eq. (7)]. When 26 was mixed up with indole
(6), the fast precipitation of a solid was observed, which was
identified as 2-pyridine carboxylic acid (30) [Eq. (8)]. Inter-
estingly, the resulting reaction mixture gave product when
Figure 3. X-ray structure of 3-methylTIPS-EBX (15e). Selected bond
À
À
lengths [ꢃ] and angles [8]: C8 I1: 2.043(7), I1 O1: 2.385(4); C8-I1-C7:
95.2(2), C8-I1-C7-C6: 34.6(5).
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J. Waser et al.
TIPS-EBX (1) was added, indicating that the reaction be-
tween AuIII complex 26 and indole (6) indeed formed an
active catalyst. A possible explanation is that indole (6) is
electron-rich enough to reduce AuIII to AuI in situ. Up to
now, no product resulting from the oxidation of indole (6),
such as indole dimers could be observed by NMR spectros-
copy, and further investigations will be required to under-
stand what is happening in this reaction. Furthermore, gold
2-pyridinecarboxylate dichloride (26) gave no product in the
case of 2-hexylthiophene (8), which would be in accordance
with the lower reduction potential of thiophenes.
a simple p activation mechanism. An in-depth investigation
will be required to distinguish definitively these two alterna-
tives and further develop this promising research area.
Experimental Section
General procedure for pyrrole alkynylation using pyridine: AuCl (2.3 mg,
0.010 mmol, 0.05 equiv) was added to a stirring solution of pyridine
(19 mL, 0.24 mmol, 1.2 equiv), TIPS-EBX (1) (103 mg, 0.240 mmol,
1.2 equiv) and the corresponding pyrrole (0.200 mmol, 1.0 equiv) in
Et2O[39] (4 mL) under air. The reaction was sealed and stirred at room
temperature for 15 h. Et2O (10 mL) was added, the organic layer was
washed twice with 0.1m NaOH (15 mL). The aqueous layers were com-
bined and extracted with Et2O (20 mL). The organic layers were com-
bined, washed with saturated NaHCO3 (20 mL), brine (20 mL), dried
with MgSO4 and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography.
1-(Phenylethynyl)-1,2-benziodoxol-3(1H)-one (Ph-EBX, 5e): Trimethyl-
silyltriflate (7.50 mL, 41.5 mmol, 1.1 equiv) was added to a suspension of
compound 4 (10.0 g, 37.7 mmol, 1 equiv) in CH2Cl2 (100 mL) at RT. The
resulting yellow mixture was stirred for 1 h, followed by the dropwise ad-
dition of trimethyl(phenylethynyl)silane (8.10 mL, 41.5 mmol, 1.1 equiv)
(slightly exothermic). The resulting suspension was stirred for 6 h at RT,
during this time a white solid was formed. A saturated solution of
NaHCO3 (100 mL) was then added and the mixture was stirred vigorous-
ly. The resulting suspension was filtered on a glass filter of porosity 4.
The two layers of the mother liquors were separated and the organic
layer was washed with sat. NaHCO3 (100 mL), dried over MgSO4, fil-
tered and evaporated under reduced pressure. The resulting mixture was
combined with the solid obtained by filtration and boiled in CH3CN
(300 mL). The mixture was cooled down, filtered and dried under high
vacuum to afford 5e (6.08 g, 17.4 mmol, 46%) as a colorless solid. Mp
(Dec.) 155–1608C (lit 153–1558C); 1H NMR (400 MHz, CDCl3) (ca.
0.03 mmolmLÀ1): d=8.46 (m, 1H, ArH), 8.28 (m, 1H, ArH), 7.80 (m,
2H, ArH), 7.63 (m, 2H, ArH), 7.48 ppm (m, 3H, ArH); 13C NMR
(101 MHz, CDCl3): d=163.9, 134.9, 132.9, 132.5, 131.6, 131.3. 130.8,
128.8, 126.2, 120.5, 116.2, 106.6, 50.2 ppm.[17]
With the results of these control experiments, the fact that
AuIII is active for the alkynylation of indole unfortunately
does not allow the conclusion that a redox mechanism is im-
probable, as reduction to AuI could occur in situ.
Conclusion
3-Methyl-1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (15e):
Trimethylsilyltriflate (2.10 mL, 11.6 mmol, 1.1 equiv) was added dropwise
to a stirred solution of compound 4 (2.93 g, 10.5 mmol, 1.0 equiv) in ace-
tonitrile (45 mL). After 20 min, compound 14 (2.94 g, 11.6 mmol,
1.1 equiv) was then added dropwise, followed, after 30 min, by the addi-
tion of pyridine (934 mL, 11.6 mmol, 1.1 equiv). The mixture was stirred
20 min. The solvent was then removed under reduced pressure and the
yellow crude oil was dissolved in dichloromethane (30 mL). The organic
layer was washed with 1m HCl (20 mL) and the aqueous layer was ex-
tracted with CH2Cl2 (30 mL). The organic layers were combined, washed
with a saturated solution of NaHCO3 (40 mL), dried over MgSO4, filtered
and the solvent was evaporated under reduced pressure. Recrystallization
from acetonitrile (ca. 10 mL) and washing with pentane afforded 15e
(2.79 g, 6.31 mmol, 60%) as colorless crystals. Mp (Dec.) 138–1458C;
1H NMR (400 MHz, CDCl3) (ca. 0.04 mmolmLÀ1): d=8.21 (dd, 1H, J=
6.8, 2.5 Hz, ArH), 7.50 (m, 2H, ArH), 2.87 (s, 3H, CH3), 1.10 (m, 21H,
TIPS). 13C NMR (101 MHz, CDCl3): d=166.8, 140.3, 138.0, 133.3, 131.7,
130.8, 119.1, 112.5, 66.9, 24.0, 18.5, 11.2 ppm. IR: n˜ =2946 (w), 2867 (w),
2244 (w), 1649 (m), 1562 (w), 1464 (w), 1326 (w), 1281 (w), 998 (w), 907
(s), 884 (w), 763 (w), 728 (s), 687 (s), 647 cmÀ1 (m). HRMS (ESI): m/z
calcd for C19H28O2ISi+: 443.0903 [M+H]; found: 443.0893.
In this full account, we have reported a more efficient proto-
col for the alkynylation of pyrroles, which gave high yields
even in the case of challenging tetrasubstituted pyrroles.
The structure of the ethynyl benziodoxolone has been sys-
tematically modified, and in the case of thiophene, the trans-
fer of arylacetylenes has been achieved for the first time.
Important conclusions could already be drawn on the reac-
tion mechanism: 1) A mechanism involving attack on iodine
or SET processes is less probable, 2) Electrophilic attack on
the indole is rate limiting, as demonstrated by competitive
experiments, and 3) Re-aromatization through proton trans-
fer is fast, as no significant kinetic isotope effect could be
observed. We further demonstrated that the alkynylation of
indole (6) could also be catalyzed by AuIII complex 26, and
in this case a more reproducible reaction kinetic was ob-
served. Electron-withdrawing groups and a methyl group in
3- and 6 positions accelerated the reaction. Control experi-
ments showed that the AuIII catalyst reacted with indole (6)
to form a potentially reduced, not yet identified gold spe-
cies. This last result does not permit to exclude a mechanism
involving changes of oxidation state on gold. In conclusion,
the results obtained concerning the influence of the reagent
structure, the reaction kinetics and the oxidation state of
gold can be used to further support both a redox cycle or
6-Methyl-1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (15f):
Trimethylsilyltriflate (1.50 mL, 8.27 mmol, 1.1 equiv, freshly distilled) was
added dropwise to a stirred solution of compound (4) (2.09 g, 7.52 mmol,
1.0 equiv) in acetonitrile (30 mL). After 20 min, compound 14 (2.10 g,
8.27 mmol, 1.1 equiv) was then added dropwise, followed, after 20 min,
by the addition of pyridine (667 mL, 8.27 mmol, 1.1 equiv). The mixture
was stirred 20 min. The solvent was then removed under reduced pres-
sure and the yellow crude oil was dissolved in dichloromethane
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Direct Alkynylation of Heterocycles
FULL PAPER
(150 mL). The organic layer was washed with 1m HCl (150 mL) and the
aqueous layer was extracted with CH2Cl2 (150 mL). The organic layers
were combined, washed with a saturated solution of NaHCO3 (150 mL),
dried over MgSO4, filtered and the solvent was evaporated under re-
duced pressure. Recrystallization from acetonitrile and wash with cold
acetonitrile afforded 15 f (2.84 g, 6.60 mmol, 88%) as colorless crystals.
Mp: 123–1258C. 1H NMR (400 MHz, CDCl3): d=8.25 (m, 1H, ArH),
7.53 (d, 2H, J=5.2 Hz, ArH), 2.90 (s, 3H, CH3), 1.15 ppm (m, 21H,
TIPS). 13C NMR (101 MHz, CDCl3): d=166.8, 146.7, 135.0, 133.3, 128.7,
124.2, 118.3, 113.3, 68.7, 22.4, 18.5, 11.2 ppm; IR: n˜ =3055 (w), 2938 (m),
2873 (m), 2865 (m), 2244 (w), 2089 (w), 1626 (s), 1612 (s), 1586 (m), 1550
(m), 1450 (m), 1382 (w), 1329 (m), 1276 (w), 1253 (w), 1157 (w), 1076
(w), 1018 (w), 998 (w), 911 (w), 884 (m), 846 (m), 817 (m), 770 (m), 706
(s), 679 (s), 649 cmÀ1 (m); HRMS (ESI): m/z calcd for C19H28IO2Si+:
443.0898 [M+H]+; found: 443.0896.
For other elimination-type syntheses of aromatic acetylenes, see:
d) A. Orita, J. Otera, Chem. Rev. 2006, 106, 5387.
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1-[(Triisopropylsilyl)ethynyl]-3,3-dimethyl-3(1H)-1,2-benziodoxole (23):
Trimethylsilyltriflate (250 mL, 1.38 mmol, 1 equiv) was added to a stirring
solution of 4 (408 mg, 1.38 mmol, 1 equiv) in THF (40 mL) at RT. The so-
lution was stirred at RT for 20 min and then cooled to À788C. In the
meantime, nBuLi (2.5m in hexanes, 550 mL, 1.38 mmol, 1 equiv) was
added to a stirring solution of triisopropylacetylene (310 mL, 1.38 mmol,
1 equiv) in THF (10 mL) at À788C. The solution was stirred for 30 min
at À788C and then added via cannula to the first solution. The reaction
was stirred for 1 h at À788C, warmed to RT and stirred 4 h. The reaction
was quenched with saturated NH4Cl (20 mL). The layers were separated
and the aqueous layers were extracted with CH2Cl2 (20 mL). The organic
layers were combined, washed with brine, dried over MgSO4, filtered and
reduced under vacuum. The resulting oil was then purified by column
chromatography (PET/Et2O 6:4) to afford 23 (524 mg, 1.18 mmol, 86%)
as a yellow oil which crystallized at À188C. Rf (PET/Et2O 6:4)=0.15;
Mikhaleva, Tetrahedron 2008, 64, 5541. Using
a stoichiometric
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1
Mp 59–618C; H NMR (400 MHz, CDCl3) (ca. 0.16 mmolmLÀ1): d=8.23
(dd, 1H, J=8.2, 0.9 Hz, ArH), 7.52 (td, 1H, J=7.3, 1.0 Hz, ArH), 7.41
(ddd, 1H, J=8.6, 7.2, 1.5 Hz, ArH), 7.35 (dd, 1H, J=7.5, 1.5 Hz, ArH),
1.44 (s, 6H, Me), 1.12 ppm (s, 21H, TIPS); 13C NMR (101 MHz, CDCl3):
d=148.0, 130.4, 129.2, 127.4, 126.5, 111.0, 105.8, 80.8, 75.7, 31.5, 18.6,
11.4 ppm; IR: n˜ =2945 (m), 2864 (m), 2064 (w), 1690 (w), 1562 (w), 1462
(m), 1436 (m), 1355 (w), 1244 (w), 1162 (w), 1116 (w), 1073 (w), 999 (m),
968 (m), 883 (m), 756 (m), 691 cmÀ1(s); HRMS (ESI): m/z calcd for
C20H32OISi+: 443.1267 [M+H]; found: 443.1276.
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Acknowledgements
We thank EPFL for funding and F. Hoffmann-La Roche Ltd for an unre-
stricted research grant. We thank Dr. Fides Benfatti and Dr. Reto Frei
for proofreading the manuscript. We thank Dr. Davinia Fernꢄndez Gon-
zꢄlez for preparation of TMS-EBX (5a).
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[tris(2,4-di-tert-butylphenyl)phosphate]gold
and
acetoni-
trile[(2-biphenyl)di-tert-butylphosphine]gold(I)
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Received: January 18, 2012
Published online: March 21, 2012
5666
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