Catalytic electrophilic halogenation of silyl-protected and terminal alkynes: Trapping gold(I) acetylides vs. a Bronsted acid-promoted reaction

Article abstract of DOI:10.1002/adsc.201200491

In the presence of a cationic gold(I) catalyst and N-halosuccinimide, both trimethylsilyl-protected and terminal alkynes are converted into alkynyl halides. Further experiments showed that silyl-protected alkynes undergo electrophilic iodination and bromination under Bronsted acid catalysis, whilst terminal alkynes require a cationic gold catalyst. The former reactions probably proceed via activation of the electrophile, whilst the latter reactions proceed via a gold(I) acetylide intermediate. Gold-catalysed halogenation was further combined with gold-catalysed hydration and subsequent annulation to provide convenient routes to iodomethyl ketones and five-membered aromatic heterocycles. Copyright

Full text of DOI:10.1002/adsc.201200491

FULL PAPERS
DOI: 10.1002/adsc.201200491
Catalytic Electrophilic Halogenation of Silyl-Protected and
Terminal Alkynes: Trapping Gold(I) Acetylides vs. a Brønsted
Acid-Promoted Reaction
a,b
a
a
a,
Pavel Starkov, Filippo Rota, Jarryl M. D’Oyley, and Tom D. Sheppard *
a
Department of Chemistry, University College London, Christopher Ingold Laboratories, London WC1H 0AJ, U.K.
Fax : +(44)-(0)20-7679-7463; phone: +(44)-(0)20-7679-2467; e-mail: tom.sheppard@ucl.ac.uk
Present Address: Department of Organic Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel
b
Received: June 5, 2012; Revised: September 28, 2012; Published online: November 13, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200491.
Abstract: In the presence of a cationic gold(I) cata- proceed via a gold(I) acetylide intermediate. Gold-
lyst and N-halosuccinimide, both trimethylsilyl-pro- catalysed halogenation was further combined with
tected and terminal alkynes are converted into al- gold-catalysed hydration and subsequent annulation
kynyl halides. Further experiments showed that silyl- to provide convenient routes to iodomethyl ketones
protected alkynes undergo electrophilic iodination and five-membered aromatic heterocycles.
and bromination under Brønsted acid catalysis,
whilst terminal alkynes require a cationic gold cata-
lyst. The former reactions probably proceed via acti- Keywords: alkynes; Brønsted acids; electrophilic hal-
vation of the electrophile, whilst the latter reactions ogenation; gold; haloalkynes; heterocycles
[
6]
Introduction
tion at benzyl tricholoroacetamidates, and the syn-
thesis of naphthalenes, benzofulvenes and dibenzo-
[7]
Homogeneous gold catalysis has attracted a vast pentalenes starting from 1,2-diethynylarenes.
amount of interest within the past decade. Most of Recently, a few reports have appeared of Au(I)/
[
1]
[
8]
these transformations involve the gold catalyst initial- Au
ACHTUNGENTRNUNG( III) catalytic systems with PhI ACHTUNGTRNENUNG( OAc) and/or Se-
2
ly acting as a p-acid to activate carbon-carbon p-sys- lectfluor as terminal oxidants which achieve carbon-
[
9]
tems such as alkynes and allenes (and to a lesser carbon cross-coupling via C-alkynylation. Although
degree, alkenes and dienes) towards nucleophilic several mechanistic pathways may be operating, there
attack (Scheme 1, path a). In several instances – those is clear evidence that gold ACHUTNGRNEGUN( III) acetylides arising from
mostly dealing with the activation of alkenes and gold(I) precursors are essential for these reactions.
dienes – the role of the gold catalyst has been ques-
tioned, however. The silver salt employed for the gen-
eration of cationic gold may act as a catalyst in its
own right. In addition, small quantities of strong
Brønsted acid can also be generated, which can pro-
tonate unsaturated carbon-carbon bonds and promote
[2]
reaction. For this reason, control experiments under
acidic and/or basic conditions are desirable.
A second method of catalytic activation is possible
with terminal alkynes – in situ generation of a gold(I)
acetylide. This process remains relatively unexplored
with only a handful of examples reported to date
[
3–9]
(
Scheme 1, path b).
These include a gold-catalysed
three-component coupling between alkynes, alde-
[5a]
hydes and amines to give propargylic amines, a cy-
ACHTUNGTRENNUNGc lisation/alkynylation cascade of 2-formyl-1-ethynylar- Scheme 1. Activation of alkynes by gold via formation of
[
5b]
enes with terminal alkynes,
nucleophilic substitu- either a p-complex (path a) or a gold(I) acetylide (path b).
Adv. Synth. Catal. 2012, 354, 3217 – 3224
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Pavel Starkov et al.
FULL PAPERS
Hence, a better understanding of the two reactivity protection/hydration of silyl-protected alkynes under
modes of alkynes in the presence of gold catalysts, exceptionally mild conditions, we wished to gain an
and the reactivity of the proposed Au(I) acetylides as insight into the role of the gold catalyst and the po-
nucleophiles would be desirable.
tential generation of a gold(I) acetylide intermediate
Herein, we report our observations on the cationic in these reactions.
gold(I)- and Brønsted acid-catalysed electrophilic hal-
A plausible mechanism is depicted in Scheme 3.
ogenation (iodination and bromination) of both ter- Coordination of Au to the alkyne generates cation 3,
[
10]
minal and trimethylsilyl-protected alkynes. We dis- perhaps best represented by resonance form 3’, where
cuss the potential intermediacy of gold(I) acetylides the AuÀC bond and/or the SiÀC bond stabilise(s) the
and cations generated through Brønsted acid catalysis carbocation. The alcohol nucleophile then attacks the
in these reactions. We also extend the halogenation silicon atom resulting in alkynylgold(I) species 4 and
reaction to yield a-iodo ketones and five-membered the protonated silyl ether 5. Cation 5 can in turn pro-
aromatic heterocycles directly from terminal alkynes. tonate the gold acetylide to give the terminal alkyne 2
and regenerate the Au(I) cation.
Results and Discussion
Halogenation of Trimethylsilyl-Protected Alkynes
Gold-Catalysed Silyl Transfer
In an attempt to trap the gold(I) acetylide intermedi-
During the course of our investigations on the Au-cat- ate 4, trimethylsilylalkyne 1a was treated with Au
[
11]
alysed reaction of boronic acids with alkynes,
we catalyst in the presence of N-iodosuccinimide
observed that trimethylsilylalkynes cleanly underwent (Scheme 4). Pleasingly, the corresponding iodoalkyne
protodesilylation in the presence of catalytic quanti-
[
12]
ties of Ph PAuNTf . In order to investigate this Au-
3
2
[
13]
catalysed CÀSi bond cleavage in greater detail, we
explored the reaction of three simple silylacetylenes
in the presence of 2-iodophenol as a silyl trap
(
Scheme 2, a).
Interestingly, complete silyl transfer to the phenol
was observed in under three hours in the case of tri-
methylsilylacetylene, whereas transfer of a triethylsilyl
group was considerably slower (66% conversion in
16 h) and triisopropylsilylacetylene was completely
inert under these reaction conditions. In a similar
manner, and only in the presence of methanol, trime-
thylsilyl-protected alkyne 1a was deprotected and
then gradually converted to 2-bromoacetophenone
(
Scheme 2, b). Whilst these transformations may find
use in selective protection of phenols and direct de-
Scheme 3. Plausible mechanism for the gold-catalysed silyl
transfer reaction.
Scheme 2. Gold-catalysed silyl transfer from alkynes to (a)
Scheme 4. Gold-catalysed iodination of a trimethylsilyl
alkyne.
2-iodophenol and (b) methanol.
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Catalytic Electrophilic Halogenation of Silyl-Protected and Terminal Alkynes
Table 1. Acid-catalysed halogenation of TMS-protected al- lylalkynes, which are available commercially or can
kynes.
be conveniently prepared by Sonogashira coupling of
aryl halides. This provides a useful alternative to the
existing silver-catalysed methods for halodesilylation
[
16i,j]
of silylalkynes.
[
a,b]
Halogenation of Terminal Alkynes
Entry
1
Product
Yield [%]
The formation of gold acetylides directly from termi-
nal alkynes and cationic Au catalyst was recently pro-
posed as a key step in a number of Au-mediated
[
c]
7a
7b
7c
88, 92
[
4–9]
transformations.
We therefore decided to explore
[c]
2
3
42, 47 (96)
whether such an acetylide could be trapped with N-io-
dosuccinimide to give the corresponding iodoalkyne
directly from a terminal alkyne. Pleasingly, iodination
of terminal alkynes was found to occur in the pres-
ence of only 1 mol% Ph PAuNTf at room tempera-
91
3
2
ture in CH Cl (Table 2). We investigated the applica-
2
2
tion of this reaction to a range of simple alkynes 2
4
5
6
7d
90
(
Table 2).
Simple arylalkynes were iodinated in moderate to
excellent yield, including both electron-rich (Table 2,
entries 1, 3, 4, 11, and 12), electron-deficient (en-
tries 7, 9, and 10) and heterocyclic (entries 2 and 6)
examples. In all cases, good to excellent conversion to
the iodoalkyne was observed and the low isolated
yields obtained in some cases are due to the difficul-
ties encountered in the purification of the product.
Several aliphatic alkynes, including TIPS-acetylene,
could also be iodinated although the resulting
7e
8a
(60)
[d]
66 (85)
[a]
[b]
[c]
[d]
Isolated yield.
Conversions given in parentheses.
TfOH was used instead of Tf NH.
Isolated as an inseparable mixture of haloalkyne and
starting material; yield determined by H NMR.
[14]
2
1
iodoalk ACHUTNRGNENUGy nes (entries 13–16) could not be readily puri-
fied. The reactions were very clean, however, with the
crude reaction mixture generally containing only
7a was generated with no sign of the homocoupled starting materials, succinimide and the iodoalkyne
product 6. product. Iodination of 2o proceeded with moderate
In order to determine whether the iodination might conversion but the iodoalkyne 7o (Table 2, entry 16)
be catalysed by traces of acid present in the Au cata- could not be separated from starting material and an
[3]
lyst, we examined the reaction of alkyne 1a with unidentified by-product. However, it was possible to
NIS in the presence of a catalytic quantity of TfOH use the crude iodoalkyne in subsequent transforma-
(
Table 1). Interestingly, with 2 mol% TfOH, iodoalk- tions without difficulty (vide infra, Scheme 7).
ACHTUNGTRENNUNGy ne 7a was formed in good yield after stirring for 24 h As with the trimethylsilylalkynes, bromination was
at ambient temperature (entry 1). Triflimide (Tf NH) found to be less efficient (Table 2; entries 17 and 18)
2
was also able to catalyse the halogenation, giving an but good yields of alkynyl bromides were obtained
excellent yield of the iodoalkyne after only 1 h.
when the reaction mixture was heated under reflux in
The Tf NH-catalysed halogenation conditions were CH Cl . In comparison, bromination of 2f in 1,4-diox-
2
2
2
applied to the synthesis of a selection of haloalkynes ane was recently reported to require as much as
[
15,16]
(
(
Table 1).
The formation of arylalkynyl halides 10 mol% (t-Bu) PAuNTf to give 8f in 52% isolated
3 2
[10]
entries 1–4) was considerably more efficient than the yield, while Ph PAuNTf was reported by the same
3
2
halogenation of an alkynylsilane bearing an aliphatic authors to be ineffective. In our hands, however,
group (entry 5). Bromination (entry 6) was slightly 1 mol% Ph PAuNTf proved to be sufficient to effec-
3
2
less efficient than iodination (entry 1). Notably, al- tively promote both iodinations and brominations in
kynes bearing both electron-donating (entry 2) and chlorinated solvents (polar aprotic solvents such as
electron-withdrawing (entries 3 and 4) aryl substitu- acetonitrile were found to be unsuitable for the reac-
ents could be halogenated effectively. This acid-cata- tion). Alkynes containing basic nitrogen functionality
lysed halogenation reaction offers an extremely con- and methyl propiolate did not readily undergo halo-
venient route to haloalkynes directly from trimethylsi- genation (Figure 1).
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Table 2. Gold-catalysed halogenation of terminal alkynes.
Table 2. (Continued)
[a,b]
Entry
Product
Yield [%]
[
d]
1
1
7
8
8j
79 (96)
83 (94)
[d]
8f
[a,b]
Entry
1
Product
Yield [%]
[
[
[
a]
Isolated yield.
Conversions given in parentheses.
Isolated as a mixture of haloalkyne and starting alkyne;
yield determined by H NMR.
b]
[14]
7f
90 (>99)
c]
1
[d]
Reaction was heated under reflux.
2
3
4
7g
7h
7i
89 (92)
87 (96)
79 (>99)
Figure 1. Terminal alkynes that did not undergo gold-cata-
lysed iodination.
5
6
7j
78
7k
77 (83)
Mechanism of the Halogenation Reactions
In control experiments, the reaction of 4-tolylacety-
lene 2h with NIS in the absence of Au catalyst, or in
7
8
9
7l
71 (85)
the presence of Tf NH alone, did not lead to the for-
2
mation of iodoalkyne 7h. This suggests that: (i) cat-
ionic Au is necessary for the halogenation of terminal
alkynes; (ii) the silyl group is essential for the Brønst-
ed acid-mediated reaction. The gold(I)- and acid-cata-
lysed halodesilylations showed a similar chemoselec-
tivity in competition experiments (Table 3). When
a 1:1 mixture of trimethylsilyl alkynes 1a and 1d was
treated with a substoichiometric quantity of NIS in
the presence of either Ph PAuNTf (entry 1) or
[c]
7a
7m
7d
7n
7o
60 (90)
[d]
58 (91)
[c]
10
11
12
34 (72)
3
2
Tf NH (entry 2), the more electron-rich alkyne 1a
2
was iodinated selectively in both cases. The gold-cata-
lysed reaction was slower with only 44% conversion
after 1 hour whereas the acid-catalysed reaction had
already reached completion.
These observations support the fact that both cata-
lysts mediate the halogenation via similar reaction
[c]
29 (75)
(60)
mechanisms with the Au catalyst either acting as
[d]
[2f,17]
1
3
4
7p
7q
(79)
(71)
a Lewis acid or as a source of protic acid.
The
Au-catalysed halogenation of a mixture of the two
terminal alkynes 2a and 2d reached completion within
an hour, and also led to preferential iodination of the
more electron-rich alkyne but the selectivity was
lower (entry 3). This suggests that this reaction pro-
ceeds via a different mechanism from the Au/acid-cat-
alysed halogenation of TMS-protected alkynes.
1
1
1
5
6
7r
(45)
(32)
7e
Plausible mechanisms for the acid and gold cata-
lysed halogenation reactions are shown in Scheme 5.
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Catalytic Electrophilic Halogenation of Silyl-Protected and Terminal Alkynes
Table 3. Halogenation of a mixture of electronically differ-
ent TMS-protected or terminal alkynes.
[
14]
Entry
Y
Catalyst
[Au]
H
[Au]
Conversion
1
2
3
SiMe3
SiMe3
H
7a (44%), 7d (0%)
7a (80%), 7d (0%)
7a (69%), 7d (11%)
+
Scheme 6. Halogenation reactions in the presence of a base.
In the presence of the gold catalyst, small quantities
of gold acetylide 4 can be formed from the terminal
[10]
alkyne 2. After trapping this acetylide with NXS to ther the gold- nor Brønsted acid-catalysed halogena-
give haloalkyne 7 (X=I) or 8 (X=Br) and succini- tion reactions proceeded under these conditions and
mide, the gold catalyst is regenerated. Notably, this is the silylalkyne remained unchanged. In order to con-
achieved with a commercially available catalyst firm that the base did not inhibit the gold catalyst, we
(
Ph PAuNTf ) under simple homogeneous reaction also carried out the halogenation of terminal alkyne
3 2
conditions without the intermediacy of a silver 2f in the presence of 2,6-di-tert-butylpyridine. Al-
[2g,11d]
salt.
The higher reactivity of more electron-rich though the reaction was slower than usual, a 25%
alkynes is perhaps due to a stronger interaction with conversion to the haloalkyne was observed after 1 h.
the cationic gold catalyst which may facilitate genera- These observations confirm that the halogenation of
tion of the gold acetylide.
trimethylsilylalkynes proceeds under Brønsted acid
The halogenation of trimethylsilylalkynes in the catalysis (Scheme 5, Y=H), with the gold catalyst
presence of either gold or Tf NH catalyst probably simply acting as a source of a small quantity of acid
2
[
18]
proceeds via activation of the electrophile (10).
(presumably Tf NH). This mechanism would account
2
This activated electrophile is then able to react with for the much higher reactivity of electron-rich alkynes
the silylalkyne to give silicon-stabilised carbocation due to the increased stability of carbocation 11.
1
1, which subsequently undergoes silyl transfer to suc-
cinimide to generate the haloalkyne 7/8.
In order to determine whether the gold catalyst is Direct Synthesis of a-Iodoketones and Aromatic
involved in the halogenation of trimethylsilylalkynes Heterocycles from Terminal Alkynes
or simply acts as a source of Brønsted acid, we stud-
ied the iodination of 1a in the presence of the hin- Since the halogenation reactions were generally very
dered base, 2,6-di-tert-butylpyridine (Scheme 6). Nei- clean, we envisaged the use of in situ generated hal-
Scheme 5. Plausible mechanisms for the gold and acid-catalysed electrophilic halogenations.
Adv. Synth. Catal. 2012, 354, 3217 – 3224
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Pavel Starkov et al.
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Conclusions
In summary, we have shown that trimethylsilyl-pro-
tected acetylenes are halodesilylated by treatment
with N-halosuccinimide in the presence of a low cata-
lytic loading of Brønsted acid. Furthermore, terminal
alkynes are efficiently converted into either iodoal-
kynes or bromoalkynes in an Au-catalysed process in
moderate to excellent yield. This latter reaction is not
catalysed by Brønsted acid and probably proceeds via
trapping of an in situ generated gold(I) acetylide. We
have also demonstrated gold-catalysed tandem iodina-
tion/hydration of terminal alkynes, which can be fur-
ther extended via annulation, to provide an effective
route to a variety of five-membered aromatic hetero-
cycles.
Scheme 7. Direct conversion of terminal alkynes into iodo-
methylketones.
oalkynes in subsequent transformations. Hence, iodi-
nation of 2j and 2o was combined with Au-catalysed Experimental Section
[19]
alkyne hydration to give iodoacetophenones 12 and
1
1
3 (Scheme 7). In CH Cl , a mixture of iodo ketone Full experimental details are provided in the Supporting In-
2 2
[20]
formation.
2 and its dimethyl acetal was formed.
Switching
the solvent to chloroform, however, gave the iodo
ketone 12 directly in good yield. Pleasingly, this over-
all transformation was also achieved with 4-ethynyl-
Brønsted Acid-Catalysed Halogenation of
Trimethylsilyl Alkynes
ACHTUNGTRENNUNGa nisole 2o, despite the fact that we had previously
been unable to isolate the corresponding iodoalkyne Brønsted acid (TfOH or Tf NH, 2 mol%) was added to a so-
2
7
o from the halogenation reaction (vide supra, lution of alkyne or trimethylsilylalkyne (1 equiv.) and NXS
(
1 equiv.) in CH Cl (0.1M). The reaction mixture was
2 2
Table 2).
stirred at room temperature and monitored by NMR or
TLC. Upon completion, the solvent was evaporated and the
crude material was purified by filtration through a silica pad
eluting with PE/EtOAc.
This reaction sequence was then extended by a sub-
[
21]
sequent condensation of the a-iodo ketone to form
either a thiazole (15), an imidazole (16) or an azain-
dolizine (14, 17) directly from a terminal alkyne with
no requirement to purify any of the intermediate
compounds (Scheme 8). Overall, in a single operation,
these sequences provide an expedient access to func-
tionalised five-membered aromatic heterocycles from
simple terminal alkynes, demonstrating the synthetic
utility of these gold-catalysed tandem processes.
Gold-Catalysed Halogenation of Terminal Alkynes
[
Ph PAuNTf] ·PhMe (0.5 mol%) was added to a solution of
3 2
terminal alkyne (1 equiv.) and NXS (1 equiv.) in CH Cl2
2
(
0.1M) and the mixture was left to stir at room temperature.
Upon completion, the mixture was concentrated and puri-
fied by filtration through a silica pad eluting with PE/
EtOAc.
Scheme 8. Concise synthesis of five-membered aromatic heterocycles from terminal alkynes.
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Catalytic Electrophilic Halogenation of Silyl-Protected and Terminal Alkynes
Acknowledgements
Bertrand, Proc. Natl. Acad. Sci. USA 2007, 104, 13569–
3573.
1
This work was supported by the Engineering and Physical
Sciences Research Council (EP/E052789/1), the Leverhulme
Trust (F/00 134/CL) and the UCL PhD program in Drug
Discovery.
[6] C. Li, F. Mo, W. Li, J. Wang, Tetrahedron Lett. 2009, 50,
6053–6056.
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