Synthesis of 1-chloroalkynes from alkynylsilanes using trichloroisocyanuric acid as chlorinating agent

Article abstract of DOI:10.1055/s-0028-1088020

A new method is reported for preparing 1-chloroalkynes from alkynylsilanes using trichloroisocyanuric acid (TCCA) as chlorinating agent and AgNO ₃ for in situ desilylation. The method is selective for trimethylsilyl-protected alkynes relative t

Full text of DOI:10.1055/s-0028-1088020

PAPER
1469
Synthesis of 1-Chloroalkynes from Alkynylsilanes Using Trichloroisocyanuric
Acid as Chlorinating Agent
S
ynthesis of 1-Chloroa
i
lkynes
e
from
A
lkynylsila
H
nes øjer Vilhelmsen, Asbjørn Sune Andersson, Mogens Brøndsted Nielsen*
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen Ø, Denmark
Fax +4535320212; E-mail: mbn@kiku.dk
Received 27 November 2008; revised 13 January 2009
of bromo- and iodoalkynes from trimethylsilylalkynes us-
Abstract: A new method is reported for preparing 1-chloroalkynes
from alkynylsilanes using trichloroisocyanuric acid (TCCA) as
chlorinating agent and AgNO3 for in situ desilylation. The method
is selective for trimethylsilyl-protected alkynes relative to triisopro-
pylsilyl-protected alkynes.
ing N-bromosuccinimide (NBS) or N-iodosuccinimide
(NIS) as halogenating agent also deserves mention;15 here
desilylation was accomplished in situ under essential neu-
tral conditions using AgNO3.
Key words: alkynes, chlorination, electrophilic additions, imides,
protecting groups
O
Cl
Cl
O
N
N
1-Haloalkynes are involved in numerous metal-catalyzed
coupling reactions via oxidative insertion of the metal to
the carbon–halogen bond.1 Thus, the Cadiot–
Chodkiewicz2 cross-coupling between a haloalkyne and a
terminal alkyne furnishes unsymmetrically substituted
butadiynes. Of the three haloalkynes (Cl, Br, I), 1-chloro-
alkynes generally exhibit higher stability than both 1-bro-
mo- and 1-iodoalkynes, which renders 1-chloroalkynes
attractive as building blocks, being easy-to-handle, for the
synthesis of acetylenic scaffolds. The drawback is, how-
ever, that 1-chloroalkynes are less reactive under the stan-
dard Cadiot–Chodkiewicz conditions and poor yields of
cross-coupled products are obtained.3 This problem was
to a large extent overcome by the development of an effi-
cient Cu(I)-catalyzed coupling reaction between alkynyl-
silanes and 1-chloroalkynes by Nishihara et al.4 This
coupling is conveniently performed under neutral condi-
tions without any base. Other important reactions of 1-
chloroalkynes include metal-catalyzed cycloaddition re-
actions,5 nucleophilic substitution reactions,6 and the
Claisen rearrangement of aryl g-chloropropargyl ethers.7
O
N
Cl
TCCA
Figure 1 Structure of trichloroisocyanuric acid (TCCA)
To our knowledge only one example describes the reac-
tion between alkynes and TCCA. Thus, Hiegel and co-
workers8c have demonstrated that TCCA reacts with
alkynes in the presence of water in acetone or in acetoni-
trile to form a,a-dichloro ketones and in methanol to form
a,a-dichlorodimethyl ketals. We became interested in in-
vestigating the outcome of treating alkynylsilanes with
TCCA under conditions that provide in situ desilylation as
it is attractive to employ the, in general, more stable sily-
lated alkynes as starting materials rather than the corre-
sponding unprotected terminal alkynes.
Treatment of 4-(trimethylsilylethynyl)benzonitrile (1)
with TCCA in slight excess (1.1 molar equiv) and AgNO3
in wet acetone provided, after stirring for first 30 minutes
on an ice bath (owing to heat evolution) and then at 40 °C
for 24 hours, the chloroalkyne 2 in a yield of 84%
(Scheme 1). Subjecting (trimethylsilylethynyl)benzene to
the chlorination conditions seemed to provide quantita-
tively (chloroethynyl)benzene (3) according to TLC in-
spection. However, isolation of the pure, volatile
chloroalkyne product was in this case more tedious and
was accomplished in a yield of only 37% after column
chromatography. We reckon that H2O plays a role as nu-
cleophile in the AgNO3-promoted desilylation reaction.
To ascertain reproducibility in regard to the water content
of the acetone solvent, a large excess of H2O relative to
the alkyne reactant was added (20 molar equiv) in all ex-
periments. To minimize the formation of by-products, it is
crucial that the reaction mixture is cooled in an ice-bath
during the addition of the reagents and left at this temper-
ature for ca. 30 minutes. Subjecting the mixture subse-
quently to microwave heating for five minutes at 150 °C
We report here a new convenient method for preparing 1-
chloroalkynes from alkynylsilanes using the cheap re-
agent trichloroisocyanuric acid (TCCA, Figure 1) as chlo-
rinating agent. Several papers8 have demonstrated that
trihaloisocyanuric acids are efficient halogenating agents
owing to their ability to transfer a halogen atom to unsat-
urated substrates. Toxic and corrosive X2 can hereby be
avoided. Besides chlorine,9 the following chlorinating re-
agents were previously employed for making 1-chloro-
alkynes from acetylides: hypochlorites,6b,10 tosyl or mesyl
chlorides,7,11 N-chlorosuccinimide (NCS),12 and tetra-
chloromethane.13 1-Chloroalkynes have also been pre-
pared from chloroisoxazolinones.14 A one-pot synthesis
SYNTHESIS 2009, No. 9, pp 1469–1472
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x
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x
x
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Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088020; Art ID: T20708SS
© Georg Thieme Verlag Stuttgart · New York

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M. H. Vilhelmsen et al.
PAPER
TMS
Cl
Table 1 Products p-RC6H4C≡CCl Prepared from
p-RC6H4C≡CSiMe3
TCCA, AgNO3
acetone–H2O
0 °C, 30 min
Entry
R
Conditionsa
1-Chloroalkyne (%)
84 (2)
then
40 °C, 24 h (84%) or
microwave heating
150 °C, 5 min (98%)
1
2
3
4
5
6
7
8
CN
CN
H
40 °C, 24 h
NC
NC
1
2
mw, 150 °C, 5 min
40 °C, 24 h
98 (2)
Scheme 1
37 (3)
OMe
NO2
NO2
t-Bu
t-Bu
reflux, 3 d
10 (5)
furnished an alternative and convenient method of obtain-
ing 2 in nearly quantitative yield.
40 °C, 24 h
50 (8)
Introduction of an electron-donating methoxy substituent
at the para position slows down the reaction considerably.
Thus, chlorination of compound 4 required refluxing for
three days (Scheme 2). Hereby, the 1-chloroalkyne prod-
uct 5 was isolated in a yield of 10%, while the a,a,a-
trichloro ketone 6 and the terminal alkyne 7 were the ma-
jor products and isolated in yields of 31 and 17%, respec-
tively. Enforcing desilylation of 4 by using a fluoride
source (Bu4NF) instead of AgNO3 was found to have no
significant influence on the ratio between chloroalkyne
and ketone products. Product assignments were per-
formed by comparing NMR spectral data with those
present in the literature for 512,16 and 6.17
mw, 150 °C, 5 min
40 °C, 1 h
42 (8)
82 (9)
mw, 150 °C, 5 min
84 (9)
a First, TCCA, AgNO3, acetone–H2O, 0 °C, 30 min (5 min for entry
8), then as indicated; mw = microwave heating.
present in the product 11. The reaction proceeded in high
yield at low temperature, which is explained by the pres-
ence of the electron-withdrawing carbonyl group. It
should be noted that 1,5-disubstituted penta-1,4-diyne-3-
ones are particularly important building blocks for acety-
lenic scaffolding. They have, for example, been employed
as precursors for tetraethynylethenes and bisacetylenic
dithiafulvenes.19 Most of the standard alkyne chlorination
procedures as mentioned above involve formation of the
acetylide from the terminal alkyne using a strong base.
Such conditions would be detrimental for compound 10 as
a nucleophilic acetylide can attack the electrophilic carbo-
nyl group present in 10 as previously reported.20 This at-
tack is obviously avoided by employing our mild TCCA/
AgNO3 conditions.
MeO
TMS
4
TCCA, AgNO3
acetone–H2O, 0 °C
TCCA, Bu4NF (in THF)
acetone–H2O, 0 °C, 1 h
then r.t., 0.5 h
then reflux, 3 d
5 (10%), 6 (31%), 7 (17%)
5 (11%), 6 (25%)
O
O
MeO
MeO
Cl
TCCA, AgNO3
acetone
0 °C, 5 h
5
6
7
i-Pr3Si
TMS
i-Pr3Si
Cl
O
10
11
91%
CCl3
Scheme 3
MeO
H
Treatment of compound 10 with NCS and AgNO3 in ace-
tone resulted in desilylation only, while no chlorination
took place according to a TLC analysis. This result bears
resemblance to the work of Hofmeister et al.21 who found
that a terminal alkyne could be converted to the bromo- or
iodoalkyne by NBS or NIS in the presence of AgNO3,
while NCS did not react under these conditions.
Scheme 2
The yields of chlorination of a selection of p-substituted
phenylethynylsilanes are listed in Table 1. In general,
good yields of 1-chloroalkynes were obtained, except for
R = OMe (entry 4) as described above.
In conclusion, we have developed an efficient and mild
method for preparing 1-chloroalkynes from readily avail-
able and generally stable trimethylsilyl-protected alkynes
using TCCA and AgNO3 as reagents. Microwave heating
was found to enhance the reaction considerably. The reac-
tion shows good versatility; however, the a-trichloro ke-
tone was found to be the major product when the alkyne
is substituted with the p-methoxyphenyl group. Triisopro-
pylsilyl can be employed as an alkyne protecting group
Gratifyingly, we found that the reaction conditions are se-
lective towards trimethylsilyl (TMS)-substituted alkynes
relative to triisopropylsilyl (TIPS)-substituted ones. Thus,
treating the differentially protected penta-1,4-diyn-3-one
(10)18 with TCCA/AgNO3 in acetone (Scheme 3) fur-
nished selective chlorination at the TMS-substituted
alkyne position, while the less labile TIPS group remained
Synthesis 2009, No. 9, 1469–1472 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Chloroalkynes from Alkynylsilanes
1471
HRMS-ESI: m/z [M + H]+ calcd for C8H5ClNO2: 182.0009; found:
182.0007.
that withstands the conditions. In addition, the mild con-
ditions allow for the presence of an electrophilic carbonyl
group in the starting material, which would not be tolerat-
ed under chlorination conditions under which nucleo-
philic acetylides are generated.
1-Chloro-5-(triisopropylsilyl)penta-1,4-diyn-3-one (11)
To an ice-cooled solution of 1018 (252 mg, 0.82 mmol) in acetone
(10 mL) were added TCCA (200 mg, 0.86 mmol) and AgNO3 (14
mg, 0.82 mmol). The reaction mixture was protected from light and
stirred for 5 h on an ice bath. Filtration through a short plug of silica
(CH2Cl2–cyclohexane, 1:2) furnished the product 11 as a colorless
oil (202 mg, 91%).
1H NMR (300 MHz, CDCl3): d = 1.11/1.09 [2 s, 21 H, i-CH(CH3)2].
13C NMR (75 MHz, CDCl3): d = 158.7, 104.4, 98.4, 73.7, 69.9,
18.4, 10.9.
Chemicals were purchased from Aldrich and Merck and used as re-
ceived. Acetone, purchased from LAB-SCAN (HPLC grade), was
used directly without any purification. Compound 10 was prepared
according to Ref. 18. TLC analyses were carried out using alumi-
num sheets precoated with silica gel 60F (Merck 5554). The plates
were inspected under UV light. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded on a Varian instrument, using the
residual solvent as the internal standard. All chemical shifts are
quoted on the d scale (ppm), and all coupling constants (J) are ex-
pressed in Hz. Electron Impact (EI) mass spectra were recorded on
a Jeol JMS-HX/HX110A instrument, while Electrospray Ionization
(ESI) mass spectra were recorded on a Micromass Q-TOF spec-
trometer. IR spectra were obtained on a Bio-Rad Merlin instrument.
Microwave heating was performed using a Biotage Initiator 2.0 mi-
crowave system; the power was set to ‘normal’; hereby the temper-
ature was automatically retained at the set value of 150 °C.
Microanalyses were performed at Department of Chemistry, Uni-
versity of Copenhagen.
MS (ESI): m/z = 269 [M]+.
Acknowledgment
The Danish Research Agency is acknowledged for financial support
(grant # 2111-04-0018). MHV and ASA thank the University of
Copenhagen for PhD scholarships.
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