Chloramine Salt Mediated Oxidative Halogenation of Terminal Alkynes with KI or NaBr: Practical Synthesis of 1-Bromoalkynes and 1-Iodoalkynes

Article abstract of DOI:10.1055/s-0037-1610259

A direct oxidative halogenation of terminal alkynes has been realized using chloramine-B as the oxidant and KI or NaBr as the halogen source. This reaction enables a general and practical access to synthetically valuable 1-bromoalkynes and 1-iodoalkynes i

Full text of DOI:10.1055/s-0037-1610259

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
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X. Liu et al.
Letter
Synlett
Chloramine Salt Mediated Oxidative Halogenation of Terminal
Alkynes with KI or NaBr: Practical Synthesis of 1-Bromoalkynes
and 1-Iodoalkynes
Xiaozu Liu
chloramine salt
R
X
R
H
Guojun Chen
Chenglong Li
Peijun Liu*
KI, MeCN
or NaBr, MeCN/H2O
X = I, Br
27 examples
up to 98% yield
Practical approach
Simple operation
Generic Drug Research Center of Guizhou Province, Green
Pharmaceuticals Engineering Research Center of Guizhou
Province, School of Pharmacy, Zunyi Medical University,
Zunyi, 563000, P. R. of China
Gram-scale synthesis
General access to 1-bromoalkynes and 1-iodoalkynes
pjliu@zmc.edu.cn
Received: 27.06.2018
Accepted after revision: 26.07.2018
Published online: 22.08.2018
use of hazardous or toxic halogenating reagents that are
harmful to the environment, thereby restricting their prac-
tical applications.
DOI: 10.1055/s-0037-1610259; Art ID: st-2018-k0395-l
R
X
(X = Cl, Br, I)
Abstract A direct oxidative halogenation of terminal alkynes has been
realized using chloramine-B as the oxidant and KI or NaBr as the halo-
gen source. This reaction enables a general and practical access to syn-
thetically valuable 1-bromoalkynes and 1-iodoalkynes in good to excel-
lent yields under mild reaction conditions.
DBU, N-haloimide
or Ag/C3N4, NXS
path c
path b
path a
R
I
R
Br
R
H
Key words oxidative halogenation, 1-bromoalkynes, 1-iodoalkynes,
chloramine salt, terminal alkynes
chloramine salt
KI or NaBr
this work
1-Haloalkynes, particularly 1-bromoalkynes and 1-iodo-
alkynes, are highly versatile synthons with the association
of dual functional groups, which exhibit tunable electro-
philic and nucleophilic reactivities in many impressive
chemical transformations for the assembly of valuable
target structures.1 Thus, the importance of 1-haloalkynes
has triggered substantial research efforts directed towards
the development of efficient methods for their prepara-
tion.2–4 Among these achievements, the direct oxidative
R
X
X = I, Br
Scheme 1 Oxidative halogenation of terminal alkynes
Moreover, general and convenient methods that allow
for facile access to 1-iodoalkynes and 1-bromoalkynes have
yet to be well-demonstrated (Scheme 1, path c).5,6 In 2014,
Liang and Jin described a DBU-mediated halogenation of
terminal alkynes with N-haloimides.5 Very recently, a gen-
eral, versatile, and highly efficient Ag/C3N4 catalyst for the
direct halogenation of terminal alkynes has been developed
by Chen and co-workers.6 The two methods are very valu-
able, but the use of toxic halogenating regent is required.
Therefore, the development of general, practical, and envi-
ronmentally friendly protocols for the iodination and bro-
mination of terminal alkynes utilizing a preferred reagent
system is still highly desirable.
halogenation of terminal alkynes represents
a most
straightforward approach and has been extensively
explored.3,4 In this regard, various iodinating conditions, in-
cluding strong base/I2,3a–c ionic liquids,3d metal catalysts,3e–h
anodic oxidation,3i morpholine-mediated system,3j,k KI or
Me3SI/PhI(OAc)2,3l,m and N-iodosuccinimide system,3e,g,3n–p
can be used for the direct oxidative iodination of terminal
alkynes (Scheme 1, path a). Meanwhile, several procedures
have been documented for the direct bromination of termi-
nal alkynes using different brominating reagents, such as N-
bromosuccinimide system,4a–f base/Br2,4g,h DBU/Cl3CBr,4i
CBr4/KOH/18-crown-6,4j PPh3/CBr4,4k and TsNBr2/DBU4l
(Scheme 1, path b). Despite the merits of the reports, some
of them involve inevitable limitations such as the use of ex-
pensive metal catalysts, harsh reaction conditions, and the
As a source of chloronium cations and nitrogen anions,
chloramine-T (CT) exhibits diverse chemical properties to-
ward a variety of functional groups.7 Recently, we have dis-
covered that chloramine-B (CB), a congener of CT, was capa-
ble of working well for regioselective dichloroimination of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
X. Liu et al.
Letter
Synlett
indoles in the presence of AcOH.8a In line with our interest
in chloramine salt mediated transformations,8b–d we herein
report the direct oxidative halogenation of terminal alkynes
with KI or NaBr as a halogen source using chloramine-B an
oxidizing agent.
yield (Table 2, entries 13 and 14). Moreover, unactivated al-
iphatic alkyne 1p was also an applicable substrate in the re-
action, which furnished 2p in 93% yield (Table 2, entry 15).
When 1,4-diethynylbenzene 1q was applied to this reac-
tion, the anticipated bisiodinated product 2q was formed in
excellent yield (Table 2, entry 16), indicating good availabil-
ity of this protocol.
Initial investigations for conversion of terminal alkynes
into 1-iodoalkynes were carried out using phenylacetylene
(1a) as the model substrate. The reaction of 1a (0.5 mmol)
with tetrabutylammonium iodide (TBAI, 0.6 mmol) in the
presence of CB (0.75 mmol) in MeCN (3 mL) at room tem-
perature for 2 h led to C–H iodination to provide the desired
1-iodoalkyne 2a in 88% isolated yield (Table 1, entry 1). En-
couraged by this result, a subsequent survey of other iodide
salts was performed (Table 1, entries 2–4). Of these condi-
tions, KI gave the best result to afford 2a in 96% yield (Table
1, entry 4). CT was also effective for this reaction, affording
2a in 84% yield (Table 1, entry 5). Green solvents such as
H2O and MeOH delivered the product in inferior yields (Ta-
ble 1, entries 6 and 7). Additionally, no reaction occurred in
the absence of KI (Table 1, entry 8).
Table 2 Synthesis of 1-Iodoalkynesa
KI, chloramine-B
R
R
I
MeCN
1
2
Entry
1
Substrate
Product
Yield (%)b
98
Me
Me
I
I
1b
1c
1d
2b
2
3
4
5
6
7
8
9
98
97
89
88
92
96
93
95
Me
Me
Table 1 Conditions Survey for the Iodination of Phenylacetylenea
2c
2d
iodide salt
chloramine salt
I
tBu
tBu
solvent, rt, 2 h
1a
2a
I
Entry
Iodide salt
Chloramine salt
Solvent
Yield (%)b
MeO
MeO
1
2
3
4
5
6
7
8
TBAI
NH4I
NaI
KI
CB
CB
CB
CB
CT
CB
CB
CB
MeCN
MeCN
MeCN
MeCN
MeCN
H2O
88
73
90
96
84
67
74
NR
I
2e
1e
F
F
KI
I
1f
2f
KI
Cl
Cl
KI
MeOH
MeCN
–
a Reaction conditions: 1a (0.5 mmol), iodide salt (0.60 mmol), chloramine
salt (0.75 mmol), solvent (3 mL), 2 h, room temperature.
b Isolated yield.
I
2g
2h
1g
1h
Next, the optimal reaction conditions obtained above
were applied to the reaction of 1 with KI (Table 2). A wide
range of terminal arylethynes 1b–m bearing either elec-
tron-donating groups (e.g., methyl, tert-butyl, and methoxy
substituents) or electron-withdrawing groups (e.g., halo-
gen, trifluoromethyl, cyano, and ester moieties) on the phe-
nyl rings reacted smoothly to give the desired correspond-
ing products 2b–m in excellent to almost quantitative
yields (Table 2, entries 1–12). The electronic nature and po-
sition of a substituent on the benzene ring had only a mar-
ginal effect on the efficiency of this reaction. Notably, het-
eroarylethynes like 3-ethynylpyridine (1n) and 3-ethyn-
ylthiophene (1o) were also found to be applicable to the
present iodination, providing 2n in 96% yield and 2o in 95%
Br
Br
F
I
F
I
1i
2i
Cl
Cl
I
2j
1j
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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X. Liu et al.
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Synlett
Table 2 (continued)
(Table 3, entry 9). Moreover, 1,4-diethynylbenzene 1q could
be served as a suitable substrate to generate the desired
bisbrominated product 3q in good yield (Table 3, entry 10).
As demonstrated in Scheme 2, gram-scale experiments
were successfully conducted employing 1i and 1l as the
substrates, showcasing the practicality of the present halo-
genation of terminal alkynes.
Entry
Substrate
Product
Yield (%)b
96
F3C
F3C
10
I
1k
2k
NC
NC
F
F
11
12
13
14
15
97
97
96
95
93
KI (1.2 equiv)
chloramine-B (1.5 equiv)
I
1l
2l
MeCN, rt, 2 h
MeO2C
MeO2C
I
1i, 1.0 g
2i, 1.9 g, 93%
I
NC
1m
2m
NC
NaBr (1.5 equiv)
chloramine-B (3.0 equiv)
MeCN/H2O (3:1)
70 °C, 24 h
N
S
N
Br
1l, 1.0 g
3l, 1.3 g, 77%
I
2n
1n
Scheme 2 Gram-scale experiments
S
On the basis of the previous works,3l,m,9 a plausible reac-
tion pathway of this transformation was proposed in
Scheme 3. An initial interaction of CB with halide ion gener-
ates the XCl or X2, together with a reductive product N-
sodiobenzenesulfonamide anion A formed. Subsequent co-
ordination of XCl or X2 to the triple bond of terminal alkyne
1 produces the π-coordinated species B, which could be
easily converted into 1-haloalkyne 2 (3) via an intermolec-
ular deprotonation facilitated by A, along with the release
of the N-sodiobenzenesulfonamide C.
I
2o
1o
I
1p
2p
I
16
90c
1q
I
2q
O
O
Na
S
N
a Reaction conditions: 1 (0.5 mmol), CB (0.75 mmol), KI (0.6 mmol), MeCN
(3 mL), 2 h, room temperature.
Cl
b Isolated yield.
c CB (2.0 mmol), KI (1.2 mmol), 4 h.
O
O
X
Na
S
N
O
O
O
O
S
Na
NHNa
S
H
Encouraged by the above results, we next focused our
attention on exploring the possibility of the CB oxidative
system for bromination of terminal alkynes. Using NaBr as
the bromine source, a variety of terminal arylethynes could
undergo a similar process to deliver the corresponding bro-
minated products in moderate to excellent yields under
modified reaction conditions (Table 3). Among them, the
reactions of arylethynes having either electron-donating
groups or halogen substituents on the phenyl rings with
NaBr furnished the 1-bromoalkynes 3b–l in 76–93% yields
(Table 3, entries 1–6). Heteroarylethynes like 3-ethynylpyr-
idine 1n and 3-ethynylthiophene 1o were also compatible
with the reaction conditions but providing lower yields (Ta-
ble 3, entries 7 and 8). Aliphatic alkyne 1p also underwent
the transformation smoothly, furnishing 3p in 81% yield
N
A
C
XCl or X2
X
H
R
R
R
1
XCl (X2)
2 (X = I)
3 (X= Br)
B
Scheme 3 A plausible reaction mechanism for the synthesis of 1- halo-
alkynes
In summary, we have developed a chloramine salt me-
diated oxidative halogenation of terminal alkynes with KI
or NaBr, which enables the general and practical prepara-
tion of various 1-bromoalkynes and 1-iodoalkynes.10,11 This
current reaction features simple operation, environmental-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
X. Liu et al.
Letter
Synlett
Table 3 Synthesis of 1-Bromoalkynesa
ly benign reaction conditions, broad substrate scope, and
impressive yields. Further studies on the applications of
this strategy are ongoing in our laboratory.
chloramine-B, NaBr
R
R
Br
MeCN/H2O (3:1)
1
3
Funding Information
Entry Substrate
Product
Yield (%)b
92
Financial support from the National Natural Science Foundation of
China (No. 21562052 and 21462055), the Guizhou Provincial Depart-
ment of Science and Technology (No. LH[2014]7547, and
LH[2014]7554), 15851 Talent Project Funding of Zunyi city (No.
201423), as well as National First-Rate Construction Discipline of
Guizhou Province (Pharmacy) (YLXKJS-YX-04), and the Fifth Batch of
Me
Me
1
Br
Br
3b
3d
1b
1d
tBu
tBu
MeO
Cl
Talent Base in Guizhou Province (2016) are gratefully acknowledged.
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a
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Supporting Information
3
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610259.
S
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References and Notes
4
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N
N
S
7
64c
67c
1n
Br
3n
S
8
9
Br
3o
1o
Br
81
1p
3p
Br
10
71d
1q
Br
3q
a Reaction conditions: 1 (0.5 mmol), CB (1.5 mmol), NaBr (0.75 mmol),
MeCN/H2O (3:1, 4 mL), 70 °C, 24 h.
b Isolated yield.
c Reaction time: 9 h.
d CB (3.0 mmol), NaBr (1.5 mmol)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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(10) General Procedure for the Synthesis of 1-Iodoalkynes
A 25 mL round-bottom flask with a magneton was charged with
terminal alkyne 1 (0.5 mmol), KI (99 mg, 1.2 equiv), and MeCN
(3 mL) under air at room temperature, and then chloramine-B
(160 mg, 1.5 equiv) was added. The mixture was stirred for 2 h.
After that, the reaction mixture was filtered. The filtrate was
concentrated under reduced pressure. Purification of the
residue by flash column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent afforded the desired
product 2.
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(11) General Procedure for the Synthesis of 1-Bromoalkynes
A 25 mL round-bottom flask with a magneton was charged with
terminal alkyne 1 (0.5 mmol), NaBr (77 mg, 1.5 equiv), and
MeCN/H2O (3:1, 4 mL,) under air at room temperature, and then
chloramine-B (320 mg, 3.0 equiv) was added. The mixture was
stirred at 70 °C for 24 h. After that, the reaction mixture was
cooled to room temperature and then filtered. The filtrate was
concentrated under reduced pressure. Purification of the
residue by flash column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent afforded the desired
product 3.
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