Synthesis of alkynes under dry reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2021.153051

An easy synthetic method was developed under dry reaction conditions for the preparation of terminal alkynes from 1,1-dibromoalkenes and in the presence of succinimide which acts as a nucleophile and proton donor. It was demonstrated with the synthesis of a broad spectrum of terminal alkynes and extended to synthesize internal alkynes under tandem reaction conditions.

Full text of DOI:10.1016/j.tetlet.2021.153051

Tetrahedron Letters 71 (2021) 153051
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Tetrahedron Letters
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Synthesis of alkynes under dry reaction conditions
⇑
Maddali L.N. Rao , Sk Shamim Islam
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy synthetic method was developed under dry reaction conditions for the preparation of terminal
alkynes from 1,1-dibromoalkenes and in the presence of succinimide which acts as a nucleophile and
proton donor. It was demonstrated with the synthesis of a broad spectrum of terminal alkynes and
extended to synthesize internal alkynes under tandem reaction conditions.
Received 3 March 2021
Revised 24 March 2021
Accepted 27 March 2021
Available online 1 April 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
1,1-Dibromoalkenes
1-Bromoalkynes
Dry conditions
Terminal alkynes
Internal alkynes
Alkynes are valuable synthons in organic chemistry for the syn-
thesis of natural products, pharmaceuticals, and functional materi-
als [1]. Terminal alkynes are also useful in several chemical
transformations [2], including the preparation of conjugated diy-
nes [3], heterocycles [4], in Sonogashira [5] and click reactions
[6]. Importantly, 1,1-dibromoalkenes are easily accessible from
aldehydes and serve as robust precursors in the preparation of ter-
minal alkynes [7,8]. The preparation of terminal alkynes [8] from
1,1-dibromoalkenes occurs through the carbene pathway, b-elimi-
nation, or 1-bromoalkyne formation. Some of these reactions are
known to involve strong and air-sensitive bases [7b-d,8] such as
n-BuLi, LDA, Grignard reagents, and inorganic bases under aqueous
conditions. In continuation of our interest in developing synthetic
tools using 1,1-dibromoalkenes [9,10], it was interest to develop an
efficient method for the synthesis of terminal alkynes under dry
conditions. It led to the successful development of an effective pro-
tocol for the preparation of terminal alkynes from 1,1-dibro-
moalkenes and succinimide under dry conditions (Scheme 1).
The dual role of succinimide was envisaged as a good nucle-
ophile in the DMSO solvent [11] and a proton donor in the reaction
course. Our established protocol is more valuable and synthetically
advantageous in comparison to various reported methods [8],
which involve strong bases, pyrophoric reagents, and longer reac-
tion times. Further, our dry protocol can be extended to one-pot
tandem functionalizations.
Br
Succinimide
Ar
Ar
K2CO3, DMSO
90 oC, 2 h
Br
Scheme 1. Preparation of terminal alkynes.
different conditions (Table 1). The initial screening was performed
with K3PO4 in dry DMSO at 60 °C for 6 h (Table 1, entry 1). These
conditions afforded the corresponding terminal alkyne (2a) in
65% yield and minor amount 1-bromoalkyne (1.1). It was further
screened with NaHCO3 and K2CO3 (Table 1, entries 2 and 3). Of
these two bases, K2CO3 proved as more useful to furnish the alkyne
2a in 74% yield. It was further screened to set the protocol condi-
tions. For example, the reaction performed in 2 h conditions also
gave alkyne 2a in 76% yield (Table 1, entry 4). However, the reac-
tion with 1 h conditions afforded only 53% yield (Table 1, entry
5). The reaction temperature with 70 °C proved to be low-yielding
(Table 1, entry 6). The additional decrease in K2CO3 loading fur-
nished a lowered yield (Table 1, entry 7). Also, the use of 1 equiv
succinimide provided 36% yield (Table 1, entry 8). Another control
reaction without succinimide did not furnish the alkyne 2a and
gave the corresponding 1-bromoalkyne in 72% yield (Table 1, entry
9). The formation of 1-bromoalkyne indicated the vital role of suc-
cinimide in the overall reaction course in furnishing the alkyne 2a.
This screening thus furnished the reaction conditions comprising
1,1-dibromoalkene (1 equiv), succinimide (2 equiv), K2CO3 (6
equiv) in DMSO at 90 °C for 2 h as the standardized protocol
(Table 1, entry 4).
To establish the reaction protocol, the reaction of 1,1-dibro-
moalkene (1a) was screened in the presence of succinimide under
⇑
Corresponding author.
E-mail address: maddali@iitk.ac.in (M.L.N. Rao).
https://doi.org/10.1016/j.tetlet.2021.153051
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Maddali L.N. Rao and S. Shamim Islam
Tetrahedron Letters 71 (2021) 153051
Table 1
Table 2
Screening conditions.a,b
Synthesis of terminal alkynes.a,b
Entry
Base
Temp. (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
K3PO4
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
60
90
90
90
90
70
90
90
90
6
6
6
2
1
2
2
2
2
65
58
74
76
53
61
49c
36d
e
–
a
Reaction conditions: 1a (0.375 mmol, 1 equiv), succinimide (0.75 mmol, 2
equiv), base (2.25 mmol, 6 equiv), dry DMSO (3 mL), temp., time.
b
Isolated yields.
K2CO3 (4 equiv).
Succinimide (1 equiv).
Without succinimide.
c
d
e
The synthetic efficacy of the above established protocol was fur-
ther examined in the preparation of a variety of terminal alkynes
involving different 1,1-dibromoalkenes (Table 2). The initial study
using electronically rich 1,1-dibromoalkenes (1a-1d) furnished the
corresponding terminal acetylenes 2a-2d in 64–86% yields. Inves-
tigations using 1-naphthyl, 2-naphthyl, and 9-anthracenyl substi-
tuted 1,1-dibromoalkenes (1e-1g) delivered the corresponding
terminal alkynes 2e-2g in 75–96% yields. Also, 1,1-dibromoalkenes
(1h and 1i) with electron-withdrawing groups provided the corre-
sponding terminal alkynes 2h and 2i in good yields. Halogenated
1,1-dibromoalkene such as 1-bromo-4-(2,2-dibromovinyl)benzene
(1j) afforded the terminal alkyne 2j in 75% yield. Our protocol was
also applied to heteroaromatic 1,1-dibromoalkenes (1k and 1l) and
gave the corresponding terminal alkynes 2k and 2l in good yields.
Similarly, 4-(2,2-dibromovinyl)-N,N-diphenylaniline (1m) also
reacted well to give terminal alkyne 2m in 69% yield. Notably, this
study revealed the higher reactivity of electron-rich 1,1-dibro-
moalkenes over electron-deficient ones under the established opti-
mized conditions (Table 2).
The reactivities of various functionalized 1,1-dibromoalkenes
such as 1,3-dienyldibromide, 3-en-1-ynyldibromide, bis/tris-dibro-
moalkenes were further investigated under the optimized condi-
tions (Table 3). The reaction of 1,3-dienyldibromide (1n) thus
selectively provided (E)-but-1-en-3-ynylbenzene (2n) in high
yield. Similarly, the reactivity of 3-en-1-ynyldibromide (1o) was
proved to be selective to afford 1-(buta-1,3-diynyl)-4-methylben-
zene (2o) in good yield. Next, the reactivity enumerated with
bis- and tris-substituted systems. For example, the reaction of
1,4-bis(2,2-dibromovinyl)benzene (1p) gave the corresponding
1,4-diethynylbenzene (2p) in high yield. The study of tris(4-(2,2-
dibromovinyl)phenyl)amine (1q) notably furnished the tris(4-
ethynylphenyl)amine (2q) in 46% yield.
In comparison, our synthetic protocol was found to be more
direct without involving protection/deprotection processes, as
reported in the literature for the preparation of star-shaped tris
(4-ethynylphenyl)amine (2q) [12].
a
Reaction conditions: 1,1-dibromoalkene (0.375 mmol, 1 equiv), succinimide
(0.75 mmol, 2 equiv), K2CO3 (2.25 mmol, 6 equiv), dry DMSO (3 mL), 90 °C, 2 h.
The successful development of the dry protocol and its applica-
tion in the synthesis of various terminal alkynes prompted us to
adopt this method in the one-pot synthesis of internal alkynes
involving the Sonogashira reaction. For that, a brief screening
was done for step 2 involving the Sonogashira coupling, and it
was to establish an overall one-pot two-step protocol (Table 4).
b
Isolated yields.
It was carried out in a step-wise manner involving the stan-
dardized protocol in step 1 followed by the Sonogashira reaction
using p-tolyliodide (3a) under palladium-catalyzed conditions in
2

Maddali L.N. Rao and S. Shamim Islam
Tetrahedron Letters 71 (2021) 153051
Table 3
Table 5
Synthesis of functional alkynes.a,b
Synthesis of internal alkynes.a,b,c
I
1) Succinimide/K2CO3
Br
DMSO, 90 oC, 2 h
Ar
Ar
Ar
+
Ar
Br
2) PdCl2(PPh3)2/CuI
NEt3, 90 oC, 5 h
4a-4e
3a-3c
1
one-pot
Entry
Ar-I
I
Internal alkyne
Yield (%)
1,1-Dibromide
MeO
MeO
MeO
Me
1
1a
3a
3b
68
62
4a
Me
I
OMe
2
1f
4b
OMe
I
1g
1i
3
4
3c
3b
65
57
NPh2
OMe
4c
4d
4e
NPh2
I
NC
OMe
I
a
Reaction conditions: 1,1-dibromoalkene (0.375 mmol, 1 equiv),
Ph
Ph
succinimide (0.75 mmol, 2 equiv), K2CO3 (2.25 mmol, 6 equiv), dry DMSO
N
NPh2
5
1m
3c
58
(3 mL), 90 °C, 2 h.
b
Isolated yields.
Succinimide (4 equiv), K2CO3 (12 equiv), DMSO (4 mL).
Succinimide (6 equiv), K2CO3 (18 equiv), DMSO (4 mL).
NPh2
c
d
a
Reaction conditions: step 1: 1,1-dibromoalkene (0.375 mmol,
1
equiv),
succinimide (0.75 mmol, 2 equiv), K2CO3 (2.25 mmol, 6 equiv), dry DMSO (3 mL),
90 °C, 2 h. Step 2: Ar-I (0.562 mmol, 1.5 equiv), NEt3 (1.875 mmol, 5 equiv), CuI
(0.018 mmol, 0.05 equiv), PdCl2(PPh3)2 (0.006 mmol, 0.016 equiv), 90 °C, 5 h.
Table 4
Screening conditions.a,b
b
Homo-coupled 1,3-diynes from terminal alkynes formed in minor amounts.
Isolated yields.
c
MeO
MeO
Br
1) Succinimide/K2CO3
DMSO, 90 oC, 2 h
MeO
MeO
Br
Me
2) PdCl2(PPh3)2/CuI
NEt3, 90 o
C
OMe
To test this one-pot protocol, few reactions have been
attempted with different 1,1-dibromoalkenes and aryl iodides to
synthesize internal alkynes (Table 5). Thus the reactions carried
out with 1,1-dibromoalkenes (1a, 1f, 1g, 1i, and 1m) and in combi-
nation with different aryl iodides (3a-3c) furnished electronically
various internal alkynes 4a-4e in 57–68% yields. The symmetrical
internal alkyne 4e is a highly used substrate in optoelectronics
devices [13]. Overall, this one-pot tandem synthesis of internal
alkynes directly from 1,1-dibromoalkenes proved to as a versatile
method under dry reaction conditions with minimized steps in a
cost-effective manner [8].
A control reaction carried out earlier (Table 1, entry 9) is elabo-
rated below in Scheme 2. This reaction in the absence of succin-
imide furnished 1-bromoalkyne exclusively (Scheme 2) [9a],
indicating the important role of succinimide in terminal alkyne
formation.
A representative mechanistic protocol is given in Scheme 3
involving the initial formation of 1-bromoalkyne (1.1) from 1,1-
dibromoalkene (1a). This 1-bromoalkyne thus involves in X-philic
reaction with in situ formed succinimide ion generates the acety-
lide anion [14] (1.2) and N-bromosuccinimide (NBS) [15]. Further,
acetylide anion gets protonated [15] with succinimide and gives
terminal alkyne (2a). All these elementary steps get completed in
a facile manner under the established protocol conditions.
4a
MeO
p-tolyliodide (3a)
1a
one-pot
Entry
3a (equiv)
Time (h)
Yield (%)
1
2
3
1.5
1.0
1.5
4
4
5
61
56
68
a
Reaction conditions: step 1: 1a (0.375 mmol, 1 equiv), succinimide (0.75 mmol,
2 equiv), K2CO3 (2.25 mmol, 6 equiv), dry DMSO (3 mL), 90 °C, 2 h. Step 2: 3a, NEt3
(1.875 mmol, 5 equiv), CuI (0.018 mmol, 0.05 equiv), PdCl2(PPh3)2 (0.006 mmol,
0.016 equiv), 90 °C, time.
b
Isolated yields.
step 2 (Table 4, entry 1). This two-step one-pot operation afforded
internal alkyne 4a in 61% yield. Encouraged by this, further screen-
ing was done with p-tolyliodide (1 equiv), resulting in the internal
alkyne in the 56% yield (Table 4, entry 2). However, some improve-
ment was seen with increasing reaction time and internal alkyne
was obtained in 68% yield (Table 4, entry 3). So, this protocol
was taken as an optimized condition and successfully explored in
the synthesis of internal alkynes involving a tandem two-step
one-pot process (Table 5).
3

Maddali L.N. Rao and S. Shamim Islam
Tetrahedron Letters 71 (2021) 153051
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from 1,1-dibromoalkenes. This protocol effectively utilizes succin-
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[16] and applied to synthesize internal alkynes [17] under tandem
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[16] General procedure for terminal alkynes preparation: To an oven-dried Schlenk
tube, 1,1-dibromoalkene (1 equiv), succinimide (2 equiv), K2CO3 (6 equiv)
were added along with dry DMSO (3 mL). This mixture was stirred at 90 °C for
2 h. After that, the mixture was cooled to room temperature and extracted
with ethyl acetate (30 mL) and washed with water (10 mL) followed by brine
solution (10 mL). The organic extract was dried over dry MgSO4 and
concentrated. The pure product was obtained by silica gel column
chromatography using ethyl acetate/hexane as eluent.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We acknowledge the financial support (Project No.
EMR/2017/005221) received from Science and Engineering
Research Board (SERB), New Delhi for generous funding. S. S. I.
thanks University Grants Commission (UGC), New Delhi for the
research fellowship.
[17] General procedure for internal alkynes preparation: To an oven-dried Schlenk
tube, 1,1-dibromoalkene (1 equiv), succinimide (2 equiv), K2CO3 (6 equiv)
were added along with dry DMSO (3 mL). This mixture was stirred at 90 °C for
2 h. After that, the contents in Schlenk tube were bought to room temperature
and added aryl iodide (1.5 equiv), NEt3 (5 equiv), CuI (0.05 equiv), PdCl2(PPh3)2
(0.016 equiv) successively under nitrogen atmosphere. The reaction mixture
was stirred at 90 °C for 5 h. The internal alkyne was isolated following the
workup and purification protocol given for terminal alkyne preparation.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153051.
4