Na2S-mediated synthesis of terminal alkynes from: Gem -dibromoalkenes

Article abstract of DOI:10.1039/c7ob02431b

The Na₂S-mediated facile synthesis of terminal alkynes from gem-dibromoalkenes, at 20/40 °C under open flask conditions has been developed. Various precursors derived from heteroaromatic/aromatic/aliphatic aldehydes were found compatible. The reaction is proposed to proceed through the Fritsch-Buttenberg-Wiechell (FBW) rearrangement involving the corresponding vinyl carbene. Using mild reaction conditions with inexpensive Na₂S·9H₂O under air atmosphere has significant advantages over earlier routes.

Full text of DOI:10.1039/c7ob02431b

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Takeharu Haino et al.
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DOI: 10.1039/C7OB02431B
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Na2S mediated synthesis of terminal alkynes from gem-
dibromoalkenes
Radhey M. Singh,a* Durgesh Nandini,a,b Kishor Chandra Bharadwaj,a uptaa and Raj Pal Singhb
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
H
R
Br
Br
Na2S-mediated facile synthesis of terminal alkynes from gem-
dibromoalkenes, at 20/40 °C under open flask conditions has
been developed. Various precursors derived from
heteroaromatic/aromatic/aliphatic aldehydes were found
compatible. The reaction is proposed to go through the
Fritsch-Buttenberg-Wiechell (FBW) rearrangement involving
the corresponding vinyl carbene. Mild reaction conditions
using inexpensive Na2S.9H2O under air, are significant
advantages over earlier routes.
n-BuLi
Corey-Fuchs
reaction
R
H
THF, -78 °C
Cs2CO3, (2.5 eq.), 115 °C
Yang (2011)
H
R
Br
Br
TBAF(4-8 eq.), TPP, 80 °C
R
H
Development of new methodology for the synthesis of organic
molecules has always been challenging to both organic and
medicinal chemists when it is based on cost, reaction
conditions and applications. For example, terminal alkynes are
useful functional groups and versatile intermediates,1 widely
used in the synthesis of natural products, pharmaceuticals and
functional materials.2,3 They are used as precursors in azide-
alkyne cycloaddition reactions,4 carbon-carbon bond
formations,5 hydroamination,6 carbohalogenation7 and
oxidative cross coupling reactions.8 Amongst available
methods in the literature9-13 for alkyne synthesis, gem-
dibromoalkenes14a prepared from aldehydes via one-carbon
Zhang (2015)
DBU (4 eq.), rt
Ramana (2015)
This Work
Na2S (0.5 eq.)
H
R
Br
Br
R
H
20/40 °C, open flask
Fig. 1. Access to terminal alkynes from gem-dibromo-1-alkenes.
homologation have been identified as valuable precursors. However, these reactions require either excess of base and/or
Corey-Fuchs reactions,14b has been a classical method for the high temperature. Therefore, development of new
synthesis of alkynes using gem-dibromoalkenes. However methodology for terminal alkynes that tolerates some of these
these reactions proceed in the presence of strong and air drawbacks is highly desirable. Importantly, given the huge
sensitive bases such as BuLi,14b,15d LDA,15a Grignard reagents,15c importance, application & commercialization of alkynes, a
t-BuOK,15e and others.15b Further, they require very low catalytic route for their synthesis would be highly desirable.
temperature and inert atmosphere. Recently, efforts have As our continued interest in exploring reactivity and synthetic
been directed for alternate methods. Yang has reported applications of 2-chloroquinyl-3-caboxaldehydes,19 we recently
synthesis of terminal alkynes16 using cesium carbonate (Figure explored
the
application
of
2-chloro-3(2,2-
1). Zhang17a have used tetra-n-butyl ammonium fluoride17b dibromovinyl)quinoline for the corresponding synthesis of furo
and TPP for the same. Ramana utilized DBU for conversion of (2,3-b) quinolines.20 The reaction was then tried for synthesis
these precursors to terminal alkyne.18
of thiophene-fused quinolines from these precursors. Initially,
reaction of 2-chloro-3(2,2-dibromovinyl)quinoline, (1a) was
investigated with 1 eq. of Na2S.9H2O in 2mL DMSO at 40 oC
under air. The reaction afforded thiophene-fused quionline
(
2a) in 55% yield. However, it was interesting to observe the
formation of terminal alkyne (3a) in 25% yield (Scheme 1).
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Br
Br
Br
Na2S.9H2O
Na2S.9H2O (0.5 eq.)
+
R
R
Br
S
N
N
Cl
40 °C, 24 h
DMSO
X
R1
N
Cl
X
R1
DMSO, 20 °C
2a (55%)
3a (25%)
1
1a
3
X=C, N
Scheme 1. Reaction of 2-chloro-3(2,2-dibromovinyl)quionline (1a) with Na2S.
This result was enthralling because it led to synthesis of alkyne
under ambient conditions using Na2S.9H2O as
a cheap,
N
Cl
N
Cl
N
Cl
commercial and stable reagent. Thus we focused our attention
for the development of this method. We report herein a base-
free, efficient synthesis of terminal alkynes at rt under open
flask conditions in good yields.
3a (2h, 75%)
3c (3h, 83%)
3b (3h, 81%)
O
Systematic study began for exclusive synthesis of terminal
alkyne. Results are summarized in table 1. Further increase of
the temperature to 50 °C lead to reduced yield (entry 2).
Interestingly when reaction temperature was lowered to 20 °C,
reaction was completed in 2h affording alkyne as single
N
Cl
N
Cl
O
N
Cl
3e (3h, 82%)
3f (3h, 83%)
3d (3h, 78%)
Br
o
product in 72% yield. Further lowering of temperature to 0 C
N
Cl
Cl
N
Cl
N
Cl
didn’t afford reaction. After establishment of 20 °C as reaction
temperature for synthesis of terminal alkyne, optimization of
reaction was performed by screening mole variations of
Na2S.9H2O and solvents. When 0.5 eq. of Na2S was used, we
were delighted to observe a complete reaction in 2h with an
yield of 75% (entry 5). This was intriguing, as it suggested
reaction to proceed in catalytic pathway. Further decrease of
mole equivalent of reagent to 0.25 eq. lead to reduced yield of
62%. Similarly, screening of various solvents like DMF, CH3OH,
CH3CN, DCM and benzene (entries 7-11) gave inferior results.
Thus, a combination of substrate 1a (1 mmol) and Na2S.9H2O
(0.5 eq.) in 2mL DMSO at 20 °C under open flask, was
identified as best reaction condition (entry 5, table 1). Having
an optimized condition in hand the scope of the reaction was
investigated with substituted 2-chloro-3-(2,2-dibromovinyl)
quinolines.
O
3h (2h, 68%)
3g (3h, 74%)
3i (2h, 70%)
N
Cl
N
3k (4h, 65% )
3j (3h, 71%)
MeO
O2N
3m (16h, 55%)
3n (14h, 68%)
3l (14h, 67%)
3
Table 1. Optimization of the reaction conditions.
Me
3p (15h, 65%)
Br
3o (18h, 58%)
S
3r (14h, 60%)
3q (18h, 42%)
Br
Na2S.9H2O
Br
solvent,
T °C
N
Cl
N
Cl
Scheme 2. Substrate scope for terminal alkyne synthesis.a
aFor 3l-3r, reaction were carried out at 40 o
1a
3a
C
Entry
Na2S
(eq.)
1.0
Solvent
Temperature
Time
Yielda
(%)
25
Results of corresponding terminal alkynes 3b-3j are listed in
scheme 2. Substrates with electron-donating groups at 6 and 7
positions led to enhance yields of terminal alkynes relative to
substrates with electron withdrawing groups. However, lower
yields were observed with electron donating groups at position
8. The reaction was extendable to pyridine framework 3k. We
were able to get single crystal structure for one of the alkyne
(°C)
40
50
20
0
(h)
24
24
2
1
2b
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
1.0
20
1.0
72
4
1.0
2
-
5
0.5
0.25
0.5
20
20
20
20
20
20
20
2
75
6
6
62
7
3
70
(
3b) which further confirmed the structure (Figure 2).21 We
8
0.5
CH3OH
CH3CN
DCM
3.5
5
68
were also able to carry out reaction of 1f on 1.122 g (3 mmol)
scale to obtain 3f in 79% yield. To broaden the scope of the
reaction, gem-dibromovinyl derivatives of aromatic/other
hetroaromatic and aliphatic analogues were also evaluated
under the optimized conditions. Results are summarized in
scheme 2. The reaction of these gem-dibromovinyl derivatives
9
0.5
55
10
11
0.5
8
SM
SM
0.5
Benzene
8
aIsolated yield.b 60% of 2a was observed.
2 | J. Name., 2012, 00, 1-3
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Reaction opens up gateways for the development of catalytic
and mild routes for the synthesis of terminal alkynes. Further
work in this direction is under progress.
Authors are thankful to DRDO for financial support
(ERIP/ER/1203055/M/01/1471). DN is thankful to Director,
CFEES, DRDO, New Delhi and Department of Chemistry, BHU
for providing laboratory facility. KCB and TG are thankful to
CSIR and UGC for fellowships, respectively.
Fig
.
2. ORTEP diagram of 3b.
Conflicts of interest
H
There are no conflicts to declare.
Br
Br
N
Cl
Cl
N
1a
Notes and references
A
1
The Chemistry of Carbon-Carbon Triple bond; S. Patai, Ed.;
Wiley: New-York 1978.
Na2S
Br2
1,2-shift
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were less reactive than hetero aromatic analogues and
proceeded at 40 °C in 14-18h affording terminal alkynes 3l-
3r17a,22 in 42-68% respectively. Phenyl ring bearing electron-
donating groups were relatively more reactive than those with
electron-withdrawing groups and afforded better yields of
terminal alkynes.
4
5
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to afford vinylene carbene
A
A
undergoes rearrangement leading to terminal alkyne. NaSBr
and NaBr react together to regenerate Na2S along with
formation of bromine which can exist in equilibrium. To rule
out the possibility of Na2S acting as a base, the reaction of
(Z)2-bromovinylbenzene25 was examined for the synthesis of
terminal alkyne under optimized reaction condition (Scheme
4). However reaction failed to proceed and starting material
was recovered. This further ruled out Na2S acting as base.
In summary, we have developed a catalytic route for the
synthesis of terminal alkynes from gem-dibromoalkenes. This
route is superior over other methods because of cheap and
commercial availability of reagent. The reactions proceeds
without base at 20/40 oC under open atmosphere in good
yields. Different heteroaromatic, aromatic and aliphatic gem-
dibromoalkenes afforded corresponding terminal alkynes from
this method.
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X
Br
DMSO, 40 oC, 24 h
Scheme 4. Reaction of 1-bromovinylbenzene with Na2S.9H2O
.
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Br
Na2S (catalytic)
R
Br
X
R1
R
X
R1
X=C, N
DMSO, 20/40 °C
open flask