Iodine-mediated regio- and stereoselective iodothiocyanation of alkynes in aqueous ethanol

Article abstract of DOI:10.1039/c8ob02216j

Iodothiocyanation of alkynes with ammonium thiocyanate (NH₄SCN) and molecular iodine (I₂) has been demonstrated in aqueous ethanol, which enables efficient synthesis of a series of functional β-iodo vinylthiocyanates in good to excellent yields under mild reaction conditions without the need for any protection.

Full text of DOI:10.1039/c8ob02216j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Iodine-mediated Regio- and Stereoselective Iodothiocyanation of
Alkynes in Aqueous Ethanol
Xianghua Zeng a*, Lu Chen b*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Iodothiocyanation of alkynes with ammonium thiocyanate exclusive Z-configuration via a AgOAc-catalyzed thiocyanation
(NH4SCN) and molecular iodine (I2) has been demonstrated in of haloalkynes with alkali thiocyanates salts (Scheme 1, eq.2).11
aqueous ethanol, which enables efficient synthesis of a series Recently, the He’s group reported an practical protocol for the
of functional β-iodo vinylthiocyanates in good to excellent synthesis of Z-vinyl thiocyanates through ultrasound-promoted
yields under mild reaction conditions and without need for Brønsted acid ionic liquid-catalyzed hydrothiocyanation of
any protection.
activated alkynes (Scheme 1, eq.3).12 Despite the significant
utility, these transformations suffer from one or more issues
for such as limited substrate scope, use of noble metal catalyst,
Heteroatom-containing
compounds,
especially
organosulfurs, constitute a significantly important branch of complicated operation and low selectivity, etc. Hence, the
organic chemicals, existing in numerous agrochemicals, development of efficient and simple methods for direct
biomedicals, pharmaceuticals and functional materials. In construction of alkenyl thiocyanates is highly demanded.
addition, many of them serve as useful building block for
Previous work
various synthetic purposes, including the preparation of
important antibiotics and heterocycles.1 As a result, some
synthetic strategies have been nicely developed to prepare
various valuable sulfur-based molecules.2 In the past decades,
the thiocyanation as well as the cyanation of organosulfur
compounds were used for the synthesis of heteroaromatic
compounds and attracted considerable attention.3 In general,
thiocyanate salts are the SCN sources used to introduce a
sulfur functionality to a substrate, such as Pb(SCN)2,4 KSCN,5
NaSCN,6 AgSCN 7 and NH4SCN 8 being probably most employed.
In 1990, Kitamura and co-authors reported the use of
bromoalkenes as substrates to obtain thiocyanate under
photochemical conditions (Scheme 1, eq.1).9 In 2017, Wang
and co-authors reported the first direct thiocyanation of
ketene dithioacetals in the presence of N-chlorosuccinimide
(NCS) and NH4SCN under transition-metal-free conditions. 10 In
the same year, Jiang and co-authors demonstrated that they
were able to prepare the vinyl thiocyanates in high yields with
R
R
R1
Br
R
R
R1
SCN-
poor functional
group tolerance
(1)
(2)
hv, 20-70 oC
SCN
KSCN, AgOAc
NCS
R
X
H
R
X
HOAc, 100 oC, 3 h
only H
X = Br
NCS
R
EWG
KSCN, Ionic Liquid
Ultrasound, H2O
(3)
R
EWG
only H
H
This work
I2 (0.55 eq)
SCN
R2
NH4SCN (1.1 eq)
I
22 examples
75-96% yield
R1
(4)
EtOH/H2O(2:1)
80 oC, Air
R1
R2
green solvent
inexpensive SCN resource
R1 = aryl, alkyl, COOMe
R2 = H, aryl, alkyl
broad range of alkyne substrates
excellent functional group tolerance
Scheme 1 Methods for the synthesis of Z-vinyl thiocyanates
As part of our program aimed at developing new
synthetic methodologies for preparation of heterocycles and
heteroatom-containing compounds,13 herein, we report,
under metal-free and air atmospheric conditions using
environmentally friendly aqueous ethanol medium, a high
regio- and stereoselective synthesis of alkenyl thiocyanates via
iodothiocyanation of various alkynes with I2 and NH4SCN.
First, we attempted to promote the reactivity of
phenylacetylene with NH4SCN in the presence of I2 as the
iodine source and MeCN as the solvent at 80 oC under air
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(Table 1, entries 1). In the course of this reaction, we obtained the transformation of various terminal arylacetylenes
the β-iodo vinylthiocyanate with good isolated yield (75%) and their structures, see the supporting information (SI). For
excellent stereo-selectivity (Z : E = 10:1). We then move to instance, 1-ethynyl-4-methylbenzene 1b), 1-ethyl-4-
solvent screening, the addition of H2O to the reaction system ethynylbenzene 1c and 1-ethynyl-4-propylbenzene 1d
increased the yield to some extent. Especially, when the ratio efficiently reacted at 80 C with NH4SCN and I2 giving the
1 (for
(
(
)
(
)
o
，
of MeCN and H2O is 2:1, the isolated product yield reached up desired β-iodo vinylthiocyanates in 90%-92% yields with
to 87% with high stereo-selectivity (Z : E = 10:1) . Gratifyingly, exclusive regioselcetivity and excellent stereoselectivity (Table
among various solvents combining with H2O (2 : 1) tested, 2, 2a-2d).
EtOH further improved the yield to 90% (Table 1, entries 2-8).
Table 2 Efficient synthesis of β-iodo vinylthiocyanates
SCN
However, the use KSCN or NaSCN as the SCN source led to
I2 (0.55 eq)
R2
relatively poor product stereo-selectivity (Table 1, entries 9
and 10). Meanwhile, we also test the influence of Iodine
source, the use of KI, NIS, HI and N(Et)4I only resulted in
moderate to poor yields (Table 1, entries 11-14). Further,
performing the reaction under N2 or O2 conditions showed that
the presence of air was more efficient to promote this reaction
(Table 1, entries 15 and 16). Finally, a decrease of reaction
time or temperature led to diminished yield (Table 1, entry 17-
18). When we enlarged the scale of this reaction, the good
iolated yield 88% of 2a was obtained as expected (Table 1,
entry 19).
I
NH4SCN (1.1 eq)
R1
R1
EtOH/H2O(2:1)
80 oC, 24h, air
R2
1
2
SCN
SCN
I
SCN
SCN
I
I
2c, 90%
Z/E=15:1
2a, 90%
Z/E=10:1
2b, 91%
Z/E=15:1
SCN
SCN
I
I
I
Table 1 Screening of reaction conditionsa
O
O
2f, 93%
Z/E=15:1
2e, 89%
Z/E=25:1
2d, 92%
Z/E=15:1
SCN
SCN
SCN
Entry Solvent
1 d
[Iodine] [SCN]
Yield[%]b Z/Ec
NH4SCN 75 10:1
I
I
I
MeCN
I2
I2
I2
I2
S
2
MeCN/H2O
THF/H2O
DMF/H2O
NH4SCN 92(87)
10:1
5:1
Cl
F
2i, 83%
3
NH4SCN 35
NH4SCN 70
NH4SCN 46
NH4SCN 39
NH4SCN 93(90)
NH4SCN 87
2g, 89%
Z/E=10:1
2h, 92%
Z/E=10:1
Z/E=10:1
4
7:1
SCN
5
Dioxane/H2O I2
Acetone/H2O I2
5:1
I
SCN
SCN
6
5:1
I
I
I
7
EtOH/H2O
DMSO/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
I2
10:1
10:1
8:1
S
8
I2
2j, 88%
Z/E=10:1
2l, 92%
Z/E=10:1
SCN
2k, 90%
Z/E=10:1
9
I2
KSCN
92
90
SCN
10
11
12
13
14
15 e
16 f
17 g
18 h
I2
NaSCN
8:1
O
I
SCN
I
O
KI
NH4SCN 52
NH4SCN 67
NH4SCN 28
NH4SCN 31
NH4SCN 46
NH4SCN 90
NH4SCN 78
NH4SCN 65
NH4SCN 88
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:1
NIS
O2N
O
HI
2o, 90%
Z/E=15:1
2n, 91%
Z/E=10:1
2m, 85%
Z/E=3:1
N(Et)4I
SCN
SCN
SCN
I2
I2
I2
I2
I2
I
O
I
Br
I
O
2r, 96%
Z/E=25:1
2p, 90%
2q, 82%
Z/E=5:1
19i
Z/E=25:1
a
SCN
SCN
SCN
General reaction conditions: Phenylacetylene (0.40 mmol), iodine
source (I2 = 0.55 equiv, KI, NIS, HI, N(Et)4I = 1.1 equiv), and thiocyanate
source (1.1 equiv) in solvent (1.0 mL different kinds of solvent，0.5 mL
I
I
I
H2O) at 80 oC for 24 hours under air atmosphere. b isolated yield. c The
Z/E ratio was determined by 1H NMR spectroscopy. d MeCN (1.5 mL).
2u, 92%
Z/E=25:1
2t, 75%
2s, 93%
Z/E=25:1
e
h
N2 atmosphere f O2 atmosphere. g 6h. 60 oC i Phenylacetylene (20
Z/E=10:1
mmol mmol, ), I2 (11 mmol), and thiocyanate source (22 mmol) in
EtOH/H2O (20.0 mL) at 80 oC for 24 hours under air atmosphere.
Reaction conditions: Unless otherwise stated, phenylacetylene (0.40
mmol), iodine source (0.55 equiv), and NH4SCN (1.1 equiv) in
EtOH/H2O (2:1, 1.5 mL) at 80 oC for 24h under air atmosphere
With the availability of the optimized reaction conditions
(Table 1, Entry 7), we subsequently examined the generality of
the synthetic protocol. As shown in Table 2, we firstly tested
2 | J. Name., 2012, 00, 1-3
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Then, the substrate exploration showed that the more
COMMUNICATION
In contrast, upon addition of 0.55 equivalent of I2 to the
electron-rich 1-ethynyl-4-methoxybenzene (1e) and 1-ethoxy- same reaction, a gem-diiodo vinylthiocyanate 2v’ was afforded
4-ethynylbenzene (1f) also exhibited good reactivity to result in 87% yield (Scheme 2, eq 2). These two experiments indicate
in the difunctionalization products in excellent yields with that the molecular iodine plays a crucial role in activation of
preferred Z form (Table 2, 2e-2f). Meanwhile, we investigated the C-C triple bond14 and generation of the desired product.
influence of electron-withdrawing groups
(
1g and 1h),
Meanwhile, it indicates that the iodide substituted alkyne
including the -F and -Cl on the aryl ring, which still afforded is also adaptable to this transformation. Furthermore, by
satisfactory yields (2g and 2h). Clearly, the results show that replacing H2O with D2O in the optimal conditions, the reaction
the substituents on the aryl ring, regardless of electron-rich or of pheylacetylene 1a with NH4SCN and I2 resulted in the β-iodo
electron-poor ones, have no significant impact on the product vinylthiocyanate in a mixed form in 90% yield, and the ratio of
formation. Interestingly, the heteroaryl acetylenes, including non-deuterium (2a-H) and deuterium-labelling products 2a-
D
2-ethynylthiophene (1i) and 3-ethynylthiophene (1j) also were is 3.3 : 1 (Scheme 2, eq 3). Such a result further provide
able to serve as effective coupling partners and generated the evidence that the reaction involving a haloalkyne intermediate
can be ruled out.15
thiocyanates in high yields (Table 2, 2i and 2j).
On the basis of the above findings, a plausible reaction
pathway is depicted in Scheme 3. Initially, the presence of I2
leads to an electrophilic addition to the C-C triple bond of
To further expand the substrate scope, we then turned
our attention to the application of terminal alkyl acetylenes 1.
As illustrated in Table 2, representative examples with alkyl
chains, such as the n-hexyl, n- butyl, cyclopropyl and t-butyl
ones, underwent efficient coupling to produce the desired
substrate
1 .
and forms a cyclic iodonium ion 1’ 16 Then, SCN-
undergoes nucleophilic attack to more substituted site of 1’
and leads to succedent ring opening,17 which affords the
difunctionalization product 2. Noteworthy, the Iodide anion is
products in 85-92% yields (Table 2, 2k-2m). Then, the
functional groups containing substrates, such as 1-nitro-4-
(prop-2-yn-1-yloxy)benzene (1n), methyl propiolate (1o), ethyl
propiolate (1p), 3-bromoprop-1-yne (1q) and 2-methylbut-1-
en-3-yne (1r), were proven to be well tolerated, affording the
corresponding products in 82-96% yields (Table 2, 2n-2r).
Noteworthy, in case of the reaction of substrate 2r, the alkenyl
group was kept in the final product, indicating that the
reaction undergoes in a chemoselective manner. In addition to
the terminal alkynes, we finally focused on the reactions of
internal alkynes, including the diaryl (1s), arylalkyl (1t) and
dialkyl (1u) ones. The results show that all the reactions
smoothly afforded the desired products in good yields (Table
in situ oxidized to molecular I2 which participates the
reaction.18 Thus, it is not necessary to add stoichiometric
amount of I2 the present reaction (Scheme 3).
I
NCS
R1
I
SCN-
R1
R2
I2
I-
R1
R2
R2
1
1'
2
O2
Scheme 3 Proposed mechanism for the reaction
Conclusions
9-
2, 2s-2u). In comparison with previously reported protocols
12, it is the first example demonstrated for the preparation of
difunctionalized alkenes with internal alkynes.
In summary, we have developed a new environmentally
friendly, economical and straightforward approach for
versatile synthesis of vinyl thiocyanates from readily available
and inexpensive NH4SCN and I2 with various aryl and alkyl
alkynes. In comparison with the reported protocols, the
developed chemistry is also amenable to the transformation of
internal alkynes, including the halosubstituted ones. The
transformation proceeds in aqueous ethanol medium under
mild conditions, furnishing the various desired products in
good to excellent yields upon isolation. The protocol is
adaptable to a broad substrate scope with good functional
group tolerance, which offers an important basis for efficient
preparation of functional alkenes from non-activated alkynes.
To gain mechanistic insight into the reaction, several
control experiments were performed. First, we performed the
reaction of (iodoethynyl)benzene 1v and NH4SCN under the
optimal conditions without addition of I2, which failed to give
the difunctionalization product 2v (Scheme 2, eq 1).
SCN
I
I
(eq 1)
NH4SCN(1.1 eq)
EtOH/H2O(2:1)
80 oC, 24h, air
2v
, -
1v
1v
SCN
I
NH4SCN(1.1 eq)
I2 (0.55 eq)
I
(eq 2)
I
EtOH/H2O(2:1)
80 oC, 24h, air
2v' 87% yield
Acknowledgements
The authors are grateful to the funds of the Natural Science
Foundation of Zhejiang Province (LY17B030011), Science
Foundation for Young Teachers of Wuyi University (2016zk03,
2015td01), the Foundation of the Department of Education of
SCN
SCN
H
H
NH4SCN(1.1 eq)
I2 (0.55 eq)
I
I
(eq 3)
+
D
EtOH/D2O (2:1)
80 oC, 24h, air
2a-H
2a-D
1a
Guangdong Province
(2017KZDXM085,
2016KTSCX144,
90% yield, H/D=3.3:1
H/D ratio was determined by NMR
2016KCXTD005), Science and Technology Foundation of
Jiangmen City (2017012)
Scheme 2 The control experiments and proposed reaction
mechanism
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