Silver-Catalyzed Regio- and Stereoselective Thiocyanation of Haloalkynes: Access to (Z)-Vinyl Thiocyanates

Article abstract of DOI:10.1002/adsc.201601142

A regio- and stereoselective method for the preparation of (Z)-vinyl thiocyanate derivatives by silver-catalyzed thiocyanation of haloalkynes is reported. This method features practical, free of ligand, broad substrate scope, excellent stereoselectivity and gram-scale synthesis. Significantly, the halogen atom of haloalkynes is retained, which allows the synthesis of 2,5-diphenylthiophene, thiazol-2-amine and trifluoromethyl sulfides derivatives via simple transformation. (Figure presented.).

Full text of DOI:10.1002/adsc.201601142

UPDATES
DOI: 10.1002/adsc.201601142
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Silver-Catalyzed Regio- and Stereoselective Thiocyanation of
Haloalkynes: Access to (Z)-Vinyl Thiocyanates
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Guangbin Jiang,a Chuanle Zhu,a Jianxiao Li,a Wanqing Wu,a,* and
Huanfeng Jianga,*
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a
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou 510640, People’s Republic of China
Fax: (+86) 20-87112906; e-mail: cewuwq@scut.edu.cn; jianghf@scut.edu.cn
Received: October 15, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601142
substrate scope or poor efficiency. Thus the develop-
ment of efficient and facile methods for the construc-
tion of alkenyl tiocyanates is highly demanded.
Abstract: A regio- and stereoselective method for
the preparation of (Z)-vinyl thiocyanate derivatives
by silver-catalyzed thiocyanation of haloalkynes is
reported. This method features practical, free of
ligand, broad substrate scope, excellent stereo-
selectivity and gram-scale synthesis. Significantly,
the halogen atom of haloalkynes is retained, which
allows the synthesis of 2,5-diphenylthiophene, thia-
zol-2-amine and trifluoromethyl sulfides derivatives
via simple transformation.
Keywords: haloalkynes; vinyl thiocyanates; thiocya-
nation; silver
35 The incorporation of sulphur atom can partially
36 modify the physical and biological properties of the
37 parent molecules,[1] thus sulfur atom containing com-
38 pounds are significant oriented targets in synthetic[2]
39 and medicinal chemistry.[3] Among them, thiocyanates
40 not only exhibit excellent biological and pharmaceut-
41 ical activities, such as antifungal, antibacterial, antipar-
Scheme 1. Applications of thiocyanates.
Due to the sp hybridization of the carbon linked to
42 asitic,[4] but also serve as useful and important the bromine, haloalkynes have emerged as practical
43 precursors for the synthesis of trifluoromethyl sul- and versatile synthons and found broad applications in
44 fides,[5] sulfonyl chlorides,[6] thiols,[7] thiocarbamates,[8] the field of synthetic and medicinal chemistry.[19] The
45 heterocycles,[9] disulfides,[10] thioethers[11] and gold- nucleophilic addition of haloalkynes is one of the most
46 thiolates[12] (Scheme 1). In this context, considerable straightforward and promising methods for the syn-
47 efforts have been made to develop efficient methods thesis of substituted alkene derivatives. Previously, we
48 for the synthesis of thiocyanates. Interestingly, in a have reported the nucleophilic addition of fluoride,
49 sharp contrast to the abundant methods for the iodide, and oxide to haloakynes,[20] delivering the
50 construction of alkyl[13] and aromatic[14] thiocyanates, corresponding substituted vinyl products in high yields
51 the access to vinyl tiocyanate derivatives is still with excellent regio- and chemselectivities. Inspired by
52 limited, in spite of their versatile transformation these elegant works, as well as our continuous efforts
53 abilities in synthetic chemistry. Previously, some on exploiting the potential reactivities and applica-
54 elegant methods for the synthesis of vinyl thiocyanates tions of haloalkynes, herein, we report the silver-
55 have been independently reported by Kumada,[15] catalyzed nucleophilic addition of inexpensive inor-
56 Cousseau,[16] Taniguchi[17] and Becker[18] (Scheme 2, a– ganic alkali thiocyanates salts to haloalkynes, afford-
57 d). However, these methods either suffer limited ing the desired organic vinyl thiocyanates in high
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Table 1. Optimization of the reaction conditions [a]
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Entry Catalyst
[SCN]
Solvent
Yield [%][b]
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1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
–
NaSCN
NaSCN
NaSCN
NaSCN
NaSCN
NaSCN
NH4SCN
LiSCN
KSCN
CuSCN
Pb(SCN)2 HOAc
KSCN
KSCN
KSCN
KSCN
KSCN
DMF
HOAc
H2O
n.d.
4
n.d.
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Dioxane n.d.
EtOH
DMSO
HOAc
HOAc
HOAc
HOAc
trace
n.d.
25
trace
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7
n.d.
61
54
85
92 (84)
21
n.d.
33
84
81
79
78
59 (49)
25 (21)
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–
–
–
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19[c]
20[d]
21[e]
22[f]
23[g]
24[h]
AgCl
Ag2CO3
AgNO3
AgOAc
Pd(OAc)2
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
Scheme 2. Methods for the synthesis of vinyl thiocyanates.
Pd(PPh3)4 KSCN
Cu(OAc)2 KSCN
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
27 yields with exclusive Z-type configuration (Scheme 2,
28 e). Remarkably, the halogen atoms of haloalkynes
29 were retained in the obtained vinyl thiocyanates,
30 providing ample potential for further applications.
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The initial experiment was carried out with
32 bromoalkyne 1a and NaSCN in DMF at 1008C in the
33 absence of catalysts under air (Table 1, entry 1).
34 However, no desired product was detected. On the
35 basis of our previous experience, different solvents
36 were investigated (Table 1, entries 2–6). Excitingly, a
37 solvent of HOAc afforded the desired vinyl thiocya-
38 nate 5a in 4% GC yield (Table 1, entry 2). Encour-
39 aged by this primary results, different thiocyanate
40 sources were investigated (Table 1, entries 7–11).
41 KSCN increased the yield of 5a to 34% (Table 1,
42 entry 9). To further improve the yield of the product,
43 different silver salts were screened as the Lewis acid
44 catalysts (Table 1, entries 12–15). To our delight,
[a] Reaction conditions: 1a (0.2 mmol), 4 (0.4 mmol) and
catalyst (10 mol%) in solvent (2 mL) at 1008C for 3 h.
[b] GC yield with dodecane as internal standard. n. d.=not
detected. The number in the parentheses is isolated yield.
[c] At 808C.
[d] Catalyst (5 mol%).
[e] KSCN (4d) (1.5 equiv.).
[f] At 1208C.
[g] 2a was used for product 6a.
[h] 3a was used for product 7a.
With the optimized reaction conditions in hand,
45 product 5a was obtained in 84% isolated yield with the generality of silver-catalyzed vinyl thiocyanates
46 AgOAc as the catalyst (Table 1, entry 15). Further- construction reaction was examined. The scope of
47 more, other types of Lewis acid catalysts such as bromoalkynes was firstly explored by the adoption of
48 palladium salts or copper salts were examined, no KSCN 4d as the reaction partner, and the results were
49 superior results were obtained (Table 1, entries 16– summarized in Table 2. To our delight, a broad
50 18). Additionally, decreasing the reaction temperature, spectrum of bromoalkynes with different substitution
51 the catalyst loading, the equivalents of KSCN or patterns and substituent groups on the phenyl ring
52 increasing the reaction temperature would erode the could be tolerated in this catalytic system, providing
53 yield of 5a slightly (Table 1, entries 19–22). With the desired vinyl thiocyanates in high yields with
54 chloroalkyne 2a or iodoalkyne 3a as the substrate, the exclusive Z-type configuration. Generally, both elec-
55 corresponding product 6a or 7a was also obtained in tron-withdrawing (F, Cl, Br, CN, CF3) and electron-
56 reasonable yield (Table 1, entries 23–24).
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donating substituents (Me, Et, n-Pr, OMe, OEt) on
the phenyl ring of bromoalkynes afforded the desired
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Table 2. Substrate scope of bromoalkynes[a],[b]
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[a] Reaction conditions: 1 (0.2 mmol), 4d (0.4 mmol) and AgOAc (10 mol%) in HOAc (2 mL) at 1008C for 3 h.
45 [b] Isolated yield.
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48 products in high yields (5a–5u). These results showed tives (5w–5an) in moderate to excellent yields.
49 that this new transformation was tolerant towards the Bromoalkynes derived from various linear and
50 electronic nature effects of the aromatic ring. It was branched alkyl alkynes with different chain length
51 worth to note that the product structure of 5a was were perfectly applicable under the standard reaction
52 confirmed by NOE analysis (see the Supporting conditions, affording the desired thiocyanates in high
53 Information). Bromoalkynes derived from 3-ethy- yields (5w–5ag). Steric hindered bromoalkynes de-
54 nylthiophene was also found to be suitable substrate, rived from ethynylcyclopropane, ethynylcyclopentane,
55 delivering the corresponding product 5v in 75% yield. and 1-ethynylcyclohex-1-ene could also give the corre-
56 Furthermore, alkyl bromoalkynes were tolerated well, sponding products 5ah–5aj in high yields. Interest-
57 and gave the corresponding vinyl thiocyanate deriva- ingly, the internal alkynyl group was found to be inert
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to this catalytic system, which further demonstrated diphenylthiophene product (8a) was obtained in 63%
the priority of the haloalkyne moiety in synthetic isolated yield via a Sonogashira coupling and cycliza-
chemistry (5ak). It was worth to mention that alkyl tion process. Under the treatment of ammonium
alkynes derived bromoalkynes that contained valuable hydroxide, 5a was transformed smoothly to the
cyano and chloro groups gave the addition products in desired thiazol-2-amine product 9a in 67% yield.
high yields as well, providing ample potential for Furthermore, various trifluoromethyl sulfides (10a,
further applications (5al–5am). Additionally, the 10d, 10v) were synthesized in high yields. Finally, two
double thiocyanation product 5an was obtained in control experiments were performed to gain more
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74% yield.
insight into the mechanism (Scheme 4). When 2 equiv.
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Next, the synthetic utility of this thiocyanation of radical inhibitor 2,2,6,6-tetramethyl-1-piperidiny-
11 reaction was explored. A gram-scale reaction of 1.8 g loxy (TEMPO) and butylated hydroxytoluene (BHT)
12 of 1a was carried out under the standard reaction were used under the standard conditions, the desired
13 conditions, providing 1.96 g of the desired product 5a product 5a was also obtained in 81% and 77% yields,
14 in 82% isolated yield (Scheme 3, up). In addition, we respectively. This observation demonstrated that the
15 further investigated the synthetic applications of these reaction should not be a radical process. On the base
16 thiocyanatio products (Scheme 3, down). Valuable 2,5- of the above-mentioned results and our previous
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reports,[20] we proposed that this new approach would
be a silver-catalyzed nucleophilic addition process.
In summary, we have developped a silver-catalyzed
thiocyanation reaction of haloalkynes with inexpen-
sive alkali thiocyanates salts, affording the desired
organic vinyl thiocyanates in high yields with exclusive
Z-type configuration. Remarkably, the halogen atoms
of haloalkynes were retained in the vinyl thiocyanate
products. The gram-scale experiment and the diverse
synthetic applications of the resultant vinyl thiocya-
nates further verified the significance of this method.
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Experimental Section
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General Procedure for the Synthesis of (Z)-Vinyl
Thiocyanates
A mixture of haloalkynes 1 (0.2 mmol), potassium thiocya-
nate 4d (0.4 mmol, 2 equiv.) and AgOAc (10 mol%) was
stirred in HOAc (2 mL) at 1008C for 3 h. Then a plenty of
saturated sodium bicarbonate solution was added to quench
the reaction. The aqueous solution was extracted with
dichloromethane (33 20 mL) and the combined organic layer
was dried with anhydrous MgSO4, filtered, the solvent was
removed and the crude product was purified by a column
chromatography (silica gel, PE/EA=50/1) to afford the pure
product.
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45 Scheme 3. Gram-scale experiment and further synthetic
Acknowledgements
applications[a],[b]
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This work was supported by the National Key Research and
Development Program of China (2016YFA0602900), the
National Natural Science Foundation of China (21490572,
and 21420102003, and 21502055), and Pearl River S&T Nova
Program of Guangzhou (201610010160) for financial sup-
port.
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