Copper-catalyzed efficient dithiocyanation of styrenes: Synthesis of dithiocyanates

Article abstract of DOI:10.1080/00397911.2016.1194997

A novel Cu-catalyzed intermolecular chemoselectivity dithiocyanation of styrenes with ammonium thiocyanate has been developed under mild conditions. This reaction exhibits a wide range of functional-group tolerance in styrenes to afford various dithiocyanates. The reaction mechanism was primarily investigated and a radical process was proposed.

Full text of DOI:10.1080/00397911.2016.1194997

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Copper-Catalyzed Efficient Dithiocyanation of
Styrenes: Synthesis of Dithiocyanates
Yunhe Lv, Weiya Pu, Hao Cui, Jialin He & Qinmei Zhang
To cite this article: Yunhe Lv, Weiya Pu, Hao Cui, Jialin He & Qinmei Zhang (2016): Copper-
Catalyzed Efficient Dithiocyanation of Styrenes: Synthesis of Dithiocyanates, Synthetic
Communications
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Date: 22 June 2016, At: 03:53

Copper-Catalyzed Efficient Dithiocyanation of Styrenes: Synthesis of Dithiocyanates
Yunhe Lv1,, Weiya Pu1, Hao Cui1, Jialin He1, Qinmei Zhang1
1College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang,
China
Address correspondence to Yunhe Lv
Abstract
A novel Cu-catalyzed intermolecular chemoselectivity dithiocyanation of styrenes with
ammonium thiocyanate has been developed under mild conditions. This reaction exhibits
a wide range of functional-group tolerance in styrenes to afford various dithiocyanates.
The reaction mechanism was primarily investigated and a radical process was proposed.
KEYWORDS: CuBr; Dithiocyanation; Styrenes, Selectfluor; Oxidative radical
addition.
INTRODUCTION
Organic thiocyanates constitute an important class of biologically active compounds.[1]
Additionally, these compounds are useful precursors for the synthesis of thiols, sulfides,
disulfides, thioesters, thiocarbamates, and sulfur heterocycles.[2] Therefore, efficient
incorporation of the thiocyano group into organic molecules has drawn much attention.
Recently, difunctionalization has become a powerful tool in modern synthetic chemistry.[3]
1

In particular, catalytic difunctionalization is strongly appealing because it enables the
introduction of both thiocyano group and other functional groups to organic molecules in
one synthetic operation and provides facile access to complex, densely functionalized
organic thiocyanates.[4] Furthermore, dithiocyanate derivatives are found to exhibit good
fungicidal activity.[5] Thus, the simple and direct dithiocyanation of alkenes is of great
importance. However, few examples of this dithiocyanation of alkenes have been
reported. Conventional methods for synthesizing dithiocyanate derivatives[6] include the
following (Scheme 1): (1) using PhI(OAc)2/TMSCNS or KSCN reagent combination;[6a,b]
(2) Cerium (IV) ammonium nitrate (CAN) mediated thiocyanation of styrenes;[6c] (3)
FeCl3-promoted thiocyanation of styrenes.[6]d] However, many of these methods often
involve the use of stoichiometric amount of metal or expensive reagents and the
formation of mixture of products resulting in low yields of dithiocyanates. In addition,
some of them demand additives especially for the thiocyanation of electron-deficient
styrenes. Hence, the development of new methods for synthesizing dithiocyanate
derivatives from readily available materials is highly desired. Herein, we report a novel
copper-catalyzed intermolecular dithiocyanation of alkenes to give a variety of vicinal
dithiocyanate derivatives. To the best of our knowledge, an example of Cu-catalyzed
dithiocyanation of styrenes with ammonium thiocyanate has not been reported until this
work.
RESULTS AND DISCUSSION
2

At the outset of our investigation, styrene 1a and ammonium thiocyanate 2 were selected
as the model substrates to optimize the reaction conditions including catalysts, oxidants,
solvents and reaction temperature under air (1 atm). The results are summarized in Table
1. Various copper catalysts were tested (0.10 equiv) with 2 equiv of selectfluor as a
oxidant and CH2Cl2 as a solvent at 90 oC for 3 h (Table 1, entries 1-5). Among the various
copper catalysts used, CuBr provided the expected product with high yield (Table 1, entry
5). Encouraged by this result, we surveyed other oxidants, such as K2S2O8, TBHP, and
H2O2, and the results demonstrated that this reaction proceeded most efficiently when
selectfluor served as the oxidant (Table 1, entry 5-8). Acetonitrile and 1,2-dichloroethane
(DCE) were effective to provide 3b in 61% and 65% yield, respectively(Table 1, entries 9
and 10). Furthermore, the reaction in the absence of CuBr or selectfluor did not work
(Table 1, entries 11 and 12). The best yield of 3a (81%; entry 5) was obtained at 90 °C,
whereas at higher temperatures no appreciable increase in yield was obtained. On the
contrary, the use of temperatures below 90 °C reduced the reactivity and conversion
(Table 1, entries 13 and 14). In addition, Other commercially available SCN sources such
as NaSCN and KSCN could also afford the desired product 3a, but in lower yields
(entries 15 and 16).
With the optimized reaction conditions in hand, the substrate scope of this transformation
was investigated. As described in Table 2, styrenes 1 with different substituents on the
aromatic ring, including electron-donating and electron-withdrawing groups, can be
3

transformed into the corresponding products 3 in moderate to excellent yields. No
obvious electronic effect on the phenyl ring of styrenes was observed. Halo-substituted
styrenes (1c-j) were tolerated in the dithiocyanation reaction, and could be very useful for
further transformations. In addition, the cyclic alkene substrates were studied, and we are
delighted to find that the desired product 3s could be synthesized efficiently in 58% yield.
Furthermore, the SCN group of the product 3a could be readily converted to
SCF3-substituted product 4 in the presence of TMSCF3 and Cs2CO3 (eq. 1), thus
demonstrating the synthetic utility of the dithiocyanate products.
A preliminary mechanism investigation suggested that the reaction probably involved a
thiocyanate radical (Scheme 2). When radical scavengers, such as TEMPO and BHT
were added to the reaction of 1-bromo-2-vinylbenzene 1d under the optimal condition,
the yields of 3d were decreased dramatically. Additionally, the radical intermediate was
trapped by a radical scavenger, TEMPO (2,2,6,6-tetra-methylpiperidine-N-oxyl), and the
TEMPO-captured product was isolated in 60% yield. The results indicates that the
reaction probably proceeded via a free radical process.
4

Although the mechanistic details of this transformation are not very clear at the moment,
based on the experimental results and literature precedent,[6] a plausible mechanism was
proposed in Scheme 3. Initially, the oxidation of thiocyanate anion by selectfluor in the
presence of CuBr generates an electrophilic thiocyanate radical I.[6,7] Subsequent radical
addition of I to styrene 1a produces carbon-centered radical II, which was further
oxidized to the corresponding carbocation III by Cu(II).[8] Finally, the nucleophilic
reaction of thiocyanate anion with the carbocation III forms the desired product 3a.
CONCLUSION
In conclusion, a novel Cu-catalyzed intermolecular chemoselectivity dithiocyanation of
styrenes with ammonium thiocyanate has been developed for the synthesis of
dithiocyanates.[9] The readily available starting reagents, low loading of the copper
catalyst, and broad substrate scope are the characteristic features of this protocol.
Importantly, the SCN group in the products could be easily converted into various
functional groups, which would make these products more useful in organic synthesis.
Investigation of the detailed mechanism and application of this methodology for a broad
range of difunctionalization reactions of alkenes are underway in our laboratory.
EXPERIMENTAL
General Procedure For The Preparation Of 3:
5

To a solution of the styrene 1a (31.2 mg, 0.3 mmol) in CH2Cl2 (3.0 ml) was added the
NH4SCN 2 (45.7 mg, 0.6 mmol), Selectfluor(212.6 mg, 0.6 mmol), and CuBr (4.3 mg,
0.03 mmol) in a sealed tube. The sealed tube was then tightly sealed with a screw cap and
the reaction was stirred for the 3.0 h at 90 oC. After the reaction finished, the reaction
mixture was cooled to room temperature. The mixture was extracted with CH2Cl2 (3 ×
5.0 mL), the combined organic phases were dried over anhydrous Na2SO4 and the solvent
was evaporated under vacuum. The residue was purified by column chromatography to
give the corresponding products 3a (53.5 mg, 81%).
(1,2-Dithiocyanatoethyl)Benzene 3a
White solid. mp: 104-106 oC [1]H NMR (400 MHz; CDCl3): δ = 3.63 (dd, J1 = 9.6 Hz, J2
= 13.6 Hz, 1H), 3.78 (dd, J1 = 6.0 Hz, J2 = 13.6 Hz, 1H), 4.65 (dd, J1 = 6.0 Hz, J2 = 9.6 Hz,
1H), 7.36-7.39 (m, 2H), 7.44-7.47 (m, 3H); [1][3]C NMR (100 MHz, CDCl3): δ = 38.3,
51.5, 109.7, 110.1, 127.5, 129.7, 130.3, 134.1. HRMS (ESI-TOF) Calcd for C10H9N2S2,
[M+H]+ m/z 221.0207; Found 221.0216.
1-(1-(2-Bromophenyl)-2-Thiocyanatoethoxy)-2,2,6,6-Tetramethylpiperidine 4
Yellow oil. 1H NMR (400 MHz; CDCl3): δ = 0.88 (s, 3H), 1.06 (s, 3H), 1.20 (s, 3H), 1.34
(s, 4H), 1.46 (m, 2H), 1.53 (s, 3H), 3.58 (dd, J1 = 3.6 Hz, J2 = 13.2 Hz, 1H), 3.70 (dd, J1 =
6.0 Hz, J2 = 12.8 Hz, 1H), 5.54 (dd, J1 = 3.6 Hz, J2 = 6.0 Hz, 1H), 7.21 (dt, J1 = 1.6 Hz, J2
= 7.6 Hz, 1H), 7.37-7.41 (m, 1H), 7.55-7.57 (m, 2H); 13C NMR (100 MHz, CDCl3): δ =
6

16.9, 20.4, 33.2, 34.2, 39.1, 40.3, 59.8, 60.7, 82.7, 112.4, 122.3, 127.4, 129.3, 129.5,
132.7, 138.9. HRMS (ESI-TOF) Calcd for C18H26BrN2OS, [M+H]+ m/z 397.0949; Found
397.0955.
FUNDING
We gratefully acknowledge the Foundation of Henan Educational Committee
(15A150029) and the Science & Technology Foundation of Henan Province for financial
support.
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9

Table 1. Optimization of the reaction
conditions.a
Entry
Catalyst
CuSO4
Cu(OAc)2
CuCl
CuI
Oxidant
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
DCE
T (oC)
90
Yield(%)b
20
1
selectfluor
selectfluor
selectfluor
selectfluor
selectfluor
TBHPc
2
90
27
3
90
30
4
90
76
5
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
-
90
81
6
90
trace
0
7
Na2S2O8
90
d
8
H2O2
90
0
9
selectfluor
selectfluor
selectfluor
-
90
61
10
11
12
13
14
15
16
90
65
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
90
trace
0
CuBr
CuBr
CuBr
CuBr
CuBr
90
selectfluor
selectfluor
selectfluor
selectfluor
120
60
78
trace
56e
52f
90
90
a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), oxidant (0.6 mmol), catalysts (0.03
mmol), solvent (3.0 mL), 3 h.
10

b Yield of the isolated product.
c TBHP (70% in water).
d H2O2 30% in water.
e NaSCN was used.
f KSCN was used.
11

Table 2. Substrate scope of the styrenes
a Standard reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), Selectfluor (0.6 mmol),
CuBr(0.03 mmol), CH2Cl2 (3.0 mL), 90 oC, 3 h.
b Yield of the isolated products.
12

Scheme 1. Dithiocyanation of alkenes.
13

Scheme 2. Preliminary mechanism studies.
14

Scheme 3. Proposed mechanism.
15