2
Tetrahedron
Introduction
without phase transfer reagent to give the product 2a in 61%
yield (Table 1, entry 1). Then we decreased the 1a to 3 equiv, the
yield was dropped slightly (Table 1, entry 2). When 1.5 equiv 1a
was used, the yield dramatically decreased to 44% (Table 1, entry
3). Balancing the yield and cost, we decided to use 3 equiv 1a to
further screen the reaction conditions. When a phase-transfer
reagent, 18-crown-6, was used, the yield of 2a increased
significantly in the mixed phase of the organic phase and aqueous
phase (Table 1, entry 4). Phase transfer reagent was demonstrated
to promote the reaction by increasing the nucleophilicity of the
potassium thiocyanate clearly.9 The reaction could be conducted
in CHCl3 with similar yield (Table 1, entry 5). The reaction failed
to occur in DMF or DMSO may due to the polarity issues (Table
1, entries 6 and 7). The catalytic amount of 18-crown-6 showed
limited effect to promote this reaction (Table 1, entry 8). Other
phase-transfer reagent, such as quaternary ammonium salt TBAB,
was demonstrated to be ineffective in the transformation (Table 1,
entry 9).
Organosulfur compounds widely exist in our daily life. They
are ubiquitous present in the natural products and drug
structures.1 As an important sulfur-containing group, thiocyano
groups own various bioactivities, such as antiparasitic
compounds, HDAC inhibitor psammaplin B, and fasicularin,2
which are widely used in organic synthesis. In addition, the
cyano group in -SCN could also be considered as both protecting
group and leaving group, just like a mask for the synthesis of
diverse organosulfur compounds.3 Thiocyano groups not only
avoid the disadvantages in odors and toxicities for traditional
organic sulfur compounds, but also easily convert to other
organosulfurs such as thioethers, disulfides, thiophosphonates,
and thiocarbamates.4
Therefore, the above advantages make thiocyano groups
attract more and more attention of organic and medicinal
chemists in recent years. However, the methodologies for the
synthesis of thiocyanates, especially for the alkynylthiocyanates,
are still very limited. Heteroatom-substituted internal alkynes
could be used as important precursors in the synthesis of natural
products and drugs.5 In previous studies, alkynyl iodonium
triflates were prepared firstly and then reacted with potassium
thiocyanate in DMF to provide alkynylthiocyanates in two steps
(Scheme 1a).6 Tedious manipulations were required in work-up
process. Although several modifications are developed later, it is
still not satisfactory to afford alkynylthiocyanates efficiently.7
Table 1. Optimization of the reaction conditionsa.
OTs
I
Ph
OH
Ph
KSCN, Catalyst
Ph
I
Ph
SCN
2a
Ph
OTs
Organic phase:H2O
CHCl3
1a
Alkyne
equivalent
6
3
1.5
3
3
3
3
Organic
phase
DCM
DCM
DCM
DCM
CHCl3
DMF
Entry
Reagent
Yield(%)b
1
2
3
4
5
6
7
8c
9
-
-
-
61
58
44
80
74
NR
NR
61
42
Recently,
Zhao’s
group
reported
a
Ag-catalyzed
thiocyanofunctionalization of terminal alkynes to access
alkynylthiocyanates (Scheme 1b).8 This methodology has several
advantages including broad substrate scope and high yields, but it
requires precious metal silver as a catalyst. Therefore, it is still
highly desired to develop a new and convenient method for the
synthesis of alkynylthiocyanates. Herein, we disclose a one-pot
synthesis of alkynylthiocyanates from terminal alkynes,
[hydroxy(tosyloxy)iodo]benzene and potassium thiocyanate by
phase-transfer reagent involving the hypervalent iodine
intermediates in transition metal-free conditions (Scheme 1c).
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
TBAB
DMSO
DCM
DCM
3
3
aThe reaction conditions: [Hydroxy(tosyloxy)iodo]benzene (1 mmol), 1-
phenylethyne 1a (3 mmol) in chloroform (1 mL) heated to reflux for 20
minutes, then diluting the mixture with organic solvent (15 mL). An aqueous
solution of potassium thiocyanate (1 mmol in 15 mL H2O) and phase-transfer
reagent (1 mmol) were added to the mixture and stirred at room temperature
for 12 h.
bIsolated yield based on [hydroxy(tosyloxy)iodo]benzene.
c10 mol% 18-crowns-6 was used.
The Previous work
R
I
DMF
(a)
(b)
R
SCN
OTf
KSCN
+
With the optimized conditions in hand, we explored the
substrate scope of the synthesis of alkynylthiocyanates from
terminal alkynes, [hydroxy(tosyloxy)iodo]benzene and potassium
thiocyanate in “one-pot” manner. Various terminal alkynes were
used as substrates without inert gas protection. The
alkynylthiocyanates could be acquired in good yields (up to 80%)
(Table 2). For the para-substituted phenylethynes, good yields
were generally obtained (Table 2, entries 2-6). The obvious
electronic effect was observed. If the para-substituted groups
were electron donating groups (such as methyl, ethyl, tert-butyl)
(Table 2, entries 2-4), the yields for 2b, 2c and 2d were much
higher than 2e and 2f which substituted by electron withdrawing
group (such as chloro and bromo) (Table 2, entries 5-6). Good
yield (2g) could be obtained using meta-substituted phenylethyne
as substrates (Table 2, entry 7). The yield (2h) for ortho-
substituted phenylethyne was slightly lower than the para- and
meta-substituted derivatives, which may due to the steric
hindrance effect (Table 2, entry 8). The ortho-substituted
phenylethyne (1h) could be recovered in 32% yield. In addition,
I
OTf
O
O
Ag2O
THF, 65oC
R
SCN
N
SCN
+
R
H
OTs
This work
I
Ph
OH
Ph
KSCN, 18-crown-6
CH2Cl2:H2O=1:1, rt
R
I
R
R
SCN
(c)
OTs
CHCl3, reflux
intermediate in situ
Features:
Access alkynylthiocyanates under transition-metal free conditions
Phase-transfer reagent was used in two phase reaction
Scheme 1. Approaches for the synthesis of alkynylthiocyanates.
Initially, phenylethyne 1a and potassium thiocyanate were
selected as model substrates for the optimal reaction conditions.
Treating 1a with [hydroxy(tosyloxy)iodo]benzene in chloroform
afforded crude alkynyl iodonium intermediate. After diluting the
crude alkynyl iodonium mixture with organic solvent, an aqueous
solution of potassium thiocyanate was added to the mixture and
stirred at room temperature for 12 h. 6 equiv 1a was firstly used
this
method
could
be
extended
to
prepare
heteroalkynylthiocyanates 2i using 3-ethynylthiophene 1i as
substrate (Table 2, entry 9). Unfortunately, the alkyl substituted