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Angewandte
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Table 1: Catalyst screening.[a]
Entry
Catalyst
Yield [%][b]
Remaining 2a [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Pd(OAc)2
[Pd(dba)2]
CuII
0
0
0
0
42/40[c]
36
32
37
7
45
30
45
21
9
CuIBr
Scheme 2. Classical and new routes to isothioureas.
CuICl
CuIBr·(CH3)2S
CuIOAc
CuI2S
process.[14a] Isocyanides are readily obtained from amines by
formylation and dehydration with a variety of dehydrating
agents.[15,16] Isocyanides have been widely studied and have
emerged as highly useful C1 building blocks in modern
organic chemistry.[16,17] Owing to their unique nature, isocya-
nides can react with electrophiles, nucleophiles, and radi-
cals.[16] They can also insert into metal–carbon and metal–
heteroatom bonds in transition-metal-catalyzed reac-
tions.[18–20] A reaction between isocyanides and thiosulfonates,
however, has not been reported previously.
20
0
21
21
60
36
32
63
72
39
42
51
63
30
48
54
54
42
36
CuI2O
(CuIOTf)2·toluene
CuIICl2
24
39
37
21
0
18
28
32
20
34
33
32
29
27
15
CuIIBr2
CuIIOTf2
Ag(OTf)
ZnCl2
Sc(OTf)3
In(OTf)3
GaCl3
AlCl3
The synthesis of N-tert-butyl-S-methyl-N’-phenyliso-
thiourea (4a) from the commercial reactants aniline (1a), S-
methyl methanethiosulfonate (2a), and tert-butyl isocyanide
(3a) was chosen as the test system for optimization studies.[21]
Avariety of Pd and Cu species were tested (Table 1, entries 1–
13). CuI was found to be the best catalyst, and the addition of
a base was found to inhibit the reaction (see Table S2 in the
Supporting Information). The choice of an appropriate
sulfenylating reagent is essential for the desired coupling, as
dimethyl disulfide did not give 4a (see Scheme S1 in the
Supporting Information). Pleasingly, the reaction proceeds
smoothly under air and does not require an inert atmosphere.
A catalyst loading of 1 mol% was sufficient at a reaction
temperature of 758C (see Table S1). The reaction tolerates
a wide range of solvents (see Table S4); renewable 2-
methyltetrahydrofuran (2-MeTHF) was chosen with respect
to the overall sustainability of the process. Serendipitously, we
discovered that the yield of 4a can be further improved by the
addition of 4 ꢀ molecular sieves (MS) to the reaction mixture
(Table 2, entry 1).
The scope of the reaction was investigated under the
optimal conditions (1a (1.7 mmol), 2a (1.0 mmol), 3a
(2.5 mmol), CuI (1 mol%), 4 ꢀ MS (300 mg), 2-MeTHF
(2.5 mL), 758C, 20 h, air; Table 2). Anilines bearing electron-
donating and weakly electron-withdrawing substituents were
tolerated well, and the corresponding isothioureas were
obtained in high yields (Table 2, entries 2–6 and 12–15).
When MS were omitted, substantially lower yields were
observed. The difference is remarkable for the electron-rich
substrates 4-methoxy- and 2-methylthioaniline. The corre-
sponding isothioureas 4l and 4o were obtained in only 18 and
38% yield, respectively, without MS (Table 2, entries 12 and
15). Good yields were observed for anilines bearing moder-
ately electron-withdrawing substituents (Table 2, entries 7
and 8). When very strongly electron-withdrawing groups were
present (3-NO2, 4-NO2, 4-CN), a lower yield was observed,
FeBr3 (98%)
FeCl2 (99.999%)
BF3·OEt2
B(C6F5)3
–
[a] Reaction conditions: aniline (1a, 1 mmol), S-methyl methanethio-
sulfonate (2a, 1 mmol), tert-butyl isocyanide (3a, 1 mmol), catalyst
(5 mol%), 2-MeTHF (5 mL), 758C, 20 h, Ar. [b] The yield was determined
by 1H NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal
standard. [c] Yield of the isolated product.
and in this case the addition of MS did not influence the yield
(Table 2, entries 9–11). This result motivated us to further
study the reaction conditions for these specific substrates.
Pleasingly, the yield of 4i–k could be improved by using more
of the catalyst (2.5 mol%) and more 3a (3.3 equiv; Table 2,
entries 9–11). Secondary anilines can also be used, as
exemplified by N-methylaniline (1p; Table 2, entry 16). The
developed reaction can be extended to challenging hetero-
aromatic amines of the azole and azine type (Table 2,
entries 18–23). Interestingly, cyanamide could also be used
as a substrate (Table 2, entry 17).
Next, the scope of the reaction with respect to the
isocyanide reagent was investigated with 1a or 1b and 2a as
coupling partners (Table 3). After all, reactions of isocyanides
under transition-metal/Lewis acid catalysis are often limited
to tertiary isocyanides.[18] Gratifyingly, our method also
tolerates primary and secondary isocyanides to yield the
desired isothioureas in moderate to high yield. With isopropyl
isocyanide (3g), a reduced yield of 5k was observed owing to
the low boiling point of 3g. The yield was improved to 65%
by using a sealed vial (Table 3, entry 11). For pentyl (3b),
benzyl (3 f), and isopropyl isocyanide (3g), the influence of
the electronic nature of the aniline was also investigated. We
found that besides tertiary, also primary and secondary
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 12849 –12854