AlCl3-catalyzed insertion of isocyanides into nitrogen-sulfur bonds of sulfenamides

Article abstract of DOI:10.1016/j.tetlet.2015.01.096

Lewis acid-catalyzed insertion of isocyanides 2 into nitrogen-sulfur bonds of sulfenamides 1 was developed. This method provided a convenient method for the synthesis of isothioureas 3. Among Lewis acids examined, AlCl₃ brought about the best result. Acetic acid assisted one-pot preparation of unsymmetrical ureas was also described.

Full text of DOI:10.1016/j.tetlet.2015.01.096

Tetrahedron Letters 56 (2015) 1531–1534
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Tetrahedron Letters
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AlCl3-catalyzed insertion of isocyanides into nitrogen–sulfur bonds
of sulfenamides
b
a
a
Daisuke Shiro a, Shin-ichi Fujiwara b, , Susumu Tsuda , Takanori Iwasaki , Hitoshi Kuniyasu ,
⇑
Nobuaki Kambe a,
⇑
a Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
b Department of Chemistry, Osaka Dental University, Hirakata, Osaka 573-1121, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Lewis acid-catalyzed insertion of isocyanides 2 into nitrogen–sulfur bonds of sulfenamides 1 was devel-
oped. This method provided a convenient method for the synthesis of isothioureas 3. Among Lewis acids
examined, AlCl3 brought about the best result. Acetic acid assisted one-pot preparation of unsymmetrical
ureas was also described.
Received 9 December 2014
Revised 10 January 2015
Accepted 14 January 2015
Available online 7 February 2015
Ó 2015 Published by Elsevier Ltd.
Keywords:
Insertion
Sulfenamide
Isocyanide
Isothiourea
Lewis acid
Pd(PPh3)4
Introduction
(5 mol%)
O
(1)
(2)
+
R2NSAr
R2NSAr
CO
ArS NR2
pyridine
80 °C, 10 h
Sulfenamides, R2NSR0, are synthetically interesting and impor-
tant compounds due to their wide availability1,2 and the unique
reactivity of the N–S bond.1 Sulfenamides have been utilized as
aminating reagents3 and sulfenyating reagents4 in addition to as
aminyl radical precursors5 and catalysts for the oxidation of alco-
hols.6 Furthermore, unsaturated molecules such as carbon monox-
ide and alkynes can be inserted into the N–S bond of sulfenamides.
For example, Kurosawa and co-workers revealed for the first time
in 1999 that the reaction of sulfenamides with carbon monoxide
was catalyzed by Pd(PPh3)4 in pyridine to provide thiocarbamates
in high yields (Scheme 1, Eq. 1).7,8 Mitsudo and co-workers dis-
closed that the reaction of sulfenamides with alkynes was cat-
alyzed by [RuCl2(CO)2]2 in DMF to provide the corresponding
adducts with high regio- and stereoselectivity (Scheme 1, Eq.
2).9–13
20 kg/cm2
[RuCl2(CO)2]2
(5 mol%)
ArS
NR2
R1
2 equiv
R2
+
R1 R2
DMF
40 °C, 6 h
Scheme 1. Insertion of CO and alkynes into sulfenamides.
AlCl3 (30 mol%)
NR'
Et2N SAr
3
R2NSAr
+
R'NC
toluene
80 °C, 2 h
2
1
Scheme 2. AlCl3-catalyzed syntheses of isothioureas from isocyanides and
sulfenamides.
Here we wish to report that AlCl3 catalyzes insertion of iso-
cyanides 2 into N–S bonds of sulfenamides 1 giving rise to the for-
mation of isothioureas 3 (Scheme 2).
Results and discussions
It was reported that thiophthalimides reacted with isocyanides
without a catalyst in refluxing acetonitrile to give insertion prod-
ucts.14 However, when we heated a mixture of S-phenyl-N,N-di-
ethylsulfenamide 1a and 2,6-xylyl isocyanide 2a in acetonitrile
⇑
Corresponding authors. Tel.:+81 72 8643022; fax: +81 72 8643122 (S.F.); tel.:
+81 6 68797388; fax: +81 6 68797391 (N.K.).
E-mail addresses: fujiwara@cc.osaka-dent.ac.jp (S.-i. Fujiwara), kambe@chem.
eng.osaka-u.ac.jp (N. Kambe).
http://dx.doi.org/10.1016/j.tetlet.2015.01.096
0040-4039/Ó 2015 Published by Elsevier Ltd.

1532
D. Shiro et al. / Tetrahedron Letters 56 (2015) 1531–1534
Table 2
Pd(PPh3)4
(5 mol%)
AlCl3-catalyzed reaction of isocyanides with sulfenamides leading to isothioureas
NXy
O
+
+
Et2NSPh
XyNC
AlCl3 (30 mol%)
NR'
R2N SAr
3
Et2N SPh
Et2N NHXy
pyridine
80 °C, 14 h
R2N SAr
1
R'NC
+
toluene
80°C, 2 h
1a
2a
3a, n.d.
4a, 3%
2
Xy = 2,6-dimethylphenyl
run
1
isocyanide
isothiourea
yielda
79%
sulfenamide
Scheme 3. Reaction of
Pd(PPh3)4.
a
sulfenamide with an isocyanide in the presence of
NXy
SPh
NSPh
XyNC
N
GaCl3 or
TiCl4 (10mol%)
NAr
SEt
SEt
1b
2a
3b
NXy
EtS
R R
+
ArNC
R
SEt
toluene
R
30 °C, 2 h
2a
2a
N
2
NSPh
SPh
69%
70%
78%
47%
93%
35%
Ar = 2,6-dichlorophenyl
1c
3c
Scheme 4. Lewis acid-catalyzed insertion of isocyanides to
dithioacetals.
a
C–S bond of
NXy
Et2NSp-tol
3
Et2N Sp-tol
Table 1
Screening of Lewis acids
1d
3d
Lewis acid
NDipp
(10 mol%)
4b
5c
6
Et2NSPh
DippNC
NXy
O
Et2N SPh
Et2NSPh
XyNC
+
+
solvent
80 °C, time
Et2N NHXy
Et2N SPh
1a
2b
3e
1a, 2 equiv
2a
3a
4a
NC6H4-p-OMe
yield
run
1
Lewis acid
GaCl3
TiCl4
solvent
DMF
time
24 h
24 h
24 h
1a
p-MeOC6H4NC
3a, %a,b
4a, %a,b
Et2N SPh
2c
3f
72
8
NBn
2
DMF
32
72
50
9
BnNC
Et2N SPh
1a
1a
2d
3g
3
InCl4
DMF
NCy
4
5
AlCl3
ZrCl4
DMF
DMF
24 h
24 h
72
70
2
CyNC
7
Et2N SPh
2e
3h
14
1
2
Conditions: sulfenamide (0.4 mmol), isocyanide (0.4 mmol), AlCl3
(30 mol%), toluene (0.4 mL), 80°C, 2 h. a Isolated yield. b DippNC =
2,6-diisopropylphenylisocyanide. c p-MeOC6H4NC (2 equiv), 5 h.
6
7
8
BBu3
BPh3
DMF
DMF
DMF
24 h
24 h
24 h
58
72
66
9
4
B(C6F5)3
14
14 h, desired isothiourea 3a was not formed and the corresponding
urea 4a, a hydrolyzed product of 3a, was obtained in 3% yield
(Scheme 3). Even after several trials by the use of other metal cat-
alysts such as Rh(PPh3)3Cl the yields of 3a and 4a were not
improved so much.
9
BF3 OEt2
DMF
24 h
72
10
10c
CH3COOH
AlCl3
DMF
DMF
30 h
24 h
24 h
2 h
6
79 (78)
3
Recently, Chatani and co-workers disclosed that isocyanides
reacted with dithioacetals to give insertion products in the pres-
ence of Lewis acids such as GaCl3 and TiCl4 (Scheme 4).15
Then we conducted the reaction of sulfenamide 1a with iso-
cyanide 2a in the presence of Lewis acids and the results are given
in Table 1. When 2,6-xylyl isocyanide 2a (0.4 mmol) was allowed
to react with sulfenamide 1a (2 equiv) in the presence of GaCl3
(10 mol %) in DMF at 80 °C for 24 h, isothiourea 3a was formed in
72% yield (run 1). In this reaction, 8% of urea 4a was also obtained;
however, multiple insertion products incorporating more than one
isocyanide molecules were not detected. In the case of TiCl4, urea
4a became the major product (run 2). InCl3, ZrCl4, and BPh3 exhib-
ited similar activities as GaCl3, and the use of AlCl3 gave the best
selectivity (runs 3–9). Interestingly, when 1 equiv of acetic acid
was employed as an additive, urea 4a was formed in 79% yield
(run 10). Since 13% of isocyanide 2a remained unreacted in run
4, we used 30 mol % of AlCl3 but the yield of 3a was improved only
11d
12d
13d,e
75
AlCl3
toluene
toluene
81
n.d.
AlCl3
80 (77)
n.d.
Conditions:2a (0.4 mmol), 1a (2 equiv),Lewis acid (1 equiv), solvent(0.4
mL). a NMR yields.b Isolated yield in parentheses. cCH3COOH (1 equiv).
d AlCl3 (30 mol%).e 1a (1 equiv).
under similar conditions, insertion reaction did not proceed at all.
Then we examined the palladium catalyzed system developed for
azathiolation of carbon monoxide shown in Scheme 1. When a pyr-
idine (0.4 mL) solution of sulfenamide 1a (0.4 mmol), isocyanide
2a (0.4 mmol), and Pd(PPh3)4 (5 mol %) was heated at 80 °C for

D. Shiro et al. / Tetrahedron Letters 56 (2015) 1531–1534
1533
preparative TLC. So the isolation was performed by recycling pre-
parative HPLC.
R'NC
2
AlCl3
R2N SPh
AlCl3
R'N
C
SPh
+
AlCl3
R2N
R2N SPh
The reaction pathway for the present AlCl3-catalyzed insertion
of isocyanides into sulfenamides is not clear yet but a possible
pathway was depicted in Scheme 5. The N–S bond in sulfenamide
1 is activated by the coordination of AlCl3 to the nitrogen atom
generating A. Then isocyanide 2 attacks the sulfur atom of the
intermediate A to generate an ion pair B and C which then react
with each other to afford isothiourea 3.
Isothioureas are useful and interesting compounds as inhibitors
of nitric oxide synthases (NOS)18 and Lewis base organocatalysts.19
As for the synthesis of isothioureas, they have been usually pre-
pared by the alkylation of isolated or in situ generated thioureas.20
Our method described here is synthetically useful since various
isothioureas are obtained by a convenient one-pot procedure from
easily available substrates.
1
B
C
)
(
)
(
(A)
AlCl3
NR'
R2N SPh
3
Scheme 5. A possible reaction pathway.
slightly (runs 4 and 11). Use of toluene as the solvent retarded the
formation of urea 4a (run 12). Isothiourea 3a was obtained in good
yields when the amount of sulfenamide 1a was reduced to 1 equiv
and the reaction time was shortened to 2 h (run 13).16,17
Finally, we undertook a one-pot synthesis of unsymmetrical
ureas 4 under the reaction conditions employed in run 10 in
Table 2,21 and the results are summarized in Table 3. In all runs
unsymmetrical ureas 4 were obtained in moderate to high yields.22
Table
2 summarizes the results obtained using several
sulfenamides 1 and isocyanides 2 under the optimized reaction
conditions (run 13 in Table 1). 2,6-Xylyl isocyanide 2a was also
inserted into sulfenamides 1b, 1c, and 1d affording the correspond-
ing isothioureas 3b, 3c, and 3d in 79%, 69%, and 70% yields,
respectively (runs 1–3). The reaction of sterically hindered 2,6-
diisopropylphenyl isocyanide 2b gave isothiourea 3e in 78% yield
(run 4). Insertion of p-methoxyphenyl isocyanide 2c was inefficient
and 3f was formed in 47% yield even when the reaction was run
using 2 equiv of 2c for prolonged reaction time (5 h) (run 5).
Aliphatic isocyanides could also be employed as suitable reagents.
For example, the reaction of benzyl isocyanide 2d with sulfenamide
1a afforded the corresponding product 3g in 93% yield (run 6).
However, the desired product 3h was obtained in a low yield
(35%) when cyclohexyl isocyanide 2e was employed (run 7). These
isothioureas 3g and 3h, obtained from aliphatic isocyanides, were
labile and easily hydrolyzed to ureas during purification by
Conclusions
We have developed a simple and convenient reaction for the
synthesis of isothioureas by Lewis acid-catalyzed insertion of
isocyanides into the N–S bond of sulfenamides. Since only a few
classical preparative methods of isothioureas are available, the
present new approach would attract considerable attention as a
practical supplemental method for isothiourea synthesis.
Acknowledgment
D.S. expresses his special thanks to the JSPS Japanese-German
Graduate Externship Program on ‘Environmentally Benign Bio-
and Chemical Processes’, Japan, for financial support for the stay
in RWTH Aachen.
Table 3
Acetic acid-assisted preparation of unsymmetrical ureas from isocyanides and
sulfenamides
Supplementary data
CH3COOH
(1 equiv)
O
Supplementary data (characterization data of new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.01.096.
R2NSPh
1,
R'NC
DMF (0.4 mL)
80 °C, 30 h
R2N NHR'
2 equiv
2
4
run
1
isocyanide
urea
yielda
77%
References and notes
sulfenamide
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V. Russ. Chem. Rev. 1996, 65, 421.
2. (a) Barton, D. H. R.; Hesse, R. H.; O’Sullivan, A. C.; Pechet, M. M. J. Org. Chem.
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Bialecki, M. J. Org. Chem. 1992, 57, 4784; (c) Makosza, M.; Bialecki, M. J. Org.
Chem. 1998, 63, 4878.
4. (a) See Ref. 3a.; (b) Foray, G.; Peñéñory, A. B.; Rossi, R. A. Tetrahedron Lett. 1997,
38, 2035; (c) Zyk, N. V.; Beloglazkina, E. K.; Belova, M. A. Russ. Chem. Bull. Int. Ed.
2000, 49, 180; (d) Sobhani, S.; Fielenbach, D.; Marigo, M.; Wabnitz, T. C.;
Jørgensen, K. A. Chem. Eur. J. 2005, 11, 5689.
O
XyNC
NSPh
N
NHXy
4b
1b
2a
O
NSPh
2a
81%
2
N
NHXy
1c
4c
5. (a) Bowman, W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron Lett. 1991, 32, 6441;
(b) Bowman, W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron Lett. 1992, 33, 4993;
(c) Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1993, 34, 6877; (d) Bowman, W.
R.; Clark, D. N.; Marmon, R. J. Tetrahedron 1994, 50, 1275; (e) Barbieri, A.;
Montevecchi, P. C.; Nanni, D.; Navacchia, M. L. Tetrahedron 1996, 52, 13255; (f)
Maxwell, B. J.; Tsanaktsidis, J. J. Am. Chem. Soc. 1996, 118, 4276.
6. Matsuo, J.; Iida, D.; Yamanaka, H.; Mukaiyama, T. Tetrahedron 2003, 59, 6739.
7. Kuniyasu, H.; Hiraike, H.; Morita, M.; Tanaka, A.; Sugoh, K.; Kurosawa, H. J. Org.
Chem. 1999, 64, 7305.
O
3
4
Et2NSPh
DippNC
72%
50%
Et2N NHDipp
1a
2b
4d
O
1a
p-MeOC6H4NC
Et2N NHC6H4-p-OMe
8. For Pd-catalyzed insertion of carbon monoxide into cyclic sulfenamides:
Rescourio, G.; Alper, H. J. Org. Chem. 2008, 73, 1612.
2c
4e
9. Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T. Tetrahedron Lett. 2004, 45, 1469.
10. Phoshorous (V) oxohalide assisted insertion of sulfenamides into alkynes: Zyk,
N. V.; Beloglazkina, E. K.; Belova, M. A.; Zefirov, N. S. Russ. Chem. Bull. Int. Ed.
2000, 49, 1846.
1
2
Conditions:sulfenamide (0.8 mmol), isocyanide (0.4 mmol),
CH3COOH (0.4 mmol), DMF (0.4 mL), 80 °C, 30 h. a Isolated yield.
b DippNC= 2,6-diisopropylphenylisocyanide.

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D. Shiro et al. / Tetrahedron Letters 56 (2015) 1531–1534
11. For the related insertion of alkynes into cyclic sulfenamides: (a) Spitz, C.;
Lohier, J.-F.; Santos, J. S.-D. O.; Reboul, V.; Metzner, P. J. Org. Chem. 2009, 74,
3936; (b) Spitz, C.; Lohier, J.-F.; Reboul, V.; Metzner, P. Org. Lett. 2009, 11, 2776;
(c) Spitz, C.; Reboul, V.; Metzner, P. Tetrahedron Lett. 2011, 52, 6321.
18. (a) Garvey, E. P.; Oplinger, J. A.; Tanoury, G. J.; Sherman, P. A.; Fowler, M.;
Marshall, S.; Harmon, M. F.; Paith, J. E.; Furfine, E. S. J. Biol. Chem. 1994, 269,
26669; (b) Southan, G. J.; Szabó, C.; Thiemermann, C. Br. J. Pharmacol. 1995,
114, 510.
12. For the reaction of sulfenamides with
a
-diazocarbonyl compounds: Li, Y.; Shi,
19. For recent reviews, see: (a) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc.
Rev. 2012, 41, 2109; (b) Candish, L.; Nakano, Y.; Lupton, D. W. Synthesis 2014,
1823.
20. (a) Sprague, J. M.; Johnson, T. B. J. Am. Chem. Soc. 1937, 59, 1837; (b) Sandin, H.;
Swanstein, M.-L.; Wellner, E. J. Org. Chem. 2004, 69, 1571; (c) Lange, J. H. M.;
Verhoog, S.; Sanders, H. J.; van Loevezijn, A.; Kruse, C. G. Tetrahedron Lett. 2011,
52, 3198.
21. Typical procedure: Into a 5-mL flask equipped with a reflux condenser were
placed 2,6-xylyl isocyanide 2a (0.4 mmol), sulfenamide 1a (0.8 mmol), DMF
(0.4 mL), and acetic acid (0.4 mmol) at room temperature under N2. The
mixture was heated at 80 °C for 30 h, then filtered through the celite pad with
AcOEt, and volatiles were removed in vacuo. After the yield was determined by
1H NMR (79%), the crude product was purified by preparative TLC (silica gel,
hexane/Et2O = 10:1, Rf = 0.10) to obtain 3-(2,6-dimethylphenyl)-1,1-
diethylurea 4a in 78% yield as a white needle.
Y.; Huang, Z.; Wu, X.; Xu, P.; Wang, J.; Zhang, Y. Org. Lett. 2011, 13, 1210.
13. For Pd-catalyzed four component coupling of sulfenamides, carbon monoxide,
alkynes, and diselenides: (a) Knapton, D. J.; Meyer, T. Y. Org. Lett. 2004, 6, 687;
(b) Knapton, D. J.; Meyer, T. Y. J. Org. Chem. 2005, 70, 785.
14. Chupp, J. P.; D’Amico, J. J.; Leschinsky, K. L. J. Org. Chem. 1978, 43, 3553.
15. Tobisu, M.; Ito, S.; Kitajima, A.; Chatani, N. Org. Lett. 2008, 10, 5223.
16. Typical procedure: Into a 5-mL flask equipped with a reflux condenser were
placed 2,6-xylyl isocyanide 2a (0.4 mmol), sulfenamide 1a (0.4 mmol), toluene
(0.4 mL), and AlCl3 (0.12 mmol) at room temperature under N2. The mixture
was heated at 80 °C for 2 h, then filtered through the celite pad with AcOEt, and
volatiles were removed in vacuo. After the yield was determined by 1H NMR
(80%), the crude product was purified by preparative TLC (silica gel, hexane/
Et2O = 10:1, Rf = 0.60) to obtain phenyl N0-(2,6-dimethylphenyl)-N,N-
diethylcarbamimidothioate 3a in 77% yield as a colorless oil.
17. According to a reviewer’s suggestion, the reaction of 2 equiv of sulfenamide 1a
with isocyanide 2a was carried out in toluene in the presence of 10 mol % of
AlCl3 at 80 °C for 24 h, a similar result as in runs 12 and 13 was also obtained.
22. Since the formation of unsymmetrical ureas was confirmed in the reaction
mixture before purification, the oxygen source would be water contaminated
in DMF.