Ultrasound irradiation promoted catalyst-free construction of formamidine framework using isocyanide as building blocks

Article abstract of DOI:10.1016/j.tetlet.2011.03.100

Reactions of isocyanides with 2-mercaptobenzothiazole and 2-mercaptobenzoxazole afforded a series of compounds containing formamidine framework in moderate to high yields. These organic transformations were performed under mild and catalyst-free condition

Full text of DOI:10.1016/j.tetlet.2011.03.100

Tetrahedron Letters 52 (2011) 2771–2775
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ultrasound irradiation promoted catalyst-free construction of formamidine
framework using isocyanide as building blocks
⇑
⇑
Tong-Hao Zhu, Xu Zhu, Xiao-Ping Xu , Tao Chen, Shun-Jun Ji
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Reactions of isocyanides with 2-mercaptobenzothiazole and 2-mercaptobenzoxazole afforded a series of
compounds containing formamidine framework in moderate to high yields. These organic transforma-
tions were performed under mild and catalyst-free conditions. In addition to promoting the reactions,
the use of ultrasound irradiation also allowed the process to be carried out under air atmosphere. A pos-
sible reaction mechanism was proposed based on the experimental results.
Received 11 November 2010
Revised 14 March 2011
Accepted 22 March 2011
Available online 30 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanide
Formamidine
Catalyst-free
Ultrasound irradiation
Formamidine, as one of the most important nitrogen-containing
compounds, has attracted more and more research interest since its
synthetic utility was firstly studied by Meyers and Hoeve.1 Later on,
wide application of formamidines in organic synthesis,2 biochemis-
try,3 and coordination chemistry4 had been discovered. It was also a
key motif in many bio-active molecules such as pesticide.5 In view of
the requirement for insightful understanding of the properties and
applications of formamidine derivatives, the synthetic methodology
of which had been another focus of research. Three main methods
established in an early period for the synthesis of formamidines
had been summarized by Du,6 which include combinatorial synthe-
sis of DMF-DMA-primary amine, DMF-dimethyl sulfate-primary
amine, and metathesis between formamidines and secondary
amines. Nevertheless, a highly efficient method with wider general-
ity of substrates for the synthesis of functional molecules with
structural diversity and complexity is still desirable.
Reaction based on the isocyanide building blocks has been dem-
onstrated to be a convenient access to compounds with structural
diversity and complexity since the midst of last century,7 which pro-
moted us to direct our research interest toward isocyanide-based
reaction chemistry. During the course of extending our findings to
the synthesis of heterocycles (Scheme 1, Eq. 1),8 we unexpectedly
found that the reaction of tert-butyl isocyanide, 2-mercaptobenzo-
thiazole, and gem-dicyano olefin generated a formamidine deriva-
tive (Scheme 1, Eq. 2). On the basis of this result, we can see that
the gem-dicyano olefin did not participate in the reaction, which
may be due to the steric hindrance of the olefin acceptor. The
formation of the formamidine framework obviously indicated the
insertion of tert-butyl isocyanide into N–H bond occurred. The
[S@CNC@N(tBu)] backbone in the product is very similar to the b-
ketiminate ligand, and the latter has found significant applications
in coordination chemistry and organometallic catalysis.9 Compared
to the harsh and strong acidic conditions which are often required in
the synthesis of b-ketiminate ligand, the neutral and mild conditions
demonstrated in our case were superior in constructing such scaf-
fold. In view of this, we repeated the reaction without the use of
the gem-dicyano olefin (Scheme 2), the same result was obtained
eventually. Inspired by this interesting result, we focused our atten-
tion on the synthesis of various formamidine derivatives.
Interaction of isocyanide with compound containing active N–H
bond, as an eco-friendly method for the construction of formami-
dine scaffold, has previously been established by Saegusa et al.
via group IB and IIB metal-catalysis.10 However, the use of high cat-
alyst loading (>20 mol %) and elevated reaction temperature made
the procedure less efficient and economical. Chupp’s group firstly
disclosed the reaction of isocyanide with heterocyclic amide/thio-
amide such as benzimidazoline-2-thione under catalyst-free con-
dition.11 However, some limitations such as low to moderate
yields, the complicated workup for each reaction as well as the
requirement of inert gas atmosphere hindered its wide application
in organic synthesis. Based on the limitations from previous contri-
butions as well as the new result we obtained above, herein we de-
scribe an efficient method for the construction of formamidine
scaffold under mild and catalyst-free conditions.
The reaction of tert-butyl isocyanide 2a with 2-mercaptobenzo-
thiazole 1a in the mixture of MeCN and H2O was selected as a tem-
plate for the optimization of reaction conditions. In our earlier
⇑
Corresponding authors. Tel./fax: +86 0512 65880307 (S.-J.J.).
E-mail addresses: xuxp@suda.edu.cn (X.-P. Xu), chemjsj@suda.edu.cn (S.-J. Ji).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.100

2772
T.-H. Zhu et al. / Tetrahedron Letters 52 (2011) 2771–2775
R3
CN
CN
HN
R2
NC
N
R1
S
(Eq. 1)
(Eq. 2)
H
R1
R2
R3 NC
SH
CN
CN
S
S
N
S
N
R2
R
3 = tBu
;
=
N
tBu
Scheme 1.
S
N
Table 2
S
N
S
Substrate scope studya
tBu NC
SH
X
N
X
R1
Ultrasound irradiation
50 oC, MeCN
S
R2 NC
R1
SH
N
1a
2a
3a
tBu
N
N
R2
1
2
Scheme 2.
3
t
X = S, O
R2 = Bu, Cyclohexyl
R1 = H, NO2, OMe 2,6-dimethylphenyl
work, water was found to have an acceleration effect on the syn-
thesis of imino-pyrrolidine-thione.8 However, in the present case,
this positive effect hasn’t been exhibited via a high-throughput
screening. Thus, acetonitrile was used as the sole solvent for the
further study. The influence of solvent-volume on the reaction
was firstly explored. As can be seen from Table 1, under traditional
stirring condition at room temperature, varying the volume of sol-
Entry
Product
Time (h) Yieldb (%) Mp (°C)
S
N
S
1
3a
3b
3c
3d
6
83
73
93
75
105–106
144–146
245–248
N
O
N
S
Table 1
Optimization of reaction conditiona
2
3
4
28
22
22
N
S
S
N
S
tBu NC
SH
N
O2N
S
N
S
N
1a
2a
3a
tBu
N
b
Entry Solvent
Vsol (mL) T (°C)
Reaction conditionc Yieldd (%)
S
N
1
2
3
4
5
6
7
8
CH3CN
1.0
0.5
0.1
1.0
1.0
1.0
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
rt
rt
rt
A
A
A
B
B
C
C
C
C
C
C
C
C
C
C
C
C
C
28
31
33
48
Messy
61
75
83
59
51
77
53
75
73
72
65
70
80
S
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
MeOH
PhMe
CH2Cl2
CHCl3
Et2O
H3CO
115–118
131–133
50
Reflux
50
50
50
50
50
50
50
50
50
50
50
50
50
N
S
N
(131–132)c
S
9
10
11
12
13
14
15
16
17
18
5
6
3e
22
22
76
91
N
THF
O
N
1,4-Dioxane 0.1
CH3NO2
DMF
S
0.1
0.1
3f
105–107
N
a
b
c
All the reactions were performed for 6 h.
Volume of solvent.
A: conventional stirring; B: conventional heating and stirring; C: ultrasonic
irradiation.
d
Isolated yield.

T.-H. Zhu et al. / Tetrahedron Letters 52 (2011) 2771–2775
2773
Table 2 (continued)
Entry
Product
Time (h) Yieldb (%) Mp (°C)
O2N
S
S
N
N
7
3g
22
95
242–244
108–110
S
N
S
H3CO
8
3h
22
12
12
74
85
69
N
S
S
N
151–153
(150–151)
c
9
3i
N
Figure 1. Crystal structure of compound 3b.
vent from 1 to 0.1 mL led to only a little increase of product yield
(entries 1–3). So we tested the reaction at a higher temperature.
We were delighted to find that the desired product 3a could be ob-
tained in 48% yield when the reaction was performed at 50 °C.
However, performing the reaction at even higher temperature
made the reaction messy (entries 4 and 5), which may be due to
the fact that I-MCR is often highly inert atmosphere-dependant
at high temperature.12 Thus, a more efficient procedure that can
be carried out under relatively mild reaction conditions becomes
desirable. With the devolopment of new synthetic technology in
organic chemistry, ultrasound irradiation has been considered as
a clean and efficient technique for organic synthesis during the last
three decades.13 In general, sonication increases reaction rates and
yields without using harsh conditions, and we also have realized a
few organic transformations by using this promising technique.14
Taking these advantages into account, we carried out the above
reaction under ultrasound irradiation condition at 50 °C. As ex-
pected, the template reaction could proceed smoothly to afford
the desired product 3a in 61% yield (entry 6). In addition, it was
found that a decrease of the volume of solvent led to an increase
of product yield to 83% (entries 7 and 8). Morever, it should be
noted that the use of ultrasound irradiation also allowed the tem-
plate reaction to be performed without the protection of inert
atmosphere. The effect of solvent on the reaction was also investi-
gated under ultrasound irradiation condition. As is shown in en-
tries 9–18, the model reaction can proceed well in all the
solvents screened such as alcohol, DMF, and ethers. Among them,
the best result (83% yield, entry 8) was obtained when MeCN
was used as solvent. In the meantime, the addition of other metal
catalyst (ZnCl2 or CuCl) showed no acceleration for the reaction
rate.
O
N
166–167
(167–168)
c
S
10
3j
N
O2N
292–294
(>290)c
S
N
S
11
12
3k
12
12
92
71
N
S
S
N
N
H3CO
3l
158–159
N
N
N
13
3m 16
34
164.1–164.4
S
N
N
After the optimal reaction conditions were established, we con-
tinued to explore the generality of the protocol.15 The outcome was
listed in Table 2. We could clearly see that when 2-mercaptobenzo-
thiazoles with either electron-donating substituent or electron-
withdrawing group were introduced, the reactions also worked
well leading to moderate to high yields of the desired products (en-
tries 3, 4, 7, 8, 11, and 12).
N
14
3n
20
21
211.1–212.0
S
N
N
Compared to 2-mercaptobenzothiazole with methoxy group,
substrate with nitro group exhibited higher reactivity (entries 3,
7, and 11). In addition, 2-mercaptobenzoxazole was proven to be
another type of good candidate for the protocol, showing good
a
Reaction condition: 1 (0.5 mmol), 2 (0.5 mmol), 0.1 (or 0.2 mL) MeCN, ultra-
sonic irradiation at 50 °C.
b
Isolated yield.
See Ref. 9.
c

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T.-H. Zhu et al. / Tetrahedron Letters 52 (2011) 2771–2775
S
S
S
N
S
S
SH
SH
C
N R
N
)))
H
H
R
N
C
N
+
SH
N
S
N
S
S
SH
N
A
Scheme 3.
reactivity which is comparable with 6-methxoy-2-mercaptobenzo-
thiazole (entries 2, 6, and 10). The corresponding products were
isolated in high yield (up to 91%) and the definite structure of 3b
was unanimously confirmed by X-ray single crystal diffraction
(Fig. 1).16
21042007), Nature Science Basic Research of Jiangsu Province for
Higher Education (No. 10KJB150016), and Key Project in Science
&
Technology Innovation Cultivation Program of Soochow
University.
Cyclohexyl isocyanide and 2,6-di-methylphenyl isocyanide were
further employed to study the generality of isocyanide. It was obvi-
ous to find that 2,6-di-methylphenyl isocyanide showed higher
reactivity than cyclohexyl and tert-butyl isocyanides (entries 10–
12), but the isolated yields of final products were similar to the form-
ers. 2-Mercaptobenzimidazole, which has the similar skeleton with
2-mercaptobenzothiazole and 2-mercaptobenzoxazole, was also se-
lected to test the scope of thio-compound. It can be seen 2-mercap-
tobenzimidazole was less reactive than other thio-compounds, only
poor yields of final products could be obtained. Moreover, in the case
of 2,6-di-methylphenyl isocyanide, the reaction could hardly occur
and thus no desired product was isolated. We also unexpectedly
found that 4,5-dihydrothiazole-2-thiol was almost inert in this reac-
tion. It was supposed that the benzene ring may stabilize the in situ
formed intermediate during the reaction process. With this question
in mind, we turned our attention to the reaction mechanism and the
role of ultrasound irradiation played in the reaction. As is known,
isomerization of 2-mercaptobenzothiazole often occurred under ba-
sic conditions,17 leading to the formation of N-centered nucleo-
philes. Whereas, in our cases, N-centered attachment can take
place even without the use of extra base. According to Chupp’s find-
ings,11 an introduction of extra energy, such as heating, can be an
alternative method to promote the isomerization of 2-mercapto-
benzothiazole. Therefore, we propose the mechanism as follows
(Scheme 3): under ultrasonic irradiation condition at 50 °C, 2-mer-
captobenzothiazole was isomerized to N-centered nucleophiles
with hydrogen transfer to another 2-mercaptobenzothiazole mole-
cule, an ion pair species (A) was thus formed. The nitrogen with neg-
ative charge then attacked the isocyanide, the latter further attacked
the hydrogen attached to the nitrogen atom in A. The free 2-mercap-
tobenzothiazole molecule again went into next cycle. On the basis of
above analysis, we believed that the ultrasonic irradiation played an
important role in the formation of N-centered nucleophile while this
may be the rate-determining step in the reaction. Moreover, the use
of ultrasonic irradiation enabled the reaction to proceed smoothly
under mild conditions even without the use of inert atmosphere.
In summary, we disclosed an easy access to the formamidine
framework by direct reactions of isocyanides with compounds con-
taining active N–H bonds. Ultrasound irradiation was demon-
strated to promote the reactions effectively. Moreover, ultrasound
irradiation allowed the organic transformations to be performed
under mild and catalyst-free conditions without the need of inert
atmosphere.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.100.
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Acknowledgments
The work was partially supported by the National Natural
Science Foundation of China (No. 20672079, 20910102041,

T.-H. Zhu et al. / Tetrahedron Letters 52 (2011) 2771–2775
2775
(g) Shen, Z. L.; Ji, S. J.; Wang, S. Y. Tetrahedron 2005, 61, 10552; (h) Zhou, W. J.;
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125.63, 120.69, 116.97, 57.76, 30.26. HR-MS (m/z) calcd for C12H14N2S2 (M+):
250.0598, found: 250.0606.
16. Crystallographic data for the structure of 3b reported in this Letter has been
deposited at the Cambridge Crystallographic Data Centre as supplementary
publication with CCDC No. 787050. Copies of this information may be obtained
free of charge from The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
(e-mail: linstead@ccdc.cam.ac.uk or deposit@ccdc.cam.ac.uk; fax: +44 01223
336033).
15. General experimental procedure. To
a mixture of 2-mercaptobenzothiazole
(0.5 mmol) and tert-butyl isocyanide (0.5 mmol) was added 0.1 mL of
acetonitrile. The reaction mixture was irradiated by ultrasound in an
appropriate time at 50 °C until the thio-compound was completely
consumed (checked by TLC). Then the solvent was evaporated under the
reduced pressure. The residue was purified by flash column chromatography
with ethyl acetate and petroleum ether as eluents to afford pure product 3a.
3-((Tert-butylimino)methyl)benzo[d]thiazole-2(3H)-thione (3a): white solid; mp:
105–106 °C. 1H NMR (400 MHz, CDCl3) d 9.23 (s, 1H –N@CH–NR2), 8.88 (d,
J = 8.5 Hz, 1H-ArH), 7.46–7.37 (m, 2H-ArH), 7.34 (d, J = 7.6 Hz, 1H-ArH), 1.40 (s,
9H –CH3). 13C NMR (75 MHz, CDCl3) d 193.21, 144.47, 140.21, 127.33, 126.48,
Structural parameters for 3b: data collection: Rigaku Mercury CCD area
detector; crystal size: 0.40 Â 0.20 Â 0.15 mm3; C12H14N2OS, Mr = 234.31,
monoclinic, space group
P
21/m, a = 9.5881(17), b = 6.7134(10),
c = 9.7209(17) Å, b = 101.528(4), V = 613.10(18) Å3, Z = 2, Dcalcd = 1.269 g cmÀ3
R[I >2 (I)] = 0.0490, wR[I >2 (I)] = 0.1134.
,
r
r
17. (a) Halasa, A. F.; Smith, G. E. P., Jr. J. Org. Chem. 1973, 38, 1353; (b) DAmico, J. J.;
Suba, L.; Ruminski, P. G. J. Heterocyclic Chem. 1985, 22, 1479. and references
therein.