Samarium diiodide promoted synthesis of N,N′-disubstituted amidines

Article abstract of DOI:10.1016/S0040-4039(02)00129-6

An efficient one-step preparation of an N,N′-disubstituted amidine by the direct nucleophilic addition of an amine to the parent nitrile using catalytic amounts of SmI₂ under relatively mild conditions is developed. Alkyl, benzyl and aryl amidi

Full text of DOI:10.1016/S0040-4039(02)00129-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1867–1869
Samarium diiodide promoted synthesis of N,N%-disubstituted
amidines
Fan Xu, Jianhua Sun and Qi Shen*
Department of Chemistry, Suzhou University, Suzhou 215006, China
Received 6 November 2001; revised 8 January 2002; accepted 18 January 2002
Abstract—An efficient one-step preparation of an N,N%-disubstituted amidine by the direct nucleophilic addition of an amine to
the parent nitrile using catalytic amounts of SmI2 under relatively mild conditions is developed. Alkyl, benzyl and aryl amidines
are prepared in moderate to good yields from the corresponding nitriles. © 2002 Elsevier Science Ltd. All rights reserved.
Amidines are very important compounds widely used as
antibiotics, diuretics, antiphlogistic drugs, anthelmintics
and wide-spectrum acaricides.1,2 They are also valuable
synthons for the preparation of azacyclic compounds.3
As a result of their importance, several methods for
their preparation are reported in detail in the literature.
These include condensation reactions of amines with
amides,2 nitriles,4,5 carboxylic acids,6 or orthoformates7
in the presence of condensation agents such as POCl3,
P2O5, PCl3 or catalysts such as AlCl3, Cu2O, HOAc,
and the Beckmann-type rearrangement of ketoximes.8
In recent years, rare earth metal triflates have been
found to be effective Lewis acids for promoting the
amination of nitriles affording amidines in good yields.9
mol% (relative to the nitrile) of SmI2. The results are
summarized in Table 1.11
As shown in Table 1, alkyl, benzyl, phenyl and het-
eroaryl nitriles can react with amines to give the corre-
sponding amidines in moderate to good yields. The
condensation occurs smoothly starting from different
primary amines (Table 1, entries 1, 4 and 8). However,
no amidine is obtained when i-C3H7NH2 is used as the
reagent (Table 1, entry 3). The mole ratio of nitrile to
amine is a key factor in the condensation reaction. For
example, the reaction of acetonitrile with n-butylamine
gives N,N%-di-n-butyl-acetamidine in 58% yield at 80°C
after 24 h in the case of a 1:2 nitrile:amine mole ratio,
while 86% yield is obtained from a 1:3 mole ratio.
When the mole ratio is increased beyond 1:4, the yield
does not increase any further (entries 4, 6 and 7). The
effect of reaction temperature was investigated with the
same reaction. It was observed that lower temperatures
lead to lower yields (entries 5 and 6).
SmI2 has been found to be a mild and versatile reducing
or coupling agent for a variety of reactions. More
recently, the use of SmI2 as a precatalyst in organic
synthesis, for reactions such as aldol reactions, Michael
additions, Diels–Alder reactions and ring opening reac-
tions, has received great attention.10 As a part of our
studies to explore the utility of SmI2-catalyzed car-
bonꢀnitrogen bond forming reactions, we have investi-
gated the catalytic activity of SmI2 in the condensation
of amines with nitriles for the preparation of N,N%-di-
substituted amidines (Scheme 1). Herein, we wish to
report our preliminary results.
It was noticed that the yield of amidine increases to a
maximum at first and then gradually decreases as time
passes (Table 2). The reason might be due to the
formation of a by-product. Further examination shows
s-triazine, the main by-product, is formed by the
cyclotrimerization of the nitrile besides the desired
amidine and its yield increases slowly and continuously
as the reaction time progresses. It seems that the
amidine already formed can be transformed into s-tri-
The reaction was carried out at 55 or 80°C for 1 or 2
days, using the nitrile and amine in the presence of 2.5
NR'
Keywords: samarium diiodide; synthesis; catalysis; N,N%-disubstituted
amidine.
2.5 mol% SmI2
RCN
2R'NH2
C
NHR'
R
+
* Corresponding author. Fax: 86-512-5112371; e-mail: qshen@
suda.edu.cn
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00129-6

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F. Xu et al. / Tetrahedron Letters 43 (2002) 1867–1869
Table 1. SmI2-catalyzed preparation of N,N%-disubstituted amidines
Entry
R
R%
Product
Mole ratio (RCN:R%NH2)
Temp. (°C)
Time (h)
Isolated yield (%)a
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
n-C3H7
n-C3H7
i-C3H7
n-C4H9
n-C4H9
n-C4H9
n-C4H9
3a
3a
3b
3c
3c
3c
3c
1:2
1:3
1:2
1:2
1:3
1:3
1:4
1:2
1:3
1:3
1:3
1:3
1:1.5
55
55
55
80
55
80
80
80
55
80
55
55
80
24
24
24
24
24
24
24
24
24
24
48
24
24
59
78
0
58
18
86
86
n-C6H13 3d
54(35b)
58
59
52
45
35
9
n-C3H7
n-C4H9
n-C3H7
n-C3H7
-CH2
3e
3f
3g
3h
10
11
12
13
Ph
4-Py
PhCH2
Ph
N
Ph C
N
H
3i
a The reaction was carried out in an open system.
b The reaction was carried out in a closed system.
azine still further. In order to confirm this inference,
some supplementary experiments with an N,N%-disub-
stituted amidine were tried. The N,N%-disubstituted
amidine alone cannot be transformed into s-triazine no
matter whether SmI2 is used or not. However, s-triazine
is obtained in the presence of the corresponding nitrile
and a catalytic amount of SmI2. For example, the
reaction of N,N%-di-n-butyl-benzamidine with benzoni-
trile in a 1:2 mole ratio at 80°C for 24 h gave 2,4,6-
triphenyl-s-triazine in 27% yield in the presence of 7.5
mol% (relative to the amidine) SmI2, while no s-triazine
was detected without SmI2. According to these experi-
ments, the course of the reaction can be thought to
occur as shown in Scheme 2.
According to Scheme 2, the reaction carried out in an
open system should favor the formation of the amidine
because of the smooth escape of NH3. On the contrary,
the reaction should be in favor of the formation of
s-triazine in a closed system. The comparable experi-
mental data for the reaction of PhCN with n-
C6H13NH2 obtained from the two different systems,
respectively, support our hypothesis (Table 1, entry 8).
Table 2. Yield of amidine 3e and s-triazine at different
reaction timesa
The color change of the reaction mixture from dark
blue to light brown or white obviously indicates that
the real active species for this reaction is the Sm(III) ion
rather than the Sm(II) ion, although the true mecha-
nism and actual Sm(III) intermediates are not yet clear.
Entry
Time (h)
Isolated yield (%)
Amidine s-Triazine
1
2
3
4
5
8
12
15
18
24
59
71
76
62
58
12
14
15
17
22
In summary, SmI2 has been found to be an efficient
catalyst under mild reaction conditions and with good
yields for the condensation of nitriles with amines to
form N,N%-disubstituted amidines. This methodology
gives us the chance to make better use of SmI2 in
organic synthesis.
a Reaction conditions: 1:3 PhCN: n-C3H7NH2, 2.5 mol% SmI2 rela-
tive to PhCN, 55°C, open system.
NR'
R'NH2
C
+ NH3
NHR'
R
NH
RCN
SmI2
SmI2
RCN
C
NHR'
R
RCN + 2R'NH2
N
R
2RCN
R
R
N
+
R'NH2
N
Scheme 2.

F. Xu et al. / Tetrahedron Letters 43 (2002) 1867–1869
1869
Acknowledgements
m/z 142 (M+). Compound 3c: elemental analysis: calcd
for C10H22N2: C, 70.52; H, 13.02; N, 16.45. Found: C,
70.33; H, 12.85; N, 16.76%. 1H NMR (400 MHz, CDCl3):
l=0.93 (t, J=7.2 Hz, 6H), 1.37 (m, 4H), 1.54 (m, 4H),
1.92 (s, 3H), 3.14 (t, J=7.6 Hz, 4H). MS (EI): m/z 170
(M+). Compound 3d: elemental analysis: calcd for
C14H30N2: C, 74.26; H, 13.36; N, 12.38. Found: C, 73.82;
H, 13.49; N, 12.71%. 1H NMR (400 MHz, CDCl3):
l=0.89 (m, 6H), 1.30 (m, 12H), 1.52 (m, 4H), 1.86 (s,
3H), 3.11 (m, 4H). MS (EI): m/z 226 (M+). Compound
3e: elemental analysis: calcd for C13H20N2: C, 76.42; H,
The authors would like to thank the National Science
Foundation of China (29872031), State Key Labora-
tory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences for
financial support.
References
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