Ph3P/I2-mediated synthesis of N,N′-disubstituted and N,N,N′-trisubstituted amidines

Article abstract of DOI:10.1016/j.tetlet.2016.10.069

A convenient one-pot protocol for the synthesis of N,N′-disubstituted and N,N,N′-trisubstituted amidines is reported. In the presence of the Ph₃P–I₂/Et₃N system, a variety of secondary amides were smoothly reacted with primary or secondary amines to afford the corresponding amidines in good to excellent yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2016.10.069

Tetrahedron Letters 57 (2016) 5351–5354
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ph3P/I2-mediated synthesis of N,N0-disubstituted and
N,N,N0-trisubstituted amidines
⇑
Wong Phakhodee , Sirilak Wangngae, Nittaya Wiriya, Mookda Pattarawarapan
Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
a r t i c l e i n f o
a b s t r a c t
A convenient one-pot protocol for the synthesis of N,N0-disubstituted and N,N,N0-trisubstituted amidines
is reported. In the presence of the Ph3P–I2/Et3N system, a variety of secondary amides were smoothly
reacted with primary or secondary amines to afford the corresponding amidines in good to excellent
yields under mild conditions.
Article history:
Received 12 September 2016
Revised 13 October 2016
Accepted 18 October 2016
Available online 19 October 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Amidine
Triphenylphosphine
Iodine
Amide
Dehydration
Introduction
amines (Scheme 1). Additionally, in the synthesis of imidoyl chlo-
rides, highly toxic and moisture-sensitive dehydrating agents such
8f
Amidines are important structural elements which are widely
distributed among natural products as well as in drugs and agro-
chemicals.1 So far, a number of amidine-containing molecules have
been shown to exhibit important biological and pharmacological
properties such as anti-inflammatory, antiviral, antifungal,
antibacterial, antibiotic, antihypertensive, and anesthetic activi-
ties.2 Moreover, amidines have been used as key precursors in
the synthesis of a variety of N-containing heterocycles such as
aziridines, pyrroles, imidazoles, oxazoles, pyridines, pyrimidines,
and quinazolines.3 Their applications as ligands in metal coordina-
tion or as catalysts in organic synthesis are also well-documented.4
Several methods have been reported for the synthesis of ami-
dine derivatives.3 Among various precursors including amides,
thioamides, thioimidic esters, and nitriles, amides are potentially
useful substrates due to their low cost, ready availability, and ease
of preparation. While electrophilic activation of primary amides
can lead to an efficient one-pot synthesis of N-monosubstituted
and N,N-disubstituted amidines,5 the common procedures for the
synthesis of N,N0-disubstituted or N,N,N0-trisubstituted amidines
still require an extra step to prepare activated secondary amide
intermediates such as iminium sulfonates,6 iminium triflates,7 imi-
doyl chlorides,8 or imidoylbenzotriazoles,9 before the addition of
as PCl5,8a,b,10 SOCl2,8c–e,9b and (COCl)2 are used at elevated
temperatures with long reaction times. Although
a one-pot
process has been developed using TiCl4 under microwave
irradiation11 or a nano-MgO catalyst under solvent-free condi-
tions,12 these methods suffer from a limited substrate scope and
difficulty in the handling or preparation of reagents.
Based on our previous experience, the combination of triph-
enylphosphine (Ph3P) and iodine (I2) was found to be very effective
either as a dehydrating or desulfurization reagent for promoting
the synthesis of amides, esters, and guanidines under mild condi-
tions.13 Although amidines of both acyclic and cyclic systems have
previously been prepared using triphenylphosphonium anhydride
trifluoromethane sulfonate (Hendrickson reagent),14 this reagent
is expensive, difficult to handle, and requires extra-dry conditions.
Since the direct one-pot synthesis of highly substituted acyclic
amidines from secondary amides has never been reported
using the Ph3P–I2 system, this prompted us to develop a practical
one-pot approach for the synthesis of substituted amidines using
these inexpensive, readily available, and low toxicity reagents
(Scheme 1).
Benzanilide and piperidine were chosen as model substrates for
optimization of the reaction conditions using the Ph3P/I2 combina-
tion as a dehydrating reagent (Table 1). Screening common organic
bases showed that the reactions in the presence of DBU, pyridine,
or DMAP did not lead to product formation (Entries 1–3). This
could be due to rapid decomposition of the reactive intermediates
⇑
Corresponding author. Tel.: +66 5394 3341; fax: +66 5389 2277.
E-mail address: wongp2577@gmail.com (W. Phakhodee).
http://dx.doi.org/10.1016/j.tetlet.2016.10.069
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

5352
W. Phakhodee et al. / Tetrahedron Letters 57 (2016) 5351–5354
Previous studies;
in the presence of these bases. Using imidazole, however, resulted
OSO2Ar
R2
in exclusive formation of the corresponding imidoylimidazole
without the desired amidine product (Entry 4). Fortunately, the
reaction was very efficient in the presence of triethylamine (Entry
5). Changing this base to diisopropylethylamine also led to amidine
formation, however, the reaction was incomplete as significant
amount of the starting material remained (Entry 6).
For comparison, the effect of the additive was also examined
using triethylamine as the base where it was found that the reac-
tion did not proceed using CCl4, bromine, or NBS (Entries 7–9).
Additionally, no conversion was observed when the substrates
were subjected to the conditions in entry 5 without the addition
of Ph3P (data not shown). These results indicated that the Ph3P/
I2–Et3N combination was the most effective in promoting amidine
formation at ambient temperature.
R1
R1
N
OEt
R2
N
BF4
R3 R4
N
O
H
NHR3R4
R2
R1
N
H
R2
OTf
R1
N
R2
R1
N
H
OTf
Cl
Bt
R2
R2
R1
R1
N
N
This study;
O
With the optimized reaction conditions in hand, the scope of
amine nucleophiles was evaluated using benzanilide (Table 2)
and the reaction was found to be applicable to a broad range of
amines. While primary aliphatic amines were slightly less effective
requiring longer times to provide the corresponding amidines in
moderate yields (Entries 1–2), secondary aliphatic amines, includ-
ing acyclic and cyclic substrates, exhibited good reactivity (Entries
3–9). Interestingly, highly hindered substituted amidines could be
prepared even with the sterically hindered diisopropyl amine
(Entry 7). However, the reaction was sluggish and gave a complex
mixture when using less nucleophilic primary aromatic amines
such as aniline or 2-methylaniline (data not shown). Nevertheless,
activated amidine such as imidoylimidazole 2j could be readily
prepared in excellent yield (Entry 10). This compound has previ-
ously been synthesized from the reaction of benzanilide with N,
N0-thionyldiimidazole in 57% yield.15
I
OPPh3
R3 R4
N
Ph3P, I2
Et3N
NHR3R4
R2
R2
R1
N
R1
N
H
R2
or
R1
N
I
R2
R1
N
Scheme 1. Synthesis of N,N0-disubstituted and N,N,N0-trisubstituted amidines.
Table 1
Optimization of the reaction conditionsa
O
N
+
HN
N
H
N
The reactivity of other amide substrates was also examined
(Table 2, entries 11–18). When electron withdrawing or donating
groups were presented in N-arylbenzamide derivatives, no sub-
stituent effect was observed (Entries 11 and 12). Unlike other
reported conditions that only work well with N-phenylbenza-
mide,12,16,17 these conditions enabled the synthesis of various
trisubstituted amidines from N-arylacetamide substrates in good
to excellent yields (Entries 13–16). Long chain N-phenylated
secondary amide 1h also gave amidine 2q, albeit with lower
yield, possibly due to steric hindrance of the starting amide (Entry
17). The reaction of N-cyclohexylbenzamide also proceeded
smoothly at room temperature to afford amidine 2r in good yield
(Entry 18).
Entry
Additive
Base
Yield (%)
1
2
3
4
5
6
7
8
9
I2
I2
I2
I2
I2
I2
CCl4
Br2
NBS
DBU
nr
nr
nr
Pyridine
DMAP
Imidazole
Et3N
DIEA
Et3N
—(95)b
81
55
nrc
nrc
nrc
Et3N
Et3N
a
Reaction conditions: benzanilide (0.28 mmol), piperidine (0.34 mmol), Ph3P
(0.42 mmol), additive (0.42 mmol), base (1.4 mmol), CH2Cl2 (2 mL), 0 °C–rt, 2 h.
b
Yield of the corresponding imidoylimidazole.
nr = no reaction.
c
Table 2
Synthesis of substituted amidines using Ph3P/I2/Et3Na
O
R3 R4
i) Ph3P, I2 Et3N, CH2Cl2
N
R2
R1
N
H
R2
R1
N
3
4
ii)
NHR R
1
2
Entry
1
Amide 1
NHR3R4
Amidine 2
Time (h)
5
Yield (%)
80
H2N
O
2a
N
H
1a
H2N
2
1a
2b
5
74
OMe
3
4
5
6
7
1a
1a
1a
1a
1a
NHMe2
NHEt2
NHBu2
NHBn2
NHiPr2
2c
2d
2e
2f
4
4
4
2
4
76
91
93
82
71
2g

W. Phakhodee et al. / Tetrahedron Letters 57 (2016) 5351–5354
5353
Table 2 (continued)
Entry
Amide 1
NHR3R4
Amidine 2
Time (h)
2
Yield (%)
8
1a
2h
81
80
99
N
H
O
9
1a
2i
2j
2
1
N
H
H
N
10
1a
N
NO2
O
N
H
11
12
NHEt2
2k
2l
1
1
84
81
1b
OMe
O
N
NHBu2
H
1c
Cl
O
13
14
15
NHEt2
NHBu2
2m
2n
2o
2p
1
1
1
2
87
92
82
76
H3C
N
H
1d
Br
O
O
O
H3C
N
H
1e
OEt
OEt
NHBu2
H3C
N
H
1f
O
16
17
H3C
N
H
N
H
1g
O
N
H
NHEt2
NHBu2
2q
2r
5
3
66
72
4
1h
O
18
N
H
1i
a
Reaction conditions: amide (0.28 mmol), amine (0.34 mmol), Ph3P (0.42 mmol), iodine (0.42 mmol), Et3N (1.4 mmol), CH2Cl2 (2 mL), 0 °C–rt.
R3
nes proceeded smoothly to give the corresponding isoindol-1-one
derivatives 3 in reasonable yields.
R4
O
N
i) Ph3P, I2 Et3N, CH2Cl2
ii) NHR3R4
NH
N
It should be noted that the reaction of benzamide with dibuty-
lamine gave no conversion. This may be in part due to low solubil-
ity of the substrate as well as the low acidity of the amide protons
which make it difficult to form reactive intermediate under the
applied conditions.18 Tertiary amide such as N-benzoylpiperidine
also did not react, suggesting that deprotonation of the amide N–
H is a crucial step in amidine formation.
O
O
3
HN
N
N
HN
N
N
OMe
O
O
O
The mechanism for the transformation of an amide into an ami-
dine was thus proposed to involve a two-step reaction (Scheme 3).
After formation of the reactive triphenylphosphonium iodide I,13b
phosphorylation proceeds at the oxygen atom of the amide
functional group with the deprotonation of the amide N–H. The
formed imidinium intermediate II could be converted into
imidoyl iodide III, both of which could undergo displacement
with an amine to furnish the corresponding amidine.
3c
(88%, 3 h)
3a
(77%, 3 h)
3b
(57%, 1.5 h)
Scheme 2. Synthesis of isoindol-1-one derivatives.
Having established a successful reaction with acyclic amides,
the scope of the reaction was further extended to cyclic secondary
amides (Scheme 2). The reaction of phthalimide with various ami-

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W. Phakhodee et al. / Tetrahedron Letters 57 (2016) 5351–5354
O
I
OPPh3
R2
R3 R4
N
R1
N
H
I
NHR3R4
I
I
Ph3P + I2
R2
R1
N
R2
Ph3P
I
Ph3P
R1
N
II
Et3N
I
I
R2
R1
N
III
Scheme 3. Proposed mechanism for the Ph3P-I2 mediated synthesis of substituted amidine.
3. Aly, A. A.; Nour-El-Din, A. M. ARKIVOC 2008, 153.
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mild and effective reagent system for mediating the one-pot ami-
dation of secondary amides. A variety of amidines could be directly
prepared from readily accessible N-substituted amides under mild
conditions without requirement of an extra preparative step for
the activated intermediates. Other more acidic amide substrates
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Acknowledgements
Financial support from The Thailand Research Fund through the
Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0206/2556) to
S.W. and the National Research University Project under Thailand’s
Office of the Higher Education Commission are gratefully
acknowledged.
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Supplementary data
Supplementary data (general experimental method, spectro-
scopic data, 1H and 13C NMR spectra of representative products)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2016.10.069.
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