An unexpected coupling reaction between isocyanides and carboxylic acids: a method for the synthesis of highly stable symmetrical and unsymmetrical alkylamidine and arylamidine carbocations

Article abstract of DOI:10.1016/j.tetlet.2010.05.132

An unexpected coupling reaction between isocyanides and carboxylic acids which led to the synthesis of highly stable symmetrical and unsymmetrical alkylamidine and arylamidine carbocations under mild reaction conditions is described. The structures of these compounds were confirmed by IR, mass, ¹H NMR, ¹³C NMR, and single-crystal X-ray diffraction studies and a plausible mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2010.05.132

Tetrahedron Letters 51 (2010) 4091–4094
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Tetrahedron Letters
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An unexpected coupling reaction between isocyanides and carboxylic acids:
a method for the synthesis of highly stable symmetrical and unsymmetrical
alkylamidine and arylamidine carbocations
*
Ahmad Shaabani , Ali Hossein Rezayan, Afshin Sarvary, Sajjad Keshipour, Hamid Reza Khavasi
Department of Chemistry, Shahid Beheshti University, G. C., PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An unexpected coupling reaction between isocyanides and carboxylic acids which led to the synthesis of
highly stable symmetrical and unsymmetrical alkylamidine and arylamidine carbocations under mild
reaction conditions is described. The structures of these compounds were confirmed by IR, mass, 1H
NMR, 13C NMR, and single-crystal X-ray diffraction studies and a plausible mechanism is proposed.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 April 2010
Revised 12 May 2010
Accepted 28 May 2010
Available online 1 June 2010
Keywords:
Isocyanide
Carboxylic acid
Stable carbocation
Carbocations are well known as key reactive intermediates in
many organic reactions.1,2 The generation of carbocations in protic
solvents is problematic because they can easily react with protic
solvents.3,4 However, in superacidic media at low temperatures,
carbocations are sufficiently long-lived for spectroscopic detec-
tion.1–10 The stability of carbocations is increased by charge delo-
calization over aromatic rings1 or when bound to a heteroatom
carrying a lone electron pair.6,7 Such resonance-stabilized carboca-
tions are common intermediates of metabolic and synthetic organ-
ic reactions, and the formation of these intermediates and the
study of their chemical reactivity are of interest to both organic
chemists and biochemists.
The reaction of carboxylic acids with isocyanides forms the ba-
sis of the Passerini and Ugi reactions, which are much admired in
combinatorial chemistry. Anthranilic acid provides dibenzo-1,5-
diazocine-2,6-dione derivatives by a double Ugi four component
reaction. In contrast, the prototypical combination of an acid with
an isocyanide is a relatively obscure reaction and poorly repre-
sented under ambient conditions.11–16
from the reaction of isocyanides and benzoic acid in which not only
is the stable carbocation produced at room temperature but also
O
OH
OH
O
H
MeOH
O
O
+
2
R
N C
2
r.t., 24 h
1
H
N
H
N
R
R
Entry
R
Yield (%)
52
H
cyclohexyl
3a
3a,b
2,6-dimethyphenyl
3b
48
Scheme 1. Synthesis of symmetrical alkylamidine- and arylamidine-acid zwitter-
ionic compounds.
As a part of our ongoing research program on isocyanide chem-
istry,17 herein we report a hitherto unknown reaction between
2-hydroxybenzoic acid (1) and isocyanides 2, to give symmetrical
alkylamidine- and arylamidine-acid zwitterionic compounds 3a,b
(Scheme 1). To the best of our knowledge, this is the first example
of isolated and structurally characterized carbocations derived
O
OH
OH
O
O
MeOH
r.t.
+
R
N C
H3N R
OH
1
2c,d
4a = 55%
4b = 61%
2c = 1,1,3,3-tetramethylbutyl
2d = tert-butyl
* Corresponding author. Tel.: +982129902800; fax: +982122431663.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
Scheme 2. Synthesis of salts 4a and 4b.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.132

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A. Shaabani et al. / Tetrahedron Letters 51 (2010) 4091–4094
1,3-di(cyclohexyl)amidine- or 1,3-di(2,6-dimethylphenyl)amidine-
ortho hydroxy benzoic acid zwitterions 3a and 3b, respectively. It
should be noted that the reaction of 1,1,3,3-tetramethylbutyl and
tert-butyl isocyanides 2c,d with 2-hydroxybenzoic acid (1) under
the same reaction conditions led to salts 4a,b (Scheme 2).
It is noteworthy that compounds 3a,b are similar to urea-acid
salts which are used as redox-active receptors,18a whilst compounds
4a,b are important materials for the synthesis of gelators.18b
The structures of compounds 3a,b and 4a,b were deduced from
their IR, mass, 1H NMR, and 13C NMR spectral data. For example,
the 1H NMR spectrum of 3a exhibited a singlet for a phenolic proton
at d = 15.44, two NH protons at d = 9.80 and 9.47, one carbocationic
proton at d = 7.90, two CH–N cyclohexyl protons at d = 3.60 and
3.35, three signals for the aromatic moiety at d = 6.65, 7.17 and
7.69, and a multiplet due to the two cyclohexyl rings at d = 1.17–
1.83 ppm. The 1H-decoupled 13C NMR spectrum of 3a showed 16
distinct resonances in agreement with the proposed structure. The
mass spectra of these compounds displayed amidine fragments of
the suggested structures at appropriated m/z values, for example,
for compound 3a: MS (EI, 70 eV) m/z (%): 209 (C13H25N2+) (70).
These crystalline solids are stable at room temperature for
months and melt at 175–177 °C (3a) and 189–190 °C (3b). The
13C NMR spectrum of 3a shows a signal due to the N–CH–N carbon
atom at 152.2 ppm (on the basis of HMQC and DEPT NMR data).
This value is similar to (d = 149.4)6,19a and indicates significant sta-
bilization of the cationic carbon. The structure of compound 3a was
determined unambiguously by X-ray crystallography.
The general view of the molecular structure is shown in Figure 1.
It is interesting to note that interactions between the carbocation
and the anion are observed. Hydrogen bonds form between the
nitrogen atoms of the carbocation and the oxygen atoms of the
anion.6
In the crystalline state, the positive charge of compound 3a is
delocalized by the two amine groups. This delocalization was con-
sistent with the observation that the N1–C7 bond length
[1.296(2) Å] was similar to the N2–C7 bond length [1.308(2) Å].
These are significantly shorter than the typical N–C bond lengths
(N1–C6 and N2–C8 [1.471(2) Å] and [1.466(2) Å], respectively)
and longer than imine bond lengths.19
Figure 1. ORTEP diagram for 3a.
Table 1
Effect of solvent on the reaction yielda
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
H2O
EtOH
37
40
52
0
0
0
MeOH
CH3CN
CH2Cl2
C6H5CH3
n-Hexane
0
a
Cyclohexyl isocyanide (2.0 mmol), 2-hydroxybenzoic acid (1.0 mmol), solvents,
rt, 24 h.
In order to find the best solvent, the reaction of cyclohexyl iso-
cyanide (2) and 2-hydroxybenzoic acid (1) was examined in water
and various organic solvents at room temperature. As shown in
Table 1, methanol was the best solvent with respect to yield (Table
1, entry 3). It is interesting to note that the reaction proceeded in
protic solvents, but not in aprotic solvents (Table 1).
does not require a strongly acidic medium for its formation or
stabilization.
As indicated in Scheme 1, treatment of cyclohexyl 2a or 2,6-
dimethylphenyl 2b isocyanide with 2-hydroxybenzoic acid in meth-
anol at room temperature led to the formation of the corresponding
NH
H
O
O
H
N
H
N
O
OH
NH2
H
6
MeOH
r.t., 24 h
+
N C
O
O
H
N
5
2c
H
N
H
7, 53%
Scheme 3. Synthesis of unsymmetrical amidine carbocation 7.

A. Shaabani et al. / Tetrahedron Letters 51 (2010) 4091–4094
4093
The structure of compound 7 was deduced from its IR, 1H NMR,
and 13C NMR spectral data. The mass spectrum of this compound
displayed a molecular ion peak at the appropriated m/z value.
The structure of 7 was confirmed unambiguously by single-
crystal X-ray analysis (Fig. 2).
We previously reported the reaction of benzoic acid and
meta- and para-substituted (H, Me, Cl, NO2) benzoic acids with
various isocyanides which led to benzoic acid-isocyanide salt-
s.11,12a The results described herein have shown that an OH or
an NH2 group at an ortho position of a benzoic acid plays an
important role in this reaction, as we obtained different products
in comparison to those previously reported by Gloede14a,b and
our group.11
Although the precise mechanistic details of this reaction are not
known, plausible pathways (A and B) for the formation of products
3a,b and 7 are proposed in Scheme 4. It is important to note that
analysis of the reaction mixture by gas chromatography–mass
spectrometry (GC–MS) identified the formation of methyl formate
and methyl 2-hydroxybenzoate as by-products, which supports
the proposed mechanism.
In conclusion, we have described two unexpected and interest-
ing reactions between isocyanides and ortho-hydroxy- and ortho-
amino-substituted benzoic acids in which several highly stable
symmetrical and unsymmetrical alkylamidine and arylamidine
carbocations are formed. The high stability of these carbocations
can be attributed to delocalization of the positive charge by the
two amine groups. Further reactivity studies and investigation of
the synthetic applications of this methodology are in progress in
our laboratory.
Figure 2. ORTEP diagram of 7: Selected bond lengths [Å]: N1–C8 1.316(4), N2–C8
1.300(4), N1–C7 1.421(4), N2–C9 1.453(4), and selected bond angles [deg]: N1–C8–
N2 123.0(2), C7–N1–C8 123.4(2), C8–N2–C9 124.3(3).
In order to further investigate the scope and limitations of this
unusual reaction, we applied it to 2-aminobenzoic acid (5). In the
event, reaction of 2-aminobenzoic acid (5) with 1,1,3,3-tetrameth-
ylbutyl isocyanide (2c) in methanol at room temperature gave
highly stable unsymmetrical amidine carbocation 7. The desired
product 6 was not obtained under the given reaction conditions
(Scheme 3).
It is worth noting that other isocyanides such as cyclohexyl, 2,6-
dimethylphenyl, tert-butyl, and benzyl isocyanides failed to give
analogous products.
O
OMe
MeOCHO
XH
15
O
R
O
R
N
OH
R
H
N
O
O
CH
N
N
H
H
XH
R
CH
NH
MeOH
H N
XH
XH
R
R
3a,b
14
16
O
OH
X
N
O
X
N
R
O
X
O
N
MeOH
R
O
R
X
-H
O
R
N
O
R
HN
H
H
R N CH
N
N
R
OH
XH
9
C
H
R
C
H
11
10
13
12
O
[A]:
X = O
O
O
O
OH
O
O
[B]:
R N C
+
HC N R
R
XH
XH
X = NH
XH
N
2
1
8
17
O
X
O
X
O
O
O
O
R
N
H
X
H
R
N
H
1
8
19
H
7
N
R
Scheme 4. Proposed mechanistic pathways.

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A. Shaabani et al. / Tetrahedron Letters 51 (2010) 4091–4094
11. Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007, 48, 6137–
Acknowledgment
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We gratefully acknowledge the financial support from the Re-
search Council of Shahid Beheshti University.
Supplementary data
Crystallographic data (3a: CCDC 759357; 7: 759358). Supple-
mentary data (experimental procedures and spectral data) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.05.132.
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