A Green One-Pot Synthesis of vic -Amidino (Hetero)aromatic Acids from 1,2-Dinitriles

Article abstract of DOI:10.1055/s-0036-1588933

Phthalonitrile undergoes partial hydration in MeOH-H₂O media in the presence of an equimolar amount of NaOH to afford 2-carbamimidoylbenzoic acid in good yield in one step. This and similar vic-amidino (hetero)aromatic acids also could be synthesized from corresponding 1,2-dinitriles by hydrolysis in aqueous MeOH catalyzed by an equimolar amount of NaOH of in situ generated 1,1-dimethoxy-1H-isoindol-3-amine or its counterparts. Protonation of the synthesized amidino acids, esterification, and reamination of the parent amidino benzoic acid with N-nucleophiles were performed.

Full text of DOI:10.1055/s-0036-1588933

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–G
letter
A
V. A. Tkachuk et al.
Letter
Synlett
A Green One-Pot Synthesis of vic-Amidino (Hetero)aromatic Acids
from 1,2-Dinitriles
Volodymyr A. Tkachuka
Iryna V. Omelchenkob
NaOH/MeOH/H2O (X = Y = CH, 12 g scale)
Olga V. Hordiyenko*a
NH2
NH2
NaOMe
MeOH
X
Y
X
Y
X
Y
CN
CN
H2O
NH
OH
a Taras Shevchenko National University of Kyiv, Chemistry
Department, 64/13 Volodymyrs’ka str., Kyiv, 01601,
Ukraine
two points of
modification
N
reflux
r. t.
OMe
MeO
ov_hordiyenko@univ.kiev.ua
O
b SSI ‘Institute for Single Crystals’ National Academy of
Science of Ukraine, 60 Lenina Ave., Kharkiv 61001,
Ukraine
X = CH, C-OMe, C-Morph, Y = CH; X = CH, Y = N
up to 72%
Received: 17.10.2016
Accepted after revision: 20.12.2016
Published online: 18.01.2017
idoyl)benzoic acids demonstrated fungicide8a,b and chemo-
kine receptor CXCR3 antagonist activity.8c Derivatives of 2-
amidino acids with heterocyclic core are even less known.
The first reported were 4-[(N′-hydroxycarbamimidoyl)im-
idazol-5-yl]carbamides,9a obtained from 4-cyano-5-imid-
azolecarbamide, and its 1-methyl derivative,9b later pyra-
zine10a,b and pyridine10c derivatives were prepared. Only
one method used β,β,γ,γ-tetracyanoalkanones as aliphatic
precursors for the synthesis of pyridine-based substituted
amidino acids.11
Recently, our group reported that upon preparation of
1-imino-1H-isoindol-3-amine 3 by phthalonitrile ammo-
nolysis, 2-carbamimidoylbenzoic acid (5a) was isolated in
23% yield.2 The goal of the present research was to discover
how acid 5a could have formed, in order to develop a meth-
od for its preparation. Among the possible ways, a partial
hydrolysis of 1-imino-1H-isoindol-3-amine 3 was consid-
ered by us. According to a literature report12 it is stable in
water, but upon brief boiling can be transformed into 3-imi-
no-1H-isoindol-1-one tautomer 4 (Scheme 1). It is stable in
water, but upon brief boiling can be transformed into 3-imi-
no-1H-isoindol-1-one tautomer 4. To confirm or contradict
this hypothesis, a series of experiments under various neu-
tral, acidic, or basic conditions at variable temperature was
conducted. None of these attempts afforded the desired
amidino acid 5a.
DOI: 10.1055/s-0036-1588933; Art ID: st-2016-b0702-l
Abstract Phthalonitrile undergoes partial hydration in MeOH–H2O
media in the presence of an equimolar amount of NaOH to afford 2-
carbamimidoylbenzoic acid in good yield in one step. This and similar
vic-amidino (hetero)aromatic acids also could be synthesized from cor-
responding 1,2-dinitriles by hydrolysis in aqueous MeOH catalyzed by
an equimolar amount of NaOH of in situ generated 1,1-dimethoxy-1H-
isoindol-3-amine or its counterparts. Protonation of the synthesized
amidino acids, esterification, and reamination of the parent amidino
benzoic acid with N-nucleophiles were performed.
Key words green chemistry, phthalonitrile, partial hydration, 2-carba-
mimidoylaromatic acids, 3-carbamimidoyl-2-pyridinecarboxylic acid,
protonation, esterification, reamination
Acids having both carboxylic and amidinic groups,
namely, carbamimidoyl carboxylic acids, are mostly repre-
sented by their parent 1,3- and 1,4-isomers and a wide
range of substituted derivatives that attracted attention for
the first time as arginine mimics.1 The 1,2-isomer was un-
known until recently,2 and only a very limited number of its
derivatives have been described. Usually, the amidinic
group is generated from a cyano group through an imi-
noester by the Pinner protocol,3 and for 3- and 4-amidino
benzoic acids this route can be realized successfully.4 For 2-
cyano benzoic acid/ester/amide bearing bulky substituents
at benzene ring into 2-amidino acids, more drastic condi-
tions were described.5 Other known procedures used
phthalic acid derivatives as starting compounds: amides
and thioamides,6a halogenimides,6b mixed esters and am-
ides,6c,d o-phthalaldehyde.6e Only very recently were alkyl
2-amidinobenzoate nitrates obtained from phthalonitrile,
acetoxime and Co(NO3)2·6H2O via a cobalt intermediate
which was transformed into the ester on treatment with
(NH4)2S in an alcohol.7 Substituted 2-(N-hydroxycarbamim-
We suggested that one of the intermediates in the syn-
thesis of 1-imino-1H-isoindol-3-amine 3 – 1,1-dimethoxy-
1H-isoindol-3-amine (2), but not the compound 3 itself,
could undergo hydrolysis. It was synthesized by treatment
of phthalonitrile with NaOMe in anhydrous MeOH on ice
cooling according to a known method.13 Upon its hydrolysis
in aqueous MeOH in the presence of an equimolar amount
of NaOH, the expected 2-amidinobenzoic acid 5a was iso-
lated as its methanol solvate (according to X-ray data) in
50% yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

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V. A. Tkachuk et al.
Letter
Synlett
NH
O
NH2
N
NH2
N
NaOH
CN
NaOMe
MeOH
MeOH/H2O
NH2
OH
H2O
[2] +
50%
56%
CN
1
OMe
NH
5a
2
MeO
3
NH2
NH2
N
NaOH
Ref. 12
H2O
MeOH/H2O
NH2
O–
72%
O
4
O
Scheme 1 Synthesis of 2-carbamimidoylbenzoic acid (5a)
In the developing of optimum conditions for the effi-
cient synthesis of acid 5a, phthalonitrile was found to be
the best parent compound, and isolation of intermediate di-
methoxy derivative 2 was not necessary. Phthalonitrile was
easily transformed into acid 5a upon dissolution in a mix-
ture of MeOH and H2O with an equimolar amount of NaOH;
heating and further reflux for 15–20 minutes led to the
elimination of ammonia (method A). The appearance of
small colorless crystals of acid 5a on the liquid surface di-
rectly upon cooling of the reaction mixture was evidence of
its formation, and the major product 5a crystallized as its
methanol solvate in 72% yield. The yellow-orange reaction
solution had a characteristic flower aroma. When neces-
sary, it was hot filtered to remove phthalocyanine impuri-
ties before it was allowed to crystallize. Acidification of the
mother liquor with AcOH to neutral pH after separation of
the major product allowed for additional crystals of 5a to
be isolated, and increase the total yield to about 77%. This
simple reaction and isolation procedure can be scaled up
easily to give 12 grams of acid 5a.
a zwitterionic structure both in crystal and in solution due
to the formation of intermolecular hydrogen bonds that can
lead to stabilization of the zwitterionic form.
A similar reaction for aromatic 1,2-dinitriles had not yet
been described, so we explored its scope, firstly for substi-
tuted phthalonitriles. Thus, 3-nitrophthalonitrile 6 was
subjected to the same reaction conditions (method A) but
the major isolated product of the reaction was 3-methoxy-
phthalonitrile 7 that crystallized upon cooling from the re-
action mixture in 59% yield. That was a result of nucleophil-
ic substitution of the nitro group to the methoxy which is
typical of 3- and 4-nitrophthalonitriles.14 The filtrate was
allowed to stand overnight, and additional material crystal-
lized. It was found to be a two-component mixture in the
1
ratio of 1:3 as judged by H NMR spectroscopy in D2O. LC–
MS analysis led to the identification of 2-amidino-6(3)-ni-
tro- 5b (210 [M + H]+) and 2-amidino-6(3)-methoxybenzoic
acid 5c (195 [M + H]+; Scheme 2).
When pure 3-methoxyphthalonitrile 7 was introduced
by method A, unreacted starting material precipitated
while the reaction mixture cooled. Therefore, in order to in-
crease the conversion of nitrile 7, additional heating of the
reaction mixture for 30 minutes was carried out after the
beginning of ammonia elimination, and a single crystalline
product, 2-carbamimidoyl-3-methoxy benzoic acid 5c, was
isolated in 41% yield. Its structure (as its methanol solvate)
was proven by X-ray diffraction data. However, according to
LC–MS of the filtrate obtained after separation of 5c, it ap-
It was found that 1-imino-1H-isoindol-3-amine (3),
upon its interaction with 0.5 equivalents of in situ generat-
ed dimethoxy derivative 2 could also be transformed into
acid 5a in 56% yield. The analytical data (1H NMR, 13C NMR,
X-ray diffraction, mp) of the synthesized acid 5a were in ac-
cordance with previously isolated material.2 During the
performed research it was shown that amidino acid 5a has
Scheme 2 Synthesis of 3-methoxy-amidinobenzoic acid 5c and its molecular structure according to the X-ray diffraction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

C
V. A. Tkachuk et al.
Letter
Synlett
peared that much more complete hydrolysis of 7 was
achieved and the yield of target acid 5c decreased because
of formation of 3-methoxy analogues of phthalimide, ami-
noisoindolone 4, and phthalamic acid. In order to increase
the yield of 5c, 1,1,4-trimethoxy-1H-isoindol-3-amine (8)
was tested as a starting compound (Scheme 2, method B). It
was generated in situ from 3-methoxyphthalonitrile (7) by
treatment with MeONa in MeOH according to the method13
and then treated with water. The obtained suspension was
refluxed for 20–25 minutes until the solution became clear
and liberation of ammonia began. The colorless crystals of
5c precipitated upon cooling in 62% yield.
The formation of the 3-methoxy isomer can be ex-
plained by the nucleophilic attack of the methoxide anion
at the more electrophilic carbon atom of the nitrile group at
the 1-position while the other nitrile is less electrophilic
due to the donor properties of the neighboring MeO group.
From this point of view, the 3-nitro group in 6 would in-
stead promote the formation of amidino acid 5b that was
not isolated. In addition, no other isomeric acids of 5c and
5b were detected.
heating at room temperature for two hours before ammo-
nia elimination began. The insoluble solid was filtered off,
and the filtrate was allowed to stand for one day. Small
light-cream-colored crystals were collected but they were
not identified because of their insolubility in any appropri-
ate solvent.
Some heterocyclic vic-dinitriles were also studied in the
reaction. Refluxing of 2,3-dicyanopyridine (10) in an aque-
ous methanolic solution of NaOH was proceeded to 61%
conversion and produced crystals that consisted of two
1
compounds 5e and 5g in a 3:1 ratio according to the H
NMR spectrum (Scheme 4). Better results were achieved by
method B when dimethoxy derivative 11 was generated in
situ from dinitrile 10. Nucleophilic attack proceeded regio-
selectively at the more electrophilic α-cyano group, giving
rise to 3-carbamimidoylpyridine-2-carboxylic acid (5e) in
69% yield. No isomeric acid 5g was isolated.
When 3-morpholino dinitrile 915 was subjected to the
reaction conditions by method B, the crystals of amidino
acid 5d were obtained in 61% yield (Scheme 3). Only one
structural isomer was isolated, as revealed by the presence
of only one set of signals in the 1H NMR spectrum. Its struc-
ture was assigned as the 3-isomer based on the relative ar-
rangement of the carboxylic and amidinic groups that is ex-
pected to be the same as in acid 5c due to the donor charac-
ter of morpholine residue.
Scheme 4 Synthesis of amidino picolinic acid 5e and its molecular
structure according to X-ray diffraction
NH
H2N
CN
O
Other heterocyclic nitriles – 2,3-dicyanopyrazine (12),
2,3-dicyanoquinoxaline (15), and 4,5-dicyanoimidazole
(18) – did not afford the expected acids under any of the
applied conditions, but instead underwent hydration of one
or two cyano groups (Scheme 5 and Scheme 6). Previously,
pyrazine-2,3-dicarbonitrile 15 was found to react with
MeOH under basic conditions to form diimino ester; its
treatment with HCl afforded a diamide or an amido ester.17a
Our attempted conversion of 2,3-dicyanopyrazine (12) into
an amidino acid by methods A or B via in situ formed 5,5-
dimethoxy-5H-pyrrolo[3,4-b]pyrazin-7-ylamine (13) failed,
probably due to complete hydrolysis to diacid 14 which was
identified by LC–MS. The hydrolysis of the individual 5,5-
dimethoxy derivative 13 obtained by a literature method17b
led to the same result. The hydrolysis of 2,3-dicyanoquinox-
aline (15) under the conditions of method B ceased after
the formation of the sodium salt of known 3-carbamoyl-2-
quinoxaline carboxylic acid17c isolated as its crystalline hy-
drate 17 (Scheme 5).
N
CN
1) NaOMe, MeOH
2) H2O
N
O
O
OH
61%
9
5d
Scheme 3 Synthesis of morpholine-substituted amidino acid 5d
Attempts to obtain the corresponding amidino acid
from benzene-1,2,4,5-tetracarbonitrile failed. In an experi-
ment conducted according to method A, the reaction mix-
ture turned blue-black and a precipitate which was sup-
posed to be the corresponding phthalocyanine16 formed
immediately after heating for five minutes. By method B,
the pale-rose benzene-1,2,4,5-tetracarbonitrile on treat-
ment with MeONa in MeOH was turned into a gray suspen-
sion which after one hour stirring at room temperature and
adding water was subjected to heating. Similarly to method
A, the solution turned dark within five minutes and a pre-
cipitate emerged. Therefore, in the next experiment, after
the addition of water the suspension was stirred without
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

D
V. A. Tkachuk et al.
Letter
Synlett
by equimolar amounts of the bases NaOH and KOH. When
smaller amounts of bases were used, the yields decreased
due to the formation of (aza-) phthalocyanines as side
products. With excess base, an acid remained in solution as
the potassium or sodium salt, and could be recovered by
evaporation of the solvent. Salts have a much better solubil-
ity compared to acids. Use of K2CO3, Na2CO3, or NaHCO3 in-
stead of NaOH decreased the yields of the desired products.
It is interesting to note that each nitrile reaction mixture
had its own specific floral scent.
Like parent amidino acid 5a, the acids 5с–е also exist in
zwitterionic form both in crystal and in solution. Due to
their (hetero)aromatic nature, they are not readily soluble
in water at ambient temperature; however, they can be
crystallized from water without undesirable hydrolysis.
Amidino acids 5а,с–е exhibit a high stability under reflux in
water in a neutral medium and moderate stability in an al-
kaline or weakly acid medium. They readily form water-sol-
uble salts with alkali from which they can be recovered
upon acidification to the equivalence point. It should be
mentioned that their low water-solubility did not allow for
a full set of signals to be detected by 13С NMR spectroscopy,
nor for the molecular ions to be visible in LC–MS spectra.
Hydrochloride 21а was crystallized in 81% yield from an
aqueous solution of the potassium salt of acid 5а, itself gen-
erated in situ from 5a and K2CO3, after addition of diluted
0.1 М HCl to adjust the slight acidic pH and slow the evapo-
ration of the mixture at ambient temperature (Scheme 7).
Hydrochlorides 21а,c,e were readily obtained in quantita-
tive yields by bubbling dry HCl through a stirred suspension
of the powdered amidino acids 5a,c,e in anhydrous Et2O in
an ice bath for 1–2 hours.
NaOH, MeOH/H2O
MeO
O
OMe
R1
R2
N
N
CN
CN
NaOMe
MeOH
N
N
H2O
OH
OH
N
N
N
NH2
R1 = R2 = H (12)
O
R1 + R2 = (CH)4 (15)
14
13
NH2
MeO
OMe
NaOMe
MeOH
N
N
O
H2O
N
ONa
24%
N
N
NH2
16
17
O
Scheme 5 Hydrolysis of 2,3-dicyanopyrazine (12) and 2,3-dicyanoqui-
noxaline (15)
1) NaOMe, MeOH
2) H2O
CONH2
CONH2
CN
CN
3) AcOH
N
N
N
+
CO2Me
CN
N
N
N
H
H
H
18
19 (87%)
20
Scheme 6 Hydrolysis of 4,5-dicyanoimidazole (18)
After sequential treatment of 4,5-dicyanoimidazole (18)
by method A or B, diamide 1918a was identified as a major
product (87% yield, Scheme 6). The latter compound was
the only product of 4,5-dicyanoimidazole (18) hydrolysis
with H2SO4.18b In one of our experiments, the methyl ester
of 4-cyano-1H-imidazol-5-carboxylic acid (20)18c was iso-
lated as crystals suitable for X-ray study, but in poor yield.
Similarly, when 1H-1,2,3-triazole-4,5-dicarbonitrile
was treated according to methods A and B, hydrolysis of
both cyano groups led to the formation of a mixture of 5-
cyano-1H-1,2,3-triazole-4-carboxamide (74%) and 1H-
1,2,3-triazole-4,5-dicarboxamide (26%, LC–MS).
Amidino acid formation via 1,1-dimethoxy-3-aminoiso-
indolenines or their aza analogues could be explained on
the basis of pyrrole ring opening of the corresponding in-
termediate by nucleophilic attack of the hydroxide anion at
the dimethoxy carbon followed by hydrolysis.
When Et2O was changed to anhydrous MeOH, HCl bub-
bling at ambient temperature afforded methyl 2-amidino-
benzoate 22a. In anhydrous EtOH or i-PrOH, esterification
failed, probably due to formation of insoluble hydrochlo-
ride 21а. Nevertheless, methyl 22а and ethyl 2-amidino-
benzoate hydrochloride 22b were successfully prepared
under reflux of 5a with excess SOCl2 in methanol or ethanol
(Scheme 8).
Crystalline ester hydrochlorides 22a,b are stable for a
long period of time, but when in contact with moisture, and
especially in aqueous solution, they hydrolyze slowly to
Among the alcohols used, only aqueous MeOH allowed
to produce final products in preparative yields by method
A. The progress of the reaction was equally well promoted
1
form phthalimide 23. The latter is easily identified by H
NMR spectroscopic analysis of a DMSO-d6 solution, where-
Scheme 7 Synthesis of hydrochlorides 21a,c,e and the molecular structure of 21a according to X-ray diffraction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

E
V. A. Tkachuk et al.
Letter
Synlett
NH2
a) R = Me: HCl, MeOH, r.t.
b) ROH (R = Me, Et),
SOCl2, reflux
Cl
NH2
N
O
aq NaHCO3 (10%)
or Et3N, MeOH
NH3
5a
NH
O
97–98%
96%
O
O
4
22a,b
23
OR
H2O
Scheme 8 Esterification of 5a and transformations of esters 22a,b
in a singlet of aromatic protons at δ = 7.78 ppm is observed.
Free bases are unstable: an attempted transformation of ester
hydrochlorides 22a,b into bases on treatment with NaHCO3
or Et3N in MeOH immediately led to intramolecular cycliza-
tion to 3-amino-1H-isoindol-1-one (4, Scheme 8) that had
been synthesized earlier from 2-cyanobenzamide in 80%
yield.19 The tautomeric structure of 4 has been proven by X-
ray diffraction.
which provides a simple direct synthetic entry to a new
type of 1,2-amidino acids from vic-dinitriles when the ste-
ric arrangement of cyano groups would allow the pyrrole
ring closure. The crystalline amidino acids exist in zwitteri-
onic form. This new variety of compounds has potential to
be modified at both the carboxylic and the amidinic func-
tions. Selected examples of chemical behavior of the sim-
plest amidino benzoic acid were demonstrated: protona-
tion, esterification, re-amination with N-nucleophiles in-
cluding hydrazine hydrate, hydroxylamine, and 1,2-
ethylenediamine. The bifunctional scaffolds of this type
could be introduced into peptide chain to mimic an argi-
nine turn. The studies of vic-amidino (hetero)aromatic ac-
ids are in progress in our laboratory and will be reported
soon.
Re-amination is a characteristic feature of amidines, and
selected transformations of amidino acid 5a with hydrazine
hydrate, hydroxylamine, and ethylenediamine were per-
formed (Scheme 9). Six-membered heterocyclization oc-
curred upon interaction with hydrazine hydrate in MeOH
and afforded 4-aminophthalazin-1(2H)-one (24) in quanti-
1
tative yield. Its structure was confirmed by LC–MS, H, 13C
NMR data, and comparative analysis with data of phthalazi-
none 24 that was known to be prepared from 4.20 When
amidino acid 5а was treated with hydroxylamine in MeOH,
five-membered heterocyclization resulted, quantitatively,
in the known 3-(hydroxyimino)-2,3-dihydro-1H-isoindol-
1-one (25).21 Heating of a suspension of 5а in EtOH with an
excess of 70% aqueous 1,2-ethylenediamine followed by
acidification with 10 M HCl to neutral pH afforded 2-(4,5-
dihydro-1H-imidazol-2-yl)benzoic acid (26) in 66% yield.
Its water-solubility and the structure bearing protonated
cyclic amidinic pattern are similar to the parent compound
5a.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588933.
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References and Notes
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NH2
70% aq
H2N(CH2)2NH2
EtOH, reflux
N
NH2NH2•H2O
MeOH
quantitative
N
N
H
O
5a
NH
73%
24
26
O
HN
OH
NOH
(5) Morrissey, M.; Buckman, B.; Mohan, R. WO 9807725A1, 1998;
Chem. Abstr. 1998, 128, 204736
NH2OH•HCl, Et3N
NH
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MeOH
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quantitative
O–
25
O
Scheme 9 Selected re-amination reactions of 5a
In summary, a one-pot green synthesis of vic-amidino
(hetero)aromatic acids from the corresponding 1,2-dini-
triles by hydrolysis in aqueous MeOH catalyzed by equimo-
lar amount of NaOH of in situ generated 1,1-dimethoxy-1H-
isoindol-3-amine or its counterparts was elaborated.22,23
This transformation appears to be a general phenomenon
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

F
V. A. Tkachuk et al.
Letter
Synlett
(c) Anilkumar, G. N.; Zeng, Q.; Rosenblum, S. B.; Kozlowski, J. A.;
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°С. IR (KBr): 3395, 3232, 3092, 2954, 2829, 1667, 1579, 1538,
1468, 1437, 1384 cm–1 1H NMR of MeOH solvate (400 MHz,
.
D2O, 25 °С): δ = 3.32 (s, 2 H, MeOH), 7.52 (d, J = 7.6 Hz, Jm = 0.8
Hz, 1 H, H3), 7.56 (dd, J1 = 7.6 Hz, J2 = 7.6 Hz, Jm =1.2 Hz, 1 H, H4),
7.63 (dd, J1 = 7.6 Hz, J2 = 7.6 Hz, Jm =1.2 Hz, 1 H, H5), 7.73 (d, J =
(9) (a) Yamada, Y.; Kumashiro, I. GB 1158965A, 1969; Chem. Abstr.
1969, 71, 101889 (b) Ajinomoto, C. FP 1437211, 1966; Chem.
Abstr. 1966, 64, 84604
1
7.6 Hz, 1 H, H6). H NMR (400 MHz, D2O, 25 °С): δ = 7.72–7.80
(10) (a) Al-Raqa, S. Y.; ElSharief, A. M. S.; Khali, S. M. E.; Al-Amri, A.
M. Heteroat. Chem. 2006, 17, 634. (b) Ovdiichuk, O. V.;
Hordiyenko, O. V.; Arrault, A. Tetrahedron 2016, 72, 3427.
(c) Ovdiichuk, O. V.; Hordiyenko, O. V.; Medviediev, V. V.;
Shishkin, O. V.; Arrault, A. Synthesis 2015, 47, 2285.
(11) Nasakin, O. E.; Sheverdov, V. P.; Moiseeva, I. V.; Lyschikov, A. N.;
Ershov, O. V.; Nesterov, V. N. Tetrahedron Lett. 1997, 38, 4455.
(12) Elvidge, J. A.; Linstead, R. P. J. Chem. Soc. 1954, 442.
(13) Baumann, F.; Bienert, B.; Rösch, G.; Vollmann, H.; Wolf, W.
Angew. Chem. 1956, 4, 133.
(14) (a) Siegl, W. O. J. Heterocycl. Chem. 1981, 18, 1613. (b) Cookson,
R. C.; Dance, J.; Godfrey, M. Tetrahedron 1968, 24, 1529. (c) Hu,
M.; Brasseur, N.; Yildiz, S. Z.; Van Lier, J. E.; Leznoff, C. C. J. Med.
Chem. 1998, 41, 1789.
(15) Peri, F.; Lorenzetti, C.; Cimitan, S.; Grob, M. WO 2008083918A1,
2008; Chem. Abstr. 2008, 149, 178125
(m, 2 H, H3 + H4), 7.85 (dd, J1 = 7.2 Hz, J2 = 7.2 Hz, 1 H, H5), 7.93
(d, J = 7.6 Hz, 1 H, H6). 13C NMR (100 MHz, D2O, 25 °С): δ = 171.3
(СООH), 166.9 (C(NH2)=NH), 135.2 (С1), 129.8, 127.7, 126.7,
125.8 (С2), 125.7. Anal. Calcd for C8H8N2O2: C, 58.53; H, 4.91; N,
17.06. Found: C, 58.24; H, 4.99; N, 17.38.
2-Carbamimidoyl-3-methoxybenzoic Acid (5с)
Method В; colorless crystals of MeOH solvate (ca. 1:1); yield
1.40 g (62%); mp 190–191 °С (subl.). IR (KBr): 3338, 3069, 1686,
1615, 1579, 1522, 1466, 1432, 1377 cm–1 1H NMR (400 MHz,
.
D2O, 25 °С): δ = 3.33 (s, 3 H, CH3OH), 3.89 (s, 3 Н, OСH3), 7.25 (d,
J = 8.4 Hz, 1 H, HAr), 7.36 (d, J = 8.0 Hz, 1 H, HAr), 7.58 (dd, J1 = 8.0
Hz, J2 = 8.4 Hz, 1 H, H5). 13C NMR (100 MHz, D2O, 25 °С): δ =
175.2 (СООH), 168.5 (C(NH2)=NH), 157.9, 140.3, 134.8, 123.1,
119.4, 115.8, 58.5 (CH3O), 50.9 (CH3OH). Anal. Calcd for
C9H10N2O3×СH3OH: C, 53.09; H, 6.24; N, 12.38. Found: C, 53.30;
H, 6.31; N, 12.76.
(16) Wöhrle, D.; Marose, U.; Knoop, R. Makromol. Chem. 1985, 186,
2209.
2-Carbamimidoyl-3-morpholin-4-ylbenzoic Acid (5d)
Method В; pale yellow crystals of MeOH solvate (ca. 1:1); yield
1.71 g (61%); mp 194–195 °С (dec.). IR (KBr): 3360, 3244, 3064,
2962, 2924, 2858, 2826, 1688, 1610, 1574, 1520, 1430, 1386
(17) (a) Kojima, T.; Nagasaki, F.; Ohtsuka, Y. J. Heterocycl. Chem.
1980, 17, 455. (b) Biitseva, A. V.; Rudenko, I. V.; Hordiyenko, O.
V.; Omelchenko, I. V.; Arrault, A. Synthesis 2015, 47, 3733.
(c) Chattaway, F. D.; Humphrey, W. G. J. Chem. Soc. 1929, 645.
(18) (a) Ohtsuka, Y. J. Org. Chem. 1976, 41, 713. (b) Woodward, D. W.
US 2534331, 1950; Chem. Abstr. 1950, 45, 29788 (c) Chu, D. C.
K.; Cho, J. H.; Kim, H.-J. WO 2007047793, 2007; Chem. Abstr.
2007, 146, 462472
1
cm–1. H NMR (400 MHz, D2O, 25 °С): δ = 3.10 (m, 4 H, Hmorph),
3.45 (s, 4 H, MeOH), 3.95 (m, 4 H, Hmorph), 7.55 (d, J = 7.6 Hz, 1 H,
H4), 7.60 (d, J = 7.6 Hz, 1 H, H6), 7.71 (2×d, J1 = 7.6 Hz, J2 = 7.6 Hz,
1 H, H5). 1H NMR (400 MHz, D2O + HCl, 25 °С): δ = 2.88 (m, 4 H,
H
morph), 3.20 (s, 2 H, MeOH), 3.72 (m, 4 H, Hmorph), 7.58–7.64 (m,
2 H, H4,5), 7.82 (d, J = 6.4 Hz, 1 H, H6). 13C NMR (100 MHz, D2O +
HCl, 25 °С): δ = 168.0 (СООH), 167.0 (C(NH2)=NH), 150.6, 132.8,
129.3, 128.2, 127.7, 127.6, 66.9, 52.7, 48.8. Anal. Calcd for
(19) Spiessens, L. I.; Anteunis, M. J. O. Bull. Soc. Chim. Belg. 1983, 92,
965.
(20) Elvidge, J. A.; Redman, A. P. J. Chem. Soc., Perkin Trans. 1 1972,
2820.
C12H15N3O3·СH3OH: C, 55.50; H, 6.81; N, 14.94. Found: C, 55.84;
H, 6.78; N, 14.63.
(21) Müller, G. Ber. Dtsch. Chem. Ges. 1886, 19, 1491.
(22) Synthesis of Amidino Acids 5a,c–e; General Procedure
Method A
3-Carbamimidoylpyridine-2-carboxylic Acid (5e)
Method В; colorless crystals; yield 1.14 g (69%); mp 250–251 °С.
IR (KBr): 3016, 2360, 1706, 1583, 1565, 1526, 1446, 1428, 1377
To a solution of NaOH (0.4 g, 10 mmol) in aq MeOH (25 mL;
MeOH–H2O, 3:2) 1,2-dinitrile (10 mmol) was added, and the
obtained suspension was brought to reflux with stirring. The
resulting clear solution was refluxed for 15–20 min before the
elimination of ammonia began. Then the hot reaction mixture,
if necessary, was filtered through cotton wool in order to sepa-
rate the phthalocyanine impurities. The solution was left to cool
at r.t. overnight during which time well-firmed crystals were
formed. The crystals were filtered off, washed with MeOH (10
mL), and dried in air. Acidification of the mother liquior with
AcOH (ca. 1 mL) to neutral pH produced an additional portion of
target product.
cm–1 1H NMR (400 MHz, D2O, 25 °С): δ = 7.61 (dd, J1 = 7.6 Hz,
.
J2 = 7.6 Hz, 1 H, H5), 8.04 (d, J = 8 Hz, JM = 1.2 Hz, 1 H, H4), 8.70 (d,
J = 4.4 Hz, 1 H, H6). 13C NMR (100 MHz, D2O, 25 °С): δ = 170.3,
169.0, 162.5, 153.6, 139.6, 133.0, 126.7. 1H NMR (400 MHz, D2O
+ HCl, 25 °С): δ = 8.03–8.06 (m, 1 H, H5), 8.49 (d, J = 7.2 Hz, 1 H,
H4), 8.80 (d, J = 4 Hz, 1 H, H6). 13C NMR (100 MHz, D2O + HCl, 25
°С): δ = 164.0 (СООH), 161.7 (C(NH2)=NH), 146.6, 144.6, 143.1,
129.2, 128.2. Anal. Calcd for C7H7N3O2: C, 50.91; H, 4.27; N,
25.44. Found: C, 51.28; H, 4.34; N, 25.75.
2-(4,5-Dihydro-1H-imidazol-2-yl)benzoic Acid (26)
To a suspension of 2-carbamimidoylbenzoic acid (5a, 0.328 g, 2
mmol) in EtOH (10 mL) was added an excess of 70% ethylenedi-
amine solution in water (1.5 mL, 18 mmol). This reaction
mixture was refluxed until no more ammonia gas was fixed by
pH paper. The obtained clear solution was evaporated under
reduced pressure to a volume of about 5 mL and acidified with a
few drops of 10 M HCl to neutral pH with stirring. After stand-
ing for 2 h, fine colorless crystals were formed and separated by
filtration, washed with EtOH (2 mL), and dried. Colorless crys-
tals of hydrate (1:1); yield 0.277 g (73%); mp 222–223 °С. IR
(KBr): 3382, 3218, 3106, 2944, 2896, 2686, 1628, 1604, 1577,
1556, 1380, 1286 cm–1. 1H NMR (400 MHz, D2O, 25 °С): δ = 4.07
(s, 4 H, CH2), 7.55 (d, J = 7.6 Hz, 1 H, H3), 7.59 (2 × d, J1 = 7.6 Hz,
J2 = 7.2 Hz, 1 H, H4), 7.68 (2 × d, J1 = 7.2 Hz, J2 = 7.2 Hz, 1 H, H5),
Method B
To a freshly prepared solution of MeONa obtained by dissolving
sodium metal (0.23 g, 10 mmol) in MeOH (15 mL), 1,2-dinitrile
(10 mmol) was added. The resulting suspension was stirred at
ambient temperature until TLC showed no starting nitrile. The
obtained solution or suspension was diluted with distilled
water (10 mL), brought to reflux with stirring, and kept under
reflux for 20–25 min before the elimination of ammonia began.
The further workup was as in method A.
2-Carbamimidoylbenzoic Acid (5а)
Method А; colorless crystals of MeOH solvate (ca. 1:0.7) which
lost MeOH on standing in air; yield 1.34 g (72%); mp 179–180
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

G
V. A. Tkachuk et al.
Letter
Synlett
7.76 (d, J = 7.2 Hz, 1 H, H6). 13C NMR (100 MHz, D2O, 25 °С): δ =
173.6 (СООH), 168.7 (C(NH)=NH), 138.0, 132.8, 130.1, 129.0,
128.4, 122.0, 45.0 (2 CH2). Anal. Calcd for C10H10N2O2·H2O: C,
57.68; H, 5.81; N, 13.45. Found: C, 58.03; H, 6.19; N, 13.80. LC–
MS: m/z (%) = 191 (100) [M + H]+.
SHELXL modules.25 Crystallographic data, details of the data
collection and processing, structure solution and refinement
are summarized in Table S1 (see Supporting Information). CCDC
numbers 1509778 (20) and 1509780–1509785 (5e, 4, 21a, 5c,
17) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(23) X-ray diffraction studies of compounds 5c,e, 17, 20, 21a, and 4
were performed on an ‘Xcalibur 3’ diffractometer (graphite-
monochromated Mo Kα radiation (λ = 0.71073), CCD detector,
ω scans). Structure 4 was studied at both low and room tem-
perature. Structures were solved by direct method and refined
against F2 within anisotropic approximation for all nonhydro-
gen atoms using OLEX2 program package24 with SHELXS and
(24) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
(25) Sheldrick, G. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008,
64, 112.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G