The first proton sponge-based amino acids: Synthesis, acid-base properties and some reactivity

Article abstract of DOI:10.1039/c5ob01065a

The first hybrid base constructed from 1,8-bis(dimethylamino)naphthalene (proton sponge or DMAN) and glycine, N-methyl-N-(8-dimethylamino-1-naphthyl)aminoacetic acid, was synthesised in high yield and its hydrobromide was structurally characterised and used to determine the acid-base properties via potentiometric titration. It was found that the basic strength of the DMAN-glycine base (pK_a = 11.57, H₂O) is on the level of amidine amino acids like arginine and creatine and its structure, zwitterionic vs. neutral, based on the spectroscopic (IR, NMR, mass) and theoretical (DFT) approaches has a strong preference to the zwitterionic form. Unlike glycine, the DMAN-glycine zwitterion is N-chiral and is hydrolytically cleaved with the loss of glycolic acid on heating in DMSO. This reaction together with the mild decarboxylative conversion of proton sponge-based amino acids into 2,3-dihydroperimidinium salts under air-oxygen was monitored with the help of the DMAN-alanine amino acid. The newly devised amino acids are unique as they combine fluorescence, strongly basic and redox-active properties.

Full text of DOI:10.1039/c5ob01065a

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Biomol. Chem., 2015, DOI: 10.1039/C5OB01065A.
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The first proton spongeꢀbased amino acids: synthesis, acidꢀbase
properties and some reactivity
Valery A. Ozeryanskii, ∗a Anastasia Yu. Gorbacheva,a Alexander F. Pozharskii,a
Marina P. Vlasenko,a Alexander Yu. Tereznikov b and Margarita S. Chernov’yants b
a Department of Organic Chemistry, Southern Federal University, Zorge str. 7, 344090 Rostov-on-
Don, Russian Federation. E-mail: vv_ozer2@sfedu.ru
b Department of Analytical Chemistry, Southern Federal University, Zorge str. 7, 344090 Rostov-
on-Don, Russian Federation
Abstract: The first hybrid base constructed of 1,8ꢀbis(dimethylamino)naphthalene (proton sponge
or DMAN) and glycine, NꢀmethylꢀNꢀ(8ꢀdimethylaminoꢀ1ꢀnaphthyl)aminoacetic acid, was
synthesised in high yield and its hydrobromide was structurally characterised and used to determine
the acidꢀbase properties via potentiometric titration. It was found that the basic strength of the
DMANꢀglycine base (pKa = 11.57, H2O) is on the level of amidine amino acids like arginine and
creatine and its structure, zwitterionic vs neutral, based on the spectroscopic (IR, NMR, mass) and
theoretical (DFT) approaches, have strong preference to the zwitterionic form. Unlike glycine, the
DMANꢀglycine zwitterion is Nꢀchiral and is hydrolytically cleaved with the loss of glycolic acid on
heating in DMSO. This reaction together with the mild decarboxylative conversion of proton
spongeꢀbased amino acids into 2,3ꢀdihydroperimidinium salts under airꢀoxygen was monitored with
the help of the DMANꢀalanine amino acid. The newly devised amino acids are unique as they
combine fluorescent, strongly basic and redoxꢀactive properties.
Introduction
Amino acids in the form of proteins are Nature's main chemical constituents that perform crucial
role in biosynthesis and function of biological systems, including humans. Outside proteins,
individual amino acids are easily involved in proton transfer processes to give molecules with
charge separated states providing acidꢀbase control in tissues and bloodstream and even acting as
neurotransmitters.1,2 Apart from 23 proteinogenic amino acids, unnatural amino acids (nonꢀstandard
amino acids used in synthetic biology) are presently added to the genetic codes to deeply

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understand structure and function of proteins,3 to introduce labels and fluorescent tags,4 while redox
active amino acids are used to probe and modulate electron transfer.5 New applications as well as
new amino acid compounds with unusual physicochemical and biological properties are
continuously sought.6
From the other side, 1,8ꢀbis(dimethylamino)naphthalene (proton sponge or DMAN, 1), known
for its remarkable proton accepting (pKa = 12.10 in H2O)7 and high electron donating properties (IP1
= 7.05 eV),8 was successfully chosen as a key fragment to construct new hybrid structures with
unique physicochemical behaviour. Over the past decade, by our group and others, this molecule
was linked, mainly via its 4ꢀcarbon atom, to fullerene C60 (redox active compounds),9 4ꢀ
aminonaphthalimide and other electronꢀaccepting groups (pHꢀsensitive fluorescent switches and
colorimetric indicators),10,11 phosphane ligands12 and magnetic cobalt nanoparticles (homogeneous
catalysis and heterogeneous catalysts).13 At the same time, nitrogen derivatization was rarely
explored in DMAN chemistry with the exception of expanding the Nꢀalkyl groups14,15 including
chiral alkyls16 and a few Nꢀacyl derivatives.17 In this context, the main idea of the present work was
to synthesize and investigate reactivity and acidꢀbase properties of proton spongeꢀbased amino acids
2, bearing in mind easiness of formation 1H+, which may lead to 2Z (zwitterionic) as a result of
interꢀ or intramolecular prototropy (Scheme 1). A question of Nꢀchirality of αꢀamino acids is also
discussed.
Scheme 1 Protolytic equilibria between DMAN (1) and its chelated monocation (1H+), and between
neutral (2) and zwitterionic (2Z) DMANꢀbased amino acids.

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Results and discussion
Synthesis, proton transfer reactions and acidꢀbase properties
The protonated DMANꢀbased amino acids, 6a and 6b, were readily synthesized according to
Scheme 2. We started with the proton sponge itself, which was successively monoꢀNꢀdemethylated
to give 318 and then quaternized with methyl esters of αꢀbromoacetic or propionic acids to yield
previously unknown glycine and alanine derivatives either in the form of hydrobromides (4a,b) or
as free bases (5a,b). Both forms could be used to produce airꢀstable and nonꢀhygroscopic salts 6a,b
on heating with aqueous HBr.
Scheme 2 Preparation of hydrobromides 6a and 6b.
Structures of compounds 4–6 were proven using a set of analytical methods. Thus, salts 4 and 6
possess intramolecular Hꢀbonds, and the chelated NH proton resonates in their 1H NMR spectra at δ
= 16.2–17.8 ppm, depending on solvent and substituents. Relatively large 3J(NH,8ꢀNMe2) constants
(3.8–4.5 Hz) are evident for the NH proton is being markedly shifted more to the 8ꢀNMe2 group
than to the other nitrogen, apparently due to electronꢀaccepting nature of the carboxymethyl group,
making the 8ꢀNMe2 fragment more basic.19 The solid state structure of hydrobromide 6a is in
agreement with the solution measurements with the only exception is that the Br– counterion is now
involved in Hꢀbonding with the OH hydrogen. Further details on both Hꢀbonds, [NHN]+ and
[OHBr]–, are given in Fig. 1.

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Fig. 1 ORTEP plot for Xꢀray structure of 6a with two Hꢀbonds marked in blue (P = 50%, 100 K).
Key lengths (Å) and angles (o): N(2)–H(2N) 1.08(4), H(2N)...N(1) 1.59(4), N(2)...N(1) 2.610(4),
N(2)–H(2N)...N(1) 156(2), O(2)–H(2O) 0.95(6), H(2O)...Br(1) 2.22(5), O(2)...Br(1) 3.154(4),
O(2)–H(2O)...Br(1) 165(3).
1
All three N–Me groups in salts 4a and 6a are displayed in the H and 13C NMR spectra as
separate peaks, which proved the [NHN]+ bond in their molecules is a good lock for preventing
stereoconversion, and hence the DMANꢀglycine derivatives adopt Nꢀchirality. This is in contrast to
proton sponges with Nꢀbenzyl substituents, which are quite stereolabile in the NMR timeꢀscale even
in the form of salts.20 The NMR picture is even more complex in the case of alanine derivatives 4b
and 6b, which owing to two stereogenic centres, the N(1) and C(α) atoms, exist as a mixture of
diastereomers.
Hydrobromide 6a was used to estimate the acidꢀbase strength of proton spongeꢀbased amino
acids, as it is soluble in water and does not capture any solvent molecule even being recrystallized
from aqueous alcohol. This salt was subjected to potentiometric titration (see the ESI for details)
and the results presented in Scheme 3 (in water scale) are average of at least three runs.

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Scheme 3 Protolytic equilibria constants between anionic 7 and cationic 6a counterparts of amino
acid 2a given in the form of zwitterion 2aZ.
As seen, the nitrogen basicity of the DMANꢀglycine base (2a) (pKa = 11.57) is somewhat lower
than that of the parent DMAN (pKa = 12.10) and is on the level of arginine (pKa = 12.48) and
creatine (pKa = 10.57), the most basic natural amino acids. Noteworthy, the isoelectric point of 2a
lies near the physiological pH values and is almost equal to that of histidine (pHi = 7.60).1,21
It was rather intriguing to find out the real form (neutral 2 or zwitterionic 2Z) the proton
sponges extended by acidic groups adopt in different media. To do so, both amino acids 2a,b were
isolated using deprotonation of salts 6a,b by aqueous ammonia as depicted in Scheme 4.
Subsequent extraction with CH2Cl2 was quite fortunate owing to hydrophobic naphthyl and methyl
substituents and gave high yields of pure amino acids. Compounds 2a,b are hygroscopic, readily
soluble in water and alcohols, while their insolubility in Et2O and hydrocarbons provides a strong
hint that DMANꢀbased amino acids possess zwitterionic structures 2Z in the condensed state.
Scheme 4 Isolation of amino acids 2a,b.
In fact, other spectroscopic techniques (IR and NMR) confirmed this conclusion. Thus, IR
spectra recorded in KBr contain strong vibration bands of a carboxylate fragment near 1625–1626
and 1395–1398 cm–1. The 1H NMR spectra of 2a,b (in DMSOꢀd6, CD3CN or CDCl3) display the N–
Me signals near or well above 3.0 ppm and a very lowꢀfield peak (δ 17.7–18.1 ppm) of the chelated
[NHN]+ proton, which are characteristic for the proton sponge cations.14

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At the same time, gas phase EIꢀMS behaviour of 2a and 2b very close resembles much of the
fragmentation mode of neutral DMAN 1.22 Some details of the fragmentation are given in the ESI
(see Fig. S1). The main pathways being the loss of Nꢀmethylglycine and Nꢀmethylalanine or their
Nꢀdeprotonated radicals to give Nꢀmethylbenz[c,d]indolium ion (m/z 168, 100%). Gas phase
decarboxylation of amino acids 2a,b is not a characteristic feature of these compounds and the
probability of [M – CO2]+ fragmentation route does not exceed 17% in both cases.
DFT calculations undertaken to establish relative stability of the proton spongeꢀbased amino
acids (B3LYP/6ꢀ31G**, see Table S1 in the ESI) have shown that neutral 2a is by 16.0 kcal/mol
more stable in the gas phase over zwitterion 2aZ, although solvation (DMSO) strongly minimize
this difference (up to 2.3 kcal/mol) and even make 2aZ by 2.3 kcal/mol more stable over 2a in H2O
media. Although we did not try water clusters, one water molecule calculated to form Hꢀbridged
structures of type 2aꢀH2O (see the ESI for details) is also able to decrease the energy difference
between 2a and 2aZ to a somewhat over 2 kcal/mol.
Interestingly that in the gas phase the NH proton in calculated zwitterion 2aZ, obviously due to
electrostatic attraction between the opposite charges, is shifted more to the N(1) nitrogen atom
(Table S1). On the whole, these results are in line with the wellꢀknown fact that zwitterionic forms
of the αꢀamino acids are less stable than their neutral counterparts in the gas phase, starting from
glycine to the most basic arginine,23 although there is a general trend of enhanced zwitterion
stabilization with increasing basicity.24
Thermal behaviour, hydrolytic scission and oxidative transformations
The first step to investigate any unusual reactivity the proton sponge moiety can bring to DMANꢀ
based amino acids was an attempted intramolecular acylation in ester 5a. There were some close

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precedents in the literature, although much more successful for sixꢀmembered ring cyclisations
(Scheme 5).25
CH2CO2Et
N
N
N
N
O
PPA
X
210 o
C
Me
Me
(CH2)2CO2H
N
N
N
N
PPA
O
120 oC, 3 h
83%
O
O
(CH2)2CN
N
N
N
N
57% HClO4
O
reflux, 2.5 h
99.5%
Scheme 5 Literature examples of orthoꢀacylation.
In our case, as compound 5a is more flexible with its nitrogen atoms not involved in the
pyrimidine ring, the orthoꢀcyclisation may lead to benzo[g]indolone derivative 8.
Me
Me2N
N
O
8
We have shown that compound 5a on heating with 57% HClO4 is completely destroyed, heating
with conc. aqueous HCl gave only carboxylic acid 6a as chloride, and heating in PPA at 110–120
oC for 4 h followed by KOH neutralisation and methylene chloride extraction gave nothing but
anion 7, which was isolated in 95% yield as hygroscopic potassium salt and fully characterised by
spectral data.
Dissolution of ester 5a together with one equivalent of Lewis acid BF3·Et2O in anhydrous
o
CH2Cl2 followed by layering with Et2O and keeping the reaction mixture at –20 C for 6 d resulted
in diffusion crystallisation of the product, which, in fact, turned out to be the hydrogen
tetrafluoroborate salt of 5a, 5a·HBF4 (yield 19%), but not the expected difluoroborate complex;
most of 5a remained unchanged. A similar reaction was earlier observed for some heterocyclic

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superbasic compounds,26 and may be rationalise in light of the wellꢀknown tendency of strongly
destabilised neutral proton sponges to remove electrostatic and steric strain, so the protonation is
frequently the simplest way.14
Thermolysis of hydrobromide 6a in DMSOꢀd6 has proved this salt is stable below 130 oC, but a
o
spontaneous decomposition occurred above 135 C to yield complex mixture of unidentifiable
products. From the other hand, potassium salt 7 was found unchanged in this solvent even at 150 oC
for 30 h. Unlike its cationic and anionic forms, the amino acid 2a, via transient diaminonaphthalene
3, already at 120–125 oC gave 1,3ꢀdimethylꢀ2,3ꢀdihydroperimidine (9), which then gradually turned
into other oxidation products; the main one being aromatic perimidinium salt 10. Interestingly,
DMANꢀalanine amino acid 2b produces the same reaction products (see Fig. S2 for a representative
run) and, hence, the overall transformation may be described by Scheme 6.
Me
–
H
+
H
Me
CO
+
2
Me2N
N
Me2N
N
R
H2O-DMSO, 125 o
– HOCHRCO2H
C
3
2Z R = H,Me
HOCHRCO2H
2
3
1
+
N
Me
Me
Me
Me
N
N
N
4
5
9
HOCHRCO2H
DMSO
X–
8
7
6
10
9
Scheme 6 Transformation of amino acids 2Z on heating in wet DMSO.
Apparently, the reaction starts with hydrolytic cleavage of the amino acid side chain to give 3
and a corresponding hydroxyacid. In a separate experiment (heating with 1 equiv. of glycolic acid
in DMSOꢀd6), we have shown that diamine 3 is indeed oxidised into heterocyclic product 9 and
then into 10. No transformations of type 3 → 9 and 9 → 10 occur until glycolic or lactic acids are
1
added to hot DMSO. In the H NMR spectra, compounds 9 and 10 have very characteristic singlet
peaks of the C(2)ꢀprotons at δ 4.14 and 9.0–9.2 ppm, respectively, which are easily identified and
monitored. The X– in 10 is glycolate or lactate anions and the yields of 3, 9, and 10 did not exceed
35%, 19%, and 65% at their maximum (see Table S2). It should also be stressed that

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transformations 2 → 10 were never complete as oxyacids gradually turn amino acids 2 into more
inert cationic forms 6 (there is raising in acidity in the reaction mass because the basicity of
aromatic amines 3 and 9 is very low7b,14) thus providing inhibition.
Finally, another interesting transformation of amino acids 2a,b was found, in which the amino
acid side chain is now involved. To specify, hydrobromide 6a is able to cyclize quantitatively into
2,3ꢀdihydroperimidinium salt 12a under airꢀoxygen in the presence of 1 equiv. or lesser of a mild
base such as DMAN or pyridine (Scheme 7, Table 1).
Me
Me
Me
Me
Me
Me
+
N
H
+
N
N
N
CH2CO2H
O2-air, B:
Br–
Br–
20–25 o
B—HBr
OH–
C
6a
12a
B: – B—HBr
Me
Me
Me
H
– H2O
Br–
– B:
N
N
+
–
CH2CO2
H2C
N:
Me
Me
Me
Me
Me
+
N
N
N
Me
CH2CO2H
[O]
– e, – H, – CO2
2a
11
Scheme 7 Proposed baseꢀpromoted oxidative mechanism of conversion 6a → 12a.
Table 1 Baseꢀpromoted oxidation of hydrobromide 6a into perimidinium salt 12a
Run Solvent
Base
Time (d) Degree of conversion (%)a
1
2
3
4
5
DMSO DMAN
DMSO DMAN
DMSO DMAN
4b
2
4
24
6
42
Py
Py
Py
Py
1
30
4
100c
a Yields based on 1H NMR. b Without airꢀbubbling. c Isolated yield 60%.
The reaction starts with the in situ generation of equilibrium amounts of 2a, which then after
oxidative decarboxylation produces methyleneiminium cation 11, quickly cyclizing into 1,1,3ꢀ

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10
trimethyl cation isolated as bromide 12a. Earlier, cyclization of DMAN into 2,3ꢀ
dihydroperimidinium salts was well documented under the action of different oxidants such as
transition metal complexes,27 carbonium centres in the orthoꢀposition28 or simple airꢀoxygen owing
to strong electronꢀdonating substituents in the aromatic ring.29 Next, we have proved that methyl
ester 4a(5a) is inert in this reaction, which is evident that the decarboxylation step should precede
the cyclization in accord with Scheme 7.30 We also found that strong ionic bases such as KOH,
generating only anion 7, inhibit the process, and no reaction was observed without adding a base or
keeping the reaction mass in an inert atmosphere. As seen from Table 1 (cf. runs 2 and 5), milder
bases provide faster turnout, as the initially formed salt B·HBr has to take HBr off and let B enter
the catalytic cycle back. Similarly to 6a, the reaction of salt 6b ends after six days of oxidation at
room temperature in pyridine to give heterocyclic salt 12b as the only isolable product.
Me
Me
Me
+
Me
N
N
Br–
12b
Structures of compounds 12a,b were established using a set of analytical methods and, in the
case of 12a, Xꢀray diffraction data. Interestingly, bromide 12a crystallises as dihydrate with the
bromide anion and water molecules have been found to form endless uneven ribbons of alternating
roughly fiveꢀmembered Hꢀbonded cycles, while the 2,3ꢀdihydroperimidinium cations are situated at
both sides of the ribbon with no appreciable interaction between them (Fig. 2). This type of water
and anion arrangements is rarely observed in crystal engineering of organic molecules (cf. ref. 31).

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Fig. 2 ORTEP plot for Xꢀray crystal structure of 12a with the ribbonꢀlike Hꢀbond network between
bromide and water molecules (P = 50%, 120 K). Key lengths (Å) and angles (o): O(1)...Br(1)
3.319(2), O(2)–H...Br(1) 173(2), O(2)...Br(1) 3.361(2), O(2)–H...Br(1) 170(2), O(1)...O(2)
2.733(2), O(1)–H...O(2) 176(2), O(2)...O(1) 2.756(3), O(2)–H...O(1) 168(3).
Unlike simple proton salts of DMAN and neutral DMAN 1, DMANꢀbased amino acids and
derivatives are all fluorescent in solutions when protonated to form [NꢀHꢀN]+ bridges (compounds
2, 4, and 6) but are not fluorescent when their nitrogen atoms are neutral (compounds 5 and 7). This
opens a simple possibility to introduce pHꢀsensitive fluorescent tags into supramolecular motifs and
protein molecules.
Conclusions
In summary, we have for the first time obtained and studied proton sponges fused via nitrogen
atoms with alanine and glycine residues. The proton sponge moiety renders to these hybrids high
basicity and unusual reactivity, which depends on the form (anionic, neutral, or cationic) the
DMANꢀbased amino acids treated. The most reactive form is neutral, which in fact zwitterionic in

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condensed media. Unlike most amino acids, this form could be 'disassembled' on heating in wet
DMSO to give 1ꢀdimethylaminoꢀ8ꢀmethylaminonaphthalene and the corresponding oxyacid, while
oxidation with airꢀoxygen, although slowly, gave 2,3ꢀdihydroperimidinium salts as a result of
decarboxylation and heterocyclization. Overall, these compounds may find an application, when
redoxꢀactive and fluorescent amino acids are sought, combining the properties of strong but mild
nitrogen bases.
Experimental
13
General. NMR spectra were recorded on a Bruker DPXꢀ250 (250 MHz for 1H, 62.9 MHz for C)
spectrometer with the solvent residual peaks as the internal standard (δ/ppm, J/Hz). IR spectra were
measured on a FT FSMꢀ1202 spectrometer. Mass spectra were obtained from a Finnigan MAT
INCOS 50 instrument (electron impact, 70 eV). Thin layer chromatography was carried out on
Al2O3 and on silica gel (70–230 mesh, Aldrich). The progress of reactions and the purity of
products were monitored by TLC on Al2O3 and Silufol plates; development with iodine and
bromine vapours. The melting points were measured in sealed capillaries and are uncorrected. The
solvents
were
purified and
dried
by standard
methods. 1ꢀDimethylaminoꢀ8ꢀ
methylaminonaphthalene (3) was prepared as described previously.18 Methyl 2ꢀbromopropionate
(97%) was purchased from Alfa Aesar.
Methyl NꢀmethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)aminoacetate hydrobromide (4a). Methyl
bromoacetate (1.04 mL, 1.1 mmol) was added to a solution of amine 3 (200 mg, 1.0 mmol) in dry
toluene (7 mL) and acetonitrile (7 mL). The mixture was refluxed with CaCl2ꢀtube protection until
the starting amine is consumed (~3 h, TLC control, Silufol plates, CHCl3). The solvent was
evaporated, the crude product was recrystallized from acetonitrile and washed with diethyl ether to
1
afford 4a (321 mg, 91%) as light grey crystals; mp 125–127 °C. H NMR (DMSOꢀd6): δ = 2.90 (s,
3H, 1ꢀNMe), 3.29 and 3.45 (both d, J = 4.4 and J = 4.4, 6H, 8ꢀNMe2), 3.69 (s, 3H, OMe), 4.36
(ABq, J = 17.2, 2H, N–CH2CO), 7.71 (t, J = 7.7, J = 8.1, 1H, 3ꢀH), 7.77 (t, J = 7.7, J = 8.1, 1H, 6ꢀ

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H), 7.99 (dd, J = 1.0, J = 7.7, 1H, 2ꢀH), 8.07 (t, J = 1.7, J = 8.1, 1H, 4ꢀH), 8.17 (d, J = 7.4, 1H, 5ꢀ
13
H), 8.27 (dd, J = 1.0, J = 7.7, 1H, 7ꢀH), 16.80 (br. s, 1H, NHN+). C NMR (DMSOꢀd6): δ = 46.8
(1ꢀNMe), 47.7 and 47.8 (8ꢀNMe2), 53.2 (OMe), 58.8 (N–CH2), 120.9, 122.0, 124.6, 127.3, 128.3,
129.1, 131.1, 135.9, 142.3, 147.2, 171.5 (C=O). IR (Nujol) (ν/cm–1): 3467, 3411; 1732 (C=O);
1630; 1608, 1524 (Ar); 1228, 1208 (C–O–C). C16H21BrN2O2 (353.25): calcd. C 54.40, H 5.99, N
1
7.93; found C 54.36, H 6.01, N 7.88. H NMR (CD3СN, data for HBF4 salt; mp 137–139 °C): δ =
2.91 (s, 3H, 1ꢀNMe), 3.27 and 3.40 (both d, both J = 4.7, both 3H, 8ꢀNMe2), 3.73 (s, 3Н, OMe),
4.19 (s, 2Н, N–CH2CO), 7.67–7.83 (m, 3Н), 7.97–8.04 (m, 2Н), 8.12 (dd, J = 1.0, J = 8.4, 1H),
16.90 (br. s, 1Н, NHN+). MS (data for HBF4 salt), m/z (I (%)): 273 [M]+ (18), 272 (100), 213 (43),
199 (68), 198 (46), 197 (86), 184 (52), 183 (52), 182 (78), 170 (57), 169 (29), 168 (95), 167 (25),
154 (21), 127 (30), 99 (62), 91 (15), 49 (29), 42 (20).
Methyl 2ꢀ[NꢀmethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)amino]propionate hydrobromide (4b).
Methyl 2ꢀbromopropionate (0.70 mL, 6.25 mmol) was added to a solution of diaminonaphthalene 3
(250 mg, 1.25 mmol) in dry ethyl acetate (15 mL). The mixture was refluxed for 100–130 h with
CaCl2ꢀtube and light protection until the starting amine is consumed (TLC control, Silufol plates,
CHCl3). The solvent was evaporated and the residue was recrystallized from acetonitrile to afford
4b (357 mg, 78%) as light yellow crystals with mp 186–188 °C (decomp.). 1H NMR (CD3СN): δ =
1.05 (d, J = 7.0, 2.3Н), 1.70 (d, J = 6.7, 0.9Н), 2.91 (s, 2.3Н), 2.98 (s, 1Н), 3.18 (d, J = 2.4, 0.25Н),
3.30 (d, J = 4.5, 2.4Н), 3.40–3.47 (m, 5.2Н, 8ꢀNMe2), 3.89 (s, 2H), 4.17–4.25 (m, 0.7H, N–CH),
4.29–4.37 (m, 0.3Н, N–CH), 7.62–7.87 (m, 2.8Н), 7.97–8.19 (m, 3Н), 16.83 (br. s, 0.3Н, NHN+),
13
17.57 (br. s, 0.7Н, NHN+). C NMR (CD3CN): δ = 16.2, 17.2, 42.0, 45.3, 45.7, 46.2, 47.0, 47.8,
52.2, 53.0, 63.2 and 64.2 (N–CH), 120.6, 120.7, 121.1, 121.5, 123.8, 125.6, 126.5, 126.7, 127.4,
127.5, 128.6, 128.8, 130.5, 130.7, 135.5, 135.6, 140.9, 141.3, 142.1, 146.2, 173.3 and 174.7 (С=О).
C17H23BrN2O2 (367.28): calcd. C 55.59, H 6.31, N 7.63; found C 55.48, H 6.44, N 7.59.
Methyl NꢀmethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)aminoacetate (5a). 10% aqueous KOH (15
mL) was added to a solution of hydrobromide 4a (300 mg, 0.85 mmol) in acetonitrile (3 mL). The

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mixture was shaken and extracted with nꢀhexane (3 × 10 mL). The extract was dried with
anhydrous Na2SO4. The crude product obtained after solvent evaporation was purified by column
1
chromatography (silica gel, ethyl acetate) to afford 5a (171 mg, 74%) as light brown oil. H NMR
(CDCl3): δ = 2.65 (br. s, 6H, 8ꢀNMe2), 3.10 (s, 3H, 1ꢀNMe), 3.47 and 3.76 (both br. s, 2H, N–
CH2CO), 3.69 (s, 3H, OMe), 6.95 (dd, J = 1.3, J = 7.3, 1H, 2ꢀH), 7.04 (dd, J = 1.3, J = 7.3, 1H, 7ꢀ
13
H), 7.26–7.33 (m, 2H, 6ꢀH, 3ꢀH), 7.34–7.40 (m, 2H, 5ꢀH, 4ꢀH). C NMR (CDCl3): δ = 40.3 (1ꢀ
NMe), 42.2 and 47.5 (8ꢀNMe2), 51.5 (OMe), 59.7 (N–CH2), 113.6, 113.8, 120.2, 122.8, 122.9,
125.8, 126.0, 138.3, 149.4, 150.8, 172.1 (C=O). IR (liquid film) (ν/cm–1): 3051, 2993, 2950, 2864,
2828, 2785 (C–H); 1751 (C=O); 1607, 1575, 1504 (Ar); 1247, 1225, 1202, 1174, 1140 (C–O–C).
C16H20N2O2 (272.34): calcd. C 70.56, H 7.40, N 10.29; found C 70.50, H 7.42, N 10.36.
Methyl 2ꢀ[NꢀmethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)amino]propionate (5b). The compound
was prepared from hydrobromide 4b (367 mg, 1 mmol) similarly to 5a. The crude product obtained
after solvent evaporation was purified by column chromatography (silica gel, EtOAc) to afford 5b
(260 mg, 91%) as colourless oil. 1H NMR (CDCl3): δ = 0.86–0.91 (m, 1Н), 1.06 (br. d, J = 7.2, 2Н),
1.27 (br. s, 1.4Н), 1.51 (br. d, J = 6.4, 0.9Н), 2.56 (s, 2Н), 2.65 (s, 2.8Н), 2.87 (br. s, 0.9Н), 3.04
(br. s, 0.9Н), 3.10 (s, 1.8Н), 3.38 (br. s, 0.7Н), 3.74 (s, 1.7Н), 3.97–4.12 (m, 0.7Н, N–CH), 6.92–
7.02 (m, 1.5Н), 7.16 (br. d, J = 6.6, 0.3Н), 7.25–7.41 (m, 3.2Н). MS, m/z (I (%)): 286 [M]+ (63),
227 (33), 199 (100), 198 (34), 197 (35), 184 (48), 168 (30). C17H22N2O2 (286.37): calcd. C 71.30, H
7.74, N 9.78; found C 71.36, H 7.70, N 9.71.
NꢀMethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)aminoacetic acid hydrobromide (6a). A solution of
methyl ester hydrobromide 4a (200 mg, 0.56 mmol) in 45% aqueous HBr (4.4 mL) was heated on
o
water bath at 100 C for 1 h. The crude product obtained after evaporation of volatiles to dryness
was washed with diethyl ether to afford 6a (184 mg, 96%) as light brown crystals (fluorescent in
1
solutions under UVꢀlight); mp 236–238 ºC (decomp.). H NMR (DMSOꢀd6): δ = 2.90 (s, 3H, 1ꢀ
NMe), 3.25 and 3.41 (both br. d, J = 4.1 and 3.8, 6H, 8ꢀNMe2), 4.25 (ABq, J = 17.1, 2H, N–CH2),
7.67–7.78 (m, 2H, 6ꢀH, 3ꢀH), 7.97 (d, J = 7.3, 1H, 2ꢀH), 8.06 (d, J = 7.9, 1H, 4ꢀH), 8.16 (d, J = 8.2,

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1H, 5ꢀH), 8.24 (d, J = 7.6, 1H, 7ꢀH), 13.14 (br. s, 1H, CO2H), 17.07 (s, 1H, NHN+). 13C NMR
(DMSOꢀd6): δ = 46.6 (1ꢀNMe), 47.5 and 47.6 (8ꢀNMe2), 59.1 (N–CH2), 120.9, 121.9, 124.4, 127.2,
128.2, 128.9, 130.9, 135.8, 142.5, 147.3, 172.2 (C=O). MS, m/z (I (%)): 259 [M]+ (8), 258 (49), 214
(30), 199 (70), 198 (27), 197 (56), 184 (67), 183 (82), 182 (70), 170 (66), 169 (28), 168 (100), 167
(25), 154 (21), 127 (32), 99 (48), 91 (16), 82 (23), 80 (24), 44 (28), 42 (23). C15H19BrN2O2
(339.23): calcd. C 53.11, H 5.65, N 8.26; found C 53.20, H 5.57, N 8.30.
2ꢀ[NꢀMethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)amino]propionic acid hydrobromide (6b). The
compound was prepared from hydrobromide 4b (150 mg, 6.6 mmol) as described above for 6a. The
residue obtained after solvent evaporation was recrystallized from acetonitrile to afford light grey
1
crystals of compound 6b (130 mg, 90%); mp 228–230 °C (decomp.). H NMR (CD3CN): δ = 1.16
(d, J = 7.0, 2.5Н), 1.72 (d, J = 7.0, 1.4Н), 2.94 (d, J = 1.0, 3.8Н), 3.25 (d, J = 4.5, 2.8Н), 3.32–3.40
(m, 4.5Н), 4.14–4.23 (m, 0.8Н), 4.30–4.40 (m, 0.3Н), 7.65–7.78 (m, 2.7Н), 7.86 (dd, J = 1.3, J =
7.4, 0.7Н), 7.93–8.16 (m, 3Н), 16.98 (br. s, 0.2Н, NHN+), 17.78 (br. s, 0.7Н, NHN+). 13C NMR
(DMСOꢀd6): δ =17.1, 17.9, 42.5, 45.7, 45.9, 46.4, 47.3, 47.9, 63.0 and 64.0 (N–CH), 120.8, 212.2,
122.0, 124.2, 126.3, 126.8, 127.0, 127.7, 127.8, 128.6, 129.0, 130.5, 130.8, 135.3, 135.5, 141.6,
142.2, 142.7, 147.1, 174.5 and 175.8 (С=О). C16H21BrN2O2 (353.25): calcd. C 54.40, H 5.99, N
7.93; found: C 54.44, H 5.93, N 7.90.
NꢀMethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)aminoacetic acid, zwitterion (2aZ). 25% aqueous
ammonia (0.2 mL) was added to a solution of hydrobromide 6a (100 mg, 0.3 mmol) in water (1.4
mL). The resulting mixture was evaporated to dryness and the solid residue was extracted with
methylene chloride (5 × 20 mL). The crude product obtained after solvent evaporation was washed
with diethyl ether to afford amino acid 2aZ (58 mg, 77%) as brown hygroscopic caramel,
quickly liquefying on air (fluorescent in solutions under UVꢀlight); mp 63–65 ºC (decomp. with
1
water loss then decomp. above 203–205 ºC). H NMR (CDCl3): δ = 2.94 (s, 3H, 1ꢀNMe), 3.32 and
3.53 (both s, 6H, 8ꢀNMe2), 4.00 (ABq, J = 16.1, 2H, N–CH2), 7.55–7.67 (m, 3H, 2ꢀH, 3ꢀH, 6ꢀH),
7.83 (d, J = 7.7, 1H, 4ꢀH), 7.90 (d, J = 8.2, 1H, 5ꢀH), 8.19 (d, J = 7.5, 1H, 7ꢀH), 17.67 (br. s, 1H,

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NHN+). 13C NMR (CDCl3): δ = 46.8 (1ꢀNMe), 47.3 and 48.6 (8ꢀNMe2), 61.4 (N–CH2), 120.0, 122,
123.7, 127.3, 127.7, 128.9, 130.4, 136.0, 142.5, 146.3, 172.6 (C=O). IR (ν/cm–1), (KBr): 3432 (br.
–
–
H2O); 2938 (C–H); 1625 (νasCO2 ), 1395 (νsCO2 ); 1605, 1468 (Ar); 1034, 835, 773, 747. MS, m/z
(I (%)): 258 [M]+ (27), 226 [M – MeOH]+ (29), 214 [M – CO2]+ (17), 199 [M – CH2CO2H]+ (52),
198 [M – CH3CO2H]+ (32), 197 [M – CH3CO2H – H]+ (65), 184 [M – CH2CO2H – Me]+ (57), 183
(72), 182 (73), 170 [M – N(Me)CH2CO2H]+ (54), 169 [M – MeNHCH2CO2H]+ (30), 168 [M –
MeNHCH2CO2H – H]+ (100), 167 (33), 154 (29), 140 (15), 128 (21), 127 (50), 126 (18), 115 (17),
99 (45), 91 (19), 82 (21), 80 (22), 77 (20), 44 (14), 42 (26). C15H18N2O2 (258.32): calcd. C 69.74, H
7.02, N 10.84; found C 69.81, H 6.95, N 10.93.
2ꢀ[NꢀMethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)amino]propionic acid, zwitterion (2bZ) was
prepared similarly to 2aZ from hydrobromide 6b (28 mg, 0.079 mmol). The crude product obtained
after solvent evaporation was washed with diethyl ether to afford brown caramel (15.4 mg, 70%
yield), quickly liquefying on air (fluorescent in solutions under UVꢀlight) with mp 80–82 °C
1
(decomp.). Н NMR (CDCl3): δ = 1.20–1.14 (m, 3Н), 2.84 (d, 1.7Н), 3.02 (s, 0.9Н), 3.08 (s, 3Н),
3.30 (s, 3Н), 3.36 (s, 3.3Н), 3.54–3.62 (m, 0.6Н), 3.96 (m, 4Н), 7.42–7.48 (m, 1.1Н), 7.55–7.68 (m,
3.6Н), 7.88 (br. d, 1Н), 7.91 (br. d, 1Н), 8.09 (d, 1Н), 18.10 (br. s, 1Н, NHN+). 13C NMR (CDCl3):
δ = 9.2, 18.0, 29.9, 36.1, 44.5, 46.8, 47.2, 47.9, 48.3, 66.8 and 64.7 (N–CH), 118.0, 122.12, 122.15,
123.0, 124.6, 126.7, 126.8, 127.4, 127.7, 127.9, 129.7, 130.5, 136.5, 138.0, 142.7, 144.5, 147.0,
147.7, 175.9 and 176.6 (С=О). IR (ν/cm–1), (KBr): 3430 (br. H2O); 2956, 2924, 2854 (C–H); 1626
–
–
(νasCO2 ), 1398 (νsCO2 ); 1627, 1466 (Ar); 1034, 774. MS, m/z (I (%)): 272 [M]+ (28), 228 (18),
213 (21), 199 (68), 198 (28), 197 (41), 185 (17), 184 (100), 183 (84), 182 (70), 170 (32), 169 (22),
168 (100), 167 (57), 154 (22), 127 (26), 44 (10), 42 (16), 29 (16), 28 (30), 27 (60), 18 (30), 14 (19).
C16H20N2O2 (272.34): calcd. C 70.56, H 7.40, N 10.29; found C 70.60, H 7.45, N 10.21.
Potassium NꢀmethylꢀNꢀ(8ꢀdimethylaminonaphthꢀ1ꢀyl)aminoacetate (7).
A
solution of
hydrobromide 6a (50 mg, 0.14 mmol) in water (1 mL) was neutralized with 10% aqueous KOH to
pH 8 and evaporated to dryness. The solid residue was extracted with methylene chloride (2 × 20

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mL). After that, the solvent was evaporated to afford acetate 7 (41 mg, 95%) as brownish
1
hygroscopic caramel, quickly liquefying on air; mp 128–130 °C (decomp). H NMR (CDCl3): δ =
2.83 (s, 6H, 8ꢀNMe2), 2.97 (s, 1H, 1ꢀNMe), 3.65–3.72 (m, 2H, N–CH2–CO), 7.19–7.26 (m, 1H, 7ꢀ
H), 7.29–7.39 (m, 3H, 2ꢀH, 3ꢀH, 6ꢀH), 7.47–7.54 (m, 2H, 4ꢀH, 5ꢀH). 1H NMR (DMSOꢀd6): δ = 2.66
(s, 6H, 8ꢀNMe2), 2.94 (s, 3H, 1ꢀNMe), 3.47 (br. s, 2H, N–CH2), 6.93 (dd, J = 7.5, J = 1.2, 1H), 6.99
13
(dd, J = 7.4, J = 1.2, 1H), 7.22–7.37 (m, 4H). C NMR (DMSOꢀd6): δ = 41.7 (1ꢀNMe), 44.0 and
46.3 (8ꢀNMe2), 60.7, 114.8, 115.5, 120.0, 122.9, 123.4, 126.4, 126.5, 137.9, 149.3, 150.2, 172.9
(C=O). C15H17KN2O2 (296.41): calcd. C 60.78, H 5.78, N 9.45; found C 60.85, H 5.71, N 9.50.
1,1,3ꢀTrimethylꢀ2,3ꢀdihydroꢀ1Hꢀperimidinꢀ1ꢀium bromide (12a). Air was bubbled through a
solution of hydrobromide 6a (68 mg, 0.2 mmol) in pyridine (5 mL) for 4 days at room temperature.
The solvent was evaporated and the crude oxidation product was washed with diethyl ether, the
solid residue was dissolved in ethanol and purified with activated charcoal on boiling. After that the
mixture was filtered and evaporated to dryness to afford light brown crystals of salt 12a (35 mg,
1
60%) with mp 167–169 °С (decomp.). Н NMR (CD3CN): δ = 3.33 (s, 3Н, 3ꢀNMe), 3.59 (br. s,
6.3Н, 1ꢀNMe2), 5.05 (br. s, 2Н, N–CH2–N), 7.03 (dd, J = 1.1, J = 7.4, 0.9H, 4ꢀH), 7.56 (dd, J = 1.1,
J = 8.2, 1Н, 6ꢀН), 7.60–7.67 (m, 2Н, 8ꢀН, 5ꢀН), 7.85 (d, J = 7.7, 1H, 9ꢀH), 8.04 (dd, J = 0.5, J =
8.2, 1H, 7ꢀH). 13С ЯМР (CD3CN): δ = 36.7 (1ꢀNMe), 51.4 (8ꢀNMe2), 78.6 (NCH2N), 108.2, 115.0,
119.1, 125.8, 128.4, 130.3, 134.7, 139.4, 139.9. C14H17BrN2·2H2O (329.23): calcd. C 51.07, H 6.43,
N 8.51; found C 51.14, H 6.40, N 8.53.
1,1,2,3ꢀTetramethylꢀ2,3ꢀdihydroꢀ1Hꢀperimidinꢀ1ꢀium bromide (12b). Compound was prepared
similarly to 12a from hydrobromide 6b (84 mg, 0.2 mmol) for 6 days. After boiling with activated
charcoal and filtration, ethanol was evaporated to afford 12b as light brown caramel (38 mg, 52%)
1
with mp 78–80 °C (decomp.). Н NMR (CD3CN): δ = 1.26 (br. d, J = 6.3, 1Н, N–C(Me)–N), 3.22
(s, 3.1Н, 3ꢀNMe), 3.52 and 3.78 (both s, both 3Н, 1ꢀNMe2), 5.68 (ABq, J = 6.2, 1H, N–CH–N),
6.98 (d, J = 7.6, 1Н, 4ꢀН), 7.55 (d, J = 7.9, 1Н, 6ꢀН), 7.61–7.70 (m, 2Н, 5ꢀН, 8ꢀН), 7.86 (d, J = 7.9,
13
1Н, 9ꢀН), 8.06 (d, J = 8.5, 1Н, 7ꢀН). С NMR (CD3CN): δ = 11.9 (N–CMe–N), 36.8, 50.8, 57.6

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(N–Me); 84.2 (N–CH–N); 110.1, 115.5, 117.4, 119.8, 127.1, 129.8, 131.4, 135.3, 137.3, 138.3.
C15H19BrN2·2H2O (343.26): calcd. C 52.49, H 6.75, N 8.16; found C 52.41, H 6.84, N 8.10.
XꢀRay diffraction analysis. Crystals suitable for Xꢀray studies were grown up by slow evaporation
from solutions of compounds in appropriate solvents or solvent mixtures at room temperature: 6a
(MeOH), 12a (Py–EtOH). The structures were solved by direct method and refined by the fullꢀ
matrix leastꢀsquares against F2 in anisotropic (for nonꢀhydrogen atoms) approximation. All
hydrogen atoms were placed in geometrically calculated positions and were refined in isotropic
approximation in riding model with the Uiso(H) parameters equal to n·Ueq(Ci) (n = 1.2 for CH
and CH2 groups and n = 1.5 for CH3 groups), where U(Ci) are respectively the equivalent thermal
parameters of the atoms to which corresponding H atoms are bonded. The H(O) hydrogen atoms
were found in the difference Fourier synthesis and refined in isotropic approximation without
constrains. The main crystallographic data and some experimental details are given in Table S3.
CCDC 1400689 and 1400690 contain the supplementary crystallographic data for this paper.
Acknowledgements
Financial support from the Russian Foundation for Basic Research (project RFBR 14ꢀ03ꢀ31301) is
greatly acknowledged. The authors acknowledge the Scientific and Educational Laboratory of
Resonance Spectroscopy (Department of Natural and High Molecular Compounds Chemistry of
Southern Federal University) for NMR measurements. XꢀRay experiments were performed by Drs.
Zoya A. Starikova and K. Y. Suponitsky (A. N. Nesmeyanov Institute of Organoelement
Compounds, Moscow, Russian Federation).
Electronic supplementary information (ESI) available: Details of potentiometric titration; main
fragmentation pathways of 2a+· under electron impact; DFT quantumꢀchemical calculations of
1
13
amino acid 2a; data for thermolysis of 2a,b; copies of H and C NMR spectra; crystal data and
structure refinement for compounds 6a and 12a (CCDC 1400689 and 1400690). For ESI see DOI:

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...
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C5OB01065A
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28 O. V. Ryabtsova, A. F. Pozharskii, A. V. Degtyarev and V. A. Ozeryanskii, Mendeleev
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29 V. A. Ozeryanskii, M. P. Vlasenko and A. F. Pozharskii, Tetrahedron, 2013, 69, 1919–1929.
30 For a synthesis of heterocycles, namely benzimidazole Nꢀoxides, via baseꢀpromoted cyclization
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19, 187–195. This method requires refluxing with NaOH in aqueous dioxane and is realized as
cyclization followed up by decarboxylation.
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(CCDC, structure REVCIF); (b) A. G. Shipov, E. P. Kramarova, T. P. Murasheva, A. A.
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Table of contents entry
The first hybrid bases constructed of 1,8ꢀbis(dimethylamino)naphthalene and glycine or alanine
residues were synthesised, structurally characterised and unusual channels of their reactivity
revealed.