Synthesis of 4,5-bis(dimethylamino)quinolines and the dual direction of their protonation

Article abstract of DOI:10.1007/s10593-013-1380-4

A study on the synthesis of derivatives of 4,5-bis(dimethylamino)quinoline, which is a quinoline analog of 1,8-bis(dimethylamino)naphthalene (also known by its trade name Proton Sponge) was carried out. The first two representatives of this series were obtained. Depending on the aggregate state, solvent, and structural features, these compounds may be protonated either at the quinoline heteroatom or peri-NMe₂ groups.

Full text of DOI:10.1007/s10593-013-1380-4

Chemistry of Heterocyclic Compounds, Vol. 49, No. 9, December, 2013 (Russian Original Vol. 49, No. 9, September, 2013)
SYNTHESIS OF 4,5-BIS(DIMETHYLAMINO)QUINOLINES
AND THE DUAL DIRECTION OF THEIR PROTONATION
E. A. Shmoilova1, O. V. Dyablo1*, and A. F. Pozharskii1
A study on the synthesis of derivatives of 4,5-bis(dimethylamino)quinoline, which is a quinoline analog
of 1,8-bis(dimethylamino)naphthalene (also known by its trade name Proton Sponge) was carried out.
The first two representatives of this series were obtained. Depending on the aggregate state, solvent,
and structural features, these compounds may be protonated either at the quinoline heteroatom or peri-
NMe2 groups.
Keywords: 4,5-bis(dimethylamino)quinoline, proton sponges, quinolines, basicity, proton transfer,
tautomerism.
The formation and study of neutral organic superbases is an interesting and rapidly developing field in
modern organic chemistry [1, 2]. The discovery of so-called proton sponges has served as an impetus for this
work [3, 4]. The first proton sponge was 1,8-bis(dimethylamino)naphthalene (1), which has abnormally high
basicity for an arylamine: pKa = 12.1 in water [5], 7.5 in DMSO [6], and 18.62 in acetonitrile [7]. Since such
basicity is due to the spatial proximity of the dimethylamino groups, which destabilizes the base, research on the
creation of other superbases started using this compound as a model. For example, this approach was found to
be valid for quino[7,8-h]quinoline (2) (pKa = 12.8 in water [8, 9]) and, especially, for vinamidine 3 synthesized
by Schwesinger [10] (pKa = 31.94 in acetonitrile). However, strictly speaking, quinolines 2 and 3 are not proton
sponges, since unlike the latter they are kinetically active, i.e., at a rate close to diffusion they add and donate a
proton and react readily enough at the nitrogen atoms with various Lewis acids. Therefore bases 2 and 3 should
be characterized as proton-sponge-like compounds [1].
In this regard, it was of interest to obtain previously unreported 4,5-bis(dimethylamino)quinoline (4),
especially since this compound has two special features. Firstly, it is difficult to predict whether quinoline 4
would behave as a proton sponge or would undergo protonation at the ring nitrogen atom due to the strong
+M-effect of the peri-dimethylamino groups. Secondly, quinoline 4 is very similar to 4-dimethylaminopyridine
(5), which is known for its strong catalytic activity in a whole series of reactions, especially in transacylation
[11, 12]. We could predict with high probability that quinoline proton sponge 4 would be more basic than
pyridine 5 and if its protonation occurs at the heteroatom the catalytic activity of quinoline 4 would be much
greater. Hence, we undertook a study to create methods for the synthesis of quinoline 4 and its derivatives.
By analogy with proton sponge 1, 4,5-dinitroquinoline or one of the two isomeric peri-nitroamino-
quinolines may serve as precursors for quinoline 4. However, a problem arises, quinoline, in contrast to
naphthalene, cannot be nitrated as readily at both peri positions and, especially at the heterocycle. Thus, we
_______
*To whom correspondence should be addressed, e-mail: dyablo@sfedu.ru.
1Southern Federal University, 7 Zorge St., Rostov-on-the-Don 344090, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1404-1419, September, 2013.
Original article submitted May 31, 2013.
1308
0009-3122/13/4909-1308©2013 Springer Science+Business Media New York

could only plan the consecutive introduction of a nitro group or dimethylamino groups (for example, through
aminodehalogenation) to its peri positions, relying on different methods for activating the heterocycle and
protecting the other terminal atoms in this ring, which compete with the atoms in the peri positions. Among the
activation methods, we looked promising introduction of an N-oxide functionality into the heterocycle or
inclusion of metallation steps in the synthesis scheme.
N
N
Me2N
NMe2
N
N
N
N
N
N
2
1
3
Me2N
NMe2
N
NMe2
N
5
4
Metallation. Relatively easily available 4-dimethylaminoquinoline (6) [13] and 5-dimethylamino-
quinoline (11), obtained by the methylation of 5-aminoquinoline (10), were selected as reagents for metallation.
We came out of their structural similarity to 1-dimethylaminonaphthalene, which is metallated with high
regioselectivity by n-butyllithium or tert-butyllithium at position 8. If quinolines 6 and 11 would undergo
similar metallation, the subsequent action of electrophiles such as tosyl azide might lead us in two or three steps
to the target 4,5-bis(dimethylamino)quinoline (4).
Although the direct metallation of the quinoline system is well known [15-23], we found that quinoline
6 adds n-butyllithium or tert-butyllithium at the C=N bond quite rapidly (over 1 h) in the temperature range
from -15 to +20°C. The immediate hydrolysis of adducts 7a,b gives 2-alkyl-2,3-dihydroquinolones 8a,b. When
the metallation reaction time is extended to 96 h, LiH is cleaved in the case of adduct 7a, leading to 2-n-butyl-
4-dimethylaminoquinoline (9) after hydrolysis. Thus, only quinolone 8a after 1 h, or only quinoline 9 (96 h), or
a mixture of these compounds (24 h) was found in the reaction mixture depending on the reaction time as
1
indicated by H NMR spectroscopy (Table 1). Adduct 7b with a tert-butyl substituent gives only quinolone 8b
independently of the reaction time. The addition of a ligand, namely, N,N,N',N'-tetramethylethylidenediamine
(TMEDA), does not affect the reaction course but slightly reduces the rate of elimination of LiH.
1309

5-Dimethylaminoquinoline (11), similar to its isomer 6 adds alkyllithiums to the C=N bond
1
independently of the temperature (-15°C or +20°C) and in the presence or absence of TMEDA. The H NMR
spectra of the reaction mixtures after hydrolysis show signals related to 2-alkyl-1,2-dihydro-5-dimethyl-
aminoquinolines 13a,b and 2-alkyl-5-dimethylaminoquinolines 14a,b (Table 1). These products are readily
separated by column chromatography but dihydro derivatives 13a,b proved to be unstable and oxidized upon
standing over few hours to give quinolines 14a,b. Seemingly, quinolines 14a,b might be formed directly from
adducts 12a,b by elimination of lithium hydride in the step preceding hydrolysis.
NMe2
H
N
H
R
13a,b
H2O
NMe2
NH2
NMe2
2 MeI
RLi
H
R
NaNH2
NH3
O2
(air)
Et2O
Ar
N
N
N
Li
10
– LiH
11
12a,b
NMe2
12–14 a R = n-Bu, b R = t-Bu
N
R
14a,b
The treatment of quinolines 6 and 11 with n-BuLi or t-BuLi as metallating agents at -78°C over 1-2 h
with the subsequent addition of CD3OD lead only to the partial lithiation at position 2 and 8 in quinoline 11
(formation of deutero derivatives 15b and 16) and at position 2 in quinoline 6 (formation of compound 15a).
Evidence for this assumption is found in the reduction of the integral intensity by about 20% of the
corresponding signals in the 1H NMR spectra of the crude mixtures.
Thus, our experiments showed that quinolines 6 and 11 are not metallated at the peri position relative to
the NMe2 group. The lack of a directing effect may be related to a strong conjugation of the 4- and 5-di-
methylamino groups with the quinoline nitrogen atom such that these groups become planar and coplanar to the
ring system. On the other hand, at low temperature, electron-withdrawing and coordinating effects of the ring
heteroatom begin to appear, leading to partial metallation at position 2 and/or 8.
1310

TABLE 1. Conditions for the Metallation of Quinolines 6 and 11 and
Reaction Product Yields
Reaction
temperature,
°С
Yield*, %
Com-
RLi
Time, h
96
pound
8
9
13
14
n-BuLi
20
0 (9*2)
100
—
—
6
(91*2)
20
-15
-15
-15
20
24
24
1
50 (56*2)
50 (66*2)
100
100
—
50 (37*2)
—
—
—
—
50 (33*2)
—
—
—
—
—
—
—
—
—
—
t-BuLi
n-BuLi
1
—
—
96
24
24
1
100*2
77
—
11
20
—
23
-15
-15
-15
-15
—
77
23
—
71
29
t-BuLi
24
1
—
50
50
—
75.5
15.5
_______
*According to 1H NMR spectra of the reaction mixture.
*2Reactions were carried out in the presence of TMEDA.
Use of 4-nitro- and 5-nitroquinoline 1-oxides. Kaneko et al. [24] have reported the synthesis of
4,5-diaminoquinoline (17) from 4-nitroquinoline 1-oxide (18) by deoxygenation of oxide 18 using phosphorus
tribromide to give 4-nitroquinoline, which was then consecutively nitrated at position 5 and reduced to give
diamine 17. However, we were unable to reproduce this result due to difficulties in removing the N-oxide
function, already noted repeatedly by other workers [25, 26]. We found that treatment of oxide 18 with
phosphorus trichloride in chloroform at 60°C gives a 1:1 mixture of 4-chloro- (19a) and 2,4-dichloroquinolines
(19b). As already reported by Denny et al. [25], the use of PBr3 in chloroform at 20°C led to a mixture of
predominantly 2,4-dibromo- (20a) along with 2-bromo-4-nitroquinoline (20b). At lower temperatures (from
-15° to 0°C), starting N-oxide 18 remained unchanged.
We also were unable to make a nitration of 4-nitroquinoline 1-oxide (18) since this compound was
completely inert to a nitrating mixture of concentrated nitric and sulfuric acids in the temperature range from
70 to 150°C. On the other hand, 5-nitroquinoline 1-oxide (21) described by Ochiai [27] underwent nitration to
give 4,5-dinitroquinoline 1-oxide (22). However, the reaction proceeded slowly (16 h) under very vigorous
conditions (130-140°C) to give a yield of only 20%, while product 22 was very difficult to separate from
1311

starting oxide 18 even using preparative thin-layer chromatography. A series of experiments was carried out on
the reduction of quinoline 22 with hydrogen in the presence of 5% Pd/C in methanol or acetic acid.
Unfortunately, these experiments were unsuccessful, and no traces of diamine 17 or its N-oxide 23 were
detected. Apparently, under these conditions not only the nitro group but also the heterocycle itself is getting
reduced. Such behavior has been reported repeatedly for quinolines [28-32] and quinoline 1-oxides [33].
Electrophilic substitution in 4-dimethylaminoquinoline and 4-chloroquinoline. We then attempted
the introduction of the required substituents into the quinoline peri positions by bromination and nitration of
4-dimethylaminoquinoline and 4-chloroquinoline. We proceeded from the fact that bromination of unsubstituted
quinoline occurred at positions 5 or 8 by bromine or bromosuccinimide (NBS) in sulfuric acid [34]. The
substituents at position 4 were found to have a significant effect on the direction of the halogenation. Thus,
4-dimethylaminoquinoline (6) is brominated by NBS in sulfuric acid exclusively at position 3 to give bromide
24. It is interesting that a small amount (5%) demethylation product 25 is formed along with the bromide 24
(67% yield) when using the Br2/Ag2SO4/H2SO4 system as the brominating agent. 4-Chloroquinoline (19a) in
both cases gives a mixture of brominated compounds difficult to separate into individual components.
1
According to H NMR spectroscopy, the 7-bromide is the predominant product. Indeed, upon treating this
mixture with dimethylamine, we isolated 7-bromo-4-dimethylaminoquinoline (26) as a pure compound.
Since the bromination of 4-R-quinolines does not affect position 5, we turned our attention to the nitration
of 4-chloroquinolines 19a-c. The literature data on this question are contradictory. There have been reports that the
nitration of 4-chloroquinoline 19a by the nitrating mixture of concentrated nitric and sulfuric acids at -5° to 0°C
gives a mixture of 8-nitro- (27a) and 5-nitro-4-chloroquinolines (28a) in 59 and 20% yield, respectively [35-37].
1312

On the other hand, Simpson and Wright [38] reported that only the 8-nitro isomer was obtained at -15°C
in 28% yield. We found that chloride 19a reacts with the nitrating mixture at 20°C to give exclusively 8-nitro
derivative 27a, while lowering the reaction temperature to 0°C leads to a 95:5 mixture of chloroquinolines 27a
and 28a. While 8-nitro derivative 27a could be readily isolated as a pure compound by fractional
recrystallization from ethanol, 5-nitro derivative 28a could not be isolated as a pure compound even by
chromatography.
The nitration of 2,4-dichloroquinoline (19b) requires more vigorous conditions than the analogous
reaction of 4-chloroquinoline (19a). The reaction for 2,4-dichloroquinoline begins only upon heating the
reaction mixture to 60°C and leads to a 73:11:16 mixture of 8-nitro- (27b), 5-nitro- (28b), and 7-nitro-
2,4-dichloroquinolines (29b) with 68% overall yield. Isomers 27b and 29b were isolated as pure compounds by
fractional crystallization from isooctane and ethanol, while the desired product, namely, 2,4-dichloro-5-nitro-
quinoline (28b) could not be separated from other isomers.
The nitration of 4-chloro-2-methylquinoline (19c) has been described by Adams [39] and Denny [40].
These authors reported the formation of two isomers, specifically, 5-nitro- (28c) and 8-nitro-4-chloro-2-methyl-
quinolines (27c). Our results show that the nitration of chloroquinoline 19c by the nitrating mixture at 20°C
leads exclusively to 8-nitro derivative 27c in almost quantitative yield. The same reaction at 0°C gives an 87:6:7
mixture of compounds 27c, 28c, and 29c with 80% overall yield. Column chromatography on silica gel using
chloroform as the eluent gave 4-chloro-2-methyl-8-nitroquinoline 27c as a pure compound, while isomers 28c
and 29c could not be separated.
Use of 5-haloquinoline N-oxides. Quinoline 1-oxide is known to be nitrated at position 4 at 60°C [27].
We anticipated that the nitration of 5-haloquinoline N-oxides 30a,b would proceed similarly. However, this
reaction unfortunately led to 5-halo-8-nitroquinoline 1-oxides 31a,b as the only products as indicated by
1H NMR spectroscopy and the chemical properties of these oxides. In particular, heating oxide 31b with excess
of dimethylamine in ethanol in a sealed ampoule at 150-155°C gave a mixture of 5-dimethylamino-8-nitro-
quinoline (32) and 5-bromo-2,8-bis(dimethylamino)quinoline (33), indicating that the bromine and hydrogen
atoms as well as the nitro group may undergo nucleophilic aromatic substitution in this compound.
Synthesis of 4,5-bis(dimethylamino)-8-methyl-2-R-quinolines. Hence, the synthesis of 4,5-bis-
(dimethylamino)quinolines may be simplified when a substituent is present at position 8. In this case, the
nitration of suitable precursors should proceed exclusively at position 5. This assumption proved entirely correct
for diamines 37a,b, which we synthesized by the consecutive nitration of 4-chloro-8-methylquinolines 34a,b,
following substitution of chlorine by a dimethylamino group in the resultant 5-nitroquinolines 35a,b, and
reduction of the obtained nitro compounds 36a,b [41].
We were unable to carry out the methylation of amine 37a using two equivalents of iodomethane in
liquid ammonia in the presence of sodium amide, which is probably a consequence of the low acidity of the
5-NH2 group. Only the starting compound could be isolated from the reaction mixture. Another alkylation
method proposed for primary aryl- and hetarylamines with low NH acidity entails prior conversion of the amine
to an azide, reduction of this azide by sodium in liquid ammonia to give the dianion, and treatment of this
intermediate with an alkyl halide [42]. We obtained azide 38 in good yield but, unfortunately, only tar formation
ensued upon the action of sodium in liquid ammonia on this compound.
1313

The target compounds 39a,b were obtained by methylation of amines 37a,b using excess dimethyl
sulfate in methanol in the presence of sodium carbonate. This reaction proceeds rather slowly and
monomethylation products 40a (9% yield) and 40b (21% yield) were also isolated and characterized. Our recent
brief communication concerning the synthesis of compounds 39a,b was recently published.
Quinolines 39a,b readily form picrates and perchlorates. An X-ray structural analysis of the picrates
(CCDC deposits 888288 and 888289 at the Cambridge Crystallographic Data Center) showed that the picrate of
base 39a has structure 41a, where the proton is chelated by two peri-NMe2 groups as in ordinary proton
sponges. On the other hand, diamine 39b forms picrate 42b·PicO-, in which the proton is localized next to
nitrogen atom of the heterocycle.
MeHN
NMe2
Me2N
NMe2
Me2SO4
+
37a,b
Na2CO3
N
R
N
R
MeOH, H2O
Me
40a,b
Me
39a,b
H+
H
Me
N Me
Me
Me
+
N
Me2N
NMe2
+
N
R
N
R
Me
H
Me
41a,b
37, 39, 41, 42 a R=NMe2, b R=Me
42a,b
More complicated behavior is observed upon the protonation of peri-diamines 39a,b in solution. The 1H
NMR spectra of the picrate and perchlorate of compound 39a show an equilibrium of two protonated forms
(41a ⇄ 42a). The ratio of these forms depends on the polarity of the solvent (Table 2). In low-polarity solvents,
like CDCl3 and ClCD2CD2Cl, cation 42a predominates, while in more polar solvents, like CD3CN, DMSO-d6, and
CD3COCD3, the contents of both forms becomes comparable. Under the same conditions, the salts of
1314

4,5-bis(dimethylamino)-2,8-dimethylquinoline (39b) are protonated only at the nitrogen atom in heterocycle
(form 42b). Switching from apolar to polar solvents does not lead to the appearance of any substantial
concentration of form 41b.
TABLE 2. Chemical Shifts of the NH Protons in the 1H NMR Spectra of
the Picrate of Diamine 39a and the Contents of Protonated Forms 41a
and 42a
The content of the
protonated forms, %
The dipole moment
of the solvent, D

NH, ppm
Solvent
41а
42а
41а
42а
CDCl3
1.15
1.85
3.38
4.26
4.26
2.70
17.07
17.45
17.37
17.07
17.07
17.78
9.12
8.01
8.17
9.12
9.12
8.85
15
5
85
95
50
45
45
42
ClCD2CD2Cl
CD3CN
50
55
55
58
DMSO-d6
DMSO-d6*
Acetone-d6
An unexpected result was discovering much higher basicity of diamine 39b in comparison to 39a. The
ionization constants pKa were determined by the competitive method [43, 44]. The pKa value for diamine 39b
for protonation at the nitrogen atom in the ring was found to be 7.2, which is only slightly less than the basicity
of naphthalene proton sponge 1. The pKa values of diamine 39a corresponding to protonation of the peri-
dimethylamino groups and ring nitrogen atom are equal to 6.5 and 6.3, respectively. We assume that solvation
of the NH proton in form 42a is markedly hindered in the salt derivatives of compound 39a due to the steric
effect of the branched 2-NMe2 group together with the 8-Me group. It is precisely this effect, which leads to
relative destabilization of this form and produces conditions for protonation of the molecule at the peri-NMe2
groups. This behavior is entirely analogous to the drop in basicity when going from 2,6-dimethylpyridine to 2,6-
diisopropylpyridine and 2,6-di-tert-butylpyridine [45]. This explanation can also account for the particularly
remarkable finding; low rate of interconversion of forms 41 and 42 on the NMR time scale when the NH
protons corresponding to these forms appear as separate though slightly broadened peaks. The activation energy
for proton transfer in this case is close to 20 kcal/mol [46]. It is known that the protonation-deprotonation of
ordinary amines [47] and even sterically unhindered peri-diaminonaphthalenes [48] proceeds at a rate close to
diffusion.
Thus, we have synthesized the first two representatives of 4,5-bis(dimethylamino)quinolines and shown
that the direction of their protonation significantly depends on the aggregate state, solvent used, and nature of
the substituents on the quinoline ring. We are the first to report the protonation of dimethylamino groups
conjugated with the heteroatom in the azine series for the case of 2,4,5-tris(dimethylamino)-8-methylquinoline,
i.e., this diamine displays proton sponge properties.
EXPERIMENTAL
1
The IR spectra were recorded on an FSM-1202 spectrometer for vaseline mulls. The H and 13C NMR
spectra were recorded on a Bruker DPX-250 spectrometer (250 and 62.9 MHz, respectively) in DMSO-d6
(perchlorates and picrates of compounds 39a,b) and CDCl3 (other compounds) with TMS as internal standard.
The electron impact mass spectra were recorded on a Finnigan MAT INCOS 50 mass spectrometer at 70 eV.
The combustion elemental analysis was carried out by the Pregl–Dumas method. The melting points were
determined in glass capillaries on an SMP 30 apparatus. The purity of the products and the course of the
1315

reactions were followed by thin-layer chromatography on Brockmann grade IV alumina plates using chloroform
as the eluent. AcrosealTM n-butyllithium in hexane supplied by Acros, a solution of t-butyllithium in pentane
supplied by Sigma-Aldrich, and 99% 5-aminoquinoline supplied by Alfa Aesar were used in this work.
4-Dimethylaminoquinoline (6). Liquid dimethylamine (1.1 ml) was added to a solution of 4-chloro-
quinoline (0.344 g, 2.1 mmol) in ethanol (3 ml) at -10°C. The mixture was transferred to a glass ampoule,
sealed, and maintained at 150-155°C for 3 h. Upon cooling, the ampoule was opened. The mixture was
evaporated to dryness, and the residue was dissolved in a minimal amount of methylene chloride. The solution
was passed through an alumina column using CH2Cl2 as the eluent. The first fraction eluted contained 0.045 g
(13%) starting 4-chloroquinoline, Rf 0.9. The second fraction gave 0.21 g (58%) 4-dimethylaminoquinoline (6)
1
as a viscous yellow oil, Rf 0.4. Н NMR spectrum, δ, ppm (J, Hz): 2.94 (6Н, s, NMe2); 6.73 (1Н, d, J = 5.3,
Н‐3); 7.40-7.46 (1Н, m, Н-7); 7.58-7.64 (1Н, m, Н-6), 8.03 (2Н, m, Н-5,8); 8.64 (1Н, d, J = 4.6, Н-2). The
other spectral characteristics of this compound correspond to the values reported by McCurdy et al. [13].
Reaction of 4-Dimethylaminoquinoline (6) with n-BuLi and t-BuLi (General Method). 1.6 M
n-butyllithium (0.31 ml, 0.5 mmol) in hexane or 1.7 M t-butyllithium (0.29 ml, 0.5 mmol) in pentane was added
to a solution of 4-dimethylaminoquinoline (6) (0.034 g, 0.2 mmol) in absolute ether (2 ml) under an argon
atmosphere at -15°C. At the end of the reaction, water (0.5 ml) was added, and the mixture was maintained for
1 h at 20°C. The ethereal layer was removed, and the solvent was distilled off. The residue was subjected to
chromatography on alumina using CH2Cl2 as the eluent.
2-n-Butyl-2,3-dihydroquinolin-4-one (8a) was obtained according to the general procedure from
amine 6 and n-butyllithium. The reaction mixture was maintained for 1 h at -15°C. Yield 0.034 g (85%), pale-
1
yellow crystals, mp 65-67°С (octane). IR spectrum, ν, cm-1: 1658 (С=О), 3335 (N–H). Н NMR spectrum, δ,
ppm (J, Hz): 0.91 (3Н, t, J = 6.9, (СН2)3СН3); 1.28-1.37 (4Н, m, (СН2)2СН3); 1.59-1.67 (2Н, m,
СН2(СН)2СН3); 2.45 (1Н, dd, 2J = 16.1, 3J = 12.6) and 2.65 (1Н, dd, 2J = 16.1, 3J = 3.8, 3-СH2); 3.54-3.66 (1Н,
m, 2-СН); 4.32 (1Н, br. s, NH); 6.64 (1Н, d, J = 8.5, Н-8); 6.67-6.73 (1Н, m, Н-6); 7.24-7.30 (1Н, m, Н-7);
7.79 (1Н, d, J = 7.6, Н-5). Mass spectrum, m/z (Irel, %): 203 [M]+ (25), 146 [M-Bu]+ (100). Found, %: С 76.83;
Н 8.45; N 6.90. С13H17NO. Calculated, %: С 76.81; Н 8.43; N 6.89.
2-t-Butyl-2,3-dihydroquinolin-4-one (8b) was obtained according to the general procedure from amine
6 and t-butyllithium. The reaction mixture was maintained for 1 h at -15°C. Yield 0.024 g (60%), pale-yellow
crystals, mp 148-149°С (octane). IR spectrum, ν, cm-1: 1659 (С=О), 3352 (N–H). 1Н NMR spectrum, δ, ppm (J,
2
3
2
3
Hz): 1.00 (9Н, s, С(СН3)3); 2.49 (1Н, dd, J = 15.9, J = 13.8) and 2.63 (1Н, dd, J = 15.9, J = 3.7, 3-СН2);
3.27-3.35 (1Н, m, 2-СН); 4.31 (1Н, br. s, NH); 6.66-6.74 (2Н, m, Н-6,8); 7.24-7.32 (1Н, m, Н-7); 7.79 (1Н, dd,
3J = 7.9, J = 1.7, Н-5). Mass spectrum, m/z (Irel, %): 203 [M]+ (8), 146 [M-Bu]+ (100). Found, %: С 76.82;
4
Н 8.44; N 6.91. С13H17NO. Calculated, %: С 76.81; Н 8.43; N 6.89.
2-n-Butyl-4-dimethylaminoquinoline (9) was obtained according to the general procedure from amine
6 and n-butyllithium. The reaction mixture was maintained for 96 h at 20°C. Yield 0.029 g (63%), yellow oil.
1Н NMR spectrum, δ, ppm (J, Hz): 0.94 (3Н, t, J = 7.4, (СН2)3СН3); 1.35-1.50 (2Н, m, (СН2)2СН2СН3); 1.69-
1.82 (2Н, m, СН2СН2СН2СН3); 2.86 (2Н, t, J = 8.1, СН2(СН)2СН3); 2.99 (6Н, s, N(СН3)2); 6.65 (1Н, s, Н-3);
7.33-7.40 (1Н, m, Н-7); 7.54-7.60 (1Н, m, Н-6); 7.94-8.00 (2Н, m, Н-5,8). Mass spectrum, m/z (Irel, %): 228
[M]+ (8), 186 [M-C3H6]+ (100). Found, %: С 78.89; Н 8.83; N 12.28. С15H20N2. Calculated, %: С 78.90; Н 8.83;
N 12.27.
5-Dimethylaminoquinoline (11). Finely cut sodium (0.107 g, 4.7 mmol) and several crystals of ferric
nitrate were added to liquid ammonia (10 ml). As soon as the mixture became colorless, 5-aminoquinoline (10)
(0.288 g, 2 mmol) was added. After 5 min, iodomethane (0.26 ml, 0.528 g, 4 mmol) was added. The mixture
was stirred for 1 h. Cooling was then discontinued, permitting ammonia to evaporate freely. The residue was
subjected to chromatography on an alumina column using CH2Cl2 as the eluent and collecting two fractions.
The first fraction (Rf 0.7) contained dimethylaminoquinoline 11. Yield 0.261 g (76%), yellow-brown oil.
1Н NMR spectrum, δ, ppm (J, Hz): 2.87 (6Н, s, N(CH3)2); 6.48 (1Н, dd, 3J = 8.3, 4J = 0.9, Н-6); 7.34-7.39 (1Н,
m, Н-3); 7.56-7.62 (1Н, m, Н-7); 7.74 (1Н, d, J = 8.5, Н-8); 8.52 (1Н, dd, 3J = 8.5, 4J = 1.6, Н-4); 8.85 (1Н, dd,
1316

4
3J = 8.5, J = 1.6, Н-2). Found, %: С 76.69; Н 7.05; N 16.26. С11H12N2. Calculated, %: С 76.71; Н 7.02;
N 16.27. The second fraction (Rf 0.4) contained the starting 5-aminoquinoline 10. Yield 0.057 g (20%), as gray-
brown crystals.
2-n-Butyl-1,2-dihydro-5-dimethylaminoquinoline (13a) and 2-n-butyl-5-dimethylaminoquinoline
(14a) were obtained from amine 11 and n-butyllithium according to the general method given above for the
metallation of amine 6. The mixture was maintained for 96 h at 20°C. After evaporation of ether, the residue
was dissolved in CH2Cl2 and subjected to chromatography on an alumina column using 1:1 CH2Cl2–hexane as
the eluent. The first fraction (Rf 0.9) gave 1,2-dihydroquinoline 13a. Yield 0.035 g (76%), dark-yellow oil.
1Н NMR spectrum, δ, ppm (J, Hz): 0.89 (3Н, t, J = 7.4, (СН2)3СН3); 1.31-1.36 (4Н, m, (СН2)2СН3); 1.53-1.59
(2Н, m, СН2(СН2)2СН3); 2.69 (6Н, s, N(CH3)2); 4.03-4.10 (1Н, m, 2-CH); 5.54-5.59 (1Н, m, 3-СН); 6.14
3
4
3
4
(1Н, d, J = 7.9, 4-СН); 6.28 (1Н, dd, J = 8.1, J = 0.9, Н-6); 6.64 (1Н, dd, J = 9.9, J = 0.8, Н-8); 6.85-6.92
(1Н, m, Н-7). Found, %: С 78.20; Н 9.61; N 12.17. С15H22N2. Calculated, %: С 78.21; Н 9.63; N 12.16. The
second fraction (Rf 0.7) gave quinoline 14b. Yield 0.008 g (18%), yellow-brown oil. 1Н NMR spectrum, δ, ppm
(J, Hz): 0.95 (3Н, t, J = 7.4, (СН2)3СН3); 1.39-1.48 (2Н, m, (СН2)2СН2СН3); 1.72-1.84 (2Н, m,
СН2СН2СН2СН3); 2.95 (2Н, t, J = 8.1, СН2(СН2)2СН3); 2.86 (6Н, s, N(CH3)2); 7.02 (1Н, dd, 3J = 7.5, 4J = 1.1,
Н-6); 7.26 (1Н, d, J = 8.8, Н-3); 7.52-7.58 (1Н, m, Н-7); 7.67-7.71 (1Н, m, Н-8); 8.42 (1Н, dd, 3J = 9.1, 4J = 0.7,
Н-4). Mass spectrum, m/z (Irel, %): 228 [M]+ (21), 186 [M-C3H6]+ (100). Found, %: С 78.89; Н 8.84; N 12.25.
С15H20N2. Calculated, %: С 78.90; Н 8.83; N 12.27.
2-tert-Butyl-1,2-dihydro-5-dimethylaminoquinoline (13b) and 2-tert-butyl-5-dimethylamino-
quinoline (14b) were obtained analogously from amine 11 and tert-butyllithium. The residue after evaporation
of ether was dissolved in CH2Cl2 and subjected to chromatography on an alumina column using 2:1 CH2Cl2–
hexane as the eluent. The first fraction (Rf 0.9) gave 1,2-dihydroquinoline 13b. Yield 0.035 g (76%), dark-
yellow oil. 1Н NMR spectrum, δ, ppm (J, Hz): 1.25 (9Н, s, С(СН3)3); 2.68 (6Н, s, N(CH3)2); 3.83 (1Н, d, J = 4.4,
2-CH); 3.98 (1Н, br. s, NH); 5.56 (1Н, dd, 3J = 10.2, 3J = 4.6, 3-СН); 6.08-6.12 (1Н, m, Н-8); 6.22 (1Н, dd, 3J = 8.1,
4J = 0.9, Н-6); 6.73 (1Н, ddd, 3J = 10.2, 4J = 1.3, 5J = 0.7, 4-СН); 6.82-6.89 (1Н, m, Н-7). Found, %: С 78.20;
Н 9.62; N 12.16. С15H22N2. Calculated, %: С 78.21; Н 9.63; N 12.16. The second fraction (Rf 0.7) gave
1
quinoline 14b. Yield 0.008 g (17%), yellow-brown oil. Н NMR spectrum, δ, ppm (J, Hz): 1.45 (9Н, s,
3
4
3
С(СН3)3); 2.86 (6Н, s, N(CH3)2); 7.01 (1Н, dd, J = 7.5, J = 0.8, Н-6); 7.48 (1Н, d, J = 8.9, Н-3); 7.50-7.56
(1Н, m, Н-7); 7.71 (1Н, d, J = 8.4, Н-8); 8.42 (1Н, d, J = 8.9, Н-4). Found, %: С 78.88; Н 8.82; N 12.24.
С15H20N2. Calculated, %: С 78.90; Н 8.83; N 12.27.
Metallation of 4-dimethylaminoquinoline (6) at -78°C was carried out according to the general
method using n-butyllithium (reaction time 2 h) or tert-butyllithium (reaction time 1 h). At the end of the
reaction, CD3OD (0.5 ml) was added, and the mixture was maintained for 20 min at -78°C and then, cooling
was discontinued. After warming to room temperature, D2O (0.5 ml) was added. After 1 h, the ethereal layer
1
was separated, and ether was evaporated off. The H NMR spectrum of the product was identical to the
spectrum of dimethylaminoquinoline 6 with the exception of reduced integral intensity of the signal H-2 at
8.64 ppm by 18% (from n-butyllithium) and by 21% (from tert-butyllithium), which indicates the presence of
~18-21% of 2-deutero-4-dimethylaminoquinoline (15a) in the reaction mixture.
Metallation of 5-dimethylaminoaminoquinoline (11) at -78°C was carried out as described above for
1
4-dimethylaminoquinoline (6). The H NMR spectrum of the product was identical to the spectrum of
dimethylaminoquinoline 11 with the exception of a decrease in the integral intensity of the signal H-8 at
7.74 ppm by 22% (from n-butyllithium) and by 17% (from tert-butyllithium) and the signal for H-2 at 8.85 ppm by
15% (from n-butyllithium) and by 20% (from tert-butyllithium). This result indicates the presence of ~17-22% of
8-deutero-5-dimethylaminoquinoline (16) and ~15-20% of 2-deutero-5-dimethylaminoquinoline (15b) in the
reaction mixture.
4-Chloroquinoline (19a) and 2,4-Dichloroquinoline (19b). PCl3 (4.5 ml) was added to a solution of
4-nitroquinoline 1-oxide 18 [17] (3.1 g, 16.3 mmol) in chloroform (35 ml) cooled to 0°C. The mixture was
heated at reflux for 1 h. Upon cooling, the mixture was neutralized by adding 5% aqueous sodium hydroxide
1317

(20 ml). The chloroform layer was separated, and the solvent was distilled off. The residue was subjected to
chromatography on an alumina column using 1:2 CH2Cl2–hexane as the eluent. The first fraction (Rf 0.8) gave
dichloroquinoline 19b. Yield 1.014 g (31%), colorless crystals, mp 63-64°С (petroleum ether) (mp 67°С [49]).
1Н NMR spectrum, δ, ppm (J, Hz): 7.49 (1Н, s, Н-3); 7.60-7.66 (1Н, m, Н-7); 7.74-7.81 (1Н, m, Н-6); 8.02
3
4
3
4
(1Н, dd, J = 8.4, J = 1.4, Н-5); 8.18 (1Н, dd, J = 8.8, J = 1.4, Н-8). The second fraction (Rf 0.5) gave
1
4-chloroquinoline 19a. Yield 1.754 g (66%), pale-yellow oil, which crystallized upon cooling. Н NMR
spectrum, δ, ppm (J, Hz): 7.46 (1Н, d, J = 4.6, Н-3); 7.58-7.65 (1Н, m, Н-7); 7.71-7.78 (1Н, m, Н-6); 8.05 (1Н,
d, J = 8.1, Н-5); 8.21 (1Н, dd, 3J = 8.4, 4J = 1.4, Н-8); 8.76 (1Н, d, J = 4.6, Н-2). The spectral characteristics of
4-chloroquinoline (19a) corresponded to the data given by Ruchelman et al. [37].
4,5-Dinitroquinoline 1-oxide (22). A mixture of 86% nitric acid (0.61 ml, 13.3 mmol) and
concentrated sulfuric acid (1.47 ml, 27 mmol) was added to a solution of 5-nitroquinoline 1-oxide (21) [50]
(2.114 g, 11.1 mmol) in concentrated sulfuric acid (15 ml). The mixture was stirred for 16 h at 130-140°C and
then poured onto ice (50 g). The precipitate was filtered off and washed thoroughly with water. The resultant
mixture of oxides 21 and 22 was separated by preparative thin-layer chromatography on alumina using
chloroform as the eluent. The first fraction with Rf 0.7 gave 4,5-dinitroquinoline 1-oxide (22) (0.240 g, 10%)
and the second fraction with Rf 0.5 gave starting N-oxide 21. Oxide 22 was obtained as pale-yellow crystals, mp
1
3
232-235°С (n-BuOH) (260-262°С (AcOH) [27]. Н NMR spectrum, δ, ppm (J, Hz): 7.95 (1Н, dd, J = 8.8,
3J = 7.7, Н-7); 8.08 (1Н, d, J = 6.9, Н-3); 8.39 (1Н, dd, 3J = 7.7, 4J = 1.3, Н-6); 8.55 (1Н, d, J = 6.9, Н-2); 9.01
(1Н, dd, J = 8.8, J = 1.1, Н-8). Found, %: С 45.95; Н 2.18; N 17.77. С9H5N3О5. Calculated, %: С 45.97;
Н 2.14; N 17.87.
3
4
General Method for the Bromination of 4-R-Quinolines. NBS (0.196 g (1.1 mmol) (method A) or
Ag2SO4 (0.312 g, 1 mmol) and Br2 (0.057 ml, 1 mmol) (method B) was added to a solution of 4-R-quinoline
(1 mmol) in concentrated sulfuric acid (2 ml). The mixture was maintained at 20°C for 48 h (method A) or 24 h
(method B) and then poured onto ice (10 g). The mixture was neutralized by adding concentrated ammonium
hydroxide and extracted with chloroform. The product was purified as described below.
3-Bromo-4-dimethylaminoquinoline (24) was obtained as a yellow oil according to method A from
amine 6. The product was purified by chromatography on an alumina column using 2:1 CH2Cl2–hexane as the
1
eluent, Rf 0.9. Yield 0.2 g (80%). Н NMR spectrum, δ, ppm (J, Hz): 3.11 (6Н, s, NMe2); 7.46-7.52 (1Н, m,
Н-7); 7.60-7.67 (1Н, m, Н-6); 8.01 (1Н, d, J = 8.5, Н-5); 8.09 (1Н, d, J = 8.5, Н-8); 8.77 (1Н, s, Н-2). Mass
spectrum, m/z (Irel, %): 252 [M (81Br)]+ (88), 250 [M (79Br)]+ (100), 171 [M-Br]+ (96). Found, %: С 52.62;
Н 4.41; Br 31.81; N 11.17. С11H11BrN2. Calculated, %: С 52.61; Н 4.42; Br 31.82; N 11.16.
3-Bromo-4-methylaminoquinoline (25) was obtained as the minor product (0.012 g, 5%) in a mixture
with the major product, dimethylaminoquinoline 24 (obtained in 67% yield) upon the bromination of amine 6
according to method B. Methylaminoquinoline 25 was purified to remove dimethylaminoquinoline 24 by
chromatography on an alumina column using 2:1 CH2Cl2–hexane as the eluent. The fraction with Rf 0.7 gave
1
methylaminoquinoline 25. Yellow-orange crystals, mp 127-128°С (EtOH). Н NMR spectrum, δ, ppm (J, Hz):
3.38 (3Н, d, J = 5.7, СН3); 4.99 (1Н, br. s, NH); 7.39-7.45 (1Н, m, Н-7); 7.58-7.65 (1Н, m, Н-6); 7.96 (1Н, d,
J = 8.4, Н-5); 8.14 (1Н, d, J = 8.5, Н-8); 8.64 (1Н, s, Н-2). Mass spectrum, m/z (Irel, %): 238 [M (81Br)]+ (92),
236 [M (79Br)]+ (100), 156 [M-Br]+ (63). Found, %: С 50.65; Н 3.81; Br 33.72; N 11.83. С10H9BrN2.
Calculated, %: С 50.66; Н 3.83; Br 33.70; N 11.82.
7-Bromo-4-dimethylaminoquinoline (26) was obtained during treatment of the crude mixture obtained
upon the bromination of 4-chloroquinoline (19a) according to method A or B with subsequent evaporation of
chloroform to dryness, with dimethylamine (3 ml) and ethanol (2 ml). The mixture was transferred to a sealed
ampoule, heated at 150-155°C for 6 h, and then evaporated. The residue was subjected to chromatography using
CH2Cl2 as the eluent. The fraction with Rf 0.9 gave dimethylaminoquinoline 26. Yield 0.198 g (79%), yellow-
1
orange oil. Н NMR spectrum, δ, ppm (J, Hz): 2.98 (6Н, s, СН3); 6.73 (1Н, d, J = 5.2, Н-3); 7.65 (1Н, dd,
4
3J = 9.0, J = 2.2, Н-6); 7.86 (1Н, d, J = 9.0, Н-5); 8.17 (1Н, d, J = 2.2, Н-8); 8.61 (1Н, d, J = 5.2, Н-2). Mass
1318

spectrum, m/z (Irel, %): 252 [M (81Br)]+ (81), 250 [M (79Br)]+ (83), 171 [M-Br]+ (100). Found, %: С 52.60;
Н 4.41; Br 31.82; N 11.18. С11H11BrN2. Calculated, %: С 52.61; Н 4.42; Br 31.82; N 11.16.
2,4-Dichloro-8-nitroquinoline (27b) and 2,4-Dichloro-7-nitroquinoline (29b). A mixture of fuming
nitric acid (0.11 ml, 2.8 mmol) and concentrated sulfuric acid (0.24 ml, 4.4 mmol) was added dropwise to a
solution of 2,4-dichloroquinoline (19b) (0.396 g, 2 mmol) in concentrated sulfuric acid (3 ml) at 50°C. The
temperature was raised to 60°C. The mixture was stirred for 8 h and poured onto a mixture of ice (100 g) and
ammonium hydroxide (12 ml). The yellow-green precipitate consisting of a mixture of 5-, 7-, and 8-nitro-2,4-di-
chloroquinolines was filtered off. Consecutive recrystallization from isooctane and ethanol gave pure 2,4-di-
1
chloro-7-nitroquinoline (29b). Yield 0.053 g (11%), colorless crystals, mp 188-190°С (EtOH). Н NMR
3
4
spectrum, δ, ppm (J, Hz): 7.66 (1Н, s, Н-3); 8.16 (1Н, d, J = 9.2, Н-5); 8.54 (1Н, dd, J = 9.2, J = 2.5, Н-6);
9.12 (1Н, d, J = 2,2, H-8). Found, %: С 44.50; Н 1.69; Cl 29.15; N 11.51. С9H4Cl2N2O2. Calculated, %:
С 44.48; Н 1.66; Cl 29.17; N 11.53.
The residue after evaporation of the ethanol was recrystallized from isooctane to give 2,4-dichloro-
1
8-nitroquinoline (27b). Yield 0.238 g (49%), fine colorless needles, mp 103-105°С (isooctane). Н NMR
spectrum, δ, ppm (J, Hz): 7.64 (1Н, s, Н-3); 7.72 (1Н, dd, 3J = 8.5, 3J = 7.6, Н-6); 8.09 (1Н, dd, 3J = 7.6, 4J = 1.4,
3
4
Н-5); 8.41 (1Н, dd, J = 8.5, J = 1.3, Н-7). Found, %: С 44.51; Н 1.68; Cl 29.19; N 11.51. С9H4Cl2N2O2.
Calculated, %: С 44.48; Н 1.66; Cl 29.17; N 11.53.
4-Chloro-2-methyl-8-nitroquinoline (27c) was obtained analogously to dichloroquinoline 27b from
4-chloro-2-methylquinoline 19c (0.355 g, 2 mmol) at 20°C for 1.5 h. Yield 0.432 g (97%), pale-yellow crystals,
1
mp 111-113°С (mp 112-113°С [40]). Н NMR spectrum, δ, ppm (J, Hz): 2.72 (3Н, s, СН3); 7.50 (1Н, s, Н-3);
7.61 (1Н, dd, 3J = 8.4, 3J = 7.6, Н-6); 7.96 (1Н, dd, 3J = 7.5, 4J = 1.3, Н-5); 8.37 (1Н, dd, 3J = 8.5, 4J = 1.3, Н-7).
5-Haloquinoline 1-oxides were obtained from 5-haloquinolines [51] analogously to the procedure for
obtaining 5-bromoquinoline 1-oxide (30b) [52].
5-Chloroquinoline 1-oxide (30a). Pale-yellow crystals, mp 135-137°С (isooctane). 1Н NMR spectrum,
δ, ppm (J, Hz): 7.35 (1H, dd, J = 8.7, J = 6.1, Н-3); 7.73-7.55 (2H, m, Н-6,7); 8.07 (1H, d, J = 8.7, Н-4); 8.52
(1H, d, J = 6.0, Н-2); 8.65 (1H, d, J = 8.4, Н-8).
5-Chloro-8-nitroquinoline 1-oxide (31a) was obtained analogously to oxide 22 from
5-chloroquinoline 1-oxide 30a (0.359 g, 2 mmol) at 70-80°C for 3 h. Yield 0.426 g (95%), yellow-green
crystals, mp 229-232°С (EtOH). 1Н NMR spectrum, δ, ppm (J, Hz): 7.53 (1Н, dd, 3J = 8.8, 3J = 6.0, Н-3); 7.65
(1Н, d, J = 8.1, Н-6); 7.76 (1Н, d, J = 8.2, Н-7); 8.16 (1Н, d, J = 8.8, Н-4); 8.52 (1Н, d, J = 6.0, Н-2). Found,
%: С 48.15; Н 2.27; Cl 15.80; N 12.49. С9H5ClN2O3. Calculated, %: С 48.13; Н 2.24; Cl 15.78; N 12.47.
5-Bromo-8-nitroquinoline 1-oxide (31b) was obtained from N-oxide 30b (0.224 g, 1 mmol)
analogously to N-oxides 22 and 31a at 55-60°C for 3 h. Yield 0.148 g (55%), yellow crystals, mp 228-229°С
(EtOH). 1Н NMR spectrum, δ, ppm (J, Hz): 7.50-7.56 (1Н, m, Н-3); 7.58 (1Н, d, J = 8.0, Н-6); 7.96 (1Н, d, J = 8.0,
Н-7); 8.14 (1Н, d, J = 8.9, Н-4); 8.50 (1Н, d, J = 6.1, Н-2). Mass spectrum, m/z (Irel, %): 270 [M (81Br)]+ (86),
268 [M (79Br)]+ (100), 115 (92). Found, %: С 40.20; Н 1.89; Br 29.73; N 10.44. С9H5BrN2O3. Calculated, %:
С 40.18; Н 1.87; Br 29.70; N 10.41.
5-Dimethylamino-8-nitroquinoline (32) and 5-Bromo-2,8-bis(dimethylamino)quinoline (33). A
mixture of oxide 31b (0.134 g, 0.5 mmol), ethanol (2 ml), and dimethylamine (2 ml) was placed into a sealed
ampoule and heated at 150-155°C for 6 h. The solvent was evaporated off, and the residue was subjected to
chromatography on an alumina column using CH2Cl2 as the eluent. The first fraction (Rf 0.9) gave quinoline 33
as a yellow-brown oil, which slowly crystallized upon storage in a refrigerator. Yield 0.046 g (34%), mp
73-74°С. 1Н NMR spectrum, δ, ppm (J, Hz): 3.06 (6Н, s, 8-N(СН3)2); 3.23 (6Н, s, 2-N(СН3)2); 6.82 (1Н, d, J = 8.4,
Н-3); 6.90 (1Н, d, J = 9.5, Н-7); 7.31 (1Н, d, J = 8.4, Н-4); 8.19 (1Н, d, J = 9.5, Н-6). Mass spectrum, m/z (Irel, %):
295 [M (81Br)]+ (48), 293 [M (79Br)]+ (50), 279 [M-Me]+ (100). Found, %: С 53.10; Н 5.47; Br 27.28; N 14.30.
С13H16BrN3. Calculated, %: С 53.07; Н 5.48; Br 27.16; N 14.28.
The second fraction (Rf 0.6) gave nitroquinoline 32. Yield 0.046 g (32%), yellow crystals, mp 56-57°С.
3
1Н NMR spectrum, δ, ppm (J, Hz): 3.00 (6Н, s, N(СН3)2); 6.92 (1Н, d, J = 8.5, Н-6); 7.45 (1Н, dd, J = 8.6,
1319

3J = 4.2, Н-3); 8.09 (1Н, d, J = 8.5, Н-7); 8.48 (1Н, dd, 3J = 8.5, 4J = 1.6, Н-4); 9.02 (1Н, dd, 3J = 4.1, 4J = 1.3,
Н-2). Mass spectrum, m/z (Irel, %): 217 [M]+ (100), 187 [M-2Me]+ (71). Found, %: С 60.79; Н 5.11; N 19.32.
С11H11N3O2. Calculated, %: С 60.82; Н 5.10; N 19.34.
The syntheses for products 34-37, 39, 40a,b, and the picrates and perchlorates of compounds 37a,b
were described in our previous work [41].
5-Azido-2,4-bis(dimethylamino)-8-methylquinoline (38). A solution of sodium nitrite (0.041 g,
0.6 mmol) in water (1 ml) was added to a solution of amine 37a (0.127 g, 0.52 mmol) in concentrated
hydrochloric acid (2 ml) cooled to 0-5°C. After 10 min, a solution of sodium azide (0.04 g, 0.61 mmol) in water
(1 ml) was added. The mixture was maintained at 0-2°C for 30 min, neutralized by adding concentrated
ammonium hydroxide, and extracted with hexane. The organic layer was subjected to chromatography on an
alumina column using hexane as the eluent to give methylquinoline 38. Yield 0.124 g (89%), pale-yellow oil. IR
spectrum, ν, cm-1: 2111 (N3). 1Н NMR spectrum, δ, ppm (J, Hz): 2.55 (3Н, s, 8-CH3); 2.84 (6Н, s, 4-N(CH3)2);
3.18 (6Н, s, 2-N(CH3)2); 6.20 (1Н, s, H-3); 6.81 (1Н, d, J =7.6, Н-6); 7.29 (1Н, d, J = 7.6, Н-7). Mass spectrum,
m/z (Irel, %): 270 [M]+ (16), 227 [M-N3-H]+ (100). Found, %: С 62.23; Н 6.73; N 31.11. С14H18N6. Calculated,
%: С 62.20; Н 6.71; N 31.09.
Diamine 39a Perchlorate. Light-yellow crystals, mp 234-235°C (EtOH). 1H NMR spectrum (indicates
the presence of forms 41a and 42a), , ppm (J, Hz): 2.44 (3H, s, 8-Me, 42a); 2.54 (3H, s, 8-Me, 41a); 2.72 (6H,
br. s, 5-NMe2, 42a); 2.98 (6H, d, J = 0.9, 4-NMe2, 41a); 3.02 (6H, s, 4-NMe2, 42a); 3.17 (6H, d, J = 3.6,
5-NMe2, 41a); 3.21 (6H, s, 2-NMe2, 41a); 3.28 (6H, s, 2-NMe2, 42a); 5.90 (1Н, d, J = 1.9, Н-3, 42а); 6.81 (1Н,
d, J = 8.3, Н-6, 42а); 7.37 (1Н, d, J = 8.2, Н-7, 42а); 7.45 (1Н, s, Н-3, 41а); 7.55-7.62 (2Н, m, Н-6,7, 41а);
9.12 (1H, br. s, NH, 42a); 17.08 (1H, br. s, NH, 41a).
1
Diamine 39a Picrate. Yellow-orange crystals, mp 198-200°C (EtOH). Н NMR spectrum, δ, ppm (J,
Hz): 2.44 (3H, s, 8-Me, 42a); 2.54 (3H, s, 8-Me, 41a); 2.72 (6H, br. s, 5-NMe2, 42a); 2.98 (6H, d, J = 0.9,
4-NMe2, 41a); 3.02 (6H, s, 4-NMe2, 42a); 3.17 (6H, d, J = 3.6, 5-NMe2, 41a); 3.21 (6H, s, 2-NMe2, 41a); 3.28
(6H, s, 2-NMe2, 42a); 5.90 (1Н, d, J = 1.9, Н-3, 42а); 6.81 (1Н, d, J = 8.3, Н-6, 42а); 7.37 (1Н, d, J = 8.2, Н-7,
42а); 7.45 (1Н, s, Н-3, 41а); 7.55-7.62 (2Н, m, Н-6,7, 41а); 8.58 (2Н, s, Н PicO, 41a, 42a); 9.12 (1H, br. s,
NH, 42a); 17.08 (1H, br. s, NH, 41a). Found, %: С 52.67; Н 5.45; N 19.54. С22H27N7O7. Calculated, %:
С 52.69; Н 5.43; N 19.55.
Diamine 39b Perchlorate. Light-brown crystals, mp 157-158°C (EtOH). 1H NMR spectrum
(demonstrates the presence of only one form 42b), , ppm (J, Hz): 2.46 (3Н, s, 8-Mе); 2.57 (3Н, br. s, 5-NMe2);
2.61 (3H, s, 2-Me); 2.91 (3Н, br. s, 5-NMe2); 2.99 (3H, br. s, 4-NMe2); 3.28 (3H, br. s, 4-NMe2); 6.87-6.90 (2H,
m, Н-3,7); 7.48 (1Н, d, J = 8.2, Н-6); 11.58 (1H, br. s, NH).
Diamine 39b Picrate (exists as the crystal monohydrate). Orange cubes, mp 95-97°C (EtOH). 1Н NMR
spectrum, δ, ppm (J, Hz): 2.46 (3Н, s, 8-Mе); 2.57 (3Н, br. s, 5-NMe2); 2.61 (3H, s, 2-Me); 2.91 (3Н, br. s,
5-NMe2); 2.99 (3H, br. s, 4-NMe2); 3.28 (3H, br. s, 4-NMe2); 6.87-6.90 (2H, m, Н-3,7); 7.48 (1Н, d, J = 8.2,
Н-6); 8.58 (2Н, s, Н PicO); 11.58 (1H, br. s, NH). Found, %: С 51.42; Н 5.33; N 17.15. С21H26N6O8.
Calculated, %: С 51.43; Н 5.34; N 17.13.
This work was carried out with the financial support of the Russian Foundation for Basic Research
(grant 11-03-00073).
REFERENCES
1.
2.
A. F. Pozharskii, V. A. Ozeryanskii, and E. A. Filatova, Khim. Geterotsikl. Soedin., 208 (2012). [Chem.
Heterocycl. Compd., 48, 200 (2012)].
T. Ishikawa (editor), Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and
Related Organocatalysts, Wiley, Chichester (2009).
1320

3.
4.
R. W. Alder, P. S. Bowman, W. R. S. Steele, and D. R. Winterman, Chem. Commun. (London), 723
(1968).
A. F. Pozharskii and V. A. Ozeryanskii, in: Z. Rappoport (editor), The Chemistry of Anilines, Part 2,
Wiley, Chichester (2007), p. 931.
5.
6.
7.
F. Hibbert, J. Chem. Soc., Perkin Trans. 2, 1862 (1974).
R. L. Benoit, D. Lefebvre, and M. Fréchette, Can. J. Chem., 65, 996 (1987).
I. Kaljurand, A. Kütt, L. Sooväli, T. Rodima, V. Mäemets, I. Leito, and I. A. Koppel, J. Org. Chem., 70,
1019 (2005).
8.
9.
M. A. Zirnstein and H. A. Staab, Angew. Chem., Int. Ed., 26, 460 (1987).
H.-U. Wüstefeld, W. C. Kaska, F. Schüth, G. D. Stucky, X. Bu, and B. Krebs, Angew. Chem., Int. Ed.,
40, 3182 (2001).
10.
R. Schwesinger, M. Mißfeldt, K. Peters, and H. G. von Schnering, Angew. Chem., Int. Ed., 26, 1165
(1987).
11.
12.
F. B. Scriven, Chem. Soc. Rev., 12, 129 (1983).
M. R. Heinrich, H. S. Klisa, H. Mayr, W. Steglich, and H. Zipse, Angew. Chem., Int. Ed., 42, 4826
(2003).
13.
14.
15.
A. McCurdy, L. Jimenez, D. A. Stauffer, and D. A. Dougherty, J. Am. Chem. Soc., 114, 10314 (1992).
A. J. Kirby and J. M. Percy, Tetrahedron, 44, 6903 (1988).
J. Verbeek, A. V. E. George, R. L. P. de Jong, and L. Brandsma, J. Chem. Soc., Chem. Commun., 257
(1984).
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Y. Kondo, M. Shilai, M. Uchiyama, and T. Sakamoto, J. Am. Chem. Soc., 121, 3539 (1999).
B. Klei and J. H. Teuben, J. Chem. Soc., Chem. Commun., 659 (1978).
F. Mongin and G. Quéguiner, Tetrahedron, 57, 4059 (2001).
D. L. Comins, H. Hong, J. K. Saha, and G. Jianhua, J. Org. Chem., 59, 5120 (1994).
A.-S. Rebstock, F. Mongin, F. Trécourt, and G. Quéguiner, Tetrahedron Lett., 43, 767 (2002).
A. Godard, J.-M. Jacquelin, and G. Quéguiner, J. Organomet. Chem., 354, 273 (1988).
Y. Tagawa, T. Kawaoka, and Y. Goto, J. Heterocycl. Chem., 34, 1677 (1997).
A.-S. Rebstock, F. Mongin, F. Trécourt, and G. Quéguiner, Org. Biomol. Chem., 2, 291 (2004).
C. Kaneko, A. Yamamoto, and M. Gomi, Heterocycles, 12, 227 (1979).
P. D. Woodgate, J. M. Herbert, and W. A. Denny, Heterocycles, 26, 1029 (1987).
J. W. Bunting and W. G. Meathrel, Can. J. Chem., 52, 951 (1974).
E. Ochiai, J. Org. Chem., 18, 534 (1953).
Yu. N. Bubnov, M. E. Gurskii, and T. V. Potapova, Izv. Akad. Nauk, Ser. Khim., 2807 (1996). [Russ.
Chem. Bull., 45, 2665 (1996)].
29.
30.
31.
32.
33.
34.
F. W. Vierhapper and E. L. Eliel, J. Org. Chem., 40, 2729 (1982).
M. Hönel and F. W. Vierhapper, J. Chem. Soc., Perkin Trans. 1, 2607 (1982).
M. Hönel and F. W. Vierhapper, Monatsh. Chem., 115, 1219 (1984).
K. A. Skupinska, E. J. McEachern, R. T. Skerlj, and G. J. Bridger, J. Org. Chem., 67, 7890 (2002).
B. Zacharie, N. Moreau, and C. Dockendorff, J. Org. Chem., 66, 5264 (2001).
A. I. Tochilkin, I. R. Kovel'man, E. P. Prokof'ev, I. N. Gracheva, and M. V. Levinskii, Khim. Geterotsikl.
Soedin., 1084 (1988). [Chem. Heterocycl. Compd., 24, 8892 (1988)].
R. H. Baker, C. J. Albisetti, R. M. Dodson, G. R. Lappin, and B. Riegel, J. Am. Chem. Soc., 68, 1532
(1946).
35.
36.
37.
R. W. Gouley, G. W. Moersch, and H. S. Mosher, J. Am. Chem. Soc., 69, 303 (1947).
L. A. Ruchelman, J. E. Kerrigan, T.-K. Li, N. Zhou, A. Liu, L. F. Liu, and E. J. LaVoie, Bioorg. Med.
Chem., 12, 3731 (2004).
38.
39.
J. C. E. Simpson and P. H. Wright, J. Chem. Soc., 1707 (1948).
A. Adams and D. H. Hey, J. Chem. Soc., 2092 (1950).
1321

40.
41.
42.
W. A. Denny, G. J. Atwell, P. B. Roberta, R. F. Anderson, M. Boyd, C. J. L. Lock, and W. R. Wilson,
J. Med. Chem., 35, 4832 (1992).
O. V. Dyablo, E. A. Shmoilova, A. F. Pozharskii, V. A. Ozeryanskii, O. N. Burov, and Z. A. Starikova,
Org. Lett., 14, 4134 (2012).
A. F. Pozharskii, E. A. Zvezdina, V. I. Sokolov, and I. S. Kashparov, Chem. Ind. (Chichester, U. K.), 256
(1972).
43.
44.
45.
46.
T. Birchal and W. I. Jolly, J. Am. Chem. Soc., 88, 5439 (1966).
H. A. Staab, A. Kirsch, T. Barth, C. Krieger, and F. A. Neugebauer, Eur. J. Org. Chem., 1617 (2000).
B. Kanner, Heterocycles, 18, 411 (1982).
E. A. Filatova, I. V. Borovlev, A. F. Pozharskii, Z. A. Starikova, and N. V. Vistorobskii, Mendeleev
Commun., 10, 178 (2000).
47.
48.
49.
50.
51.
F. Hibbert, Acc. Chem. Res., 17, 115 (1984).
V. A. Ozeryanskii, A. F. Pozharskii, A. Filarowski, and G. S. Borodkin, Org. Lett., 15, 2194 (2013).
J. Azizian, H. Kefayati, M. Mehrdad, K. Jadidi, and Y. Sarrafi, Iran J. Chem. Chem. Eng., 20, 20 (2001).
R. W. Gouley, G. W. Moersch, and H. S. Mosher, J. Am. Chem. Soc., 69, 303 (1947).
M. Karramkam, F. Dolle, H. Valette, L. Besret, Y. Bramoulle, F. Hinnen, F. Vaufrey, C. Franklin,
S. Bourg, C. Coulon, M. Ottaviani, M. Delaforge, C. Loch, M. Bottlaender, and C. Crouzela, Bioorg.
Med. Chem., 10, 2611 (2002).
52.
E. Ochiai and T. Okamoto, J. Pharm. Soc. Jpn, 68, 88 (1948); Chem. Abstr., 47, 8073 (1953).
1322