Salts of 2- or 3-haloalkylamines in the synthesis of N-aminoalkyl derivatives of heterocyclic and aromatic amines

Article abstract of DOI:10.1007/s11172-016-1570-1

Reactions of 2-haloethyl- or 3-halopropylamine salts with NH-substrates (indoline, 1,2,3,4-tetrahydroquinoline, aniline, and N-ethylaniline) in the presence of NaHCO₃ in water furnished various N-aminoalkyl derivatives of heterocyclic and aromatic amines.

Full text of DOI:10.1007/s11172-016-1570-1

Russian Chemical Bulletin, International Edition, Vol. 65, No.9, pp. 2211—2215, September, 2016
2211
Salts of 2ꢀ or 3ꢀhaloalkylamines in the synthesis of Nꢀaminoalkyl derivatives
of heterocyclic and aromatic amines
T. P. Vasilyeva, D. V. Vorobyeva, and S. N. Osipov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: dꢀ20@mail.ru
Reactions of 2ꢀhaloethylꢀ or 3ꢀhalopropylamine salts with NHꢀsubstrates (indoline, 1,2,3,4ꢀ
tetrahydroquinoline, aniline, and Nꢀethylaniline) in the presence of NaHCO3 in water furnished
various Nꢀaminoalkyl derivatives of heterocyclic and aromatic amines.
Key words: 1ꢀ(aminoalkyl)indolines, Nꢀ(aminoalkyl)ꢀ1,2,3,4ꢀtetrahydroquinolines, Nꢀphenylꢀ
alkylenediamines, Nꢀ(aminoalkyl)ꢀNꢀethylanilines, 2ꢀ or 3ꢀhaloalkylamine salts, aminoalkylꢀ
ation, aromatic and heterocyclic amines.
In continuation of the works studying nitrogenꢀconꢀ
taining heterocyclic compounds such as benzimidazole,1
3,4ꢀdihydroꢀ2Hꢀpyrrole, pyrrolidine,2 and 2,3ꢀdihydroꢀ
1Hꢀisoindole3 derivatives, we investigated a possibility of
aminoalkylation of NHꢀheterocycles, namely, indoline and
1,2,3,4ꢀtetrahydroquinoline. The interest to 1ꢀ(aminoꢀ
alkyl)indolines and tetrahydroquinolines is equally caused
by both their use as reagents for the preparation of more
complex compounds and the biological activity of the
products of these reactions (antidepressants, antihyperꢀ
tensive and antihistamine agents, repellents, antioxiꢀ
dants, etc.).4—11 However, practical application of these
compounds is restricted by the absence of convenient preꢀ
parative methods for the preparation of the starting aminoꢀ
alkylated NHꢀheterocycles. Therefore, the development
of new methods for the synthesis of heterocyclic alkyleneꢀ
diamines is an actual issue.
The purpose of the present work is the development of
optimal conditions for the synthesis from indoline 1 of
1ꢀ(aminoalkyl)indolines 2 and 3 and 1ꢀ(2ꢀdimethylꢀ
aminoalkyl)ꢀ or 1ꢀ(3ꢀdimethylaminoalkyl)indolines 4 and 5,
as well as the study of a possibility of application of comꢀ
mercially available 1,2,3,4ꢀtetrahydroquinoline (6) for the
preparation of Nꢀ(aminoalkyl)tetrahydroquinolines 7 and
8 and 1ꢀ(2ꢀdimethylaminoalkyl)ꢀ or 1ꢀ(3ꢀdimethylaminoꢀ
alkyl)tetrahydroquinolines 9 and 10. Note that dimethylꢀ
aminoalkylated Nꢀheterocycles 4, 5, and 10 are new comꢀ
pounds. It was reported that direct aminoethylation of
indoline 1 and tetrahydroquinoline 6 using 2ꢀbromoethylꢀ
amine hydrobromide in organic solvents gave low yields:
27% for 1ꢀ(2ꢀaminoethyl)indoline (2)4,5 and 7% for Nꢀ(βꢀ
aminoethyl)tetrahydroquinoline (7).9 There are known
twoꢀstep approaches to the preparation of compounds 2
(see Ref. 6) and 7 (see Ref. 12). The first of them includes
the reaction of NHꢀheterocycles 1 or 6 with Nꢀ(2ꢀbromoꢀ
ethyl)phthalimide and subsequent treatment of products
with hydrazine hydrate. The disadvantage of this method
consists in the necessity to use a double excess of the
NHꢀheterocycle and the low yields (below 35%). Another
twoꢀstep synthesis, which includes a prolonged (11 h)
reflux of a mixture of 1 or 6, chloroacetonitrile, and sodiꢀ
um carbonate in aqueous toluene with subsequent reducꢀ
tion of formed products with lithium aluminum hydride
gives low (less than 15%) yields of 1ꢀ(aminoethyl)ꢀsubstiꢀ
tuted Nꢀheterocycles 2 and 7 (see Ref. 8).
By the present time, no preparative procedures for the
direct aminopropylation of indoline 1 and tetrahydroquinꢀ
oline 6 have been described. There is known a single exꢀ
ample of a twoꢀstep synthesis of 1ꢀ(3ꢀaminopropyl)ꢀ
indoline (3)7 or 1ꢀ(3ꢀaminopropyl)tetrahydroquinoline
(8)9,13 by cyanethylation of NHꢀheterocycles 1 or 6 upon
treatment with acrylonitrile in acetic acid upon prolonged
heating with subsequent reduction of obtained Nꢀ(βꢀ
cyanoethyl)ꢀsubstituted products. The disadvantages of
this method are the long time of the process and the use of
toxic acrylonitrile, as well as special nickel catalysts for
the reduction.
Results and Discussion
We have developed a new approach to the synthesis of
indoline Nꢀaminoalkyl derivatives from indoline 1 and
commercially available 2ꢀ or 3ꢀhaloalkylamine hydroꢀ
halides in aqueous medium, using sodium hydrogen carbꢀ
onate as an acceptor of hydrogen halides (instead of exꢀ
cessive 1). The optimal conditions were selected on a model
reaction of 1 with 2ꢀbromoethylamine hydrobromide in
the presence of NaHCO3 (Scheme 1).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2211—2215, September, 2016.
1066ꢀ5285/16/6509ꢀ2211 © 2016 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Vasilyeva et al.
Scheme 1
Since Nꢀaminoalkyltetrahydroquinolines frequently
exhibit various kinds of physiological activity,8—11 it
seemed interesting to extend the developed method to tetraꢀ
hydroquinoline 6. The latter turned out to be less active
than indoline 1, and it was necessary to use larger excess of
hydrohalides (1.3—1.4 equiv. per 1 equiv. of 6) in order to
increase its conversion (see Scheme 2 and Table 1).
Scheme 2
n = 2 (2, 4), 3 (3, 5)
Reagents: i. NaHCO3, H2O; ii. Br(CH2)nNH2•HBr;
iii. Cl(CH2)nNMe2•HCl.
It turned out that the order of mixing of the three
components and their ratio play a decisive role in this
reaction. First, it was found that the addition of 1 equiv. of
the hydrobromide to a mixture of 1 with an excess of
NaHCO3 (2 equiv.) in water and subsequent heating of
the reaction mixture (for more than 5 h) gave the target
product 2 in low yield (5%), with recovering of 84% of the
starting indoline 1 by distillation. This negative result can
be explained by the fact that in the presence of excessive
NaHCO3, the hydrobromide instead of reacting with inꢀ
doline 1 undergoes cyclization to ethyleneimine, which upon
heating in water hydrolyzes and polymerizes. A thorough
selection of conditions (the ratio of reagents, the order of
their mixing, temperature) resulted in the minimization of
the side cyclization reaction and in the increase of converꢀ
sion of compound 1. This was achieved upon slow addiꢀ
tion of 1—1.2 equiv. of solid NaHCO3 (method A) or its
aqueous solution (method B) to the mixture of 1 equiv. of 1
and 1.2 equiv. of the hydrobromide in water at 95 °C with
subsequent reflux of the reaction mixture for 2—2.5 h.
After alkalization with aqueous NaOH, the target product 2
was isolated by distillation in vacuo in 70% yield (Table 1).
At the equimolar ratio of reagents (1 : 1 : 1), the converꢀ
sion of indoline 1 was lower, which resulted in the deꢀ
crease in the yield and purity of compound 2.
Similar conditions were used for aminoalkylation of 1
upon treatment with 3ꢀbromopropylamine hydrobromide and
2ꢀ(dimethylamino)ethyl chloride or 3ꢀ(dimethylamino)ꢀ
propyl chloride hydrochlorides (see Scheme 1). As it was
expected, 3ꢀhalopropylamines turned out to be less reacꢀ
tive: even with an increased excess of hydrohalides and at
more prolonged heating the conversion of 1 was incomꢀ
plete. After thorough fractional distillation (for removal of
unreacted 1), the target Nꢀsubstituted heterocycles, namely,
3ꢀaminopropylꢀ (3), 2ꢀdimethylaminoethylꢀ (4), and 3ꢀdiꢀ
methylaminopropyl indolines (5) were isolated in the pure
form in moderate and good yields (see Table 1).
n = 2 (7, 9), 3 (8, 10)
Reagents: i. NaHCO3, H2O; ii. Br(CH2)nNH2•HBr;
iii. Cl(CH2)nNMe2•HCl.
The aminoalkylation products 7—9 were obtained in
acceptable yields, except 1ꢀ(3ꢀdimethylaminopropyl)ꢀ
tetrahydroquinoline (10), the low yield of which (20%) we
relate to the low reactivity of both compound 6 and hydroꢀ
chloride Cl(CH2)3NMe2•HCl. Our attempts to increase
the yield of 10 using excess of reagents (2.2 equiv. of hydroꢀ
chloride and NaHCO3 each) and lesser amount of water
(half as large) or increasing the time of heating (up to 22 h)
were unsuccessful. Using the synthesis of 1ꢀ(2ꢀaminoꢀ
ethyl)tetrahydroquinoline (7) as an example, it was shown
that in comparison with standard method A, an increase
in the volume of the solvent (by a factor of 5, method C)
leads to a sharp decrease in the rate of alkylation and, as
a result, in the yield of product 7 (by a factor of 2) even at
more prolonged heating (see Table 1), which agrees with
the SN2ꢀmechanism of this reaction.
It turned out that aminoalkylation of NHꢀheterocycles 1
and 6 takes place selectively: even a prolonged reflux of tetraꢀ
hydroquinoline 6 with a large excess of 2ꢀbromoethylꢀ
amine hydrobromide and NaHCO3 (2.4 equiv. each) gives
only diamine 7, whereas the product of further alkylation
of the latter, the corresponding triamine, is not formed
(see Table 1).
It was interesting to demonstrate a possibility of the
synthesis of arylamine Nꢀaminoalkyl derivatives within
the framework of the developed method, using 2ꢀ or
3ꢀbromoalkylamine hydrobromides. Aniline and Nꢀethylꢀ

NꢀAminoalkyl heterocyclic and aromatic amines
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2213
Table 1. Physicochemical characteristics of Nꢀsubstituted ethyleneꢀ or propylenediamines
Starting
NHꢀ
substrate
Method
of synthesis
Conditionsa
Final
diamine
Yield
(%)
B.p./°C
(p/Torr)
nD
(Т/°C)
Found
Calculated
Molecular
formula
(%)
Ratio of
τ/h
С
H
N
reagents
c
e
1
А
1 : 1.2 : 1
1.75
2.5
2
69
103—108 (2)b 1.5830 (20)
74.04 8.81 17.33
74.07 8.64 17.28
C10H14N2
B
А
1 : 1.2 : 1.2
1 : 1.4 : 1.4 6—7
2
3
70
61
198—102 (1)b 1.5822 (22)
105—109 (1)d 1.5729 (21)
—
—
—
—
74.75 9.04 15.72
75.00 9.09 15.91
75.74 9.51 14.78
75.79 9.47 14.74
76.49 9.80 13.69
76.47 9.80 13.73
C11H16N2
А
А
1 : 1.2 : 1
1.1
3.5
4
5
77
196—97 (1)
193—95 (1)
1.5495 (19)
1.5435 (18)
C12H18N2
1 : 1.2 : 1.2
57f
C13H20N2
6
А
C
1 : 1.3 : 1.3
1 : 1.3 : 1.4
3.5
16
7
7
79
121—127 (2)g 1.5810 (22)
110—114 (1)g 1.5910 (20)
—
—
—
—
42h
74.98 9.09 15.86
75.00 9.09 15.91
C11H16N2
А
А
1 : 2.4 : 2.4
11i
7
8
62
129—130 (2)g 1.5890 (23)
119—124 (1)l 1.5800 (19)
—
—
—
—
1 : 1.4 : 1.4 13.5j
41k
75.76 9.45 14.73
75.79 9.47 14.74
76.36 9.78 13.59
76.47 9.80 13.73
77.07 10.07 12.79
77.06 10.09 12.84
C12H18N2
А
А
1 : 1.4 : 1.4
1 : 1.4 : 1.4
4.5
11n
9
60
180—82 (0.2)m 1.5580 (19)
123—126 (1) 1.5488 (26)
C13H20N2
C14H22N2
10
20o
PhNH2
А
D
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1
2
11
11
30p
66
188—90 (1)q 1.5850 (25)
188—92 (1)q 1.5868 (20)
—
—
—
—
70.23 9.13 20.37
70.59 8.82 20.59
71.87 9.38 18.66
72.00 9.33 18.67
73.09 9.81 16.83
73.17 9.76 17.07
74.17 10.07 15.71
74.16 10.11 15.73
C8H12N2
D
D
D
1 : 1.4 : 1.4
1 : 1.2 : 1.2
1 : 1.2 : 1.2
6.5
2.5
3.5
12
13
14
41
63
70
108—109 (1)r 1.5749 (24)
C9H14N2
C10H16N2
C11H18N2
PhNHEt
196—98 (1)s
1.5642 (21)
120—121 (2)d 1.5528 (28)
a Reagents: NHꢀsubstrate : haloalkylamine hydrohalide : NaHCO3; τ is the time of reflux. b Cf. Ref. 8. c Found: M+ 162, calculated
M 162. d Cf. Ref. 7. e Found: M+ 176, calculated M 176. f A mixture of the starting compound 1 and the product 5 (~10%, ~1 : 1) with
b.p. 70—92 °C (1 Torr) was also obtained. g Cf. Ref. 9. h A mixture of the starting compound 1 and the product 7 (~20%, ~1 : 3) with
i
b.p. 96—106 °C (1 Torr) was also obtained. The synthesis of compound 7 under these conditions reached completion within 2.75 h
j
(TLC); no product of further aminoalkylation of compound 7 was found even after heating for 11 h. The conversion of the starting
compound 6 was ~70%. k A mixture of the starting compound 6 and the product 8 (~18%, ~1 : 1) with b.p. 70—113 °C (1 Torr) was also
obtained. l Cf. Refs 9 and 13. m Cf. Refs 10 and 11. n The conversion of the starting compound 6 was below 50%. o Apart from
compound 10, the unreacted compound 6 (2.48 g, 37%; b.p. 102—110 °C (1 Torr)) was also recovered. p The low yield under these
conditions is explained by the high solubility of compound 11 in water. q Cf. Ref. 21. r Cf. Ref. 23. s Cf. Ref. 25.
aniline were chosen as the objects of studies because of the
expected reaction products, which are Nꢀphenylethyleneꢀ
diamine (11), Nꢀphenylpropyleneꢀ1,3ꢀdiamine (12),
Nꢀ(2ꢀaminoethyl)ꢀNꢀethylaniline (13), and Nꢀ(3ꢀaminoꢀ
propyl)ꢀNꢀethylaniline (14), are widely used in the synꢀ
thesis of new Nꢀheterocycles,14 potentially bioactive comꢀ
pounds,15,16 antidepressant,7,17—19 antiviral,20 antimicroꢀ
bial,21 antimalarial,22 and radioprotective agents,23 as well
as for modification of biopolymers.24
Similar conditions (method A) were used for aminoꢀ
ethylation of aniline with 2ꢀbromoethylamine hydroꢀ
bromide. In this case, the reaction reached completion
rapidly enough (within 1 h), but the yield of the target
product was low because of the losses during isolation
(compound 11 is soluble in water). The yield of 11 was
increased from 30 to 66% when amount of water was deꢀ
creased during synthesis and isolation of the product
(method D, see Table 1). Similarly (method D), Nꢀethylꢀ
aniline was used to obtain the corresponding aminoethylꢀ
ation product, compound 13 (Scheme 3).
The method developed in the present work is favorably
distinguished from the frequently used known method for
the preparation of compounds 1117 and 1318 (prolonged
reflux of arylamine with hydrobromide in toluene) as more
rapid (heating for 1—2 h against 16—24 h) and economiꢀ
cal (no need to use an organic solvent and a double excess
of arylamine). The same conditions, but with more proꢀ
longed heating (3.5—6.5 h) of 3ꢀbromopropylamine hydroꢀ
bromide with arylamines in the presence of NaHCO3 in
water, were used to obtain the corresponding Nꢀ(3ꢀaminoꢀ

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Vasilyeva et al.
Scheme 3
their spectroscopic characteristics and TLC analysis reꢀ
sults are summarized in Table 2.
In conclusion, based on the reaction of NHꢀsubstrates
with haloalkylamine salts in aqueous medium and using
NaHCO3 as an acceptor of hydrogen halides (instead
of the second mole of the NHꢀsubstrate) at the molar
ratio of reagents NHꢀsubstrate : hydrohalide : NaHCO3,
equal to 1 : (1.2—1.4) : (1—1.4), we have developed
a convenient method for the synthesis of 1ꢀ(aminoalkyl)ꢀ
indolines and Nꢀ(aminoalkyl)tetrahydroquinolines, as
well as Nꢀ(aminoalkyl)arylamines, which are of interꢀ
est for medicinal chemistry. Thus, there is a recent
publication on the application of some arylamides based
on 1ꢀ(aminoethyl)ꢀ and, especially, 1ꢀ(3ꢀaminopropyl)ꢀ
indolines and 1ꢀ(3ꢀaminopropyl)tetrahydroquinoꢀ
lines 2, 3, 7, and 8 as anticancer agents.26 Our studies
resulted in the obtaining of known compounds 2, 3, 7—9,
and 11—14 in better yields and new Nꢀheterocycles 4,
5, and 10.
Compound
11
12
R
H
H
n
2
3
Compound
13
14
R
Et
Et
n
2
3
propyl)ꢀNꢀarylamines 12 and 14 (see Scheme 3 and Table 1).
The known method for the preparation of propylenediꢀ
amines 1223 and 147 is a twoꢀstep synthesis: 3ꢀarylaminoꢀ
propionitriles were synthesized first by cyanethylation of
arylamines, which then were reduced using LiAlH4.
The yields and physicochemical properties of obtained
compounds (2—5 and 7—14) are given in Table 1, whereas
Table 2. 1H NMR spectra of the synthesized compounds (CDCl3) and the data of their TLC analysis
Compound
δ, J/Hz
Rfa
2
1.35 (s, 2 Н, NH2); 3.01 (m, 4 Н, 2ꢀСН2 + 3ꢀСН2); 3.18 (t, 2 Н, CH2NH2, J = 7.2); 3.42 (t, 2 Н,
>NСH2, J = 7.2); 6.59 (d, 1 Н, Ar, J = 7.8); 6.74 (t, 1 Н, Ar, J = 7.4); 7.14 (t, 2 Н, Ar, J = 7.8)
1.24 (s, 2 Н, NH2); 1.80—1.84 (m, 2 Н, С—СН2—С); 2.89 (t, 2 Н, CH2NH2, J = 6.9);
3.02 (t, 2 Н, 3ꢀСН2, J = 8.2); 3.19 (t, 2 Н, >NСH2, J = 7.1); 3.40 (t, 2 Н, 2ꢀСН2, J = 8.2);
6.56 (d, 1 Н, Ar, J = 8.1); 6.71 (t, 1 Н, Ar, J = 7.3); 7.11—7.16 (m, 2 Н, Ar)
2.40 (s, 6 Н, NMe2); 2.62 (t, 2 Н, CH2NMe2, J = 7.2); 3.05 (t, 2 Н, 3ꢀСН2, J = 8.3);
3.28 (t, 2 Н, >NСH2, J = 7.2); 3.46 (t, 2 Н, 2ꢀСН2, J = 8.3); 6.58 (d, 1 Н, Ar, J = 8.0);
6.73 (t, 1 Н, Ar, J = 7.1); 7.13—7.17 (m, 2 Н, Ar)
1.83—1.88 (m, 2 Н, С—СН2—С); 2.33 (s, 6 Н, NMe2); 2.45 (t, 2 Н, CH2NMe2, J = 7.4);
3.04 (t, 2 Н, 3ꢀСН2, J = 8.3); 3.17 (t, 2 Н, >NСH2, J = 7.2); 3.42 (t, 2 Н, 2ꢀСН2, J = 8.3);
6.57 (d, 1 Н, Ar, J = 8.0); 6.72 (t, 1 Н, Ar, J = 7.3); 7.11—7.32 (m, 2 Н, Ar)
1.26 (s, 2 Н, NH2); 2.03 (t, 2 Н, 4ꢀСН2, J = 5.9); 2.84 (t, 2 Н, CH2NH2, J = 6.4); 3.00 (t, 2 Н, >NСH2,
J = 6.4); 3.37—3.43 (m, 4 Н, 2ꢀСН2 + 3ꢀСН2); 6.65—6.72 (m, 2 Н, Ar); 7.01—7.12 (m, 2 Н, Ar)
1.10 (br.s, 2 Н, NH2); 1.61—1.66 (m, 2 Н, 4ꢀСН2); 1.82—1.86 (m, 2 Н, С—СН2—С);
2.62—2.69 (m, 4 Н, >NСH2 + CH2NH2); 3.15—3.23 (m, 4 Н, 2ꢀСН2 + 3ꢀСН2);
6.42—6.50 (m, 2 Н, Ar); 6.83 (d, 1 Н, Ar, J = 7.4); 6.94 (t, 1 Н, Ar, J = 7.4)
2.02—2.04 (m, 2 Н, 4ꢀСН2); 2.38 (s, 6 Н, NMe2); 2.54—2.59 (m, 2 Н, 3ꢀСН2);
2.82 (t, 2 Н, 2ꢀСН2, J = 6.3); 3.39 (t, 2 Н, CH2NMe2, J = 5.6); 3.45—3.50 (m, 2 Н, >NСH2);
6.61—6.68 (m, 2 Н, Ar); 7.00—7.03 (m, 1 Н, Ar); 7.10—7.15 (m, 1 Н, Ar)
0.15—0.19b
3
4
5
0.18b
0.20c
0.18c
7
8
0.30d
0.20d
9
0.21c
10
1.82—1.87 (m, 2 Н, С—СН2—С); 2.02—2.05 (m, 2 Н, 4ꢀСН2); 2.33 (s, 6 Н, NMe2);
2.40 (t, 2 Н, CH2NMe2, J =7.2); 3.35—3.41 (m, 4 Н, 2ꢀСН2 + 3ꢀСН2); 6.63—6.70 (m, 2 Н, Ar);
7.01—7.13 (m, 2 Н, Ar)
0.17—0.21c
11
12
1.41 (br.s, 2 Н, NH2); 3.00 (t, 2 Н, CH2NН2, J = 5.7); 3.24 (t, 2 Н, CH2NH, J = 5.7); 4.08 (br.s, 1 Н,
NH); 6.71 (dd, 2 Н, Ar, J = 8.6, J = 1.0); 6.78 (t.t, 1 Н, Ar, J = 7.3, J = 1.1); 7.23—7.28 (m, 2 Н, Ar)
1.33 (br.s, 2 Н, NH2); 1.80—1.85 (m, 2 Н, С—СН2—С); 2.91 (t, 2 Н, CH2NН2, J = 6.7);
3.25 (t, 2 Н, CH2NH, J = 6.8); 6.68 (d, 2 Н, Ar, J = 8.1); 6.76 (t, 1 Н, Ar, J = 7.4);
7.24 (t, 2 Н, Ar, J = 7.9)
1.22 (t, 3 Н, СH3, J = 7.0); 1.34 (s, 2 Н, NH2); 2.98 (t, 2 Н, CH2NН2, J = 6.7);
3.40—3.48 (m, 4 Н, СН2—N—СН2); 6.75—6.82 (m, 3 Н, Ar); 7.27—7.32 (m, 2 Н, Ar)
2.65 (t, 3 Н, СH3, J = 7.1); 2.74 (s, 2 Н, NH2); 3.21—3.28 (m, 2 Н, С—СН2—С); 4.27 (t, 2 Н, CH2NН2, 0.23f
J = 7.1); 4.81—4.90 (m, 4 Н, СН2—N—СН2); 8.14—8.21 (m, 3 Н, Ar); 8.70—8.74 (m, 2 Н, Ar)
0.14e
0.19f
13
14
0.29f
a An orange spot in visible light, a crimson spot under UV light. b The Me2CO—CCl4 solvent system, 1 : 3. c The AcOEt—Et3N solvent system,
50 : 1. d The Me2CO—CCl4 solvent system, 2 : 1. e The AcOEt—Et3N solvent system, 10 : 1. f The AcOEt—PriNH2 solvent system, 10 : 1.

NꢀAminoalkyl heterocyclic and aromatic amines
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2215
Experimental
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1
H NMR spectra were recorded on Bruker Avanceꢀ300 (for
compounds 2—5 and 7—13) or Bruker Avanceꢀ400 spectroꢀ
meters (for compound 14) (300 and 400 MHz) relative to Me4Si.
Elemental analysis of compounds was performed in the Laboraꢀ
tory of Elemental Analysis of the A. N. Nesmeyanov Institute of
Organoelement Compounds of the Russian Academy of Sciences.
The starting NHꢀsubstrates 1, 6, and PhNHR (R = H, Et) are
commercially available reagents. Reaction progress was moniꢀ
tored on Merck plates (60 Fꢀ254, 0.25 mm). Reaction condiꢀ
tions, yields, and constants of compounds 2—5 and 7—14 are
summarized in Table 1, their 1H NMR spectra and TLC analysis
data are given in Table 2.
Aminoalkylation of NHꢀsubstrates upon treatment with 2ꢀhaloꢀ
ethylꢀ or 3ꢀhalopropylamine salts. Method A. Synthesis of diꢀ
amines 2—5 and 7—11. A mixture of the corresponding NHꢀsubꢀ
strate (0.415 mol) (see Table 1), 2ꢀ or 3ꢀhaloalkylamine hydroꢀ
halide and water (100 mL) was heated to 95 °C (in a bath) with
stirring, then NaHCO3 was added in small portion. After stirring
for ~15 min at 95 °C, the reaction mixture was refluxed with
stirring using a heating mantle until completion of the reaction.
The amount of hydrohalide and NaHCO3, as well as the time of
heating are given in Table 1. The mixture was allowed to cool
down to ~20 °C, followed by the addition of a 40% aqueous
NaOH (75 mL) and water until dissolution of the precipitate
(~250 mL). The organic layer was separated, the aqueous layer
was extracted with diethyl ether and CH2Cl2 (twice). The comꢀ
bined organic layers were washed with saturated aqueous soluꢀ
tion of NaCl and dried with MgSO4. The solvent was evaporated
in vacuo, the residue was distilled.
Method B. Synthesis of 1ꢀ(2ꢀaminoethyl)indoline (2). A hot
solution of NaHCO3 (10.08 g, 0.12 mol) in water (45 mL) was
added to a hot (~95 °C) mixture of indoline (11.9 g, 0.1 mol),
2ꢀbromoethylamine hydrobromide ((24.6 g, 0.12 mol), and water
(12 mL) with stirring over 30 min. The reaction mixture was kept for
~15 min at 95 °C in a bath, then refluxed for ~2.5 h until reaction
reached completion, and workedꢀup similarly to method A.
Method C. Synthesis of Nꢀ(2ꢀaminoethyl)ꢀ1,2,3,4ꢀtetrahydroꢀ
quinoline (7). Solutions of 2ꢀbromoethylamine hydrobromide
(13.32 g, 0.065 mol) in water (35 mL) and NaHCO3 (5.88 g,
0.07 mol) in hot water (52 mL) were added from two dropping
funnels to 1,2,3,4ꢀtetrahydroquinoline 6 (6.65 g, 0.05 mol) at
95 °C (in a bath) with stirring. After ~15 min, the reaction mixꢀ
ture was refluxed using a heating mantle for ~16 h and workedꢀup
similarly to method A.
Method D. Synthesis of anilines 11—14. A mixture of aniline
(or PhNHEt) (0.05 mol)), 2ꢀbromoethylꢀ (or 3ꢀbromopropyl)ꢀ
amine hydrobromide and water (6 mL) was heated to 95 °C (in
a bath), Then, NaHCO3 was added in small portions with stirring.
After ~15 min (at 95 °C), the reaction mixture was refluxed with
stirring using a heating mantle until reaction reached compleꢀ
tion. The amount of hydrobromide and NaHCO3 and the time
of heating are given in Table 1. Still warm reaction mixture was
diluted with 50% aqueous КOH (11 mL) and water (16 mL). The
organic layer was separated, the aqueous layer was saturated
with NaCl and extracted with chloroform (4×20 mL), each time
adding NaCl into the aqueous phase. The combined organic
layers were dried with MgSO4 and fractionally distilled in vacuo.
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 15ꢀ03ꢀ03287).
Received October 29, 2015;
in revised form February 19, 2016