Reactions of 3-[N-chloroacetylamino-N-(4-nitrophenyl)]-2-formylindole with alkylamines

Article abstract of DOI:10.1007/s11172-007-0249-z

The reactions of 3-[N-chloracetylamino-N-(4-nitrophenyl)]-2-formylindole (1a) with 2-(N, N-dialkylamino)ethylamines afford complex condensation products 7b,c consisting of two similar but not identical diazepinoindole fragments. For the reaction of compou

Full text of DOI:10.1007/s11172-007-0249-z

Russian Chemical Bulletin, International Edition, Vol. 56, No. 8, pp. 1595—1602, August, 2007
1595
Reactions of 3ꢀ[NꢀchloroacetylaminoꢀNꢀ(4ꢀnitrophenyl)]ꢀ2ꢀformylindole
with alkylamines*
S. Yu. Ryabova,a A. S. Shashkov,b L. M. Alekseeva,a E. A. Lisitsa,a and V. G. Granika
ꢀ
aState Scientific Center for Antibiotics,
3a ul. Nagatinskaya, 117003 Moscow, Russian Federation.
Fax: +7 (495) 225 6104. Eꢀmail: vggranik@mail.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328
The reactions of 3ꢀ[NꢀchloracetylaminoꢀNꢀ(4ꢀnitrophenyl)]ꢀ2ꢀformylindole (1a) with
2ꢀ(N,Nꢀdialkylamino)ethylamines afford complex condensation products 7b,c consisting of
two similar but not identical diazepinoindole fragments. For the reaction of compound 1a with
3ꢀ(N,Nꢀdiethylamino)propylamine, the process occurs in a different manner, and the predomiꢀ
nant product is 4ꢀethylaminopropylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2,3,4,5,6ꢀhexahydro[1,4]diꢀ
azepino[6,5ꢀb]indole hydrocloride (14). Two routes of these unexpected transformations were
proposed. The structures of the synthesized products were proved by the 1H and 13С NМR,
HMBC, and HSQC (direct protonꢀcarbon correlation) spectra.
Key words: 3ꢀ[NꢀchloroacetylaminoꢀNꢀ(4ꢀnitrophehyl)]ꢀ2ꢀformylindole, ethanolamine,
benzylamine, 2ꢀ(diethylamino)ethylamine, 2ꢀ(dimethylamino)ethylamine, 3ꢀ(diethylamiꢀ
no)propylamine, condensation, cyclization, 1,2,3,6ꢀtetrahydro[1,4]diazepino[6,5ꢀb]indoles,
1,2,3,4,5,6ꢀhexahydro[1,4]diazepino[6,5ꢀb]indoles.
Scheme 1
In the recent years, we have studied the synthesis,
properties, and transformations of differently substituted
3ꢀNꢀarylaminoꢀ2ꢀformylindoles.1,2 The use of these comꢀ
pounds in heterocyclic synthesis provided the developꢀ
ment of novel, often unusual approaches to the preparaꢀ
tion of a whole series of indoleꢀcontaining heterocycles,
such as pyrido[3,2ꢀb]indoles, indolo[3,2ꢀb]quinolines,
pyrrolo[1,2ꢀa]indoles, [1,4]diazepino[6,5ꢀb]indoles, and
pyrimido[5,4ꢀb]indoles, and a series of heterotetracyclic
compounds, including representatives of new heterocyꢀ
clic systems.
We have recently studied the reactions of 3ꢀ(Nꢀarylꢀ
Nꢀchloroacetylamino)ꢀ2ꢀformylindoles 1 with paraꢀsubꢀ
stituted anilines (Scheme 1) resulting in the synthesis
(without isolation of intermediate compounds 2) of earꢀ
lier unknown 1,4ꢀdiarylꢀ2ꢀoxoꢀ1,2,3,6ꢀtetrahydro[1,4]diꢀ
azepino[6,5ꢀb]indoliumꢀ4 chlorides (3).3 They manifested
antihypoxic activity on the models for hypoxic and hypoꢀ
baric hypoxia at the level of the Pyracetam drug.
It is quite evident that the stabilization of intermediate
2 and final product 3 is caused, to a great extent, by the
conjugation with the aromatic ring. Therefore, when aliꢀ
phatic amines are introduced into the reaction with
formylindole 1а, some unexpected phenomena could be
* Dedicated to Academician V. A. Tartakovsky on the occasion
of his 75th birthday.
R = NO2 (a), H (b), Cl (c), OEt (d)
R´ = H, OMe, Cl
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1536—1542, August, 2007.
1066ꢀ5285/07/5608ꢀ1595 © 2007 Springer Science+Business Media, Inc.

1596
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Ryabova et al.
predicted due to the absence of this conjugation and new
biologically active compounds of the diazepinoindole seꢀ
ries could be synthesized by the analogous3 process.
The reactions of compound 1а with equimolar
amounts of ethanolamine (4а), benzylamine (4b),
2ꢀ(N,Nꢀdiethylamino)ethylamine (4c), 2ꢀ(N,Nꢀdimethylꢀ
amino)ethylamine (4d), and 3ꢀ(N,Nꢀdiethylamino)proꢀ
pylamine (4e) were carried out, as with arylamines, on
reflux in isopropyl alcohol.3 It turned out that the direcꢀ
tion of these reactions depends on the structure of amine
used. For the reactions of 2ꢀformylindole 1а with ethanolꢀ
amine and with benzylamine, the process was similar to
the reactions with arylamines,3 and the correspondꢀ
ing 4ꢀsubstituted 1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2,3,6ꢀtetraꢀ
hydro[1,4]diazepino[6,5ꢀb]indoliumꢀ4 chlorides (5a,b)
were isolated. Chloride 5b was reduced with sodium
borohydride according to a described method3 to form
4ꢀbenzylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ3ꢀoxoꢀ1,2,3,4,5,6ꢀhexaꢀ
hydro[1,4]diazepino[6,5ꢀb]indole (6) (Scheme 2).
An insignificant amount of undissolved byꢀproduct 7а
containing no chlorine was separated upon the recrystalꢀ
lization of chloride 5b from methanol. In the mass specꢀ
trum of compound 7a the most intense was the peak
corresponding to the peak 411 [М – HCl + H]+ in the
mass spectrum of the major substance 5b. However, the
lowꢀintensity peak 821 [M + H]+ and the cluster peaks
843 [M + Na]+ and 859 [M + K]+ were observed, indicatꢀ
ing the formation of a dimer. The IR spectrum of comꢀ
pound 7а, as compared to the spectrum of compound 5b,
contained no absorption band at 1690 cm–1 (C=N+) and
exhibited two bands at 1674 and 1664 cm–1 correspondꢀ
ing to two carbonyl groups (Table 1). The 1Н NMR specꢀ
trum of compound 7а also differed substantially from the
spectrum of the major substance 5b: the spectrum exhibꢀ
ited a double set of the sameꢀtype signals from protons in
both the aromatic and aliphatic regions. The total body of
the physicochemical data assumed that a molecule of
byꢀproduct 7а contained two structurally similar but not
identical fragments.
The reactions of 2ꢀformylindole 1а with diethylaminoꢀ
ethylamine 4с and with dimethylaminoethylamine 4d gave
no expected [1,4]diazepino[6,5ꢀb]indoliumꢀ4 chlorides
of the type 5. The major products obtained in satisfactory
yields are dihydrochlorides 7b,c (Scheme 3), whose
1Н NMR spectra are analogous (doubling of the most part
of signals) to the spectrum of byꢀproduct 7а.
Scheme 2
The structures of compounds 7а—c as 16,28ꢀdisubstiꢀ
tuted 12,19ꢀbis(4ꢀnitrophenyl)ꢀ1,4,12,16,19,28ꢀhexaazaꢀ
heptacyclo[13.11.1.12,14.03,11.05,10.020,27.021,26]octacosaꢀ
3(11),5(10),6,8,20(27),21,(26),22,24ꢀoctaeneꢀ13,18ꢀdiꢀ
ones were determined on the basis of the detailed considꢀ
eration of the 1Н NMR and HMBC spectra of these comꢀ
pounds. The 1Н NMR spectra of all three compounds
contain, along with the doubled sameꢀtype signals (see
Experimental), "unpaired signals": the signal from N(4)H
(δ 11.28, 11.61, and 11.56), the signal from the protons
of one methylene group Н2С(17) in the form of the
AB system (δ 3.67 and 4.40, 3.62 and 4.35, 3.63 and 4.31,
Jgem = 15.0—15.4 Hz), the mutually split doublets of the
Н(14) and Н(15) protons (δ 3.57 and 4.35, 3.80 and 4.59,
3.77 and 4.56, Jvic = 7.2—7.5 Hz), and the singlet of the
H(2) proton (δ 7.10, 7.58, and 7.41).* Note that the apꢀ
pearance of the singlet signal in the region of aromatic
protons seems strange, because the signals of protons of
the benzene fragments and protons of the aryl and phenyl
substituents cannot be singlets. This signal belongs to the
proton at the sp3ꢀhybridized C(2)carbon atom** and it is
so downfield due to some strong deshielding effects. The
* The chemical shift of the proton (δ 7.10) was calculated by the
correlation peak in the HMBC spectrum.
** The HSQC spectrum (direct proton—carbon correlation)
of compound 7b contains the correlation peak H(2)/C(14)
7.58/68.8 ppm.
R = CH2OH (a), Ph (b)

Reactions of 2ꢀformylindoles with alkylamines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1597
Table 1. Yields, elemental analysis data, and mass and IR spectra of the synthesized compounds
Comꢀ Yield M.p./°С Mol.
Found
Calculated
Molecular
formula
MS,
m/z
IR,
(%)
N
pound (%)
(solꢀ
weight
ν
max/cm–1
vent)
С
H
NH
C=N+
CO
(OH) (N+H)
5a
5b
84
46
242—243 400 56.44 4.36 13.75 C19H17ClN4O4
365 [M – HCl + H]+,
337 [M – HCl + H –
– CO]+, 729 [2 M –
– 2 HCl + H]+
411 [M – HCl + H]+,
383 [M – HCl + H –
– CO]+, 433 [M – HCl –
+ Na]+, 821 [2 M –
– 2 HCl + H]+
3533,
3477,
3311
1680
1645
1635
(decomp.
EtOH)
56.93 4.28 13.98
253—254 446 64.30 4.44 12.54 C24H19ClN4O3
3520— 1690
3470
(decomp.
MeOH)
64.50 4.29 12.54
6
91
204—206 412 69.86 4.67 13.15 C24H20N4O3
(MeOH) 69.89 4.89 13.58
413 [M + H]+, 435
[M + Na]+, 451
[M + K]+, 825 [2 M +
+ H]+, 847 [2 M +
+ Na]+, 863 [2 M + K]+
3350
—
—
1678
7a
7b
2.4 238—240 820
(MeOH)
—
—
—
C48H36N8O6
821 [M+H]+, 843
3664,
3524,
1674,
1664
[M + Na]+, 859 [M +
+ K]+, 411 [M/2 + H]+ 3470
70
37
242—243 910 60.15 6.06 15.11 C46H26Cl2N10O6 420 [(M– 2 HCl)/2 +
(MeOH) 60.59 5.75 15.36
+ H]+, 839 [M – 2 HCl 3470,
+ H]+
3120
238—240 854 55.73 5.59 15.46 C42H44Cl2N10O6• 821 [M – 2 HCl + К]+, 3429
3600,
2557— 1690,
2425
1674
7с
14
2463
1670
(MeOH)
55.44 5.54 15.40 3 Н2О
805 [M – 2 HCl + Na]+,
783 [M – 2 HCl + Н]+,
392 [(M– 2 HCl)/2 +
+ H]+
408 [M – HCl + H]+,
815 [2 (M – HCl) + H]+
27
238—240 443 59.59 5.95 15.75 C22H26ClN5O3
(MeOH) 59.52 5.90 15.78
3234
2478
1680
strong shift of the H(2) signal in the spectrum can be
related to both the immediate closeness to two nitrogen
atoms and (most likely, this is the main reason) an anisoꢀ
tropic effect of the circular currents of two aromatic (inꢀ
dole) parts of the molecule, which are geminal toward
this proton.
tain diazepinoindole fragment, because the spectra are
intricate and, in addition, the detailed decoding of these
fragments did not solve the problems of structure deterꢀ
mination. Structures 7а,b were unambiguously proved by
the HMBC spectra. In the spectrum of dimer 7а (the
chemical shifts are given in Experimental), one of the
protons of the H2С(17) group has a correlation peak with
the carbon atom of N(16)CH2Ph; both protons of H2С(17)
have correlation peaks with the С(15) and С(18) atoms;
Н(14) has correlation peaks with N(28)CH2Ph, С(2),
С(13), and С(15); Н(15) has correlation peaks with
N(16)CH2Ph and the С(13), С(14), С(17), С(20),
and С(27) carbon atoms; Н(2) has a correlation peak
with С(14). Similar correlation peaks for the protons in
positions 2, 14, 15, and 17 are also observed in the HMBC
spectrum of compound 7b (see Experimental). Since in
the spectra of compound 7b the signal from H(2) is not
overlapped by other aromatic signals, we can determine
the quaternary carbon atoms having correlation peaks with
this proton in the aromatic spectral region: these are С(11),
1
The consideration of the Н NMR spectra of comꢀ
pounds 7а—с show that the rather nonꢀstandard condenꢀ
sation of two diazepinoindole molecules occurs in these
cases: for one of the molecules the nitrogen atom and one
of the methylene groups of the diazepine cycle are "crossꢀ
linking" sites, whereas for another molecule the both
methylene groups are these sites. The 13С NMR spectra
of compounds 7а,b also exhibit a double set of signals for
the sameꢀtype carbon atoms and signals of the "unpaired"
carbon atoms linked with the "unpaired" protons. The
signals were assigned (see Experimental) according to the
HSQC (for protonated atoms) and HMBС (for quaterꢀ
nary atoms) spectra. We did not assign the signals of the
carbon atoms of the indole and substituents to some cerꢀ

1598
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Ryabova et al.
Scheme 3
R = Ph (a), CH2N+Et2Cl– (b), CH2N+Me2Cl– (c)
С(3), С(27), and С(26) (δ 114.3, 124.7, 126.9, and 135.1,
respectively).
The structure of compound 7с was determined on the
basis of similarity of its 1Н NMR spectra to the above
discussed spectra of compounds 7а,b.
condensation of the formyl group at the amino group of
the reactant, resulting in the preliminary formation of the
corresponding carbinolamine 8. If aromatic amine was
chosen as the reactant,3 than, as mentioned above, the
condensation was followed by fast dehydration to form
the Schiff base stabilized by the conjugation.
In this case, this stabilization does not occur and
carbinolamine 8 is further transformed into diazepinoꢀ
indole 9 and then into compound 10 including the aroꢀ
matized 10ꢀπꢀelectron system. In parallel, most likely,
the starting compound 1а is transformed into carbanion
11 capable of attacking the electronꢀdeficient position 5
of compound 10 to form anion 12, which is further subꢀ
jected to the attack of the initial amine yielding anions 13
and then polycyclic compounds 7a—c. Note that comꢀ
pounds 7b and 7c were isolated as dihydrochlorides,
which are formed due to the presence of the —NЕt2 and
—NМе2 groups.
One more important fact should be mentioned: the
yields of the products isolated in these ambiguously ocꢀ
curring processes are not quantitative. The mother liquors
contain intricate mixtures of substances, and the study of
their spectra gave no reliable data on the structure of the
byꢀproducts. Therefore, assumptions on probable schemes
of the processes are based on general concepts and the
structures of the final products.
When describing the formation of these compounds
via Scheme 3, we took into account that amines taken in
some excess were introduced into all reactions and the
excess created a certain basic level of the reaction meꢀ
dium. Unambiguously, the first step of the reaction is the

Reactions of 2ꢀformylindoles with alkylamines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1599
Scheme 4
The reaction of 2ꢀformylindole 1а with diethylaminoꢀ
propylamine 2d proceeded in a different manner and afꢀ
forded 4ꢀethylaminopropylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ
1,2,3,4,5,6ꢀhexahydro[1,4]diazepino[6,5ꢀb]indole (14)
hydrochloride (Scheme 4). The 1Н NMR spectrum of
this compound (see Experimental) exhibits the signal from
one methyl group, the signals from the methylene groups
of the CH2CH2CH2(N+H2)CH2CH3 substituent (see
Scheme 4), the signal from Н2С(2´), which is the most
upfield and followed by Н2С(1´), the signals from Н2С(3´)
and H2C(4´) manifesting the downfield shifts (one signal
with the intensity 4 Н), and the signal from the (N+H2)
group. The structure of the substituent in position 4 also
agrees with the HMBC spectrum: the protons of Н2С(1´)
have correlation peaks with С(3), С(5), С(3´), C(2´); the
protons of Н2С(2´) have correlation peaks with С(1´)
and С(3´); the general signal from Н2С(3´) and H2C(4´)
has correlation peaks with СН3, C(1´), С(2´), С(3´),
and С(4´).
Then, judging from the structure of the final
product, deꢀethylation occurs with the rejection of
ethylene or ethyl chloride and formation of comꢀ
pound 17, which is further transformed into
diazepinoindole hydrochloride 14. The generalꢀ
ized scheme of formation of compound 14 is shown in
Scheme 4.
Questions that need special interpretation arise when
considering this scheme. First, it is necessary to answer
why the difference between the reactions of compound 1а
with diethylaminoethylꢀ and diethylaminopropylamines
is so considerable. It cannot be excluded that the esꢀ
sence is in the ratio of rates of particular reactions,
which can depend on the basicity of the reactants, rather
than in the dramatic change in the directions of the proꢀ
cesses.
Another problem that cannot be explained on the
basis of Scheme 4 is a reason for which the tricyꢀ
clic compound containing the hexahydrodiazepine
ring is formed finally in the absence of solvents.
It is reasonable to assume that tricycle 14 is formed
through the Oꢀalkylation of compound 17 by the
starting compound 1а to form derivative 18, which
further undergoes Oꢀprotonation to compound 19
and prototropic shift to form diazepinoindole 14
(Scheme 5).
It seems probable that in the first step in this
case (as well as for the synthesis of compounds 7а—с)
carbinolamine 15 is formed and then undergoes
intramolecular cyclization to diazepinoindole 16.*
* Perhaps, the predominant formation of compound 16, in this
case, compared to process 9→10 postulated in Scheme 3, is due
to a higher basicity of 3ꢀ(diethylamino)propylamine (4е)4 than
that of 2ꢀ(diethylamino)ethylamine (4с)5 (by the first step pKa =
10.44 (4е) and 9.15 (4с), and by the second step pKa = 8.34 (4e)
and 7.07 (4c)).
Very unusual transformations described in the present
publication and subsequent assumptions undoubtedly need
further detailed investigation.

1600
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Ryabova et al.
Scheme 5
4ꢀBenzylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2,3,6ꢀtetrahydro[1,4]ꢀ
diazepino[6,5ꢀb]indoliumꢀ4 chloride (5b). Benzylamine (0.17 mL,
1.54 mmol) was added with stirring and reflux to a suspension of
2ꢀformylindole 1a (0.5 g, 1.4 mmol) in PriOH (10 mL). The
mixture was refluxed for 1 h. A hot new precipitate that formed
was filtered off, washed with isopropyl alcohol and acetone, and
dried. Chloride 5b was obtained (0.39 g) and further used withꢀ
out purification. Methanol (60 mL) was added, and the mixture
was refluxed for 10 min. An insoluble residue of 7a was filtered
off. 16,28ꢀDibenzylꢀ12,19ꢀbis(4ꢀnitrophenyl)ꢀ1,4,12,16,19,28ꢀ
hexaazaheptacyclo[13.11.1.12,14.03,11.05,10.020,27.021,26]octaꢀ
cosaꢀ3(11),5(10),6,8,20(27),21,(26),22,24ꢀoctaeneꢀ13,18ꢀdione
(7а) was obtained in a yield of 0.02 g. 1Н NMR, δ: 3.22, 3.58,
Experimental
IR spectra of the synthesized compounds were recorded on
an FSMꢀ1201 instrument in Nujol. Mass spectra of the comꢀ
pounds were measured on a Waters ZQꢀ2000 mass spectrometer
(electrospray, sample injection missing the chromatographic colꢀ
umn). 1Н NMR spectra were obtained on a Bruker ACꢀ300
spectrometer in DMSOꢀd6 using standard procedures of the
Company. 13С NMR, HMBC, and HSQC spectra were reꢀ
corded on a Bruker DRXꢀ500 spectrometer in DMSOꢀd6. The
course of the reactions and individual character of the subꢀ
stances were monitored on Silicagel 60 F254 plates (Merck) in
chloroform—methanol (10 : 1) and ethyl acetate—isopropyl alꢀ
cohol—ammoniа (5 : 3 : 1) systems. The yields, elemental analyꢀ
sis data, and other physicochemical characteristics of the synꢀ
thesized compounds are presented in Table 1.
4ꢀHydroxyethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2,3,6ꢀtetraꢀ
hydro[1,4]diazepino[6,5ꢀb]indoliumꢀ4 chloride (5a). Ethanolꢀ
amine (0.093 mL, 1.54 mmol) was added with stirring to a
suspension of 2ꢀformylindole 1a (0.5 g, 1.4 mmol) in PriOH
(10 mL), and the mixture was refluxed for 20 min. The mixture
was cooled, and the precipitate was filtered off, washed with
isopropyl alcohol and acetone, and dried. Chloride 5a was obꢀ
tained in a yield of 0.3 g. 1Н NMR, δ: 3.82, 4.26 (both br.t,
2 Н each, СH2СН2OH, J = 4.5 Hz); 4.83 (s, 2 H, H2C(3)); 5.36
(br.s, 1 H, OH); 6.32 (d, 1 H, H(10), Jо = 8.4 Hz); 6.94 (t, 1 H,
H(9), Jо = 8.4 Hz); 7.44 (t, 1 H, H(8), Jо = 8.4 Hz); 7.61 (m,
3.66, 3.91 (all d, 1 Н each, N(16)CН2Ph, N(28)CН2Ph, Jgem
=
14.0 Hz, Jgem = 12.9 Hz); 3.67, 4.40 (both d, 1 Н each, Н2C(17),
Jgem = 15.0 Hz); 3.57, 4.35 (both d, 1 Н each, Н(14)), Н(15)),
Jvic = 7.5 Hz); 5.58, 6.36 (both d, 1 Н each, 2 Н of benzene
fragments, Jо = 8.3 Hz); 6.71, 6.94, 7.04, 7.91 (three t, one d,
1 Н each, 4 H of benzene fragments, Jо = 8.6 Hz); 7.08—7.29
(m, 13 Н, Ph, Ph, 2 H of benzene fragments, Н(2)); 7.38, 7.72,
8.29, 8.32 (all d, 2 Н each, N(12)C6H4 NO2, N(19)C6H4NO2,
Jо = 8.6 Hz); 11.28 (br.s, 1 Н, N(4)Н).
13C NMR, δ: 53.0 (С(15)); 55.2 (С(17)); 56.5, 57.7
(N(16)CН2Ph, N(28)CН2Ph); 67.2 (С(2)); 68.2 (С(14)); 111.2,
111.7, 118.6, 118.8, 119.5, 120.2, 122.0, 122.6, 123.9,
124.0, 127.5, 128.1, 128.2, 128.3, 128.4, 129.0 (С(6)—C(9)),
С(22)—C(25)), (N(12)С6Н4NO2 and N(19)С6Н4NO2,
N(16)CН2Ph and N(28)CН2Ph)*); 114.0, 114.4, 120.0, 121.0,
3 Н, H(7), H(3´), H(5´)); 8.38 (d, 2 H, H(2´), H(6´), Jо
=
9.0 Hz); 9.49 (s, 1 H, H(5)); 12.76 (br.s, 1 H, N(6)H).
* The chemical shifts of the signals from the protonated atoms.

Reactions of 2ꢀformylindoles with alkylamines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1601
125.2, 127.5, 134.8, 136.1, 136.7, 137.3, 144.9, 145.0, 145.9,
146.8, 169.2, 170.3 (С(10), С(20), С(11), С(21), С(3), С(27),
С(5), С(26)), (N(16)CН2Ph and N(28)CН2Ph, N(12)С6Н4NO2
and N(19)С6Н4NO2)*), С(13), С(18).
HMBC, δ: 4.40/56.5 Н(17)/N(16)CН2Ph; 3.67, 4.40/53.0
Н2C(17)/С(15); 3.67, 4.40/170.3 Н2C(17)/С(18); 3.57/57.7
Н(14)/N(28)CН2Ph; 3.57/53.0 Н(14)/С(15); 3.57/67.2
67.2 (С(2)); 68.8 (С(14)); 111.4, 111.9, 118.3, 119.2, 119.5,
120.3, 122.3, 122.7, 124.0, 124.1, 128.0, 129.3 (С(6)—С(9),
С(22)—С(25), (N(12)С6Н4NO2 and N(19)С6Н4NO2)*); 114.0,
114.3, 120.1, 121.0, 124.9, 126.9, 135.1, 135.8, 145.0, 145.6,
145.7, 146.6, 169.8, 170.3 (С(10), С(20), С(11), С(21), С(3),
С(27), С(5), С(26), (N(12)С6Н4NO2 and N(19)С6Н4NO2)**;
С(18); С(13)).
Н(14)/С(2);
3.57/169.2
Н(14)/С(13);
4.35/56.5
HMCB, δ: 4.35/48.7 Н(17)/N(16)СН2СН2N+Н(СН2Me)2;
Н(15)/N(16)CН2Ph; 4.35/55.2 Н(15)/С(17); 4.35/68.2
Н(15)/С(14); 4.35/169.2 Н(15)/С(13); 4.35/114.0 Н(15)/С(20);
4.35/127.5 Н(15)/С(27); 7.10/68.2 Н(2)/(С(14).
After compound 7а was separated, the mother liquor was
clarified with active carbon and evaporated by 1/4 of the volꢀ
ume, and a precipitate of chloride 5b was filtered off (0.29 g,
46%). 1Н NMR, δ: 4.67 (s, 2 H, H2C(3)); 5.46 (s, 2 H, CH2Ph);
3.62,
4.35/169.8
4.35/57.4
Н2С(17)/С(15);
3.62,
3.80/49.3
Н2С(17)/С(18);
Н(14)/N(28)СН2СН2N+Н(СН2Me)2; 3.80/57.4 Н(14)/С(15);
3.80/67.2 Н(14)/С(2); 3.80/170.0 Н(14)/С(13); 4.59/48.7
Н(15)/N(16)СН2СН2N+Н(СН2Me)2; 4.59/53.0 Н(15)/С(17);
4.59/68.8 Н(15)/С(14); 4.59/170.3 Н(15)/С(13); 4.59/114.0
Н(15)/С(20); 4.59/127.0 Н(15)/С(27); 7.58/68.8 Н(2)/С(14);
7.58/114.3 Н(2)/С(11); 7.58/124.7 Н(2)/С(3); 7.58/128.9
Н(2)/С(27); 7.58/135.8 Н(2)/С(26).
6.28 (d, 1 H, H(10), Jо = 8.4 Hz); 6.92 (t, 1 H, H(9), Jо
=
8.4 Hz); 7.40—7.64 (m, 9 H, H(8), H(3´), H(5´), H(7), Ph);
8.35 (d, 2 H, H(2´), H(6´), Jо = 9.0 Hz); 9.91 (s, 1 H, H(5));
13.10 (br.s, 1 H, N(6)H).
16,28ꢀBis[2ꢀN,Nꢀdimethylamino)ethyl]ꢀ12,19ꢀbis(4ꢀ
n i t r o p h e n y l ) ꢀ 1 , 4 , 1 2 , 1 6 , 1 9 , 2 8 ꢀ h e x a a z a h e p t a c y c l o ꢀ
[ 1 3 . 1 1 . 1 . 1 2 , 1 4 . 0 3 , 1 1 . 0 5 , 1 0 . 0 2 0 , 2 7 . 0 2 1 , 2 6 ] o c t a c o s a ꢀ
3(11),5(10),6,8,20(27),21,(26),22,24ꢀoctaeneꢀ13,18ꢀdione diꢀ
hydrochloride (7с). 2ꢀ(Dimethylamino)ethylamine (0.066 mL,
0.55 mmol) was added with stirring and reflux to a suspension of
2ꢀformylindole 1a (0.18 g, 0.5 mmol) in PriOH (10 mL), and the
mixture was refluxed for 30 min. The mixture was cooled down,
and the precipitate was filtered off, washed with isopropanol and
acetone, and dried. Compound 7c was obtained in a yield of
0.08 g. 1Н NMR, δ: 2.56—3.56 (m, 20 Н, (N(16)С2Н4N+HMe2
and N(28)С2Н4N+HMe2); 3.63, 4.31 (both d, 1 Н each,
Н2C(17), Jgem = 15.4 Hz); 3.77, 4.56 (both d, 1 Н each, Н(14),
Н(15), Jvic = 7.1 Hz); 6.15, 6.33, 7.39, 8.16 (all d), 6.74, 6.93
4ꢀBenzylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2,3,4,5,6ꢀhexahydroꢀ
[1,4]diazepino[6,5ꢀb]indole (6). Sodium borohydride (0.03 g,
0.79 mmol) was slowly added with stirring in small portions
to a suspension of chloride 5b (0.18 g, 0.4 mmol) in methaꢀ
nol (10 mL). A solution was formed in 15 min, and a new
precipitate began to form in 30 min. The reaction mixture
was additionally stirred for 30 min at ambient temperature.
The precipitate was filtered off, washed with methanol, and
dried. Compound 6 was obtained in a yield of 0.15 g. 1Н NMR,
δ: 3.85 (s, 2 H, H2C(3)); 3.98 (s, 2 H, H2C(5)); 3.97 (s,
2 H, CH2Ph); 6.46 (d, 1 H, H(10), Jо = 8.4 Hz); 6.83 (t, 1 H,
H(9), Jо = 8.4 Hz); 7.08 (t, 1 H, H(8), Jо = 8.4 Hz); 7.22—7.44
(m, 6 H, H(7), CH2Ph); 7.57 (d, 2 Н, H(3´), H(5´), Jо
=
7.08, 7.30 (all t) (all 1 Н, Н(6)—Н(9), Н(22)—Н(25), Jо =
8.4 Hz); 8.26 (d, 2 H, H(2´), H(6´), Jо = 9.0 Hz); 11.53 (br.s,
1 H, N(6)H).
8.3 Hz); 7.41 (s, 1 Н, Н(2)); 7.62, 7.83, 8.26, 8.36 (all d, 2 Н each,
N(12)С6Н4NO2 and N(19)С6Н4NO2, Jо = 8.9 Hz); 10.37 (br.s,
2 Н, N(16)С2Н4N+HMe2 and N(28)С2Н4N+HMe2)); 11.58
(br.s, 1 Н, N(4)Н).
16,28ꢀBis[2ꢀN,Nꢀdiethylamino)ethyl]ꢀ12,19ꢀbis(4ꢀ
n i t r o p h e n y l ) ꢀ 1 , 4 , 1 2 , 1 6 , 1 9 , 2 8 ꢀ h e x a a z a h e p t a c y c l o ꢀ
[ 1 3 . 1 1 . 1 . 1 2 , 1 4 . 0 3 , 1 1 . 0 5 , 1 0 . 0 2 0 , 2 7 . 0 2 1 , 2 6 ] o c t a c o s a ꢀ
3(11),5(10),6,8,20(27),21,(26),22,24ꢀoctaeneꢀ13,18ꢀdione diꢀ
hydrochloride (7b). 2ꢀ(Diethylamino)ethylamine (0.16 mL,
1.11 mmol) was added with stirring and reflux to a suspension of
2ꢀformylindole 1a (0.36 g, 1.01 mmol) in PriOH (10 mL), and
the mixture was refluxed for 10 min. The mixture was cooled
down, and the precipitate was washed with PriOH and acetone,
and dried. Compound 7b was obtained in a yield of 0.32 g.
1Н NMR, δ: 1.04—1.19, 2.63—3.51 (both m, 28 Н,
N(16)С2Н4N+HEt2 and N(28)С2Н4N+HEt2); 3.62, 4.35
(both d, 1 Н each, Н2С(17), Jgem=15.4 Hz); 3.80, 4.59 (both d,
1 Н each, Н(14), Н(15), Jvic=7.2 Hz); 6.14, 6.34, 7.35, 8.18
(all d), 6.73, 6.93 7.07, 7.30 (all t) (all d and t; 1 Н each,
Н(6)—Н(9), Н(22)—Н(25), Jо=8.3 Hz); 7.58 (s, 1 Н, Н(2));
7.64, 7.83, 8.26, 8.37 (all d, 2 Н each, N(12)С6Н4NO2 and
N(19)С6Н4NO2, Jо=8.8 Hz); 10.46, 10.57 (both br.s, 1 Н each,
N(16)С2Н4N+HEt2 and N(28)С2Н4N+HEt2); 11.61 (br.s,
1 Н, N(4)Н).
4ꢀEthylaminopropylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2,3,4,5,6ꢀ
hexahydro[1,4]diazepino[6,5ꢀb]indole hydrochloride (14).
3ꢀ(Diethylamino)propylamine (0.09 mL, 0.55 mmol) was
added with stirring and reflux to a suspension of 2ꢀformylindole
1a (0.18 g, 0.5 mmol) in PriOH (10 mL), and the mixture
was refluxed for 2 h. The mixture was cooled down, and the
precipitate that formed was filtered off. The mother liquor was
evaporated, the residue was triturated with ether, and the preꢀ
cipitate was filtered off. Compound 14 was obtained in a yield
of 0.06 g.
1Н NMR, δ: 1.20 (t, 3 Н, СН2СН3, Jo = 7.5 Hz); 1.88 (m,
2 Н, Н2С(2´)); 2.77 (t, 2 Н, H2С(1´)); 2.92 (m, 4 Н, H2(3´),
H2С(4´)); 3.39 (s, 2 Н, Н2(3)); 4.09 (s, 2 Н, Н2C (5)); 6.43 (d),
6.82, 7.07 (both t), 7.40 (d) (1 Н each, Н(10)—Н(7), Jo
=
8.4 Hz); 7.57, 8.25 (both d, 2 Н each, C6H4NO2, Jo = 9.0 Hz);
8.82 (br.s, 2 Н, C2H4N+H2Et).
13C NMR, δ: 10.9 (СН3); 23.6 (С(2´)); 41.8 (С(4´)); 44.2
(С(3´)); 49.1 (С(5)); 53.5 (С(1´)); 57.4 (С(3)); 111.9, 117.3,
119.4, 121.6 (С(7), С(10), С(9), С(8)); 124.3, 126.3, 144.3,
145.7 (C6H4NO2); 114.5, 120.7, 130.0, 134.3 (С(10b), С(10а),
С(5а), С(6а)).
13C NMR, δ: 8.18—8.56 (N(16)(СН2)2N+Н(СН2Me)2
and
N(28)(СН2)2N+Н(СН2Me)2);
46.2—49.3
(N(16)СН2СН2N+Н(СН2Me)2
and
N(28)СН2СН2N+Н(СН2Me)2); 53.0 (С(17)); 57.4 (С(15));
* The chemical shifts of the signals from the quaternary atoms.
* The chemical shifts of the signals from the protonated atoms.
** The chemical shifts of the signals from the quaternary atoms.

1602
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Ryabova et al.
3. S. Yu. Ryabova, L. M. Alekseeva, N. A. Rastorgueva, E. A.
Lisitsa, D. M. Papakhin, V. A. Parshin, and V. G. Granik,
Izv. Akad. Nauk, Ser. Khim., 2006, 2193 [Russ. Chem. Bull.,
Int. Ed., 2006, 55, 2278].
4. C. Tissier and P. Barillier, Compt. Rend. C, 1969, 268, 1953.
5. J. Bjerrum, G. Schwarzenbach, and L. G. Sillen, Stability
Constants, London, Chem. Soc., 1957, 105 pp.
References
1. S. Yu. Ryabova, Doc. Sci. (Chem.) Thesis, State Scientific
Center for Antibiotics, Moscow, 2005, 451 pp. (in Russian).
2. K. F. Suzdalev and M. N. Babakova, in Izbrannye metody
sinteza i modifikatsii geterotsiklov. Khimiya sinteticheskikh
indol´nykh sistem [Selected Methods for Synthesis and Modifiꢀ
cations of Heterocycles. Chemistry of Synthetic and Indole Sysꢀ
tems], Ed. V. G. Kartsev, IBS PRESS, Moscow, 2004, 3, 403
(in Russian).
Received January 31, 2007;
in revised form February 26, 2007