Reaction of pyrano[3,4-b]indolones with aliphatic amines and N,N-dimethylhydrazine

Article abstract of DOI:10.1002/jhet.478

The synthesis of a number of indolylacetamides and indolylacetohydrazides in very good yields from the reaction of pyranoindolones with aliphatic amines and N,N-dimethylhydrazine, respectively, is described. The reactivity difference with aromatic amines

Full text of DOI:10.1002/jhet.478

1344
Reaction of Pyrano[3,4-b]indolones with Aliphatic Amines and
N,N-Dimethylhydrazine
Vol 47
Despina Livadiotou, Dimitra Hatzimimikou, Constantinos A. Tsoleridis,*
and Julia Stephanidou-Stephanatou*
Laboratory of Organic Chemistry, Department of Chemistry, University of Thessaloniki,
Thessaloniki 54124, Macedonia, Greece
*E-mail: tsolerid@chem.auth.gr or ioulia@chem.auth.gr
Received October 23, 2009
DOI 10.1002/jhet.478
Published online 23 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of a number of indolylacetamides and indolylacetohydrazides in very good yields from
the reaction of pyranoindolones with aliphatic amines and N,N-dimethylhydrazine, respectively, is
described. The reactivity difference with aromatic amines but also with methylhydrazine and aromatic
hydrazines is discussed.
J. Heterocyclic Chem., 47, 1344 (2010).
INTRODUCTION
the indole ring [6,7], we embarked in a more detailed
study of the reactions between pyranoindolones and ali-
phatic amines and also N,N-dimethylhydrazine.
From the reaction between 1-methylpyranoindolone
and aromatic amines in boiling bromobenzene, only
Schiff bases 1 were isolated [1], whereas from the same
reaction in boiling isopropanol, 2-acetyl-indoloacetic
acid amides 2 were formed [2] (Fig. 1).
Concerning the reaction of pyranoindolones with ali-
phatic amines as nucleophiles only some scattered
reports were found in the literature. Thus, by refluxing
1-methylpyranoindolone with ethanolic ammonia (2-ace-
tyl-3-indolyl)acetamide was formed [3], whereas with
methanolic dimethyl amine, the corresponding N,N-
dimethylacetamide was isolated in 44% [4]. Recently,
the synthesis of the N-benzyl-(2-acetyl-3-indolyl)aceta-
mide was reported from the reaction of 1-methylpyra-
noindolone with benzylamine in boiling DMF, which
was eventually cyclized to a b-carbolinone by reflux
with triethylamine in acetic acid [5].
Since the reaction of pyranoindolone 3a with dime-
thylamine in protic solvents (boiling methanol) has
been, as mentioned above, reported to give the N,N-di-
methyl-2-acetyl-1H-indole-3-acetamide (5a) in 44%
yield and since such reactions show a strong solvent
effect, initially the pyranoindolones 3a–3f were allowed
to react with two molar equivalents of dimethylamine in
refluxing bromobenzene for 20 min, whereupon the
indole-3-acetamides 5a–5f were isolated in much better
yields (Table 1, Scheme 1).
The reaction proceeded smoothly also at lower tem-
peratures (refluxing toluene or benzene for 4–6 h) and
even at room temperature, though a longer reaction time
(12 h) was necessary for the completion of the reaction
(Table 1). Next, the reaction was repeated with another
secondary amine morpholine, but also with the primary
amine benzylamine at room temperature for 12 h, and in
all cases, the corresponding indole-3-acetamides 6 and 7
were isolated as the only reaction products in very good
yields (Table 1). Indolylacetohydrazides 8 were isolated,
when N,N-dimethylhydrazine was used as nucleophile.
Compounds 7 and 8 were isolated as a mixture of two
rotamers, as was confirmed from their NMR spectra
ranging from 10:1 (major to minor) in compound 7a to
2:1 in compound 8d (see Experimental). The molar ratio
of the rotamers depends on their relative stability, which
is based on the volume and the electronic properties of
In addition, recently, we studied the reaction of pyra-
noindolones with bisnucleophiles, such as methylhydra-
zine, whereupon 1,2-diazepinoindoles were isolated [6],
and also the reaction with aromatic hydrazines, such as
phenyl- and benzoylhydrazine, leading to the synthesis
of b-carbolinones [7].
RESULTS AND DISCUSSION
In the light of the above results and in continuation of
our research into the synthesis of compounds containing
C
V
2010 HeteroCorporation

November 2010
Reaction of Pyrano[3,4-b]indolones with Aliphatic Amines
and N,N-Dimethylhydrazine
1345
Table 1
Reaction conditions and products.
Temp
(ꢀC)
Yield
(%)
Entry Amine Solvent
Time
Product
3a
3b
3c
3d
3e
3f
3e
3e
3e
3a
3d
3e
3a
3d
3e
3b
3d
3e
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4c
4c
4c
4d
4d
4d
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhMe
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
156
156
156
156
156
156
111
80
20 min
20 min
20 min
20 min
20 min
20 min
4 h
6 h
12 h
12 h
12 h
5a
5b
5c
5d
5e
5f
5e
5e
5e
6a
6d
6e
7a
7d
7e
8b
8d
8e
69
72
65
71
69
66
60
78
65
71
68
82
61
65
97
53
51
47
Figure 1. Products from the reaction of pyranoindolones with aromatic
amines.
the substituents. The formation of the two rotamers is
expected due to the high proportion of double bond
character of the CAN amide bond resulting thus to hin-
dered free rotation at low and ambient temperatures. As
a result, in the case of different N-substituents, the
NMR spectra of the two rotamers (in products 7 and 8)
are practically different. In the case of two identical N-
substituents (products 5 and 6), these substituents are in
different magnetic environment and experience different
chemical shifts.
25
25
25
25
25
25
25
25
25
25
12 h
12 h
12 h
12 h
12 h
12 h
12 h
Concerning the reaction mechanism for the formation
of products 5–8 attack of the amines to the carbonyl car-
bon, being the strongest electrophilic center (Scheme 2)
is observed in all cases. This result is not in agreement
with the results previously obtained with aromatic
amines, and also with the bisnucleophiles methylhydra-
zine, phenyl-, and benzoylhydrazine, where under the
same reaction conditions, initial attack to the less elec-
trophilic center, namely C-1 was always observed
[1,6,7]. The different behavior can be explained by the
enhanced nucleophilicity of the aliphatic amines thus
attacking the strongest electrophilic center. All isolated
products 5–8 are new, with exception of 5a and 7a.
The assigned molecular structures of all compounds
5–8 are based on rigorous spectroscopic analysis includ-
ing IR, NMR (1H, 13C, COSY, NOESY, HETCOR, and
COLOC), MS, and elemental analysis data.
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1346
D. Livadiotou, D. Hatzimimikou, C. A. Tsoleridis, and J. Stephanidou-Stephanatou
Vol 47
Scheme 2
Fluka silica gel 60. TLC was performed using precoated silica
gel glass plates 0.25 mm containing fluorescent indicator
UV254 purchased from Macherey–Nagel using a 3:1 mixture of
petroleum ether–ethyl acetate. Petroleum ether refers to the
fraction boiling between 60 and 80ꢀC. NMR spectra were
recorded at room temperature on a Bruker AM 300 spectrome-
ter at 300 MHz for 1H and 75 MHz for 13C, respectively,
using CDCl3 as solvent. In the case of insoluble substances, 5–
20% of DMSO-d6 was added, whereas in one case, only
DMSO-d6 was used, as indicated. Chemical shifts are
expressed in d values (ppm) relative to TMS as internal stand-
Regarding the structure of the isolated indole-3-acet-
amides 5–8, the assignment of 5e is described. The ele-
mental analysis and mass spectra unequivocally estab-
lished the reaction of one molecule of pyranoindolone 3e
with one molecule of dimethylamine with the loss of a
water molecule, a fact that was also confirmed from the
13C NMR spectrum, where 16 different signals were
observed. Moreover, in the IR spectra, a carbonyl at 1657
1
ard for H and relative to TMS (0.00 ppm) or to CDCl3 (77.05
ppm) for 13C NMR spectra; in the case of DMSO-d6 solutions,
the signal of the solvent at 39.7 ppm was used for calibration.
Coupling constants nJ are reported in Hz. Second order 1H
NMR spectra were analyzed by simulation [8]. IR spectra
were recorded on a Perkin–Elmer 1600 series FTIR spectrome-
ter and are reported in wave numbers (cmꢁ1). Low-resolution
electron impact mass spectra were recorded on a 6890N GC/
MS system (Agilent Technology); in some cases, LC-MS (ESI,
1.65 eV) spectra were recorded on LCMS-2010 EV system
(Shimadzu). Elemental analyses performed with a Perkin–
Elmer 2400-II CHN analyzer. Structural assignments of the
derived compounds were established by analysis of their IR,
MS, and NMR spectra (1H, 13C, DEPT, COSY, NOESY, HET-
COR, and COLOC).
1
cmꢁ1 was identified. In the H NMR, the presence of the
four indole aromatic protons resonating as a double dou-
blet of doublets at d 7.60 (J ¼ 8.0 Hz, J ¼ 1.0 Hz, and J
¼ 0.5 Hz), a double doublet of doublets at d 7.12 (J ¼
8.0 Hz, J ¼ 7.1 Hz, and J ¼ 1.1 Hz) [8], a multiplet at d
7.33–7.34 for two protons with their carbons resonating
at 120.4, 120.3, 125.3, and 110.2 ppm, respectively, was
identified. The 3-position methylene protons appear as a
singlet at d 4.09, whereas in addition to the ethyl group,
three N-methyl groups appeared at d 3.00, 3.16, and 3.93
with their carbons resonating at 35.8, 37.4, and 32.6
ppm, respectively. Moreover, in addition to the character-
istic COLOC correlations for the indole aromatic ring
protons, the indole N-methyl group protons gave COLOC
correlations with the quaternary carbons at 135.0 (C-2)
and at 138.5 ppm (C-7a), whereas the 3-methylene pro-
tons correlated with the quaternary carbons at 135.0 (C-
2) and at 126.9 (C-3a), 114.9 (C-3), and with the amide
carbonyl carbon at 170.0 ppm, as depicted in Figure 2. In
8e, the amide carbonyl carbon correlates as expected
with the amide proton instead of the N-methyl protons.
In conclusion, a direct method for the systematic syn-
thesis of a number of indolylacetamides and indolylace-
tohydrazides has been described. Moreover, the reaction
of pyranoindolones with aliphatic amines and N,N-dime-
thylhydrazine does not show a solvent effect and pro-
ceeds with initial attack to the strongest electrophilic
center, a result which is not in agreement with the
results previously obtained with aromatic amines, and
also with the bisnucleophiles methylhydrazine, phenyl-,
and benzoylhydrazine, where initial attack to the less
electrophilic center was always observed.
General procedure for the reaction of pyrano[3,4-
b]indol-3(9H)-ones (3a–3f) with amines 4. To a stirred and
refluxing solution of pyranoindolone 3 (1.0 mmol) in bromo-
benzene (15 mL), amine 4a (1.5 mmol) was added and reflux-
ing and stirring was continued for 20 min. The solvent was
distilled off under reduced pressure and the resulting residue
was subjected to column chromatography on silica gel using
petroleum ether–EtOAc (5:1) as eluent, slowly increasing the
polarity up to 3:1 to give 2-(2-acyl-1H-indol-3-yl)-N,N-dime-
thylacetamide 5.
The reaction conditions given in Table 1 are followed for
the preparation of compounds 6–8.
From indolopyranones 3 and amine 4a.
2-(2-Acetyl-1H-indol-3-yl)-N,N-dimethylacetamide (5a). 0.168
g, 69% Yield, yellow solid, mp 78–80ꢀC (ethanol); IR (nujol)
1
m
max: 3178, 1663, 1633 cmꢁ1; H NMR (CDCl3): d ¼ 1.74 (s,
3H, 2-CH3), 3.07 (s, 3H, 3-NCH3), 3.21 (s, 3H, 3-NCH3), 4.07
(s, 2H, 3-CH2), 7.01 (ddd, J ¼ 8.0, 7.2, 1.2 Hz, 1H, 5-H), 7.06
(dd, J ¼ 7.8, 1.2 Hz, 1H, 7-H), 7.16 (dd, J ¼ 7.8, 7.2 Hz, 1H,
6-H), 7.49 (d, J ¼ 8.0 Hz, 1H, 4-H), 9.92 (s br, 1H, 1-H); 13C
NMR (CDCl3):
d
¼
27.0 (2-CH3), 30.1 (3-CH2), 36.1
(NACH3), 37.7 (NACH3), 110.3 (C-7), 114.9 (C-3), 120.3 (C-
5), 120.4 (C-4), 125.4 (C-6), 127.0 (C-3a), 135.1 (C-2), 138.6
EXPERIMENTAL
Melting points were measured on a Bu¨chi apparatus and are
uncorrected. Column chromatography was carried out using
Figure 2. Diagnostic COLOC correlations between protons and car-
2
bons (via JCAH and 3JCAH) in compounds 5e and 8e.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Reaction of Pyrano[3,4-b]indolones with Aliphatic Amines
and N,N-Dimethylhydrazine
1347
(C-7a), 171.7 (3-C¼¼O), 191.6 (2-C¼¼O); EIMS: m/z (%) 244
(45, Mþ), 199 (35), 172 (100). Anal. Calcd for C14H16N2O2
(244.29): C, 68.83; H, 6.60; N, 11.47%. Found: C, 69.05; H,
6.73; N, 11.35%.
2), 138.5 (C-7a), 170.0 (3-CO), 196.4 (2-CO); EIMS: m/z (%)
¼ 272 (42, Mþ), 200 (100). Anal. Calcd for C16H20N2O2
(272.34): C, 70.56; H, 7.40; N, 10.29%. Found: C, 70.47; H,
7.33; N, 9.95%.
N,N-dimethyl-2-(2-propionyl-1H-indol-3-yl)acetamide (5b).
0.186 g, 72% Yield, yellow solid, mp 145–147ꢀC (ethanol); IR
2-(2-Butyryl-1-methyl-1H-indol-3-yl)-N,N-dimethylacetamide
(5f). 0.189 g, 66% Yield, yellow solid, mp 109–111ꢀC (etha-
1
1
(nujol) mmax: 3202, 1670, 1634 cmꢁ1; H NMR (CDCl3): d ¼
nol); IR (nujol) mmax: 1654, 1637 cmꢁ1; H NMR (CDCl3): d
0.77 (t, J ¼ 7.1 Hz, 3H, 2-CH2CH3), 2.17 (q, J ¼ 7.1 Hz, 2H,
2-CH2CH3), 3.15 (s, 3H, 3-NCH3), 3.28 (s, 3H, 3-NCH3), 4.14
(s, 2H, 3-CH2), 7.07 (dd, J ¼ 8.0, 7.2 Hz, 1H, 5-H), 7.13 (d, J
¼ 8.0 Hz, 1H, 7-H), 7.22 (dd, J ¼ 7.8, 7.2 Hz, 1H, 6-H), 7.56
(d, J ¼ 7.8 Hz, 1H, 4-H), 9.98 (s br, 1H, 1-H). 13C NMR
(CDCl3): d ¼ 7.3 (2-CH2CH3), 30.2 (3-CH2), 36.1 (NACH3),
37.7 (NACH3), 113.4 (C-7), 115.8 (C-3), 120.0 (C-5), 120.3
(C-4), 125.5 (C-6), 128.2 (C-3a), 132.4 (C-2), 136.4 (C-7a),
171.7 (3-C¼¼O), 194.3 (2-C¼¼O). EIMS: m/z (%) 258 (35,
Mþ), 213 (45), 186 (100). Anal. Calcd for C15H18N2O2
(258.32): C, 69.74; H, 7.02; N, 10.84%. Found: C, 69.70; H,
6.93; N, 10.93%.
¼ 0.99 (t, J ¼ 7.3 Hz, 3H, 2-CH2CH2CH3), 1.77 (sextet, J ¼
7.3 Hz, 2H, 2-CH2CH2CH3), 2.85 (t, J ¼ 7.3 Hz, 2H, 2-
CH2CH2CH3), 2.98 (s, 3H, CONCH3), 3.13 (s, 3H, CONCH3),
3.90 (s, 3H, 1-CH3), 4.06 (s, 2H, 3-CH2), 7.12 (ddd, J ¼ 8.0,
7.1, 1.1 Hz, 1H, 5-H), 7.31–7.35 (m, 2H, 6-H, 7-H), 7.62 (dd,
J ¼ 8.0, 1.0 Hz, 1H, 4-H); 13C NMR (CDCl3): d ¼ 13.9 (2-
CH2CH2CH3), 17.9 (2-CH2CH2CH3), 31.0 (3-CH2), 32.6 (1-
CH3), 35.9 (CONCH3), 37.5 (CONCH3), 44.8 (2-
CH2CH2CH3), 110.3 (C-7), 114.9 (C-3), 120.4 (C-5), 120.6
(C-4), 125.4 (C-6), 127.0 (C-3a), 135.3 (C-2), 138.6 (C-7a),
170.1 (3-CO), 196.2 (2-CO); EIMS: m/z (%) ¼ 286 (Mþ, 37),
241 (25), 214 (100). Anal. Calcd for C17H22N2O2 (286.37): C,
71.30; H, 7.74; N, 9.78%. Found: C, 71.57; H, 7.76; N,
9.55%.
2-(2-Butyryl-1H-indol-3-yl)-N,N-dimethylacetamide (5c). 0.186
g, 65% Yield, yellow solid, mp 153–155ꢀC (ethanol); IR
(nujol) mmax
:
3321, 3178, 1669, 1634 cmꢁ1
;
1H NMR
From indolopyranones 1 and amine 4b.
2-Acetyl-3-(2-oxo-2-piperidin-1-ylethyl)-1H-indole (6a). 0.202
g, 71% Yield, yellow solid, mp 190–191ꢀC (ethanol); IR
(CDCl3): d ¼ 0.81 (t, J ¼ 7.4 Hz, 3H, 2-CH2CH2CH3), 1.39
(sextet, J ¼ 7.4 Hz, 2H, 2-CH2CH2CH3), 2.20 (t, J ¼ 7.4 Hz,
2H, 2-CH2CH2CH3), 3.13 (s, 3H, CONCH3), 3.27 (s, 3H,
CONCH3), 4.15 (s, 2H, 3-CH2), 7.06 (ddd, J ¼ 8.0, 7.1, 1.2
Hz, 1H, 5-H), 7.10–7.24 (m, 2H, 6-H, 7-H), 7.56 (dd, J ¼ 8.0,
1.0 Hz, 1H, 4-H), 9.82 (s, 1H, 1-H); 13C NMR (CDCl3): d ¼
13.7 (2-CH2CH2CH3), 17.0 (2-CH2CH2CH3), 30.3 (3-CH2),
36.1 (CONCH3), 37.7 (CONCH3), 41.4 (2-CH2CH2CH3),
113.2 (C-7), 115.9 (C-3), 120.1 (C-5), 120.3 (C-4), 125.6 (C-
6), 126.9 (C-3a), 132.3 (C-2), 136.3 (C-7a), 171.5 (3-CO),
193.8 (2-CO); EIMS: m/z (%) 286 (Mþ, 37), 241 (25), 214
(100). Anal. Calcd for C17H22N2O2 (286.37): C, 71.30; H,
7.74; N, 9.78%. Found: C, 71.37; H, 7.76; N, 9.65%.
1
(nujol) mmax: 3174, 1663, 1623 cmꢁ1; H NMR: d ¼ 1.60–1.70
(m, 2H, 40-H), 1.70–1.75 (m, 4H, 30-H, 50-H), 1.92 (s, 3H, 2-
CH3), 3.60–3.70 (m, 2H, 20-H), 3.70–3.80 (m, 2H, 60-H), 4.15
(s, 2H, 3-CH2), 7.08 (ddd, J ¼ 8.1, 7.2, 1.2 Hz, 1H, 5-H), 7.15
(dd, J ¼ 8.0, 1.2 Hz, 1H, 7-H), 7.23 (ddd, J ¼ 8.0, 7.2, 1.0
Hz, 1H, 6-H), 7.57 (dd, J ¼ 8.1, 1.0 Hz, 1H, 4-H), 10.09 (s br,
13
1H, 1-H); C NMR (CDCl3): d ¼ 24.7 (C-40), 25.9 (C-30),
26.4 (C-50), 27.3 (2-CH3), 30.0 (3-CH2), 43.5 (C-60), 47.1 (C-
20), 113.4 (C-7), 116.4 (C-3), 120.2 (C-4), 120.4 (C-5), 125.7
(C-6), 128.2 (C-3a), 132.6 (C-2), 136.4 (C-7a), 169.6 (3-
C¼¼O), 191.4 (2-C¼¼O); EIMS: m/z (%) 284 (48, Mþ), 199
(100), 172 (80), 143 (60), 130 (50), 112 (98). Anal. Calcd for
C17H20N2O2 (284.35): C, 71.81; H, 7.09; N, 9.85%. Found: C,
71.75; H, 7.22; N, 9.82%.
2-(2-Acetyl-1-methyl-1H-indol-3-yl)-N,N-dimethylacetamide
(5d). 0.183 g, 71% Yield, yellow solid, mp 111–113ꢀC (etha-
1
nol); IR (nujol) mmax: 1654, 1640 cmꢁ1; H NMR (CDCl3): d
¼ 2.58 (s, 3H, 2-CH3), 2.98 (s, 3H, CONCH3), 3.15 (s, 3H,
CONCH3), 3.93 (s, 3H, 1-CH3), 4.07 (s, 2H, 3-CH2), 7.13
(ddd, J ¼ 8.0, 7.1, 1.1 Hz, 1H, 5-H), 7.31–7.37 (m, 2H, 6-H,
7-H), 7.60 (dd, J ¼ 8.0, 0.9 Hz, 1H, 4-H) [8]; 13C NMR
(CDCl3): d ¼ 30.9 (3-CH2 and 2-CH3), 32.6 (1-CH3), 35.9
(CONCH3), 37.5 (CONCH3), 110.4 (C-7), 116.0 (C-3), 120.4
(C-5), 120.6 (C-4), 125.8 (C-6), 127.0 (C-3a), 135.1 (C-2),
138.8 (C-7a), 170.0 (3-CO), 192.8 (2-CO); EIMS: m/z (%) ¼
258 (45, Mþ), 213 (15), 186 (100). Anal. Calcd for
C15H18N2O2 (258.31): C, 69.74; H, 7.02; N, 10.84%. Found:
C, 70.14; H, 6.85; N, 10.45%.
2-Acetyl-1-methyl-3-(2-oxo-2-piperidin-1-ylethyl)-1H-indole
(6d). 0.203 g, 68% Yield, yellow solid, mp 138–139ꢀC (etha-
1
nol); IR (nujol) mmax: 1657, 1637 cmꢁ1; H NMR (CDCl3): d
¼ 1.40–1.55 (m, 4H, 30-H, 50-H), 1.55–1.70 (m, 2H, 40-H),
2.54 (s, 3H, 2-CH3), 3.47–3.60 (m, 4H, 20-H, 60-H), 3.89 (s,
3H, 1-CH3), 3.98 (s, 2H, 3-CH2), 7.10 (ddd, J ¼ 8.2, 7.1, 1.0
Hz, 1H, 5-H), 7.30 (ddd, J ¼ 8.1, 1.0, 0.8 Hz, 1H, 7-H), 7.32
(ddd, J ¼ 8.1, 7.1, 1.0 Hz, 1H, 6-H), 7.57 (ddd, J ¼ 8.2, 1.0,
13
0.8 Hz, 1H, 4-H); C NMR (CDCl3): d ¼ 24.3 (C-40), 25.5
(C-30), 26.3 (C-50), 30.6 (3-CH2), 30.7 (2-CH3), 32.4 (1-CH3),
43.0 (C-60), 46.6 (C-20), 110.1 (C-7), 116.2 (C-3), 120.1 (C-4),
120.4 (C-5), 125.5 (C-6), 126.8 (C-3a), 134.6 (C-2), 138.5 (C-
7a), 167.9 (3-C¼¼O), 192.5 (2-C¼¼O); LCMS: m/z (%) 321
[100, (M þ Na)þ], 298 (Mþ, 20), 257 (5). Anal. Calcd for
C18H22N2O2 (298.38): C, 72.46; H, 7.43; N, 9.39%. Found: C,
72.84; H, 7.22; N, 9.28%.
N,N-dimethyl-2-(2-propionyl-1-methyl-1H-indol-3-yl)-aceta-
mide (5e). 0.188 g, 69% Yield, yellow solid, mp 99–100ꢀC
1
(ethanol); IR (nujol) mmax: 1657 cmꢁ1; H NMR (CDCl3): d ¼
1.22 (t, J ¼ 7.2 Hz, 3H, 2-CH2CH3), 2.91 (q, J ¼ 7.2 Hz, 2H,
2-CH2CH3), 3.00 (s, 3H, CONCH3), 3.16 (s, 3H, CONCH3),
3.93 (s, 3H, 1-CH3), 4.09 (s, 2H, 3-CH2), 7.12 (ddd, J ¼ 8.0,
7.1, 1.1 Hz, 1H, 5-H), 7.328 (ddd, J ¼ 7.9, 1.1, 0.5 Hz, 1H, 7-
H), 7.332 (ddd, J ¼ 7.9, 7.1, 1.0 Hz, 1H, 6-H), 7.60 (ddd, J ¼
8.0, 1.0 Hz, 0.5 Hz, 1H, 4-H) [8]; 13C NMR (CDCl3): d ¼ 8.3
(2-CH2CH3), 30.8 (3-CH2), 32.6 (1-CH3), 35.7 (2-CH2CH3),
35.8 (CONCH3), 37.4 (CONCH3), 110.2 (C-7), 114.9 (C-3),
120.3 (C-5), 120.4 (C-4), 125.3 (C-6), 126.9 (C-3a), 135.0 (C-
1-Methyl-3-(2-oxo-2-piperidin-1-ylethyl)-2-propionyl-1H-indole
(6e). 0.256 g, 82% Yield, yellow solid, mp 111–113ꢀC (etha-
1
nol); IR (nujol) mmax: 1655, 1635 cmꢁ1; H NMR (CDCl3): d
¼ 1.23 (t, J ¼ 7.2 Hz, 3H, 2-CH2CH3), 1.48–1.60 (m, 4H, 30-
H, 50-H), 1.60–1.70 (m, 2H, 40-H), 2.92 (q, J ¼ 7.2 Hz, 2H, 2-
CH2CH3), 3.52–3.63 (m, 4H, 20-H, 60-H), 3.94 (s, 3H, 1-CH3),
4.10 (s, 2H, 3-CH2), 7.13 (ddd, J ¼ 8.1, 7.0, 1.0 Hz, 1H, 5-H),
Journal of Heterocyclic Chemistry
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D. Livadiotou, D. Hatzimimikou, C. A. Tsoleridis, and J. Stephanidou-Stephanatou
Vol 47
7.35 (dd, J ¼ 8.0, 1.0 Hz, 1H, 7-H), 7.35 (ddd, J ¼ 8.0, 7.0,
1.0 Hz, 1H, 6-H), 7.63 (dd, J ¼ 8.1, 1.0 Hz, 1H, 4-H); 13C
NMR: d ¼ 8.4 (2-CH2CH3), 24.6 (C-40), 25.7 (C-30), 26.5 (C-
50), 31.1 (3-CH2), 32.7 (1-CH3), 36.0 (2-CH2CH3), 43.3 (C-60),
47.0 (C-20), 110.3 (C-7), 115.2 (C-3), 120.4 (C-4), 120.6 (C-
5), 125.5 (C-6), 127.1 (C-3a), 135.1 (C-2), 138.7 (C-7a), 168.4
(3-C¼¼O), 196.6 (2-C¼¼O); LCMS: m/z (%) 335 [100, (M þ
Na)þ], 312 (Mþ, 20), 257 (5). Anal. Calcd for C19H24N2O2
(312.41): C, 73.05 H, 7.74; N, 8.97%. Found: C, 73.24; H,
7.37; N, 8.73%.
2-(1-Methyl-2-propionyl-1H-indol-3-yl)-N-benzylacetamide
(7e). 0.324 g, 97% Yield, yellow solid, mp 149–151ꢀC (etha-
nol); IR (nujol) mmax: 3285, 1652, 1637 cmꢁ1. Beacuse of am-
ide partial double bond, two rotamers in a ratio of 3.5:1 were
observed in the NMR spectra of compound 7e. Major rotamer:
1H NMR (CDCl3 þ DMSO-d6): d ¼ 2.62 (s, 3H, 2-CH3), 3.96
(s, 3H, 1-CH3), 4.04 (s, 2H, 3-CH2), 4.38 (d, J ¼ 5.9 Hz, 2H,
NACH2), 6.34 (br t, 1H, CONH), 7.05–7.45 (m, 8H, 5-H, 6-H,
7-H and C6H5), 7.74 (d, J ¼ 8.5 Hz, 1H, 4-H); 13C NMR
(CDCl3 þ DMSO-d6): d ¼ 29.7 (3-CH2), 31.1 (2-CH3), 34.1
(1-CH3), 43.5 (NACH2), 110.5 (C-7), 115.6 (C-3), 120.8 (C-
5), 121.2 (C-4), 126.5 (C-6), 126.7 (C-3a), 127.3 (C-40), 127.4
(C-20, C-60), 128.6 (C-30, C-50), 136.4 (C-2), 138.9 (C-7a),
140.6 (C-10), 170.2 (3-C¼¼O), 192.6 (2-C¼¼O). Minor rotamer:
1H NMR (CDCl3 þ DMSO-d6): d ¼ 2.62 (s, 3H, 2-CH3), 3.85
(s, 3H, 1-CH3), 3.90 (s, 2H, 3-CH2), 4.32 (d, J ¼ 5.9 Hz, 2H,
NACH2), 7.05–7.45 (m, 7H, 5-H, 7-H, and C6H5), 7.47 (ddd,
J ¼ 8.0, 8.0, 1.0 Hz, 1H, 6-H), 7.78 (d, J ¼ 7.8 Hz, 1H, 4-H),
8.34 (br t, 1H, CONH); 13C NMR (CDCl3 þ DMSO-d6): d ¼
31.3 (2-CH3), 32.9 (3-CH2), 33.8 (1-CH3), 43.3 (NACH2),
109.2 (C-7), 115.6 (C-3), 120.8 (C-5), 121.2 (C-4), 126.6 (C-
6), 126.7 (C-3a), 127.3 (C-40), 127.5 (C-20, C-60), 128.7 (C-30,
C-50), 137.5 (C-2), 138.2 (C-7a), 143.5 (C-10), 172.4 (3-C¼¼O),
192.5 (2-C¼¼O); GCMS: m/z (%) 334 (30, Mþ), 277 (5), 227
(10), 202 (90), 200 (100), 172 (75), 144 (42). Anal. Calcd for
C21H22N2O2 (334.41): C, 75.42; H, 6.63; N, 8.38%. Found: C,
75.34; H, 6.55; N, 8.43%.
From indolopyranones 1 and hydrazine 4c.
2-(2-Acetyl-1H-indol-3-yl)-N-benzylacetamide (7a). 0.187 g,
61% Yield, yellow solid, mp 148–149ꢀC (ethanol). IR (nujol)
m
max: 3324, 1650, 1638 cmꢁ1. Because of amide partial double
bond, two rotamers in a ratio of 10:1 were observed in the
NMR spectra of compound 7a. Major rotamer: 1H NMR
(CDCl3 þ DMSO-d6): d ¼ 2.61 (s, 3H, 2-CH3), 4.08 (s, 2H, 3-
CH2), 4.35 (d, J ¼ 5.0 Hz, 2H, NACH2), 7.05–7.45 (m, 9H, 5-
H, 6-H, 7-H, CONH and C6H5), 7.77 (d, J ¼ 8.2 Hz, 1H, 4-H),
10.95 (br s, 1H, 1-H); 13C NMR (CDCl3 þ DMSO-d6): d ¼
28.1 (3-CH2), 33.2 (2-CH3), 43.0 (NACH2), 112.4 (C-7), 115.8
(C-3), 120.4 (C-5), 120.7 (C-4), 126.0 (C-6), 126.8 (C-40),
127.0 (C-20, C-60), 127.6 (C-3a), 128.2 (C-30, C-50), 132.2 (C-
2), 136.3 (C-7a), 138.2 (C-10), 170.6 (3-C¼¼O), 191.7 (2-C¼¼O).
Minor rotamer: 1H NMR (CDCl3 þ DMSO-d6): d ¼ 2.62 (s,
3H, 2-CH3), 4.08 (s, 2H, 3-CH2), 4.35 (d, J ¼ 5.0 Hz, 2H,
NACH2), 7.05–7.45 (m, 9H, 5-H, 6-H, 7-H, CONH and C6H5),
7.65 (d, J ¼ 7.8 Hz, 1H, 4-H), 10.50 (br s, 1H, 1-H); 13C NMR
(CDCl3 þ DMSO-d6): d ¼ 28.2 (3-CH2), 32.3 (2-CH3), 43.0
(NACH2), 112.1 (C-7), 116.3 (C-3), 119.9 (C-5), 120.8 (C-4),
125.7 (C-6), 126.8 (C-40), 128.0 (C-20, C-60), 127.6 (C-3a),
128.4 (C-30, C-50), 132.5 (C-2), 136.0 (C-7a), 138.2 (C-10),
174.2 (3-C¼¼O), 191.2 (2-C¼¼O); GCMS: m/z (%) 306 (Mþ, 5),
173 (80), 91 (100). Anal. Calcd for C19H18N2O2 (306.36): C,
74.49 H, 5.92; N, 9.14%. Found: C, 74.56; H, 5.83; N, 9.17%.
2-(2-Acetyl-1-methyl-1H-indol-3-yl)-N-benzylacetamide (7d).
0.208 g, 65% Yield, yellow solid, mp 129–131ꢀC (ethanol); IR
(nujol) mmax: 3285, 1652, 1637 cmꢁ1. Beacuse of amide partial
double bond, two rotamers in a ratio of 3.5:1 were observed in
the NMR spectra of compound 7d. Major rotamer: 1H NMR
(CDCl3 þ DMSO-d6): d ¼ 2.62 (s, 3H, 2-CH3), 3.96 (s, 3H,
1-CH3), 4.04 (s, 2H, 3-CH2), 4.38 (d, J ¼ 5.9 Hz, 2H,
NACH2), 6.34 (br t, 1H, CONH), 7.05–7.45 (m, 8H, 5-H, 6-H,
7-H and C6H5), 7.74 (d, J ¼ 8.5 Hz, 1H, 4-H); 13C NMR
(CDCl3 þ DMSO-d6): d ¼ 29.7 (3-CH2), 31.1 (2-CH3), 34.1
(1-CH3), 43.5 (NACH2), 110.5 (C-7), 115.6 (C-3), 120.8 (C-
5), 121.2 (C-4), 126.5 (C-6), 126.7 (C-3a), 127.3 (C-40), 127.4
(C-20, C-60), 128.6 (C-30, C-50), 131.8 (C-2), 137.5 (C-7a),
138.9 (C-10), 170.2 (3-C¼¼O), 192.6 (2-C¼¼O). Minor rotamer:
1H NMR (CDCl3 þ DMSO-d6): d ¼ 2.62 (s, 3H, 2-CH3), 3.85
(s, 3H, 1-CH3), 3.90 (s, 2H, 3-CH2), 4.32 (d, J ¼ 5.9 Hz, 2H,
NACH2), 7.05–7.45 (m, 7H, 5-H, 7-H and C6H5), 7.47 (ddd, J
¼ 8.0, 8.0, 1.0 Hz, 1H, 6-H), 7.78 (d, J ¼ 7.8 Hz, 1H, 4-H),
8.34 (br t, 1H, CONH); 13C NMR (CDCl3 þ DMSO-d6): d ¼
31.3 (2-CH3), 32.9 (3-CH2), 33.8 (1-CH3), 43.3 (NACH2),
109.2 (C-7), 115.6 (C-3), 120.8 (C-5), 121.2 (C-4), 126.6 (C-
6), 126.7 (C-3a), 127.3 (C-40), 127.5 (C-20, C-60), 128.7 (C-30,
C-50), 132.2 (C-2), 136.4 (C-7a), 138.2 (C-10), 172.4 (3-C¼¼O),
192.5 (2-C¼¼O); LCMS: m/z (%) 343 [100, (M þ Na)þ]. Anal.
Calcd for C20H20N2O2 (320.39): C, 74.98 H, 6.29; N, 8.74%.
Found: C, 74.84; H, 6.18; N, 8.73%.
From indolopyranones 1 and hydrazine 4d.
N0,N0-dimethyl-2-(2-propionyl-1H-indol-3-yl)acetohydrazide
(8b). 0.145 g, 53% Yield, yellow solid, mp 216–217ꢀC (etha-
nol); IR (nujol) mmax: 3354, 3194, 1669, 1651, 1644 cmꢁ1
.
Beacuse of amide partial double bond, two rotamers in a ratio
of 7:3 were observed in the NMR spectra of compound 8b.
Major rotamer: 1H NMR: d ¼ 1.18 (t, J ¼ 7.1 Hz, 3H, 2-
CH2CH3), 2.49 (s, 6H, N(CH3)2), 2.85 (q, J ¼ 7.1 Hz, 2H, 2-
CH2CH3), 3.97 (s, 2H, 3-CH2), 3.97 (s, 3H, 1-CH3), 7.01 (brs,
1H, CONH), 7.13–7.18 (m, 1H, 5-H), 7.26–7.35 (m, 2H, 6-H
and 7-H), 7.74 (d, J ¼ 8.3 Hz, 1H, 4-H), 9.51 (br s, 1H, 1-H).
Minor rotamer: 1H NMR: d ¼ 1.13 (t, J ¼ 7.1 Hz, 3H, 2-
CH2CH3), 2.61 (s, 6H, N(CH3)2), 2.87 (q, J ¼ 7.2 Hz, 2H, 2-
CH2CH3), 4.34 (s, 2H, 3-CH2), 6.29 (br s, 1H, CONH), 7.08–
7.12 (m, 1H, 5-H), 7.26–7.35 (m, 2H, 6-H and 7-H), 7.68 (d, J
¼ 8.0 Hz, 1H, 4-H), 9.34 (br s, 1H, 1-H); LCMS: m/z (%) ¼
296 [100, (M þ Na)þ]. Anal. Calcd for C15H19N3O2 (273.33):
C, 65.91; H, 7.01; N, 15.37%. Found: C, 65.97; H, 7.13; N,
15.45%.
N0,N0-dimethyl-2-(1-methyl-2-acetyl-1H-indol-3-yl)acetohydra-
zide (8d). 0.139 g, 51% Yield, yellow solid, mp 176–177ꢀC
(ethanol); IR (nujol) mmax: 3193, 1657, 1640 cmꢁ1. Because of
amide partial double bond, two rotamers in a ratio of 2:1 were
observed in the NMR spectra of compound 8d. Major rotamer:
1H NMR (CDCl3 þ DMSO-d6): d ¼ 2.40 (s, 6H, N(CH3)2),
2.68 (s, 3H, 2-CH3), 3.92 (s, 2H, 3-CH2), 4.00 (s, 3H, 1-CH3),
7.05 (brs, 1H, NH), 7.21 (ddd, J ¼ 8.0, 8.0, 1.2 Hz, 1H, 5-H),
7.32–7.45 (m, 2H, 6-H and 7-H), 7.74 (d, J ¼ 8.1 Hz, 1H, 4-
H); 13C NMR (CDCl3 þ DMSO-d6): d ¼ 29.4 (3-CH2), 30.9
(2-CH3), 32.6 (1-CH3), 47.1 (N(CH3)2), 110.3 (C-7), 115.4 (C-
3), 120.6 (C-5), 120.8 (C-4), 126.2 (C-6), 126.5 (C-3a), 134.9
(C-2), 138.6 (C-7a), 167.6 (3-C¼¼O), 192.7 (2-C¼¼O). Minor
rotamer: 1H NMR (CDCl3 þ DMSO-d6): d ¼ 2.49 (s, 6H,
N(CH3)2), 2.57 (s, 3H, 2-CH3), 3.96 (s, 3H, 1-CH3), 4.29 (s,
Journal of Heterocyclic Chemistry
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Reaction of Pyrano[3,4-b]indolones with Aliphatic Amines
and N,N-Dimethylhydrazine
1349
2H, 3-CH2), 6.56 (br s, 1H, NH), 7.15 (ddd, J ¼ 8.0, 8.0, 1.2
Hz, 1H, 5-H), 7.32–7.45 (m, 2H, 6-H and 7-H), 7.71 (d, J ¼
8.1 Hz, 1H, 4-H); 13C NMR (CDCl3 þ DMSO-d6): d ¼ 8.4
(2-CH2CH3), 30.7 (3-CH2), 32.4 (2-CH3), 32.7 (1-CH3), 48.4
(N(CH3)2), 110.1 (C-7), 115.5 (C-3), 120.1 (C-5), 120.7 (C-4),
125.5 (C-6), 127.2 (C-3a), 134.7 (C-2), 138.5 (C-7a), 172.6 (3-
C¼¼O), 192.6 (2-C¼¼O); LCMS: m/z (%) ¼ 296 [100, (M þ
Na)þ]. Anal. Calcd for C15H19N3O2 (273.33): C, 65.91; H,
7.01; N, 15.37%. Found: C, 65.86; H, 7.15; N, 15.30%.
(3-CH2), 32.9 (2-CH2CH3), 35.8 (1-CH3), 48.7 (N(CH3)2),
110.3 (C-7), 114.3 (C-3), 120.3 (C-5), 120.8 (C-4), 125.4 (C-
6), 127.2 (C-3a), 135.1 (C-2), 138.6 (C-7a), 172.8 (3-C¼¼O),
196.62 (2-C¼¼O); EIMS: m/z (%) ¼ 287 (42, Mþ), 200 (100).
Anal. Calcd for C16H21N3O2 (287.36): C, 66.88; H, 7.37; N,
14.62%. Found: C, 66.76; H, 7.23; N, 14.68%.
N0,N0-dimethyl-2-(1-methyl-2-propionyl-1H-indol-3-yl)acetohy-
drazide (8e). 0.135 g, 47% Yield, yellow solid, mp 186–188ꢀC
(ethanol); IR (nujol) mmax: 3195, 1661, 1645 cmꢁ1. Beacuse of
amide partial double bond, two rotamers in a ratio of 7:3 were
observed in the NMR spectra of compound 8e. Major rotamer:
1H NMR: d ¼ 1.25 (t, J ¼ 7.2 Hz, 3H, 2-CH2CH3), 2.47 (s,
6H, N(CH3)2), 2.95 (q, J ¼ 7.2 Hz, 2H, 2-CH2CH3), 3.93 (s,
2H, 3-CH2), 3.98 (s, 3H, 1-CH3), 6.80 (brs, 1H, NH), 7.22
(ddd, J ¼ 8.0, 8.0, 1.0 Hz, 1H, 5-H), 7.32–7.45 (m, 2H, 6-H
and 7-H), 7.72 (dd, J ¼ 8.1, 1.0 Hz, 1H, 4-H); 13C NMR: d ¼
8.4 (2-CH2CH3), 29.7 (3-CH2), 33.1 (1-CH3), 36.2 (2-
CH2CH3), 47.3 (N(CH3)2), 110.5 (C-7), 114.5 (C-3), 120.7 (C-
5), 121.1 (C-4), 126.2 (C-6), 126.7 (C-3a), 135.3 (C-2), 138.8
(C-7a), 167.8 (3-C¼¼O), 196.55 (2-C¼¼O). Minor rotamer: 1H
NMR: d ¼ 1.24 (t, J ¼ 7.2 Hz, 3H, 2-CH2CH3), 2.55 (s, 6H,
N(CH3)2), 3.02 (q, J ¼ 7.2 Hz, 2H, 2-CH2CH3), 3.91 (s, 3H,
1-CH3), 4.27 (s, 2H, 3-CH2), 6.16 (brs, 1H, NH), 7.12–7.17
(m, 1H, 5-H), 7.32–7.45 (m, 2H, 6-H and 7-H), 7.70 (dd, J ¼
8.1, 1.0 Hz, 1H, 4-H); 13C NMR: d ¼ 8.4 (2-CH2CH3), 32.5
REFERENCES AND NOTES
[1] Doitsides, N.; Mentzafos, D.; Mitkidou, S.; Terzis, A.; Ste-
phanidou-Stephanatou, J. Synth Commun 1995, 25, 1411.
[2] Tolkunov, S. V.; Tolkunov, V. S.; Dulenko, V. I. Chem
Heterocycl Compd 2004, 40, 481.
[3] Plieninger, H.; Mu¨ller, W.; Weinerth, K. Chem Ber 1964,
97, 667.
[4] Modi, S. P.; Archer, S. J Org Chem 1989, 54, 5189.
[5] Tolkunov, V. S.; Vysotsky, Y. B.; Gorban, O. A.; Shish-
kina, S. V.; Shishkin, O. V.; Dulenko, V. I. Chem Heterocycl Compd
2005, 41, 515.
[6] Hatzimimikou, D.; Livadiotou, D.; Tsoleridis, C. A.; Ste-
phanidou-Stephanatou, J. Synlett 2008, 1773.
[7] Livadiotou, D.; Hatzimimikou, D.; Neochoritis, C.; Terzidis,
M.; Tsoleridis, C.; Stephanidou-Stephanatou, J. Synthesis 2008, 3273.
[8] The multiplicities and chemical shifts of the aromatic pro-
tons have been confirmed after simulation with program SpinWorks,
version 2.5, Available at: ftp://davinci.chem.umanitoba.ca/pub/marat/
SpinWorks/.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet