Reaction of 1-(oxiran-2-ylmethyl)-1H-indole-3-carboxaldehyde with amines

Article abstract of DOI:10.1016/j.mencom.2011.07.021

Interaction of 1-(oxiran-2-ylmethyl)-1H-indole-3-carboxaldehyde with primary amines occurs at oxirane moiety and leads to b-aminoalcohols. Quantum-chemical calculations show that these products are more stable than possible alternative Schiff bases arisin

Full text of DOI:10.1016/j.mencom.2011.07.021

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 231–233
Reaction of 1-(oxiran-2-ylmethyl)-1H-indole-3-carboxaldehyde with amines
Konstantin F. Suzdalev,a Sophia V. Den’kina,*a Alena A. Starikova,a
Vladimir V. Dvurechensky,a Mikhail E. Kletskyb and Oleg N. Burovb
a Institute of Physical and Organic Chemistry, Southern Federal University, 344006 Rostov-on-Don,
Russian Federation. Fax: +7 863 243 4667; e-mail: sofia1984@inbox.ru
b Department of Chemistry, Southern Federal University, 344006 Rostov-on-Don, Russian Federation.
E-mail: alll3@yandex.ru
DOI: 10.1016/j.mencom.2011.07.021
Interaction of 1-(oxiran-2-ylmethyl)-1H-indole-3-carboxaldehyde with primary amines occurs at oxirane moiety and leads to b-amino-
alcohols. Quantum-chemical calculations show that these products are more stable than possible alternative Schiff bases arising from
aldehyde group of the considered bielectrophiles.
1-(Oxiran-2-ylmethyl)-1H-indole-3-carboxaldehyde 1† is of
interest as a versatile reactant for organic synthesis having two
unequivalent reaction sites, namely aldehyde and oxirane frag-
ments. Herein, reaction of bifunctional compound 1 with primary
amines was investigated. We supposed that the refluxing of
compound 1 with amines in propan-2-ol can lead to formation
of Schiff bases 2 similar to other indole-3-carboxaldehydes.1,2
Moreover, our calculation of Fukui indices f + (Scheme 1) shows
that the most electrophilic center in molecule 1 is the carbonyl
group.3,4
However, we found out that oxirane ring opening did first occur
affording b-aminoalcohols 3a–g (Scheme 1, Table 1, entries 1–7).‡
Increase in the reaction time in the case of anilines having pKa > 5
led to the bis-adducts 4a,b (entries 1,7, in parentheses). In the
case of anilines with electron-withdrawing groups reaction did not
occur (entries 8–10). When aliphatic cyclohexylamine (entry 11)
was used bis-adduct 4c was at once formed.§
We could not exclude initial formation of Schiff bases 2 and
further, as far as this reaction is reversible, more thermodynami-
cally stable products 3a–g accumulation in the reaction mixture.
0.15
0.22
O
NR
O
NR
0.05
NH2R
0.06
0.03
0.02
NH2R
PriOH
NH2R
PriOH
0.31
0.06
0.00
N
N
N
N
0.06
HO
HO
0.00
0.00
0.00
O
O
NHR
NHR
2a R = 4-MeOC6H4
2b R = H for model reaction
1
3a R = 4-MeOC6H4
3b R = Ph
4a R = 4-MeOC6H4
4b R = 4-MeC6H4
4c R = cyclohexyl
3c R = 2-MeOC6H4
3d R = 2-MeC6H4
3e R = 4-BrC6H4
3f R = 2-EtOC6H4
3g R = 4-MeC6H4
3h R = H for model reaction
epibromohydrin
NR
O
NH2R
BuOH
NH
NH
R = 4-MeOC6H4
6
5
Scheme 1 Fukui indices f+ of compound 1 and its reactions with amines.
Table 1 Reactions of bifunctional compound 1 with amines RNH2.a
†
Synthesisof1-(oxiran-2-ylmethyl)-1H-indole-3-carboxaldehyde1.Sodium
hydroxide (9.2 g, 0.22 mol) in water (10 ml) was added to 1H-indole-
3-carboxaldehyde (30 g, 0.2 mol) in DMSO (40 ml). The reaction mixture
was stirred for 1–1.5 h. To this solution epibromohydrin (51 ml, 0.6 mol)
was added, and the mixture was stirred for 1 h, then poured into water
(300 ml) and extracted with benzene. The extract was dried with sodium
sulfate and concentrated. The solid residue was recrystallized from benzene.
Yield 40%, mp 90–92°C. 1H NMR (CDCl3) d: 2.49 (dd, 1H, OCH2, J 4.6
and 2.5 Hz), 2.86 (dd, 1H, OCH2, J 4.6 and 4.0 Hz), 3.29–3.40 (m, 1H,
OCH), 4.15 (dd, 1H, NCH2, J 15.6 and 5.2 Hz), 4.56 (dd, 1H, NCH2,
J 15.6 and 3.3 Hz), 7.26–7.48 (m, 3H, HInd-5,6,7), 7.76 (s, 1H, HInd-2),
8.29–8.38 (m, 1H, HInd-4), 10.00 (s, 1H, CH=O). 13C NMR (CDCl3) d:
45.5, 48.9, 50.6, 110.3, 119.1, 122.6, 123.5, 124.7, 125.6, 137.9, 139.3,
185.1. IR (n/cm–1): 1646 (C=O), 1611, 1574, 1528 (C–CAr). Found (%):
C, 71.34; H, 5.49; N, 6.93. Calc. for C12H11NO2 (%): C, 71.63; H, 5.51;
N, 6.96.
pKa of
the amine duration/h
Reaction
Entry
R
Product Yield (%)
1
2
3
4
5
6
7
8
9
4-MeOC6H4
Ph
2-MeOC6H4
2-MeC6H4
4-BrC6H4
2-EtOC6H4
4-MeC6H4
4-O2NC6H4
2-O2NC6H4
4-MeO2CC6H4
Cyclohexyl
5.29
4.58
4.49
4.39
3.91
4.47
5.12
1.02
–0.29
3.78
10.64
1.5 (10)
3
2.5
6
4
3
2 (8)
25
20
11.5
(3)
3a (4a)
3b
50 (30)
26
3c
65
3d
35
3e
26
3f
43
3g (4b)
—
34 (23)
—
—
—
10
11
—
—
(4c)
(43)
a Parentheses are data related to bis-adduct 4.
© 2011 Mendeleev Communications. All rights reserved.
– 231 –

Mendeleev Commun., 2011, 21, 231–233
Table 2 Total (E) and relative (DE) energies, total (EZPE) and relative (DEZPE) energies with zero-point energy correction, total (Esolv) and relative (DEsolv
energies in solutions calculated by the B3LYP/6-311++G(d,p).
)
Structure
E (a.u.)
DE/kJ mol–1
EZPE (a.u.)
DEZPE /kJ mol–1
Esolv (a.u.)
DEsolv /kJ mol–1
1 + NH3
2b
2b + H2O
3ha
NH3
H2O
–725.81259
–649.34369
–725.80222
–725.85510
–56.58272
–76.45853
0.0
—
27.2
–111.8
—
–725.57326
–649.12616
–725.56341
–725.60958
–56.54845
–76.43725
0.0
—
26.0
–95.5
—
–725.84395
–649.36817
–725.83789
–725.88130
–56.59005
–76.46972
0.0
—
15.9
–98.0
—
—
—
—
a Characteristics of the energetically most stable conformer 3h are given.
In order to verify this suggestion we independently synthesized
compound 2a from 1H-indole-3-carboxaldehyde 5 via Schiff base
6.¶ However, boiling of starting material 2a in wet propan-2-ol
did not lead to b-aminoalcohol 3a, whereas only resinification
took place. This experiment rules out thermodynamic control and
shows that oxirane ring opening is a quicker process.
To explain experimental facts and compare the stability of
reaction products 2b or 3h obtained by two alternative pathways,
quantum chemical calculations for model reaction of compound
1 with ammonia (R = H) were carried out. Table 2 indicates that
the total energy of system 2b + H2O is higher than the starting
reaction point energy. The energy difference between them is
15.9 kJ mol–1 with taking into account solvation. This result
demonstrates endothermic character of the attack of aldehyde group
of compound 1 by ammonia molecule. At the same time the
addition of ammonia to oxirane ring leading to compound 3h
looks more preferable than system 1 + ammonia by more than
90 kJ mol–1.
Taking into consideration the ability of amines to form asso-
ciates,6 we calculated another potential supramolecular mechanism
of reaction with ammonia dimer (Scheme 2). Two competitive
processes start with the formation of pre-reaction complexes 1'
‡
General procedure for the synthesis of 1-[3-(arylamino)-2-hydroxypropyl]-
CH2, CH), 6.57 (d, 2H, HAr, J 9.2 Hz), 6.75 (d, 2H, HAr, J 8.9 Hz), 6.89
(d, 2H, HAr, J 8.8 Hz), 7.16 (d, 2H, HAr, J 8.9 Hz), 7.25–7.38 (m, 3H,
1H-indole-3-carboxaldehydes 3a–f. To compound 1 (0.2 g, 1 mmol) in
propan-2-ol (3 ml), an aniline (2 mmol) was added and the mixture was
refluxed for appropriate time (see Table 1). In case of 3a,c–f, the formed
precipitate was filtered off and recrystallised. In case of 3b,g, the solvent
was evaporated, benzene (2 ml) was added to the obtained oil (and heated
in case of 3g), the formed precipitate was filtered off and recrystallized
with benzene.
HInd-5,6,7), 7.63 (s, 1H, HInd-2), 8.39–8.49 (m, 1H, HInd-4), 8.59 (s, 1H,
CH=). 13C NMR (CDCl3) d: 49.0, 51.0, 55.9, 56.2, 69.4, 110.2, 114.8 (2C),
115.2, 115.3 (2C), 115.4 (2C), 116.9, 122.1, 122.2 (2C), 122.3, 123.8, 126.7,
134.1, 137.7, 142.3, 146.5, 153.2, 157.9. IR (n/cm–1): 3356, 3179 (OH,
NH), 1609 (C=N), 1590, 1572 (C–CAr). Found (%): C, 72.42; H, 6.31;
N, 9.74. Calc. for C26H27N3O3 (%): C, 72.71; H, 6.34; N, 9.78.
For 3a: yield 50%, mp 159–161°C (propan-2-ol). 1H NMR (CDCl3) d:
1.35–2.21 (bp, 2H, NH, OH), 3.03–3.16 (m, 1H, NCH2), 3.24–3.35 (m,
1H, NCH2), 3.73 (s, 3H, OMe), 4.17–4.50 (m, 3H, CH, CH2), 6.57–6.66
(m, 2H, HAr), 6.72–6.82 (m, 2H, HAr), 7.27–7.41 (m, 3H, HInd-5,6,7), 7.80
(s, 1H, HInd-2), 8.22–8.32 (m, 1H, HInd-4), 9.87 (s, 1H, CH=O). 13C NMR
(CDCl3) d: 49.1, 51.2, 56.2, 69.3, 110.4, 114.7, 115.4, 115.5, 118.7,
122.2, 122.7, 123.5, 124.6, 125.7, 137.9, 140.2, 142.1, 153.4, 185.1. IR
(n/cm–1): 3337, 3369 (OH, NH), 1645 (C=O), 1614, 1576 (C–CAr). Found
(%): C, 70.07; H, 6.19; N, 8.61. Calc. for C19H20N2O3 (%): C, 70.35; H,
6.21; N, 8.64.
For 4b: the solvent was evaporated; diethyl ether (2 ml) and light petro-
leum (3 ml) were added to the obtained oil. The formed precipitate was
filtered off and recrystallized from benzene. Yield 23%, mp 105–107°C.
1H NMR (CDCl3) d: 2.22 (s, 3H, Me), 2.35 (s, 3H, Me), 2.50–2.71 (m, 1H,
NH), 3.02–3.15 (m, 1H, NCH2), 3.22–3.33 (m, 1H, NCH2), 3.64–3.90 (m,
1H, OH), 4.15–4.39 (m, 3H, CH, CH2), 6.49–6.57 (m, 2H, HAr), 6.93–7.02
(m, 2H, HAr), 7.06–7.20 (m, 4H, HAr), 7.25–7.38 (m, 3H, HInd-5,6,7), 7.64
(s, 1H, HInd-2), 8.41–8.49 (m, 1H, HInd-4), 8.59 (s, 1H, CH=). 13C NMR
(CDCl3) d: 20.8, 21.4, 48.3, 51.0, 69.3, 110.3, 114.1 (2C), 115.2, 115.8,
121.1, 122.1, 123.7, 126.8, 128.0, 130.1 (2C), 130.3 (2C), 134.4, 135.1,
137.7, 145.9, 150.8, 154.2. IR (n/cm–1): 3367, 3178 (NH, OH), 1612 (C=N),
1587, 1571 (C–CAr). Found (%): C, 78.87; H, 6.88; N, 10. 61. Calc. for
C26H27N3O (%): C, 78.56; H, 6.85; N, 10. 57. MS, m/z (%): 397 (4.9 [M+]).
For 4c: the formed precipitate was filtered off and recrystallized from
benzene.Yield 43%, mp 136–138°C. 1H NMR (CDCl3) d: 0.70–1.95 [m,
22H, NH, OH, (CH2)10], 2.14–2.34 [m, 1H, NH(CH)cyclohexyl], 2.35–2.53 (m,
1H, NCH2), 2.62–2.82 (m, 1H, NCH2), 2.94–3.21 [m, 1H, =N(CH)cyclohexyl],
3.74–3.99 (m, 1H, CH), 4.00–4.27 (m, 2H, CH2), 7.01–7.40 (m, 3H,
1
For 3b: yield 26%, mp 138–140°C (benzene). H NMR (CDCl3) d:
2.74–2.97 (m, 1H, NH), 3.10–3.24 (m, 1H, NCH2), 3.28–3.42 (m, 1H,
NCH2), 3.81–4.09 (bp, 1H, OH), 4.12–4.49 (m, 3H, CH, CH2), 6.60–6.82
(m, 3H, HAr), 7.08–7.45 (m, 5H, HAr), 7.78 (s, 1H, HInd-2), 8.20–8.31 (m,
1H, HInd-4), 9.77 (s, 1H, CH=O). 13C NMR (CDCl3) d: 48.1, 51.3, 69.1,
110.6, 114.0, 118.5, 118.9, 120.0, 122.5, 123.5, 124.5, 125.6, 129.8, 130.1,
137.9, 140.6, 148.1, 185.3. IR (n/cm–1): 3363 (OH, NH), 1651 (C=O), 1632,
1602 (C–CAr). Found (%): C, 73.74; H, 6.18; N, 9.56. Calc. for C18H18N2O2
(%): C, 73.45; H, 6.16; N, 9.52.
H
Ind-5,6,7), 7.47 (s, 1H, HInd-2), 8.19–8.36 (m, 1H, HInd-4), 8.48 (s, 1H,
CH=). 13C NMR (CDCl3) d: 25.3 (4C), 26.3, 33.9, 35.3 (4C), 49.8, 51.0,
57.1, 69.0, 70.6, 110.0, 115.0, 121.3, 122.2, 123.1, 126.7, 132.2, 137.7,
152.6. IR (n/cm–1): 3056 (NH, OH), 1637 (C=N), 1574, 1536 (C–CAr).
Found (%): C, 75.25; H, 9.21; N, 10.97. Calc. for C24H35N3O (%): C, 75.55;
H, 9.25; N, 11.01. MS, m/z (%): 381 (14.8 [M+]).
For 3c: yield 65%, mp 160–162°C (propan-2-ol–acetonitrile, 4:1).
1H NMR (CDCl3) d: 2.99–3.28 (m, 2H, NCH2), 3.74 (s, 3H, OMe), 4.02–
4.39 (m, 3H, CH, CH2), 4.42–4.67 (bp, 1H, NH), 4.67–4.84 (bp, 1H, OH),
6.33-6.81 (m, 4H, HAr), 7.10–7.37 (m, 3H, HInd-5,6,7), 7.78 (s, 1H, HInd-2),
8.09–8.25 (m, 1H, HInd-4), 9.83 (s, 1H, CH=O). 13C NMR (CDCl3) d:
47.8, 51.3, 55.8, 68.9, 110.1, 110.6, 110.7, 117.7, 118.5, 121.7, 122.5,
123.3, 124.4, 125.7, 138.0, 138.2, 140.7, 147.6, 185.2. IR (n/cm–1): 3330,
3408 (OH, NH), 1632 (C=O), 1614, 1600 (C–CAr). Found (%): C, 70.63;
H, 6.23; N, 8.67. Calc. for C19H20N2O3 (%): C, 70.35; H, 6.21; N, 8.64.
For characteristics of compounds 3d–g, see Online Supplementary
Materials.
¶
Synthesis of 1-(oxiran-2-ylmethyl)-3-[(4-methoxyphenylimino)methyl]-
1H-indole 2a: compound 6 (2.5 g, 10 mmol) in DMSO (7 ml) was added
to sodium hydride (0.5 g of 60% suspension in mineral oil, 12.5 mmol)
for 20 min. The reaction mixture was stirred for 1 h at room temperature.
Then epibromohydrin (2.5 ml, 30 mmol) was added to a cooled solution.
The reaction mixture was stirred for 30 min at room temperature and then
quenched with water (5 ml). The formed precipitate was filtered off and
recrystallized from benzene. Yield 59%, mp 94–96°C. 1H NMR (CDCl3)
d: 2.42–2.48 (dd, 1H, OCH2, J 4.6 and 2.5 Hz), 2.77–2.84 (dd, 1H, OCH2,
J 4.6 and 3.9 Hz), 3.24–3.34 (m, 1H, CH), 3.82 (s, 1H, OMe), 4.09–4.21
(dd, 1H, NCH2, J 15.3 and 5.4 Hz), 4.41–4.52 (dd, 1H, NCH2, J 15.3
and 2.8 Hz), 6.85–7.46 (m, 7H, HInd-5,6,7, 4HAr), 7.55 (s, 1H, HInd-2),
8.42–8.57 (m, 1H, HInd-4), 8.63 (s, 1H, CH=). IR (n/cm–1): 1619 (C=N),
1593, 1572, 1539 (C–CAr). Found (%): C 74.19; H, 5.90; N, 9.10. Calc.
for C19H18N2O2 (%): C, 74.49; H, 5.92; N, 9.14.
§
General procedure for the synthesis of bis-adducts 4a–c. To compound
1 (0.2 g, 1 mmol) in propan-2-ol (3 ml), an amine (2 mmol) was added
and the mixture was refluxed for appropriate time (see Table 1).
For 4a: the solvent was evaporated; diethyl ether (2–3 ml) was added to
the obtained oil. The precipitate was filtered off and recrystallized from
benzene. Yield 30%, mp 106–108°C. 1H NMR (CDCl3) d: 1.44–1.84 (bp,
1H, NH), 2.65–2.92 (bp, 1H, OH), 2.99–3.14 (m, 1H, NCH2), 3.18–3.30
(m, 1H, NCH2), 3.73 (s, 1H, OMe), 3.81 (s, 1H, OMe), 4.13–4.41 (m, 3H,
– 232 –

Mendeleev Commun., 2011, 21, 231–233
H
and B' are both exothermic processes. However, the origination
H
H
of intermediate B' is more energetically preferable than generation
of adduct with the carbonyl group A' at 115.3 kJ mol–1.
Thus, in the case of bifunctional compound 1 nucleophilic
oxirane ring opening proceeds faster and gives most stable
products in comparison with the addition of the nucleophile at the
aldehyde group. Reactivity of compound 1 towards amines can
be explained by the strain of oxirane ring rather than polarization
effect of carbonyl group.
N
H
N
H
H
H
H
O
H
N
H
N
H
O
H
N
N
O
O
1'
A'
1 + (NH3)2
Online Supplementary Materials
O
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.07.021.
O
N
References
H
O
H
N
H
H
1 R. Bucourt and M. Vignau, Bull. Soc. Chim. Fr., 1961, 1190.
2 W. E. Noland, G. M. Christensen, S. J. Sauer and G. G. S. Dutton, J. Am.
Chem. Soc., 1955, 77, 456.
N
O
N
H
H
N
H
H
H
N
H
3 M. J. Frisch, G. W.Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, M. Klene, X.Li, J. E. Knox, H. P. Hratchian,
J. B.Cross,V. Bakken, C.Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O.Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P.Y. Ayala,
K. Morokuma, G.A.Voth, P. Salvador, J. J. Dannenberg,V. G. Zakrzewski,
S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. V.Ortiz, Q. Cui, A. G. Baboul,
S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M.A.Al-Laham, C.Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez and J. A. Pople, Gaussian 03, Gaussian Inc.,
Wallingford CT, 2004.
H
H
1''
B'
Scheme 2 The model reactions of compound 1 with ammonia dimer.
and 1'' between compound 1 and ammonia dimer, as shown in
Scheme 2. Calculations indicate that the total energies of com-
plexes 1' and 1'' are lower than the starting reaction point energy
(Table 3). The formation of intermediate B' requires minimum
structural change of complex 1'', whereas the formation of inter-
mediate A' from complex 1' is a multistep process. More detailed
calculation demonstrates that the formation of intermediates A'
Table 3 Total (E) and relative (DE) energies calculated in the gas phase by
the B3LYP/6-311++G(d,p) method.
4 R. G. Parr, L. von Szentpály and S. Liu, J. Am. Chem. Soc., 1999, 121,
1922.
5 A. Albert and E. P. Serjeant, Ionization Constants of Acids and Bases:
a Laboratory Manual, Methuen, London, 1962, p. 139.
6 F. Bergero, C. E. S. Alvaro, N. S. Nudelman and S. R. De Debiaggi, J. Mol.
Struct. (Theochem), 2009, 896, 18.
Structure
E (a.u.)
DE/kJ mol–1
1 + (NH3)2
1'
1''
A'
B'
(NH3)2
–782.40059
–782.41090
–782.41043
–782.40661
–782.45055
–113.17071
0.0
–27.2
–26.0
–15.8
–131.1
—
Received: 18th November 2010; Com. 10/3630
– 233 –