Reaction of phthalaldehyde with aminoethanol under different conditions: Products and mechanisms of their formation

Article abstract of DOI:10.1002/jhet.1121

Analysis of amino acids and very efficient disinfection procedures are based on the reaction of phthalaldehyde (OPA) with primary amines. In this contribution, aminoethanol (=kolamin) as a nitrogen-containing nucleophile was used for the investigation of its reaction mechanism with OPA performed in basic aqueous buffered media (pH 9.5), where an influence of hydration or solvation is expected, and in anhydrous acetonitrile. Depending on the detailed reaction conditions, seven products were isolated and their structures determined by NMR, mass spectrometry, and X-ray structure analysis. Reaction mechanisms are proposed, which involve hydride transfers to OPA (Cannizzaro-type reaction).

Full text of DOI:10.1002/jhet.1121

1202
Reaction of Phthalaldehyde with Aminoethanol under Different
Conditions: Products and Mechanisms of Their Formation
Vol 49
*
Jiří Klíma, Miroslav Polášek, Jiří Ludvík, and Jiří Urban
J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Dolejškova 3,18223 Prague 8,
Czech Republic
E-mail: jiri.urban@jh-inst.cas.cz
Received May 20, 2011
*
DOI 10.1002/jhet.1121
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
Analysis of amino acids and very efficient disinfection procedures are based on the reaction of phthalal-
dehyde (OPA) with primary amines. In this contribution, aminoethanol (= kolamin) as a nitrogen-containing
nucleophile was used for the investigation of its reaction mechanism with OPA performed in basic aqueous
buffered media (pH 9.5), where an influence of hydration or solvation is expected, and in anhydrous aceto-
nitrile. Depending on the detailed reaction conditions, seven products were isolated and their structures
determined by NMR, mass spectrometry, and X-ray structure analysis. Reaction mechanisms are proposed,
which involve hydride transfers to OPA (Cannizzaro-type reaction).
J. Hetercycl Chem., 49, 1202 (2012).
INTRODUCTION
is also complicated by the existence of three forms of OPA
being in equilibrium in aqueous media: unhydrated dialdehyde
form, monohydrated monoaldehyde form, and the cyclic
1,3-phthalandiol [12,13].
The complex mechanism involving parallel reactions of
species being in equilibrium is not known. The first attempt
to elucidate this process including its kinetics is based on
the detailed polarographic and spectroscopic investigation
of the reaction of OPA with the most simple amine-ammonia
[14]. In the unpublished preliminary experiments with other
nucleophiles, we have found that the number of (even rela-
tively) stable intermediates and products is high and depends
on the concentration of reactants, their stoichiometry, the
The reaction of phthalaldehyde [= ortho-phthalaldehyde
(OPA)] with amines was generally studied several times already
[1–4]. This reaction is significant among others from the analyt-
ical point of view because the analysis of amino acids in biolog-
ical samples (e.g., in food) is based on the reaction of a primary
amine group with OPA to form fluorescent species [1,5–7]. In
addition to this, OPA is used also as a disinfection agent for ster-
ilization of surgery instruments and materials (e.g., made from
plastics) that cannot undergo a high-temperature treatment.
The activity is based on the reaction of OPA with primary
amino and thio groups of peptides, leading to their cross-linking
and final denaturation [8–11]. The detailed reaction mechanism
© 2012 HeteroCorporation

September 2012
Reaction of Phthalaldehyde with Aminoethanol under Different
Conditions: Products and Mechanisms of Their Formation
1203
sequence and rate of their mixing, and the composition of the
media (Klíma, Urban, and Rulíšková, unpublished results).
In this article, the reaction of OPA with 2-aminoethanol
(kolamin) has been studied under conditions close to the
analytical ones: at laboratory temperature; at concentrations
10ꢀ2 to 10ꢀ3 mol lꢀ1; in aqueous buffered solutions pH9.5;
and, for comparison in acetonitrile, where the hydration of
OPA does not take place. The main stress was given to the
isolation and identification of stable intermediates and pro-
ducts that give indices concerning the understanding of the
reaction mechanism.
confirmed using X-ray structure analysis [15,16]. The
mechanism of their formation will be discussed below.
In aqueous media, different reaction conditions were used
in order to bind up the previous study [14]: (a) in borate
buffer pH 9.5, OPA and kolamin were mixed in the ratio
1:1.7 (again, a slight excess of kolamin), where a second-
order kinetics is expected; (b) in a OPA : kolamin : HCl
mixture 1:10:5 (a fivefold excess of kolamin in a kolamin
buffer pH9.5), where the reaction should follow first-order
kinetics; and (c) in borate buffer pH 9.5, OPA and kolamin
were mixed in the ratio 2:1 and 4:1 (an excess of OPA).
From the borate buffer (reaction a), two compounds were
isolated using column chromatography and identified:
compound I and 2-(2-hydroxyethyl)-3-[(2-hydroxyethyl)
imino]-2,3-dihydro-1H-benzo[c]pyrrol-1-on (III). From
the kolamin buffer (reaction b), compound III and
1′-[(2-hydroxyethyl)imino]-2′-(2-hydroxyethyl)-3′-hydroxy-
3′-[2-(2-hydroxyethyl)-2,3-dihydro-1H-benzo[c]pyrrol-1-on-3-
yl]-2′,3′-dihydro-1′H-benzo[c]pyrrol (IV) were isolated
and identified. As a side product, 2-hydroxymethyl benzalde-
hyde was isolated. In a repeated experiment under condition
(b), when the mixing of components was performed more
slowly, a new compound 1-[(2-hydroxyethyl)imino]-2-(2-
hydroxyethyl)-3-hydroxy-3-[2′-(2-hydroxyethyl)isoindol-1′-yl]
RESULTS AND DISCUSSION
In acetonitrile, where OPA exists completely in its most
reactive unhydrated dialdehyde form, the reaction of OPA
with a slight excess of kolamin (molar ratio 1:1.25) leads to
a mixture of products. Some of them are polar, and on the
TLC they do not move from the start. Two main organic pro-
ducts, however, were isolated and identified (see
EXPERIMENTAL) as 2-(2-hydroxyethyl)-2,3-dihydro-1H-
benzo[c]pyrrol-1-on (I) and (3R*,1′S*,3′R*)-3-(3′-hydroxy-1′
H,3′H-benzo[c]furan-1′-yl)-2-(200-hydroxyethyl)-2,3-dihydro-
1H-benzo[c]pyrrol-1-one (II) (Fig. 1). Their structures were
H
1'
O
2'
O
N
CH2CH2OH
3'
3
2
N
N
N
CH2CH2OH
CH2CH2OH
CH2CH2OH
1
O
O
O
II
I
III
CH2CH2OH
O
1
N
HOH2CH2C
2'
N
HOH2CH2C
1'
N
2
3
H
O
3'
3'
1
H
O
N
2'
N
2
CH2CH2OH
1'
N
CH2CH2OH
3
IV
CH2CH2OH
V
CHO
1´
1´
N
HO
O
3
3
OH
2
2
N
CH2CH2OH
1
1
CH2CH2OH
O
O
VII
VI
Figure 1. Structures of isolated products I–VII.
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Suggested reaction pathways. The different pathways for
the formation of compounds I–V are shown in Schemes 1
(formation of I and II), 2 (formation of III), 3 (formation
of IV and VI), 4 (formation of V), and 5 (formation of VII).
Our hypothesis is that these compounds can be generated
through intermediates A, B, and C shown in Scheme 1:
intermediate A would lead to compound III (Scheme 2);
intermediate B would be the precursor of compound I
(Scheme 1), and intermediate C would give compounds II
(Scheme 1), IV and VI (Scheme 3), V (Scheme 4), and VII
(Scheme 5).
In acetonitrile, compound II is formed together with
compound I. According to our hypothesis, intermediate A
would be converted to intermediate B, which would give
compound I by proton transfer (proton tautomerism)
(Scheme 1) [4]. Nucleophilic addition of intermediate B
to a second molecule of OPA would give intermediate C,
which would cyclize to afford compound II (Scheme 1).
The ratio of compounds I and II depends namely on the
OPA : kolamin ratio and on the overall concentration of
both reactants.
(V) was isolated as yellowish crystals. Besides that, unisolable
species were formed, most probably of macromolecular nature.
Under excess of OPA (condition c), the mixture after the
reaction contains also some unreacted starting material. The
main product at millimolar concentration is compound I.
The next product is 2-(2-hydroxyethyl)-3-(2-formylbenzoyl)-
2,3-dihydro-1H-benzo[c]pyrrol-1-one (VI), isolated only
under an excess of OPA. When kolamin is present in excess,
compound VI reacts readily with kolamin, giving rise to the
product IV (cf. Scheme 3). At higher concentration of OPA
(0.1 M), besides compound I, three diastereoisomers of spiro
[2-(2-hydroxyethyl)-2,3-dihydro-1H-benzo[c]pyrrol-1-on-3,
2′-indan-1′,3′-diol] (VII) were separated and isolated.
The structure of compound III was unambiguously con-
firmed using X-ray analysis [17]. The structure of compound
IV was determined from the analysis of its 1H and 13C NMR
spectra and confirmed using a comparison with the spectra of
compounds I–III. Compound IV is not fully stable. In acidic
media, it decomposes yielding compounds I and III.
However, the reverse reaction has not been observed.
The structure of compound V was determined from the
analysis of its 1H and 13C NMR spectra. They exhibit signals
both of isoindol and isoindoline, the latter being consistent
with those of compounds III and IV. The interpretation
and spectral data are in agreement with the compound having
the same skeleton (but different substitution) prepared from
OPA and an amine in a different way [3].
Compound II exhibits three chiral centers. Hence, eight
stereoisomers are possible, and four diastereoisomeric
couples could have been formed. According to the NMR
analysis, one diastereoisomer largely predominates (90%
pure). Its relative configuration 3R*, 1′S*, 3′R* was
determined by X-ray structure analysis.
In the formation of compounds III (Scheme 2), IV, and
VI (Scheme 3), oxidations have occurred. As repeated
experiments proved that all compounds were formed both
in the presence of oxygen as well as under deoxygenated
nitrogen, we propose that a Cannizzaro-type reaction
intervenes in the formation of these compounds, the
The structure of compounds VI and VII was determined
1
from the analysis of their H and 13C NMR spectra and
from their mass spectra. In the case of compound VII,
the isolation of all three possible diastereoisomers (two
meso-forms, one DL pair) was helpful because the meso-
forms exhibit a typical symmetry in the NMR spectra.
Scheme 1
O
CH2CH2OH
HO
C
NH2CH2CH2OH
-H2O
N
N
H
CHO
CHO
CHO
OHC
OHC
O
C
HO
O
N
H
H
CH2CH2OH
II
N
N
CH2CH2OH
H
HO
O
O
C
A
B
H
I
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Reaction of Phthalaldehyde with Aminoethanol under Different
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Scheme 2
OHC
= ArCHO
O
-
O
-
O
N
H
O
O
NH2CH2CH2OH
-
HO
+
N
-
N
proton transfer
CH2CH2OH
H
H
H
HO
A
HO
-
OCH2Ar
H
hemiaminal
anion
ArCH2OH
O
CH2CH2OH
O=CHAr
N
H
III
O
-
H
H
_
-
ArCH2O
HOCH2CH2N
oxidative agent (hydride acceptor) being OPA. Thus, OPA
has a dual role, electrophilic substrate and oxidative agent.
The isolation of 2-hydroxybenzaldehyde supports this
hypothesis (cf. Schemes 2, 3, and 4). The reaction would
certainly proceed also by effect of atmospheric oxygen;
however, the absence of oxygen in our conditions (due to
the inert nitrogen atmosphere) supports the possibility of
the Cannizzaro-type oxidation.
In aqueous media in borate buffer pH9.5, OPA and
kolamin were mixed in the ratio 1:1.7, and compounds
I and III were formed in the molar ratio 7:5 (yield 30%).
Compound III can be obtained from intermediate A as
shown in Scheme 2, and its formation must involve two
oxidation steps with OPA as hydride acceptor as already
mentioned. A hemiaminal anion is a very good hydride
donor because the hydride transfer is assisted by electron
pairs, both on the oxygen anion and on the nitrogen.
Furthermore, in such buffered solution, the base-catalyzed
proton transfers are fast.
Under excess of OPA in the borate buffer, intermediate VI
was isolated, whereas in the presence of free kolamin, it
reacts further to form compound IV as shown in Scheme 3.
The identification of compound VI supports the suggested
reaction pathway. This compound can be obtained directly
from intermediate C (Scheme 1) by oxidation with OPA as
depicted in Scheme 3.
The mechanism of the formation of the product V is
shown in Scheme 4 starting from intermediate C (Scheme 1)
in equilibrium with the tautomers D and E. Dehydration of
the latter followed by five subsequent steps gives compound
V. This product is formed (yield 15%) when kolamin is
added to the concentrated solution of OPA (0.164 M) very
slowly. Compounds III, IV, and V are formed only in
aqueous basic solutions (borate or kolamin buffer).
Under excess of OPA and at higher OPA concentration
(0.1 M) in the buffered aqueous solution, the three
diastereoisomers of the spiro compound VII were isolated
(yield 22%). The precursor (cf. Scheme 5) is the same as in
Scheme 4. Under these conditions, the cyclization of tautomer
D to compound VII competes with its tautomerization to E
and dehydration of the latter (cf. Scheme 4).
CONCLUSIONS
The reaction of OPA with kolamin was performed in basic
aqueous buffered media (pH 9.5), where an influence of
hydration or solvation is expected, and in nonaqueous
acetonitrile. This reaction has a broad number of variations,
very sensitive to reaction conditions. Depending on the
medium, molar ratio of the reacting compounds, total
concentration of reactants, the order and rate of their mixing,
and so forth, seven new products were isolated and their
structure determined by NMR, mass spectrometry, and
X-ray structure analysis. Reaction mechanisms for their
formation were suggested. Because of the fact that all
isolated compounds were formed both in the presence of
oxygen and under a nitrogen atmosphere, the observed
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J. Klíma, M. Polášek, J. Ludvík, and J. Urban
Vol 49
Scheme 3
-
ArCH2O
OHC
CHO
-
-
O
HO
(-H2O)
2x
NH2CH2CH2OH
C
O
H
(-H2O)
O=CHAr
N
N
CH2CH2OH
CH2CH2OH
O
O
VI
O=CHAr (OPA)
H
CH2CH2OH
CH2CH2OH
C=N
NH
NH
O
CH2CH2OH
1) HO
-
NH
CH2CH2OH
-
OH
N
OH
2) proton
transfer
-
(-ArCH2O
)
N
CH2CH2OH
CH2CH2OH
O
O
H
N
O
N
CH2CH2OH
CH2CH2OH
HO
CH2CH2OH
CH2CH2OH
NH
N
_
NH
OH
IV
OH
(-H2O)
proton
N
transfer
CH2CH2OH
CH2CH2OH
O
O
acetonitrile. Typical source conditions were as follows: ESI+,
capillary voltage 3.8 kV; cone voltage, 30 V; source temperature,
100ꢃC; desolvation temperature, 200ꢃC; desolvation gas, N2
oxidation processes most probably involve OPA as oxidant
(as hydride acceptor) and follow a variation of the
Cannizzaro reaction. This conclusion is supported also by
the isolation of 2-hydroxymethylbenzaldehyde. OPA acts
here simultaneously as a substrate and an oxidation agent.
(200 l hꢀ1). Syringe pump flow was typically 5 ml minꢀ1
.
Collision-induced dissociation (CID) mass spectra were obtained
in a way in which the ions of interest (i.e., protonated molecules
of analyte) were mass selected by the first quadrupole, activated
by collisions with argon at 15eV collision energy at a pressure of
1.02ꢂ 10ꢀ2 mbar, and products of these collisions were analyzed
by the second quadrupole.
EXPERIMENTAL
Chemicals. Phthalaldehyde (Sigma), min.97%; kolamin
(Lachema, Czech Republic), distilled; sodium borateꢁ10H2O
(Lachema), p.a.; HCl (Lach-Ner, Czech Republic), 35%, p.a.;
acetonitrile (Fluka), puriss. p.a.; and deionized water were used.
Instrumentation. The 1H and 13C NMR spectra (ppm, Hz) were
measured on the spectrometer Varian 300 MHz (299.970 MHz for 1H
and 75.434 MHz for 13C).
Mass spectra were measured using the Quattro Premiere XE
tandem quadrupole mass spectrometer (Waters) consisting of two
quadrupole mass analyzers and a T-wave collision cell. The samples
were directly infused into the electrospray ion source using built-in
syringe pump as approximately 5 ꢂ 10ꢀ5 mol lꢀ1 solutions in 50%
The melting points were measured using the Kofler block and
are not corrected.
Synthetic procedures and characterization.
2-(2-Hydroxyethyl)-2,3-dihydro-1H-benzo[c]pyrrol-1-on (I)
and (3R*,1′S*,3′R*)-3-(3′-hydroxy-1′H,3′H-benzo[c]furan-
1′-yl)- 2-(200-hydroxyethyl)-2,3-dihydro-1H-benzo[c]pyrrol-1-
on (II). Phthalaldehyde (1.33 g) was dissolved in 80 mL of
acetonitrile, and under stirring 0.76 g (0.75 mL) of kolamin was
added. After 4 h at room temperature, acetonitrile was evaporated,
and the n chromatography (silica gel, chloroform–ethanol 10%).
Yield: 308 mg (16%) of compound I (recrystallized from toluene,
mp 117–119ꢃC) and 256 mg (13%) of compound II (recrystallized
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Reaction of Phthalaldehyde with Aminoethanol under Different
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1207
Scheme 4
OHC
OHC
OHC
HO
HO
O
H
H
H
H
proton
proton
transfer
(-H2O)
transfer
N
N
N
H
CH2CH2OH
CH2CH2OH
CH2CH2OH
OH
O
HO
D
E
C
O=CHAr (OPA)
H
_
NH
CH2CH2OH
C=N
NH
CHO
CH2CH2OH
O
-
NH
2x NH2CH2CH2OH
(-H2O)
O
N
-
1)HO
OH
N
OH
2)proton
transfer
N
CH2CH2OH
CH2CH2OH
CH2CH2OH
H
O
HO
CH2CH2OH
CH2CH2OH
NH
CH2CH2OH
N
N
_
-
CH2CH2OH
NH
(-ArCH2O )
proton
transfer
(-H2O)
OH
OH
V
N
CH2CH2OH
N
CH2CH2OH
Scheme 5
5.206 (d, 1H, 3-H, J= 7.2), 5.706 (d, 1H, 3′-H, J= 7.2), 6.007
(s, 1H, 1′-H), 6.874 (d, 1H, Ar–H, J= 6.6), 7.340 (m, 5H, Ar–H),
7.630 (d, 1H, 7-H, J=7.2). 13C NMR (dimethyl sulfoxide d6): d
42.79 (t, CH2–N), 58.88 (t, CH2–O), 62.96 (d, C-3), 80.17
(d, C-3′), 100.51 (d, C-1′), 121.34 (d, Ar–H), 122.63 (d, 2x Ar–H),
123.18 (d, Ar–H), 128.42 (d, Ar–H), 128.65 (d, Ar–H), 128.87
(d, Ar–H), 130.85 (d, Ar–H), 133.33 (s, C-7a), 138.31 (s, C-7′a),
141.10 and 141.68 (s, C-3a and 3′a), 167.81 (s, C-1).
2-(2-Hydroxyethyl)-3-[(2-hydroxyethyl)imino]-2,3-dihydro-1H-
benzo[c]pyrrol-1-on (III). Phthalaldehyde (500 mg) is dissolved in
2500 mL of distilled water containing 3 g of sodium tetraborate
(pH 9.5). Then, 405 mg (400 mL) of kolamin is added and stirred
for 2 h under laboratory temperature. The reaction mixture
was evaporated to dryness using reduced pressure at room
temperature. The obtained solid was dissolved in the mixture
ethylacetate–water and shaken. The organic phase was dried by
Na2SO4 and evaporated to dryness. The obtained products were
separated by column chromatography (silica gel, chloroform–
ethanol 10%). Yield: 126 mg of compound I and 90 mg of
compound III (recrystallized from the mixture chloroform–
toluene, mp 110–112ꢃC). Compound III, 1H NMR (dimethyl
sulfoxide d6): d 3.548 (t, 2H, CH2–N, J = 6), 3.725 (m, 4H, 2x
CH2), 3.972 (t, 2H, CH2–O, J = 6), 7.676 (m, 2H, 5,6-H), 7.761
(d, 1H, 4-H, J = 7.19), 8.037 (d, 1H, 7-H, J = 7.19). 13C NMR
(dimethyl sulfoxide d6): d 41.14 (t, CH2–N), 53.03 (t, CH2–N),
proton
O
O
transfer
OH
OH
VII
CH2CH2OH
N
N
H
CH2CH2OH
O
O
C
D
from the mixture chloroform–heptane, mp 228–230ꢃC). Compound
I, H NMR (deuteriochloroform): d 3.678 (t, 2H, CH2–N, J=5.1),
3.839 (t, 2H, CH2–O, J= 5.1), 4.215 (br s, 1H ,OH), 4.454 (s, 2H,
3-H), 7.358 (m, 2H, 4-,6-H), 7.453 (t, 1H, 5-H, J= 7.5), 7.708
(d, 1H, 7-H, J=8.1).13C NMR (deuteriochloroform): d 45.52
(t, CH2–N), 51.42 (t, C-3), 60.95 (t, CH2–O), 122.46 (d, C-6 or 7),
123.24 (d, C-7 or 6), 127.73 (d, C-4), 131.18 (d, C-5), 132.27 (s,
1
1
C-7a), 141.42 (s, C-3a), 169.34 (s, C-1). Compound II, H NMR
(dimethyl sulfoxide d6): d 3.288 (dt, 1H, CH2–N, J1 = 13.8, J2 = 6),
3.630 (m, 2H, CH2–O), 3.368 (s, 2H, 1′-OH, H2O), 3.879 (dt, 1H,
CH2–N, J1 = 13.8, J2 = 6 ), 4.820 (t, 1H, J=5.1 CH2–OH);
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Vol 49
58.83 (t, CH2–O), 62.61 (t, CH2–O), 123.41 (d, C-4), 126.72 (d,
C-7), 129.92 (s, C-3a), 132.43 (d, C-5), 132.77 (s, C-7a), 133.83
(d, C-6), 151.42 (s, C-3), 167.38 (s, C-1).
at laboratory temperature under nitrogen gas, then evaporated to
dryness, extracted by ethylacetate, and the products separated by
column chromatography (60g of silica gel, chloroform as eluent).
Isolated substances: 18mg of OPA, 133 mg of I, and 42 mg of VI.
The latter was recrystallized from the chloroform–toluene mixture,
1′-[(2-Hydroxyethyl)imino]-2′-(2-hydroxyethyl)-3′-hydroxy-3′-
[2-(2-hydroxyethyl)-2,3-dihydro-1H-benzo[c]pyrrol-1-on-3-yl]-2′,
3′-dihydro-1′H-benzo[c]pyrrol (IV). Kolamin [5.06 g (5 mL)] was
mixed with 412.5 mL 0.1 M HCl giving rise to a kolamin buffer,
pH 9.5. This solution was added for 10 s under stirring to the
solution of 1.1 g OPA in 30 mL ethanol. After 2 h at room
temperature, the reaction mixture was evaporated to dryness under
reduced pressure. The solid was dissolved in the mixture
chloroform–water and shaken. The aqueous phase was once more
washed by chloroform; the two organic phases were combined,
dried by Na2SO4, and evaporated to dryness. The obtained
products were separated by column chromatography (silica gel,
chloroform–ethanol 10%). Yield: 123 mg of compound III
and 192 mg of compound IV (recrystallized from toluene, mp
199–201ꢃC). Compound IV 1H NMR (deuteriochloroform):
d 3.979 (m, 12H, CH2–N and CH2–O), 4.880 (s, 1H, 3-H), 5.245
(br s, 4H, OH), 7.083 (m, 2H, Ar–H), 7.243 (m, 4H, Ar–H), 7.702
(d, 1H, 7′-H, J = 6.3), 7.837 (d, 1H, 7-H, J=7.5). 13C NMR
(deuteriochloroform): d 38.71 (t, CH2–N2′), 44.98 (t, CH2–N2),
50.76 (t, CH2–N═), 60.58 (d, C-3), 62.36 (t, CH2–O), 63.09
(t, CH2–O), 64.06 (t, CH2–O), 91.84 (s, C-3′), 122.71 (d, Ar–H),
123.68 (d, Ar–H), 123.98 (d, Ar–H), 126.63 (d, Ar–H), 129.12
(d, Ar–H), 129.56 (s, C-7′a), 129.92 (d, Ar–H), 130.87 (d, Ar–H),
132.27 (d, Ar–H), 132.43 (s, C-7a), 140.51 (s, C-3a and 3′a),
159.71 (s, C-1′), 167.24 (s, C-1).
mp 158–160ꢃC. 1H NMR (deuteriochloroform):
d 3.715
(t, 2H, CH2–N, J = 5.6), 3.862 (t, 2H, CH2–O, J = 5.6), 4.435 (br
s, 1H, OH), 4.960 (s, 1H, 3-H), 7.268 (m, 3H, Ar–H), 7.726 (m,
3H, Ar–H), 7,898 (d, 1H, 3′-H, J = 7.5), 8.097 (d, 1H, 6′-H,
J = 7.5), 10.128 (s, 1H, CHO). 13C NMR (deuteriochloroform): d
43.54 (t, CH2–N), 59.86 (t, CH2–O), 66.52 (d, C-3), 122.61 (d,
Ar–H), 123.48 (d, Ar–H), 127.34 (d, Ar–H), 128.66 (d, Ar–H),
129.45 (d, Ar–H), 130.92 (d, Ar–H), 132.78 (d, Ar–H), 133.52 (s,
C-7a), 134.01 (d, Ar–H), 136.72 (s, Ar), 137.83 (s, Ar), 141.57 (s,
C-3a), 168.26 (s, C-1), 190.89 (d, CHO), 196.11 (s, CO). The
analogous reaction where the molar excess of OPA was 4:1
(400mg of OPA and 45mL of kolamin) was performed in the
same way. Using TLC, the same substances were found in the
reaction mixture; only the amount of the unreacted OPA was higher.
Spiro[2-(2-hydroxyethyl)-2,3-dihydro-1H-benzo[c]pyrrol-1-on-
3,2′-indan-1′,3′-diol] (VII). Phthalaldehyde (600 mg) was
dissolved in 40 mL of 50% ethanol containing 50 mg of sodium
tetraborate. Kolamin [140mg (138ml)] was added and stirred for
4 h at laboratory temperature. The product was evaporated to
dryness and extracted by ethylacetate. The solid was purified
using column chromatography (100 g of silica gel, chloroform,
and chloroform–ethanol 10% as eluent). The unreacted OPA was
separated. Products: besides compound I, 36 mg of compound
VII-1, 49mg of VII-2, and 71 mg of VII-3 were isolated
(compounds VII 1 and 3 are meso-forms, the product VII-2 is a
Decomposition of compound IV. Fifty milligrams of
compound IV was dissolved in 15 mL of ethanol, and several
drops of concentrated HCL was added. After 4 h, the solution
was neutralized by addition of NaHCO3, filtered and evaporated
to dryness. The products were separated using TLC; the two
obtained pure substances were identical with compounds I and
III (checked by NMR).
1
DL pair). Compound VII-1 H NMR (dimethyl sulfoxide d6): d
2.958 (t, 2H, CH2–N, J = 5.7), 3.440 (t, 2H, CH2–O, J = 5.7),
3.420 (br s, OH, H2O), 5.447 (s, 2H, 1′, 3′-H), 6.145 (bs, 2H,
2xOH), 7.371 (s, 4H, 4′-7′-H), 7.491 (t, 1H, 6-H, J = 7.5), 7.621
(t, 1H, 5-H, J =7.5), 7.657 (d, 1H, 4-H, J = 7.5), 7.922 (d, 1H,
7-H, J = 7.5). 13C NMR (dimethyl sulfoxide d6): d 45.80
(t, CH2–N), 59.19 (t, CH2–O), 76.62 (d, C-1′, 3′), 83.26 (s, C-3),
122.50 (d, Ar–H), 122.62 (d, Ar–H), 123.40 (d, 2x Ar–H), 128.84
(d, Ar–H), 128.90 (d, 2x Ar–H), 132.28 (d, Ar–H), 133.16
(s, C-7a), 142.87 (s, C-3′a, 7′a), 147.80 (s, C-3a), 170.23 (s, C-1).
CID ms (m/z (%)): 312(M+ H+; 20), 294(8), 276(100), 258(2),
250(3), 248(23), 234(1), 233(8), 232(8), 219(6), 207(1), 205(1),
204(1), 176(3), 159(1).
1-[(2-Hydroxyethyl)imino]-2-(2-hydroxyethyl)-3-hydroxy-3-
[2′-(2-hydroxyethyl)isoindol-1′-yl] (V). Kolamin [1.012 g (1 mL)]
was mixed with 82.5 mL 0.1 M HCl. This solution was added very
slowly (for 2 min) under stirring to the solution of 220 mg of OPA
in 10 mL ethanol. After a night in a refrigerator, yellowish crystals
were formed, isolated by filtration, washed with water, and dried.
The recrystallization was not performed because of the expected
decomposition. Compound V, 1H NMR (deuteriochloroform): d
3.446–3.876 (br s, 4H, 4xOH), 3.572 (m, 4H), (2xCH2N), 3.894
(t, 2H, CH2N, J= 5.14), 4.056 (t, 2H, CH2O, J= 5.14), 4.458
(m, 4H, 2xCH2), 6.71 (m, 1H, Ar–H), 6.895 (m, 1H, Ar–H), 7.150
(d, 1H, Ar–H, J = 7.5), 7.233 (s, 1H, 3′-H), 7.331–7.518 (m, 4H,
Ar–H), 8.029 (d, 1H, Ar–H, J=7.5).
13C NMR (deuteriochloroform): d 45.59 (t, CH2N), 46.46
(t, CH2N), 51.10 (t, CH2N═), 61.81 (t, CH2O), 63.59 (t, CH2O),
63.86 (t, CH2O), 92.64 (s, C-1′), 111.38 (d, Ar–H), 111.92
(s, C-3a), 118.36 (d, Ar–H), 118.76 (d, Ar–H), 121.12 (s, C-7a),
121.86 (d, 2xAr–H), 123.47 (d, Ar–H), 124.30 (s, C-3′a), 126.31
(d, Ar–H), 128.60 (s, C-7′a), 129.69 (d, Ar–H), 131.53 (d, Ar–H),
147.40 (s, C-1), 158.53 (s, C-3′).
1
Compound VII-2 H NMR (dimethyl sulfoxide d6): d 3.440
(m, N–CH2CH2–OH, H2O), 5.017 (s, 1H, 3′-H)*, 5.470 (s, 1H,
1′-H)*, 5.673 (br s, 1H, OH), 6.084 (br s, 1H, OH), 7.400 (m, 7H,
Ar–H), 7.637 (d, 1H, 7-H, J = 7.2). 13C NMR (dimethyl sulfoxide):
d 45.04 (t, CH2–N), 59.12 (t, CH2–O), 75.66 (d, C-1′)*, 78.53 (s,
C-3), 78.60 (d, C-3′)*, 122.72 (d, Ar–H), 124.00 (d, Ar–H),
125.33 (d, Ar–H), 125.38 (d, Ar–H), 128.65 (d, Ar–H), 129.31
(d, Ar–H), 129.73 (d, Ar–H), 131.58 (d, Ar–H), 132.50 (s, C-7a),
143.12 (s, C-7′a)*, 143.72 (s, C-3′a)*, 146.59 (s, C-3a), 169.56
(s, C-1). CID ms (m/z (%)): 312(M+ H+; 22), 294(100), 276(67),
258(3), 250(34), 248(26), 234(7), 233(31), 232(22), 219(1), 207
(7), 205(3), 204(3), 176(90), 159(3).
2-(2-Hydroxyethyl)-3-(2-formylbenzoyl)-2,3-dihydro-1H-benzo
[c]pyrrol-1-on (VI). Phthalaldehyde (300 mg) was dissolved in
8 mL of ethanol, and this solution was added to 500 mL of water
with dissolved sodium tetraborate (600 mg). Kolamin [69mg
(68 mL)] was then slowly added under stirring to the solution. The
reaction mixture (excess of OPA was 2:1) was then stirred for 4 h
Compound VII-3 1H NMR (dimethyl sulfoxide d6): d 3.480 (br
s, OH, H2O), 3.720 (m, 4H, N–CH2CH2–O), 5.460 (s, 2H, 1′, 3′-H),
5.600 (br s, 2H, 2xOH), 7.154 (t,1H, Ar–H, J = 7.5), 7.310 (m, 6H,
Ar–H), 7.586 (d, 1H, 7-H, J = 7.5). 13C NMR (dimethyl sulfoxide
d6): d 43.15 (t, CH2–N), 59.29 (t, CH2–O), 72.28 (d, C-1′,3′),
85.75 (s, C-3), 122.49 (d, Ar–H), 123.81 (d, 2xAr–H), 124.16 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Reaction of Phthalaldehyde with Aminoethanol under Different
Conditions: Products and Mechanisms of Their Formation
1209
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Ar–H), 128.20 (d, Ar–H), 128.62 (d, 2xAr–H), 130.60 (d, Ar–H),
133.47 (s, C-7a), 141.82 (s, C-3′a, 7′a), 144.65 (s, C-3a), 169.51
(s, C-1). CID ms (m/z (%)): 312(M + H+; 49), 294(100), 276(67),
258(3), 250(39), 248(26), 234(7), 233(34), 232(21), 219(2), 207
(7), 205(4), 204(4), 176(29), 159(2).
Acknowledgment. This work was supported by the grant KONTAKT
ME-09002 (Ministry of Education, Youth and Sports of the Czech
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet