An unexpected route for the synthesis of a new spiroheterocyclic system from ninhydrin

Article abstract of DOI:10.1016/j.tetlet.2015.07.081

Abstract The reaction of ninhydrin with amines leads to the formation of Ruhemann's purple. This study presents the synthesis of Ruhemann's purple and a new benzo-fused spiroheterocyclic system by the reaction between ninhydrin and phenylethylamine. The s

Full text of DOI:10.1016/j.tetlet.2015.07.081

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected route for the synthesis of a new spiroheterocyclic
system from ninhydrin
Yovanny Quevedo-Acosta a, Adrián Pérez-Redondo b, Rodolfo Quevedo a,
⇑
a Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, Departamento de Química, Carrera 30 No. 45-03, Bogotá, Colombia
b Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871 Alcalá de Henares-Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of ninhydrin with amines leads to the formation of Ruhemann’s purple. This study presents
the synthesis of Ruhemann’s purple and a new benzo-fused spiroheterocyclic system by the reaction
between ninhydrin and phenylethylamine. The structure was established using spectroscopic data and
X-ray crystal structure analysis.
Received 17 July 2015
Revised 28 July 2015
Accepted 29 July 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Ninhydrin
Phenylethylamine
Pictet–Spengler
Phenylacetaldehyde
Ruhemann’s purple
We have observed that the hydroxylation degree on the aro-
matic ring influences the reactivity of b-phenylethylamines to
non-enolizable aldehydes. The product obtained depends on the
hydroxylation degree of the original phenylethylamine ring.
When the reaction is performed between dopamine and formalde-
hyde, the corresponding 1,2,3,4-tetrahydroisoquinoline is obtained
by a Pictet–Spengler reaction; when the reaction is performed
between tyramine and formaldehyde, an azacyclophane is obtained
by a double aromatic Mannich reaction; and when the reaction is
performed between phenylethylamine and formaldehyde, a triple
amine–aldehyde condensation leads to the corresponding hexahy-
dro-1,3,5-triphenyl-1,3,5-triazine.1–3
On the other hand, ninhydrin 1 is a highly electrophilic
tricarbonyl compound derived from indane. The electrophilic
character is high due to the presence of three consecutive
electron-withdrawing groups, the most electrophilic of which is
carbon 2. The presence of three electrophilic groups makes it very
interesting from a chemical perspective, and it has been the object
of many studies aimed at obtaining heterocyclic compounds with
great structural diversity.4
form an aldehyde and Ruhemann’s purple 2 by interaction with a
second molecule of ninhydrin (Scheme 1).9
Recent studies showed that dopamine
3 (3,4-dihydroxy-
phenethylamine) does not form the expected Ruhemann’s purple
2 and, when reacting with ninhydrin, produces a mixture of
spiro-tetrahydroisoquinoline-type 4 regioisomers by a Pictet–
Spengler condensation (Scheme 2).10
We here extend our studies on the reactivity of phenylethy-
lamines and describe the reaction of b-phenylethylamine with
ninhydrin as a synthetic method to produce a new benzo-fused
spiroheterocyclic system. The synthesis described involves a tri-
component condensation between phenylacetaldehyde generated
in situ, phenylethylamine, and ninhydrin.
Our studies show that phenylethylamine 5 exposed to ninhy-
drin 1 does not present the usual behavior described for amines
and, along with Ruhemann’s purple 2, predominantly produces a
compound that is violet in solution form and colorless in the solid
state 6.11 The analysis of 1H NMR and 13C NMR spectra showed a
greater number of signals than those expected for the Schiff base
or the corresponding tetrahydroisoquinoline. The additional
signals indicate the presence of a third aromatic unit with two
aliphatic carbons, most likely from a phenylacetaldehyde molecule
formed in situ.
The reaction of ninhydrin 1 with amines usually leads to a sin-
gle product known as Ruhemann’s purple 2; as a result, it is used in
a variety of analytical techniques.5–9 This reaction starts with the
formation of a Schiff base, which tautomerizes and hydrolyzes to
The structure of the new compound was determined by IR spec-
troscopic analysis, NMR (1H, 13C, COSY, HMQC and HMBC) and
mass spectrometry (EI-MS and ESI-MS). In the HMBC experiment,
we obtained key data that assisted in determining the structure,
⇑
Corresponding author. Fax: +57 1 316 5220.
E-mail address: arquevedop@unal.edu.co (R. Quevedo).
http://dx.doi.org/10.1016/j.tetlet.2015.07.081
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Quevedo-Acosta, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.07.081

2
Y. Quevedo-Acosta et al. / Tetrahedron Letters xxx (2015) xxx–xxx
-
O
O
O
O
R
2
O
R
O
+
NH
N
2
+
2
O
O
1
Scheme 1. Ruhemann’s purple formation from ninhydrin.
HO
O
HO
HO
NH
O
NH
MeOH
HO
HO
O
+
+
O
OH
O
O
NH
2
O
1
3
4
Scheme 2. Reaction of dopamine with ninhydrin.
H
H
O
H
N
O
98.0
O
119.8
127.6
8.72
H
Figure 1. Selected HMBC correlations of spiro[furan-2,10-isoindoline] 6.
such as a proton at 8.72 ppm that correlates with two sp2 carbons
at 119.8 and 127.6 ppm and with a quaternary sp3 carbon at
98.0 ppm. The sp2 carbons were assigned to the unit from the
phenylacetaldehyde, whereas the sp3 carbon was assigned to the
unit from ninhydrin. According to the correlation of the protons
from the adjacent aromatic ring and the aliphatic protons from
the phenylethylamine, we established that this carbon is linked
to three electron-withdrawing groups (Fig. 1). The structure of this
product was confirmed by X-ray crystallography (Fig. 2). The
resulting compound corresponds to a spiro[furan-2,10-isoindoline]
6 product of the three-component reaction between ninhydrin 1,
phenylethylamine 5, and phenylacetaldehyde (Scheme 3). The dis-
tances and bond angles within the spiroheterocyclic fragment are
similar to those found in the structure of 5-methyl-3H,
30H-spiro[benzofuran-2,10-isoindole]-3,30-dione.12
Figure 2. ORTEP diagram of one of the two crystallographically independent
molecules of the spiro[furan-2,10-isoindoline] 6.
O
O
+
NH
2
O
1
5
Previous studies have demonstrated that the imine or enamine
produced by the condensation between 1,3-dicarbonyl compounds
and primary amines reacts with ninhydrin to form dihydroxyin-
denopyrrole hemiaminals. It was also demonstrated that the
oxidative cleavage of certain dihydroxy-indenopyrroles and the
subsequent hydrolysis and cyclization yield spiro[isobenzofuran-
1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50-tetraones.13–15
MeOH
O
O
O
HO
O
N
N
+
O
O
Initially,
a
mechanism similar to that proposed for
1,3-dicarbonilic compounds was suggested for the formation of
compound 6.13–15 To confirm this mechanism, first, the imine
was synthesized from the phenylacetaldehyde and phenylethy-
lamine, and then, it was reacted with ninhydrin. Under these con-
ditions, it was not possible to obtain experimental evidence of the
formation of 6, which would make it possible to propose that the
formation of this spiroheterocycle follows a different mechanism.
When the three-component reaction between ninhydrin 1,
phenylethylamine 3 and recently distilled phenylacetaldehyde
was performed, and when ninhydrin and phenylacetaldehyde
2
6
Scheme 3. Reaction of ninhydrin with phenylethylamine.
mixture was first reacted, followed by the addition of phenylethy-
lamine, complex mixtures were obtained and it was not possible to
obtain experimental evidence of the formation of 6. Compound 6
was obtained only when phenylacetaldehyde was generated
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Y. Quevedo-Acosta et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
O
O
O
O
OH
NH
OH
O
O
O
O
O
-
OH
O
NH
O
N
O
O
7
O
O
OH
HO
O
-
O
H
O
-
O
O
O
N
-
O
O
N
O
O
N
O
O
O
8
O
H
O
O
N
6
O
N
O
O
HO
Scheme 4. Mechanism proposed for the synthesis of spiro[furan-2,10-isoindoline] 6.
in situ. Considering these observations, the process to obtain 6 can
be rationalized by the initial nucleophilic addition of the amine to
ninhydrin. The hemiaminal formed 7 might then follow the reac-
tion toward the formation of Ruhemann’s purple, or else an oxida-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
081. CCDC-1411989 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
tive cleavage can occur, followed by
a cyclization through
interaction with a second ninhydrin molecule, to form the corre-
sponding isoquinolinetrione 8 (Scheme 4). The highly electrophilic
isoquinolinetrione undergoes nucleophilic attack by phenylac-
etaldehyde or by its enolate ion, the formation of which is cat-
alyzed by the alkaline nature of Ruhemann’s purple 3. After the
nucleophilic attack, compound 6 is formed by a rearrangement
and subsequent dehydration (Scheme 4). The proposed reaction
mechanism does not depend on the solvent used, which was either
toluene (yield: 45%) or methanol (yield: 46%).
In conclusion, in this Letter, we present a new example of a
benzo-fused spiroheterocyclic system (spiro[furan-2,10-isoindo-
line]), produced by the three-component reaction between ninhy-
drin, phenylethylamine, and phenylacetaldehyde generated in situ.
References and notes
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Acknowledgments
We would like to thank the Universidad Nacional de Colombia
(DIB research project No. 28217) and Universidad de Alcalá
(CCG2014/EXP-019) for providing financial support.
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4
Y. Quevedo-Acosta et al. / Tetrahedron Letters xxx (2015) xxx–xxx
methanol. The mixture was stirred at room temperature until the
NMR (100 MHz, CDCl3) d (ppm): 35.1, 42.3, 98.06, 119.82, 121.18, 124.21,
125.42, 126.48, 127.58, 128.48, 128.82, 129.01, 131.02, 131.69, 132.87, 138.65,
139.60, 168.39, 173.86, 195.49; EIMS: (m/z) 381.2, 352.2, 336.2, 336.2, 277.2,
262.1, 249.1, 234.2, 221.2, 206.2, 178.2, 161.1, 146.2, 118.1, 104.1, 77.1, 63.1;
ESI-MS: (m/z) 382.136 Calcd 382.143.
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removed under reduced pressure. The obtained residue was purified by
column chromatography on silica gel using toluene as the mobile phase.
A crystalline solid was obtained, melting point: 144 °C. Spectroscopic data: IR
(KBr): (cmꢀ1) 3392, 3057, 3025, 2969, 2933, 2866, 1946, 1886, 1832, 1705,
1608, 1587; 1H NMR (400 MHz, CDCl3) d (ppm): 2.96 (m, 2H), 3.44 (ddd, 1H,
J1 = 14.5 Hz, J2 = 9.7 Hz, J3 = 6.4 Hz), 3.79 (ddd, 1H, J1 = 14.4 Hz, J2 = 9.6 Hz,
J3 = 6.1 Hz), 7.19 (m, 3H), 7.25 (d, 2H, J = 7.6 Hz), 7.29 (m, 1H), 7.37 (tt, 1H,
J1 = 7.58 Hz, J2 = 1.26 Hz), 7.44 (dt, 2H, J1 = 7.3 Hz, J2 = 1.01 Hz), 7.55 (dddd, 2H,
J1 = 14.1 Hz, J2 = 12.6 Hz, J3 = 7.6 Hz, J4 = 1.5 Hz), 7.74 (dd, 2H, J1 = 8.3 Hz,
J2 = 1.3 Hz), 7.87 (ddd, 1H, J1 = 6.3 Hz, J2 = 1.5 Hz, J3 = 0.8 Hz), 8.71 (s, 1H); 13C
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