Synthesis and transformations of ethyl 3-formyl-1H-indole-2-carboxylate. Preparation of aplysinopsin and β-carboline thiohydantoin analogues

Article abstract of DOI:10.1515/znb-2006-0407

Various aplysinopsin and β-carboline thiohydantoin analogues were prepared starting from ethyl 3-formyl-1H-indole-2-carboxylate by condensation with the active methylene group of 2-thiohydantoin, rhodanine, or thiobarbituric acid derivatives.

Full text of DOI:10.1515/znb-2006-0407

Synthesis and Transformations of Ethyl
-Formyl-1H-indole-2-carboxylate.
3
Preparation of Aplysinopsin and β-Carboline Thiohydantoin Analogues*
Renata Jak sˇ e, David Bevk, Amalija Golobi cˇ , Jurij Svete, and Branko Stanovnik
Faculty of Chemistry and Chemical Technology, University of Ljubljana, A sˇ ker cˇ eva 5, P.O. Box 537,
1
000 Ljubljana, Slovenia
Reprint requests to Prof. Dr. Branko Stanovnik. E-mail: Branko.Stanovnik@fkkt.uni-lj.si
Z. Naturforsch. 61b, 413 – 419 (2006); received January 6, 2006
Various aplysinopsin and β-carboline thiohydantoin analogues were prepared starting from
ethyl 3-formyl-1H-indole-2-carboxylate by condensation with the active methylene group of 2-thio-
hydantoin, rhodanine, or thiobarbituric acid derivatives.
Key words: Aplysinopsin Analogues, β-Carbolines, Thiohydantoins
Introduction
Recently, a series of alkyl 2-substituted 3-(dimethyl-
amino)prop-2-enoates and related enaminones have
been prepared as versatile reagents for the preparation
of various dehydroalanine derivatives, heterocyclic
systems, and natural product analogues. In extension,
chiral cyclic enamino lactams and lactones, derived
from α-amino acids and (+)-camphor have been used
Fig. 1. Naturally occurring aplysinopsins.
Aplysinopsins (Fig. 1) were first isolated from the
in the synthesis of functionalised heterocycles, such sponge genus Thorecta of the Australian Great Bar-
as heteroarylalanines, heteroarylalaninols, heteroaryl- rier Reef [7, 8] and others [9 – 12]. Their signifi-
propanediols, 3-heteroaryl-(+)-camphors, and hetero- cant biological activities caused an increased inter-
cyclic compounds with an α-amino acid or a dipep- est in aplysinopsin-type alkaloids. Some of them are
tide structural element incorporated into the ring sys- active as a specific cytotoxin of cancer cells and
tem [1, 2]. Recently, alkyl 2-substituted 3-(dimethyl- affect neurotransmission [8]. Several synthetic ap-
amino)prop-2-enoates and related enaminones have proaches towards aplysinopsin-type structures have
been employed in combinatorial synthesis of het- been reported. However, poor yields, purification
erocycles and N-acyldehydroalanine esters [3] and difficulties and formation of Z and E isomers
in the synthesis of natural product analogues, such are generally encountered in these procedures [11 –
as aplysinopsins [4], meridianins [5], and dipod- 14]. These inconveniences have been circumvented
azines [6].
by the Staudinger aza/Wittig reaction followed by
3
-(Dimethylamino)prop-2-enoates and their chiral electrocyclic ring closure [15– 19]. Recently, two
analogues are usually prepared by treatment of a suit- novel and stereoselective synthetic approaches to-
ably functionalised methylene compound with for- wards aplysinopsins have been developed: a) a three-
mamide acetal, e.g. with N,N-dimethylformamide step synthesis from alkyl 3-dimethylamino-2-[(2,2-di-
dimethyl acetal (DMFDMA) or with tert-butoxy- substituted 1-vinyl)amino]propenoates [4a] and, b) a
bis(dimethylamino)methane (Bredereck’s reagent) [1]. one-step synthesis from 5-[(dimethylamino)methyl-
idene]hydantoin derivatives and analogues [4b, e]. In
Presented in part at the 7th Conference on Iminium Salts
ImSaT-7), Bartholom a¨ /Ostalbkreis, September 6 – 8, 2005.
this manner, aplysinopsins, thioaplysinopsins, and
analogues, in which the hydantoin moiety is re-
*
(
0
932–0776 / 06 / 0400–0413 $ 06.00 ꢀc 2006 Verlag der Zeitschrift f u¨ r Naturforschung, T u¨ bingen · http://znaturforsch.com
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14
R. Jak sˇ e et al. · Synthesis and Transformations of Ethyl 3-Formyl-1H-indole-2-carboxylate
placed with 1,4,5,6-tetrahydro-1,2,4-(1H,4H)-triazin-
6
-one and 2,4,6-(1H,3H,5H)-pyrimidinetrione, have
been prepared [4f].
Ethyl β-carboline-3-carboxylate derived from in-
dole derivatives was shown to bind with high affinity
to the so-called benzodiazepine receptors in the central
nervous system [20]. The above considerations might
become an important basis for the design of ethyl β-
carboline-3-carboxylate-like compounds in the quest
of new biologically active molecules [21 – 24].
However, the aplysinopsins and derivatives of analo-
gous systems could not be prepared from indole deriva-
tives bearing electron withdrawing groups, such as an
ethoxycarbonyl group attached at 2-position of the in-
dole nucleus, by our enaminone methodology reported
previously [1a, c, f].
Therefore, we developed a new method, as an ex-
tension of our work in this field. We now report
an alternative synthesis in relation to our enaminone
methodology via condensation of ethyl 3-formyl-1H-
indole-2-carboxylate with a suitable nucleophile, such
as 2-hydantoin, rhodanine, or barbituric acid deriva-
tive. Aplysinopsin and thioaplysinopsin analogues, and
β-carboline derivatives were thus prepared starting
from 3-formyl-1H- (12) and ethyl 3-formyl-1-H-2-
carboxylate (2).
Fig. 2. ORTEP view of the asymmetric unit of compound 4
with labeling of non-hydrogen atoms. Ellipsoids are drawn
at 50% probability level.
lene group of the 2-thiohydantoin derivative 5 and
the formyl group of ethyl 3-formyl-1H-indol-2-carb-
oxylate (2). Thioaplysinopsin derivatives 6a – f were
formed as intermediates. Simultaneously, cyclocon-
densation between the hydantoin thioamide NH group
and the ester group of the indole nucleus occurred
in acetic acid/NaOAc under reflux, forming the fi-
nal products 7a – f. The orange-coloured solids, that
eventually precipitated from the reaction mixture, were
highly insoluble. The precipitates were purified by
washing with water, absolute ethanol and diethyl
ether.
Results and Discussion
Ethyl 3-formyl-1H-indol-2-carboxylate(2) was pre-
pared by formylation of ethyl indole-2-carboxylate (1)
Aplysinopsin-like products 9 and 11 were isolated
when the condensation reaction was carried out with
substituted rhodanines 8 or thiobarbituric acid (10)
by POCl in dimethyl formamide (Scheme 1) [25, 26].
3
Formylation of indole-2-acetonitrile (3) under the
same reaction conditions produced 4-formyl-1H-
indol-2-acetonitrile 3 (Fig. 2).
β-Carboline thiohydantoin derivatives (Scheme 2)
were prepared by condensation of the activated methy-
(Scheme 3).
Ethyl 3-formyl-1H-indole-2-carboxylate (2) and
indole-3-carboxaldehyde (12) were also used in the
formation of azomethine imines. 5,5-Dimethylamino-
3-pyrazolidinone reacted with both of them in anhy-
drous ethanol in the presence of catalytic amounts of
trifluoroacetic acid. The (Z)-configuration at the C=N
double bond was confirmed by the NOESY spectrum
of compound 15, which showed interactions among
the methylidene proton and the two methyl groups
(Scheme 4).
Structure Determination
Structures of novel compounds were confirmed by
1
13
Scheme 1. Reagents and conditions: (i) NaOAc/AcOH, re- IR, H, and C NMR methods, and by elemental
flux.
analyses for C, H, and N. The (Z)-configuration of
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R. Jak sˇ e et al. · Synthesis and Transformations of Ethyl 3-Formyl-1H-indole-2-carboxylate
415
Compound
R
Reaction time (h)
Yield [%]
5a, 6a, 7a
5b, 6b, 7b
5c, 6c, 7c
5d, 6d, 7d
5e, 6e, 7e
5f, 6f, 7f
H
Et
5
5
7
4
8
6
74
49
65
52
20
36
CH2Ph
Ph
4-Me-C6H4
3,4-Cl-C6H4
Scheme 2. Reagents and condi-
tions: (i) NaOAc/AcOH, reflux.
Compound
R
H
Ph
H
X
S
S
NH
Reaction time (h)
Yield [%]
Scheme 4. Reagents and conditions: (i) EtOH, TFA, r.t.
9
9
9
1
a
b
c
8
5
8.5
1
60
85
67
69
This method represents an extension to our enaminone
methodology reported previously, according to which
only at 2-position unsubstituted or alkyl- or aryl- sub-
stituted derivatives can be used.
1
Scheme 3. Reagents and conditions: (i) NaOAc/AcOH, re-
flux.
compound 15 was confirmed by a NOESY NMR ex-
periment, and the structure of compound 4 was es-
tablished by X-ray crystal structure analysis. In favor
of the (Z)-configuration of intermediates 6a – f speaks
also the cyclization into the corresponding β-carboline
derivatives 7a – f, which takes place under relatively
mild reaction conditions.
Experimental Section
Melting points were taken on a Kofler micro hot stage.
The 1H NMR spectra were obtained on a Bruker Avance
DPX 300 (300 MHz) spectrometer in [D ]-DMSO or CDCl
as solvent with TMS as the internal standard. MS spectra
were recorded on an AutoSpecQ spectrometer, IR spectra
on a Perkin-Elmer 1310 infrared spectrophotometer and el-
emental analyses for C, H and N on a Perkin-Elmer CHN
Analyser 2400.
6
3
Conclusion
Various aplysinopsin analogues with an ester group
attached at 2-position of the indole and β-carboline
ring system were prepared in fair yields by conden-
sation of ethyl 3-formyl-1H-indole-2-carboxylate with
Procedure for the preparation of ethyl 3-formyl-1H-indole-2-
carboxylate and (1-formyl-1H-indol-3-yl)acetonitrile (2,4)
Compounds 1a,c (0.050 mol) were dissolved in 20 ml
heterocyclic active methylene compounds 5, 8, and 10. of N,N-dimethylformamide (DMF) and dropwise added to
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R. Jak sˇ e et al. · Synthesis and Transformations of Ethyl 3-Formyl-1H-indole-2-carboxylate
◦
a mixture of POCl3 (5 ml, 0.55 mol) and DMF (16 g, 5 h, 74% yield (0.20 g). – M. p. 343 – 345 C. – IR (KBr):
−1
1
0
.22 mol), and the mixture was stirred at room temperature ν = 1720, 1664, 1614, 1510, 1490 cm . – H NMR ([D ]-
6
for 1 h. The reaction mixture was then poured on crushed DMSO): δ = 7.32 (ddd, 1H, J = 0.8, 7.2, 7.9 Hz, 5’-H),
ice and aqueous NaOH solution (50 ml, 4.8 M) was slowly 7.51 (ddd, 1H, J = 1.1, 7.2, 8.3 Hz, 6’-H), 7.61 (dd, 1H,
added. The reaction mixture had to remain acidic until ap- J = 0.8, 8.3 Hz, 7’-H), 8.03 (s, 1H, 3-H), 8.24 (dd, 1H,
proximately three quarters of the prepared NaOH solution J = 1.1, 7.9 Hz, 4’-H), 12.95 (s, 1H, NH), 13.13 (s, 1H, NH).
1
3
was added. The last quarter was added instantaneously. The
–
C NMR ([D ]-DMSO): δ = 105.4, 114.1, 121.4, 122.6,
6
solution was brought to boiling and then cooled to room tem- 122.7, 123.8, 126.1, 128.3, 132.0, 140.6, 152.6, 162.6, 176.2.
perature. A white precipitate was collected by filtration and – MS (EI): m/z = 269 (M ). – C H N O S (359.41):
+
2
0 13 3 2
washed with water to give 2 or 4.
calcd. C 66.84, H 3.65, N 11.69; found C 67.07, H 3.71,
N 11.48.
Ethyl 3-formyl-1H-indole-2-carboxylate (2)
2
-Ethyl-1,5-dioxo-2,3,5,6-tetrahydro-1H-imidazo-
This compound was prepared from compound 1a (9.45 g,
[1’,5’:1,6]pyrido[3,4-b]indole-3(2H)-thione (7b)
0
1
1
.050 mol), 1 h, 91% yield (9.87 g). – M. p. 185 –
◦
86 C (from ethanol). – IR (KBr): ν = 1723, 1635, 1576,
This compound was prepared from compound 2 (0.22 g,
−1
1
533 cm . – H NMR ([D ]-DMSO): δ = 1.41 (t, 3H,
J = 7.1 Hz, CH ), 4.47 (q, 2H, J = 7.1 Hz, CH ), 7.30 (ddd,
6
0.001 mol) and 3-ethyl-2-thiohydantoin (5b) (0.14 g,
0.001 mol), 5 h, 49% yield (0.15 g). – M. p. 275 – 277 C. –
◦
−1
3
2
1
6
8
1
1
–
2
H, J = 1.1, 6.8, 7.9 Hz, 5’-H), 7.40 (ddd, 1H, J = 1.1,
.8, 8.3 Hz, 6’-H), 7.58 (dd, 1H, J = 1.1, 8.3 Hz, 7’-H),
.26 (dd, 1H, J = 1.1, 7.9 Hz, 4’-H), 10.62 (s, 1H, CHO),
IR (KBr): ν = 1731, 1665, 1619, 1573, 1512, 1490 cm . –
1
H NMR ([D ]-DMSO): δ = 1.22 (t, 3H, J = 6.8 Hz, CH ),
6
3
3
.95 (q, 2H, J = 6.8 Hz, CH ), 7.33 (ddd, 1H, J = 1.1, 7.7,
2
2.80 (s, 1H, NH). – 13C NMR ([D ]-DMSO): δ = 114.0,
6
8.3 Hz, 5’-H), 7.51 (ddd, 1H, J = 1.1, 7.7, 8.3 Hz, 6’-H),
.62 (dd, 1H, J = 1.1, 8.3 Hz, 7’-H), 8.16 (s, 1H, 3-H), 8.25
19.3, 123.2, 124.3, 125.6, 126.7, 133.5, 136.6, 161.0, 188.4.
7
+
MS (EI): m/z = 217 (M ); HRMS: calcd. 217.0739; found
(dd, 1H, J = 1.1, 8.3 Hz, 4-H), 12.99 (s, 1H, NH). – MS (EI):
17.0744. – C H NO (217.22): calcd. C 66.35, H 5.10,
+
1
2
11
3
m/z = 297 (M ). – C15H11N O S (297.34): calcd. C 60.59,
H 3.73, N 14.13; found C 60.92, H 3.86, N 14.44.
3
2
N 6.45; found C 66.07, H 5.32, N 6.52.
(1-Formyl-1H-indol-3-yl)acetonitrile (4)
2-Benzyl-1,5-dioxo-2,3,5,6-tetrahydro-1H-imidazo-
This compound was prepared from compound 1c (7.8 g, [1’,5’:1,6]pyrido[3,4-b]indole-3(2H)-thione (7c)
0
1
1
.050 mol), 2 h, 33% yield (3.03 g). – M. p. 125 –
This compound was prepared from compound 2 (0.22 g,
◦
26 C (from ethanol). – IR (KBr): ν = 3106, 2255, 1699,
0
0
.001 mol) and 3-benzyl-2-thiohydantoin (5c) (0.21 g,
−1
1
612 cm . – H NMR ([D ]-DMSO): δ = 4.16 (s, 2H,
6
◦
.001 mol), 7 h, 65% yield (0.23 g). – M. p. > 350 C. –
CH ), 7.39 (ddd, 1H, J = 1.5, 6.8, 7.2 Hz, 5’-H), 7.43 (ddd,
2
−1
IR (KBr): ν = 3232, 1738, 1673, 1618, 1514, 1504 cm
.
1
7
4
1
H, J = 1.5, 6.8, 7.2 Hz, 6’-H), 7.70 (dd, 1H, J = 1.5, 6.8 Hz,
1
–
7
6
8
H NMR ([D ]-DMSO): δ = 5.14 (s, 2H, CH ), 7.27 –
6
2
’-H), 7.85 (s, 1H, 2’-H), 8.25 (dd, 1H, J = 1.5,6.8 Hz,
.40 (m, 6H, Ph, 5’-H), 7.52 (ddd, 1H, J = 1.1, 7.2, 8.3 Hz,
’-H), 7.62 (dd, 1H, J = 1.1, 8.3 Hz, 7’-H), 8.22 (s, 1H, 3-H),
+
’-H), 9.33 (s, 1H, CHO). – MS (EI): m/z = 184 (M ),
+
85 (MH ); HRMS: calcd. 184.0637; found 184.0642. –
.27 (dd, 1H, J = 0.8, 8.38 Hz, 4’-H), 13.04 (s, 1H, NH). –
C H N O (184.20): calcd. C 71.73, H 4.38, N 15.21; found
C 71.51, H 4.69, N 15.13.
1
1
8
2
+
MS (EI): m/z = 359 (M ); HRMS calcd. 359.0728, found
3
59.0738. – C H N O S (359.41): calcd. C 66.84, H 3.65,
20 13 3 2
N 11.69; found C 67.07, H 3.71, N 11.48.
General procedure for the preparation of aplysinopsin and
β-carboline thiohydantoin analogues (7a − f, 9a − c, 11)
2-Phenyl-1,5-dioxo-2,3,5,6-tetrahydro-1H-imidazo–
Compound 2 (1 mmol) and the nucleophile 5a – f, 8, 10
were dissolved in a mixture of of acetic acid (10 ml) and
sodium acetate (0.2 g), and the mixture was heated under
reflux for 1 – 8.5 h. The solution was concentrated in vacuo,
the precipitate was collected by filtration, and washed with
water, ethanol and diethyl ether to give 7a – f, 9a – c, and 11.
[
1’,5’:1,6]pyrido[3,4-b]indole-3(2H)-thione (7d)
This compound was prepared from compound 2 (0.22 g,
.001 mol) and 3-phenyl-2-thiohydantoin (5d) (0.19 g,
0
0
◦
.001 mol), 4 h, 52% yield (0.18 g). – M. p. > 350 C. – IR
−1
1
(
KBr): ν = 1738, 1673, 1617, 1502 cm . – H NMR ([D ]-
6
DMSO): δ = 7.35 (ddd, 1H, J = 1.1, 6.8, 7.2 Hz, 5’-H),
7
7
4
.44 – 7.61 (m, 6H, Ph, 6’-H), 7.64 (dd, 1H, J = 1.1, 8.3 Hz,
’-H), 8.26 (s, 1H, 3-H), 8.30 (dd, 1H, J = 1.1, 6.8 Hz,
’-H), 13.06 (s, 1H, NH). – MS (EI): m/z = 345 (M ). –
1
,5-Dioxo-2,3,5,6-tetrahydro-1H-imidazo[1’,5’:1,6]pyr-
ido[3,4-b]indole-3(2H)-thione (7a)
+
This compound was prepared from compound 2 (0.22 g, C H N O S (345.38): calcd. C 66.08, H 3.21, N 12.17;
1
9
11
3
2
0
.001 mol) and 2-thiohydantoin (5a) (0.12 g, 0.001 mol), found C 66.34, H 3.32, N 12.42.
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R. Jak sˇ e et al. · Synthesis and Transformations of Ethyl 3-Formyl-1H-indole-2-carboxylate
417
+
2
-(4-Methylphenyl)-1,5-dioxo-2,3,5,6-tetrahydro-1H-imid-
137.5, 161.3, 167.5, 194.3. – MS (EI): m/z = 408 (M ), 409
(MH ); HRMS calcd. 376.0882; found 376.0890.
+
azo[1’,5’:1,6]pyrido-[3,4-b]indole-3(2H)-thione (7e)
This compound was prepared from compound 2 (0.22 g, Ethyl 3-[(Z)-(4-imino-2-oxothiazolidin-5-ylidene)methyl]-
.001 mol) and 3-(4-methylphenyl)-2-thiohydantoin (5e) 1H-indole-2-carboxylate (9c)
0
(
0.21 g, 0.001 mol), 8 h, 20% yield (0.07 g). – M. p. >
This compound was prepared from compound 2 (0.22 g,
.001 mol) and 4-imino-2-oxo-1,3-thiazolidine (8c) (0.12 g,
◦
3
1
3
50 C. – IR (KBr): ν = 1720, 1709, 1670, 1629, 1575,
0
0
−1
+
518 cm . – MS (EI): m/z = 359 (M ); HRMS: calcd
◦
.001 mol), 8.5 h, 67% yield (0.21 g). – M. p. 215 – 219 C.
59.0728, found 359.0740. – C H N O S (359.41): calcd.
20
13
3
2
−1
–
IR (KBr): ν = 3306, 3135, 1691, 1641, 1603 cm . –
C 66.84, H 3.65, N 11.69; found C 66.75, H 3.66, N 11.55.
1
H NMR ([D ]-DMSO): δ = 1.35 (t, 3H, J = 7.1 Hz, CH ),
6
3
4
8
.38 (q, 2H, J = 7.1 Hz, CH ), 7.20 (ddd,1H, J = 1.1, 7.2,
2
2
-(3,4-Dichlorophenyl)-1,5-dioxo-2,3,5,6-tetrahydro-1H-
.3 Hz, 5’-H), 7.37 (ddd,1H, J = 1.1, 7.2, 8.3 Hz, 6’-H), 7.55
imidazo[1’,5’:1,6]-pyrido[3,4-b]indole-3(2H)-thione (7f)
(dd, 1H, J = 1.1, 8.3 Hz, 7’-H), 7.77 (dd, 1H, J = 1.1, 8.3 Hz,
4
1
6
’-H), 8.21 (s, 1H, 2-H), 8.92 (s, 1H, NH), 9.24 (s, 1H, NH),
2.37 (s, 1H, NH). – C NMR ([D6]-DMSO): δ = 15.0,
1.8, 114.2, 117.0, 121.6, 122.6, 124.8, 124.9, 126.3, 126.8,
This compound was prepared from compound 2 (0.22 g,
.001 mol) and 3-(3,4-dichlorophenyl)-2-thiohydantoin (5f)
0.14 g, 0.001 mol), 6 h, 36% yield (0.15 g). – M. p. >
1
3
0
(
3
1
4
◦
137.2, 137.4, 161.6, 176.2, 180.9. – MS (EI): m/z = 315
(M ). – C15H13N3O3S (315.35): calcd. C 57.13, H 4.16,
N 13.33; found C 57.19, H 4.18, N 13.09.
50 C. – IR (KBr): ν = 1736, 1673, 1614, 1575, 1502,
+
−1
+
474 cm . – MS (EI): m/z = 413 (M ); HRMS calcd.
12.9792, found 412.9806. – C H N O SCl ×1/3H O
19
9
3
2
2
2
(
414.27): calcd. C 54.30, H 2.32, N 10.00; found C 54.47,
Ethyl 3-[(4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)yl-
idene)methyl]-1H-indole-2-carboxylate (11)
H 2.59, N 9.78.
This compound was prepared from compound 2 (0.22 g,
.001 mol) and 2-thiobarbituric acid (10) (0.14 g, 0.001 mol),
Ethyl 3-[(Z)-(4-oxo-2-thioxothiazolidin-5-yliden)methyl]-
0
1
1
H-indole-2-carboxylate (9a)
◦
h, 69% yield (0.24 g). – M. p. 285 C (EtOH, decomp.).
−1
This compound was prepared from compound 2 (0.22 g, – IR (KBr): ν = 3300, 1684, 1562, 1534, 1503 cm . –
1
0
.001 mol) and rhodanine (8a) (0.13 g, 0.001 mol), 8 h, 60%
H NMR ([D6]-DMSO): δ = 1.35 (t, 3H, J = 6.8 Hz, CH3),
◦
yield (0.20 g). – M. p. 293 – 295 C (EtOH). – IR (KBr): ν = 4.38 (q, 2H, J = 6.8 Hz, CH2), 7.19 (ddd, 1H, J = 1.1, 7.2,
−
312, 1682, 1599, 1572 cm . – H NMR ([D ]-DMSO): 8.3 Hz, 5’-H), 7.35 (ddd, 1H, J = 1.1, 7.2, 7.9 Hz, 6’-H),
6
1
1
3
δ = 1.38 (t, 3H, J = 7.1 Hz, CH ), 4.43 (q, 2H, J = 7.1 Hz, 7.42 (dd, 1H, J = 1.1, 7.9 Hz, 7’-H), 7.55 (dd, 1H, J = 1.1,
3
CH ), 7.29 (ddd, 1H, J = 1.1, 7.2, 8.3 Hz, 5’-H), 7.41 (ddd, 8.3 Hz, 4’-H), 8.88 (s, 1H, 2-H), 12.24 (s, 1H, NH), 12.33
2
1
3
1
7
1
H, J = 1.1, 7.2, 8.3 Hz, 6’-H), 7.58 (dd, 1H, J = 1.1, 8.3 Hz, (s, 1H, NH), 12.87 (s, 1H, NH). – C NMR ([D6]-DMSO):
’-H), 7.81 (dd, 1H, J = 1.1, 8.3 Hz, 4’-H), 8.35 (s, 1H, 2-H), δ = 14.9, 62.3, 114.1, 116.3, 117.8, 122.7, 124.4, 126.1,
2.69 (s, 1H, NH), 13.69 (s, 1H, NH). – 1 C NMR ([D6]- 126.7, 131.5, 137.0, 148.6, 160.1, 161.4, 162.6, 179.4. –
3
+
DMSO): δ = 15.0, 62.2, 114.4, 115.4, 122.3, 122.5, 124.6, MS (EI): m/z = 343 (M ). – C16H13N3O4S (343.36): calcd.
26.4, 126.6, 128.0, 128.4, 137.4, 161.3, 169.9, 196.0. – C 55.97, H 3.82, N 12.24; found C 55.72, H 4.05, N 12.39.
MS (EI): m/z = 332 (M )M; HRMS calcd. 332.0289; found
32.0298.
1
+
General procedure for the preparation of azomethine imines
14, 15)
3
(
Ethyl 3-[(Z)-(4-oxo-3-phenyl-2-thioxothiazolidin-5-yliden)-
methyl]-1H-indole-2-carboxylate (9b)
Compounds (2, 12) (1 mmol) and 5,5-dimethylpyrazo-
lidin-3-one (13) (0.11 g, 1 mmol) were dissolved in ethanol
(
(
10 ml), a catalytic amount of trifluoroacetic acid was added
5 drops) and the mixture was either left to react at r. t. or
This compound was prepared from compound 2 (0.22 g,
.001 mol) and phenylrhodanine (8b) (0.21 g, 0.001 mol),
0
5
heated under reflux for 2 h. The volatile components were
evaporated in vacuo, water (5 ml) was added, the precipitate
was collected by filtration and washed with ethanol and di-
ethyl ether.
◦
h, 60% yield (0.35 g). – M. p. 251 – 253 C. – IR (KBr):
−1
ν = 3306, 2988, 1712, 1682, 1591, 1573, 1495 cm . –
1
H NMR ([D ]-DMSO): δ = 1.38 (t, 3H, J = 7.1 Hz, CH ),
6
3
4
6
1
4
.41 (q, 2H, J = 7.1 Hz, CH ), 7.34 (ddd, 1H, J = 1.1,
2
.8, 8.3 Hz, 5’-H), 7.42 – 7.58 (m, 2H, Ph, 6’-H), 7.62 (dd,
H, J = 1.1, 8.3 Hz, 7’-H), 7.92 (dd, 1H, J = 1.1, 8.3 Hz,
’-H), 8.53 (s, 1H, 2-H), 12.76 (s, 1H, NH). – 13C NMR
5
,5-Dimethyl-1-[2-(ethoxycarbonyl)-1H-indol-3-yl]-3-pyr-
azolidinone-(1Z)-azomethine imine (14)
(
1
[D6]-DMSO): δ = 15.0, 62.2, 114.6, 115.4, 122.4, 122.7,
This compound was prepared from compound 2 (0.22 g,
23.9, 124.6, 126.7, 128.7, 129.1, 129.6, 130.2, 130.3, 136.3, 0.001 mol), reflux 2 h, 52% yield (0.16 g). – M. p. 115 –
Unauthenticated
Download Date | 3/10/16 12:10 PM

4
18
R. Jak sˇ e et al. · Synthesis and Transformations of Ethyl 3-Formyl-1H-indole-2-carboxylate
◦
18 C. – IR (KBr): ν = 2984, 1713, 1650, 1594, 1506, direct methods using SIR97 [28]. The positions of hy-
1
1
3
4
8
−1
1
459, 1411 cm – H NMR ([D ]-DMSO): δ = 1.40 (t, drogen atoms were obtained from the difference Fourier
6
H, J = 7.1 Hz, CH ), 1.70 (s, 6H, CH ), 2.71 (s, 2H, CH ), maps. We employed full-matrix least-squares refinements
3
3
2
.43 (q, 2H, J = 7.1 Hz, CH ), 7.20 (ddd, 1H, J = 0.8, 7.1, on F values with anisotropic displacement factors for all
2
.3 Hz, 5’-H), 7.37 (ddd, 1H, J = 1.1, 7.1, 8.3 Hz, 6’-H), 7.54 non-hydrogen atoms and with isotropic displacement fac-
(
1
1 dd, H, J = 0.8, 8.3 Hz, 7’-H), 8.33 (s, 1H, 2-H), 8.51 (dd, tors for hydrogen atoms using Xtal3.4 [29]. In the final cy-
H, J = 1.1, 8.3 Hz, 4’-H), 12.78 (s, 1H, NH). – 13C NMR cle of the refinement we used 1722 reflections (included
(
[D6]-DMSO): δ = 15.0, 29.0, 45.4, 62.6, 73.3, 111.5, 113.8, were those ”less than” reflections for which Fc was larger
1
–
3
22.3, 125.2, 126.5, 127.0, 130.3, 131.3, 137.5, 161.4, 180.5. than Fo) and 159 parameters. The resulting crystal data
+
MS (EI): m/z = 313 (M ); HRMS calcd. 313.1426, found and details concerning data collection and refinement are
13.1420. – C H N O (313.36): calcd. C 67.92, H 4.18, quoted in Table 1. An ORTEP [30] drawing of the content
1
7 19 3 3
N 15.84; found C 68.03, H 4.23, N 15.79.
of the asymmetric unit showing the atom-labeling scheme
is presented in Fig. 2. The crystallographic data for com-
pound 4 have been deposited with the Cambridge Crystal-
lographic Data Center with the deposition number: CCDC
5
,5-Dimethyl-1-[1H-indol-3-yl]-3-pyrazolidinone-(1Z)-
azomethine imine (15)
2
94093. These data can be obtained, free of charge via
This compound was prepared from 3-formylindole (12)
http://www.ccdc.cam.ac.uk/conts/retrieving.html.
(
1
1
0.15 g, 0.001 mol), r. t. 24 h, 82% yield (0.20 g). – M. p.
◦ ◦
73 – 175 C, 290 – 295 C. – IR (KBr): ν = 1637, 1581,
−1
1
497, 1451, 1410, 1369 cm
– H NMR ([D ]-DMSO):
6
Acknowledgements
δ = 1.66 (s, 6H, CH ), 2.56 (s, 2H, CH ), 7.22 (ddd, 1H,
3
2
J = 1.5, 6.8, 7.2 Hz, 5’-H), 7.25 (ddd, 1H, J = 1.5, 6.8,
The financial support from the Slovenian Research
Agency through grants P0-0502-0103, P1-0179, and J1-
6
with thanks the financial support from the pharmaceutical
companies Krka d.d. (Novo mesto, Slovenia) and Lek d.d.,
a new Sandoz Company (Ljubljana, Slovenia). The crystal-
lographic data were collected on the Nonius Kappa CCD
diffractometer in the Laboratory of Inorganic Chemistry,
Faculty of Chemistry and Chemical Technology, University
7
1
.2 Hz, 6’-H), 7.51 (dd, 1H, J = 1.5, 6.8 Hz, 7’-H), 8.01 (s,
H, 2-H), 8.15 (dd, 1H, J = 1.5, 6.8 Hz, 4’-H), 8.71 (d, 1H,
689-0103-04 is gratefully acknowledged. We acknowledge
J = 3.0 Hz, 2’-H), 12.11 (s, 1H, NH). – MS (EI): m/z = 241
+
+
(
–
M ), 242 (MH ); HRMS calcd. 241.1215, found 241.1222.
C H N O (241.29): calcd. C 69.69, H 6.27, N 17.41;
1
15
4 3
found C 69.37, H 6.38, N 17.20.
X-ray crystal structure analysis
Diffraction data for compound 4 were collected on a No- of Ljubljana, Slovenia. We acknowledge with thanks the fi-
nius Kappa CCD diffractometer with graphite monochro- nancial contribution of the Ministry of Education, Science
mated Mo-Kα radiation. The data were processed using and Sport, Republic of Slovenia through grants X-2000 and
the DENZO [27] program. The structure was solved by PS-511-103.
[
1] For recent reviews see: a) B. Stanovnik, J. Svete,
Mini-Reviews in Organic Chemistry 2, 211 (2005);
b) J. Svete, J. Heterocycl. Chem. 42, 361 (2005);
c) B. Stanovnik, J. Svete, Chem. Rev. 104, 2433
thesis 1087 (2005); e) U. Gro sˇ elj, D. Bevk, R. Jak sˇ e,
A. Meden, B. Stanovnik, J. Svete, Tetrahedron: Asym-
metry 16, 2187 (2005).
[3] a) S. Pirc, D. Bevk, S. Goli cˇ Grdadolnik, J. Svete,
ARKIVOC (xiv), 37 (2003); b) J. Westman, R. Lundin,
(2004); d) J. Svete, Monatsh. Chem. 135, 629 (2004);
ˇ
e) J. Svete, J. Heterocycl. Chem. 39, 437 (2002);
f) B. Stanovnik, J. Svete, Synlett 1077 (2000);
g) B. Stanovnik, J. Svete, Targets in Heterocyclic Sys-
tems 4, 105 (2000); h) B. Stanovnik, J. Heterocycl.
Chem. 36, 1581 (1999).
Synthesis 1025 (2003); c) P. Ceba sˇ ek, J. Wagger,
D. Bevk, R. Jak sˇ e, J. Svete, B. Stanovnik, J. Comb.
ˇ
Chem. 6, 356 (2004); d) P. Ceba sˇ ek, D. Bevk,
S. Pirc, B. Stanovnik, J. Svete, J. Comb. Chem. 7, 95
(2005).
[
2] For recent publications see: a) U. Gro sˇ elj, D. Bevk,
R. Jak sˇ e, A. Meden, S. Pirc, S. Re cˇ nik, B. Stanovnik,
J. Svete, Tetrahedron: Asymmetry 15, 2367 (2004);
b) U. Gro sˇ elj, D. Bevk, R. Jak sˇ e, S. Re cˇ nik, A. Meden,
B. Stanovnik, J. Svete, Tetrahedron 61, 3991 (2005);
c) L. Pezdirc, V. Jovanovski, D. Bevk, R. Jak sˇ e,
S. Pirc, A. Meden, B. Stanovnik, J. Svete, Tetrahedron
[4] a) L. Seli cˇ , R. Jak sˇ e, K. Lampi cˇ , L. Goli cˇ , S. Goli cˇ
Grdadolnik, B. Stanovnik, Helv. Chim. Acta 83, 2802
(2000); b) R. Jak sˇ e, S. Re cˇ nik, J. Svete, A. Golobi cˇ ,
L. Goli cˇ , B. Stanovnik, Tetrahedron 57, 8395 (2001);
c) U. Gro sˇ elj, A. Drobni cˇ , S. Re cˇ nik, J. Svete,
B. Stanovnik, A. Golobi cˇ , N. Lah, I. Leban, A. Meden,
S. Goli cˇ Grdadolnik, Helv. Chim. Acta 84, 3403
(2001); d) L. Seli cˇ , S. Re cˇ nik, B. Stanovnik, Heterocy-
cles 57, 577 (2002); e) R. Jak sˇ e, V. Kro sˇ elj, S. Re cˇ nik,
6
1, 3977 (2005); d) U. Gro sˇ elj, D. Bevk, R. Jak sˇ e,
A. Meden, S. Re cˇ nik, B. Stanovnik, J. Svete, Syn-
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R. Jak sˇ e et al. · Synthesis and Transformations of Ethyl 3-Formyl-1H-indole-2-carboxylate
419
G. Sor sˇ ak, J. Svete, B. Stanovnik, S. Goli cˇ Grdadol-
nik, Z. Naturforsch. 57b, 453 (2002); f) L. Seli cˇ ,
B. Stanovnik, Tetrahedron 57, 3159 (2001).
[18] G. Delmas, P. Deplat, J. M. Chezal, O. Chavignon,
A. Gueiffier, Y. Blache, J. L. Chabard, G. Dauphin, J. C.
Teulade, Heterocycles 43, 1229 (1996).
[
5] R. Jak sˇ e, J. Svete, B. Stanovnik, A. Golobi cˇ , Tetrahe-
[19] O. Chavignon, J. C. Teulade, D. Roche, M. Made-
sclaire, Y. Blache, A. Gueiffier, J. L. Chabard,
G. Dauphin, J. Org. Chem. 59, 6413 (1994).
[20] C. Braestrup, M. C. P. Nielsen, C. E. Olsen, Proc. Natl.
Acad. Sci. USA 77, 2288 (1980).
ˇ
dron 60, 4601 (2004); b) Z. Casar, D. Bevk, J. Svete,
B. Stanovnik, Tetrahedron 61, 7508 (2005).
6] J. Wagger, D. Bevk, A. Meden, J. Svete, B. Stanovnik,
Helv. Chim. Acta 89, 240 (2006).
7] R. Kazlaukas, P. T. Murphy, R. J. Quinn, R. J. Wells,
Tetrahedron Lett. 1, 61 (1977).
8] J. T. Baker, R. J. Wells, in J. T. Beal (ed.); Natural
Products as Medicinal Agents, p. 299, Reinhardt Hip-
pokrates Verlag, Stuttgart (1981).
[
[
[
[21] C. Braestrup, M. C. P. Nielsen, J. Neurochem. 37, 333
(1981).
[22] C. Braestrup, M. Nielsen, “β-Carbolines and Benzo-
diazepine Receptor” in F. Bloom, J. Barchas, M. San-
dler, E. Usdin (eds):, “β-Carbolines and Tetrahydroiso-
quinolines”, p. 215 – 226. A. R. Liss Inc., New York
(1982).
[23] F. Brana, M. Garrido, M. L. Lopez Rodriguez,
P. Miguel, M. J. Morcillo, A. Riano, J. Heterocycl.
Chem. 27, 703 (1990).
[9] K. H. Hollenbeak, F. J. Schmitz, Lloydia 10, 479
(
1977).
10] a) P. Djura, D. J. Faulkner, J. Org. Chem. 45, 735
1980); b) S. Aoki, Y. Ye, K. Higuchi, A. Takashima,
[
(
Y. Tanaka, I. Kitagawa, M. Kobayashi, Chem. Pharm.
Bull. 49, 1372 (2001).
[24] M. F. Brana, M. Garrido, M. L. Lopez, P. de Miguel,
A. Riano, Synth. Commun. 20, 1793 (1990).
[25] E. H. P. Young, J. Chem. Soc. 3493 (1958).
[
[
[
11] G. Guella, I. Mancini, H. Zibrowius, F. Pietra, Helv.
Chim. Acta 71, 773 (1988).
12] G. Guella, I. Mancini, H. Zibrowius, F. Pietra, Helv.
Chim. Acta 72, 1444 (1989).
[26] A. C. Shabica, E. E. Howe, J. B. Ziegler, M. Tishler, J.
Am. Chem. Soc. 68, 1156 (1946).
[27] Z. Otwinowski, W. Minor. Methods Enzymol. 276, 307
(1997).
[28] A. Altomare, M. C. Burla, M. Camalli, G. Cascarano,
C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni,
G. Polidori, R. Spagna, J. Appl. Crystallogr. 32, 115
(1999).
13] A. Dalkafouki, J. Ardisson, N. Kunesch, L. Lacombe,
J. E. Poisson, Tetrahedron Lett. 39, 5325 (1991).
14] P. Djura, D. J. Faulkner, J. Org. Chem. 45, 735 (1979).
15] P. Molina, M. J. Vilaplana, Synthesis 1197 (1994).
16] P. Molina, P. Almendros, P. M. Fresneda, Tetrahedron
[
[
[
5
0, 2241 (1994).
[
17] J. M. Chezal, G. Delmas, S. Mavel, H. Elakmaoui,
J. Metin, A. Diez, Y. Blache, A. Gueiffier, M. Rubi-
ralta, J. C. Teulade, O. Chavignon, J. Org. Chem. 62,
[29] S. R. Hall, G. S. D. King, J. M. Stewart, The Xtal3.4
User’s Manual, University of Western Australia, Lamb,
Perth (1995).
4
085 (1997).
[30] L. J. Farrugia, J. Appl. Crystallogr. 30, 565 (1997).
Unauthenticated
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