Convenient synthesis of 1-aryl-9H-β-carboline-3-carbaldehydes and their transformation into dihydropyrimidinone derivatives by Biginelli reaction

Article abstract of DOI:10.1016/j.tet.2014.06.073

In the present work, a practical synthesis of 1-aryl-β-carboline-3-carbaldehydes as versatile building blocks and their application in Biginelli reaction is reported. The starting material of the four-step synthesis is racemic tryptophan methyl ester. The procedure involves a Pictet-Spengler cyclization, a dehydrogenation, an ester reduction, and an alcohol oxidation step. The β-carboline-3-carbaldehydes were further transformed using a Biginelli reaction into derivatives containing a pharmacologically significant dihydropyrimidine ring at position-3.

Full text of DOI:10.1016/j.tet.2014.06.073

Tetrahedron xxx (2014) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of 1-aryl-9H-b-carboline-3-carbaldehydes
and their transformation into dihydropyrimidinone derivatives
by Biginelli reaction
ꢀ
a
,
b
,
*
, Andr aꢀ s Dancs oꢀ , D aꢀ vid Frigyes , Bal aꢀ zs Volk ,*,
a
a
a
P eꢀ ter Abr aꢀ nyi-Balogh
b
a
Gy o€ rgy Keglevich , M aꢀ ty aꢀ s Milen
Egis Pharmaceuticals Plc., Chemical Research Division, PO Box 100, H-1475 Budapest, Hungary
a
b
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, H-1521 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present work, a practical synthesis of 1-aryl-b-carboline-3-carbaldehydes as versatile building
Received 13 April 2014
Received in revised form 31 May 2014
Accepted 17 June 2014
Available online xxx
blocks and their application in Biginelli reaction is reported. The starting material of the four-step
synthesis is racemic tryptophan methyl ester. The procedure involves a PicteteSpengler cyclization,
a dehydrogenation, an ester reduction, and an alcohol oxidation step. The b-carboline-3-carbaldehydes
were further transformed using a Biginelli reaction into derivatives containing a pharmacologically
significant dihydropyrimidine ring at position-3.
Keywords:
Nitrogen heterocycles
Ó 2014 Elsevier Ltd. All rights reserved.
b
-Carbolines
Dihydropyrimidines
Biginelli reaction
O
1. Introduction
N
O
O
The
synthetic indole alkaloids.
counterparts such as dihydro-
bolines can be found in plants, mammalians, marine invertebrates,
b-carbolines constitute an important class of natural and
N
1
O
O
b
b
-Carbolines and their saturated
-carbolines and tetrahydro- -car-
N
O
H
b
N
O
N
H
2
foods, drinks, and fruits. Both simple and complicated b-carboline
O
derivatives exhibit significant biological and pharmaceutical ac-
1
2
3
4
5
9
tivities including antimicrobial, antimalarial, antithrombotic,
parasiticidal,6 anti-HIV,7 anti-Alzheimer,8 and antifungal effects.
Scheme 1.
Moreover, tadalafil (1, Scheme 1) is a commercially available drug
for the treatment of erectile dysfunction.10 Another important
containing a dihydropyrimidinone druglike scaffold at the C-3 po-
sition. A retrosynthetic analysis of the planned heterocyclic com-
pounds 3 is outlined in Scheme 2. The final step was envisaged as
a Biginelli reaction of 1-aryl-9H-b-carboline-3-carbaldehydes 4.
Only a few examples of similar aldehyde derivatives are known in
the literature: Cao et al. reported the synthesis and study of the
representative of the
b-carboline family is the anxiolytic drug
abecarnil (2), a partial agonist acting selectively at the benzodiaz-
11
epine site of the
A
g-aminobutyric acid A (GABA ) receptor.
In recent years the synthesis and biological activity of 1,3-
12
disubstituted
have previously reported the synthesis of novel fused tetracyclic
carboline derivatives such as oxadiazolo-pyridoindoles, triazolo-
b-carbolines have been extensively studied. We
b
-
in vitro cytotoxic activity of some 9-substituted 1-(3,4,5-
14
trimethoxyphenyl)-
b
-carboline-3-carbaldehydes, but their ap-
13
pyridoindoles, and azetopyridoindoles. In the present paper we
focus on the synthesis of new 1,3-disubstituted -carbolines
plication in Biginelli reaction is not reported. We planned to elab-
orate an improved process for the synthesis of aldehydes 4 and to
extend it to various 1-aryl groups, starting from esters 5 by de-
hydration of the C-ring and subsequent transformation of the ester
group to a formyl moiety. Synthesis of 5 was anticipated by the
esterification of racemic tryptophan (6) followed by the
b
*
Corresponding authors. Tel.: þ36 1 8035874; fax: þ36 1 8035613; e-mail ad-
ꢀ
dresses: abpeter@gmail.com (P. Abranyi-Balogh), volk.balazs@egis.hu (B. Volk).
ꢀ
http://dx.doi.org/10.1016/j.tet.2014.06.073
0
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
ꢀ
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2
P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
O
NH
HN
H CO
HO
3
R2
R1
O
O
O
N
N
NH
Ar
NH
2
O
N
H
N
H
N
H
N
H
Ar
Ar
3
4
5
6
Scheme 2.
PicteteSpengler reaction of racemic tryptophan methyl ester with
resolution mass spectrometry. Among the synthesized b-carboline
the appropriate aromatic aldehydes.
derivatives alcohols 9a,b,d,e and all the aldehydes (4aef) are new.
Table 1
2
. Results and discussion
Yields of the reaction sequence leading to 1-aryl-9H-
b-carboline-3-carbaldehydes (4)
Entry
Ar
Yield of Yield of Yield of Yield of Overall
The starting material of the synthesis of 1-aryl-b-carboline-3-
5
(%)
8 (%)
9 (%)
4 (%)
yield
carbaldehydes (4) was racemic tryptophan (6). This compound
was esterified using the literature method (thionyl chloride,
methanol, room temperature, 24 h) and the ester (7) was isolated in
7
/4 (%)
1
2
3
4
5
6
a
b
c
d
e
f
Ph
96
66
74
68
77
78
83
78
81
74
98
96
95
95
93
97
79
86
87
60
69
84
57
43
51
30
45
47
6 4
4-MeOeC H
4-CleC
4-O NeC H
1,3-Benzodioxol-5-yl 86
2-Thienyl 78
8
9% yield.15 This intermediate was subjected to a PicteteSpengler
6 4
H
reaction with six different aromatic aldehydes (Scheme 3). The
2
6 4
catalyst was trifluoroacetic acid and dichloromethane was used as
the solvent.10a,12f
The reaction was carried out at room temperature
in order to avoid possible side products and the decomposition
caused by heating of the solution. The tetrahydro- -carboline esters
5) were prepared in good to excellent yields (66e96%) as di-
astereomeric mixtures. The next step of the synthesis was the
aromatization of the C ring of the -carboline skeleton. Three
methods found in the literature were tried. The reaction with ele-
b
(
The aldehyde key intermediates (4) were successfully reacted in
a Biginelli reaction (Scheme 4) with urea (10) and four different
dioxo compounds [pentane-2,4-dione (11a), ethyl acetoacetate
(11b), ethyl isobutyrylacetate (11c), and ethyl benzoylacetate
b
-
b
mental sulfur in xylene1
2dee,16
or with 10% Pd/C in xylene pro-
17
2 2
(11d)]. The reaction was catalyzed by NiCl $6H O and the solvent
duced the aromatic ester in a yield of 50e60%. The best reagent was
was boiling ethanol containing a catalytic amount of concd aq hy-
18
22
2
-iodoxybenzoic acid (IBX) that gave 74e83% yield. Although
some of lithium containing reagents (LiAlH , LiBH ) are known for
and a patent applica-
-activated NaBH that
drochloric acid solution. The reaction did not take place when N-
2
3
bromosuccinimide was applied as the catalyst. The reactions
were followed by TLC and HPLCeMS until the starting material
disappeared or the conversion was measured constant. The isolated
2-oxo-1,2,3,4-tetrahydropyrimidine (12aev) derivatives have not
been described before.
4
4
1
4c,17,19
the reduction of 8 esters to alcohols 9,
2
0
tion mentions NaBH
4
too, we applied CaCl
2
4
21
has been used successfully in our laboratory. The solvent was
a mixture of dichloromethane and ethanol at room temperature.
The products 9 were isolated in almost quantitative yields
Only a few target compounds were prepared in a yield exceeding
80%, in most cases the Biginelli products were obtained in medium
yields (ca. 40e75%). A possible explanation for the moderate yield is
a side-reaction, the product of which was successfully isolated in
47% yield in one case when 4c was treated with ethyl benzoylace-
tate (11d) and urea (Scheme 5). Obviously, aldehyde 4c and 11d
gave a Knoevenagel-type by-product [13, (E) isomer], which latter is
unable to react with urea to give target compound 12l.
(
93e98%). Alcohols 9 were oxidized by using activated manganese
17
dioxide (MnO
2
)
to give the expected aldehydes 4 in a yield of
6
0e87%. Accordingly the synthesis of the expected key in-
termediates 4 was accomplished in a total yield of 30e57% (Table 1).
The reactions were followed by thin layer chromatography (TLC)
and HPLCeMS. The identification and characterization of the sub-
strates was performed with IR and NMR spectroscopy and high-
Cl
Cl
Cl
Cl
Scheme 3.
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P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
3
Scheme 4.
Scheme 5.
3
. Conclusions
dimensions of 2.1ꢀ50 mm. A gradient elution of 5 min was used at
a flow rate of 0.5 mL/min [initial: 10% acetonitrile (ACN), 0.01 M
ammonium acetate (AmAc); 5 min: 90% ACN, 0.01 M AmAc]. The
reactions were monitored by analytical TLC on silica gel 60 PF254
and LCeMS chromatography. Analytical samples of new com-
pounds were obtained by crystallization.
A four-step versatile synthesis of new 1-aryl-b-carboline-3-
carbaldehydes is reported starting from the easily available race-
mic tryptophan methyl ester through a PicteteSpengler cyclization
with an aromatic aldehyde as the first step. Among the known
possibilities for the dehydrogenation of the tetrahydro-b-carboline
esters thus obtained, the application of IBX provided the highest
yields in our hands. For the reduction of the aromatic ester function
4
.2. General procedure for the synthesis of tetrahydro-
carboline carboxylate derivatives. Preparation of compounds
aef
b-
to the corresponding alcohol, the use of Ca(BH
from CaCl and NaBH proved to be a versatile method and the
oxidation to the corresponding carbaldehydes was achieved by
using activated MnO . Due to the applicability of the formyl moiety
4 2
) generated in situ
5
2
4
Racemic tryptophan methyl ester (7) (41.3 mmol, 9.0 g) and the
2
appropriate aldehyde (1.1 equiv, 45.4 mmol, 4.6 mL of
benzaldehyde, 5.5 mL of 4-methoxybenzaldehyde, 6.4 g of 4-
chlorobenzaldehyde, 6.9
thiophene-2-carbaldehyde, 6.8
carbaldehyde) were dissolved in dichloromethane (100 mL) and
cooled to 0 C with an ice bath. To this solution was added dropwise
TFA (6.4 mL), and the mixture was stirred at 26 C until the starting
material disappeared. The reaction mixture was then basified with
in various chemical reactions, these new aldehydes are versatile
intermediates in organic and medicinal chemistry. In the present
work the aldehydes were taken into a three-component Biginelli
g
of 4-nitrobenzaldehyde, 4.2
g of
g
of benzo[d][1,3]dioxol-5-
reaction with urea and
b-keto esters. Accordingly, a series of new,
potentially bioactive -carbolinyl-dihydropyrimidinone derivatives
b
ꢁ
were synthesized. In one case a Knoevenagel-type side-reaction
was observed.
ꢁ
3
10% NaHCO (150 mL) and extracted with dichloromethane
(
2ꢀ30 mL). The organic layer was washed with water (30 mL), dried
4
4
. Experimental section
4
over MgSO , filtered, and evaporated under reduced pressure. The
residue was purified by recrystallization to give the esters 5 as di-
astereomers. Spectroscopic data of the products are in accord with
the literature (5a,
.1. General
2
4a
24b
24c
24b
24d
24e
5b,
5c,
5d,
5e,
5f ).
Commercially available reagents were purchased from
SigmaeAldrich and were used without further purification. All
melting points were measured with a KoflereBo e€ tius micro-
4.3. General procedure for the dehydrogenation of tetrahy-
dro- -carboline carboxylate derivatives. Preparation of
carboline carboxylates 8aef
1
13
apparatus and were not corrected. H and C NMR spectra were
recorded with a Varian Unity Inova 500 spectrometer (500 and
b
b-
1
13
1
25 MHz for H and C NMR spectra, respectively) or with a Bruker
1
13
Avance III spectrometer (400 and 100 MHz for H and C NMR
spectra, respectively). DMSO-d was used as the solvent and TMS
To a solution of tetrahydro-b-carboline carboxylate di-
6
astereomeric mixtures (5aef) [26.1 mmol, 8.0 g methyl-1-phenyl-
(5a), 8.8 g methyl-1-(4-methoxyphenyl)- (5b), 8.9 g methyl-1-(4-
chlorophenyl)- (5c), 9.2 g methyl-1-(4-nitrophenyl)- (5d), 9.1 g
methyl-1-(1,3-benzodioxol-5-yl)- (5e), 8.2 g methyl-1-thiophene-
was used as the internal standard. The FTIR spectra of KBr pellets or
neat samples were recorded with a Bruker Vector 22 spectrometer.
Mass spectra were recorded on a Bruker Maxis Impact Q-TOF
spectrometer coupled to a Dionex UltiMate 3000 RRLC (Rapid
Resolutions Liquid Chromatograph) system. The chromatographic
column used was a Waters Acquity BEH C18 column with
2-yl-2,3,4,9-tetrahydro-1H-
dichloromethane (100 mL) and acetonitrile (100 mL) at 26 C were
added TBAB (0.5 equiv, 13.1 mmol, 4.2 g) and IBX (2 equiv,
b
-carboline-3-carboxylate
(5f)]
in
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P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
ꢀ
4
5
2.2 mmol, 14.6 g). The reaction mixture was stirred until the
(C]), 133.7 (C]), 132.5 (C]), 131.4 (HC]), 130.9 (HC]), 124.0
(HC]), 123.1 (HC]), 121.1 (HC]), 120.2 (HC]), 113.8 (HC]), 113.0
starting material disappeared. The reaction mixture was diluted
with saturated Na (100 mL) and 25% aq NH (30 mL) and
extracted with dichloromethane/methanol 7:3 (3ꢀ100 mL). The
combined organic layers were dried (MgSO ), concentrated, and
the residue purified by flash chromatography (silica gel 60 PF254
using hexane/dichloromethane and dichloromethane/methanol as
the eluents to afford esters 8aef. Spectroscopic data of the products
are in accord with the literature (8a,b,d, 8c,
S
2 2
O
3
3
(HC]), 61.5 (CH
2
) ppm. HRMS calcd for C18
H
14
N
3
O
3
[MþH]þ
320.1030; found 320.1034.
4
)
4.4.4. [1-(1,3-Benzodioxol-5-yl)-9H-
b
-carbolin-3-yl]methanol
ꢁ
(9e). Yield: 5.39 g (93%), yellow crystals, mp 205e207 C (DMF/
ꢂ1
1
H
2
O). IR (KBr, cm ): 3154, 3090, 2905,1666,1502,1244,1041, 741. H
NMR (DMSO-d , 400 MHz):
11.37 (br s, 1H, NH), 8.25 (d, J¼7.8 Hz,
H, ArH), 8.11 (s,1H, ArH), 7.64e7.62 (m,1H, ArH), 7.57e7.51 (m, 3H,
ArH), 7.24(t, J¼7.4 Hz,1H, ArH), 7.14 (d, J¼8.5 Hz,1H, ArH), 6.14 (s, 2H,
OeCH
eO), 5.35 (t, J¼5.8 Hz, 1H, OH), 4.77 (d, J¼5.7 Hz, 2H,
6
CH ) ppm. C NMR (DMSO-d , 100 MHz): d 150.6 (C]), 147.7 [two
18
24a
25a
25b
8e,
8f ).
6
d
1
4
.4. General procedure for the synthesis of (
b-carbolin-3-yl)
methanol derivatives. Preparation of compounds 9aef
2
13
2
To a solution of
.5 g methyl-1-phenyl- (8a), 6.1 g methyl 1-(4-methoxyphenyl)-
8b), 6.1 g methyl 1-(4-chlorophenyl)- (8c), 6.3 g methyl 1-(4-
nitrophenyl)- (8d), 6.3 g methyl 1-(1,3-benzodioxol-5-yl)- (8e),
.6 methyl 1-(thiophene-2-yl)-9H- -carboline-3-carboxylate
8f)] and crushed CaCl (2 equiv, 36.4 mmol, 4.0 g) in dichloro-
b
-carboline carboxylate derivatives [18.2 mmol,
signals: 147.74 (OeC]), 147.70 (OeC])], 141.6 (C]), 140.5 (C]),
132.6 (C]),131.8 (C]),130.2 (C]),128.1 (HC]),122.5 (HC]),121.6
(HC]), 121.1 (C]), 119.5 (HC]), 112.5 (HC]), 110.0 (HC]), 108.7
5
(
2 2
(HC]),108.6 (HC]),101.4 (OeCH eO), 64.9 (CH ) ppm. HRMS calcd
5
(
g
b
for C19
H
15
N
2
O
3
[MþH]þ 319.1077; found 319.1093.
2
methane (100 mL) and ethanol (100 mL) NaBH
4
(5 equiv,
4.5. General procedure for the oxidation of (
methanol derivatives. Preparation of aldehydes 4aef
b-carbolin-3-yl)
ꢁ
9
0.9 mmol, 3.5 g) was added in small portions at 26 C. The reaction
mixture was stirred until the starting material disappeared, it was
then concentrated in vacuo and quenched with dichloromethane/
methanol (1:1, 250 mL). Then 1 M aq solution of hydrochloric acid
The (b-carbolin-3-yl)methanol derivative [15.9 mmol, 4.4 g
1-phenyl- (9a), 4.9 g 1-(4-methoxyphenyl)- (9b), 4.9 g 1-(4-
chlorophenyl)- (9c), 5.1 g 1-(4-nitrophenyl)- (9d), 5.1 g 1-(1,3-
(
80 mL) and 1 M NaOH (80 mL) were added. The mixture was
separated and extracted with dichloromethane/methanol 7:3
benzodioxol-5-yl)- (9e), 4.5 g [1-(thiophene-2-yl)-9H-b-carbo-
(
3ꢀ100 mL). The combined organic layers were dried over MgSO
4
,
line-3-yl]methanol (9f)] was suspended in dioxane (200 mL) and
activated manganese dioxide (10 equiv, 159.3 mmol, 13.9 g) was
added. The reaction mixture was refluxed until the starting mate-
rial disappeared. The suspension was filtered and concentrated at
reduced pressure. Pure products were obtained by recrystallization.
Compounds 4aef are new.
filtered, and concentrated. The crude product was purified by re-
crystallization. Spectroscopic data of products 9c and 9f are in ac-
cord with the literature.
2
5b
Alcohols 9a,b,d,e are new compounds
and they are characterized below.
4
.4.1. (1-Phenyl-9H-
b-carbolin-3-yl)methanol (9a). Yield: 4.90 g
ꢁ
ꢂ1
(
98%), white crystals, mp 176e177 C (i-PrOH). IR (KBr, cm ): 3266,
4.5.1. 1-Phenyl-9H-
b
-carbolin-3-carbaldehyde (4a). Yield 3.40
g
1
ꢁ
1
(
(
699, 1416, 1243, 1056, 734. H NMR (DMSO-d
br s, 1H, NH), 8.27e8.25 (m, 1H, ArH), 8.21 (s, 1H, ArH), 8.04e8.00
m, 2H, ArH), 7.67e7.65 (m, 1H, ArH), 7.59e7.56 (m, 2H, ArH),
6
, 500 MHz):
d
11.57
(79%), light brown crystals, mp 313e314 C (decomp., dioxane/
ꢂ1
1
EtOH). IR (KBr, cm ): 3362, 1683, 1585, 1285. H NMR (DMSO-d
400 MHz): 12.17 (br s, 1H, NH),10.18 (s,1H, CHO), 8.88 (s, 1H, ArH),
8.75e8.73 (m, 1H, ArH), 8.07 (d, J¼7.4 Hz, 2H, ArH), 7.76e7.71 (m,
6
,
d
7
.53e7.51 (m, 2H), 7.25 (t, J¼7.3 Hz, 1H, ArH), 5.39 (t, J¼5.7 Hz, 1H,
13
13
OH), 4.79 (d, J¼5.6 Hz, 2H, CH
2
) ppm. C NMR (DMSO-d
6
,
1H, ArH), 7.69e7.58 (m, 4H, ArH), 7.38e7.35 (m, 1H, ArH) ppm.
C
125 MHz):
d
150.8 (C]), 141.6 (C]), 140.9 (C]), 138.5 (C]), 132.1
NMR (DMSO-d , 100 MHz): 193.1 (CHO), 143.7 (C]), 142.7 (C]),
6
d
(
(
(
C]), 130.2 (C]), 128.8 (HC]), 128.7 (HC]), 128.5 (HC]), 128.1
141.8 (C]), 137.2 (C]), 131.6 (C]), 129.4 (C]), 129.3 (HC]), 129.0
(HC]), 128.7 (HC]), 128.5 (HC]), 122.3 (HC]), 121.5 (C]), 120.8
HC]), 121.6 (HC]), 121.1 (C]), 119.5 (HC]), 112.5 (HC]), 110.3
HC]), 64.8 (CH
75.1179; found 275.1184.
2
) ppm. HRMS calcd for C18
15
H N
2
O [MþH]þ
(HC]), 113.9 (HC]), 112.9 (HC]) ppm. HRMS calcd for C18
13 2
H N O
2
[MþH]þ 273.1022; found 273.1028.
4
.4.2. [1-(4-Methoxyphenyl)-9H-
b
-carbolin-3-yl]methanol
4.5.2. 1-(4-Methoxyphenyl)-9H-
b
-carboline-3-carbaldehyde
ꢁ
ꢁ
(9b). Yield: 5.80 g (96%), white crystals, mp 176e177 C (MeCN). IR
(4b). Yield 4.00 g (83%), pale yellow crystals, mp 242e244
C
ꢂ1
1
ꢂ1
1
(
4
KBr, cm ): 3156, 1654, 1515, 1246, 738. H NMR (DMSO-d
00 MHz): 11.38 (br s, 1H, NH), 8.27e8.23 (m, 1H, ArH), 8.11 (s, 1H,
ArH), 8.02e7.98 (m, 2H, ArH), 7.65e7.62 (m, 1H, ArH), 7.55e7.51
m, 1H, ArH), 7.26e7.22 (m, 1H, ArH), 7.18e7.15 (m, 2H, ArH), 5.39 (t,
J¼5.7 Hz, 1H, OH), 4.78 (d, J¼5.7 Hz, 2H, CH ), 3.87 (s, 3H, CH ) ppm.
159.7 (OeC]), 150.7 (C]), 141.6
C]), 140.9 (C]), 131.9 (C]), 131.0 (C]), 130.1 (C]), 129.9 (HC]),
28.1 (HC]), 121.6 (HC]), 121.2 (C]), 119.5 (HC]), 114.2 (HC]),
6
,
(MeCN). IR (KBr, cm ): 3286, 1675, 1511, 1245, 1024, 844, 752. H
d
6
NMR (DMSO-d , 400 MHz): d 12.01 (br s, 1H, NH), 10.17 (s, 1H, CHO),
8.78 (s, 1H, ArH), 8.46e8.43 (m, 1H, ArH), 8.07e8.03 (m, 2H, ArH),
7.75e7.72 (m, 1H, ArH), 7.65e7.61 (m, 1H, ArH), 7.38e7.34 (m, 1H,
(
13
2
3
ArH), 7.24e7.20 (m, 2H, ArH), 3.90 (s, 3H, CH
3
) ppm. C NMR
1
3
C NMR (DMSO-d
6
, 100 MHz):
d
(DMSO-d , 100 MHz): 193.3 (CHO), 160.2 (MeOeC]), 143.4 (C]),
6
d
(
1
142.7 (C]), 141.7 (C]), 135.4 (C]), 130.1 (HC]), 129.9 (HC]),
129.3 (C]), 129.0 (C]), 122.3 (HC]), 121.6 (C]), 120.8 (HC]),
1
12.5 (HC]), 109.8 (HC]), 64.9 (CH
2
), 55.5 (CH
3
) ppm. HRMS calcd
3
114.4 (HC]), 113.6 (HC]), 113.1 (HC]), 55.6 (CH ) ppm. HRMS
calcd for C19H N O
15 2 2
þ
[MþH]þ 303.1128; found 303.1137.
for C19
H
17
N
2
O
2
[MþH] 305.1285; found 305.1291.
4
5
.4.3. [1-(4-Nitrophenyl)-9H-
b
-carbolin-3-yl]methanol (9d). Yield:
4.5.3. 1-(4-Chlorophenyl)-9H-
b
-carboline-3-carbaldehyde
ꢁ
ꢁ
.50 g (95%), yellow crystals, mp 257e259 C (DMF/EtOH). IR (KBr,
(4c). Yield 4.30 g (87%), pale yellow crystals, mp 267e268 C (di-
ꢂ1
1
ꢂ1
1
cm ): 3351, 3097, 1628, 1523, 1353, 783. H NMR (DMSO-d
4
6
,
oxane). IR (KBr, cm ): 3291, 1683, 1561, 1286, 737. H NMR (DMSO-
, 400 MHz): 12.06 (br s, 1H, NH), 10.17 (s, 1H, CHO), 8.83 (s, 1H,
00 MHz): 12.35 (br s, 1H, NH), 8.65 (br s, 1H, ArH), 8.52 (d,
d
d
6
d
J¼9.4 Hz, 2H, ArH), 8.48 (d, J¼8.0 Hz, 1H, ArH), 8.31 (d, J¼7.8 Hz, 2H,
ArH), 8.45 (d, J¼7.8 Hz, 1H, ArH), 8.11e8.06 (m, 2H, ArH), 7.73e7.70
ArH), 7.76e7.70 (m, 2H, ArH), 7.42e7.38 (m, 1H, ArH), 4.97 (s, 2H,
(m, 3H, ArH), 7.64 (t, J¼7.6 Hz, 1H, ArH), 7.37 (t, J¼7.4 Hz, 1H,
1
3
13
CH
2
), 4.0 (br s, 1H, OH together with water) ppm. C NMR (DMSO-
ArH) ppm. C NMR (DMSO-d
6
, 100 MHz):
d
193.0 (CHO), 143.4
d
6
, 100 MHz):
d
148.5 (C]), 147.2 (O
2
NeC]), 143.9 (C]), 135.8
(C]), 141.8 (C]), 141.4 (C]), 136.2 (C]), 135.5 (C]), 134.0 (C]),
ꢀ
Please cite this article in press as: Abr ꢀa nyi-Balogh, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.073

ꢀ
ꢀ
P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
5
ꢁ
ꢂ1
1
30.5 (CleC]), 129.6 (HC]), 129.1 (C]), 128.9 (HC]), 122.3
crystals, mp 272e273 C (EtOH/CHCl /DMF). IR (KBr, cm ): 3637,
3
1
(
HC]), 121.5 (C]), 120.9 (HC]), 114.2 (HC]), 113.0 (HC]) ppm.
3232, 3111, 1700, 1623, 1466, 1233. H NMR (DMSO-d
6
, 500 MHz):
11.51 (br s, 1H, NH), 9.17 (br s, 1H, NH), 8.24 (d, J¼7.9 Hz, 1H, ArH),
.08e8.06 (m, 2H, ArH), 7.95 (s, 1H, ArH), 7.80 (br s, 1H, NH),
HRMS calcd for C18
H12ClN
2
O [MþH]þ 307.0633; found 307.0637.
d
8
4
3
3
.5.4. 1-(4-Nitrophenyl)-9H-
.00 g (60%), yellow crystals, mp 305e306 C (DMF). IR (KBr, cm ):
284, 1684, 1510, 1347, 1237. H NMR (DMSO-d
b
-carboline-3-carbaldehyde (4d). Yield
7.68e7.50 (m, 5H, ArH), 7.25 (t, J¼7.4 Hz, 1H, ArH), 5.56 (m, 1H, CH),
ꢁ
ꢂ1
13
3 6
2.27 (m, 6H, CH ) ppm. C NMR (DMSO-d , 125 MHz): d 195.0
1
6
, 500 MHz):
d
12.12
(MeeC]O), 152.9 (HNeCOeNH), 151.6 (C]), 147.5 (C]), 141.7
(C]), 141.2 (C]), 138.4 (C]), 132.2 (C]), 130.2 (C]), 128.8 (HC]),
128.7 (HC]), 128.5 (HC]), 128.3 (HC]), 121.6 (HC]), 121.0 (C]),
119.7 (HC]), 112.6 (HC]), 110.4 (HC]), 109.8 (C]), 56.2 (CH), 30.5
(br s,1H, NH),10.15 (s,1H, CHO), 8.86 (s, 1H, ArH), 8.47e8.43 (m, 3H,
ArH), 8.33e8.31 (m, 2H, ArH), 7.71e7.69 (m, 1H, ArH), 7.65e7.62 (m,
13
1
1
1
H, ArH), 7.38e7.34 (m, 1H, ArH) ppm. C NMR (DMSO-d
25 MHz): 192.8 (CHO), 147.7 (O NeC]), 143.6 (C]), 143.5 (C]),
41.9 (C]), 140.0 (C]), 135.8 (C]), 130.2 (C]), 130.0 (HC]), 129.4
6
,
d
2
(CH
3
), 18.9 (CH
3
) ppm. HRMS calcd for C24
H
21
N
4
O
2
[MþH]þ
397.1659; found 397.1656.
(
(
3
HC]), 124.0 (HC]), 122.4 (HC]), 121.4 (C]), 121.0 (HC]), 114.8
HC]), 113.0 (HC]) ppm. HRMS calcd for C18
18.0873; found 318.0864.
H
12
N
3
O
3
[MþH]þ
4.6.2. Ethyl
6-methyl-2-oxo-4-(1-phenyl-9H-b-carbolin-3-yl)-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (12b). Yield 0.42
g
ꢁ
ꢂ1
74%), pale yellow crystals, mp 174e176 C (EtOH). IR (KBr, cm ):
(
1
4
.5.5. 1-(1,3-Benzodioxol-5-yl)-9H-
b
-carboline-3-carbaldehyde
3422, 3302, 3105, 1697, 1633, 1451, 1238, 1096. H NMR (DMSO-d
500 MHz):
6
,
ꢁ
(4e). Yield 3.70 g (69%), light brown crystals, mp 264e266
C
d
11.48 (br s, 1H, NH), 9.15 (s, 1H, NH), 8.24 (d, J¼7.8 Hz,
ꢂ1
(
1
1
1
decomp., dioxane). IR (KBr, cm ): 3278, 1679, 1559, 1313, 1290,
1H, ArH), 8.08 (m, 2H, ArH), 7.91 (s,1H, ArH), 7.66e7.59 (m, 4H, ArH,
NH), 7.56e7.51 (m, 2H, ArH), 7.25 (t, J¼7.4 Hz, 1H, ArH), 5.46 (d,
1
124. H NMR (DMSO-d
6
, 500 MHz): 11.99 (br s, 1H, NH), 10.16 (s,
H, CHO), 8.77 (s,1H, ArH), 8.43 (d, J¼7.6 Hz,1H, ArH), 7.74e7.72 (m,
H, ArH), 7.64e7.61 (m, 3H, ArH), 7.37e7.34 (m, 1H, ArH), 7.19 (d,
J¼3.0 Hz, 1H, CH), 4.03e4.01 (m, 2H, CH
2
), 2.27 (s, 3H, CH
3
), 1.11 (t,
165.8
13
J¼7.2 Hz, 3H, CH
3
) ppm. C NMR (DMSO-d
6
, 125 MHz): d
13
J¼8.1 Hz, 1H, ArH), 6.18 (s, 2H, OeCH
2
eO) ppm. C NMR (DMSO-d
6
,
(EtOeC]O), 153.1 (HNeCOeNH), 151.6 (C]), 148.5 (HNeC]), 141.7
(C]), 141.1 (C]), 138.5 (C]), 132.3 (C]), 130.0 (C]), 128.8 [two
signals: 128.83 (HC]), 128.78 (HC])], 128.5 (HC]), 128.3 (C]),
121.5 (HC]), 121.1 (C]), 119.7 (HC]), 112.6 (HC]), 110.3 (HC]),
1
1
(
(
(
25 MHz): d 193.0 (CHO), 148.1 (OeC]), 147.7 (OeC]), 143.1 (C]),
42.2 (C]), 141.6 (C]), 135.2 (C]), 131.3 (C]), 129.2 (C]), 128.8
HC]), 122.8 (HC]), 122.1 (HC]), 121.4 (C]), 120.6 (HC]), 113.5
HC]), 112.9 (HC]), 108.7 (HC]), 108.6 (HC]), 101.5
99.2 (C]), 59.2 (CH
calcd for C25
2 3 3
), 55.9 (CH), 18.0 (CH ), 14.3 (CH ) ppm. HRMS
OeCH
2
eO) ppm. HRMS calcd for C19
H
13
N
2
O
3
[MþH]þ 317.0921;
H
23
N
4
O
3
[MþH]þ 427.1765; found 427.1766.
found 317.0922.
4
.6.3. Ethyl 6-(1-methylethyl)-2-oxo-4-(1-phenyl-9H-
b-carbolin-3-
4
3
.5.6. 1-Thiophen-2-yl-9H-
b
-carboline-3-carbaldehyde (4f). Yield
yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12c). Yield 0.44 g
ꢁ
ꢁ
ꢂ1
.70 g (84%), pale yellow crystals, mp 300e302 C (decomp., di-
(74%), white crystals, mp 257e258 C (EtOH). IR (KBr, cm ): 3413,
ꢂ1
1
1
oxane). IR (KBr, cm ): 3299, 1675, 1589, 1241. H NMR (DMSO-d
6
,
3256, 2973, 1676, 1627, 1455, 1264, 1091. H NMR (DMSO-d
6
,
5
8
2
00 MHz): 11.99 (br s, 1H, NH), 10.13 (s, 1H, CHO), 8.77 (s, 1H, ArH),
.44 (d, J¼7.9 Hz, 1H, ArH), 8.19e8.18 (m, 1H, ArH), 7.84e7.80 (m,
500 MHz): 11.50 (br s, 1H, NH), 8.81 (br s, 1H, NH), 8.21 (d,
d
J¼7.9 Hz, 1H, ArH), 8.12e8.10 (m, 2H, ArH), 7.90e7.89 (m, 1H, ArH),
7.68e7.51 (m, 6H, ArH, NH), 7.26 (t, J¼7.5 Hz, 1H, ArH), 5.45 (d,
J¼3.2 Hz, 1H, CH), 4.17 (sp, J¼6.9 Hz, 1H, CH), 4.01 (q, J¼7.0 Hz, 2H,
13
H, ArH), 7.68e7.65 (m, 1H, ArH), 7.40e7.37 (m, 2H, ArH) ppm.
, 125 MHz): 192.6 (CHO), 142.9 (C]), 142.1 (C]),
41.8 (C]), 136.9 (C]), 133.4 (C]), 130.0 (C]), 129.2 (HC]), 129.1
HC]), 128.7 (HC]), 127.1 (HC]), 122.2 (C]), 121.5 (HC]), 121.1
C
NMR (DMSO-d
1
6
d
CH
2
), 1.18 (d, J¼7.1 Hz, 3H, CH
3
), 1.17 (d, J¼6.9 Hz, 3H, CH
3
), 1.10 (t,
165.8
13
(
(
[
J¼6.4 Hz, 3H, CH
3
) ppm. C NMR (DMSO-d
6
, 125 MHz): d
HC]), 113.8 (HC]), 113.2 (HC]) ppm. HRMS calcd for C16
MþH] 279.0587; found 279.0596.
H
11
N
2
OS
(EtOeC]O),156.5 (HNeC]),153.4 (HNeCOeNH),151.6 (C]),141.7
(C]), 141.2 (C]), 138.4 (C]), 132.3 (C]), 130.0 (C]), 128.8 (HC]),
þ
1
28.7 (HC]), 128.4 (HC]), 128.3 (HC]), 121.3 (HC]), 121.1 (C]),
119.7 (HC]), 112.7 (HC]), 110.2 (HC]), 98.3 (C]), 59.2 (CH ), 56.0
) ppm. HRMS calcd
4
.6. General procedure for the synthesis of
hydropyrimidinone derivatives. Preparation of compounds
2aev
b-carbolinyl-di-
2
3 3 3
(CH), 27.1 (CH), 19.3 (CH ), 19.2 (CH ), 14.2 (CH
for C27
1
27
H N
4
O
3
[MþH]þ 455.2078; found 455.2072.
A
suspension of
b-carbolin-3-carbaldehyde derivatives
4.6.4. Ethyl
2-oxo-6-phenyl-4-(1-phenyl-9H-b-carbolin-3-yl)-
[1.32 mmol, 0.36 g 1-phenyl- (4a), 0.40 g 1-(4-methoxyphenyl)-
(4b), 0.41 g 1-(4-chlorophenyl)- (4c), 0.39 g 1-(4-nitrophenyl)-
(4d), 0.42 g 1-(1,3-benzodioxol-5-yl)- (4e), 0.37 g 1-(thiophene-2-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (12d). Yield 0.46
g
ꢁ
ꢂ1
(71%), white crystals, mp 288e289 C (EtOH/CHCl
3
). IR (KBr, cm ):
1
3404, 3341, 3081, 1670, 1494, 1238. H NMR (DMSO-d
6
, 500 MHz):
yl)-9H-
b
-carboline-3-carbaldehyde (4f)], urea (10) (1.5 equiv,
-keto ester [1.32 mmol, 0.13 mL
d 11.69 (br s, 1H, NH), 9.21 (br s, 1H, NH), 8.29e8.26 (m, 1H, ArH),
1.97 mmol, 0.12 g), the appropriate
b
8.12 (d, J¼7.5 Hz, 2H, ArH), 8.10 (s, 1H, ArH), 7.74 (br s, 1H, NH),
7.69e7.67 (m, 2H, ArH), 7.62e7.59 (m, 2H, ArH), 7.54e7.52 (m, 1H,
ArH), 7.41e7.35 (m, 5H, ArH), 7.29e7.26 (m, 1H, ArH), 5.54 (d,
pentane-2,4-dione (11a), 0.17 mL ethyl acetoacetate (11b), 0.21 mL
ethyl isobutyrylacetate (11c), 0.23 mL ethyl benzoylacetate (11d)],
NiCl
2
$6H
2
O catalyst (0.25 equiv, 0.07 g), and concd aq HCl solution
J¼3.1 Hz, 1H, CH), 3.74e3.71 (m, 2H, CH
2
), 0.74 (t, J¼7.1 Hz, 3H,
13
(five drops) in EtOH (20 mL) was heated under reflux until the
CH
3
) ppm. C NMR (DMSO-d
6
, 125 MHz): 165.5 (EtOeC]O),
d
starting material disappeared or the conversion did not grow. After
cooling, the reaction mixture was concentrated. Water (30 mL) was
added and the mixture was extracted with chloroform/methanol
152.8 (HNeCOeNH), 151.7 (C]), 149.2 (HNeC]), 141.7 (C]), 140.4
(C]), 138.2 (C]), 135.7 (C]), 132.7 (C]), 130.8 (C]), 129.2 (C]),
128.8 [two signals: 128.84 (HC]), 128.79 (HC])], 128.5 [two sig-
nals: 128.54 (HC]), 128.51 (HC])], 127.8 (HC]), 121.6 (HC]),
121.0 (C]), 119.8 (HC]), 111.7 (HC]), 110.9 (HC]), 100.3 (C]),
7:3 (3ꢀ50 mL). The combined organic layer was dried over MgSO
4
,
filtered, and concentrated in vacuo. The crude product was purified
by flash chromatography (silica gel 60 PF254) with dichloro-
methane/methanol 97:3 eluent. Compounds 12aev are new.
2 3 25 4 3
59.0 (CH ), 56.3 (CH), 13.6 (CH ) ppm. HRMS calcd for C30H N O
[MþH]þ 489.1935; found 489.1916.
4
.6.1. 5-Acetyl-6-methyl-4-(1-phenyl-9H-
b
-carbolin-3-yl)-3,4-
(63%), white
4.6.5. 5-Acetyl-4-[1-(4-methoxyphenyl)-9H-b-carbolin-3-yl]-6-
methyl-3,4-dihydropyrimidin-2(1H)-one (12e). Yield 0.52 g (90%),
dihydropyrimidin-2(1H)-one (12a). Yield 0.33
g
ꢀ
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P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
ꢀ
6
yellow crystals, mp 270e272 C (decomp., EtOH). IR (KBr, cme1):
ꢁ
109.8 (HC]), 100.6 (C]), 59.0 (CH
(CH ) ppm. HRMS calcd for C31
519.2025.
2
3
), 56.4 (CH), 55.5 (OeCH ), 13.6
1
[MþH]þ 519.2027; found
3
d
404, 3237, 2929, 1699, 1609, 1148. H NMR (DMSO-d
6
, 500 MHz):
3
27 4 4
H N O
11.44 (br s, 1H, NH), 9.13 (br s, 1H, NH), 8.23e8.21 (m, 1H, ArH),
.03 (d, J¼8.8 Hz, 2H, ArH), 7.88 (s, 1H, ArH), 7.79 (br s, 1H, NH),
8
7
.65e7.63 (m, 1H, ArH), 7.55e7.54 (m, 1H, ArH), 7.24 (t, J¼7.9 Hz, 1H,
4.6.9. 5-Acetyl-4-[1-(4-chlorophenyl)-9H-
b-carbolin-3-yl]-6-
ArH), 7.16 (d, J¼8.8 Hz, 2H, ArH), 5.56 (d, J¼3.3 Hz, 1H, CH), 3.88 (s,
methyl-3,4-dihydropyrimidin-2(1H)-one (12i). Yield 0.43 g (75%),
13
ꢁ
ꢂ1
3
H, CH
3
), 2.27 (s, 3H, CH
3
), 2.26 (s, 3H, CH
3
) ppm. C NMR (DMSO-
pale yellow crystals, mp 285e287 C (MeCN). IR (KBr, cm ): 3637,
1
d
6
,
125 MHz):
d
195.0 (MeeC]O), 159.8 (OeC]), 152.9
6
3235, 3158, 1709, 1588, 1242, 747. H NMR (DMSO-d , 500 MHz):
(
(
(
(
(
HNeCOeNH), 151.5 (C]), 147.3 (C]), 141.7 (C]), 141.2 (C]), 131.9
C]), 130.9 (C]), 130.0 (C]), 129.8 (HC]), 128.2 (HC]), 121.5
HC]), 121.0 (C]), 119.6 (HC]), 114.3 (HC]), 112.6 (HC]), 109.9
11.54 (br s, 1H, NH), 9.15 (br s, 1H, NH), 8.26e8.24 (m, 1H, ArH),
8.10e8.07 (m, 2H, ArH), 7.96 (s, 1H, ArH), 7.81 (br s, 1H, NH),
7.67e7.65 (m, 2H, ArH), 7.65e7.63 (m, 1H, ArH), 7.57e7.54 (m, 1H,
HC]), 109.3 (C]), 56.2 (CH), 55.5 (CH
3
), 30.4 (CH
3
), 18.9
ArH), 7.28e7.25 (m, 1H, ArH), 5.57 (d, J¼3.3 Hz, 1H, CH), 2.28 (s, 3H,
[MþH]þ 427.1765; found
CH
3
), 2.26 (s, 3H, CH
) ppm. C NMR (DMSO-d
13
, 125 MHz):
d
194.9
CH
3
) ppm. HRMS calcd for C25
23
H N
4
O
3
3
6
4
27.1768.
(MeeC]O), 152.9 (HNeCOeNH), 151.7 (C]), 147.6 (C]), 141.8
C]), 139.8 (C]), 137.2 (C]), 133.4 (CleC]), 132.2 (C]), 130.5
(
4
2
.6.6. Ethyl 4-[1-(4-methoxyphenyl)-9H-
b
-carbolin-3-yl]-6-methyl-
(C]), 130.2 (HC]), 128.8 (HC]), 128.5 (HC]), 121.7 (HC]), 121.0
(C]), 119.8 (HC]), 112.6 (HC]), 110.4 (HC]), 109.8 (C]), 56.1
-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12f). Yield 0.40 g
ꢁ
1
ꢂ1
(
67%), white crystals, mp 220e221 C (MeCN). IR (KBr, cm ): 3242,
3 3 4 2
(CH), 30.5 (CH ), 18.9 (CH ) ppm. HRMS calcd for C24H20ClN O
[MþH]þ 431.1269; found 431.1269.
6
1700, 1650, 1444, 1227, 1095, 694. H NMR (DMSO-d , 500 MHz):
d
11.45 (br s,1H, NH), 9.18 (d, J¼1.7 Hz,1H, NH), 8.22 (d, J¼7.9 Hz,1H,
ArH), 8.05 (d, J¼8.7 Hz, 2H, ArH), 7.86 (s,1H, ArH), 7.66e7.64 (m, 2H,
ArH, NH), 7.54 (t, J¼7.6 Hz, 1H, ArH), 7.25 (t, J¼7.5 Hz, 1H, ArH),
4.6.10. Ethyl 4-[1-(4-chlorophenyl)-9H-b-carbolin-3-yl]-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12j). Yield 0.46 g
ꢁ
7
CH
CH
.16e7.14 (m, 2H, ArH), 5.45 (d, J¼3.1 Hz, 1H, CH), 4.05e4.00 (m, 2H,
(76%), white crystals, mp 286e288 C (decomp., MeCN). IR (KBr,
ꢂ1
1
2
), 3.88 (s, 3H, CH
3
), 2.26 (s, 3H, CH
3
), 1.12 (t, J¼7.1 Hz, 3H,
cm ): 3389, 3236, 3106,1707,1450,1229, 1092. H NMR (DMSO-d
500 MHz):
6
,
) ppm. 13C NMR (DMSO-d
, 125 MHz):
d
165.9 (EtOeC]O),
d
11.52 (br s, 1H, NH), 9.15 (br d, J¼1.8 Hz, 1H, NH),
3
6
159.8 (OeC]), 153.1 (HNeCOeNH), 151.5 (C]), 148.4 (C]), 141.6
8.26e8.24 (m, 1H, ArH), 8.12e8.10 (m, 2H, ArH), 7.93 (s, 1H, ArH),
7.66e7.63 (m, 4H, ArH, NH), 7.57e7.54 (m, 1H, ArH), 7.28e7.25 (m,
(
(
(
1
4
C]), 141.1 (C]), 132.0 (C]), 131.0 (C]), 129.8 (HC]), 128.1
HC]), 121.4 (HC]), 121.1 (C]), 119.6 (HC]), 114.2 (HC]), 112.6
HC]), 109.6 (HC]), 99.3 (C]), 59.1 (CH
8.0 (CH ), 14.3 (CH ) ppm. HRMS calcd for C26
57.1870; found 457.1873.
1H, ArH), 5.45 (d, J¼3.2 Hz, 1H, CH), 4.03e4.01 (m, 2H, CH
2
), 2.27 (s,
) ppm. C NMR (DMSO-d
165.8 (EtOeC]O), 153.1 (HNeCOeNH), 151.7 (C]),
148.5 (C]), 141.7 (C]), 139.8 (C]), 137.2 (C]), 133.4 (C]), 132.3
C]), 130.2 [two signals: 130.22 (CleC]), 130.18 (HC])], 128.8
(HC]), 128.4 (HC]), 121.6 (HC]), 121.0 (C]), 119.8 (HC]), 112.6
13
2
), 55.9 (CH), 55.5 (CH
3
),
3H, CH
3
), 1.12 (t, J¼7.3 Hz, 3H, CH
3
6
,
þ
3
3
H
25
N
4
O
4
[MþH]
125 MHz): d
(
4
.6.7. Ethyl 4-[1-(4-methoxyphenyl)-9H-b-carbolin-3-yl]-6-(1-
methylethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(HC]), 110.6 (HC]), 99.2 (C]), 59.2 (CH
14.3 (CH ) ppm. HRMS calcd for C25 22ClN
found 461.1377.
2
), 55.9 (CH), 18.0 (CH
3
),
ꢁ
þ
(
12g). Yield 0.37 g (57%), white crystals, mp 301e302 C (decomp.,
3
H
4
O
3
[MþH] 461.1375;
ꢂ1
1
DMF). IR (KBr, cm ): 3360, 3213, 3123, 1677, 1622, 1099. H NMR
DMSO-d , 500 MHz): 11.43 (br s, 1H, NH), 8.78 (br s, 1H, NH),
.19e8.17 (m, 1H, ArH), 8.07 (d, J¼8.7 Hz, 2H, ArH), 7.82 (s, 1H, ArH),
.66e7.60 (m, 2H, ArH, NH), 7.55e7.52 (m, 1H, ArH), 7.26e7.23 (m,
H, ArH), 7.13 (d, J¼3.1 Hz, 2H, ArH), 5.43 (d, J¼3.1 Hz, 1H, CH), 4.16
), 3.88 (s, 3H, CH ),
), 1.16 (d, J¼7.1 Hz, 3H, CH ), 1.09 (t,
, 125 MHz): 165.8
(
8
7
1
6
d
4.6.11. Ethyl 4-[1-(4-chlorophenyl)-9H-b-carbolin-3-yl]-6-(1-
methylethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
ꢁ
(12k). Yield 0.67 g (84%), pale yellow crystals, mp 278e279
C
ꢂ1
(
1
sp, J¼7.0 Hz, 1H, CH), 4.00 (q, J¼7.0 Hz, 2H, CH
2
3
(EtOH/CHCl
3
). IR (KBr, cm ): 3375, 3213, 3124, 1704, 1686, 1621,
1
.18 (d, J¼7.3 Hz, 3H, CH
3
3
6
1228, 1093. H NMR (DMSO-d , 500 MHz): d 11.53 (br s, 1H, NH),
13
J¼7.1 Hz, 3H, CH
3
) ppm. C NMR (DMSO-d
6
d
8.80 (br s, 1H, NH), 8.22e8.20 (m, 1H, ArH), 8.14e8.12 (m, 2H, ArH),
7.91 (s, 1H, ArH), 7.65e7.63 (m, 4H, ArH, NH), 7.57e7.54 (m, 1H,
ArH), 7.28e7.25 (m, 1H, ArH), 5.45 (d, J¼3.1 Hz, 1H, CH), 4.17 (sp,
(
(
EtOeC]O), 159.8 (OeC]), 156.4 (C]), 153.4 (HNeCOeNH), 151.4
C]), 141.6 (C]), 141.2 (C]), 131.9 (C]), 131.0 (C]), 129.8 [two
signals: 129.80 (C]), 129.76 (HC])], 128.1 (HC]), 121.3 (HC]),
21.1 (C]), 119.6 (HC]), 114.1 (HC]), 112.6 (HC]), 109.5 (HC]),
J¼7.0 Hz, 1H, CH), 3.99 (q, J¼7.0 Hz, 2H, CH ), 1.17 (d, J¼6.7 Hz, 3H,
2
13
1
CH
3
), 1.16 (d, J¼6.8 Hz, 3H, CH
3
), 1.08 (t, J¼7.1 Hz, 3H, CH
3
) ppm.
C
9
8.3 (C]), 59.3 (CH
), 14.2 (CH
85.2183; found 485.2179.
2
), 55.9 (CH), 55.5 (CH
3
), 27.1 (CH), 19.4 (CH
3
),
NMR (DMSO-d
6
, 125 MHz):
d 165.8 (EtOeC]O), 156.6 (C]), 153.4
þ
19.2 (CH
3
3
) ppm. HRMS calcd for C28
H
29
N
4
O
4
[MþH]
(HNeCOeNH), 151.7 (C]), 141.7 (C]), 139.8 (C]), 137.2 (C]), 133.4
(CleC]), 132.2 (C]), 130.3 (C]), 130.2 (HC]), 128.7 (HC]), 128.4
4
(HC]), 121.4 (HC]), 121.0 (C]), 119.8 (HC]), 112.6 (HC]), 110.5
4
.6.8. Ethyl 4-[1-(4-methoxyphenyl)-9H-
b
-carbolin-3-yl]-2-oxo-6-
(HC]), 98.2 (C]), 59.3 (CH
2
), 55.9 (CH), 27.1 (CH), 19.4 (CH
26ClN
3
), 19.2
[MþH]
þ
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(12h). Yield
(CH ), 14.2 (CH ) ppm. HRMS calcd for C27
3
3
H
4
O
3
ꢁ
ꢂ1
0
3
5
.30 g (44%), white crystals, mp 270e271 C (EtOH). IR (KBr, cm ):
315, 3199, 3081, 1691, 1669, 1497, 1241, 754. H NMR (DMSO-d
489.1688; found 489.1679.
1
6
,
00 MHz): 11.47 (br s, 1H, NH), 9.21 (br s, 1H, NH), 8.26 (d,
d
4.6.12. Ethyl 4-[1-(4-chlorophenyl)-9H-b-carbolin-3-yl]-2-oxo-6-
J¼7.9 Hz, 1H, ArH), 8.11 (d, J¼8.8 Hz, 2H, ArH), 7.97 (s, 1H, ArH), 7.75
br s, 1H, NH), 7.66 (d, J¼8.2 Hz, 1H, ArH), 7.55 (t, J¼7.4 Hz, 1H, ArH),
.40e7.36 (m, 3H, ArH), 7.34e7.32 (m, 2H, ArH), 7.26 (t, J¼7.4 Hz,1H,
ArH), 7.15 (d, J¼8.7 Hz, 2H, ArH), 5.52 (d, J¼3.2 Hz, 1H, CH), 3.88 (s,
H, OeCH ), 3.74e3.72 (m, 2H, CH ) ppm.
), 0.74 (t, J¼7.1 Hz, 3H, CH
NMR (DMSO-d , 125 MHz): 165.6 (EtOeC]O), 159.8
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(12l). Yield
). IR (KBr,
ꢁ
(
7
0.25 g (36%), white crystals, mp 266e268 C (EtOH/CHCl
3
ꢂ1
1
cm ): 3342, 3202, 1691, 1666, 1493, 1252, 746. H NMR (DMSO-d
6
,
500 MHz): 11.57 (br s, 1H, NH), 9.21 (br s, 1H, NH), 8.30e8.28 (m,
d
3
3
2
3
1H, ArH), 8.16 (d, J¼8.6 Hz, 2H, ArH), 8.06 (s, 1H, ArH), 7.76 (br s, 1H,
NH), 7.67e7.64 (m, 3H, ArH), 7.59e7.57 (m, 1H, ArH), 7.41e7.39 (m,
4H, ArH), 7.34e7.33 (m, 1H, ArH), 7.30e7.26 (m, 1H, ArH), 5.54 (d,
1
3
C
6
d
(
(
MeOeC]), 152.9 (HNeCOeNH), 151.2 (C]), 148.9 (HNeC]), 141.7
C]), 141.2 (C]), 135.7 (C]), 132.1 (C]), 131.0 (C]), 129.9 (C]),
J¼3.2 Hz, 1H, CH), 3.74e3.72 (m, 2H, CH
2
), 0.74 (t, J¼7.1 Hz, 3H,
, 125 MHz): 165.5 (EtOeC]O),
152.8 (HNeCOeNH), 151.4 (C]), 149.0 (HNeC]), 141.8 (C]), 139.9
13
129.8 (HC]), 128.8 (HC]),128.5 (HC]), 128.2 (HC]), 127.8 (HC]),
CH
3
) ppm. C NMR (DMSO-d
6
d
121.5 (HC]), 121.1 (C]), 119.6 (HC]), 114.2 (HC]), 112.7 (HC]),
ꢀ
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ꢀ
ꢀ
P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
7
(
(
(
(
(
C]), 137.2 (C]), 135.6 (C]), 133.4 (C]), 132.4 (C]), 130.4
J¼7.1 Hz, 3H, CH
3
) ppm. 13C NMR (DMSO-d
6
, 125 MHz):
d
165.9
CleC]), 130.2 (C]), 128.8 [two signals: 128.80 (HC]), 128.77
HC])], 128.5 [two signals: 128.54 (HC]), 128.49 (HC])], 127.8
HC]), 121.6 (HC]), 121.0 (C]), 119.8 (HC]), 112.6 (HC]), 110.8
(EtOeC]O),153.3 (HNeCOeNH),151.4 (C]),148.6 (HNeC]),147.9
[two signals: 147.93 (OeC]), 147.87 (OeC])], 141.7 (C]), 140.9
(C]),132.7 (C]),132.0 (C]),130.0 (C]),128.3 (HC]),122.4 (HC]),
121.5 (HC]), 121.1 (C]), 119.7 (HC]), 112.7 (HC]), 109.9 (HC]),
2 3
HC]), 100.5 (C]), 59.1 (CH ), 56.3 (CH), 13.6 (CH ) ppm. HRMS
calcd for C30
H N
24 4
O
3
[MþH]þ 523.1531; found 523.1528.
108.8 (HC]),108.5 (HC]),101.5 (OeCH
2
eO), 99.2 (C]), 59.2 (CH
2
),
5
5.9 (CH), 18.0 (CH
3
), 14.4 (CH
3
) ppm. HRMS calcd for C26H N O
23 4 5
þ
4
3
.6.13. 5-Acetyl-6-methyl-4-[1-(4-nitrophenyl)-9H-
b
-carbolin-3-yl]-
[MþH] 471.1663; found 471.1663.
,4-dihydropyrimidin-2(1H)-one (12m). Yield 0.39 g (70%), yellow
ꢁ
ꢂ1
crystals, mp 270 C (decomp., EtOH/CH
3
d
2
Cl
2
). IR (KBr, cm ): 3394,
, 500 MHz):
4.6.17. Methyl
4-[1-(1,3-benzodioxol-5-yl)-9H-b-carbolin-3-yl]-6-
1
247, 3113, 1711, 1624, 1344, 1236. H NMR (DMSO-d
6
(1-methylethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(12q). Yield 0.43 g (67%), pale yellow crystals, mp 275e276
ꢁ
11.71 (br s, 1H, NH), 9.18 (br s, 1H, NH), 8.43 (d, J¼8.8 Hz, 2H, ArH),
C
ꢂ1
8
.35 (d, J¼8.9 Hz, 2H, ArH), 8.30e8.28 (m, 1H, ArH), 8.06 (s, 1H,
(DMF/H
2
O). IR (KBr, cm ): 3338, 3208, 3061, 2962, 1694, 1622,
1
ArH), 7.84 (br s, 1H, NH), 7.66e7.65 (m, 1H, ArH), 7.60e7.57 (m, 1H,
ArH), 7.30e7.27 (m, 1H, ArH), 5.60 (d, J¼3.2 Hz, 1H, CH), 2.30 (s, 3H,
6
1224, 1097. H NMR (DMSO-d , 500 MHz): 11.47 (br s, 1H, NH), 8.87
(br s, 1H, NH), 8.21 (d, J¼7.5 Hz, 1H, ArH), 7.84 (s, 1H, ArH),
13
CH
3
), 2.26 (s, 3H, CH
3
) ppm. C NMR (DMSO-d
6
, 125 MHz):
NeC]),
47.3 (C]), 144.6 (C]), 141.9 (C]), 138.4 (C]), 132.7 (C]), 131.1
d 194.8
7.66e7.64 (m, 4H, ArH, NH), 7.54 (t, J¼7.5 Hz, 1H, ArH), 7.28e7.25
(
MeeC]O), 152.9 (HNeCOeNH), 152.0 (C]), 147.8 (O
2
(m,1H, ArH), 7.12 (d, J¼8.3 Hz,1H, ArH), 6.14 (s, 2H, OeCH
2
eO), 5.41
), 1.18e1.16
, 125 MHz): 166.3
1
(s, 1H, CH), 4.17 (sp, J¼6.5 Hz, 1H, CH), 3.54 (s, 3H, CH
3
13
(
(
(
[
C]), 129.6 (HC]), 128.8 (HC]), 123.9 (HC]), 121.8 (HC]), 120.9
C]), 120.0 (HC]), 112.6 (HC]), 111.5 (HC]), 109.8 (C]), 56.1
(m, 6H, CH
3
) ppm. C NMR (DMSO-d
6
d
(MeOeC]O), 156.8 (HNeC]), 153.4 (HNeCOeNH), 151.1 (C]),
147.8 [two signals: 147.84 (OeC]), 147.80 (OeC])], 141.6 (C]),
140.9 (C]), 132.6 (C]), 131.9 (C]), 130.0 (C]), 128.2 (HC]), 122.3
CH), 30.5 (CH
3
), 19.0 (CH
3
) ppm. HRMS calcd for C24
H
20
N
5
O
4
þ
MþH] 442.1510; found 442.1507.
(HC]), 121.4 (HC]), 121.0 (C]), 119.6 (HC]), 112.6 (HC]), 109.6
4
.6.14. Ethyl 6-methyl-4-[1-(4-nitrophenyl)-9H-
b
-carbolin-3-yl]-2-
(HC]), 108.7 (HC]), 108.4 (HC]), 101.4 (OeCH eO), 98.0 (C]),
2
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12n). Yield 0.37 g
55.7 (CH), 51.0 (OeCH
25 4 5
HRMS calcd for C27H N O
3 3 3
), 27.1 (CH), 19.3 (CH ), 19.2 (CH ) ppm.
ꢁ
ꢂ1
[MþH]þ 485.1819; found 485.1819.
(
59%), yellow crystals, mp 300e303 C (DMF). IR (KBr, cm ): 3219,
1
3
115, 2974, 1708, 1665, 1344, 1232, 1100. H NMR (DMSO-d
6
,
5
00 MHz): 11.69 (br s, 1H, NH), 9.18 (br s, 1H, NH), 8.42 (d,
d
4.6.18. Ethyl 4-[1-(1,3-benzodioxol-5-yl)-9H-b-carbolin-3-yl]-2-oxo-
J¼8.6 Hz, 2H, ArH), 8.36 (d, J¼8.5 Hz, 2H, ArH), 8.29 (d, J¼7.7 Hz, 1H,
6-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12r). Yield:
ꢁ
ArH), 8.03 (s, 1H, ArH), 7.69e7.65 (m, 2H, ArH, NH), 7.60e7.57 (m,
0.32 g (45%), light brown crystals, mp 274e275 C (DMF/H
2
O). IR
ꢂ1
1
1
4
CH
(
(
1
H, ArH), 7.30e7.27 (m, 1H, ArH), 5.48 (d, J¼2.1 Hz, 1H, CH),
(KBr, cm ): 3344, 3203, 2982, 1693, 1667, 1492, 1242, 741. H NMR
(DMSO-d , 500 MHz): 11.47 (br s, 1H, NH), 9.21 (br s, 1H, NH), 8.25
.04e4.01 (m, 2H, CH
2
), 2.28 (s, 3H, CH
,125 MHz):
HNeCOeNH), 152.1 (C]), 148.7 (O
C]), 141.9 (C]), 138.4 (C]), 132.8 (C]), 130.8 (C]), 129.5 (HC]),
28.8 (HC]), 123.9 (HC]), 121.7 (HC]), 120.9 (C]), 120.0 (HC]),
3
), 1.12 (t, J¼7.0 Hz, 3H,
6
d
) ppm. 13C NMR (DMSO-d
d
165.8 (EtOeC]O),153.1
(d, J¼8.0 Hz,1H, ArH), 7.98 (s,1H, ArH), 7.74 (br s,1H, NH), 7.68e7.65
(m, 3H, ArH), 7.55 (t, J¼7.7 Hz,1H, ArH), 7.43e7.41 (m, 5H, ArH), 7.26
(t, J¼7.5 Hz, 1H, ArH), 7.13 (d, J¼7.5 Hz, 1H, ArH), 6.13 (s, 2H,
3
6
2
NeC]), 147.3 (C]), 144.6
OeCH
(t, J¼5.5 Hz, 3H, CH
2
eO), 5.50 (d, J¼3.2 Hz, 1H, CH), 3.75e3.71 (m, 2H, CH
2
d
), 0.74
165.9
13
1
12.6 (HC]), 111.7 (HC]), 99.1 (C]), 59.2 (CH
2
), 55.9 (CH), 18.0
3
) ppm. C NMR (DMSO-d
6
, 125 MHz):
(
CH ), 14.3 (CH ) ppm. HRMS calcd for C25
3
3
H
22
N
5
O
5
[MþH]þ
(EtOeC]O),152.9 (HNeCOeNH),151.0 (C]),148.9 (HNeC]),147.9
(OeC]), 147.8 (OeC]), 141.6 (C]), 140.9 (C]), 135.6 (C]), 132.7
472.1615; found 472.1617.
(C]), 132.0 (C]), 130.1 (C]), 128.8 (HC]), 128.5 (HC]), 128.2
4
.6.15. 5-Acetyl-4-[1-(1,3-benzodioxol-5-yl)-9H-
b
-carbolin-3-yl]-6-
(HC]), 127.8 (HC]), 122.4 (HC]), 121.5 (HC]), 121.1 (C]), 119.7
(HC]), 112.7 (HC]), 110.1 (HC]), 108.8 (HC]), 108.4 (HC]), 101.4
methyl-3,4-dihydropyrimidin-2(1H)-one (12o). Yield 0.26 g (43%),
pale yellow crystals, mp 295e297 C (decomp., DMF/H
cm ): 3402, 3238, 3096, 2932,1704,1664,1468,1236,1097. H NMR
ꢁ
2
O). IR (KBr,
(OeCH
HRMS calcd for C31H N O
2 2 3
eO), 100.5 (C]), 59.0 (CH ), 56.3 (CH), 13.6 (CH ) ppm.
ꢂ1
1
[MþH]þ 533.1819; found 533.1810.
25 4 5
(
(
(
6
DMSO-d , 500 MHz): d 11.46 (br s, 1H, NH), 9.17 (br s, 1H, NH), 8.22
d, J¼6.9 Hz,1H, ArH), 7.90 (s,1H, ArH), 7.81 (br s,1H, NH), 7.66e7.61
4.6.19. 5-Acetyl-6-methyl-4-(1-thiophen-2-yl-9H-b-carbolin-3-yl)-
3,4-dihydropyrimidin-2(1H)-one (12s). Yield 0.31 g (60%), pale yel-
m, 3H, ArH), 7.57e7.54 (t, J¼7.5 Hz, 1H, ArH), 7.24 (t, J¼7.4 Hz, 1H,
ꢁ
ArH), 7.14 (d, J¼8.0 Hz, 1H, ArH), 6.15 (s, 2H, OeCH
2
eO), 5.55 (d,
) ppm. C NMR
low crystals, mp 304e305 C (decomp., MeCN/CHCl
3
/DMF). IR (KBr,
13
ꢂ1
1
J¼3.0 Hz, 1H, CH), 2.27 (s, 3H, CH
3
), 2.26 (s, 3H, CH
3
cm ): 3336, 3300, 3109,1674,1620,1446,1239. H NMR (DMSO-d
500 MHz):
6
,
(
(
(
DMSO-d
6
,125 MHz):
d
195.0 (MeeC]O),153.0 (HNeCOeNH),151.7
d
11.45 (br s,1H, NH), 9.17 (br s,1H, NH), 8.22 (d, J¼7.8 Hz,
C]), 147.9 [two signals: 147.89 (OeC]), 147.86 (OeC])], 147.5
C]), 141.7 (C]), 140.9 (C]), 132.6 (C]), 131.9 (C]), 130.1 (C]),
1H, ArH), 8.09 (d, J¼3.5 Hz, 1H, ArH), 7.93 (s, 1H, ArH), 7.81 (br s, 1H,
NH), 7.73e7.70 (m, 2H, ArH), 7.61e7.55 (m, 1H, ArH), 7.33e7.28 (m,
1
28.3 (HC]), 122.4 (HC]), 121.6 (HC]), 121.0 (C]), 119.6 (HC]),
2H, ArH), 5.52 (d, J¼3.3 Hz, 1H, CH), 2.32 (s, 3H, CH
3
), 2.26 (s, 3H,
13
112.7 (HC]), 109.6 (C]), 108.8 (HC]), 108.5 (HC]), 101.4
CH ) ppm. C NMR (DMSO-d , 125 MHz): d 194.8 (MeeC]O), 152.8
3
6
(
C
OeCH
2
eO), 56.1 (CH), 30.5 (CH
3
), 18.9 (CH
3
) ppm. HRMS calcd for
(HNeCOeNH), 151.4 (C]), 147.3 (HNeC]), 143.9 (C]), 141.8 (C]),
135.8 (C]),130.6 (C]),130.0 (C]),128.6 (HC]),128.5 (HC]),125.8
þ
25 21
H N
4
O
4
[MþH] 441.1557; found 441.1558.
(HC]), 121.5 (HC]), 120.9 (C]), 120.0 (HC]), 112.8 (HC]), 110.0
4
.6.16. Ethyl 4-[1-(1,3-benzodioxol-5-yl)-9H-
b
-carbolin-3-yl]-6-
3 3
(HC]), 109.9 (C]), 55.8 (CH), 30.4 (CH ), 18.9 (CH ) ppm. HRMS
methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
calcd for C22H
19
N
4
O
2
S [MþH]þ 403.1223; found 403.1221.
ꢁ
(12p). Yield 0.29 g (47%), pale yellow crystals, mp 273e275
C
ꢂ1
(
EtOH/THF). IR (KBr, cm ): 3402, 3239, 3097, 2933,1704,1664,1491,
4.6.20. Ethyl 6-methyl-2-oxo-4-(1-thiophen-2-yl-9H-b-carbolin-3-
1
1
(
(
236,1097. H NMR (DMSO-d
br s,1H, NH), 8.23 (d, J¼7.8 Hz,1H, ArH), 7.87 (s,1H, ArH), 7.66e7.62
m, 4H, ArH, NH), 7.54 (t, J¼7.6 Hz, 1H, ArH), 7.25 (t, J¼7.5 Hz, 1H,
eO), 5.42 (d,
), 2.26 (s, 3H, CH ), 1.13 (t,
6
, 500 MHz):
d
11.46 (br s,1H, NH), 9.21
yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12t). Yield 0.45 g
ꢁ
(81%), pale yellow crystals, mp 285e287 C (EtOH/CHCl
3
). IR (KBr,
ꢂ1
1
cm ): 3374, 3241, 3113, 1707, 1659, 1436, 1223, 1085. H NMR
ArH), 7.14 (d, J¼7.8 Hz, 1H, ArH), 6.15 (s, 2H, OeCH
2
(DMSO-d
6
, 500 MHz): d 11.42 (br s, 1H, NH), 9.19 (br s, 1H, NH),
J¼2.7 Hz, 1H, CH), 4.07e3.99 (m, 2H, CH
2
3
8.26e8.23 (m,1H, ArH), 8.09 (d, J¼3.7 Hz,1H, ArH), 7.88 (s,1H, ArH),
ꢀ
Please cite this article in press as: Abr aꢀ nyi-Balogh, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.073

ꢀ
ꢀ
8
P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
Domínguez, G.; P
eꢀ rez-Castells, J. Targets Heterocycl. Syst. 2008, 12, 212e257; (e)
Domínguez, G.; P eꢀ rez-Castells, J. Eur. J. Org. Chem. 2011, 7243e7253; (f) Singh,
V.; Batra, S. Curr. Org. Synth. 2012, 9, 513e528.
. (a) Allen, J. R. F.; Holmstedt, B. R. Phytochemistry 1980, 19, 1573e1582; (b)
Airaksinen, M. M.; Kari, I. Med. Biol. 1981, 59, 190e211; (c) McNulty, J.; Still, I. W.
J. Curr. Org. Chem. 2000, 4, 121e138; (d) Herraiz, T.; Sanchez, F. J. Chromatogr., A
997, 765, 265e277; (e) Herraiz, T.; Galisteo, J. J. Agric. Food Chem. 2003, 51,
156e7161; (f) Herraiz, T.; Papavergou, E. J. Agric. Food Chem. 2004, 52,
2652e2658; (g) Herraiz, T.; Chaparro, C. Life Sci. 2006, 78, 795e802.
. (a) Molina, P.; Fresneda, P. M.; Garcia-Zafra, S.; Almendros, P. Tetrahedron Lett.
994, 35, 8851e8853; (b) Youssef, D. T. A.; Shaala, L. A.; Asfour, H. Z. Mar. Drugs
013, 11, 1061e1070.
. (a) Winkler, J. D.; Londregan, A. T.; Hamann, M. T. Org. Lett. 2006, 8, 2591e2594;
b) Shilabin, A. G.; Kasanah, N.; Tekwani, B. L.; Hamann, M. T. J. Nat. Prod. 2008,
1, 1218e1221; (c) Gupta, L.; Srivastava, K.; Singh, S.; Puri, S. K.; Chauhan, P. M.
S. Bioorg. Med. Chem. Lett. 2008, 18, 3306e3309.
5. Lin, N.; Zhao, M.; Wang, C.; Peng, S. Bioorg. Med. Chem. Lett. 2002, 12, 585e587.
. Rivas, P.; Cassels, B. K.; Morello, A.; Repetto, Y. Comp. Biochem. Physiol. 1999, 122,
7e31.
. (a) Xu, Z.; Chang, F.-R.; Wang, H. K.; Kashiwada, Y.; McPhail, A. T.; Bastow, K.
F.; Tachibana, Y.; Cosentino, M.; Lee, K. H. J. Nat. Prod. 2000, 63, 1712e1715;
(b) Yu, X.; Lin, W.; Li, J.; Yang, M. Bioorg. Med. Chem. Lett. 2004, 14,
127e3130; (c) Guan, H.; Chen, H.; Peng, W.; Ma, Y.; Cao, R.; Liu, X.; Xu, A.
Eur. J. Med. Chem. 2006, 41, 1167e1179; (d) Tang, J. G.; Wang, Y. H.; Wang, R.
R.; Dong, Z. J.; Yang, L. M.; Zheng, Y. T.; Liu, J. K. Chem. Biodivers. 2008, 5,
447e460; (e) Brahmbhatt, K. G.; Ahmed, N.; Sabde, S.; Mitra, D. Bioorg. Med.
Chem. Lett. 2010, 20, 4416e4419.
7
.72e7.70 (m, 2H, ArH), 7.61 (br s, 1H, NH), 7.59e7.57 (m, 1H, ArH),
7
1
3
.32 (t, J¼4.3 Hz, 1H, ArH), 7.29e7.28 (m, 1H, ArH), 5.39 (d, J¼2.9 Hz,
H, CH), 4.03e4.01 (m, 2H, CH
H, CH
) ppm. 13C NMR (DMSO-d
52.9 (HNeCOeNH), 151.4 (C]), 148.6 (C]), 144.1 (C]), 141.8
2
), 2.28 (s, 3H, CH
3
), 1.12 (t, J¼7.0 Hz,
2
3
6
, 125 MHz):
d 165.3 (EtOeC]O),
1
1
7
(
(
(
C]), 135.9 (C]), 130.3 (C]), 130.1 (C]), 128.5 (HC]), 125.6
HC]), 121.5 (HC]), 121.0 (C]), 120.0 (HC]), 112.8 (HC]), 110.4
HC]), 99.2 (C]), 59.1 (CH ), 55.7 (CH), 18.0 (CH ), 14.3 (CH ) ppm.
2 3 3
3
4
1
2
HRMS calcd for C23
H
21
N
4
O
3
S [MþH]þ 433.1329; found 433.1329.
(
7
4.6.21. Ethyl 6-(1-methylethyl)-2-oxo-4-(1-thiophen-2-yl-9H-b-car-
bolin-3-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12u). Yield
ꢁ
0
.34 g (55%), pale yellow crystals, mp 299e301 C (EtOH/CHCl
3
/
ꢂ1
1
6
DMF). IR (KBr, cm ): 3326, 1674, 1625, 1455, 1226, 1101. H NMR
DMSO-d , 500 MHz): 11.43 (br s, 1H, NH), 8.80 (br s, 1H, NH),
.22e8.20 (m, 1H, ArH), 8.10e8.09 (m, 1H, ArH), 7.87 (s, 1H, ArH),
.73e7.71 (m, 2H, ArH), 7.60e7.56 (m, 2H, ArH, NH), 7.32e7.26 (m,
2
(
8
7
2
6
d
7
3
H, ArH), 5.40 (d, J¼2.4 Hz, 1H, CH), 4.18 (sp, J¼7.1 Hz, 1H, CH), 4.00
(
3
q, J¼7.1 Hz, 2H, CH
2
), 1.21 (d, J¼7.1 Hz, 3H, CH ), 1.17 (d, J¼7.0 Hz,
3
13
H, CH
3
), 1.11 (t, J¼7.1 Hz, 3H, CH
3 6
) ppm. C NMR (DMSO-d ,
125 MHz):
d
165.7 (EtOeC]O), 156.6 (HNeC]), 153.3
8
. Rook, Y.; Schmidtke, K.; Gaube, F.; Schepmann, D.; W u€ nch, B.; Heilmann, J.;
Lehmann, J.; Winckler, T. J. Med. Chem. 2010, 53, 3611e3617.
9. Soriano-Agat oꢀ n, F.; Lagoutte, D.; Poupon, E.; Roblot, F.; Fournet, A.; Gantier, J. C.;
Hockuemiller, R. J. Nat. Prod. 2005, 68, 1581e1587.
0. (a) Daugan, A.; Grondin, P.; Ruault, C.; de Gouville, A.-C. M.; Coste, H.; Kirilovsky,
J.; Hyafil, F.; Labaudini eꢁ re, R. J. Med. Chem. 2003, 46, 4525e4532; (b) Daugan, A.;
Grondin, P.; Ruault, C.; de Gouville, A.-C. M.; Coste, H.; Linget, J. M.; Kirilovsky, J.;
Hyafil, F.; Labaudini eꢁ re, R. J. Med. Chem. 2003, 46, 4533e4542; (c) Zhang, Y.; He,
(
(
(
(
HNeCOeNH),151.5 (C]),144.1 (C]),141.8 (C]),136.2 (C]),130.3
C]), 130.1 (C]), 128.5 (HC]), 128.4 (HC]), 125.6 (HC]), 121.4
HC]), 121.0 (C]), 120.0 (HC]), 112.8 (HC]), 110.5 (HC]), 98.1
1
2 3 3
C]), 59.2 (CH ), 55.8 (CH), 27.0 (CH), 19.4 (CH ), 14.2 (CH ) ppm.
HRMS calcd for C25
H
25
N
4
O
3
S [MþH]þ 461.1642; found 461.1640.
Q.; Ding, H.; Wu, X.; Xie, Y. Org. Prep. Proced. Int. 2005, 37, 99e102.
4
.6.22. Ethyl 2-oxo-6-phenyl-4-(1-thiophen-2-yl-9H-b-carbolin-3-
1
1. (a) Stephens, D. N.; Schneider, H. H.; Kehr, W.; Andrews, J. S.; Rettig, K. J.; Turski,
L.; Schmiechen, R.; Turner, J. D.; Jensen, L. H.; Petersen, E. N. J. Pharmacol. Exp.
Ther. 1990, 253, 334e343; (b) Turski, L.; Stephens, D. N.; Jensen, L. H.; Petersen,
E. N.; Meldrum, B. S.; Patel, S.; Hansen, J. B.; L o€ scher, W.; Schneider, H. H.;
Schmiechen, R. J. Pharmacol. Exp. Ther. 1990, 253, 344e352; (c) Duka, T.; Sch u€ tt,
B.; Krause, W.; Dorow, R.; McDonald, S.; Fichte, K. Br. J. Clin. Pharmacol. 1993, 35,
386e394; (d) Ruscher, K.; Rzeczinski, S.; Thein, E.; Freyer, D.; Victorov, I. V.;
Lam, T. T.; Dirnagl, U. Neuropharmacology 2007, 52, 1488e1495.
2. (a) Hassani, M.; Cai, W.; Holley, D. C.; Lineswala, J. P.; Maharjam, B. R.;
Ebrahimian, G. R.; Seradj, H.; Stocksdale, M. G.; Mohammadi, F.; Marvin, C.
C.; Gerdes, J. M.; Beall, H. D.; Behforouz, M. J. Med. Chem. 2005, 48,
7733e7749; (b) Cao, R.; Peng, W.; Chen, H.; Hou, X.; Guan, H.; Chen, Q.; Ma,
Y.; Xu, A. Eur. J. Med. Chem. 2005, 40, 249e257; (c) Zhao, M.; Bi, L.; Wang,
W.; Wang, C.; Baudy-Floc’h, M.; Ju, J.; Peng, S. Bioorg. Med. Chem. 2006, 14,
6998e7010; (d) Formagio, A. S. N.; Tonin, L. T. D.; Foglio, M. A.; Madjarof, C.;
de Carvalho, J. E.; da Costa, W. F.; Cardoso, F. P.; Sarragiotto, M. H. Bioorg.
Med. Chem. 2008, 16, 9660e9667; (e) Dong, J.; Shi, X.-X.; Yan, J.-J.; Xing, J.;
Zhang, Q.; Xiao, S. Eur. J. Org. Chem. 2010, 6987e6992; (f) Savariz, F. C.;
Foglio, M. A.; de Carvalho, J. E.; Ruiz, A. L. T. G.; Duarte, M. C. T.; da Rosa, M.
F.; Sarragiotto, M. H. Molecules 2012, 17, 6100e6113; (g) Shinji, T.; Tominari,
C.; Asuka, O.; Takashi, N.; Shiroh, W.; Noriyuki, H.; Minoru, I.; Satoshi, H. Eur.
yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12v). Yield 0.53 g
ꢁ
(
(
(
8
7
81%), pale yellow crystals, mp 291e292 C (MeCN/CHCl
KBr, cm ): 3339, 3106, 1699, 1678, 1647, 1454, 1243, 1107. H NMR
3
/DMF). IR
ꢂ1
1
DMSO-d
.28e8.27 (m, 1H, ArH), 8.13 (d, J¼3.2 Hz,1H, ArH), 8.00 (s,1H, ArH),
.74e7.72 (m, 3H, ArH, NH), 7.60e7.57 (m, 1H, ArH), 7.39e7.37 (m,
H, ArH), 7.32 (t, J¼3.2 Hz, 1H, ArH), 7.31e7.28 (m, 1H, ArH), 5.49 (d,
J¼2.9 Hz, 1H, CH), 3.77e3.71 (m, 2H, CH ), 0.73 (t, J¼7.1 Hz, 3H,
, 125 MHz): 165.4 (EtOeC]O),
52.7 (HNeCOeNH), 151.2 (C]), 149.2 (HNeC]), 144.1 (C]), 141.8
C]), 136.2 (C]), 135.8 (C]), 130.4 (C]), 130.2 (C]), 128.7 (HC]),
28.6 (HC]), 128.5 (HC]), 127.7 (HC]), 125.7 (HC]), 121.6 (HC]),
21.1 (C]), 120.1 (HC]), 112.8 (HC]), 110.7 (HC]), 100.4 (C]),
6
, 500 MHz):
d
11.48 (br s, 1H, NH), 9.24 (br s, 1H, NH),
1
5
2
) ppm. 1 C NMR (DMSO-d
3
CH
1
(
1
3
6
d
1
5
9.0 (CH
2
), 56.3 (CH), 13.6 (CH
3
) ppm. HRMS calcd for C28
H
23
N
4
O
3
S
þ
[MþH] 495.1485; found 495.1480.
J. Org. Chem. 2013, 1805e1810.
4
(
.6.23. Ethyl
phenylcarbonyl)prop-2-enoate (13). The compound was isolated as
a by-product during the preparation of 12l. Yield 0.30 g (47%), pale
(2E)-3-[1-(4-chlorophenyl)-9H-
b
-carbolin-3-yl]-2-
13. (a) Milen, M.; Aꢀ br ꢀa nyi-Balogh, P.; Dancs oꢀ , A.; Simig, G.; Keglevich, G. Lett. Org.
ꢀ
ꢀ
ꢀ
Chem. 2010, 7, 377e382; (b) Milen, M.; Abranyi-Balogh, P.; Mucsi, Z.; Dancso, A.;
K o€ rtv eꢀ lyesi, T.; Keglevich, G. Curr. Org. Chem. 2011, 15, 1811e1825; (c) Milen, M.;
ꢀ
ꢀ
ꢀ
ꢀ
Abranyi-Balogh, P.; Mucsi, Z.; Dancso, A.; Frigyes, D.; Pongo, L.; Keglevich, G.
Curr. Org. Chem. 2013, 17, 1894e1902.
ꢁ
ꢂ1
yellow crystals, mp 301e302 C (MeCN). IR (KBr, cm ): 3369, 1715,
1
1
672, 1627, 1227. H NMR (DMSO-d
NH), 8.60 (s, 1H, ArH), 8.27e8.25 (m, 1H, ArH), 8.11 (s, 1H, CH),
.90e7.89 (m, 2H, ArH), 7.65e7.64 (m, 1H, ArH), 7.60e7.55 (m, 2H,
ArH), 7.46e7.42 (m, 4H, ArH), 7.39 (d, J¼8.8 Hz, 2H, ArH), 7.34e7.31
m, 1H, ArH), 4.21 (q, J¼7.1 Hz, 2H, CH ), 1.18 (t, J¼7.1 Hz, 3H,
CH , 125 MHz): 194.0 (PheC]O), 164.9
) ppm. 13C NMR (DMSO-d
6
, 500 MHz):
d
11.79 (br s, 1H,
14. (a) Cao, R.; Wu, J.; Yu, F.; Wang, Z.; Peng, W. Chinese Pat. Appl. CN 101429198;
Chem. Abstr. 2009, 151, 33818; (b) Wang, Z.; Wu, J.; Zhang, S.; Cao, R.; Qin, M.;
Fei, M.; Shu, Z.; Wenxi, F.; Jie, S.; Fulian, H.; Fan, Z.; Chunhai, M. Chinese Pat.
Appl. CN 103070862; Chem. Abstr. 2013, 158, 695522; (c) Wu, Q.; Cao, R.; Feng,
M.; Guan, X.; Ma, C.; Liu, J.; Song, H.; Peng, W. Eur. J. Med. Chem. 2009, 44,
7
533e540.
(
2
1
5. (a) Liu, Z.; Xu, F. Tetrahedron Lett. 1989, 30, 3457e3460; (b) Peter, H.; Erugger,
M.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1963, 46, 577e586.
3
6
d
[
(
1
1
C(O)eOEt], 141.5 (C]), 141.0 [two signals: 141.04 (HC]), 141.03
C])], 140.4 (C]), 137.0 (C]), 135.8 (C]), 133.6 (C]), 133.0 (C]),
32.9 (CleC]), 130.2 (HC]), 130.0 (C]), 129.8 (C]), 128.8 (HC]),
16. Formagio, A. S. N.; Santos, P. R.; Zanoli, K.; Ueda-Nakamura, T. Eur. J. Med. Chem.
2009, 44, 4695e4701.
17. Cain, M.; Weber, R. W.; Guzman, F.; Cook, J. M.; Barker, S. A.; Rice, K. C.; Crawley,
J. N.; Paul, S. M.; Skolnick, P. J. Med. Chem. 1982, 25, 1081e1091.
18. Panarese, J. D.; Waters, S. P. Org. Lett. 2010, 12, 4086e4089.
28.7 (HC]), 128.6 (HC]), 128.5 (HC]), 121.8 (HC]), 121.1 (HC]),
19. Sung, Y.-I.; Koike, K.; Nikaido, T.; Ohmoto, T.; Sankawa, U. Chem. Pharm. Bull.
1
2 3
20.6 (C]), 119.1 (HC]), 112.9 (HC]), 61.0 (CH ), 14.2 (CH ) ppm.
[MþH]þ 481.1313; found 481.1311.
1984, 32, 1872e1877.
HRMS calcd for C29
H22ClN
2
O
3
20. Tworowski, D.; Matsievitch, R. PCT Int. Pat. Appl. WO 2007110868; Chem. Abstr.
2007, 147, 427370.
21. Bristol, J. A.; Gold, E. H.; Lovey, R. G.; Long, J. F. J. Med. Chem. 1981, 24, 927e932.
2
2
2
2. Lu, J.; Bai, Y. Synthesis 2002, 466e470.
3. Hazarkhani, H.; Karimi, B. Synthesis 2004, 1239e1242.
4. (a) Hu, M.; Weng, Q.; Zeng, Y.; Zhong, G.; Zhang, Y. Molecules 2010, 15,
References and notes
1
. (a) Torreilles, J.; Gu eꢀ rin, M.-C.; Previero, A. Biochimie 1985, 67, 929e947; (b)
7775e7791; (b) Kundu, B.; Saha, B.; Sawant, D.; Sharma, S. Tetrahedron Lett.
Love, B. E. Org. Prep. Proced. Int. 1996, 28, 1e64; (c) Cao, R.; Peng, W.; Wang, Z.;
Xu, A. Curr. Med. Chem. 2007, 14, 479e500; (d) Rosillo, M.; Gonz ꢀa lez-G oꢀ mez, A.;
2007, 48, 1379e1383; (c) Abadi, A. H.; Ahmed, N. S.; Gary, B. D.; Piazza, G. A.;
ꢀ
Please cite this article in press as: Abr ꢀa nyi-Balogh, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.073

ꢀ
ꢀ
P. Abranyi-Balogh et al. / Tetrahedron xxx (2014) 1e9
9
Tinsley, H. N.; Laufer, S. Arch. Pharm. 2011, 344, 149e157; (d) Beghyn, T. B.;
Bourin, A.; Charton, J.; Deprez, B.; Laconde, G.; Leroux, F.; Cos, P.; Maes, L. J. Med.
Chem. 2011, 54, 3222e3240; (e) Bhaduri, S.; Kaur, G.; Sharma, K. Indian J. Chem.,
Sect. B: Org. Med. Chem. 2006, 45, 2710e2715.
25. (a) Dong, J.; Shi, X.-X.; Xiao, S.; Xing, J.; Yan, J.-J.; Zhang, Q. Eur. J. Org. Chem.
2010, 36, 6987e6992; (b) Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.;
Agarwal, S. K.; Bhaduri, A. P.; Singh, S. N.; Fatima, N.; Chatterjee, R. K. Bioorg.
Med. Chem. 1999, 7, 1223e1236.
ꢀ
Please cite this article in press as: Abr aꢀ nyi-Balogh, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.073