Reactivity of 4-tert-butyldimethylsiloxy-1,2,3,6-tetrahydropyridines with hydrazines

Article abstract of DOI:10.3390/11110929

The reactivity of 6-(nitrophenyl or trimethoxyphenyl)-4-tert- butyldimethylsiloxy-1,2,3,6-tetrahydropyridine derivatives with hydrazines under acid conditions is described. The structure of the products isolated - hydrazones, pyrazolines or pyridazinones

Full text of DOI:10.3390/11110929

Molecules 2006, 11, 929-939
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Reactivity of 4-tert-Butyldimethylsiloxy-1,2,3,6-tetrahydro-
pyridines with Hydrazines
Javier Figueroa, Esther Caballero*, Pilar Puebla, Fernando Tomé and Manuel Medarde
Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, Campus Miguel de
Unamuno, 37007 Salamanca, Spain
*Author to whom correspondence should be addressed; e-mail: escab@usal.es
Received: 2 November 2006; in revised form: 29 November 2006 / Accepted: 29 November 2006 /
Published: 30 November 2006
Abstract: The reactivity of 6-(nitrophenyl or trimethoxyphenyl)-4-tert-butyldimethyl-
siloxy-1,2,3,6-tetrahydropyridine derivatives with hydrazines under acid conditions is
described. The structure of the products isolated − hydrazones, pyrazolines or
pyridazinones − depended on the conditions used. In addition, a systematic study of the
reaction outcomes was carried out by introducing variations on the substituents of the
tetrahydropyridine ring.
Keywords: Siloxy-1,2,3,6-tetrahydropyridines, hydrazones, pyrazolines, pyridazinones.
Introduction
The Fischer reaction of piperidones with phenylhydrazines has been described for the preparation
of compounds with the carboline structure. The (α, β or γ) carboline derivatives represent a large
number of naturally and synthetic indole alkaloids with interesting biological and pharmaceutical
activities [1]. β-Carboline-type alkaloids are the best known, owing to their antiviral, antitumor and
antimicrobial activities [2, 3]. γ-Carbolines have also shown antipsychotic, antibiotic or antitumor
activities [4, 5]. This Fischer reaction has been described to give the carbolines in good to moderate
yields under a variety of acidic conditions. For instance, the reaction between N-methyl-4-piperidone
and tolylhydrazine in glacial acetic acid gives the corresponding carboline in 60% yield; if the reaction
is carried out with trifluoroacetic acid, the yield increases up to 87% [6]. The reaction also depends on

Molecules 2006, 11
930
the substituents of the phenylhydrazine. In some cases, the formation of the phenylhydrazone (an
enehydrazone tautomer) occurs, but no cyclization to the carboline is detected [7].
In previous work we used the hetero Diels-Alder reaction to synthesize 1-benzyl-4-(tert-butyl-
dimethylsiloxy)-6-(nitro or methoxyphenyl)-1,2,3,6-tetrahydropyridine-2-carboxylates, which are
interesting starting materials for the synthesis of differently substituted carbolines. Here we describe
the reactivity of those compounds towards hydrazine and phenylhydrazine; the reaction was expected
to produce different substituted-γ-carbolines of particular interest due to the coexistence of an ester and
different aromatic groups. The different conditions used for this reaction in no case allowed us to
obtain carbolines, although different pyrazoline and pyridazinone derivatives were isolated.
Representative pyrazoline and pyridazinone derivatives are included in pharmacologically important
compounds due to their anti-inflammatory, analgesic, antihypertensive, antibacterial, anticancer
activity as well as inhibitors of the kinesin spindle protein (KSP) [8,9,10,11].
Results and Discussion
As starting materials we used ethyl 1-benzyl-4-(tert-butyldimethylsiloxy)-6-(nitro or
methoxyphenyl)-1,2,3,6-tetrahydropyridine-2-carboxylates 1-3, obtained by a hetero Diels-Alder
reaction between the siloxydienes 4-6 and the imine 7 (Scheme 1).
Scheme 1.
OTBDMS
TBDMSO
10% ZnCl2
N
COOEt
+
Bn
CH2Cl2 ,∆
Ar
N
COOEt
7
Bn
Ar
1 Ar = 2-NO2Ph
2 Ar = 3-NO2Ph
3 Ar = 3,4,5-OMe
4 Ar = 2-NO2Ph
5 Ar = 3-NO2Ph
6 Ar = 3,4,5-OMe
As previously mentioned, carbolines can be obtained by the reaction of 4-piperidones with
phenylhydrazines under acid conditions. We have used the tetrahydropyridine 4-sylilenolether directly
instead of the corresponding ketone, because the reaction conditions should lead to the hydrolysis of
the silylenolether to the corresponding ketone. In fact, in previous work we had carried out the Fischer
indolization of other related silylenolethers with good results [12]. Encouraged by those findings,
compound 1 was reacted at reflux with p-methoxyphenylhydrazine, 1:1 glacial acetic acid/EtOH and a
few drops of 37% HCl, producing the hydrazone 8 (Scheme 2). The structure of 8 was established by
1H- and 13C-NMR spectroscopy, which revealed the presence of the two isomeric hydrazones (Z/E).
Different conditions to facilitate tautomerization to the enehydrazine and diaza-Cope breakdown
of the N-N bond have been examined [13]. We used H2SO4/HOAc at 75ºC, but only degradation of the
starting material was detected.

Molecules 2006, 11
931
Scheme 2.
OTBDMS
N-NH
OMe
NH-NH
OMe
H
H2N N
OMe
NO2
NO2
NO2
2 eq.
N
COOEt
N
COOEt
N
COOEt
HOAc/EtOH 1:1
HCl 37%
Reflux, 6h
Bn
1
Bn
Bn
8
enehydrazine
H+
HN
OMe
NH
MeO
NO2
N
COOEt
N
COOEt
Bn
Bn
NO2
γ-carboline. Not detected
By reacting compound 1 with p-methoxyphenylhydrazine in the presence of BF3·Et2O/HOAc at
reflux pyrazoline 9 was obtained in 65% yield (Scheme 3). This compound was characterized by
1
13
1
HRMS, H- and C-NMR data. In the H-NMR spectra we observed three double doublets at 2.91,
3.85 and 5.88 ppm, corresponding to the pyrazoline ring. The olefinic protons resonate at 7.66 and
5.82 ppm as doublets with J=15.8Hz, indicating an E stereochemistry. The regiochemistry of
compound 9 was established by HMBC connectivities: the olefinic proton at 5.82 ppm with the
quaternary carbon (C=N) at 145 ppm; the olefinic proton at 7.66 ppm with the CH2 carbon at 41.5
ppm; and the aromatic CH at 7.29 ppm (dd J=8.0, 1.2Hz) with the CH at 61.4 ppm.
Scheme 3.
COOEt
OTBDMS
NO2
H
N
H2N N
OMe
NO2
N
2 eq.
1 eq. BF3.OEt2/HOAc
Reflux, 8h
N
COOEt
Bn
1
9
OMe
Based on these results, we carried out the reaction between 1 and hydrazine monohydrate under the
same reaction conditions. The resulting reaction mixture afforded 10 in 63% yield after purification by
1
crystallization from ether/hexane (Scheme 4). The H and 13C-NMR data of 10 showed signals
representative of a monosubstituted pyridazinone.

Molecules 2006, 11
932
Scheme 4.
OTBDMS
NO2
NO2
2 eq. NH2NH2
N
COOEt
N
Bn
1 eq. BF3.Et2O/HOAc
Reflux, 6h
NH
O
10
1
To investigate whether the substituents on the aryl group of the cycloadduct might have some
influence in the observed reactivity, we studied the reactions of 2 and 3 with hydrazines. When
p-methoxyphenylhydrazine was added to 3, under the same conditions described above for 8, the
formation of hydrazone 11 was observed. The same results were detected upon replacing the acetic
acid by the Lewis acid BF3·Et2O. However, when the acid medium was generated by one equivalent of
BF3·Et2O in acetic acid, the major reaction product was the pyrazoline 12 (77%) (Scheme 5).
Scheme 5.
COOEt
N-NH
OMe
N
N
MeO
MeO
N
COOEt
12
Bn
NO2
11
EtOH/AcOH 1:1/HCl conc.
OMe
or
OMe
1 eq. BF3.Et2O/EtOH
Reflux, 20h
H
1 eq. BF3.Et2O/HOAc
Reflux, 24h
H2N N
OMe
H
OTBDMS
H2N N
OMe
2 eq.
2 eq.
N
COOEt
Bn
R
R
OCH3
2: R= 3-NO2
3: R= 3,4,5-OMe
2 eq. NH2NH2
2 eq. NH2NH2
H3CO
OCH3
1 eq. BF3.Et2O
EtOH
Reflux, 3h
1 eq. BF3.Et2O/HOAc
Reflux, 24h
COOEt
N
NH
+
HN
Bn
N
N
MeO
MeO
O
NH
N
H
O
15: R= 3-NO2
16: R= 3,4,5-OMe
13
14
OMe

Molecules 2006, 11
933
When hydrazine monohydrate and 3 were used under these conditions, compound 13 was isolated
(41%) by crystallization (from ether/hexane), and hence the reaction outcome was similar to the case
1
of 1. H-NMR of the mother liquor revealed signals corresponding to a minor pyrazoline 14, which
could not be purified, and this structure was proposed by comparison with related compounds.
When 2 and 3 were treated with hydrazine and BF3·OEt2/EtOH in the absence of other inorganic
acids at reflux, 15 (54%) and 16 (60%) were isolated. The structure of these pyridazinones was
confirmed through NMR experiments (Scheme 6).
Scheme 6. Important connectivities found in the HMBC spectra of 15, and 1H- and 13C-
NMR assignments.
8.15 ; 123.2
H
H
H
NO2
H
NO2
148.7
H
7.77 ; 132.4 H
6.95 ; 129.0 H
H
8.31 ; 121.7
H
137.5
H
6.84 ; 131.8
H
H
H
H
2.61, 3.05 ; 28.1
N
H
N
NH
3.42 ; 51.4
HN
NH
HN
H
H
H
H
O
O
H
139.3
H
128.2
In order to understand these transformations we checked the reactivity of 1 in the different acid
media used in the previous transformations, without added hydrazines (Scheme 7). The reaction of 1
with BF3·Et2O/HOAc yielded the enone 17, produced by hydrolysis of the enol-ether, ring opening and
the elimination of BnNH2. Treatment of 1 with HCl led to the hydrolysis of the enol to the ketone 18,
with conservation of the piperidine structure.
Scheme 7.
OTBDMS
O
O
NO2
1 eq. BF3.Et2O/HOAc
Reflux, 4h
HCl 37%
NO2
NO2
N
COOEt
THF
rt, 4h
Bn
N
COOEt
COOEt
Bn
1
17
18
The results reported here are summarized in Scheme 8. The carbonyl derivatives can be postulated
as the precursors of most of the isolated derivatives, for example, through the route from 18 to 8 and
11, and then to other products, or a similar pathway through compound 17 or intermediate hydrazones.
This mechanism is also supported by the described syntheses of these types of compound from
conjugated ketones [14, 15, 16, 17].
The major differences are due to the presence of Lewis acid (BF3·Et2O), which facilitates the
evolution to pyrazolines and pyridazinones, and to the use of hydrazine or phenylhydrazine as the

Molecules 2006, 11
934
nucleophilic reagent. The stronger nucleophilic character of the unsubstituted nitrogen of the
hydrazones from the hydrazine must be responsible for the formation of the final products 10, 13, 15
or 16, whereas the lower reactive nitrogen of the hydrazones derived from the phenylhydrazine only
reacts, with the double bond conjugated with the aromatic ring, after the double elimination of
benzylamine. In this case, the absence of reaction with the carboxylate favours the formation of
pyrazolines as the major reaction product.
Scheme 8. Proposal for the formation of pyrazolines and pyridazinones.
O
OTBDMS
O
HOAc; BF3-Et2O
HCl/THF
r.t.; 4 h
reflux; 4 h
Ar
N
COOEt
Ar
N
COOEt
Ar
COOEt
17
Bn
Bn
18
1-3
R-NH-NH2
R-NH-NH2
H
N
H
H
N
N
N
R
N
R
N
R
Ar
HN
COOEt
Ar
N
COOEt
Ar
COOEt
Bn
Bn
Ar
Ar
COOEt
N
N
NH
NH
N
HN
N
Ar
O
O
Bn
R
15, 16
10, 13
9, 12, 14
Conclusions
Adequate control of the reaction conditions allows the selection of final products from the reaction
of the title compounds with hydrazines. These transformations are of interest for the synthesis of
pyrazolines and pyridazinones, whose biological activity will be communicated in due course.
Acknowledgements
Financial support came from the Junta de Castilla y León (SA048/03, SA129A06), the Spanish
MEC (CTQ2004-00369) and European FEDER funds.

Molecules 2006, 11
935
Experimental
General
Melting points were determined on a Büchi 510 instrument and are uncorrected. NMR spectra
were recorded on a Bruker ARX 400 and on a Bruker AC 200 spectrometer with TMS as internal
standard. Mass spectra were obtained on a VGTS-250 mass spectrometer by using the electrospray
ionization technique (ESI). Flash chromatography was performed with Merck 60 silica gel (0.063-0.2
or 0.040-0.063 mm).
Synthesis of Ethyl 1-benzyl-4-(2-(4-methoxyphenyl)hydrazono)-6-(2-nitrophenyl)piperidine-2-
carboxylate (8)
Compound 1 (100 mg, 0.20 mmol) was dissolved in EtOH/glacial AcOH (1:1 v/v, 16 mL)
containing HCl (37%, 180 µL). Then, p-methoxyphenylhydrazine (2 equivalents) was added at reflux
for 6 h. Ethanol was evaporated in vacuo and the residue was washed with a saturated solution of
Na2CO3. The mixture was extracted with EtOAc and the organic layer was washed with a NaCl
solution to pH 7, dried with Na2SO4, and evaporated in vacuo. The product was purified by flash
chromatography (hexane/ether 1:1), affording 104 mg (54%) of 8 as a brown oil. 1H-NMR (400 MHz,
CDCl3) δ (ppm): 8.10 (1H, m), 7.30-7.70 (8H, m), 6.72 (4H, s), 5.48 (1H, m), 4.20 (2H, c, J=7.0 Hz),
3.85 (1H, m), 3.70 (3H, s), 3.68 (2H, m), 3.52 (1H, s), 2.90-2.60 (2H, m), 2.60 (1H, m), 1.29 (3H, t,
J=7.0 Hz); 13C-NMR (100 MHz) δ (ppm): 174.1, 148.4, 147.5 x 2, 139.9, 139.5, 138.2, 134.4, 128.7 x
5, 127.3, 126.8, 125.2, 114.5 x 2, 114.3 x 2, 61.9, 61.1, 58.4, 55.7, 52.0, 46.1, 33.8, 14.4; HRMS (ESI)
m/z calcd for C28H30N4O5 [M+1] 503.2288, found 503.2279.
Synthesis of Ethyl 1-benzyl-4-(2-(4-methoxyphenyl)hydrazono)-6-(3,4,5-trimethoxyphenyl)piperidine-
2-carboxylate (11)
Following the procedure described for 8, 50 mg (40 % yield) of 11 were obtained as a brown oil.
1H-NMR (200 MHz, CDCl3) δ (ppm): 7.0-7.50 (5H, m), 6.88 (2H, d, J=8.8 Hz), 6.72 (2H, d, J=8.8
Hz), 6.55 (1H, s), 6.54 (1H, s), 4.70 (1H, m), 4.20 (2H, m), 4.10 (2H, m), 3.88 (3H, s), 3.82 (6H, s),
13
3.71 (3H, s), 3.60 (1H, m), 2.50-2.80 (4H, m), 1.23 (3H, m); C-NMR (50.3 MHz) δ (ppm): 174.2,
153.7, 153.4, 148.5, 141.3, 139.6x2, 138.8, 137.0, 128.4x2, 127.5, 127.2 x 2, 115.2 x 2, 114.3 x 2,
102.8 x 2, 67.0, 61.1, 61.0, 58.5, 56.2 x 2, 55.6, 52.0, 46.9, 34.8, 14.4; HRMS (ESI) m/z calcd. for
C31H37N3O6 [M+] 547.2685, found 547.2678.
Synthesis of (E)-Ethyl 3-(1-(4-methoxyphenyl)-5-(2-nitrophenyl)-4,5-dihydro-1H-pyrazol-3-yl)acrylate
(9) and (E)-Ethyl 3-(1-(4-methoxyphenyl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-3-yl)acrylate (12)
p-Methoxyphenylhydrazine hydrate (2 equivalents) and BF3·OEt2 (1 equivalent) were added to a
solution of 1 or 2 (0.79 mmol) in glacial HOAc (60 mL) and the mixture was stirred at reflux for 8 h.
The reaction was cooled and neutralized with a saturated Na2CO3 solution, extracted with EtOAc and

Molecules 2006, 11
936
the organic layer was washed with a NaCl solution to pH 7, dried with Na2SO4, evaporated in vacuo,
and purified by flash chromatography (hexane/ether 1:1) to give 9 and 12 respectively.
1
Compound 9: Brown oil (65% yield); H-NMR (400 MHz, CDCl3) δ (ppm): 8.12 (1H, d, J= 8.0 Hz),
7.66 (1H, d, J=15.8 Hz), 7.55 (1H, t, J=8.0 Hz), 7.46 (1H, t, J=8.0 Hz), 7.29 (1H, d, J=8.0 Hz), 6.86
(2H, d, J=9.2 Hz), 6.75 (2H, d, J=9.2 Hz), 5.88 (1H, dd, J=12.7, 6.5 Hz), 5.82 (1H, d, J=15.8 Hz), 4.25
(2H, q, J=6.7 Hz), 3.85 (1H, dd, J=17.3, 12.7 Hz), 3.72 (3H, s), 2.91 (1H, dd, J=17.3, 6.5 Hz), 1.30
(3H, t, J=6.7 Hz); 13C-NMR (100 MHz) δ (ppm): 166.5, 154.3, 147.2, 145.0, 136.5 x2, 136.3, 134.5,
128.8, 127.9, 125.5, 120.3, 114.7 x2, 114.6 x2, 61.4, 60.4, 55.5, 41.5, 14.2; HRMS (ESI) m/z calcd. for
C21H21N3O5 [M+1] 396.1553, found 396.1538.
Compound 12: Brown oil (77% yield); 1H-NMR (200 MHz, CDCl3) δ (ppm): 8.10 (1H, s), 8.11 (1H,
m), 7.70 (1H, d, J=15.8 Hz), 7.50-7.60 (2H, m), 6.93 (2H, d, J=8.7 Hz), 6.75 (2H, d, J=8.7 Hz), 5.79
(1H, d, J= 15.8 Hz), 5.41 (1H, dd, J=12.7, 7.0 Hz), 4.23 (2H, q, J=7.4 Hz), 3.72 (3H, s), 3.67 (1H, dd,
13
J=16.6, 12.7 Hz), 2.88 (1H, dd, J=16.6, 7.0 Hz), 1.30 (3H, t, J=7.4 Hz); C-NMR (50.3 MHz) δ
(ppm): 166.6, 154.6, 148.9, 144.6, 136.7x2, 136.3, 131.9, 130.6, 123.1, 121.2, 120.4, 115.4x2,
114.7x2, 64.7, 60.6, 55.5, 41.4, 14.3; HRMS (ESI) m/z calcd. for C21H21N3O5 [M+] 395.1485, found
395.1470.
Synthesis of (E)-6-(2-nitrostyryl)pyridazin-3(2H)-one (10) and (E)-6-(3,4,5-trimethoxystyryl)-
pyridazin-3(2H)-one (13)
Hydrazine monohydrate (2 equivalents) and BF3.OEt2 (1 equivalent) were added to a solution of 1
or 3 (0.13 mmol) in glacial HOAc (25 mL) and the resulting mixture was stirred at reflux for 8 h. The
reaction was cooled and neutralized with a saturated Na2CO3 solution, then extracted with EtOAc and
the organic layer was washed with NaCl solution to pH 7, dried with Na2SO4, evaporated in vacuo, and
the product was purified by crystallization in ether.
Compound 10: Brown solid (63% yield); 1H-NMR (200 MHz, DMSO-d6) δ (ppm): 8.01 (1H, d, J=8.0
Hz), 7.95 (1H, d, J=8.0 Hz), 7.87 (1H, d, J=8.0 Hz), 7.75 (1H, t, J=8.0 Hz), 7.59 (1H, t, J=8.0 Hz),
7.58 (1H, d, J=16.4 Hz), 7.10 (1H, d, J=16.4 Hz), 6.95 (1H, d, J=9.9 Hz); 13C-NMR (50.3 MHz) δ
(ppm): 162.9, 150.6, 145.7, 136.2, 133.7, 133.5, 132.4, 131.2, 131.9, 131.1, 129.2, 127.2; HRMS (ESI)
m/z calcd. for C12H9N3O3 [M+] 243.0650, found 243.0643.
1
Compound 13: Brown solid purified by crystallization from ether (41% yield; H-NMR (200 MHz,
CDCl3) δ (ppm): 7.63 (1H, d, J=9.9 Hz), 7.08 (1H, d, J=16.4 Hz), 7.00 (1H, d, J=9.9 Hz), 6.89 (1H, d,
J=16.4 Hz), 6.73 (2H, s), 3.90 (6H, s), 3.87 (3H, s); 13C-NMR (50.3 MHz) δ (ppm): 161.1, 153.6 x 2,
145.0, 139.1, 133.2, 131.4, 130.6, 130.0, 123.0, 104.2 x 2, 61.0, 56.2 x 2; HRMS (ESI) m/z calcd. for
C15H16N2O4 [M+Na] 311.1002, found 311.1018.

Molecules 2006, 11
937
Synthesis of (E)-6-(3-nitrostyryl)-4-(benzylamino)-4,5-dihydropyridazin-3(2H)-one (15) and (E)-6-
(3,4,5-trimethoxystyryl)-4-(benzylamino)-4,5-dihydropyridazin-3(2H)-one (16)
Hydrazine monohydrate (2 equivalents) and BF3.OEt2 (1 equivalent) were added to a solution of 2
or 3 (0.13 mmol) in EtOH (25 mL) and the mixture was stirred at reflux for 3 h. The reaction was
cooled and neutralized with a saturated Na2CO3 solution. The solvent was evaporated in vacuo and the
crude product was dissolved in EtOAc and washed with a solution of NaHCO3.
Compound 15: White solid (54% yield); mp 139-140 ºC (ether/hexane); 1H-NMR (400 MHz, CDCl3) δ
(ppm): 8.70 (1H, br s), 8.31 (1H, s), 8.15 (1H, d, J=7.0 Hz), 7.77 (1H, d, J=7.0 Hz), 7.55 (1H, t, J=7.0
Hz), 7.35-7.37 (5H, m), 6.95 (1H, d, J=16.5 Hz), 6.84 (1H, d, J=16.5 Hz), 3.96 (2H, s), 3.42 (1H, dd,
J=12.0, 6.7 Hz), 3.05 (1H, dd, J=16.6, 6.8 Hz), 2.61 (1H, dd, J=16.6, 11.6 Hz); 13C-NMR (100 MHz) δ
(ppm): 168.1, 150.9, 148.7, 139.3, 137.5, 132.4, 131.8, 129.8, 129.0, 128.6 x 2, 128.2 x 2, 127.3,
123.2, 121.7, 51.6, 51.4, 28.1; HRMS (ESI) m/z calcd. for C19H18N4O3 [M+Na] 373.1271, found
373.1254.
Compound 16: Brown solid (60% yield); mp 126-127 ºC (ether/hexane); 1H-NMR (200 MHz, CDCl3)
δ (ppm): 8.55 (1H, br s), 7.30-7.38 (5H, m), 6.77 (2H, s), 6.70 (2H, s), 3.86 (6H, s), 3.84 (3H, s), 3.80
(2H, s) 3.41 (1H, dd, J=12.4, 6.6 Hz), 3.08 (1H, dd, J=16.4, 6.9 Hz), 2.59 (1H, dd, J=16.4, 12.2 Hz);
13C-NMR (50.3 MHz) δ (ppm): 168.4, 153.5, 153.4, 152.1, 139.5, 139.1, 135.0, 131.3, 128.6 x 2,
128.2 x 2, 127.3, 125.4, 104.3 x 2, 61.0, 56.2 x 2, 51.6, 51.5, 28.1; HRMS (ESI) m/z calcd. for
C22H25N3O4 [M+] 395.1853, found 395.1848.
Synthesis of (2E,5E)-ethyl 6-(2-nitrophenyl)-4-oxohexa-2,5-dienoate (17)
To a solution of 1 (120 mg, 0.24 mmol) in glacial HOAc (30 mL), BF3.OEt2 (1 equivalent) was
added; the mixture was stirred at reflux for 3 h. The reaction was cooled and neutralized with a
saturated Na2CO3 solution, extracted with EtOAc and the organic layer was washed with an NaCl
solution to pH 7, dried with Na2SO4, evaporated in vacuo and purified by flash chromatography
1
(hexane/ether 1:1) to give 45 mg (69 %) of 17 as a brown oil. H-NMR (200 MHz, CDCl3) δ (ppm):
8.13 (1H, d, J=15.8 Hz), 8.08 (1H, d, J=7.5 Hz), 7.5-7.7 (3H, m), 7.46 (1H, d, J=15.8 Hz), 6.83 (2H, d
13
J=15.8 Hz), 4.28 (2H, q, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz); C-NMR (50.3 MHz) δ (ppm): 188.2,
165.4, 148.5, 141.0, 137.6, 133.8, 132.0, 130.9, 130.5, 129.5, 129.2, 125.2, 61.5, 14.2.
Synthesis of Ethyl 1-benzyl-6-(2-nitrophenyl)-4-oxopiperidine-2-carboxylate (18)
Compound 1 (105 mg, 0.21 mmol) dissolved in THF (5 mL) was treated with 37% HCl (20 µL)
and then stirred for 4 h. The reaction mixture was washed with saturated NaHCO3, dried and
evaporated. The residue was chromatographed (hexane/EtOAc 7:3) to afford 18 (60 mg, 75 %) as an
orange oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.03 (1H, d, J=8.0 Hz), 7.78 (1H, d, J=8.1 Hz), 7.67
(1H, t, J=8.0 Hz), 7.43 (1H, t, J=8.1 Hz), 7.30-7.24 (5H, m), 4.99 (1H, dd, J=8.0, 5.6 Hz), 4.26 (2H, q,
J=7.2 Hz), 3.88 (1H, dd, J=6.4, 2.0 Hz), 3.61 (1H, d, J=13.6 Hz), 3.46 (1H, d, J=13.6 Hz), 2.99 (1H,

Molecules 2006, 11
938
dd, J=15.6, 5.6 Hz), 2.75 (1H, dd, J=14.8, 6.4 Hz), 2.60 (1H, dd, J=14.8, 2.0 Hz), 2.58 (1H, dd,
13
J=15.6, 8.0 Hz), 1.33 (3H, t, J=7.2 Hz); C-NMR (100 MHz) δ (ppm): 204.7, 171.2, 149.9, 137.5,
137.4, 133.2, 128.8, 128.6 x5, 127.5, 124.1, 61.1, 58.2, 56.8, 55.0, 47.3, 42.7, 14.3; HRMS (ESI) m/z
calcd. for C21H22N2O5 [M+] 382.1529, found 382.1536.
References
1. Southon, I.W.; Buckingham, J. “Dictionary of Alkaloids”; Chapman & Hall: London, 1989.
2. Yamashita, T.; Kawai, N.; Tokuyama, H.; Fukuyama T. Stereocontrolled Total Synthesis of (-)-
Eudistomin C. J. Am. Chem. Soc. 2005, 127, 15038-15039.
3. Cao, R.; Peng, W.; Chen, H.; Hou, X.; Guan, H.; Chen, Q.; Ma, Y.; Xu, A. Synthesis and in Vitro
Cytotoxic Evaluation of 1,3-Bisubstituted and 1,3,9-Trisubstituted β-Carboline Derivatives. Eur.
J. Med. Chem. 2005, 40, 249-257.
4. Wynne, J.H.; Stalick, W.M. Syntheses of Functionalized 1,4-Disubstituted γ-Carbolines. J. Org.
Chem. 2003, 68, 4845-4849.
5. Snyder, S.A.; Vosburg, D.A.; Jarvis, M.G.; Markgraf, J.H. Intramolecular Hetero Diels–Alder
Routes to γ-Carboline Alkaloids. Tetrahedron 2000, 56, 5329-5335.
6. Zhang, L-H.; Meier, W.; Wats, E.; Costello, T.D.; Ma, P. ; Ensinger, C.L. ; Rodgers, J.M.;
Jacobson, I.C.; Rajagopalan, P. Pictet-Spengler Reaction in Trifluoroacetic Acid. Large Scale
Synthesis of Pyridoindolobenzodiazepine as an Atypical Antipsychotic Agent. Tetrahedron Lett.
1995, 36, 8387-8390.
7. Suzuki, H.; Tsukakoshi, Y.; Tachikawa, T.; Miura, Y.; Adachi, M.; Murakami, Y. A New
Synthesis of 4-Oxygenated β-Carboline Derivatives by Fischer Indolization. Tetrahedron Lett.
2005, 46, 3831-3834.
8. Azarifar, D.; Shaebanzadeh, M. Synthesis and Characterization of New 3,5-Dinaphthyl
Substituted 2-Pyrazolines and Study of Their Antimicrobial Activity. Molecules 2002, 7, 885-895.
9. Hamad, A-S, S.; Hashem, A. I. A Facile Method for the Synthesis of 6-Aryl-1-(3-
Chloropropanoyl)-4-[(E)-1-(2-Furyl)Methylidene)]-1,2,3,4- Tetrahydro-3-Pyridazinones and 2-(2-
Chloroethyl)-5-[α-Aracyl-β-(2-Furyl)]-(E)-Vinyl-1,3,4-Oxadiazoles. Molecules 2000, 5, 895-907.
10. Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.; Secci, D.; Chimenti, P.; Ferlini, C.; Scambia,
G. Synthesis of Some Pyrazole Derivatives and Preliminary Investigation of Their Affinity
Binding to P-glycoprotein. Bioorg. Med. Chem. Lett. 2005, 15, 4632-4635.
11. Cox, C. D.; Torrent, M.; Breslin , M. J.; Mariano, B. J.; Whitman, D. B. ; Coleman, P.J.; Buser,
C. A. ; Walsh, E. S.; Hamilton , K.; Schaber, M. D.; Lobell, R. B.; Tao, W.; South, V. J.; Kohl, N.
E.; Yan, Y.; Kuo, L. C.; Prueksaritanont, T.; Slaughter, D. E.; Li, Ch.; Mahan, E.; Lu, B. ;
Hartman, G. D. Kinesin Spindle Protein (KSP) Inhibitors. Part 4: Structure-Based Design of 5-
Alkylamino-3,5-diaryl-4,5-dihydropyrazoles as Potent, Water-soluble Inhibitors of the Mitotic
Kinesin KSP. Bioorg. Med. Chem. Lett. 2006, 16, 3175-3179.
12. Caballero, E.; Adeva, M.; Calderón, S.; Sahagún, H.; Tomé, F.; Medarde, M.; Fernández,
J.L.; López-Lázaro, M.; Ayuso, M.J. Synthesis and Cytotoxic Activity of Different Open
Indolo-carbazole Alkaloid Analogues. Bioorg. Med. Chem. 2003, 11, 3413-3421.
13. Reed, B. G.W.; Cheng’s P.T.W.; McLean T. The Regioselectivity of the Formation of Dihydro-
and Tetrahydrocarbazoles by the Fischer Indole Synthesis. Can. J. Chem. 1982, 60, 419-424.

Molecules 2006, 11
939
14. Elguero J. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.R.; Rees, C.W.; Scriven,
E.F.V. Eds.; Pergamon Press: Oxford, 1996; Vol. 3, p. 1.
15. Calvo, L.A.; Gonzalez-Nogal, A.M.; Gonzalez-Ortega, A.; Sañudo, M.C. Synthesis of Silylated β-
Enaminones and Applications to the Synthesis of Silyl Heterocycles. Tetrahedron Lett. 2001, 42,
8981-8984.
16. Ursic, U.; Bevk, D.; Toplak, R.; Groselj, U.; Meden, A.; Svete, J.; Stanovnik, B. Synthesis of
Methyl 2-[(Benzyloxycarbonyl)amino]-3-cyanopropenoate and its Transformations into
Derivatives of Pyrrole, 2,5-Dioxoimidazolidine, 1H-Pyrazole, and 4,6-Diaminopyridazine
Heterocycles 2006, 68, 949-966.
17. Stanovnik, B.; Svete, J. Synthesis of Heterocycles from Alkyl 3-(Dimethylamino)propenoates and
Related Enaminones. Chem. Rev. 2004, 104, 2433-2480.
Sample Availability: Available from the authors.
© 2006 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.