1,1-Disubstituted tetrahydroisoquinolines from enaminones via Pictet-Spengler reaction

Article abstract of DOI:10.1081/SCC-120022477

Enaminones, prepared by condensation of homoveratrylamine with 1,3-dicarbonyl compounds, undergo intramolecular cyclization in acidic media to afford 1,1-disubstituted tetrahydroisoquinolines in good yields. Further modification of the title compounds is

Full text of DOI:10.1081/SCC-120022477

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1,1-Disubstituted Tetrahydroisoquinolines from
Enaminones via Pictet–Spengler Reaction
Atanas P. Venkov a & Plamen A. Angelov a
a Department of Organic Chemistry, University of Plovdiv, Plovdiv, Bulgaria
Published online: 21 Aug 2006.
To cite this article: Atanas P. Venkov & Plamen A. Angelov (2003) 1,1-Disubstituted Tetrahydroisoquinolines from Enaminones
via Pictet–Spengler Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:17, 3025-3033, DOI: 10.1081/SCC-120022477
To link to this article: http://dx.doi.org/10.1081/SCC-120022477
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 17, pp. 3025–3033, 2003
1,1-Disubstituted Tetrahydroisoquinolines from
Enaminones via Pictet–Spengler Reaction
*
Atanas P. Venkov and Plamen A. Angelov
Department of Organic Chemistry, University
of Plovdiv, Plovdiv, Bulgaria
ABSTRACT
Enaminones, prepared by condensation of homoveratrylamine with
1,3-dicarbonyl compounds, undergo intramolecular cyclization
in acidic media to afford 1,1-disubstituted tetrahydroisoquinolines
in good yields. Further modification of the title compounds is
demonstrated.
Key Words: Enaminones; Tetrahydroisoquinolines; Cyclization;
Pictet-Spengler reaction.
The various reactivities associated with the conjugated system
N–C¼C–C¼O make the b-enaminones valuable reagents with versatile
*Correspondence: Atanas P. Venkov, Department of Organic Chemistry,
University of Plovdiv, 24 Tsar Asen str., 4000 Plovdiv, Bulgaria; E-mail:
venkov@argon.acad.bg.
3025
DOI: 10.1081/SCC-120022477
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3026
Venkov and Angelov
applications in the heterocyclic synthesis.[1,2] Surprisingly, however, the
potential of enaminones as imine analogs in the Pictet–Spengler reac-
tion[3] has received very little attention. There are only two reports for
cyclization of tryptamine-derived enaminones to the corresponding 1,1-
disubstituted b-carbolines.[4,5] This, along with recent reports concerning
the synthesis[6,7] and anticonvulsant activity[8] of some 1,1-disubstituted
tetrahydroisoquinolines, prompted us to investigate Pictet–Spengler type
cyclization of homoveratrylamine-derived enaminones 3.
The enaminones 3 were obtained by condensation of homoveratryl-
amine 1 with the corresponding 1,3-dicarbonyl compounds 2 (Sch. 1,
Table 1).
The cyclization of enaminones 3 was examined in the presence of
acids as AcOH, HCO2H, TFA, methanolic HCl, CF3SO3H, CH3SO3H
and H3PO4. After a survey of the reaction conditions, it was found that
the cyclization to the expected 1,1-disubstituted tetrahydroisoquinolines
4 is successful only in orthophosphoric or in methanesulphonic acid
(MSA). All the other acids in this survey either left the enaminones 3
unchanged or caused cleavage of the enamine C-N bond leading to
recovery of the starting amine 1 and 1,3-dicarbonyl compound 2.
Scheme 1.

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1,1-Disubstituted Tetrahydroisoquinolines
Table 1. Yields and physical data of enaminones 3a–i.
3027
Yield
(%)
M.p.
(ꢀC)
3
a
1H-NMR,a ꢀ (ppm), J (Hz)
98
37–40
1.75 (s, 3H), 1.99 (s, 3H), 2.80 (t, 2H, J ¼ 6.9),
3.41–3.49 (m, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.92
(s, 1H), 6.71–6.84 (m, 3H), 10.92 (s, 1H)
1.80 (s, 3H), 2.82 (t, 2H, J ¼ 7.0), 3.42–3.47 (m, 2H),
3.85 (s, 3H), 3.87 (s, 3H), 4.43 (s, 1H), 6.75–6.84
(m, 3H), 7.23 (s, 1H), 7.61–7.64 (m, 2H), 8.11–8.15
(m, 2H), 9.42 (s, 1H)
b
c
d
98
81–83
98
70
43–45
oil
1.24 (t, 3H, J ¼ 7.1), 1.79 (s, 3H), 2.78 (t, 2H, J ¼ 7.0),
3.38–3.47 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.07
(q, 2H, J ¼ 7.1), 4.41 (s, 1H), 6.69–6.86 (m, 3H),
8.67 (s, 1H)
1.27 (t, 3H, J ¼ 7.1), 2.67 (t, 2H, J ¼ 7.0), 3.24–3.32
(m, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 4.14 (q, 2H,
J ¼ 7.1), 4.55 (s, 1H), 6.55–6.60 (m, 3H), 7.17–7.40
(m, 5H), 8.63 (s, 1H)
e
f
85
95
121–122
39–43
1.74 (s, 3H), 2.78 (t, 2H, J ¼ 7.1), 3.36–3.47 (m, 2H),
3.85 (s, 3H), 3.87 (s, 3H), 4.30 (s, 1H), 4.79 (s, 2H),
6.73–6.83 (m, 3H), 9.26 (s, 1H)
1.75 (s, 3H), 2.78 (t, 2H, J ¼ 7.1), 3.36–3.44 (m, 2H),
3.85 (s, 3H), 3.86 (s, 3H), 4.38 (s, 1H), 6.69–6.78
(m, 3H), 6.82 (s, 1H), 6.97–7.46 (m, 5H),
9.35 (s, 1H)
g
h
i
98
80
98
135–137
182–183
oil
1.87 (s, 3H), 2.87 (t, 2H, J ¼ 7.0), 3.53–3.58 (m, 2H),
3.85 (s, 3H), 3.86 (s, 3H), 5.62 (s, 1H), 6.75–6.84
(m, 3H), 7.36–7.42 (m, 3H), 7.83–7.87 (m, 2H),
11.57 (s, 1H)
In DMSO-d6: 1.85 (s, 3H), 2.74 (t, 2H, J ¼ 6.9),
3.38–3.46 (m, 2H), 3.71 (s, 3H), 3.75 (s, 3H), 4.65
(s, 1H), 6.74–6.88 (m, 3H), 7.00 (d, 1H, J ¼ 3.6),
7.35 (d, 1H, J ¼ 3.6), 9.13 (s, 1H), 11.2 (s, 1H)
1.09–1.20 (m, 6H), 1.79 (s, 3H), 2.30–3.10 (m, 4H),
3.30–3.75 (m, 4H), 3.86 (s, 3H), 3.87 (s, 3H), 4.51
(s, 1H), 6.72–6.91 (m, 3H), 9.70 (s, 1H)
1
aUnless otherwise noted H-NMR spectra were run in CDCl3.
The cyclization reactions in MSA and orthophosphoric acid were
carried out without solvent. The transformation of 3 to 4 (Sch. 1) in
MSA proceeded more readily with the enaminoamides 3e–i than with
the enaminoketones 3a,b or enaminoesters 3c,d. The enaminoamides

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3028
Venkov and Angelov
Table 2. Tetrahydroisoquinolines 4 obtained fromenaminones 3 (Sch. 1).
H3PO4 at 100ꢀC
MSA at r.t.
4
Time (days)
Yield %
Time (h)
Yield %
M.p. (oC)
a
b
c
d
e
f
5
5
5
5
2
2
2
5
2
—
—
—
—
89
85
80
31
85
4
81a
38a
71
27
95
52
10
95
95
86–87a
133–134a
oil
4
3
5
93–94
134–135b
54–57
1
8 (at 60ꢀC)
g
h
i
8 (at 60ꢀC)
147–149
156–157c
82–83c
1
1
aAs N-acetyl derivatives.
bFromacetonitrile.
cFromethylacetate.
afforded the corresponding tetrahydroisoquinolines 4e–i in good yields
after 2 days at r.t., while the other enaminones failed to react even after
5 days at this temperature (Table 2).
Elevation of the temperature up to 100ꢀC in most cases led to com-
plex mixtures of products and low yields of the target compounds 4.
The cyclization of enaminones 3 in orthophosphoric acid was carried
out at 100ꢀC for the time specified in Table 2 and led to the correspond-
ing tetrahydroisoquinolines 4 in good to moderate yields (Table 2, 4a–i).
The low yield of 4d can be attributed to steric hindrance of the phenyl
group (R1 ¼ C6H5), while those of 4f and 4g were due to side reactions
of 3f and 3g resulting in release of aniline and p-nitroaniline respectively.
In order to avoid the cleavage of the anilide groups in these cases the
reactions were carried out at lower temperature (60ꢀC), but even so the
yields were far worse than those obtained in MSA at r.t.
Unlike 4c–i (Table 2), products 4a and 4b, when purified by column
chromatography on neutral alumina, underwent an elimination reaction
and were completely converted to 6,7-dimethoxy-1-methyl-3,4-dihydro-
isoquinoline 5. Compound 5 was identified by comparison with authentic
sample obtained earlier.[9] The same conversion was observed when 4a,b
were allowed to stand at room temperature in dichloromethane solution.
N-acetyl derivatives of 4a and 4b are, however, stable and were used for
the analytical characterizations. The acetylation of the free bases 4a,b
was carried out in dichloromethane without their isolation, using acetyl
chloride in the presence of triethylamine.

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1,1-Disubstituted Tetrahydroisoquinolines
3029
As cyclic secondary amines, products 4 are suitable for various
further transformations. Particularly interesting was the opportunity to
use b-aminoamides, such as 4e–h, for synthesis of pyrimido[6,1-a]isoqui-
nolin-2-ones. This type of heterocyclic compounds are reported to pos-
sess various biological activities.[10] The preliminary experiments showed
that 4e–h react readily with formaldehyde to afford the corresponding
pyrimido[6,1-a]isoquinolin-2-ones 6 in excellent yields (95–97%).
In conclusion, the reported Pictet–Spengler type synthesis extends
the range of the classic reaction, revealing concise and viable route to
1,1-disubstituted tetrahydroisoquinolines. The synthesized compounds
can be used as building blocks for the construction of more compli-
cated heterocycles.
Experimental
Melting points were determined on a Boettus hotstage apparatus and
are uncorrected. Unless otherwise noted, NMR spectra were recorded
on a Bruker 250 MHz device using CDCl3 as solvent. Chemical shifts
(ꢀ, ppm) are downfield from TMS as internal standard and coupling
constants are in Hz. Mass spectra were recorded on a Jeol JMS-D300
spectrometer (70 eV). All new compounds had elemental analyses within
0.4% of the theoretical values as well as correct parent ion peaks by mass
spectrometry.
Enaminones 3a–i (Table 1) - General Procedure
Homoveratrylamine (10 mmol) was added to a solution of the corre-
sponding 1,3-dicarbonyl compound (10 mmol) in 20 mL dichloromethane
(methanol for 3e and 3h). Anhydrous Na2SO4 (3 g) was added when
dichloromethane was used as solvent. The reaction mixtures were stirred
overnight at r.t. (8 h at 50ꢀC for enaminone 3h and 14 days at r.t. for
3d). After completion of the reaction, the sulphate was filtered off and
the solvent removed by distillation. For enaminone 3e, the methanolic
solution was poured into ice water and the precipitated product filtered
off, washed with ether and dried. Enaminone 3h crystallized directly from
the reaction mixture.
Enaminones 3 can be used without purification, only compound 3d,
has to be purified by column chromatography on silica gel (silica gel 60,
70–230 mesh, Merck) using mixture of ether–petroleum ether (1:1) as
eluent.

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Venkov and Angelov
1,1-Disubstituted Tetrahydroisoquinolines 4 (Table 2)
General procedure in MSA. Mixture of MSA (9 g) and enaminone 3
(3 mmol) was stirred at room temperature for the time given in Table 2.
The reaction mixture was quenched with water (150 mL) and the acidic
solution extracted with dichloromethane (2 ꢁ 10 mL) to remove any
nonbasic side products. The water layer was then brought to pH 10
by addition of 25% aq. NH3 (with proper cooling) and the product
4 extracted with dichloromethane (3 ꢁ 20 mL). The products 4, after
distillation of the solvent were purified by recrystallization or column
chromatography on neutral alumina using ether or mixture of ether–
petroleumether (1:1) as eluents.
General procedure in H3PO4. Mixture of orthophosphoric acid (9 g)
and enaminone 3 (3 mmol) was stirred at the conditions shown in Table 2.
The reaction mixtures were worked up as described above.
N-acetyl derivatives of 4a and 4b. Triethylamine (3 mmol) was added
to the dichloromethane extract (60 mL) of 4a or 4b, obtained according
to the above procedure. Then, acetylchloride (3 mmol) was added drop-
wise to the stirred solution and after 30 min the reaction mixture was
washed with 10% aqueous HCl (50 mL) and water (50 mL). The obtained
N-acetyl tetrahydroisoquinolines were purified by column chromatogra-
phy on neutral alumina, using ether (for 4b) and ether–petroleumether
(1:1) (for 4a) as eluents.
4a, N-acetyl. Anal. calcd. for C17H23NO4: C 66.86, H 7.59, N 4.59%;
found: C 66.91, H 7.60, N 4.65%; 1H-NMR: 1.71 (s, 3H), 1.93
(s, 3H), 2.18 (s, 3H), 2.70–2.74 (m, 1H), 3.01–3.08 (m, 1H), 3.04 (d, 1H,
J ¼ 17.4), 3.41–3.51 (m, 1H), 3.82–3.90 (m, 1H), 3.86 (s, 6H), 4.60 (d, 1H,
J ¼ 17.4), 6.58 (s, 1H), 6.66 (s, 1H); 13C-NMR: 25.2, 27.7, 29.6, 30.8, 44.4,
52.1, 55.6, 56.1, 59.7, 108.3, 110.4, 127.6, 133.8, 147.0, 147.6, 170.3, 206.0.
4b, N-acetyl. Anal. calcd. for C22H25NO4: C 71.91, H 6.86, N 3.81%;
1
found: C 71.92, H 6.85, N 3.79%; H-NMR: 1.83 (s, 3H), 2.15 (s, 3H),
2.71–2.81 (m, 1H), 2.99–3.10 (m, 1H), 3.52–3.62 (m, 1H), 3.59 (d, 1H,
J ¼ 17.7), 3.73 (s, 3H), 3.82–3.92 (m, 1H), 3.83 (s, 3H), 5.25 (d, 1H, J ¼
17.7), 6.58 (s, 1H), 6.65 (s, 1H), 7.34–7.48 (m, 3H), 7.81–7.85 (m, 2H);
13C-NMR: 25.4, 28.9, 29.8, 44.7, 51.1, 55.6, 56.0, 60.2, 108.4, 110.6,
127.5, 127.7, 128.3, 132.6, 134.1, 137.6, 147.0, 147.6, 170.3, 198.9.
4c: Anal. calcd. for C16H23NO4: C 65.51, H 7.90, N 4.77%; found: C
65.59, H 7.98, N 4.83%; 1H-NMR: 1.16 (t, 3H, J ¼ 7.1), 1.51 (s, 3H), 2.68
(d, 1H, J ¼ 14.8), 2.72 (t, 2H, J ¼ 5.8), 2.92 (d, 1H, J ¼ 14.8), 3.06–3.19
(m, 2H), 3.32 (br s, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.06 (q, 2H, J ¼ 7.1),
6.55 (s, 1H), 6.64 (s, 1H); 13C-NMR: 13.8, 28.8, 29.3, 38.5, 45.4, 54.5,
55.4, 55.8, 60.0, 108.5, 111.3, 126.8, 133.1, 147.0, 171.3.

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1,1-Disubstituted Tetrahydroisoquinolines
3031
4d: Anal. calcd. for C21H25NO4: C 70.96, H 7.09, N 3.94%; found: C
70.90, H 7.12, N 3.87%; 1H-NMR: 1.06 (t, 3H, J ¼ 7.1), 2.61–3.06
(m, 5H), 3.18 (s, 2H), 3.79 (s, 3H), 3.87 (s, 3H), 3.97 (q, 2H, J ¼ 7.1),
6.61 (s, 1H), 6.63 (s, 1H), 7.20–7.34 (m, 5H); 13C-NMR 13.6, 30.3, 42.5,
49.1, 53.9, 55.8, 56.0, 61.5, 109.0, 114.2, 126.2, 127.9, 129.9, 131.5, 134.6,
146.5, 148.1, 171.2.
4e: Anal. calcd. for C14H20N2O3: C 63.62, H 7.63, N 10.60%; found:
C 63.73, H 7.72, N 10.74%; 1H-NMR (DMSO-d6): 1.34 (s, 3H), 2.35 (d,
1H, J ¼ 14.3), 2.49–2.57 (m, 2H), 2.62 (d, 1H, J ¼ 14.3), 2.85–2.99 (m,
2H), 3.32 (br s, 1H), 3.69 (s, 3H), 3.71 (s, 3H), 6.57 (s, 1H), 6.74 (s, 1H),
7.74 (s, 2H); 13C-NMR: 28.5, 30.4, 39.5, 47.3, 54.3, 55.8, 56.1, 111.8,
113.9, 129.0, 137.7, 147.8, 148.0, 172.5.
4f: Anal. calcd. for C20H24N2O3: C 70.57, H 7.11, N 8.23%; found:
1
C 70.62, H 7.19, N 8.37%; H-NMR: 1.54 (s, 3H), 1.76 (br s, 1H), 2.56
(d, 1H, J ¼ 15.9), 2.73–2.80 (m, 2H), 2.94 (d, 1H, J ¼ 15.9), 3.15–3.29
(m, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.52 (s, 1H), 6.67 (s, 1H), 7.02–7.49
(m, 5H), 11.15 (s, 1H); 13C-NMR: 29.0, 29.4, 38.3, 48.0, 54.5, 55.6, 55.9,
108.5, 111.4, 119.6, 123.4, 125.9, 128.7, 132.7, 138.3, 147.4, 147.5, 169.1.
4g: Anal. calcd. for C20H23N3O5: C 62.33, H 6.02, N 10.90%; found:
1
C 62.49, H 5.91, N 10.63%; H-NMR: 1.57 (s, 3H), 1.69 (br s, 1H), 2.63
(d, 1H, J ¼ 16.0), 2.71–2.90 (m, 2H), 2.98 (d, 1H, J ¼ 16.0), 3.16–3.38
(m, 2H), 3.82 (s, 3H), 3.86 (s, 3H), 6.53 (s, 1H), 6.66 (s, 1H), 7.58–7.65
(m, 2H), 8.12–8.18 (m, 2H), 11.88 (s, 1H); 13C-NMR: 29.2, 29.5, 39.2,
48.2, 54.9, 55.9, 56.1, 109.0, 111.8, 121.5, 125.9, 129.3, 137.8, 138.4, 144.5,
147.4, 147.5, 170.0.
4h: Anal. calcd. for C17H21N3O3S: C 58.77, H 6.09, N 12.09%;
1
found: C 58.90, H 6.18, N 12.31%; H-NMR: 1.56 (s, 3H), 2.67 (d,
1H, J ¼ 16.1), 2.73–2.90 (m, 2H), 3.03 (d, 1H, J ¼ 16.1), 3.12–3.35 (m,
2H), 3.82 (s, 3H), 3.84 (s, 3H), 6.53 (s, 1H), 6.65 (s, 1H), 6.89 (d, 1H,
J ¼ 3.6), 7.40 (d, 1H, J ¼ 3.6), 12.10 (br s, 1H); 13C-NMR: 29.0, 29.3,
38.3, 46.5, 54.5, 55.7, 56.0, 108.4, 111.5, 113.0, 126.2, 132.0, 137.3,
147.6, 157.9, 168.6.
4i: Anal. calcd. for C18H28N2O3: C 67.47, H 8.81, N 8.74%;
1
found: C 67.38, H 8.95, N 8.52%; H-NMR: 1.04 (t, 3H, J ¼ 7.1), 1.16
(t, 3H, J ¼ 7.1), 1.53 (s, 3H), 2.62 (d, 1H, J ¼ 15.5), 2.72–2.77 (m, 2H),
2.88 (d, 1H, J ¼ 15.5), 3.03–3.15 (m, 5H), 3.84 (s, 3H), 3.85 (s, 3H), 6.57
(s, 1H), 6.62 (s, 1H); 13C-NMR: 12.8, 14.2, 29.0, 29.6, 38.6, 39.9, 41.9,
42.1, 54.9, 55.5, 56.0, 108.8, 111.6, 127.5, 134.6, 146.8, 147.0, 170.1.
Hexahydropyrimido[6,1-a]isoquinolin-2-ones (6) - General procedure.
36% aqueous H2CO (1.1 mmol) and anhydrous Na2SO4 (300 mg) were
added to a solution of the corresponding 1,1-disubstituted tetrahydro-
isoquinoline (1 mmol) in 5 mL dichloromethane (or acetonitrile for 4e).

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The mixtures were stirred overnight at r.t., the sulphate filtered off and
washed with dichloromethane (2 ꢁ 10 mL). The organic phase was then
washed with water, dried and the solvent removed by distillation.
6e: Yield 95%, m.p. 181–182oC; Anal. calcd. for C15H20N2O3: C
65.20, H 7.30, N 10.14%; found: C 65.25, H 7.38, N 10.21%;
1H-NMR: 1.45 (s, 3H), 2.64 (s, 2H), 2.80–3.00 (m, 4H), 3.86 (s, 6H),
4.14 (dd, 1H, J ¼ 2.8, 10.5), 4.42 (d, 1H, J ¼ 10.5), 6.57 (s, 1H), 6.63 (s,
1H), 7.98 (s, 1H); 13C-NMR: 21.0, 28.9, 43.5, 44.3, 54.7, 55.6, 55.8, 60.9,
107.9, 111.1, 125.0, 133.8, 147.4, 170.3.
6f: Yield 97%, m.p. 175–176ꢀC; Anal. calcd. for C21H24N2O3: C
1
71.57, H 6.86, N 7.95%; found: C 71.61, H 6.90, N 8.03%; H-NMR:
1.58 (s, 3H), 2.84 (s, 2H), 2.87–3.15 (m, 4H), 3.85 (s, 6H), 4.32 (d, 1H,
J ¼ 10.8), 4.82 (d, 1H, J ¼ 10.8), 6.58 (s, 1H), 6.67 (s, 1H), 7.27–7.42
(m, 5H); 13C-NMR: 22.4, 28.9, 43.8, 44.6, 55.5, 55.6, 55.8, 69.0, 107.9,
111.0, 124.9, 126.2, 127.0, 129.1, 133.4, 140.2, 147.4, 167.2.
6g: Yield 95%, m.p. 189–190ꢀC; Anal. calcd. for C21H23N3O5:
C 63.47, H 5.83, N 10.57%; found: C 63.41, H 5.85, N 10.48%;
1H-NMR: 1.61 (s, 3H), 2.81–3.21 (m, 6H), 3.87 (s, 3H), 3.89 (s, 3H),
4.42 (d, 1H, J ¼ 10.8), 5.02 (d, 1H, J ¼ 10.8), 6.59 (s, 1H), 6.66 (s, 1H),
7.49–7.58 (m, 2H), 8.24–8.30 (m, 2H); 13C-NMR: 22.5, 28.9, 43.7, 44.8,
55.5, 55.6, 55.8, 69.5, 108.0, 111.2, 125.0, 128.3, 132.9, 133.4, 145.2, 144.5,
147.4, 167.6.
6h: Yield 95%, m.p. 59–61ꢀC; Anal. calcd. for C18H21N3O3S:
C 60.15, H 5.89, N 11.69%; found: C 60.22, H 5.96, N 11.54%;
1H-NMR: 1.56 (s, 3H), 2.78–3.20 (m, 6H), 3.86 (s, 3H), 3.88 (s, 3H),
5.01 (d, 1H, J ¼ 12.0), 5.35 (d, 1H, J ¼ 12.0), 6.59 (s, 1H), 6.67 (s, 1H),
7.04 (d, 1H, J ¼ 3.6), 7.53 (d, 1H, J ¼ 3.6); 13C-NMR: 23.1, 29.2, 43.1,
45.3, 55.0, 55.7, 56.0, 66.5, 108.2, 111.3, 114.7, 125.3, 133.0, 137.1, 147.6,
147.7, 157.8, 166.5.
ACKNOWLEDGMENT
We acknowledge financial support fromthe Fund for Scientific
Research of the Plovdiv University.
REFERENCES
1. Greenhill, J.V. Chem. Soc. Rev. 1977, 6, 277–294.
2. Lue, P.; Greenhill, J.V. Adv. Heterocycl. Chem. 1996, 67, 207–343.
3. Cox, E.D.; Cook, J.M. Chem. Rev. 1995, 95, 1797–1842.

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4. Maclaren. J.A. Aust. J. Chem. 1977, 30, 2045–2051.
5. Kirkpatrick, A.; Maclaren, J.A. Aust. J. Chem. 1983, 36, 833–838.
6. Horiguchi, Y.; Kodama, H.; Nakamura, M.; Yoshimura, T.;
Hanezi, K.; Hamada, H.; Saitoh, T.; Sano, T. Chem. Pharm. Bull.
2002, 50(2), 253–257.
7. Bois-Choussy, M.; Cadet, S.; Paolis, M.D.; Zhu, J. Tetrahedron
Lett. 2001, 42(27), 4503–4506.
8. Ohkubo, M.; Kuno, A.; Katsuta, K.; Ueda, Y.; Shirakawa, K.;
Nakanishi, H.; Nakanishi, I.; Kinoshita, T.; Takasugi, H. Chem.
Pharm. Bull. 1996, 44(1), 95–102.
9. Venkov, A.; Ivanov, I. Tetrahedron 1996, 52, 12299–12308.
10. Kobor, J.; Fulop, F.; El-Gharib, M.S.; Bernath, G. J. Heterocyclic
Chem. 1984, 21, 149–153 and references cited therein.
Received in the UK November 19, 2002

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