Racemic and diastereoselective synthesis of aryl and heteroaryl tetrahydroisoquinolines via the Pictet-Spengler reaction

Article abstract of DOI:10.1002/jhet.5570430121

New tetrahydroisoquinolines were synthesized by the Pictet-Spengler reaction. Influence of a wide range of aryl and heteroaryl aldehydes, was investigated in the cyclization step with 3,4-dimethoxyphenylethylamine 1, L-DOPA 2 and L-3,4-dimethoxyphenylalan

Full text of DOI:10.1002/jhet.5570430121

Racemic and Diastereoselective Synthesis of Aryl and Heteroaryl
Tetrahydroisoquinolines via the Pictet-Spengler Reaction
Sylvain Aubry[a], Stéphane Pellet-Rostaing[a], René Faure[b] and Marc Lemaire[a]
Jan-Feb 2006
139
*
[a]Laboratoire de Catalyse et Synthèse Organique, Université Claude Bernard Lyon 1, UMR 5181, Bât. 308, 43
Bd. Du 11 novembre 1918, 69622 Villeurbanne cedex, France.
[b]Laboratoire de Sciences et Stratégies Analytiques, Université Claude Bernard Lyon 1, UMR 5180, Bâtiment
Raulin 2 rue Victor Grignard, 69622 Villeurbanne cedex, France.
Received June 22, 2005
New tetrahydroisoquinolines were synthesized by the Pictet-Spengler reaction. Influence of a wide range
of aryl and heteroaryl aldehydes, was investigated in the cyclization step with 3,4-dimethoxyphenylethyl-
amine 1, L-DOPA 2 and L-3,4-dimethoxyphenylalanine methyl ester 3. Compounds 2 and 3 served as
probes to assess the efficiency of two Pictet-Spengler reactions with respect to their diastereoselectivity, in
order to obtain optically active diastereoisomers. Cis- and trans-diastereoisomers were obtained in short
reaction times with moderate to good isolated yields (20-79%). Both nmr and X-ray analyses confirmed the
expected diastereoisomer configurations.
J. Heterocyclic Chem., 43, 139 (2006).
Introduction.
Spengler cyclization in a two-step procedure. More
recently, Liu [32] described the phenolic condensation of
aldehydes and L-DOPA methyl ester with NaOAc in
AcOH as a highly diastereoselective method to prepare
chiral tetrahydroisoquinolines. Due to their interesting
structures, 3,4-dimethoxyphenylethylamine 1, L-DOPA 2
and L-3,4-dimethoxyphenylalanine methyl ester 3 allowed
the preparation of numerous achiral and chiral building
blocks for the synthesis of bioactive compounds. Starting
from these materials, we propose here the synthesis of new
tetrahydroisoquinolines incorporating substituted aromatic
moieties and different heterocyclic units such as thio-
phene, benzo[b]thiophene and pyrrole. Although tetrahy-
droisoquinoline structures incorporating indole subunits
have already been obtained from 1,2,3,4-tetrahydro-2-
aryl-isoquinoline [51], the direct introduction of hetero-
cyclic structures from 3,4-dimethoxyphenylethylamine 1
by the Pictet-Spengler reaction at the C(1) position has not
yet been assessed. Moreover, the diastereoselectivity of the
Pictet-Spengler reaction starting from chiral L-DOPA 2
and L-3,4-dimethoxyphenylalanine methyl ester 3 was
evaluated and pure cis- and trans-adducts could be
obtained in good yields.
The synthesis of tetrahydroisoquinolines has received
particular attention in the field of medicinal chemistry due
to their biological activity [1-4]. Tetrahydroisoquinolines
were essentially studied as neurotoxic compounds, and are
proven to be involved in some pathologies of the central
nervous system [5-8]. This family of compounds is also
used in a number of cardiovascular diseases, for the treat-
ment of cardiac ischemia or pulmonary embolism, and
plays a role as a venous and arterial antithrombotic agent
[9]. One of the most promising methods for the synthesis
of many tetrahydroisoquinoline derivatives is the Pictet-
Spengler cyclization [10-12].
The Pictet-Spengler reaction has been widely investi-
gated with tetrahydro-β-carbolines [13-20] and tetrahydro-
isoquinolines [21-51], especially in the asymmetric series
[42]. The knowledge and synthetic applications of this
reaction were pioneered and extensively studied by
Kametani and co-workers [21-29] who extended its use to
many heterocyclic systems. More recently, Jacobsen [19]
reported the asymmetric synthesis of tetrahydro-β-carbo-
lines with a thiourea as chiral ligand. Ohwada [43,44]
developed a diastereoselective process based on the Pictet-
Spengler reaction in superacidic conditions with several 2-
alkyl-N-benzylidene-2-phenylethylamines as substrates.
Koomen [45,46] described the preparation of enantiopure
terahydroisoquinolines via a chiral N-sulfinyl Pictet-
Results and Discussion.
The Pictet-Spengler cyclization usually involves the
condensation of β-arylethylamines and carbonyl deriva-

140
S. Aubry, S. Pellet-Rostaing, R. Faure and M. Lemaire
Vol. 43
tives, via an intramolecular electrophilic cyclization to
afford tetrahydroisoquinolines and their derivatives. The
Pictet-Spengler reaction is carried out in protic solvents
[21-32] or in acidic conditions [43-50] through imine inter-
mediates. Although the use of 3-activated β-arylethy-
lamines, such as dopamine, allowed a direct cyclization
[21-32] through phenolic condensation, a two-step proce-
dure was required when 3,4-dimethoxyphenylethylamine 1
was used. This result can be explained by the lower elec-
tron-donating effect of the methoxy groups compared to
the hydroxy groups of the dopamine. Thus, the tetrahy-
droisoquinolines 4-10 were obtained using Ohwada's pro-
cedure [43,44] via the formation of imine intermediates
With L-DOPA 2 and benzaldehyde, the Pictet-Spengler
cyclization, performed in various polar solvents, led selec-
tively to the corresponding cis- and trans-1-phenyl-6,7-
dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acids 11a and 11b (Scheme 3). When the reaction was car-
ried out in water at room temperature, a quantitative con-
version and a cis/trans ratio of 80/20 were obtained. A
selective precipitation provided the cis-diastereoisomer
11a in 60% yield (Table 2). When the reaction was per-
formed in methanol at room temperature, a cis/trans mix-
ture of 70/30 was obtained (Table 2). The selective precip-
itation of this mixture only provided the trans-
diastereoisomer 11b in 20% yield: this may be caused by
Scheme 1
Scheme 2
and cyclization in trifluoroacetic acid (scheme 1). The
nature of the functional group on the aromatic ring of the
aldehyde exerted a strong influence on the reaction time.
An increase of the reaction rate was observed with elec-
tron-withdrawing groups in the p-position of arylaldehy-
des, in comparison with the unsubstituted phenyl.
However, the presence of a methoxy electron-donating
group decreased both the rate and the yield of the cycliza-
tion. This phenomenon was also observed in the case of
benzo[b]thiophene and 2-phenyl benzo[b]thiophene (Table
1). When oxo-phenyl-acetic acid ethyl ester was con-
densed with 1 followed by the cyclization in trifluoroacetic
acid, the yield decreased dramatically (39%), probably due
to the incomplete conversion of 1 into the imine intermedi-
ate, as determined by TLC. Because of its instability, the
mixture was used immediately in the cyclization step and
the 1,1-disubstituted compound 10 was purified by column
chromatography.
the lesser polarity of the solvent. When the same reactions
were refluxed, the cyclization was significantly acceler-
ated (Table 2). When the reaction was conducted in ethanol
at 60 °C both diastereoisomer precipitation occurred
(Table 2).
Table 1
Synthesis of some new racemic tetrahydroisoquinolines
Table 2
Experimental Conditions of the Pictet-Spengler Reaction with L-DOPA
Compound
R
R
Time Yield
(h) (%) [a]
1
2
2 and Benzaldehyde
Conditions
Time (h)
Ratio
cis/trans [a]
Isolated Yield [b] (%)
4
5
6
7
8
9
10
C H [44,58]
H
H
H
H
H
1.5
0.75
0.75
6
3
8
73
75
79
65
68
62
39
6
5
4-NC-C H
6
5
4-O N-C H [59,60]
H O/20 °C
4
0.25
4
0.25
0.25
80/20
75/25
70/30
65/35
70/30
60 (cis)
56 (cis)
20 (trans)
2
6 5
2
4-MeO-C H [58]
H O/80 °C
6 5
2
3-benzo[b]thiophene
MeOH/20 °C
MeOH/60 °C
EtOH/60 °C
3-(2-C H -benzo[b]thiophene)
H
22 (trans)
6
5
C H
COOEt
3
25 (cis/trans : 70/30)
6
5
1
[a] Determined by H NMR experiments; [b] Obtained by precipitation.
[a] Isolated yields.

Jan-Feb 2006 Racemic and Diastereoselective Synthesis of Aryl and Heteroaryl Tetrahydroisoquinolines
141
The influence of various aryl and heteroaryl aldehydes on
the chirality of the Pictet-Spengler cyclization with prelimi-
nary synthesized L-3,4-dimethoxyphenylalanine methyl
ester trifluoroacetate salt 3 (see the experimental section)
was then studied. Depending on the nature of the sub-
stituents on the aromatic moieties and the heterocyclic units,
the derivatives 12-19 were obtained (Scheme 3) with
cis/trans ratios ranging from 30/70 to 87/13 (Table 3). When
electron-donating groups, such as methoxy, are incorporated
Both cis- and trans-diastereoisomers were isolated, sep-
1
arated by chromatography and characterized by H nmr
13
and C nmr spectra. Cis- and trans-isomers displayed dis-
tinctive features in terms of polarity and spectroscopic
data. In the present series of tetrahydroisoquinolines 12-
19, the cis-isomer is less polar than the trans-isomer, as
indicated by the TLC Rf values [52]. The signal assign-
ments were made on the basis of NOESY and HSQC 2D
experiments. For the conformational determination of
at the p-position of the aromatic aldehyde or the
benzo[b]thiophene-3-carboxaldehyde structure, the elec-
tronic delocalisation, lead to a 50/50 ratio. However, ary-
laldehydes bearing electron-withdrawing groups (cyano,
nitro) at the p-position, led to an increase in the ratio in
favour of the cis-adducts. Moreover, a predominant cis-ratio
was obtained when 2-phenyl-benzo[b]thiophene-3-carbox-
aldehyde was used, certainly due to steric hindrance. With
benzaldehyde or thiophene-2-carboxaldehyde, cis/trans
ratios of 75/25 (Table 3) and 30/70 (Table 3) were obtained
respectively. Thus in the latter case, a ratio in favour of the
trans-adducts was observed. On the other hand, no cycliza-
tion occurred with 1-methylpyrrole-2-carboxaldehyde.
compounds 12-19, the NOESY [53-55] experiment dis-
played correlation peaks which correspond to a typical
interaction between both H(1) and H(3) protons. This con-
firmed the expected cis-structures of the compounds 12a
and 13a. Thus, the two resonance signals at 5.01 ppm and
3.76 ppm correlated by a cross-peak were attributed to the
H(1) and H(3) protons of the cis-compound 12a. In the
trans-isomer 12b, the H(1) and H(3) protons were charac-
terized by a singlet at 5.19 ppm and a doublet-doublet at
3.72 ppm respectively, without NOE correlation. More
generally, we noticed that the chemical shifts of the three
singlets corresponding to the signals of H(1), H(5) and
H(8) of the cis-isomers were upfield relative to the assign-
Table 3
Results of the Pictet-Spengler reaction with the O-methylated analogue of L-DOPA 3
Compound
R
Time (h)
[a]
Ratio [b] Overall yield
Isolated
yield cis (%)
Isolated yield
trans (%)
cis/trans
(%) [c]
12a, 12b
13a, 13b
14a, 14b
15a, 15b
16a, 16b
17a, 17b
18a, 18b
19
C H
4-NC-C H
1.5
0.75
0.75
6
2
12
2
75/25
87/13
84/16
50/50
50/50
85/15
30/70
-
74
79
76
69
72
49
70
traces
56
70
58
31
34
36
18
-
12
0
10
30
31
8
6
5
6
5
4-O N-C H
6 5
2
4-MeO-C H
3-(benzo[b]thiophene)
3-(2-C H -benzo[b]thiophene)
6
5
6
5
2-(thiophene)
2-(1-methylpyrrole)
45
-
24
1
[a] Determined by TLC after complete consumption of the imine intermediate; [b] Determined by H NMR experiment; [c] Isolated yield.

142
S. Aubry, S. Pellet-Rostaing, R. Faure and M. Lemaire
Vol. 43
Table 4
Chemical shift of H(1), H(5), H(8), C(1), C(3) resonance signals
Compound
δ (ppm)
δ (ppm)
δ (ppm) δ (ppm) δ (ppm)
H(1)
H(5)
H(8)
C(1)
C(3)
11a (cis)
11b (trans)
12a (cis)
12b (trans)
13a (cis)
14a (cis)
14b (trans)
15a (cis)
15b (trans)
16a (cis)
16b (trans)
17a (cis)
17b (trans)
18a (cis)
4.87
5.09
5.01
5.19
5.08
5.20
5.32
5.03
5.23
5.57
5.71
5.54
5.63
5.37
5.41
6.41
6.51
6.56
6.59
6.57
6.60
6.66
6.62
6.64
6.71
6.70
6.68
6.72
6.54
6.54
5.88
6.15
6.09
6.28
5.97
6.00
6.22
6.18
6.34
6.34
6.57
6.22
6.25
6.32
6.47
59.1
52.6
56.9
52.5
56.5
56.5
52.6
57.0
52.4
56.9
52.5
56.3
52.4
56.9
51.8
62.3
58.8
63.2
59.3
62.7
62.4
58.4
62.6
58.6
57.9
53.8
57.2
55.2
58.3
55.0
Figure 2. Crystal structure of 13a.
18b (trans)
To conclude, the Pictet-Spengler reaction was extended to
the synthesis of new tetrahydroisoquinolines. From 3,4-
dimethoxyphenylethylamine 1 and several aryl and het-
eroaryl aldehydes the desired tetrahydroisoquinolines were
isolated as racemic mixtures. Whatever the nature of the sub-
stituent on the aromatic or heterocyclic subunit (electron-
donating or electron-withdrawing groups) cyclization
occurred with good yields. This reaction was also extended
to chiral tetrahydroisoquinolines by a diasteroselective pro-
cedure from chiral L-DOPA 2 and L-3,4-dimethoxy-
phenylalanine methyl ester 3 with aryl and heteroaryl alde-
hydes structures with a better selectivity towards the cis-con-
figuration. This study could now be applied to a wide range
of targets with a methodological interest in the construction
of polycyclic structures incorporating heterocycles.
ments of the trans-diastereoisomers (Table 4). Conversely,
the signals of the C(1) and C(3) for carbon atoms in cis-
isomers appeared at a lower field in the nmr spectra than
those of the corresponding trans-isomers, as already
described by Cook and co-workers [19,52] for the tetrahy-
dro-β-carboline analogues. Conformational analysis [56]
and examination of molecular models showed two possi-
ble half chair conformations (A or B, Figure 1) for the cis-
isomer 13a. Conformer A should represent the structure of
the more stable species due to the unfavoured interactions
between both the axial methyl ester and p-cyano-phenyl
groups in the conformer B.
EXPERIMENTAL
Reactants and solvents were supplied by Aldrich, Acros,
Lancaster, Alfa Aeser and Fluka. NMR spectra were recorded
1
13
either on a Bruker AMX 300 ( H: 300MHz; C: 75MHz) or a
1
13
Bruker DPX 500, ( H: 500MHz; C: 100MHz) spectrometer in
appropriate deuterated solvents. The chemical shifts (δ ppm) and
coupling constants (Hz) are reported in the standard fashion. In
the NMR spectra, the nature of the carbon atoms was determined
by recording DEPT 135 spectra, and is given in brackets. The fol-
lowing abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, broad,
thio = thiophene, benzothio = benzo[b]thiophene. Low-resolu-
tion mass spectra were recorded using a thermo Finnigan LCQ
Advantage instrument using positive electron spray ionization
mode. Thin layer chromatography (TLC) was performed with
Merck 60 F254 silica gel plates. Rf values refer to TLC on Merck
60 F254 silica gel plates. Flash chromatography was performed
using Merck Si 60 (40-63µm) silica. Elemental analyses were
performed by the 'Service Central d'Analyses du CNRS' (Solaize,
France). Optical rotations were measured at 23°C using a Perkin-
Elmer 241 polarimeter. Melting points were measured on a
Figure 1. NOE effect observed in the cis-isomer.
In order to confirm these structural hypotheses, the solid
state structure of compound 13a was determined by X-ray
[57] crystallography (Figure 2). The tetrahydroisoquino-
line crystallizes in a half-chair conformation. As expected,
it presents a cis-configuration with the same axial orienta-
tion of C(1)-H(1) and C(3)-H(3) bonds and pseudo equato-
rial positions for the ester and p-cyanophenyl substituents.
A similar tetrahydro-β-carboline structure was previously
reported by Bailey and co-workers [16].

Jan-Feb 2006 Racemic and Diastereoselective Synthesis of Aryl and Heteroaryl Tetrahydroisoquinolines
143
Kofler bench.
Anal. Calcd. for C H N O . 0.2H O: C, 72.58; H, 6.11; N,
18 18 2 2 2
9.41. Found: C, 72.42; H, 6.18; N, 9.40.
General Procedure for the Synthesis of Tetrahydroisoquinolines
(4)-(10) from 3,4-Dimethoxyphenylethylamine (1).
1-(4-Nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (6) [59,60].
To a solution of (1) (1mmol) stirred in 3 mL of dichloro-
methane with 3Å molecular sieves under argon was added alde-
hyde (1.1 mmol) dissolved in 3 mL of dichloromethane. The
solution was then stirred between 0.5 h and 12 h depending on
the nature of the aldehyde. The reaction progress was monitored
by TLC (diethyl ether/petroleum ether = 2/1). When the reaction
was complete the solution was diluted with 5 mL of
dichloromethane, filtered, washed with 10 mL of dichloro-
methane, dried on magnesium sulphate and evaporated. The
Schiff base was then engaged in the next step without further
purification.
The corresponding Schiff base (1 mmol) solution was sus-
pended in trifluoroacetic acid (100 mmol) and warmed at 72 °C
under argon between 0.75 and 8 hours. The reaction was con-
trolled by TLC (ethyl acetate/n-heptane = 5/5). After complete
consumption of the Schiff base the solution was diluted with
dichloromethane and neutralised with saturated aqueous sodium
hydrogen carbonate until pH 9-10. The aqueous phase was then
extracted twice with 20 mL of ethyl acetate. The organic layers
were then dried on magnesium sulfate, filtered, evaporated and
This compound was obtained as a pale yellow solid in 79%
yield (248 mg), mp 140-141 °C (ethyl acetate/n-heptane); H nmr
(deuteriochloroform): δ 1.61 (broad s, 1H, NH, deuterium oxide-
exchangeable), 2.75 (dt, 1H, J = 4.5, 16 Hz, CH H CH N), 2.90
1
A
B
2
(m, 1H, CH H CH N), 3.04 (ddd, 1H, CH CH H N, J = 4.7,
A
B
2
2
A B
7.7, 12.2 Hz), 3.11 (dt, 1H, CH CH H N, J = 5.5, 12.2 Hz), 3.61
2
A B
(s, 3H, 7-OCH ), 3.83 (s, 3H, 6-OCH ), 5.09 (s, 1H, 1-H), 6,12
3
3
(s, 1H, 8-H), 6,60 (s, 1H, 5-H), 7.46 (d, 2H, 2'-H, 6'-H, J = 8.8
Hz), 8.15 (d, 2H, J = 8.8 Hz, 3'-H, 5'-H); C nmr (deuteriochlo-
13
roform): δ 29.5 (CH ), 42.0 (CH ), 56.2 (OCH ), 56.3 (OCH ),
2
2
3
3
61.0 (CH), 111.0 (ArCH), 112.1 (ArCH), 124.0 (2ArCH), 128.1
(ArC), 128.6 (ArC),130.2 (2ArCH), 147.6(ArC), 147.7 (ArC),
+
148.4 (ArC), 152.7 (ArC); ms: m/z 315.1 ([M+H] ).
Anal. Calcd. for C H N O : C, 64.23; H, 5.79; N, 8.81.
17 18
2 4
Found: C, 64.10; H, 5.90; N, 8.58.
1-(4-Methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (7) [58].
This compound was obtained as a pale yellow solid in 65%
yield (194 mg), mp 95-96 °C (ethyl acetate/n-heptane); H nmr
1
purified on flash chromatography (SiO , n-heptane/ethyl
2
(deuteriochloroform): δ 1.90 (broad s, 1H, NH, deuterium oxide-
acetate = 5/5→ ethyl acetate) to provide the racemic mixture of
the corresponding amine.
exchangeable), 2.63 (dt, 1H, J = 4.7, 15.7 Hz, CH H CH N),
A
B
2
2.81 (m, 1H, CH H CH N), 2.92 (ddd, 1H, CH CH H N, J =
A
B
2
2
A B
1-Phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4)
[44,58].
4.7, 7.9, 12.2 Hz), 3.11 (dt, 1H, CH CH H N, J = 5.2, 11.9 Hz),
2
A B
3.54 (s, 3H, 7-OCH ), 3.77 (s, 3H, 6-OCH ), 4.99 (s, 1H, 1-H),
3
3
This compound was obtained as a white solid in 73% yield
6.07 (s, 1H, 5-H), 6.56 (s, 1H, 8-H), 7.3 (d, 2H, 3'-H, 5'-H, J =
8.3 Hz,), 7.51 (d, 2H, 2'-H, 6'-H, J = 8.3 Hz,); C nmr (deuteri-
13
(196 mg), mp 127-128 °C (ethyl acetate/n-heptane), (lit. mp [44]:
1
133-134°C, ethanol/n-hexane); H nmr (deuteriochloroform): δ
ochloroform): δ 29.7 (CH ), 42.4 (CH ), 55.6 (CH ), 56.2 (2
2
2
3
1.89 (br s, 1H, NH, deuterium oxide-exchangeable), 2.63 (dt, 1H,
OCH ), 61.3 (CH), 111.3 (ArCH), 111.8 (ArCH), 114.1 (2ArCH),
3
CH H CH N, J = 4.9, 15.9 Hz), 2.82 (m, 1H, CH H CH N),
128.0 (ArC), 130.3 (2ArCH), 130.6 (ArC), 137.5 (ArC), 147.4
(ArC), 147.9 (ArC), 159.2 (ArC); ms: m/z 300.1 ([M+H] ).
A
B
2
A
B
2
+
2.96 (ddd, 1H, CH CH H N, J = 4.6, 8, 12.1 Hz), 3.12 (dt, 1H,
2
A B
CH CH H N, J = 5.1, 12 Hz), 3.53 (s, 3H, 7-OCH ), 3.79 (s,
Anal. Calcd. for C H N O : C, 72.22; H, 7.07; N, 4.68.
2
A
B
3
17 18
2 4
3H, 6-OCH ), 5.00 (s, 1H, 1-H), 6.17 (s, 1H, 8-H), 6.56 (s, 1H, 5-
H), 7.12-7.30 (m, 5H, phenyl protons); C nmr (deuteriochloro-
Found: C, 72.00; H, 7.21; N, 4.49.
3
13
1-(Benzo[b]thiophene-3-yl)-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline (8).
form): δ 29.7 (CH ), 42.3 (CH ), 56.2 (2 OCH ), 61.8 (CH),
C
2
2
3
111.3 (ArCH), 111.8 (ArCH), 127.7 (ArCH), 128.1 (ArC), 128.8
(2ArCH), 129.3 (2ArCH), 130.2 (ArC), 145.3 (ArC), 147.4
This compound was obtained as a white solid in 68% yield (221
mg), mp 51-52 °C (ethyl acetate/n-heptane); H nmr (deuteriochlo-
+
1
(ArC), 148.0 (ArC); ms: m/z 270 ([M+H] ).
roform): δ 1.94 (broad s, 1H, NH, deuterium oxide-exchangeable),
Anal. Calcd. for C H NO . 0.2H O: C, 74.83; H, 7.11; N,
5.13. Found: C, 74.90; H, 7.30; N, 4.99.
17 19
2
2
2.86 (m, 2H, CH H CH N, CH H CH N), 3.05 (dt, 1H,
A
B
2
A
B
2
CH CH H N, J = 5.6, 12.2 Hz), 3.14 (ddd, 1H, J = 5.3, 7.1, 12.2
2
A B
1-(4-Cyanophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (5).
Hz, CH CH H N), 3.57 (s, 3H, 7-OCH ), 3.82 (s, 3H, 6-OCH ),
2
A
B
3
3
5.45 (s, 1H, 1-H), 6.35 (s, 1H, 8-H), 6.60 (s, 1H, 5-H), 6.94 (s, 1H,
13
This compound was obtained as a white solid in 75% yield
2'-H), 7.36 (m, 2H, 5'-H, 6'-H), 7.86 (m, 2H, 4'-H, 7'-H); C nmr
1
(220 mg), mp 127-128 °C (ethyl acetate/n-heptane); H nmr
(deuteriochloroform): δ 29.6 (CH ), 41.4 (CH ), 55.7 (CH), 56.3
2
2
(deuteriochloroform): δ 2.02 (br s, 1H, NH deuterium oxide-
(2 OCH ), 111.0 (ArCH), 111.9 (ArCH), 122.9 (ArCH), 122.9
3
exchangeable), 2.65 (dt, 1H, J = 4.7, 16 Hz, CH H CH N), 2.83
(ArCH), 124.6 (ArCH), 124.8 (ArCH), 125.8 (CH
), 128.0
A
B
2
benzothio
(m, 1H, CH H CH N), 2.96 (ddd, 1H, CH CH H N, J = 4.9,
(ArC), 129.2 (ArC), 138.4 (C
147.6 (ArC), 148.2 (ArC); ms: m/z 326.1 ([M+H] ).
), 139.7 (ArC), 141.4 (ArC),
A
B
2
2
A B
benzothio
+
7.6, 12.4 Hz), 3.05 (dt, 1H, J = 5.7, 12.1 Hz, CH CH H N), 3.54
2
A B
(s, 3H, 7-OCH ), 3.77 (s, 3H, 6-OCH ), 4.99 (s, 1H, 1-H), 6.07
Anal. Calcd. for C H NO S: C, 70.12; H, 5.88; N, 4.30.
3
3
19 19
2
(s, 1H, 8-H), 6.56 (s, 1H, 5-H), 7.3 (d, 2H, 2'-H, 6'-H, J = 8.3 Hz),
7.51 (d, 2H, 3'-H, 5'-H, J = 8.3 Hz); C nmr (deuteriochloro-
Found: C, 70.02; H, 5.85; N, 4.26.
13
1-(2-Phenyl-benzo[b]thiophene-3-yl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (9).
form): δ 29.4 (CH ), 41.9 (CH ), 55.2 (2 OCH ), 61.2 (CH),
2
2
3
111.0 (ArCH), 111.5 (ArC), 112.1 (ArCH), 119.2 (CN), 128.1
(ArC), 128.6 (ArC), 130.1 (2ArCH), 132.5 (2ArCH), 147.5
This compound was obtained as a white solid in 62% yield
(248 mg), mp 80-81 °C (ethyl acetate/n-heptane); H nmr (deu-
1
+
(ArC), 148.3 (ArC), 150.7 (ArC); ms: m/z 295.1 ([M+H] ).

144
S. Aubry, S. Pellet-Rostaing, R. Faure and M. Lemaire
Vol. 43
teriochloroform): δ 1.70 (broad s, 1H, NH, deuterium oxide-
exchangeable), 2.72 (m, 1H, CH H CH N), 3.07 (ddd, 1H,
+
ms: m/z 286 ([M+H] ).
Anal. Calcd. for C H N0 . 0.4 H O: C, 65.70; H, 5.40; N,
A
B
2
16 15
4
2
CH H CH N, J = 4.1, 8.1, 11.8 Hz), 3,17 (m, 1H,
A
B
2
4.79. Found: C, 65.51; H, 5.22; N, 4.79.
CH CH H N), 3.38 (m, 1H, CH CH H N), 3.52 (s, 3H, 7-
2
A
B
2
A B
trans-1-Phenyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic Acid (11b).
OCH ), 3.86 (s, 3H, 6-OCH ), 5.49 (s, 1H, 1-H), 6.27 (s, 1H, 8-
3
3
H), 6.66 (s, 1H, 5-H), 7.14 (ddd, 1H, 5'-H, J = 1.2, 7.5, 8.1 Hz),
7.24 (ddd, 1H, 6'-H, J = 1.3, 7.5, 7.9 Hz), 7.40-7.50 (m, 5H,
phenyl protons), 7.62 (dd, 1H, 4'-H, J = 1.3, 8.1 Hz), 7.78 (d, 1H,
This compound was obtained as a white solid in 20% yield (57
23
mg), mp 270-272 °C (methanol); [α]
-11.0 (c 0.5, 0.01 M
D
13
1
7'-H, J = 7.9 Hz); C nmr (deuteriochloroform): δ 30.0 (CH ),
sodium hydroxide); H nmr (deuterium oxide/sodium deuterox-
2
44.9 (CH ), 56.1 (CH), 56.3 (2 OCH ), 110.3 (ArCH), 112.2
ide): δ 2.68 (dd, 1H, CH CH CHN, J = 10, 16.5 Hz), 2.89 (dd,
1H, CH CH CHN, J = 4.7, 16.2 Hz), 3.41 (dd, 1H, 3-H, J = 4.7,
10 Hz), 5.09 (s, 1H, 1-H), 6.15 (s, 1H, 8-H), 6.51 (s, 1H, 5-H),
7.20-7.32 (m, 5H, phenyl protons); C nmr (deuterium
oxide/sodium deuteroxide): δ 31.3 (CH ), 52.5 (CH), 58.7 (CH),
115.3 (ArCH), 115.8 (ArCH), 123.2 (ArC), 123.3 (ArC), 127.7
(ArCH), 128.8 (2ArCH), 129.2 (2ArCH), 145.4 (ArC), 151.7
2
3
A
B
(ArCH), 122.4 (ArCH), 124.4 (ArCH), 124.5 (ArCH), 125.3
(ArCH), 127.7 (ArC), 128.9 (ArCH), 129.2 (2ArCH), 130.1
A
B
13
(2ArCH), 130.3 (C
), 133.6 (ArC), 134.7 (ArC),
benzothio
139.1(C
), 139.8 (ArC), 142.4 (ArC), 147.8 (ArC), 148.0
benzothio
2
+
(ArC); ms: m/z 402.1 ([M+H] ).
Anal. Calcd. for C H NO S. 0.1H O: C, 74.46; H, 5.76; N,
25 23
2
2
+
3.46. Found: C, 74.38; H, 5.78; N, 3.30.
(ArC), 153.3 (ArC), 181.6 (C=O); ms: m/z 286 ([M+H] ).
Anal. Calcd. for C
Found: C, 67.00; H, 5.29; N, 4.80.
H N0 : C, 67.26; H, 5.30; N, 4.91.
16 15 4
1-Phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-car-
boxylic Ethyl Ester (10).
Synthesis of L-3,4-Dimethoxyphenylalanine Methyl Ester (3).
This compound was obtained as a colourless oil in 39% yield
(133 mg); Rf = 0.2 (ethyl acetate/n-heptane = 1/1); H nmr (deu-
1
L-3,4-Dihydroxyphenylalanine Methyl Ester (20) [61-63].
teriochloroform): δ 1.19 (t, 3H, CH CH O, J = 7.2 Hz), 2.54
3
2
(broad s, 1H, NH, deuterium oxide-exchangeable), 2.63 (dt, 1H,
To L-DOPA (2) (10 g, 0.0507 mol) in 500 mL of dry methanol
stirred at 0 °C was slowly added thionyl chloride (12 g, 0.101
mol) during 1 h. The solution was then refluxed over a period of
24 hours before being cooled and coevaporated with 100 mL of
toluene giving amine chlorhydrate (20) in 99% yield (12.55 g,) as
a white solid, mp 174-175 °C (methanol/dichloromethane), (lit.
mp [61]: 172-174 °C, lit. mp [62]: 170-171 °C, lit. mp [63]:
CH H CH N, J = 4.5, 15.8 Hz), 2.82 (m, 1H, CH H CH N),
A
B
2
A
B
2
2.92 (m, 1H, CH CH H N), 3.11 (dt, 1H, CH CH H N, J =
2
A
B
2
A B
4.5, 12.9 Hz), 3.59 (s, 3H, 7-OCH ), 3.79 (s, 3H, 6-OCH ), 4.21
3
3
(q, 1H, J = 7.2 Hz, 0.5 OCH CH ), 4.22 (q, 1H, J = 7.2 Hz, 0.5
2
3
OCH CH ), 6.53 (s, 1H, 8-ArH), 6.64 (s, 1H, 5-ArH), 7.15 (m,
2
3
13
5H, phenyl protons); C nmr (deuteriochloroform): δ 14.6
23
22
(CH ), 29.6 (CH ), 40.8 (CH ), 56.1 (OCH ), 56.3 (OCH ), 62.1
170.5-171.5 °C); [α]
+7.9 (c 1, methanol) (lit. [α]
[63]:
3
2
2
3
3
D
D
1
(OCH ), 70.0 (C), 111.3 (ArCH), 113.8 (ArCH), 127.6 (ArC),
+14.7 (c 12.5, methanol)); H nmr (deuterium oxide): δ 3.06 (dd,
1H, CH H CHN, J = 7.7, 14.6 Hz), 3.18 (dd, 1H, CH H CHN,
2
127.8 (ArCH), 128.3 (2ArCH), 128.5 (2ArCH), 129.1 (ArC),
145.4 (ArC), 146.9 (ArC), 148.6 (ArC), 174.7 (C=O); ms: m/z
A
B
A B
J = 5.9, 14.6 Hz), 3.82 (s, 3H, OCH ), 4.35 (t, 1H, J 6.6,
3
+
342 ([M+H] ).
CH CHN), 6.68 (dd, 1H, 6-H, J = 1.8, 8.1 Hz), 6.78 (d, 1H, 2-H,
2
13
Anal. Calcd. for C
H
NO : C, 70.38; H, 6.74; N, 4.10.
J = 1.8 Hz), 6.78 (d, 1H, 5-H, J = 8.2 Hz); C nmr (deuterium
20 23
4
Found: C, 70.25; H, 6.89; N, 3.82.
oxide): δ 35.4 (CH ), 54.0 (OCH ), 54.8 (CH), 117.1 (ArCH),
2
3
117.4 (ArCH), 122.3 (ArCH), 126.6 (ArC), 144.2 (ArC), 144.8
General Procedure for the Synthesis of Tetrahydroisoquinolines
(11a), (11b) from L-DOPA (2).
+
(ArC), 170.6 (C=O); ms: m/z 212 ([M+H] ).
Anal. Calcd. for C H NO Cl: C, 48.48; H, 5.70; N, 5.66.
10 14
4
Benzaldehyde (0.116 g, 1.1 mmol) was added to a solution of
L-DOPA (2) (0.197 g, 1 mmol) dissolved in 2 mL of water,
methanol or ethanol and potassium carbonate (0.152 g, 1.1
mmol) preliminary added at 0 °C under argon. The mixture was
stirred at room temperature or at reflux between 0.25 and 4 hours.
The reaction was stopped when the precipitation of the corre-
sponding amino-acid occurred. Then the product was collected
by filtration and washed with 5 ml of cold reaction solvent.
Found: C, 48.24; H, 5.42; N, 5.36.
(L)-N-tert-Butoxycarbonyl-3,4-dihydroxyphenylalanine Methyl
Ester (21) [61,64,65].
To L-3,4-dihydroxyphenylalanine methyl ester (20) (12.5 g,
0.0505 mol) in 275 mL of methanol were added triethylamine
3
(0.196 mol, 27.5 cm ) and di-tert-butyl dicarbonate (12.2 g,
0.056 mol) at room temperature. The solution was then stirred
during 2 h. After completion (monitored by TLC, ethyl acetate),
the solvent was evaporated and the residue was acidified with 1
M hydrochloric acid at 0 °C. The solution was then extracted
with ethyl acetate (3x50 mL) and the organic layer was dried on
magnesium sulfate and evaporated. The crude product was puri-
cis-1-Phenyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic Acid (11a).
This compound was obtained as a white solid in 60% yield
23
(171 mg), mp 280-281 °C (water/isopropyl alcohol); [α]
-16.2
D
1
(c 0.5, 0.01 M sodium hydroxide); H nmr (deuterium
oxide/sodium deuteroxide): δ 2.77 (m, 2H, CH H CHN,
fied by flash chromatography (SiO , ethyl acetate/n-heptane =
2
9/1) giving (21) in 92% yield (14.1 g) as a white solid, mp 134-
135 °C (methanol), (lit. mp [61]: 133-135°C, lit. mp [64]: 140-
141 °C (methanol/water), lit. mp [65]: 135°C); Rf = 0.4 (ethyl
A
B
CH H CHN), 3.43 (dd, 1H, 3-H, J = 4.9, 11.7 Hz), 4.87 (s, 1H,
A
B
1-H), 5.88 (s, 1H, 8-H), 6.41 (s, 1H, 5-H), 7.32 (m, 5H, phenyl
13
23
26
protons); C nmr (deuterium oxide/sodium deuteroxide): δ 32.4
acetate); [α]
+6.9 (c 1, methanol), (lit. [α]
[61]: +7.6, (c
D
D
25
1
(CH ), 59.1 (CH), 62.3 (CH), 114.0 (ArCH), 116.0 (ArCH),
1.2, methanol), lit. [α]
[65]: +7 (c 1, methanol); H nmr (deu-
2
D
125.1 (ArC), 126.3 (ArC), 128.2 (ArCH), 129.1 (2ArCH), 129.4
(2ArCH), 144.4 (ArC), 148.0 (ArC), 150.6 (ArC), 181.0 (C=O);
teriochloroform): δ 1.41 (s, 9H, O(CH ) ), 2.90 (dd, 1H, CH H-
3 3
A
CHN, J = 6.5, 13.9 Hz), 2.99 (dd, 1H, CH H CHN, J = 5.6,
B
A B

Jan-Feb 2006 Racemic and Diastereoselective Synthesis of Aryl and Heteroaryl Tetrahydroisoquinolines
145
13.9 Hz), 3.72 (s, 3H, CO CH ), 4.53 (m, 1H, CH CHN), 5.08
General Procedure for the Synthesis of Tetrahydroisoquinolines
2
3
2
(d, 1H, NH, deuterium oxide-exchangeable, J =8.2 Hz), 6.50 (d,
1H, 6-H, J = 1.8, 9.9 Hz), 6.66 (broad s, 1H, 2-H), 6.75 (d, 1H, 5-
(12)-(18) from L-3,4-Dimethoxyphenylalanine Methyl Ester (3).
At 0 °C, to a solution of amino ester salt (3) (1 mmol) stirred in
3 mL of dichloromethane/isopropyl alcohol (2/1) with 3Å molec-
ular sieves under argon were preliminary added sodium methox-
ide (1.1 mmol) and aldehyde (1.1 mmol) in 3 mL of
dichloromethane. The solution was then stirred at room tempera-
ture or at reflux between 0.75 h and 12 h depending on the nature
of aldehyde. The reaction progress was monitored by TLC (ethyl
acetate/n-heptane = 3/7). When the reaction was complete the
solution was diluted with 5 mL of dichloromethane, filtered,
washed with 10 mL of dichloromethane and evaporated. The
Schiff base was then engaged in the next step without further
purification.
The Schiff base (1 mmol) contained in trifluoroacetic acid (100
mmol) was heated at reflux under argon between 1 and 6 hours.
The reaction was controlled by TLC (ethyl acetate/heptane =
1/1). After complete consumption of the Schiff base the solution
was diluted with 20 mL of dichloromethane and neutralized with
saturated aqueous sodium hydrogen carbonate solution until pH
9-10. The aqueous phase was then extracted twice with 20 mL of
ethyl acetate. The organic layers were then dried on magnesium
sulfate, filtered, evaporated and purified by flash chromatogra-
13
H, J = 8.1 Hz); C nmr (deuteriochloroform): δ 28.2 (3CH ),
3
37.6 (CH ), 52.4 (OCH ), 54.7 (CH), 80.6 (C), 115.4 (ArCH),
2
3
116.1 (ArCH), 121.4 (ArCH), 128.1 (ArC), 143.1 (ArC), 144.0
+
(ArC), 155.6 (NC=O), 172.9 (C=O); ms: m/z 334 ([M+Na] ),
+
312 ([M+H]) ).
Anal. Calcd. for C H NO . 0.2H O: C, 57.21; H, 6.74; N,
15 21
6
2
4.45. Found: C, 57.18; H, 6.96; N, 4.12.
(L)-N-tert-Butoxycarbonyl-3,4-dimethoxyphenylalanine Methyl
Ester (22) [32,66,67].
To a stirred solution of 100 mL of N,N-dimethylformamide
and potassium carbonate (55.9 g, 0.405 mol) were added L-
tert-butoxycarbonyl-3,4-dihydroxyphenylalanine methyl ester
(21) (14 g, 0.045 mol) and methyl iodide (27.5 g, 0.202 mol).
The mixture was then stirred for 24 hours. Monitoring by TLC
(ethyl acetate/ n-heptane: 7/3) indicated the disappearance of
starting material. The mixture was then filtered, extracted with
60 mL of ether and washed twice with 20 mL of 1 M
hydrochloric acid. The organic layer was then dried on magne-
sium sulfate, filtered, evaporated and purified on flash chro-
matography (SiO , ethyl acetate/n-heptane = 9/1→7/3) giving
2
phy (SiO , n-heptane/ethyl acetate = 8/2→6/4) to separate both
2
(22) in 89% yield (13.6 g) as a colourless oil, Rf = 0.4
diastereoisomers.
23
1
(AcOEt/n-heptane = 1/1); [α]
+6.0 (c 1, methanol); H nmr
D
(deuteriochloroform): δ 1.34 (s, 9H, O(CH ) ), 2.93 (t, 1H,
CH H CHN, J = 6 Hz), 2.94 (m, 1H, CH H CHN), 3.64 (s,
cis-1-Phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic Acid Methyl Ester (12a).
3 3
A
B
A B
3H, 4-OCH ), 3.78 (s, 6H, 3-OCH , CO CH ), 4.47 (dd, 1H,
3
3
2
3
This compound was obtained as a white solid in 56% yield
CH CHN, J = 6, 13.7 Hz), 4.98 (broad d, 1H, NH, deuterium
2
(183 mg), mp 120-121 °C (AcOEt ethyl acetate/n-heptane); Rf =
oxide-exchangeable), 6.56 (m, 2H, 6-H, 2-H), 6.72 (d, 1H, 5-
23
0.3 (ethyl acetate/n-heptane = 7/3); [α]
- 1.7 (c 1, chloro-
D
H, J = 9 Hz); δ (75 MHz, CDCl ) 28.7 (3CH ), 38.2 (CH ),
C
3
3
2
1
form). H nmr (deuteriochloroform): δ 2.58 (broad s, 1H, NH,
deuterium oxide-exchangeable), 2.99 (m, 2H, CH H CHN,
52.6 (OCH ), 54.8 (CH), 56.1 (OCH ), 56.2 (OCH ), 80.2 (C),
3
3
3
A
B
111.6 (ArCH), 112.7 (ArCH), 121.7 (ArCH), 128.8 (ArC),
148.4 (ArC), 149.2 (ArC), 155.4 (NC=O), 172.8 (C=O); ms:
CH H CHN), 3.50 (s, 3H, 7-OCH ), 3.68 (s, 3H, CO CH ),
A
B
3
2
3
3.76 (m, 1H, 3-H), 3.77 (s, 3H, 6-OCH ), 5.01 (s, 1H, 1-H), 6.09
+
+
3
m/z 362 ([M+Na] ), 240 ([M+H-CO t-Bu] ).
2
13
(s, 1H, 8-H), 6.56 (s, 1H, 5-H), 7.25 (m, 5H, phenyl protons);
C
Anal. Calcd. for C H NO : C, 60.16; H, 7.42; N, 4.13.
17 25
6
nmr (deuteriochloroform): δ 32.6 (CH ), 52.6 (OCH ), 56.2
2
3
Found: C, 59.84; H, 7.32; N, 4.11.
(CH), 56.3 (2 OCH ), 56.9 (CH), 63.2 (CH), 110.9 (ArCH), 111.7
3
(L)-3,4-Dimethoxyphenylalanine Methyl Ester Trifluoroacetate
(3) [68-70].
(ArCH), 126.4 (ArC), 128.3 (ArCH), 129.0 (2ArCH), 129.4
(2ArCH), 130.5 (ArC), 144.2 (ArC), 147.8 (ArC), 148.1 (ArC),
+
173.3 (C=O); ms: m/z 328 ([M+H] ).
To (L)-tert-butoxycarbonyl-3,4-dimethoxyphenylalanine
methyl ester (22) (13.6 g, 0.0402 mol) was added 100 mL of a
solution of trifluoroacetic acid in dichloromethane (5/95). The
resulting mixture was stirred over a period of 5 hours. The mix-
ture was then coevaporated with toluene giving a residual solid
which was dissolved in ethyl acetate. A few drops of cyclohexane
were added giving (3) in 90% yield (11.3 g) as a white solid, mp
150-152 °C (methanol/dichloromethane), (lit. mp [68]: 158-159
Anal. Calcd. for C H NO . 1/6H O: C, 69.09; H, 6.41; N,
19 21
4
2
4.24. Found: C, 69.07; H, 6.56; N, 4.28.
trans-1-Phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic Acid Methyl Ester (12b).
This compound was obtained as a white solid in 12% yield (39
mg), mp 115-116 °C (ethyl acetate/n-heptane); Rf = 0.15 (ethyl
23
1
23
20
acetate/n-heptane = 1/1); [α]
-8.2 (c 0.35, chloroform); H
°C (ethanol/ether)); [α]
+3.2 (c 1, methanol), (lit. [α]
[68]:
D
D
D
1
nmr (deuteriochloroform): δ 2.18 (broad s, 1H, NH, deuterium
oxide-exchangeable), 2.94 (dd, 1H, CH H CHN, J = 8.6, 16
+6.8, (c 2, methanol)); H nmr (deuterium oxide): δ 3.19 (dd, 1H,
CH H CHN, J = 7.6, 14.5 Hz), 3.27 (dd, 1H, CH H CHN, J =
A
B
A
B
A B
Hz), 3.08 (dd, 1H, CH H CHN, J = 5.1, 16 Hz), 3.61 (s, 3H,
5.9, 14.4 Hz), 3.64 (s, 3H, 4-OCH ), 3.80 (s, 6H, 3-OCH ,
A
B
3
3
CO CH ), 3.64 (s, 3H, 7-OCH ), 3.72 (dd, 1H, 3-H, J = 5.1, 8.7
CO CH ), 4.38 (dd, 1H, CH CHN, J = 5.9, 7.6 Hz), 6.82 (dd, 1H,
2
3
3
2
3
2
Hz), 3.79 (s, 3H, 6-OCH ), 5.19 (s, 1H, 1-H), 6.28 (s, 1H, 8-H),
6-H, J = 1.8, 8 Hz), 6.88 (d, 1H, 2-H, J = 1.8 Hz), 6.97 (d, 1H, 5-
3
13
13
6.59 (s, 1H, 5-H), 7.11-7.22 (m, 5H, phenyl protons); C nmr
H, J= 8 Hz); C nmr (deuterium oxide): δ 35.5 (CH ), 53.9
2
(deuteriochloroform): δ 31.5 (CH ), 51.7 (OCH ), 52.5 (CH),
(OCH ), 54.4 (CH), 55.8 (2 OCH ), 111.3 (ArCH), 112.7
2
3
3
3
56.2 (2OCH ), 59.3 (ArCH), 111.2 (ArCH), 111.5 (ArCH), 128.4
(ArCH), 122.5 (ArCH), 126.8 (ArC), 148.1 (ArC), 148.7 (ArC),
3
+
+
(ArC), 128.7 (ArCH), 129.0 (2ArCH), 129.4 (2ArCH), 130.6
(ArC), 145.0 (ArC), 147.8 (ArC), 148.3 (ArC), 174.3 (C=O); ms:
170.4 (C=O); ms: m/z 240 ([M+H]) , 223 ([M+H-NH ] ).
3
Anal. Calcd. for C H F NO : C, 47.60; H, 5.14; N, 3.96.
14 18
3
6
+
m/z 328 ([M+H] ).
Found: C, 47.81; H, 5.33; N, 4.10.

146
S. Aubry, S. Pellet-Rostaing, R. Faure and M. Lemaire
Vol. 43
Anal. Calcd. for C H NO . 1/6H O: C, 69.04; H, 6.54; N,
This compound was obtained as a white solid in 31% yield
19 21
4
2
4.10. Found: C, 69.09; H, 6.41; N, 4.24.
(111 mg), mp 129-130 °C (ethyl acetate/n-heptane); Rf = 0.2
25
(ethyl acetate/heptane = 1/1); [α]
-20.5 (c 0.6, chloroform);
H nmr (deuteriochloroform): δ 2.37 (broad s, 1H, NH, deu-
D
cis-1-(4-Cyanophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic Acid Methyl Ester (13a).
1
terium oxide-exchangeable), 3.07 (m, 2H, CH H CHN, CH H-
A
B
A
This compound was obtained as a white solid in 70% yield
CHN), 3.59 (s, 3H, 7-OCH ), 3.75 (s, 3H, CO CH ), 3.80 (s,
B
3
2
3
(246 mg), mp 128-129 °C (ethyl acetate/n-heptane); Rf = 0.3
3H, 4'-OCH ), 3.83 (m, 1H, 3-H), 3,85 (s, 3H, 6-OCH ), 5.03 (s,
3
3
23
(ethyl acetate/n-heptane = 1/1); [α]
-1.9 (c 1.75, chloroform);
1H, 1-H), 6.18 (s, 1H, 8-H), 6.62 (s, 1H, 5-H), 6.86 (d, 2H, 3'-H,
D
1
13
H nmr (deuteriochloroform): δ 2.44 (broad s, 1H, NH, deu-
terium oxide-exchangeable), 3.00 (m, 2H, CH H CHN, CH H-
5'-H, J = 8.5 Hz), 7.24 (d, 2H, 2'-H, 6'-H, J = 8.5 Hz); C nmr
(deuteriochloroform): δ 32.6 (CH ), 52.5 (OCH ), 55.6 (CH),
A
B
A
2
3
CHN), 3.51 (s, 3H, 7-OCH ), 3.69 (s, 3H, CO CH ), 3.77 (s,
56.3 (2 OCH ), 56.9 (OCH ), 62.6 (CH), 110.9 (ArCH), 111.6
B
3
2
3
3
3
3H, 6-OCH ), 3.74 (m, 1H, 3-H), 5.08 (s, 1H, 1-H), 5.97 (s, 1H,
(ArCH), 114.3 (2ArCH), 126.4 (ArC), 130.5 (2ArCH), 130.9
(ArC), 136.5 (ArC), 147.7 (ArC), 148.1 (ArC), 159.5 (ArC),
173.4 (C=O); ms: m/z (ESI) 358 ([M+H).
3
8-H), 6.57 (s, 1H, 5-H), 7.39 (d, 2H, 2'-H, 6'-H, J = 8.3 Hz), 7.54
13
(d, 2H, 3'-H, 5'-H, J = 8.2 Hz); C nmr (deuteriochloroform): δ
32.4 (CH ), 52.6 (OCH ), 56.2 (CH), 56.3 (2 OCH ), 56.5 (CH),
Anal. Calcd. for C
H NO : C, 67.22; H, 6.44; N, 3.92.
2
3
3
20 23 5
62.7 (CH), 110.5 (ArCH), 111.8 (ArCH), 112.0 (ArC), 119.2
(CN), 126.6 (ArC), 129.0 (ArC), 130.3 (2ArCH), 132.8 (2ArCH),
147.9 (ArC), 148.4 (ArC), 149.8 (ArC), 173.1 (C=O); ms: m/z
Found: C, 67.43; H, 6.51; N, 3.92.
trans-1-(4-Methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic Acid Methyl Ester (15b).
+
353 ([M+H] ).
Anal. Calcd. for C H N O . 0.1H O: C, 67.64; H, 5.69; N,
7.89. Found: C, 67.72; H, 5.67; N, 7.95.
This compound was obtained as a white solid in 30% yield (107
20 20
2
4
2
mg), mp 119-120 °C (ethyl acetate/n-heptane); Rf = 0.1 (ethyl
23
1
acetate/n-heptane = 1/1); [α]
-34.3 (c 0.6, chloroform); H nmr
(deuteriochloroform): δ 2.15 (broad s, 1H, NH, deuterium oxide-
exchangeable), 2.99 (dd, 1H, CH H CHN, J = 8.5, 16.2 Hz), 3.10
D
cis-1-(4-Nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic Acid Methyl Ester (14a).
A
B
This compound was obtained as a pale yellow solid in 58%
(dd, 1H, CH H CHN, J = 5.1, 16 Hz), 3.67 (s, 3H, CO CH ), 3.72
A
B
2
3
yield (215 mg), mp 126-127 °C (ethyl acetate/n-heptane); Rf =
(s, 3H, 7-OCH ), 3.78 (m, 1H, 3-H), 3.79 (s, 3H, 4'-OCH ), 3,88
3
3
23
0.2 (ethyl acetate/n-heptane = 1/1); [α]
-11.2 (c 1, chloro-
D
(s, 3H, 6-OCH ), 5.23 (s, 1H, 1-H), 6.34 (s, 1H, 8-H), 6.64 (s, 1H,
3
1
form); H nmr (deuteriochloroform): δ 2.12 (broad s, 1H, NH,
deuterium oxide-exchangeable), 3.00 (m, 2H, CH H CHN,
5-H), 6.82 (d, 2H, 3'-H, 5'-H, J = 8.6 Hz), 7.09 (d, 2H, 2'-H, 6'-H, J
13
A
B
= 8.6 Hz); C nmr (deuteriochloroform): δ 31.4 (CH ), 51.7
2
CH H CHN), 3.59 (s, 3H, 7-OCH ), 3.78 (s, 3H, CO CH ),
A
B
3
2
3
(OCH ), 52.4 (CH), 55.6 (OCH ), 56.2 (2 OCH ), 58.6 (CH),
3
3
3
3.82 (m, 1H, 3-H), 3.86 (s, 3H, 6-OCH ), 5.20 (s, 1H, 1-H), 6.00
3
111.2 (ArCH), 111.5 (ArCH), 114.1 (2ArCH), 126.0 (ArC), 128.8
(ArC), 130.2 (2ArCH), 137.2 (ArC), 147.8 (ArC), 148.2 (ArC),
(s, 1H, 8-H), 6.60 (s, 1H, 5-H), 7.53 (d, 2H, 2'-H, 6'-H, J = 8.5
13
Hz), 8.20 (d, 2H, 3'-H, 5'-H, J = 8.7 Hz); C nmr (deuteriochlo-
+
159.2 (ArC), 174.3 (C=O); m/z (ESI) 358 ([M+H] , 100%).
roform): δ 32.4 (CH ), 52.7 (OCH ), 56.3 (2 OCH ), 56.5 (CH),
2
3
3
Anal. Calcd. for C H NO . 0.1H O: C, 67.22; H, 6.44; N,
20 23
5
2
62.4 (CH), 110.5 (ArCH), 111.9 (ArCH), 124.2 (2ArCH), 126.6
(ArC), 128.9 (ArC), 130.4 (2ArCH), 147.9 (ArC), 148.0 (ArC),
148.5 (ArC), 151.9 (ArC), 173.1 (C=O); ms: m/z 373.1
3.92. Found: C, 66.74; H, 6.54; N, 3.77.
cis-1-(Benzo[b]thiophen-3-yl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic Acid Methyl Ester (16a).
+
([M+H] ).
Anal. Calcd. for C H N O : C, 61.28; H, 5.41; N, 7.52.
Found: C, 61.02; H, 5.49; N, 7.43.
19 20
2 6
This compound was obtained as a pale yellow solid in 34% yield
(130 mg), mp 66-67 °C (ethyl acetate/n-heptane); Rf = 0.5 (ethyl
23
1
acetate/n-heptane = 1/1); [α]
-10.9 (c 1, chloroform); H nmr
(deuteriochloroform): δ 2.53 (broad s, 1H, NH, deuterium oxide-
exchangeable), 3.15 (dd, 1H, CH H CHN, J = 4.2, 15.5 Hz),
D
trans-1-(4-Nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic Acid Methyl Ester (14b).
A
B
This compound was obtained as a pale yellow solid in 58%
3.21(dd, 1H, CH H CHN, J = 11, 15.4 Hz), 3.53 (s, 3H, 7-OCH ),
A
B
3
yield (37 mg), mp 118-119 °C (ethyl acetate/n-heptane); Rf = 0.1
3.74 (s, 3H, CO CH ), 3.88 (s, 3H, 6-OCH ), 3.92 (dd, 1H, J = 4.1,
2
3
3
23
(ethyl acetate/n-heptane = 1/1); [α]
-19.8 (c 0.9, chloroform);
D
10.7 Hz, 3-H), 5.57 (s, 1H, 1-H), 6.34 (s, 1H, 8-H), 6.71 (s, 1H, 5-
H), 7.25 (dd, 1H, 5'-H, J = 7.6, 7.9 Hz), 7.30 (dd, 1H, 6'-H, J = 7.6,
8.2 Hz), 7.45 (s, 1H, 2'-H), 7.69 (d, 1H, 4'-H, J = 8.2 Hz), 7.85 (d,
1
H nmr (deuteriochloroform): δ 2.45 (broad s, 1H, NH, deu-
terium oxide-exchangeable), 2.94 (dd, 1H, CH H CHN, J = 7.7,
A
B
16.2 Hz), 3.10 (dd, 1H, CH H CHN, J = 5.1, 16 Hz), 3.66 (s,
13
A
B
1H, 7'-H, J = 7.9 Hz); C nmr (deuteriochloroform): δ 32.5 (CH ),
2
3H, CO CH ), 3.70 (s, 3H, 7-OCH ), 3.76 (dd, 1H, 3-H, J = 5.2
2
3
3
52.6 (OCH ), 56.2 (OCH ), 56.3 (OCH ), 57.9 (CH), 56.9 (CH),
3
3
3
,8.9 Hz), 3.86 (s, 3H, 6-OCH ), 5.32 (s, 1H, 1-H), 6.22 (s, 1H, 8-
3
110.1 (ArCH), 111.8 (ArCH), 123.2 (C
H), 124.0 (ArCH),
benzothio
H), 6.66 (s, 1H, 5-H), 7.33 (d, 2H, 2'-H, 6'-H, J = 8.7 Hz), 8. 07
124.4 (ArCH), 124.8 (ArCH), 125.9 (ArCH), 126.2 (ArC), 129.3
13
(d, 2H, 3'-H, 5'-H, J = 8.7 Hz); C nmr (deuteriochloroform): δ
(ArC), 138.0 (C
148.3 (ArC), 173.3 (C=O); ms: m/z (ESI) 384.1 ([M+H] ).
), 138.5 (ArC), 141.4 (ArC), 148.0 (ArC),
benzothio
31.2 (CH ), 52.6 (OCH ), 52.2 (CH), 56.3 (2 OCH ), 58.4 (CH),
+
2
3
3
110.8 (ArCH), 111.8 (ArCH), 124.3 (2ArCH), 127.0 (ArC),
128.0 (ArC), 130.0 (2ArCH), 147.6 (ArC), 148.1 (ArC), 148.7
Anal. Calcd. for C H NO S: C, 65.78; H, 5.52; N, 3.65.
21 21
4
Found: C, 66.09; H, 5.63; N, 3.59.
+
(ArC), 152.4 (ArC), 174.0 (C=O); ms: m/z 373.1 ([M+H] ).
Anal. Calcd. for C H N O : C, 61.28; H, 5.41; N, 7.52.
Found: C, 61.11; H, 5.48; N, 7.51.
trans-1-(Benzo[b]thiophen-3-yl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic Acid Methyl Ester (16b).
19 20
2 6
This compound was obtained as a pale yellow solid in 31% yield
(119 mg), mp 69-70 °C (ethyl acetate/n-heptane); Rf = 0.3 (ethyl
cis-1-(4-Methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic Acid Methyl Ester (15a).

Jan-Feb 2006 Racemic and Diastereoselective Synthesis of Aryl and Heteroaryl Tetrahydroisoquinolines
147
23
1
cis-1-(Thiophen-2-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic Acid Methyl Ester (18a).
acetate/n-heptane = 1/1); [α]
+20.9 (c 1, chloroform); H nmr
(deuteriochloroform): δ 2.47 (broad s,1H, NH, deuterium oxide-
exchangeable), 2.92 (dd, 1H, CH H CHN, J = 9.4, 16.2 Hz), 3.08
D
A
B
This compound was obtained as a pale yellow oil in 18% yield
(dd, 1H, CH H CHN, J = 4.8, 16 Hz), 3.71 (s, 6H, CO CH , 7-
OCH ), 3.80 (dd, 1H, 3-H, J = 4.9, 9.4 Hz), 3.91 (s, 3H, 6- OCH ),
5.71 (s, 1H, 1-H), 6.57 (s, 1H, 8-H), 6.70 (s, 1H, 5-H), 6.82 (s, 1H,
2'-H), 7.40 (ddd, 1H, 5'-H, J = 1.3, 7.2, 8.3 Hz), 7.46 (ddd, 1H, 6'-H,
J = 1.3, 7.2, 7.9 Hz), 7.89 (ddd, 1H, 4'-H, J = 0.8, 1.2, 7.9 Hz), 7.98
(ddd, 1H, 7'-H, J = 0.8, 1.1, 8.1 Hz); C nmr (deuteriochloroform):
δ 31.7 (CH ), 52.0 (OCH ), 52.5 (CH), 53.8 (CH), 56.3 (OCH ),
56.5 (OCH ), 111.0 (ArCH), 111.6 (ArCH), 122.4 (CH
23
A
B
2
3
(60 mg); Rf = 0.3 (ethyl acetate/n-heptane = 1/1); [α]
-65.5 (c
D
1
3
3
1, chloroform); H nmr (deuteriochloroform): δ 2.50 (broad s,
1H, NH, deuterium oxide-exchangeable), 2.99 (m, 2H, CH H-
A
CHN, CH H CHN), 3.59 (s, 3H, 7-OCH ), 3.70 (s, 3H,
B
A
B
3
CO CH ), 3.78 (m, 1H, 3-H), 3.80 (s, 3H, 6-OCH ), 5.37 (s, 1H,
2
3
3
13
1-H), 6.32 (s, 1H, 8-H), 6.54 (s, 1H, 5-H), 6.80 (dd, 1H, 4'-H, J =
3.4, 4.9 Hz), 7.06 (d, 1H, J = 3.4 Hz, 3'-H), 7.20 (d, 1H, 5'-H J =
2
3
3
),
13
3
benzothio
4.9 Hz); C nmr (deuteriochloroform): δ 32.3 (CH ), 52.6
2
123.5 (ArCH), 124.8 (ArCH), 125.0 (ArC), 126.1 (2ArCH), 127.8
(OCH ), 56.3 (2 OCH ), 56.9 (CH), 58.3 (CH), 110.5 (ArCH),
3
3
(ArC), 138.3 (C
), 139.5 (ArC), 141.4 (ArC), 147.9 (ArC),
benzothio
111.6 (ArCH), 125.9 (ArC), 126.1 (CthioH), 126.5 (CthioH),
126.6 (CthioH), 130.0 (ArC), 147.8 (Cthio), 147.9 (ArC), 148.4
+
148.5 (ArC), 174.1 (C=O); ms: m/z (ESI) 384.1 ([M+H] ).
Anal. Calcd. for C H NO S. 0.2H O : C, 65.16; H, 5.53; N,
+
21 21
4
2
(ArC), 173.0 (C=O); ms: m/z 334.1 ([M+H] ).
3.62. Found: C, 65.12; H, 5.56; N, 3.52.
Anal. Calcd. for C H NO S. 0.4H O: C, 59.54; H, 5.81; N,
17 19
4
2
4.11. Found: C, 59.77; H, 5.86; N, 3.86.
cis-1-(2-Phenyl-benzo[b]thiophen-3-yl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic Acid Methyl Ester (17a).
trans-1-(Thiophen-2-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic Acid Methyl Ester (18b).
This compound was obtained as a white solid in 36% yield
(165 mg), mp 70-72 °C (ethyl acetate/n-heptane); Rf = 0.3 (ethyl
This compound was obtained as a pale yellow oil in 45% yield
23
1
acetate/n-heptane = 3/7); [α]
+94 (c 0.5, chloroform); H nmr
(deuteriochloroform): δ 2.54 (broad s, 1H, NH,deuterium oxide-
exchangeable), 3.14 (m, 2H, CH H CHN, CH H CHN), 3.54
23
D
(150 mg); Rf = 0.2 (ethyl acetate/n-heptane = 1/1); [α]
-17.8 (c
D
1
2.25, chloroform); H nmr (deuteriochloroform): δ (300 MHz,
H
A
B
A B
CDCl ) 2.46 (broad s, 1H, NH, deuterium oxide-exchangeable),
3
(s, 3H, 7-OCH ), 3.76 (s, 3H, CO CH ), 3.83 (dd, 1H, 3-H, J =
3
2
3
2.85 (dd, 1H, CH H CHN, J = 9.4, 16 Hz), 2.98 (dd, 1H, CH H-
A
B
A
4.5, 8.8 Hz), 3.85 (s, 3H, 6-OCH ), 5.54 (s, 1H, 1-H), 6.22 (s, 1H,
3
CHN, J = 5.1, 16.2 Hz), 3.64 (s, 3H, CO CH ), 3.67 (s, 3H, 7-
B
2
3
8-H), 6.68 (s, 1H, 5-H), 7.13 (m, 1H, 5'-H), 7.23 (m, 1H, 6'-H),
7.34 (m, 3H, phenyl protons), 7.46 (m, 1H, 4'-H), 7.54 (m, 2H,
OCH ), 3.77 (s, 3H, 6-OCH ), 3.81 (dd, 1H, 3-H, J = 4.9, 9.5 Hz),
3
3
5.41 (s, 1H, 1-H), 6.47 (s, 1H, 8-H), 6.54 (s, 1H, 5-H), 6.80 (d, 1H,
3'-H, J = 3.3 Hz), 6.82 (dd, 1H, 4'-H, J = 3.6, 4.9 Hz), 7.13 (d, 1H,
13
phenyl protons), 7.68 (d, 1H, J = 7.9, 7'-H); C nmr (deuteri-
ochloroform): δ 32.5 (CH ), 52.5 (OCH ), 56.3 (CH), 56.4 (2
2
3
13
5'-H, J = 4.9 Hz); C nmr (deuteriochloroform): δ 31.4 (CH ),
2
OCH ), 57.2 (CH), 110.2 (ArCH), 112.2 (ArCH), 122.3 (ArCH),
3
51.8 (CH), 52.5 (OCH ), 55.0 (CH), 56.2 (OCH ), 56.3 (OCH ),
3
3
3
124.3 (ArCH), 124.5 (2ArCH), 126.2 (ArC), 128.9 (ArCH),
111.1 (ArCH), 111.6 (ArCH), 125.5 (ArC), 125.6 (CthioH), 126.4
(CthioH), 126.8 (CthioH), 128.3 (ArC), 147.7 (Cthio), 148.5
129.1 (2ArCH), 129.7 (ArC), 130.1 (2ArCH), 132.6 (C
),
benzothio
134.6 (C
), 138.9 (ArC), 139.8 (ArC), 142.8 (ArC),
benzothio
+
(ArC), 149.6 (ArC), 174.0 (C=O); m/z 334.1 ([M+H] ).
+
148.13 (ArC), 148.4 (ArC), 173.3 (C=O); ms: m/z 460 ([M+H] ).
Anal. Calcd. for C H NO S: C, 70.57; H, 5.48; N, 3.05.
Anal. Calcd. for C H NO S. 0.3H O: C, 60.26; H, 5.79; N,
17 19
4
2
27 25
4
4.13. Found: C, 60.19; H, 5.95; N, 3.84.
Found: C, 70.42; H, 5.73; N, 2.84.
Acknowledgments.
trans-1-(2-Phenyl-benzo[b]thiophen-3-yl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid Methyl Ester
(17b).
The authors thank the 'Ministère de l'Enseignement Supérieur
et de la Recherche' for the grant to S.A's Ph.D and wish to thank
Mrs Christine Clozel for correcting the manuscript.
This compound was obtained as a white solid in 8% yield (37
mg), mp 72-74 °C (ethyl acetate/n-heptane); Rf 0.3 (ethyl
23
1
acetate/n-heptane = 3/7); [α]
-52.6 (c 1, chloroform); H nmr
(deuteriochloroform): δ 2.50 (broad s, 1H, NH, deuterium oxide-
exchangeable), 3.16 (m, 1H, CH H CHN), 3.26 (m, 1H,
D
REFERENCES AND NOTES
A
B
[*] Author to whom correspondence should be addressed. E-mail:
marc.lemaire@univ-lyon1.fr
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13
phenyl protons), 7.80 (ddd 1H, 7'-H, J = 0.8, 1.1, 8.1 Hz);
C
nmr (deuteriochloroform): δ 30.3 (CH ), 51.6 (OCH ), 52.4
2
3
(CH), 55.2 (CH), 56.2 (OCH ), 56.3 (OCH ), 110.0 (ArCH),
3
3
111.6 (ArCH), 122.4 (ArCH), 124.4 (ArCH), 124.5 (ArCH),
125.0 (ArC), 125.1 (ArCH), 128.5 (ArC), 128.9 (ArCH), 129.0
(2ArCH), 130.2 (2ArCH), 133.3 (C
), 134.5 (C
),
benzothio
benzothio
139.0 (ArC), 139.8 (ArC), 143.0 (ArC), 148.0 (ArC), 148.1
+
(ArC), 174.5 (C=O); ms: m/z 460 ([M+H] ).
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1
1 1
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