One-pot α-amidosulfone-mediated variation of the pictet-Spengler tetrahydroisoquinoline synthesis, suitable for amide-type substrates

Article abstract of DOI:10.1002/ejoc.201402487

The development of Pictet-Spengler reactions from amide substrates is a challenging problem. We report here that the reaction between amide-type compounds (including carbamates, amides, ureas and diketopiperazines), aldehydes and p-toluenesulfinic acid constitutes an efficient method for the preparation of tetrahydroisoquinolines or pyrazino-[2,1-b]isoquinolines. Unlike previously known methods, this one-pot Pictet-Spengler protocol avoids the need for strong Lewis or Br?nsted acid catalysts.

Full text of DOI:10.1002/ejoc.201402487

Job/Unit: O42487
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Date: 01-08-14 11:36:31
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FULL PAPER
DOI: 10.1002/ejoc.201402487
One-Pot α-Amidosulfone-Mediated Variation of the Pictet–Spengler
Tetrahydroisoquinoline Synthesis, Suitable for Amide-Type Substrates
Francisco J. Arroyo,[a] Pilar López-Alvarado,[a] A. Ganesan,[b] and J. Carlos Menéndez*[a]
Keywords: Stereoselective synthesis / Cyclization / Nitrogen heterocycles / Amides
The development of Pictet–Spengler reactions from amide
substrates is a challenging problem. We report here that the
reaction between amide-type compounds (including carb-
amates, amides, ureas and diketopiperazines), aldehydes
and p-toluenesulfinic acid constitutes an efficient method for
the preparation of tetrahydroisoquinolines or pyrazino-
[2,1-b]isoquinolines. Unlike previously known methods, this
one-pot Pictet–Spengler protocol avoids the need for strong
Lewis or Brønsted acid catalysts.
be clearly advantageous to have a method that enables Pic-
tet–Spengler chemistry from amides and aldehydes under
mild conditions.
Introduction
The Pictet–Spengler reaction is one of the main methods
for synthesizing tetrahydroisoquinolines (THQs) and tetra-
hydro-β-carbolines,[1] and has found widespread use in the
synthesis of natural products.[1a,2] It involves the generation
of highly reactive iminium ions[3] as intermediates and is
normally carried out using arylethylamines and aldehydes
in the presence of strong Brønsted[4] or Lewis[5] acids. On
the other hand, there is little precedence for the use of
amides as starting materials for this reaction. Although the
N-acyliminium Pictet–Spengler method, which involves
acylation of the intermediate iminium ion forming an N-
acyliminium ion reactive species,[6] allows the preparation
of N-acyl-tetrahydroisoquinolines and carbolines, in many
situations there are strategic advantages to be gained by
carrying out the reaction directly from an amide precursor.
Most examples from the literature involve the use of either
very strong acids or high temperatures;[7] such requirements
introduce obvious limitations in terms of substrate scope.
Some examples of the use of comparatively mild acid condi-
tions are also known, although they are restricted to phen-
ethyl carbamate substrates.[8] Noyori-type chemistry involv-
ing the use of acetals in the presence of TMS triflate has
also been applied to some variants of the Pictet–Spengler
reaction.[9] Although in most cases acetals can be easily pre-
pared from the corresponding carbonyl compounds, in or-
der to avoid this additional step, and in view of the much
broader range of commercially available aldehydes, it would
With this goal in mind, we set out to develop a protocol
based on the chemistry of α-amidosulfones that invokes
generation of acyliminium intermediates by elimination of
sulfinic acid. Although these species have found many syn-
thetic applications,[10] there is very little precedence for their
use in the synthesis of heterocycles. Indeed, the only type
of substrates previously examined for a transformation re-
lated to the one described here were relatively highly reac-
tive cyclic carbamates derived from the oxazolidin-2-one
system.[11] These reactions required a two-step protocol in-
volving the isolation of the α-amidosulfone intermediate in
the presence of magnesium sulfate as a dehydrating agent
and its subsequent cyclization in the presence of the strong
Lewis acid TiCl4.[12]
Results and Discussion
We first examined the reaction of acyclic carbamate 1
with a variety of aldehydes in the presence of toluenesulfinic
acid rather than the conventionally employed benzenesulf-
inic acid. These reactions were carried out in dichlorometh-
ane at 45 °C, without any dehydrating reagent. Under these
conditions, we obtained tetrahydroquinoline derivatives 3a–
3o, which were isolated directly in one step, normally in
good to excellent yields (Scheme 1, Table 1).[13] Compari-
sons of this result with literature precedent involving a ox-
azolidin-2-one substrate bearing a 3,4-methylenedioxy-
phenyl pendant side chain show that, although apparently
trivial, the replacement of benzenesulfinic acid by tolu-
enesulfinic acid increases the reactivity for all steps of the
process (see the mechanistic discussion for a more detailed
explanation). This new THQ synthesis can be performed
under mild conditions of temperature and acidity and, as
[a] Departmento de Química Orgánica y Farmacéutica,
Universidad Complutense, Facultad de Farmacia,
Plaza de Ramón y Cajal sn, 28040 Madrid, Spain
E-mail: josecm@ucm.es
http://www.campusmoncloa.es/en/groups/biohet/
[b] School of Pharmacy, University of East Anglia,
NR4 7TJ Norwich, United Kingdom
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402487.
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F. J. Arroyo, P. López-Alvarado, A. Ganesan, J. C. Menéndez
FULL PAPER
shown in Table 1, its scope covers both aliphatic (Table 1, pound 4 only in moderate yield after an extended reaction
Entries 1 and 2) and aromatic aldehydes (Table 1, Entries time (Table 1, Entry 16).
3–15). In the latter case, either electron-withdrawing or elec-
We next undertook the study of reactions starting from
tron-releasing substituents could be accommodated in the urea derivative 5, prompted by the fact that ureas have
phenyl ring (Table 1, Entries 4–9 and 10–14, respectively), rarely been studied as Pictet–Spengler substrates; normally
and were associated with good to excellent yields with the only reactive aldehydes, such as formaldehyde have been
only exception being some substrates containing a 2,4-di- studied.[14] We also were motivated by the synthetic rele-
methoxy substituent (Table 1, Entries 12 and 13). Com- vance of isoquinoline-derived ureides.[15] As shown in
pound 3o, bearing a 2-naphthyl group, was isolated in Scheme 2 and Table 2, compounds 6a–6f were readily ob-
quantitative yield (Table 1, Entry 15). On the other hand, tained from either aromatic or aliphatic aldehydes by per-
the reaction between N-(3,4-dimethoxyphenylethyl)acet- forming the reactions in refluxing CH2Cl2 or AcOEt.
amide 2 and propanal proceeded sluggishly, and gave com- Furthermore, the reaction could be controlled to give
double cyclization products by simply adjusting the tem-
perature. Thus, the reaction between 5 and two molecules
of aldehyde in toluene at 120 °C gave exclusively com-
pounds 7a and 7b, displaying a trans relationship between
both R substituents as elucidated by single crystal X-ray
diffraction study of 7a (Figure 1). Importantly, previous
preparations of such tetrasubstituted ureas have been based
on the application of multistep procedures.[16]
Scheme 1. Synthesis of 2-acyltetrahydroisoquinolines.
Table 1. Results obtained in the 2-acyltetrahydroisoquinoline syn-
thesis.
Scheme 2. Pictet–Spengler reactions between urea derivative 5 and
aldehydes.
Table 2. Scope and yields of the Pictet–Spengler reactions between
urea 5 and aromatic or aliphatic aldehydes.
Entry
R
Reaction conditions
% Yield
1
2
3
4
5
6
7
8
9
6a
6b
6c
6c
6d
6e
6f
Ph
CH2Cl2, 45 °C
AcOEt, 80 °C
CH2Cl2, 45 °C
AcOEt, 80 °C
CH2Cl2, 45 °C
AcOEt, 80 °C
CH2Cl2, 45 °C
toluene, 120 °C
toluene, 120 °C
49
75
85
85
85
60
52
55
62
4-BrC6H4
3-NO2C6H4
3-NO2C6H4
4-Cl–C6H4
Et
nPr
2-ClC6H4
Et
7a
7b
2
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One-Pot Pictet–Spengler Tetrahydroisoquinoline Synthesis
Figure 1. Crystal structure of compound 7a.
Diketopiperazines (DKPs) are the simplest cyclic pept-
ides and are considered privileged structures in drug discov-
ery.[17] They are also versatile building blocks in the synthe-
sis of bioactive molecules, many of which contain pyraz-
ino[1,2-b]isoquinoline or pyrazino[1,2-b]carboline struc-
tural fragments and are therefore accessible by the applica-
tion of Pictet–Spengler chemistry.[18,19] For this reason, we
examined the reaction between DKPs and aldehydes in the
presence of p-toluenenesulfinic acid. We chose compounds
8a–8c as substrates because of their relationship to starting
materials used for the preparation of members of the im-
portant saframycin-ecteinascidin family of anticancer alka-
loids (Scheme 3, Scheme 4).[20] In this way, we hoped to de-
vise a very short synthesis of pyrazino[2,1-b]isoquinoline
derivatives 9a–9o, which have been used as the starting
point for the preparation of several kinds of anticancer
saframycin analogues[21] (Scheme 4).
Scheme 4. Synthesis of tricyclic saframycin precursors 8a–8c.
pounds 9, generally in good to excellent yields and with
complete chemodifferentiation between both NH groups
(Scheme 4). As summarized in Table 3, the less hindered
substrate 8a was, as expected, the most reactive and enabled
cyclizations to proceed at 45 °C for the case of aliphatic
aldehydes (Table 3, Entries 1 and 2), whereas the aromatic
aldehydes required heating at 120 °C (Table 3, Entries 3–7),
but the yields were very good in all cases. As observed for
previous substrates, no significant differences in yield were
observed between benzaldehyde derivatives carrying elec-
tron-releasing and electron-withdrawing substituents. For
the more hindered starting materials 8b and 8c, a slightly
higher temperature was required (Table 3, Entries 8–16),
which was not fully compatible with the use of volatile ali-
phatic aldehydes (Table 3, Entries 8 and 13). Otherwise, the
reactions continued to work well, and the use of cinnamal-
dehyde was also successful (Table 3, Entry 12). All reactions
proceeded with full diastereoselectivity, and gave exclusively
compounds 9 with a trans relationship between the
hydrogen atoms at the two stereocenters, as established by
NOE studies. This route to compounds bearing scaffold 9
Table 3. Results obtained in 2-acyltetrahydroisoquinoline synthesis.
Entry
R1
R2
R3
R4
R
T [°C] % Yield
Scheme 3. Symmetry-based plan for the synthesis of tricyclic safra-
mycin precursors 9.
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
H
H
H
H
H
H
H
OMe OMe
OMe OMe
OMe OMe
OMe OMe
OMe OMe
OMe OMe
OMe OMe
H
H
H
H
H
H
H
H
H
H
H
H
Et
nPr
Ph
p-BrC6H4
m-NO2C6H4
o-NO2C6H4
o-ClC6H4
45
99
84
74
73
81
80
87
27
85
83
68
82
20
83
85
71
45
120
120
120
120
120
120
135
135
135
135
140
140
140
140
The preparation of starting materials 8a–8c was initiated
by a pseudo-three component double aldol condensation
between 1,4-diacetyl-2,5-piperazinedione and aromatic
aldehydes as previously described in the literature (Et3N,
DMF, 150 °C)[17c,22] or in modified conditions for the case
of the more hindered 2,4,5-trimethoxy-3-methylbenzalde-
hyde (Cs2CO3 in a 5:1 AcOEt-DMSO mixture, 80 °C, 86%
yield vs. 64% using the standard method), followed by se-
lective reduction of one of the exocyclic double bonds with
Zn0 in acetic acid.[23] The application of our α-amidosulf-
one-mediated Pictet–Spengler conditions to compounds
8a–8c, using toluene as solvent, provided the desired com-
9g
9h OMe
9i OMe
9j OMe
9k OMe
9l OMe
9m OMe Me
9n OMe Me
9o OMe Me
9p OMe Me
H
H
H
H
H
OMe Et
OMe C6H5
OMe p-BrC6H4
OMe m-NO2C6H4
OMe PhCH=CH
9
10
11
12
13
14
15
16
OMe OMe Et
OMe OMe Ph
OMe OMe p-BrC6H4
OMe OMe m-NO2C6H4
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F. J. Arroyo, P. López-Alvarado, A. Ganesan, J. C. Menéndez
FULL PAPER
is much faster and more efficient than previously reported cess propanal and toluenesulfinic acid afforded 60% of
approaches.[9,21]
compound 13. Besides the expected isoquinoline ring, 13
Regarding the mechanism of our variation of the Pictet– displays a sulfone side chain at the non-cyclized benzene
Spengler reaction, we first discarded the possibility that p- ring that can be explained from the reaction of this elec-
toluenesulfinic acid (pKa = 1.48) could act simply as a tron-rich aromatic ring with 12. Therefore, it can be pro-
Brønsted acid by verifying that the more acidic benzenesulf- posed that the arylsulfonylalkyl chain at the nitrogen of 10
inic acid (pKa = –0.43) completely failed to promote the must also have arisen from intermediate 12.[24] A parallel
reaction. According to the mechanism generally accepted pathway involving initial attack of the amide nitrogen onto
for this type of reaction, non-isolated intermediate 10 must the aldehyde, followed by addition of the sulfinic acid to the
be involved, arising from the three-component reaction in- resulting iminium intermediate[10b,25] cannot be completely
volving the amide-type substrate, the aldehyde and the ar- discarded. However, besides its complexity, this mechanism
enesulfinic acid. This intermediate progresses to (E)-N-acyl- has the disadvantage of invoking the same acyliminium spe-
iminium cation 11a, presumably by acid-promoted loss of cies usually invoked as an intermediate of the Pictet–Speng-
the sulfinic acid unit. Intermediate 11a then cyclizes to af- ler reaction. Such a mechanism would render the arenesulf-
ford the observed trans products. Formation of the alterna- inic acid unnecessary, a possibility that was ruled out dur-
tive Z-acyliminium species 11b, which would have afforded ing our initial experiments (Table 1).
the cis final products (not observed), is presumably ham-
pered by steric interactions between R1 and the amide carb-
onyl moiety (Scheme 5). This mechanism helps to explain
the above-mentioned higher reactivity associated with the
use of toluenesulfinic acid over benzenesulfinic acid. Thus,
the presence of the electron-releasing p-methyl substituent
should facilitate nucleophilic attack by the arenesulfinic
acid needed for the generation of 10, and it should also
increase the rate of protonation involved in the formation
of N-acyliminium cation 11 from 10.
Figure 2. Structures of intermediate 12 and compound 13.
Conclusions
In conclusion, we have developed a one-pot Pictet–
Spengler protocol that, unlike most previously known
methods, allows the efficient preparation of tetrahydroiso-
quinolines from amide-type substrates, aldehydes and p-
toluenesulfinic acid, without the need for strong Lewis or
Brønsted acid catalysts.[26] The application of this method
to the very efficient preparation of a library of pyrazino-
[2,1-b]isoquinolines, important precursors to anticancer
saframycin analogues, was also achieved.
Experimental Section
General Experimental Information: All reagents (Aldrich, Fluka,
SDS, Acros, Fisher, Panreac) and solvents (SDS) were of commer-
cial quality and were used as received. Reactions were monitored
by thin layer chromatography, on aluminium plates coated with
silica gel with fluorescent indicator (Merck Silica gel 60 F254). Sepa-
rations by flash chromatography were performed on silica gel (SDS
Scheme 5. Reaction mechanism.
60 ACC 40–63 μm). Melting points were measured with a Reichert
723 hot stage microscope, and are uncorrected. Infrared spectra
were recorded with a Perkin–Elmer Paragon 1000 FT-IR spectro-
photometer, with all compounds examined as thin films on NaCl
disks. NMR spectra were obtained using a Bruker Avance 250 spec-
Although the precise details for generation of 10 are not
completely clear, there is some evidence for an electrophilic
species in the reaction medium that derives from the ad-
dition of the aldehyde to toluenesulfinic acid (12, see Fig-
1
trometer operating at 250 MHz for H and 63 MHz for 13C (CAI
ure 2). Thus, the reaction between urea derivative 5 and ex- de Resonancia Magnética Nuclear, Universidad Complutense).
4
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One-Pot Pictet–Spengler Tetrahydroisoquinoline Synthesis
Mass spectra were obtained by the CAI de Espectrometría de
Masas, UCM. Elemental analyses were determined by the CAI de
Microanálisis Elemental, Universidad Complutense, using a Leco
932 CHNS combustion microanalyzer.
yellow oil, yield 0.31 g, 90%. IR (neat): ν = 2934, 2350, 1695, 1564,
˜
1
1357, 1013, 853 cm–1. H NMR (250 MHz, CDCl3): δ = 7.56 (dd,
J = 7.9, 1.4 Hz, 1 H, H5Ј), 7.21–6.90 (m, 3 H, H2Ј, H3Ј, H5Ј), 6.62
(s, 1 H, H5), 6.50 (s, 1 H, H8), 6.43 (s, 1 H, H1), 4.10 (m, 3 H,
OCH2CH3, H3), 3.82 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3), 3.46–
3.21 (m, 1 H, H3), 3.00–2.85 (m, 1 H, H4), 2.73 (m, 1 H, H4), 1.16
(t, J = 7.0 Hz, 3 H, OCH2CH3) ppm. 13C NMR (63 MHz, CDCl3):
δ = 155.8 (CO), 147.9, 147.6 (2ϫ C-OCH3), 143.0 (C1Ј), 133.0 (C5Ј),
129.9, 128.7, 127.4 (C3Ј, C4Ј, C6Ј), 127.1, 126.6 (C4a, C8a), 124.1
(C2Ј), 111.2 (C5), 110.4 (C8), 61.5 (OCH2CH3), 57.2 (C1), 55.8 (2ϫ
OCH3), 39.3 (C3), 28.1 (C4), 14.5 (OCH2CH3) ppm. C20H22BrNO4
(420.30): calcd. C 57.15, H 5.28, N 3.33; found C 57.32, H 5.40, N
3.39.
General Procedure for the Synthesis of Compounds 3a–3o: To a solu-
tion of compound 1 (1.0 equiv.) in dichloromethane (56 equiv.) was
added p-toluenesulfinic acid (1.0 equiv.) and the suitable aldehyde
(1.1–2.0 equiv.). The reaction mixture was heated to 45 °C and
stirred for 12 h. The cooled reaction mixture was then poured onto
50 mL of a saturated aqueous solution of NaHCO3 and extracted
with dichloromethane (3ϫ 20 mL). The combined organic layers
were dried with anhydrous Na2SO4 and filtered. The solvent was
evaporated under reduced pressure, and the mixture was purified
by flash column chromatography using a gradient of petroleum
ether/diethyl ether as eluent. Characterization data for representa-
tive compounds 3 are given below. For full characterization data,
see the Supporting Information.
Ethyl (؎)-6,7-Dimethoxy-1-(2,4,5-trimethoxyphenyl)-3,4-dihydro-
isoquinoline-2(1H)-carboxylate (3m): Obtained according to the ge-
neral procedure using compound 1 (0.2 g, 0.84 mmol) as starting
material, p-toluenesulfinic acid (0.13 g, 0.84 mmol), 2,4,5-tri-
methoxybenzaldehyde (0.41 g, 2.10 mmol) and dichloromethane
(3.0 mL) as solvent, the reaction was heated to 45 °C and stirred
for 24 h. Purification by flash column chromatography on silica gel
using 2:8 petroleum ether/diethyl ether as eluent afforded product
Ethyl
(؎)-1-Ethyl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-
carboxylate (3a): Obtained according to the general procedure
using compound 1 (0.2 g, 0.84 mmol) as starting material, p-tolu-
enesulfinic acid (0.13 g, 0.84 mmol), propanal (1.0 mL, 1.37 mmol)
and dichloromethane (3.0 mL) as solvent. Purification by flash col-
umn chromatography on silica gel using a 7:3 petroleum ether/di-
3m as a yellow solid, yield 0.22 g, 57%. IR (neat): ν = 2934, 2350,
˜
1
1695, 1351, 882 cm–1. H NMR (250 MHz, CDCl3): δ = 6.56 (s, 1
H, H5), 6.48 (s, 1 H, H3Ј), 6.45 (s, 1 H, H8), 6.40 (s, 1 H, H6), 6.38
(s, 1 H, H1), 4.16–3.92 (m, 3 H, OCH2CH3, H3), 3.79 (s, 3 H,
OCH3), 3.77 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 3.65 (s, 3 H,
OCH3), 3.59 (s, 3 H, OCH3), 3.37–3.19 (m, 1 H, H3), 2.86 (m, 1
ethyl ether mixture as eluent afforded product 3a as a brown oil,
1
yield 0.16 g, 69%. IR (neat): ν = 2961, 2934, 2350, 1695 cm–1. H
˜
NMR (250 MHz, CDCl3): δ = 6.54 (s, 2 H, H5, H8), 5.04–4.85 (m,
1 H, H1), 4.27–3.90 (m, 3 H, OCH2CH3, H3), 3.80 (s, 3 H, OCH3),
3.78 (s, 3 H, OCH3), 3.29–3.05 (m, 1 H, H3), 2.96–2.68 (m, 1 H,
H4), 2.57 (m, 1 H, H4), 1.82–1.65 (m, 2 H, H1Ј), 1.22 (t, J = 7.1 Hz,
3 H, OCH2CH3), 0.92 (t, J = 7.4 Hz, 3 H, H2Ј) ppm. 13C NMR
(63 MHz, CDCl3): δ = 155.9 (CO), 147.5, 147.2 (2ϫ C-OCH3),
130.0, 129.7, 126.0, 125.7 (C4a, C8a), 111.4, 111.3, 110.0, 109.8 (C5,
C8), 61.2 (OCH2CH3), 55.9, 55.8 (OCH3), 55.5 (C1), 37.9, 37.1 (C3),
29.7, 29.4 (C1Ј), 28.0, 27.8 (C4), 14.6 (OCH2CH3), 10.9 (C2Ј) ppm.
C16H23NO4 (293.36): calcd. C 65.51, H 7.90, N 4.77; found C
65.63, H 7.95, N 4.67.
H, H4), 2.64 (m,
1 J = 7.1 Hz, 3 H,
H, H4), 1.17 (t,
OCH2CH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 155.3 (CO),
151.8, 149.0, 147.5 (C2Ј, C4Ј, C5Ј), 147.2, 142.2 (C6, C7), 128.0 (C8a),
126.8 (C4a), 123.0 (C1Ј), 114.3 (C6Ј), 111.0 (C5), 110.5 (C8), 97.7
(C3Ј), 61.0 (OCH2CH3), 56.6, 56.4, 55.9, 55.7, 55.6 (4ϫ OCH3),
52.5 (C1), 38.5 (C3), 27.9 (C4), 14.5 (OCH2CH3) ppm. C23H29NO7
(431.48): calcd. C 64.02, H 6.77, N 3.25; found C 64.11, H 6.81, N
3.33.
General Procedure for the Synthesis of (؎)-6,7-Dimethoxy-NЈ-(3,4-
dimethoxyphenethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbox-
amides 6a–6f:To a solution of compound 5 (1.0 equiv.) in dichloro-
methane or ethyl acetate (5.0 mL) were added the corresponding
aryl or alkyl aldehyde (3 equiv.) and p-toluenesulfinic acid (1.1–
3.0 equiv.) and the reaction mixture was heated at 45 or 80 °C,
respectively, for 12 h. The mixture was quenched with a saturated
solution of NaHCO3, extracted with dichloromethane (2ϫ 30 mL)
and concentrated under reduced pressure. The crude material was
purified by flash column chromatography using a mixture of di-
ethyl ether/ethyl acetate to give compounds 6a–6f. Characterization
data for representative compounds 6 are given below. For full char-
acterization data, see the Supporting Information.
Ethyl (؎)-6,7-Dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate (3c): Obtained according to the general procedure
using compound 1 (0.2 g, 0.84 mmol) as starting material, p-tolu-
enesulfinic acid (0.13 g, 0.84 mmol), benzaldehyde (1.0 mL,
0.98 mmol, 1.17 equiv.) and dichloromethane (3.0 mL) as solvent.
Purification by flash column chromatography on silica gel using
2:8 petroleum ether/diethyl ether as eluent afforded product 3c as
a yellow oil, yield 0.19 g, 66%. IR (neat): ν = 2931, 2341, 1670,
˜
1
1630, 1500, 1361, 1022, 851 cm–1. H NMR (250 MHz, CDCl3): δ
= 7.30 (s, 5 H, H2Ј, H3Ј, H4Ј, H5Ј, H6Ј), 6.72 (s, 1 H, H5), 6.54
(s, 1 H, H8), 6.43 (br. s, 1 H, H1), 4.37–4.00 (m, 3 H, OCH2CH3,
H3), 3.91 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.28–3.09 (m, 1 H,
H3), 3.09–2.82 (m, 1 H, H4), 2.71 (d, J = 15.1 Hz, 1 H, H4), 1.31(t,
J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (63 MHz, CDCl3): δ
= 155.3 (CO), 147.8, 147.2 (C6, C7), 142.5 (C1Ј), 128.4, 128.0,
127.2 (C2Ј, C3Ј, C4Ј, C5Ј, C6Ј), 126.9, 126.7 (C4a, C8a), 111.1 (C5),
110.8 (C8), 61.3 (OCH2CH3), 56.9 (C1), 55.7, 55.6 (OCH3), 37.4
(C3), 27.8 (C4), 14.6 (OCH2CH3) ppm. C20H23NO4 (341.41): calcd.
C 70.36, H 6.79, N 4.10; found C 70.43, H 6.76, N 4.23.
(؎)-6,7-Dimethoxy-NЈ-(3,4-dimethoxyphenethyl)-1-phenyl-1,2,3,4-
tetrahydroisoquinoline-2-carboxamide (6a): Obtained according to
the general procedure using compound 5 (0.20 g, 0.51 mmol) as
starting material, p-toluenesulfinic acid (0.24 g, 1.53 mmol,
3 equiv.), benzaldehyde (0.16 g, 1.5 mmol) and refluxing dichloro-
methane (5.0 mL) as solvent. Purification by flash column
chromatography on silica gel using 8:2 diethyl ether/ethyl acetate
Ethyl (؎)-1-(2-Bromophenyl)-6,7-dimethoxy-3,4-dihydroisoquinol- as eluent afforded compound 6a as a pale brown solid, yield 0.11 g,
ine-2(1H)-carboxylate (3g): Obtained according to the general pro-
cedure using compound 1 (0.2 g, 0.84 mmol) as starting material,
p-toluenesulfinic acid (0.13 g, 0.84 mmol), 2-bromobenzaldehyde
(0.17 g, 0.92 mmol) and dichloromethane (3.0 mL) as solvent. Puri-
fication by flash column chromatography on silica gel using 1:9
petroleum ether/diethyl ether as eluent afforded product 3g as a
49%; m.p. 128–130 °C. IR (neat): ν = 3320, 2820, 1644, 1501, 1230,
˜
1
1190, 805, 748 cm–1. H NMR (250 MHz, CDCl3): δ = 7.31–7.17
(m, 5 H, H2Ј, H3Ј, H4Ј, H5Ј, H6Ј), 6.80 (d, J = 8.7 Hz, 1 H, H5ЈЈЈ),
6.75–6.69 (m, 2 H, H2ЈЈЈ, H6ЈЈЈ), 6.67 (s, 1 H, H5), 6.62 (s, 1 H, H8),
6.31 (s, 1 H, H1), 4.59 (t, J = 5.6 Hz, 1 H, NH), 3.90 (s, 3 H,
OCH3), 3.89 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.80 (s, 3 H,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42487
/KAP1
Date: 01-08-14 11:36:31
Pages: 9
F. J. Arroyo, P. López-Alvarado, A. Ganesan, J. C. Menéndez
FULL PAPER
OCH3), 3.60–3.46 (m, 3 H, H1ЈЈ, H3), 3.46–3.32 (m, 1 H, H3), 2.88– tracted with dichloromethane (2ϫ 30 mL) and the combined ex-
2.75 (m, 3 H, H2ЈЈ, H4), 2.67 (dt, J = 15.8, 5.1 Hz, 1 H, H4) ppm. tracts were dried with anhydrous Na2SO4 and concentrated under
13C NMR (63 MHz, CDCl3): δ = 157.5 (CO), 149.0, 148.1, 147.6, reduced pressure. The crude was purified by flash column
147.5 (4ϫ C-OCH3), 143.0 (C1Ј), 132.0 (C1ЈЈЈ), 128.0 (C3Ј, C5Ј), chromatography, eluting with a gradient of petroleum ether/diethyl
128.0 (C8a), 127.8 (C2Ј, C6Ј), 127.3 (C4Ј), 127.1 (C4a), 120.7, 112.0 ether, to give compounds 7a and 7b.
(C2ЈЈЈ, C6ЈЈЈ), 111.4 (C5ЈЈЈ), 111.2 (C4, C8), 57.1 (C1), 56.1, 56.0, 55.8
(؎)-(R*R*)-Bis[1-(2-chlorophenyl)-6,7-dimethoxy-3,4-dihydroiso-
(4 ϫ OCH3), 42.3 (C1ЈЈ), 39.4 (C3), 35.8 (C2ЈЈ), 27.8 (C4) ppm.
quinolin-2(1H)-yl]methanone (7a): Obtained according to the gene-
C
28H32N2O5 (476.57): calcd. C 70.57, H 6.77, N 5.88; found C
ral procedure using compound 5 (0.20 g, 0.51 mmol) as starting
material, p-toluenesulfinic acid (0.24 g, 1.53 mmol, 3 equiv.), 2-
chlorobenzaldehyde (0.22 g, 1.52 mmol) and toluene (5.0 mL) as
solvent at 120 °C. Purification by flash column chromatography on
silica gel using 1:9 petroleum ether/diethyl ether as eluent afforded
70.66, H 6.60, N 5.70.
(؎)-6,7-Dimethoxy-NЈ-(3,4-dimethoxyphenethyl)-1-(3-nitrophenyl)-
1,2,3,4-tetrahydroisoquinoline-2-carboxamide (6c): Obtained ac-
cording to the general procedure using compound 5 (0.20 g,
0.51 mmol) as starting material, p-toluenesulfinic acid (0.24 g, the product 7a as a white solid, yield 0.28 g, 56%; m.p. 225–226 °C.
1
1.53 mmol, 3 equiv.), 3-nitrobenzaldehyde (0.23 g, 1.5 mmol) and
refluxing dichloromethane (5.0 mL) as solvent. Purification by
flash column chromatography on silica gel using 8:2 diethyl ether/
IR (neat): ν = 1649, 1502, 1233, 1194 cm–1. H NMR (250 MHz,
˜
CDCl3): δ = 7.40 (dd, J = 7.8, 1.3 Hz, 2 H, H3Ј, H3ЈЈЈ), 7.19 (td, J
= 7.6, 1.8 Hz, 2 H, H4Ј, H4ЈЈЈ), 7.09 (td, J = 7.5, 1.4 Hz, 1 H, H5Ј,
ethyl acetate as eluent afforded compound 6c as a pale yellow solid, H5ЈЈЈ), 6.81 (dd, J = 7.6, 1.7 Hz, 1 H, H6Ј, H6ЈЈЈ), 6.61 (s, 2 H, H5,
yield 0.23 g, 85%; m.p. 153–155 °C. IR (neat): ν = 3400, 2830, 1930,
H8), 6.54 (s, 1 H, H1, H1ЈЈ), 6.40 (s, 2 H, H5ЈЈ, H8ЈЈ), 3.87 (s, 6 H,
2ϫ OCH3), 3.70 (s, 6 H, 2ϫ OCH3), 3.59–3.47 (m, 2 H, H4), 3.29–
3.13 (m, 2 H, H4ЈЈ), 3.06–2.92 (m, 1 H, H3), 2.71–2.50 (m, 2 H,
H3ЈЈ) ppm. 13C NMR (63 MHz, CDCl3): δ = 163.5 (NCON), 148.1,
˜
1
1643, 1519, 1347, 1260, 1130, 809, 745 cm–1. H NMR (250 MHz,
CDCl3): δ = 8.06 (ddd, J = 8.1, 2.0, 0.9 Hz, 1 H, H6Ј), 8.00 (dd, J
= 2.2, 1.8 Hz, 1 H, H4Ј), 7.59 (m, 1 H, H2Ј), 7.42 (t, J = 7.9 Hz, 1
H, H5Ј), 6.79–6.63 (m, 5 H, H2ЈЈЈ, H5ЈЈЈ, H6ЈЈЈ), 6.51 (s, 1 H, H1), 147.7 (4ϫ COCH3), 141.2 (C1Ј, C1ЈЈЈ), 134.7 (C2Ј, C2ЈЈЈ), 131.4 (C6Ј,
4.61 (t, J = 5.6 Hz, 1 H, NH), 3.87 (s, 3 H, OCH3), 3.84 (s, 3 H, C6ЈЈЈ), 129.9 (C3Ј, C3ЈЈЈ), 128.6 (C4Ј, C4ЈЈЈ), 127.0, 126.9 (C4a, C8a,
OCH3), 3.80 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.62–3.44 (m, 2
C4aЈЈ, C8aЈЈ), 126.3 (C5Ј, C5ЈЈЈ), 111.1, 110.9 (C5, C8, C5ЈЈ, C8ЈЈ), 56.0,
H, H1ЈЈ), 3.34 (t, J = 6.2 Hz, 2 H, H3), 2.84–2.70 (m, 3 H, H2ЈЈ
,
55.9 (4 ϫ OCH3), 55.2 (C1, C1ЈЈ), 42.5 (C3, C3ЈЈ), 28.2 (C4,
H4), 2.61 (dt, J = 15.8, 5.7 Hz, 1 H, H4) ppm. 13C NMR (63 MHz, C4ЈЈ) ppm. C35H34Cl2N2 (553.57): calcd. C 66.35, H 5.41, N 4.42;
CDCl3): δ = 157.4 (NCON), 149.1, 148.6 (2ϫ COCH3), 148.4 (C3Ј), found C 66.20, H 5.30, N 4.46.
147.9, 147.7 (2ϫ COCH3), 145.5 (C1Ј), 134.1 (C2Ј), 131.7 (C1ЈЈЈ),
(؎)-(R*R*)-Bis[1-ethyl-6,7-dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl]methanone (7b): Obtained according to the general pro-
cedure using compound 5 (0.20 g, 0.51 mmol) as starting material,
p-toluenesulfinic acid (0.18 g, 1.12 mmol, 2.2 equiv.), propionalde-
129.3 (C5ЈЈЈ), 127.0 (C4a, C8a), 122.4, 122.3 (C4ЈЈ, C6ЈЈ), 120.7 (C5ЈЈ),
112.0 (C2ЈЈЈ), 111.4, 111.4 (C5, C8), 111.0 (C6ЈЈЈ), 56.2, 56.1 (OCH3,
C1), 56.0, 55.9, 55.8 (3ϫ OCH3), 42.3 (C1Ј), 40.0 (C3), 35.8 (C2ЈЈ),
27.6 (C4) ppm. C28H31N3O7 (521.57): calcd. C 64.48, H 5.99, N
hyde (0.23 g, 2.04 mmol, 4.0 equiv.) and dichloromethane (5.0 mL)
8.06; found C 64.46, H 5.78, N 7.90.
as solvent at 45 °C. Purification by flash column chromatography
(؎)-6,7-Dimethoxy-NЈ-(3,4-dimethoxyphenethyl)-1-propyl-1,2,3,4-
tetrahydroisoquinoline-2-carboxamide (6f): Obtained according to
the general procedure using compound 5 (0.20 g, 0.51 mmol) as
on silica gel using diethyl ether as eluent afforded the product 7
(0.17 mmol) as a white solid, yield 0.30 g, 62%; m.p. 154–156 °C.
1
IR (neat): ν = 3020, 1930 cm–1. H NMR (250 MHz, CDCl ): δ =
˜
3
starting material, p-toluenesulfinic acid (0.24 g, 1.53 mmol, 6.57 (s, 2 H, H8, H8ЈЈ), 6.56 (s, 2 H, H5, H5ЈЈ), 4.71 (dd, J = 8.9,
3 equiv.), butyraldehyde (0.11 g, 1.53 mmol) and refluxing ethyl
acetate (5.0 mL) as solvent. Purification by flash column
chromatography on silica gel using 8:2 diethyl ether/ethyl acetate
as eluent afforded the product 6f as a pale brown solid, yield 0.12 g,
5.2 Hz, 1 H, H1, H1ЈЈ), 3.84 (s, 12 H, 4ϫ OCH3), 3.84–3.76 (m, 2
H, H3), 3.37 (ddd, J = 13.4, 11.6, 4.4 Hz, 2 H, H3ЈЈ), 2.85 (ddd, J
= 17.5, 11.4, 6.3 Hz, 2 H, H4), 2.61 (dd, J = 16.3, 2.5 Hz, 2 H,
H4ЈЈ), 1.86–1.66 (m, 4 H, H1Ј, H1ЈЈЈ), 0.95 (t, J = 7.3 Hz, 6 H, H2Ј,
H2ЈЈЈ) ppm. 13C NMR (63 MHz, CDCl3): δ = 164.9 (NCON), 147.7,
52%; m.p. 78–80 °C. IR (neat): ν = 3320, 2960, 1610, 1530, 1340,
˜
1
1231, 930, 810 cm–1. H NMR (250 MHz, CDCl3): δ = 6.73 (d, J 147.4 (C6, C6ЈЈ, C7, C7ЈЈ), 130.5 (C8a, C8aЈЈ), 125.7 (C5a, C5aЈЈ), 111.5
= 8.7 Hz, 1 H, H5ЈЈЈ), 6.69–6.59 (m, 2 H, H2ЈЈЈ, H6ЈЈЈ), 6.54 (s, 1 H, (C5, C5ЈЈ), 110.0 (C8, C8ЈЈ), 57.3 (C1, C1ЈЈ), 56.1, 56.0 (4ϫ OCH3),
H5), 6.52 (s, 1 H, H8), 4.87 (dd, J = 7.8, 5.9 Hz, 1 H, H1), 4.57 (t,
40.4 (C3, C3ЈЈ), 30.0 (C1Ј, C1ЈЈЈ), 28.4 (C4, C4ЈЈ), 11.4 (C3Ј, C3ЈЈЈ) ppm.
J = 5.2 Hz, 1 H, NH), 3.80 (s, 3 H, OCH3), 3.80 (s, 6 H, 2ϫ C27H36N2O5 (468.59): calcd. C 69.21, H 7.74, N 5.98; found C
OCH3), 3.76 (s, 3 H, OCH3), 3.73–3.59 (m, 1 H, H3), 3.54–3.33 (m, 69.39, H 7.51, N 5.75.
2 H, H1ЈЈ), 3.31–3.17 (m, 1 H, H3), 2.82–2.57 (m, 4 H, H4, H2ЈЈ),
General Procedure for the Synthesis of (Z)-3-(Dimethoxybenzylid-
1.80–1.49 (m, 2 H, H1Ј), 1.41–1.23 (m, 2 H, H2Ј), 0.87 (t, J = 7.3 Hz,
ene)-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione
3 H, H3Ј) ppm. 13C NMR (63 MHz, CDCl3): δ = 157.4 (NCON),
Derivatives 9: To a solution of the suitable compound 8
148.8, 147.5, 147.4, 147.1 (4ϫ OCH3), 131.9 (C1ЈЈЈ), 130.3 (C4a),
(1.00 equiv.) (for their synthesis, see the Supporting Information)
126.0 (C8a), 120.6, 111.9 (C6ЈЈЈ,C2ЈЈЈ), 111.2, 111.1 (C5ЈЈЈ, C4a), 110.1
in toluene (0.5–2.0 mL), p-toluenesulfinic acid (0.96–4.00 equiv.)
(C8), 55.9, 55.8, 55.7 (4ϫ OCH3), 54.5 (C1), 42.2 (C1ЈЈ), 39.1 (C1Ј),
and the suitable alkyl or aryl aldehyde (1.3–29.9 equiv.) were added.
38.3 (C3), 35.8 (C2ЈЈ), 27.5 (C4), 20.0 (C2Ј), 14.0 (C3Ј) ppm.
The reaction mixture was stirred at 45–140 °C (see Table 3) for
C25H34N2O5 (442.55): calcd. C 67.85, H 7.74, N 6.33; found C
12 h. The reaction was then quenched with saturated aqueous solu-
67.92, H 7.55, N 6.44.
tion of NaHCO3, extracted with dichloromethane (2 ϫ 20 mL),
General Procedure for the Synthesis of (؎)-(R*S*)-Bis[6,7-dimeth-
oxy-3,4-dihydroisoquinolin-2(1H)-yl]methanones 7: To a solution of
compound 5 (1.0 equiv.) in toluene (5.0 mL) was added the suitable
aldehyde (3 equiv.) and p-toluenesulfinic acid (2.2–3.0 equiv.) and
the solution was heated in an oil bath at 120 °C for 12 h. The mix-
ture was quenched with a saturated solution of NaHCO3 and ex-
dried with anhydrous Na2SO4 and filtered. The solution was con-
centrated in vacuo and purified by flash column chromatography
using petroleum ether/diethyl ether as eluent to provide compounds
9a–9p. Characterization data for representative compounds 9 are
given below. For full characterization data, see the Supporting In-
formation.
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42487
/KAP1
Date: 01-08-14 11:36:31
Pages: 9
One-Pot Pictet–Spengler Tetrahydroisoquinoline Synthesis
(؎)-(6R*,11aS*,3Z)-3-(3,4-Dimethoxybenzylidene)-6-ethyl-8,9-di-
methoxy-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-
dione (9a): Obtained according to the general procedure using com-
pound 8a (0.10 g, 0.23 mmol) as starting material, p-toluenesulfinic
acid (0.049 g, 0.32 mmol), propionaldehyde (0.40 g, 6.89 mmol)
and toluene (2.0 mL) as solvent at 45 °C. Purification by flash col-
umn chromatography on silica gel using 1:9 petroleum ether/diethyl
ether as eluent afforded product 9a as an orange solid, yield 0.11 g,
C-OCH3), 127.0, 125.8, 123.3, 121.6 (C3, C6a, C10a, CAr), 116.5,
115.5, 113.8, 113.74, 108.4, 108.2 (C8, C9, C3, 3ϫ CHAr), 57.0,
55.9, 55.8, 55.7 (4ϫ OCH3), 51.7 (C11a), 50.6 (C6), 29.4 (C11), 26.0
(CH2-C6), 11.1 (CH3) ppm. C25H28N2O6 (452.51): calcd. C 66.36,
H 6.24, N 6.19; found C 66.20, H 6.43, N 6.20.
(؎)-(6R*,11aS*,3Z)-3-(2,5-Dimethoxybenzyl)-7,10-dimethoxy-6-(3-
nitrophenyl)-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-
1,4-dione (9k): Obtained according to the general procedure using
compound 8b (0.1 g, 0.23 mmol) and 3-nitrobenzaldehyde (0.071 g,
0.47 mmol) as starting materials, p-toluenesulfinic acid (0.049 g,
0.39 mmol), and toluene (1.0 mL) as solvent at 120 °C. Purification
by flash column chromatography on silica gel using 1:9 petroleum
ether/diethyl ether as eluent afforded product 9k as a yellow solid,
99%; m.p. 192–193 °C. IR (neat): ν = 3200, 2930, 1700, 1655 cm–1.
˜
1H NMR (250 MHz, CDCl3): δ = 8.10 (s, 1 H, NH), 7.01 (s, 1 H,
CH-C3), 6.96 (dd, J = 8.3, 1.8 Hz, 1 H, H6ЈЈ), 6.90 (d, J = 8.3 Hz,
1 H, H5ЈЈ), 6.82 (d, J = 1.7 Hz, 1 H, H2ЈЈ), 6.64 (s, 1 H, H7), 6.56
(s, 1 H, H10), 5.74 (dd, J = 10.4, 4.4 Hz, 1 H, H6), 4.50 (dd, J =
12.1, 4.4 Hz, 1 H, H11a), 3.90 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
3.86 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.27 (dd, J = 16.0, 4.4 Hz,
1 H, H11), 3.05 (dd, J = 15.9, 12.2 Hz, 1 H, H11), 1.96–1.79 (m, 2
H, H1Ј), 1.02 (t, J = 7.4 Hz, 3 H, H2Ј) ppm. 13C NMR (63 MHz,
CDCl3): δ = 165.2, 157.3 (C1, C4), 149.7, 149.4, 148.2, 148.1 (4ϫ
C-OCH3), 128.4, 125.9, 124.4, 123.0 (C1ЈЈ, C3, C6a, C10a), 120.6,
116.8, 111.9, 111.7, 111.1, 109.8 (CHAr, CH-C3), 56.1, 56.0 (4ϫ
OCH3), 54.0 (C11a), 52.8 (C6), 34.2 (C11), 29.4 (C1Ј), 11.1 (C2Ј) ppm.
C25H30N2O6 (454.52): calcd. C 66.06, H 6.65, N 6.16; found C
66.00, H 6.60, N 6.19.
yield 0.09 g, 68%; m.p. 102–103 °C. IR (neat): ν = 3180, 2910, 1689,
˜
1627 cm–1. 1H NMR (250 MHz, CDCl3): δ = 8.71 (s, 1 H, NH),
8.18–7.96 (m, 2 H, H5ЈЈ, H6ЈЈ), 7.68–7.44 (m, 2 H, H2ЈЈ, H4ЈЈ), 7.29
(s, 1 H, H6), 7.04 (s, 1 H, CH-C3), 6.92–6.70 (m, 5 H, CHAr), 4.18
(dd, J = 12.4, 4.7 Hz, 1 H, H11a), 3.87 (s, 3 H, OCH3), 3.83 (s, 3
H, OCH3), 3.77 (s, 3 H, OCH3), 3.61 (s, 3 H, OCH3), 3.53 (dd, J
= 17.7, 4.6 Hz, 1 H, H11), 2.86 (dd, J = 17.5, 12.5 Hz, 1 H,
H11) ppm. 13C NMR (63 MHz, CDCl3): δ = 164.9 (C1), 157.4 (C4),
154.5, 151.5, 150.6, 150.4 (4ϫ C-OCH3), 148.8 (C-CNO2), 143.0
(C-C6), 134.9 (C6ЈЈ), 129.8 (C4ЈЈ), 125.6, 123.4 (C3, CAr), 123.4,
123.3 (C5ЈЈ, C2ЈЈ), 123.3 (C6a), 122.4 (C10a), 116.8 (CHAr), 116.0
(C6Ј), 114.7 (CH-C3), 114.0 (CHAr), 109.8, 109.1 (3ϫ CHAr), 57.2,
56.2, 56.1, 56.0 (4ϫ OCH3), 52.3 (C11a), 51.6 (C6), 29.4 (C11) ppm.
(؎)-(6R*,11aS*,3Z)-6-(4-Bromophenyl)-3-(3,4-dimethoxybenzyl)-
8,9-dimethoxy-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinol-
ine-1,4-dione (9d): Obtained according to the general procedure
using compound 8a (0.1 g, 0.23 mmol), and 4-bromobenzaldehyde
(0.2 g, 2.77 mmol) as starting materials, p-toluenesulfinic acid
(0.12 g, 0.76 mmol) and toluene (0.50 mL) as solvent at 110 °C. Pu-
rification by flash column chromatography on silica gel using 1:9
petroleum ether/diethyl ether as eluent afforded product 9d as a
C
29H29N3O8 (547.56): calcd. C 63.61, H 5.34, N 7.67; found C
63.70, H 5.56, N 7.62.
(؎)-(6R*,11aS*,3Z)-7,8,10-Trimethoxy-9-methyl-6-(3-nitrophenyl)-
3-(2,4,5-trimethoxy-3-methylbenzylidene)-2,3,11,11a-tetrahydro-6H-
pyrazino[1,2-b]isoquinoline-1,4-dione (9p): Obtained according to
the general procedure using compound 8c (0.1 g, 0.19 mmol) and
3-nitrobenzaldehyde (0.057 g, 0.69 mmol) as starting materials, p-
toluenesulfinic acid (0.050 g, 0.32 mmol), and toluene (1.0 mL) as
solvent at 140 °C for 24 h. Purification by flash column chromatog-
raphy on silica gel using 8:2 petroleum ether/diethyl ether as eluent
afforded product 9p (0.13 mmol) as a brown solid as a mixture 1:1
of rotamers in CDCl3, 25 °C, yield 0.088 g, 71%; m.p.118–120 °C.
brown solid, yield 0.21 g, 73%; m.p. 92–94 °C. IR (neat): ν = 3200,
˜
1
2930, 1693, 1625 cm–1. H NMR (250 MHz, CDCl3): δ = 7.98 (s,
1 H, NH), 7.32–7.27 (m, 4 H, H2Ј, H3Ј, H5Ј, H6Ј), 7.09 (s, 1 H, CH-
C3), 7.06 (s, 1 H, H6), 6.92 (dd, J = 8.4, 1.4 Hz, 1 H, H6ЈЈ), 6.91 (d,
J = 8.2 Hz, 1 H, H5ЈЈ), 6.81 (d, J = 1.4 Hz, 1 H, H2ЈЈ), 6.68 (s, 1 H,
H10), 6.51 (s, 1 H, H7), 4.41 (dd, J = 12.2, 4.4 Hz, 1 H, H11a), 3.90
(s, 6 H, OCH3), 3.88 (s, 6 H, OCH3), 3.76 (s, 3 H, OCH3), 3.37
(dd, J = 16.1, 4.4 Hz, 1 H, H11), 3.14 (dd, J = 16.0, 12.3 Hz, 1 H,
H11) ppm. 13C NMR (63 MHz, CDCl3): δ = 164.8 (C1), 156.7 (C4),
149.8, 149.6, 148.8, 148.5 (4ϫ C-OCH3), 140.2 (C1Ј), 131.9 (C3Ј,
C5Ј), 130.8 (C2Ј, C6Ј), 125.7, 124.5, 124.3, 122.6 (C6a, C10a, C4Ј, C3,
C1ЈЈ), 120.7 (C2ЈЈ), 117.1 (CH-C3), 111.9, 111.8 (C5ЈЈ, C6ЈЈ), 110.9
(C10), 110.6 (C7), 56.1 (4 ϫ OCH3), 54.9 (C6), 52.4 (C11a), 33.9
(C11) ppm. C29H29N2O6 (501.56): calcd. C 59.90, H 5.03, N 4.82;
found C 59.76, H 5.06, N 4.89.
IR (neat): ν = 3200, 2936, 2360, 1689, 1627 cm–1 1H NMR
.
˜
(250 MHz, CDCl3): δ = 9.61 (s, 0.5 H, NH), 9.45 (s, 0.5 H, NH),
8.19–8.14 (m, 1 H, C6Ј), 8.08–8.07 (m, 1 H, C2Ј), 7.75–7.64 (m, 1
H, C4Ј), 7.58–7.46 (m, 1 H, C5Ј), 7.28 (s, 1 H, C6), 6.99 (s, 0.5 H,
CH-C3), 6.89 (s, 0.5 H, CH-C3), 6.68 (s, 0.5 H, CHAr), 6.64 (s, 0.5
H, CHAr),4.23 (dd, J = 12.3, 4.5 Hz, 1 H, C11a), 3.82–3.52 (m, 19
H, OCH3, H11), 2.88 (dd, J = 16.8, 12.5 Hz, 1 H, H11), 2.26–2.22
(m, 6 H, CH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 164.7 (C1),
157.5 (C4), 152.5, 150.8, 149.8, 149.3, 149.1, 149.0, 148.5, 146.2
(6ϫ C-OCH3), 142.9 (C7), 134.5 (C1Ј), 129.7, 126.8, 126.1, 125.5,
124.6, 124.0 (2ϫ CMe, C1Ј, C3, C6a, C10a), 123.3, 123.2 (C2Ј,C6Ј),
121.7, 121.7, 121.6 (C3Ј), 115.0, 114.0 (CH-C3), 112.3, 112.0
(CHAr), 61.4, 61.2, 60.5, 60.5, 60.3, 60.1, 59.9, 56.0 (OCH3), 52.3
(C11a), 51.4 (C6), 29.0 (C11), 9.7, 9.6, 9.6 (2 ϫ CH3) ppm.
C33H35N3O10 (633.65): calcd. C 62.55, H 5.57, N 6.63; found C
62.50, H 5.51, N 6.53.
(؎)-(6R*,11aS*,3Z)-3-(2,5-Dimethoxybenzylidene)-6-ethyl-7,10-di-
methoxy-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-
dione (9h): Obtained according to the general procedure using com-
pound 8b (0.1 g, 0.23 mmol) and 1-propionaldehyde (0.400 g,
6.89 mmol) as starting materials, p-toluenesulfinic acid (0.049 g,
0.39 mmol) and toluene (1.0 mL) as solvent at 120 °C. Purification
by flash column chromatography on silica gel using 1:9 petroleum
ether/diethyl ether as eluent afforded product 9h as a brown solid,
yield 0.03 g, 27%; m.p. 84–85 °C. IR (neat): ν = 3200, 2930, 1693,
˜
1625 cm–1. 1H NMR (250 MHz, CDCl3): δ = 8.73 (s, 1 H, NH),
(؎)-(R*S* and R*R*)-1-Ethyl-6,7-dimethoxy-NЈ-[4,5-dimethoxy-
6.97–6.66 (m, 6 H, H8, H9, CH-C3, 3ϫ CH-Ar), 5.94 (dd, J = 11.1, 2-(1-tosylpropyl)phenethyl]-1,2,3,4-tetrahydroisoquinoline-2-carbox-
3.3 Hz, 1 H, H6), 4.49 (dd, J = 12.4, 4.8 Hz, 1 H, H11a), 3.88 (s, 3
H, OCH3), 3.82 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.75 (s, 3 H,
OCH3), 3.44 (dd, J = 17.4, 4.9 Hz, 1 H, H11), 2.75 (dd, J = 17.4,
12.4 Hz, 1 H, H11), 2.18–2.12 (m, 1 H, CH2-C6), 1.62–1.53 (m, 1 H,
amide (13): Obtained according to the general procedure using
compound 5 (0.20 g, 0.51 mmol) as starting material, p-toluenesulf-
inic acid (0.18 g, 1.12 mmol, 2.2 equiv.), propanal (0.12 g,
2.04 mmol, 4.0 equiv.) and dichloromethane (5.0 mL) as solvent.
CH2-C6), 1.02 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (63 MHz, Purification by flash column chromatography on silica gel using
CDCl3): δ = 165.5, 157.6 (C1, C4), 154.2, 151.0, 150.3, 150.0 (4ϫ
9:1 diethyl ether/ethyl acetate as eluent afforded the product 13 as
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O42487
/KAP1
Date: 01-08-14 11:36:31
Pages: 9
F. J. Arroyo, P. López-Alvarado, A. Ganesan, J. C. Menéndez
FULL PAPER
Song, C. X. Chen, J. S. Peng, Sci. China Chem. 2010, 562; c) S.
Ponnala, W. W. Harding, Eur. J. Org. Chem. 2013, 1107.
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2003, 44, 4395; b) M. Yokoya, K. Shinada-Fujino, N. Saito,
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[10] For reviews, see: a) B. Yin, Y. Zhang, L. W. Xu, Synthesis 2010,
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[11] See, for instance: S. Tussetschläger, A. Baro, S. Laschat, W.
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a pale brown solid, corresponding to a 1:1 mixture of diastereomers
A and B, yield 0.19 g, 60%; m.p. 90–92 °C. IR (neat): ν = 3300,
˜
2980, 1535 cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.57 and
7.48 ppm (2d, J = 8.2 Hz, 2 H, H2,6 Ts), 7.21 and 7.15 (2d, J =
8.1 Hz, 2 H, H3,5 Ts), 6.80 (s, 1 H, H8), 6.69 (s, 1 H, H5); 6.59,
6.56, 6.52, 6.51 (4s, 2 H, H3Ј,5Ј), 5.08 and 4.90 (2 br. s, 1 H, NH),
4.89–4.71 (m, 1 H, HαSO2), 4.41 (dd, J = 11.3, 3.4 Hz, 1 H, H1),
3.78–3.63 (m, 12 H, 4ϫ OCH3), 3.63–3.09 (m, 4 H, H3, NH-CH2),
2.85–2.47 (m, 4 H, H4, Ar-CH2), 2.36 and 2.33 (2s, 3 H, Ts-CH3),
2.30–2.14 and 2.06–1.88 (2m, 2 H, C1-CH2-CH3), 1.84–1.64 (m, 2
H, HβSO2), 0.87 (m, 3 H, HγSO2), 0.73 (m, 3 H, C1-CH2-
CH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 157.8 and 157.8
(C=O), 149.0 and 148.9 (C6), 147.6, 147.6, 147.5 (C3Ј, C4Ј), 147.2
(C7), 144.8 and 144.8 (C1 Ts), 134.9 and 134.6 (C4 Ts), 133.2 and
133.1 (C8a), 130.3, 130.2, 129.7 and 129.5 (C2,6 Ts), 129.4 and 129.3
(C3,5 Ts), 126.2 and 126.2 (C1Ј), 121.7 (C4a), 113.2 and 112.8 (C5),
111.3 and 111.3 (C2Ј), 110.8 and 110.7 (C8), 110.3 and 110.3 (C5Ј),
67.1 and 67.0 (C1), 56.0, 56.0, 55.8, 55.7 (4ϫ OCH3), 55.7 (CαSO2),
41.5, 41.4, 38.4 and 38.3 (C3, CαNH), 32.7 and 32.4 (C4), 29.8,
29.8 and 29.7 (CβSO2), 27.7 and 27.59 (CβNH), 23.2 and 22.8
(C1-CH2-CH3), 21.8 and 21.7 (CH3 Ts), 11.4, 11.3 and 11.2 (C2Ј,
CγSO2) ppm. C25H34N2O7 (474.55): calcd. C 65.36, H 7.10, N 4.48,
S 5.13; found C 65.35, H 7.16, N 4.44, S 5.16.
[13] There is literature precedence for a one-step tetrahydroisoquin-
oline synthesis that proceeds through an α-amidosulfone inter-
mediate, although only in 4% yield; see: S. Tussetschläger, B.
Angelika, S. Laschat, W. Frey, Eur. J. Org. Chem. 2007, 5590.
[14] I. Ivanov, A. Venkov, Heterocycles 2001, 55, 1569.
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[16] R. A. Batey, M. Shen, V. Santhakumar, C. Yoshina-ishii, Comb.
Chem. High Throughput Screening 2002, 5, 219.
[17] For some recent examples of drug design based on DKP scaf-
folds, see: a) A. D. Borthwick, J. Liddle, D. E. Davies, A. M.
Exall, C. Hamlett, D. M. Hickey, A. M. Mason, I. E. D. Smith,
F. Nerozzi, S. Peace, D. Pollard, S. L. Sollis, M. J. Allen, P. M.
Woollard, M. A. Pullen, T. D. Westfall, D. J. Stanislaus, J. Med.
Chem. 2012, 55, 783; b) R. Nishizawa, T. Nishiyama, K. Hi-
saichi, C. Minamoto, N. Matsunaga, Y. Takaoka, H. Nakai, S.
Jenkinson, W. M. Kazmierski, H. Tada, K. Sagawa, S. Shibay-
ama, D. Fukushima, K. Maeda, H. Mitsuya, Bioorg. Med.
Chem. Lett. 2011, 21, 1141; c) M. L. Bolognesi, H. N. Ai Tran,
M. Staderini, A. Monaco, A. López-Cobeñas, S. Bongarzone,
X. Biarnés, P. López-Alvarado, N. Cabezas, M. Caramelli, P.
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J. C. Menéndez, J. Org. Chem. 2000, 65, 1743; b) P. López-
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D. W. Lin, T. Masuda, M. B. Biskup, J. D. Nelson, P. S. Baran,
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Male, Chem. Commun. 2012, 48, 1958.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental data and copies of the 1H NMR and 13C
NMR spectra of all compounds.
Acknowledgments
Financial support from the Spanish Ministerio de Economy Com-
petitividad (MINECO) through grant CTQ-2012-33272-BQU is
gratefully acknowledged.
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[24] An alternative possibility is a direct reaction of propanal with
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Received: April 25, 2014
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42487
/KAP1
Date: 01-08-14 11:36:31
Pages: 9
One-Pot Pictet–Spengler Tetrahydroisoquinoline Synthesis
Heterocyclic Chemistry
A one-pot variation of the Pictet–Spengler
reaction has been developed that, unlike
previous protocols, allows efficient prepa-
ration of tetrahydroisoquinolines from am-
ide-type substrates and aldehydes. Pyraz-
ino[2,1-b]isoquinolines, precursors to safra-
mycin analogues, were readily prepared us-
ing this new and flexible method.
F. J. Arroyo, P. López-Alvarado,
A. Ganesan, J. C. Menéndez* ........... 1–9
One-Pot α-Amidosulfone-Mediated Vari-
ation of the Pictet–Spengler Tetrahydroiso-
quinoline Synthesis, Suitable for Amide-
Type Substrates
Keywords: Stereoselective synthesis / Cycli-
zation / Nitrogen heterocycles / Amides
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9