Elaboration of 1-benzoyltetrahydroisoquinoline derivatives employing a Pictet-Spengler cyclization with α-chloro-α-phenylthioketones. Synthesis of O-methylvelucryptine

Article abstract of DOI:10.1016/S0040-4039(01)01998-0

The reaction of N-tosyl-β-phenethylamines with α-chloro-α-phenylthioketones, leading to 1-benzoyl- and 1-pivaloyl-tetrahydroisoquinolines under modified Pictet-Spengler conditions, is described. The synthesis of O-methylvelucryptine employing this transformation as a key step is reported.

Full text of DOI:10.1016/S0040-4039(01)01998-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8947–8950
Elaboration of 1-benzoyltetrahydroisoquinoline derivatives
employing a Pictet–Spengler cyclization with
a-chloro-a-phenylthioketones. Synthesis of O-methylvelucryptine
Claudio C. Silveira,a,* Carmem R. Bernardi,a Antonio L. Bragaa and Teodoro S. Kaufmanb
aDepartamento de Qu´ımica, Universidade Federal de Santa Maria, 97105.900, Santa Maria, RS, Brazil
bInstituto de Qu´ımica Orga´nica de S´ıntesis (CONICET-UNR), Suipacha 570, S2002LRK Rosario, Argentina
Received 25 September 2001; revised 17 October 2001; accepted 24 October 2001
Abstract—The reaction of N-tosyl-b-phenethylamines with a-chloro-a-phenylthioketones, leading to 1-benzoyl- and 1-pivaloyl-tetra-
hydroisoquinolines under modified Pictet–Spengler conditions, is described. The synthesis of O-methylvelucryptine employing this
transformation as a key step is reported. © 2001 Elsevier Science Ltd. All rights reserved.
Being a very numerous class of natural products and
covering a wide range of structural types, 1-benzyliso-
quinoline alkaloids and their derivatives are attractive
targets for synthesis and drivers of the development of
new synthetic methodologies.1
sponding tetrahydroisoquinoline precursors, being the
3,4-dihydroisoquinolines like velucryptine (5),6 dihy-
drorugosinone (6), canelillinoxine (7),7 longifolonine8
(8) and oxo-3,4-dihydrodoryafranine (9),5 produced as
intermediates during this process.
Interestingly, the in vitro air oxidation of certain tetra-
hydroisoquinolines to produce 1-benzoyl-3,4-dihy-
droisoquinolines has been observed.9 In addition,
1-benzoylisoquinolines are also structurally related to
other oxidized alkaloids, such as oxocularines10,11 and
oxoaporphines.
1-Benzoylisoquinolines constitute a small group within
the 1-benzylisoquinolines, with most of its members
having been isolated during the past two decades. They
are represented by natural products such as xanthaline
(1) also known as papaveraldine, a degradation product
and contaminant of the pharmaceutically useful
papaverine,2 rugosinone (2),3 thalmicrinone (3)4 and the
unnamed base 4.5
Few and scattered syntheses of these compounds are
known. 1-Benzoylisoquinolines have been elaborated
by oxidation of 1-benzyl-3,4-dihydroisoquinolines
obtained by the Bischler–Napieralski cyclization,6,12
It has been proposed1 that fully aromatic members
result from biochemical dehydrogenation of their corre-
Keywords: 1-benzoyltetrahydroisoquinolines; Pictet–Spengler; a-chloro-a-phenylthioketones; O-methylvelucryptine.
* Corresponding author. Tel./fax:+ 55 55 220 8754; e-mail: silveira@quimica.ufsm.br
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01998-0

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C. C. Sil6eira et al. / Tetrahedron Letters 42 (2001) 8947–8950
strategy as the key step for the elaboration of the
natural product 4 and O-methylvelucryptine (12).
The synthesis of the organosulfur reagents was conve-
niently carried out in three high-yielding steps from
acetophenone and pinacolone, as shown in Scheme 1.
The starting methylketones were cleanly a-brominated
with bromine in diethyl ether (72–87%), the resulting
bromides were nucleophilically displaced with thiophe-
nolate (83–84%) and the product subsequently chlori-
nated with N-chlorosuccinimide under benzoyl
peroxide promotion (65–73%).18
Scheme 1. Reagents and conditions: (a) Br2, Et2O, rt (72–
87%); (b) NaH, PhSH, THF, rt (83–84%); (c) NCS, Cl4C,
BPO (65–73%).
and in a one-pot reaction of phenethylamines with
vicinal diketoesters under modified Pictet–Spengler con-
ditions, involving hydrolysis and decarboxylation of a
1,1-disubstituted tetrahydroisoquinoline carboxylate
intermediate.9 Non-natural 1-benzoylisoquinolines have
also been obtained by photolysis of berberinium salts13
and as intermediates during the synthesis of phthalide-
isoquinolines from modified berberines.14
As shown in Table 1, upon reaction of the organo-
chalcogen ketones with N-tosyl-b-phenethylamines
under Lewis-acid catalysis, smooth production of the
expected 1-substituted tetrahydroisoquinoline deriva-
tives was observed.
Yields were fair to good. Oxygenated aromatic rings,
including the improperly activated system of entries 5
and 6 were cleanly transformed with SnCl4, while deac-
tivated (entries 11 and 12) or unactivated (entries 9, 10,
13 and 14) ring systems, required more drastic condi-
tions (ZnCl2 in refluxing 1,2-dichloroethane).
Recently, a-chloro-a-methylthiocarbonyl derivatives
have been employed as masked aldehydes in isoquino-
line syntheses,15 including the cyclization of unactivated
aromatic rings16 and we have informed on the use of
a-chloro-a-phenylselenocarboxylates as aldehyde surro-
gates in the elaboration of 1,2,3,4-tetrahydroisoquino-
line-1-carboxylates by means of a modified Pictet–Spen-
gler type cyclization.17 Here, we wish to report the
synthesis of 1-benzoyl- and 1-pivaloyl-tetrahydroiso-
quinoline derivatives by Pictet–Spengler con-
densation of substituted b-phenethylamines with the
a-chloro-a-phenylthioketones 10 and 11 and the of this
In a pairwise comparison, it was observed that methoxy
substituted phenethylamines performed better with 11
than with its congener 10 (entries 1–6), while no significant
differences were observed in the yields of products when
the starting phenethylamine carried other substituents.
The elaboration of 1-benzoyl-2-tosyl-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (entry 2) is representative
Table 1. Synthesis of 1-benzoyl- and 1-pivaloyl-tetrahydroisoquinoline derivatives by reaction of a-chloro-a-phenylthio-
ketones with N-tosyl-b-phenethylamines under Lewis-acid promotion
Entry
R
R1
R2
R3
Reaction conditionsa
Yield (%)b
1
2
3
4
5
6
7
8
t-Butyl
Ph
t-Butyl
Ph
t-Butyl
Ph
t-Butyl
Ph
t-Butyl
Ph
t-Butyl
Ph
t-Butyl
Ph
t-Butyl
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
OCH2O
OCH2O
H
H
H
H
Me
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
SnCl4, CH2Cl2, −78°C“rt 5 h
SnCl4, CH2Cl2, −78°C“rt 5 h
SnCl4, CH2Cl2, −78°C“rt 5 h
SnCl4, CH2Cl2, −78°C“rt 5 h
SnCl4, CH2Cl2, −78°C“rt 5 h
SnCl4, CH2Cl2, −78°C“rt 5 h
SnCl4, CH2Cl2, −78°C“rt 5 h
SnCl4, CH2Cl2, −78°C“rt 5 h
ZnBr2, ClCH2CH2Cl, reflux 8 h
ZnBr2, ClCH2CH2Cl, reflux 8 h
ZnBr2, ClCH2CH2Cl, reflux 8 h
ZnBr2, ClCH2CH2Cl, reflux 8 h
ZnBr2, ClCH2CH2Cl, reflux 8 h
ZnBr2, ClCH2CH2Cl, reflux 8 h
SnCl4, CH2Cl2, −78°C“rt 5 h
64
73
46
62
32
56
58
57
77
82
61
54
60
60
51
H
OCH2O
OCH2O
H
H
Cl
Cl
H
H
OMe
9
10
11
12
13
14
15c
Me
OMe
a A 5.0:1.0:1.3 relationship between Lewis acid, b-phenethylamine and haloketone, respectively, was used.
b Isolated yield after column chromatography purification.
c Reaction of 10 with the N-carbamoyl-b-phenethylamine.

C. C. Sil6eira et al. / Tetrahedron Letters 42 (2001) 8947–8950
8949
obtained by O-methylation of longifolonine.21 To this
end, a-halo-a-phenylthioketone 14 was prepared from
the commercially available 4-methoxy acetophenone
following the strategy outlined in Scheme 1 and reacted
with N-tosyl-b-phenethylamine 15 at −78°C under
SnCl4 catalysis, to afford tetrahydroisoquinoline 13 in
66% yield.
In turn (Scheme 2), this was submitted to a microwave-
assisted eliminative detosylation with potassium
fluoride supported on alumina,22 cleanly furnishing the
final product 12 in 77% yield.
Analogously, submission of the tetrahydroisoquinoline
product prepared by the reaction of the corresponding
3,4-methylenedioxy phenethylamine with 14 (SnCl4,
CH2Cl2, −78°C to rt, 5 h, 54% yield) to reaction with
KF/Al2O3 under microwave irradiation (490 W, 60 s),
provided the unnamed base 4 in 49% yield.5,23
Scheme 2. Reagents and conditions: (a) 14, SnCl4, CH2Cl2,
−78°C (66%); (b) 37% KF/Al2O3, microwave (490 W, 10 s,
77%).
This and all new products were fully characterized by
1
spectral means, including IR, H and 13C NMR spec-
troscopy, and mass spectrometry.
of a typical experimental procedure. Under an argon
atmosphere, a mixture of N-tosyl-b-phenethylamine
(335 mg, 1 mmol) and a-chloro-a-phenylthiocarbonyl
reagent 11 (1.3 mmol, 1.3 equiv.) were dissolved in
methylene chloride (5 mL), cooled to −78°C and treated
dropwise with SnCl4 (0.585 mL, 5 mmol, 5 equiv.). The
reaction was slowly warmed to room temperature and
stirred until complete absence of starting material (by
TLC) was observed. Then, the reaction mixture was
poured on water, the organic products were extracted
with methylene chloride (3×20 mL), dried (MgSO4),
concentrated and chromatographed, furnishing the cor-
responding 1-benzoyl 1,2,3,4-tetrahydroisoquinoline
(330 mg, 73%).
In conclusion, this work demonstrated the usefulness of
a-halo-a-phenylthioketones as convenient building
blocks for the elaboration of 1-benzoylisoquinoline
derivatives by Pictet–Spengler condensation with acti-
vated b-phenethylamines under Lewis-acid catalysis.
This transformation, in conjunction with a microwave-
assisted oxidative removal of the sulfonyl moiety, was
employed for the synthesis of O-methylvelucryptine
and the unnamed natural product 4.
It is noteworthy that the latter constitutes an interesting
and unprecedented use of the KF/Al2O3 reagent, the
scope and limitations of which are currently under
study. The synthetic strategy may be useful for the
elaboration of other 1-benzoylisoquinolines.
Yields of cyclized products with the sulfur-based
reagents were more consistent and generally higher
than those previously recorded for the modified Pictet–
Spengler condensation of N-sulfonyl-b-phenethyl-
amines with a-chloro-a-phenylselenocarboxylates;17
therefore, attempts to evaluate the performance of the
analogous selenium reagents in this transformation
were made. Thus, the a-chloro-a-phenylselenoketone
derived from pinacolone was uneventfully prepared by
radical halogenation of the corresponding a-selenoke-
tone.19 Unfortunately, however, its reaction with
phenethylamines furnished a complex mixture consist-
ing mostly in unidentifiable products, and very low
yield of the required tetrahydroisoquinolines.
Acknowledgements
The authors thank Fundac¸a˜o Vitae (Grant No. B-
11487/9B004), FAPERGS, CNPq and CAPES for
financial support. T.S.K. thanks CONICET.
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