G Model
CCLET 5229 No. of Pages 4
Chinese Chemical Letters
Communication
Synthesis of tetrahydroisoquinolines through TiCl4-mediated
cyclization and Et3SiH reduction
a,b
Zeyu Shia, Qiong Xiaoa,b, , Dali Yin
*
a
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese
Academy of Medical Sciences, Beijing 100050, China
b
Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 27 July 2019
Received in revised form 4 September 2019
Accepted 11 September 2019
Available online xxx
A versatile and efficient telescoped reaction sequence for the synthesis of tetrahydroisoquinolines
(THIQs) is reported that uses TiCl4 to promote cyclization of a benzylaminoacetal derivative and Et3SiH
for reduction of the intermediate 4-hydroxy-THIQ. This method is complimentary to the classical
Pomeranz-Fritsch and related reactions since it tolerates electron-withdrawing substituents and allows
access to 8-substituted THIQs.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Tetrahydroisoquinoline
TiCl4
Cyclization
Et3SiH
Telescoped reaction
Tetrahydroisoquinoline (THIQ) is an important structural
motif found in many alkaloid natural products [1] and several
drugs including nomifensine [2], hydrastinine [3], dehydroeme-
tine [4] and ecteinascidin 743 [5]. Beyond the classic Pictet-
Spengler reaction and selective hydrogenation of isoquinolines,
there are few reactions that can be used to synthesize THIQ
conveniently [6]. The Pictet-Spengler reaction (Scheme 1)
involves condensation of phenethylamines with an aldehyde
or ketone to form an intermediate iminium ion that undergoes
ring closure by electrophilic aromatic substitution, which limits
the substrate scope to electron-rich aromatic systems. A Br
ønsted acid catalyst in protic solvent is typically employed with
heating thereby restricting the chemoselectivity. Because of the
mechanism, meta-substituted phenethylamine analogues tend
to afford 6-substituted THIQ over the 8-substituted THIQ
regioisomers [7]. The related Bischler-Napieralski and Pictet-
Gams cyclization of phenylethylamides suffer from these same
limitations. Complimentary to the above methods, the Pomer-
anz-Fritsch reaction is another strategy for the preparation of
isoquinolines, especially 8-substituted THIQs. The reaction
involves the acid-promoted condensation of a benzaldehyde
with a 2,2-dialkoxyethylamine, but is also restricted to electron-
rich benzaldehyde derivatives. Besides, other synthesis routes of
THIQ derivatives such as visible-light-promoted transition-
metal-free approach [8] and silver-catalyzed radical cascade
cyclization have been reported [9].
Here, we describe the serendipitous discovery of a one-pot
route for the synthesis of THIQs via TiCl4 mediated ring-closure of
benzylaminoacetal derivatives (Table 1).
Our initial goal was to synthesize THIQ analogue 1f through a
Jackson-modifed Pomerantz-Fritsch reaction of 1a to afford 1b
followed by hydrogenation [10]. Unfortunately, the desired
product 1b was not observed using 6 mol/L aqueous HCl in
dioxane and only 1c arising from acetal hydrolysis under the
aqueous conditions was obtained in 85% yield. We next explored
non-aqueous condition employing the Lewis acid AlCl3 in
dichloromethane (DCM) and were heartened to observe 1b about
10% yield (just LC–MS confirmed).
Subsequently, we screened several Lewis acids to promote the
cyclization of 1a to 1b including BF3 OEt2 [11], Bi(OTf)3, InCl3, and Al
Á
(OTf)3 in DCM at room temperature, but all exclusively furnished 1c
(Table 1, entries 3–6). The substrate 1a decomposed with Eaton’s
reagent (Table 1, entry 7) and there was no reaction with SmI2
(Table 1, entry 8). To our surprise, treatment of 1a with TiCl4 in DCM
at room temperature afforded 7-bromo-8-methoxy-2-tosyl-
1,2,3,4-tetrahydroisoquinolin-4-ol (1d) in an impressive 85% yield
(Table 1, entry 9). Based on our previous experience with reduction
of benzyl ketones and alcohols with TiCl4/Et3SiH, we hypothesized
* Corresponding author at: State Key Laboratory of Bioactive Substances and
Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical
College and Chinese Academy of Medical Sciences, Beijing, 100050, China.
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z. Shi, et al., Synthesis of tetrahydroisoquinolines through TiCl4-mediated cyclization and Et3SiH reduction,