Multicomponent Synthesis of Tetrahydroisoquinolines

Article abstract of DOI:10.1021/acs.orglett.8b01159

A multicomponent synthesis of tetrahydroisoquinolines from carboxylic acids, alkynyl ethers, and dihydroisoquinolines is described. This process features readily available starting materials, simple experimental procedures for achievement of molecule comp

Full text of DOI:10.1021/acs.orglett.8b01159

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Multicomponent Synthesis of Tetrahydroisoquinolines
Linwei Zeng,† Bo Huang,† Yangyong Shen,† and Sunliang Cui*,†,‡
†Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A multicomponent synthesis of tetrahydroiso-
quinolines from carboxylic acids, alkynyl ethers, and
dihydroisoquinolines is described. This process features readily
available starting materials, simple experimental procedures for
achievement of molecule complexity, and structural diversity.
The preliminary control experiment and crossover reaction
provide important insight into the reaction mechanism. The
formed tetrahydroisoquinolines could be transformed to an
array of compounds.
ulticomponent reactions (MCRs) are defined as a
gler reaction.6 Li and co-workers proposed a cross-dehydrogen-
Mprocess that employs three or more starting materials ative coupling (CDC) strategy for direct functionalization of
THIQs.7 Recently, the CDC method for THIQs synthesis has
in a one-pot reaction to form a single product that contains
essentially all of the reactants.1 Due to the simple experimental
been well applied with visible-light catalysis by Wu, Xiao, Jiang,
and Yu.8 Notably, the asymmetric CDC functionalization of
procedures and one-pot character, the MCRs have become
THIQs has been developed by Liu.9 Meanwhile, Zhang,
excellent tools for rapid formation of small molecules with the
Mashima, Zhou, Zhao, and many other groups have,
respectively, developed the enantioselective synthesis of
THIQs via hydrogenation and kinetic resolution.10 Alter-
natively, the hydrogen-transfer-mediated reaction has also been
explored for preparation THIQs.11 Very recently, Clayden and
co-workers disclosed an elegant synthesis of 1-aryl THIQs via
an acid-mediated ring contraction from cyclic ureas.12
Interestingly, Zhu, Martin, Ma, and Sun proved that the
MCRs could deliver THIQs via Ugi reaction, cyclization and
aza-Diels−Alder reaction.13 Despite these advances, the general
and straightforward synthetic method toward THIQs and facile
derivatization is in high demand.
Electron-rich alkynes such as ynamines, ynamides, alkynyl
ethers, and alkynyl thioethers have been widely used as versatile
tools in organic synthesis, especially in heterocycle synthesis.14
Previously, we established a ynamide-involving Ugi-type four-
component synthesis of β-amino amides, and the scope is
limited to anilines and aryl aldehydes.15 As a continuation of
our efforts in MCRs and heterocycle synthesis,16 we are
interested in the MCRs development toward THIQs and their
application in divergent synthesis. Herein, we report a
multicomponent synthesis of THIQs from carboxylic acids,
alkynyl ethers and dihydroisoquinolines; this protocol offers
ample opportunities for derivatization to access an array of
compounds (Scheme 1).
achievement of brevity and diversity. In the past decades,
several MCRs have been well developed and widely used in
natural product synthesis and drug discovery.2 For example, the
Ugi four-component reaction has been a powerful and efficient
method for accessing α-amino amides both in academia and
industry.3 Therefore, the development of MCRs for con-
struction of biological interesting molecules continues to attract
considerable attention for their obvious atom- and step-
economy.
Tetrahydroisoquinolines (THIQs) are privileged structural
motifs often occurring in natural products and pharmaceuticals
(Figure 1).4 Thus, much effort has been devoted to the
synthesis of THIQs,5 and the traditional methods include
Bischler−Napieralski cyclization/reduction and Pictet−Spen-
We commenced our study by investigating benzoic acid 1a,
ynamide 2a, and dihydroisoquinoline 3a. Initially, we carried
out the reaction by mixing 1a and 2a in DCM at room
Figure 1. Representative biologically interesting tetrahydroisoquino-
lines.
Received: April 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
optimize the reaction. The combination of Ag2O with Lewis
acids such as BF3·Et2O, Cu(OTf)2, and Sc(OTf)3 was found to
be inferior, and the product was formed in decreased yields
(entries 6−9). Next, a survey of solvent showed that toluene
and THF were effective to give comparable yields (entries 10
and 11), while DMF was not optimal and the yield dropped
significantly (entry 12). Gratifyingly, when the reaction was
conducted in dioxane, the THIQ 5a could be generated in good
yields (entries 13 and 14). On the other hand, when ynamide
2a was subjected to this condition, 4a could be formed in 27%
yield (entry 15).
Scheme 1. Multicomponent Synthesis of
Tetrahydroisoquinolines
With the optimized reaction conditions in hand, we next set
out to explore the substrate scope (Figure 2). Various
temperature under argon to give the α-acyloxy enamide
intermediate and then added 3a and catalytic BF3·Et2O as
additive to trap the intermediate, but the desired tetrahy-
droisoquinoline product 4a was not formed (Table 1, entry 1).
a
Table 1. Reaction Optimization
b
c
entry alkyne
additive
BF3·Et2O
BF3·Et2O
BF3·Et2O
Ag2O
temp (°C)
solvent
yield (%)
1
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
rt
80
rt
DCM
DCE
0
0
2
3
DCM
DCM
DCE
trace
trace
73
4
rt
5
Ag2O
80
rt
6
Ag2O/BF3·Et2O
Ag2O/BF3·Et2O
Ag2O/Cu(OTf)2
Ag2O/Sc(OTf)3
Ag2O
DCM
DCE
0
7
80
80
80
80
80
80
80
100
100
55
8
DCE
71
9
DCE
69
10
11
12
13
14
15
toluene
THF
67
Ag2O
66
Ag2O
DMF
dioxane
dioxane
dioxane
48
Ag2O
81
d
Ag2O
84 (80 )
Ag2O
27
a
Reaction conditions: 1a (0.25 mmol), 2 (0.3 mmol), and additive
were added to solvent (2 mL) and stirred for 5 h, then 3a (0.25 mmol)
b
was added and kept for 3 h. Ag2O (5 mol %), Lewis acid (5 mol %).
c
d
Yield refers to isolated product. 5 mmol scale.
Raising the temperature to 80 °C in DCE also did not give the
product (entry 2). At this stage, we hypothesized that the
alkynyl ether could be used to replace ynamide to serve as a C2
building block because the alkoxyl group showed different
electronic properties with ynamide which might lead to new
reactivity.17 Next, the alkynyl ether 2b was subjected to the
reaction, and various parameters were tested. BF3·Et2O was
employed as additive, and the reaction did not yield the desired
THIQ 5a, due to the failure of α-acyloxy enol ester
intermediate formation (entry 3). Inspired by the fact that
Ag2O could facilitate the formation of α-acyloxy enol esters
from carboxylic acid and ethynyl ether, we attempted the
reaction with 5 mol % of Ag2O at room temperature and failed
to observe the formation of product (entry 4). To our delight,
when the reaction was conducted at 80 °C, the THIQ product
5a was isolated in 73% yield (entry 5). The product was
characterized by standard analysis, and the structure was
confirmed by X-ray analysis. This encouraged us to further
Figure 2. Substrate scope. Reaction conditions: 1 (0.25 mmol), 2 (0.3
mmol), and additive (5 mol %) were added to solvent (2 mL) and
stirred for 5 h, then 3 (0.25 mmol) was added and kept for 3 h. Yield
refers to isolated product.
B
DOI: 10.1021/acs.orglett.8b01159
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Organic Letters
Letter
substituted benzoic acids proceeded well in the process to
deliver products in good to excellent yields, and valuable groups
such as nitro, methoxy, chloro, trifluoromethyl, and iodo were
tolerated (5b−g). Moreover, 1-naphthyl carboxylic acid,
unsaturated cinnamic acid, and heteroaromatic carboxylic
acids containing furan, thiophene, and indole participated
well in the MCRs to deliver the corresponding THIQs (5h−l).
Alkyl carboxylic acids, including phenylacetic acid, 3-phenyl-
propiolic acid, cyclohexanecarboxylic acid, and piperidine-4-
carboxylic acid, were found to be suitable (5m−p). Notably,
when N-protected amino acids such as glycine, L-proline, L-
alanine, and L-phenylalanine were subjected to this process, the
reaction furnished the THIQs in good yields in up to 92:8 dr
(5q−t). Furthermore, diverse alkynyl ethers were also tested
and found applicable (5u−y). When the internal alkynyl ether
(2f) was used, the THIQ product (5y) was formed with high
diastereoselectivity (dr 93:7), albeit in 34% yield. On the other
hand, a variety of dihydroisoquinolines were tested in this
process. Many substitutions such as nitro, methoxy, hydroxyl,
thiophene, and indole ring were well tolerated in this process
(5z−f′). In addition, the structure of 5f′ was confirmed by X-
ray analysis. Given the importance of THIQs in natural
products and medicinal chemistry, this method provided a
simple and efficient access to these molecules with the
achievement of sufficient structural diversity.
Scheme 3. Control Experiment and Crossover Reaction
intermediate 11a. Either with or without Ag2O, 11a coupled
with 3a to give the THIQ 5a in comparable yield, indicating
that Ag2O was not essential in this step. Meanwhile, a crossover
reaction was also conducted. When the prepared α-acyloxy enol
esters 11b and 11c were subjected to the reaction with
dihydroisoquinoline 3a in dioxane at 100 °C, only 5b and 5u
were exclusively detected.
On the basis of these results and the literature,19 a plausible
reaction mechanism for this multicomponent reaction was
proposed in Scheme 4. Initially, carboxylic acids 1 couple with
To demonstrate the synthetic utility, a diversification was
carried out to deliver an array of compounds with the core
structure of THIQ (Scheme 2). For example, hydrogenation of
Scheme 4. Proposed Reaction Mechanism
Scheme 2. Diversification of Tetrahydroisoquinolines
the alkynyl ether 2 to give the α-acyloxy enol ester A. Addition
of dihydroisoquinoline 3 to A forms the species B, which
undergoes intramolecular rearrangement to produce the THIQ
5. Thus, this multicomponent reaction process is different than
the previous multicomponent synthesis of β-amino amides. In
this process, the α-acyloxy enol ester intermediate A is reactive
toward nucleophilic addition by the electron-rich dihydroiso-
quinoline 3. With respect to ynamide, the α-acyloxy enamide
intermediate generated from carboxylic acid and ynamide was
less reactive toward addition by dihydroisoquinoline, no matter
whether Lewis acid is added or not.
In summary, a multicomponent synthesis of tetrahydroiso-
quinolines has been developed. In this reaction, the alkynyl
ether serves as a C2 building block to enable the rapid assembly
with carboxylic acid and dihydroisoquinoline to furnish the
privileged tetrahydroisoquinoline with structural diversity.
Moreover, control experiments and crossover reactions were
conducted to elucidate a plausible reaction mechanism. The
formed tetrahydroisoquinolines are transformed into an array
of useful compounds.
5q removed the Cbz-protecting group with concomitant
lactamization to furnish the tricyclic 1,4-diazepane-2,5-dione 6
in excellent yield, and this compound is a type of antitumor
UCB13-UEV enzyme inhibitor.18 On the other hand,
hydrolysis of 5q to 7 and further coupling with L-leucine
methyl ester gave the peptidomimetic 8 in 92% yield.
Additionally, hydrogenation/lactamization of 5g′ delivered
the eight-membered heterocycle 9. For the indole-containing
THIQ 5f′, a fragmentation/cyclization cascade occurred to give
3H-pyrrolo[1,2-a]indol-3-one 10 upon treatment with DBU.
To gain insights into the reaction mechanism, control
reactions were conducted (Scheme 3). Benzoic acid 1a was
coupled with 2a in the presence of Ag2O to deliver
C
DOI: 10.1021/acs.orglett.8b01159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01159.
■
S
Full experimental procedures, characterization data, and
NMR spectra data (PDF)
Accession Codes
CCDC 1810979 and 1829219 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slcui@zju.edu.cn.
ORCID
Sunliang Cui: 0000-0001-9407-5190
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural
Science Foundation of China (21472163).
■
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