Modular One-Step Three-Component Synthesis of Tetrahydroisoquinolines Using a Catellani Strategy

Article abstract of DOI:10.1002/anie.201806780

Reported is a modular one-step three-component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza-Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2-alkyl- and 2-aryl-substituted aziridines to access 1,3-cis-substituted and 1,4-cis-substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.

Full text of DOI:10.1002/anie.201806780

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Accepted Article
Title: Modular One-Step Three-Component Synthesis of
Tetrahydroisoquinolines via a Catellani Strategy
Authors: Qianghui Zhou, Guangyin Qian, Miao Bai, Shijun Gao, Han
Chen, Siwei Zhou, Hong-Gang Cheng, and Wei Yan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806780
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10.1002/anie.201806780
Angewandte Chemie International Edition
COMMUNICATION
Modular One-Step Three-Component Synthesis of Tetrahydroiso-
quinolines via a Catellani Strategy
Guangyin Qian, Miao Bai, Shijun Gao, Han Chen, Siwei Zhou, Hong-Gang Cheng*, Wei Yan and
Qianghui Zhou*
Dedicated to Prof. E. J. Corey on the occasion of his 90th birthday
Abstract: Reported is a modular one-step three-component
synthesis of tetrahydroisoquinolines via a Catellani strategy. This
process exploits aziridines as the alkylating reagents through
palladium/norbornene cooperative catalysis to enable
a
Catellani/Heck/aza-Michael addition cascade. This mild, chemo-
selective, and scalable protocol has broad substrate scope (43
examples, up to 90% yield). The most striking feature of this
protocol is the excellent regioselectivity and diastereoselectivity
observed for 2-alkyl and 2-aryl substituted aziridines to access
1,3-cis-substituted
and
1,4-cis-substituted
tetrahydroiso-
quinolines respectively. Moreover, this is a versatile process with
high step- and atom-economy.
The 1,2,3,4-tetrahydroisoquinoline core[1] is widely studied as a
privileged scaffold for the preparation of therapeutically active
compounds.[2] This heterocycle scaffold is prevalent in bioactive
natural products[1a,3] and therapeutic agents,[2,4-5] for instance, the
potent antitumor alkaloid (-)-quinocarcin,[3] the antimusca-
rinic drug solifenacin (astellas),[4] and the antichorea drug
tetrabenazine[5] (Figure 1A). As such, a growing effort has been
directed toward the efficient preparation of this valuable scaffold.
The traditional methods[6] (Pomeranz-Fritsch, Bischler-
Napieralsky, Pictet-Spengler,[6c] and intramolecular Friedel-
Crafts[7]) really work well only with electron-rich systems. Other
methods also have been developed that do not rely on the
electronic characteristics of the aromatic ring.[8] For example,
transition metal catalyzed hydrogenation[9] or nucleophilic
addition[10] to 3,4-dihydroisoquinolines, or intramolecular Heck
reaction[11] etc (Figure 1B).[12] However, these methods generally
require specially functionalized substrates or harsh reaction
conditions, significantly limiting their scopes. Therefore,
development of general and efficient approaches for the direct
synthesis of tetrahydroisoquinolines from readily available
starting materials would be a highly desirable yet challenging
subject.[8]
The Catellani reaction, firstly introducted by Prof. Catellani,[13]
utilizes the palladium/norbornene (NBE) cooperative catalysis to
facilitate sequential ortho C–H bond activation and ipso coupling
of aryl iodide, thereby allowing the precise functionalization of
ortho and ipso positions simultaneously.[14-15] Through twenty
years of development, this reaction has become a powerful tool
Figure 1. Approaches to access tetrahydroisoquinolines
for the synthesis of highly substituted arenes. Notably, Lautens,
Catellaniand othershave developed a gamut of elegant Catellani-
type annulations to access diversified benzo-fused rings.[16]
Recently, our group identified that epoxides could act as alkylating
reagents for the Catellani reaction, providing an efficient strategy
for the synthesis of isochromans.[16j] Inspired by this discovery, we
envisaged that the readily available aziridines[17] might also act as
alkylating reagents to enable a Catellani/Heck/aza-Michael
addition cascade[18] for the direct synthesis of tetrahydroiso-
quinolines, as depicted in Figure 1C. Prior to the start of this
project, applying aziridines as the alkylating reagents in Catellani
reaction had not been reported.[19] Until recently, the Liang group
reported an elegant related research (Figure 1E).[20] Based on the
[*]
G. Qian, M. Bai, S. Gao, H. Chen, S. Zhou, Dr. H.-G. Cheng, W.
Yan, Prof. Dr. Q. Zhou
College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, 430072 (China)
E-mail: hgcheng@whu.edu.cn, qhzhou@whu.edu.cn
Homepage: http://qhzhou.whu.edu.cn/
Prof. Dr. Q. Zhou
The Institute for Advanced Studies, Wuhan University, Wuhan,
430072 (China)
Supplementary information for this article is given via a link at the
end of the document.
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10.1002/anie.201806780
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COMMUNICATION
previous mechanistic studies,[15] we surmised that, just like
epoxides, aziridines 2 might react with the key ANP intermediate
C to form intermediate D, which would lead to palladium circle E
after the extrusion of NBE. Then, E reacted with olefin 3 via a
Heck reaction to afford uncyclized product 4' and regenerated the
Pd(0) catalyst. Finally, 4' would be readily transformed to
tetrahydroisoquinoline 4 through a base promoted aza-Michael
addition (Figure 1D). Such a sequence would enable the
formation of one C-N bond and two C-C bonds, the creation of a
benzylic stereogenic center, and direct construction of the
tetrahydroisoquinoline scaffold in a single operation, representing
a versatile step- and atom-economic process.[21,22] Nevertheless,
we speculated the innate challenges for this process would
include: a proper N-substitution might be needed to ensure the
reactivity of the aziridines; the tuning of the regioselectivity of the
aziridine ring cleavage and the diastereoselectivity of the
intramolecular aza-Michael addition.
provide significantly increased yields (entries 5-6). Gratifyingly,
the readily available NBE derivative N5 was among the best,[25]
affording 4a in the highest yield (85%) (entry 7). Further reducing
the loading of N5 to 20 mol% led to a slightly lower yield (79%,
entry 8). Additional optimization of the base, the ligand and the
palladium catalyst did not provide obvious improvement in the
efficiency (see the Supplementary Information (SI) for details).
Finally, the optimal conditions involved the increase of 1a to 1.2
equiv and the concentration to 0.2 M, which furnished 4a in 82%
yield (81% isolated yield) (entry 10). It is worth mentioning that the
current transformation is advantageous, not only for its high atom
economy–since aziridine 2a and olefin 3a can be incorporated
into the product 4a in its entirety, but also for its high step
economy–the tetrahydroisoquinoline motif can be built in just one
step from three types of substrates. In addition, the identification
of N5 as a catalytic mediator is another striking feature.
With the above optimal conditions identified, we first examined
the scope of aryl iodides, with aziridine 2a and olefin 3a as the
reaction partners (Table 2). Gratifyingly, aryl iodides containing
electron-donating and electron-withdrawing groups all proved to
be competent substrates, providing the desired products in
62–86% yield. The reaction system also exhibited high chemo-
selectivity: various functional groups were tolerated including
benzyloxy (product 4d), methoxy (product 4o), TBS-protected
hydroxymethyl (product 4e), fluoride (products 4g and 4i),
chloride (products 4h and 4n), bromide (products 4j and 4m), and
methyl ester (product 4k), providing handles for further product
diversification. Importantly, heteroaryl iodides (1o-q) were also
demonstrated to be suitable substrates, wherein their reaction
with 2a and 3a afforded products 4o-q in 28-74% yield.
To probe this intriguing process, our efforts commenced with
the model reaction using readily available 2-iodotoluene (1a, 1.0
equiv), 1-tosylaziridine (2a, 1.0 equiv) and ethyl acrylate (3a, 1.5
equiv) as the reactants (Table 1). Initially, Pd(OAc)2 was chosen
as the catalyst (10 mol%), norbornene as the mediator (3.0 equiv),
K2CO3 as the base (2.0 equiv), MeCN as the solvent (0.1 M), and
tri-2-furanylphosphine as the ligand. To our delight, when the
o
reaction was run at 80 C under argon, the desired product 4a
was indeed obtained in 67% yield (entry 1). Lowering the reaction
temperature from 80 oC to 70 oC led to a cleaner reaction, which
improved the yield to 87% (entry 2). Following studies focused on
identifing the optimal mediator. Various readily available
norbornene derivatives were then examined, including the Yu
mediator (N2)[23], the potassium salf of 5-norbornene-2-carboxylic
acid (N3)[16j], and the Dong mediator (N4)[24] (entries 4-6). Switched
to a 50 mol% loading of the mediator, the yield of 4a dropped
dramatically to 39% for N1 (entry 3), while only a trace amount of
4a was obtained for N2 (entry 4). In contrast, N3 and N4 could
Table 2. Reaction scope with respect to the aryl iodide.[a]
Table 1. Optimization of reaction conditions.[a]
Entry
[NBE]
x
Temp. (oC)
Yield (%)[b]
1
2
N1
N1
3.0
3.0
80
70
67
87 (85)[c]
[a] All reactions were performed on a 0.2 mmol scale. Reported yields are for
the isolated products. TBS = t-butyldimethylsilyl, Bn = benzyl.
3
4
N1
N2
N3
N4
N5
N5
N5
N5
0.5
0.5
0.5
0.5
0.5
0.2
0.2
0.2
70
70
70
70
70
70
70
70
39
Then, the scope of olefin 3 was explored (Table 3A). An array
of mono-substituted olefins with electron-withdrawing groups are
suitable substrates (3a-i), including acrylates (3a-d),[26-27] the
Weinreib amide of acylic acid (3e), as well as alkyl vinyl ketones
(3f-h), providing the desired products in good to excellent yields.
Notably, for phenylvinylketone (3i), the ligand should be switched
to DavePhos to obtain a good yield.
Next, the scope of N-substitution of aziridine 2 was examined
(Table 3B). Besides 4-toluenesulfonyl (Ts), benzenesulfonyl (Bs)
(2b) and 4-nitro-benzenesulfonyl (Ns) (2c) were also compatible,
but the latter delivered the corresponding product in a much lower
yield. Interestingly, N-benzyloxycarbonyl (N-Cbz) and N-t-
butoxycarbonyl substitution (N-Boc) substituted aziridines (2d
and 2e) were competent substrates to deliver the corresponding
uncyclized products 4ad and 4ae solely (see the SI). As to the N-
7
57
5
6
74
7
85
8
79
9[d]
10[d,e]
81
82 (81)[c]
[a] All reactions were performed on a 0.1 mmol scale. [b] GC yield with
biphenyl as an internal standard. [c] Isolated yield in parentheses. [d] 1.2
equiv of 1a was used. [e] The reaction was performed in 0.2 M solution. Ts
= p-toluenesulfonyl, TFP = tri-2-furanylphosphine.
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benzyl substituted aziridine 2f, only a trace amount of the product
was detected, which indicates that an electron-withdrawing N-
substitution of aziridine is necessary to ensure enough reactivity.
for 2-alkyl substituted N-Ts-aziridines. Further exploration
demonstrated that 2-aryl substituted N-Ts-aziridines (2J-N) were
also suitable substrates for this protocol. However, the obtained
products were specifically changed to 1,4-cis-substituted
tetrahydroisoquinolines (4J''-N''), indicating a totally reversed
regioselectivity of the ring cleavage. Importantly, the structure of
products 4F, 4I and 4J'' were unambiguously assigned by X-ray
crystallographic analysis (CCDC 1847841, 1847842 and 1847839)
(see the SI for details). The observed two distinct kinds of
regioselectivity can be rationalized as follows: the former is
controlled by the steric hindrance of the aziridine ring, while the
latter is governed by the innate static electronic property of the 2-
aryl-substituted aziridine ring.[30]
Table 3. Reaction scope with olefin and N-substitution of aziridine.[a]
To demonstrate the synthetic value of the obtained products,
we investigated follow-up chemistry. As shown in Scheme 1A,
uncyclized products 4da' and 4F' underwent facile aza-Michael
addition in the presence of base K2CO3 or Cs2CO3 to provide
tetrahydroisoquinolines 4da and 4F in excellent yields. The fact
that 4F was obtained as the single diastereomer demonstrates
the excellent diastereoselectivity of the aza-Michael addition
process,[16h] that is in sharp constrast to the reported oxa-Michael
addition process.[16j] As depicted in Scheme 1B, a two-step lactam
formation process was developed for 4D to afford 5, including acid
mediated deprotection of the N-Boc and base promoted
intramolecular cyclization. Similarly, 4I can be transformed to 6
through an acid promoted one-step lactone formation process.
Meanwhile, the formation of 5 and 6 also indicates that 4D and 4I
are 1,3-cis-substituted tetrahydroisoquinolines. Lastly, the
removal of the N-Ts group in 4ac was achieved with the aid of
magnesium in methanol under ultrasound[31] to deliver
intermediate 7, which led to β-lactam 8 through a facile two-step
process[32] (Scheme 1C). More efforts are underway to utilize this
versatile process as the key step for the preparation of complex
natural products and therapeutics.
[a] All reactions were performed on a 0.2 mmol scale. Reported yields are
for the isolated products. [b] On a 4.0 mmol scale. [c] 24 mol% DavePhos
was applied instead of TFP. [d] Uncyclized product was obtained. Bs =
benzenesulfonyl, Ns = 4-nitro-benzenesulfonyl, Cbz = benzyloxycarbonyl,
Boc = t-butoxycarbonyl.
To further illustrate the synthetic utility of this protocol,
we examined the reaction scope of 2-substituted N-Ts-aziridine 2
(Table 4).[28] Reaction with simple N-Ts-2-methyl aziridine (2A)
and N-Ts-2-ethyl aziridine (2B) gave the 1,3-cis-substituted
tetrahydroisoquinolines 4A and 4B in 51% and 78% yield,
respectively. Other N-Ts-aziridines with functionalized alkyl
substitutions, including 2-hydroxyethyl (2C),[29] N-Boc-protected
aminomethyl (2D) and various protected 2-hydroxymethyl (2E-H),
gave the corresponding products 4C–H in moderate to good
yields. Interestingly, as to the case of 2F and 2G, the uncyclized
products 4F' and 4G' were also isolated in 20% and 27% yield
respectively. Notably, a free hydroxy group (for 2C and 2I) was
compatible with this protocol. If enantiomerically pure aziridine 2E
was used, the reaction proceeded with stereoretention to afford
the corresponding chiral product 4E with 98% ee. The formation
of 1,3-cis-substituted tetrahydroisoquinolines 4A-I and the
stereoretention experiment indicated the C-N bond cleavage
specifically took place at the less bulkier site of the aziridine ring
Table 4. Reaction scope with respect to 2-substituted aziridine.[a]
Scheme 1. Follow-up chemistry.
In summary, we have developed a modular one-step three-
component synthesis of tetrahydroisoquinolines via a Catellani
strategy. This process exploits aziridines as the alkylating
reagents through palladium/norbornene cooperative catalysis to
enable a Catellani/Heck/aza-Michael addition cascade. This mild,
chemo-selective, and scalable protocol is compatible with a range
of aryl iodides, aziridines as well as olefins, providing a versatile
platform to access diversified tetrahydroisoquinolines. The most
striking feature of this process is the excellent regioselectivity and
diastereoselectivity observed for 2-alkyl and 2-aryl substituted
aziridines to access 1,3-cis-substituted and 1,4-cis-substituted
[a] All reactions were performed on a 0.1 mmol scale. Reported yields are for
the isolated products. [b] 24 mol% DavePhos was applied instead of TFP. [c]
50 mol% N5 was used. [d] Enantiopure 2E was applied. [e] The reaction
temperature was increased to 80 oC.
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[16] For selected works, see: a) M. Lautens, S. Piguel, Angew. Chem. Int. Ed.
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[17] Aziridines are prepared in a few steps from olefins or substituted 2-amino-
1-ol, see: a) J. L. Jat, M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin,
D. Devarajan, D. H. Ess, L. Kürti, J. R. Falck, Science 2014, 343, 61; b) Z.
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tetrahydroisoquinolines respectively. Moreover, this is a process
with high step- and atom-economy. Owing to these advantages,
we believe this chemistry will be welcomed by synthetic chemists
and medicinal chemists.
Acknowledgements
We are grateful to the National Key Research and Development
Program of China (No. 2016YFB0101203), the National “1000-
Youth Talents Plan”, the Innovation Team Program of Wuhan
University (Program No. 2042017kf0232) and start-up funding
from Wuhan University for financial support. We thank Prof.
Wenjing Xiao from CCNU for donating some aziridine substrates,
Mr. Chuanxin Du and Ms. Yuanyuan Xia for technical assistance.
Keywords: Catellani reaction • cooperative catalysis • aziridine •
tetrahydroisoquinoline • aza-Michael addition
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[20] While this study was in progress, an elegant related transformation was
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than the small scale (0.2 mmol) (See SI, part 9).
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crystallographic analysis. CCDC 1847835 contains the supplementary
crystallographic data for this paper.
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[28] Reactions with disubstituted N-Ts-aziridines suffered from low yields,
while trisubstituted N-Ts-aziridines were not reactive under the current
conditions.
[29] For 2C, DavePhos was used as the ligand to obtain a good yield (70%).
The yield could be further increased to 88% if 50 mol% of N5 was used.
[30] The excellent regioselectivities in palladium and Ni catalyzed aziridine
cleavage were documented. For 2-alkyl substituted aziridines, see: a) M.
L. Duda, F. E. Michael, J. Am. Chem. Soc. 2013, 135, 18347; b) J. E. Ney,
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Guangyin Qian, Miao Bai, Shijun Gao,
Han Chen, Siwei Zhou, Hong-Gang
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Modular One-Step Three-Component
Synthesis of Tetrahydroisoquinolines
via a Catellani Strategy
A modular one-step, three-component synthesis of tetrahydroisoquinolines via a
Catellani strategy was developed. In this process, aziridines act as the alkylating
reagents to enable
a Catellani/Heck/aza-Michael addition cascade through
palladium/norbornene cooperative catalysis. This mild, chemo-selective, and
scalable protocol is compatible with a wide range of readily available aryl iodides,
aziridines as well as olefins (43 examples, up to 90% yield). The most striking feature
of this process is the excellent regioselectivity and diastereoselectivity observed for
2-alkyl and 2-aryl substituted aziridines to access 1,3-cis-substituted and 1,4-cis-
substituted tetrahydroisoquinolines respectively. Moreover, this is a versatile process
with high step- and atom-economy.
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10.1002/anie.201806780
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This article is protected by copyright. All rights reserved.