Reactions Catalysed by a Binuclear Copper Complex: Relay Aerobic Oxidation of N-Aryl Tetrahydroisoquinolines to Dihydroisoquinolones with a Vitamin B1 Analogue

Article abstract of DOI:10.1002/chem.201604750

N-Aryl tetrahydroisoquinolines were oxidised to dihydroisoquinolones through the relay catalysis of a binuclear paddle-wheel copper complex and a vitamin B1 analogue with oxygen as oxidant. Mechanistic studies revealed that the copper catalyst oxidises amines to the corresponding iminium salts, which are then oxygenated to lactam products by catalysis of the vitamin B1 analogue.

Full text of DOI:10.1002/chem.201604750

A Journal of
Accepted Article
Title: Binuclear Copper Complex Catalysed Reactions: Relay
Aerobic Oxidation of N-Aryltetrahydroisoquinolines to
Dihydroisoquinolones with a VB1 Analogue
Authors: Yuxia Liu, Chao Wang, Dong Xue, Miao Xiao, Jiao Liu,
Chaoqun Li, and Jianliang Xiao
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10.1002/chem.201604750
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Binuclear Copper Complex Catalysed Reactions: Relay Aerobic
Oxidation of N-Aryltetrahydroisoquinolines to Dihydroisoquinol-
ones with a VB1 Analogue
Yuxia Liu,[a] Chao Wang,*[a] Dong Xue,[a] Miao Xiao,[a] Jiao Liu,[a] Chaoqun Li,[a] and Jianliang Xiao*[a,b]
Abstract:
N-aryltetrahydroisoquinolines
were
oxidised
to
dihydroisoquinolones through the relay catalysis of a binuclear
paddle-wheel copper complex and a vitamin B1 analogue with
oxygen as oxidant. Mechanistic studies revealed that the copper
catalyst oxidises amines to the corresponding iminium salts, which
were then oxygenated to lactam products by the catalysis of the
vitamin B1 analogue.
Introduction
The paddle-wheel type Cu(II)-carboxylate dimers are well-known
binuclear copper complexes.[1] Although they have been
extensively studied as superoxide dismutase mimetics in
2]
bioinorganic and medicinal chemistry,[1a,
their potential as
catalysts for organic synthesis has rarely been explored thus
far.[3] Traditional methods of reacting Cu(II) salts with carboxylic
acids may lead to copper complexes of various structures
depending on the synthetic conditions. However, the binuclear
Scheme 2. Oxidation of N-aryltetrahydroisoquinolines to dihydroisoquinolones.
Cu(II)-salicylate complex
1 can be prepared easily and
reproducibly by reacting CuCl with cheap salicylic acid under
oxygen (Scheme 1). In the previous study,[4] we have shown that
1 is a powerful catalyst for the oxidative coupling of N-
aryltetrahydroisoquinolines with various nucleophiles. Herein, we
disclose that 1 forms a novel relay catalytic system with a
vitamin B1 analogue that allows for the oxidation of N-
aryltetrahydroisoquinolines to lactams via iminium intermediates
with oxygen (1 bar) as oxidant under mild conditions (Scheme 2).
Relay or cooperative catalysis has been actively pursued by
chemists, offering the potential of more environmental friendly
processes and novel activity and selectivity patterns than single
catalytic systems. Great progress has been made in this area in
recent years.[5] For example, relay catalysis has been applied to
the selective transformation of amines, where the amine
substrates are catalytically oxidised to iminium salts often with
stoichiometric organic oxidants, followed by organocatalytic
nucleophilic addition.[6] We envisioned that in the absence of a
nucleophile the iminium salts generated via the catalysis of 1[4]
might be trapped by oxygen with a suitable catalyst to form
amides or lactams, an important class of organic compounds.
The direct α-oxidation of amines to lactams is an appealing
transformation but examples are rare.[7] Dihydroisoquinolones
and their derivatives are important examples of lactams, which
exist as core structures in many natural and biologically active
compounds.[8] Traditional methods for the synthesis of
dihydroisoquinolones generally rely on multiple-step synthesis.[8c,
Scheme 1. Synthesis of binuclear copper complex Cu(Sal)2(NCMe)]2 1.
[a]
[b]
Y. X. Liu, Prof. Dr. C. Wang, Prof. Dr. D. Xue, M. Xiao, J. Liu, Prof.
Dr. C. Q. Li, Prof. Dr. J. L. Xiao
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry
of Education and School of Chemistry and Chemical Engineering,
Shaanxi Normal University
Xi’an, 710062 (China)
E-mail: c.wang@snnu.edu.cn
Prof. Dr. J. L. Xiao
9]
The direct oxidation of tetrahydroisoquinolines to lactams is
one of the most direct ways for accessing these compounds.
The
formation
of
dihydroisoquinolone
from
N-
phenyltetrahydroisoquinoline in cross-dehydrogenative-coupling
(CDC) reactions[10] has been observed sporadically, often as a
byproduct.[11] However, neither the substrate scope nor the
reaction mechanism of these oxidation processes has ever been
reported. A hemiaminal was believed to be the intermediate for
the lactam product (Scheme 2).[11e]
Department of Chemistry
University of Liverpool
Liverpool, L69 7ZD, (UK)
E-mail: j.xiao@liv.ac.uk
Supporting information for this article is given via a link at the end of
the document.
Results and Discussion
1
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1. Relay oxidation of amines to lactams
isolated yield, which could be turned into the potent estrogen
receptor modulators using established methods (Scheme 5).[9, 13]
Complex
1
was tested for the oxidation of N-
phenyltetrahydroisoquinoline (2a), aiming for the lactam product
3a (Scheme 3). Initially, a hemiaminal product 3a’ was formed
exclusively when 2a was subjected to the aerobic catalysis of 1
in CH3CN for 12 h (Scheme 3, entry 1). Interestingly, with the
addition of 2 mol% of n-tetrabutyl ammonium chloride (TBAC), a
higher yield of 3a’ was detected, accompanied with a trace
amount of the amide product 3a (Scheme 3, entry 2). This is in
line with the accelerating effect of chloride anion on the oxidation
of 2a noted before.[4] Much to our surprise, when a catalytic
amount of a thiazolium salt 4,[12] a vitamin B1 (VB1) analogue,
was introduced, the yield of 3a was boosted remarkably
(Scheme 3, entries 3-4). VB1 (5) could also promote the
formation of 3a, albeit with a much lower activity (Scheme 3,
entry 5). In this case, the majority of 2a remained unreacted and
no 3a’ was observed, possibly because of the amino group in
VB1 deactivating 1. Although 4 may function via carbene
formation as in the case of organocatalysis (vide infra), the
commonly-used carbene catalyst precursors, such as 6 and 7,
did not promote the formation of 3a (Scheme 3, entries 6-7).
Scheme 4. Cu-catalysed aerobic oxidation of N-aryltetrahydroisoquinolines.
See the SI for experimental details. Isolated yield. [a] 5 mol% 1, 10 mol%
TBAC. [b] 10 mol% 1, 20 mol% TBAC, 60 oC. [c] 5 mol% 1, 10 mol% TBAC,
60 oC.
Scheme 3. Catalytic oxidation of N-phenyltetrahydroisoquinoline (See the SI
for experimental details).
Having found the effect of this 1/4 binary catalyst, the
substrate scope for the oxidation of 2 to amides was next
examined and the results are shown in Scheme 4. Both electron
donating and electron withdrawing groups on the N-phenyl ring
could be tolerated (3a-l). In general, electron donating
substituents brought about a higher activity than electron
withdrawing ones (e.g. 3b-3c vs 3h and 3k). The sterically bulky
naphthyl substrate reacted efficiently (3m), so did 6,7-dimethoxyl
N-aryltetrahydroisoquinolines (3o-r); but the sterically more
demanding substrate 3n was less reactive, necessitating a
higher catalyst loading and higher reaction temperature,
probably due to difficulty in coordinating to the catalyst.
Scheme 5. Potential application of 1/4 catalysed aerobic oxidation.
2. Mechanistic observations
Mechanistic studies were carried out to probe how the amines
were oxidised to amides. In the catalytic reaction, 2a was
converted to 3a under the joint catalysis of 1/4. As presented
before,[4] on stirring an equal amount of 2a and 1 under O2, an
To demonstrate the potential application of the chemistry, the
tetrahydroisoquinolines 2s and 2t were oxidized under the relay
catalysis of 1 and 4, furnishing the lactams 3s and 3t in excellent
2
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iminium salt 8 was observed (Scheme 6).[14] The 1H NMR
spectrum of 8 is broad, which indicates that the anion in 8 ion-
pairs with the cation and is paramagnetic, differing from that
observed in the CDC reactions reported by Klussmann and co-
workers.[14b] However, the structure of the anion remains unclear
(denoted as X-), and efforts to grow single crystals of 8 have
failed so far.[4] Treating the in situ formed
amount of and Na2CO3 (2 equiv.) under 1 bar of O2
afforded the amide 3a in 88% yield in 3 h. However, this
latter reaction could not take place under Ar or without
8 with catalytic
4
4
,
and in both cases, the hemiaminal intermediate 3a’ was
observed.[14b, 15] The base, Na2CO3, is also essential for a
high yield of 3a under this condition. In its absence, only
46% of 3a was observed in 12 h, along with 54% of 3a’
These observations show that the amide is formed from
.
2
3
via the oxidation of the iminium intermediate, and it is the
VB1 analogue that catalyses the oxygenation of the iminium
cation, forming a relay catalyst with 1.
Scheme 7. Reaction of 4 with O2 with or without 9.
reaction of 9 afforded the amide product in a higher yield of 92%,
suggesting that 2a could act as an effective base in the catalytic
reactions (Scheme 4), in which no extra base was added.
Scheme 6. Observation of iminium formation and transformation.
To understand further this unprecedented thiazolium-
catalysed conversion of iminium salts to amides, stoichiometric
reactions were carried out (Scheme 7). When 1 equivalent of 4
was treated with 2 equivalents of Na2CO3 under an atmosphere
of O2 in MeCN, cyclcodithiadiazecinedion 10 and thiazolinone 11
were isolated in 15 and 65% yield, respectively. The structure of
10 was confirmed by X-ray diffraction analysis. However, neither
10 nor 11 was catalytically active in the oxidation of iminium ions.
In addition, they could not be inter-converted under the reaction
conditions. Similar products were obtained by Morel et al when a
thiazolium iodide was treated with KOH.[17] Under such
conditions, the thiazolium was believed to be converted into a
carbene, which dimerizes, affording a filvalene that reacts with
O2 to give the disulfide heterocycle and thiazolinone.
As noted, 3a’ was proposed to be an intermediate for amide
formation.[11e] However, it may only serve as a reservoir of the
iminium salt[14b, 15a] in our system. Indeed, 3a’ could be isolated
and characterized and it is inter-convertible with the
corresponding iminium salt 9[16] upon acid and base treatment
(See SI for details). Further, 3a’ showed a similar reactivity to
that of 8. The formation of 3a’ is likely to be due to the reaction
of 8 with residual water in the solvent. If 3a’ was an intermediate
for 3a, the oxygen of the amide product would come from H2O
rather than O2. However, isotope labeling showed that the
oxygen atom in the amide originates from O2, which supports 8
rather than 3a’ as the intermediate for the product 3a. Thus, in
the oxygenation of 2a catalysed by 1/4 with normal oxygen gas,
the product formed constitutes almost exclusively 16O-containing
3a. However, with oxygen gas containing 18O2, the major part of
the product became 18O labeled (Eq 1, See SI for details).
To gain more evidence that 4 catalyses the oxygenation of 8,
the reactivity of iminium salt 9 was studied (Scheme 6). Stirring
9 with 20 mol% of 4 and 2 equivalents of Na2CO3 in CH3CN (1
mL) under an O2 atmosphere afforded 3a in 61% yield in 12 h,
thus showing 4 to be a catalyst for the iminium oxygenation. The
slower rate in forming 3a from 9 than 8 may stem from 9 existing
as a contact ion pair in solution.[14b]
The formation of carbenes from thiazolium salts and their
dimerization into ethylenic species and reactions with
electrophiles have long been known[18] since Breslow’s
seminal work[19] and studied in the context of thiamine or
VB1 catalysis.[20] In the current case, 10 and 11 could be
generated via the pathways shown in Scheme 8. Carbene
dimers and the related Breslow intermediates are known to
react with O2, forming reactive dioxentane species that
17-18]
readily decompose to oxygenation products.[12,
However, attempts to detect and isolate the thiazolyl
carbene were not successful. Treating
4 with Na2CO3 under
Interestingly, replacing Na2CO3 with the substrate 2a in the
1
Ar in CH3CN led to a complex mixture, as revealed by H
NMR. This may be a result of carbene dimerization followed
by rearrangements.[18a]
3
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Insightfully, when the above reaction was conducted in
the presence of 1 equivalent of 9, the expected amide 3a
was obtained in 95% yield, alongside 11 in 93% yield.
Na2CO3 was found indispensable for all these reactions that
afford 10
was noted. These observations support the hypothesis that
is deprotonated in the oxygenation, affording a carbene
, 11 and 3a (Scheme 7). Without it, no reaction
4
intermediate that attacks the iminium cation and triggers the
reaction with O2. Although N-heterocyclic carbenes (NHCs),
generated from imidazolium or thiazolium salts, have been
shown to catalyse oxidative coupling reactions with
oxidants generally stronger than O2,[12] there appears to be
no example of oxidation of imines or iminium ions to an
amide by such carbene catalysts.
Scheme 9. Proposed mechanism for the relay catalysis of 1-4 (The nature of
X- is not defined; for
a suggestion, see reference 4. However, the
deprotonation could be effected with any base present in the system).
Conclusions
This paper discloses a mild and efficient method for the
Scheme 8. Possible pathways for the formation of 10 and 11 from 4.
oxidation
of
N-aryltetrahydroisoquinolines
to
dihydroisoquinolones, which is enabled by the relay
catalysis of a binuclear Cu catalyst and a VB1 analogue.
Mechanistic studies revealed that the Cu catalyst converts
the amine to an iminium intermediate, which is then
oxygenated by the catalysis of the VB1 analogue. The
oxygenation of iminium salts to amides catalysed by NHCs
appears unprecedented in the literature.
3. Suggested mechanism for the relay oxidation
Based on the evidence above and literature (vide infra), a
mechanistic scenario for the relay catalysis of 1/4 is presented in
Scheme 9. In the presence of O2, 1 converts 2a to 8.[4] Under the
catalytic conditions, 4 is deprotonated by 2a to a carbene
intermediate, which attacks the iminium cation of 8 to generate
12. Deprotonation of this leads to the electron-rich ethylenic
Breslow-type intermediate[19] 13, which could react with O2 to
form the dioxentane 14 and an equilibrating peroxide. The
latter may readily decompose into the carbene catalyst and
the peroxide 15, which then attacks another iminium cation,
forming the peroxo dimer 16, decomposition of which leads
to the lactam product.
Experimental Section
General procedure for the oxygenation of 2: In a Schlenk tube equipped
with a magnetic stir bar, 2 (0.25 mmol), 1 (0.0025 mmol, 3 mg), TBAC
(0.005 mmol, 2.8 mg), and 4 (0.05 mmol, 13.4 mg) were added. MeCN
(1.0 mL) was then introduced with a syringe. The reaction tube was
degassed with oxygen gas (3 times), and kept under an oxygen
atmosphere by using a balloon. After stirring at 30 oC or 60 oC for the
time indicated, the reaction mixture was diluted with water, and then
extracted with DCM (3 x 15 mL). The organic layers were combined,
washed with brine, and dried over Na2SO4. The solvent was removed via
rotary evaporation and the crude product purified by column
chromatography on silica gel using ethyl acetate/petroleum ether to
afford the desired product.
The striking difference in the catalytic activity between
4
and or may be due to the hydroxyl group in , which
6
7
4
could stabilize the peroxide anion via hydrogen bonding
and thus promote the oxidation of 13 by O2.[21] Whilst
evidence for the formation of the intermediates 12-16 is
lacking in this study, literature examples of carbene
nucleophilic addition, formation of enamine compounds and
their reaction with O2 to form oxygenation products are well
known.[12] In particular, species similar to 13 have been
shown to form and react with O2 in bioprocesses, such as
the Krebs cycle.[22]
Acknowledgements
4
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5
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COMMUNICATION
A novel relay catalytic system
consisting of a binuclear copper and a
vitamin B1 analogue is disclosed,
which allows for the aerobic oxidation
of N-aryltetrahydroisoquinolines to
dihydroisoquinolones under mild
conditions.
Yuxia Liu, Chao Wang,* Dong Xue, Jiao
Liu, Chaoqun Li, Jianliang Xiao*
Page No. – Page No.
Binucear Copper Complex Catalysed
Reactions: Relay Aerobic Oxidation
of N-Aryltetrahydroisoquinolines to
Dihydroisoquinolones with a VB1
Analogue
6
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