Sodium nitrite-catalyzed aerobic oxidative Csp2-Csp3 coupling: Direct construction of the 4-aryldihydroisoquinolinone moiety

Article abstract of DOI:10.1002/adsc.201300832

A bioinspired approach for the construction of the 4- aryldihydroisoquinolinone moiety via direct oxidative Csp²-Csp ³ coupling has been developed, which uses inexpensive sodium nitrite as catalyst and environmentally benign oxygen in the air as terminal oxidant.

Full text of DOI:10.1002/adsc.201300832

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DOI: 10.1002/adsc.201300832
Sodium Nitrite-Catalyzed Aerobic Oxidative
2
3
À
Csp Csp Coupling: Direct Construction of the
4-Aryldihydroisoquinolinone Moiety
Bo Su,+a Meng Deng,+a and Qingmin Wanga,*
a
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, Peopleꢀs Republic of China
Fax : (+86)-022-2350-3952; e-mail: wang98h@263.net or wangqm@nankai.edu.cn
+
These authors contributed to the work equally
Received: September 12, 2013; Revised: November 24, 2013; Published online: March 11, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300832.
Abstract: A bioinspired approach for the construc-
tion of the 4-aryldihydroisoquinolinone moiety via
direct oxidative Csp Csp coupling has been devel-
oped, which uses inexpensive sodium nitrite as cata-
lyst and environmentally benign oxygen in the air
as terminal oxidant.
the biomimic synthesis of cherylline-type products,[8,9]
construction of 4-aryltetryhydroisoquinoline via direct
oxidative coupling has not been developed successful-
ly to the best of our knowledge.
2
3
À
Recently, we explored an aerobic oxidative dehy-
drogenative coupling system for the construction of
polymethoxy-substituted phenanthrenes, biaryls and
spirocyclohexadienones, in which environmentally
friendly sodium nitrite was used as catalyst at ambient
temperature.[11] As a continuation of our interest in
developing efficient and environmentally benign cata-
lytic oxidative coupling reactions, we report herein
the sodium nitrite-catalyzed construction of the 4-ar-
yldihydroisoquinolinone moiety via direct biomimic
Keywords: 4-arylisoquinolinones; biogenetic synthe-
sis; cherylline; oxidative coupling reaction; sodium
nitrite
2
3
[12]
À
Tetrahydroisoquinoline is an interesting structural Csp Csp oxidative coupling.
motif that is present in a large number of natural Inspired by the biogenesis of cherylline, compounds
products[1] and synthetic biologically active com- 1a and 3a were initially synthesized for the oxidative
pounds.[2] Because of their important physiological ac- coupling reaction (Scheme 3). Gratifyingly, both com-
tivities,[3] much attention has been paid on the devel- pounds 1a and 3a gave the desired coupled products
opment of their synthetic methodology. Some of these 2a and 4a, respectively, under previously optimized
are described graphically in Scheme 1, key strategies conditions, and the latter gave a much higher yield.
of which include: a) Bischler–Napieralski cycliza- The structure of compound 4a was unambiguously
tion;[4] b) palladium-catalyzed a-arylation of dihydro- confirmed by a combination of NMR and HR-mass
ACHTUNGTRENNUNG
isoquinolinone;[5] c) nucleophilic addition of b-amino- spectroscopy and single-crystal X-ray analysis
carbanion to benzyne;[6] d) intramolecular Friedel– (Figure 1).[13] Compound 3a was then selected as the
Crafts cyclization of benzylic alcohol;[7] e) base-cata- model substrate to investigate for optimal reaction
lyzed cyclization of para-hydroxybenzyl alcohol;[8] conditions, which were summarized in Table 1.
and f) Lewis acid-catalyzed cyclization of masked
It was gratifying to find that the desired coupled
para-quinone methides.[9] Although these methods product 4a was obtained in 63% yield when 3a was
could generally provide good yields, multistep synthe- treated with 0.1 equiv. of NaNO2 in TFA under an at-
sis of the substrates are always indispensable. As pro- mosphere of air (entry 1), while no indentified prod-
posed in the biogenesis of the Amaryllidaceae alka- uct was isolated when the weak acid AcOH was em-
loid cherylline (Scheme 2), oxidative dehydrogenative ployed (entry 2). To decrease the usage of acid and
coupling was undoubtedly the most desirable ap- make the reaction conditions much milder, different
proach, in which phenolic oxidation to para-quinone solvents were then screened (entries 3–7), among
methide and subsequent formal 1,6-addition oc- which DCM showed the best result. It was worthy of
curred.[10] Although much effort had been devoted to note that when MeCN was used as solvent, the reac-
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Bo Su et al.
Scheme 1. Common strategies for the construction of the 4-aryltetrahydroisoquinoline moiety.
Scheme 2. Biogenesis of cherylline.
Scheme 3. Selection of model substrates.
tion became relatively slow (entries 5 and 6). On ex-
panding the duration of the reaction or increasing the
usage of NaNO2, by-products also increased (not
shown). With DCM used as solvent, the concentration
of acid and reaction time were also investigated (en-
tries 7–12), which showed that DCM/TFA (10:1) was
optimal and reaction time had a great influence on
the yield.
With the optimized reaction conditions in hand,
then the substrate scope was examined, which was
listed in Table 2. Substrates 3a–3h, which have two
methoxy groups on the vicinal positions of a phenolic
hydroxy group, gave the desired coupled products 4a–
4h in moderate to good yields, respectively. It was
noteworthy that the yield of different substrates
varied with reaction time, so the reaction process Figure 1. X-ray crystal structure of 4a.[13]
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Sodium Nitrite-Catalyzed Aerobic Oxidative Csp Csp Coupling
Table 1. Optimization of the reaction conditions.[a]
Entry
NaNO2 (equiv-)
Solvents (12 mL)
Time [min]
Conversion[b] [%]
Yield[b] [%]
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
TFA
AcOH
10
10
10
10
30
20
10
10
15
20
30
15
100
100
100
100
74.7
92.3
100
80.0
97.0
100
100
88.5
63.2
0
toluene/TFA (5:1)
CHCl3/TFA (5:1)
MeCN/TFA (5:1)
MeCN/TFA (5:1)
DCM/TFA (5:1)
DCM/TFA (10:1)
DCM/TFA (10:1)
DCM/TFA (10:1)
DCM/TFA (10:1)
DCM/TFA (19:1)
57.3
54.1
67.4
66.6
85.0
73.1
89.3
77.8
69.5
72.2
9
10
11
12
[a]
General reaction conditions: 3a (187 mg, 0.5 mmol), solvents (12 mL), at room temperature and under an atmosphere of
air unless otherwise noted.
Conversion and yield were determined by HPLC.
[b]
should be monitored by TLC as closely as possible. positions, could also give a 55% yield of desired prod-
When substrate 3i with only one methoxy group at uct, indicating that electron-donating groups could
the vicinal position to the phenolic hydroxy group stabilize the intermediate of the reaction.
was subjected to the optimized reaction conditions,
To explore the mechanism of the oxidative coupling
no identifiable product was obtained. This was be- reaction, compound 5 with the OH replaced by OMe
lieved to be due to the fact that the vicinal position of was prepared. When it was subjected to the oxidative
the phenolic hydroxy group was much easier to be coupling conditions, no desired coupling reaction oc-
oxidized, giving various undesired intermediates, curred and the starting material was completely re-
which then furnished different by-products. To mini- covered (Scheme 4), which indicated that the phenolic
mize this undesired oxidation, we decided to intro- hydroxy group was indispensable and essential for the
duce a bromine atom at the vicinal position. Another occurrence of the oxidative coupling reaction.
advantage of the installation of the bromine atom is
Based on the preliminary experimental results and
that the resulting aryl bromide can be converted to previous investigations, a plausible mechanism for the
numerous motifs via transition metal-catalyzed cross- present oxidative coupling was proposed as shown in
coupling reactions, which will largely expand the Scheme 5. The reaction proceeds with a typical radial
structural diversities. Gratifyingly, substrates 3j–3l un- mechanism via the one-electron transfer from sub-
derwent the reaction smoothly and produced the de- strate 3 to the strong NO+ cation and subsequent de-
sired coupled products 4j–4l, respectively, in moderate protonation, giving hexadienone radical 6 and an NO
yields. However, substrate 3m could only gave 14% radical. After abstraction of a hydrogen radical by the
coupled product, which was proposed to be due to NO2 radical, which was generated from oxidation of
the relatively weaker nucleophicity of the lower aryl NO by oxygen, para-quinone methide intermediate 7
group. With the two methoxy groups substituted by was formed. An alternative approach to intermediate
bromide, substrate 3n gave no desired coupled prod- 7 is that hexadienone radical 6 was oxidized by NO+
uct, which demonstrated that an electron-donating to a hexadienone cation species, which could be sub-
À
group at the vicinal position of the phenolic hydroxy sequently deprotonated with CF3CO2 . Activated by
group was crucial for the oxidative coupling reaction. a Brønsted acid, the resulting para-quinone methide 7
Substrate 3o with two tert-butyl groups at the vicinal cyclized to cation species 9 via nucleophilic 1,6-addi-
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Table 2. Scope of the substrates.[a]
Scheme 4. Control experiment.
4-aryldihydroisoquinolinone moiety has been devel-
oped using O2 in air as the terminal oxidant at ambi-
ent temperature which, to the best of our knowledge,
is the first biogenetic approach to cherylline-type
products via direct oxidative coupling.
Experimental Section
2
À
General Procedure for the NaNO2-Catalyzed Csp
Csp3 Oxidative Coupling Reaction (3a as an
Example)
To a solution of compound 3a (181 mg, 0.5 mmol) in DCM
(10 mL) and CF3COOH (1 mL) was added NaNO2 (3.5 mg,
0.05 mmol) in one portion at room temperature. Then the
reaction mixture was stirred under an atmosphere of air,
and monitored by TLC. The reaction was quenched with sa-
turated aqueous Na2SO3 (5 mL, 1M), and DCM (30 mL)
was added. After separation, the organic layer was washed
subsequently with water (40 mL), saturated aqueous
NaHCO3 (40 mL) and brine (40 mL), dried over with
MgSO4, and concentrated under reduced pressure. The resi-
due was purified by column chromatography on silica gel to
give compound 4a as a light yellow solid; yield: 126 mg
(70%); mp 223–2258C; 1H NMR (400 MHz, CDCl3): d=
6.86 (brs, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.39 (s, 2H), 4.63
(s, 1H), 4.54 (d, J=15.6 Hz, 1H), 4.34 (dd, J=15.6, 4.0 Hz,
1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H); 13C NMR
(100 MHz, CDCl3): d=172.8, 148.8, 148.3, 147.1, 134.2,
129.9, 126.9, 123.4, 111.3, 108.1, 105.0, 56.4, 56.0, 56.0, 51.5,
44.9; HR-MS (ESI): m/z=382.1264, calcd. for C19H21NNaO6
(M+Na)+: 382.1261.
Acknowledgements
We are grateful to the National Key Project for Basic Re-
search (2010CB126106), the National Natural Science Foun-
dation of China (21132003, 21121002, 21372131), Tianjin
Natural Science Foundation (11JCZDJC20500) and Special-
ized Research Fund for the Doctoral Program of Higher
Education (20130031110017) for generous financial support
for our programs.
[a]
General reaction conditions: 3 (187 mg, 0.5 mmol), sol-
vents (12 mL), and yields referred to isolated yields.
tion, which subsequently yielded the 4-aryldihydroiso-
quinolinone 4 after rearomatization.
In conclusion, a novel sodium nitrite-catalyzed oxi-
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dative Csp Csp coupling for the construction of the
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Sodium Nitrite-Catalyzed Aerobic Oxidative Csp Csp Coupling
Scheme 5. Plausible mechanism for the oxidative coupling reaction.
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