Base-promoted aerobic oxidation of: N -alkyl iminium salts derived from isoquinolines and related heterocycles

Article abstract of DOI:10.1039/c9gc03629f

Potassium tert-butoxide-promoted aerobic oxidation of N-alkyl iminium salts is reported. The reaction is atom-economical and environmentally friendly. Iminium salts derived from isoquinoline, quinoline, phenanthridine, phenanthroline, and phthalazine were successfully transformed into their corresponding unsaturated lactams with up to 95% yield under mild conditions in the absence of photocatalysts and metallic or organic catalysts. Owing to the general substrate scope, low cost, feasibility of scale up, wide availability of reagents, and green reaction conditions, this method shows great potential for preparing isoquinolones and related compounds. The method was applied for atom- and step-economical total synthesis of natural products such as norketoyobyrine.

Full text of DOI:10.1039/c9gc03629f

Green Chemistry
View Article Online
View Journal
PAPER
Base-promoted aerobic oxidation of N-alkyl
iminium salts derived from isoquinolines and
Cite this: DOI: 10.1039/c9gc03629f
related heterocycles†
Li-Gang Bai,‡§ Yue Zhou,‡ Xin Zhuang, Liang Zhang, Jian Xue, Xiao-Long Lin,
Tian Cai * and Qun-Li Luo
*
Potassium tert-butoxide-promoted aerobic oxidation of N-alkyl iminium salts is reported. The reaction is
atom-economical and environmentally friendly. Iminium salts derived from isoquinoline, quinoline, phe-
nanthridine, phenanthroline, and phthalazine were successfully transformed into their corresponding
unsaturated lactams with up to 95% yield under mild conditions in the absence of photocatalysts and
metallic or organic catalysts. Owing to the general substrate scope, low cost, feasibility of scale up, wide
availability of reagents, and green reaction conditions, this method shows great potential for preparing
isoquinolones and related compounds. The method was applied for atom- and step-economical total
synthesis of natural products such as norketoyobyrine.
Received 22nd October 2019,
Accepted 28th November 2019
DOI: 10.1039/c9gc03629f
rsc.li/greenchem
oxygen as the terminal oxidant would be desirable in the
chemical community and is a key focus of green chemistry.6
Introduction
Oxidation is a fundamental transformation in organic chem-
Bases are also typically electron donors.7 Oxygen molecules
istry and is commonly used to convert a variety of organic com- tend to be more reactive under an electron-rich alkaline
pounds. Oxygen (O2), also known as dioxygen or molecular environment than under neutral conditions. Numerous
oxygen, is an abundant, inexpensive, clean, and atom-econ- studies have reported that some organic molecules are prone
omical oxidant.1 It constitutes approximately one fifth of the to oxidation by oxygen (air) in a simple manner under alkaline
Earth’s atmosphere, and reacts exothermically with most conditions, whereas they can coexist in air for a long time
elements. However, oxygen has a triplet ground state, which under neutral conditions.8 We envisaged that certain photo-
poses a high barrier to reactions with molecules that are catalytic or metal-mediated oxidations may be promoted by
usually in the singlet state.2 Two activating strategies for oxi- the use of certain bases.
dation with oxygen are commonly used. One is the activation
Isoquinolones and quinolones are present in various
of oxygen by converting oxygen molecules from triplet (3O2) to natural products and bioactive molecules.9 Hence, synthetic
singlet oxygen (1O2) or other reactive oxygen species (ROS).3 methodologies for these structural scaffolds have drawn con-
The other is the activation of the substrate or catalyst by siderable interest.10 Oxidation of N-alkyl iminium salts derived
forming radicals through a single electron transfer process from isoquinolines and related heterocycles is a particularly
between the substrate and catalyst.4 These strategies often straightforward strategy for the synthesis of isoquinolones and
require expensive photocatalysts and/or metal complexes as their analogues. Traditional approaches to this oxidation rely
promoters.5 Therefore, the development of environmentally on the use of an excess of potassium ferricyanide as the
friendly, mild, and low-cost oxidation approaches based on oxidant, which unavoidably generates a large amount of
harmful metal waste.10e,f In contrast, oxidation with oxygen as
a
green oxidant is an environmentally friendly method
(Scheme 1).10e–h Using limited examples, Gngnon-Dubois et al.
showed an access to isoquinolones and quinolones via an
ultrasonic irradiation-accelerated nucleophilic addition of qui-
nolinium and isoquinolinium salts with potassium tert-butox-
ide (t-BuOK) followed by silica gel-catalyzed aerobic oxida-
tion.10h In 2017, Fu et al. realized photocatalytic oxidation of
N-alkyl iminium salts with air.10e In 2018, Huang and Fu
achieved the carbene-catalyzed aerobic oxidation of N-alkyl iso-
Key Laboratory of Applied Chemistry of Chongqing Municipality, College of
Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
China. E-mail: qlluo@swu.edu.cn, caitian@swu.edu.cn
†Electronic supplementary information (ESI) available: Characterization data of
the products; 1H NMR, 13C NMR and MS spectra for new compounds. See DOI:
10.1039/c9gc03629f
‡These authors contributed equally.
§New address: College of Chemistry and Molecular Sciences, Wuhan University,
430072 Wuhan, China.
This journal is © The Royal Society of Chemistry 2019
Green Chem.

View Article Online
Paper
Green Chemistry
Table 1 Optimization of the reaction conditionsa
Entry
Base (equiv.)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (1.5)
t-BuOK (1)
KOH (3)
DMSO
t-BuOH
DMF
Dioxane
DCM
Toluene
MeCN
THF
MeCN
THF
DMSO
DMSO
DMSO
DMSO
DMSO
82
52
Trace
Trace
Trace
Trace
Messy
Messy
31
17
76
95
80
9
10
11
12
13
14
15b
t-BuOK (2)
t-BuOK (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
33
86
a Reaction conditions: 1a (0.3 mmol), base, solvent (3 mL) at room
temperature (RT) for 16 h (entries 1–10), or solvent (1.5 mL) at RT for
24 h (entries 11–15). b Hydrogen peroxide–urea (UHP, 1.5 equiv.) was
employed.
Scheme 1 Selected literature precedents on aerobic oxidation of azine-
derived N-alkyl iminium salts (a), idea (b) and advantages (c) of this work.
Cs2CO3 (entry 14 vs. 13). A decrease in the amount of t-BuOK
to 2 equivalents gave the best result (entry 12).12,13
quinolinium salts.10f Herein, we describe t-BuOK-promoted
aerobic oxidation of N-alkyl iminium salts. Compared to the
previous methods, the main advantages of our process include
lower reagent costs, less organic waste generation and energy
consumption, and no requirement of a special reaction setup.
Through the use of this method, the total synthesis of the
natural alkaloid norketoyobyrine was accomplished using a
concise route starting from isoquinoline and other inexpensive
commercial chemicals.
Analysis of the composition of the final reaction mixture by
NMR spectroscopy showed that 15%–30% of dimethyl sulfone
was formed, but no dimethyl sulfide was detected.13 We
inferred that ROS were produced in situ in the aerobic oxi-
dation process, because ROS are capable of converting sulfox-
ides to sulfones.14 Cs2CO3 is a weaker base than t-BuOK but is
not as efficient as the latter for oxidation (entry 14). Hydrogen
peroxide was explored as an additional oxidant. A combination
of hydrogen peroxide–urea (UHP) and Cs2CO3 also realized the
transformation with high yield (entry 15), and provides a green
alternative for use with strong base-sensitive substrates.
With the optimized conditions in hand (Table 1, entry 12),
we selected a series of isoquinolinium salts 1 to evaluate the
Results and discussion
We began our investigation by selecting 2-benzylisoquinolin-2- reaction scope (Table 2). The reactivity of isoquinolinium salts
ium bromide 1a as a model substrate (Table 1). In a dimethyl containing various N-alkyl groups (1a–1r) was first investi-
sulfoxide (DMSO) solution of potassium tert-butoxide, electron gated. Substrates bearing an N-benzyl or a linear N-alkyl group
transfer between donors and electron-deficient π systems (elec- gave the corresponding isoquinolones in very good to excellent
tron acceptors) often occurs readily.11 N-Alkyl isoquinolinium yields (2a–2e). Substrates bearing a cyclopropylmethyl, 2-meth-
salts are electron-deficient π systems. We envisaged that elec- oxyethyl or a branched alkyl group also led to the oxidation
tron transfer from a base or other electron donor species to products in good yields (2f–2h). In contrast, N-diphenylmethyl,
the salts should also readily occur in DMSO. Thus, we con- N-allyl, and N-cinnamyl isoquinolinium salts failed to produce
ducted the oxidation of 1a in air at room temperature (RT) the intended isoquinolones 2i–2k under the standard con-
with the use of DMSO as the solvent and t-BuOK as a base. ditions, presumably because of the relatively strong acidity of
Rewardingly, the desired isoquinolinone 2a was obtained in these N-alkyl groups. Through the use of UHP and a weak
good yield (entry 1). Solvent screening experiments showed base, 2i–2k were obtained successfully. Substituents on the
that tert-butanol also realized the transformation with moder- N-benzyl group of isoquinolinium salts had little effect on the
ate yield. Other tested solvents gave disappointing results oxidation, except for the nitro groups (2q vs. 21–2p). The nitro
(entries 3–8). Base screening experiments (entries 9–14) indi- substituents are strongly electron withdrawing and capable of
cated that t-BuOK was superior to KOH (entry 11 vs. 1) and increasing the acidity of the benzyl hydrogen atom, which
Green Chem.
This journal is © The Royal Society of Chemistry 2019

View Article Online
Green Chemistry
Paper
Table 2 Reaction scope of N-alkyl isoquinolinium saltsa
Table 3 Reaction scope of other N-alkyl iminium saltsa
a Conditions: 1 (0.3 mmol), t-BuOK (0.6 mmol), DMSO (1.5 mL) at RT
for 24 h unless otherwise noted. Yields of isolated products. b 1
(0.3 mmol), Cs2CO3 (0.45 mmol), and UHP (0.45 mmol).
a Reaction conditions: 1 (0.3 mmol), t-BuOK (0.6 mmol), and DMSO
(1.5 mL) at RT for 24 h unless otherwise noted. Yields of isolated pro-
ducts. b 1 (0.3 mmol), Cs2CO3 (0.45 mmol), and UHP (0.45 mmol). c 1
(0.3 mmol), t-BuOK (1.2 mmol), and DMSO (3 mL).
ditions, the oxidation of N-diphenylmethyl substrate 1i gener-
ated 76% of benzophenone and 64% of isoquinolin-1(2H)-one
2i′, whereas the oxidation of N-(1-phenyl)ethyl substrate 1h
gave 76% of the intended oxidation product 2h (eqn (1)
and (2)).
might obstruct the oxidation of 1q in a strongly alkaline
solution.1,8c,11c Through the use of UHP and Cs2CO3, 1q was
converted into 2q with acceptable yield. Bis(isoquinolinium) salt
1r was oxidized to 2r in 73% yield under standard conditions.
Substituted isoquinolinium salts 1s–1w were then evaluated.
The reactivity of the 6-position substituted substrates was similar
to that of their unsubstituted counterparts (2s–2t vs. 2a–2e).
However, 3-bromo and 5-bromo isoquinolinium salts generated
a certain amount of the debrominative oxygenation product 2a,
accompanied by the desired isoquinolones in moderate yields
(2u–2v). Furthermore, 5-nitro-isoquinolone 2w was obtained in
poor yield, which further suggests that the nitro group prevented
oxidation under standard conditions.
We next extended our method to other N-alkyl iminium
salts. All reactions proceeded smoothly and led to the for-
mation of the desired unsaturated lactams 4 in mostly good
yields under optimal conditions (Table 3). Debrominative oxy-
genation of 5-bromo quinolinium 3g was also observed (13%
of 4b plus 51% of 4g). UHP-mediated oxidation overcame the
debromination and produced 4g in good yield.
Phenanthridinium salts showed lower reactivity than the other
tested iminium salts and required a prolonged reaction time
of 36 h for full conversion (4l–4n).
ð1Þ
ð2Þ
t-BuOK-mediated oxidation of 1j mainly yielded the double
bond-shifted product 2j′,15 whereas the UHP-mediated method
gave the “normal” oxidation product 2j (eqn (3) and (4)).
Under standard conditions, 2j quantitatively converted to
(E)-2j′, whereas (E)-2j′ and (Z)-2j′ did not isomerize into each
other (eqn (5) and (6)). Meanwhile, 1k was oxidized into cyclic
2k′, rather than the “normal” oxidation product 2k (eqn (7)).
ð3Þ
ð4Þ
Analysis of the unexpected outcomes of the oxidation
helped us probe the reaction mechanism. Under standard con-
This journal is © The Royal Society of Chemistry 2019
Green Chem.

View Article Online
Paper
Green Chemistry
cation A provides radical B.11,17 The cross coupling of carbon
radical B with diradical molecular oxygen leads to alkylperoxyl
radical C.10e Alkylperoxyl radical C is converted to α-hydroperoxy-
α-carbon radical D via hydrogen atom transfer (HAT).18 Radical
D gives the final product F and a hydroxyl radical.18 A hydroxyl
radical evolves into hydrogen peroxide or other ROS that further
oxidize A to yield F via pathways such as path b.3,19
The utility of our protocol is exemplified in Scheme 3. Gram-
scale preparation by this oxidation was feasible. The reaction
efficiency was slightly affected when 1a was used on a 6 mmol
scale for both t-BuOK-promoted aerobic oxidation and UHP-
mediated oxidation. The bromination of oxidation product 2a
with N-bromosuccinimide (NBS) under mild conditions led to
ð5Þ
ð6Þ
ð7Þ
Mechanistic studies (Scheme 2a) indicated that the yield
was hardly affected when the reaction was performed in the 4-bromo isoquinolinone 5 in excellent yield (Scheme 3a).
dark but sharply decreased under an inert atmosphere. The
reaction was greatly limited by the radical inhibitor butylated
Our oxidative method was successfully applied to the atom-
and step-economical total synthesis of natural products
hydroxytoluene (BHT, 2 equivalents),16 but accelerated by the (Scheme 3b). Consequently, norketoyobyrine (9) was syn-
free radical 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO, 2
equivalents).
thesized in 61% total yield via the three-step sequence of oxi-
dation, cyclization and dehydrogenative oxidation from isoqui-
The reaction mechanism was further studied by high nolinium salt 6. Reduction of intermediate 8 (dihydronorke-
resolution mass spectroscopy (HRMS) with an ESI source
toyobyrine) delivered demethoxycarbonyldihydrogambirtan-
(Fig. S6–S11†).13 Under standard conditions, mass peaks at
nine (8a) via a known process.20 Gao et al. reported an elegant
m/z = 220.11 (M − 79 peak of 1a) and 274.06 (M + 39 peak of strategy for constructing natural products such as 9.9a Our syn-
2a) were detected; however, that at m/z = 375.24 was not
thetic precursors for norketoyobyrine were more easily pre-
detected in the reaction mixture. On addition of TEMPO to the
pared compared to those using Gao et al.’s method. Our
reaction mixture, a new mass peak at m/z = 375.24 (M − 1 peak method used no protective groups and no unwanted carbon
of 1aB, Scheme 2a) was detected, which resulted from a radical
intermediate being trapped by TEMPO. In the absence of
t-BuOK, the addition of TEMPO did not lead to the formation
of either 2a or 1aB. These observations indicate that the oxi-
dation of 1a was actually initiated by t-BuOK.
atoms were removed. Special and/or expensive reagents were
avoided in each step.
According to previous work and the above results, a poss-
ible mechanism for the t-BuOK-promoted aerobic oxidation is
proposed in Scheme 2b. The reaction was initiated along path
a. A single electron transfer (SET) from the base to iminium
Scheme 3 Gram-scale synthesis and bromination of 2a (a), total synth-
eses of norketoyobyrine and its related compounds (b), and formal
synthesis of topoisomerase I inhibitor 10 (c). Conditions: (i) t-BuOK
(2 equiv.); (ii) UHP (1.5 equiv.), Cs2CO3 (1.5 equiv.); (iii) BF3·Et2O, MeCN,
85 °C; and (iv) CeCl3·7H2O (0.1 equiv.), air, i-PrOH, 50 °C.
Scheme 2 Mechanistic insights (a) and the proposed mechanism (b).
Green Chem.
This journal is © The Royal Society of Chemistry 2019

View Article Online
Green Chemistry
Paper
Our oxidative method was also applicable to the formal syn- bonate (147 mg, 0.45 mmol) and urea hydrogen peroxide
thesis of topoisomerase
inhibitor 10 (Scheme 3c).9c (42 mg, 0.45 mmol) in a 5 mL flask was added dimethyl sulfox-
I
Compared with other green methods for the synthesis of 10 ide (1.5 mL). The mixture was continuously stirred at room
reported in the most recent literature,10f our protocol required temperature until 1 or 3 was consumed as indicated by TLC
neither the NHC catalyst nor cooling of the reaction system to (typically for 24 h). Then it was diluted with water (5 mL) and
far below ambient temperature. These features are beneficial extracted with ethyl acetate (3 × 5 mL). The combined organic
in terms of reducing organic waste generation and energy phase was dried over anhydrous Na2SO4, filtered, and concen-
consumption.
trated under reduced pressure. The crude product was purified
by column chromatography on silica gel to give the desired
product 2 (for 1) or 4 (for 3).
Conclusions
Gram-scale preparation of 2a
In conclusion, we report here a mild and environmentally
(i) Preparation through t-BuOK-promoted aerobic oxi-
benign aerobic oxidative method for the simple synthesis of a dation. To a mixture of N-benzylisoquinolin-2-ium bromide 1a
wide variety of isoquinolinones and related heterocyclic deriva- (1.80 g, 6.0 mmol) and potassium tert-butoxide (1.35 g,
tives. In the absence of commonly used promoters, such as 12.0 mmol) in a 100 mL flask was added DMSO (30 mL) with
metallic reagents, photocatalysts, and other additives, a series stirring. The reaction mixture was continuously stirred in air at
of N-heterocycle-derived N-alkyl iminium salts were success- room temperature until 1a was consumed as indicated by TLC
fully oxidized into their corresponding unsaturated lactams (ca. 72 h). Then it was diluted with ethyl ester (70 mL) and
with the sole use of a base, a solvent, and ambient atmosphere water (70 mL) and extracted with EtOAc (3 × 70 mL). The com-
at room temperature. The reaction was scaled up to produce bined organic phase was dried over anhydrous Na2SO4, fil-
grams of N-alkyl isoquinolin-1(2H)-one under mild conditions. tered, and concentrated under reduced pressure. The crude
Mechanistic studies indicated that the oxidation was initiated product was purified by column chromatography on silica gel
by t-BuOK, and the experimental observations were prelimina- (petroleum ether/ethyl acetate = 5 : 1) to provide N-benzyl iso-
rily in agreement with a radical mechanism. Through the use of quinolin-1(2H)-one 2a as a yellow solid (1.32 g, 93% yield).
the method, a highly efficient total synthesis of the natural alka-
(ii) Preparation through UHP-mediated oxidation. To a
loid norketoyobyrine was accomplished in a concise manner mixture of N-benzylisoquinolin-2-ium bromide 1a (1.80 g,
starting from isoquinoline and other inexpensive commercial 6.0 mmol), cesium carbonate (2.93 g, 9.0 mmol) and urea
chemicals. The method combines several advantages, such as hydrogen peroxide (847 mg, 9.0 mmol) in a 100 mL reaction
broad generality, low cost, wide availability of reagents, limited flask was added DMSO (30 mL) with stirring. The reaction
production of harmful waste, and ease of use. Overall, the mixture was continuously stirred in air at room temperature
present method ranks among the most economical and green- until 1 was consumed as indicated by TLC (ca. 24 h). Then it
est methods reported for the oxidation of N-alkyl iminium salts. was diluted with ethyl ester (70 mL) and water (70 mL) and
extracted with EtOAc (3 × 70 mL). The combined organic phase
was dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate = 5 : 1) to provide N-benzylisoquinolin-1(2H)-one 2a as
a yellow solid (1.22 g, 86%).
Experimental
General procedures for the oxidation of N-alkyl iminium salts
1 & 3
The isolated products were confirmed by 1H NMR and 13C
NMR. The characterization data are described in the ESI.† The
Bromination of 2a with N-bromosuccinimide
exact time for each reaction is shown in Tables 2 and 3.
A 10 mL reaction flask was charged with a solution of
Procedure (i), through t-BuOK-promoted aerobic oxidation. N-benzylisoquinolin-1(2H)-one 2a (71 mg, 0.3 mmol) and NBS
To a mixture of N-alkyl iminium salt 1 or 3 (0.3 mmol) and (133 mg, 0.75 mmol) in DMSO (1.5 mL). The reaction mixture
potassium tert-butoxide (67 mg, 0.6 mmol) in a 5 mL reaction was continuously stirred at 40 °C until 2a was consumed as
flask was added dimethyl sulfoxide (1.5 mL). The mixture was indicated by TLC (ca. 18 h). Then it was diluted with ethyl
continuously stirred at room temperature until 1 or 3 was con- acetate (5 mL) and water (5 mL) and extracted with EtOAc (3 ×
sumed as indicated by thin-layer chromatography (TLC, typi- 5 mL). The combined organic phase was washed with water
cally for 24 h). Then it was diluted with water (5 mL), and and saturated brine, dried over anhydrous Na2SO4, filtered,
extracted with ethyl acetate (3 × 5 mL). The combined organic and concentrated under reduced pressure. The crude product
phase was dried over anhydrous Na2SO4, filtered, and concen- was purified by column chromatography on silica gel (pet-
trated under reduced pressure. The crude product was purified roleum ether/ethyl acetate = 5 : 1) to provide N-benzyl-4-bro-
by column chromatography on silica gel to give the desired moisoquinolin-1(2H)-one 5 as a white solid (87 mg, 93%).10c
product 2 (for 1) or 4 (for 3).
1H NMR (600 MHz, CDCl3) δ 8.40 (d, J = 8.0 Hz, 1H), 7.73 (d,
Procedure (ii), through UHP-mediated oxidation. To a J = 8.1 Hz, 1H), 7.69–7.60 (m, 1H), 7.48 (t, J = 7.6 Hz, 1H),
mixture of N-alkyl iminium salt 1 or 3 (0.3 mmol), cesium car- 7.29–7.26 (m, 3H), 7.25–7.20 (m, 3H), 5.12 (s, 2H). 13C NMR
This journal is © The Royal Society of Chemistry 2019
Green Chem.

View Article Online
Paper
Green Chemistry
(151 MHz, CDCl3) δ 161.4, 136.3, 135.47, 133.0, 131.8, 129.0, Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 161.2, 138.0, 136.1,
128.5, 128.15, 128.10, 127.9, 126.6, 125.9, 100.2, 51.8.
132.6, 132.3, 128.1, 127.5, 126.07, 125.9, 125.5, 124.5, 123.5,
119.4, 119.1, 112.5, 111.6, 99.0, 40.4, 19.3.
Oxidation of 3,4-dihydroisoquinolin-1(2H)-one 8. To a 10 mL
Total synthesis of norketoyobyrine (9)
Aerobic oxidation of iminium salt 6. A 100 mL flask was flask was added a mixture of 8 and 9 (29 mg, ratio: 4 : 1,
charged with 2-(2-(1H-indol-3-yl)ethyl)isoquinolin-2-ium 0.1 mmol) in i-PrOH (4 mL). The flask was placed in an oil-
iodide 6 (800 mg, 2 mmol), cesium carbonate (977 mg, bath at 50 °C and stirred until the solid was completely dis-
3.0 mmol) and UHP (282 mg, 3.0 mmol), and cooled in an ice- solved. Then CeCl3·7H2O (0.01 mmol, 4 mg) was added. The
bath. Then DMSO (7.5 mL) and DMF (7.5 mL) were added with reaction mixture was stirred until 8 was consumed as indicated
stirring. The reaction mixture was continuously stirred in an by TLC (ca. 2.5 h). It was cooled to RT, neutralized to pH 8–9
ice-bath until 6 was consumed as indicated by TLC (ca. 36 h). with saturated NaHCO3, and completely extracted with EtOAc
It was diluted with ethyl acetate (15 mL) and water (15 mL) (8 × 3 mL). The combined organic layers were washed with
and extracted with EtOAc (3 × 15 mL). The combined organic saturated brine, dried over anhydrous Na2SO4, filtered, and
phase was washed with water and saturated brine, dried over concentrated under reduced pressure to afford the crude
anhydrous Na2SO4, filtered, and concentrated under reduced product, which was purified by silica gel chromatography (PE/
pressure. The crude product was purified by column chromato- CH2Cl2 = 1 : 5) to give norketoyobyrine 9 as a yellow solid
graphy on silica gel (petroleum ether/ethyl acetate = 2 : 1) to (23 mg, 80%).9a 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H),
provide 2-(2-(1H-indol-3-yl)ethyl) isoquinolin-1(2H)-one 7 as a 8.24 (d, J = 8.5 Hz, 1H), 7.75–7.67 (m, 1H), 7.62 (d, J = 7.9 Hz,
1
yellow solid (519 mg, 90% yield), m. p. 120–130 °C. H NMR 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 0H), 7.43 (d, J =
(600 MHz, CDCl3) δ 8.49 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.70 8.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.11–7.03 (m, 2H), 4.40 (t,
(d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (d, J = 7.4 Hz, J = 6.6 Hz, 2H), 3.09 (t, J = 6.6 Hz, 2H). 13C NMR (101 MHz,
1H), 7.47 (d, J = 8.3 Hz, 1H), 7.43–7.33 (m, 1H), 7.21 (t, J = DMSO-d6) δ 161.7, 138.5, 136.6, 133.1, 132.8, 128.6, 128.0,
7.4 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J = 126.6, 126.4, 126.0, 125.0, 124.0, 120.0, 119.6, 113.0, 112.1,
7.3 Hz, 1H), 6.32 (d, J = 7.3 Hz, 1H), 4.30 (t, J = 7.3 Hz, 2H), 99.5, 40.9, 19.8.
3.42–3.14 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 162.1, 137.2,
136.4, 132.1, 132.0, 127.8, 127.3, 126.6, 126.3, 125.8, 122.5,
122.2, 119.6, 118.7, 112.4, 111.2, 105.4, 50.3, 25.0. HRMS
Conflicts of interest
(ESI-TOF) calcd for C19H16N2NaO [M + Na]+: 311.1155; found
311.1153.
There are no conflicts to declare.
Cyclization of isoquinolone 7. A 10 mL screwtop pressure
Schlenk tube was charged with a solution of 2-(2-(1H-indol-3-
yl) ethyl)isoquinolin-1(2H)-one 7 (29 mg, 0.1 mmol) in CH3CN
(2 mL). BF3·Et2O (43 μL, 0.35 mmol) was added with stirring.
Acknowledgements
The tube was sealed with a screw stopper and stirred for 48 h The authors thank the financial support from the NSFC of
at 85 °C. After cooling it to RT, the mixture was diluted with di- China (20971105), the Natural Science Foundation of
chloromethane (5 mL) and water (5 mL) and extracted with di- Chongqing (cstc2017jcyjAX0423), and the Fundamental
chloromethane (3 × 5 mL). The combined organic phase was Research Funds for the Central Universities (XDJK2019AA003).
dried over anhydrous CaCl2, and concentrated under reduced
pressure. The crude product was purified by column chromato-
graphy on silica gel (PE/DCM = 1 : 10) to provide 24 mg of a
Notes and references
yellow solid. The 1H NMR spectrum indicated that it consisted
of dihydronorketoyobyrine 8 and norketoyobyrine 9 in a ratio
of 4 to 1. Thus, the total yield of the two compounds was 85%.
Dihydronorketoyobyrine 8 (major).20a 1H NMR (400 MHz,
DMSO-d6) δ 11.11 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.55 (d, J =
6.9 Hz, 1H), 7.47 (t, J = 6.3 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H),
7.40–7.33 (m, 2H), 7.13–7.06 (m, 1H), 7.02 (t, J = 7.4 Hz, 1H),
5.15–4.94 (m, 2H), 3.60 (dd, J = 15.8, 3.8 Hz, 1H), 2.96 (dd, J =
12.4, 3.1 Hz, 2H), 2.89 (d, J = 11.7 Hz, 1H), 2.82–2.69 (m, 1H).
13C NMR (151 MHz, DMSO-d6) δ 164.3, 137.4, 136.9, 134.19,
132.49, 129.3, 128.4, 127.7, 127.6, 126.7, 121.7, 119.2, 118.4,
1 K. Fang, G. Li and Y. She, J. Org. Chem., 2018, 83, 8092.
2 W. T. Borden, R. Hoffmann, T. Stuyver and B. Chen, J. Am.
Chem. Soc., 2017, 139, 9010.
3 Y. Nosaka and A. Y. Nosaka, Chem. Rev., 2017, 117, 11302.
4 Y. Li, S. A. Rizvi, D. Hu, D. Sun, A. Gao, Y. Zhou, J. Li and
X. Jiang, Angew. Chem., Int. Ed., 2019, 58, 13499.
5 W. Fan and P. Li, Angew. Chem., Int. Ed., 2014, 53, 12201.
6 M. Liu, H. Wang, H. Zeng and C.-J. Li, Sci. Adv., 2015, 1,
e1500020.
7 A. Studer and D. P. Curran, Nat. Chem., 2014, 6, 765.
8 For selected examples, see: (a) W. E. Doering, G. Cortes and
L. H. Knox, J. Am. Chem. Soc., 1947, 69, 1700;
(b) W. E. Doering and R. W. Haines, J. Am. Chem. Soc.,
1954, 76, 482; (c) G. E. Lewis, J. Org. Chem., 1965, 30, 2433;
(d) T. Siu, D. Qin and S. J. Danishefsky, Angew. Chem., Int.
111.6, 107.8, 52.2, 39.6, 34.8, 21.1. Norketoyobyrine
9
(minor).9a 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.25
(d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 5.6 Hz,
1H), 7.58 (d, J = 5.3 Hz, 1H), 7.41 (br.s, 2H), 7.22 (t, J = 7.6 Hz,
1H), 7.12–7.06 (m, 2H), 4.41 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.6
Green Chem.
This journal is © The Royal Society of Chemistry 2019

View Article Online
Green Chemistry
Paper
Ed., 2001, 40, 4713; (e) Y.-F. Liang and N. Jiao, Angew. 14 For an example of oxidation of sulfoxides to sulfones with
Chem., Int. Ed., 2014, 53, 548.
peroxides, see: S.-K. Wang, X. You, D.-Y. Zhao, N.-J. Mou
9 (a) K. Li, J. Ou and S. Gao, Angew. Chem., Int. Ed., 2016, 55,
and Q.-L. Luo, Chem. – Eur. J., 2017, 23, 11757.
14778; (b) K. H. Raitio, J. R. Savinainen, J. Vepsäläinen, 15 The isolated major isomer of 2j′ was the Z-configuration
J. T. Laitinen, A. Poso, T. Jävinen and T. Nevalainen, J. Med.
Chem., 2006, 49, 2022; (c) D. B. Khadka and W.-J. Cho,
Bioorg. Med. Chem., 2011, 19, 724.
that is less stable than the E-configuration. The ratio of Z/E
isomers is approximately 2 : 1 at 22 °C. When the reaction
temperature was increased to 33 °C, the ratio of Z/E
isomers decreased to 1 : 1 (Fig. S5†). For an explanation of
the unexpected stereoselectivity, see the ESI.†
10 For selected examples, see: (a) C. S. Yeung, T. H. H. Hsieh
and V. M. Dong, Chem. Sci., 2011, 2, 544; (b) D. Wang,
R. Zhang, R. Deng, S. Lin, S. Guo and Z. Yan, J. Org. Chem., 16 For an example of a free radical mechanism being affected
2016, 81, 11162; (c) W.-K. Luo, X. Shi, W. Zhou and L. Yang, by TEMPO and BHT, see ref. 14.
Org. Lett., 2016, 18, 2036; (d) T.-H. Wang, W.-C. Lee and 17 (a) SET between ground-state t-BuOK and neutral molecule
T.-G. Ong, Adv. Synth. Catal., 2016, 358, 2751; (e) Y. Jin,
L. Ou, H. Yang and H. Fu, J. Am. Chem. Soc., 2017, 139,
14237; (f) G. Wang, W. Hu, Z. Hu, Y. Zhang, W. Yao, L. Li,
Z. Fu and W. Huang, Green Chem., 2018, 20, 3302;
(g) A. Motaleb, A. Bera and P. Maity, Org. Biomol. Chem.,
2018, 16, 5081; (h) M. Gngnon-Dubois and A. Meola, Synth.
Commun., 1995, 25, 2999.
benzophenone occurred at 70 °C. See: G. Nocera, A. Young,
F. Palumbo, K. J. Emery, G. Coulthard, T. McGuire, T. Tuttle
and J. A. Murphy, J. Am. Chem. Soc., 2018, 140, 9751.
Accordingly, SET between ground-state t-BuOK and cation
acceptor A can occur at RT since cations are more suscep-
tible to electrons than neutral molecules.(b) For an example
of t-BuOK-initiated free radical reactions at RT, see: W.-T. Li,
W.-H. Nan and Q.-L. Luo, RSC Adv., 2014, 4, 34774; (c) t-
BuOK may induce certain species to yield other electron
donor(s) in DMSO. It cannot be ruled out that other in situ
formed electron donors initiate the oxidation. For examples
of t-BuOK-promoted free radical reactions, see ref. 11.
11 (a) G. A. Russell, E. G. Jansen, H.-D. Becker and
F. Smentowski, J. Am. Chem. Soc., 1962, 84, 2652;
(b) G. A. Russell, A. J. Moye and K. Nagpal, J. Am. Chem.
Soc., 1962, 84, 4154; (c) G. A. Russell and E. G. Janzen,
J. Am. Chem. Soc., 1962, 84, 4153; (d) G. A. Russell,
E. G. Janzen and E. T. Strom, J. Am. Chem. Soc., 1962, 84, 18 I. Hermans, J. Peeters and P. A. Jacobs, J. Org. Chem., 2007,
4155. 72, 3057.
12 The NMR spectra of the reaction mixture showed that the 19 The oxidation with UHP-Cs2CO3 supports path b. Only one
substrate (1a) was completely converted to the intended
compound (2a). Considering the environmental friendli-
pathway for reactive oxygen species-mediated oxidation is
shown; others may be operative.
ness and excellent yield obtained by the use of t-BuOK, we 20 (a) G. D. Pandey and K. P. Tiwari, Synth. Commun., 1980,
did not further try organic bases.
13 For details, see the ESI.†
10, 523; (b) I. Ninomiya, T. Naito and H. Takasugi, J. Chem.
Soc., Perkin Trans. 1, 1976, 1865.
This journal is © The Royal Society of Chemistry 2019
Green Chem.