Palladium(II)-catalyzed oxidative C-H/C-H coupling and eliminative S NH reactions in direct functionalization of imidazole oxides with indoles

Article abstract of DOI:10.1021/jo301618b

Two novel synthetic approaches to realize the direct C(sp²)-H bond functionalization in cyclic nitrones are reported. Palladium(II)-catalyzed oxidative C-C coupling of 2,2-dialkyl-4-phenyl-2H-imidazole 1-oxides with indoles was shown to result

Full text of DOI:10.1021/jo301618b

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Article
Palladium(II)-Catalyzed Oxidative C–H/C–H Coupling and Eliminative SNH
Reactions in Direct Functionalization of Imidazole Oxides with Indoles
Mikhail V. Varaksin, Irina A. Utepova, Oleg Nikolaevich Chupakhin, and Valery N. Charushin
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2012
Downloaded from http://pubs.acs.org on September 21, 2012
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Palladium(II)ꢀCatalyzed Oxidative C–H/C–H Coupling and Eliminative SNH Reactions in
Direct Functionalization of Imidazole Oxides with Indoles
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Mikhail V. Varaksin,†,‡ Irina A. Utepova,† Oleg N. Chupakhin,*,†,‡ and Valery N. Charushin†,‡
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†Ural Federal University, 19 Mira Str., 620002 Ekaterinburg, Russia
‡Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S.
Kovalevskaya Str., 620041 Ekaterinburg, Russia
chupakhin@ios.uran.ru
ABSTRACT: Two novel synthetic approaches to realize the direct C(sp2)–H bond functionalization
in cyclic nitrones are reported. Palladium(II)ꢀcatalyzed oxidative C–C coupling of 2,2ꢀdialkylꢀ4ꢀ
phenylꢀ2Hꢀimidazole 1ꢀoxides with indoles was shown to result in the formation of 5ꢀindolylꢀ3ꢀyl
H
derivatives, while nucleophilic substitution of hydrogen (SN ) at C(5) of the same imidazole system
was found to afford the corresponding deoxygenated compounds.
INTRODUCTION
Modern trends in organic synthesis are known to be associated with the soꢀcalled green chemistry,
which prompts to develop novel atom efficient and environmentally benign synthetic methods.1 In
this respect, the formation of new C−C bonds has always been in a focus of attention as the key
element of diverse synthetic methodologies. From a variety of methods, enabling to carry out the
C−C bond linkage of two organic fragments, e.g., two aromatic or heteroaromatic rings, it should be
mentioned the wellꢀspread crossꢀcoupling reactions, especially those, which provide the direct C−H
functionalization, as elegant and advanced synthetic methodologies of the last decade (Scheme 1).
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Scheme 1. Principal Strategies for the C−C Bond Formationa
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aX = (Pseudo)Halides; Y = Organometallics; TM = Transition Metal Catalyst
Indeed, a huge number of transition metalꢀcatalyzed (Pd, Ni, Cu, etc.) crossꢀcoupling reactions
(Suzuki, Negishi, Stille, Kumada, Hiyama, etc.) (1)2 have found wide applications in laboratory and
industrial scale syntheses. The first mode of these transformations (1) is based on C−X/C−Y
coupling of halides or triflates (X = Hal, OTf) with organoelement compounds, bearing the C−Y
bond (Y = B, Zn, Sn, Si, Mg, etc.). However, besides metalꢀcomplex catalysts, the C−X/C−Y
coupling methodology (1) requires a preliminary incorporation of halogen or other auxiliary groups
into the starting materials, thus limiting the scope of these reactions. The second type of crossꢀ
couplings, the C−X(Y)/C−H mode (2),3 is also based on interaction of (pseudo)halides (X = Hal,
OTf, etc.) or organometallics (Y = Mg, Zn, Sn, etc.) with compounds R−H, which do not have to
contain any preliminarily introduced functional groups. It should be noted that two next approaches
exploit direct C−H bond functionalization. Due to innovative character of the C−H/C−H coupling
strategies, that do correspond to the green chemistry principle of atom economy,1,4 the modes (3)
and (4)5 were put at the first positions in the «List of More Aspirational Reactions» of top
pharmaceutical companies,6 as the most advanced methodologies, aimed at reducing human impacts
on the environment. These transformations can be carried out both catalytically (3) and also without
any metalꢀcomplex catalysis (4). A great deal of Pd(II)ꢀcatalyzed C−H/C−H crossꢀcouplings (3) in
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the series of aromatic and heteroaromatic compounds have been performed using Ag(I) and Cu(II)
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H
as oxidative agents. Nucleophilic substitution of hydrogen (SN ), the mode (4),7 does not require any
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transition metals as catalysts for C−H/C−H couplings. The methodology (4) provides direct
nucleophilic C−H functionalization of arenes, bearing nitro, cyano and other electronꢀwithdrawing
groups, as well it is effective in the series of πꢀdeficient azaaromatic compounds, such as azines and
their Nꢀactivated forms (Nꢀoxides, quaternary salts, etc.).7
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Although the C−H/C−H coupling methodologies (3) and (4) have extensively been used to
modify arenes, azines, and azoles, no examples of the C−H functionalization in the series of nonꢀ
aromatic heterocyclic compounds, e.g., 2,2ꢀdialkyl substituted imidazole 1ꢀoxides, have been
reported in the literature so far. Meanwhile, nitrones are of interest for many practical applications.
Indeed, these derivatives8 are known as biologically active substances, precursors for stable
nitroxide radicals, free radical traps, stabilizers of polymers, lightꢀsensitive additives, and also as
other components of advanced materials.
The paper is focused upon the development of new synthetic approaches to C−substituted
azomethine derivatives using both catalytic and nonꢀcatalytic C−H/C−H crossꢀcoupling reactions of
cyclic nitrones with indoles. The latter were chosen because their fragments are presented well in
various organic compounds used in pharmaceutical and fragrance industries, material science,
agriculture, etc.9
RESULTS AND DISCUSSION
Cyclic nitrones,10 bearing the azadiene fragment and a hydrogen atom at the αꢀposition to the N+−O−
group, can be regarded as nonꢀaromatic analogues of azine Nꢀoxides. The latter are known to
undergo Pdꢀcatalyzed oxidative C−C coupling reactions with a wide range of fiveꢀmembered
heteroaromatic compounds such as indoles, pyrroles, thiophenes, and others.11 In order to estimate
the scope of the C−H/C−H crossꢀcoupling reactions, for the first time we have extended our studies
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to the chemistry of nonꢀaromatic compounds, and have attempted to realize the C−C coupling of
imidazole nitrones 1aꢀc with indoles 2aꢀc (Scheme 2). The reactions were carried out in 1,4ꢀdioxane
in the presence of pyridine (base), palladium(II) acetate (catalyst), and copper(II) acetate (oxidant)
to give the C−C coupling products 3aꢀi with the retention of the Nꢀoxide function in the imidazole
ring in moderateꢀtoꢀgood yields.
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Scheme 2. Palladium(II)ꢀCatalyzed Oxidative Coupling of Imidazole Nitrones 1aꢀc with
Indoles 2aꢀc
To optimize the reaction conditions, a series of experiments have been performed. Yields of
compounds 3aꢀi proved to depend on the reaction time (Table 1.1), ratio of reagents (Table 1.2), as
well as quantities of catalyst (Table 1.3) and oxidant (Table 1.4). The C−C coupling of bicyclic
imidazole nitrone 1c with Nꢀmethylindole 2b, leading to 3h, has been chosen as the model reaction.
The data obtained indicate that optimal conditions, providing the best yields of products 3aꢀi, can be
achieved by refluxing of the reaction mixture in 1,4ꢀdioxane for 24 h (Table 1, entry 1.3) using the
following ratio of reagents: nitrone (2 equiv), indole (1 equiv) (Table 1, entry 2.4), Pd(OAc)2 (0.1
equiv) (Table 1, entry 3.3), and Cu(OAc)2ꢁH2O (1.5 equiv) (Table 1, entry 4.3). Yields of
synthesized indolyl substituted nitrones are given in table 2.
Table 1. Optimization of the Reaction Conditions for Palladium(II)ꢀCatalyzed Oxidative
Coupling of Imidazole Nitrones 1bꢀc with Indoles 2c
1. Yields of compound 3h depending on the reaction time
entry
reaction time (h)
yield (%)
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1.1
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2. Yields of compound 3h depending on the ratio of reagents
entry
2.1
nitrone 1b (equiv)
indole 2c (equiv)
yield (%)
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2.2
2.3
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3. Yields of compound 3h depending on quantity of Pd(OAc)2
entry
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Pd(OAc)2 (mol %)
yield (%)
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3.2
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3.3
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3.4
3.5
4. Yields of compound 3h depending on quantity of Cu(OAc)2
entry
4.1
Cu(OAc)2 (equiv)
yield (%)
0.5
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35
70
95
4.2
4.3
1.5
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Table 2. Yields of Compounds 3aꢀi
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entry
nitrone 1
indole 2
product 3
yield (%)
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R1 = R2 = Me (1a)
R1 = R2 = Me(1a)
R1 = R2 = Me (1a)
R1 = Me, R2 = Et (1b)
R1 = Me, R2 = Et (1b)
R1 = Me, R2 = Et (1b)
R1 = R2 = (CH2)5 (1c)
R1 = R2 = (CH2)5 (1c)
R1 = R2 = (CH2)5 (1c)
R3 = R4 = H (2a)
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R3 = H, R4 = Me (2b)
R3 = Me, R4 = H (2c)
R3 = R4 = H (2a)
R3 = H, R4 = Me (2b)
R3 = Me, R4 = H (2c)
R3 = R4 = H (2a)
3g
3h
3i
R3 = H, R4 = Me (2b)
R3 = Me, R4 = H (2c)
As mentioned above, the crossꢀcoupling of 1aꢀc with 2aꢀc can be accomplished in the
presence of Pd(II) acetate. Attempts to use acetates of other transition metals, such as Ni(OAc)2 and
Co(OAc)2, under the same reaction conditions were unsuccessful, with only starting materials and
their decomposition products being found in the reaction mixtures. The choice of Ni(II) and Co(II)
catalysts for testing is due to previous good results with their using in direct C−H bond
functionalization of heterocycles.3h,i,12
The C−C bond formation by the C−H/C−H coupling reactions without any catalyst was earlier
stated to be a thermodynamically unfavorable.13 However, the activation energy can be considerably
decreased by using an appropriate catalyst and an oxidant. According to the current concept, the
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oxidative C−H/C−H coupling is a cyclic process involving Pd(II) redox transformations. The most
plausible mechanism for describing these interactions has been proposed on the basis of the
literature data (Scheme 3).5h,14 At the first stage, Pd(OAc)2 reacts with imidazole nitrones 1aꢀc, it
activates the C(sp2)−H bond14a,15 in the azomethine fragment. The C−H bond cleavage is supposed
to occur at the cyclopalladation step,16 thus resulting in organopalladium intermediates (1aꢀ
c)PdOAc. The intramolecular PdꢁꢁꢁO−−N+ bond formation facilitates the C−H activation. In other
words, the complexꢀinduced proximity effect (CIPE)17 of the Nꢀoxide moiety may be of great
importance for these transformations. Interaction of (1aꢀc)PdOAc with indoles 2aꢀc affords
organometallic compounds (1aꢀc)Pd(2aꢀc) which are transformed into the corresponding C−C
coupling products 3aꢀi and Pd(0). Herein, Cu(II) is regarded as an oxidant for conversion of Pd(0)
into Pd(II), recovering the latter as acetate for the next catalytic cycle. Thus, the suggested
mechanism is likely to be able to describe the C−H/C−H coupling process in a simplified form,
while it has previously been postulated as a thermodynamically unfavorable one.
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Scheme 3. Plausible Catalytic Cycle for the Oxidative C−H/C−H CrossꢀCoupling of Imidazole
1ꢀOxides 1aꢀc with Indoles 2aꢀc
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R1
Ph
N
R2
1a-c
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N
O
H
Cu(0)
Pd(OAc)2
HOAc
Cu(OAc)2
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R1
Ph
N
Pd(0)
R2
N
O
AcOPd
(1a-c)PdOAc
R1
Ph
Pd
R3
N
H
R2
N
O
R1
Ph
N
N
R3
2a-c
R2
N
R4
R4
N
O
HOAc
(1a-c)Pd(2a-c)
N
R3
3a-i
R4
Another approach to cause the direct C−H functionalization of imidazole is substitution of
H
hydrogen (SN ) in nitrones 1aꢀc by action of nucleophilic indoles 2aꢀc. The methodology enables to
obtain the C−H/C−H coupling products under very mild reaction conditions without any transition
metal catalysis.7 It has been established that nucleophilic attack of indoles 2aꢀc at unsubstituted
carbon C(5) of imidazole 1ꢀoxide 1aꢀc takes place in the presence of acetyl chloride (Scheme 4) and
results in the formation of heterocyclic derivatives 4aꢀi which can be regarded as the deoxygenated
analogues of compounds 3aꢀi (Table 3). Comparing with the Pdꢀcatalyzed crossꢀcoupling (Scheme
2), the SNH reaction is a faster process taking only a few minutes (contrary to 24 h refluxing in 1,4ꢀ
dioxane). Moreover, the presented synthetic approach is characterized by the simplicity in isolation
and purification of the products (4aꢀi)ꢁHCl. Indeed, unlike the starting materials 1aꢀc and 2aꢀc,
hydrochlorides (4aꢀi)ꢁHCl possess a limited solubility in nonpolar solvents (benzene, toluene,
hexane) and, therefore, they are fully precipitated from the reaction solutions. The subsequent
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hydrolysis of the salts (4aꢀi)ꢁHCl with NaHCO3 in aqueous ethanol affords indolylꢀsubstituted
imidazoles 4aꢀi in good 80ꢀ95% yields.
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Scheme 4. SNH Coupling of Nitrones 1aꢀc with Indoles 2aꢀc
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Table 3. Yields of Compounds 4aꢀi
entry
nitrone 1
indole 2
product 4aꢀi
yield (%)
90
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R1 = R2 = Me (1a)
R1 = R2 = Me(1a)
R1 = R2 = Me (1a)
R1 = Me, R2 = Et (1b)
R1 = Me, R2 = Et (1b)
R1 = Me, R2 = Et (1b)
R1 = R2 = (CH2)5 (1c)
R1 = R2 = (CH2)5 (1c)
R1 = R2 = (CH2)5 (1c)
R3 = R4 = H (2a)
4a
4b
4c
4d
4e
4f
R3 = H, R4 = Me (2b)
R3 = Me, R4 = H (2c)
R3 = R4 = H (2a)
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92
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R3 = H, R4 = Me (2b)
R3 = Me, R4 = H (2c)
R3 = R4 = H (2a)
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90
4g
4h
4i
R3 = H, R4 = Me (2b)
R3 = Me, R4 = H (2c)
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According to the common concept,7 the SNH reactions proceed via two (AdditionꢀElimination)
steps. At the first stage, an addition of nucleophilic indoles 2aꢀc to the activated nitrones A occurs,
with the shortꢀlived σHꢀadducts B being formed (Scheme 5). Elimination of acetic acid from the
H
intermediate B, at the second step, leads to the SN products in the form of hydrochlorides (4aꢀ
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i)ꢁHCl. Their precipitation from reaction solutions shifts the dynamic equilibrium towards the direct
reaction, thus providing good yields of indolyl substituted imidazoles 4aꢀi.
Scheme 5. Plausible Mechanism for NonꢀCatalytic SNH Transformation of Imidazole 1ꢀOxides
1aꢀc by Action of Indoles 2aꢀc
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It should be mentioned that the observed C−H functionalization of imidazole Nꢀoxides, which
H
do not contain a cyclic πꢀconjugated system, is a quite rare example of the SN reactions in nonꢀ
aromatic heterocycles.
The compounds 3aꢀi and 4aꢀi were characterized by 1H, 13C NMR and IR spectroscopy, mass
spectrometry, and elemental analysis. The Xꢀray diffraction studies for compounds 3b and 4e were
also carried out. The values of bond lengths and bond angles in both cases are close to standard
1
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ones.18 The obtained data are given in the Supporting Information. The H and C NMR spectra19
1
proved to be in full correspondence with the structures. In particular, the H NMR spectra of
compounds 3a,c,d,f,g,i and 4a,c,d,f,g,i contain the N−H signals at δ 11.19ꢀ11.59 ppm, which
diminish after addition of CF3COOD. All mass spectra have peaks of molecular ions [M+H]+, and in
case of imidazole Nꢀoxides 3aꢀi the [M+H]+ are 16 amu higher than those for their deoxygenated
analogues 4aꢀi. Absorption bands, corresponding to the stretching vibrations of N−H groups at ν
3120ꢀ3270 cmꢀ1, are also presented in the IR spectra of 3a,c,d,f,g,i and 4a,c,d,f,g,i.
CONCLUSIONS
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In summary, two synthetic approaches to the new heterocyclic compounds, bearing imidazole and
indole fragments linked to each other, have been advanced. Both methods exploit nucleophilic C–H
bond functionalization that is realized either via the palladium(II)ꢀcatalyzed oxidative C–C crossꢀ
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coupling reaction (1) or by nucleophilic substitution of hydrogen (SN ) without any metal catalysis
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(2) (Scheme 6).
Scheme 6. Nucleophilic «Addition – Elimination» Protocol. Catalytic Activation of C–H Bond
(1) and Activation of πꢀSystem for Nucleophilic Attack (2)
The features of the palladium(II)ꢀcatalyzed C–H bond activation (Scheme 6.1) are following:
(a) at the first step, action of a base on the Nꢀoxide causes leaving the hydrogen atom as a proton and
results in the organometalic compound; (b) at the second stage, interaction of the latter with a
nucleophilic reagent takes place; (c) as a result of reductive elimination, the C–C coupling product is
formed, with M(II) being reduced into M(0) (the «Metalation – Nucleophilic Addition – Reductive
H
Elimination» protocol). Meanwhile, the SN approach is based on a direct nucleophilic attack at
unsubstituted carbon of cyclic πꢀconjugated system (Scheme 6.2) to give σHꢀadducts followed by
elimination of a proton with the auxiliary group (the «Nucleophilic Addition – Elimination»
protocol).
In conclusion, it should be noted that new imidazoles obtained may be of interest as potential
biologically active compounds, free radical traps, ligands for complexations with metals, as well as
precursors for stable nitroxide radicals.
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EXPERIMENTAL SECTION
Synthesis of 2ꢀethylꢀ2ꢀmethylꢀ4ꢀphenylꢀ2Hꢀimidazole 1ꢀoxide (1b)
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A mixture of (E)ꢀ2ꢀoxoꢀ2ꢀphenylacetaldehyde oxime (1.49 g, 0.01 mol), butanꢀ2ꢀone (6.26 mL, 0.12
mol), NH4OAc (4.62 g, 0.06 mol), and glacial acetic acid (6.86 mL, 0.12 mol) was heated under
reflux for 2 h. The reaction mixture was cooled, and water (500 mL) was added. The organic phase
was separated, and the aqueous phase was extracted with CHCl3 (3 × 100 mL). The combined
organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by recrystallization from heptane. Yield 279 mg (85%), mp 68ꢀ70 °C, Rf
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0.2 (CHCl3). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 8.30 (s, 1H), 8.11ꢀ7.86 (m, 2H),
7.66ꢀ7.38 (m, 3H), 2.06 (dq, J = 14.6, 7.3 Hz, 1H), 1.86 (dq, J = 14.6, 7.3 Hz, 1H), 1.50 (s, 3H),
0.63 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSOꢀd6) ppm: δ 165.6, 131.8, 130.9, 129.0, 127.3,
126.6, 103.6, 29.9, 23.4, 6.8. IR (DRA): 3080, 2984, 2934, 1543, 1570, 1510, 1441, 1418, 1323,
1233, 1177, 1116, 965, 844 cmꢀ1. MS (ESI): m/z 203 [M+H]+. Anal. Calcd for C12H14N2O: C, 71.26;
H, 6.98; N, 13.85. Found: C, 71.33; H, 7.03; N, 13.68.
General procedure for the synthesis of 3aꢀi
A mixture of corresponding nitrone 1aꢀc (2 mmol), indole 2aꢀc (1 mmol), Pd(OAc)2 (22.5 mg, 0.1
mmol), Cu(OAc)2ꢁH2O (450 mg, 1.5 mmol), and pyridine (0.08 mL, 1 mmol) in 1,4ꢀdioxane (10
mL) was heated at 110 °C for 24 h. The reaction mixture was cooled to room temperature, filtered
through neutral alumina and concentrated in vacuo. The residue was subjected to silica gel column
chromatography with the EtOAc–hexane mixture as an eluent, and the resulting eluate was
concentrated to dryness under reduced pressure.
5ꢀ(1HꢀIndolꢀ3ꢀyl)ꢀ2,2ꢀdimethylꢀ4ꢀphenylꢀ2Hꢀimidazole 1ꢀoxide (3a). Yield 161 mg (53%), mp
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120ꢀ122 °C, Rf 0.2 (hexane/EtOAc, 6:4). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 11.58
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(m, 1H, J = 7.4 Hz), 7.76 (d, J = 2.6 Hz, 1H), 7.62 (m, 2H), 7.51ꢀ7.29 (m, 4H), 7.04 (t, J = 7.4 Hz,
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1H), 6.83 (d, J = 7.9 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 1.61 (s, 6H). C NMR (400 MHz, DMSOꢀ
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d6) ppm: δ 166.1, 135.8, 133.2, 132.0, 130.6, 128.5, 128.4, 128.0, 124.7, 121.8, 121.2, 119.4, 112.0,
101.3, 98.4, 24.6. IR (DRA): 3123, 3098, 2914, 2854, 1568, 1540, 1510, 1471, 1435, 1370, 1236,
1210, 950, 780 cmꢀ1. MS (ESI): m/z 304 [M+H]+. Anal. Calcd for C19H17N3O: C, 75.23; H, 5.65; N,
13.85. Found: C, 75.03; H, 5.65; N, 13.64.
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2,2ꢀDimethylꢀ5ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ4ꢀphenylꢀ2Hꢀimidazole 1ꢀoxide (3b). Yield 279 mg
(88%), mp 164ꢀ167 °C, Rf 0.3 (hexane/EtOAc, 6:4). 1H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm:
δ 7.91 (s, 1H), 7.66–7.57 (m, 2H), 7.50ꢀ7.36 (m, 2H), 7.33 (m, 2H), 7.10 (dd, J = 11.1, 4.0 Hz, 1H),
6.83ꢀ6.69 (m, 2H), 3.88 (s, 3H), 1.61 (s, 6H). 13C NMR (400 MHz, DMSOꢀd6) ppm: δ 165.9, 136.3,
133.2, 132.5, 131.5, 130.6, 128.5, 128.0, 125.0, 121.8, 121.2, 119.6, 110.3, 100.3, 98.4, 32.9, 24.6.
IR (DRA): 2981, 2931, 1573, 1548, 1511, 1461, 1408, 1330, 1238, 1173, 1151, 1116, 1006, 945,
776 cmꢀ1. MS (ESI): m/z 318 [M+H]+. Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24.
Found: C, 75.76; H, 6.08; N, 13.07. The crystallographic data can be obtained free of charge from
the Supporting Information via the Internet at http://pubs.acs.org, as well as from the Cambridge
Crystallographic Data Centre at http://www.ccdc.cam.ac.uk/data_request/cif (deposition no. CCDC
889116).
2,2ꢀDimethylꢀ5ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ4ꢀphenylꢀ2Hꢀimidazole 1ꢀoxide (3c). Yield 207 mg
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(65%), mp 190ꢀ193 °C, Rf 0.25 (hexane/EtOAc, 6:4). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1)
ppm: δ 11.37 (s, 1H), 7.62 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.28 (m, 3H), 6.98 (m, 1H), 6.77 (m,
2H), 2.17 (s, 3H), 1.62 (s, 6H). 13C NMR (400 MHz, DMSOꢀd6) ppm: δ 165.8, 137.7, 135.5, 132.8,
132.1, 130.7, 128.4, 128.3, 127.5, 126.4, 120.9, 119.3, 119.0, 111.1, 98.5, 24.9, 13.3. IR (DRA):
3214, 3191, 2996, 1577, 1557, 1512, 1447, 1382, 1336, 1232, 1173, 1013, 923 cmꢀ1. MS (ESI): m/z
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318 [M+H]+. Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C, 75.88; H, 6.28; N,
12.98.
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2ꢀEthylꢀ5ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀmethylꢀ4ꢀphenylꢀ2Hꢀimidazole 1ꢀoxide (3d). Yield 168 mg (53%),
mp 85ꢀ88 °C, Rf 0.25 (hexane/EtOAc, 6:4). 1H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 11.59
(m, 1H), 7.71 (d, J = 2.8 Hz, 1H), 7.61 (d, 2H), 7.49ꢀ7.30 (m, 4H), 7.05 (t, J = 7.5 Hz, 1H), 6.86 (d,
J = 8.0 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 2.14 (dq, J = 14.3, 7.2 Hz, 1H), 2.00 (dq, J = 14.4, 7.2 Hz,
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1H), 1.61 (s, 3H), 0.67 (t, J = 7.3 Hz, 3H). C NMR (400 MHz, DMSOꢀd6) ppm: δ 167.1, 135.8,
133.3, 133.1, 130.6, 128.5, 128.4, 128.0, 124.8, 121.8, 121.1, 119.4, 112.0, 101.1, 100.7, 30.2, 23.8,
6.8. IR (DRA): 3187, 3087, 2917, 2854, 1570, 1544, 1512, 1481, 1433, 1366, 1228, 1212, 952, 783
cmꢀ1. MS (ESI): m/z 318 [M+H]+. Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found:
C, 75.43; H, 6.33; N, 13.24.
2ꢀEthylꢀ2ꢀmethylꢀ5ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ4ꢀphenylꢀ2Hꢀimidazole 1ꢀoxide (3e). Yield 305 mg
(92%), mp 125ꢀ128 °C, Rf 0.3 (hexane/EtOAc, 6:4). 1H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm:
δ 7.88 (s, 1H), 7.62 (m, 2H), 7.49ꢀ7.38 (m, 2H), 7.33 (m, 2H), 7.11 (m, 1H), 6.80 (m, 2H), 3.88 (s,
3H), 2.14 (dq, J = 14.5, 7.3 Hz, 1H), 2.00 (dq, J = 14.5, 7.3 Hz, 1H), 1.61 (s, 3H), 0.65 (t, J = 7.3
Hz, 3H). 13C NMR (400 MHz, DMSOꢀd6) ppm: δ 167.0, 136.3, 133.0, 132.4, 130.7, 128.5, 127.9,
125.1, 121.8, 121.0, 119.6, 110.4, 100.8, 100.1, 65.0, 32.9, 30.2, 23.8, 6.7. IR (DRA): 2991, 2965,
2923, 1725, 1568, 1511, 1463, 1427, 1284, 1220, 1132, 950, 824 cmꢀ1. MS (ESI): m/z 332 [M+H]+.
Anal. Calcd for C21H21N3O: C, 76.11; H, 6.39; N, 12.68. Found: C, 76.33; H, 6.56; N, 12.58.
2ꢀEthylꢀ2ꢀmethylꢀ5ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ4ꢀphenylꢀ2Hꢀimidazole 1ꢀoxide (3f). Yield 278 mg
(84%), mp 169ꢀ172 °C, Rf 0.3 (hexane/EtOAc, 6:4). 1H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm:
δ 11.37 (s, 1H), 7.62 (m, 2H), 7.38 (m, 1H), 7.32ꢀ7.23 (m, 3H), 6.97 (s, 1H), 6.82ꢀ6.71 (m, 2H),
2.16 (m, 4H), 2.02 (m, 1H), 1.62 (d, J = 8.3 Hz, 3H), 0.68 (m, 3H). 13C NMR (400 MHz, DMSOꢀd6)
ppm: δ 166.9, 137.7, 135.5, 133.5, 132.7, 130.7, 128.4, 127.4, 126.5, 120.8, 119.3, 119.0, 118.6,
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111.1, 100.9, 30.0, 24.1, 13.2, 6.7. IR (DRA): 3213, 3059, 1574, 1510, 1445, 1341, 1228, 1086, 951,
751 cmꢀ1. MS (ESI): m/z 332 [M+H]+. Anal. Calcd for C21H21N3O: C, 76.11; H, 6.39; N, 12.68.
Found: C, 76.33; H, 6.23; N, 12.48.
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2ꢀ(1HꢀIndolꢀ3ꢀyl)ꢀ3ꢀphenylꢀ1,4ꢀdiazaspiro[4.5]decaꢀ1,3ꢀdiene 1ꢀoxide (3g). Yield 189 mg (55%),
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mp 180ꢀ182 °C, Rf 0.25 (hexane/EtOAc, 6:4). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ
11.59 (m, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.62 (m, 2H), 7.33ꢀ7.45 (m, 4H), 7.03 (t, J = 7.0 Hz, 1H),
6.84ꢀ6.71 (m, 2H), 2.21ꢀ2.07 (m, 2H), 2.01ꢀ1.86 (m, 5H), 1.47 (m, 3H). 13C NMR (400 MHz,
DMSOꢀd6) ppm: δ 166.4, 135.8, 133.4, 132.1, 130.5, 128.5, 128.4, 128.1, 124.7, 121.7, 121.2,
119.3, 111.9, 101.2, 100.7, 35.0, 24.6, 23.0. IR (DRA): 3226, 3142, 2932, 2857, 1569, 1511, 1499,
1434,1388, 1298, 1242, 989, 778 cmꢀ1. MS (ESI): m/z 344 [M+H]+. Anal. Calcd for C22H21N3O: C,
76.94; H, 6.16; N, 12.24. Found: C, 76.89; H, 6.08; N, 12.45.
2ꢀ(1ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ3ꢀphenylꢀ1,4ꢀdiazaspiro[4.5]decaꢀ1,3ꢀdiene 1ꢀoxide (3h). Yield 339
mg (95%), mp 165ꢀ167 °C, Rf 0.25 (hexane/EtOAc, 6:4). 1H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1)
ppm: δ 7.94 (s, 1H), 7.63 (m, 2H), 7.50ꢀ7.37 (m, 2H), 7.33 (m, 2H), 7.10 (t, J = 7.4 Hz, 1H), 6.77 (t,
J = 7.5 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 2.22ꢀ2.07 (m, 2H), 2.03ꢀ1.84 (m, 5H), 1.46
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(m, 3H). C NMR (400 MHz, DMSOꢀd6) ppm: δ 166.2, 136.3, 133.4, 132.6, 131.7, 130.5, 128.4,
128.0, 125.0, 121.8, 121.1, 119.5, 110.3, 100.7, 100.2, 35.0, 32.9, 24.5, 23.0. IR (DRA): 2935,
2859,1573, 1511, 1497, 1371, 1297, 1178, 1113, 829, 766 cmꢀ1. MS (ESI): m/z 358 [M+H]+. Anal.
Calcd for C23H23N3O: C, 77.28; H, 6.49; N, 11.76. Found: C, 77.28; H, 6.60; N, 11.76.
2ꢀ(2ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ3ꢀphenylꢀ1,4ꢀdiazaspiro[4.5]decaꢀ1,3ꢀdiene 1ꢀoxide (3i). Yield 296
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mg (83%), mp 256ꢀ260 °C, Rf 0.2 (hexane/EtOAc, 6:4). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1)
ppm: δ 11.32 (s, 1H), 7.68ꢀ7.60 (m, 2H), 7.38 (m, 1H), 7.31ꢀ7.21 (m, 3H), 6.99 (m, 1H), 6.78 (m,
2H), 2.21ꢀ2.11 (m, 5H), 2.03ꢀ1.87 (m, 5H), 1.54ꢀ1.42 (m, 3H). 13C NMR (400 MHz, DMSOꢀd6)
ppm: δ 166.1, 137.7, 135.5, 133.0, 132.3, 130.6, 128.4, 127.5, 126.4, 120.8, 119.3, 119.0, 111.1,
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100.7, 98.6, 35.3, 24.6, 23.0, 13.2. IR (DRA): 3266, 3058, 2946, 2923, 2858, 1570, 1551, 1510,
1482, 1446, 1311, 1167, 778 cmꢀ1. MS (ESI): m/z 358 [M+H]+. Anal. Calcd for C23H23N3O: C,
77.28; H, 6.49; N, 11.76. Found: C, 77.51; H, 6.49; N, 11.58.
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To a stirring solution of the corresponding nitrone 1aꢀc (1 mmol) and indole 2aꢀc (1 mmol) in
benzene (15 mL), AcCl (0.07 mL, 1 mmol) was added dropwise at 5 °C. After 5 min, the reaction
mixture was warmed to room temperature, and formed precipitate of (4aꢀi)ꢁHCl was filtered off,
washed with benzene and dried in air for 24 h. Then, to the suspension of the corresponding (4aꢀ
i)ꢁHCl in EtOH (20 mL), 10% aq solution of NaHCO3 (1.25 mL, 1.5 mmol) was added, the mixture
was heated under reflux for 30 min. Finally, the reaction mixture was cooled and filtered through
silica gel and concentrated in vacuo. The residue was purified by recrystallization from the heptane–
benzene mixture.
3ꢀ(2,2ꢀDimethylꢀ5ꢀphenylꢀ2Hꢀimidazolꢀ4ꢀyl)ꢀ1Hꢀindole (4a). Yield 250 mg (90%), mp 255ꢀ258
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°C, Rf 0.3 (hexane/EtOAc, 8:2). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 11.22 (m, 1H),
8.26 (d, J = 7.7 Hz, 1H), 7.61ꢀ7.55 (m, 2H), 7.55ꢀ7.45 (m, 3H), 7.37 (d, J = 7.7 Hz, 1H), 7.18ꢀ7.05
(m, 2H), 6.89 (d, J = 2.8 Hz, 1H), 1.57 (s, 6H). 13C NMR (400 MHz, DMSOꢀd6) ppm: δ 164.8,
158.1, 136.1, 134.6, 129.6, 128.5, 128.4, 128.3, 126.4, 122.7, 122.0, 120.6, 111.8, 108.0, 101.4,
24.8. IR (DRA): 3205, 3110, 2932, 2752, 1599, 1570, 1510, 1442, 1178, 1138, 1034, 1006, 935, 785
cmꢀ1. MS (ESI): m/z 288 [M+H]+. Anal. Calcd for C19H17N3: C, 79.41; H, 5.96; N, 14.62. Found: C,
79.61; H, 6.00; N, 14.44.
3ꢀ(2,2ꢀDimethylꢀ5ꢀphenylꢀ2Hꢀimidazolꢀ4ꢀyl)ꢀ1ꢀmethylꢀ1Hꢀindole (4b). Yield 256 mg (85%), mp
98ꢀ100 °C, Rf 0.3 (hexane/EtOAc, 8:2). 1H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 8.24 (d, J
= 7.9 Hz, 1H), 7.63ꢀ7.44 (m, 5H), 7.38 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 7.3
Hz, 1H), 6.86 (s, 1H), 3.70 (s, 3H), 1.56 (s, 6H). 13C NMR (400 MHz, DMSOꢀd6) ppm: δ 164.6,
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157.7, 136.7, 134.2, 132.2, 129.8, 128.4, 128.3, 126.8, 122.8, 122.1, 120.8, 110.2, 107.1, 101.3,
32.9, 24.8. IR (DRA): 2990, 2927, 2826, 1599, 1570, 1509, 1444, 1340, 1257, 1163, 1098, 1163,
921, 747 cmꢀ1. MS (ESI): m/z 302 [M+H]+. Anal. Calcd for C20H19N3: C, 79.70; H, 6.35; N, 13.94.
Found: C, 79.72; H, 6.24; N, 14.04.
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3ꢀ(2,2ꢀDimethylꢀ5ꢀphenylꢀ2Hꢀimidazolꢀ4ꢀyl)ꢀ2ꢀmethylꢀ1Hꢀindole (4c). Yield 277 mg (92%), mp
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174ꢀ177 °C, Rf 0.25 (hexane/EtOAc, 8:2). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 11.20
(s, 1H), 7.57ꢀ7.49 (m, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.26 (m, 3H), 7.03 (d, J = 7.9 Hz, 1H), 6.97 (t, J
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= 7.2 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 2.13 (s, 3H), 1.58 (s, 6H). C NMR (400 MHz, DMSOꢀd6)
ppm: δ 164.3, 159.3, 136.9, 135.2, 133.2, 129.9, 128.3, 128.0, 127.1, 121.0, 119.3, 119.1, 110.8,
105.4, 101.2, 24.6, 12.6. IR (DRA): 3204, 3068, 2930, 2869, 1602, 1574, 1510, 1428, 1271, 1200,
1013, 938, 748 cmꢀ1. MS (ESI): m/z 302 [M+H]+. Anal. Calcd for C20H19N3: C, 79.70; H, 6.35; N,
13.94. Found: C, 79.67; H, 6.52; N, 13.84.
3ꢀ(2ꢀEthylꢀ2ꢀmethylꢀ5ꢀphenylꢀ2Hꢀimidazolꢀ4ꢀyl)ꢀ1Hꢀindole (4d). Yield 253 mg (84%), mp 245ꢀ
1
248 °C, Rf 0.2 (hexane/EtOAc, 8:2). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 11.26 (m,
1H), 8.23 (d, J = 7.8 Hz, 1H), 7.60ꢀ7.46 (m, 5H), 7.38 (d, J = 7.9 Hz, 1H), 7.19ꢀ7.06 (m, 2H), 6.89
(d, J = 2.9 Hz, 1H), 2.05 (qq, J = 14.5, 7.3 Hz, 2H), 1.54 (s, 3H), 0.79 (t, J = 7.3 Hz, 3H). 13C NMR
(400 MHz, DMSOꢀd6) ppm: δ 165.5, 158.6, 136.1, 134.7, 129.6, 128.4, 128.4, 128.3, 126.5, 122.7,
122.0, 120.7, 111.8, 108.0, 103.6, 30.9, 23.2, 8.4. IR (DRA): 3141, 3104, 2972, 2877, 1599, 1566,
1509, 1494, 1364, 1258, 1246, 1140, 997, 878, 750 cmꢀ1. MS (ESI): m/z 302 [M+H]+. Anal. Calcd
for C20H19N3: C, 79.70; H, 6.35; N, 13.94. Found: C, 79.83; H, 6.33; N, 13.96.
3ꢀ(2ꢀEthylꢀ2ꢀmethylꢀ5ꢀphenylꢀ2Hꢀimidazolꢀ4ꢀyl)ꢀ1ꢀmethylꢀ1Hꢀindole (4e). Yield 258 mg (82%),
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mp 100ꢀ102 °C, Rf 0.25 (hexane/EtOAc, 8:2). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ
8.23 (d, J = 7.8 Hz, 1H), 7.60ꢀ7.45 (m, 5H), 7.38 (d, J = 8.2 Hz, 1H), 7.22 (m, 1H), 7.14 (t, J = 7.5
13
Hz, 1H), 6.87 (s, 1H), 3.70 (s, 3H), 2.15ꢀ1.96 (m, 2H), 1.55 (s, 3H), 0.78 (t, J = 7.3 Hz, 3H). C
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NMR (400 MHz, DMSOꢀd6) ppm: δ 165.2, 158.2, 136.7, 134.3, 132.1, 129.7, 128.4, 128.3, 126.9,
122.7, 122.0, 120.8, 110.2, 107.1, 103.5, 32.8, 30.8, 23.2, 8.3. IR (DRA): 2971, 2875, 1559, 1510,
1463, 1446, 1340, 1297, 1098, 1007, 908, 736 cmꢀ1. MS (ESI): m/z 316 [M+H]+. Anal. Calcd for
C21H21N3: C, 79.97; H, 6.71; N, 13.32. Found: C, 79.96; H, 6.86; N, 13.25. The crystallographic
data can be obtained free of charge from the Supporting Information via the Internet at
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http://www.ccdc.cam.ac.uk/data_request/cif (deposition no. CCDC 889117).
3ꢀ(2ꢀEthylꢀ2ꢀmethylꢀ5ꢀphenylꢀ2Hꢀimidazolꢀ4ꢀyl)ꢀ2ꢀmethylꢀ1Hꢀindole (4f). Yield: 283 mg (90%),
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mp 182ꢀ185 °C, Rf 0.25 (hexane/EtOAc, 8:2). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ
11.22 (s, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.42ꢀ7.23 (m, 4H), 7.03 (d, J = 7.9 Hz, 1H), 6.97 (t, J = 7.5
Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 2.13ꢀ2.04 (m, 5H), 1.56 (s, 3H), 0.76 (t, J = 7.3 Hz, 3H). 13C NMR
(400 MHz, DMSOꢀd6) ppm: δ 165.1, 160.0, 136.7, 135.3, 133.2, 129.9, 128.3, 127.9, 127.20, 121.0,
119.4, 119.0, 110.9, 105.5, 103.5, 30.5, 23.3, 12.6, 8.2. IR (DRA): 3163, 3064, 2927, 1575, 1510,
1490, 1427, 1310, 1185, 1008, 975, 738 cmꢀ1. MS (ESI): m/z 316 [M+H]+. Anal. Calcd for
C21H21N3: C, 79.97; H, 6.71; N, 13.32. Found: C, 79.96; H, 6.87; N, 13.06.
3ꢀ(3ꢀPhenylꢀ1,4ꢀdiazaspiro[4.5]decaꢀ1,3ꢀdienꢀ2ꢀyl)ꢀ1Hꢀindole (4g). Yield 294 mg (90%), mp 240ꢀ
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244 °C, Rf 0.2 (hexane/EtOAc, 8:2). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm: δ 11.19 (m,
1H), 8.27 (d, J = 7.3 Hz, 1H), 7.60ꢀ7.55 (m, 2H), 7.54ꢀ7.44 (m, 3H), 7.37 (d, J = 7.5 Hz, 1H), 7.12
(m, 2H), 6.90 (d, J = 2.8 Hz, 1H), 2.11ꢀ1.84 (m, 4H), 1.83ꢀ1.58 (m, 6H). 13C NMR (400 MHz,
DMSOꢀd6) ppm: δ 164.9, 158.0, 136.1, 134.9, 129.6, 128.4, 128.4, 126.4, 122.7, 122.1, 120.7,
111.8, 108.2, 103.5, 35.0, 25.4, 24.0. IR (DRA): 3149, 3066, 2987, 2858, 1562, 1510, 1447, 1175,
1105, 1008, 979, 765, cmꢀ1. MS (ESI): m/z 328 [M+H]+. Anal. Calcd for C22H21N3: C, 80.70; H,
6.46; N, 12.83. Found: C, 80.81; H, 6.41; N, 12.80.
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1ꢀMethylꢀ3ꢀ(3ꢀphenylꢀ1,4ꢀdiazaspiro[4.5]decaꢀ1,3ꢀdienꢀ2ꢀyl)ꢀ1Hꢀindole (4h). Yield 258 mg
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(82%), mp 130ꢀ132 °C. Rf 0.25 (hexane/EtOAc, 8:2). H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1)
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ppm: δ 8.27 (d, J = 7.8 Hz, 1H), 7.61ꢀ7.56 (m, 2H), 7.55ꢀ7.45 (m, 3H), 7.37 (d, J = 8.1 Hz, 1H),
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7.23 (m, 1H), 7.15 (m, 1H), 6.88 (s, 1H), 3.70 (s, 3H), 2.05ꢀ1.86 (m, 4H), 1.81ꢀ1.62 (m, 6H). C
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NMR (400 MHz, DMSOꢀd6) ppm: δ 164.6, 157.6, 136.7, 134.5, 132.0, 129.7, 128.4, 128.4, 126.8,
122.7, 122.2, 120.9, 110.2, 107.4, 103.4, 35.0, 32.9, 25.4, 24.0. IR (DRA): 2927, 2855, 1599, 1566,
1510, 1446, 1369, 1336, 1220, 1096, 1009, 953, 902, 738 cmꢀ1. MS (ESI): m/z 342 [M+H]+. Anal.
Calcd for C23H23N3: C, 80.90; H, 6.79; N, 12.31. Found: C, 81.12; H, 6.98; N, 12.21.
2ꢀMethylꢀ3ꢀ(3ꢀphenylꢀ1,4ꢀdiazaspiro[4.5]decaꢀ1,3ꢀdienꢀ2ꢀyl)ꢀ1Hꢀindole (4i). Yield 300 mg
(88%), mp 216ꢀ220 °C, Rf 0.2 (hexane/EtOAc, 8:2). 1H NMR (400 MHz, DMSOꢀd6/CCl4, 1:1) ppm:
δ 11.20 (s, 1H), 7.54 (m, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.26 (m, 3H), 7.03 (d, J = 7.9 Hz, 1H), 6.97
(t, J = 7.2 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 2.11 (s, 3H), 1.98ꢀ1.88 (m, 4H), 1.79ꢀ1.65 (m, 6H). 13C
NMR (400 MHz, DMSOꢀd6) ppm: δ 164.3, 159.3, 136.8, 135.3, 133.4, 129.8, 128.3, 128.0, 127.2,
121.0, 119.3, 119.1, 110.8, 105.8, 103.4, 35.0, 25.3, 23.9, 12.6. IR (DRA): 3245, 3173, 3073, 2977,
2852, 1901, 1573, 1516, 1488, 1422, 1300, 1249, 1300, 1189, 1008, 849 cmꢀ1. MS (ESI): m/z 342
[M+H]+. Anal. Calcd for C23H23N3: C, 80.90; H, 6.79; N, 12.31. Found: C, 81.03; H, 7.01; N, 12.21.
ACKNOWLEDGMENTS
The spectral data were obtained at the «Integrated research and expert assessment of organic
materials» laboratory (Ural Federal University). The research was financially supported by the
Council on Grants of the President of the Russian Federation (Program for State Support of Leading
Scientific Schools of the Russian Federation, Grant NShꢀ5505.2012.3), the Russian Foundation for
Basic Research (Project no. 10ꢀ03ꢀ00756ꢀa), and the Civilian Research and Development
Foundation (CRDF REC 005), and the Ural Federal University development program with the
financial support of young scientists.
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Supporting Information. General experimental methods, copies of NMR (1H and 13C) spectra, and
Xꢀray crystallographic data. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Graphical Abstract
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