Metal-free, base promoted sp2 C-H functionalization in the sulfonamidation of 1,4-naphthoquinones

Article abstract of DOI:10.1039/c8ob00818c

A novel, metal-free, base promoted sp² C-H functionalization in the sulfonamidation of 1,4-naphthoquinones via a [3 + 2] cycloaddition reaction using sulfonyl azides under mild reaction conditions is reported. In this straightforward atom- and step-economical protocol, the active alkene moiety of quinone undergoes a thermal azide-alkene [3 + 2] cycloaddition followed by proton abstraction, ring opening and elimination of a nitrogen molecule to form sulfonamidation products in good yield and all the synthesized sulfonamidation derivatives exhibit good absorption and emission characteristics. In addition, the electrochemical properties of both 1,4-naphthoquinone and menadione sulfonamidation derivatives are studied and significant redox potentials are observed. Other important features of this methodology are readily accessible and easy to handle starting materials, milder conditions, reaction with a wide range of substrates and shorter reaction times with good yields.

Full text of DOI:10.1039/c8ob00818c

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Metal-free, Base Promoted sp2 C-H Functionalization in Sulfonamidation of
1,4-Naphthoquinones
Devenderan Ramanathan,a Kasi Pitchumani*a,b
a School of Chemistry, Madurai Kamaraj University, Madurai-625 021
b Centre for green chemistry Process, Madurai Kamaraj university, Madurai-625 021
Abstract:
A novel metalꢀfree, base catalysed sp2 CꢀH functionalization in the sulfonyl
amidation of 1,4ꢀnaphthoquinones via a [3+2] cycloaddition reaction using sulfonyl
azides under mild reaction conditions is reported. In this straightforward, atomꢀ and stepꢀ
economical protocol, the active alkene moiety of quinone undergoes a thermal azideꢀ
alkene [3+2] cycloaddition followed by proton abstraction, ring opening and elimination
of nitrogen molecule to form the sulfonamidation products in good yield and all the
synthesized sulfonamidation derivatives exhibit good absorption and emission
characteristics. In addition, the electrochemical properties of both 1,4ꢀnaphthoquinone
and menadione sulfonamidation derivatives are studied and significant redox potentials
are observed. Other important features of this methodology are readily accessible and
easy to handle starting materials, milder conditions, reaction with a wide range of
substrates and shorter reaction times with good yields.
Key words:
ꢀ MetalꢀFree
ꢀ [3+2]ꢀcycloaddition
ꢀ No byꢀproducts
ꢀ Roomꢀtemperature reaction
ꢀ Shortꢀreaction time
ꢀ Significant absorption, emission and electrochemical properties
1

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Introduction
Carbon–carbon and carbonꢀheteroatom bond formation by direct functionalization of
carbon–hydrogen bonds of organic compounds has recently emerged as a powerful method.1 Due
to the ubiquitous nature of C−H functionalities in almost every molecular scaffold, the C−H
bond activation represents a “hot” topic.2 Among the various C−H bond activations, the C−H
bond amination allows the conversion of lowꢀcost products, such as simple hydrocarbons, active
alkenes and aromatic compounds into high addedꢀvalue nitrogenꢀcontaining derivatives such as
natural products, pharmaceutical drugs and functional materials.1,2 This dual C–H/N–H
activation3,4 technique has received tremendous attraction in recent years, since the enormous
synthetic potential required for this class of organic transformations and selective CꢀN bond
formation5 is still a major challenge for organic chemists and the wide range of catalytic systems
developed for catalytic C−H amination bears testimony to the importance of this C−H
functionalization reaction. Transition metal catalyzed amination of aryl (pseudo) halides with
amines or amides involving a combination of suitable ligands under basic conditions with the
stoichiometric amount of metal catalysts has been developed under various conditions.3ꢀ5
However, this procedure generates stoichiometric amounts of byproducts such as hydrogen
halides or their base salts. Direct amination reactions of arenes in the presence of external
oxidants6 too generates the stoichiometric amount of byproducts.
Fig 1. Representative examples of antiꢀcancer drugs based on 1,4ꢀnaphthoquinone and
sulfonamide moieties.10
The arylsulfonamide moiety is an important functional group with significant
pharmaceutical activity and plays a vital role as a structural design motif in medicinal
chemistry, in cancer chemotherapy (Fig. 1), diuretics and hypoglycemia. Apart from their
commercialized applications as antibacterial/antibiotic agents, sulfonamides are also
2

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known to inhibit several enzymes such as carbonic anhydrase, cysteine protease, HIV
protease and cyclooxygenase.7ꢀ9
Naphthoquinones are privileged molecular scaffolds in medicinal chemistry due to
their unique redox properties. They serve as vital links in the electron transport chains in
the metabolic pathways and participate in multiple biological oxidative processes. The
redox cycling of quinones present in many natural products with important biological
activities may be initiated by either a oneꢀ or twoꢀelectron reduction.11 Quinones are both
oxidants and electrophiles, and the relative contributions of these properties to both their
toxic and therapeutic activities are influenced by their chemical structure and the
substituent effects in the quinone nucleus. The quinone moiety in many drugs such as
mitoxantrone, ametantrone and doxorubicin show potent antitumor activity and have been
used as effective classes of anticancer agents and recently our group have reported a
novel synthesis and anticancer activity of naphtho[2,1ꢀb]furanꢀ2,5ꢀdiones and
benzo[de]chromeneꢀ2,6ꢀdiones obtained from 2ꢀ and 5ꢀhydroxynaphthoquinones.12
Previous report:
a) Synthesis of naphtho[2,3-d][1,2,3]triazole-4,9-diones
b) Sulfonamidation of 1,4-naphthoquinone using a Ruthenium catalyst
Present work: Metal-free sulfonamidation of 1,4-naphthoquinone
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Recently, the groups of Chang13 and Wang14 have reported a synthesis of
naphtho[2,3ꢀ ][1,2,3]triazoleꢀ4,9ꢀdione derivatives via [3+2] cycloaddition reactions of
d
1,4ꢀnaphthoquinone with various aromatic and aliphatic azides using various Lewis acid
catalysed harsher reaction conditions.13ꢀ15 Reddy et al. have reported sulfonamidation of
1,4ꢀnaphthoquinone using sulfonyl azides in the presence of ruthenium catalyst.16 In our
previous works, sulfonyl azide was used as one of the starting materials for
Nꢀ
sulfonylketenimine formation. Hence it is planned to couple sulfonyl azide (as a dipole)
with 1,4ꢀnaphthoquinone (dipolarophile) at room temperature in the presence of a base, as
only a few compounds have been reported so far in these easily available and medicinally
important sulfonamide derivatives, despite the observation that these sulfonamide
derivatives show the good medicinal property. The observed results of the present metalꢀ
free base catalysed CHꢀfunctionalization/sulfonamidation of 1,4ꢀnaphthoquinones using
sulfonyl azides are discussed below.
Results and Discussion
Initially, the reaction was studied using 1,4ꢀnaphthoquinone (1), pꢀtoluenesulfonyl
azide (2a) as starting materials, dimethyl sulfoxide as solvent and potassium carbonate as
a base in ambient conditions. The starting materials were consumed completely within 10
minutes and afforded the sulfonyl amidation product namely,
Nꢀ(1,4ꢀdioxoꢀ1,4ꢀ
dihydronaphthalenꢀ2ꢀyl)ꢀ4ꢀethylbenzenesulfonamide (3a) in good yield and its structure
was confirmed unambiguously by NMR and HRMSꢀESI analyses. The reaction
conditions were optimized further with various bases and solvents. Among the various
bases used, inorganic bases like sodium, potassium and cesium carbonate gave better
yields within 10 minutes (Table 1, entries 1ꢀ3). Uses of other inorganic bases like NaOH
and KOH gave only moderate yield and took longer time (30 min.) than other bases
(Table 1, entries 4 and 5). Further, we have utilized several other organic bases, which
failed to give the desired sulfonyl amidation product (Table 1, entries 6ꢀ10).
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Table 1. Optimization of reaction conditionsa
Entry
1
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1,4ꢀdioxane
THF
DMF
CH2Cl2
CHCl3
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Base
K2CO3
Na2CO3
Cs2CO3
NaOH
Time (min)
10
Yield (%)b
66
63
58
59
53
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21c
22d
23e
24
10
10
30
30
10
10
10
10
120
120
60
120
10
10
10
10
20
KOH
Pyrrolidine
Morpholine
Et3N
DIPEA
Pyridine
KSF mont.
HT (5:1)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ꢀ
ꢀ
71
ꢀ
52
68
60
62
69
71
72
ꢀ
15
20
120
120
120
15
PTSA
HCl
DBU
ꢀ
ꢀ
58
a Reaction Conditions: 1,4ꢀNaphthoquinone (1.0 mmol), pꢀtoluenesulfonyl azide (1. mmol), solvent 3.0 mL, base
b
c
d
e
(1.2 0 mmol), rt; Isolated yield; Absence of base; Presence of pꢀtoluenesulfonic acid; Presence of Hydrochloric
acid.
In addition, we have also employed heterogeneous base catalysts HT (5:1) and
KSFꢀmontmorillonite. The reaction was slow in hydrotalcite (60 min.) but the yield was
higher compared to other bases (Table 1, entry 12). In KSF, the reaction was very slow
even after 120 minutes (Table 1, entry 11). In this type of sulfonyl amidation reaction,
solvents played a crucial role. Among the various solvents, DMSO (71%) gave better
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yield compared to other solvents like 1,4ꢀdioxane, THF, CH2Cl2, CHCl3, CH3CN and
DMF,(table 1, entries 12ꢀ19). Further, the time variation study was also carried out in
potassium carbonate as base and DMSO as a solvent. The reaction yield had increased
(Table 1, entries 19 and 20) when the reaction time was increased from 10 to 15 and 20
minutes. Without the base, there was no reaction and this result indicated the importance
of base in this sulfonamidation reaction (Table 1, entry 21). In addition, in the presence of
acids like PTSA and HCl, the reaction did not proceed even after a long time (Table 2,
entries 22 and 23). The reaction was also checked in the presence of DBU as a base. The
reaction was found to be exothermic and the sulfonamidation product was obtained only
in moderate yield (58%) (Table 2, entry 24).
With the optimized reaction conditions, the substrate scope of various active
alkenes with various sulfonyl azides was explored utilizing various sulfonyl azides,
substitutions like electronꢀdonating, electronꢀwithdrawing groups, halogenꢀsubstituted,
fused ring and nonꢀaromatic systems (Table 2).
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Table 2. Substrate scope in sulfonamidation of 1,4ꢀnaphthoquinonea
O
O
O
O
O
O
CH3
OCH3
I
O
O
O
O
S
N
S
S
S
N
N
N
O
H
O
O
H
O
H
H
O
O
3c: 82%
3a : 71%
3b: 70%
3d: 76%
O
OCH3
O
Br
O
O
OCH3
CH3
N
O
O
O
O
S
N
S
CH3
S
S
N
O
H
N
N
O
H
O
O
H
H
O
O
O
O
3h: 70%
3g: 85%
3e: 84%
3f: 78%
O
O
O
O
NO2
O
Cl
Cl
Cl
F
O
S
O
O
O
S
S
N
S
N
O
N
H
O
H
N
O
H
O
H
O
O
3i: 68%
O
O
3k: 55%
3l: 43%
3j: 66%
O
O
O
CH3
CH3
OH
O
NH2
O
O
O
CH3
S
N
S
S
S
N
N
H
N
O
H
O
O
H
O
H
O
O
O
O
3m: 58%
3n: 59%
3p: No reaction
3o: No reaction
O
H
N
O
O
O
H
CH3
N
N
CH3
OCH3
O
O
S
NH
NH
S
OCH3
S
N
O
N
H
O
O O
S
O
H
O O
O
OH
O
O
3s: No reaction
7: 76 %
CH3
3q: No reaction
CH3
3r: No reaction
aReaction conditions: 1,4ꢀNaphthoquinone (1.0 mmol), sulfonyl azide (1.0 mmol), potassium carbonate (1.2
mmol), DMSO (3.0 mL), rt, 15 minutes.
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Among them, all electronꢀdonating and fused ring substituted sulfonyl azides such
as methyl (3aꢀ71%), methoxy (3eꢀ84%, 3fꢀ78%), isopropyl (3dꢀ76%), biphenyl (3cꢀ82%)
and dansyl substituents (3gꢀ85%) gave the corresponding sulfonyl amidation product in
good to excellent yield. Among the electronꢀwithdrawing ones, nitro (3l–43%), 2,4,5ꢀ
trichloro (3kꢀ55%), halogens, bromo (3hꢀ70%), iodo (3iꢀ68%) and nonꢀaromatic,
cyclopropyl (3nꢀ59%) substitutions, halogen substituted benzenesulfonyl azides gave
better yield. An aliphatic sulfonyl azide namely methanesulfonyl azide also gave (3mꢀ
58%) better yields.
Attempts were also made to synthesise various 2ꢀsubstitutedꢀ1,4ꢀnaphthoquinones,
like
2ꢀhydroxyꢀ1,4ꢀnaphthoquinone,
2ꢀaminoꢀ1,4ꢀnaphthoquinone,
2ꢀ((4ꢀ
methoxyphenyl)amino)naphthaleneꢀ1,4ꢀdione and 2ꢀ(pyridinꢀ2ꢀyl amino)naphthaleneꢀ1,4ꢀ
dione. However, despite our best efforts, the expected sulfonamidation products were not
formed. This is attributed to the resonance interaction between the hydroxyl group and
amino group with the double bond in basic conditions which decreases the double bond
character of naphthoquinone, making it less reactive towards sulfonyl azides (Table 2,
3o-3r). In a similar reaction with 2ꢀmethoxyꢀ1,4ꢀnaphthoquinone, it was observed that the
starting material is consumed completely, but there was no formation of the expected
sulfonamidation product (Table 2, 3s).
In addition, the reactivity of 5ꢀhydroxyꢀ1,4ꢀnaphthoquinone was also studied with tosyl
azide in the presence of base. All the starting materials were consumed within half an hour and
the sulfonamidation product (7) was formed regioselectively in 76% yield (Table 2).
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Table 3. Substrate scope in sulfonamidation of 2ꢀmethylꢀ1,4ꢀnaphthoquinonea
aReaction conditions; 2ꢀMethylꢀ1,4ꢀnaphthoquinone (1.0 mmol), sulfonyl azide (1.0 mmol), potassium carbonate
(1.2 mmol), DMSO (3.0 mL), rt, 30 minutes.
Sulfonyl amidation reaction was also extended to a sterically hindered naphthoquinone,
namely 2ꢀmethylꢀ1,4ꢀnaphthoquinone (menadione), instead of 1,4ꢀnaphthoquinone. Surprisingly,
the same type of sulfonyl amidation product was observed in good yield but the reaction time
had to be increased to 30 minutes. Due to the presence of methyl group in the 2nd position, the
[3+2] cycloaddition reaction took place with a longer time. When the effect of substitutions in
sulfonyl azide was studied, the same type of results was observed as in 1,4ꢀnaphthoquinone
(Table 3). Electronꢀrich sulfonyl azides like 4ꢀmethyl (5a, 76%), 4ꢀphenyl (5c, 88%) and 4ꢀ
bromo (5d, 78%) substituted benzenesulfonyl azides gave better yields than unsubstituted (5b,
74%) and fluoro (5e, 51%) substituted benzenesulfonyl azides.
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Scheme 1. Reaction of 1,4ꢀnaphthoquinones with diphenyl phosphoryl azide.
When diphenyl phosphoryl azide was used instead of sulfonyl azide to react with
1,4ꢀnaphthoquinone and 2ꢀmethylꢀ1,4ꢀnaphthoquinone under the same reaction
conditions, the reaction is not successful and only the respective amines namely 2ꢀaminoꢀ
1,4ꢀnapththoquinone (8, 56%) and 2ꢀaminoꢀ3ꢀmethylꢀ1,4ꢀnaphthoquinone (9, 60%) are
obtained (Scheme 1). In addition, when the reaction was studied with other dipolarophile
substrates like
pꢀbenzoquinone, flavone, dimethyl and diethylacetylene dicarboxylate
(DMAD, DMED) and acrylonitrile with sulfonyl azide, the reaction was not successful
even after 24hrs.
Scheme 2. Gram scale reaction for sulfonamidation of 1,4ꢀnaphthoquinone.
With industrial and biological applications in mind, gram scale reaction was also
carried out using 1,4ꢀnaphthoquinone (5.0 mmol, 0.79 g), tosyl azide (5.0 mmol, 0.985 g),
potassium carbonate (6.0 mmol, 0.830 g) and dimethyl sulfoxide (8.0 mL) in room
temperature. The reaction gave selectively 66 % (1.08 g) of yield (Scheme 2).
Scheme 3. Plausible mechanism for sulfonamidation of 1,4ꢀnaphthoquinone.
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Based on the obtained experimental results, a plausible reaction mechanism was
proposed (Scheme 3). In a major pathway, 1,4ꢀnaphthoquinone and sulfonyl azide
undergo a thermal [3+2] cycloaddition, a thermodynamically favoured process,17 to yield
the cycloadduct (A). Since the ring opening reverse process is also thermally allowed, the
somewhat less stable [3+2] adduct, formed in a particular percentage, undergoes
irreversibly a base catalysed proton abstraction, ring opening and nitrogen extrusion
reaction cascade, shifting the equilibrium in step 1 towards the adduct 3.
Scheme 4. DMSO mediated minor pathway.
A subsequent minor pathway (Scheme 4) is also likely, involving interaction
between DMSO (a good dipolarophile) and sulfonyl azide (a relatively sluggish 1,3ꢀ
dipole) which may generate an oxathiatriazoline intermediate C,18 which may react
further with 1,4ꢀnaphthoquinone in the presence of base to yield the final product,.
Quinones are well known to participate in multiple biological oxidative processes
due to their ability to generate reactive oxygen species. The fundamental feature of
quinone is its ease of reduction, and hence its ability to act as an oxidizing agent. In folk
medicine, plants containing naphthoquinones are often employed for the treatment of
various diseases and several quinonoid derivatives isolated from traditional medicinal
plants are being investigated for their anticancer properties.
Their electrochemical properties are also very important due to their bioreductive
activation, either to semiquinone or to hydroquinone. There are several examples of
correlations between electrochemical potentials and biological activities. For example, a
definite correlation has been found between redox potentials and the inhibitory effects of
naphthoquinones on Epstein–Barr virus early antigen activation and with their
cytotoxicity. Another important significance of quinones in biological system is their one
electron reduction, catalyzed by NADPHꢀcytochrome P450 reductase which yields
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unstable semiquinones. Quinones transfer electrons to molecular oxygen (O2), and return
to their original quinoidal formation, thus generating a superoxide anion radical (.O2ꢀ).
Superoxide can be converted to hydrogen peroxide (H2O2) via a superoxide dismutase
(SOD)ꢀcatalysed reaction, followed by the formation of a hydroxyl radical (.HO) by the
ironꢀcatalyzed reduction of peroxide via the Fenton reaction. All of these highly reactive
species may react directly with DNA or other cellular macromolecules, such as lipids and
proteins, leading to cell damage.
Cyclic voltammetry investigations of quinones in the presence of oxygen in aprotic
media have been considered as an useful tool for studying the interaction of oxygen and
the superoxide anion radical with quinones and their radical anions. Both their toxic and
therapeutic activities were influenced by their chemical structure, particularly substituent
effects and the characteristics of the quinone nucleus. These unique features prompted us
to study the photophysical and redox properties of the synthesized molecules in aqueous
solution.
The absorbance and emission properties of sulfonylamidation products of both
1,4ꢀnaphthoquinone (331 nm) and 2ꢀmethylꢀ1,4ꢀnaphthoquinone (menadione, 332 nm)
derivatives (Figs. 2 and 3) are studied in DMSO solution (1x10ꢀ4 M). The
sulfonamidation products of 1,4ꢀnaphthoquinone, exhibited a weak absorbance maximum
in the region of 455 to 488 nm, ascribed to the intramolecular chargeꢀtransfer process
(ICT) from the sulfonamido group to the 1,4ꢀnaphthoquinone core and emission at 540 to
603 nm (Fig. 2). All the molecules, except 3g, show dual emission. While the shorter
wavelength emission band is due to the localized emission, the longer emission is
attributed to the twisted intramolecular charge transfer (TICT). In 3g, three emission
bands, are observed due to the presence of dansyl groups.
Fig.2 Absorbance and PL spectrum of (3a-3n
)
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Menadione sulfonamidation derivatives also exhibit absorbance in the visible
range of 485 to 506 and emission at 560 to 598 nm (Fig. 3). In this case also, except 5d
and 5e, all the compounds show dual emission but the halogenꢀsubstituted sulfonamides
5d and 5e show the broad emission spectrum. Compared to menadione and 1,4ꢀ
naphthoquinone, menadione sulfonamidation derivatives have shown higher absorbance
and emission values
.
Fig.3 Absorbance and PL spectrum of (5a-5f
)
In view of the potential redox properties of the naphthoquinone moiety in multiple
biological oxidative processes19 in nature, the electrochemical properties of the
synthesized sulfonamidation products of 1,4ꢀnaphthoquinone and menadione (Fig.4) are
also evaluated. In aprotic solvents, the reduction of sulfonamidation derivatives occurs
through three successive oneꢀelectron transfers for all the derivatives except 1,4ꢀ
naphthoquinone, which shows two successive oneꢀelectron transfers. The radical anion
intermediate 1,4ꢀ NQꢀ. formed in first oneꢀelectron transfer, EPc1 is subsequently reduced
to quinone dianion 1,4ꢀNQ2ꢀ in a second Epc2 step. Compared to both the starting
materials 1,4ꢀnaphthoquinone and menadione, their sulfonamidation products show
interesting modifications in redox properties. While the first redox wave is reduced more
(with weaker current intensity), the second redox wave in weakly reduced (with equal
current intensity). Another interesting feature is a larger value of E1/2 for the first redox
wave and lower value of E1/2 for the second redox wave.
In addition to the two quasiꢀreversible steps, a third redox wave (broad and illꢀ
defined cathodic and anodic peaks) at more negative potential is observed for the
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sulfonamidation products, which is likely the result of the reduction of the sulfonamide
moiety to afford its radical anion.
Fig. 4 Cyclic voltammogram of 1,4ꢀnapnthoquinone and menadione sulfonamidation
derivatives in selective.
Conclusions
A novel synthetic protocol for sp2CꢀH functionalization/sulfonamidation is
developed via baseꢀpromoted [3+2] cycloaddition of 1,4ꢀnaphthoquinones and sulfonyl
azides to synthesize sulfonamides. For the first time, this type of sp2 CꢀH
functionalization/sulfonamidation reactions is reported via [3+2] cycloaddition using
sulfonyl azides. A variety of sulfonamides are prepared in moderate to excellent yields
within a short reaction time. This method utilizes inexpensive and readily available
reagents, simple experimental procedure, generates nonꢀtoxic byꢀproducts (N2),
demonstrates good functional group compatibility and proves to be versatile for a range of
sulfonyl azides and various types of active alkenes such as 1,4ꢀnaphthoquinone and 2ꢀ
methylꢀ1,4ꢀnaphthoquinone. A suitable mechanism is proposed. All the sulfonamidation
derivatives of 1,4ꢀnaphthoquinone and menadione exhibit good absorption, emission
properties and compared to the starting materials both sulfonamidation products shows
good redox potential values.
Acknowledgements
DR gratefully acknowledges financial support from UGC, New Delhi, India for Nonꢀ
NET fellowship. KP acknowledges the financial support provided by CSIR, New Delhi,
India.
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