Base-Promoted Denitrogenative/Deoxygenative/Deformylative Benzannulation of N-Tosylhydrazones with 3-Formylchromones for Diverse and Polyfunctionalized Xanthones

Article abstract of DOI:10.1021/acs.orglett.8b03106

A simple and efficient base-promoted denitrogenative/deoxygenative/deformylative benzannulation is developed for the construction of biologically interesting polyfunctionalized xanthones starting from N-tosylhydrazones and two molecules of 3-formylchromon

Full text of DOI:10.1021/acs.orglett.8b03106

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Base-Promoted Denitrogenative/Deoxygenative/Deformylative
Benzannulation of N‑Tosylhydrazones with 3‑Formylchromones for
Diverse and Polyfunctionalized Xanthones
Rajeev Shrestha and Yong Rok Lee*
School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
S
* Supporting Information
ABSTRACT: A simple and efficient base-promoted deni-
trogenative/deoxygenative/deformylative benzannulation is
developed for the construction of biologically interesting
polyfunctionalized xanthones starting from N-tosylhydrazones
and two molecules of 3-formylchromones. This unprece-
dented protocol proceeds via a cascade diazo formation/
Michael addition/denitrogenation/[4 + 2] cycloaddition/
elimination/ring opening. The synthesized xanthones possess
potent UV-filter, fluorescent sensor, and antioxidant properties.
developments of novel protocols using N-tosylhydrazones in
ver the past decade, N-tosylhydrazones have been widely
1
Oused as precursors or sources of diazo compounds. organic synthesis, there are no reports on the reaction of N-
tosylhydrazones with 3-formylchromones so far. In this regard,
the reaction of N-tosylhydrazones with 3-formylchromones in
the presence of base was examined aiming to synthesize fused
pyrazoles B (Scheme 1). However, the first attempt in the
presence of a mild base leads to unexpected xanthones C
(Scheme 1).
They have also been employed as versatile starting materials
and powerful building blocks in organic synthesis.2 In
3
3,4
pioneering work, Barluenga, Valdes, and Wang5 developed
new methodologies for the formation of C−C, C−O, C−N,
C−B, and C−Si bonds starting from N-tosylhydrazones.
Subsequently, a number of transition-metal-catalyzed and
transition-metal-free transformations of N-tosylhydrazones via
cyclopropanation,6 C−H insertion,7 ring expansion,8 coupling
reactions,9 and construction of heterocycles10 have been
demonstrated. In addition, cycloaddition reactions between
N-tosylhydrazones and electron-deficient alkenes or alkynes
have been well reported;11 for example, the reaction of N-
tosylhydrazones and α,β-unsaturated carbonyl compounds,
such as cinnamaldehydes, in the presence of base provides
pyrazoles A (Scheme 1).12 Despite remarkable and excellent
́
Xanthones are important oxygenated heterocycles found in
many natural products exhibiting prominent biological and
pharmacological activities.13 Molecules bearing a xanthone
moiety exhibit potent anticancer,14 antimicrobial,15 antima-
larial,16 anticonvulsant,17 anticholinesterase,18 anti-HIV,19
antioxidant,20 antiangiogenesis,21 anti-inflammatory,22 antialz-
heimer,23 and cholesterol acyltransferase inhibitory activities.24
In addition, some of these compounds are evaluated and
utilized as major drug candidates.25 Owing to their importance
and effectiveness, various biosynthetic pathways26 and
synthetic approaches27 for xanthones have been demonstrated.
Although several approaches for the synthesis of xanthones
have been described, more facile and efficient protocols for
diverse and functionalized xanthones are still highly desirable.
This paper reports the construction of diverse and
polyfunctionalized xanthones bearing a 2-hydroxybenzoyl
group by mild base-promoted condensation reactions of N-
tosylhydrazones with 4-oxo-4H-chromene-3-carbaldehydes
(Scheme 2). To the best of our knowledge, this is the first
example for the construction of substituted xanthones by
decomposition of N-tosylhydrazones under mild base con-
ditions.
Scheme 1. Base-Promoted Benzannulation between N-
Tosylhydrazones and α,β-Unsaturated Carbonyls
The study was initiated by the optimization of the reaction
between (E)-N′-benzylidene-4-methylbenzenesulfonohydra-
Received: September 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03106
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
analysis of its spectral data. The H NMR spectrum of 3a
revealed the characteristic OH peak at δ 11.86 ppm as a broad
singlet and two aromatic protons on the new-made benzene
ring at δ 8.66 (d, J = 2.2 Hz) and 8.11 ppm (d, J = 2.2 Hz),
which appeared as doublets due to long-range couplings. The
13C NMR spectrum showed two carbonyl and one hydroxyl-
containing carbon peaks at δ 199.5, 176.7, and 163.3 ppm,
respectively. The structure of 3a was further confirmed by the
single-crystal X-ray crystallographic analysis of structurally
related compound 3k (Figure 1).
Scheme 2. Novel Strategy for Diverse and
Polyfunctionalized Xanthones from N-Tosylhydrazones
zide (1a) and 2 equiv of 4-oxo-4H-chromene-3-carbaldehyde
(2a) with different bases and solvents (Table 1). The initial
a
Table 1. Optimization of the Reaction Conditions
Figure 1. X-ray structure of compound 3k.
b
entry
base (equiv)
solvent
temp (°C) time (h) yield (%)
With the optimized conditions in hand, the generality of the
reaction was further investigated by employing different N-
tosylhydrazones 1a−1g with diverse 4-oxo-4H-chromene-3-
carbaldehydes 2a−2h to afford a variety of xanthone
derivatives (Table 2). The reaction of 1a with 2b−2d bearing
electron-donating groups such as 6-methyl, 6-isopropyl, and 6-
methoxy provided products 3b−3d in 85, 84, and 87% yields,
respectively (entries 1−3). Furthermore, the combination of
1a with 2e−2g bearing the electron-withdrawing groups 6-
bromo, 6-chloro, and 6-fluoro afforded products 3e−3g in 67−
74% yields (entries 4−6). In addition, the reaction of 1a with
2h bearing both an electron-donating and electron-with-
drawing group provided desired product 3h in 79% yield
(entry 7). These results show that 4-oxo-4H-chromene-3-
carbaldehydes 2b−2d bearing electron-donating groups
provide the desired products in slightly higher yields than
substrates 2e−2g bearing electron-withdrawing groups while
maintaining a remarkable functional group tolerance. More-
over, the reactions of 2a with 1b−1e bearing electron-donating
groups such as 4-methyl, 2,5-dimethyl, 3-methoxy, and 3,5-
dimethoxy on the benzene ring of the benzylidene-4-
methylbenzenesulfonohydrazide for 3−4 h produced desired
products 3i−3l in the range 76−82% yields (entries 8−11).
Treatment of 2a with 1f−1g bearing an electron-withdrawing
group such as 2-bromo and 2-chloro on the benzene ring
successfully afforded products 3m and 3n in 75 and 71%
yields, respectively (entries 12−13). This protocol provides a
rapid synthetic route to diverse xanthone derivatives bearing
various electron-donating or electron-withdrawing substituents
on the benzene ring of the xanthone moiety.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
K2CO3 (1)
Cs2CO3 (1)
KOH (1)
TEA (1)
TEA (0.5)
TEA (2)
DBU (1)
DABCO (1)
TEA (1)
TEA (1)
TEA (1)
TEA (1)
TEA (1)
TEA (1)
TEA (1)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
THF
90
90
90
90
90
90
90
90
90
reflux
90
reflux
50
120
90
5
5
5
3
3
3
3
5
10
10
8
10
6
62
68
64
83
61
72
73
68
31
55
62
43
68
76
83
DMF
ethanol
DMSO
DMSO
DMSO
3
3
c
a
Reaction conditions: 1a (0.5 mmol), 2a (1 mmol) in solvent (5 mL).
Isolated yields after column chromatography. 3 mL of DMSO was
b
c
used.
attempt with the inorganic bases K2CO3 (1 equiv) and Cs2CO3
(1 equiv) in DMSO at 90 °C for 5 h provided product 3a in 62
and 68% yield, respectively (entries 1−2). With a stronger
base, KOH (1 equiv), the yield of 3a did not significantly
change (64%, entry 3). In an attempt to increase the yield,
other organic bases were next screened. With 1 equiv of TEA
in DMSO at 90 °C for 3 h, 3a was produced in 83% yield
(entry 4). Decreasing the loading of TEA to 0.5 equiv or
increasing it to 2 equiv did not improve the yield (entries 5−
6). Further attempts to increase the yield of 3a by using other
stronger organic bases such as DBU (1 equiv) and DABCO (1
equiv) were not successful (entries 7−8). Using other
nonpolar and polar solvents such as toluene, THF, DMF,
and ethanol provided 3a in 31, 55, 62, and 43% yields,
respectively (entries 9−12). In addition, when the reaction was
carried out at lower (50 °C) or higher (120 °C) temperatures,
the yield of 3a did not improve (entries 13−14). Decreasing
the amount of DMSO to 3 mL provided 3a in the same yield
(83%, entry 15). The structure of 3a was identified by the
To demonstrate the versatility of this reaction, further
reactions between a variety of N-tosylhydrazones bearing
polyaromatic or heteroaromatic rings and 3-formylchromones
with or without polyaromatic rings were next examined
(Scheme 3). Reactions of (Z)-4-methyl-N′-(naphthalen-1-
ylmethylene) benzenesulfonohydrazide (1h) with 2a, 2b, 2d,
or 2f provided the products 4a−4d in 68, 78, 81, and 74%
yields, respectively. Similarly, treatment of (Z)-4-methyl-N′-
(naphthalen-2-ylmethylene) benzenesulfonohydrazide (1i)
B
DOI: 10.1021/acs.orglett.8b03106
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Organic Letters
Letter
Table 2. Synthesis of Various Xanthone Derivatives 3b−3n by Reaction of 1a−1g with 2a−2h
entry
1
2
time (h)
product (3)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a: R1 = R2 = R3 = R4 = H
2b: R5 = Me, R6 = H
2c: R5 = i-Pr, R6 = H
2d: R5 = OMe, R6 = H
2e: R5 = Br, R6 = H
2f: R5 = Cl, R6 = H
2g: R5 = F, R6 = H
2h: R5 = Cl, R6 = Me
2a: R5 = R6 = H
3
3
3
3
3
3
3
3
4
3
4
4
4
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
85
84
87
74
69
67
79
82
76
78
77
75
71
1a: R1 = R2 = R3 = R4 = H
1a: R1 = R2 = R3 = R4 = H
1a: R1 = R2 = R3 = R4 = H
1a: R1 = R2 = R3 = R4 = H
1a: R1 = R2 = R3 = R4 = H
1a: R1 = R2 = R3 = R4 = H
1b: R1 = R2 = H, R3 = Me, R4 = H
1c: R1 = Me, R2 = R3 = H, R4 = Me
1d: R1 = H, R2 = OMe, R3 = R4 = H
1e: R1 = H, R2 = OMe, R3 = H, R4 = OMe
1f: R1 = Br, R2 = R3 = R4 = H
1g: R1 = Cl, R2 = R3 = R4 = H
2a: R5 = R6 = H
2a: R5 = R6 = H
2a: R5 = R6 = H
2a: R5 = R6 = H
2a: R5 = R6 = H
Scheme 3. Synthesis of Diverse Xanthone Derivatives 4a−4i
by the Reaction of 1h−1k with 2a, 2b, 2d, 2f, or 2i
Scheme 4. Synthesis of Xanthone Derivatives 5a−5d by the
Reaction of 1l−1n with 2i or 2a
with 2a proceeded successfully to afford 5a in 53% yield, and
that with 2i provided 5b in 56% yield. Similarly, treatment of
1m, bearing a 1-cyclohexenyl group, with 2a afforded desired
product 5c in 46% yield. Moreover, a reaction of 1n bearing an
alkenyl and electron-withdrawing chloro group on the
cyclohexene ring with 2a provided the product 5d in 52%
yield.
To understand the substitution effect, the competing
reaction of 1a with two different 4-oxo-4H-chromene-3-
carbaldehydes, 2d and 2g bearing an electron-donating and
electron-withdrawing group, respectively, was examined
(Scheme 5). Thus, treatment of 1a (0.5 mmol) with 2d (1
mmol) and 2g (1 mmol) afforded products 3d (19%) and 3g
(31%), along with crossed products 3o (9%) and 3p (20%).
This result indicates that the electron-withdrawing fluoro
group on the 4-oxo-4H-chromene-3-carbaldehyde renders
good Michael acceptor properties to the substrate and hence
favors the formation of products compared to the 4-oxo-4H-
chromene-3-carbaldehyde containing the electron-donating
methoxy group.
with 2a provided the product 4e in 69% yield. In addition, a
combination of (Z)-4-methyl-N′-(phenanthren-9-ylmethylene)
benzenesulfonohydrazide (1j) with 2a afforded the desired
product 4f in 57% yield, and that of (Z)-4-methyl-N′-
(thiophen-2-ylmethylene) benzenesulfonohydrazide (1k)
with 2a afforded 4g in 48% yield. Further reactions of 1h or
1j with 4-oxo-4H-benzo[h]chromene-3-carbaldehyde (2i)
afforded the products 4h and 4i in 61 and 48% yields,
respectively. These reactions provide a rapid synthetic route to
diverse xanthone derivatives bearing polyaromatics and
heteroaromatics on the benzene ring of the xanthone moiety.
Importantly, this benzannulation protocol is not restricted to
N-tosylhydrazones bearing aryl and heteroaryl groups. As
shown in Scheme 4, the reaction of 1l bearing an alkenyl group
Based on the experimental results and literature precedent,
the plausible mechanism for the formation of 3a is depicted in
Scheme 6. Under basic conditions, N-tosylhydrazone 1a gives
C
DOI: 10.1021/acs.orglett.8b03106
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 5. Further Reaction for the Competition of Two
Different 4-Oxo-4H-chromene-3-cabaldehydes 2d and 2g
Detailed experimental procedures, characterization data,
GC-Mass and HRMS spectra, fluorescence spectra, and
photophysical data (PDF)
Accession Codes
CCDC 1822370 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yrlee@yu.ac.kr. Fax: +82-53-810-4631. Tel: +82-53-
810-2529.
Scheme 6. Plausible Mechanism for the Formation of 3a
ORCID
Yong Rok Lee: 0000-0002-4048-8341
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korean
government (MSIT) (2018R1A2B2004432) and the Priority
Research Centers Program (2014R1A6A1031189). This
research was supported by the Nano Material Technology
Development Program of the Korean National Research
Foundation (NRF) funded by the Korean Ministry of
Education, Science, and Technology (2012M3A7B4049675).
REFERENCES
■
diazo compound 6,1 which undergoes Michael addition with
2a to give diene intermediate 8 via elimination of the nitrogen
molecule from 7. The facile Diels−Alder reaction of in situ
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cycloadduct 9.28 Finally, the adduct 9 undergoes elimination of
formic acid followed by aromatization and ring opening to
furnish product 3a. The detection of formic acid by GC-MS in
the crude reaction mixture supports the suggested reaction
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In conclusion, we have developed a novel methodology for
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fluorescence sensing properties for Fe3+ ions, and antioxidant
activities comparable to standard BHT.
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* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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D
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