1-Nicotinoylbenzotriazole: A Convenient Tool for Site-Selective Protection of 5,7-Dihydroxycoumarins

Article abstract of DOI:10.1055/s-0039-1690104

1-Nicotinoylbenzotriazole (NicBt) was uncovered as an efficient protecting agent for the site-selective acylation of resorcinol-type phenolic groups with almost equal reactivity. The use of NicBt allows selective protection of the 7-OH group in 5,7-dihydr

Full text of DOI:10.1055/s-0039-1690104

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–H
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R. F. Fatykhov et al.
Paper
Synthesis
1-Nicotinoylbenzotriazole: A Convenient Tool for Site-Selective
Protection of 5,7-Dihydroxycoumarins
Ramil F. Fatykhova
Igor A. Khalymbadzha*a,b
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0-0
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2-8
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4
3-
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Oleg N. Chupakhina,b
Valery N. Charushina,b
Anna K. Inyutinaa
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2
4
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1
1
3
O
C
R
H
O
O
R
LG
OH
X
N
Pavel A. Slepukhinb
Victor G. Kartsevc
O
O
O
O
base
HO
O
O
O
N
N
a Department of Organic and Biomolecular Chemistry, Ural Federal
University, Mira 19, 620002 Ekaterinburg, Russian Federation
i.a.khalymbadzha@urfu.ru
up to 87% yield
High regioselectivity
Simple workup
Gram-scale synthesis
b Institute of Organic Synthesis, Ural Branch of the Russian Acade-
my of Sciences, Kovalevskoy 22, 620219 Ekaterinburg, Russian
Federation
c InterBioScreen Ltd., Institutsky Prospect 7a,
142432 Chernogolovka, Russian Federation
Received: 13.03.2019
Accepted after revision: 07.06.2019
Published online: 26.06.2019
Me
O
Me
Me
O
Me
O
O
DOI: 10.1055/s-0039-1690104; Art ID: ss-2019-t0173-op
Abstract 1-Nicotinoylbenzotriazole (NicBt) was uncovered as an effi-
cient protecting agent for the site-selective acylation of resorcinol-type
phenolic groups with almost equal reactivity. The use of NicBt allows
selective protection of the 7-OH group in 5,7-dihydroxycoumarins in
one simple scalable step, while combination of the nicotinoylation with
tosylation–denicotinoylation or silylation–denicotinoylation yields 5-
OH-protected 5,7-dihydroxycoumarins. Furthermore, nicotinoylated
5,7-dihydroxycoumarins proved useful in a gram-scale three-step
preparation of a 2,2-dimethylpyrano[2,3-f]coumarin, a key intermedi-
ate for the synthesis of calanolide A, an HIV reverse transcriptase and
Mycobacterium tuberculosis inhibitor, and its active analogues.
O
O
O
O
X
OH
O
1
2
Calanolide A
X = H, Cl, Br
Me
Me
O
OMe Me
N
NMe
R2N
O
O
O
HO
O
O
3
4
Key words esterification, protecting groups, phenols, acylation, natu-
R = Me, Et
ral products, total synthesis
R + R = (CH2)5
Figure 1 Biologically active compounds containing an asymmetrically
substituted 5,7-dihydroxycoumarin core
Derivatives of asymmetrically O-substituted 5,7-dihy-
droxycoumarins attract immense attention as an important
class of biologically active compounds. For example, tetra-
cyclic coumarin natural products isolated from plants of the
genus Calophyllum have anti-HIV activity.1 Among them,
calanolide A (1) (Figure 1) was identified as an inhibitor of
HIV reverse transcriptase and Mycobacterium tuberculosis.2
Synthetic calanolide analogue 23 showed higher activity
against HIV compared to the parent compound. O-Amino-
alkyl derivatives 34 demonstrated anticancer activity and
compound 4 can be used for the prevention and treatment
of brain lesions, in particular, stroke, dementia and Parkin-
son’s disease.5
coumarin at position C8 to give 8-acyl-5,7-dihydroxycou-
marins3,6 or by preparation of 7-monoprotected 5,7-dihy-
droxycoumarins.3a,7 The latter approach is tedious, since the
reactivity of hydroxyl groups in positions 5 and 7 is equal.
For example, direct methylation with dimethyl sulfate in
the presence of potassium carbonate7c or acylation with
acyl chloride in the presence of aluminum chloride7a lead to
a mixture of products with low yield of the desired com-
pound. A general method for producing 7-monoprotected
coumarins (Scheme 1) consists of an exhaustive tosylation
followed by the selective removal of one of the protecting
groups with tetrabutylammonium fluoride (TBAF).3a,7 Thus,
the drawbacks of known methods are multistep proce-
dures. In addition, the purification of products can be car-
ried out efficiently only using chromatography. Therefore,
A general approach to asymmetrically substituted 5,7-
dihydroxycoumarin derivatives is a deactivation of one hy-
droxyl group at position C5 or C7 of 5,7-dihydroxycouma-
rin. Usually, the deactivation of a hydroxyl group is carried
out either by a Friedel–Crafts acylation of 5,7-dihydroxy-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
R. F. Fatykhov et al.
Paper
Synthesis
the development of a novel and efficient one-step strategy
to access O-monosubstituted 5,7-dihydroxycoumarins is
highly desirable.
hand, weakly basic pyridine (pKa = 3.310a) produced the de-
sired product 6a in only 10% yield even after 72 hours (Table
1, entry 10). The use of an extra quantity of TEA also did not
change the yield of 6a (Table 1, entry 11).
In continuation of our work on the site-selective modifi-
cation of benzopyrones,8 we aimed to develop a new meth-
od for the selective protection of the hydroxyl groups in
5,7-dihydroxycoumarins. To address the challenge of selec-
tivity, we utilized a protective group capable of forming a
hydrogen bond for the regioselective protection of 5,7-di-
hydroxycoumarins. In the present work (Scheme 1), we re-
port a one-step scalable protocol for the direct nicotinoyla-
tion of the 7-OH group of 5,7-dihydroxycoumarins.
Table 1 Optimization of the Nicotinoylation Reaction Conditionsa
OH Me
O
OH Me
X
O
O
O
N
base, solvent
O
HO
O
O
N
OTs R2
5a
6a
TsCl
pyridine
TBAF
THF
R1
O
Entry
X
Base (equiv)
Solvent
Yield (%)b
TsO
O
Previous
work
R = Ts
(70–82%)
1
N3
TEA (1.1)
TEA (1.1)
TEA (1.1)
DIPEA (2.2)
TEA (1.1)
THF
THF
46
44
2c
3
N3
O
N
N
N3
acetone 71
OH R2
OH R2
N
N
acetone 38, mixtured,e
acetone NRf
R1
O
R1
4
Cl
TEA, acetone
R = Nic
(70–87%)
5
OMe
RO
O
HO
O
O
This work
Simple workup
Gram scale
N
N
N
6
TEA (1.1)
acetone 87
Scheme 1 Different approaches for the synthesis of 7-O-substituted
(1-benzotriazolyl, Bt)
5,7-dihydroxycoumarins
7
Bt
Bt
Bt
Bt
Bt
DIPEA (1.1)
DMAP (1.1)
DBU (1.1)
acetone 86
8
acetone 87
It was found that the reaction of nicotinoyl azide with
5,7-dihydroxy-4-methylcoumarin (5a) in the presence of a
slight excess of triethylamine (TEA) in THF at room tem-
perature gave single product 6a in moderate yield (Table 1,
entry 1), while refluxing did not increase the yield (Table 1,
entry 2). Next, we optimized the reaction conditions. A no-
table improvement in the product yield was achieved when
acetone was used as solvent (Table 1, entry 3). When nicoti-
noyl azide was replaced with nicotinoyl chloride hydrochlo-
ride, and diisopropylethylamine (DIPEA) was used as base,
the desired product 6a and the 5,7-di-O-nicotinoylated
product were obtained as a 4:1 mixture (Table 1, entry 4).
Reaction with methyl nicotinate (Table 1, entry 5) gave a
mixture of the starting materials. Further, our attention was
drawn to the work of Katritzky and co-workers,9 who de-
scribed N-acylbenzotriazole derivatives as effective C-, N-
and O-acylating agents. We found that using the benzotri-
azolyl moiety as leaving group gave very good yields of
monoprotected product 6a as a pure crystalline substance,
without the formation of any byproducts (Table 1, entry 6).
It should be noted that utilizing bases with close basicity
(TEA, DIPEA and DMAP, conjugate acids in DMSO: pKa = 9.0,
8.510a and 7.9,10b respectively) in this reaction did not sig-
nificantly affect the yield (Table 1, entries 7 and 8). Howev-
er, using a stronger base (DBU, conjugate acid in DMSO: pKa
= 13.910a) led to a complex mixture of mono- and diacylated
products and reactants (Table 1, entry 9). On the other
9
acetone complex mixturee
10g
11
pyridine (1.1) acetone 10
TEA (1.5) acetone 85
a Reaction conditions, unless otherwise noted: 5a (0.5 mmol), nicotinoyl de-
rivative (0.5 mmol), base, solvent (5 mL), room temperature, overnight.
b Yield of isolated product based on 5a.
c Temperature: 66 °C.
d 4:1 mixture of 6a with 5,7-di-O-nicotinoylated product.
e Based on NMR study.
f NR: no reaction.
g Reaction time: 72 h.
Since the use of DIPEA or DMAP did not provide any ad-
vantages over TEA in terms of yield or convenience, we later
used TEA (Table 1, entry 6) for the selective protection of
various 5,7-dihydroxycoumarin derivatives (Scheme 2). All
of the 5,7-dihydroxycoumarins afforded 7-O-nicotinoyl de-
rivatives 6a–i as pure crystalline substances in fair to very
good yields. 5,7-Dihydroxy-4-(trifluoromethyl)coumarin
(5h) did not form a crystalline precipitate of 6h from ace-
tone due to its high solubility. However, a solid was ob-
tained when acetone was replaced with ethyl acetate. Cou-
marins with other positions of the hydroxyl groups, such as
6,7-dihydroxycoumarin and 7,8-dihydroxycoumarin, yield-
ed a mixture of isomers in this nicotinoylation reaction.
5,7-Dihydroxyflavone (chrysin, 5j) was used in the reaction
and gave the anticipated product 6j in 59% yield. Interest-
ingly, the acylation of resorcinol and its 4-chloro derivative
© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H

C
R. F. Fatykhov et al.
Paper
Synthesis
with 1-nicotinoylbenzotriazole in the presence of TEA in
ethyl acetate gave the monosubstituted products 6k, 6l in
good yields.
selectivity was observed. Reactions with 1-isonicotinoyl-,
picolinyl-, pyrazinylcarbonyl- and 2-(indol-3-yl)acetylben-
zotriazole also failed. These results indicated the crucial
role of one nitrogen heteroatom in the 3-nicotinoyl ring for
the selectivity of this reaction.
In order to demonstrate the opportunities of this meth-
od, we modified the free 5-OH group and removed the nic-
otinoyl protective group (Scheme 3). Acylation of coumarin
6c with acetic anhydride yielded the corresponding deriva-
tive 7 in 94% yield. Unfortunately, upon deprotecting with
HCl, compound 7 lost both the nicotinoyl and acetyl groups,
yielding 5,7-dihydroxycoumarin 5c. However, the acetyl de-
rivative 7 formed single crystals and such a single crystal
was used in an X-ray diffraction experiment which provid-
ed solid evidence for the 7-OH nicotinoylated structure
(Figure 2).
OH R2
OH R2
NicBt (1.0 equiv)
TEA (1.1 equiv)
R1
O
R1
O
acetone, rt, 12 h
HO
O
NicO
O
5
6
OH
OH Me
NicO
NicO
O
O
NicO
NicO
NicO
O
O
O
O
6b (62%)
6a (87%)
OH C3H7
OH Me
Ph
O
6d (72%)
OH
O
O
6c (79%)
OH
O
NicO
O
6f (70%)
O
6e (84%)
OH
OH CF3
NicO
O
O
NicO
O
O
6h (65%)a
6g (87%)
OH
O
O
OH Me
NHAc
O
NicO
Ph
NicO
O
Figure 2 X-ray crystal structure (CCDC 1894797) of 7
6i (76%)
6j (59%)
OH
OH
Tosylation and silylation of 6c with p-toluenesulfonyl
chloride and tert-butyldiphenylsilyl chloride (TBDPSCl), or-
thogonal protecting groups, yielded more promising deriv-
atives 8 and 10. Compound 8 was deprotected with HCl
solution to obtain 5-O-tosylated product 9 completing the
exchange of protective groups in the 7-OH and 5-OH posi-
tions. Silylated derivative 10, upon treatment with Am-
berlyst 16 resin, yielded 5-O-silylated product 11 (Scheme
3). Thus, the proposed method can also be considered as a
simple tool to 5-OH-protected derivatives of 5,7-dihydroxy-
coumarins, a class of compounds characterized by tedious
multistep preparation and not previously substantially de-
scribed (to our knowledge, the only published article6c pre-
sented a selective synthesis of 5-benzyloxy-7-hydroxycou-
marins).
Cl
NicO
NicO
6l (60%)a
6k (66%)a
Scheme 2 Scope of the nicotinoylation. a EtOAc used as solvent.
The site of nicotinoylation was established using 2D 1H–
13C HMBC experiments. Thus, compounds 6 were character-
ized by cross peaks between the OH hydrogen and the C6
and C4a benzene ring carbons (see Supporting Information,
Figure S7). Obviously, if a free hydroxyl group was present
at the 7-position, cross peaks between OH and both C6 and
C8 would be registered in the HMBC spectrum.
To gain insight into the selective nature of this reaction,
the role of the type and position of the heteroatom for the
regioselectivity was investigated. When the pyridine ring
was replaced by furan or benzene, a mixture of the 5,7-
diprotected product and the starting 5,7-dihydroxycouma-
rin 5a was formed (according to 1H NMR data) and thus no
Since the 5,7-dihydroxycoumarin scaffold is part of the
anti-HIV calanolide-type alkaloids 1, 2, we exploited selec-
tively protected 6c for the synthesis of the calanolide A pre-
cursor 2,2-dimethylpyranocoumarin 13. Annulations of a
2,2-dimethylpyran ring are usually carried out with 3-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H

D
R. F. Fatykhov et al.
Paper
Synthesis
OH C3H7
OAc C3H7
Ac2O (5 equiv)
DMAP (20 mol%)
HCl, 60 °C
MeOH
rt, pyridine
HO
HO
O
5c
O
NicO
NicO
O
O
O
O
7, 94%
OTs C3H7
OTs C3H7
TsCl (1.5 equiv)
DMAP (20 mol%)
TEA (1 equiv)
aq HCl
reflux
O
O
O
O
rt, DCM
OH C3H7
9, 90%
8, 75%
TBDPSO
C3H7
TBDPSO
C3H7
Amberlyst
60 °C
MeOH
NicO
O
O
TBDPSCl (1.5 equiv)
TEA (1.5 equiv)
6c
HO
O
NicO
O
rt, DCM
OEt
11, 57%
10, 62%
OEt
145 °C
solvent free
1.
Amberlyst
60 °C
MeOH
O
C3H7
O
C3H7
2. TNP (1.5 equiv),
EtOAc
NicO
O
O
HO
O
O
.
13, 99%
12 TNP, 50%
Scheme 3 Synthetic opportunities of the novel method
chloro-3-methylbut-1-yne7a in the presence of various cat-
alysts or with 3-methylbut-2-enal11 or its diethyl ace-
tal3a,4,7b,12 in the presence of pyridine or picoline13 in high
boiling solvents (e.g., toluene). Since the pyridine core was
present in compounds 6 as the nicotinoyl moiety, one may
assume that the reaction may be carried out without addi-
tional bases. We used 1,1-diethoxy-3-methylbut-2-ene in
the Claisen rearrangement with coumarin 6c under sol-
vent- and base-free conditions at 145 °C, yielding pyrano-
coumarin 12 (Scheme 3). Compound 12 was isolated from
the reaction mixture by addition of picric acid (2,4,6-trini-
trophenol, TNP), giving pure pyranocoumarin 12 as the sol-
id crystalline picrate. Removal of the nicotinoyl group with
Amberlyst 16 resin in methanol yielded the desired pyrano-
coumarin 13 in almost quantitative yield (Scheme 3).
Notably, the synthesis of 13 from 5c on a 10-mmol scale
gave 13 in 37% overall yield (1.05 g), demonstrating the
practical applicability of the method for the large-scale syn-
thesis of calanolide-type pyranocoumarins and the stereo-
selective synthesis of calanolide A itself14 (Scheme 4).
In summary, we have developed a method for the site-
selective protection of one of the hydroxyl groups in benzo-
pyrones using a benzotriazole derivative of pyridinecarbox-
ylic acid. The scope of the reaction was demonstrated by
the conversion of various coumarins and 1,3-dihydroxy-
benzenes with 1-nicotinoylbenzotriazole. Combination of
the nicotinoylation with tosylation–denicotinoylation or si-
lylation–denicotinoylation allows the preparation of 5-OH-
protected 5,7-dihydroxycoumarins.
1H and 13C NMR spectra were recorded at ambient temperature on a
Bruker Avance II 400 MHz spectrometer at 400 and 100 MHz, respec-
tively, in DMSO-d6 or DMSO-d6/CCl4 as a solvent. Chemical shifts ()
are given in parts per million (ppm) relative to the deuterated solvent
[ = 2.5 ppm for DMSO-d6 and for the mixture of DMSO-d6/CCl4 (1:1)
for 1H and  = 39.52 ppm for DMSO-d6 and for the mixture of DMSO-
d6/CCl4 (1:1) for 13C]. Abbreviations are as follows: s (singlet), d (dou-
blet), dd (doublet of doublets), t (triplet), dt (doublet of triplets), m
(multiplet), q (quartet), quint (quintet), br s (broad signal). Coupling
constants (J) are reported in hertz (Hz). IR spectra were recorded on a
Bruker Alpha (ATR, ZnSe) IR-Fur spectrophotometer. Elemental analy-
ses were carried out using a CHNS/O analyzer Perkin-Elmer 2400 Se-
ries II instrument. Reactions were monitored using TLC (silica gel
plates). Visualization was accomplished with UV light (254 or 365
nm).
1H-1,2,3-Benzotriazol-1-yl(pyridin-3-yl)methanone, 1H-1,2,3-ben-
zotriazol-1-yl(pyridin-4-yl)methanone,
1H-1,2,3-benzotriazol-1-
yl(pyridin-2-yl)methanone, 1H-1,2,3-benzotriazol-1-yl(furan-2-
yl)methanone and 1-(1H-1,2,3-benzotriazol-1-yl)-2-(1H-indol-3-
yl)ethanone were synthesized in accordance with procedures de-
scribed by Katritzky and co-workers.9 All of the NMR spectra of the
known compounds were in full accordance with the published data.
Resorcinol (5k), 4-chlororesorcinol (5l) and 5,7-dihydroxy-2-phenyl-
4H-chromen-4-one (5j) were purchased from Sigma-Aldrich and used
OEt
ref 14
NicBt (10 mmol)
OEt
Amberlyst
.
5c
10
mmol
13
37%, 3 steps
6c
1
Calanolide A
12 TNP
MeOH
145 °C
TEA (11 mmol)
acetone
TNP (1.5 equiv)
Scheme 4 Gram-scale synthesis of 13
© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H

E
R. F. Fatykhov et al.
Paper
Synthesis
without further purification. 5,7-Dihydroxy-2H-chromen-2-one
(5b),12b 1,3-dihydroxy-6H-benzo[c]chromen-6-one (5g)15 and 5,7-di-
hydroxy-4-(trifluoromethyl)-2H-chromen-2-one (5h)16 were pre-
pared according to known methods. Other coumarins 5a,c–f,i were
synthesized according to the modified procedure described by Shar-
ghi and Jokar.17
Anal. Calcd for C18H15NO5: C, 66.46; H, 4.65; N, 4.31. Found: C, 66.53;
H, 4.79; N, 4.29.
3-Benzyl-5-hydroxy-4-methyl-2-oxo-2H-chromen-7-yl Nicotinate
(6d)
White solid; yield: 139 mg (72%); mp 223–225 °C.
IR-Fur (neat): 1743, 1700, 1604, 1428, 1285, 1157 cm–1
.
Nicotinoyl Derivatives 6; General Procedure
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 10.80 (s, 1 H, OH-5), 9.30–
9.22 (br s, 1 H, H-2′), 8.88–8.81 (m, 1 H, H-6′), 8.47–8.42 (m, 1 H, H-
4′), 7.63–7.57 (m, 1 H, H-5′), 7.28–7.10 (m, 5 H, Ph), 6.72 (d, J = 2.3 Hz,
1 H, H-8), 6.70 (d, J = 2.3 Hz, 1 H, H-6), 3.97 (s, 2 H, CH2), 2.65 (s, 3 H,
CH3).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 162.4 (C=O), 160.2 (C-2),
157.3 (C-5), 153.8 (C-8a), 153.7 (C-6′), 151.5 (C-7), 150.5 (C-2′), 149.2
(C-4), 138.8 (Ci), 137.1 (C-4′), 127.9 (Cm), 127.6 (Co), 125.6 (Cp), 124.6
(C-3′), 123.4 (C-5′), 121.7 (C-3), 107.5 (C-4a), 104.8 (C-6), 100.4 (C-8),
31.8 (CH2), 19.3 (CH3).
To a solution of coumarin 5 (0.5 mmol) and 1-nicotinoylbenzotriazole
(112 mg, 0.5 mmol) in anhydrous acetone (5 mL) was added TEA (76
L, 0.55 mmol). The mixture was then stirred overnight at room tem-
perature. The formed precipitate was collected by filtration, washed
with acetone and dried under air to give the corresponding 6.
5-Hydroxy-4-methyl-2-oxo-2H-chromen-7-yl Nicotinate (6a)
White solid; yield: 129 mg (87%); mp 269–271 °C.
IR-Fur (neat): 1737, 1615, 1428, 1292, 1085 cm–1
.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 10.85 (s, 1 H, OH-5), 9.25
(d, J = 1.6 Hz, 1 H, H-2′), 8.85 (dd, J = 1.6, 4.9 Hz, 1 H, H-6′), 8.44 (dt,
Jd = 8.0 Hz, Jt = 1.9 Hz, 1 H, H-4′), 7.60 (dd, J = 4.9, 8.0 Hz, 1 H, H-5′),
6.71 (d, J = 2.3 Hz, 1 H, H-8), 6.69 (d, J = 2.3 Hz, 1 H, H-6), 6.01 (d, J =
1.0 Hz, 1 H, H-3), 2.62 (d, J = 1.0 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 162.5 (C=O), 158.8 (C-2),
157.4 (C-8a), 155.2 (C-5), 153.8 (C-6′), 153.7 (C-4), 152.3 (C-7), 150.3
(C-2′), 137.1 (C-4′), 124.6 (C-3′), 123.5 (C-5′), 112.2 (C-3), 107.0 (C-
4a), 104.6 (C-6), 100.7 (C-8), 23.1 (CH3).
Anal. Calcd for C23H17NO5: C, 71.31; H, 4.42; N, 3.62. Found: C, 71.21;
H, 4.53; N, 3.49.
9-Hydroxy-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl
Nicotinate (6e)
White solid; yield: 136 mg (84%); mp 255–257 °C.
IR-Fur (neat): 1744, 1735, 1712, 1615, 1292, 1112 cm–1
.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 10.71 (s, 1 H, OH-9), 9.24
(d, J = 1.4 Hz, 1 H, H-2′), 8.84 (dd, J = 1.4, 4.7 Hz, 1 H, H-6′), 8.44 (dt,
Jd = 7.9 Hz, Jt = 1.9 Hz, 1 H, H-4′), 7.60 (dd, J = 4.7, 7.9 Hz, 1 H, H-5′),
6.74 (d, J = 1.8 Hz, 1 H, H-8), 6.66 (d, J = 1.8 Hz, 1 H, H-6), 3.35 (t, J = 7.5
Hz, 2 H, CH2-1), 2.72 (t, J = 7.5 Hz, 2 H, CH2-3), 2.1 (quint, J = 7.5 Hz, 2
H, CH2-2).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 162.6 (C=O), 158.4 (C-4),
156.0 (C-9), 155.3 (C-5a), 155.1 (C-9b), 153.9 (C-6′), 151.9 (C-7), 150.5
(C-2′), 137.2 (C-4′), 124.7 (C-3′), 124.1 (C-3a), 123.6 (C-5′), 106.4 (C-
9a), 104.1 (C-8), 100.5 (C-6), 35.6 (C-1), 29.1 (C-3), 22.1 (C-2).
Anal. Calcd for C16H11NO5: C, 64.65; H, 3.73; N, 4.71. Found: C, 64.71;
H, 3.64; N, 4.78.
5-Hydroxy-2-oxo-2H-chromen-7-yl Nicotinate (6b)
White solid; yield: 88 mg (62%); mp 246–248 °C.
IR-Fur (neat): 1737, 1614, 1444, 1287, 1109, 1075 cm–1
.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 11.16 (s, 1 H, OH-5), 9.25
(d, J = 1.3 Hz, 1 H, H-2′), 8.88 (dd, J = 1.3, 4.8 Hz, 1 H, H-6′), 8.45 (dt,
Jd = 8.0 Hz, Jt = 1.7 Hz, 1 H, H-4′), 8.10 (d, J = 9.7 Hz, 1 H, H-4), 7.64 (dd,
J = 4.8, 8.0 Hz, 1 H, H-5′), 6.85 (d, J = 1.7 Hz, 1 H, H-8), 6.72 (d, J = 1.7
Hz, 1 H, H-6), 6.32 (d, J = 9.7 Hz, 1 H, H-3).
Anal. Calcd for C18H13NO5: C, 66.87; H, 4.05; N, 4.33. Found: C, 66.78;
H, 4.15; N, 4.28.
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 162.9 (C=O), 159.8 (C-2),
155.5 (C-5), 155.1 (C-8a), 154.2 (C-6′), 153.3 (C-7), 150.6 (C-2′), 138.8
(C-4), 137.5 (C-4′), 124.8 (C-3′), 123.9 (C-5′), 113.0 (C-3), 106.6 (C-4a),
104.2 (C-6), 100.9 (C-8).
1-Hydroxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yl
Nicotinate (6f)
White solid; yield: 118 mg (70%); mp 223–225 °C.
IR-Fur (neat): 1742, 1733, 1703, 1614, 1292, 1277, 1080 cm–1
.
Anal. Calcd for C15H9NO5: C, 63.61; H, 3.20; N, 4.95. Found: C, 63.50;
H, 3.34; N, 4.83.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 10.63 (s, 1 H, OH-1), 9.26
(d, J = 1.6 Hz, 1 H, H-2′), 8.85 (dd, J = 1.6, 4.8 Hz, 1 H, H-6′), 8.45 (dt,
Jd = 7.9 Hz, Jt = 1.9 Hz, 1 H, H-4′), 7.60 (dd, J = 4.8, 7.9 Hz, 1 H, H-5′),
6.70–6.65 (m, 2 H, H-2 + H-4), 3.20–3.12 (br s, 2 H, CH2-10), 2.48–2.40
(br s, 2 H, CH2-7), 1.81–1.70 (br s, 4 H, CH2-8 + CH2-9).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 162.6 (C=O), 159.8 (C-6),
156.9 (C-1), 153.9 (C-6′), 153.4 (C-4a), 151.0 (C-3), 150.4 (C-2′), 148.9
(C-10a), 137.2 (C-4′), 124.7 (C-3′), 123.6 (C-5′), 119.8 (C-6a), 107.2 (C-
10b), 104.7 (C-2), 100.5 (C-4), 29.1 (CH2-10), 24.1 (CH2-7), 21.6 (CH2-
9), 20.7 (CH2-8).
5-Hydroxy-2-oxo-4-propyl-2H-chromen-7-yl Nicotinate (6c)
White solid; yield: 128 mg (79%); mp 229–231 °C.
IR-Fur (neat): 1739, 1613, 1434, 1290, 1150, 1082 cm–1
.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 10.90 (s, 1 H, OH-5), 9.27
(s, 1 H, H-2′), 8.91–8.83 (m, 1 H, H-6′), 8.52–8.45 (m, 1 H, H-4′), 7.68–
7.60 (m, 1 H, H-5′), 6.72 (s, 2 H, H-6 + H-8), 5.97 (s, 1 H, H-3), 3.00–
2.90 (m, 2 H, C-4-CH2), 1.75–1.61 (m, 2 H, CH2CH2CH3), 1.09–0.96 (m,
3 H, CH3).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 162.2 (C=O), 159.0 (C-2),
157.3 (C-4), 157.0 (C-8a), 155.6 (C-5), 153.3 (C-6′), 152.1 (C-7), 150.0
(C-2′), 137.8 (C-4′), 124.9 (C-3′), 123.7 (C-5′), 111.7 (C-3), 106.4 (C-
4a), 104.8 (C-6), 100.9 (C-8), 37.3 (C-4-CH2), 22.3 (CH2CH2CH3), 13.7
(CH3).
Anal. Calcd for C19H15NO5: C, 67.65; H, 4.48; N, 4.15. Found: C, 67.57;
H, 4.57; N, 4.03.
1-Hydroxy-6-oxo-6H-benzo[c]chromen-3-yl Nicotinate (6g)
White solid; yield: 145 mg (87%); mp >300 °C.
IR-Fur (neat): 1744, 1735, 1608, 1416, 1289, 1087 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H

F
R. F. Fatykhov et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6):  = 11.54 (s, 1 H, OH-1), 9.31–9.25 (br
s, 1 H, H-2′), 9.15–9.11 (m, 1 H, H-10), 8.94–8.89 (m, 1 H, H-6′), 8.50–
8.46 (m, 1 H, H-4′), 8.30–8.26 (m, 1 H, H-7), 7.96–7.92 (m, 1 H, H-9),
7.69–7.62 (m, 2 H, H-5′ + H-8), 6.98 (d, J = 2.4 Hz, 1 H, H-4), 6.90 (d, J =
2.4 Hz, 1 H, H-2).
13C NMR (100 MHz, DMSO-d6):  = 182.6 (C-4), 164.3 (C-2), 162.8
(C=O), 160.8 (C-5), 156.3 (C-8a), 155.6 (C-7), 154.5 (C-6′), 150.7 (C-2′),
137.6 (C-4′), 132.4 (C(Ph)), 130.4 (Ci(Ph)), 129.2 (C(Ph)), 126.6 (C(Ph)),
124.8 (C-3′), 124.1 (C-5′), 108.5 (C-4a), 105.8 (C-3), 105.5 (C-6), 101.8
(C-8).
13C NMR (100 MHz, DMSO-d6):  = 163.1 (C=O), 160.2 (C-6), 157.3 (C-
1), 154.4 (C-6′), 152.5 (C-4a), 151.0 (C-3), 150.7 (C-2′), 137.6 (C-4′),
135.2 (C-9), 134.2 (C-10a), 129.5 (C-7), 128.1 (C-8), 126.8 (C-10),
125.0 (C-3′), 124.1 (C-5′), 119.7 (C-6a), 105.7 (C-2), 104.5 (C-10b),
101.8 (C-4).
Anal. Calcd for C21H13NO5: C, 70.19; H, 3.65; N, 3.90. Found: C, 70.31;
H, 3.53; N, 3.79.
3-Hydroxyphenyl Nicotinate (6k)
EtOAc used as solvent. Recrystallized from EtOAc.
White solid; yield: 71 mg (66%); mp 182–184 °C (Lit.18 183–183.5 °C).
Anal. Calcd for C19H11NO5: C, 68.47; H, 3.33; N, 4.20. Found: C, 68.25;
H, 3.66; N, 4.03.
IR-Fur (neat): 1735, 1597, 1484, 1427, 1238, 1143 cm–1
.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 9.57 (s, 1 H, OH), 9.23 (d,
J = 1.5 Hz, 1 H, H-2′), 8.84 (dd, J = 1.5, 4.8 Hz, 1 H, H-6′), 8.43 (dt, Jd =
7.9 Hz, Jt = 1.9 Hz, 1 H, H-4′), 7.60 (dd, J = 4.8, 7.9 Hz, 1 H, H-5′), 7.24–
7.17 (m, 1 H, H-5), 6.73–6.61 (m, 3 H, H-2 + H-4 + H-6).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 163.0 (C=O), 158.3 (C-1),
153.7 (C-6′), 151.0 (C-3), 150.4 (C-2′), 137.1 (C-4′), 129.5 (C-5), 125.1
(C-3′), 123.6 (C-5′), 113.0 (C-2 or C-4 or C-6), 111.6 (C-2 or C-4 or C-
6), 108.8 (C-2 or C-4 or C-6).
5-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl Nicoti-
nate (6h)
EtOAc used as solvent.
Pale yellow solid; yield: 114 mg (65%); mp 257–259 °C.
IR-Fur (neat): 1738, 1614, 1402, 1279, 1229, 1148, 1084 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 11.61–11.44 (br s, 1 H, OH-5), 9.26
(d, J = 1.8 Hz, 1 H, H-2′), 8.91 (dd, J = 1.8, 4.8 Hz, 1 H, H-6′), 8.47 (dt,
Jd = 1.8 Hz, Jt = 8.0 Hz, 1 H, H-4′), 7.66 (dd, J = 4.8, 8.0 Hz, 1 H, H-5′),
7.02 (d, J = 2.3 Hz, 1 H, H-8), 6.87 (s, 1 H, H-3), 6.83 (d, J = 2.3 Hz, 1 H,
H-6).
13C NMR (100 MHz, DMSO-d6):  = 162.9 (C=O), 158.4 (C-2), 155.9 (C-
5), 155.5 (C-8a), 154.4 (C-6′), 153.7 (C-7), 150.7 (C-2′), 138.6 (q, J =
33.8 Hz, C-4), 137.7 (C-4′), 124.8 (C-3′), 124.1 (C-5′), 121.7 (q, J = 274
Hz, CF3), 115.6 (q, J = 7.4 Hz, C-3), 105.7 (C-6), 101.8 (C-4a), 101.7 (C-
8).
4-Chloro-3-hydroxyphenyl Nicotinate (6l)
EtOAc used as solvent. Recrystallized from acetonitrile.
White solid; yield: 75 mg (60%); mp 171–173 °C.
IR-Fur (neat): 1741, 1612, 1391, 1221, 1094, 727 cm–1
.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 10.28 (s, 1 H, OH), 9.28–
9.19 (br s, 1 H, H-2′), 8.88–8.79 (m, 1 H, H-6′), 8.47–8.37 (m, 1 H, H-
4′), 7.62–7.53 (m, 1 H, H-5′), 7.31 (d, J = 8.6 Hz, 1 H, H-5), 6.86 (d, J =
1.8 Hz, 1 H, H-2), 6.67 (dd, J = 8.6, 1.8 Hz, 1 H, H-6).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 162.8 (C=O), 153.7 (C-6′ +
C-3), 150.4 (C-2′), 149.1 (C-1), 137.0 (C-4′), 129.6 (C-5), 124.8 (C-3′),
123.4 (C-5′), 117.4 (C-4), 112.5 (C-6), 109.9 (C-2).
Anal. Calcd for C16H8F3NO5: C, 54.71; H, 2.30; N, 3.99. Found: C, 54.52;
H, 2.67; N, 3.79.
3-Acetamido-5-hydroxy-4-methyl-2-oxo-2H-chromen-7-ylNicoti-
nate (6i)
Anal. Calcd for C12H8ClNO3: C, 57.73; H, 3.23; N, 5.61. Found: C, 57.63;
H, 3.41; N, 5.53.
White solid; yield: 135 mg (76%); mp >300 °C.
IR-Fur (neat): 1732, 1716, 1670, 1614, 1292, 1088 cm–1
.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 11.30–11.01 (br s, 1 H,
OH-5), 9.40 (s, 1 H, NH), 9.31–9.21 (br s, 1 H, H-2′), 8.91–8.86 (m, 1 H,
H-6′), 8.51–8.42 (m, 1 H, H-4′), 7.70–7.63 (m, 1 H, H-5′), 6.91 (d, J = 2.1
Hz, 1 H, H-8), 6.79 (d, J = 2.1 Hz, 1 H, H-6), 2.44 (s, 3 H, CH3), 2.05 (s, 3
H, CH3(Ac)).
13C NMR (100 MHz, DMSO-d6/CCl4, 1:1):  = 168.6 (C=O(Ac)), 163.0
(C=O), 157.8 (C-2), 157.5 (C-5), 154.3 (C-6′), 153.1 (C-8a), 152.1 (C-7),
150.6 (C-2′), 147.2 (C-4), 137.6 (C-4′), 124.9 (C-3′), 124.1 (C-5′), 119.3
(C-3), 107.2 (C-4a), 105.4 (C-8), 101.1 (C-6), 22.5 (CH3(Ac)), 18.5
(CH3).
Functionalization of the Free 5-OH Group of Compound 6c
5-Acetoxy-2-oxo-4-propyl-2H-chromen-7-yl Nicotinate (7) by Acy-
lation of 6c
To a suspension of 6c (162.5 mg, 0.5 mmol) in pyridine (4 mL) was
added Ac2O (236 L, 2.5 mmol), and 4-dimethylaminopyridine (12
mg, 0.1 mmol) and the mixture was stirred at room temperature until
reaction completion, as monitored by TLC (about 2 h). Then, the reac-
tion mixture was poured into ice and the formed precipitate was col-
lected by filtration, washed with water and dried under air to give 7.
Anal. Calcd for C18H14N2O6: C, 61.02; H, 3.98; N, 7.91. Found: C, 60.80;
H, 4.13; N, 7.87.
White solid; yield: 172 mg (94%); mp 169–171 °C.
IR-Fur (neat): 1769, 1743, 1714, 1612, 1256, 1182, 1139, 1108, 1070
cm–1
.
5-Hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl Nicotinate (6j)
Recrystallized from DMF.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 9.27 (d, J = 1.5 Hz, 1 H, H-
2′), 8.88 (dd, J = 1.5, 4.8 Hz, 1 H, H-6′), 8.47 (dt, Jd = 7.9 Hz, Jt = 1.5 Hz, 1
H, H-4′), 7.63 (dd, J = 4.8, 7.9 Hz, 1 H, H-5′), 7.36 (d, J = 2.3 Hz, 1 H, H-
8), 7.21 (d, J = 2.3 Hz, 1 H, H-6), 6.28 (s, 1 H, H-3), 2.86–2.78 (m, 2 H,
C-4-CH2), 2.38 (s, 3 H, CH3(Ac)), 1.73–1.60 (m, 2 H, CH2CH2CH3), 1.10–
1.02 (m, 3 H, CH2CH3).
Pale yellow solid; yield: 106 mg (59%); mp 188–190 °C.
IR-Fur (neat): 1737, 1652, 1617, 1280, 1147, 1079 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 12.88 (s, 1 H, OH-5), 9.27 (d, J = 1.6
Hz, 1 H, H-2′), 8.92 (dd, J = 1.6, 4.8 Hz, 1 H, H-6′), 8.48 (dt, Jd = 8.0 Hz, Jt
= 1.6 Hz, 1 H, H-4′), 8.13–8.08 (m, 2 H, Ph), 7.70–7.54 (m, 4 H, H-5′ +
Ph), 7.31 (d, J = 1.8 Hz, 1 H, H-8), 7.15 (s, 1 H, H-3), 6.90 (d, J = 1.8 Hz,
1 H, H-6).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H

G
R. F. Fatykhov et al.
Paper
Synthesis
13C NMR (100 MHz, DMSO-d6):  = 168.8 (C=O(Ac)), 162.9 (C=O(Nic)),
158.7 (C-2), 154.8 (C-8a), 154.5 (C-4), 154.4 (C-6′), 151.6 (C-7), 150.6
(C-2′), 147.8 (C-5), 137.6 (C-4′), 124.6 (C-3′), 124.1 (C-5′), 115.2 (C-3),
114.5 (C-6), 110.8 (C-4a), 108.8 (C-8), 36.3 (C-4-CH2), 21.6
(CH2CH2CH3), 21.1 (CH3(Ac)), 13.6 (CH2CH3).
2,2-Dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromen-5-yl
Nicotinate Hydropicrate (12·TNP) by Annulation of a 2,2-Dimeth-
ylpyran Ring to 6c
A mixture of 6c (325 mg, 1.0 mmol) and 3-methylbut-2-enal diethyl
acetal (708 L, 3.75 mmol) was heated at 145 °C for 50 min. Then, the
mixture was cooled, diluted with EtOAc (7 mL) and filtered. The re-
sulting solution was added to a solution of picric acid (TNP; 344 mg,
1.5 mmol) in EtOAc (10 mL). The obtained crystals were collected by
filtration, washed with EtOAc and dried to give 12 as a salt with TNP.
Anal. Calcd for C20H17NO6: C, 65.39; H, 4.66; N, 3.81. Found: C, 65.24;
H, 4.65; N, 3.67.
2-Oxo-4-propyl-5-(tosyloxy)-2H-chromen-7-yl Nicotinate (8) by
Tosylation of 6c
Yellow crystals; yield: 310 mg (50%); mp 193–195 °C.
IR-Fur (neat): 1765, 1717, 1523, 1361, 1275, 1118 cm–1
.
To a suspension of 6c (162.5 mg, 0.5 mmol) in DCM (5 mL) were add-
ed sequentially TEA (70 L, 0.5 mmol), DMAP (12.0 mg, 0.1 mmol)
and TsCl (142.9 mg, 0.75 mmol). The resulting mixture was stirred at
room temperature until reaction completion, as monitored by TLC
(about 0.25 h). Then, the reaction mixture was diluted with DCM (20
mL), washed with water and dried over Na2SO4. The solvent was re-
moved in vacuo and the crude residue was recrystallized from MeOH
to give 8.
1H NMR (400 MHz, DMSO-d6/CCl4, 1:1):  = 10.40–10.16 (br s, 1 H,
OH(TNP)), 9.32 (d, J = 1.4 Hz, 1 H, H-2′), 8.91 (dd, J = 1.4, 4.8 Hz, 1 H,
H-6′), 8.58 (s, 2 H, Hm(TNP)), 8.55 (dt, Jd = 7.9 Hz, Jt = 1.5 Hz, 1 H, H-4′),
7.69 (dd, J = 7.9, 4.8 Hz, 1 H, H-5′), 6.89 (s, 1 H, H-6), 6.43 (d, J = 10 Hz,
1 H, H-4), 6.08 (s, 1 H, H-9), 5.76 (d, J = 10 Hz, 1 H, H-3), 2.97–2.87 (m,
2 H, C-10-CH2), 1.76–1.63 (m, 2 H, CH2CH2CH3), 1.54 (s, 6 H, C-2-
(CH3)2), 1.10–1.03 (m, 3 H, CH2CH3).
White solid; yield: 180 mg (75%); mp 145–147 °C.
IR-Fur (neat): 1740, 1724, 1588, 1473, 1371, 1258, 1013 cm–1
13C NMR (100 MHz, DMSO-d6):  = 162.6 (C=O), 160.7 (Ci(TNP)), 159.1
(C-8), 156.7 (C-10), 154.2 (C-6a), 153.3 (C-6′), 151.3 (C-10b), 149.7 (C-
2′), 147.9 (C-5), 141.8 (Co(TNP)), 139.1 (C-4′), 130.2 (C-3), 125.2
(Cm(TNP)), 125.0 (C-3′), 124.6 (C-5′), 124.2 (Cp(TNP)), 115.3 (C-4),
113.5 (C-9), 110.8 (C-4a), 107.5 (C-10a), 103.6 (C-6), 78.4 (C-2), 37.4
(C-10-CH2), 27.3 (C-2-(CH3)2), 22.8 (CH2CH2CH3), 13.7 (CH2CH3).
.
1H NMR (400 MHz, DMSO-d6):  = 9.28–9.23 (br s, 1 H, H-2′), 8.95–
8.89 (m, 1 H, H-6′), 8.50–8.44 (m, 1 H, H-4′), 7.92–7.84 (m, 2 H,
Ho(Ts)), 7.71–7.63 (m, 1 H, H-5′), 7.58–7.48 (m, 3 H, H-8 + Hm(Ts)),
7.27–7.21 (m, 1 H, H-6), 6.36 (s, 1 H, H-3), 2.81–2.71 (m, 2 H, C-4-
CH2), 2.41 (s, 3 H, CH3(Ts)), 1.54–1.40 (m, 2 H, CH2CH2CH3), 0.87–0.77
(m, 3 H, CH2CH3).
Anal. Calcd for C29H24N4O12: C, 56.13; H, 3.90; N, 9.03. Found: C,
56.07; H, 4.09; N, 8.93.
13C NMR (100 MHz, DMSO-d6):  = 162.7 (C=O), 158.4 (C-2), 154.9 (C-
8a), 154.5 (C-6′), 154.1 (C-4), 151.6 (C-7), 150.7 (C-2′), 146.8 (Cp(Ts)),
145.8 (C-5), 137.7 (C-4′), 130.8 (Ci(Ts)), 130.5 (Cm(Ts)), 128.5 (Co(Ts)),
124.6 (C-3′), 124.1 (C-5′), 115.6 (C-3), 112.5 (C-6), 111.0 (C-4a), 110.0
(C-8), 36.2 (C-4-CH2), 21.6 (CH2CH2CH3), 21.2 (CH3(Ts)), 13.3
(CH2CH3).
Removal of the Nicotinoyl Group
7-Hydroxy-4-propyl-5-(tosyloxy)-2H-chromen-2-one (9)
Compound 8 (479 mg, 1 mmol) was added to 5 N HCl and the reaction
mixture was refluxed for 8 h. Then, the reaction mixture was cooled
to room temperature and diluted with water. The formed precipitate
was collected by filtration, washed with water and dried under air to
give 9.
Anal. Calcd for C25H21NO7S: C, 62.62; H, 4.41; N, 2.92; S, 6.69. Found:
C, 62.50; H, 4.77; N, 2.79; S, 6.60.
5-((tert-Butyldiphenylsilyl)oxy)-2-oxo-4-propyl-2H-chromen-7-yl
Nicotinate (10) by Silylation of 6c
White solid; yield: 337 mg (90%); mp 179–181 °C.
IR-Fur (neat): 1684, 1626, 1449, 1375, 1262, 1183, 1008 cm–1
.
To a suspension of 6c (195 mg, 0.6 mmol) in DCM (5 mL) were added
TEA (125 L, 0.9 mmol) and TBDPSCl (247 mg, 0.9 mmol). The mix-
ture was stirred at room temperature until reaction completion, as
monitored by TLC (about 5 h). Then, the mixture was washed with
water and dried over Na2SO4. The solvent was evaporated in vacuo
and the residue was crystallized from MeOH to give 10.
1H NMR (400 MHz, DMSO-d6):  = 10.97 (s, 1 H, OH-7), 7.85 (d, J = 8.2
Hz, 2 H, Ho(Ts)), 7.54 (d, J = 8.2 Hz, 2 H, Hm(Ts)), 6.68 (d, J = 2.4 Hz, 1 H,
H-8), 6.52 (d, J = 2.4 Hz, 1 H, H-6), 6.08 (s, 1 H, H-3), 2.75–2.65 (m, 2 H,
CH2), 2.44 (s, 3 H, CH3(Ts)), 1.52–1.37 (m, 2 H, CH2), 0.85–0.74 (m, 3 H,
CH3).
13C NMR (100 MHz, DMSO-d6):  = 160.2 (C-7), 159.0 (C-2), 156.0 (C-
8a), 155.0 (C-4), 146.7 (Cp(Ts) or C-5), 145.6 (C-5 or Cp(Ts)), 131.5
(Ci(Ts)), 130.5 (Cm(Ts)), 128.6 (Co(Ts)), 111.9 (C-3), 106.4 (C-6 or C-8),
105.0 (C-4a), 102.0 (C-8 or C-6), 36.3 (C-4-CH2), 21.7 (CH2CH2CH3),
21.2 (CH3(Ts)), 13.4 (CH3).
Colourless crystals; yield: 210 mg (62%); mp 153–155 °C.
IR-Fur (neat): 1716, 1607, 1139, 1098, 1076, 812 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.09 (br s, 1 H, H-2′), 8.79–8.78 (m, 1 H,
H-6′), 8.21–8.18 (m, 1 H, H-4′), 7.73–7.71 (m, 4 H, Ph), 7.48–7.36 (m, 7
H, H-5′ + Ph), 6.83 (d, J = 2.3 Hz, 1 H, H-8), 6.24 (s, 1 H, H-3), 6.23 (d, J =
2.3 Hz, 1 H, H-6), 3.33 (t, J = 7.4 Hz, 2 H, C-4-CH2), 1.79 (sextet, J = 7.4
Hz, 2 H, CH2CH3), 1.14 (s, 9 H, tBu), 1.04 (t, J = 7.4 Hz, 3 H, CH2CH3).
Anal. Calcd for C19H18O6S: C, 60.95; H, 4.85; S, 8.56. Found: C, 60.83;
H, 4.99; S, 8.46.
13C NMR (100 MHz, DMSO-d6):  = 162.5 (C=O), 160.5 (C-2), 157.3 (C-
4), 156.0 (С-8а), 154.9 (С-5), 154.2 (C-6′), 151.7 (C-7), 151.4 (C-2′),
137.6 (С-4′), 135.4 (4 C, Ph), 131.2 (2 C, Ci(Ph)), 130.6 (2 C, Ph), 128.4
(4 C, Ph), 125.0 (C-3′), 123.5 (С-5′), 112.5 (C-3), 110.24 (C-6), 110.21
(C-4a), 104.3 (C-8), 37.6 (C-4-CH2), 26.8 (C(CH3)3), 21.3 (CH2CH3), 19.5
(C(CH3)3), 13.7 (CH2CH3).
5-((tert-Butyldiphenylsilyl)oxy)-7-hydroxy-4-propyl-2H-
chromen-2-one (11)
Compound 10 (165 mg, 0.293 mmol) was dissolved in MeOH, Am-
berlyst 16 resin, 4.8 eq/kg (165 mg) was added and the mixture was
refluxed with stirring until reaction completion, as monitored by TLC
(about 5 h). Then, the reaction mixture was cooled to room tempera-
Anal. Calcd for C34H33NO5Si: C, 72.44; H, 5.90; N, 2.48. Found: C,
72.28; H, 6.05; N, 2.37.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H

H
R. F. Fatykhov et al.
Paper
Synthesis
ture and the Amberlyst resin was filtered off. The filtrate was cooled
to –15 °C and the precipitate formed was collected by filtration and
dried under air to give 11.
(5) Ostrowska, K.; Olejarz, W.; Wrzosek, M.; Głuszko, A.; Nowicka,
G.; Szczepański, M.; Materek, I. B.; Kozioł, A. E.; Struga, M.
Biomed. Pharmacother. 2017, 95, 1412.
(6) (a) Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; Kucherenko, A.;
Sheinkman, A. K.; Vilaychack, V.; Lin, L.; Chen, W.; Greenwood,
E. M.; Pengsuparp, T.; Pezzuto, J. M.; Hughes, S. H.; Flavin, T. M.;
Cibulski, M.; Boulanger, W. A.; Shone, R. L.; Xu, Z.-Q. J. Med.
Chem. 1996, 39, 1303. (b) Zembower, D. E.; Liao, S.; Flavin, M. T.;
Xu, Z.-Q.; Stup, T. L.; Buckheit, R. W.; Khilevich, A.; Mar, A. A.;
Sheinkman, A. K. J. Med. Chem. 1997, 40, 1005. (c) Zhang, J.;
Kirchhoff, E. W.; Zembower, D. E.; Jimenez, N.; Sen, P.; Xu, Z.-Q.;
Flavin, M. T. Org. Process Res. Dev. 2000, 4, 577.
(7) (a) Fox, M. E.; Lennon, I. C.; Meek, G. Tetrahedron Lett. 2002, 43,
2899. (b) Liu, Z.-J.; Guo, X.-Y.; Liu, G. Chin. Chem. Lett. 2016, 27,
51. (c) Sun, I.; Hua, J.; Song, X.; Wu, D.; Kong, L.; Sun, Y.; Wang,
D.; Wang, Y.; Chen, N.; Liu, G. Eur. J. Med. Chem. 2013, 67, 39.
(8) (a) Khalymbadzha, I. A.; Chupakhin, O. N.; Fatykhov, R. F.;
Charushin, V. N.; Schepochkin, A. V.; Kartsev, V. G. Synlett 2016,
27, 2606. (b) Khalymbadzha, I. A.; Fatykhov, R. F.; Chupakhin, O.
N.; Charushin, V. N.; Tseitler, T. A.; Sharapov, A. D.; Inytina, A.
K.; Kartsev, V. G. Synthesis 2018, 50, 2423. (c) Gorbunov, E. B.;
Rusinov, G. L.; Ulomskii, E. N.; El’tsov, O. S.; Rusinov, V. L.;
Kartsev, V. G.; Charushin, V. N.; Khalymbadzha, I. A.;
Chupakhin, O. N. Chem. Nat. Compd. 2016, 52, 708.
Colourless crystals; yield: 76 mg (57%); mp 205–207 °C.
IR-Fur (neat): 1694, 1582, 1449, 1355, 1168, 813 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.73–7.71 (m, 4 H, Ph), 7.46–7.37 (m, 6
H, Ph), 6.56 (d, J = 2.3 Hz, 1 H, H-8), 6.48 (s, 1 H, OH), 6.05 (s, 1 H, H-3),
5.90 (d, J = 2.3 Hz, 1 H, H-6), 3.29 (t, J = 7.3 Hz, 2 H, C-4-CH2), 1.76
(sextet, J = 7.3 Hz, 2 H, CH2CH3), 1.11 (s, 9 H, tBu), 1.03 (t, J = 7.3 Hz, 3
H, CH2CH3).
13C NMR (100 MHz, CDCl3):  = 162.4 (C-2), 159.4 (C-4), 159.0 (C-7),
156.7 (C-8a), 155.3 (C-5), 135.4 (4 C, Ph), 131.4 (2 C, Ci(Ph)), 130.4 (2
C, Ph), 128.3 (4 C, Ph), 108.9 (C-3), 105.8 (C-6 or C-4a), 105.7 (C-4a or
C-6), 97.8 (C-8), 37.6 (C-4-CH2), 26.7 (C(CH3)3), 21.4 (CH2CH3), 19.5
(C(CH3)3), 13.8 (CH2CH3).
Anal. Calcd for C28H30O4Si: C, 73.33; H, 6.59. Found: C, 73.21; H, 6.68.
5-Hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-
8-one (13)
To a solution of 12·TNP (1.00 g, 1.61 mmol) in MeOH (50 mL) was
added Amberlyst 16 resin (1.0 g) and the resulting mixture was
stirred overnight at 60 °C. Then, the Amberlyst resin was filtered off
and washed with MeOH. The combined MeOH solution was diluted
with water (250 mL) and cooled to 0 °C. The formed precipitate was
collected by filtration, washed with water and dried under air to pro-
vide 13 (457 mg, 99%) as a white solid. The 1H and 13C NMR spectra
were in full accordance with the published data.4
(9) (a) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65,
8210. (b) Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org.
Chem. 2003, 68, 5720. (c) Katritzky, A. R.; Wang, Z.; Wang, M.;
Wilkerson, C. R.; Hall, C. D.; Akhmedov, N. G. J. Org. Chem. 2004,
69, 6617. (d) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005,
1656. (e) Katritzky, A. R.; Khelashvili, L.; Munawar, M. A. J. Org.
Chem. 2008, 73, 9171.
(10) (a) Lepore, S. D.; Khoram, A.; Bromfield, D. C.; Cohn, P.; Jairaj, V.;
Silvestri, M. A. J. Org. Chem. 2005, 70, 7443. (b) Augustin-
Nowacka, D.; Makowski, M.; Chmurzynski, L. J. Chem. Thermo-
dyn. 2002, 34, 391.
Funding Information
We are grateful to the Russian Science Foundation (project #18-73-
00163, synthesis of compounds 6–11) and the Ministry of Education
and Science of the Russian Federation (project 4.6351.2017/8.9, syn-
(11) (a) Sakthivel, P.; Ilangovan, A.; Kaushik, M. P. Eur. J. Med. Chem.
2016, 122, 302. (b) Mun, J.; Jabbar, A. A.; Devi, N. S.; Yin, S.;
Wang, Y.; Tan, C.; Culver, D.; Snyder, J. P.; Van Meir, E. G.;
Goodman, M. M. J. Med. Chem. 2012, 55, 6738. (c) Yan, J.; Chen,
J.; Zhang, S.; Hu, J.; Huang, L.; Li, X. J. Med. Chem. 2016, 59, 5264.
(d) Yang, Z.; Wu, W.; Wang, J.; Liu, L.; Li, L.; Yang, J.; Wang, G.;
Cao, D.; Zhang, R.; Tang, M.; Wen, J.; Zhu, J.; Xiang, W.; Wang, F.;
Ma, L.; Xiang, M.; You, J.; Chen, L. J. Med. Chem. 2014, 57, 7977.
(e) Trost, B. M.; Bringley, D. A.; Zhang, T.; Cramer, N. J. Am.
Chem. Soc. 2013, 135, 16720.
(12) (a) Nayak, M.; Kim, I. J. Org. Chem. 2015, 80, 11460. (b) Melliou,
E.; Magiatis, P.; Mitaku, S.; Skaltsounis, A.-L.; Chinou, E.;
Chinou, I. J. Nat. Prod. 2005, 68, 78.
(13) (a) Bulman Page, P. C.; Appleby, L. F.; Day, D.; Chan, Y.; Buckley,
B. R.; Allin, S. M.; McKenzie, M. J. Org. Lett. 2009, 11, 1991.
(b) Strong, A. L.; Jiang, Q.; Zhang, Q.; Zheng, S.; Boue, S. M.;
Elliott, S.; Burow, M. E.; Bunnell, B. A.; Wang, G. ACS Med. Chem.
Lett. 2014, 5, 143.
thesis of compounds 12 and 13).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690104.
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References
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 30, A–H