Synthesis of 6-chloronicotinates of steroidal 3β,5α,6β- triols and 3β,5-dihydroxy-6-ketones

Article abstract of DOI:10.1007/s10600-009-9265-6

New esters of 3β,5α,6β-trihydroxysteroids and 3β,5-dihydroxy-6-ketosteroids containing 6-chloropyridine groups characteristic of the alkaloid epibatidine were synthesized by acylation with 6-chloronicotinoylchloride.

Full text of DOI:10.1007/s10600-009-9265-6

Chemistry of Natural Compounds, Vol. 45, No. 2, 2009
SYNTHESIS OF 6-CHLORONICOTINATES OF STEROIDAL
3β,5α,6β-TRIOLSAND 3β,5-DIHYDROXY-6-KETONES
N. V. Kovganko,* Yu. G. Chernov, S. N. Sokolov,
Zh. N. Kashkan, and V. L. Survilo
UDC 547.92
New esters of 3β,5α,6β-trihydroxysteroids and 3β,5-dihydroxy-6-ketosteroids containing 6-chloropyridine
groups characteristic of the alkaloid epibatidine were synthesized by acylation with 6-chloronicotinoylchloride.
Key words: 3β,5α,6β-trihydroxysteroids, 3β,5-dihydroxy-6-ketosteroids, 6-chloronicotinates, 6-chloronicotinoyl-
chloride, synthesis.
Steroids with C -C -sterol skeletons and 3β,5α,6β-triol or 3β,5-dihydroxy-6-ketone groups are interesting as
27 29
biologically active compounds. These triols and dihydroxyketones have in several instances been identified in plants [1]. It
was recently found that some of these compounds have pronounced insecticidal activity [2]. We hypothesized that the insecticidal
activity of these steroids can be increased significantly by adding α-chloropyridine rings to their molecules. This group is a
biologically important structural element of several effective modern insecticides such as imidacloprid, thiacloprid, nitenpyram,
and acetamiprid, which are neonicotinoids [3]. It is also noteworthy that the 6-chloropyridine group occurs in the natural
analgesic epibatidine, which was isolated from the Ecuadorian frog Epipedobates tricolor [4]. Furthermore, the literature
suggests that compounds containing a pyridine ring occur among phytoecdysteroids, which are structurally related to the
aforementioned compounds [5].
R
R
R
1
HO
HO
HO
HO
O
HO
HO
O
HO
O
OH
a: R = H; b: R = Et
1a, b
2a, b
3
6
+
R
1
R
1
Br
R
1
R
1
H
H
HO
HO
O
O
O
OH
4
5a, b
8a, b
7a, b
O
O
4, 5a: R = H, 5b: R = Et
7a,b, 8a,b: R = H, R =
1
O
X
N
O
4, 5a,b, 6: R =
7a,8a:X = Br; 7b, 8b: X = Cl
1
Cl
N
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141, Belarus, Minsk, ul. Akad.
Kuprevicha, 5/2, e-mail: kovganko@iboch.bas-net.by. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 175-179,
March-April, 2009. Original article submitted October 23, 2008.
©
200
0009-3130/09/4502-0200 2009 Springer Science+Business Media, Inc.

13
TABLE 1. Chemical Shifts of C Atoms (CDCl , δ, ppm) in C NMR Spectra of 5a–b, 7a–b, and 8a–b
3
C atom
5a
5b
7a–b*
8a–b*
1
2
3
4
5
6
7
8
9
32.560
26.309
72.476
29.502
80.463
212.201
41.739
37.317
44.282
43.117
21.371
39.449
42.546
56.279
23.921
28.077
56.166
12.015
14.013
35.749
18.618
36.091
23.921
39.530
28.010
22.562
22.818
32.545
26.310
72.514
29.500
80.442
212.287
41.751
37.322
44.268
43.115
21.366
39.513
42.556
56.276
23.925
28.093
56.054
11.960
14.008
36.101
18.687
33.813
26.101
45.729
29.070
18.687
36.072
26.738
74.081 (74.046)
25.920
49.867
203.789
58.483
40.175
45.852
41.294
20.882
38.627
42.658
52.222
22.761
27.809
55.701
12.390
12.699
35.672
18.639
36.027
23.756
39.448
28.020
22.559
22.828
36.330
26.174
74.547 (74.509)
26.853
56.667
210.273
46.646
37.938
53.778
40.976
21.487
39.413
42.980
556.418
23.996
28.010
56.084
12.018
13.099
35.694
18.636
36.067
23.799
39.453
28.010
22.557
22.821
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
-O-C=O
Cl-Py
19.828
23.021
12.013
164.170
124.144 (CH), 125.237 (C),
164.190
124.154 (CH), 125.245 (C),
163.938 (163.786)
124.136 (CH), 125.635
164.003 (163.851)
124.108 (CH), 125.709
139.595 (CH), 151.165 (CH), 139.598 (CH), 151.168 (CH), (125.309) (C), 128.002 (CH), (125.383) (C), 127.974 (CH),
155.677 (C)
155.682 (C)
139.181 (139.600) (CH),
146.768 (C), 151.413
139.151 (139.567) (CH),
146.716 (C), 151.428
(151.170) (CH), 157.961 (151.182) (CH), 155.569 (C)
(155.615) (C)
______
*Data for 6-chloronicotinates 7b and 8b are given in parentheses.
We performed one of the possible chemical transformations of steroidal 3β,5α,6β-triols 1 and 3β-5-dihydroxy-6-
ketones 2 and 3 with the goal of adding to them an α-chloropyridine ring. The transformation consisted of preparing the esters
of these compounds with 6-chloronicotinic acid. 6-Chloronicotinoylchloride that was needed to add 6-chloronicotinic acid to
1-3 was prepared in high yield by reacting 6-methoxynicotinic acid and thionylchloride in refluxing DMF.
Subsequent acylation of 3β,5α,6β-triol 1a by an equimolar amount of 6-chloronicotinoylchloride in refluxing toluene
in the presence of 4-dimethylaminopyridine produced in >70% yield the mono-6-chloronicotinate. The structure of the product
was established using PMR spectra. Thus, resonances of protons of the steroidal part and the 6-chloronicotinoic acid in a 1:1
ratio in the spectra established that the molecule contained both these groups. In this instance, two structural isomers of the
ester as the 3- or 6-(6-chloronicotinate) were possible in principle. The structure of the product from monoacylation of triol 1a
was 3-(6-chloronicotinate) (4) according to the chemical shift of axial proton H-3α, which appeared in the PMR spectrum in
deuteropyridine as a broad multiplet with δ 6.13 ppm. This unambiguously indicated that this proton was geminal to the ester
group.
201

Monoacylation of 5-hydroxy-6-ketosteroids 2a-b and 3 by 6-chloronicotinoylchloride in toluene in the presence of
4-dimethylaminopyridine produced in high yields the corresponding 3-(6-chloronicotinates) 5a-b and 6, respectively. The
structures of these compounds were proved unambiguously by PMR spectra in which resonances of all characteristic protons
13
occurred in the expected ranges. The structures of 5a-b were also confirmed by C NMR spectra (Table 1).
We attempted to add a 7(8)-double bond to the synthesized 6-chloronicotinate of 3β,5α-dihydroxy-6-ketone 5a. We
planned to add the group characteristic of ecdysteroids through bromination of the α-position to the 6-ketone with subsequent
dehydrobromination. The reaction of 5a with Br and HBr in the presence of LiBr in CH CO H:CHCl was rather complicated.
2
3
2
3
Under these conditions, not only the steroid but also the pyridine group of the starting compound underwent reactions. We
isolated 7α-bromo-6-ketones 7 and 6-ketosteroids 8 as corresponding mixtures of 6-bromo- and 6-chloronicotinates from the
products. Despite several attempts, mixtures of 7a-b and 8a-b could not be separated into pure components.
13
The structures of these compounds were established using PMR and C NMR spectra. In particular, the presence in
the PMR spectra of 7a-b of a characteristic doublet at δ 4.21 ppm, which corresponded to resonance of methine proton H-7β
geminal to the Br atom, was interesting. It was also important for proving the structure that the resonance of methine proton
H-3α (δ 5.33 ppm) in the PMR spectrum of starting steroid 5a was shifted to weak field compared with the position of the
resonance for the analogous proton in the spectra of 7a-b (δ 5.01 ppm). This occurred because of the 5α-hydroxy group in the
1,3-diaxial orientation relative to H-3α in 5a. These data led to the conclusion that 7a-b lacked a 5α-hydroxy group. This was
13
also confirmed by the fact that the resonances of C-5, C-6, and C-7 in C NMR spectra had chemical shifts characteristic of
7α-bromo-6-ketosteroids without 5α-hydroxy groups [6].
13
13
The structures of 8a-b were proved analogously using PMR and C NMR spectra. The C NMR spectra in which
the chemical shifts of C-5, C-6, and C-7 suggest that these compounds contain a saturated 6-ketone and lack any functional
groups on C-5 and C-7 are interesting.
The formation of 7a-b and 8a-b by the action on 5a of the Br :HBr mixture in pyridine is not unexpected. First, it is
2
noteworthy that the axial 5α-hydroxy group in 5a hinders significantly bromination at the α-position to the 6-ketone on C-7 to
form the 5α-hydroxy-7α-bromo-6-ketone. Therefore, the more active reagent in this instance was the HBr. We hypothesized
2
that it caused both reduction of the 5α-hydroxy group to 6-ketosteroids 8a-b and nucleophilic substitution by an S mechanism
N
to form 7a-b.
Thus, methods for synthesizing new derivatives of steroidal 3β,5α,6β-triols and 3β-5-dihydroxy-6-ketones that
contained an added 6-chloronicotinic acid were developed. Biological activity of the synthesized compounds will be reported
separately.
EXPERIMENTAL
Melting points were determined on a Kofler block. IR spectra in KBr disks were recorded on a UR-20 instrument at
−1
13
700-3600 cm . PMR and C NMR spectra in deuterated solvents were obtained on a Bruker Avance 500 NMR spectrometer
1
13
(operating frequency 500.13 MHz for H and 125.75 MHz for C). Chemical shifts are given relative to TMS (internal
standard). The course of reactions and purity of products were monitored using Merck Kieselgel 60F plates.
254
6-Chloroniccotinoylchloride. A suspension of 6-methoxynicotinic acid (15.31 g, 0.1 mol) in thionylchloride
(44 mL, 0.6 mol) was refluxed for 2 h, treated over 30 min with DMF (7.71 mL, 0.1 mol), and refluxed for another 3 h. When
the reaction was finished, residual thionylchloride and DMF were distilled at reduced pressure (water aspirator) from the
reaction flask with heating in an oil bath at from 20 to 80°C. The product was slowly distilled in vacuo (0.5-1.0 mm Hg) to
afford 6-chloronicotinoylchloride (14.62 g, 0.083 mol, 83%), bp 72-78°C. The distilled product was recrystallized from
petroleum ether to isolate analytically pure 6-chloronicotinoylchloride (12.11 g, 0.069 mol, 69%), mp 45-48°C (petroleum
ehter) (lit. [7] mp 45-47°C). PMR spectrum (CDCl , δ, ppm, J/Hz): 7.52 (1H, d, J = 8.5, H-5), 8.32 (1H, dd, J = 8.5, J = 2.5,
3
1
2
H-4), 9.09 (1H, d, J = 2.5, H-2).
5α-Cholestan-3β,5,6β-triol-3-(6-chloronicotinate) (4). A mixture of 1a (0.44 g, 1.05 mmol) (synthesized by the
literature method [8]) and 6-chloronicotinoylchloride (0.20 g, 1.14 mmol) in toluene (30 mL) was refluxed for 2 h 20 min.
According to TLC, the reaction proceeded only slightly. Then, the mixture was treated with 4-dimethylaminopyridine
(0.015 g), refluxed for another 6 h, and cooled to room temperature. The toluene was evaporated in vacuo in a rotary evaporator.
202

The solid was dissolved in CH Cl (80 mL); washed successively with water (2 × 20 mL), aqueous NaHCO solution
2
2
3
(5%, 2 × 20 mL), and water (20 mL); and dried over MgSO . The solvent was evaporated. The solid (0.58 g) was rapidly
4
chromatographed over a short column of silica gel with elution by CH Cl :CH OH (50:1) to afford crude product (0.50 g).
2
2
3
Recrystallization from CH CN (70 mL) gave chromatographically pure homogeneous 4 (0.36 g), mp 220-223°C. A second
3
−1
crystallization of the mother liquor isolated additional 4 (0.060 g). Total yield 0.42 g (71.4%). IR spectrum (ν, cm ): 3440
(OH), 1700 (O–C=O), 1590 (C=C
), 780 (C–Cl). PMR spectrum (C D N, δ, ppm, J/Hz): 0.76 (3H, s, 18-Me), 0.90 (6H, d,
arom
5 5
J = 6.5, 26-Me, 27-Me), 1.04 (3H, d, J = 6.5, 21-Me), 1.65 (3H, s, 19-Me), 2.99 (1H, t, J = 12, H-7α), 4.22 (1H, br.s, H-6α),
6.13 (1H, m, W/2 = 23, H-3α), 7.53 (1H, d, J = 8.5, H-5′), 8.31 (1H, dd, J = 8.5, J = 2.5, H-4′), 9.20 (1H, d, J = 2.5, H-2′).
1
2
3β,5-Dihydroxy-5α-cholestan-6-one 3-(6-chloronicotinate) (5a). A mixture of 2a (0.87 g, 2.08 mmol) (prepared
by the literature method [8]), 6-chloronicotinoylchloride (0.39 g, 2.2 mmol), and 4-dimethylaminopyridine (0.03 g) in toluene
(50 mL) was refluxed for 7.5 h and cooled. Toluene was removed in a rotary evaporator. The solid was dissolved in CH Cl
2
2
(150 mL); washed successively with water (2 × 50 mL), NaHCO solution (5%, 2 × 50 mL), and water (50 mL); and dried over
3
MgSO . Solvent was distilled. The solid (1.08 g) was rapidly chromatographed over a short column of silica gel with elution
4
by CH Cl :CH OH (100:1) to isolate crude product (0.88 g). Crystallization from dichloroethane gave 5a (0.72 g), mp 264-
2
2
3
266°C. Crystallization of the mother liquors from dichloroethane (10 mL) isolated additional 5a (0.08 g). Total yield 0.80 g
−1
(68.9%). IR spectrum (ν, cm ): 3440 (OH), 1715 (O–C=O), 1705 (C=O), 1590 (C=C
), 780 (C–Cl). PMR spectrum
arom
(CDCl , δ, ppm, J/Hz): 0.66 (3H, s, 18-Me), 0.86 (3H, d, J = 6.5, 26-Me), 0.87 (3H, d, J = 6.5, 27-Me), 0.88 (3H, s, 19-Me),
3
0.92 (3H, d, J = 6.5, 21-Me), 2.15 (1H, dd, J = 13, J = 4.5, H-4α), 2.77 (1H, t, J = 12, H-7α), 5.33 (1H, m, W/2 = 23, H-3α),
1
2
7.41 (1H, d, J = 8.5, H-5′), 8.21 (1H, dd, J = 8.5, J = 2.5, H-4′), 8.96 (1H, d, J = 2.5, H-2′); (C D N, δ, ppm, J/Hz): 0.67 (3H,
1
2
5 5
s, 18-Me), 0.917 (3H, d, J = 6.5, 26-Me), 0.920 (3H, d, J = 6.5, 27-Me), 0.97 (3H, s, 19-Me), 0.98 (3H, d, J = 6.5, 21-Me), 2.61
(1H, dd, J = 13, J = 4.5, H-4α), 3.16 (1H, t, J = 12, H-7α), 5.92 (1H, m, W/2 = 23, H-3α), 7.53 (1H, d, J = 8.5, H-5′), 8.30
1
2
(1H, dd, J = 8.5, J = 2.5, H-4′), 9.19 (1H, d, J = 2.5, H-2′).
1
2
(24R)-3β,5-Dihydroxy-5α-stigmastan-6-one 3-(6-chloronicotinate) (5b). A mixture of 2b (0.89 g, 2 mmol) prepared
from 1b by the literature method [1]), 6-chloronicotinoylchloride (0.37 g, 2.1 mmol), and 4-dimethylaminopyridine (0.05 g,
0.04 mmol) in toluene (40 mL) was refluxed for 5 h with passage of a weak stream of Ar through the mixture. Toluene was
evaporated at reduced pressure. The solid was dissolved in CH Cl (100 mL); washed successively with water (30 mL),
2
2
aqueous NaHCO solution (5%, 2 × 30 mL), and water (2 × 30 mL); and dried over MgSO . The desiccant was filtered off and
3
4
washed with CH Cl (2 × 50 mL). The CH Cl was evaporated in vacuo. The solid was chromatographed over a column of
2
2
2
2
silica gel with elution by CH Cl (100 mL) and then CH Cl :CH OH (100:1, 800 mL) to afford crude product (0.94 g) that
2
2
2
2
3
was recrystallized from dichloroethane to afford 5b (0.79 g, 1.35 mmol, 68%), mp 233-237°C. PMR spectrum (CDCl , δ,
3
ppm, J/Hz): 0.66 (3H, s, 18-Me), 0.88 (3H, s, 19-Me), 0.92 (3H, d, J = 6.5, 21-Me), 2.15 (1H, dd, J = 13, J = 4.5, H-4α), 2.73
1
2
(1H, s, 5α-OH), 2.77 (1H, t, J = 12.5, H-7α), 5.33 (1H, m, W/2 = 23, H-3α), 7.41 (1H, d, J = 8.5, H-5′), 8.21 (1H, dd, J = 8.5,
1
J = 2.5, H-4′), 8.96 (1H, d, J = 2.5, H-2′).
2
3β,5-Dihydroxy-5β-chloestan-6-one (3). Compound 2a (35.4 g) was dissolved with heating in CH OH (1.2 L),
3
treated with water (100 mL) and KOH (240 g), refluxed for 4 h, left overnight at room temperature, evaporated in a rotary
evaporator to half the volume, acidified to pH 3.4 by adding HCl (36%), diluted with water (1.5 L), left overnight in a refrigerator,
and extracted with CH Cl (1.0 L). The resulting crystals were filtered off. The organic layer of the filtrate was separated from
2
2
the aqueous layer. The aqueous layer was extracted with additional portions of CH Cl (400 and 200 mL). The combined
2
2
organic extract was treated with water (750 mL). The resulting crystalline precipitate was filtered off. The organic layer of the
filtrate was separated. The majority of the solvent was distilled at normal pressure; the residue, in vacuo in a rotary evaporator
to afford an oily product (27.8 g). A portion of the product (5.0 g) was chromatographed over a column of silica gel with
elution by CH Cl :CH OH (100:1, 80:1, 40:1) to afford 3 (4.7 g, 74%).
2
2
3
3β,5-Dihydroxy-5β-cholestan-6-one 3-(6-chloronicotinate) (6). A mixture of 3 (0.87 g, 2.08 mmol), 6-chloro-
nicotinoylchloride (0.39 g, 2.2 mmol), and 4-dimethylaminopyridine (0.03 g) in toluene (50 mL) was refluxed for 12 h and
cooled. Toluene was evaporated in a rotary evaporator. The solid was dissolved in CH Cl (150 mL); washed successively
2
2
with water (2 × 50 mL), aqueous NaHCO solution (5%, 2 × 50 mL), and water (50 mL); and dried over MgSO . Solvent was
3
4
distilled. The solid (1.20 g) was rapidly chromatographed over a short column of silica gel with elution by CH Cl (300 mL)
2
2
and then CH Cl :CH OH (100:1, total volume 808 mL) to afford crude product (0.85 g). Crystallization from petroleum ether
2
2
3
(bp 85-92°C) gave 6 (0.66 g), mp 199-201.5°C. A second crystallization of the solid after evaporation of mother liquor from
203

−1
petroleum ether (10 mL) produced additional 6 (0.06 g). Total yield 0.72 g (59%). IR spectrum (ν, cm ): 3450 (OH), 1700
(O–C=O, C=O), 1590 (C=C ), 780 (C–Cl). PMR spectrum (C D N, δ, ppm, J/Hz): 0.63 (3H, s, 18-Me), 0.92 (6H, d,
arom
5 5
J = 6.5, 26-Me, 27-Me), 0.95 (3H, s, 19-Me), 1.00 (3H, d, J = 6.5, 21-Me), 5.55 (1H, br.s, H-3α), 5.70 (1H, br.s, 5α-OH), 7.49
(1H, d, J = 8.5, H-5′), 8.48 (1H, dd, J = 8.5, J = 2.5, H-4′), 9.37 (1H, d, J = 2.5, H-2′).
1
2
Further elution by CH Cl :CH OH (100:1) isolated starting 3 (0.23 g, 12.3%).
2
2
3
Bromination of (24R)-3β,5-dihydroxy-5α-cholestan-6-one 3-(6-chloronicotinate) (5a). Steroid 5a (0.56 g, 1 mmol)
was dissolved with heating to 70°C in a mixture of acetic acid (20 mL) and CHCl (10 mL); treated at this same temperature
3
with a solution of Br (2 M, 0.65 mL, 1.3 mmol of pure Br ) in HOAc, LiBr (0.09 g, 1 mmol), and HBr (40%, 0.14 mL, 1 mmol
2
2
HBr); refluxed for 6 h, and evaporated at reduced pressure. The solid was dissolved in CH Cl (40 mL); washed successively
2
2
with saturated aqueous NaHCO (2 × 30 mL), aqueous Na SO solution (10%, 30 mL), and water (2 × 30 mL), and dried over
3
2
3
MgSO . The desiccant was filtered off and washed with CH Cl (2 × 20 mL). The CH Cl was evaporated in vacuo. The solid
4
2
2
2
2
was chromatographed over a column of silica gel with elution by dichloroethane (1900 mL) and dichloroethane:CH OH
3
(100:1, 400 mL) to afford the following fractions.
Fraction 1: A mixture of 7a and 7b (0.16 g). Recrystallization of the mixture of 7a and 7b from petroleum ether
(bp 70-80°C) and EtOAc (8 mL:0.8 mL) gave a mixture of 7a-b (0.12 g) in a 2:1 ratio, respectively (according to PMR
spectra). PMR spectrum (CDCl , δ, ppm, J/Hz): 7a: 0.70 (3H, s, 18-Me), 0.83 (3H, s, 19-Me), 0.869 (3H, d, J = 6.5, 26-Me),
3
0.875 (3H, d, J = 6.5, 27-Me), 0.93 (3H, d, J = 6.5, 21-Me), 3.37 (1H, dd, J = 12.5, J = 3.0, H-5α), 4.21 (1H, d, J = 3.5,
1
2
H-7β), 5.01 (1H, m, W/2 = 23, H-3α), 7.59 (1H, d, J = 8.0, H-5′), 8.12 (1H, dd, J = 8.0, J = 2.5, H-4′), 8.94 (1H, d, J = 2.5,
1
2
H-2′); 7b: 0.70 (3H, s, 18-Me), 0.83 (3H, s, 19-Me), 0.869 (3H, d, J = 6.5, 27-Me), 0.875 (3H, d, J = 6.5, 26-Me), 0.93 (3H, d,
J = 6.5, 21-Me), 3.37 (1H, dd, J = 12.5, J = 3.0, H-5α), 4.21 (1H, d, J = 3.5, H-7β), 5.01 (1H, m, W/2 = 23, H-3α), 7.42 (1H,
1
2
d, J = 8.0, H-5′), 8.24 (1H, dd, J = 8.0, J = 2.5, H-4′), 8.98 (1H, d, J = 2.5, H-2′).
1
2
Fraction 2: A mixture of 8a and 8b (0.27 g) in a 2:1 ratio, respectively (according to PMR spectra). PMR spectrum
(CDCl , δ, ppm, J/Hz): 8a: 0.67 (3H, s, 18-Me), 0.83 (3H, s, 19-Me), 0.866 (3H, d, J = 6.5, 26-Me), 0.871 (3H, d, J = 6.5,
3
27-Me), 0.92 (3H, d, J = 6.5, 21-Me), 4.95 (1H, m, W/2 = 23, H-3α), 7.58 (1H, d, J = 8.0, H-5′), 8.11 (1H, dd, J = 8.5, J = 2.5,
1
2
H-4′), 8.94 (1H, d, J = 2.0, H-2′); 8b: 0.67 (3H, s, 18-Me), 0.83 (3H, s, 19-Me), 0.866 (3H, d, J = 6.5, 26-Me), 0.871 (3H, d,
J = 6.5, 27-Me), 0.92 (3H, d, J = 6.5, 21-Me), 4.95 (1H, m, W/2 = 23, H-3α), 7.41 (1H, d, J = 8.0, H-5′), 8.23 (1H, dd, J = 8.5,
1
J = 2.5, H-4′), 8.98 (1H, d, J = 2.0, H-2′).
2
REFERENCES
1.
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