Expansion of the aromatic part of Cinchona alkaloids. Annulation of quinolines with phenoxazine motifs

Article abstract of DOI:10.1016/j.tet.2017.11.072

An oxidative cross-coupling strategy for quinoline ring annulation in Cinchona alkaloids has been developed. Key-reaction optimization by changing oxidants and adjusting the nucleophilicity of the 2-aminophenols led to cupreine and cupreidine expanded with the phenoxazinone unit in 56–75% yield. The stereochemical integrity of the obtained alkaloid structures was confirmed by combined experimental and computed CD and NMR data. The conformational study revealed a fast equilibrium of the three conformers, differing in the orientation of the pyrido[a-3,2]phenoxazine moiety.

Full text of DOI:10.1016/j.tet.2017.11.072

Tetrahedron 74 (2018) 308e315
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expansion of the aromatic part of Cinchona alkaloids. Annulation of
quinolines with phenoxazine motifs
Małgorzata W a˛ si nꢀ ska-Kałwa, Mirosław Giurg, Przemysław J. Boraty nꢀ ski, Jacek Skar z_ ewski*
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 August 2017
Received in revised form
An oxidative cross-coupling strategy for quinoline ring annulation in Cinchona alkaloids has been
developed. Key-reaction optimization by changing oxidants and adjusting the nucleophilicity of the 2-
aminophenols led to cupreine and cupreidine expanded with the phenoxazinone unit in 56e75%
yield. The stereochemical integrity of the obtained alkaloid structures was confirmed by combined
experimental and computed CD and NMR data. The conformational study revealed a fast equilibrium of
the three conformers, differing in the orientation of the pyrido[a-3,2]phenoxazine moiety.
20 November 2017
Accepted 27 November 2017
Available online 2 December 2017
©
2017 Elsevier Ltd. All rights reserved.
Keywords:
Cinchona alkaloids
Oxidative cross-coupling
Quinoline ring annulation
Phenoxazinones
Conformational study
1. Introduction
conjugation of quinine with other biologically active compounds
has introduced promising cytotoxic and inhibitory properties.
16
Cinchona alkaloids constitute a privileged class of easily avail-
able natural compounds widely used in organic synthesis. In
On the other hand, various phenoxazinones are well known for
their biological activities. A notable example is actinomycin D, a
1
17
particular, the last decades have witnessed a remarkable develop-
ment of their applications in asymmetric reactions in the roles of
natural polypeptide antibiotic containing a phenoxazinone moiety,
which is an approved anti-cancer drug. Additionally, some phe-
18
chiral ligands,2 organocatalysts, and phase-transfer catalysts.
3
4
A
noxazinone compounds are used as synthetic dyes and fluo-
19
unique chiral architecture and multiple functional groups render
rophores. All of these prompted us to develop new Cinchona
alkaloid derivatives with an extended aromatic system incorpo-
rating the phenoxazinone fragment.
them interesting targets for structural modifications. Catalytically
valuable ethers,5 thioureas, and squaramides were obtained by
6
7
transforming the 9-OH group. Modifications of the quinoline moi-
0
ety are much less abundant. Specifically, conversion of the C-6
2
. Results and discussion
8
9
methoxy group into an OH group and NR
2
groups, and trans-
0
0
formations at C-2 and C-3 with organometallic compounds were
We decided to focus on the annulation of cupreine and cuprei-
performed.10 Moreover, the C-5 position was modified by instal-
0
dine in order to extend their quinoline moieties and obtain phe-
noxazinone hybrids (Fig. 1).
The well established synthetic route to phenoxazinones relies
on the intramolecular oxidative coupling of two ortho-amino-
phenols (Scheme 1). Many different oxidants have been used for
the efficient self-condensation of various substituted 2-
aminophenols, including
NaIO
the presence of activators
dimerization is catalyzed by phenoxazinone synthase. A mecha-
nism of the formation of the phenoxazinone system has been
1
1
12
lation of nitrogen substituents such as urea and thiourea that
11a,13
resulted in the formation of fused oxazolinone ring.
Recently,
annulation of the quinoline has led to a tetrazole alkaloid deriva-
tive, which was an effective organocatalyst. However, other aro-
matic annulations have not been reported so far.
14
Beside their extraordinary catalytic potency, Cinchona alkaloids
20
21,22
K
2
Cr
2
O ,
7
PbO
2
,
3 6
K Fe(CN) ,
15
are known for their medicinal applications.
Moreover,
22,23
24
2,25
3
,
benzoquinones, as well as oxygen and peroxides in
2
26
or laccase. In nature, the oxidative
27
*
Corresponding author.
E-mail address: jacek.skarzewski@pwr.wroc.pl (J. Skar z_ ewski).
2
8
proposed (Scheme 1).
https://doi.org/10.1016/j.tet.2017.11.072
040-4020/© 2017 Elsevier Ltd. All rights reserved.
0

M. W a˛ si nꢀ ska-Kałwa et al. / Tetrahedron 74 (2018) 308e315
309
Fig. 1. Phenoxazine-based Cinchona alkaloid derivatives 1 and 2.
Scheme 1. Simplified mechanism for oxidative homo-condensation of substituted o-aminophenols.
However, the synthesis of unsymmetrical condensation prod-
ucts by the oxidative cross-coupling between two different de-
rivatives of 2-aminophenol still presents a challenge. As proved by
the Takusagawa,21 Moody, and Gu groups it requires a specific
oxidant and strictly controlled reaction conditions. Nonetheless the
desired products were obtained in modest yields only.
22
23
Thus, prior to modification of Cinchona alkaloids, we explored
Scheme 3. Synthesis of 7.
the feasibility of cross-coupling of simple reactants using H
ebselen or horseradish peroxidase, and MnO /ligand oxidations
51e91% yield, for the details, see Supplementary material). When
2 2
O /
2
(
available 10,11-dihydroquinine and 10,11-dihydroquinidine with an
aqueous solution of hydrobromic acid at reflux. Then, nitration
with fuming nitric acid was carried out affording the 5 -nitro de-
rivatives 12 and 14 in 68% and 81% yields, respectively. Subsequent
catalytic hydrogenation of the nitro compounds gave the corre-
sponding 5 -amino alkaloids 13 and 15. For each corresponding
step of the syntheses noticeably higher yields were obtained for the
quinidine-derived products (Scheme 4).
2
9
these conditions were applied in the reaction of 2-aminophenol
with 5-amino-6-hydroxyquinoline (6) the outcome was homo-
coupling of 2-aminophenol only. By lowering the nucleophilicity
of o-aminophenol by acetylation at nitrogen (as in 5a), we obtained
up to 1% of the heterocoupled product 8. However, the desired
0
0
product 8 was isolated in 10% yield when sodium iodate (NaIO
was used as an oxidant. Thus, for further tests we applied NaIO to
run the reaction with substituted N-acetyl-o-aminophenols
Scheme 2). The use of 5-methoxy-aminophenol (5b) resulted in
3
)
3
Ultimately, we carried out the oxidative cross-coupling reaction
in the same manner as for the model experiments. The 5 -amino
0
(
better yields, presumably because of higher stability of the oxidized
intermediate (cf. Scheme 1).
derivatives of cupreine 13 and cupreidine 15 when subjected to the
reaction with the selected aminophenol 5b afforded the desired
cross-coupling products in good yields (Scheme 5).
We also synthesized 5-amino-6-hydroxy-4-methyl-quinoline
(
7) (Scheme 3), which is chemically closer to the Cinchona alkaloid
In prospect of further modifications of new Cinchona analogs, a
free amino group at the 10 position of the phenoxazinone moiety is
0
aromatic unit. The oxidative cyclocondensation proceeded with
even higher yield than for 6 (Scheme 2).
desirable. For this purpose the amino group in 2-amino-5-
methoxyphenol was protected with a Boc group giving 5c. Using
the same protocol, we obtained the condensation products 1b and
2b in 72e75% yield, the highest in the series. Deprotection was
carried out with an excess of trifluoroacetic acid in dichloro-
Overall, these model experiments confirmed that sodium iodate
was a suitable oxidant in the cross-coupling reaction. Moreover, it
seems that the presence of a substituent at the 4 position of the
quinoline ring significantly improves the reaction efficiency. With
this consideration in mind, we prepared modified Cinchona alka-
loids amenable for the coupling. The derivatives 13 and 15 with 5 -
amino and 6 -hydroxyl groups were prepared in 3e4 step pro-
cedures (Scheme 4). 10,11-Dihydrocupreine (3) and 10,11-
dihydrocupreidine (4) were obtained by treating commercially
0
methane and furnished the desired 10 -amines 1c and 2c in good
0
yields.
0
A preliminary test showed that the free amine 1c exhibited
some stereoselectivity in the copper-catalyzed Henry reaction (see
Supplementary material). Biological assays of the Cinchona
Scheme 2. Oxidative coupling of 5a-b with 5-amino-6-hydroxyquinolines 6 and 7 giving pyrido[3,2-a]phenoxazin-9-ones 8 and 9.

310
M. W a˛ si nꢀ ska-Kałwa et al. / Tetrahedron 74 (2018) 308e315
0
0
Scheme 4. Synthesis of 5 -amino-10,11-dihydrocupreine (13) and 5 -amino-10,11-dihydrocupreidine (15).
Scheme 5. Aromatic oxidative cross-coupling of Cinchona alkaloid derivatives.
alkaloid-phenoxazinone hybrids for cytotoxic and inhibitory
properties are under-way.
rotamers was fast on the NMR time-scale down to 190 K. Conse-
quently, an upper limit for the rotational barrier was estimated at
9
kcal/mol. This is in agreement with the results of a PM6 geometry
scan (see Supplementary material), and very close to the value
2
.1. Conformation
reported for unmodified alkaloids (8.3 kcal/mol by dynamic
31
NMR).
The stereodifferentiating and catalytic properties of Cinchona
To confirm the stereochemical identity of the two di-
astereoisomers, CD spectra of 1a and 2a were recorded. For each of
the compounds, both long-wavelength (450, 355 nm) and short-
wavelength (315, 290, 270 nm) Cotton effects revealed nearly
perfect mirror-images (Fig. 3). The CD spectra remain in qualitative
agreement with TD-DFT calculation (see Supplementary material).
alkaloids depend on their conformation. Therefore, it was inter-
esting to examine how a substantial alteration to the aromatic ring
system of the alkaloids would affect their conformational proper-
ties. Thus, we employed NMR and CD spectroscopy combined with
DFT calculation. It was found that for the obtained phenoxazine
hybrids 1a and 2a there exists an equilibrium of three conformers.
Their proposed structures differing only slightly in energy calcu-
lated at the DFT/B3LYP/CC-pVDZ level of theory are shown in Fig. 2.
Their presence was consistent with the observed NOESY in-
teractions. Similar conformations were observed for unmodified
quinine and quinidine.30
3. Conclusion
In conclusion, an unprecedented quinoline moiety annulation in
Cinchona alkaloids has been developed. The method is based on
simple oxidative cross-coupling of electron rich N-acylated 2-
aminophenols with quinoline-derived aminophenols by applica-
tion of sodium iodate. The analysis of a series of theoretical and
experimental data showed that enlargement of the quinoline ring
The best fit of experimental and GIAO/DFTchemical shifts for 13C
1
and H nuclei was obtained for a 0.1:0.6:0.3 ratio of syn-closed(1),
anti-open, and syn-closed(2) conformer populations (for more de-
tails, see Supplementary material). The interconversion of the

M. W a˛ si nꢀ ska-Kałwa et al. / Tetrahedron 74 (2018) 308e315
311
0 0 0
1 2
t : C2 eC1 eC9eC8 and t : C1 eC9eC8eN1 for 1a (top) and 2a (bottom) at the DFT/B3LYP/CC-pVDZ level of
Figure 2. Computed low energy conformers and dihedral angles
theory.
referenced to the respective residual 1H or 13C signals of the sol-
ꢁ
4
vents. CD and UV spectra were recorded for 4 ꢀ 10 M solutions in
dichloromethane in 2-mm quartz cuvettes on a JASCO J-1500 cir-
cular dichroism spectrophotometer. Infrared spectra (4000-
ꢁ
1
4
7
00 cm ) were collected on a Fourier transform, Bruker VERTEX
0V spectrometer using diamond ATR accessory. High resolution
mass spectra were collected using electrospray ionization on Wa-
ters LCT Premier XE TOF instrument. Quinine and dihydroquinidine
hydrochloride were purchased from Buchler GmbH. Compounds
3
2
33
34
5
b, 5c, and 6 were prepared according to the literature
procedures.
4.2. General procedure for nitration of 3 and 4. Preparation of 12
and 14
A 100 mL flat bottomed flask was charged with fuming nitric
ꢂ
acid (4.0 mL) and cooled to ꢁ5 C. Dihydrocupreine (3) or dihy-
Fig. 3. Comparison of experimental CD spectra of 2a (blue) and 1a (red).
drocupreidine (4) (1.0 g, 3.2 mmol) was carefully added in small
portions, keeping the temperature below 0 C. The reaction mixture
ꢂ
ꢂ
by 5,6-annulation does not affect the conformation or dynamics
significantly as compared to the native Cinchona alkaloids.
was allowed to stir for 15 min at ca. ꢁ5 C, then poured onto 20 g of
crushed ice. The pH was brought to 8e9 using 25% NaOH aqueous
solution. The precipitate was filtered, and dissolved in 3/1 v/v
chloroform/methanol solution. The aqueous filtrate was evaporated
to dryness under reduced pressure, and the residual solid was
extracted several times with 3/1 v/v chloroform/methanol solution.
4
. Experimental section
4
.1. General
2 4
The combined organic phases were dried over Na SO , evaporated
under reduced pressure and subjected to column chromatography
on silica gel (70e230 mesh) with 3/1 v/v chloroform/methanol.
Melting point were determined using an Electrothermal IA
9
1100 digital melting-point apparatus using the standard open
1
13
capillary method and are uncorrected. H and C NMR spectra
400, 600 MHz and 100, 151 MHz, respectively) were collected on
Jeol 400yh and Bruker Avance II 600 instruments. NMR spectra
recorded in CDCl , methanol-d , DMSO-d , and CF CO D were
0
13
(
4.2.1. 10,11-Dihydro-5 -nitro-cupreine (12)
Dark red solid (0.77 g, 68%) mp 140e142 C (dec). R
ꢂ
f
¼ 0.48 (3/1,
ꢁ
1
3
4
6
3
2
v/v chloroform/methanol);nmax (ATR)/cm 2200e3500 (br), 3039,

312
M. W a˛ si nꢀ ska-Kałwa et al. / Tetrahedron 74 (2018) 308e315
2
957, 2931, 2877, 1608, 1504 (s), 1416, 1315 (br),1257, 1118, 975, 822,
(d, J ¼ 8.9 Hz, 1H), 6.30 (s, 1H), 4.10 (dd, J ¼ 9.9, 9.4 Hz, 1H), 3.76
746, 542, 468; (400 MHz, CD
d
H
3
OD) 8.59 (d, J ¼ 4.7 Hz, 1H), 7.94 (d,
(ddd, J ¼ 12.5, 8.3,1.8 Hz,1H), 3.46e3.36 (m, 2H), 3.26 (ddd, J ¼ 12.5,
9.1, 9.1 Hz, 1H), 2.26 (dd, J ¼ 13.1, 9.9 Hz, 1H), 1.97 (s, 1H), 1.95e1.89
(m,1H),1.88e1.83 (m, 2H),1.68e1.51 (m, 2H),1.21 (ddd, J ¼ 13.1, 9.4,
J ¼ 9.3 Hz, 1H), 7.92 (d, J ¼ 4.7 Hz, 1H), 7.36 (d, J ¼ 9.3 Hz, 1H), 5.45
(
(
1
d, J ¼ 0.8 Hz, 1H), 4.24e4.13 (m, 1H), 3.60e3.49 (m, 2H), 3.15e3.25
m, 1H), 2.99 (ddd, J ¼ 12.8, 4.4, 2.8 Hz, 1H), 2.13e2.0 (m, 3H),
4.9 Hz,1H), 0.96 (t, J ¼ 7.4 Hz, 3H);
C 3
d (150 MHz, CD OD) 147.9,147.4,
.99e1.89 (m, 1H), 1.88e1.77 (m, 1H), 1.40e1.23 (m, 3H), 0.84 (t,
146.6, 145.3, 129.2, 122.7, 121.1, 120.9, 119.7, 71.2, 62.8, 51.4, 50.5,
J ¼ 7.4 Hz, 3H);
d
C
(100 MHz, CD
3
OD) 158.7, 146.4, 142.7, 141.8, 134.6,
36.3, 26.4, 25.5, 24.7, 19.0, 11.8; HRMS (ESI-TOF) calcd. for
þ
1
34.2, 127.5, 122.5, 120.3, 67.9, 62.2, 57.8, 46.0, 36.8, 27.9, 25.8, 25.7,
C
19
H
26
N
3
O
2
[MþH] : 328.2020, found: 328.2011.
þ
19.0, 11.9; HRMS (ESI-TOF) calcd for C19
H N
24 3
O
4
[MþH] : 358.1761,
found: 358.1755.
4.4. General procedure for the synthesis of phenoxazinone
derivatives of Cinchona alkaloids 1a, 1b and 2a, 2b
0
4
.2.2. 10,11-Dihydro-5 -nitro-cupreidine (14)
ꢂ
Dark red solid (0.93 g, 81%), mp 145e146 C (dec) R
v/v chloroform/methanol);
f
¼ 0.48 (3/1,
To a mixture of the amino alkaloid derivative 13 or 15 (1.0 equiv)
and N-acyl-2-amino-5-methoxyphenol 5b or 5c (1.5 equiv) in
ꢁ
1
nmax (ATR)/cm 3322 (br), 2959, 2934,
1
(
7
618, 1515, 1423, 1311, 1243, 1116, 989, 837, 750, 450, 443;
600 MHz, CD
OD) 8.50 (d, J ¼ 4.6 Hz, 1H), 7.86 (d, J ¼ 4.6 Hz, 1H),
.85 (d, J ¼ 9.4 Hz,1H), 7.28 (d, J ¼ 9.4 Hz,1H), 5.50 (s,1H), 3.83 (ddd,
J ¼ 12.5, 8.8, 2.2 Hz, 1H), 3.54e3.45 (m, 2H), 3.39 (dd, J ¼ 12.8,
.9 Hz, 1H), 3.26 (ddd, J ¼ 12.2, 9.4, 9.4 Hz, 1H), 2.24 (dd, J ¼ 12.8,
0.4 Hz, 1H), 1.94 (s, br, 1H), 1.91e1.80 (m, 3H), 1.62e1.51 (m, 2H),
.03 (ddd, J ¼ 13.4, 9.3, 5.3 Hz, 1H), 0.94 (t, J ¼ 7.4 Hz, 3H);
150 MHz, CD OD) 161.2, 145.3, 142.1, 141.0, 135.0, 133.8, 129.2,
d
H
3
methanol, a solution of NaIO (1.5 equiv) in water was added
dropwise at room temperature. The resulting mixture was stirred
for three hours, and extracted with chloroform. The combined
3
organic phases were dried over anhydrous Na
2
SO
4
, filtered, and the
ꢂ
9
1
1
(
solvent was evaporated at 30 C under reduced pressure. The
products were purified by column chromatography on silica gel
(70e230 mesh) with chloroform/methanol 10:1 or 20:1 v/v.
d
C
3
1
22.0, 120.6, 68.1, 62.3, 52.2, 50.5, 36.2, 26.6, 25.3, 24.4, 18.4, 11.8;
4.4.1. (R)-(10-Acetamino-9-oxo-pyrido[3,2-a]phenoxazin-1-
yl)((1S,2S,5R)-5-ethylquinuclidin-2-yl)methanol (1a)
þ
HRMS (ESI-TOF) calcd for C19
H N
24 3
O
4
[MþH] : 358.1761, found:
3
58.1763.
Prepared according to the general procedure using 13 (82.0 mg,
0
.25 mmol) and 2-hydroxy-5-metoxyacetanilide (5b, 68.0 mg,
0
4
.3. General procedure for the synthesis of 5 -amino derivatives of
0.38 mmol), in methanol (3.0 mL) and solution of NaIO (73.8 mg,
3
alkaloids, 13 and 15
0.38 mmol) in water (3.0 mL). The crude was subjected to column
chromatography (10/1, v/v chloroform/methanol) giving desired
product 1a as a dark red solid (66.0 mg, 0.14 mmol, 56%) mp
0
To a 100 mL pressure vessel equipped with a stir bar, 5 -nitro
derivative 12 or 14 (1.0 equiv) in methanol and 5% palladium on
charcoal (0.08 equiv) were added. The reactor was then flushed
with argon and the atmosphere was replaced with 3 bar of
hydrogen. The mixture was stirred for three hours, and palladium
was removed by filtration through Celite. The reaction was
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (70e230 mesh) with 3/1, v/v chloro-
form/methanol.
ꢂ
241.5e243.5 C (dec) R
n
f
¼ 0.36 (10/1, v/v chloroform/methanol);
ꢁ
1
max (ATR)/cm 3265, 2955, 2926, 2875, 1611, 1585, 1565, 1488,
1437, 1366, 1338, 1158, 1004, 873, 835, 591, 522, 469; (600 MHz,
CDCl
d
H
3
) 8.92 (d, J ¼ 4.6 Hz, 1H), 8.56 (s, 1H), 8.54 (s, 1H), 8.24 (d,
J ¼ 9.2 Hz, 1H), 8.12 (d, J ¼ 4.6 Hz, 1H), 7 0.69 (d, J ¼ 9.2 Hz, 1H), 6.99
(s, 1H), 6.46 (s, 1H) 4.55 (dd, J ¼ 17.7, 10.9 Hz, 1H) 4.09 (dd, J ¼ 10.9,
9.6 Hz, 1H), 3.58 (dd, J ¼ 13.3, 10.5 Hz, 1H), 3.25 (ddd, J ¼ 17.7, 6.4,
2.9 Hz, 1H), 2.96 (d, J ¼ 13.3 Hz, 1H) 2.26 (s, 3H), 2.13e2.02 (m, 3H),
1
.82 (m, 1H), 1.72 (ddd, J ¼ 12.0, 12.0, 6.7 Hz, 1H), 1.32e1.24 (m, 1H)
0
4
.3.1. 5 -Amino-10,11-dihydro-cupreine (13)13
1.17e1.13 (m, 2H), 0.72 (t, J ¼ 7.4 Hz, 3H);
C 3
d (100 MHz, CDCl ) 178.7,
Following the general procedure above 12 (1.0 g, 2.8 mmol) in
169.1, 150.3, 147.94, 147.92, 146.9, 146.6, 142.4, 137.7, 136.0, 129.1,
methanol (10.0 mL) was converted into the title compound 13 as a
dark brown solid (0.44 g, 1.34 mmol, 48%), mp 125e127 C (dec)
123.2, 122.6, 119.0, 113.0, 103.5, 68.6, 59.6, 57.1, 44.7, 36.2, 27.4, 25.5,
ꢂ
þ
24.9, 24.4,19.9,11.7; HRMS (ESI-TOF) calcd for C27
473.2183, found: 473.2190.
29
H N
4
O
4
[MþH] :
ꢁ
1
R
2
f
¼
0.77 (3/1, v/v chloroform/methanol);
300e3500 (br), 2956, 2926, 1573 (v), 1459, 1382, 1260 (br), 1144,
(600 MHz, CD OD) 8.57 (d,
J ¼ 4.6 Hz, 1H), 7.70 (d, J ¼ 4.6 Hz, 1H), 7.53 (d, J ¼ 8.9 Hz, 1H), 7.40
d, J ¼ 8.9 Hz, 1H), 6.1 (d, J ¼ 2.5 Hz, 1H), 4.18 (ddd, J ¼ 10.7, 7.2,
.0 Hz, 1H), 4.00e4.10 (m, 1H), 3.53 (dd, J ¼ 12.7, 10.5 Hz, 1H), 3.21
ddd, J ¼ 12.5,11.6, 5.4 Hz,1.2 Hz,1H), 2.87 (ddd, J ¼ 12.5, 5.6, 2.8 Hz,
H), 2.19e2.04 (m, 3H), 2.02e1.94 (m, 1H), 1.92e1.81 (m, 1H),
.71e1.60 (m 1H), 1.48e1.30 (m, 2H), 0.87 (t, J ¼ 7.4 Hz, 3H);
100 MHz, CD OD) 147.8, 147.3, 146.4, 145.2, 129.5, 122.2, 121.0,
nmax (ATR)/cm
1115, 1044, 944, 830, 804, 519, 437;
d
H
3
4.4.2. (R)-(10-tert-Butyloxycarbonyl-amino-9-oxo-pyrido[3,2-a]
phenoxazin-1-yl)((1S,2S,5R)-5-ethylquinuclidin-2-yl)methanol (1b)
Prepared according to the general procedure using 13 (0.22 g,
0.67 mmol), tert-butyl-(2-hydroxy-5-methoxyphenyl)carbamate
(5c, 0.24 g, 1.0 mmol) in methanol (8.0 mL) and solution of NaIO
3
(0.198 g, 1.0 mmol) in water (8.0 mL). The crude product was pu-
(
3
(
1
1
(
d
C
rified on column chromatography (10/1 v/v chloroform/methanol)
3
giving desired product as a dark red solid (0.267 g, 0.50 mmol, 75%)
ꢂ
1
20.9, 120.2, 71.6, 62.6, 57.6, 45.0, 36.7, 27.6, 25.7, 25.6, 18.4, 11.9;
mp 189.0e191.5 C (dec) R
n
f
¼ 0.45 (20/1 v/v chloroform/methanol).
þ
ꢁ1
HRMS (ESI-TOF) calcd for C19
H
26
N
3
O
2
[MþH] : 328.2020; found:
max (ATR)/cm 3352, 2928, 2871, 1732, 1616, 1588, 1565, 1493,
3
28.2015.
H 3
1339, 1142, 1013, 841, 642, 602, 523, 436; d (400 MHz, CDCl ) 8.94
(
d, J ¼ 4.6 Hz, 1H), 8.27 (d, J ¼ 9.2 Hz, 1H), 8.14 (s, 1H), 8.07 (d,
0
4
.3.2. 5 -Amino-10,11-dihydro-cupreidine (15)
J ¼ 4.6 Hz,1H), 7.98 (s,1H), 7.74 (d, J ¼ 9.2 Hz,1H), 6.82 (br.,1H), 6.52
(s, 1H), 5.09 (s, br, 1H) 4.40e4.25 (m, 1H), 4.03 (ddd, J ¼ 9.6, 9.6,
3.7 Hz, 1H), 3.41 (dd, J ¼ 13.0, 10.5 Hz, 1H), 3.14 (ddd, J ¼ 12.1, 12.1,
3.6 Hz, 1H), 2.83 (d, J ¼ 13.1 Hz, 1H), 2.10e1.95 (m, 3H), 1.83e1.63
(m, 2H), 1.56 (s, 9H), 1.50e1.40 (m, 1H), 1.21 (dq, J ¼ 8.7, 7.3 Hz, 2H),
Following the general procedure above 14 (923 mg, 2.58 mmol)
in methanol (9.0 mL) was converted into the title compound 15 as a
dark brown solid (656 mg, 2.0 mmol, 77%), mp 120e121 C (dec)
ꢂ
e1
R
(
1
f
¼ 0.77, (3/1, v/v chloroform/methanol);
nmax (ATR)/cm 3131
br), 3042, 2958, 2934, 2876, 1572 (v), 1460, 1400, 1382, 1291, 1143,
115, 1038, 946, 826, 795, 520, 441; (600 MHz, CD OD) 8.57 (d,
J ¼ 4.5 Hz, 1H), 7.75 (d, J ¼ 4.5 Hz, 1H), 7.53 (d, J ¼ 8.9 Hz, 1H), 7.39
0.76 (t, J ¼ 7.3 Hz, 3H);
C 3
d (100 MHz, CDCl ) 178.4, 151.7, 150.3, 148.0,
d
H
3
147.9, 147.1, 146.5, 142.5, 139.0, 135.7, 129.0, 123.4, 123.0, 119.1, 109.9,
103.6, 82.4, 77.2, 59.5, 57.3, 44.5, 36.5, 28.2, 27.5, 26.0, 24.6, 24.0,

M. W a˛ si nꢀ ska-Kałwa et al. / Tetrahedron 74 (2018) 308e315
313
þ
1
1.8; HRMS (ESI-TOF) calcd for C30
H N
35 4
O
5
[MþH] : 531.2602,
0.5 mmol) in dichloromethane (1.0 mL) and trifluoroacetic acid
(0.67 mL, 8.8 mmol). Followed by purification was furnished the
found: 531.2614.
desired product as a dark red solid (0.125 g, 2.9 mmol, 59%), mp
ꢂ
4
.4.3. (S)-(10-Acetamino-9-oxo-pyrido[3,2-a]phenoxazin-1-
231.1e233.0 C R
f
¼ 0.45 (15/1 v/v chloroform/methanol);
n
max
ꢁ
1
yl)((1S,2R,5R)-5-ethylquinuclidin-2-yl)methanol (2a)
(ATR)/cm 3305, 3176, 2961, 2878, 1670, 1582, 1566, 1385, 1260,
1178 (br.), 1114 (br.), 1008, 828, 798, 719, 598, 521; (400 MHz,
CDCl
Prepared according to the general procedure using 15 (82.0 mg,
d
H
0
0
0
.25 mmol), 2-hydroxy-5-metoxyacetanilide (5b, 68.0 mg,
.375 mmol) in methanol (3.0 mL) and solution of NaIO (73.8 mg,
.375 mmol) in water (3.0 mL). The crude product was purified on
3
)
d
8.89 (d, J ¼ 4.6 Hz, 1H), 8.11 (d, J ¼ 4.6 1H), 8.10 (d,
3
J ¼ 9.1 Hz, 1H), 7.60 (d, J ¼ 9.1 Hz, 1H), 7.17 (br., 1H), 6.93 (s, 1H), 6.11
(s, 1H), 5.62 (br., 2H), 4.67 (dd, J ¼ 18.2, 12.0 Hz, 1H), 3.84 (t,
J ¼ 9.9 Hz, 1H), 3.55 (t, J ¼ 11.8 Hz, 1H), 3.30 (ddd, J ¼ 12.4, 11.9,
3.0 Hz, 1H), 2.66e2.58 (m, 1H), 2.19e2.09 (m, 1H), 2.07e1.98 (m,
column chromatography (10/1, v/v chloroform/methanol) giving
desired product as a dark red solid (81.0 mg, 0.17 mmol, 68%) mp
ꢂ
ꢁ
211e212 C (dec) R
f
¼ 0.42 (20/1, v/v chloroform/methanol);
n
max
2H), 1.87e1.70 (m, 2H), 1.13e0.93 (m, 3H), 0.66 (t, J ¼ 7.4 Hz, 3H);
d
C
1
(
ATR)/cm 3259, 2956, 2926, 2878, 1689, 1607, 1586, 1565, 1493,
436, 1368, 1338, 1158, 1005, 875, 838, 590, 520, 469; (600 MHz,
CD
OD) 9.01 (d, J ¼ 4.8 Hz, 1H), 8.54 (d, J ¼ 1.3 Hz, 1H), 8.31 (dd,
(100 MHz, CDCl ) 178.8, 149.5, 147.9, 147.4, 147.2, 146.6, 146.5, 140.8,
3
1
d
H
132.0, 129.2, 121.6, 121.6, 119.4, 103.3, 99.1, 69.0, 60.2, 57.5, 45.3,
35.8, 27.3, 25.0, 24.0, 18.9, 11.6; HRMS (ESI-TOF) calcd for
3
þ
J ¼ 9.2, 2.3 Hz, 1H), 8.28 (d, J ¼ 4.8 Hz, 1H), 7.96 (dd, J ¼ 9.2, 2.3 Hz,
C
25
27
H N
4
O
3
[MþH] : 431.2078, found: 431.2078.
1
1
1
H), 6.98 (d, J ¼ 1.3 Hz, 1H), 6.58 (d, J ¼ 2.9 Hz, 1H), 4.20e4.28 (m,
H), 4.18 (ddd, J ¼ 12.5, 8.9, 2.2 Hz, 1H), 3.59 (dd, J ¼ 12.5, 10.2 Hz,
H), 3.54e3.52 (m, 1H), 3.46e3.41 (m, 1H), 2.39e2.33 (m, 1H), 2.32
4
.5.2. (S)-(10-Amino-9-oxo-pyrido[3,2-a]phenoxazin-1-
yl)((1S,2R,5R)-5-ethylquinuclidin-2-yl)methanol (2c)
Prepared according general procedure using 2b (0.950 g,
.8 mmol) in dichloromethane (2.5 mL) and trifluoroacetic acid
(
1
(
1
5
s, 3H), 2.03e1.99 (m, 1H), 1.98e1.93 (m, 1H), 1.89e1.85 (m, 2H),
.71e1.62 (m, 2H), 1.18e1.13 (m, 1H), 1.01 (t, J ¼ 7.4 Hz, 3H);
100 MHz, CD OD) 180.6, 172.9, 151.2, 150.4, 150.2, 148.7, 148.0,
44.7, 139.8, 135.8, 131.2, 124.1, 123.4, 121.3, 114.5, 104.4, 70.7, 61.4,
d
C
1
(
3
0.86 mL, 27.0 mmol). Followed by purification was furnished the
desired product as a dark red solid (0.645 g, 1,5 mmol, 83%), mp
3.0, 51.5, 36.3, 26.5, 25.4, 24.6, 24.4, 18.9, 11.8; HRMS (ESI-TOF)
ꢂ
2
75.6e276.9 C (dec); R
f
¼ 0.42 (15/1 v/v CHCl
3
/MeOH); nmax (ATR)/
þ
calcd for C27
H
29
N
4
O
4
[MþH] : 473.2183, found: 473.2201.
ꢁ1
cm 3200e3600 (br), 3130, 2957, 2933, 2880, 1572 (br), 1515, 1461,
382, 1277 (br), 1141, 1117, 1040, 826, 790, 720, 607, 520, 438;
400 MHz, CDCl
1
d
H
4
.4.4. (S)-(10-tert-Butyloxycarbonyl-amino-9-oxo-pyrido[3,2-a]
(
3
) 8.89 (d, J ¼ 4.6 Hz, 1H), 8.12 (d, J ¼ 4.6 Hz, 1H),
phenoxazin-1-yl)((1S,2R,5R)-5-ethylquinuclidin-2-yl)methanol (2b)
Prepared according to the general procedure using 15 (1.08 g,
3
8
1
9
.09 (d, J ¼ 9.2 Hz, 1H), 7.59 (d, J ¼ 9.2 Hz, 1H), 7.28 (br., 1H), 7.21 (s,
H), 6.05 (s, 1H), 5.82 (br., 1H), 5.45 (s, br, 2H), 4.23 (ddd, J ¼ 13.0,
.1, 2.1 Hz, 1H), 3.79 (dd, J ¼ 10.1, 9.6 Hz, 1H), 3.68 (dd, J ¼ 12.5,
.30 mmol), tert-butyl-(2-hydroxy-5-methoxyphenyl)carbamate
(5c, 1.18 g, 4.93 mmol) in methanol (20.0 mL) and solution of NaIO
3
1
1
1
(
1
1
0.6 Hz, 1H), 3.37 (ddd, J ¼ 12.2 9.6, 9.6 Hz, 1H), 3.11 (dd, J ¼ 12.2,
(
0.976 g, 4.93 mmol) in water (20.0 mL). The crude product was
1.0 Hz 1H), 2.23 (dd, J ¼ 10.1, 7.1 Hz, 1H), 1.92e1.88 (m, 1H),
.82e1.70 (m, 2H), 1.70e1.50 (m, 3H), 0.95 (t, J ¼ 4.6 Hz, 3H), 0.82
ddd, J ¼ 9.6, 7.1, 3.9 Hz, 1H); (100 MHz, CDCl ) 178.7, 149.9, 147.4,
47.11, 147.07, 147.0, 146.1, 140.7, 132.6, 129.2, 121.5, 121.3, 119.1,
purified on column chromatography (10/1, v/v chloroform/meth-
anol) giving desired product as a dark red solid (1.26 g, 2.37 mmol,
7
d
C
3
ꢂ
2%) mp 148e149 C (dec) R
f
¼ 0.45 (20/1, v/v chloroform/meth-
ꢁ1
anol);
n
max (ATR)/cm 3339, 2956, 2931, 2876, 1726, 1614, 1587,
(600 MHz,
03.2, 99.3, 68.9, 60.8, 51.5, 50.3, 35.2, 25.4, 24.2, 23.6, 18.3, 11.5;
HRMS (ESI-TOF) calcd for C25
1565, 1493, 1340, 1141, 1014, 840, 648, 602, 521, 435;
d
H
þ
27
H N
4
O
3
[MþH] : 431.2078, found:
CDCl
8
1
3
) 8.91 (d, J ¼ 4.6 Hz, 1H), 8.24 (d, J ¼ 9.2 Hz, 1H), 8.11 (s, 1H),
431.2078.
.09 (d, J ¼ 4.6 Hz, 1H), 7.87 (s, 1H), 7.69 (d, J ¼ 9.2 Hz, 1H), 7.22 (br.,
H), 6.37 (s, 1H), 5.56 (br., 2H), 4.03 (dd, J ¼ 10.5 Hz, 1H), 3.50 (dd,
J ¼ 12.6,10.4 Hz,1H), 3.31e3.42 (m,1H), 3.23e3,12 (m,1H), 2.17 (dd,
J ¼ 12.0 Hz, 1H), 1.98e1.86 (m, 1H), 1.80e1.70 (m, 3H), 1.55 (s, 9H),
4.6. 5-Amino-4-methylquinolin-6-ol (7)
1
.66e1.49 (m, 2H), 1.07e0.98 (m, 1H), 0.93 (t, J ¼ 7.4 Hz, 3H);
d
C
To a solution of NaOH (6.3 g, 0.16 mol) in methanol and water
(76 mL, 1:1, v/v), KBH (2.12 g, 39.3 mmol) and 5% Pd on charcoal
(
100 MHz, CDCl
3
) 178.2, 151.7, 150.3, 147.7, 147.4, 147.0, 146.4, 142.3,
4
1
38.8, 135.6, 129.2, 122.8, 122.5, 119.1, 110.0, 103.5, 82.5, 77.2, 60.4,
(0.098 g, 0.046 mmol, 0.6 mol%) was added. To the vigorously
stirred mixture, a solution of 6-hydroxy-4-methyl-5-nitroquinoline
(11) (1.59 g, 7.80 mmol) in methanol (40 mL) was added dropwise
51.8, 49.8, 35.6, 28.2, 25.5, 24.4, 24.3, 19.5, 11.6; HRMS (ESI-TOF)
þ
calcd for C30
H N
35 4
O
5
[MþH] : 531.2602, found: 531.2596.
ꢂ
over 3 h at room temperature (þ25 C). The resulting mixture then
4.5. General procedure for Boc deprotection of 1b and 2b to 1c and
was allowed to stir for 15 min. When the reaction was completed
the palladium was removed by filtration through a Celite pad and
washed with methanol. The reaction mixture was evaporated un-
der vacuum and the residue was treated with water (60 mL) and
concentrated HCl (22 mL). The pH was brought to 8e9 value using
2
c
Deprotection of 1 mmol of Boc was performed using trifluoro-
acetic acid (TFA) (15 equiv) in dichloromethane for two hours at
room temperature. After evaporation of solvent at 30 C under
reduced pressure, the residue was dissolved with 10/1 chloroform/
ꢂ
NaHCO
layer was extracted with ethyl acetate (5 ꢀ 100 mL). The combined
organic layers were dried over anhydrous Na SO , and the solvent
3
(6.0 g). The insoluble material was filtered and the aqueous
methanol solution (10 mL), neutralized with 5% aqueous NaHCO
15 mL) and extracted with CHCl
(5 ꢀ 30 mL). The combined
organic layers were dried over Na SO , filtered, and concentrated
under reduced pressure. Purification by column chromatography
10/1, v/v chloroform/methanol) gave products 1c and 2c in the
form of dark red solids.
3
2
4
(
3
was removed in vacuo to give the desired product as a brown solid
ꢂ
2
4
(0.635 g, 3.64 mmol, 47%), mp 251e252 C, R
f
¼ 0.3 (AcOEt);
n
max
ꢁ
1
(ATR)/cm 3376, 2924, 2852, 1606, 1575, 1515, 1383, 1298, 1272,
1255, 1194, 1139, 916, 819, 811, 548; (600 MHz, DMSO-d ) 9.58
(br., 1H), 8.36 (d, J ¼ 4.2 Hz, 1H), 7.27 (d, J ¼ 8.8 Hz, 1H), 7.23 (d,
J ¼ 8.8 Hz, 1H), 6.98 (d, J ¼ 4.2 Hz, 1H), 4.71 (br., 2H), 2.92 (s, 3H);
(100 MHz, DMSO-d
(
d
H
6
d
C
4.5.1. (R)-(10-Amino-9-oxo-pyrido[3,2-a]phenoxazin-1-
6
) 146.5, 144.2, 143.2, 140.6, 130.6, 121.7, 120.0,
þ
yl)((1S,2S,5R)-5-ethylquinuclidin-2-yl)methanol (1c)
119.1, 118.6, 23.4; HRMS (ESI-TOF) calcd for C10
175.0866, found: 175.0877.
H
11
N
2
O [M þ H] :
Prepared according to the general procedure using 1b (0.267 g,

314
M. W a˛ si nꢀ ska-Kałwa et al. / Tetrahedron 74 (2018) 308e315
4.7. General procedure for preparation of 8 and 9
4.9. 4-Methyl-5-nitroquinolin-6-ol (11)
To a mixture of 5-aminoquinoline 6 or 7 (1.0 equiv) and N-
acethyl-2-aminophenol derivative 5a or 5b (1.5 equiv) in methanol,
a solution of NaIO (1.5 equiv) in water was added dropwise at
room temperature. The resulting mixture was stirred for up to three
hours at room temperature, then the organic solvent was removed
under reduced pressure (20 mmHg). The precipitate was filtered
and the residue extracted with hot methanol and concentrated to
afford pure product.
To conc. H
2 4
SO (17.0 mL), 6-hydroxy-4-methylquinoline (10)
ꢂ
(2.00 g, 12.6 mmol) was added in portions at 0 C. After 5 min, KNO
(1.88 g, 18.5 mmol, 1.5 equiv) was added and the reaction mixture
was stirred at 0 C for 30 min. Then it was poured onto 60 g of
4
crushed ice. The pH was brought to 8e9 using 25% aq NH OH. The
3
3
ꢂ
precipitate was filtered to give 11 as a green solid (1.41 g,
ꢂ
6.90 mmol, 55%), mp 249e250 C; R
f
¼ 0.5 (ethyl acetate);
n
max
ꢁ
1
(ATR)/cm 3046, 2984, 2366 (br), 1591, 1521, 1508, 1380, 1304,
279, 1249, 1225, 1155, 1100, 974, 843, 782, 711, 567, 519, 422;
(600 MHz, DMSO-d
) 11.57 (br., 1H), 8.66 (d, J ¼ 4.4 Hz, 1H), 8.09 (d,
J ¼ 9.2 Hz,1H), 7.55 (d, J ¼ 9.2 Hz,1H), 7.43 (d, J ¼ 4.4 Hz,1H), 2.45 (s,
3H); (150 MHz, DMSO-d ) 148.3, 148.1, 141.7, 138.7, 133.6, 132.6,
1
d
H
4.7.1. 10-Acetaminopyrido[3,2-a]phenoxazin-9-one (8)
6
Prepared according to the general procedure using 5-amino-6-
hydroxyquinoline (6, 40.0 mg, 0.25 mmol), N-(2-hydroxy-5-
methoxyphenyl)acetamide (5b) (68.0 mg, 0.375 mmol) in meth-
d
C
6
125.7, 120.9, 120.0, 17.7; HRMS (ESI-TOF) calcd for C10
9
H N
2
O
3
þ
anol (3.0 mL) and NaIO
3
(74.0 mg, 0.375 mmol) in water (3.0 mL). 8
[M þ H ]: 205.0608, found: 205.0621.
was obtained as orange solid (23.0 mg, 0.075 mmol, 30%),
ꢂ
mp > 300 C (dec), R
f
¼ 0.6 (20/1 v/v chloroform/methanol). For
Acknowledgments
ꢁ
1
8
$TFA:
379, 1182 (s), 1131 (s), 813, 799, 717, 498, 479;
CF
COOD) 10.17 (d, J ¼ 8.5 Hz, 1H), 9.17 (br., 1H), 8.80 (s br, 1H), 8.49
dd, J ¼ 9.2, 2.9 Hz, 1H), 8.27 (dd, J ¼ 8.7, 5.6 Hz, 1H), 8.24 (d,
J ¼ 9.2 Hz, 1H), 6.90 (s, 1H), 2.43 (s, 3H); (150 MHz, CF COOD)
83.6,177.7,152.2,151.9, 146.3,145.9,145.7,140.2,138.0,131.2,130.2,
n
max (ATR)/cm 3330, 3199, 2918, 2850,1673,1580 (s),1483,
1
d
H
(600 MHz,
We thank the Wrocław Center for Networking and Super-
computing for allotment of computer time (grant 362). The work
was financed from a statutory activity subsidy from the Polish
Ministry of Science and Higher Education for the Faculty of
Chemistry of Wrocław University of Science and Technology.
3
(
d
C
3
1
1
C
28.2, 126.4, 125.8, 119.2, 106.8, 24.7; HRMS (ESI-TOF) calcd for
þ
17
H
12
N
3
O
3
[M þ H] : 306.0873, found: 306.0886.
Appendix A. Supplementary data
4
.7.2. 10-Acetamino-1-methylpyrido[3,2-a]phenoxazin-9-one (9)
Prepared according general procedure using 5-amino-6-
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.11.072.
hydroxy-4-methylquinoline (7, 44.0 mg, 0.25 mmol), N-(2-
hydroxy-5-methoxyphenyl)acetamide (5b, 68.0 mg, 0.375 mmol)
in methanol (3.0 mL) and NaIO
References
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(
3.0 mL). 9 was obtained as a red solid (32.0 mg, 0.1 mmol, 40%),
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ꢂ
2009.
mp > 300 C (dec); R
f
¼ 0.62 (20/1 v/v chloroform/methanol);
n
max
2. (a) Kacprzak K, Gawro
nꢀ ski J. Synthesis. 2001;2001:961e998;
e1
(
ATR)/cm 3292, 2961, 2923, 2851, 1688, 1598, 1548, 1513, 1489,
(
b) Diaz de Villegas MD, G ꢀa lves JA, Etayo P, Badorrey R, L oꢀ pez-Ram-de-Víu P.
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386, 1260, 1160, 1015 (br), 796, 762, 469;
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H
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3
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4
8
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(
c) Bolm C, Dinter CL, Seger A, H o€ cker H, Brozio J. J Org Chem. 1999;64:
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(
d
C
3
5730e5731.
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2
3
46.4,143.9,140.2,138.7,133.7,129.1,128.6,127.8,127.5,118.8,106.0,
8.4, 24.8; HRMS (ESI-TOF) calcd for C18
20.1030, found: 320.1046.
þ
H
14
N
3
O
3
[M þ H] :
6
7. (a) Cosimi E, Engl OD, Saadi J, Ebert M-O, Wennemers H. Angew Chem Int Ed.
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016;55:13127e13131;
4.8. 4-Methylquinolin-6-ol (10)
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. Marcelli T, Maarseveen JH, Hiemstra H. Angew Chem Int Ed. 2006;45:
7496e7504.
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Using a modified patent procedure,35 to a solution of p-hydrox-
9
yaniline (1.36 g,12.5 mmol) and anhydrous zinc(II)chloride (0.260 g,
(
b) Bernal P, Fern aꢀ ndez R, Lassaletta JM. Chem Eur J. 2010;16:7714e7718;
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1
.59 mmol) in ethanol/water 95/5 v/v (7.0 mL) at 40 C, dry iron(III)
chloride (5.4 g, 34 mmol) was added and the temperature was
increased to 80 C. Then, methyl vinyl ketone (1.0 mL, 0.876 g,
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10561e10574.
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1
0. (a) Jaric M, Haag BA, Manolikakes SM, Knochel P. Org Lett. 2011;13:2306e2309;
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1
2.5 mmol) was slowly injected with a syringe over 1 h. The reaction
(
ꢂ
was stirred at 80 C for an additional 15 h before cooling to room
5164e5167.
1
1. (a) Liu X, Sun B, Deng L. Synlett. 2009:1685e1689;
temperature and quenching with 10% aqueous sodium hydroxide
(b) Brandes BS, Bella M, Kjærsgaard A, Jørgensen KA. Angew Chem Int Ed.
(
25 mL). The insoluble material was filtered off through a pad of
2006;45:1147e1151.
Celite and rinsed several times with ethyl acetate. The aqueous layer
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2007;17:3599e3602;
was extracted with ethyl acetate (5 ꢀ 50 mL), and dried over anhy-
1
2 4
drous Na SO , and filtered. The solvent was removed in vacuo, and
the residue was purified by column chromatography using ethyl
acetate to give the desired product 10 as a pale yellow solid (1.03 g,
ꢂ
36
ꢂ
6
.5 mmol, 54%), mp 217e218 C (lit. mp 222e224 C);
n
max (ATR)/
cm 2983, 2909, 2844, 2546 (br), 1616, 1467, 1404, 1245, 1230, 896,
42, 741, 539, 422; (600 MHz, CD
OD) 8.46 (d, J ¼ 4.2 Hz,1H), 7.32
dd, J ¼ 9.0, 2.3 Hz,1H), 7.27 (d, J ¼ 2.3 Hz,1H), 7.26 (d, J ¼ 4.2 Hz,1H),
.62 (s, 3H); (150 MHz, CD OD) 157.4, 147.5, 145.3, 143.5, 131.1,
30.9, 123.1, 123.0, 106.3, 18.8.
(b) Skiera I, Antoszczak M, Trynda J, et al. Chem Biol Drug Des. 2015;86:
ꢁ
1
911e917;
8
(
2
1
d
H
3
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(
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