Copper-catalyzed direct coupling of benzoxazin-2-ones with indoles for the synthesis of diverse 3-indolylbenzoxazin-2-ones: Access to natural cephalandole A

Article abstract of DOI:10.1039/c7ra10634c

A novel and facile copper-catalyzed direct coupling for the synthesis of diverse and functionalized 3-indolyl benzoxazin-2-ones from benzoxazin-2-ones and indoles has been developed. This newmethodology offers an easy and rapid approach to a variety of 3-indolylbenzo[b][1,4]oxazin-2-ones in high yield. As an application of this protocol, a gram-scale synthesis of naturally occurring cephalandole A has also been accomplished.

Full text of DOI:10.1039/c7ra10634c

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Copper-catalyzed direct coupling of benzoxazin-2-
ones with indoles for the synthesis of diverse
Cite this: RSC Adv., 2017, 7, 55288
3-indolylbenzoxazin-2-ones: access to natural
cephalandole A†
a
a
b
Rameshwar Prasad Pandit,
Jae-Jin Shim,
Sung Hong Kim
a
and Yong Rok Lee
*
Received 26th September 2017
Accepted 28th November 2017
A novel and facile copper-catalyzed direct coupling for the synthesis of diverse and functionalized 3-indolyl
benzoxazin-2-ones from benzoxazin-2-ones and indoles has been developed. This new methodology offers
an easy and rapid approach to a variety of 3-indolylbenzo[b][1,4]oxazin-2-ones in high yield. As an application
of this protocol, a gram-scale synthesis of naturally occurring cephalandole A has also been accomplished.
DOI: 10.1039/c7ra10634c
rsc.li/rsc-advances
its structure was later revised into 3 by organic structure
determination using atomic resolution scanning probe
Introduction
12
Benzoxazines and benzoxazin-2-ones are important heterocyclic microscopy. Moreover, molecules bearing these skeletons
compounds found in natural products and biologically active have been also used as valuable building blocks for the
1,2
13,14
molecules (Fig. 1). These compounds possess a wide range of synthesis of pharmaceuticals and photoactive materials.
3
pharmaceutical properties such as antihypertensive, anti-
Owing to the importance of benzoxazin-2-ones, several
4
5
6
15,16
fungal, antimycobacterial, anti-inammatory, bacterial histi- methods for their synthesis have been reported.
The general
7
dine protein kinase inhibitory, and D2 receptor antagonist methods for benzoxazin-2-ones include the domino reaction of
8
17
activities. In addition, compound 1 exhibits a potent effect of o-aminophenol with b-nitroacrylates, cleavage of resin-bound
18
pyruvate kinase activators for the treatment of hereditary non- pseudooxazolones with 2-aminophenols, and TFA-catalyzed
9
spherocytic hemolytic anemia and sickle cell anemia and tandem reaction of benzoxazoles with 2-oxo-2-arylacetic
10
19
compound 2 is useful for the treatment of lung cancer.
Naturally occurring alkaloid, cephalandole A was originally azinones and enantioselective addition of indoles to ketimines
acids. In addition, enantioselective hydrogenation of benzox-
1
1
isolated from Taiwanese orchid Cephalanceopsis gracilis and to
give
chiral
dihydrobenzoxazinones
have
been
2
0,21
accomplished.
Although several methodologies for the synthesis of
benzoxazin-2-ones and dihydrobenzoxazinones have been
developed, there are no reports on the direct coupling of
benzoxazin-2-ones with indoles for the construction of
3
-indolylbenzoxazin-2-ones so far. Recently, an iron-catalyzed
3
oxidative sp carbon–hydrogen bond functionalization of
dihydrobenzoxazin-2-ones with indoles for the synthesis of
3
-indolyldihydrobenzoxazin-2-ones
has been described
22
(Scheme 1a). As a part of continuing efforts to develop new
23
synthetic protocols for nitrogen heterocycles, we herein report
the copper-catalyzed direct coupling of benzoxazin-2-ones with
indoles for the formation of diverse 3-indolyl benzoxazin-2-ones
in air (Scheme 1b).
Fig. 1 Selected examples of naturally occurring and pharmaceutically
active molecules bearing benzoxazin-2-one moiety.
a
School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic
Results and discussion
of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631; Tel: +82-53-810-2529
b
Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu
Our initial study commenced with the model reaction between
benzoxazin-2-one 4a and N-methylindole 5a for the optimiza-
tion of reaction condition (Table 1). Various metals were
4
†
1
1566, Republic of Korea
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0.1039/c7ra10634c
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(
entries 16 and 17). The structure of 6a was determined by
1
spectroscopic analysis. The H NMR spectrum of 6a showed
a characteristic singlet singlet for indolyl C2 proton at
d 8.60 ppm and N-methyl peak on indolyl moiety at d 3.85 ppm.
With the optimized reaction condition in hand, we further
investigated the substrates scope employing different indoles
5b–5m (Table 2). Reaction of 4a with indoles 5b–5d bearing
N-ethyl, N-benzyl, and N-phenyl moieties provided the desired
products 6b–6d in 91, 67, and 72% yield, respectively. Treat-
ment of 4a with N-arylated indoles 5e–5g having electron-
donating or electron-withdrawing groups on the N-aryl ring,
such as 4-Me, 4-OMe, and 4-Cl afforded the corresponding
products 6e–6g in 76%, 70%, and 77% yield, respectively.
Indoles 5h–5l bearing electron-donating or electron-
withdrawing groups on the benzene ring were successful to
afford the desired products. For example, reaction with
N-methylindoles 5h–5i bearing electron-donating groups like
methyl at 5- and 6-position on the aryl ring provided 6h (72%)
and 6i (70%), respectively. The reaction of N-methylindoles
Scheme
1 Strategies for direct coupling of indoles to dihy-
drobenzoxazinones and benzoxazinones.
examined as catalysts under several solvents in air. When using
ꢀ
10 mol% of CoCl , ZnCl and NiCl2 at 80 C for 24 h in
2
2
dichloroethane, product 6a was isolated in 32, 40, and 41%
yields, respectively (entries 1–3, Table 1). Encouraged by these
results, we screened other catalysts for the reaction. With
1
8
0 mol% of FeCl
9% respectively (entries 4–5). However, additional attempt
, Cu(OAc) , and
, failed to further increase the yield (entries 6–8).
3 2
and CuCl , the yield of 6a increased to 80 and
5j–5l bearing electron-withdrawing groups (5-F, 6-Cl, and
5
-CO Me) afforded products 6j–6l in 66, 61, and 78% yield,
2
using other copper catalysts such as CuF
Cu(OTf)
2
2
respectively.
2
To demonstrate the versatility of this coupling reaction,
further reactions between various substituted benzoxazin-2-
ones 4b–4g and several N-substituted indoles 5a, 5b, 5d, and
Results of solvent screening showed that tetrahydrofuran (THF)
was the best solvent (94%) among the solvents such as dioxane
(87%), ethanol (66%), and water (60%) (entries 9–12). Changes
5g were examined (Table 3). The reactions of 4b–4e bearing
in the loading of CuCl to 5 mol%, 2 mol%, and 13 mol% did
2
electron-donating groups such as 6-methyl, 7-methyl, 6-tert-
butyl, and 6-phenyl with N-substituted indoles 5a, 5b, 5d, or 5g
provided products 7a–7g in the range of 60–88% yield. The
not improve the yield of 6a (entries 13–15). In addition, the
effect of temperature was next studied. It was found out that
decreasing or increasing temperature decreased the yield of 6a
a
Table 1 Optimization of reaction condition for the synthesis of 6a
ꢀ
b
Entry
Catalyst
Solvent
Temp ( C)
Time [h]
Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
CoCl
ZnCl
2
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
THF
Dioxane
EtOH
2
H O
THF
THF
THF
THF
THF
2
2
2
2
2
2
2
2
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
50
70
24
24
24
24
24
24
24
12
12
12
12
12
12
24
6
32
40
41
80
89
80
78
85
94
87
87
60
91
78
82
90
85
2
NiCl
FeCl
CuCl
2
3
2
CuF
Cu(OAc)
Cu(OTf)
2
(10 mol%)
2
(10 mol%)
(10 mol%)
2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
2
2
2
2
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(5 mol%)
0
1
2
3
4
5
6
7
(2 mol%)
(13 mol%)
(10 mol%)
(10 mol%)
12
10
a
b
Reaction conditions: 4a (0.5 mmol), 5a (0.5 mmol), and catalyst (10 or 5 mol%) in solvent (3.0 mL) under air. Yield of the isolated product 6a aer
column chromatography.
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Table 2 Formation of diverse 3-indolylbenzoxazine-2-ones 6b–6l Table 3 Formation of diverse 3-indolylbenzoxazin-2-ones 7a–7i from
a
from 4a with N-substituted indoles 5b–5l
different benzoxazin-2-ones 4b–4g with N-substituted indoles 5a, 5b,
a
5d, or 5g
a
Reaction condition: 4b–4g (0.5 mmol), 5a, 5b, 5d, 5g (0.5 mmol), CuCl
2
ꢀ
(10 mol%), THF (3.0 mL), 60 C, time (h), and isolated yields.
a
Reaction condition: 4a (0.5 mmol), 5b–5l (0.5 mmol), CuCl
2
(10 mol%),
Scheme 2 One-pot gram-scale synthesis of natural alkaloid cepha-
landole A (3).
ꢀ
THF (3.0 mL), 60 C, time (h), and isolated yield.
reactions of 4f and 4g bearing electron-withdrawing groups of 6-
F and 6-Cl with 5a afforded the products 7h and 7i in 82% and
93% yield, respectively.
The utility of this new methodology for the gram-scale
synthesis of naturally occurring cephalandole A (3) was next
demonstrated (Scheme 2). Upon treatment of 4a with indole 5m
ꢀ
at 60 C for 12 h in THF, 3 was obtained in 75% yield. This one-
Scheme 3 Control experiments for 8 and 6a.
pot protocol has several advantages such as higher yield, fewer
steps, and lower cost. The synthesized compound was
conrmed to be natural product 3 by comparison of its spec-
22
troscopic data with those previously reported.
To elucidate the mechanism of this coupling reaction, we
performed a control experiment (Scheme 3). The reaction
between 4a with 5a in the absence of CuCl
2
in THF at room
temperature for 30 h provided compound 8 in 93% yield.
Further reaction of 8 in the presence of 10 mol% of CuCl
2
in
ꢀ
THF at 60 C for 1 h furnished 6a in 96% yield. These results
suggest that compound 8 might be the intermediate in the
coupling reaction.
Based on the above experiment, the mechanism for the
formation of 6a is proposed as shown in Scheme 4. First, CuCl
2
Scheme 4 Proposed mechanism for the formation of 6a.
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catalyst binds to 4a gives complex 4a , which subsequently
RSC Advances
0
3-(1-Ethyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (6b).
undergoes nucleophilic attack by 5a to give 9. Deprotonation Prepared from 4a (74 mg, 0.5 mmol) and N-ethylindole 5b
and protonation of 9 would afford intermediate 8, which (72 mg, 0.5 mmol) according to general procedure in 6 h as
2
4
ꢀ
1
undergoes air oxidation to give 6a
a yellow solid (132 mg, 91%); mp 180–182 C; H NMR (600
MHz, CDCl
3
) d 8.90–8.86 (m, 1H), 8.69 (s, 1H), 7.85 (dd, J ¼ 7.8,
1
7
.8 Hz, 1H), 7.41–7.33 (m, 5H), 7.29–7.27 (m, 1H), 4.25 (q, J ¼
Conclusions
1
3
.2 Hz, 2H), 1.55 (t, J ¼ 7.2 Hz, 3H); C NMR (150 MHz, CDCl )
3
d 152.76, 147.39, 145.03, 136.50, 135.60, 132.45, 128.51, 128.22,
In summary, a novel and efficient copper-catalyzed direct
coupling of benzoxazin-2-ones with indoles for the synthesis of
diverse and functionalized 3-indolylbenzoxazin-2-ones has been
developed. This methodology provides a rapid synthetic route to
natural cephalandole A and its derivatives. The proposed
protocol has a wide substrate scope for both benzoxazin-2-ones
and indoles.
1
4
27.26, 125.31, 123.68, 123.32, 122.15, 115.95, 110.62, 109.74,
1.78, 15.25; ATR-IR (neat) 2973, 1725, 1528, 1386, 737 cm
ꢁ1
;
+
HRMS (EI) m/z (M ) calcd for C18
90.1053.
-(1-Benzyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (6c).
Prepared from 4a (74 mg, 0.5 mmol) and N-benzylindole 5c
104 mg, 0.5 mmol) according to general procedure in 6 h as
14 2 2
H N O : 290.1055; found:
2
3
(
ꢀ
1
a yellow solid (111 mg, 67%); mp 160–162 C; H NMR (600
MHz, CDCl
) d 8.90 (d, J ¼ 7.8 Hz, 1H), 8.75 (s, 1H), 7.87 (dd, J ¼
.8, 1.2 Hz, 1H), 7.41–7.25 (m, 9H), 7.17 (d, J ¼ 7.2 Hz, 2H), 5.41
Experimental
3
7
Imino cyclic esters were synthesized in the laboratory according
to known procedure. All indoles were prepared by either
N-alkylation or N-arylation according to known method.
1
3
25
(s, 2H); C NMR (150 MHz, CDCl
3
) d 152.70, 147.44, 145.09,
26
136.95, 136.68, 136.17, 132.39, 128.94, 128.74, 128.31, 128.02,
27.30, 126.80, 125.36, 123.63, 123.61, 122.34, 116.01, 111.07,
10.34, 50.90; ATR-IR (neat) 2920, 1701, 1534, 1285, 739 cm
HRMS (EI) m/z (M ) calcd for C H N O : 352.1212; found:
1
1
Solvents were used without further purication. Merck pre-
coated silica gel plates (Art. 5554) with uorescent indicator
were used for analytical TLC. Flash column chromatography
was performed using silica gel 9385 (Merck). Melting points are
uncorrected and were determined on Fisher-Johns Melting
Point Apparatus. H NMR and C NMR spectra were recorded
on a Varian VNS (600 and 150 MHz, respectively) spectrometer
in CDCl using d ¼ 7.24 and 77.00 ppm as solvent chemical
ꢁ1
;
+
2
3
16 2 2
3
52.1214.
-(1-Phenyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (6d).
Prepared from 4a (74 mg, 0.5 mmol) and N-phenylindole 5d
96 mg, 0.5 mmol) according to general procedure in 12 h as
3
1
13
(
ꢀ
1
a yellow solid (121 mg, 72%); mp 169–171 C; H NMR (600
MHz, CDCl
) d 8.95 (d, J ¼ 8.4 Hz, 1H), 8.87 (s, 1H), 7.89 (dd, J ¼
.8, 1.2 Hz, 1H), 7.58–7.53 (m, 5H), 7.45–7.72 (m, 1H), 7.41–7.36
3
3
shi. Chemical shis (d) are expressed in units of ppm and
coupling constants (J) values are given in Hz. Multiplicities are
abbreviated as follows; s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼
quartet, m ¼ multiplet, dd ¼ doublet of doublet and td ¼ triplet
of doublet. FT-IR (neat) spectra were recorded on ATR (Perki-
nElmer Spectrum 2) and HRMS was obtained on JEOL JMS-700
spectrometer at Korean Basic Science Institute.
7
(
1
3
m, 3H), 7.34–7.29 (m, 2H); C NMR (150 MHz, CDCl ) d 152.56,
3
1
1
1
7
47.38, 145.14, 138.57, 136.86, 135.87, 132.29, 129.76, 129.00,
28.43, 127.75, 127.43, 125.38, 124.91, 123.98, 123.70, 122.76,
16.03, 112.37, 110.92; ATR-IR (neat) 3056, 1734, 1531,
ꢁ
1
+
14 2 2
36 cm ; HRMS (EI) m/z (M ) calcd for C22H N O : 338.1055;
found: 338.1052.
-(1-(p-Tolyl)-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one
6e). Prepared from 4a (74 mg, 0.5 mmol) and 1-(p-tolyl)-1H-
3
General procedure for synthesis of 3-indolylbenzoxazin-2-ones
(
To the solution of imino cyclic esters (0.5 mmol) and indoles indole 5e (104 mg, 0.5 mmol) according to general procedure in
ꢀ
1
(
0.5 mmol) in THF (3.0 mL), CuCl
2
(7 mg, 10 mol%) was added 12 h as a yellow solid (133 mg, 76%); mp 175–177 C; H NMR
ꢀ
at room temperature and heated at 60 C for 3–24 h. Upon (600 MHz, CDCl ) d 8.94 (d, J ¼ 7.8 Hz, 1H), 8.84 (s, 1H), 7.89
3
completion of reaction as indicated by thin layer chromatog- (dd, J ¼ 7.8, 1.2 Hz, 1H), 7.51 (d, J ¼ 8.4 Hz, 1H), 7.44 (d, J ¼
1
3
raphy, the reaction mixture was concentrated under reduced 8.4 Hz, 2H), 7.36 (m, 7H), 2.45 (s, 3H); C NMR (150 MHz,
pressure, and the crude material was puried by column chro- CDCl ) d 152.60, 147.43, 145.15, 137.78, 137.04, 136.03, 132.35,
3
matography (hexane/ethyl acetate ¼ 20 : 1) to afford the desired 130.30, 128.91, 128.41, 127.37, 125.37, 124.80, 123.88, 123.65,
compounds.
122.66, 116.03, 112.14, 110.97, 21.14; ATR-IR (neat) 3050, 1734,
ꢁ
1
+
3-(1-Methyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (6a). 1530, 1244, 1078, 741 cm ; HRMS (EI) m/z (M ) calcd for
Prepared from 4a (74 mg, 0.5 mmol) and N-methylindole 5a C H N O : 352.1212; found: 352.1212.
2
3
16 2 2
(
65 mg, 0.5 mmol) according to general procedure in 3 h as
3-(1-(4-Methoxyphenyl)-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-
ꢀ
1
a yellow solid (130 mg, 94%); mp 195–197 C; H NMR 2-one (6f). Prepared from 4a (74 mg, 0.5 mmol) and 1-(4-
3
(600 MHz, CDCl ) d 8.87–8.83 (m, 1H), 8.60 (s, 1H), 7.85–7.82 methoxyphenyl)-1H-indole 5f (111 mg, 0.5 mmol) according to
(
m, 1H), 7.38–7.32 (m, 5H), 7.27 (dd, J ¼ 7.2, 1.6 Hz, 1H), 3.85 general procedure in 12 h as a yellow solid (128 mg, 70%); mp
1
3
ꢀ
1
(s, 3H); C NMR (150 MHz, CDCl ) d 152.70, 147.32, 145.01, 148–150 C; H NMR (600 MHz, CDCl ) d 8.94 (d, J ¼ 8.4 Hz, 1H),
3
3
1
1
2
37.40, 137.12, 132.38, 128.52, 28.20, 127.02, 125.29, 123.53, 8.81 (s, 1H), 7.89 (dd, J ¼ 7.8, 1.8 Hz, 1H), 7.47–7.44 (m, 3H), 7.41–
23.40, 122.19, 115.94, 110.48, 109.61, 33.47; ATR-IR (neat) 7.36 (m, 3H), 7.33–7.29 (m, 2H), 7.06 (d, J ¼ 9.0 Hz, 2H), 3.89
ꢁ1
+
13
927, 1728, 1531, 1077, 736 cm ; HRMS (EI) m/z (M ) calcd for (s, 3H); C NMR (150 MHz, CDCl ) d 159.12, 152.61, 147.43,
3
17 12 2 2
C H N O : 276.0899; found: 276.0901.
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1
1
1
45.13, 137.35, 136.22, 132.36, 131.46, 128.88, 128.39, 127.20, methyl-1H-indole 5k (83 mg, 0.5 mmol) according to general
26.40, 125.37, 123.85, 123.62, 122.61, 116.02, 114.86, 111.95, procedure in 12 h as a yellow solid (95 mg, 61%); mp 241–
ꢁ
1
ꢀ
1
10.87, 55.63; ATR-IR (neat) 2921, 1726, 1518, 1251, 739 cm
;
243 C; H NMR (600 MHz, CDCl ) d 8.76 (d, J ¼ 8.4 Hz, 1H), 8.59
3
+
HRMS (EI) m/z (M ) calcd for C H N O : 368.1161; found: (s, 1H), 7.83 (d, J ¼ 7.8 Hz, 1H), 7.41–7.32 (m, 3H), 7.30–7.27 (m,
2
3
16 2 3
1
3
3
68.1164.
-(1-(4-Chlorophenyl)-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin- d 152.59, 147.09, 145.10, 137.93, 137.51, 132.22, 129.44, 128.95,
-one (6g). Prepared from 4a (74 mg, 0.5 mmol) and 1-(4- 128.31, 125.53, 125.43, 124.52, 122.68, 116.04, 110.62, 109.82,
3
1H), 7.24 (s, 1H), 3.84 (s, 3H); C NMR (150 MHz, CDCl )
3
2
ꢁ
1
chlorophenyl)-1H-indole 5g (114 mg, 0.5 mmol) according to 33.59; ATR-IR (neat) 1728, 1528, 1452, 918, 746 cm ; HRMS (EI)
general procedure in 12 h as a yellow solid (143 mg, 77%); mp m/z (M ) calcd for C17
+
H
2 2
11ClN O : 310.0509; found: 310.0508.
ꢀ
1
2
8
7
1
1
1
1
09–211 C; H NMR (600 MHz, CDCl ) d 8.94 (d, J ¼ 7.8 Hz, 1H),
Methyl 1-methyl-3-(2-oxo-2H-benzo[b][1,4]oxazin-3-yl)-1H-
3
.82 (s, 1H), 7.90 (dd, J ¼ 7.8, 1.8 Hz, 1H), 7.55–7.48 (m, 5H), indole-5-carboxylate (6l). Prepared from 4a (74 mg, 0.5 mmol)
.44–7.37 (m, 3H), 7.35–7.33 (m, 1H), 7.31 (dd, J ¼ 8.4, 1.8 Hz, and methyl 1-methyl-1H-indole-5-carboxylate 5l (95 mg, 0.5
1
3
3
H); C NMR (150 MHz, CDCl ) d 152.55, 147.27, 145.17, mmol) according to general procedure in 12 h as a yellow solid
37.12, 136.73, 135.48, 133.48, 132.24, 129.99, 129.22, 128.51, (130 mg, 78%); mp 240–242 C; H NMR (600 MHz, CDCl
ꢀ
1
3
)
27.46, 126.13, 125.46, 124.21, 123.84, 122.95, 116.09, 112.72, d 9.54 (d, J ¼ 1.2 Hz, 1H), 8.65 (s, 1H), 8.04 (dd, J ¼ 8.4, 1.2 Hz,
ꢁ1
10.66; ATR-IR (neat) 2921, 1729, 1535, 1087, 740 cm ; HRMS 1H), 7.92 (dd, J ¼ 7.8, 1.8 Hz, 1H), 7.43–7.36 (m, 3H), 7.29 (dd, J
+
13
(EI) m/z (M ) calcd for C22
H
13ClN
2
O
2
: 372.0666; found: ¼ 7.8, 1.2 Hz, 1H), 3.98 (s, 3H), 3.89 (s, 3H); C NMR (150 MHz,
372.0664.
CDCl ) d 168.02, 152.55, 146.91, 145.08, 139.82, 138.06, 132.15,
3
3-(1,5-Dimethyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one 129.13, 128.64, 126.55, 126.31, 125.44, 124.79, 124.03, 115.97,
(
6h). Prepared from 4a (74 mg, 0.5 mmol) and 1,5-dimethyl-1H- 111.50, 109.36, 52.04, 33.65; ATR-IR (neat) 1734, 1531, 1456,
ꢁ1
+
14 2 4
indole 5h (72 mg, 0.5 mmol) according to general procedure in 1078, 738 cm ; HRMS (EI) m/z (M ) calcd for C19H N O :
ꢀ
1
1
(
7
1
2 h as a yellow solid (104 mg, 72%); mp 220–222 C; H NMR 334.0954; found: 334.0958.
600 MHz, CDCl ) d 8.64 (s, 1H), 8.57 (s, 1H), 7.87–7.86 (m, 1H), 6-Methyl-3-(1-methyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-
.37–7.35 (m, 2H), 7.28–7.24 (m, 2H), 7.16 (dd, J ¼ 8.4, 1.2 Hz, 2-one (7a). Prepared from 6-methyl-2H-benzo[b][1,4]oxazin-2-
3
1
3
H), 3.83 (s, 3H), 2.55 (s, 3H); C NMR (150 MHz, CDCl
3
)
one 4b (81 mg, 0.5 mmol) and N-methylindole 5a (65 mg,
d 152.74, 147.36, 144.96, 137.20, 135.79, 132.42, 131.80, 128.35, 0.5 mmol) according to general procedure in 12 h as a yellow
ꢀ
28.14, 127.22, 125.23, 124.86, 123.22, 115.91, 110.03, 109.29, solid (88 mg, 61%); mp 218–220 C; H NMR (600 MHz, CDCl )
3
1
1
3
ꢁ1
3.50, 21.80; ATR-IR (neat) 2916, 1729, 1525, 1366, 744 cm
;
d 8.88–8.85 (m, 1H), 8.61 (s, 1H), 7.65 (s, 1H), 7.38–7.32 (m, 3H),
+
13
HRMS (EI) m/z (M ) calcd for C18
90.1052.
-(1,6-Dimethyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one 129.54, 128.16, 127.07, 123.56, 123.36, 122.13, 115.52, 110.58,
H
14
N
2
O
2
: 290.1055; found: 7.19–7.15 (m, 2H), 3.87 (s, 3H), 2.44 (s, 3H); C NMR (150 MHz,
2
CDCl ) d 152.95, 147.29, 143.00, 137.42, 137.01, 135.11, 132.10,
3
3
ꢁ1
(
6i). Prepared from 4a (74 mg, 0.5 mmol) and 1,6-dimethyl-1H- 109.60, 33.48, 20.89; ATR-IR (neat) 2908, 1735, 1498, 739 cm ;
indole 5i (72 mg, 0.5 mmol) according to general procedure in HRMS (EI) m/z (M ) calcd for C18H N O : 290.1055; found:
14 2 2
+
ꢀ
1
1
2 h as a yellow solid (101 mg, 70%); mp 210–212 C; H NMR 290.1053.
3-(1-Ethyl-1H-indol-3-yl)-6-methyl-2H-benzo[b][1,4]oxazin-2-
.80 (m, 1H), 7.37–7.31 (m, 2H), 7.26–7.24 (m, 1H), 7.15 (d, J ¼ one (7b). Prepared from 6-methyl-2H-benzo[b][1,4]oxazin-2-one
(
600 MHz, CDCl ) d 8.69 (d, J ¼ 7.8 Hz, 1H), 8.52 (s, 1H), 7.83–
3
7
8
1
3
.4 Hz, 1H), 7.13 (s, 1H), 3.81 (s, 3H), 2.51 (s, 3H); C NMR (150 4b (81 mg, 0.5 mmol) and N-ethylindole 5b (72 mg, 0.5 mmol)
) d 152.69, 147.25, 144.98, 137.79, 136.75, 133.38, according to general procedure in 12 h as a yellow solid (133 mg,
MHz, CDCl
3
ꢀ
1
1
1
1
2
32.42, 128.35, 128.14, 125.22, 124.78, 123.80, 123.17, 115.89, 88%); mp 184–186 C; H NMR (600 MHz, CDCl
10.48, 109.66, 33.37, 21.85; ATR-IR (neat) 2924, 1726, 1528, (m, 1H), 8.66 (s, 1H), 7.64 (s, 1H), 7.40–7.37 (m, 1H), 7.34–7.31
3
) d 8.90–8.86
ꢁ1
+
067, 746 cm ; HRMS (EI) m/z (M ) calcd for C18
90.1055; found: 290.1056.
H
14
N
2
O
2
:
(m, 2H), 7.18–7.14 (m, 2H), 4.23 (q, J ¼ 7.2 Hz, 2H), 2.44 (s, 3H),
13
1.54 (t, J ¼ 7.2 Hz, 3H); C NMR (150 MHz, CDCl ) d 152.91,
3
3
-(5-Fluoro-1-methyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin- 147.26, 142.95, 136.44, 135.41, 135.05, 132.10, 129.44, 128.13,
2
-one (6j). Prepared from 4a (74 mg, 0.5 mmol) and 5-uoro-1- 127.25, 123.70, 123.20, 122.03, 115.47, 110.66, 109.66, 41.70,
ꢁ1
methyl-1H-indole 5j (75 mg, 0.5 mmol) according to general 20.86, 15.22; ATR-IR (neat) 1725, 1528, 1370, 1055, 744 cm
procedure in 12 h as a yellow solid (97 mg, 66%); mp 218– HRMS (EI) m/z (M ) calcd for C19
;
+
H
16
N
2
O
2
: 304.1212; found:
ꢀ
1
2
9
7
20 C; H NMR (600 MHz, CDCl
3
) d 8.60 (s, 1H), 8.51 (dd, J ¼ 304.1216.
.6, 2.4 Hz, 1H), 7.83 (dd, J ¼ 7.2, 1.8 Hz, 1H), 7.40–7.34 (m, 2H),
7-Methyl-3-(1-methyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-
2-one (7c). Prepared from 7-methyl-2H-benzo[b][1,4]oxazin-2-
1
3
.28–7.23 (m, 2H), 7.06 (td, J ¼ 9.0, 3.0 Hz, 1H), 3.85 (s, 3H);
C
NMR (150 MHz, CDCl ) d 159.52 (d, J ¼ 253.2 Hz), 152.60, one 4c (81 mg, 0.5 mmol) and N-methylindole 5a (65 mg,
3
1
1
47.08, 145.00, 138.12, 133.94, 132.22, 128.75, 128.25, 127.63, 0.5 mmol) according to general procedure in 12 h as a yellow
ꢀ
1
27.55, 125.41, 115.97, 111.56 (d, J ¼ 26.4 Hz), 110.31 (d, J ¼ 9.7 solid (122 mg, 84%); mp 216–218 C; H NMR (600 MHz, CDCl )
3
Hz), 108.98 (d, J ¼ 25.3 Hz), 33.76; ATR-IR (neat) 1726, 1529, d 8.85–8.82 (m, 1H), 8.55 (s, 1H), 7.70 (d, J ¼ 7.8 Hz, 1H), 7.36–
ꢁ
1
+
1
3
062, 791 cm ; HRMS (EI) m/z (M ) calcd for C17
H
11FN
2
O
2
:
7.31 (m, 3H), 7.16–7.13 (m, 1H), 7.05 (s, 1H), 3.83 (s, 3H), 2.43 (s,
3H); C NMR (150 MHz, CDCl ) d 152.85, 146.36, 144.86,
3
1
3
94.0805; found: 294.0809.
3-(6-Chloro-1-methyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin- 139.53, 137.34, 136.64, 130.29, 127.80, 126.98, 126.37, 123.47,
2-one (6k). Prepared from 4a (74 mg, 0.5 mmol) and 6-chloro-1- 123.25, 121.99, 116.03, 110.48, 109.51, 33.39, 21.54; ATR-IR
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ꢁ
1
+
(
neat) 1721, 1530, 1051, 741 cm ; HRMS (EI) m/z (M ) calcd for
6-Fluoro-3-(1-methyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-
2-one (7h). Prepared from 6-uoro-2H-benzo[b][1,4]oxazin-2-
C H N O : 290.1055; found: 290.1052.
1
8
14 2 2
7-Methyl-3-(1-phenyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin- one 4f (82 mg, 0.5 mmol) and N-methylindole 5a (65 mg,
2
-one (7d). Prepared from 7-methyl-2H-benzo[b][1,4]oxazin-2- 0.5 mmol) according to general procedure in 12 h as a yellow
ꢀ
1
one 4c (81 mg, 0.5 mmol) and N-phenylindole 5d (96 mg, 0.5 solid (120 mg, 82%); mp 245–247 C; H NMR (600 MHz, CDCl )
3
mmol) according to general procedure in 12 h as a yellow solid d 8.81–8.79 (m, 1H), 8.63 (s, 1H), 7.51 (dd, J ¼ 9.0, 3.0 Hz, 1H),
ꢀ
1
(
153 mg, 87%); mp 140–142 C; H NMR (600 MHz, CDCl
3
)
7.39–7.33 (m, 3H), 7.22 (dd, J ¼ 9.0, 4.8 Hz, 1H), 7.10–7.05 (m,
1
3
d 8.93 (d, J ¼ 7.8 Hz, 1H), 8.82 (s, 1H), 7.75 (d, J ¼ 7.8 Hz, 1H), 1H), 3.87 (s, 3H); C NMR (150 MHz, CDCl ) d 159.58 (d, J ¼
3
7
7
2
1
1
1
7
.57–7.52 (m, 5H), 7.44–7.41 (m, 1H), 7.36 (t, J ¼ 7.2 Hz, 1H), 242.4 Hz), 152.42, 148.02, 141.30, 137.74, 137.47, 133.01 (d, J ¼
.31 (td, J ¼ 7.8, 1.2, 1H), 7.17 (d, J ¼ 8.4 Hz, 1H), 7.08 (s, 1H), 11.8 Hz), 126.97, 123.62, 123.54, 122.47, 116.76 (d, J ¼ 9.4 Hz),
1
3
.45 (s, 3H); C NMR (150 MHz, CDCl ) d 152.72, 146.36, 115.57 (d, J ¼ 24.6 Hz), 113.71 (d, J ¼ 23.5 Hz), 110.41, 109.73,
3
ꢁ1
45.00, 140.08, 138.64, 136.77, 135.38, 130.22, 129.72, 128.02, 33.57; ATR-IR (neat) 1733, 1523, 1371, 1244, 1078, 742 cm
;
+
27.62, 127.43, 126.47, 124.86, 123.84, 123.67, 122.59, 116.12, HRMS (EI) m/z (M ) calcd for C H FN O : 294.0805; found:
12.40, 110.82, 21.60; ATR-IR (neat) 3051, 1738, 1514, 1228, 294.0804.
36 cm ; HRMS (EI) m/z (M ) calcd for C23
1
7
11
2 2
ꢁ
1
+
H
16
N
2
O
2
: 352.1212;
6-Chloro-3-(1-methyl-1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-
2-one (7i). Prepared from 6-chloro-2H-benzo[b][1,4]oxazin-2-one
found: 352.1214.
6
-(tert-Butyl)-3-(1-methyl-1H-indol-3-yl)-2H-benzo[b][1,4] 4g (91 mg, 0.5 mmol) and N-methylindole 5a (65 mg, 0.5 mmol)
oxazin-2-one (7e). Prepared from 6-(tert-butyl)-2H-benzo[b][1,4] according to general procedure in 12 h as a yellow solid (144 mg,
ꢀ
1
oxazin-2-one 4d (101 mg, 0.5 mmol) and N-methylindole 5a 93%); mp 228–230 C; H NMR (600 MHz, CDCl ) d 8.81–8.78
3
(
65 mg, 0.5 mmol) according to general procedure in 12 h as (m, 1H), 8.63 (s, 1H), 7.81 (d, J ¼ 1.2 Hz, 1H), 7.39–7.33 (m, 3H),
ꢀ
1
a yellow solid (98 mg, 60%); mp 185–187 C; H NMR (600 MHz, 7.30 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.19 (d, J ¼ 8.4 Hz, 1H), 3.87 (s,
1
3
CDCl
7
9
3
) d 8.90–8.88 (m, 1H), 8.60 (s, 1H), 7.84 (d, J ¼ 2.4 Hz, 1H), 3H). C NMR (150 MHz, CDCl ) d 152.22, 148.03, 143.57,
3
.42 (dd, J ¼ 8.4, 1.8 Hz, 1H), 7.38–7.32 (m, 3H), 7.20 (d, J ¼ 137.73, 137.47, 133.09, 130.36, 128.20, 127.54, 126.97, 123.66,
13
.0 Hz, 1H), 3.85 (s, 3H), 1.41 (s, 9H). C NMR (150 MHz, CDCl
3
)
123.58, 122.51, 116.98, 110.44, 109.74, 33.59; ATR-IR (neat)
ꢁ
1
+
d 152.96, 148.63, 147.15, 142.78, 137.37, 137.00, 131.77, 127.01, 1729, 1530, 1459, 1069, 743 cm ; HRMS (EI) m/z (M ) calcd for
1
26.13, 124.75, 123.54, 123.33, 122.10, 115.29, 110.51, 109.57, C H ClN O : 310.0509; found: 310.0508.
17 11 2 2
3
4.64, 33.43, 31.45; ATR-IR (neat) 2952, 1727, 1526, 1369, 1074,
ꢁ
1
+
741 cm ; HRMS (EI) m/z (M ) calcd for C H N O : 332.1525;
21 20 2 2
Gram-scale synthesis of cephalandole A
found: 332.1527.
The solution of 2H-benzo[b][1,4]oxazin-2-one 4a (1.0 gram,
6
-(tert-Butyl)-3-(1-(4-chlorophenyl)-1H-indol-3-yl)-2H-benzo
6.80 mmol) and indole 5m (0.81 gram, 6.80 mmol) in THF
[
b][1,4]oxazin-2-one (7f). Prepared from 6-(tert-butyl)-2H-benzo
(
15 mL), CuCl (48 mg, 10 mol%) was added at room tempera-
2
[b][1,4]oxazin-2-one 4d (101 mg, 0.5 mmol) and 1-(4-chlor-
ꢀ
ture and heated at 60 C for 12 h. Upon completion of reaction
as indicated by thin layer chromatography, the reaction mixture
was concentrated under reduced pressure, and the crude
material was puried by column chromatography (hexane/ethyl
acetate ¼ 5 : 1) to afford cephalandole A (3, 1.337 gram, 75%);
ophenyl)-1H-indole 5g (114 mg, 0.5 mmol) according to general
procedure in 12 h as a yellow solid (181 mg, 85%); mp 208–
ꢀ
1
2
(
7
(
10 C; H NMR (600 MHz, CDCl ) d 8.96 (d, J ¼ 7.8 Hz, 1H), 8.80
3
s, 1H), 7.87 (d, J ¼ 1.8 Hz, 1H), 7.53–7.45 (m, 6H), 7.40 (t, J ¼
.2 Hz, 1H), 7.33 (t, J ¼ 7.2 Hz, 1H), 7.22 (d, J ¼ 8.4 Hz, 1H), 1.42
ꢀ
1
mp 237–239 C; H NMR (600 MHz, acetone-d ) d 11.07 (s, 1H),
1
3
6
s, 9H); C NMR (150 MHz, CDCl
3
) d 152.76, 148.80, 147.05,
8
.89 (dd, J ¼ 6.6, 4.8 Hz, 1H), 8.82 (d, J ¼ 3.0 Hz, 1H), 7.89 (dd, J
7.8, 1.2 Hz, 1H), 7.59–7.55 (m, 1H), 7.49 (td, J ¼ 7.8, 1.8 Hz,
H), 7.43 (td, J ¼ 7.8, 1.8 Hz, 1H), 7.35 (dd, J ¼ 7.8, 1.2 Hz, 1H),
1
1
1
7
4
42.91, 137.13, 136.62, 135.26, 133.33, 131.68, 129.93, 127.48,
¼
26.81, 126.04, 125.03, 124.10, 123.84, 122.83, 115.41, 112.76,
10.58, 34.67, 31.45; ATR-IR (neat) 2958, 1727, 1528, 1217,
1
7
1
1
1
3
6
.30–7.26 (m, 2H); C NMR (150 MHz, acetone-d ) d 152.95,
ꢁ
1
+
42 cm ; HRMS (EI) m/z (M ) calcd for C H ClN O :
2
6
21
2 2
49.01, 146.19, 137.82, 134.53, 133.17, 129.53, 128.83, 127.32,
26.07, 124.13, 124.05, 122.43, 116.71, 112.72, 112.33; ATR-IR
28.1292; found: 428.1289.
-(1-Methyl-1H-indol-3-yl)-6-phenyl-2H-benzo[b][1,4]oxazin-
-one (7g). Prepared from 6-phenyl-2H-benzo[b][1,4]oxazin-2-
3
ꢁ
1
+
(neat) 3285, 1715, 1602, 1530, 1429 cm ; HRMS (EI) m/z (M )
2
calcd for C H N O : 262.0742; found: 262.0740.
1
6
10 2 2
one 4e (112 mg, 0.5 mmol) and N-methylindole 5a (65 mg,
.5 mmol) according to general procedure in 12 h as a yellow
0
ꢀ
1
Control experiments
3
solid (137 mg, 78%); mp 236–238 C; H NMR (600 MHz, CDCl )
d 8.91–8.88 (m, 1H), 8.63 (s, 1H), 8.05 (d, J ¼ 3.6 Hz, 1H), 7.67 (d, The solution of 4a (147 mg, 1.0 mmol) and N-methylindole 5a
J ¼ 7.2 Hz, 2H), 7.60 (dd, J ¼ 8.4, 1.8 Hz, 1H), 7.48 (t, J ¼ 7.2 Hz, (130 mg, 1.0 mmol) in THF (3.0 mL) was stirred at room
1
3
2
H), 7.40–7.34 (m, 4H), 7.33 (d, J ¼ 8.4 Hz, 1H), 3.87 (s, 3H);
C
temperature 30 h. Upon completion of reaction as indicated by
NMR (150 MHz, CDCl ) d 152.70, 147.60, 144.38, 139.75, 138.69, thin layer chromatography, the reaction mixture was concen-
3
1
1
37.45, 137.25, 132.54, 128.93, 127.62, 127.33, 127.13, 127.06, trated under reduced pressure, and the crude material was
26.42, 123.59, 123.47, 122.27, 116.21, 110.55, 109.66, 33.52; puried by column chromatography (hexane/ethyl acetate ¼
ꢁ1
ꢀ
1
ATR-IR (neat) 3055, 1743, 1515, 1240, 735 cm ; HRMS (EI) m/z 5 : 1) to afford 8 as a solid (258 mg, 93%); mp 170–172 C; H
+
(M ) calcd for C23
H
16
N
2
O
2
: 352.1212; found: 352.1210.
NMR (600 MHz, CDCl
3
) d 7.67 (d, J ¼ 7.8 Hz, 1H), 7.29 (d, J ¼
8.4 Hz, 1H), 7.26–7.23 (m, 1H), 7.16–7.13 (m, 1H), 7.07 (dd, J ¼
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7
.8, 1.2 Hz, 1H), 7.00 (td, J ¼ 7.8, 1.2 Hz, 1H), 6.98 (s, 1H), 6.87
S. A. Boyd and S. Fukumoto, Bioorg. Med. Chem., 2013, 21,
5983.
3 F. Touzeau, A. Arrault, G. Guillaumet, E. Scalbert, B. Pfeiffer,
M.-C. Rettori, P. Renard and J.-Y. M ´e rour, J. Med. Chem.,
2003, 46, 1962.
4 K. Waisser, L. Kubicov ´a , V. Buchta, P. Kubanov ´a , K. Bajerov ´a ,
L. Jir ´a skov ´a , O. Bedna ˇr ´ı k, O. Bure ˇs and P. Hol ˆy , Folia
Microbiol., 2002, 47, 488.
(
(
td, J ¼ 7.8, 1.2 Hz, 1H), 6.76 (dd, J ¼ 7.8, 1.2 Hz, 1H), 5.33
1
3
s, 1H), 3.70 (s, 4H). C NMR (150 MHz, CDCl ) d 165.15, 141.31,
3
1
1
37.10, 132.83, 127.74, 125.99, 124.99, 122.42, 120.36, 119.99,
19.24, 116.89, 115.04, 109.69, 109.63, 52.56, 32.89; ATR-IR
ꢁ
1
+
(
neat) 3346, 1735, 1529, 1119, 737 cm ; HRMS (EI) m/z (M )
calcd for C17 : 278.1055; found: 278.1058.
To the solution of 8 (139 mg, 0.5 mmol) in THF (3.0 mL),
14 2 2
H N O
CuCl
2
(7 mg, 10 mol%) was added at room temperature and
5 (a) K. Waiser, M. Pe ˇr ina, J. Kune ˇs , V. Klime ˇs ov ´a and
J. Kaustov ´a , Il Farmaco, 2003, 58, 1137; (b) S. Konda,
S. Raparthi, K. Bhaskar, R. K. Munagati, V. Guguloth,
L. Nagarapu and D. M. Akkerwar, Bioorg. Med. Chem. Lett.,
2015, 25, 1643.
ꢀ
heated at 60 C for 1 h. Upon completion of reaction as indi-
cated by thin layer chromatography, the reaction mixture was
concentrated under reduced pressure, and the crude material
was puried by column chromatography (hexane/ethyl acetate
¼
20 : 1) to afford 6a as a solid (132 mg, 96%).
6 (a) A. Khalaj, M. Abdollahi, A. Kebriaeezadeh, N. Adibpour,
Z. Pandi and S. Rasoulamini, Indian J. Pharmacol., 2002,
3
4, 184; (b) I. V. Mashevakaya, L. V. Anikina,
Conflicts of interest
Y. B. Vikharev, V. A. San, S. V. Koltsova and
A. N. Maslivets, Pharm. Chem. J., 2001, 35, 414.
There are no conicts to declare.
7
8
R. Frechette and M. A. Weidner-Wells, WO Patent Appl.
9717333, 1997.
Acknowledgements
L. D. Wise, D. J. Wustrow and T. Belliotti, WO Patent Appl.
9745419, 1997.
This research was supported by the Nano Material Technology
Development Program of the Korean National Research Foun-
9 S. U. S.-S. Michael, WO Patent 2012151440, 2012.
dation (NRF) funded by the Korean Ministry of Education, 10 C. Li and G. Xiaoxia, Patent CN 103664919 A, 2014.
Science, and Technology (2012M3A7B4049675) and Priority 11 (a) P.-L. Wu, Y.-L. Hsu and C.-W. Jao, J. Nat. Prod., 2006, 69,
Research Centers Program (2014R1A6A1031189).
1467; (b) Y.-T. Wu, Y.-L. Hsu and P.-L. Wu, Heterocycles, 2008,
5, 1191.
2 (a) J. J. Mason, J. Bergman and T. Janosik, J. Nat. Prod., 2008,
1, 1447; (b) L. Gross, F. Mohn, N. Moll, G. Meyer,
7
1
Notes and references
7
1
(a) Antibiotics and Antiviral Compounds, ed. K. Krohn, H. A.
Kirst and H. Maag, VCH, Weinheim, 1993; (b)
W. M. Abdel-Megeed and M. Jaspars, Nat. Chem., 2010, 2,
821.
Pharmaceutical Substances, ed. A. Kleemann, J. Engel, B. 13 (a) Q. Chen, M. Chen, C. Yu, L. Shi, D. Wang, Y. Yang and
Kutscher and D. Reichert, Thieme, Stuttgart, New York, 4th
edn, 2001; (c) Houben-Weyl Methods of Organic Chemistry,
Hetarenes IV, Six-Membered and Large Hetero-Rings with
Maximum Unsaturation, ed. J. Teller and E. Schaumann,
Georg Thieme, Stuttgart, 1997, vol. E9a, pp. 141–177; (d)
J. Ila ˇs , P. S. Anderluh, M. S. Dolenc and D. Kikelj,
Y. Zhou, J. Am. Chem. Soc., 2011, 133, 16432; (b)
M. Rueping, A. P. Antonchick and T. Theissmann, Angew.
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