Synthesis of some analogs of indole phytoalexins brassinin and methoxybrassenin B and their positional isomers

Article abstract of DOI:10.1135/cccc19990348

Treatment of indole-3-carboxylic acid with phosphorus trichloride and subsequent reaction of the obtained acid chloride with potassium thiocyanate afforded indol-3-ylcarbonyl isothiocyanate (13). Its treatment with sodium hydrogensulfide in the presence of methyl iodide lead to the corresponding methyl dithiocarbamate, an oxo derivative of brassinin (oxobrassinin, 14), which by methylation with methyl iodide afforded brassenin B (8). Corresponding 2-isomers, 21 and 23, were obtained by an analogous sequence, starting from indole-2-carboxylic acid. During the preparation of isooxobrassinin (21), which appeared to be unstable in the basic reaction medium, also an imidazo[3,4-a]indole derivative 22 has been isolated as an unexpected side product. Related oxobrassinin analogs and their 2-isomers were prepared by treatment of indol-3-and indol-2-ylcarbonyl isothiocyanate with methanol and amines. In the case of isothiocyanate 13, besides the expected products of nucleophilic addition to NCS group (monothiocarbamate 25a and thiourea derivatives 25b-25g), also the substitution products were obtained. Their formation could be explained by partial decomposition of the starting isothiocyanate to an unstable ketene, which reacts with methanol and amines to afford the corresponding methyl carboxylate 26a and carboxamides 26b-26g. Antifungal activity of the prepared compounds has been examined, using the fungus Bipolaris leersiae. All of the compounds exhibited lower activity than phytoalexin brassinin.

Full text of DOI:10.1135/cccc19990348

348
Kutschy, Dzurilla, Takasugi, Sabová:
SYNTHESIS OF SOME ANALOGS OF INDOLE PHYTOALEXINS
BRASSININ AND METHOXYBRASSENIN B AND THEIR POSITIONAL
ISOMERS
b
a
Peter KUTSCHYa1,*, Milan DZURILLAa2, Mitsuo TAKASUGI and Adriana SABOVÁ
a
Department of Organic Chemistry, Faculty of Natural Sciences, P. J. Šafárik University,
Moyzesova 11, 041 67 Košice, Slovak Republic; e-mail: kutschy@kosice.upjs.sk,
1
2
dzurilla@kosice.upjs.sk
b
Division of Material Science, Graduate School of Environmental Earth Science,
Hokkaido University, Sapporo 060-0810, Japan; e-mail: mtaka@ees.hokudai.ac.jp
Received Septem ber 11, 1998
Accepted October 22, 1998
Dedicated to the memory of Dr Miroslav Protiva.
Treatm en t of in dole-3-carboxylic acid with ph osph orus trich loride an d subsequen t reaction
of th e obtain ed acid ch loride with potassium th iocyan ate afforded in dol-3-ylcarbon yl
isoth iocyan ate (13). Its treatm en t with sodium h ydrogen sulfide in th e presen ce of m eth yl
iodide lead to th e correspon din g m eth yl dith iocarbam ate, an oxo derivative of brassin in
(oxobrassin in , 14), wh ich by m eth ylation with m eth yl iodide afforded brassen in B (8). Cor-
respon din g 2-isom ers, 21 an d 23, were obtain ed by an an alogous sequen ce, startin g from
in dole-2-carboxylic acid. Durin g th e preparation of isooxobrassin in (21), wh ich appeared to
be un stable in th e basic reaction m edium , also an im idazo[3,4-a]in dole derivative 22 h as
been isolated as an un expected side product. Related oxobrassin in an alogs an d th eir
2-isom ers were prepared by treatm en t of in dol-3- an d in dol-2-ylcarbon yl isoth iocyan ate with
m eth an ol an d am in es. In th e case of isoth iocyan ate 13, besides th e expected products of
n ucleoph ilic addition to NCS group (m on oth iocarbam ate 25a an d th iourea derivatives
25b–25g), also th e substitution products were obtain ed. Th eir form ation could be explain ed
by partial decom position of th e startin g isoth iocyan ate to an un stable keten e, wh ich reacts
with m eth an ol an d am in es to afford th e correspon din g m eth yl carboxylate 26a an d
carboxam ides 26b–26g. An tifun gal activity of th e prepared com poun ds h as been exam in ed,
usin g th e fun gus Bipolaris leersiae. All of th e com poun ds exh ibited lower activity th an
ph ytoalexin brassin in .
Key w ord s: In doles; Ph ytoalexin s; Brassin in ; Meth oxybrassen in B; Isoth iocyan ates.
In dole ph ytoalexin s are an in terestin g group of n atural products, exh ibitin g
an tim icrobial1 an d can cer ch em opreven tive2,3 activity. Sin ce 1986, wh en
th e first th ree in dole ph ytoalexin s, n am ed brassin in (1), m eth oxybrassin in
(2) an d cyclobrassin in (9) were isolated from Ch in ese cabbage1,4, m ore th an
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Brassinin and Methoxybrassenin B
349
twen ty related com poun ds h ave been isolated from th e plan t fam ily
Cruciferae, in cludin g m an y econ om ically im portan t vegetables. Th eir isola-
tion , structure an d biological properties h ave been sum m arized in two re-
view articles5,6. Th e un ique structural feature of th ese com poun ds is th e
presen ce of in dole rin g an d a side ch ain or an oth er h eterocycle, con tain in g
a n itrogen atom an d on e or two sulfur atom s. Usually, th ese m oieties are
lin ked to th e 3-position of in dole n ucleus via CH2 group. In th e case of
m eth oxybrassen in A (5, ref.7) an d cyclobrassin in (9, ref.1), also th e corre-
spon din g oxo derivatives, n am ely m eth oxybrassen in B (6, ref.7) an d
cyclobrassin on (10, ref.8) were isolated from cabbage an d koh lrabi, respec-
tively. Th e com poun d 3 (oxobrassin in ) h as n ot been foun d yet in
cruciferous plan ts. Isolation from plan ts does n ot afford sufficien t quan ti-
S
H CS
3
SCH
SCH
3
N
X
3
YCH
N
X
NH
3
X
S
N
N
R
N
R
H
R
R
X
X
X
Y
CH
CH
H
CH
OCH
OCH
H
CH
2
S
1
2
3
4
5
6
7
8
9
2
2
3
OCH
H
CO
CH
CO
O
10
2
3
3
CO
2
(CH )
H
CO
H
2 2
NCS
S
N
N
S
N
N
N
H
H
16
H
17
28
ties of in dole ph ytoalexin s for biological screen in g an d th erefore it is quite
im portan t to in vestigate th e syn th esis of th ese com poun ds an d th eir
an alogs. In som e cases, an an alog can be m ore active th an n atural
ph ytoalexin . It was recen tly foun d, th at h om obrassin in (4) exh ibits a
h igh er an tifun gal activity th an brassin in (1, ref.9). Preparation of in dole
ph ytoalexin s an d th eir an alogs is often com plicated by in stability of in ter-
m ediates an d low yields of fin al products, particularly, wh en
1-un substituted in doles are used. Brassin in an d its derivatives were syn th e-
sized in 12–72% overall yields from substituted in doles an d
in dole-3-carboxaldeh ydes via (in dol-3-ylm eth yl)am in e derivatives, wh ich
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

350
Kutschy, Dzurilla, Takasugi, Sabová:
were treated with carbon disulfide an d m eth yl iodide1,3,4,10–12. Brassin in
an d its derivatives can be cyclized with pyridin ium brom ide perbrom ide1,4
or N-brom osuccin im ide3,11–14 to cyclobrassin in an d its derivatives in
34–61% yields. Meth oxybrassen in
A
(5, ref.7) an d correspon din g
dem eth oxy an alog 7 (brassen in A, ref.12) were obtain ed by m eth ylation of
m eth oxybrassin in (2) an d brassin in (1) with m eth yl iodide in m eth an ol or
aceton e in th e presen ce of potassium carbon ate in 87 an d 40% yield, re-
spectively. On th e oth er h an d, n o atten tion h as been devoted yet to th e
syn th esis of th e in dole ph ytoalexin s or th eir an alogs h avin g th e side ch ain
or an oth er h eterocycle lin ked to th e 3-position of in dole rin g via C=O
group. Th e aim of th e presen t study was to syn th esize th e oxobrassin in (3),
brassen in B (8), th eir isom ers with th e side ch ain in 2-position , as well as
related m on oth iocarbam ates an d th ioureas, an d to com pare th e an tifun gal
activity of syn th esized com poun ds with ph ytoalexin brassin in . To ach ieve
th is goal, we decided to build up th e dith iocarbam ate an d dith iocarbon ate
side ch ain , presen t in target com poun ds, via in dol-3- an d in dol-2-yl-
carbon yl isoth iocyan ates (13 an d 20) as th e key in term ediates an d by usin g
th e carboxylic acids 11 an d 18 as startin g com poun ds. In th e first step,
tran sform ation of acids 11 an d 18 to acid ch lorides 12 an d 19 was required.
Previously described procedures, usin g th ion yl ch loride15–17 are suitable for
th e preparation of dilute solution s of crude ch lorides, used in th e reaction
with am in es, wh ere th e acidic residues are n eutralized by an excess of re-
agen t. Because of th eir h igh in stability, acid ch lorides 12 an d 19 can n ot be
purified by distillation or crystallization to rem ove acidic residues, wh ich
are un desired in th e n ext step. We h ave foun d, th at th e difficulties, wh ich
are frequen tly associated with th e syn th esis of h eteroaren ecarboxylic acid
ch lorides18 can be solved by usin g ph osph orus trich loride. In dole-3-
carbon yl ch loride (12) can be advan tageously prepared by treatm en t of acid
11 with an excess of ph osph orus trich loride in dry ben zen e in th e presen ce
of aceton itrile at room tem perature for 20 m in , accordin g to th e sligh tly
m odified m eth od, recen tly described for th e preparation of 3-(in dol-
3-yl)propen oyl ch loride19. Th e excess of ph osph orus trich loride was re-
m oved by con cen tration of th e obtain ed solution , an d th e reaction of crude
ch loride 12 with potassium th iocyan ate in dry aceton e afforded un stable
in dol-3-ylcarbon yl isoth iocyan ate (13). In frared spectrum of crude isoth io-
cyan ate 13, taken im m ediately after evaporation of aceton e exh ibited
characteristic absorption bands ν(N=C=S) at 1 970 cm–1 and ν(N–H) at 3 467 cm–1.
Treatm en t of fresh ly prepared isoth iocyan ate 13 with sodium
h ydrogen sulfide in th e presen ce of m eth yl iodide resulted in th e form ation
of oxobrassin in (14) in 31% yield (Sch em e 1). Meth ylation of 14 with
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Brassinin and Methoxybrassenin B
351
m eth yl iodide in dry aceton e in th e presen ce of potassium carbon ate af-
forded brassen in B (8), a dem eth oxy an alog of m eth oxybrassen in B (6) in
87% yield. An oth er an alog, in terestin g from th e poin t of view of its possi-
ble biological activity is m eth ylbrassen in B (15). It could be prepared by
m eth ylation of m eth yloxobrassin in , usin g 1-m eth ylin dole-3-carboxylic
acid as startin g com poun d. However, it was attractive to exam in e, if 15
could be obtain ed by a twofold m eth ylation of 14. It was foun d, th at by
treatm en t of 14 with an excess of m eth yl iodide in dim eth ylform am ide in
th e presen ce of two equivalen ts of lith ium h ydride, m eth ylbrassen in B (15)
is form ed in 91% yield.
S
H CS
3
O
SCH
SCH
3
3
X
O
O
NH
N
K CO , CH I
2
NaSH, CH I
3
3
3
Acetone
N
DMF/CH OH
3
N
N
H
H
H
8
11
12
13
14
H CS
3
LiH, CH I
3
DMF
X
SCH
3
O
N
OH
Cl
11
12
13
NCS
N
SCHEME 1
15
CH
3
Position al isom ers in gen eral differ in th eir biological activities. Th is was
also observed in th e case of in dole ph ytoalexin brassilexin (16), an d its an a-
log isobrassilexin (17), wh ere th e latter exh ibits a h igh er cytotoxic
activity20. Th erefore, we h ave decided to study th e preparation of isooxo-
brassin in (21) an d isobrassen in B (23, Sch em e 2). Th e syn th etic procedures,
leadin g to 21 an d 23, were expected to be iden tical with th ose, used for th e
preparation of 8 an d 14. However, th e acid 18 appeared to be sign ifican tly
less reactive toward ph osph orus trich loride in th e presen ce of aceton itrile
in ben zen e at room tem perature th an in dole-3-carboxylic acid (11) an d, un -
der th ese con dition s, n o ch loride 19 was form ed. Th e desired tran sform a-
tion was successfully brough t about by h eatin g for on e h our in ben zen e at
85–90 °C with out addition of aceton itrile. Reaction of an un stable ch loride
19 with potassium th iocyan ate in dry aceton e afforded isoth iocyan ate 20,
wh ich was used in th e n ext reaction as an un stable crude in term ediate. Sur-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

352
Kutschy, Dzurilla, Takasugi, Sabová:
prisin gly, treatm en t of 20 with sodium h ydrogen sulfide in th e presen ce of
m eth yl iodide resulted in th e form ation of a m ixture of expected
dith iocarbam ate 21 (isooxobrassin in ) in 19% yield, togeth er with a 9%
yield of un expected im idazo[3,4-a]in dole derivative 22. It was assum ed,
th at dith iocarbam ate 21 cyclized to 22 in th e sligh tly basic reaction m e-
LiH, DMF
O
S
O
X
NaSH, CH I
3
O
NH
21
SCH
+
3
DMF/CH OH
3
N
N
H
N
H
NH
22
S
18
19
20
K CO , CH I
2
3
Acetone
3
X
O
O
SCH
OH
Cl
18
19
20
3
LiH, CH I
3
N
N
DMF
N
NCS
N
H
CH
SCH
3
3
24
H CS
3
SCH
3
23
SCHEME 2
dium . Th is assum ption was con firm ed by in depen den t cyclization of 21 to
22 with lith ium h ydride in dim eth ylform am ide in 99% yield. Meth ylation
of dith iocarbam ate 21 with m eth yl iodide in dry aceton e in th e presen ce
of potassium carbon ate afforded isobrassen in B (23), a position al isom er of
brassen in B (8). Th e attem pts to prepare m eth ylisobrassen in B (position al
isomer of 15) by methylation of 23 have failed. Using methyl iodide in acetone
in th e presen ce of potassium carbon ate, n o reaction occurred, even after
prolon ged h eatin g, wh ereas in dim eth ylform am ide with lith ium h ydride
an d m eth yl iodide, a com petitive cyclization took place, followed by
m eth ylation with th e form ation of derivative 24. Structure of th e
com pounds 22 and 24 was confirm ed by spectral m ethods. In 1H NMR spec-
trum of the derivative 22, only the signals of arom atic protons at 7.38–8.28
ppm are presen t, wh ereas th e spectrum of 24 exh ibits also th e sign als of
two SCH3 groups at 1.50 ppm an d a sign al of NCH3 group at 3.15 ppm . In
th e m ass spectra, th e m/z values of m olecular ion s at 202 (100%, 21) an d
278 (4%, 24) are in accord with th e expected m olecular weigh ts.
To com pare th e an tifun gal activity of previously described brassin in
an alogs, h avin g th e m eth ylsulfan yl group replaced by an alkoxy or am in o
group12, with correspon din g oxo derivatives, we h ave also studied th e reac-
tion s of isoth iocyan ate 13 with m eth an ol an d piperidin e. Surprisin gly, in
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Brassinin and Methoxybrassenin B
353
both cases we h ave obtain ed a m ixture of addition an d substitution prod-
ucts, i.e. m on oth iocarbam ate 25a (8%) or th iourea 25f (17%), an d ester 26a
(29%) or am ide 26f (20%, Sch em e 3). To study th e gen erality of th is un ex-
pected beh aviour of isoth iocyan ate 13 in a reaction with n ucleoph ilic re-
agen ts, a series of am in es was used, affordin g in all cases a m ixture of
th iourea derivatives (25b–25g) an d am ides (26b–26g, Sch em e 3, Table I).
S
O
O
Nu
NCS
Nu
O
NH
NuH
+
N
N
N
H
H
H
13
25a-25g
26a-26g
O
C
HSCN
+
N
H
A
In the formulae 25-27:
Nu
NuH
NH
Nu
20
CH O
3
N
H
a
b
c
d
e
f
O
S
CH NH
3
27a-27g
PhCH NH
2
(CH ) CHNH
2 5
4-CH -C H -NH
3 6 4
(CH ) N
2 5
O(CH ) N
2 4
g
SCHEME 3
Preparation of com poun ds 25b–25g required th e use of an excess of am in e
to brin g th e reaction to com pletition . Most probably, th e th iocyan ic acid,
liberated durin g th e form ation of am ides, is bon ded to h ith erto un reacted
am in e, to produce correspon din g am m on ium th iocyan ates. Previously, in
th e reaction of pen t-4-yn oyl isoth iocyan ate with am in es, we were able to
isolate th ese salts because th e reaction s were perform ed in ben zen e, in
wh ich th e in soluble salts precipitated, wh ereas th e oth er products
(th ioureas an d am ides) rem ain ed in solution 21
. In dol-3-ylcarbon yl
isoth iocyan ate (13) is in soluble in ben zen e an d its reaction s with
n ucleoph iles were perform ed in aceton e. Isolation of products required th e
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

354
Kutschy, Dzurilla, Takasugi, Sabová:
use of colum n ch rom atograph y after evaporation of aceton e; h en ce, th e
h igh ly polar salts could n ot be isolated. To obtain m ore in form ation about
n ucleoph ilic addition s to h ith erto un kn own in dolylcarbon yl isoth io-
cyan ates, also th e reaction s of in dol-2-ylcarbon yl isoth iocyan ate (20) with
th e sam e n ucleoph iles h as been carried out. In th is case, h owever, th e on ly
products obtain ed in 22–45% yield were th e correspon din g m on o-
th iocarbam ate 27a an d th iourea derivatives 27b–27g (Sch em e 3, Table I).
Th ese observation s in dicate a specific reactivity of in dol-3-ylcarbon yl
isoth iocyan ate (13). A dram atic differen ce between isoth iocyan ates 13 an d
20 can n ot be explain ed on th e basis of th e presen t experien ce about th e se-
lectivity of n ucleoph ilic addition to an d substitution at isoth iocyan ato-
carbon yl group21. Substitution of NCS group was observed to proceed
sim ultan eously with n ucleoph ilic addition on ly in th e reaction s of som e
aliph atic, but n ot arom atic acyl isoth iocyan ates with am in es. Even in th e
case of pen t-4-yn oyl isoth iocyan ate, with th e prevailin g ten den cy to th e
form ation of substitution products with am in es, treatm en t with m eth an ol
afforded correspon din g m on oth iocarbam ate as th e sole reaction product21
.
On th e con trary, th e form ation of th e substitution product in th e case of
isoth iocyan ate 13 is m ost pron oun ced in th e reaction with m eth an ol. Th is
reaction is preferably perform ed at 70–75 °C, h owever th e sam e ratio of
products 25a an d 26a was obtain ed at room tem perature, wh ereas th e reac-
tion tim e was prolon ged from 10 m in to 24 h . Based on th e above m en -
tion ed fin din gs, th e form ation of ester 26a an d am ides 26b–26g is n ot
likely to proceed by direct substitution of NCS group. It can be assum ed,
th at th e reason con sists in th e activation effect of in dole n itrogen lon e pair
in to 3-position , resultin g in partial decom position of isoth iocyan ate 13 to
th iocyan ic acid an d un stable keten e in term ediate (A, Sch em e 3). Th e re-
verse reaction is also possible an d th us both isoth iocyan ate 13 an d keten e
A can be sim ultan eously presen t in th e reaction m ixture. Con sequen tly, th e
ester 26a an d am ides 26b–26g are form ed by th e addition of a n ucleoph ile
to keten e A, wh ereas m on oth iocarbam ate 25a an d th iourea derivatives
25b–25g are produced by n ucleoph ilic addition to isoth iocyan ate 13. Elec-
tron -with drawin g ch aracter of carbon yl group in th e 3-position en h an ces
th e stability of in dol-3-ylcarbon yl isoth iocyan ate (13), wh en com pared
with in dol-3-ylm eth yl isoth iocyan ate (28), a postulated in term ediate in th e
biosyn th esis of in dole ph ytoalexin s28,29, wh ich can n ot be isolated or syn -
th esized due to its in trin sic in stability12. An in teraction between th e in dole
n itrogen lon e pair an d carbon yl group in th e 3-position was suggested for
th e explan ation of in frared spectrum of 2,3-dih ydrocarbazol-4(1H)-on e,
sh owin g n o absorption in th e 1 600–1 700 cm –1 region 30. Keten e A was pro-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Brassinin and Methoxybrassenin B
355
TABLE I
Ph ysicoch em ical properties of products 25a–27g
Calculated/Foun d
% H
Com -
poun d
Form ula
M.w.
M.p., °C
Yielda
%
Solven tb
% C
% N
25a
25b
25c
25d
25e
25f
25g
26a
26b
26c
26d
26e
26f
26g
27a
C11H10N2O2S
234.3
174–176
A–C
8
24
18
38
12
17
4
56.40
56.12
4.30
4.15
11.96
11.68
C11H11N3OS
233.3
205–207
A–W
56.63
56.41
4.75
4.56
18.01
17.83
C17H15N3OS
309.4
185–187
A–W
66.00
66.13
4.89
4.97
13.58
13.52
C16H19N3OS
301.4
199–201
D–H
63.76
63.89
6.35
6.09
13.94
14.12
C11H11N3OS
309.4
183–185
E–W
66.00
66.28
4.89
5.02
13.58
13.32
C15H17N3OS
287.4
178–180
A–H
62.69
62.76
5.99
6.11
14.62
14.37
C14H15N3O2S
289.4
196–198
A–C
58.11
58.40
5.23
5.48
14.52
14.68
C10H9NO2
175.2
148–150c
M–W
29
9
68.56
68.32
5.18
5.21
7.99
7.75
C10H10N2O
174.2
166–168
A–W
68.95
68.76
5.79
5.90
16.08
15.81
C16H14N2O
250.3
175–177d
A–W
22
35
24
18
35
45
76.78
76.52
5.64
5.89
11.19
11.02
C15H18N2O2
242.3
201–202e
A–C
74.35
74.55
7.49
7.29
11.56
11.63
C16H18N2O
250.3
199–200f
E–W
76.78
76.61
5.64
5.78
11.19
10.95
C14H16N2O
228.3
159–161g
A–C
73.66
73.48
7.06
6.89
12.27
12.31
C13H14N2O
230.3
220–222
A–C
67.81
67.69
6.13
6.04
12.17
12.31
C11H10N2O2S
233.3
175–177
M–W
56.40
56.25
4.30
4.49
11.96
11.80
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

356
Kutschy, Dzurilla, Takasugi, Sabová:
TABLE I
(Continued)
Calculated/Foun d
Com -
poun d
Form ula
M.w.
M.p., °C
Yielda
%
Solven tb
% C
% H
% N
27b
27c
27d
27e
27f
27g
C11H11N3OS
233.3
228–230
E–W
22
39
25
23
45
25
56.63
56.39
4.75
4.92
18.01
17.90
C17H15N3OS
309.4
199–201
CH–P
66.00
66.19
4.89
5.05
13.58
13.48
C19H19N3OS
301.4
182–183
M–W
63.76
63.51
6.35
6.44
13.94
14.17
C17H15N3OS
309.4
195–197
E
66.00
65.83
4.89
5.11
13.58
13.39
C15H17N3OS
287.4
159–161
E–W
62.69
62.77
5.96
6.08
14.62
14.83
C14H15N3O2S
289.4
175–177
E–W
58.11
58.35
5.23
5.13
14.52
14.41
a
b
Calculated from correspon din g carboxylic acid 11 or 18. A Aceton e, C cycloh exan e, CH
ch loroform , D dich lorom eth an e, E eth an ol, H h exan e, P ligh t petroleum , W water. Ref.22
145 °C. Ref.23 178 °C. Ref.24 205–207 °C. Ref.25 200.9–201.1 °C. Ref.26 164 °C, Ref.27
c
d
e
f
g
161–163 °C.
posed as an in term ediate in th e syn th esis of in dole-3-carboxylates22 an d
in dole-3-carboxam ides23 by ph otolysis of 3-diazoquin olin -4(3H)-on e in th e
presen ce of alcoh ols an d am in es. It m ay be also in volved in th e ch em istry
of 3-trifluoroacetylin dole, wh ich with lith ium dialkyl am ides affords corre-
spon din g in dole-3-carboxam ides27. Sin ce isoth iocyan ates are less reactive
toward alcoh ols th an toward am in es, prevailin g form ation of ester 26a in
th e reaction of isoth iocyan ate 13 with m eth an ol can be explain ed by effec-
tive trappin g of keten e A with m eth an ol.
An tifun gal activity of oxobrassin in (14), brassen in B (8) an d th eir an alogs
(15, 25a–25g) as well as th eir position al isom ers (21, 23, 27a–27g) was ex-
am in ed by TLC bioassay, usin g th e fun gus Bipolaris leersiae. Th e com -
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Brassinin and Methoxybrassenin B
357
poun ds, sh owin g a distin ct an tifun gal spots were tested quan titatively an d
com pared with brassin in (1), wh ich com pletely in h ibited th e con idial ger-
m in ation of th e fun gus at a con cen tration of 0.1 m m ol l–1. All of th e sub-
stan ces exh ibited lower activity th an brassin in . In terestin gly, th e h igh est
activity was sh owen by th e m on oth iocarbam ate 27a, a position al isom er
h avin g th e SCH3 group replaced by OCH3 group, wh ich com pletely in h ib-
ited th e germ in ation at 0.25 m m ol l–1, an d by th iourea derivative 27f
(1 m m ol l–1). Th e oth er com poun ds exh ibited very low or n o activity.
Th erefore, th e preparation of furth er an alogs of m eth oxybrassen in B by
m eth ylation of 25a–25g or 27a–27g h as n ot been studied. Sim ilarly, low
activities h ave been recen tly foun d by in vestigation of th e related an alogs
of brassin in an d m eth oxybrassen in A (ref.12). It can be expected th at
an alogs of th is type will probably n ot lead to com poun ds with sign ifican t
an tifun gal activities.
EXPERIMENTAL
Th e in frared absorption spectra were recorded on an IR-75 spectrom eter (Zeiss, Jen a) in ch lo-
roform except com poun ds 25c, 25e–25g, 26c an d 26e wh ich were m easured in KBr discs;
th e waven um bers are given in cm –1 1H NMR spectra were m easured on a TESLA BS 487A
.
(80 MHz) spectrom eter in h exadeuterioaceton e (com poun ds 14, 25b –25e, 26g, 27a an d
27b ), deuterioch loroform (com poun ds 8, 15, 23, 24, 25a , 26a , 26f an d 27d ),
h exadeuteriodim eth yl sulfoxide (com poun d 22), in a m ixture of h exadeuteriodim eth yl
sulfoxide an d h exadeuterioaceton e (com poun ds 25f, 25g, 26d an d 27f) an d in a m ixture of
h exadeuteriodim eth yl sulfoxide an d deuterioch loroform (com poun ds 21, 27c, 27e an d 27g).
Ch em ical sh ifts (δ) are reported in ppm down field from tetram eth ylsilan e, couplin g con -
stan ts (J) in Hz. Th e m ass spectra were recorded on a JMS-100D spectrom eter (Jeol) at ion -
ization en ergy 70 eV. Th e reaction course was m on itored by th in layer ch rom atograph y,
usin g th e Silufol plates (Kavalier). Th e preparative colum n ch rom atograph y was perform ed
on Kieselgel Merck, Typ 9385, 230–400 m esh . An tifun gal activity was exam in ed accordin g to
previously described procedure12. In dole-3-carboxylic acid (11) was prepared by oxidation of
in dole-3-carbaldeh yde with potassium perm an gan ate31
.
In dol-3-ylcarbon yl Isoth iocyan ate (13)
To a stirred suspen sion of in dole-3-carboxylic acid (11; 806 m g, 5 m m ol) in a m ixture of dry
ben zen e (25 m l) an d dry aceton itrile (3 m l), ph osph orus trich loride (610 m g, 440 µl, 5 m m ol)
was added an d th e m ixture was stirred for 25 m in at room tem perature. Th e resultin g solu-
tion was decan ted from th e ph osph orous acid, deposited on th e flask walls, th e flask wash ed
with dry ben zen e (5 m l) an d obtain ed solution con cen trated to approxim ately 1/5 of its
origin al volum e (bath tem perature up to 30 °C), to rem ove th e excess of ph osph orus
trich loride. Th e obtain ed solution of acid ch loride 12 was diluted with dry aceton e (10 m l)
an d added in on e portion to a solution of potassium th iocyan ate (0.48 g, 5 m m ol) in dry ac-
eton e (30 m l). Th e m ixture was stirred for 30 m in at room tem perature, filtered with th e aid
of ch arcoal an d th e flask wash ed with dry aceton e (10 m l). Th e obtain ed aceton e solution of
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

358
Kutschy, Dzurilla, Takasugi, Sabová:
crude isoth iocyan ate 13 can be used for th e n ext reaction . Evaporation of th e solven t af-
forded un stable crude product. IR: 3 467 (NH), 1 970 (NCS), 1 686 (C=O).
Meth yl N-(In dol-3-ylcarbon yl)dith iocarbam ate (Oxobrassin in , 14)
An aceton e solution of crude isoth iocyan ate 13 (from 5 m m ol of acid 11) was evaporated to
dryn ess (bath tem perature up to 30 °C) an d th e obtain ed sem i-solid residue was im m ediately
d issolved in d im eth ylform am id e (12 m l), con tain in g m eth yl iod id e (1.06 g, 470 µl,
7.5 m m ol). A fresh ly prepared solution of sodium h ydrogen sulfide (430 m g, 5 m m ol) in
m eth an ol (10 m l) was th en added dropwise in to th is solution durin g 2–3 m in with stirrin g
an d water coolin g. Th e reaction m ixture was th en diluted with cold water (100 m l) an d after
stan din g at 5 °C for 30 m in th e separated precipitate was filtered off with suction , wash ed
with water an d dried. Yield 390 m g (31%), m .p. 190–193 °C (decom p., aceton e–cycloh exan e).
For C11H10N2OS2 (250.3) calculated: 52.78% C, 4.03% H, 11.19% N; foun d: 52.60% C,
4.18% H, 11.37% N. IR: 3 467 an d 3 400 (NH), 1 680 (C=O), 1 453 (NHCS). 1H NMR: 2.67 s,
3 H (SCH3); 7.29 m , 2 H, 7.59 m , 1 H, 8.29 m , 1 H an d 8.58 m , 1 H (H-arom .); 11.17 s, 1 H
(NH).
Dim eth yl N-(In dol-3-ylcarbon yl)dith iocarbon im idate (Brassen in B, 8)
To a solution of dith iocarbam ate 14 (250 m g, 1 m m ol) in dry aceton e (10 m l) was added
m eth yl iod id e (426 m g, 187 µl, 3 m m ol) an d an h yd rou s p otassiu m carbon ate (138 m g,
1 m m ol) an d th e m ixture was stirred for 165 m in at room tem perature. After pourin g in to
50 m l of cold water an d stan din g at 5 °C for 30 m in , th e separated precipitate was filtered
off with suction , wash ed with water an d dried. Yield 230 m g (87%), m .p. 143–145 °C (ace-
ton e–water). For C12H12N2OS2 (264.4) calculated: 54.52% C, 4.58% H, 10.60% N; foun d:
54.73% C, 4.32% H, 10.43% N. IR: 3 474 (NH), 1 620 (C=N–C=O). 1H NMR: 2.58 s, 6 H (2 ×
SCH3); 7.33 m , 3 H, 7.98 d, 1 H, J = 3 an d 8.25 m , 1 H (H-arom .); 11.30 s, 1 H (NH).
Dim eth yl N-[(1-Meth ylin dol-3-yl)carbon yl]dith iocarbon im idate (Meth ylbrassen in B, 15)
To a suspen sion of lith ium h ydride (16 m g, 2 m m ol) in dim eth ylform am ide (10 m l) was
added oxobrassin in (14, 250 m g, 1 m m ol) an d th e m ixture was stirred at room tem perature
for 20 m in . Meth yl iodide (568 m g, 249 µl, 4 m m ol) was th en added an d stirrin g was con -
tin ued for 1 h . Reaction m ixture was slowly poured in to 100 m l of cold water with in ten sive
stirrin g. After stan din g overn igh t at 5 °C, th e separated precipitate was filtered off with
suction , wash ed with water an d dried. Yield 240 m g (91%), m .p. 82–84 °C (dich lorom eth an e–-
h exan e). For C13H14N2OS2 (278.4) calculated: 56.09% C, 5.07% H, 10.06% N; foun d: 55.95% C,
4.93% H, 9.89% N. IR: 1 620 (C=N–C=O). 1H NMR: 2.60 s, 6 H (2 × SCH3); 3.85 s, 3 H
(NCH3); 7.30 m , 3 H, 7.82 s, 1 H an d 8.28 m , 1 H (H-arom .).
In dol-2-ylcarbon yl Isoth iocyan ate (20)
To a suspen sion of in dole-2-carboxylic acid (18; 806 m g, 5 m m ol) in dry ben zen e (25 m l)
was added ph osph orus trich loride (610 m g, 440 µl, 5 m m ol) an d th e m ixture was stirred for
1 h at 85–90 °C (bath tem perature). Th e subsequen t procedure, iden tical with th e procedure
for th e preparation of 13, afforded un stable crude isoth iocyan ate 20. IR: 3 471 (NH), 1 960
(NCS), 1 676 (C=O).
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Brassinin and Methoxybrassenin B
359
Meth yl N-(In dol-2-ylcarbon yl)dith iocarbam ate (Isooxobrassin in , 21) an d
1-Th ioxo-1H-im idazo[3,4-a]in dol-3(2H)-on e (22)
Th e crude in dol-2-ylcarbon yl isoth iocyan ate (20; from 5 m m ol of acid 18) was treated with
sodium h ydrogen sulfide in th e presen ce of m eth yl iodide, accordin g to th e procedure for
14. Th e crude product was ch rom atograph ed on 60 g of silica gel, eluen t ben zen e, affordin g
235 m g (19%) of dith iocarbam ate 21 an d 92 m g (9%) of com poun d 22.
Methyl N-(indol-2-ylcarbonyl)dithiocarbamate (21). M.p. 171–173 °C (ch loroform –ligh t
petroleum ). For C11H10N2OS2 (250.3) calculated: 52.78% C, 4.03 %H, 11.19% N; foun d:
52.94% C, 3.82% H, 10.96% N. IR: 3 455 an d 3 393 (NH), 1 685 (C=O), 1 470 (NHCS).
1H NMR: 2.68 s, 3 H (SCH3); 7.02–7.75 m , 5 H (H-arom .); 9.21 s, 1 H (NH).
1-Thioxo-1H-imidato[3,4-a]indol-3(2H)-one (22). M.p. 256–259 °C (aceton e–h exan e). For
C
10H6N2OS (202.2) calculated: 59.39% C, 2.99% H, 13.85% N; foun d: 59.53% C, 2.78% H,
14.06% N. IR: 3 434 (NH), 1 763 (C=O). 1H NMR: 7.38 s, 1 H, 7.70 m , 3 H an d 8.28 m , 1 H
(H-arom .). MS, m/z (%): 202 (M+, 100), 143 (95), 115 (52).
Cyclization of Dith iocarbam ate 21 to Im idazo[3,4-a]in dole (22)
To a stirred suspen sion of lith ium h ydride (8 m g, 1 m m ol) in dim eth ylform am ide (2 m l)
was added dith iocarbam ate 21 (50 m g, 0.2 m m ol). Th e m ixture was stirred at room tem pera-
ture for 10 m in , poured in to cold water (12 m l) an d n eutralized with diluted h ydroch loric
acid (1 : 1). Separated precipitate of 22 was filtered off with suction , wash ed with water an d
dried. Yield 40 m g (99%).
Dim eth yl N-(In dol-2-ylcarbon yl)dith iocarbon im idate (Isobrassen in B, 23)
To a solution of dith iocarbam ate 21 (125 m g, 0.5 m m ol) in dry aceton e (5 m l) was added
m eth yl iodide (213 m g, 94 µl, 1.5 m m ol) an d an h ydrous potassium carbon ate (69 m g, 0.5
m m ol) an d th e m ixture was stirred for 100 m in at room tem perature. After pourin g in to 50
m l of cold water, th e separated precipitate was filtered off with suction , wash ed with water
an d dried. Yield 110 m g (83%), m .p. 160–162 °C (aceton e–water). For C12H12N2OS2 (264.4)
calculated: 54.52% C, 4.58% H, 10.60% N; foun d: 54.46% C, 4.41% H, 10.71% N. IR: 4 370
(NH), 1 620 (C=N–C=O). 1H NMR: 2.58 s, 6 H (2 × SCH3); 7.05–7.75 m , 5 H (H-arom .); 9.40 s,
1 H (NH).
2-Meth yl-1,1-bis(m eth ylsulfan yl)-1H-im idazo[3,4-a]in dol-3(2H)-on e (24)
To a stirred suspen sion of lith ium h ydride (16 m g, 2 m m ol) in dim eth ylform am ide (10 m l)
at room tem perature was added isobrassen in B (23, 254 m g, 0.96 m m ol). After 20 m in ,
m eth yl iodide (567 m g, 294 µl, 4 m m ol) was added an d stirrin g was con tin ued for 50 m in .
Th e m ixture was th en poured in to cold water (100 m l) with in ten sive stirrin g an d set aside
for 30 m in at 5 °C. Th e separated precipitate was filtered off with suction , wash ed with wa-
ter an d dried. Yield 240 m g (90%), m .p. 138–139 °C (aceton e–water). For C13H14N2OS2
(278.4) calculated: 56.09% C, 5.07% H, 10.06% N; foun d: 55.94% C, 5.24% H, 9.90% N. IR:
1 693 (C=O). 1H NMR: 1.50 s, 6 H (2 × SCH3); 3.15 s, 3 H (NCH3); 6.95 s, 1 H, 7.32 m , 2 H
an d 7.81 m , 2 H (H-arom .). MS, m/z (%): 278 (M+, 4), 231 (100), 216 (7), 143 (14), 115 (10),
88 (49).
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

360
Kutschy, Dzurilla, Takasugi, Sabová:
Meth yl N-(In dol-3-ylcarbon yl)th iocarbam ate (25a) an d Meth yl In dole-3-carboxylate (26a)
An aceton e solution of crude isoth iocyan ate 13 (from 2 m m ol of acid 11) was evaporated to
dryn ess, th e residue dissolved in 10 m l of dry m eth an ol an d th e obtain ed solution was
h eated with stirrin g at 70–75 °C (bath tem perature) for 10 m in . After pourin g in to 100 m l of
cold water an d stan din g for 2 days at 5 °C, th e separated precipitate was filtered off with
suction , wash ed with water, dried an d ch rom atograph ed on 25 g of silica gel, eluen t cyclo-
h exan e–aceton e (2 : 1), affordin g com poun ds 25a an d 26a (Table I).
Methyl N-(indol-3-ylcarbonyl)thiocarbamate (25a). IR: 3 466 an d 3 433 (NH), 1 687 (C=O),
1 487 (NHCS). 1H NMR: 4.09 s, 3 H (OCH3); 7.35 m , 2 H, 7.62 m , 1 H, 8.36 m , 1 H an d
8.50 m , 1 H (H-arom .).
3-Substituted 1-(In dol-3-ylcarbon yl)th ioureas (25b–25g) an d N-Substituted
In dol-3-carboxam ides (26b–26g)
To an aceton e solution of crude isoth iocyan ate 13 (from 2 m m ol of acid 11) was added
m eth ylam in e (992 m g of 25% aqueous solution , 8 m m ol), ben zylam in e (429 m g, 437 µl,
4 m m ol), cycloh exylam in e (298 m g, 343 µl, 3 m m ol), p-toluidin e (429 m g, 4 m m ol),
piperidin e (340 m g, 396 µl, 4 m m ol) or m orph olin e (348 m g, 348 µl, 4 m m ol) an d th e m ix-
ture was stirred for 20 m in at room tem perature. After evaporation of th e solven t, th e resi-
due was ch rom atograph ed on 40 g of silica gel, eluen t cycloh exan e–aceton e (2 : 1) (25b,
26b; 25c, 26c; 25d , 26d ; 25g, 26g), or 80 g (25e, 26e) an d 50 g (25f, 26f) of silica gel, usin g
a m ixture ben zen e–aceton e (7 : 1) as eluen t. Th e obtain ed products were crystallized from a
suitable solven t (Table I).
1-(Indol-3-ylcarbonyl)-3-methylthiourea (25b). IR: 3 466 an d 3 260 (NH), 1 656 (C=O),
1 497 (NHCS). 1H NMR: 3.80 d, 3 H, J = 5 (NCH3); 7.25 m , 2 H, 7.55 m , 1 H, 8.22 m , 1 H
an d 8.55 m , 1 H (H-arom .); 9.70 s, 1 H an d 10.90 s, 2 H (NH).
1-Benzyl-3-(indol-3-ylcarbonyl)thiourea (25c). IR: 3 497 an d 3 342 (NH), 1 623 (C=O),
1 543 (NHCS). 1H NMR: 5.00 d, 2 H, J = 5 (CH2); 7.20–7.65 m , 8 H, 8.22 m , 1 H an d 8.60 s,
1 H (H-arom .); 9.75 s, 1 H (NH).
1-Cyclohexyl-3-(indol-3-ylcarbonyl)thiourea (25d ). IR: 3 466 an d 3 250 (NH), 1 656 (C=O),
1 500 (NHCS). 1H NMR: 1.20–1.87 m , 10 H ((CH2)5); 4.30 m , 1 H (CH); 7.25 m , 2 H, 7.55 m ,
1 H, 8.25 m , 1 H an d 8.55 d, 1 H, J = 3 (H-arom .); 9.50 s, 1 H an d 11.14 s, 2 H (NH).
1-(Indol-3-ylcarbonyl)-3-(4-methylphenyl)thiourea (25e). IR: 3 444 an d 3 357 (NH), 1 633
(C=O), 1 507 (NHCS). 1H NMR: 2.37 s, 3 H (CH3); 7.55 m , 4 H, 7.67 m , 3 H, 8.32 m , 1 H
an d 8.65 s, 1 H (H-arom .); 9.81 s, 1 H (NH).
1-[N-(Indol-3-ylcarbonyl)thiocarbamoyl]piperidine (25f). IR: 3 390 an d 2 314 (NH), 1 653
(C=O), 1 514 (NHCS). 1H NMR: 1.71 m , 6 H ((CH2)3); 3.92 m , 4 H (CH2NCH2); 7.20 m , 2 H,
7.48 m , 1 H, 8.25 m , 1 H an d 8.43 m , 1 H (H-arom .); 9.38 s, 1 H (NH).
4-[N-(Indol-3-ylcarbonyl)thiocarbamoyl]morpholine (25g). IR: 3 453 an d 3 394 (NH), 1 610
(C=O), 1 515 (NHCS). 1H NMR: 3.78 m , 8 H ((CH2)4); 7.20 m , 2 H, 7.48 m , 1 H, 8.20 m , 1 H
an d 8.42 s, 1 H (H-arom .); 9.78 s, 1 H (NH).
3-(Methylaminocarbonyl)indole (26b). IR: 3 474 an d 3 283 (NH), 1 633 (C=O). 1H NMR:
2.90 d, 3 H, J = 4 (CH3); 7.15 m , 2 H, 7.49 m , 1 H, 7.79 m , 1 H an d 8.25 m , 1 H (H-arom .).
4-(Indol-3-ylcarbonyl)morpholine (26g). IR: 3 480 (NH), 1 607 (C=O). 1H NMR: 3.70 m ,
8 H ((CH2)4); 7.15 m , 2 H, 7.50 m , 1 H an d 7.76 m , 2 H (H-arom .).
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Brassinin and Methoxybrassenin B
361
Meth yl N-(In dol-2-ylcarbon yl)th iocarbam ate (27a)
An aceton e solution of crude isoth iocyan ate 20 (from 5 m m ol of acid 18) was evaporated to
dryn ess, th e residue dissolved in 25 m l of dry m eth an ol an d th e obtain ed solution was
stirred at 70–75 °C (bath tem perature) for 10 m in . Th e m ixture was poured in to 150 m l of
cold water an d after stan din g for 20 m in , th e separated precipitate was filtered off with suc-
tion , dried an d crystallized (Table I). IR: 3 453 an d 3 407 (NH), 1 700 (C=O), 1 486 (NHCS).
1H NMR: 4.12 s, 3 H (OCH3); 7.05–7.75 m , 5 H (H-arom .); 10.75 s, 1 H an d 11.02 s, 1 H
(NH).
3-Substituted 1-(In dol-2-ylcarbon yl)th ioureas (27b–27g)
To an aceton e solution of isoth iocyan ate 20 (from
5 m m ol of acid 18) was added
m eth ylam in e (992 m g of 25% aqueous solution , 8 m m ol), ben zylam in e (563 m g, 573 µl,
5 m m ol), cycloh exylam in e (496 m g, 572 µl, 5 m m ol), p-toluidin e (536 m g, 5 m m ol),
piperidin e (511 m g, 594 µl, 6 m m ol) or m orph olin e (523 m g, 524 µl, 6 m m ol) in ben zen e
(5 m l) an d th e m ixture was stirred for 10 m in or 40 m in (27e). In th e case of th iourea 27b,
th e resulted solution was con cen trated to approxim ately on e h alf of its origin al volum e an d
water was added un til perm an en t turbidity. After stan din g at 5 °C for 30 m in , th e separated
precipitate was filtered off with suction , wash ed with water an d dried. In th e case of
th ioureas 27c–27g, th e reaction m ixture was evaporated to dryn ess an d th e oily residue
triturated with h exan e (20 m l). Th e form ed solid was filtered off, wash ed with h exan e, dried
an d crystallized from a suitable solven t (Table I).
1-(Indol-2-ylcarbonyl)-3-methylthiourea (27b). IR: 3 456 an d 3 266 (NH), 1 650 (C=O),
1 494 (NHCS). 1H NMR: 3.22 d, 3 H, J = 5 (NCH3); 7.00–7.75 m , 5 H (H-arom .); 10.80 s, 2 H
an d 11.62 s, 1 H (NH).
1-Benzyl-3-(indol-2-ylcarbonyl)thiourea (27c). IR: 3 460 an d 3 266 (NH), 1 660 (C=O),
1 493 (NHCS). 1H NMR: 4.93 d, 2 H, J = 6 (CH2); 7.10–7.73 m , 10 H (H-arom .); 10.30 s, 1 H
an d 11.30 s, 2 H (NH).
1-Cyclohexyl-3-(indol-2-ylcarbonyl)thiourea (27d ). IR: 3 460 an d 3 260 (NH), 1 660 (C=O),
1 507 (NHCS). 1H NMR: 1.15–2.30 m , 10 H ((CH2)5); 4.30 m , 1 H (CH); 7.10–7.78 m , 5 H
(H-arom .); 8.98 s, 1 H, 9.40 s, 1 H an d 10.55 s, 1 H (NH).
1-(Indol-2-ylcarbonyl)-3-methylphenylthiourea (27e). IR: 3 453 an d 3 230 (NH), 1 666
(C=O), 1 513 (NHCS). 1H NMR: 2.37 s, 3 H (CH3); 7.00–7.75 m , 9 H (H-arom .); 10.54 s, 1 H,
11.42 s, 1 H an d 12.71 s, 1 H (NH).
1-[N-(Indol-2-ylcarbonyl)thiocarbamoyl]piperidine (27f). IR: 3 460 an d 3 400 (NH), 1 674
(C=O), 1 517 (NHCS). 1H NMR: 1.69 m , 6 H ((CH2)3); 3.95 m , 4 H (CH2NCH2); 7.00–7.75 m ,
5 H (H-arom .); 9.97 s, 1 H an d 11.25 s, 1 H (NH).
4-[N-(Indol-2-ylcarbonyl)thiocarbamoyl]morpholine (27g). IR: 3 456 an d 3 400 (NH), 1 684
(C=O), 1 510 (NHCS). 1H NMR: 3.78 m , 8 H ((CH2)4); 7.00–7.72 m , 5 H (H-arom .); 10.20 s,
1 H an d 11.10 s, 1 H (NH).
We thank the Grant Agency for Sciences, Slovak Republic (grant No. 1/3229/96) for financial
support of this work.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

362
Kutschy, Dzurilla, Takasugi, Sabová:
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Collect. Czech. Chem. Commun. (Vol. 64) (1999)