Application of 2-substituted ethyl isothiocyanates and 2-aminothiols in the synthesis of the analogs of indole phytoalexin camalexin

Article abstract of DOI:10.1135/cccc19991448

Treatment of (indol-1-yl)magnesium bromide or iodide with 2-bromoethyl isothiocyanate afforded 1-(4,5-dihydrothiazol-2-yl)indole (6). Analogous reaction with 2,2-dimethoxyethyl isothiocyanate led to corresponding 1-thiocarbamoylindole derivative (7), which was cyclized to 1-(5-methoxy-4,5-dihydrothiazol-2-yl)indole (8) by treatment with boron trifluoride etherate. New analogs of camalexin, namely 4′,5′-dihydrocamalexin (12) and benzocamalexin (14) were prepared by cyclocondensation reaction of 1-(tert-butoxycarbonyl)indole-3-carbaldehyde with cysteamine and 2-aminobenzenethiol. Antifungal activity of the prepared compounds was studied, using the fungi Alternaria brassicae and Alternaria brassicicola.

Full text of DOI:10.1135/cccc19991448

1448
Dzurilla, Ružinský, Kutschy, Tewari, Kováčik:
APPLICATION OF 2-SUBSTITUTED ETHYL ISOTHIOCYANATES AND
2-AMINOTHIOLS IN THE SYNTHESIS OF THE ANALOGS OF INDOLE
PHYTOALEXIN CAMALEXIN
b
Milan DZURILLAa1,*, Martin RUŽINSKÝa2, Peter KUTSCHYa3, Jalpa P. TEWARI
and Vladimír KOVÁČIK
c
a
Department of Organic Chemistry, Faculty of Natural Sciences, P. J. Šafárik University,
1
Moyzesova 11, SK-041 67 Košice, Slovak Republic; e-mail: dzurilla@kosice.upjs.sk,
2
3
ruzinsky@kosice.upjs.sk, kutschy@kosice.upjs.sk
b
c
Department of Agricultural, Food and Nutrition Science, Faculty of Agriculture, Forestry and
Home Economics, University of Alberta, Edmonton, T6G2P5 Canada;
e-mail: jtewari@afns.ualberta.ca
Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, SK-842 38 Bratislava,
Slovak Republic; e-mail: chemkov@savba.sk
Received Jun e 15, 1999
Accepted July 23, 1999
Dedicated to Professor Milan Kratochvíl on the occasion of his 75th birthday.
Treatm en t of (in dol-1-yl)m agn esium brom ide or iodide with 2-brom oeth yl isoth iocyan ate af-
forded 1-(4,5-dih ydroth iazol-2-yl)in dole (6). An alogous reaction with 2,2-dim eth oxyeth yl
isoth iocyan ate led to correspon din g 1-th iocarbam oylin dole derivative (7), wh ich was
cyclized to 1-(5-m eth oxy-4,5-dih ydroth iazol-2-yl)in dole (8) by treatm en t with boron trifluoride
eth erate. New an alogs of cam alexin , n am ely 4′,5′-dih ydrocam alexin (12) an d ben zo-
cam alexin (14) were prepared by cyclocon den sation reaction of 1-(tert-butoxy-
carbon yl)in dole-3-carbaldeh yde with cysteam in e an d 2-am in oben zen eth iol. An tifun gal
activity of th e prepared com poun ds was studied, usin g th e fun gi Alternaria brassicae an d
Alternaria brassicicola.
Key w ord s: In doles; Ph ytoalexin s; Dih ydrocam alexin ; Ben zocam alexin ; An tifun gal activity.
Man y plan ts after th eir exposure to m icrobial path ogen s produce
an tim icrobial com poun ds kn own as ph ytoalexin s. An in terestin g exam ple
of th is proup of secon dary m etabolites is cam alexin (1), a ph ytoalexin pro-
duced by Camelina sativa1 an d Arabidopsis thaliana2. Cam alexin [3-(th iazol-
2-yl)in dole] was prepared by alkylation of (in dol-1-yl)m agn esium iodide
with 2-brom oth iazole3 or by reductive couplin g of 2-form am idoph en yl
th iazol-2-yl keton e by low-valen t titan ium 4. An alogs of cam alexin with
m odified (reduced or substituted) th iazole or with ben zoth iazole rin g h ave
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Indole Phytoalexin Camalexin
1449
n ot been described yet. On th e oth er h an d, th e isom eric com poun ds
possessing benzothiazole moiety in 1 or 2 position of indole nucleus (2, 3) were
prepared by ph otocyclization of substituted (in dol-1-yl)th ioureas5, or by
th e reaction of 1-m eth ylin dole-2-carboxylate with 2-am in oben zen eth iol in
th e presen ce of trim eth ylalum in um in toluen e6. Th iazole an d ben zo-
th iazole derivatives of in dole h ave been foun d to exh ibit an tim icrobial3
an d cytotoxic6 activity.
S
N
N
S
N
CH3
N
N
S
N
1
2
3
H
In th is paper, we h ave studied th e possibilities of th e syn th esis of
cam alexin an alogs by usin g th e en h an ced reactivity of th e position 3 in
(in dol-1-yl)m agn esium h alides again st electroph ilic reagen ts, an d by cyclo-
con den sation reaction s of in dole-3-carbaldeh yde. It is kn own , th at th e
alkylation 3,7 an d acylation 8 of in dole Grign ard reagen ts proceed with th e
form ation of 3-substituted in doles. Moreover, h eatin g of in dole with
ph en yl isoth iocyan ate at 80–90 °C with out solven t results in th e form ation
of 3-substituted in dole th ioam ide9. Based on th is in form ation , we h ave
studied th e reaction of in dole with 2-brom oeth yl an d 2,2-dim eth oxyeth yl
isoth iocyan ate with th e aim to obtain in term ediates suitable for th e syn th e-
sis of cam alexin an alogs. By h eatin g of in dole with th e above isoth io-
cyan ates at various tem peratures (40–100 °C) durin g 4–12 h with out
solven t, on ly un iden tified decom position products h ave been form ed. To
in crease th e reactivity of its position 3, in dole was tran sform ed to th e corre-
spon din g N-m agn esium brom ide (4), or iodide (5) an d th en treated with
substituted eth yl isoth iocyan ates. In th ese cases, th e n ucleoph ilic addition
to NCS group proceeded exlusively via in dole n itrogen with th e form ation
of 1-substituted in dole derivatives. 2-Brom oeth yl isoth iocyan ate afforded
with Grignard reagents 4 and 5 directly the 1-(thiazol-2-yl)indole (6), a posi-
tional isomer of dihydrocamalexin, whereas the reaction of 2,2-dimethoxyethyl
isoth iocyan ate resulted in th e form ation of stable 1-[N-(2,2-dim eth oxy-
eth yl)th iocarbam oyl]in dole (7, Sch em e 1).
We h ave foun d th at com poun d 7 can be cyclized to 8 (5′-m eth oxy deriv-
ative of 6) by treatm en t with boron trifluoride eth erate in dry dich loro-
m eth an e at room tem perature. Th e structure of com poun ds 6–8 as
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1450
Dzurilla, Ružinský, Kutschy, Tewari, Kováčik:
1-substituted in dole derivatives was con firm ed by th e absen ce of th e ab-
sorption ban d of ν(N–H) at 3 400–3 500 cm –1 in th e IR spectra wh ich
sh ould be presen t with 3-substituted isom ers. Also th e sign als correspon d-
1
in g to δ(NH) of com poun ds 6–8 in H NMR spectra are m issin g, wh ereas th e
sign als to 3 proton s at 6.65–6.69 ppm are presen t.
BrCH2CH2NCS
benzene
N
S
N
6
+
N
MgX
(CH3O)2CHCH2NCS
benzene
N
4, X = Br
5, X = I
S
NHCH2CH(OCH3)2
7
N
BF3.Et2O
dichloromethane
S
N
8
H3CO
SCHEME 1
Sin ce th e reaction between (in dol-1-yl)m agn esium h alides an d substi-
tuted eth yl isoth iocyan ates afforded on ly position al isom ers of
dih ydrocam alexin , our atten tion was n ext turn ed to cyclocon den sation re-
action s of in dole-3-carbaldeh yde with 2-am in oth iols. It sh ould be n oted
th at th e reaction of aldeh ydes an d keton es with 2-am in oth iols is a useful
m eth od for th e syn th esis of th iazolidin e an d ben zoth iazole derivatives10.
Un expectedly, th e reaction of in dole-3-carbaldeh yde with 2-am in oth iols re-
sulted in th e form ation of in tractable m ixture of decom position products.
Th erefore, we h ave used protected 1-(tert-butoxycarbon yl)in dole-3-carb-
aldeh yde, wh ich by th e reaction with cysteam in e h ydroch loride in th e
presen ce of trieth ylam in e afforded 1-(tert-butoxycarbon yl)- 3-(th iazolidin e-
2-yl)in dole (10) in 89% yield (Sch em e 2).
Attem pted oxidation of 10 to dih ydrocam alexin with cerium am m on ium
n itrate11 (CAN), pyridin ium ch loroch rom ate12 (PCC) an d 2,3-dich loro-
5,6-dicyan o-1,4-ben zoquin on e13 (DDQ) resulted in th e form ation of alde-
h yde 9 an d oth er un iden tified decom position products. Oxidation of 10
with activated m an gan ese(IV) oxide in an h ydrous dich lorom eth an e un der
n itrogen atm osph ere resulted in th e form ation of desired 1-(tert-butoxycar-
bon yl)-3-(4,5-dih ydroth iazol-2-yl)in dole (11). Th e protectin g group was
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Indole Phytoalexin Camalexin
1451
readily rem oved by treatm en t of 11 with sodium m eth oxide un der form a-
tion of 4′,5′-dih ydrocam alexin (12). All attem pts to obtain cam alexin by
oxidation of protected or deprotected dih ydrocam alexin failed. Cyclo-
con den sation reaction of aldeh yde 9 with 2-am in oben zen eth iol in m eth a-
n ol–ben zen e (2 : 1) afforded 1-(tert-butoxycarbon yl)-3-(ben zoth iazol-2-yl)-
in dole (13), th e first kn own in dole, possessin g ben zoth iazole m oiety in po-
sition 3. Deprotection with sodium m eth oxide resulted in th e form ation of
ben zocam alexin (14) in 72% yield. Th e structures of com poun ds 10–14
1
h ave been con firm ed by IR, H NMR, 13C NMR spectra an d m ass spectrom e-
try. Com poun ds 10, 11 an d 13 exh ibit in th eir IR spectra th e absorption
ban ds of ν(C=O) at 1 725–1 733 cm –1, wh ich are n ot presen t in th e spectra
of products 12 an d 14 obtain ed after rem oval of protectin g group. In stead,
absorption ban ds of ν(N–H) at 3 470 an d 3 475 cm –1 are presen t in th e IR
1
spectra of 12 an d 14. H NMR spectrum of com poun d 10 sh ows th e sign als
of CH an d NH proton s at 5.78 an d 8.36 ppm , wh ich are m issin g in th e
spectra of products 11–14, th us eviden cin g th e presen ce of C=N double
bon d.
S
S
H
C
O
N
NH
cysteamine
methanol/benzene
2-amino-
benzenethiol
N
N
N
methanol/benzene
13
Boc
Boc
Boc
10
9
MnO2
dichloromethane
CH3ONa
methanol
S
S
S
N
N
N
CH3ONa
N
N
methanol
N
12
14
H
H
Boc
11
SCHEME 2
An tifun gal activity of com poun ds 6 an d 8 was determ in ed by usin g th e
fun gi Alternaria brassicae an d Alternaria brassicicola at con cen tration s ran g-
in g from 1 to 100 µg m l–1, an d at in cubation periods 2, 10 an d 20 h . Un for-
tun ately th e oth er syn th esized com poun ds, in particular 13 an d 14, were
n ot sufficien tly soluble for th ese an tifun gal test. Th e m in im um in h ibition
con cen tration (MIC) for com plete in h ibition of germ in ation of Alternaria
brassicae was 20 µg m l–1 for cam alexin an d 40 µg m l–1 for com poun d 8,
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1452
Dzurilla, Ružinský, Kutschy, Tewari, Kováčik:
wh ereas MIC for com poun d 6 was h igh er th an 100 µg m l–1 (Table I). An alo-
gously, th e MIC value for Alternaria brassiciccola was 20 µg m l–1 for
cam alexin , wh ereas for com poun ds 6 an d 8, th e MIC values are h igh er th an
100 µg m l–1 (Table II). For Alternaria brassicae an d Alternaria brassicicola, th e
germ in ation in h ibition rates decreased with in creasin g in h ibition tim e (Ta-
bles III an d IV).
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Koffler h ot-stage apparatus an d are un corrected. Th e
in frared absorption spectra were recorded on an IR-75 (Zeiss, Jen a) in ch loroform ; th e
TABLE I
Multigroup com parison of germ in ation in h ibition rates (%) of Alternaria brassicae spores at
differen t con cen tration s of com poun ds 6 an d 8
Con cen tration a, µg m l–1
Com poun d
2
4
6
10
20
40
60
80
100
Cam alexin
35.40
17.11
17.00
50.10
17.11
19.50
66.4
74.40
99.70
32.67
48.50
99.90 100.00 100.00 100.00
6
8
24.78 27.67
22.70 31.10
48.56
98.80
55.44
99.90
64.89
83.00
99.90 100.00
a
Mean s of all germ in ation in h ibition rates (%) after 2, 10, an d 20 h .
TABLE II
Multigroup com parison of germ in ation in h ibition rates (%) of Alternaria brassicicola spores
at differen t con cen tration s of com poun ds 6 an d 8
Con cen tration a, µg m l–1
Com poun d
1
2
4
6
10
20
40
60
80
100
Cam alexin
23.60 34.40 43.90 63.90 76.10 99.40 99.20 99.90 99.60 99.30
7.40 8.20 10.90 18.40 24.00 38.00 38.20 44.90 55.90 61.80
10.30 10.30 12.10 13.80 17.70 26.50 43.60 52.10 55.60 60.90
6
8
a
Mean s of all germ in ation in h ibition rates (%) after 2, 10, an d 20 h .
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Indole Phytoalexin Camalexin
1453
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 6–8), deuterioch loroform (com -
poun ds 10–14) with tetram eth ylsilan e as an in tern al stan dard. 13C NMR spectra were m ea-
sured on BS 567 (25.15 MHz) in deuterioch loroform (com poun ds 6 an d 14). Ch em ical sh ifts
are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. Th e EI m ass spectra of com poun ds
13 an d 14 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 (TLC) on Silufol plates
(Kavalier, Czech Republic).
In dole-3-carbaldeh yde, cysteam in e an d 2-am in oben zen eth iol (Aldrich ) an d activated m an -
gan ese(IV) oxide (Fluka) were used as com m ercial ch em icals. Starting (indol-1-yl)magnesium
bromide (4) and (indol-1-yl)magnesium iodide3 (5), 1-(tert-butoxycarbonyl)indole-3-carbaldehyde14
TABLE III
Multigroup com parison of germ in ation in h ibition rates (%) of Alternaria brassicae spores at
differen t in cubation periods
In cubation periodsa, h
Com poun d
2
10
20
Cam alexin
93.50
64.90
69.00
81.20
35.70
56.50
67.50
23.10
53.60
6
8
a
Mean s of all germ in ation in h ibition rates (%) at 2, 4, 6, 10, 20, 40, 60, 80, an d 100 µg m l–1
.
TABLE IV
Multigroup com parison of germ in ation in h ibition rates (%) of Alternaria brassicicola spores
at differen t in cubation periods
In cubation periodsa, h
Com poun d
2
10
20
Cam alexin
91.40
63.70
58.00
73.60
21.60
21.98
56.80
0.00
3.90
6
8
a
Mean s of all germ in ation in h ibition rates (%) at 2, 4, 6, 10, 20, 40, 60, 80, an d 100 µg m l–1
.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1454
Dzurilla, Ružinský, Kutschy, Tewari, Kováčik:
(9), 2,2-dim ethoxyethyl isothiocyanate and 2-brom oethyl isothiocyanate15 were prepared accord-
ing to the literature procedures. Antifungal activity was determ ined according to previously re-
ported procedure16
.
1-(4,5-Dih ydroth iazol-2-yl)in dole (6)
To a solution of (in dol-1-yl)m agn esium brom ide (4) or iodide (5, 20 m m ol) in dry ben zen e
(50 m l), a solution of 2-brom oeth yl isoth iocyan ate (830 m g, 5 m m ol) in dry ben zen e
(20 m l) was added dropwise. After stirrin g for 1 h at room tem perature, th e reaction m ixture
was acidified with a solution of acetic acid (13 m l) in water (30 m l). Ben zen e layer was ex-
tracted with ch loroform (3 × 15 m l). Collected organ ic layers were wash ed with 4% sodium
h ydrogen carbon ate solution (25 m l), dried with an h ydrous sodium sulfate an d solven t
evaporated. Th e crude product was ch rom atograph ed on silica gel (aceton e–cycloh exan e
5 : 1). Yield from 4: 630 m g (63%), from 5: 400 m g (40%), m .p. 54–55.5 °C (aceton e–cyclo-
h exan e). For C11H10N2S (202.3) calculated: 65.31% C, 4.98% H, 13.84% N; foun d: 65.38% C,
5.00% H, 13.93% N. IR: 3 000, 2 860, 1 615, 1 335, 1 010, 890. 1H NMR: 3.58 t, 2 H, J = 8.8
(CH2); 4.37 t, 2 H, J = 7.7 (CH2); 6.69 d, 1 H, J = 3.5 (H-3); 7.25 m , 2 H (H-5, H-6); 7.49 d,
1 H, J = 3.5 (H-2); 7.62 m , 1 H (H-4) an d 8.47 m , 1 H (H-7). 13C NMR: 35.05 (CH2), 62.45
(CH2), 107.54 (C-3), 116.09 (C-5), 121.62 (C-6), 123.29 (C-2), 124.56 (C-4), 128.41 (C-7),
131.24 (C-9), 136.77 (C-8), 156.33 (C-2′).
1-[N-(2,2-Dim eth oxyeth yl)th iocarbam oyl]in dole (7)
To a solution of (in dol-1-yl)m agn esium iodide (5, 4 m m ol) in dry ben zen e (20 m l), a solu-
tion of 2,2-dim eth oxyeth yl isoth iocyan ate (290 m g, 2 m m ol) in dry ben zen e (15 m l) was
added dropwise. After stirrin g for 70 m in at room tem perature th e m ixture was poured in to
a solution of acetic acid (5 m l) in water (15 m l). Th e organ ic layer was separated an d th e
aqueous layer extracted with ben zen e (3 × 10 m l). Th e com bin ed extracts were wash ed with
a 4% solution of sodium h ydrogen carbon ate (20 m l), dried with an h ydrous sodium sulfate,
th e solven t was evaporated an d th e residue ch rom atograph ed on silica gel (ben zen e–aceton e
25 : 1). Yield 370 m g (70%), m .p. 63.5–66.5 °C (cycloh exan e–aceton e). For C13H16N2O2S
(264.3) calculated: 59.07% C, 6.10% H, 10.59% N; foun d: 59.09% C, 6.13% H, 10.62% N. IR:
3 400, 2 940, 2 840, 1 600, 1 245, 1 070, 890. 1H NMR: 3.45 s, 6 H [(OCH3)]2; 4.00 d, 2 H, J =
5.3 (CH2); 4.89 t, 1 H, J = 5.5 (CH); 6.65 d, 1 H, J = 3.5 (H-3); 7.22 m , 2 H (H-5, H-6); 7.90 d,
1 H, J = 3.7 (H-2); 7.61 m , 1 H (H-4) an d 8.12 m , 1 H (H-7); 8.80 s, 1 H (NH).
1-(5-Meth oxy-4,5-dih ydroth iazol-2-yl)in dole (8)
To a solution of derivative 7 (150 m g, 0.56 m m ol) in dich lorom eth an e (5 m l), boron tri-
fluoride eth erate (0.1 m l, 0.84 m m ol) was added at 0 °C an d th e m ixture was stirred for
30 m in at room tem perature. Th e resultin g solution was wash ed with a 4% solution of so-
dium h ydrogen carbon ate (6 m l), layers separated an d water layer extracted with dich loro-
m eth an e. Th e com bin ed extracts were dried wih an h ydrous sodium sulfate, solven t was
evaporated an d th e residue crystallized from dich lorom eth an e. Yield 100 m g (77%), m .p.
35–36.5 °C. For C12H12N2OS (232.3) calculated: 62.04% C, 5.20% H, 12.06% N; foun d:
62.09% C, 5.29% H, 12.15% N. IR: 3 005, 2 940, 2 830, 1 620, 1 335, 1 085, 885. 1H NMR:
3.33 s, 3 H (OCH3); 4.41 d, 2 H, J = 3.4 (CH2); 5.78 t, 1 H, J = 3.7 (CH); 6.68 d, 1 H, J = 4.7
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Analogs of Indole Phytoalexin Camalexin
1455
(H-3); 7.24 m , 2 H (H-5, H-6); 7.50 d, 1 H, J = 3.7 (H-2); 7.65 m , 1 H (H-4) an d 8.52 m , 1 H
(H-7).
1-(tert-Butoxycarbon yl)-3-(th iazolidin -2-yl)in dole (10)
To a solution of cysteam in e h ydroch loride (284 m g, 2.5 m m ol) in a m ixture of m eth an ol–
ben zen e (1 : 2, 3 m l) was added with stirrin g 1-(tert-butoxycarbon yl)in dole- 3-carbaldeh yde
(9, 254 m g, 1 m m ol) an d trieth ylam in e (304 m g, 0.42 m l, 3 m m ol). Th e m ixture was stirred
for 30 m in at room tem perature an th en con cen trated to 1/3 of its origin al volum e. Th e res-
idue was ch rom atograph ed on silica gel (cycloh exan e–aceton e 2 : 1). Yield 271 m g (89%) oil.
For C16H20N2O2S (304.4) calculated: 63.31% C, 6.62% H, 9.21% N; foun d: 63.59% C, 6.81% H,
9.84% N. IR: 3 323, 2 985, 2 930, 1 727, 1 607, 1 367, 1 155. 1H NMR: 1.66 s, 9 H (t-Bu);
3.88 m , 4 H [(CH2)]2; 5.78 d, 1 H (CH); 7.20–8.18 m , 5 H (H-arom .); 8.36 s, 1 H (NH).
1-(tert-Butoxycarbon yl)-3-(4,5-dih ydroth iazol-2-yl)in dole (11)
To a solution of com poun d 10 (304 m g, 1 m m ol) in an h ydrous dich lorom eth an e (15 m l),
m an gan ese(IV) oxide (435 m g, 5 m m ol) was added an d reaction m ixture was stirred for 48 h
at room tem perature un der n itrogen atm osph ere. Th e m ixture was filtered, filtrate con cen -
trated to 1/3 of its origin al volum e an d ch rom atograph ed on alum in ium oxide, eluen t cyclo-
h exan e–aceton e (2 : 1). Yield 78 m g (26%), m .p. 150–152 °C (eth an ol). For C16H18N2O2S
(302.4) calculated: 63.55% C, 5.99% H, 9.26% N; foun d: 63.58% C, 6.00% H, 9.29% N. IR:
2 980, 2 930, 2 850, 1 725, 1 637, 1 365, 1 150. 1H NMR: 1.67 s, 9 H (t-Bu); 3.15 t, 2 H, J =
6.5 (CH2); 3.92 t, 2 H, J = 6.5 (CH2); 7.20–8.50 m , 5 H (H-arom .).
3-(4,5-Dih ydroth iazol-2-yl)in dole (4′,5′-Dih ydrocam alexin ) (12)
To a suspen sion of com poun d 11 (100 m g, 0.3 m m ol) in m eth an ol (10 m l), sodium
(100 m g, 4.35 m m ol) was added an d th e m ixture was stirred for 2 h at room tem perature.
Durin g th is tim e th e startin g com poun d h as com pletely dissolved. After pourin g in to water
(50 m l) th e product was extracted wih dich lorom eth an e (3 × 10 m l), th e extract dried with
an h ydrous sodium sulfate, solven t evaporated an d th e obtain ed residue crystallized from
eth an ol. Yield 20 m g (33%), m .p. 85–87 °C. For C11H10N2S (202.3) calculated: 65.32% C,
4.98% H, 13.84% N; foun d: 65.44% C, 5.01% H, 13.96% N. IR: 3 470, 2 990, 2 925, 1 635,
1 225. 1H NMR: 3.10 t, 2 H, J = 6.9 (CH2); 4.02 t, 2 H, J = 6.9 (CH2); 7.52–8.51 m , 5 H
(H-arom .); 9.00 s, 1 H (NH).
1-(tert-Butoxycarbon yl)-3-(ben zoth iazol-2-yl)in dole (13)
To a solution of 2-am in oben zen eth iol (125 m g, 1 m m ol) in a m ixture m eth an ol–ben zen e
(1 : 2, 3 m l), aldeh yde 9 (245 m g, 1 m m ol) was added an d th e m ixture was stirred at room
tem perature for 25 h . After evaporation of solven t th e obtain ed crude product was crystal-
lized from eth an ol. Yield 170 m g (48%), m .p. 168–170 °C. For C20H18N2O2S (350.4) calcu-
lated: 68.55% C, 5.18% H, 7.99% N; foun d: 68.50% C, 5.14% H, 7.91% N. IR: 2 990, 1 733,
1 620, 1 370, 1 155. 1H NMR: 1.73 s, 9 H (t-Bu); 7.10–7.85 m , 5 H (in dole); 8.10–8.75 m , 4 H
(C6H4). MS, m/z (%): 350 (M+, 2), 295 (3), 251 (14), 142 (3), 56 (64), 41 (100).
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1456
Dzurilla, Ružinský, Kutschy, Tewari, Kováčik:
3-(Ben zoth iazol-2-yl)in dole (Ben zocam alexin ) (14)
To a suspen sion of 13 (275 m g, 0.78 m m ol) in m eth an ol (40 m l), sodium (420 m g,
18.3 m m ol) was added an d reaction m ixture was stirred at room tem perature for 24 h . After
pourin g in to water (250 m l) th e product was extracted with dich lorom eth an e (3 × 50 m l),
dried with an h ydrous sodium sulfate, solven t evaporated, an d th e obtain ed crude product
crystallized from eth an ol. Yield 150 m g (72%), m .p. 124–127 °C. For C15H10N2S (250.3) cal-
culated: 71.97% C, 4.03% H, 11.19% N; foun d: 71.89% C, 4.01% H, 11.08% N. IR: 3 475,
2 930, 2 860, 1 610, 1 415. 1H NMR: 7.13–7.57 m , 7 H (C6H4 + H-5, H-6, H-7); 7.66 d, 1 H, J
=
7.5 (H-2); 8.05 m , 1 H (H-4); 8.86 m , 1 H (NH). 13C NMR: 112.76, 117.58, 122.54, 123.00,
124.36, 125.25, 126.14, 126.68, 127.94, 132.95, 134.43, 138.72, 151.27, 155.80, 161.11.
MS, m/z (%): 250 (M+, 100), 248 (10), 130 (16), 124 (6), 108 (3), 69 (2).
We thank the Slovak Grant Agency for Science (grant No. 1/6080/99) for financial support of this
work.
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