Methylation of acridin-9-ylthioureas. Structure, fluorescence and biological properties of products

Article abstract of DOI:10.1135/cccc20040833

The structure, fluorescence, biological properties and S(N)-methylation reactions of ten 1,1-alkyl/aryl-disubstituted 3-(acridin-9-yl)thioureas 4 have been studied. Various reaction conditions allowed to obtain corresponding S-methyl 5 and S,N-dimethyl de

Full text of DOI:10.1135/cccc20040833

Methylation of Acridin-9-ylthioureas
833
METHYLATION OF ACRIDIN-9-YLTHIOUREAS. STRUCTURE,
FLUORESCENCE AND BIOLOGICAL PROPERTIES OF PRODUCTS
a4
Juraj BERNÁTa1, Eva BALENTOVÁa2, Pavol KRISTIANa3,*, Ján IMRICH
,
Erik SEDLÁKa5, Ivan DANIHELa6, Stanislav BÖHM , Naꢀa PRÓNAYOVÁ ,
b
c
d1
d2
Kalevi PIHLAJA and Karel D. KLIKA
a
Institute of Chemistry, Faculty of Science, P. J. Šafárik University, SK-041 67 Košice,
1
2
Slovak Republic; e-mail: bernat@kosice.upjs.sk, balentova@kosice.upjs.sk,
3
4
5
6
kristian@kosice.upjs.sk, jimrich@kosice.upjs.sk, sedlak-er@saske.sk, idanihel@kosice.upjs.sk
b
c
Department of Organic Chemistry, Institute of Chemical Technology, Prague,
CZ-166 28 Prague 6, Czech Republic; e-mail: bohm@vscht.cz
Faculty of Chemical and Food Technology, Central Laboratories, Slovak Technical University,
SK-812 37 Bratislava, Slovak Republic; e-mail: nada@cvt.stuba.sk
d
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland;
e-mail: kpihlaja@utu.fi, karkli@utu.fi
1
2
Received July 4, 2003
Accepted Novem ber 11, 2003
Th e structure, fluorescen ce, biological properties an d S(N)-m eth ylation reaction s of ten
1,1-alkyl/aryl-disubstituted 3-(acridin -9-yl)th ioureas 4 h ave been studied. Various reaction
con dition s allowed to obtain correspon din g S-m eth yl 5 an d S,N-dim eth yl derivatives 6 in
good yields. Structure an d stereoch em istry of th e syn th esized products are dem on strated by
ab in itio quan tum ch em ical calculation s an d NMR tech n iques in cludin g PDQF-COSY, selec-
tive INEPT an d NOE-differen ce experim en ts. Rem arkable upfield 13C sh ifts of reson an ce sig-
n als of carbon s C-4a, C-10a adjacen t to acridin e N-10 are ch aracteristic of h ydroiodides in
con trast to free bases. Z con figuration in isoth ioureas 7 with secon dary am in o rest in rela-
tion to E con figuration of isoth ioureas with prim ary am in o rest is discussed. Of th e obtain ed
products, som e isoth iourea salts 6 exh ibit m ore th an 2 orders of m agn itude h igh er in ten sity
of fluorescen ce, usin g 9-isoth iocyan atoacridin e as a stan dard. Th e obtain ed isoth iourea
h ydroiodides 5 an d dim eth ylisoth iourea iodides 6 sh ow rem arkable biological activity
again st Mycobacterium tuberculosis.
Keyw ord s: Acridin es; Isoth ioureas; Fluorescen ce; PDQF COSY; INEPT; NOE; DFT; Ab in itio
calculation s; An tim ycobacterial activity; NMR spectroscopy.
Acridin e derivatives h ave been lon g kn own to in teract with n ucleic acids1
an d sh owin g a large variety of biological properties2–4. Due to h igh fluores-
cen ce m an y of th em h ave been utilized as sen sitive biom arkers for in vesti-
gation of specific beh avior of biom olecules an d n atural products5. Con -
tin uin g our recen t research dealin g with fluorescen ce of 9-acridin yl deriva-
Collect. Czech. Chem. Commun. (Vol. 69) (2004)
doi:10.1135/cccc20040833

834
Bernát et al.:
tives6,7, it was in terestin g to study quatern ary acridin ium salts as a n ew in -
terestin g class of fluorogen es. In th e literature, on ly several exam ples of th is
type of com poun ds were described8. For exam ple, 10-carboxym eth yl-
acridin ium derivatives 1 9,10, derivatives of 10-m eth ylacridin ium triflate
11,12
5
2a–2d
an d 9-(h ydroxyim in o)acridin ium 3 exh ibit h igh ch em ilum i-
n escen ce, wh ich was used for th e direct detection of basic sites in DNA.
COOPh
R
NHOH
N
H
N
N
R
I
CH3
CF3SO3
1a-1b
3
2a-2d
1a, R = CH2COOH
2a, R = H
1b, R = CH2CH2COOH
2b, R = CH3
2c, R = NCS
2d, R = NH(CS)OR
In our recen t paper, we h ave foun d in terestin g fluorescen ce properties of
S-m eth ylisoth iourea h ydroiodides con tain in g prim ary am in o rests13. In th e
fram e of th is research we were in terested in differen t S(N)-m eth ylation reac-
tion s an d structure of acridin -9-ylth ioureas 4a–4j with secon dary am in o
rests (Sch em e 1) owin g to th e in fluen ce of th eir substituen ts on th e fluores-
cen ce an d biological activity of th e obtain ed products.
RESULTS AND DISCUSION
Th e startin g 1,1-disubstituted 3-(acridin -9-yl)th ioureas 4a–4j were obtain ed
by th e reaction of secon dary am in es with 9-isoth iocyan atoacridin e14. By
subsequen t m eth ylation with m eth yl iodide in aceton e, th e correspon din g
S-m eth ylisoth iourea h ydroiodides 5a–5j were form ed. From th e syn th etic
poin t of view, th e m ost in terestin g was th e differen t beh avior of th ioureas
with prim ary13 or secon dary am in o rests 4a–4i wh en attem ptin g to prepare
S,N-dim eth yl products. Th e acridin yl th ioureas with secon dary am in o rests
4a–4i were alkylated with an excess of m eth yl iodide in alkalin e m edium to
give S,N-dim eth ylated products 6a–6i, h owever, th ioureas with prim ary
am in o rests surprisin gly did n ot react un der th e sam e con dition s. Th e di-
rect N-m eth ylation of all correspon din g acridin ium h ydroiodides 5a–5i in
alkalin e m edium (K2CO3) with addition al am oun t of m eth yl iodide to
6a–6i was un successful. Th e S,N-dim eth yl derivatives (e.g. 6e, 6g) could be
obtain ed also by m eth ylation of th e free bases of correspon din g
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Methylation of Acridin-9-ylthioureas
835
isoth ioureas (e.g. 7e, 7g). Th e free bases 7e, 7g were obtain ed on ly by usin g
a stron ger base (1,4-diazabicyclo[2.2.2]octan e, DABCO). Th is m ultiple step
syn th esis of S,N-dim eth ylacridin ylisoth ioureas (4 → 5 → 7 → 6) is less con -
ven ien t th an th e sim ple m eth ylation of acridin ylth ioureas 4a–4i with ex-
cess of m eth yl iodide in th e presen ce of K2CO3. Th e course of th ese reac-
tion s is dem on strated in Sch em e 1.
Th e obtain ed values of NMR spectra th at con firm th e structure of th e
syn th esized com poun ds are given in th e Experim en tal. Th e structure eluci-
dation of com poun d 5g was accom plish ed by application of con ven tion al
S
S
NR1R2
N
NR1R2
HN
N
H
N
4a-4j
A
B
CH3I CH3I/K2CO3
acetone
acetone
SCH3
SCH3
NR1R2
N
N
NR1R2
N
CH3I/K2CO3
//
N
H
I
I
CH3
6a-6i
5a-5j
6e,6g
DABCO
CH3CN
CH3I
acetone
SCH3
N
N
NR1R2
7e,7g
4-7
R1
R2
a
Me
b
Et
c
iPr
d
Pr
e
iPr
iPr
f
g
Me
Ph
iBu
iBu
cyclohexyl cyclohexyl cyclohexyl Pr
4-7
h
i
j
R1, R2 -CH(CH3)(CH2)4- -CH(CH3)(CH2)3CH(CH3)- -(CH2)2O(CH2)2-
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

836
Bernát et al.:
1
1D an d 2D NMR experim en ts (1H an d 13C { H}, DEPT, selective INEPT, NOE
1
differen ce, 2D DQF-COSY, CHDEC). H ch em ical sh ifts an d couplin g con -
stan ts were extracted from th e 1D spectra usin g PERCH NMR software15
.
1
Th e H NMR spectrum of th is com poun d was ch aracterized by th e presen ce
of sin glets (δ 2.00 ppm , SCH3; δ 3.55 ppm , NCH3) an d th e AA′BB′C cou-
plin g system for th e five proton s of ph en yl rin g. Th e presen ce of th e carbon
atom of th e C–SCH3 group was eviden t in 13C NMR spectra. Th e ch em ical
sh ifts an d couplin g con stan ts for com poun d 5g are presen ted in Table I.
Due to th e equivalen ce of th e correspon din g proton s an d carbon s of th e
two outer rin gs of th e acridin e skeleton , seven sp2 h ybridized carbon s – four
m eth in es (CH) an d th ree quatern ary (C) carbon s – were observed in
13C NMR spectra. Th e presen ce of th e proton on n itrogen atom of acridin e
was supported by a NOE differen ce experim en t th at sh owed dipolar cou-
plin gs between th e NH (δ 13.74 ppm ) an d H-4,5 (δ 7.92 ppm ) proton s with
TABLE I
NMR data (400 MHz, DMSO-d6) for 5g
13
12
CH3
H3CS
2'
3'
5'
1'
11
4'
N
N
8
5
δ 1H, ppm (m ultiplicity, J in Hz)a
1
9
9
a
8a
6'
Position
2
3
7
6
10
N
4
a
10a
4
H
3
4
5
H-1,8
H-2,7
H-3,6
H-4,5
H-10
H-12
H-13
8.28 (ddd, JH-1(8) H-2(7) = 8.5, JH-1(8) H-3(6) = 1.4, JH-1(8) H-4(5) = 0.6)
3
3
4
7.68 (ddd, JH-2(7) H-1(8) = 8.5, JH-2(7) H-3(6) = 6.8, JH-2(7) H-4(5) = 1.1)
3
3
4
8.07 (ddd, JH-3(6) H-4(5) = 8.6, JH-3(6) H-2(7) = 6.8, JH-3(6) H-1(8) = 1.4)
3
4
5
7.92 (ddd, JH-4(5) H-3(6) = 8.6, JH-4(5) H-2(7) = 1.1, JH-4(5) H-1(8) = 0.6)
13.74 bs
2.00 s
3.55 s
3
H-2′,6′
7.58 (dddd, AA′ part of AA′BB′C system , JH-2′ H-3′
=
3JH-6′ H-5′ = 7.9,
=
5JH-6′ H-3′ = 0.5)
4JH-2′ H-6′ = 2.2, JH-2′(6′) H-4′ = 1.2, JH-2′ H-5′
4
5
3
H-3′,5′
H-4′
7.45 (dddd, BB′ part of AA′BB′C system , JH-3′ H-2′
=
3JH-5′ H-6′ = 7.9,
4JH-3′ H-5′ = 1.6, JH-3′(5′) H-4′ = 7.5, JH-3′ H-6′
=
5JH-5′ H-2′ = 0.5)
3
5
3
4
7.40 (tt, C part of AA′BB′C system , JH-4′ H-3′(5′) = 7.5, JH-4′ H-2′(6′) = 1.2
δ
13C (ppm ): 126.1 C-1,8; 127.8 C-2,7; 135.6 C-3,6; 118.7 C-4,5; 139.7 C-4a,10a; 115.4
C-8a,9a; 156.4 C-9; 167.2 C-11; 15.7 C-12; 42.1 C-13; 142.2 C-1′; 126.9 C-2′,6′; 129.6 C-3′,5′;
a
129.0 C-4′. Spin an alysis was perform ed usin g PERCH NMR software.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Methylation of Acridin-9-ylthioureas
837
34% in crease in th e sign al in ten sity. Th e ch em ical sh ifts observed for NH at
13.74 ppm , wh ich is m ore down field th an usual, can be explain ed by th e
presen ce of positive ch arge on n itrogen atom (com poun d 5g is an im -
m on ium salt). Irradiation of proton s H-2′,6′ (δ 7.58 ppm ) sh owed discern -
ible en h an cem en t of proton s H-3′,5′ (δ 7.45 ppm ) of th e ph en yl rin g an d of
th e m eth yl group on th e n itrogen atom (δ 3.55 ppm ). Selective INEPT an d
2D (DQF-COSY, CHDEC) NMR experim en ts were n ecessary for com plete as-
sign m en t of ch em ical sh ifts of all carbon s an d proton s of com poun d 5g.
Som e peculiar problem s regardin g th e course of m eth ylation reaction s of
acridin ylth ioureas 4 h ave been tried to explain by ab in itio calculation s of
tautom eric form s, con figuration , con form ation an d electron ic structures of
selected derivatives. Quan tum ch em ical calculation s B3LYP/6-31G(d,p)16,17
were carried out for com poun ds 4g, 7g an d two m odel com poun d of th e
type 7 (R1 = H, R2 = CH3; R1 = H, R2 = CH2CH3), (Tables II, III). It follows
from th ese results, th at th e m ost en ergetically stable rotam er for th iourea
4g with secon dary am in o rest (R1 = Me, R2 = Ph ) is th e on e with th e sulfur
atom of th e th ion e group m ore distan ced from th e acridin e skeleton . Th e
acridin e skeleton an d th e –NH(CS)NR1R2 groupin g take un crewed orien ta-
tion of about 43 an d 13° for am in oform A an d im in oform B, respectively
(Sch em e 2, Table II). Im in oform B is m ore stable th an am in oform A by
3.14 kcal m ol–1 (Table III). Noteworth y, th e im in oform was also con firm ed
by NMR experim en ts in sim ilar 1-(acridin -9-yl)th iosem icarbazides18.
Isoth ioureas with secon dary am in o rests (e.g. 7g) occur in th e Z con figu-
ration (Sch em e 3), wh ich is a little m ore stable th an E con figuration
(0.64 kcal m ol–1, Table III).
Th is fact is in con trast to isoth ioureas with prim ary am in o rests13 for
wh ich th e E con figuration was foun d as optim al (R1 = H, R2 = Me, ∆E =
A
B
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

838
Bernát et al.:
TABLE II
Selected structure param eters calculated by th e B3LYP/6-31G(d,p) m eth od (Sch em es 2–4)
Valen ce an gle, °
Dih edral an gle, °
Struc-
ture
C9–N1–C N1–C–N3 C–N3–Ph C–N3–Me
C9a–C9–N1–C
C9–N1–C–N3
C9–N1–C–S
A
B
C
D
E
129.4
135.1
131.6
130.8
122.1
128.9
122.2
128.7
117.0
114.3
119.3
128.5
125.9
129.7
125.9
129.8
120.4
121.8
123.2
121.8
121.8
116.4a
114.5a
116.4a
123.8
120.3
118.1
121.6
126.1
125.9
126.6b
126.6a
42.8
12.7
124.4
62.7
62.7
66.2
84.2
65.0
40
–108.1
159.3
20.9
–2.4
142.3
78.0
–18.4
–162.6
178.5
–168.8
–178.1
–168.2
F
15.0
3.1
G
H
15.7
a
b
Valen ce an gle C–N3–H. Valen ce an gle C–N3–Et. Dih edral an gles N1–C–N3–H for struc-
tures E an d G are 6.4 an d –9.37°, respectively (n egative an gle m ean s reverse clockwise direc-
tion of rotation ).
Me
N
Me
Ph
S
S
N
Me
Ph
N
N
Me
N
N
Z-configuration
E-configuration
C
D
SCHEME 3
TABLE III
B3LYP/6-31 G(d,p) calculated en ergies of som e m olecular structures un der study (Sch em es
2–4)
X,Y
Structure
A, B
C, D
E, F
G, H
EX, a.u.
–1373.1851225
–1373.1901221
0.0049996
–1412.2329351
–1412.2319157
0.0010194
–1181.2171185
–1181.2141526
0.0029659
–1220.5365802
–1220.533619
0.0029612
EY, a.u.
∆EY,X, a.u.
∆EY,X, kcal m ol–1
3.1372989
0.6396836
1.8611319
1.8581826
∆EY,X = EY – EX.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Methylation of Acridin-9-ylthioureas
839
3.49 kcal m ol–1) an d can be ascribed to th e stabilization of th e isom ers by
in tram olecular proton in teraction of th e N-3 with π-orbitals of th e arom atic
rin g19 (Sch em e 4).
H3C
H3C
N
H3C
N
S
S
S
R
H
H
R
Et
N
N
N
N
N
N
N
H
E, G
F, H
I
R = Me (E, F), Et (G, H)
SCHEME 4
Th e in teraction for structures E, F an d G, H is about 1.86 kcal m ol–1 for
both on es (Table III). We assum e th is is a reason for predom in an t E con fig-
uration of isoth ioureas with prim ary am in o rest, wh ich preven ts th e form a-
tion of S(N)-disubstituted products.
TABLE IV
Spectral ch aracteristics of selected acridin e th iourea derivatives 4b, 4c, 4e, 4f, 4g, 4i, 4j
Absorban ce
Fluorescen cea
ε410n m
m l m ol–1 cm –1
Com -
poun d
Sen sitivity
Efficien cy
Fm ax × ε410
Fm ax/ε410
n m
n m
λm ax
n m
ε
λm ax, n m
F, a.u.
m l m ol–1 cm –1
(F/F0)
4b
4c
4e
4f
4g
4i
426.4
438.8
435.2
434.0
432.2
434.0
432.2
4.15
13.44
13.59
12.31
15.43
11.65
17.07
4.02
9.33
478
(7.43)
45.96
11.5
8.9
184.76
107.30
92.38
82.92
–
11.43
1.23
0.86
0.83
–
505
(1.86)
10.38
9.99
496
(1.44)
510
(1.34)
8.3
12.00
9.62
–
(0)
0
505
(1.97)
12.2
5.20
117.36
72.9
1.27
0.37
4j
14.02
518
(0.84)
a
Fluorescen ce correspon ds to em ission of a com poun d at con cen tration 1.0 × 10–6 m ol l–1
in aceton itrile. E0 refers to m axim um in ten sity fluorescen ce of 9-isoth iocyan atoacridin e at
λem = 446 n m , at 1.0 × 10–6 m ol l–1 in aceton itrile.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

840
Bernát et al.:
Electron ic absorption spectra of th e syn th esized com poun ds 4–6 m ea-
sured in aceton itrile exh ibit a broad absorption ban d in th e ran ge 410–
438 n m for 4, 425–430 n m for 5 an d 436–441 n m for 6 (Tables IV–VI,
Figs 1, 2).
A sign ifican t in crease in fluorescen ce h as been observed for com poun ds
5, 6 com pared with startin g th ioureas 4 (Tables IV–VI). Acridin ium salts of
S(N)-dim eth yl-isoth ioureas 6a–6i exh ibited th e h igh est in ten sity of fluores-
cen ce (Table VI, Fig. 2) with th e m axim al value m ore th an 2 orders of m ag-
n itude h igh er th an 9-isoth iocyan atoacridin e used as a stan dard for relative
fluorescen ce. It is well kn own th at iodide is an efficien t quen ch er of fluo-
rescen ce20. Th erefore, th e observed h igh er fluorescen ce quan tum yield of
S(N)-dim eth ylisoth iourea an alogs m igh t be caused by steric h in dran ce of
N-m eth yl affectin g th e in teraction of cation ic n itrogen of acridin e skeleton
with iodide an ion . Th is is n ot th e case in th e S-m eth ylisoth iourea an alogs
wh ere iodide an ion s h ave free access to th e acridin e skeleton , wh ich results
in th e quen ch in g of th eir fluorescen ce. All derivatives with th e N-m eth yl-
an ilin o rest (4g, 5g, 6g) exh ibit extrem ely low fluorescen ce, wh ereas th e
h igh est fluorescen ce is observed for dipropyl an d diisobutyl derivatives 6d
10
120
5
0
300
400
500
Wavelength, nm
100
80
5c
5b
5i
5e
5d
5f
5h
5j
60
5a
5g
40
20
0
450
500
550
600
Wavelength, nm
FIG. 1
Fluorescen ce em ission spectra of S-m eth ylisoth iourea an alogs 5a–5j in con cen tration 1.0 ×
10–6 m ol l–1. In set: Represen tative electron ic absorption spectrum of S-m eth ylisoth iourea
an alog 5d
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Methylation of Acridin-9-ylthioureas
841
an d 6f. We assum e th at com bin ation s of polar an d steric effects are respon -
sible for th ese differen ces.
Th e syn th esized products were screen ed again st Mycobacterium tuberculo-
sis, eigh t of th em (5b, 5c, 5f, 5i, 6b, 6c, 6e, 6f) sh owin g rem arkable biologi-
cal activity. Th e screen in g was carried out at th e Tuberculosis An tim icrobial
Acquisition & Coordin atin g Facility (TAACF), South ern Research In stitute,
Birm in gh am (Alabam a, U.S.A.).
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Kofler h ot-stage apparatus an d are un corrected. IR
spectra (cm –1) were m easured on a Specord 75 IR spectroph otom eter (Zeiss) in ch loroform or
KBr discs. NMR spectra of com poun d 5g were acquired at 25 °C on a JEOL JNR-L-400 spec-
trom eter operatin g at 399.78 MHz for 1H NMR (in tern al tetram eth ylsilan e, TMSin t = 0 ppm )
an d 100.54 MHz for 13C NMR (TMSin t = 0 ppm ) in h exadeuteriodim eth yl sulfoxide. Spin
an alysis was perform ed usin g PERCH software15 for th e extraction of ch em ical sh ifts (ppm ,
δ-scale) an d couplin g con stan ts (J, Hz). Spectra were produced by usin g stan dard pulse se-
quen ces. 1H an d 13C NMR spectra of com poun ds 4e, 5e, 5h , 5i, 6b, 6d , 6f, 6g, 6h were ob-
tain ed on a Varian VXR spectrom eter (300.131 MHz) at room tem perature, oth er 1H NMR
spectra were taken on a Tesla BS 587A spectrom eter (80 MHz). Quan tum ch em ical calcula-
15
10
600
5
0
300
400
500
500
400
300
200
100
Wavelength, nm
6d, 6f
6b
6e
6i
6h
6c
6a
6j
6g
450
500
550
600
Wavelength, nm
FIG. 2
Fluorescen ce em ission spectra of S,N-dim eth ylisoth iourea an alogs 6a–6i in con cen tration 1.0 ×
10–6 m ol l–1. In set: Represen tative electron ic absoption spectrum of S,N-dim eth ylisoth iourea
an alog 6d
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

842
Bernát et al.:
tion s of totally optim ized structures un der study were carried out by n on -em pirical RHF
m eth od (usin g th e 6-31G(d,p)16 basis sets) an d den sity fun ction al th eory17. Elem en tal an aly-
sis was perform ed on a Perkin –Elm er an alyser CHN 2400. Th e reaction course was m on i-
tored by TLC Silufol plates (Kavalier , Czech Republic). Th e preparative colum n ch rom atog-
raph y (flash ch rom atograph y) was perform ed on th e Kieselgel Merck Typ 9385, 230–
400 m esh . Absorption spectra of acridin -9-yl derivatives were obtain ed usin g a UV-3000
Sh im adzu spectroph otom eter at con cen tration s 1.5–2.0 × 10–5 m ol l–1 in aceton itrile.
Absorption coefficien ts are expressed in m m ol–1 cm –1 (Figs 1, 2, Tables IV, V). Fluorescen ce
m easurem en ts were perform ed on a Sh im adzu RF-5000 spectrofluorom eter. Em ission spectra
were recorded in th e region 420–600 n m at th e excitation wavelen gth . Th e obtain ed fluores-
cen ce spectra are averages of 3–6 successive scan s at th e excitation wavelen gth (410 n m ).
Fluorescen ce in ten sities expressed in arbitrary un its [a.u.] (Figs 1, 2, Tables IV, V) correspon d
to em ission of com poun ds at con cen tration 1.0 × 10–6 m ol l–1 in aceton itrile. All m easure-
TABLE V
Spectral ch aracteristics of S-m eth ylisoth iourea an alogs 5a–5j
Absorban ce
Fluorescen cea
Sen sitivity
Efficien cy
Com -
ε410n m
Fm ax × ε410
Fm ax/ε410
m l m ol–1 cm –1
poun d
n m
n m
λm ax
n m
ε
λm ax, n m
(F/F0)
F, a.u.
m l m ol–1 cm –1
5a
5b
5c
5d
5e
5f
5g
5h
5i
425.0
429.5
430.5
428.7
428.6
428.6
425.2
429.4
429.6
426.8
11.89
16.01
16.27
13.70
13.47
14.69
13.62
14.27
14.21
11.05
11.34
14.18
13.43
12.48
11.83
13.42
12.14
13.36
12.78
10.85
506
(1.30)
8.06
109.7
132.0
58.1
91.400
0.711
7.736
9.829
4.655
6.475
3.584
0.376
2.657
7.934
1.954
468.8
(17.75)
1555.5
470.4
(21.36)
1772.8
725.1
906.2
645.5
55.35
474.2
1295.9
230.0
470.0
(9.40)
468.4
(12.40)
76.6
470.4
(7.78)
48.1
461.2
(0.74)
4.56
469.2
(5.75)
35.5
468.4
(16.41)
101.4
21.2
5j
469.4
(3.43)
a
Fluorescen ce correspon ds to em ission of a com poun d at con cen tration 1.0 × 10–6 m ol l–1
in aceton itrile. E0 refers to m axim um in ten sity fluorescen ce of 9-isoth iocyan atoacridin e at
λem = 446 n m , at 1.0 × 10–6 m ol l–1 in aceton itrile.
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Methylation of Acridin-9-ylthioureas
843
m en ts were perform ed at 25 °C. Fo refers to m axim um in ten sity fluorescen ce of 9-isoth io-
cyan atoacridin e at λem = 446 n m un der th e sam e con dition s.
Th e syn th esis of 3-(acridin -9-yl)-1-alkyl/arylth ioureas 4a, 4d , 4g, 4j was described in our
previous paper21. Th e sam e m eth od utilizin g th e reaction of 9-isoth iocyan atoacridin e14 with
secon dary am in es was used also for th e syn th esis of th ioureas 4b, 4c, 4e, 4f, 4h , 4i, 4j in
th is work.
3-(Acridin-9-yl)-1-cyclohexyl-1-ethylthiourea (4b ): Yield 71%, m .p. 191–193 °C. For
C
22H25N3S (363.5) calculated: 72.69% C, 6.93% H, 11.56% N; foun d: 72.41% C, 6.81% H,
11.19% N. IR (KBr): 1620 (N=C); 1588 (NCS). 1H NMR (CDCl3 an d (CD3)2SO, 3:1): 11.25 s,
1 H (NH); 8.20 d, 2 H, J = 8.0, 7.70–7.29 m , 4 H, 7.13 m , 2 H (Acr); 4.02 m , 1 H (CH (cyclo-
h exyl)); 3.45 m , 2 H (CH2 (Et)); 2.25–1.20 m , 10 H (5 × CH2 (cycloh exyl)); 1.10 m , 3 H (CH3
(Et)).
3-(Acridin-9-yl)-1-cyclohexyl-1-isopropylthiourea (4c): Yield 83%, m .p. 190–192 °C. For
C
23H27N3S (377.5) calculated: 73.17% C, 7.21% H, 11.13% N; foun d: 73.45% C, 7.33% H,
11.34% N. IR (KBr): 1620 (N=C); 1575 (NCS). 1H NMR (CDCl3 an d (CD3)2SO, 5:1): 11.32 s,
TABLE VI
Spectral ch aracteristics of S(N)-dim eth ylisoth iourea an alogs 6a–6j
Absorban ce
Fluorescen cea
Sen sitivity
Efficien cy
Com -
ε410n m
Fm ax × ε410
Fm ax/ε410
m l m ol–1 cm –1
poun d
n m
n m
λm ax
n m
ε
λm ax, n m
(F/F0)
F, a.u.
m l m ol–1 cm –1
6a
6b
6c
6d
6e
6f
441.0
441.0
441.0
441.0
441.0
441.0
436.6
441.0
441.0
13.77
17.86
18.67
17.80
15.76
17.68
14.74
18.49
17.58
8.15
10.66
10.04
10.11
8.85
482.8
(32.98)
203.8
432.0
323.8
657.2
399.3
653.1
1.50
1661.0
4605.1
3250.9
6644.3
3533.8
6308.9
14.52
25.006
40.525
32.251
65.005
45.119
67.609
0.155
483.6
(69.92)
484.4
(52.41)
484.0
(106.4)
483.6
(64.6)
9.66
485.6
(105.7)
6g
6h
6i
9.68
483.6
(0.24)
10.85
10.66
482.8
(53.65)
331.5
363.6
3596.8
3876.0
30.553
34.109
483.6
(58.85)
a
Fluorescen ce correspon ds to em ission of a com poun d at con cen tration 1.0 × 10–6 m ol l–1
in aceton itrile. E0 refers to m axim um in ten sity fluorescen ce of 9-isoth iocyan atoacridin e at
λem = 446 n m , at 1.0 × 10–6 m ol l–1 in aceton itrile.
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844
Bernát et al.:
1 H (NH); 8.22 m , 2 H, 7.52–7.30 m , 4 H, 7.17 m , 2 H (Acr); 6.10–5.30 m , 1 H (CH (iPr));
3.90 m , 1 H (CH (cycloh exyl)); 2.25–1.00 m , 16 H (5 × CH2 (cycloh exyl), 2 × CH3 (iPr)).
3-(Acridin-9-yl)-1,1-diisopropylthiourea (4e): Yield 91%, m .p. 180–182 °C. For C20H23N3S
(337.5) calculated: 71.18% C, 6.87% H, 12.45% N; foun d: 71.41% C, 6.64% H, 12.30% N. IR
(CHCl3): 1625 (N=C); 1587 (NCS). 1H NMR (CDCl3): 10.83 s, 1 H (NH); 7.91 d, 2 H, J = 7.2,
7.18–6.72 m , 6 H (Acr); 6.03 m , 1 H (CH (iPr)); 3.94 m , 1 H (CH (iPr)); 1.45 d, 6 H, J = 7.0
(2 × CH3 (iPr)); 1.43 d, 6 H, J = 7.0 (2 × CH3 (iPr)).
3-(Acridin-9-yl)-1,1-diisobutylthiourea (4f): Yield 88%, m .p. 206–211 °C. For C22H27N3S
(365.5) calculated: 72.29% C, 7.44% H, 11.50% N; foun d: 72.57% C, 7.72% H, 11.13% N. IR
(CHCl3): 1625 (N=C); 1588 (NCS). 1H NMR (CDCl3): 10.80 s, 1 H (NH); 7.85 d, 2 H, J = 7.8,
7.10–6.70 m , 6 H (Acr); 3.95 d, 2 H, J = 7.4 (NCH2 (iBu)); 3.43 d, 2 H, J = 7.4 (NCH2 (iBu));
2.70 m , 1 H (CH (iBu)); 2.08 m , 1 H (CH (iBu)); 1.15 d, 6 H, J = 6.6 (2 × CH3 (iBu)); 0.90 d,
6 H, J = 6.6 (2 × CH3 (iBu)).
3-(Acridin-9-yl)-1-(2-methylpiperidino)thiourea (4h ): Yield 82%, m .p. 200–205 °C. For
C
20H21N3S (335.5) calculated: 71.61% C, 6.31% H, 12.53% N; foun d: 70.78% C, 6.14% H,
11.84% N. IR (CHCl3): 1625 (N=C); 1581 (NCS). 1H NMR (CDCl3): 10.83 s, 1 H (NH); 7.90 m ,
2 H, 7.20–6.55 m , 6 H (Acr); 6.12–5.24 m , 1 H, 5.00–4.00 m , 1 H, 3.63–2.85 m , 1 H (NCH,
NCH2 (piperidin e)); 2.30–1.40 m , 6 H (3 × CH2 (piperidin e)); 1.40 m , 3 H (CH3).
3-(Acridin-9-yl)-1-(2,6-dimethylpiperidino)thiourea (4i): Yield 91%, m .p. 195–198 °C. For
C
21H23N3S (349.5) calculated: 72.17% C, 6.63% H, 12.02% N; foun d: 72.39% C, 6.85% H,
12.37% N. IR (CHCl3): 1623 (N=C); 1584 (NCS). 1H NMR (CDCl3 an d (CD3)2SO, 1:1):
11.19 s, 1 H (NH); 8.23 d, 2 H, J = 8.2, 7.73–7.30 m , 4 H, 7.15 m , 2 H (Acr); 5.80 m , 1 H
(NCH (piperidin e)); 4.55 m ,
1 H (NCH (piperidin e)); 2.18–1.40 m , 6 H (3 × CH2
(piperidin e)); 1.43 d, 3 H, J = 7.4 (CH3); 1.23 d, 3 H, J = 7.4 (CH3).
3-(Acridin-9-yl)-1,1-morpholinothiourea (4j)21: Yield 92%, m .p. 230–235 °C. IR (CHCl3):
1633 (N=C); 1567 (NCS). 1H NMR (CDCl3 an d (CD3)2SO, 1:1): 11.45 bs, 1 H (NH); 8.20 d,
2 H, J = 8.2, 7.77–7.33 m , 4 H, 7.17 m , 2 H (Acr); 4.50–3.50 m , 8 H (4 × CH2 (m orph olin e)).
Preparation of 3-(Acridin -9-yl)-1,1-alkyl/aryl-2-m eth ylisoth iourea Hydroiodides 5a–5j.
Gen eral Meth od
Th e suspen sion of th ioureas 4a–4j (1 m m ol) an d m eth yl iodide (1.5 m m ol) in aceton e
(15 m l) was stired at room tem perature. After stirrin g 30 m in , th e reaction m ixture becam e
clear in dicatin g th e en d of th e reaction . Th e reaction course was followed by TLC (ben zen e/
aceton e, 5:2). Th e obtain ed solution was con cen trated in vacuo, th e product was precipi-
tated by addition of eth er, filtered off, wash ed with eth er an d dried.
3-(Acridin-9-yl)-1-cyclohexyl-1,2-dimethylisothiourea hydroiodide (5a ): Yield 84%, m .p.
217–219 °C. For C22H26IN3S (491.4) calculated: 53.77% C, 5.33% H, 8.55% N; foun d:
53.49% C, 5.10% H, 8.38% N. IR (KBr): 1620 (C=N); 1565 (NCS). 1H NMR (CDCl3): 13.50 bs,
1 H (NH); 8.69 d, 2 H, J = 8.4, 8.13–7.60 m , 4 H, 7.40 m , 2 H (Acr); 4.16 m , 1 H (CH (cyclo-
h exyl)); 3.20 s, 3 H (NCH3); 2.15–0.88 m , 10 H (5 × CH2 (cycloh exyl)); 1.98 s, 3 H (SCH3).
3-(Acridin-9-yl)-1-cyclohexyl-1-ethyl-2-methylisothiourea hydroiodide (5b ): Yield 87%, m .p.
197–200 °C. For C23H28IN3S (505.4) calculated: 54.65% C, 5.58% H, 8.31% N; foun d:
54.88% C, 5.81% H, 8.54% N. IR (KBr): 1617 (C=N); 1540 (NCS). 1H NMR (CDCl3): 8.65 d,
2 H, J = 8.5, 8.00 d, 2 H, J = 8.8, 7.80 m , 2 H, 7.44 m , 2 H (Acr); 4.12 m , 1 H (NCH (cyclo-
h exyl)); 3.70 q, 2 H, J = 7.7 (NCH2 (Et)); 2.30–1.20 m , 10 H (5 × CH2 (cycloh exyl)); 1.92 s,
3 H (SCH3); 1.35 t, 3 H, J = 7.7 (CH3 (Et)).
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Methylation of Acridin-9-ylthioureas
845
3-(Acridin-9-yl)-1-cyclohexyl-1-isopropyl-2-methylisothiourea hydroiodide (5c): Yield 85%, m .p.
210–214 °C. For C24H30IN3S (519.5) calculated: 55.49% C, 5.82% H, 8.09% N; foun d:
55.79% C, 6.11% H, 8.22% N. IR (KBr): 1622 (C=N); 1566 (NCS). 1H NMR (CDCl3): 8.69 d,
2 H, J = 8.5, 8.00 d, 2 H, J = 8.4, 7.80 m , 2 H, 7.42 m , 2 H (Acr); 4.63–3.32 m , 2 H (NCH
(cycloh exyl), NCH (iPr)); 2.75–1.20 m , 10 H (5 × CH2 (cycloh exyl)); 1.84 s, 3 H (SCH3);
1.46 d, 6 H, J = 7.0 (2 × CH3 (iPr)).
3-(Acridin-9-yl)-1,1-dipropyl-2-methylisothiourea hydroiodide (5d): Yield 82%, m .p. 178–184 °C.
For C21H26IN3S (479.4) calculated: 52.61% C, 5.47% H, 8.76% N; foun d: 52.85% C,
5.63% H, 8.98% N. IR (KBr): 1620 (C=N); 1567 (NCS). 1H NMR (CDCl3): 13.60 bs, 1 H (NH);
8.68 d, 2 H, J = 8.7, 8.03 d, 2 H, J = 8.8, 7.82 m , 2 H, 7.44 m , 2 H (Acr); 3.65 t, 4 H, J = 7.7
(2 × NCH2 (Pr)); 2.25–1.38 m , 4 H (2 × CH2 (Pr)); 1.90 s, 3 H (SCH3); 1.03 t, 6 H, J = 7.4 (2 ×
CH3 (Pr)).
3-(Acridin-9-yl)-1,1-diisopropyl-2-methylisothiourea hydroiodide (5e): Yield 88%, m .p. 220–
223 °C. For C21H26IN3S (479.4) calculated: 52.61% C, 5.47% H, 8.76% N; foun d: 52.85% C,
5.71% H, 8.93% N. IR (KBr): 1626 (C=N); 1565 (NCS). 1H NMR (CDCl3): 8.66 d, 2 H, J = 8.5,
8.00 d, 2 H, J = 8.8, 7.80 m , 2 H, 7.43 m , 2 H (Acr); 4.73–3.85 m , 2 H (2 × NCH (iPr));
1.85 s, 3 H (SCH3); 1.48 d, 12 H, J = 6.6 (4 × CH3 (iPr)). 1H NMR ((CD3)2SO): 13.34 s, 1 H
(NH); 8.08 dd, 2 H, J = 8.7, 1.5 (H-1, H-8 (Acr)); 7.99 ddd, 2 H, J = 8.1, 6.6, 1.5 (H-3, H-6
(Acr)); 7.85 dd, 2 H, J = 8.1, 1.1 (H-4, H-5 (Acr)); 7.58 ddd, 2 H, J = 8.7, 6.6, 1.1 (H-2, H-7
(Acr)); 4.75–4.20 m , 2 H (2 × NCH (iPr)); 1.92 s, 3 H (SCH3); 1.39 m , 12 H (4 × CH3 (iPr)).
13C NMR ((CD3)2SO): 165.6 (N=C); 152.7 (C-9); 140.0 (C-4a, C-10a); 135.2 (C-3, C-6); 126.3
(C-1, C-8); 124.2 (C-2, C-7); 118.7 (C-4, C-5); 114.9 (C-8a, C-9a); 55.0 (CH (iPr)); 51.0 (CH
(iPr)); 19.7 (4 × CH3 (iPr)); 15.4 (SCH3).
3-(Acridin-9-yl)-1,1-diisobutyl-2-methylisothiourea hydroiodide (5f): Yield 79%, m .p. 192–
197 °C. For C23H30IN3S (507.5) calculated: 54.44% C, 5.96% H, 8.28% N; foun d: 54.70% C,
6.22% H, 8.54% N. IR (KBr): 1630 (C=N); 1545 (NCS). 1H NMR (CDCl3): 8.75 d, 2 H, J = 8.3,
8.02 m , 2 H, 7.87 m , 2 H, 7.45 m , 2 H (Acr); 3.54 d, 4 H, J = 7.5 (2 × NCH2 (iBu)); 2.25 m ,
2 H (2 × CH (iBu)); 1.92 s, 3 H (SCH3); 1.08 d, 12 H, J = 7.0 (4 × CH3 (iBu)).
3-(Acridin-9-yl)-1,2-dimethyl-1-phenylisothiourea hydroiodide (5g): Yield 89%, m .p. 210–
215 °C. For C22H20IN3S (485.4) calculated: 54.44% C, 4.15% H, 8.66% N; foun d: 54.75% C,
4.46% H, 8.91% N. IR (KBr): 1613 (C=N); 1547 (NCS). Th e values of 1H an d 13C NMR are
given in Table I.
1-(Acridin-9-yl)-2-methyl-3-(2-methylpiperidino)isothiourea hydroiodide (5h ): Yield 81%, m .p.
210–216 °C. For C21H24IN3S (477.4) calculated: 52.83% C, 5.07% H, 8.80% N; foun d:
53.04% C, 5.38% H, 8.96% N. IR (KBr): 1625 (C=N); 1540 (NCS). 1H NMR (CDCl3): 13.45 s,
1 H (NH); 8.63 d, 2 H, J = 8.5, 8.17–7.60 m , 4 H, 7.42 m , 2 H (Acr); 4.65 m , 1 H, 4.15 m ,
1 H, 3.40 m , 1 H (NCH, NCH2 (piperidin e)); 2.20–1.55 m , 6 H (3 × CH2 (piperidin e)); 2.00 s,
3 H (SCH3); 1.44 d, 3 H, J = 6.4 (CH3). 13C NMR ((CD3)2SO): 166.6 (N=C); 153.4 (C-9); 138.8
(C-4a, C-10a); 133.6 (C-3, C-6); 124.6 an d 124.4 (C-1, C-8); 122.8 (C-2, C-7); 117.5 (C-4,
C-5); 114.0 (C-8a, C-9a); 51.5 (C-2 (piperidin e)); 42.8 (C-6 (piperidin e)); 28.6 an d 23.9 an d
16.6 (C-3, C-4, C-5 (piperidin e)); 14.5 an d 14.2 (CH3, SCH3).
1-(Acridin-9-yl)-3-(2,6-dimethylpiperidino)-2-methylisothiourea hydroiodide (5i): Yield 86%,
m .p. 188–191 °C. For C22H26IN3S (491.4) calculated: 53.77% C, 5.33% H, 8.55% N; foun d:
53.98% C, 5.54% H, 8.71% N. IR (KBr): 1620 (C=N); 1545 (NCS). 1H NMR (CDCl3): 8.65 d,
2 H, J = 8.2, 8.03 d, 2 H, J = 8.3, 7.80 m , 2 H, 7.42 m , 2 H (Acr); 4.60 m , 2 H (2 × CH
(piperidin e)); 2.18 s, 3 H (SCH3); 2.05–1.60 m , 6 H (3 × CH2 (piperidin e)); 1.50 d, 6 H, J =
7.0 (2 × CH3). 1H NMR ((CD3)2SO): 13.23 s, 1 H (NH); 8.09 d, 2 H, J = 8.7 (H-1, H-8);
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

846
Bernát et al.:
7.97 m , 2 H (H-3, H-6); 7.82 d, 2 H, J = 8.1 (H-4, H-5); 7.55 m , 2 H (H-2, H-7); 4.51 m , 2 H
(2 × CH (piperidin e)); 2.01 s, 3 H (SCH3); 2.00–1.50 m , 6 H (3 × CH2 (piperidin e)); 1.40 m ,
6 H (2 × CH3 (piperidin e)). 13C NMR ((CD3)2SO): 168.6 (N=C); 153.1 (C-9); 139.9 (C-4a,
C-10a); 135.1 (C-3, C-6); 125.9 (C-1, C-8); 124.1 (C-2, C-7); 118.6 (C-4, C-5); 114.9 (C-8a,
C-9a); 52.1 (2 × CH (piperidin e)); 29.5 (2 × CH2 (piperidin e)); 19.4 (2 × CH3); 15.4 (SCH3);
12.9 (CH2 (piperidin e)).
1-(Acridin-9-yl)-2-methyl-3-morpholinoisothiourea hydroiodide (5j): Yield 75%, m .p. 200–
203 °C. For C19H20IN3OS (465.4) calculated: 49.04% C, 4.33% H, 9.03% N; foun d: 49.38% C,
4.71% H, 9.36% N. IR (KBr): 1624 (C=N); 1543 (NCS). 1H NMR (CDCl3): 13.87 s, 1 H (NH);
8.67 d, 2 H, J = 8.6, 8.06 d, 2 H, J = 8.7, 7.81 m , 2 H, 7.50 m , 2 H (Acr); 3.87 bs, 8 H (4 ×
CH2 (m orph olin e)); 1.93 s, 3 H (SCH3).
Preparation of 1,1-Disubstituted 2-Meth yl-3-(10-m eth ylacridin -9-yl)isoth iourea
Iodides (6a–6i). Gen eral Meth od
Method A: To a suspen sion of th iourea 5a–5i (0.4 m m ol) in aceton e (15 m l), m eth yl io-
dide (3 m l) an d K2CO3 (110 m g, 0.8 m m ol) were added an d th e reaction m ixture was stirred
at room tem perature for 24 h . Aceton e was evaporated to dryn ess, th e crude residue was ex-
tracted with aceton itrile an d th e excess of K2CO3 was filtered off. After addition of eth er to
a con cen trated solution of th e crude com poun d in aceton itrile, th e product precipitated in
th e form of yellow crystals.
Method B: To a solution of S-m eth ylisoth iourea 7e, 7g (1 m m ol) in aceton e (20 m l), m eth -
yl iodide (1.5 m m ol) was added an d stirred at room tem perature for 12 h . Th e solven t with
excess of m eth yl iodide was evaporated. By addition of eth er to th e evaporated residue th e
fin al products 6e, 6g were obtain ed in th e crystallin e form .
1-Cyclohexyl-1,2-dimethyl-3-(10-methylacridin-9-yl)isothiourea iodide (6a): Yield 81%, m .p.
185–190 °C. For C23H28IN3S (505.5) calculated: 54.65% C, 5.58% H, 8.31% N; foun d:
54.92% C, 5.85% H, 8.57% N. IR (KBr): 1625 (C=N); 1575 (NCS). 1H NMR (CDCl3):
8.30–7.85 m , 6 H, 7.56 ddd, 2 H, J = 8.1, 5.0, 2.9 (Acr); 4.36 s, 3 H (N+CH3); 4.12 m , 1 H
(CH (cycloh exyl)); 3.25 bs, 3 H (NCH3); 2.25–1.10 m , 10 H (5 × CH2 (cycloh exyl)); 2.08 s,
3 H (SCH3).
1-Cyclohexyl-1-ethyl-2-methyl-3-(10-methylacridin-9-yl)isothiourea iodide (6b ): Yield 88%,
m .p. 192–197 °C. For C24H30IN3S (519.5) calculated: 55.49% C, 5.82% H, 8.09% N; foun d:
55.21% C, 5.43% H, 7.87% N. IR (KBr): 1600 (C=N); 1540 (NCS). 1H NMR ((CD3)2SO): 8.21 d,
2 H, J = 9.0 (H-4, H-5 (Acr)); 8.16 d, 2 H, J = 8.7 (H-1, H-8 (Acr)); 8.07 m , 2 H (H-3, H-6
(Acr)); 7.62 m , 2 H (H-2, H-7 (Acr)); 4.22 s, 3 H (N+CH3); 4.08 m , 1 H (NCH (cycloh exyl));
3.90–3.50 m , 2 H (NCH2 (Et)); 2.10–1.20 m , 10 H (5 × CH2 (cycloh exyl)); 1.95 s, 3 H (SCH3);
1.09 m , 3 H (CH3 (Et)). 13C NMR ((CD3)2SO): 168.4 (N=C); 153.4 (C-9); 141.4 (C-4a, C-10a);
135.7 (C-3, C-6); 126.7 (C-1, C-8); 124.0 (C-2, C-7); 117.7 (C-4, C-5); 116.1 (C-8a, C-9a);
61.3 (C-1 (cycloh exyl); 42.4 (NCH2); 35.5 (N+CH3); 29.4 (C-2, C-6 (cycloh exyl)); 25.1 an d
25.0 an d 24.3 (C-3, C-4, C-5 (cycloh exyl)); 15.3 an d 14.1 (SCH3, CH3).
1-Cyclohexyl-1-isopropyl-2-methyl-3-(10-methylacridin-9-yl)isothiourea iodide (6c): Yield 79%,
m .p. 212–217 °C. For C25H32IN3S (533.5) calculated: 56.28% C, 6.05% H, 7.88% N; foun d:
56.62% C, 6.39% H, 7.49% N. IR (KBr): 1610 (C=N); 1547 (NCS). 1H NMR (CDCl3):
8.30–7.85 m , 6 H, 7.59 m , 2 H (Acr); 4.80–3.33 m , 2 H (NCH (cycloh exyl), NCH (iPr));
4.37 s, 3 H (N+CH3); 1.91 s, 3 H (SCH3); 1.45 d, 6 H, J = 6.6 (2 × CH3 (iPr)); 2.45–0.75 m ,
10 H (5 × CH2 (cycloh exyl)).
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Methylation of Acridin-9-ylthioureas
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2-Methyl-3-(10-methylacridin-9-yl)-1,1-dipropylisothiourea iodide (6d ): Yield 84%, m .p.
169–172 °C. For C22H28IN3S (493.4) calculated: 53.55% C, 5.72% H, 8.52% N; foun d:
53.27% C, 5.51% H, 8.48% N. IR (KBr): 1610 (C=N); 1580 (NCS). 1H NMR ((CD3)2SO):
8.22 d, 2 H, J = 8.7 (H-4, H-5 (Acr)); 8.16 d, 2 H, J = 8.4 (H-1, H-8 (Acr)); 8.07 m , 2 H (H-3,
H-6 (Acr)); 7.62 m , 2 H (H-2, H-7 (Acr)); 4.23 s, 3 H (N+CH3); 3.71 m , 2 H (NCH2 (Pr));
3.57 m , 2 H (NCH2 (Pr)); 1.94 s, 3 H (SCH3); 1.90 m , 2 H (CH2 (Pr)); 1.64 m , 2 H (CH2 (Pr));
1.02 m , 3 H (CH3 (Pr)); 0.81 m , 3 H (CH3 (Pr)). 1H NMR (CDCl3): 8.27–7.96 m , 6 H, 7.56 m ,
2 H (Acr); 4.35 s, 3 H (N+CH3); 3.67 m , 4 H (2 × NCH2 (Pr)); 1.96 s, 3 H (SCH3); 1.84 m , 4 H
(2 × CH2 (Pr); 1.02 m , 6 H (2 × CH3 (Pr)). 13C NMR ((CD3)2SO): 168.8 (N=C); 154.2 (C-9);
141.4 (C-4a, C-10a); 135.7 (C-3, C-6); 126.7 (C-1, C-8); 124.00 (C-2, C-7); 117.7 (C-4, C-5);
116.1 (C-8a, C-9a); 53.7 (NCH2 (Pr)); 52.9 (NCH2 (Pr)); 35.6 (N+CH3); 20.5 (CH2 (Pr)); 20.3
(CH2 (Pr)); 15.3 (SCH3); 11.0 (2 × CH3 (Pr)). 13C NMR (CDCl3): 168.8 (N=C); 154.9 (C-9);
141.7 (C-4a, C-10a); 136.4 (C-3, C-6); 126.9 (C-1, C-8); 124.5 (C-2, C-7); 117.6 (C-4, C-5);
116.6 (C-8a, C-9a); 54.4 (NCH2 (Pr)); 53.7 (NCH2 (Pr)); 36.9 (N+CH3); 21.0 (2 × CH2 (Pr));
16.1 (SCH3); 11.3 (2 × CH3 (Pr)).
1,1-Diisopropyl-2-methyl-3-(10-methylacridin-9-yl)isothiourea iodide (6e): Yield 79%, m .p.
207–210 °C. For C22H28IN3S (493.4) calculated: 53.55% C, 5.72% H, 8.52% N; foun d:
53.12% C, 5.32% H, 8.39% N. IR (CHCl3): 1620 (C=N); 1566 (NCS). 1H NMR (CDCl3):
8.30–7.90 m , 6 H, 7.59 m , 2 H (Acr); 4.75–4.00 m , 2 H (2 × NCH (iPr)); 4.42 s, 3 H (N+CH3);
1.98 s, 3 H (SCH3); 1.49 d, 12 H, J = 7.0 (4 × CH3 (iPr)).
1,1-Diisobutyl-2-methyl-3-(10-methylacridin-9-yl)isothiourea iodide (6f): Yield 80%, m .p.
190–196 °C. For C24H32IN3S (521.5) calculated: 55.28% C, 6.18% H, 8.06% N; foun d:
55.57% C, 6.43% H, 8.23% N. IR (KBr): 1605 (C=N); 1565 (NCS). 1H NMR (CDCl3):
8.30–7.85 m , 6 H, 7.53 m , 2 H (Acr); 4.46 s, 3 H (N+CH3); 3.51 m , 4 H (2 × NCH2 (iBu));
2.70–1.63 m , 2 H (2 × CH (iBu)); 2.01 s, 3 H (SCH3); 1.05 m , 12 H (4 × CH3 (iBu)). 13C NMR
(CDCl3): 169.2 (N=C); 154.9 (C-9); 141.8 (C-4a, C-10a); 136.6 (C-3, C-6); 126.8 (C-1, C-8);
124.5 (C-2, C-7); 117.9 (C-4, C-5); 116.5 (C-8a, C-9a); 60.2 (NCH2 (iBu)); 59.4 (NCH2 (iBu));
37.2 (N+CH3); 27.7 (CH (iBu)); 27.1 (CH (iBu)); 20.4 (4 × CH3 (iBu)); 16.5 (SCH3).
1,2-Dimethyl-3-(10-methylacridin-9-yl)-1-phenylisothiurea iodide (6g): Yield 88%, m .p.
195–200 °C. For C23H22IN3S (499.4) calculated: 55.31% C, 4.44% H, 8.41% N; foun d:
55.68% C, 4.75% H, 8.55% N. IR (CHCl3): 1624 (C=N); 1567 (NCS). 1H NMR (CDCl3): 8.27 dd,
2 H, J = 8.4, 1.6 (H-1, H-8 (Acr)); 8.17 dd, 2 H, J = 8.1, 1.2 (H-4, H-5 (Acr)); 8.11 ddd, 2 H,
J = 8.1, 6.6, 1.6 (H-3, H-6 (Acr)); 7.70 ddd, 2 H, J = 8.4, 6.6, 1.2 (H-2, H-7 (Acr)); 7.32 m , 5 H
(Ph ); 4.44 s, 3 H (N+CH3); 3.58 s, 3 H (NCH3); 2.15 s, 3 H (SCH3). 1H NMR ((CD3)2SO):
8.33 m , 2 H (H-1, H-8 (Acr)); 8.27 m , 2 H (H-4, H-5 (Acr)); 8.14 m , 2 H (H-3, H-6 (Acr));
7.73 m , 2 H (H-2, H-7 (Acr)); 7.57 m , 2 H (Ph ); 7.44 m , 3 H (Ph ); 4.28 s, 3 H (N+CH3);
3.54 s, 3 H (NCH3); 1.97 s, 3 H (SCH3). 13C NMR (CDCl3): 168.3 (N=C); 158.0 (C-9); 142.0
(C-1′ (Ph )); 141.5 (C-4a, C-10a); 136.9 (C-3, C-6); 130.0 (C-3′, C-5′ (Ph )); 129.4 (C-4′ (Ph ));
127.1 (C-1, C-8); 126.9 (C-2′, C-6′(Ph )); 125.2 (C-2, C-7); 117.8 (C-4, C-5); 117.1 (C-8a,
C-9a); 42.8 (NCH3); 37.4 (N+CH3); 16.6 (SCH3). 13C NMR ((CD3)2SO): 167.6 (N=C); 156.6
(C-9); 142.2 (C-1′ (Ph )); 141.3 (C-4a, C-10a); 136.3 (C-3, C-6); 129.8 (C-3′, C-5′ (Ph )); 129.2
(C-4′ (Ph )); 127.1 (C-1, C-8); 127.0 (C-2′, C-6′(Ph )); 124.7 (C-2, C-7); 117.8 (C-4, C-5); 116.4
(C-8a, C-9a); 42.2 (NCH3); 35.9 (N+CH3); 15.8 (SCH3).
2-Methyl-1-(10-methylacridin-9-yl)-3-(2-methylpiperidino)isothiourea iodide (6h ): Yield 78%,
m .p. 205–208 °C. For C22H26IN3S (491.4) calculated: 53.77% C, 5.33% H, 8.55% N; foun d:
53.46% C, 5.19% H, 8.45% N. IR (CHCl3): 1603 (C=N); 1560 (NCS). 1H NMR (CDCl3):
8.27–7.80 m , 6 H, 7.60 m , 2 H (Acr); 4.60 m , 1 H an d 4.12 m , 1 H an d 3.48 m , 1 H (NCH,
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Bernát et al.:
NCH2 (piperidin e)); 4.35 s, 3 H (N+CH3); 2.10 s, 3 H (SCH3); 2.00–1.50 m , 6 H (3 × CH2
(piperidin e)); 1.46 d, 3 H, J = 7.0 (CH3 (piperidin e)). 13C NMR (CDCl3): 168.4 (N=C); 154.7
(C-9); 141.5 (C-4a, C-10a); 136.1 (C-3, C-6); 126.8 an d 126.6 (C-1, C-8); 124.3 an d 124.2
(C-2, C-7); 117.3 (C-4, C-5); 116.4 (C-8a, C-9a); 53.0 (NCH (piperidin e)); 44.4 (NCH2
(piperidin e)); 36.6 (N+CH3); 30.0 an d 25.2 an d 17.8 (3 × CH2 (piperidin e); 16.0 an d 15.9
(SCH3, CH3 (piperidin e)).
1-(2,6-Dimethylpiperidino)-2-methyl-3-(10-methylacridin-9-yl)isothiourea iodide (6i): Yield
85%, m .p. 185–189 °C. For C23H28IN3S (505.5) calculated: 54.65% C, 5.58% H, 8.31% N;
foun d: 54.87% C, 5.78% H, 8.47% N. IR (KBr): 1600 (C=N); 1545 (NCS). 1H NMR (CDCl3):
8.34–7.87 m , 6 H, 7.58 m , 2 H (Acr); 4.58 m , 2 H (2 × CH (piperidin e)); 4.37 s, 3 H (N+CH3);
2.06 s, 3 H (SCH3); 2.25–1.50 m , 6 H (3 × CH2 (piperidin e)); 1.50 m , 6 H (2 × CH3).
Preparation of 1,1-Disubstituted 3-(Acridin -9-yl)-S-m eth ylisoth ioureas 7e, 7g.
Gen eral Meth od
To a solution of correspon din g S-m eth ylisoth iourea h ydroiodides 5e, 5g (1 m m ol) in aceto-
n itrile (30–40 m l), 1,4-diazabicyclo[2.2.2]octan e (1.5 m m ol) was added an d refluxed for 2.5 h .
Th e reaction m ixture was th en poured in to water (200 m l), extracted with eth yl acetate (3 ×
25 m l) an d dried over an h ydrous CaCl2. Th e residue obtain ed after evaporation of th e sol-
ven t was subjected to th e flash ch rom atograph y on silica gel (ben zen e/aceton e, 5:2) afford-
in g th e crystallin e product after evaporation of th e solven t.
3-(Acridin-9-yl)-1,1-diisopropyl-2-methyllisothiourea (7e): Yield 78%, m .p. 197–200 °C. For
C
21H25N3S (351.5) calculated: 71.76% C, 7.17% H, 11.95% N; foun d: 71.08% C, 7.28% H,
11.85% N. IR (CHCl3): 1620 (C=N); 1553 (NCS). 1H NMR (CDCl3): 8.18 m , 2 H, 8.12 m , 2 H,
7.77 m , 2 H, 7.43 m , 2 H (Acr); 4.37 septet, 2 H, J = 6.6 (2 × CH (iPr)); 1.54 s, 3 H (SCH3);
1.53 d, 12 H, J = 6.6 (4 × CH3 (iPr)).
3-(Acridin-9-y)l-1,2-dimethylphenylisothiourea (7g): Yield 84%, m .p. 190–193 °C. For
C
22H19N3S (357.5) calculated: 73.92% C, 5.36% H, 11.75% N; foun d: 73.87% C, 5.32% H,
11.71% N. IR(KBr): 1610 (C=N); 1545 (NCS). 1H NMR (CDCl3): 8.19 m , 2 H, 8.16 m , 2 H,
7.78 m , 2 H, 7.48 m , 2 H (Acr); 7.31 bs, 5 H (Ph ); 3.51 s, 3 H (NCH3); 1.85 s, 3 H (SCH3).
Authors are grateful to the Grant Agency VEGA of the Slovak Ministry of Education for the finan-
cial support (Grant No. 1/9245/2002).
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