Stereochemistry, tautomerism, and reactions of acridinyl thiosemicarbazides in the synthesis of 1,3-thiazolidines

Article abstract of DOI:10.1002/jhet.5570430318

Acridin-9-yl hydrazine upon treatment with various isothiocyanates (RNCS, R = methyl, allyl, phenyl, p-methoxy phenyl, and p-nitro phenyl) yielded the corresponding thiosemicarbazides with acridine substituted on the carbazide-type side. The alkyl-substit

Full text of DOI:10.1002/jhet.5570430318

May-Jun 2006
645
Stereochemistry, Tautomerism, and Reactions of Acridinyl
Thiosemicarbazides in the Synthesis of 1,3-Thiazolidines*
Eva Balentová,a,b Ján Imrich,a Juraj Bernát,a Lucia Suchá,a Mária Vilková,a
Naꢀa Prónayová,c Pavol Kristian,a Kalevi Pihlajab and Karel D. Klika**b
a Department of Organic Chemistry, P. J. ꢁafárik University, Moyzesova 11,
SK-04167 Koꢂice, The Slovak Republic
b Department of Chemistry, University of Turku, Vatselankatu 2,
FIN-20014 Turku, Finland
c Faculty of Chemical and Food Technology, Central Laboratories, Slovak Technical University, SK-81237
Bratislava, The Slovak Republic
Received August 30, 2005
NH
S
NH
S
N
HN
N
NHR
R
S
N
N
N
N
NR
BrCH2CN
base
spontaneous
NH
N
H
N
H
Acridin-9-yl hydrazine upon treatment with various isothiocyanates (RNCS, R = methyl, allyl, phenyl,
p-methoxy phenyl, and p-nitro phenyl) yielded the corresponding thiosemicarbazides with acridine
substituted on the carbazide-type side. The alkyl-substituted compounds were present in solution as
equilibria consisting of the major H-10, H-12 tautomer (either E or Z or both about the C13ꢀN14 bond) and
the minor H-10, SH tautomer (either E or Z or both). The major species for the aromatic-substituted
compounds was the H-10, H-12 E tautomer, with the evident minor species being the H-10, H-12 Z
tautomer. The thiosemicarbazides were each quantitatively converted into the analogous semicarbazides
upon treatment with mesitylnitrile oxide wherein all structures were present in solution as the H-10
tautomers with Z conformation about the C13ꢀN14 bond. Methylation of the compounds with methyl iodide
yielded S-methylated compounds wherein the Z configuration dominated in each case over the E
configuration along the N12ꢀC13 double bond. Treatment of the thiosemicarbazides with methyl
bromoacetate resulted in the formation of 1',3'-thiazolidin-4'-ones wherein the Z configuration
predominated in each case over the E configuration along the N12ꢀC13 double bond. With bromoacetonitrile
as the bifunctional electrophile, the initial 1',3'-thiazolidin-4'-imines that formed spontaneously underwent
Dimroth-type rearrangement to the regiosiomeric 1',3'-thiazolidin-4'-imines.
J. Heterocyclic Chem., 43, 645 (2006).
Introduction.
mative introductions and background information on this
type of work; overviews of the syntheses of thiosemi-
carbazides have been described [16,17] and aliphatic
thiosemicarbazides in particular have been systematically
studied [18].) In contrast to the complementary work
[10,19] where a slew of interesting structures were
realized though the primary targets of thiazolidines were
not forthcoming due to spiro formation et alia, this work
progressed closer to plan and we were able to produce
sets of 1,3-thiazolidin-4-ones and 4-imino-1,3-thiazo-
lidines with relative ease. The usefulness of thiazolidines
has been well reviewed [20ꢀ22] and described [8,9] and
the reaction mechanism of acridine- [23] and anthracene-
substituted [8,9] thioureas with methyl bromoacetate to
yield 1,3-thiazolidin-4-ones rationalized.
In this work, as part of an examination of thiosemicarba-
zides containing the acridine moiety (an extension of our
long-standing studies with acridine- [1ꢀ7] and anthracene-
substituted [8,9] thioureas for the purposes of obtaining
new and novel type structures concomitant with potential
biological applications), we focused on acridines sub-
stituted at the ꢁ-carbazide-type nitrogen {AcrꢀNHꢀ
NHꢀC(=S)ꢀNHꢀR, prepared from acridin-9-yl hydrazine
and isothiocyanates} to complement our companion
report [10] which focused on acridines substituted at the
urea-type nitrogen {AcrꢀNHꢀC(=S)ꢀNRꢀNH2, prepared
from acridin-9-yl isothiocyanate and methyl/phenyl
hydrazine}. Surprisingly, only limited synthetic exploi-
tation of 9-hydrazinylacridine [11ꢀ14] has been made.
(See also the accompanying articles [10,15] for infor-
The thiosemicarbazides prepared from 9-hydrazinyl-
acridine were subsequently transformed to semicarbazides

646
E. Balentová, J. Imrich, J. Bernát, L. Suchá, M. Vilková, N. Prónayová, P. Kristian,
K. Pihlaja and K. D. Klika
Vol 43
with mesitylnitrile oxide to broaden the range of
compounds examined as part of our long-term additional
bioactivity and fluorescence studies and moreover,
semicarbazides are more conveniently prepared from
their thio analogues; methylated with methyl iodide; and
reacted with the bifunctional electrophiles methyl
bromoacetate and bromoacetonitrile resulting in
thiazolidines:
compiled in Tables 1 and 2 whilst the homonuclear
couplings extracted by spin simulation [27] are presented
only for selected cases given the close similarity of the
couplings in the acridine moiety (see also ref [10]) but are
inclusive of examples where couplings were present in other
segments.
Thiosemicarbazides 1aꢀe.
Acridin-9-yl hydrazine [11], obtained from 9-chloro-
acridine [28] and hydrazine hydrate, upon treatment
with isothiocyanates (RNCS: R = methyl, a; allyl, b;
phenyl, c; p-methoxyphenyl, d; p-nitrophenyl, e)
yielded the corresponding thiosemicarbazides 1aꢀe
(Scheme 1). Reaction proceeded only via the ꢁ nitrogen
to provide the 1,4-disubstituted thiosemicarbazides
1aꢀe; 2,4-disubstituted thiosemicarbazides resulting
from attack by the ꢂ nitrogen were not observed
despite the use of benzene, diethyl ether, and methanol
as reaction media. The acridin-9-yl thiosemicarbazides
1aꢀe can exist in a number of tautomeric and isomeric
forms and, indeed, in solution thiosemicarbazides 1aꢀd
were present as more than one species resulting in the
NMR spectra being quite complex. For each of the four
compounds 1aꢀd, two significant species in solution,
major and minor, were discerned and for all eight of
these structures the H-10 (9,10-dihydroacridin-9-
ylidene) tautomer as indicated in Scheme 1 was
deemed to be present. This was unequivocally proven
by the non-equivalency of the side rings of the acridine
moiety (as expected for such a structure though
chemical exchange between respective signals of the
acridine skeleton could be observed); the shielding of
C-4a and C-10a to values less than 142 ppm [1,29,30]
{for the H-11 (acridine) tautomer, values in the range
147ꢀ151 ppm would be expected [31,32]}; as well as
NOE enhancements of the H-4 and H-5 protons upon
irradiation of H-10 signal.
X
S
S
N
R
BrCH2CO2CH3
or BrCH2CN
Acr
N
N
H
NHR
N
N
Acr
X = O, NH
One of the features of this work was that for the
majority of the products, a coplanar 9,10-dihydroacridin-
9-ylidenehydrazono structure was present with extended
conjugation. This is due to the propensity of the N-10
acridine nitrogen to deprive N-11 of its proton, resulting
in the formation of a 9,10-dihydroacridin-9-ylidene
structure attached through a C=N double bond to the
thiosemicarbazide moiety. Such extended coplanarity is of
interest in light of the fact that the biological activity of
acridines is often ascribed to their intercalation into the
stacked base pairs of the DNA precisely due to their
planarity [24ꢀ26].
Results and Discussion.
For an outline of the general structural protocol, see the
preceding article [10]. To limit repetitious descriptions,
structural determinations are not described in detail and
structures are essentially only presented but based on
thorough analysis with only pivotal points pertaining to
unexpected or peculiar structures being described explicitly.
For the alkyl-substituted derivatives 1a and 1b, C-13 of
the major species (89% and 91%, respectively) resonated
1
The H, 13C, and 15N chemical shifts of the compounds are
Scheme 1
S
14
HN
11 N
NHR
NH2
Cl
HN
1
8
9
H2NNH2
RNCS
8a
9a
4a
10a
N
N
H
N
5
4
10
9-chloroacridine
acridin-9-yl hydrazine
1a: R = methyl
1b: R = allyl
1c: R = phenyl
1d: R = p-methoxyphenyl
1e: R = p-nitrophenyl
The preparation of thiosemicarbazides 1aꢀe. The numbering of the R substituents begins at the N-bound carbon with 1''.

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K. Pihlaja and K. D. Klika
Vol 43
at ca. 178 ppm, typical for a C=S carbon and thus the major
species in both cases is either the E or the Z isomer of the H-
10, H-12 tautomer (as indicated in Scheme 2). Whether the
equilibrium between these two geometric isomers for the
major species of 1a and 1b is highly biased or the
interconversion is very fast was not discerned. For the minor
species of 1a and 1b, C-13 resonated at ca. 157 ppm and this
can only be accounted for by an SH tautomer. This tautomer
may exist as either a Z isomer (preferred based on similar
work [33]) and/or an E isomer, but the preference nor the
existence of an equilibrium was not ascertained. The driving
force for favoring such tautomerisation could be attributed to
the energy gain arising from the extended conjugated system,
based on the strong tendency of an acridine moiety with a
C9ꢀNHꢀR segment to adopt a 9,10-dihydro arrangement.
Intriguingly, extraordinary deshielding (9.6–9.8 ppm) was
noted for the H-1 proton for the minor species of 1a and 1b,
and indeed for many other similar structures in this work,
suggestive of the presence of a grouping with a strong
magnetic anisotropy. In this instance the strong magnetic
anisotropy was provided by the two conjugated imino bonds.
Scheme 2
S
S
R
H
HN
N
HN
N
N
H
N
R
N
H
N
H
H-10, H-12, E
H-10, H-12, Z
RHN
N
SH
HS
N
NHR
N
N
and/or
N
H
N
H
H-10, SH, Z
H-10, SH, E
Solution-state tautomers and isomers contributing to the equilibria of
thiosemicarbazides 1aꢀe. Compounds 1a and 1b were found to be an
equilibrium of the major H-10, H-12 tautomer (either E or Z or both) and
the minor H-10, SH tautomer (either E or Z or both). The major species
for compounds 1cꢀe was the H-10, H-12 E tautomer with the evident
minor species for 1c and 1d being the H-10, H-12 Z tautomer.
For phenyl and 4-methoxyphenyl thiosemicarbazides 1c
and 1d, C-13 of both the major and minor isomers (78:22

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Stereochemistry, Tautomerism, and Reactions of Acridinyl Thiosemicarbazides
649
and 65:35, respectively) of both compounds resonated in
the range of 175ꢀ177 ppm, thus all four species possess a
C=S group. Nonetheless, the major species still presented

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Vol 43
a large difference, of the order of 1.6 ppm, between the
chemical shifts of H-1 (9.80 and 9.77 ppm for 1c and 1d,
respectively) and H-8 (8.16 and 8.14 ppm, respectively) in
addition to a deshielded H-10 signal (11.99 and 11.90 ppm,
respectively) and a strongly deshielded H-12 signal (13.44
and 13.45 ppm, respectively). It is of particular note that
these chemical shifts for H-10 and H-12 were not observed
for any other derivatives in this study. By contrast, the
signals of the two minor species were much more typical of
the expected values for H-1 (both resonated at 8.37 ppm),
H-8 (8.53 and 8.54 ppm, respectively), H-10 (10.64 and
10.61 ppm, respectively), and H-12 (10.51 and 10.37 ppm,
respectively). To account for the deshieldings observed for
the major species, and the very presence of two species per
se, restricted rotation about the C13ꢀN14 thioamide bond is
postulated. For the major species of 1c and 1d, the phenyl
ring must be spatially closer to H-12 and the acridine
moiety to effect deshielding and thus it is the E isomer
represented in Scheme 2 whilst the minor species is the Z
isomer in both cases. Further differences between the major
and minor species of 1c and 1d can also be seen in the
chemical shifts of C-9 and the ortho carbons C-2' and 6'.
Greater shielding of C-2'(6') and C-9 for 1c(d) major of
between 4.5ꢀ4.9 ppm in comparison to 1c(d) minor
indicates that a steric component is present in addition to
any magnetic anisotropy.
A similar analysis of the solution-state species for the
nitro derivative 1e was precluded by its very poor
solubility and little can be said other than that the major
species in solution was also the H-10, H-12 E tautomer.
Semicarbazides 2aꢀe.
The thiosemicarbazides 1aꢀe were each converted, in
most cases quantitatively, into the analogous semicar-
bazides 2aꢀe (Scheme 3) upon treatment with mesityl-
nitrile oxide (MNO). The exchange of S by O was evident
by the appearance of an IR absorption band at 1640ꢀ1700
cmꢀ1 (ꢀC=O) and a 13C NMR signal in the range 155ꢀ158
ppm for the carbonyl carbon. In contrast to 1aꢀe, only one
species was observed in solution for each compound.
Again though, the non-equivalency of both acridine side
rings was evident as was the presence of the H-10 (9,10-
dihydroacridinylidene) tautomer. Of note, the chemical
shifts of H-12 and H-14 were shielded by more than 1
ppm in comparison to thiosemicarbazides 1 because of the
weaker electron withdrawing effect of the carbonyl group.
The stereochemistry of 2aꢀe was based on semicarbazide
2b (the overlap of H-1 and H-8 in the other derivatives
precluded stereochemical differentiation) where irradi-
ation of H-12 yielded a 20.5% enhancement of the H-1
signal (none for H-8) whilst irradiation of H-14 yielded a
4.8% enhancement of the H-8 signal (none for H-1). This
testifies to the hindered rotation about the C13ꢀN14 bond in

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Stereochemistry, Tautomerism, and Reactions of Acridinyl Thiosemicarbazides
651
The H-14 protons of the major isomers of 3a and 3b
were strongly shielded (3a, 6.40 ppm; 3b, 6.57 ppm)
due to a number of factors, including probably being in
the shielding zone of the extended imino double bond
conjugation. This is countered in the phenyl derivative
3c by the anisotropy of the phenyl ring in addition to
any conformational shift and H-14 resonates at more
typical values (major, 12.82 ppm; minor, 12.26 ppm) in
comparison to thiosemicarbazides 1.
semicarbazides 2aꢀe with the Z conformation prevalent as
indicated in Scheme 3.
Scheme 3
R
H
O
S
N
HN
NHR
NH
N
N
MNO
1',3'-Thiazolidin-4'-ones 4aꢀd.
N
H
N
H
Treatment of thiosemicarbazides 1aꢀd with methyl
bromoacetate provided 1',3'-thiazolidin-4'-ones 4aꢀd
(Scheme 5). According to literature [8,9], this reaction is a
two-step process, nucleophilic displacement of the bromine
by the sulfur of the thiosemicarbazide affords the S-
carboxyalkylated isothiosemicarbazide which is then
followed by nucleophilic attack by one of the nitrogen
atoms to the carboxylate carbon eliminating methoxide ion
and effecting cyclisation. Since the reactions were
conducted in alkaline medium, the second step proceeded
successively without isolation of the isothiosemicarbazide
intermediates. In principle, three regioisomers resulting
from attack by nitrogen atoms N-11, N-12, and N-14 are
possible, however, literature reports [20ꢀ22] on the
formation of thiazolidinone structures resulting from attack
of N-12 or N-14 are much more frequent than the formation
of six-membered thiadiazine structures resulting from attack
of the N-11 nitrogen. The only product isolated in each case
was clearly not a thiadiazine as such a structure would have
an acridine moiety and not a 9,10-dihydroacridinylidene
structure as observed. (The sole formation of only one
regioisomer was also evident by TLC.) The NMR data of
the thiazolidinone ring was also in accord with previous
studies [8,9,23]. Of the two possible regioisomeric
thiazolidinone structures, it was clearly the one resulting
from attack by N-14 as correlations were observed from the
H-3'' methyl protons in 4a and the H-3'' allyl methylene
1a-e
2a: R = methyl
2b: R = allyl
2c: R = phenyl
2d: R = p-methoxyphenyl
2e: R = p-nitrophenyl
The reaction of compounds 1aꢀe with mesitylnitrile oxide quantitatively
produced the corresponding semicarbazides 2aꢀe. All structures were present
in solution as the H-10 tautomers with Z conformation about the C13ꢀN14 bond
S-Methyl thiosemicarbazides 3aꢀc.
Treatment of thiosemicarbazides 1aꢀc with CH3I/ K2CO3 in
acetone afforded the S-methyl derivatives 3aꢀc in moderate
yields (Scheme 4). For all three compounds, two species were
present in solution (3a, 83:17; 3b, 91:9; and 3c, 60:40). For all
six structures, C-13 resonated in the expected range (159ꢀ162
ppm), as did the SꢀCH3 carbons (12ꢀ15 ppm), and again the
H-10 (9,10-dihydroacridinylidene) tautomer was evident for
all six species as was the conjugation of the imino double
bonds as evidenced by the strong deshielding of H-1 (0.8ꢀ1.5
ppm relative to H-8) in both major and minor species of 3aꢀc.
The two solution-state species were identified as the Z (major)
and E (minor) geometric isomers about the N12=C13 double
bond based on NOEs for 3a and 3b between H-1 and the
protons of the R substituents in the case of the major isomer
and between H-1 and the S-methyl protons in the minor
isomer. The predominance of the Z isomer is not surprising in
the light of previous studies [33].
Scheme 4
H3C
S
NHR
RHN
S CH3
S
N
N
HN
NHR
N
N
N
CH3I
K2CO3
N
H
N
H
N
H
Z
E
1a-c
3a: R = methyl
3b: R = allyl
3c: R = phenyl
The methylation of 1aꢀc yielded the S-methylated compounds 3aꢀc wherein the Z configuration dominated in each case over the E configuration
along the N12ꢀC13 double bond.

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Vol 43
protons in 4b to both C-4' and C-2'. Correlations to C-4'
from these protons would be improbable in the
regioisomers resulting from attack by N-12. Further
evidence in the case of 4d was a correlation observed
between the ortho protons of the phenyl ring and a 15N
NMR signal at ꢀ219.7 ppm, a chemical shift consistent
with an sp3-hybridized nitrogen. The stereochemistry of the
N12ꢀC2' bond was determined to be in favor of the sterically
less hindered Z isomer. This was based on NOE
enhancements whereby irradiation of the H-3' methyl (4a)
or the H-3' methylene protons (4b) provided enhancements
of the H-1 signals (1.4% and 2.7%, respectively) with no
enhancement of the H-8 signals; irradiation of the H-1
proton in 4c resulted in a 3.4% enhancement of the phenyl
H-2'', H-6'' signals whilst irradiation of H-8 did not enhance
any of the phenyl signals. Comparison of alkyl 4a and 4b
vs. aryl 4c and 4d thiazolidines revealed that the chemical
shifts of H-1 and H-2 are shielded in 4c and 4d by 0.5–0.6
ppm, attributable to the phenyl ring which is probably
perpendicular to the plane of the rest of molecule.
treatment with base, e.g. an esoteric spiro bicyclic structure
[1,15] resulting from attack of the nitrile nitrogen on C-9; a
spiro product resulting from attack of the methylene carbon of
bromoacetonitrile on C-9; a 1,3,4-thiadiazine structure resul-
ting from attack of N-11 onto the nitrile carbon; and the regio-
isomeric 1,3-thiazolidin-4-imines resulting from attack by
either N-12 or N-14 onto the nitrile carbon. Again, the S-
methylenenitrile intermediate generated after addition of
bromoacetonitrile was not isolated though cyclisation was
observed upon treatment with sodium methoxide. As regards
these cyclic products, the spiro structures were easy to
eliminate as candidate structures as a spiro carbon was not
observed. Because of a likely strong preference for adopting
the 9,10-dihydroacridinylidene structure, C-9 in the S-methyl-
enenitrile intermediate is not as susceptible to nucleophilic
attack in any case. As with the account presented in the
previous section, a 1,3,4-thiadiazine structure was also easily
eliminated. That left the two regioisomeric 1,3-thiazolidin-4-
imines (5 and 6) as the only candidate structures (Scheme 6)
as a result of attack by N-12 or N-14, respectively. What was
most remarkable was that upon dissolution in DMSO, the
samples of the methyl and the p-methoxy phenyl provided a
spectrum dominated by one set of signals which slowly
dissipated with time (tꢀ of the order of hours) to be
completely replaced by a new set. (In the case of the allyl
derivative, only the final set of signals was observed; in the
case of the phenyl derivative, the reaction had progressed to
the point where the initial product was only just detectable.)
Both sets of signals were consistent 1,3-thiazolidin-4-imines
(vide supra), thus it was simply a matter of deciding which of
the two regioisomers is produced first and then the course of
the Dimroth-type rearrangement that it undergoes. The two
potential initial products, 5 and 6, are interconvertable by a
Dimroth-type rearrangement (either as a result of attack by
hydroxide ion or by deprotonation of the imine to enact ring
opening), and additionally there is another Dimroth-only
rearrangement available to each structure. The most signif-
icant feature of the 1H NMR of the initially observed product
was that the methylene protons in the thiazolidine ring were
non-equivalent and resonated as an AB quartet, as opposed to
the usual observation where they resonate as a singlet due to
fast exchange [8,9]. Of the four structures presented in
Scheme 6, only one, 5, could provide such a case. In 5, steric
hindrance limits the coplanarity of the thiazolidine ring and
the acridine moiety and this, together with slow inversion at
N-3' (née 12) and hindered rotation about the N11ꢀN3' bond,
means that the introduced chiral axis renders the two protons
of the methylene group non-equivalent. Structure 5 was then
shown to rearrange to structure 6 instead of its alternate based
on the correlations of the methyl (6a) or ortho (6c and d)
protons to an sp3-hybridized nitrogen or the correlations of the
methyl (6a) or exocyclic methylene (6b) protons to both sp2-
hybridized carbon atoms of the thiazolidine ring. (Note, the
Scheme 5
O
4'
3'
1' S
S
N
R
N
HN
N
NHR
N
BrCH2CO2Me
base
N
H
N
H
Z
1a-d
4a: R = methyl
4b: R = allyl
4c: R = phenyl
4d: R = p-methoxyphenyl
The reaction of thiosemicarbazides 1aꢀd with methyl bromoacetate
yielded the 1',3'-thiazolidin-4'-ones 4aꢀd wherein the Z configuration
predominated in each case over the E configuration along the N12ꢀC13
double bond.
It is noteworthy given the results of the preceding section
that the course of the reaction reflects the likely position of
the tautomeric equilibrium of the S-carboxyalkylated
isothiosemicarbazide intermediate (N-14 amino, N-12
imino), as postulated previously [8,9]. However, given the
very different natures of the nitrogen atoms in question here
with N-12 likely to be a much stronger nucleophile in its
amino form in comparison to N-14, the result only holds
due to the high susceptibility to nucleophilic attack of the
carboxy carbon of the ester moiety.
4'-Imino-1',3'-thiazolidines 5aꢀd and 6aꢀd.
Treatment of thiosemicarbazides 1aꢀd with bromoaceto-
nitrile could potentially provide a number of products after

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Stereochemistry, Tautomerism, and Reactions of Acridinyl Thiosemicarbazides
653
Scheme 6
15
NH
NH
4'
N
11
N
1'
S
1
N
N
N 14
S
R
NH
S
NH
HN
N
NHR
N
R
5a-d
BrCH2CN
base
N
H
15 NH
N
R
1a-d
4'
1' S
S
NH
N
R
12
1
N
N
11
a: R = methyl
b: R = allyl
N
N
8
c: R = phenyl
d: R = p-methoxyphenyl
N
H
N
H
6a-d
The reaction of 1aꢀd with bromoacetonitrile initially yielded the 1',3'-thiazolidin-4'-imines 5aꢀd which underwent spontaneous Dimroth
rearrangements to regioisomeric 1',3'-thiazolidin-4'-imines 6aꢀd. The Z configuration predominated in each case over the E configuration along the
N12ꢀC13 double bond for the latter set.
was performed using Perch [27] iteration software for the
extraction of 1H chemical shifts and JH,H coupling constants. Since
the reliable extraction of small couplings approaching the
linewidth is heavily dependent on whether they are to a degree
resolvable on at least one spin for Perch to reliably extract them,
only those couplings reliably extracted by Perch are reported
whilst couplings buried in the linewidth on both interacting spins
are not reported (i.e., not extracted) even if their likely presence is
probable or is evident from homodecoupling experiments or
COSY experiments. The signs of the couplings were assumed
based on the number of intervening bonds, i.e. if n is even, nJ was
entered as a negative value; if n is odd, nJ was entered as a positive
value. NOE difference measurements were acquired using
saturation times of 6 s and with reduced resolution (3.9 Hz ptꢀ1); 1
Hz of exponential weighting was usually applied prior to Fourier
transformation. (NOE difference measurements also provided
concomitantly saturation transfer information.) DQF-COSY and
NOESY spectra were acquired in phase-sensitive mode with
spectral widths and resolution appropriately optimized from the 1-
D spectra, and processed with zero-filling (ꢁ 2, ꢁ 4) and
exponential weighting (1 Hz) applied in both dimensions prior to
Fourier transformation. 13C spectra were acquired with single-
pulse excitation, 45° flip angle, pulse recycle time of 3.5 s and
with spectral widths of 30 kHz consisting of 64 k data points
(digital resolution 0.46 Hz ptꢀ1), and with 1 Hz exponential
weighting applied prior to Fourier transformation. DEPT 135°
spectra were acquired with similar spectral windows and with a
pulse delay time of 3 s. CHDEC (CHSHFT with f1 homonuclear
decoupling), HSQC PMG [34], and HMBC BIRD experiments
were acquired in phase-sensitive mode and magnitude mode (for
imino NH proton was not observed for either structure.) The
geometry about the N12ꢀC2' bond, however, could not be
substantiated in 6.
It is interesting to note that the course of the reaction
(for the initial product 5) is in opposition to the likely
position of the tautomeric equilibrium of the S-alkylated
isothiosemicarbazide intermediate (N-14 amino, N-12
imino). This therefore is indicative of the low
susceptibility to nucleophilic attack of the nitrile carbon
by which the much stronger nucleophilic character of N-
12 comes to the fore over N-14 despite the unfavorable
equilibrium position.
EXPERIMENTAL
NMR spectra were acquired using a JEOL Alpha 500 NMR
spectrometer operating at 500 MHz for 1H, 126 MHz for 13C, and
51 MHz for 15N, a JEOL Lambda 400 NMR spectrometer
1
operating at 400 MHz for H and 100 MHz for 13C, or a Varian
VXR-300 NMR spectrometer operating at 300 MHz for 1H and 75
MHz for 13C. Spectra were recorded at 25 °C unless stated
1
otherwise in DMSO-d6 and both H and 13C chemical shifts were
referenced internally to TMS (ꢀ = 0 for both) whilst 15N spectra
were referenced externally to 90% nitromethane in CD3NO2 (ꢀ =
1
0). H spectra were acquired with single-pulse excitation, 45° flip
angle, pulse recycle time of 9.5 s and with spectral widths of 7
kHz consisting of 64 k data points (digital resolution 0.11 Hz ptꢀ1),
zero-filled to 128 k prior to Fourier transformation. Spin analysis

654
E. Balentová, J. Imrich, J. Bernát, L. Suchá, M. Vilková, N. Prónayová, P. Kristian,
K. Pihlaja and K. D. Klika
Vol 43
115.25 (C-4), 115.52 (C-9a), 118.46 (C-2), 120.26 (C-8), 121.90
(C-8a), 123.69 (C-1), 127.62 (C-6), 128.08 (C-7), 129.45 (C-3),
136.21 (C-9), 138.26 (C-10a), 141.44 (C-4a).
the latter experiment) with
appropriately optimized from the
spectral widths and resolution
1-D spectra and processed with
zero-filling (ꢀ 2, ꢀ 4), a 2ꢁ/3-shifted sinebell function (for HMBC
spectra), and exponential weighting (5 Hz, 25 Hz) applied in both
dimensions prior to Fourier transformation. Both HSQC and
General Procedure for the Preparation of 4-Substituted-1-(9,10-
dihydroacridin-9-ylidene)-thiosemicarbazides 1aꢂe.
1
HMBC spectra utilized a JHC coupling of 145 Hz, whilst the
HMBC correlations were optimized for a long-range nJHC coupling
of ca. 8 Hz. The length of the purge pulse (typically 0.7 ms) and
BIRD relaxation delay (typically 400 ms) were optimized on the
incoming FID. Experiments were performed with vendor-supplied
pulse sequences except in the case of the sign determination of
long-range couplings [35]. With minor isomers, only clearly
visible signals are reported, signals that were overlapped, broad, or
too weak to be certain are excluded. 15N were generally acquired
indirectly from the f1 dimension of FGHSQC or FGHMBC
experiments where both HSQC and HMBC spectra utilized a 1JHN
coupling of 90 Hz whilst the HMBC correlations were optimized
for a long-range nJHN coupling of ca. 8 Hz with similar processing
as per above. The f1 windows and resolution were set according
to judgment based on previous experience and affordability. In
particular cases, when sample amounts were substantial or when
strongly warranted, refocused-INEPT experiments were run for
the direct observation of 15N nuclei where the final two delays
were set to either 1/(4J) or 3/(4J).
IR spectra were recorded on a Specord M80 spectrophoto–
meter (Zeiss, Jena) in CHCl3 or KBr discs. Elemental analysis
was performed using a PerkinꢂElmer CHN 2400 analyser. EI
mass spectra were acquired on a VG Analytical 7070E instru–
ment using 70 eV for ionisation. ESI-MS analysis was
performed using a PerkinꢂElmer Sciex API-365 triple quad–
rupole mass spectrometer equipped with a pneumatically-
assisted ion spray interface with the needle voltage set at +5,000
V (ꢂ4400 V), the orifice plate voltage at +35 V (ꢂ35 V) and the
ring voltage at +220 V (ꢂ200 V) for positive (negative) ion
measurements. The nebuliser gas (purified air) flow was set at
position 9 and that for the curtain gas (N2) at position 12. The
heated nitrogen gas temperature was set at 300 °C and the gas
flow rate at 7 L min–1. Masses were scanned from m/z 100 to
3,000 in 0.30 amu steps.
To a solution of substituted isothiocyanate (0.96 mmol) in
methanol (5 mL), acridin-9-yl hydrazine (0.2 g, 0.96 mmol) in
methanol (5 mL) was added dropwise. The mixture was allowed
to stir at room temperature under nitrogen for 24 h until
completion of the reaction (monitored by TLC cyclohexane/
acetone 3:1). The solvent was then removed under vacuum,
ether added, and the resulting precipitate collected by filtration
and dried to give product 1.
4-Methyl-1-(9,10-dihydroacridin-9-ylidene)-thiosemicarbazide
(1a).
Yield 62%; mp 125–127 °C (methanol); Found: C, 63.66; H,
4.92; N, 19.92. C15H14N4S requires C, 63.80; H, 5.0; N, 19.84%;
ꢁmax(KBr)/cm–1: 1100 (C=S); 1a (major isomer, 90%). 1a (minor
isomer, 10%).
4-Allyl-1-(9,10-dihydroacridin-9-ylidene)-thiosemicarbazide (1b).
Yield 77%; mp 134–135 °C (methanol); Found: C, 66.36; H,
5.09; N, 17.91 C17H16N4S requires C, 66.21; H, 5.23; N, 18.17%;
ꢁmax(KBr)/cm–1: 1150 (C=S); 1b (major isomer, 91%). 1b (minor
isomer, 9%).
4-Phenyl-1-(9,10-dihydroacridin-9-ylidene)-thiosemicarbazide
(1c).
Yield 85%; mp 195–197 °C (methanol); Found: C, 69.95; H,
4.56; N, 16.37 C20H16N4S requires C, 69.74; H, 4.68; N, 16.27%;
ꢁmax(KBr)/cm–1:1000ꢂ1100 (C=S); 1c (major isomer, 78%). 1c
(minor isomer, 22%).
4-Methoxyphenyl-1-(9,10-dihydroacridin-9-ylidene)-thiosemi–
carbazide (1d).
Yield 92%; mp 187–188 °C (methanol); Found: C, 67.18; H,
4.97; N, 14.59 C21H18N4OS requires C, 67.36; H, 4.85; N,
14.96%; ꢁmax(KBr)/cm–1: 980 (C=S); 1d (major isomer, 65%).
1d (minor isomer, 35%).
Methyl, allyl, phenyl, 4-methoxyphenyl, and 4-nitrophenyl
isothiocyanates, methyl bromoacetate, and bromoacetonitrile were
commercial products from Aldrich. Mesitylnitrile oxide was
prepared according to ref [36]. Reactions were monitored by thin-
layer chromatography (TLC) using Silufol plates (Kavalier) with
detection at 254 nm. Preparative column chromatography was
performed using Silpearl (Kavalier). Melting points were
determined on a Boetius instrument and are uncorrected.
4-Nitrophenyl-1-(9,10-dihydroacridin-9-ylidene)-thiosemi-
carbazide (1e).
Yield 94%; mp 230–231 °C (methanol); Found: C, 61.35; H,
4.03; N, 17.66 C20H15N5O2S requires C, 61.68; H, 3.88; N,
17.98%.
General Procedure for the Preparation of 4-Substituted-1-(9,10-
dihydroacridin-9-ylidene)-semicarbazides 2aꢂe.
Acridin-9-yl hydrazine [11].
9-Chloroacridine [11] (2 g, 9.4 mmol) in methanol (30 mL) was
added to a refluxing solution of hydrazine monohydrate (0.47 g,
0.46 mL, 9.4 mmol) in methanol (30 mL) over 10 min and the
refluxing continued for an additional 20 min. Water preheated to
75 °C was then added and the resulting suspension quickly
filtered. The refrigerated filtrate provided orange needles of 9-
hydrazinoacridine. Yield 77%; mp 169 °C (methanol); Found: C,
74.32; H, 5.08; N, 20.02. C13H11N requires C, 74.62; H, 5.30; N,
20.08%; ꢀH(400 MHz; DMSO-d6; Me4Si) 6.26 (2H, br s, NH2),
6.89 (ddd, H-7), 6.89 (ddd, H-2), 6.93 (ddd, H-5), 7.07 (ddd, H-4),
7.19 (ddd, H-6), 7.29 (ddd, H-3), 7.76 (dd. H-8), 8.25 (dd, H-1),
9.70 (s, H-10); ꢀC(100 MHz; DMSO-d6; Me4Si) 114.26 (C-5),
To a solution of substituted thiosemicarbazide 1 (0.45 mmol)
in dry acetonitrile (5 mL), mesitylnitrile oxide (0.072 g, 0.45
mmol) was added. The mixture was allowed to stir for 6 h at
room temperature following which the solvent was evaporated
under reduced pressure and the solid collected by filtration,
dried, and crystallized from methanol to afford 2.
4-Methyl-1-(9,10-dihydroacridin-9-ylidene)-semicarbazide (2a).
Yield 96%; mp 225–227 °C (methanol); Found: C, 67.37; H,
5.18; N, 21.32 C15H14N4O requires C, 67.65; H, 5.30; N,
21.04%; ꢁmax(KBr)/cm–1: 1700 (C=O).

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Stereochemistry, Tautomerism, and Reactions of Acridinyl Thiosemicarbazides
655
4-Allyl-1-(9,10-dihydroacridin-9-ylidene)-semicarbazide (2b).
was added dropwise and the mixture left to stir for 2 h after
which sodium methoxide (0.029 g, 0.54 mmol) was added. The
reaction mixture was stirred for another 1 h then poured into
cold water (25 mL) and the resulting precipitate of 4 collected
by filtration, dried, and crystallized from diethyl ether.
Yield 92%; mp 122–124 °C (methanol); Found: C, 69.75; H,
5.38; N, 19.26 C17H16N4O requires C, 69.85; H, 5.52; N,
19.17%; ꢀmax(KBr)/cm–1: 1680 (C=O).
4-Phenyl-1-(9,10-dihydroacridin-9-ylidene)-semicarbazide (2c).
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-methyl-1',3'-thia-
zolidin-4'-one (4a).
Yield 95%; mp 229–231 °C (methanol); Found: C, 73.22; H,
4.92; N, 16.76 C20H16N4O requires C, 73.15; H, 4.91; N,
17.06%; ꢀmax(KBr)/cm–1:1680 (C=O).
Yield 82%; mp 288–290 °C (diethyl ether); Found: C, 63.56;
H, 4.12; N, 17.17 C17H14N4OS requires C, 63.33; H, 4.38; N,
17.38%; ꢀmax (KBr)/cm–1: 1560ꢀ1600 (C=N), 1730 (C=O); JH,H
couplings (Hz) extracted by spin simulation [27]: JH1,H2 = 8.4,
JH1,H3 = 1.5, JH1,H4 = 0.5, JH2,H3 = 7.0, JH2,H4 = 1.3, JH3,H4 = 8.3,
JH5,H6 = 8.2, JH5,H7 = 1.2, JH5,H8 = 0.5, JH6,H7 = 7.0, JH6,H8 = 1.5,
JH7,H8 = 8.2.
4-Methoxyphenyl-1-(9,10-dihydroacridin-9-ylidene)-semi-
carbazide (2d).
Yield 52%; mp 223–224 °C (methanol); Found: C, 70.67; H,
4.87; N, 15.48 C21H18N4O2 requires C, 70.38; H, 5.06; N,
15.63%; ꢀmax(KBr)/cm–1: 1640 (C=O).
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-allyl-1',3'-thia-
zolidin-4'-one (4b).
4-Nitrophenyl-1-(9,10-dihydroacridin-9-ylidene)-semicarbazide
(2e).
Yield 73%; mp 225–228 °C (diethyl ether); Found: C, 65.32; H,
4.28; N, 16.15 C19H16N4OS requires C, 65.50; H, 4.63; N, 16.08%;
ꢀmax(KBr)/cm–1: 1540 (C=N), 1620 (C=O); JH,H couplings (Hz)
Yield 86%; mp 220 °C (methanol); Found: C, 64.09; H, 4.10;
N, 18.49 C20H15N5O3 requires C, 64.34; H, 4.05; N, 18.76%;
ꢀmax(KBr)/cm–1: 1640 (C=O).
extracted by spin simulation [27]: JH1,H2 = 8.4, JH1,H3 = 1.5, JH1,H4
0.4, JH2,H3 = 7.0, JH2,H4 = 1.3, JH3,H4 = 8.3, JH5,H6 = 8.2, JH5,H7 = 1.2,
H5,H8 = 0.5, JH6,H7 = 7.0, JH6,H8 = 1.5, JH7,H8 = 8.2.
=
General Procedure for the Preparation of 4-Substituted S-Methyl
1-(9,10-dihydroacridin-9-ylidene)-isothiosemicarbazides 3aꢀc.
J
A suspension containing 1 (0.88 mmol) and anhydrous
potassium carbonate (0.122 g, 0.88 mmol) in anhydrous acetone
(5 mL) was stirred at room temperature. To this mixture
iodomethane (0.126 g, 0.055 mL, 0.89 mmol) was added
dropwise and the mixture was allowed to stir for 7 h. After the
completion of the reaction, the mixture was poured into water
(25 mL) and extracted with chloroform (3 ꢀ 20 mL). The
combined organic layers were dried over anhydrous sodium
sulfate, filtered, and the solvent evaporated off under vacuum to
provide the product 3.
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-phenyl-1',3'-
thiazolidin-4'-one (4c).
Yield 71%; mp 136–138 °C (diethyl ether); Found: C, 68.45; H,
4.20; N, 14.35 C22H16N4OS requires C, 68.73; H, 4.19; N, 14.57%;
ꢀmax (KBr)/cm–1: 1580 (C=N), 1700 (C=O); JH,H couplings (Hz)
extracted by spin simulation [27]: JH1,H2 = 8.5, JH1,H3 = 1.5, JH1,H4
=
0.4, JH2,H3 = 7.0, JH2,H4 = 1.3, JH3,H4 = 8.3, JH5,H6 = 8.2, JH5,H7 = 1.2,
JH5,H8 = 0.5, JH6,H7 = 7.0, JH6,H8 = 1.5, JH7,H8 = 8.2.
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-(4''-methoxy-
phenyl)-1',3'-thiazolidin 4'-one (4d).
S-Methyl 1-(9,10-dihydroacridin-9-ylidene)-4-methyl-isothio-
semicarbazide (3a).
Yield 74%; mp 282–284 °C (ethanol); Found: C, 66.27; H,
4.16; N, 13.19 C23H18N4O2S requires C, 66.65; H, 4.38; N,
13.52%; ꢀmax(KBr)/cm–1: 1600 (C=N), 1700 (C=O); JH,H couplings
(Hz) extracted by spin simulation [27]: JH1,H2 = 8.5, JH1,H3 = 1.5,
JH1,H4 = 0.5, JH2,H3 = 7.0, JH2,H4 = 1.2, JH3,H4 = 8.2, JH5,H6 = 8.2, JH5,H7
= 1.2, JH5,H8 = 0.4, JH6,H7 = 7.0, JH6,H8 = 1.5, JH7,H8 = 8.2.
Yield 76%; mp 190–192 °C (methanol); Found: C, 64.60; H,
5.12; N, 18.54. C16H16N4S requires C, 64.84; H, 5.44; N,
18.90%; ꢀmax(KBr)/cm–1: 1530 (C=N); 3a Z (major isomer,
83%). 3a E (minor isomer, 17%).
S-Methyl 1-(9,10-dihydroacridin-9-ylidene)-4-allyl-isothiosemi-
carbazide (3b).
General Procedure for the Preparation of 2'-(9,10-
Dihydroacridin-9-ylidene)hydrazono-3'-substituted-4'-imino-1',3'-
thiazolidines 5aꢀd and 4'-(9,10-Dihydroacridin-9-ylidene)-
hydrazono-2'-substituted imino-1',3'-thiazolidines 6aꢀd.
Yield 58%; mp 160–162 °C (methanol); Found: C, 67.39; H,
5.30; N, 17.49 C18H18N4S requires C, 67.05; H, 5.63; N, 17.38%;
ꢀmax(KBr)/cm–1: 1530 (C=N); 3b Z (major isomer, 91%). 3b E
(minor isomer, 9%).
Bromoacetonitrile (64 mg, 0.53 mmol) was added to a
solution of thiosemicarbazide 1 (0.53 mmol) in methanol (5 mL)
and the mixture left to stir for 2 h after which sodium methoxide
(0.029 g, 0.54 mmol) was added. The reaction mixture was then
left to stir for another 30 min before being poured into cold
water. The solid precipitate was collected by filtration, washed
with ether, dried, and crystallized from diethyl ether to afford 5
(which then subsequently isomerized in DMSO solution to 6).
S-Methyl 1-(9,10-dihydroacridin-9-ylidene)-4-phenyl-isothio-
semicarbazide (3c).
Yield 52%; mp 149–152 °C (diethyl ether); Found: C, 69.99;
H, 5.13; N, 15.75 C21H18N4S requires C, 70.36; H, 5.06; N,
15.63%; ꢀmax(KBr)/cm–1:1650 (C=N); 3c (major isomer, 60%).
3c (minor isomer, 40%).
General Procedure for the Preparation of 2'-(9,10-Dihydroacridin-9-
ylidene)hydrazono-3'-substituted-1',3'-thiazolidin-4'-ones 4aꢀd.
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-methyl-4'-imino-
1',3'-thiazolidine (5a).
Yield 60%; mp 232–235 °C (diethyl ether); Found: C, 63.30; H,
4.62; N, 21.53 C17H15N5S requires C, 63.53; H, 4.70; N, 21.79%.
To a solution of thiosemicarbazide 1 (0.54 mmol) in methanol
(5 mL), methyl bromoacetate (0.082 g, 0.051 mL, 0.54 mmol)

656
E. Balentová, J. Imrich, J. Bernát, L. Suchá, M. Vilková, N. Prónayová, P. Kristian,
K. Pihlaja and K. D. Klika
Vol 43
Spectrom., 18, 87ꢀ95 (2004).
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-allyl-4'-imino-
1',3'-thiazolidine (5b).
[10] K. D. Klika, E. Balentová, J. Bernát, J. Imrich, M.
Vavruꢀová, E. Kleinpeter, K. Pihlaja and A. Koch, J. Heterocyclic
Chem., 43 633 (2006).
[11] A. Albert and B. Ritchie, Org. Synth., 22, 5ꢀ8 (1942).
[12] C. L. Patel and H. Parekh, J. Ind. Chem. Soc., 65, 282ꢀ284
(1988).
Yield 29%; mp 261–263 °C (diethyl ether); Found: C, 65.34;
H, 4.62; N, 19.89. C19H17N5O requires C, 65.68; H, 4.93; N,
20.16%; JH,H couplings (Hz) extracted by spin simulation [27]:
JH1,H2 = 8.4, JH1,H3 = 1.2, JH2,H3 = 7.2, JH2,H4 = 1.2, JH3,H4 = 8.0,
JH5,H6 = 8.0, JH5,H7 = 1.2, JH6,H7 = 6.8, JH6,H8 = 1.0, JH7,H8 = 8.2.
[13] W. M. Cholody, M. F. Lhome and J. Lhomme, Tetrahedron
Lett., 28, 5029ꢀ5032 (1987).
[14] C. Pallerano and L. Savini, Farmaco, 39, 681ꢀ685 (1984).
[15] K. D. Klika, J. Imrich, M. Vilková, J. Bernát and K. Pihlaja,
J. Heterocyclic Chem., 43, 739 (2006).
[16] F. Duus, in Thioureas and Thiosemicarbazides in
Comprehensive Organic Chemistry (ed. D. Barton and W. D. Ollis),
Pergamon Press, Oxford, 1979, pp 452ꢀ461.
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-phenyl-4'-imino-
1',3'-thiazolidine (5c).
Yield 78%; mp 132–134 °C (diethyl ether); Found: C, 68.73;
H, 4.28; N, 18.45 C22H17N5S requires C, 68.91; H, 4.47; N,
18.26%.
[17] U. Kraatz, in Thiosemicarbazide in Methoden der
Organischen Chemie (Houben-Weyl), G. Thieme Verlag, Stuttgart,
1983, vol. 4, pp 506ꢀ515.
2'-(9,10-Dihydroacridin-9-ylidene)hydrazono-3'-(4''-methoxy-
phenyl)-4'-imino-1',3'-thiazolidine (5d).
[18] K. A. Jensen, U. Anthoni, B. Kägi, Ch. Larsen and C. Th.
Pedersen, Acta Chem. Scand., 22, 1ꢀ50 (1968).
Yield 75%; mp 250–253 °C (diethyl ether); Found: C, 66.43;
H, 4.39; N, 16.59 C23H19N5OS requires C, 66.81; H, 4.63; N,
16.94%.
[19] K. D. Klika, E. Balentová, J. Bernát, J. Imrich, E. Kleinpeter,
A. Koch and K. Pihlaja, submitted to Chem. Eur. J., (2005).
[20] F. C. Brown, Chem. Rev., 61, 463ꢀ521 (1961).
[21] S. P. Singh, S. S. Parmar, K. Raman and V. I. Stenberg,
Chem. Rev., 81, 175ꢀ203 (1981).
[22] G. R. Newkome and A. Nayak, Adv. Heterocycl. Chem., 25,
83ꢀ112 (1979).
[23] I. Géci, P. Valtamo, J. Imrich, H. Kivelä, P. Kristian and K.
Pihlaja, J. Heterocycl. Chem., 42, 907ꢀ918 (2005).
[24] M. Demeunynck, F. Charmantray and A. Martelli, Curr.
Pharm. Design, 7, 1703ꢀ1724 (2001).
Acknowledgements.
Financial support from the Slovak grant agency VEGA, grant
no. 1/2471/05 (J. I. and P. K.); the Slovak Ministry of Education,
International project SK-FIN (J. I. and P. K.); the Academy of
Finland, grant no. 4284 (K. P.); and CIMO (E. B.), is gratefully
acknowledged. The authors are also grateful to Jana Baranová
for assistance with the synthetic work.
[25] M. F. Braña, M. Cacho, A. Gradillas, B. de Pascual-Teresa
and A. Ramos, Curr. Pharm. Design, 7, 1745ꢀ1780 (2001).
[26] H. Suzuki and Y. Tanaka, J. Org. Chem., 66, 2227ꢀ2231
(2001).
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*) Part 2. For Part 1 see the preceding article (ref [10]). **)
Corresponding author.
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