Spontaneous cyclization of (acridin-9-ylmethyl)thioureas to spiro [dihydroacridine-9′(10′H),5-imidazolidine]-2-thiones, a novel type of acridine spirocycles

Accepted Manuscript

Spontaneous cyclization of (acridin-9-ylmethyl)thioureas to spiro

[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones, a novel type of acridine

spirocycles

Mária Vilková, Marianna Prokaiová, Ján Imrich

PII:

S0040-4020(13)01838-3

10.1016/j.tet.2013.12.001

TET 25082

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 15 July 2013

Revised Date: 18 November 2013

Accepted Date: 2 December 2013

Please cite this article as: Vilková M, Prokaiová M, Imrich J, Spontaneous cyclization of (acridin-9-

ylmethyl)thioureas to spiro [dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones, a novel type of acridine

spirocycles, Tetrahedron (2014), doi: 10.1016/j.tet.2013.12.001.

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Spontaneous cyclization of (acridin-9-ylmethyl)thioureas

to spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thiones, a novel type of acridine spirocycles

Leave this area blank for abstract info.

Mária Vilková, Marianna Prokaiová, and Ján Imrich

P. J. Safarik University, Faculty of Science, Department of Organic Chemistry,

Moyzesova 11, SK-041 67 Kosice, Slovak Republic

S

R

S

R

O

R

R²

R¹

NH

N

NH

N

R²

N

R²

R¹

N

R¹

MNO

Alkyl/aryl-ITC

rt, 0-30

min

acetonitrile,

rt, 6 h

chloroform, rt, 6 h

N

H

N

H

R²= CH₃, allyl, Ph, 4-CH₃O-Ph, 4-Br-Ph, 4-F-Ph, 4-NO₂-Ph, acridin-9-yl

R = H, n-Pr, Bn

R¹= H, CH₃

ACCEPTED MANUSCRIPT

1

Tetrahedron

journal homepage: www.elsevier.com

Spontaneous cyclization of (acridin-9-ylmethyl)thioureas to spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-thiones, a novel type of acridine spirocycles

Mária Vilková, Marianna Prokaiová, and Ján Imrich

P. J. Safarik University, Faculty of Science, Department of Organic Chemistry, Moyzesova 11, 041 67 Kosice, Slovak Republic

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

Novel acridine spirocompounds, spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

thiones have been prepared by the spontaneous cyclization of 1-substituted 3-(acridin-9-

ylmethyl)thioureas, which were obtained from 1-(acridin-9-yl)methanamine, N-(acridin-

9-ylmethyl)propan-1-amine, and N-(acridin-9-ylmethyl)benzylamine and alkyl/aryl

isothiocyanates, as continuation of our previous studies on new acridine spirocycles.

Imidazolidine-2-thiones thus obtained were subsequently transformed with mesitylnitrile

oxide to imidazolidine-2-one analogues, some of which partly reopened to the

Available online

Keywords:

acridine

urea

thiourea

spiro

corresponding (acridin-9-ylmethyl)ureas. An unusual spirocyclization via

a CH

carbanion instead of the N-1 nitrogen has been found for 3-(acridin-9-ylmethyl)-1-

(acridin-9-yl)thioureas possessing two acridine rings. Structural modifications in

1

positions 1, 3, and 4 of the spiroring together with H, ¹³C, and ¹⁵N NMR spectroscopy

and X-ray crystallography have been employed to rationalize a general propensity of

various 9-substituted acridines to undergo easy spirocyclization.

imidazolidine

¹⁵N NMR

———

Corresponding author. Tel.: +421-55-2342334; e-mail: jan.imrich@upjs.sk

ACCEPTED MANUSCRIPT

2

Tetrahedron

1. Introduction

dihydroacridin-9-yliden)-2-methylthiosemicarbazide (9) (Scheme

1).^16,20

Acridine derivatives originally developed as pigments and

H₂N

H₃C

S

N

H₂N

CH₃

N

dyestuffs are regarded currently as potent fluorescent,

intercalating, and antitumor agents.¹⁻⁵Many have been tested

against bacteria,⁶prions,⁷viruses including HIV,⁸protozoa,⁴and

other microorganisms.⁹Biological activity shown by acridine

derivatives emphasizes the importance of the synthesis of new

acridine-based structures. In our previous studies we have

described numerous syntheses of novel spiro acridine compounds

from acridin-9-ylthiocarbamates, dithiocarbamates, 2-(acridin-9-

ylthiocarbamoyl)malonic acid diethyl esters, di- and

trisubstituted thioureas, and thiosemicarbazides, in which the

thiourea moiety was either directly or via a methylene bridge

attached to the position 9 of the acridine skeleton. As products of

these spirocyclizations, we obtained only five-membered rings

attached to C-9 of the 9,10-dihydroacridin-9-ylidene moiety,

namely 5-substituted-2-alkoxy- 1^10,11and 2-aminothiazolines

2¹²,3,^13,142-alkylidenethiazolidines 4,¹⁵1,2-disubstituted-1,2,4-

triazolidine-3-thiones 5,^16,176,¹⁸and imidazolidine-2-thiones 7¹⁹

(Fig. 1). These papers highlighted a particular susceptibility of

the acridine C-9 carbon to an intramolecular nucleophilic attack

and subsequent ready formation of the five-membered spiroring

attached to acridine. However, when acridine was replaced by

1,2,3,4-tetrahydroacridine, no spirocycle 2 but its thiazolidinone

analogue has been formed.¹²

N

S

CH₃

N

S

HN

NH

N

H

N

H

N

H

8

9

5

Scheme 1. Atypical ring-opening of spiro[dihydroacridine-9'(10'H),5-1,2,4-

triazolidine]-3-thione.

When the reagent contained a reactive cyano group, we have

observed three consecutive reactions in one pot leading to a new

pentacyclic heterocycle, spiro[dihydroacridine-9(10H),2'-(2',7'-

dihydro-3'H-imidazo[1,2-c]thiazol-5'-ylidene-(acridin-9-yl/p-

nitrophenyl)amine] 11 (Scheme 2).^19,21

Ar

H

S

N

S

N

Ar

N

NH

N

BrCH₂CN

N(Et)₃

N

H

Ar = acridin-9-yl

Ar = 4-nitrophenyl

11^19,21

10

R¹

¹X

N

RR¹N

R

S

Scheme 2. The formation of novel pentacyclic spiro dihydroacridines.

N

HN

COOR²

R

N

COOMe

R

CH₃

N

H

N

H

N

H

3^13,14

1^10,11

2¹²

ZnCl₂,CH₃COOH

220 °C, 6 h

NBS, AIBN

tetrachlormethane

80 °C, 6 h

R = H

R¹

R = COOMe, CN

R = H, Me, Cl

¹= R²= Me, Et

X = O¹⁰, S¹¹

NH

N

R¹= Bn, i-Pr, c-hexyl, t-Bu

=

Bn, n-Bu, i-Pr,

2-furfurylmetyl, c-hexyl

13

R

12

Br

NH₂.2HCl

urotropin

1) aq. Na₂CO₃, benzene

(EtOOC)₂

C

S

R

chloroform, rt, 24 h

2) isothiocyanates 16a-f

benzene, rt, 12-24 h

,

CH₃

N

S

NH

N

14

15.2HCl

R¹

N

R¹

CH₃

HN

N

R

S

NH

N

18a: R = CH₃, R' = COOCH₃

18b: R = Ph, R' = COOCH₃

N

H

4¹⁵a-f

N

H

6¹⁸

N

H

5^16,

NH

HN

S

18c: R = 4-CH₃O-Ph, R' = COOCH₃

18d: R = 4-Br-Ph, R' = COOCH₃

18e: R = 4-NO₂-Ph, R' = COOCH₃

18f: R = CH₂=CH-CH₂, R' = COOCH₃

BrCH₂COOCH₃

or

BrCH₂CN

17

R'

R = H, Me, Ph

R¹= H, Me,Ph

R = H, 2-Me, 2-Br

R¹= COOMe, CN

TEA, benzene, rt

N

17a-f

N

H

19a: R = CH₃, R' = CN

19b: R = Ph, R' = CN

19c: R = 4-CH₃O-Ph, R' = CN

19d: R = 4-Br-Ph, R' = CN

19e: R = 4-NO₂-Ph, R' = CN

18a-f

19a-f

19f: R = CH₂=CH-CH₂, R' = CN

H

N

S

Scheme 3. The synthetic strategy to prepare six-membered 9-acridinyl spiro

compounds 18,19.

HN

The shown examples demonstrate that spirocyclization is a

general propensity of suitably substituted 9-acridinyl compounds

that leads to new interesting orthogonal molecules. In the current

work we originally intended to obtain novel six-membered spiro

acridine compounds 18a−f, 19a−f, for which interesting

biological activity could be anticipated, by the reaction of new

(acridin-9-ylmethyl)thioureas 17a−f with bifunctional reagents

based on acetic acid (Scheme 3). The intended role of the

methylene group inserted between the C-9 carbon of acridine and

the thiourea moiety was to decrease the spirocyclization tendency

of intermediate thioureas 17a−f to allow them to transform to the

desired six-membered thiazines 18, 19 by the reaction with

N

H

7¹⁹

Fig. 1. Structures of 9,10-dihydroacridine spirocompounds 1−7 prepared in

our laboratory.

In the spirocyclization of 4-(9,10-dihydroacridin-9-ylidene)-2-

methylthiosemicarbazide (8) we have also observed an atypical

rearrangement of primarily formed 2-methyl

spiro[dihydroacridine-9'(10'H),5-1,2,4-triazolidine]-3-thione (5)

which underwent unexpected ring-opening of the cycle through

splitting the former C-9'–N bond to give rearranged 1-(9,10-

a

ACCEPTED MANUSCRIPT

3

methyl bromoacetate or bromoacetonitrile. For this purpose, we

have prepared three sets of starting compounds comprising

spirocarbons, C-5,9', in the range 66.5−69.4 ppm. For the

explicit presence of a thiocarbonyl group, the resonance of ¹³C

signals of the 2-C=S group between 179.4–181.7 ppm was highly

disubstituted

3-(acridin-9-ylmethyl)-1-alkyl-

or

-1-(4-X-

phenyl)thioureas, trisubstituted 3-(acridin-9-ylmethyl)-3-(n-

indicative (Table 2). In the spirocycles 20a−f, a new

propyl or benzyl)-1-alkyl- or -1-(4-X-phenyl)thioureas, and 3-(1-

imidazolidine-2-thione ring formed by cyclization is orthogonal

to a dihydroacridine skeleton arising from acridine, preserving

thus a symmetry of flanking benzene rings in the latter. The

assignment of chemical shifts of H-1'–H-8' acridine protons in

the thiones 20a−f was based on the NOESY correlations between

a signal of the acridine proton NH-10' with H-4',5' signals and

subsequent COSY and TOCSY correlations starting from these

protons. Proton signals in the phenyls were assigned using the

NMR increments of para-substituents on benzene. On the top,

gHSQC and gHMBC experiments, which involved adiabatic

pulses, enabled reliable assignments of all carbon signals. In the

acridine ring, the signals of protons (6.74−6.90 ppm) and carbons

(113.9−114.7 ppm) in the 4',5' positions were the most shielded

due to +M effect of the NH-10' group. The spirocyclic structure

was also evidenced by signals of the bridge dihydroacridine C-

4'a,10'a carbons in a typical region 137−139 ppm,^10-18which

contrasted with those of aromatic acridines around 150 ppm.

(acridin-9-yl)ethyl)-3-(n-propyl)-1-(4-X-phenyl)thioureas.

We

have found, however, that also these thioureas rapidly

spirocyclized via the acridine C-9 carbon and therefore we

decided to elucidate the kinetics and selectivity of these

cyclizations to shed more light on the forces driving the

formation of these novel acridine spirocycles.

2. Results and discussion

2.1. 3-(Acridin-9-ylmethyl)-1-alkyl/arylthioureas 17a−f, 1-

alkyl/aryl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

thiones 20a−f, 1-alkyl/aryl-spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-ones 21a−f, and 3-(acridin-9-ylmethyl)-1-(4-

X-phenyl)ureas 22b−e

An initial substrate for the series of compounds I and II from

this study, 1-(acridin-9-yl)methanamine dihydrochloride²²

(15.2HCl) was prepared from 9-(bromomethyl)acridine²³(14),

which was obtained from diphenylamine (12) via 9-

methylacridine²³(13) (Scheme 3). We have improved the yield of

13 to 73% by its extraction into n-heptane instead of original

benzene. The heptane extract contained only the expected

product unlike the benzene extracts, which were contamined by

black resinous by-products. The synthon 13 reacted with N-

Interestingly,

no thiazolidine

products

of

potential

spirocyclization on C-9 via the thiourea sulfur atom have been

observed in the crude reaction mixture confirming that C-9

carbon as a hard electrophile has a greater affinity to a harder

nitrogen than softer sulfur nucleophile.

The cyclization rate was significantly influenced by the

character of a N-1 phenyl substituent. The cyclization of the

intermediate thiourea 17e to the spiroproduct 20e is a charge-

controlled reaction as indicated by significant charge values on

the reacting centers. E.g., at the B3LYP/6-311++G(2d,2p) level

of theory, the charge on N-1 was calculated to be −0.1947 e and

that on C-9' to be +0.6784 e. The negligible contributions of the

corresponding HOMO and LUMO orbitals of 2p_zfor N-1/C-9'

(0.0335 and 0.1295 occupancy values, respectively) also allude

to this notion. Repeated attempts to isolate pure thioureas 17a−f

always afforded mixtures of 17a−f and spirocycles 20a−f in

various ratios. To elucidate the relation between the structure and

reactivity of thioureas, we followed the kinetics of the reaction of

1-(acridin-9-yl)methanamine (15) with selected isothiocyanates,

phenyl (16b), 4-methoxyphenyl (16c), and methyl (16a), by

bromosuccinimide

and

azobisisobutyronitrile

in

tetrachloromethane under irradiation by a halogen lamp over 6 h

at 80 °C to give 80% of the bromide 14 which was further

transformed by a Delepine reaction to the amine 15.2HCl in 78%

yield. The free base 15, which was liberated from 15.2HCl by

treatment with aqueous sodium carbonate, was allowed to react

with a set of isothiocyanates RNCS (R = (a) methyl, (b) phenyl,

(c) 4-methoxyphenyl, (d) 4-bromophenyl, (e) 4-nitrophenyl, and

(f) allyl) in benzene at room temperature to form intermediate 3-

(acridin-9-ylmethyl)-1-substituted thioureas 17a−f (Scheme 4).

S

1

3

HN

R

H

N

1

monitoring product distribution vs. time in the H NMR spectra.

NH

N

Data shown in Fig. 2 were obtained by integration of the CH₂

proton signals of the amine 15, thioureas 17b, 17c, 17a, and

spirocompounds 20b, 20c, 20a, respectively, in the NMR spectra

of the reaction mixtures. In the reaction of 15 with phenyl

isothiocyanate, the starting amine 15 was consumed over 30 min

leaving the mixture of the thiourea 17b (80%) and the partially

formed spirocompound 20b (20%). Complete transformation to

20b proceeded much more slowly and the thiourea 17b was

depleted after 40 h. In the reaction with 4-methoxyphenyl

isothiocyanate (16c) with a weaker electrophilic character, the

reaction speed decreased several times when the amine 15 was

spent in 3 h, while the cyclization of the thiourea 17c to the

spiroproduct 20c was somewhat faster than before (27 h). The

slowest was the addition of methyl isothiocyanate (16a), in which

the starting amine 15 was reacting for two days and full

transformation to the spiroproduct 20a took more than 50 h. It

was found, in general, that spirocyclizations of 17 to 20 were

completed during 30−50 hrs indicating that the spirocyclization

rate was not very dependent on the isothiocyanate character,

R

1) aq. Na₂CO₃, benzene

2) isothiocyanates

15.2HCl

N

H

16a-f

,

benzene, rt, 12-24 h

17a-f

20a-f

O

2

1´´

R

O

H

N

a: R = CH₃

HN₃

4

NH

1

3

2

b: R = Ph

1´´

R

1´

4

¹N

8´

5´

c: R = 4-CH₃O-Ph

d: R = 4-Br-Ph

e: R = 4-NO₂-Ph

8´a

9´a

9´

2´

3´

MNO

7´

acetonitrile _6´

40 °C, 12 h

4´a

10´a

f: R = CH₂=CH-CH₂

N

4´

H

10´

22b-e

21a-f

Scheme 4. Synthesis of 1-substituted spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-thiones 20a–f and corresponding 2-ones 21a–f. In the case

of the phenyl derivatives b−e, varying amounts of the open urea forms 22b−e

were also formed.

They proved to be very unstable and spontaneously cyclized

in solution in tens of minutes to the corresponding isomeric 1-

substituted

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

unlike the first step, where

a strong influence of the

thiones 20a−f (Series I) in yields 57%–71% after crystallization

(the yields are related to the starting amine 15). The formation of

the spiro imidazolidines 20a−f was evident in the NMR spectra

(Table 1, 2) from a new signal of quaternary, sp³hybridized

isothiocyanate electrophilicity had been noted. (Fig. 2c)

ACCEPTED MANUSCRIPT

4

Tetrahedron

a)

ones 21a–f was found compared to the thiones 20a–f, while

chemical shifts of imidazolidine NH-3 protons decreased by 1.5–

1.8 ppm. The 4-methylene group of imidazolidine-2-thiones 20

had ¹H (¹³C) signals at 3.62−3.87 ppm (62.3−62.5 ppm) for alkyl

derivatives a,f and 4.08−4.25 ppm (62.5−63.1 ppm) for phenyl

derivatives b−e (Table 1, 2). Upon replacement to their 2-oxo

1

analogues 21, methylene H chemical shifts decreased by about

0.3−0.7 ppm to 3.37−3.56 ppm (a,f) and 3.54−3.64 ppm (b−e),

and methylene ¹³C chemical shifts also decreased by about 3 ppm

to 58.9−59.8 ppm (a−f). As can be seen, ¹H chemical shifts of 4-

CH₂were different with 1-alkyl vs. 1-aryl substituents, but ¹³C

ones not. Surprisingly, the 4-CH₂ring protons became more

shielded in 4-nitrophenyl derivatives 20e (4.08 ppm), 21e (3.54

ppm) than in 4-methoxy derivatives 20c (4.25 ppm), 21c (3.64

ppm), which is evidence of a cross-conjugation within the

imidazolidine-2-(thi)ones. These observations show a weaker

electronacceptor effect of the 2-oxo group compared to the 2-

thione group. The effect of S→O replacement was transferred

also to a N-1-phenyl ring, where ortho H-2'',6'' protons in the

ones 21b−21e were more deshielded (6.76–7.46 ppm) than in the

thiones 20b−20e (6.43−7.04 ppm), due to a 2-carbonyl magnetic

anisotropy, while attached carbons C-2'',6'' became more shielded

(120.2–125.6 ppm) in the ones than in the thiones (128.9–130.8

ppm), due to a weaker withdrawing effect of the carbonyl group.

Small changes in chemical shifts have been observed for the

other close protons and carbons in positions 1',8' and 8'a,9'a of

dihydroacridine because of different anisotropic effects of the

C=S versus C=O group.

b)

c)

The fraction of the urea form 22b−22e in the reaction mixture

increased in repeated experiments with extended reaction time,

raised temperature, and stronger electronacceptor character of the

para substituents on the 1-phenyl ring. Thus, the p-nitrophenyl

urea derivative 22e was found as the exclusive product after

extended reaction time. It may be assumed that aromatic ureas

22b,d,e are preferred thermodynamic products of this reaction

besides 22c (p-methoxyphenyl), in which the spiroform always

prevailed. On the other hand, with alkyl spiroderivatives, methyl

(21a) and allyl (21f), the conversion to ureas did not occur under

mild conditions, perhaps due to +I effect of the 1-substituents.

The most distinct NMR differences between the spiro and urea

structures were as follows (Tables 1, 2):

Fig. 2. The course of the reaction of 1-(acridin-9-yl)methanamine (15) with a)

phenyl isothiocyanate, b) 4-methoxyphenyl isothiocyanate, and c) methyl

isothiocyanate in CDCl₃monitored by ¹H NMR. Percentages of the amine 15

(♦), thioureas 17b, 17c, 17a (■), and spirocompounds 20b, 20c, 20a (▲) are

plotted vs. time.

a) in ureas 22b,d,e, the acridine C-9' carbon signals at 142.1–

143.9 ppm were restored, instead of the sp³spirocarbons of 21 at

63.0 ppm,

1

b) H chemical shifts of all acridine protons in ureas 22b−e were

strongly deshielded by 0.7–1.3 ppm compared to the respective

dihydroacridine protons of the spirocompounds 21b−e, due to the

withdrawing character of the aromatic acridine structure, unlike

Pure isolated spiro-2-thiones 20a−f were quantitatively

converted into the corresponding spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-ones 21a–f by treatment with

9,10-dihydroacridine, whose NH-10' group is

electrons into the flanking acridine rings,

a donor of

mesitylnitrile oxide (MNO),

a reagent specific for the

transformation of a thiocarbonyl group into a carbonyl (Scheme

4). Interestingly, the equilibrium open-chain − spiro did not

totally favor the spiroform once replacement of sulfur by oxygen

had occurred in the phenyl derivatives, but the spiroproducts

21b−e reopened partly to the ureas 22b−e in varying amounts. In

a shorter reaction time, sufficient amounts of the urea to enable

characterization were present only in the case of the phenyl

(1.12:1.0) and 4-bromophenyl derivative (4.9:1.0). Again, the

identification of the spiroderivatives 21 was readily evident by

the resonance of a quaternary sp³hybridized carbon, C-5,9', in

the range 61.7–63.0 ppm and the carbonyl resonance between

157.9–160.8 ppm (Table 2). Transformation of the 2-C=S to 2-

C=O group caused a drop in chemical shifts of atoms close to the

carbonyl: for spirocarbons C-5,9', a decrease of 5–6 ppm in the

c) the protons of the 4-CH₂group of the spiro ones 21b−e, which

are fixed above the flanking benzene rings of the dihydroacridine

due to its orthogonal orientation toward imidazolidinone, were

strongly shielded by ring currents of these benzenes to 3.54–3.64

ppm in contrast with deshielded, freely rotating 4-methylene

protons in ureas 22b−e (5.32–5.37 ppm),

d) on the other hand, carbons of the 4-CH₂group in the spiro-

structures were strongly deshielded (59.5–59.8 ppm) due to in-

plane deshielding by flanking rings compared to ureas (34.4–35.1

ppm).

ACCEPTED MANUSCRIPT

5

Table 1

¹H chemical shifts of 1-alkyl/aryl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-(thi)ones 20–21 and 3-(acridin-9-ylmethyl)-1-aryl-ureas 22 (Series I)

Dihydroacridine

Spiro ring

1-Me, 1-Ph, or 1-allyl (R)

R

1'8'

2'7'

3'6'

4'5' NH-10' NH-1 NH-3 CH₂-4

1''

2'' 6''

3'' 5''

4''

MeO

Imidazolidine-2-thiones (Acr-CH₂-NH-CS-NR-)

20a ^aCH₃

7.12 6.79 7.08 6.77

7.09 6.91 7.36 6.90

7.54 6.96 7.19 6.75

7.98

9.40

9.22

8.99

9.29

9.42

9.45

6.86

8.39

8.86

8.56

9.00

9.36

8.49

3.68

3.62

4.14

4.25

4.15

4.08

3.87

2.71

2.61

-

20a

20b

20c

20d

20e

20f

CH₃

Ph

-

6.54

6.43

6.48

7.04

7.00

6.48

7.23

7.94

7.00

-

4-CH₃O-Ph 7.60 6.95 7.16 6.74

-

3.61

4-Br-Ph

4-NO₂-Ph

allyl

7.51 7.00 7.21 6.77

7.44 6.93 7.22 6.84

7.24 6.91 7.22 6.88

-

3.74 5.31^b4.59, 4.62^c

Imidazolidine-2-ones (Acr-CH₂-NH-CO-NR-)

21a

21b

21c

21d

21e

21f

CH₃

Ph

7.19 6.91 7.21 6.90

7.29 6.83 7.16 6.87

9.30

9.34

9.27

9.39

9.53

9.31

6.58

7.20

7.05

7.35

7.76

6.67

3.37

3.57

3.64

3.54

3.56

2.36

7.02

6.76

7.02

7.46

7.02

6.59

7.22

7.95

6.89

6.85

4-CH₃O-Ph 7.38 6.86 7.16 6.82

3.57

4-Br-Ph

4-NO₂-Ph

allyl

7.23 6.83 7.18 6.89

7.16 6.83 7.20 6.95

7.32 6.88 7.19 6.85

3.39 5.35^b4.66, 4.71^c

Ureas (Acr-CH₂-NH-CO-NHR)

22b

22c

22d

22e

Ph

8.59 7.71 7.88 8.19

8.32

8.10

8.48

9.09

nd^d

6.70

nd

5.36

5.32

5.36

5.37

7.36

7.24

7.35

7.58

7.21

6.77

7.35

8.11

4-CH₃O-Ph 8.57 7.68 7.85 8.16

4-Br-Ph

3.66

8.60 7.72 7.90 8.19

8.57 7.70 7.86 8.17

4-NO₂-Ph

7.16

^aMeasured in CDCl₃; ^bδ (CH=); ^cδ (=CH₂); ^dnot determined.

Table 2

¹³C chemical shifts of 1-alkyl/aryl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-(thi)ones 20–21 and 3-(acridin-9-ylmethyl)-1-aryl-ureas 22 (Series I)

Dihydroacridine

3'6' 4'5' 8'a9'a 4'a10'a

Spiro ring

2-C=X CH₂-4

1-Me, 1-Ph, or 1-allyl (R)

2''6'' 3''5'' 4''' MeO

R

1'8'

2'7'

9'

1''

Imidazolidine-2-thiones (Acr-CH₂-NH-CS-NR-)

20a ^aCH₃

126.8 120.5 128.7 114.0 119.0

127.0 120.8 129.4 114.7 119.6

127.9 120.0 129.0 114.0 119.9

137.6

138.4

137.2

137.5

137.3

137.2

137.6

67.7

67.4

68.8

69.1

68.8

69.4

66.5

181.4

181.7

179.6

179.8

179.4

179.7

179.8

62.1

62.5

62.7

62.5

63.1

62.3

29.8

29.9

20a

20b

20c

20d

20e

20f

CH₃

Ph

137.3 128.9 127.5 126.4

4-CH₃O-Ph 128.9 120.0 128.9 114.1 119.9

130.8 130.6 112.8 157.8 54.9

137.7 130.8 130.6 119.5

144.9 129.3 122.9 144.5

4-Br-Ph

4-NO₂-Ph

allyl

127.7 120.1 129.1 114.0 119.5

127.2 120.4 128.1 114.3 119.3

127.6 119.9 128.9 113.9 119.6

46.3

134.1 115.6

Imidazolidine-2-ones (Acr-CH₂-NH-CO-NR-)

21a

21b

21c

21d

21e

21f

CH₃

Ph

126.2 120.0 128.3 114.0 119.9

126.4 120.0 128.4 114.0 121.1

138.3

137.4

137.5

137.9

61.7

63.0

61.7

160.8

158.7

158.8

158.4

157.9

160.1

58.9

59.8

59.6

59.5

59.3

25.5

138.0 122.8 127.7 122.9

130:7 125.6 113.0 155.5 54.8

137.5 124.1 130.6 120.6

144.4 120.2 123.6 141.0

4-CH₃O-Ph 127.0 119.9 128.4 113.9 121.2

4-Br-Ph

4-NO₂-Ph

allyl

126.3 120.1 128.6 114.1 119.5

125.5 120.3 128.8 113.9 120.1

127.3 119.7 128.4 113.7 120.7

43.4

135.2 115.2

Ureas (Acr-CH₂-NH-CO-NHR)^b

22b

22d

22e

Ph

4-Br-Ph

4-NO₂-Ph

124.9 126.2 130.1 129.6 124.4

125.0 126.3 130.6 128.6 124.4

125.4 126.8 130.7 130.2 125.0

148.2

nd

148.8

142.1 154.7

143.9 154.7

142.1 154.6

34.4

34.5

35.1

140.0 117.6 128.6 121.2

139.4 119.5 131.3 120.1

147.2 117.4 125.6 141.1

^aMeasured in CDCl₃. ^bThe spectrum of 22c could not be measured due to low concentration.

believed to enhance stacking interactions of our products,

which could interact as ligands with the aromatic parts of

aminoacids or nucleic acids in target biopolymers. We also

hoped that introduction of the donor n-propyl substituent to the

vicinity of C-9' carbon could diminish its electrophilicity,

rendering thus a slower spirocyclization to receive isolable

thioureas. To obtain addition products, isothiocyanates 16a−c,e

and 4-fluorophenyl isothiocyanate in chloroform were added to

a chloroform solution of the amines 23 or 24, the reaction

mixture was stirred at room temperature for 6 h to give target

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones

27a−e in yields 40−85% and 28a−e in yields 49−62% (Scheme

5). NMR monitoring showed that no signals of the

intermediate phenyl thiourea 25b was present in the crude

reaction mixture even 5 min after the start of the reaction, thus

confirming a much faster spirocyclization than in the series I.

This finding may be explained by the enhanced reactivity of

2.2 1-Alkyl/aryl-3-(n-propyl/benzyl)-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-thiones 27a–e and 28a–e and

their oxo analogues 29a–e and 30a–e

In continuation, we were interested in whether structural

modification of the starting amine could stabilize intermediate

thioureas and slow down their transformation to spiroproducts.

We therefore carried out a substitution of one amino proton in

15 with a n-propyl or benzyl substituent to obtain new starting

sec-amines, N-(acridin-9-ylmethyl)propan-1-amine²⁴(23) and

N-(acridin-9-ylmethyl)benzylamine²⁴(24) (Scheme 5, Series

II). For their synthesis, 9-(bromomethyl)acridine was stirred

with n-propylamine or benzylamine in diethyl ether for 30 h at

room temperature to give 23 and 24 in yields after

chromatographic purification of 70% and 56%, respectively.

The former amine was expected to enhance the lipophilicity of

the compounds under study, which could improve their

biological accessibility, whereas Bn in the latter one was

ACCEPTED MANUSCRIPT

6

Tetrahedron

the thiourea moiety due to its increased nucleophilicity

H

induced by the donor n-propyl substituent, not by the

diminished electrophilicity of the C-9 acridine carbon. In order

to prepare the oxo analogues of the spiroproducts, solid MNO

was added at once to a solution of spiro products 27a−e, 28a−e

H

4´´

H

3´´

H

2´´

1´´

2´´

S

6´´

H

1´´

N

H

S

4´´´

3´´´

H

6

N

H

S

H

2

1´´´

H

3

R

NH

R

R¹

4

1

H

8´

N

Br

5

2´´´

N

NH

H

9´

1´

N

R-NH₂

H

R-NCS

5´

H

10´

4´

H

chloroform, rt, 6 h

N

H

Et₂O, 30h, rt

N

23, 24

23: R = n-Pr

25a-f

26a-f

14

24: R = CH₂Ph

R

S

R

O

Fig. 3. HMBC transfers in spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-thiones 27b (Pr) and 28b (Bn).

N

a: R¹

b: R¹

c: R¹

d: R¹

e: R¹

=

CH₃

R¹

N

MNO

=

Ph

these of C-5,9' by 2−3 ppm, as expected for the negative γ-

effect, but, interestingly, ¹³C chemical shifts of 2-C=X in the

close β-position did not change at all (Tables 4, 5). Upon

change of the thiones 27, 28 to the oxo derivatives 29, 30,

chemical shifts of the C=S carbons between 179.2−181.2 ppm

decreased strongly to 156.4−159.9 ppm and this change

influenced also the chemical shifts of α-protons and carbons of

acetonitrile

rt, 6 h

4-CH₃O-Ph

4-F-Ph

4-NO₂-Ph

Acr

N

H

N

H

: R = Pr

f

:

R¹

: R = Pr

27a-e

28a-e: R = Bn

29a-e

30a-e: R = Bn

Scheme 5. Synthesis of N-(acridin-9-ylmethyl)propan-1-amine (23) and N-

(acridin-9-ylmethyl)benzylamine (24) from the bromide 14 and their

n-Pr and

Bn

(0.96)

11.8

reactions

with

isothiocyanates

to

give

1,3-disubstituted-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones 27a–f, 28a−f via

non-isolable thioureas 25a−f, 26a−f and corresponding 1,3-disubstituted-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-ones 29a–f, 30a−f.

(1.72)

20.2

(6.98)

127.0

S

(3.74)

48.7

(6.98)

128.1

-267.1

N

139.4

(7.45)

in dry acetonitrile and the reaction mixture was left to stir for 6

179.3

(6.49)

129.7

h

at room temperature to give spiro[dihydroacridine-

(4.26)

67.4

128.4

-220.6N

9'(10'H),5-imidazolidine]-2-ones 29a−e, 30a−e in yields 42%–

84% and 53%–79%, respectively.

66.2

120.3

138.1

-284.3

120.6

129.5

(6.94)

The spiro C-9' carbon signals in the thione products 27a−e,

28a−e between 64.8−66.9 ppm and in the oxo products 29a−e,

30a−e between 59.4−61.6 ppm were more shielded than those

in our previous spiroacridine structures (Table 3).

(7.17)

N

114.6

(6.72)

H

(9.21)

(0.87)

11.2

Table 3

¹³C chemical shifts of C-9' in our former studies

(1.49)

20.1

(6.84)

123.0

O

(3.26)

44.5

Compound

R

R1

δ (C-9')

Ref.

(7.01)

127.8

-298.4

N

138.3

(7.25)

157.2

COOMe, CN t-Bu 81.2-81.3 13,14

COOMe, CN

3

4

5

7

(7.01)

122.8

H

70.3-70.6

74.2

75.1

82.2

69.3

15

16

19

(3.62)

64.1

126.5

nd

N

Me

Ph

H

60.6

120.1

128.6

(6.82)

121.0

Ph

137.6

(7.16)

-284.7

N

114.1

(6.87)

H

(9.35)

Assignments of the chemical shifts of the acridine protons in

the thiones 27a−e, 28a−e were again based on NOESY

correlations between a signal of NH-10' and those of H-4',5'

and subsequent COSY or TOCSY correlations with the latter

ones. Assignments of benzyl protons started from ortho

protons which were identified by NOESY cross-peaks with

benzyl methylene protons. Concerning the spiroring, the

magnetization was transferred from 1''-(α)-methylene protons

of propyl or benzyl to the imidazolidine 2-C=S and C-4

carbons in the HMBC spectra, whereas transfers to spiro C-9'

carbon emerged from acridine H-1',8' and imidazolidine 4-CH₂

protons. The magnetization from the 4-CH₂protons was

transferred also to 2-C=S, C-9', and the acridine bridge C-

8'a,9'a carbons (Fig. 3). Replacement of H on N-3 by n-Pr or

Bn raised the ¹³C chemical shifts of 4-CH₂by 4−5 ppm, i.e.

less than the usual β-effect of carbon (9.4 ppm), and lowered

Fig. 4. Chemical shifts of representative compounds 27b and 29b.

substituents, which were upfield shifted by about 0.4−0.7 ppm

and 3−4 ppm, respectively, in the oxo analogues, in which a

similar upfield shift was observed for α/ipso and ortho phenyl

carbons, especially for p-nitrophenyl derivatives. Conversely

and similarly to Series I, the ortho protons of 1-N-Ph were

deshielded in 29, 30. Definitive assignments are illustrated in

Fig. 4 for representative compounds 27b and 29b.

ACCEPTED MANUSCRIPT

7

Table 4

¹H chemical shifts of 1-alkyl/aryl-3-(n-propyl/benzyl)-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-(thi)ones 27–30 (Series II)

Dihydroacridine

2'7' 3'6' 4'5' NH-10' CH₂-4

3-Pr

2''

1-Me, or 1-Ph (R)

2'''6''' 3'''5''' 4'''

R

1'8'

1''

3''

1'''

MeO

Imidazolidine-2-thiones (Acr-CH₂-NPr-CS-NR-)

27a

27b

CH₃

Ph

7.04 6.90 7.22 6.91

7.45 6.94 7.17 6.72

9.42

9.21

9.19

9.23

9.42

3.73

4.26

4.27

4.30

4.23

3.57

3.74

3.73

3.74

3.76

1.52

1.72

1.70

1.71

1.70

0.83

0.96

0.95

2.65

-

6.49

6.33

6.44

7.00

6.98

6.53

6.84

7.92

6.98

27c 4-CH₃O-Ph 7.45 6.95 7.18 6.72

-

3.57

27d

27e

4-F-Ph

4-NO₂-Ph

7.46 6.95 7.19 6.73

7.38 6.93 7.21 6.84

Imidazolidine-2-ones (Acr-CH₂-NPr-CO-NR-)

29a

29b

CH₃

Ph

7.14 6.89 7.19 6.89

7.25 6.82 7.16 6.87

9.30

9.35

9.27

9.35

9.55

3.36

3.62

3.69

3.67

3.60

3.11

3.26

3.27

1.39

1.49

1.52

1.48

0.80

0.87

0.89

0.84

2.37

-

7.01

6.75

6.95

7.48

7.01

6.59

6.87

7.94

6.84

29c 4-CH₃O-Ph 7.35 6.86 7.16 6.82

-

3.57

29d

29e

4-F-Ph

4-NO₂-Ph

7.29 6.87 7.17 6.87

7.12 6.81 7.20 6.99

3-Bn

CH₂2'' 6'' 3'' 5''

Imidazolidine-2-thiones (Acr-CH₂-NBn-CS-NR-)

R

4''

28a

28b

CH₃

Ph

7.01 6.88 7.21 6.90

7.36 6.89 7.16 6.70

9.43

9.20

9.17

9.21

9.36

3.62

4.15

4.13

4.17

4.10

4.89

5.07

5.04

5.05

5.06

7.34

7.52

7.50

7.51

7.49

7.34

7.44

7.43

7.41

7.24 2.71

7.34

7.32

7.35

7.33

-

7.03

-

6.50

6.34

6.44

6.96

7.03

6.55

6.87

7.93

28c 4-CH₃O-Ph 7.34 6.88 7.15 6.68

3.58

28d

28e

4-F-Ph

4-NO₂-Ph

7.35 6.87 7.16 6.70

7.29 6.86 7.17 6.77

-

Imidazolidine-2-ones (Acr-CH₂-NBn-CO-NR-)

30a

30b

CH₃

Ph

7.11 6.87 7.18 6.88

7.19 6.77 7.12 6.81

9.30

9.25

9.32

9.51

3.27

3.50

3.58

3.57

3.48

4.38

4.49

4.52

7.25

7.33

7.37

7.36

7.30

7.31

7.33

7.37

7.36

7.30

7.23 2.43

7.26

7.29

7.25

-

7.01

6.76

6.95

7.48

7.01

6.61

6.90

7.94

6.85

30c 4-CH₃O-Ph 7.29 6.82 7.14 6.79

-

30d

30e

4-F-Ph

4-NO₂-Ph

7.24 6.80 7.15 6.83

7.07 6.75 7.15 6.90

Table 5

¹³C chemical shifts of 1-alkyl/aryl-3-(n-propyl/benzyl)-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-(thi)ones 27–30 (Series II)

Dihydroacridine

3'6' 4'5' 8'a

9'a

Spiro ring

3-Pr

2''

1-Me or 1-Ph (R)

1'8'

2'7'

4'a

10'a

9'

2-

CH₂-

1''

3''

1'''

2'''

6'''

3'''

5'''

4'''

C=X

4

Imidazolidine-2-thiones (Acr-CH₂-NPr-CS-NR-)

27a

27b

27c^a

27d

27e

126.8 120.9 129.4 114.7 119.5 138.6 64.8 181.2

128.4 120.6 129.5 114.3 120.3 138.1 66.2 179.3

128.4 120.4 129.5 114.5 120.5 138.0 66.1 179.6

128.3 120.7 129.7 114.6 120.0 138.0 66.2 179.3

127.7 120.9 129.8 114.9 119.7 137.9 66.8 179.6

66.9

67.4

67.2

67.0

67.8

48.3 20.2 11.6

31.0

48.7 20.2 11.8 139.4 129.7 128.1 127.0

48.7 20.2 11.8 132.0 131.1 113.4 158.1

48.7 20.2 11.8 135.6 131.7 115.0 160.1

48.7 20.0 11.7 145.0 128.9 123.5 145.9

Imidazolidine-2-ones (Acr-CH₂-NPr-CO-NR-)

29a

29b

29c^b

29d

29e

126.6 120.6 129.0 114.6 120.2 139.0 59.9 159.9

63.8

64.1

64.0

63.9

63.8

45.0 20.6 11.6

26.6

126.5 120.1 128.6 114.1 121.0 137.6 60.6 157.2

126.9 119.9 128.5 114.0 121.0 137.6 60.6 157.3

126.6 120.1 128.6 114.1 120.6 137.6 60.7 157.1

125.6 120.5 129.0 114.4 120.0 137.6 61.0 156.4

44.5 20.1 11.2 138.3 122.8 127.8 123.0

44.6 20.1 11.2 130.9 125.7 113.1 155.6

44.5 20.0 11.1 134.5 125.1 114.5 158.1

44.4 19.9 11.1 144.6 120.1 123.7 141.1

^aδ (MeO) = 55.4 ppm; ^bδ (MeO) = 54.8 ppm.

Dihydroacridine

Spiro ring

2-C=X CH₂-4 CH₂

Imidazolidine-2-thiones (Acr-CH₂-NBn-CS-NR-)

3-Bn

2''

6''

1-Me or 1-Ph (R)

3''

5''

2'''

6'''

3'''

5'''

1'8'

2'7'

3'6'

4'5'

8'a 9'a 4'a 10'a

9'

1''

4''

1'''

4'''

28a

28b

28c^a

28d

28e

126.8

128.3

128.4

128.2

127.8

120.8

120.5

120.6

120.9

129.4

129.6

129.5

129.7

129.9

114.7

114.6

114.5

114.6

114.9

119.3

120.1

119.8

119.5

138.5

138.0

137.9

64.8

66.3

66.2

66.9

181.2

179.4

179.6

179.3

179.2

66.3

66.7

66.6

66.3

67.1

50.3

50.5

50.6

50.5

137.1

137.0

137.1

136.9

136.5

128.3

128.7

129.0

129.1

129.2

127.9

128.2

128.1

128.2

128.3

31.3

139.3

131.9

135.5

145.8

129.8

131.1

131.8

129.4

128.2

113.5

115.1

123.7

127.3

158.2

161.0

145.4

Imidazolidine-2-ones (Acr-CH₂-NBn-CO-NR-)

30a

30b

30c^b

30d

30e

126.1

127.0

127.5

127.1

126.1

120.1

120.5

120.4

120.6

120.3

128.5

129.1

129.2

129.5

114.1

114.6

114.5

114.6

114.9

119.5

121.3

121.0

120.3

138.4

138.0

138.1

138.0

59.4

61.2

61.3

61.6

159.3

157.6

157.7

157.5

156.9

62.9

64.3

64.2

64.1

64.0

46.9

47.3

47.4

47.3

47.2

137.4

137.5

137.7

137.5

136.9

127.8

128.4

129.0

128.5

128.4

129.0

128.4

129.1

127.2

127.9

127.8

127.9

128.0

26.2

138.6

131.3

134.8

144.9

123.6

126.6

126.0

120.8

128.4

113.7

115.2

124.2

123.8

156.4

158.9

141.8

^aδ (MeO) = 55.4 ppm; ^bδ (MeO) = 55.4 ppm.

X-ray single crystal measurement has shown several

interesting facts (Fig. 5, Table 6, 7). It confirmed a mutual

orthogonal position of the dihydroacridine versus

imidazolidine ring. It was surprising to find that phenyl was

also almost orthogonal toward the imidazolidine ring. This is

probably due to its sterical repulsion with the nearby acridine

ACCEPTED MANUSCRIPT

8

Tetrahedron

imidazolidine through a connecting σ-bond C1'''−N1. Such an

unusual electron arrangement might be responsible for

unexpected trends in changes of chemical shifts upon the

change of the para substituents.

Table 7

Distances and angles in the compound 28e

Distances (Å)

Angles (°)

C4a–H1', 2.319

C4b–H8', 2.301

S1–C1''', 3.143

S1–C2''', 3.997

S1–C6''', 3.650

C2–N1, 1.347

C2–N3, 1.343

C1'''–N1, 1.432

C6–N3, 1.458

N1–C2–N3, 108.50 (14)

N1–C2–S1, 125.83 (12)

N3–C2–S1, 125.66 (12)

C2–N1–C1''', 124.39 (13)

C1'''–N1–C5, 121.90 (12)

C2–N1–C5, 113.30 (13)

C2–N3–C4, 113.34 (13)

C2–N3–C6, 126.04 (14)

C4–N3–C6, 120.51 (14)

C2'''–C1'''–N1–C2, 99.9 (2)

C6'''–C1'''–N1–C2, -80.8 (2)

Fig. 5: Structure of 3-benzyl-1-(4'''-nitrophenyl)-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-thione (28e).

Table 6

Crystal data and structure refinement of the compound 28e

Compound

28e

2.3 4-(Acridin-9'-yl)-3-(n-propyl/benzyl)-

spiro[dihydroacridine-9'''(10'''H),5-imidazolidine]-2-

thiones 27f, 28f and their oxo analogues 29f, 30f

Empirical formula

Formula weight

Temperature

Wavelength

C₂₈H₂₂N₄O₂S

478.56

293(2) K

0.71073 Å

An alternative reaction course than in Series II was found

for reactions of N-(acridin-9-ylmethyl)propan-1-amine (23)

and N-(acridin-9-ylmethyl)benzylamine (24) with 9-

isothiocyanatoacridine (Series III). The reaction afforded

spirocyclic thiones 27f, 28f in the isolated yields 66% and

36%, respectively, which were next transformed to their oxo

analogues 29f, 30f with MNO in acetonitrile, to give isolated

yields 27% and 68%, respectively, after crystallization from

chloroform/n-heptane (Scheme 6). NMR spectra of these four

bis-acridine products (Tables 8, 9) showed several differences

when compared to the Me and Ph derivatives (a−e) of the

series I and II. First of all, spirocycles 27f−30f displayed only a

one-proton methine CH signal (¹H: 5.47−6.01 ppm, ¹³C:

69.8−75.0 ppm) attached to the spiro C-4,9' carbon (61.7−66.4

ppm), instead of the previous two-proton methylene (4-CH₂)

signal. Second, we have found that spirocycles 27f−30f

possessed two unsymmetrical acridine skeletons giving

altogether four aromatic spin systems in the NMR spectra,

contrary to Me and Ph derivatives (a−e) in which all

corresponding proton and carbon signals of the atom pairs, 1'8',

2'7', 3'6', 4'5', 4'a10'a, and 8'a9'a, in the acridine flanking rings

were equivalent.

Crystal system

Space group

Monoclinic

P2₁/n

11.9766(2) Å

Unit cell dimensions

15.6048(3) Å 93.680(2)°

13.0091(4) Å

2426.29(10) Å³

4; 1.310 g.cm^-3

0.167 mm^-1

Volume

Z; density (calculated)

Absorption coefficient

F(000)

1000

Crystal shape, color

Crystal size

prism, yellow

0.5276 x 0.2386 x 0.2117 mm³

3.05 – 26.00°

θ

range for data collection

-14 ≤ h ≤ 14, -19 ≤ k ≤ 19, -16 ≤ l

≤ 15

Index ranges

Reflections

collected/independent

24891/4765 [R(int) = 0.0227]

data/restraints/parameters

Goodness-of-fit on F²

Final R indices [I>2σ(I)]

R indices (all data)

4765 / 0 / 316

1.055

R1 = 0.0407, wR2 = 0.1105

R1 = 0.0648, wR2 = 0.1187

0.384; -0.314 e.Å^-3

Regarding this different reaction course, two acridine rings

of unstable, non-isolated bis-acridine thiourea intermediates

25f, 26f may allow two possible pathways of spirocyclization

to come into account (Scheme 6): (a) either an attack of an N-1

nitrogen of thiourea onto a C-9' carbon of the first, 9-

methylene-acridine ring as was the case in series I and II, or (b)

an attack of a methylene carbon onto a C-9 carbon of the

second, 9-amino-acridine ring. As the spectra have shown, the

spirocyclization of intermediate, non-isolated thioureas 25f,

26f, which reacted very fast, proceeded by the pathway (b), i.e.

by the nucleophilic attack of the CH₂-carbon of the linker

moiety onto the C-9 carbon of the amino-acridine ring despite

the fact that no special catalyst for generation of a carbanion

had been used. In our former studies,^10,12,13catalysis by sodium

methoxide was necessary to achieve spirocyclization via a

methylene carbon in similar types of reactions leading to

compounds 1−4.

Largest diff. peak and hole

ring. Moreover, the angles of the bonds going out from the N1

nitrogen are close to 120° indicating a prevailing sp²-

hybridization of the N1 nitrogen, though formally it should be

a sp³-nitrogen. Consequently, a lone electron pair on N1 is not

a sp³-hybridized orbital known from tertiary amines, but rather

a p-orbital which can overlap with the orbitals of the C=S

double bond. At the same time, this p-orbital cannot overlap

with the six π-electron system of the 4-nitrophenyl ring,

because they are mutually orthogonal. The conjugation effects

originating from the para substituents of the phenyl, which

were observed for carbon as well as nitrogen signals of the

phenyl and imidazolidine rings, must thus be transferred to

ACCEPTED MANUSCRIPT

9

HSQC and HMBC spectra, all thirteen carbon signals (Table

9). To corroborate the assignments, we used a new H2BC

technique, which enabled easier assignments of the carbons

which are two-bonds distant from the source protons. The

chemical shifts of NH-1 proton of the imidazolidine, which

decreased on going from the thiones 27f/28f (9.95/10.19 ppm),

to the ones 29f/30f (8.19/8.40 ppm), were easily differentiated

from those of acridine NH-10' one, because they displayed

HMBC transfers to imidazolidine 2-C=S and 4-CH carbons,

and to the spirocarbon C-5,9'. The magnetization from the

imidazolidine 4-CH proton was transferred to both acridines,

namely to carbons C-9''', C-8'''a, 9'''a of the aromatic acridine

ring as well as to the spirocarbon C-9' and bridge carbons C-

8'a,9'a of the dihydroacridine ring. On the other side, the

magnetization transfers from the proton 4-CH to the propyl and

benzyl protons were not observed, which prove a high mobility

of these substituents.

S

N

R

NH

N

NH

9-Acr-NCS

chloroform, rt, 6 h

N

25 f

26 f

23, 24

23: R = n-Pr

24: R = CH₂Ph

4'

NH

S

O

NH

5'

N

4

R

H

8´´´

1´´´

MNO

acetonitrile

rt, 5 h

In the aromatic acridine, the inequivalency of both flanking

rings was again observed affording altogether eight proton and

thirteen carbon signals, which have all been successfully

resolved using 2D NMR techniques. Thus, a new stereogenic

centre, the C-4 carbon of the imidazolidine renders the

asymmetry not only in the close dihydroacridine but also in the

more distant aromatic acridine. As we originally did not detect

any cross-peaks of the 4-CH proton signal at 6.01 ppm with

any of H-1',8' signals of dihydroacridine in the NOESY

spectrum of the propyl derivative 27f, unlike our former

observation,¹⁹we performed a NOESY1D and ROESY1D

irradiation of H-4 and found small NOE enhancements of H-1'

signal at 7.62 ppm (0.47% and 2.73%, respectively) and signal

N

27 f

28 f

29 f

30 f

Scheme

6.

Synthesis

of

4-(acridin-9'''-yl)-3-(n-propyl/benzyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones 27f, 28f and

their oxo analogues 29f, 30f.

To prove the structure of 27f−30f, we could not employ

crystallography, as the products had a powder form and did not

afford crystals despite repeated attempts, therefore we relied up

on NMR analysis. NOE transfers from the NH-10' proton

between 8.35−8.83 ppm allowed to disclose two separate

signals of H-4' and H-5' protons of the dihydroacridine cycle

(Table 8). Following the COSY and TOCSY transfers allowed

assignments of all eight dihydroacridine proton signals and, via

Table 8

¹H chemical shifts of 4-(acridin-9'''-yl)-3-(n-propyl/benzyl)-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-(thi)ones 27f–30f (Series III)

Series III

Dihydroacridine

4' 5' 6'

7.62 7.14 7.31 6.81 6.11 6.54 6.20 7.14

3-Pr

2''

4.14, 2.38 1.27

3.48, 2.24 1.14

4-CH

1'

2'

3'

7'

8'

NH-10' NH-1

1''

3''

0.63

0.64

27f, 2-C=S

8.83

8.47

9.95

8.19

6.01

5.82

29f, 2-C=O 7.78 7.12 7.23 6.59 6.02 6.59 6.43 7.31

3-Bn

2''6'' 3''5''

4-CH

CH₂

10.19 5.77, 3.41 6.89

8.40

4''

7.13

7.14

28f, 2-C=S

7.53 7.08 7.24 6.70 6.08 6.57 6.27 7.24

30f, 2-C=O 7.63 7.03 7.14 6.45 6.00 6.62 6.52 7.42

8.72

8.35

7.08

5.65

5.47

5.02, 3.22 6.77

4-Aromatic acridine

3''' 4''' 5''' 6'''

1'''

2'''

7'''

8'''

27f 8.13 7.46 7.69 7.97 7.94 7.69 7.31 7.46

29f 8.31 7.31 7.61 7.89 7.97 7.64 7.18 7.31

28f 8.27 7.53 7.73 7.98 7.98 7.63 7.08 6.85

30f 8.48 7.34 7.64 7.92 7.95 7.59 6.94 6.70

Table 9

¹³C chemical shifts of 4-(acridin-9'''-yl)-3-(n-propyl/benzyl)-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-(thi)ones 27f–30f (Series III)

Dihydroacridine

Spiro ring

3-Pr

1'

2'

3'

4'

5'

6'

7'

8'

9'

8'a

9'a

4'a

10'a

139.1

138.6

139.4

138.9

2-C=X

CH-4

75.0

73.9

71.0

69.8

1''

46.4

2''

20.0

3''

11.4

27f

28f

29f

30f

125.6

125.4

125.3

124.6

121.1

120.9

120.2

129.3

129.2

128.8

127.8

114.5

114.3

113.5

113.2

113.0

112.4

128.5

128.4

128.3

127.8

118.8

118.9

119.2

118.8

127.8

127.7

127.2

66.4

66.3

62.3

61.7

116.9

116.8

118.5

118.0

122.9

122.7

123.1

122.0

138.6

139.5

138.9

183.3

183.4

161.5

161.0

43.3

20.1

11.6

4-Aromatic acridine

3-Bn

2''6''

1'''

2'''

3'''

4'''

5'''

6'''

7'''

8'''

9'''

8'''a

125.8

125.6

126.2

125.7

9'''a

124.8

124.6

125.2

124.9

4'''a

148.2

147.5

148.1

148.2

10'''a

147.8

147.3

147.8

147.7

CH₂

48.5

45.3

1''

3''5''

128.7

128.2

4''

27f

125.4

126.3

125.7

126.2

126.3

125.1

124.7

129.9

129.6

129.1

130.3

129.8

129.2

130.3

130.2

129.5

129.9

129.8

129.7

128.9

126.4

126.0

125.9

124.7

123.2

122.8

123.1

122.3

136.3

135.8

136.7

135.5

28f

29f

30f

135.7

135.6

128.5

128.1

127.3

ACCEPTED MANUSCRIPT

10

Tetrahedron

ethylacridine 31,²⁵we have improved the described procedure

for the synthesis of 9-methylacridine.²³To obtain a synthon N-

[1-(acridin-9-yl)ethyl]propan-1-amine (33), the acridine 31 in

tetrachloromethane was allowed to react with NBS and AIBN

to give oily, so far undescribed, unstable 9-(1-

bromoethyl)acridine (32) in 73% yield. The bromide 32 and n-

propylamine afforded 70% of 1-(acridin-9-yl)ethyl]propan-1-

amine (33) as an oil, to which phenyl isothiocyanates 16b,c,e,

or 4-fluorophenyl isothiocyanate were added to give crude,

H-8''' at 7.46 ppm (3.20% and 24.58%, respectively). These

magnitudes coincide with interatomic distances obtained from

modeling: H-4–H-8''': 1.91 Å and H-4–H-1': 2.22 Å. These

facts prove that the both acridines are very close each to other

(e.g., the distance H-1'''–H-8': 2.52 Å) and the difference in

observed NOE enhancements here is caused by a more

compressed molecule in the present case contrary to the

structure without Pr (or Bn) substituent on the N-3 in our

former study.¹⁹

oily

1-(4'''-substituted

phenyl)-3-propyl-4-methyl-

2.4 1-Aryl-3-(n-propyl)-4-methyl-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-thiones 35b–e

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones

35b−e, which were proven by NMR to be the corresponding

spirocompounds (Scheme 7, Table 10). Despite repeated

Last modification we made was on the methylene attached

to acridine C-9' carbon, in which one methylene proton was

replaced with a methyl group (Series IV). We were interested

attempts,

preparation

of

desired

N-[1-(acridin-9-

yl)ethyl]benzylamine (34) was not successful, because the

reactive benzyl fragment could perhaps easily split-off. NMR

spectra of the dihydroacridine system of 35b–e showed an

inequivalency of the flanking rings due to the presence of a

new stereogenic C-4 centre. As the 1'-position in

dihydroacridine, the one closer to the 4-methyl substituent was

selected. The NOESY cross-peaks with two multiplets of the

4-CH(CH₃) group enabled to resolve each from other the

protons H-8' and H-1': a 4-CH quartet was closer to a signal in

the lower field (7.20−7.40 ppm, H-8') and a methyl doublet

was closer to one at a higher field (7.02−7.19 ppm, H-1').

Upon that resolution, all remaining protons and carbons were

assigned (Table 10, 11). Within the n-propyl group, the

stereogenic centre caused a great difference of chemical shifts

R

H₃C

Br

H₃C

NH

PrNH

or

BnNH

NBS, AIBN

tetrachloromethane

60 °C, 12 h

N

31

32

33, 34

R

S

33: R = n-Pr

34: R = CH₂Ph

N

R¹

N

R = n-Pr

H₃C

b: R¹

c: R¹

d: R¹

e: R¹

=

Ph

isothiocyanates 16

CHCl₃, rt

4-CH₃O-Ph

4-F-Ph

N

H

4-NO₂-Ph

35b-e

of α-protons (~0.4 ppm) and a smaller inequivalency of ꢀ-ones

(~0.1 ppm) as well as the close to methyl C-8'a,9'a carbons

were also separated each from other (119 ppm versus 116 ppm,

resp.).

Scheme 7. Synthesis of N-[1-(acridin-9-yl)ethyl]propan-1-amine (33) from

9-ethylacridine (31) and its reactions with isothiocyanates 16 to 1-aryl-3-

(n-propyl)-4-methyl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

thiones 35b–e.

if such a sterically hindered electrophilic C-9' site would still

be able to form

a spirocycle. To prepare starting 9-

Table 10

¹H chemical shifts of 1-(4-X-phenyl)-3-(n-propyl)-4-methyl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones 35b–35e (Series IV)

Dihydroacridine

4' 5' 6'

Spiro ring

NH- CH- CH₃-

3-Pr

2''

1-Ph

2'''6''' 3'''5'''

4-X

1'

2'

3'

7'

8'

1''

3''

4'''

MeO

10'

4

35b

H

7.15 6.88 7.23 6.92 6.80 7.10 6.81 7.33 9.31 3.98

0.79

0.80

0.78

3.89,3.41 1.63,1.56 0.90

3.88,3.41 1.66,1.56 0.91

3.87,3.41 1.65,1.56 0.90

3.91,3.39 1.63,1.53 0.88

7.04

6.89

7.04

7.45

7.04

6.97

35c CH₃O 7.19 6.89 7.22 6.89 6.79 7.10 6.83 7.40 9.25 4.00

6.60

6.93

7.99

3.59

35d

F

7.16 6.93 7.27 6.93 6.81 7.13 6.84 7.38 9.32 4.01

7.02 6.90 7.29 7.01 6.91 7.15 6.78 7.20 9.47 3.97

-

35e NO₂

Table 11

¹³C chemical shifts of 1-(4-X-phenyl)-3-(n-propyl)-4-methyl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones 35b–35e (Series IV)

Dihydroacridine

Spiro ring

4-X

1'

2'

3'

4'

5'

6'

7'

8'

9'

8'a

9'a

4'a

10'a

2-C=X CH-4 4-CH₃

35b

H

128.7 119.9 129.6 115.1 114.4 129.1 120.2 128.6 71.2 119.1 116.1 138.6 139.0

182.1

182.5

182.2

181.2

70.3

13.5

13.7

13.6

13.3

35c CH₃O 128.8 119.8 129.6 115.1 114.4 129.1 120.1 129.1 71.2 119.1 115.9 138.6 139.0

35d

F

128.6 120.0 129.8 114.9 114.5 129.2 120.3 128.8 71.2 118.9 115.8 138.6 139.0

127.7 120.5 129.9 115.3 114.7 129.4 120.6 127.7 71.4 118.5 115.6 138.7 139.0

35e NO₂

3-Pr

2''

1-Ph

2'''6''' 3'''5'''

4-X

1''

3''

1'''

4'''

MeO

35b

H

46.2 20.6 11.8 139.8

128.4

130.1

130.5

127.3

128.1

113.4

115.1

123.3

126.2

157.5

160.2

144.1

35c CH₃O 46.3 20.6 11.8 132.6

55.4

35d

F

46.3 20.6 11.8 136.1

46.3 20.5 11.7 145.8

35e NO₂

ACCEPTED MANUSCRIPT

11

¹⁵N NMR spectra in DMSO-D₆of 39 compounds 20a,c−f,

Table 12

21a,c,d,f, 22d,e, 27a−f, 28a−f, 29a−f, 30a−f, 35b−e

referenced to the mixture nitromethane : CDCl₃(1:1) provided

more interesting information about the structure and electronic

effects inside the molecules (Table 12). Chemical shifts of ¹⁵N

nuclei in all products, which have been detected via inverse

¹H,¹⁵N-gHMBC magnetization transfers from nearby protons,

evidenced convincingly the nitrogen hybridization. In all

spirocycles containing one dihydroacridine ring, two signals of

(thio)ureido imidazolidine nitrogens ¹⁵N-1 and ¹⁵N-3, and one

dihydroacridine ¹⁵NH-10' signal have been observed except for

four compounds (29b,e, 30c,e), where N-1 signals were not

detected due to a weak polarization transfer. Moreover, in the

nitro compounds (e), signals of ¹⁵NO₂groups have been found

around -10 ppm. Chemical shifts of imidazolidine nitrogens

correlated well with effects of the substituents in positions 1, 2,

3, 4, and 5 of the imidazolidine ring. In all spectra the signals

of N-1 were systematically deshielded compared to the signals

of N-3 by about 19−50 ppm, due to substituent effects of the

neighbor acridine and N-1 substituents. The change of 2-thio to

2-oxo analogues moved signals of both neighboring N-1 and

N-3 nitrogens upfield by ca. 30 ppm to more negative values.

So, deshielding of (thio)ureido ¹⁵N nuclei is stronger by the

C=S group than by the C=O one. This is a similar effect as that

found for ¹H and ¹³C NMR spectra of thioureas, whose protons

are more acidic and located thus at higher ppm values than the

signals of urea protons.

¹⁵N chemical shifts of the target spirocompounds

R

N-1

N-3

N-10'

N-

10'''

NO₂

Imidazolidine-2-thiones (Acr-CH₂-NH-CS-NR-)

20a CH₃

-249.6

-220.2

-221.4

-222.6

-232.9

-275.6

-272.6

-270.2

-266.2

-275.4

-284.7

-284.3

-284.1

-284.0

-284.6

20c 4-CH₃O-Ph

20d 4-Br-Ph

20e 4-NO₂-Ph

-10.3

20f

allyl

Imidazolidine-2-ones (Acr-CH₂-NH-CO-NR-)

21a CH₃

21c 4-CH₃O-Ph

21d 4-Br-Ph

-284.0

-255.4

-256.6

-266.4

-307.1

-304.7

-302.8

-307.0

-284.7

-284.6

-284.5

-284.8

21f

allyl

Ureas (Acr-CH₂-NH-CO-NHR)

22d 4-Br-Ph

22e 4-NO₂-Ph

-275.3

-268.3

-290.8

-287.9

nd

-73.1

-9.9

Imidazolidine-2-thiones (Acr-CH₂-NPr-CS-NR-)

27a CH₃

27b Ph

27c 4-CH₃O-Ph

27d 4-F-Ph

27e 4-NO₂-Ph

-251.2

-220.6

-221.4

-222.1

-223.5

-248.1

-270.6

-267.1

-268.2

-266.7

-261.5

-261.8

-284.6

-284.3

-284.1

-284.0

-280.3

-10.2

27f

Acr

-69.3

Imidazolidine-2-ones (Acr-CH₂-NPr-CO-NR-)

29a CH₃

29b Ph

29c 4-CH₃O-Ph

29d 4-F-Ph

29e 4-NO₂-Ph

-284.6

nd

-255.5

-256.1

nd

-301.7

-298.4

-299.5

-298.5

-294.6

-291.2

-284.4

-284.7

-284.6

-284.4

-280.0

In 2-thione derivatives, the replacement of N-1-methyl

(20a, 27a, 28a) by phenyl (27b, 28b) has shifted ¹⁵N-1 signals

substantially downfield from ca. -250 to ca. -220 ppm and

those of the more distant ¹⁵N-3 nitrogen to a much lesser extent

from ca. -270 to -267 ppm. A similar drift of about 31 ppm for

signals of ¹⁵N-1, though with two other sets of chemical shifts,

has been found with 3-oxo derivatives, which were again more

shielded in N-1-methyl derivatives 21a, 29a, 30a (ca. -284

ppm) than in N-1-phenyl one 30b (ca. -255 ppm).

nd

29f

Acr

-280.2

nd

Imidazolidine-2-thiones (Acr-CH(CH₃)-NPr-CS-NR-)

35b Ph

35c 4-CH₃O-Ph

35d 4-F-Ph

35e 4-NO₂-Ph

35e^a4-NO₂-Ph

-231.6

-231.9

-232.9

-233.9

-254.1

-255.6

-254.0

-248.2

-248.7

-284.1

-284.3

-284.1

-283.5

-286.5

-10.3

-11.2

Imidazolidine-2-thiones (Acr-CH₂-NBn-CS-NR-)

28a CH₃

28b Ph

28c 4-CH₃O-Ph

28d 4-F-Ph

28e 4-NO₂-Ph

-250.2

-219.6

-220.6

-221.2

-222.3

-247.3

-269.4

-265.6

-266.7

-265.2

-260.6

-259.3

-284.5

-284,1

-284.3

-284.1

-284.0

-280.3

Para-substituents on N-1-phenyls influenced the chemical

shifts of both nitrogens N-1 (the close one) and N-3 (the distant

one), which, however, moved reversely to each other under the

effect of these. Upon going from p-methoxy to p-nitro, the

chemical shifts of distant ¹⁵N-3 nitrogens became more

deshielded (less negative) by 4.9−7.3 ppm, on the other hand,

those of nitrogens ¹⁵N-1, to which the phenyls are attached,

became more shielded (more negative) by 2.4−2.9 ppm.

Especially, the p-nitro substituent caused the greatest change.

All this proves that N-1-phenyls together with the (thio)ureido

part of imidazolidine compose a common, wide-spreading

conjugated system. As the reverse trends as the size of induced

span of the chemical shifts differences, which were found in

both thio and oxo series, were surprising: para-substituents on

the N-1-phenyls affected more distant ¹⁵N-3 nitrogens to a

greater extent, than those of ¹⁵N-1. An explanation of this fact

might lie in (a) a cross-conjugation of the N-1 nitrogen

electron pair with 1-phenyl as well as the 2-thi(one) double

bond, (b) some kind of intermolecular interaction, for example,

formation of a dimeric structure mediated by hydrogen bonds

between NH-10 protons of one molecule and nitrogens or

sulfur lone electron pairs of the other, and (c) a stacking

interaction between aromatics in the dimer.

-10.4

28f

Acr

-70.0

Imidazolidine-2-ones (Acr-CH₂-NBn-CO-NR-)

30a CH₃

30b Ph

30c 4-CH₃O-Ph

30d 4-F-Ph

30e 4-NO₂-Ph

Acr

^aIn CDCl₃.

-284.0

-255.1

nd

-255.6

nd

-299.6

-296.0

-297.3

-296.2

-292.2

-287.8

-284.7

-284.8

-284.7

-284.3

-280.2

nd

30f

-279.0

-70.6

of N-1 upfield by about 2 ppm, i.e. alkyls elicited only a small

change of ¹⁵N chemical shifts. Signals of dihydroacridine NH-

nitrogens between -284.0 – -284.8 ppm were almost unaffected

by structural changes in the spiroring. In CDCl₃, a small

upfield shift has been observed for all three ¹⁵N NMR signals

(e.g. -286.5 ppm for 35e).

In bis-acridine derivatives 27f–30f, the chemical shift of

dihydroacridine nitrogen N-10' was slightly moved to -280

ppm reflecting another type of spirocyclization. On the other

hand, the chemical shift of nitrogen N-10''' was not dependent

on the change of sulfur (-69 – -70 ppm) by oxygen (-71 ppm).

Very interesting reversal effects have been observed when we

compared how the methyl substituent in position 4 of

imidazolidine-thiones 35b−e influenced the chemical shift of

N-1 and N-3, respectively, in comparison to non-methylated

27b–e. Closer N-3s were deshielded by about 13 ppm due to a

From comparison of the 3-NH, 3-N-Pr, and 3-N-Bn

derivatives it follows that substitution of H by n-Pr or Bn

moved chemical shifts of N-3 downfield by 4-5 ppm and those

ACCEPTED MANUSCRIPT

12

Tetrahedron

positive (deshielding)

ꢀ

-effect of methyl, while more

Table 13

distant N-1 signals were shifted upfield by about 11 ppm

because of the negative (shielding) δ-effect of methyl of

surprisingly large magnitude when compared with literature.²⁶

Calculated increments Z_iof spiroskeletons on phenyl ¹³C chemical shifts.

Z_ipsoZ_orthoZ_metaZ_para

Imidazolidine-2-thiones (Acr-CH₂-NH-CS-NR-)

The chemical shifts of nuclei of the 1-N-phenyl substituent

nicely reflected different effects of the para-substituents as

well as an effect coming from the spiro-dihydroacridine

skeleton. To evaluate these effects, we calculated ¹³C NMR

increments of the spiro substituent on the carbon chemical

shifts of the phenyl nuclei (Table 13), after discounting

increment magnitudes of para substituents taken from the

literature.²⁷

20c 4-CH₃O-Ph

20b Ph

10.0

8.8

1.1

0.4

0.1

-0.1

0.4

-1.3

-1.0

-1.2

-0.7

-1.1

-4.2

-2.1

-3.6

-3.9

-3.5

20d 4-Br-Ph

20e 4-NO₂-Ph

Average:

10.2

10.3

9.8

Imidazolidine-2-thiones (Acr-CH₂-NPr-CS-NR-)

27c 4-CH₃O-Ph

27b Ph

11.2

10.9

11.5

10.4

11.0

1.6

1.2

1.6

-0.5

1.0

-0.7

-0.4

-0.5

-0.1

-0.4

-3.9

-1.5

-2.0

-2.5

27d 4-F-Ph

27e 4-NO₂-Ph

Average:

We have found an interesting difference between the Z_ortho

increments in the thiones 20, 27, 28 versus the ones 21, 29, 30.

While the values of Z_orthoin the thiones remained almost

unchanged for particular para substitutents, for the ones we

have observed a clear dependence on the Hammett constants σ_p

of these substituents: the increments of the spiroskeleton

decreased from 4-CH₃O (cca -4 ppm) to 4-NO₂(-9 ppm)

derivatives. This observation can be explained by a push-pull

interaction between the spiroskeleton and the para substituents

present within the molecule. This confirms a different type of

cross-conjugation with thioureido versus ureido group: in the

thiones, the electron pair of nitrogen N-1 is markedly involved

in the cross-conjugation with the 2-C=S group, which worsens

its interaction with the para substituent, thus, the shielding

effect on ortho and para carbons is small and the push-pull

effect is minimal, if any, here. This assumption is strongly

supported by the above X-ray structure of 28e with the

orthogonal arrangement of imidazolidine vs. phenyl ring. The

ring-opening of imidazolidin-2-ones 21 to ureas 22 is

accompanied by a distinct increase of the shielding effect,

especially on the ortho carbons.

Imidazolidine-2-thiones (Acr-CH₂-NBn-CS-NR-)

28c 4-CH₃O-Ph

28b Ph

11.1

10.8

11.4

11.2

11.1

1.6

1.3

1.7

0.0

1.2

-0.6

-0.3

-0.4

0.1

-3.8

-1.2

-1.1

-3.0

-2.3

28d 4-F-Ph

28e 4-NO₂-Ph

Average:

-0.3

Imidazolidine-2-ones (Acr-CH₂-NH-CO-NR-)

21c 4-CH₃O-Ph

21b Ph

9.9

9.5

-3.9

-5.7

-6.6

-9.2

-6.4

-1.1

-0.8

-1.2

0.0

-6.5

-5.6

-2.5

-7.4

-5.5

21d 4-Br-Ph

21e 4-NO₂-Ph

Average:

10.0

9.8

-0.8

Imidazolidine-2-ones (Acr-CH₂-NPr-CO-NR-)

29c 4-CH₃O-Ph

29b Ph

10.1

9.8

-3.8

-5.7

-5.0

-9.3

-6.0

-1.0

-0.7

-1.0

0.1

-6.4

-5.5

-4.0

-7.3

-5.8

29d 4-F-Ph

29e 4-NO₂-Ph

Average:

10.4

10.0

10.1

-0.7

Imidazolidine-2-ones (Acr-CH₂-NBn-CO-NR-)

All these observations elicit the question which is a driving

force of spirocyclization in various acridine derivatives

possessing the heteroatom moiety in the position 9. The

comparison of spirocyclization course of mono- and bis-

acridine derivatives, which were studied in this work, showed

two different pathways. While mono acridines have only one

target, the C-9 carbon of acridine, at which the spirocyclization

aims (the classical pathway), bis-acridines possess two types of

such carbons C-9 in two different acridine skeletons – one is

attached to an amino group and the other to a methylene one.

The experimental result of this and the previous work¹⁹

unequivocally showed that the attacking nucleophile of the bis-

acridine substrate was the methylidene carbon and not the

amino group, so this pathway can be taken as nonclassical way

of spirocyclization, contrary to the classical way of

spirocyclization, which was observed for phenyl derivatives

a−e. For starting bis-thioureas 25f, 26f we did not observe any

product of the classical way of spirocyclization. This indicates

that nonclassical pathway of spirocyclization of bis-acridines is

considerably faster and passess through a transient state with

lower energy.

30c 4-CH₃O-Ph

30b Ph

10.5

10.1

10.7

10.3

10.4

-2.9

-4.9

-4.1

-8.6

-5.1

-0.4

-0.1

-0.3

0.6

-5.6

-4.7

-3.2

-6.6

-5.0

30d 4-F-Ph

30e

4-NO₂-Ph

Average:

-0.1

Ureas (Acr-CH₂-NH-CO-NR-)

22b Ph

11.5 -10.9

0.1

-7.3

-3.0

-7.3

-5.9

22d 4-Br-Ph

22e 4-NO₂-Ph

Average:

11.9 -11.2 -0.5

12.6 -12.0

12.0 -11.4

2.0

0.5

be the most probable as it can tear off the acidic proton from

the methylene group and form a stable carbanion strong

enough to attack the aminoacridine C-9 carbon. There are two

possibilities that nitrogen, which tears off or accepts a proton

from CH₂, comes either from the same molecule or from the

other one. In the first case, π-electrons of exocyclic double

bond C-9=CH of the dihydrotautomeric form B (Scheme 8)

attack the C-9 carbon of the aminoacridine to form the

spirocycle on aminoacridine. The final step will be the proton

transfer from NH-10 from one to other acridine nitrogen and

restoration of the aromatic character of the methine-acridine

ring. If an intermolecular catalysis is operating, several

reaction pathways may come into account. The character of

electrophilic C-9 carbon also plays an important role in this

reaction. We suppose that C-9 of aminoacridine is a more

electron-deficient carbon compared to C-9 of methylene-

acridine because of a higher electronegativity of the neighbor

Moreover, as we have found, the solution of the

spiroproduct, which had been prepared from bis-acridine and

was let to stand in the NMR sample tube in DMSO-D₆for a

very long time, was not changed or decomposed. We can

consider this product to be the most stable thermodynamic

product. Another open question is a type of catalysis that

stimulates the nonclassical way of spirocyclization. The

autocatalysis mediated by a basic nitrogen of acridine seems to

nitrogen. Consequently, the CH-group as

a

stronger

ACCEPTED MANUSCRIPT

13

nucleophile attacks the strongly electrophilic C-9 carbon of

aminoacridine. The phenyl derivatives a−e possessing only the

one acridine skeleton have the C-9 carbon electrophilic enough

to react with the terminal amino-group of thioureas but the

spirocyclization proceeds more slowly, because of lower

mutual affinity of both centers.

matrix DHB with 10 pmol/ꢀL analyte solution was used.

The sample spots were air-dried at room temperature. Ion

acceleration voltage was set to 5 kV. Samples were irradiated

by 337 nm photons from a nitrogen laser. Typically, 100 shots

were summed into a single mass spectrum. The reactions were

monitored on pre-coated TLC-sheets ALUGRAM^®SIL

G/UV₂₅₄(Macherey-Nagel, Germany). Preparative column

chromatography was performed on silicagel Merck, 230−400

mesh. Quantum chemical calculations were carried out using

the Gaussian03 program. Infrared spectra were taken on an

Avatar FT-IR 6700 spectrometer (Thermo Scientific, UK)

using an attenuated total reflectance (ATR) method in the

range of 4000 - 400 cm^-1.

NH

S

N

NH

S

N

R

N

NH

N

NH

R

H

N

H

The crystal structure was determined on an Oxford

A

B

C

Diffraction Xcalibur2 diffractometer equipped with

a

Scheme 8. Possible tautomeric forms A, B of intermediate bisacridinyl-

thioureas 25f, 26f.

Sapphire2 CCD detector. Crysalis CCD was used for data

collection while Crysalis RED was used for the cell

refinement, data reduction, and absorption correction.²⁸The

structure was solved by a direct method with SHELXS97 and

subsequent Fourier syntheses using SHELXL97.²⁹Anisotropic

displacement parameters were refined for all non-H atoms. The

H atoms were placed in calculated positions and refined riding

on their parent C or N atoms with C–H distances of 0.93 and

0.97 Å for aromatic and methylene groups, respectively, and

N–H distance of 0.86 Å. A geometric analysis was performed

using SHELXL97. DIAMOND³⁰was used for molecular

graphics.

The following conclusions can be made from observations

in this work:

1. In series I, disubstituted thioureas 17a−f were formed

slowly and their change to spirocycles was finished in

ca. two days.

2. Trisubstituted thioureas 25a−e, 26a−e of the series II

with n-Pr and Bn substituents were formed very fast

and they changed to spirocycles during 6 h. We did

not observe any signals of the thiourea intermediates

in the NMR spectra even 5 min after mixing the

starting compounds.

3.2. General procedure for the synthesis of 3-(acridin-9-

ylmethyl)-1-alkyl/arylthioureas 17a−f and 1-alkyl/aryl-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones

20a−f

3. Trisubstituted bis-acridinyl-thioureas 25f and 26f of

the series III were formed even faster than 25a−e,

26a−e, because 9-isothiocyanatoacridine is more

reactive than methyl and phenyl isothiocyanates. The

change of thioureas to spiroproducts, in contrast to

series II, proceeded through the non-classical way,

which can be explained by the higher reactivity of

CH-nucleophile and the higher electron dilution on

the C-9 centre of aminoacridine.

To an aqueous solution of 1-(acridine-9-yl)methanamine

dihydrochloride (15.2HCl, 200 mg, 0.71 mmol), an aqueous

solution of sodium carbonate (75 mg, 0.71 mmol) was added.

The free amine 15 was extracted with dry benzene (3×10 mL),

organic layers were combined, dried over magnesium sulfate,

filtered, and evaporated to 5 mL. To this well stirred solution,

isothiocyanate 16 (0.71 mmol) in 1–2 mL of dry benzene was

added at once at room temperature. The mixture turned

heterogeneous after a few min and the reaction course was

followed by TLC (eluent: cyclohexane/ethyl acetate, 2:1) until

completion. The precipitate was filtered off, washed with

diethyl ether, dried, and crystallized from a mixture of

dimethylformamide/methanol.

3. Experimental section

3.1. General information and materials

NMR spectra were recorded at room temperature on a

Varian Mercury Plus spectrometer operating at 400.13 MHz

1

for H, and 100.61 MHz for ¹³C, and a spectrometer Varian

VNMRS operating at 599.87 MHz for ¹H, 150.84 MHz for ¹³C,

and 60.79 MHz for ¹⁵N. Spectra were recorded in DMSO-d₆

unless otherwise stated with an internal standard

tetramethylsilane (TMS, 0.00 ppm). The 2D gCOSY, TOCSY,

3.2.1. 1-Methyl-spiro

[dihydroacridine-9'(10'H),5-

imidazolidine -2-thione (20a)

]

Yield 138 mg, 69%. Bright yellow solid. Mp 230.0−231.0 °C.

[Found: C 68.07; H 5.49; N 14.71; C₁₆H₁₅N₃S (281.38)

requires C 68.30; H 5.37; N 14.93%]; EI-MS (70eV): m/z (%)

NOESY, gHSQC, gHMBC (optimised for

a long-range

1

= 282 (MH⁺, 100), 251 (64), 210 (7). H NMR (400 MHz,

coupling of 8 Hz), gH2BC, and gTOXY-HSQC methods were

employed. For ¹⁵N NMR measurements, gHSQC and gHMBC

(optimised for a long-range coupling of 90 Hz) were used.

Melting points were determined on a Boetius hot-stage

apparatus and are uncorrected. Elemental analysis was

performed on a Perkin-Elmer CHN 2400 elemental analyser.

Mass spectra (MS) were measured on a MALDI-TOF IV

instrument (Shimadzu, Kratos Analytical, England) in a

positive matrix-assisted laser desorption/ionization coupled

with in-source decay (ISD) combined with a time-of-flight

analyzer. 2,5-Dihydroxybenzoic acid (DHB) was used as a

matrix. The sample (1 mg) was dissolved in acetonitrile/water

1:1 (1 mL). For the spot preparation, a mixture of 1 ꢀL of the

CDCl₃) δ_H= 7.98 (1H, s, NH-10'), 7.12 (2H, dd, J 8.0, 1.3 Hz,

H-1',8'), 7.08 (2H, ddd, J 8.0, 7.2, 1.3 Hz, H-3',6'), 6.86 (1H, s,

NH-3), 6.79 (2H, ddd, J 8.0, 7.2, 1.2 Hz, H-2',7'), 6.77 (2H, dd,

1

J 8.0, 1.2 Hz, H-4',5'), 3.68 (2H, s, H-4), 2.71 (3H, s, Me); H

NMR (600 MHz, DMSO): δ_H= 9.40 (s, 1H, NH-1), 8.39 (s,

1H, NH-3), 7.36 (2H, ddd, J 8.4, 7.2, 1.2 Hz, H-3',6'), 7.09

(2H, dd, J 8.4, 1.2 Hz, H-1',8'), 6.91 (2H, ddd, J 8.4, 6.6, 1.2

Hz, H-2',7'), 6.90 (2H, dd, J 8.4, 1.2 Hz, H-4',5'), 3.62 (2H, s,

H-4), 2.61 (3H, s, Me).

3.2.2. 1-Phenyl-spiro

[dihydroacridine-9'(10'H),5-

imidazolidine -2-thione (20b)

]

ACCEPTED MANUSCRIPT

14

Tetrahedron

Yield 139 mg, 57%. Bright yellow solid. Mp 155.0–157.0

tetrahydrofuran (5 mL), mesitylnitrile oxide (24 mg, 0.15

mmol) was added at once and the reaction mixture was left to

stir at room temperature for 6 h under TLC monitoring

(cyclohexane/ethyl acetate, 2:1). After completion of the

reaction, the precipitated product was filtered off, washed with

diethyl ether, dried, and crystallized from a mixture of

dimethylformamide/methanol.

°C. [Found: C 73.20; H 5.22; N 12.08; C₂₁H₁₇N₃S (343.45)

requires C 73.44; H 4.99; N 12.33 %]; ν_max3261, 1667, 1612,

1583, 1486, 1417, 1342, 1319, 1222, 1191, 1051, 985, 743,

694, 622, 540, 509 cm^-1; ¹H NMR (400 MHz) δ_H= 9.22 (1H,

s, NH-10'), 8.86 (1H, s, NH-3), 7.54 (2H, d, J 8.0 Hz, H-1',8'),

7.19 (2H, ddd, J 8.0, 7.4, 0.6 Hz, H-3',6'), 6.98−7.02 (3H, m,

H-3'',5'', and H-4''), 6.96 (2H, ddd, J 8.0, 7.6, 0.6 Hz, H-2',7'),

6.75 (2H, d, J 8.0 Hz, H-4',5'), 6.50−6.57 (2H, m, H-2'',6''),

4.14 (2H, s, H-4).

3.3.1. 1-Methyl-spiro

imidazolidine -2-one (21a)

[dihydroacridine-9'(10'H),5-

]

Yield 25 mg, 63%. Yellow solid. Mp 234.0−236.0 °C. [Found:

C 72.68; H 5.90; N 15.49; C₁₆H₁₅N₃O (265.31) requires C

72.43; H 5.70; N 15.84%]; ν_max3335, 1682, 1620, 1580, 1480,

1325, 1250, 755 cm^-1; ¹H NMR (400 MHz) δ_H= 9.30 (1H, s,

NH-10'), 7.17−7.23 (4H, m, 1',8',3',6'), 6.88−6.95 (4H, m, H-

2',7',4',5'), 6.58 (1H, s, NH-3), 3.37 (2H, s, H-4), 2.36 (3H, s,

Me).

3.2.3. 1-(4''-Methoxyphenyl)-

spiro

[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (20c)

Yield 170 mg, 64%. Bright yellow solid. Mp 197.0−200.0 °C.

[Found: C 70.66; H 4.98; N 11.09; C₂₂H₁₉N₃OS (373.47)

requires C 70.75; H 5.13; N 11.25%]; H NMR (400 MHz) δ_H

= 8.99 (1H, s, NH-10'), 8.56 (1H, s, NH-3), 7.60 (2H, dd, J 7.6,

1.2 Hz, H-1',8'), 7.16 (2H, ddd, J 8.4, 7.6, 1.2 Hz, H-3',6'), 6.95

(2H, ddd, J 8.4, 7.6, 1.2 Hz, H-2',7'), 6.74 (2H, dd, J 8.4, 1.2

Hz, H-4',5'), 6.47−6.50 (2H, m, H-3'',5''), 6.40−6.45 (2H, m, H-

2'',6''), 4.25 (2H, s, H-4), 3.61 (3H, s, MeO).

1

3.3.2. 1-Phenyl-spiro

[dihydroacridine-9'(10'H),5-

imidazolidine -2-one (21b), 3-(acridin-9-

]

ylmethyl)-1-phenylurea (22b)

Yield 44 mg, 90%. White solid. [Found: C 76.82; H 5.51; N

12.64; C₂₁H₁₇N₃O (327.38) requires C 77.04; H 5.23; N

12.84%]; ν_max3326, 1676, 1615, 1520, 1490, 1445, 1330,

1241, 750 cm^-1; ¹H NMR (400 MHz, mixture of products,

21b/22b = 1.12:1.0, for 21b) δ_H= 9.34 (1H, s, NH-10'), 7.29

(2H, d, J 7.6 Hz, H-1',8'), 7.14−7.24 (3H, m, NH-3,3',6'), 7.00–

7.06 (4H, m, H-2'',6'',3'',5''), 6.80−6.92 (5H, m, H-4'',4',5',2',7'),

3.57 (2H, s, H-4); (for 22b) 8.59 (2H, d, J 8.8 Hz, H-1',8'), 8.32

(1H, s, NH-1), 8.19 (2H, d, J 8.8 Hz, H-4',5'), 7.88 (2H, dd, J

8.0, 1.2 Hz, H-3',6'), 7.71 (2H, dd, J 8.0, 1.2 Hz, H-2',7'), 7.36

(2H, d, J 8.0 Hz, H-2'',6''), 7.14−7.24 (2H, m, H-3'',5''),

6.80−6.92 (1H, m, H-4''), 5.36 (2H, d, J 5.6 Hz, H-4).

3.2.4. 1-(4''-Bromophenyl)-spiro

[dihydroacridine-

9'(10'H),5-imidazolidine -2-thione (20d)

]

Yield 213 mg, 71%. Beige solid. Mp 190.0−191.0 °C. [Found:

C 59.53; H 3.90; N 9.78; C₂₁H₁₆BrN₃S (422.34) requires C

59.72; H 3.82; N 9.92%]; EI-MS (70eV): m/z (%) = 422 (MH⁺,

100), 389 (6), 344 (12), 209 (23), 195 (14); ν_max3399, 3184,

1613, 1583, 1511, 1486, 1407, 1191, 1010, 744, 620, 543, 447

cm^-1; ¹H NMR (400 MHz) δ_H= 9.29 (1H, s, NH-10'), 9.00 (1H,

s, NH-3), 7.51 (2H, d, J 7.8 Hz, H-1',8'), 7.16−7.26 (4H, m, H-

3',6',3'',5''), 7.00 (2H, t, J 7.8 Hz, H-2',7'), 6.77 (2H, d, J 8.0

Hz, H-4',5'), 6.48 (2H, d, J 8.8 Hz, H-2'',6''), 4.15 (2H, s, H-4).

3.3.3. 1-(4''-Methoxyphenyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (21c), 3-(acridin-9-ylmethyl)-1-(4-

3.2.5. 1-(4''-Nitrophenyl)-spiro

[dihydroacridine-

9'(10'H),5-imidazolidine -2-thione (20e)

]

methoxyphenyl)urea (22c)

Yield 177 mg, 64%. Yellow solid. Mp 185.0−187.0 °C.

Yield 27 mg, 50%. Bright yellow solid. [Found: C 73.77; H

5.44; N 11.74; C₂₂H₁₉N₃O₂(357.41) requires C 73.93; H 5.36;

N 11.76%]; ν_max3290, 1671, 1610, 1580, 1485, 1450, 1335,

1242, 750 cm^-1; ¹H NMR (400 MHz, mixture of products,

21c/22c = 24.0:1.0, for 21c) δ_H= 9.27 (1H, s, NH-10'), 7.38

(2H, d, J 7.6 Hz, H-1',8'), 7.16 (2H, dd, J 8.0, 7.6 Hz, H-3',6'),

7.05 (1H, s, NH-3), 6.86 (2H, t, J 7.6 Hz, H-2',7'), 6.82 (2H, d,

J 8.0 Hz, H-4',5'), 6.76 (2H, d, J 8.8 Hz, H-2'',6''), 6.59 (2H, d,

J 8.8 Hz, H-3'',5''), 3.64 (2H, s, H-4), 3.57 (3H, s, MeO); (for

22c) 8.57 (2H, dd, J 9.0, 1.2 Hz, H-1',8'), 8.16 (2H, dd, J 9.0,

1.8 Hz, H-4',5'), 8.10 (1H, s, NH-1), 7.85 (2H, ddd, J 9.0, 6.6,

1.2 Hz, H-3',6'), 7.68 (2H, ddd, J 8.4, 6.6, 1.8 Hz, H-2',7'), 7.24

(2H, d, J 9.0 Hz, H-2'',6''), 6.77 (2H, d, J 9.0 Hz, H-3'',5''), 6.70

(1H, t, J 6.0 Hz, NH-3), 5.32 (2H, d, J 6.0 Hz, H-4), 3.66 (3H,

s, MeO).

[Found: C 65.01; H 4.00; N 14.27; C₂₁H₁₆N₄O₂S (388.44)

requires C 64.93; H 4.15; N 14.42%]; ν_max3438, 3351, 1555,

1

1505, 1332, 1256, 846, 755 cm^-1; H NMR (400 MHz) δ_H

=

9.42 (1H, s, NH-10'), 9.36 (1H, s, NH-3), 7.94 (2H, dd, J 8.8,

1.6 Hz, H-3'',5''), 7.44 (2H, d, J 8.0 Hz, H-1',8'), 7.22 (2H, ddd,

J 8.0, 7.2, 1.6 Hz, H-3',6'), 7.04 (2H, dd, J 8.8, 1.6 Hz, H-

2'',6''), 6.93 (2H, dd, J 7.2, 1.6 Hz, H-2',7'), 6.84 (2H, d, J 8.0

Hz, H-4',5'), 4.08 (2H, s, H-4).

3.2.6. 1-Allyl-spiro

[dihydroacridine-9'(10'H),5-

imidazolidine -2-thione (20f)

]

Yield 140 mg, 64%. Bright yellow solid. Mp 156.0−158.0 °C.

[Found: C 70.09; H 5.32; N 13.45; C₁₈H₁₇N₃S (307.41)

requires C 70.33; H 5.57; N 13.67%]; ν_max3319, 3241, 1541,

1369, 1245, 914, 734 cm^-1; ¹H NMR (400 MHz) δ_H= 9.45 (1H,

s, NH-10'), 8.49 (1H, s, NH-3), 7.18−7.28 (4H, m, H-

1',8',3',6'), 6.84−6.94 (4H, m, H-2',7',4',5'), 5.31 (1H, ddd, J

3.3.4. 1-(4''-Bromophenyl)-spiro

[dihydroacridine-

9'(10'H),5-imidazolidine -2-one (21d), 3-(acridin-

]

17.2, 10.4, 6.0 Hz, H-2''), 4.62 (1H, dd, J 17.2, 1.6 Hz, H_trans

-

9-ylmethyl)-1-(4-bromophenyl)urea (22d)

3''), 4.59 (1H, dd, J 10.4, 1.6 Hz, H_cis-3''), 3.87 (2H, s, H-4),

3.74 (2H, d, J 6.0 Hz, H-1'').

Yield 34 mg, 56%. Yellow solid. [Found: C 62.02; H 3.76; N

10.15; C₂₁H₁₆BrN₃O (406.28) requires C 62.08; H 3.97; N

10.34%]; ν_max3300, 1673, 1615, 1585, 1490, 1450, 1325,

1238, 755 cm^-1; ¹H NMR (400 MHz, mixture of products,

21d/22d = 4.9:1.0, for 21d) δ_H= 9.39 (1H, s, NH-10'), 7.35

(1H, s, NH-3), 7.23 (2H, dd, J 7.6, 1.0 Hz, H-1',8'), 7.22 (2H,

d, J 7.2 Hz, H-3'',5''), 7.18 (2H, ddd, J 8.2, 6.6, 1.0 Hz, H-3',6'),

7.02 (2H, d, J 7.2 Hz, H-2'',6''), 6.89 (2H, d, J 8.2 Hz, H-4',5'),

6.83 (2H, dd, J 7.6, 6.6 Hz, H-2',7'), 3.54 (2H, s, H-4); (for

3.3. General procedure for the synthesis of 1-alkyl/aryl-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-ones

21a−f and 3-(acridin-9-ylmethyl)-1-(4''-X-phenyl)ureas

22b–e

To

a

solution of 1-alkyl/aryl-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-thiones 20a–f (0.15 mmol) in dry

ACCEPTED MANUSCRIPT

15

3.4.2. 1-Phenyl-3-(n-propyl)-

22d) 8.60 (2H, d, J 8.4 Hz, H-1',8'), 8.48 (1H, s, NH-1), 8.19

(2H, d, J 8.4 Hz, H-4',5'), 7.90 (2H, dd, J 8.4, 7.6 Hz, H-3',6'),

7.72 (2H, dd, J 8.4, 7.6 Hz, H-2',7'), 7.32−7.38 (4H, m, H-

2'',6'',3'',5''), 5.36 (2H, d, J 5.6 Hz, H-4).

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (27b)

Yield 207 mg, 67%. Light brown solid. Mp 257.0−258.0 °C.

[Found: C 74.59; H 6.15; N 11.08; C₂₄H₂₃N₃S (385.54)

requires C 74.77; H 6.01; N 10.90%]; ν_max3244, 1615, 1584,

1507, 1486, 1397, 1334, 1248, 1143, 896, 737, 696, 628, 538

cm^-1; ¹H NMR (600 MHz) δ_H= 9.21 (1H, s, NH-10'), 7.45 (2H,

dd, J 7.8, 1.5 Hz, H-1',8'), 7.17 (2H, ddd, J 8.1, 7.2, 1.5 Hz, H-

3',6'), 6.97−7.00 (3H, m, H- 3''',4''',5'''), 6.94 (2H, ddd, J 7.8,

7.2, 0.9 Hz, H-2',7'), 6.72 (2H, dd, J 8.1, 0.9 Hz, H-4',5'),

6.48−6.50 (2H, m, H-2''',6'''), 4.26 (2H, s, H-4), 3.74 (2H, t, J

7.2 Hz, H-1''), 1.67−1.73 (2H, m, H-2''), 0.96 (3H, t, J 7.8 Hz,

H-3'').

3.3.5. 1-(4''-Nitrophenyl)-spiro

[dihydroacridine-

9'(10'H),5-imidazolidine -2-one (21e), 3-(acridin-

]

9-ylmethyl)-1-(4-nitrophenyl)urea (22e)

Yield 33 mg, 59%. Yellow solid. [Found: C 67.81; H 4.39; N

14.81; C₂₁H₁₆N₄O₃(372.38) requires C 67.73; H 4.33, N 15.05

%]; ν_max3290, 1610, 1595, 1480, 1420, 1320, 1249, 750 cm^-1;

¹H NMR (400 MHz, mixture of products, 21e/22e = 99.0:1.0,

for 21e) δ_H= 9.53 (1H, s, NH-10'), 7.95 (2H, d, J 9.2 Hz, H-

3'',5''), 7.76 (1H, s, NH-3), 7.46 (2H, d, J 9.2 Hz, H-2'',6''), 7.20

(2H, dd, J 8.0, 6.6 Hz, H-3',6'), 7.16 (2H, d, J 8.0 Hz, H-1',8'),

6.95 (2H, d, J 8.0 Hz, H-4',5'), 6.83 (2H, dd, J 8.0, 6.6 Hz, H-

2',7'), 3.54 (2H, s, H-4); (for 22e) 9.09 (1H, s, NH-1), 8.57

(2H, d, J 8.4 Hz, H-1',8'), 8.17 (2H, d, J 9.0 Hz, H-4',5'), 8.11

(2H, d, J 9.0 Hz, H-3'',5''), 7.86 (2H, dd, J 9.0, 6.6 Hz, H-3',6'),

7.70 (2H, dd, J 8.4, 6.6 Hz, H-2',7'), 7.58 (2H, d, J 9.0 Hz, H-

2'',6''), 7.16 (1H, t, J 6.0 Hz, NH-3), 5.37 (2H, d, J 6.0 Hz, H-

4).

3.4.3. 1-(4'''-Methoxyphenyl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (27c)

Yield 188 mg, 57%. Light brown solid. Mp 199.0−200.0 °C.

[Found: C 72.01; H 6.00; N 10.30; C₂₅H₂₅N₃OS (415.55)

requires C 72.26; H 6.06; N 10.11%]; ν_max3244, 1613, 1584,

1509, 1486, 1451, 1374, 1326, 1249, 1128, 1028, 822, 746,

530, 520 cm^-1; ¹H NMR (600 MHz) δ_H= 9.19 (1H, s, NH-10'),

7.45 (2H, dd, J 8.7, 1.2 Hz, H-1',8'), 7.18 (2H, ddd, J 7.8, 7.8,

1.2 Hz, H-3',6′), 6.95 (2H, ddd, J 8.7, 7.8, 1.2 Hz, H-2',7'), 6.72

(2H, dd, J 7.8, 1.2 Hz, H-4',5'), 6.52−6.54 (2H, m, H-3''',5'''),

6.30−6.34 (2H, m, H-2''',6'''), 4.27 (2H, s, H-4), 3.73 (2H, t, J

7.8 Hz, H-1''), 3.57 (3H, s, MeO), 1.69−1.72 (2H, m, H-2''),

0.96 (3H, t, J 7.2 Hz, H-3'').

3.3.6. 1-Allyl-spiro

[dihydroacridine-9'(10'H),5-

imidazolidine -2-one (21f)

]

Yield 33 mg, 76%. White solid. Mp 207.0−208.0 °C. [Found:

C 74.07; H 6.10; N 14.19; C₁₈H₁₇N₃O (291.35): requires C

74.20; H 5.88; N 14.42%]; ν_max3340, 1625, 1580, 1455, 1245,

755 cm^-1; ¹H NMR (400 MHz) δ_H= 9.31 (1H, s, NH-10'), 7.32

(2H, dd, J 8.2, 1.2 Hz, H-1',8'), 7.19 (2H, ddd, J 8.2, 7.6, 1.2

Hz, H-3',6'), 6.88 (2H, ddd, J 8.2, 7.6, 1.2 Hz, H-2',7'), 6.85

(2H, dd, J 8.2, 1.2 Hz, H-4',5'), 6.67 (1H, s, NH-3), 5.35 (1H,

ddt, J 17.2, 10.4, 6.0 Hz, H-2''), 4.71 (1H, ddt, J 17.2, 1.6, 1.4

Hz, H_trans-3''), 4.66 (1H, ddt, J 10.4, 1.6, 1.4 Hz, H_cis-3''), 3.55

and 3.57 (2H, AB quartet, J 11.2 Hz, H-4), 3.39 (2H, ddd, J

6.0, 1.4, 1.4 Hz, H-1'').

3.4.4. 1-(4'''-Fluorophenyl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (27d)

Yield 135 mg, 42%. White solid. Mp 234.0−235.0 °C. [Found:

C 71.24; H 5.77; N 10.38; C₂₄H₂₂FN₃S (403.51) requires C

71.44; H 5.50; N 10.41%]; ν_max3261, 1613, 1584, 1508, 1486,

1

1386, 1343, 1332, 1250, 1135, 757, 629, 542, 471 cm^-1; H

3.4. General procedure for the synthesis of 1-alkyl/aryl-3-

(n-propyl)-spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-thiones 27a–e and 4-(acridin-9'''-yl)-3-(n-

propyl)-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

thione (27f)

NMR (600 MHz) δ_H= 9.23 (1H, s, NH-10'), 7.46 (2H, dd, J

8.4, 1.5 Hz, H-1',8'), 7.19 (2H, ddd, J 8.1, 6.9, 1.5 Hz, H-3',6'),

6.95 (2H, ddd, J 8.4, 6.9, 1.2 Hz, H-2',7'), 6.82−6.86 (2H, m,

H-3''',5'''), 6.73 (2H, dd, J 8.1, 1.2 Hz, H-4',5'), 6.42−6.45 (2H,

m, H-2''',6'''), 4.30 (2H, s, H-4), 3.74 (2H, t, J 7.2 Hz, H-1''),

1.69−1.74 (2H, m, H-2''), 0.96 (3H, t, J 7.2 Hz, H-3'').

To a stirred solution of N-(acridin-9-ylmethyl)propan-1-

amine (23, 200 mg, 0.8 mmol) in chloroform (3 mL),

appropriate isothiocyanate (1.2 equiv, 0.96 mmol) in a

chloroform solution (3 mL) was added at once. The reaction

mixture was stirred at room temperature for 6 h. The reaction

mixture turned heterogenous after few min and the

spiroproduct that precipitated was filtered off, washed with

diethyl ether, dried, and crystallized from the a mixture of

chloroform/diethyl ether or from chloroform/n-heptane (f).

3.4.5. 1-(4'''-Nitrophenyl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (27e)

Yield 293 mg, 85%. Yellow solid. Mp 268.0−269.0 °C.

[Found: C 66.94; H 5.07; N 13.14; C₂₄H₂₂N₄O₂S (430.52)

requires C 66.96; H 5.15; N 13.01%]; ν_max3290, 1607, 1583,

1501, 1486, 1455, 1342, 1248, 1135, 847, 755, 739, 692, 538

cm^-1; ¹H NMR (600 MHz) δ_H= 9.42 (1H, s, NH-10'),

7.90−7.94 (2H, m, H-3''',5'''), 7.38 (2H, dd, J 8.4, 1.5 Hz, H-

1',8'), 7.21 (2H, ddd, J 9.0, 8.4, 1.5 Hz, H-3',6'), 6.99−7.01

(2H, m, H-2''',6'''), 6.93 (2H, ddd, J 8.4, 1.2 Hz, H-2',7'), 6.84

(2H, dd, J 9.0, 1.2 Hz, H-4',5'), 4.23 (2H, s, H-4), 3.76 (2H, t, J

7.8 Hz, H-1''), 1.68−1.72 (2H, m, H-2''), 0.95 (3H, t, J 7.8 Hz,

H-3'').

3.4.1. 1-Methyl-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (27a)

Yield 182 mg, 70%. Yellow solid. Mp 226.0−227.0 °C.

[Found: C 70.45; H 6.40; N 13.08; C₁₉H₂₁N₃S (323.46)

requires C 70.55; H 6.54; N 12.99%]; ν_max3250, 1612, 1584,

1485, 1330, 1252, 1128, 741, 609, 522 cm^-1; ¹H NMR (600

MHz) δ_H= 9.42 (1H, s, NH-10'), 7.22 (2H, ddd, J 8.0, 7.2, 1.5

Hz, H-3',6'), 7.04 (2H, dd, J 8.1, 1.5 Hz, H-1',8'), 6.89−6.92

(4H, m, H-2',7',4',5'), 3.73 (2H, s, H-4), 3.57 (2H, t, J 7.2 Hz,

H-1''), 2.65 (1H, s, Me), 1.50−1.54 (2H, m, H-2''), 0.83 (3H, t,

J 7.2 Hz, H-3'').

3.4.6. 4-(Acridin-9'''-yl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (27f)

Yield 257 mg, 66%. Yellow solid. Mp 252.0−253.0°C. [Found:

C 76.20; H 5.25; N 11.32; C₃₁H₂₆N₄S (486.63) requires C

76.51; H 5.39; N 11.51%]; ν_max3263, 1612, 1583, 1474, 1438,

1327, 1206, 1145, 880, 741, 739, 658, 550, 468 cm^-1; ¹H NMR

ACCEPTED MANUSCRIPT

16

Tetrahedron

(600 MHz) δ_H= 9.95 (1H, s, NH-1), 8.83 (1H, s, NH-10'),

H-3''',5'''), 6.32−6.35 (2H, m, H-2''',6'''), 5.04 (2H, s, NCH₂),

8.13 (1H, dd, J 9.0 Hz, H-1'''), 7.97 (1H, dd, J 9.0, 1.8 Hz, H-

4'''), 7.94 (1H, dd, J 9.0, 0.6 Hz, H-5'''), 7.66−7.70 (2H, m, H-

3''',6'''), 7.62 (1H, dd, J 7.8, 1.2 Hz, H-1'), 7.44−7.61 (2H, m,

H-2''',8'''), 7.29−7.33 (2H, m, H-3',7'''), 7.12−7.15 (2H, m, H-

2',8'), 6.81 (1H, dd, J 7.8, 1.2 Hz, H-4'), 6.54 (1H, ddd, J 8.1,

7.2, 1.2 Hz, H-6'), 6.20 (1H, ddd, J 8.1, 7.2, 0.9 Hz, H-7'), 6.11

(1H, dd, J 8.1, 0.9 Hz, H-5'), 6.01 (1H, s, H-4), 4.12−4.17 (1H,

m, H-1''a), 2.36−2.41 (1H, m, H-1''b), 1.20−1.30 (2H, m, H-

2''), 0.63 (3H, t, J 7.8 Hz, H-3'').

4.13 (2H, s, H-4), 3.58 (3H, s, MeO).

3.5.4. 3-Benzyl-1-(4'''-fluorophenyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (28d)

Yield 163 mg, 54%. Yellow solid. Mp 272.0−273.0 °C.

[Found: C 74.63; H 5.12; N 9.04; C₂₈H₂₂FN₃S (451.56)

requires C 74.48; H 4.91; N 9.31%]; ν_max3261, 1614, 1584,

1487, 1450, 1393, 1329, 1260, 1151, 1065, 756, 634, 526, 468

cm^-1; ¹H NMR (600 MHz) δ_H= 9.21 (1H, s, NH-10'),

7.50−7.52 (2H, m, H-2'',6''), 7.41−7.44 (2H, m, H-3'',5''),

7.34−7.36 (3H, m, H-1',8',4''), 7.16 (2H, ddd, J 7.8, 7.2, 1.2 Hz,

H-3',6'), 6.84−6.90 (4H, m, H-2',7',3''',5'''), 6.70 (2H, dd, J 7.8,

1.2 Hz, H-4',5'), 6.42−6.46 (2H, m, H-2''',6'''), 5.05 (2H, s,

NCH₂), 4.17 (2H, s, H-4).

3.5. General procedure for the synthesis of 1-alkyl/aryl-3-

benzyl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

thiones

28a–e

and

4-(acridin-9'''-yl)-3-benzyl-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thione

(28f)

To

a

well

stirred

solution

of

N-(acridin-9-

3.5.5. 3-Benzyl-1-(4'''-nitrophenyl)-

spiro[dihydroacridine-9´(10'H),5-imidazolidine] -

2-thione (28e)

ylmethyl)benzylamine (24, 200 mg, 0.67 mmol) in chloroform

(3 mL) at room temperature, an appropriate isothiocyanate

(1.20 equiv, 0.80 mmol) in dry chloroform (3 mL) was added

at once. The reaction mixture turned heterogenous after few

min and the spiroproduct that precipitated was filtered off,

washed with diethyl ether, dried, and crystallized from a

mixture of chloroform/diethyl ether or chloroform/n-heptane

(f).

Yield 167 mg, 52%. Yellow solid. Mp 273.0−274.0 °C.

[Found: C 70.08; H 4.45; N 11.51; C₂₈H₂₂N₄O₂S (478.56)

requires C 70.27; H 4.63; N 11.71%]; ν_max3279, 1607, 1486,

1452, 1388, 1344, 1236, 1192, 1063, 943, 848, 760, 696, 632,

532 cm^-1; ¹H NMR (600 MHz) δ_H= 9.36 (1H, s, NH-10'),

7.91−7.94 (2H, m, H-3''',5'''), 7.49 (2H, dd, J 8.1, 1.2 Hz, H-

2'',6''), 7.39−7.42 (2H, m, H-3'',5''), 7.31−7.34 (1H, m, H-4''),

7.29 (2H, dd, J 8.4, 1.2 Hz, H-1',8'), 7.17 (2H, ddd, J 8.4, 7.2,

1.2 Hz, H-3',6'), 6.94−6.96 (2H, m, H-2''',6'''), 6.86 (2H, dd, J

8.4, 7.2, 1.2 Hz, H-2',7'), 6.77 (2H, dd, J 8.4, 1.2 Hz, H-4',5'),

5.06 (2H, s, NCH₂), 4.10 (2H, s, H-4).

3.5.1. 3-Benzyl-1-methyl-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-thione (28a)

Yield 149 mg, 60%. Light yellow solid. Mp 208.0−210.0 °C.

[Found: C 74.16; H 5.93; N 11.13; C₂₃H₂₁N₃S (371.50)

requires C 74.36; H 5.70; N 11.31%]; ν_max3278, 1612, 1583,

1518, 1483, 1450, 1383, 1320, 1255, 1239, 1155, 1090, 937,

893, 746, 729, 524, 451 cm^-1; ¹H NMR (600 MHz) δ_H= 9.43

(1H, s, NH-10'), 7.32−7.36 (4H, m, H-2'',6'',3'',5''), 7.25−7.28

(1H, m, H-4''), 7.21 (2H, ddd, J 8.4, 7.8, 1.5 Hz, H-3',6'), 7.01

(2H, dd, J 8.7, 1.5 Hz, H-1',8'), 6.90 (2H, dd, J 8.4, 1.2 Hz, H-

4',5'), 6.88 (2H, ddd, J 8.7, 7.8, 1.2 Hz, H-2',7'), 4.89 (2H, s,

NCH₂), 3.62 (2H, s, H-4), 2.71 (3H, s, Me).

3.5.6. 4-(Acridin-9'''-yl)-3-benzyl-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (28f)

Yield 129 mg, 36%. Yellow solid. Mp 227.0−228.0 °C.

[Found: C 78.60; H 4.99; N 10.57; C₃₅H₂₆N₄S (534.67)

requires C 78.62; H 4.90; N 10.48%]; ν_max3419, 3269, 1608,

1582, 1474, 1440, 1363, 1330, 1230, 1177, 1050, 759, 741,

1

513, 459, 420 cm^-1; H NMR (600MHz) δ_H= 10.19 (1H, s,

3.5.2. 3-Benzyl-1-phenyl-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-thione (28b)

NH-1), 8.72 (1H, s, NH-10'), 8.27 (1H, dd, J 7.8, 1.2 Hz, H-

1'''), 7.95−7.99 (2H, m, H-4''',5'''), 7.73 (1H, ddd, J 8.4, 6.6, 1.2

Hz, H-3'''), 7.63 (1H, ddd, J 8.4, 6.6, 1.2 Hz, H-6'''), 7.51−7.55

(2H, m, H-1',2'''), 7.22−7.26 (2H, m, H-3',8'), 7.15−7.02 (5H,

m, H-2',3'',4'',5'',7'''), 6.89 (2H, d, J 7.2 Hz, H-2'',6''), 6.85 (1H,

d, J 9.0 Hz, H-8'''), 6.70 (1H, dd, J 8.4, 1.5 Hz, H-4'), 6.57 (1H,

ddd, J 7.8, 7.5, 1.5 Hz, H-6'), 6.27 (1H, ddd, J 8.5, 7.5, 1.5 Hz,

H-7'), 6.08 (1H, dd, J 7.8, 1.5 Hz, H-5'), 5.77 (1H, d, J 15.0

Hz, NCH_a), 5.65 (1H, s, H-4), 3.41 (1H, d, J 15.0 Hz, NCH_b).

Yield 174 mg, 60%. Light brown solid. Mp 223.0−224.0 °C.

[Found: C 77.41; H 5.47; N 9.49; C₂₈H₂₃N₃S (433.57) requires

C 77.57; H 5.35; N 9.69%]; ν_max3301, 1611, 1582, 1517, 1484,

1

1432, 1310, 1220, 746, 693, 525 cm^-1; H NMR (600 MHz) δ_H

= 9.20 (1H, s, NH-10'), 7.52 (2H, d, J 7.2 Hz, H-2'',6''),

7.42−7.45 (2H, m, H-3'',5''), 7.36 (2H, d, J 7.8 1.2 Hz, H-1',8'),

7.34 (1H, t, J 8.4 Hz, H-4''), 7.16 (2H, dd, J 8.1, 1.2 Hz, H-

3',6'), 7.00−7.05 (3H, m, H-3''',4''',5'''), 6.89 (2H, ddd, J 7.8, 1.2

Hz, H-2',7'), 6.70 (2H, dd, J 8.1, 1.2 Hz, H-4',5'), 6.49−6.51

(2H, m, H-2''',6'''), 5.07 (2H, s, NCH₂), 4.15 (2H, s, H-4).

3.6. General procedure for the synthesis of 1-alkyl/aryl-3-

(n-propyl)-spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-ones 29a–e and 4-(acridin-9'''-yl)-3-(n-

propyl)-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

one (29f)

3.5.3. 3-Benzyl-1-(4'''-methoxyphenyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (28c)

To

a

solution

of

1-alkyl/aryl-3-(n-propyl)-

Yield 153 mg, 49%. Light brown solid. Mp 262.0−263.0 °C.

[Found: C 75.20; H 5.77; N 8.95; C₂₉H₂₅N₃OS (463.59)

requires C 75.13; H 5.44; N 9.06%]; ν_max3262, 1610, 1583,

1511, 1485, 1441, 1399, 1329, 1240, 1030, 755, 629, 519, 455

cm^-1; ¹H NMR (600 MHz) δ_H= 9.17 (1H, s, NH-10'), 7.50 (2H,

d, J 7.5 Hz, H-2'',6''), 7.43 (2H, m, H-3'',5''), 7.34 (2H, dd, J

7.8, 1.2 Hz, H-1',8'), 7.32−7.34 (1H, m, H-4''), 7.15 (2H, ddd, J

8.4, 7.2, 1.2 Hz, H-3',6'), 6.88 (2H, ddd, J 7.8, 7.2, 1.5 Hz, H-

2',7'), 6.68 (2H, dd, J 8.4, 1.5 Hz, H-4',5'), 6.53−6.56 (2H, m,

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones

27a−f (0.26 mmol) in dry acetonitrile (5 mL), mesitylnitrile

oxide (42 mg, 0.26 mmol) was added at once and the reaction

mixture was stirred at room temperature for 6 h. The reaction

was followed by TLC (petrolether/ethyl acetate, 2:1). After its

completion, the product was filtered off, washed with

petrolether, dried, and crystallized from

chloroform/diethyl ether or chloroform/n-heptane (f).

a mixture of

ACCEPTED MANUSCRIPT

17

3.6.1. 1-Methyl-3-(n-propyl)-

3.6.6. 4-(Acridin-9'''-yl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (29a)

2-one (29f)

Yield 64 mg, 80%. Light brown solid. Mp 209.0−210.0 °C.

[Found: C 74.03; H 6.72; N 13.45; C₁₉H₂₁N₃O (307.39)

requires C 74.24; H 6.89; N 13.67%]; ν_max3283, 1671, 1616,

1585, 1480, 1452, 1335, 1238, 1036, 986, 892, 742, 711, 623,

476, 423 cm^-1; ¹H NMR (600 MHz) δ_H= 9.30 (1H, s, NH-10'),

7.19 (2H, ddd, J 8.1, 7.2, 1.2 Hz, H-3',6'), 7.14 (2H, dd, J 7.8,

1.2 Hz, H-1',8'), 6.87−6.90 (4H, m, H-2',7',4',5'), 3.36 (2H, s,

H-4), 3.11 (2H, t, J 7.2 Hz, H-1''), 2.37 (3H, s, Me), 1.37−1.42

(2H, m, H-2''), 0.80 (3H, t, J 7.2 Hz, H-3'').

Yield 33 mg, 27%. Yellow solid. Mp 263.0−264.0 °C. [Found:

C 78.88; H 5.24; N 11.70; C₃₁H₂₆N₄O (470.56) requires C

79.12; H 5.57; N 11.91%]; ν_max3265, 1680, 1615, 1584, 1521,

1

1474, 1408, 1378, 1329, 1154, 1078, 742, 631, 496 cm^-1; H

NMR (600 MHz) δ_H= 8.47 (1H, s, NH-10'''), 8.31 (1H, d, J 9.0

Hz, H-1'''), 8.19 (1H, s, NH-1), 7.97 (1H, dd, J 7.8, 1.5 Hz, H-

5'''), 7.89 (1H, dd, J 8.4, 1.2 Hz, H-4'''), 7.78 (1H, dd, J 7.8, 1.2

Hz, H-1'), 7.64 (1H, ddd, J 8.4, 6.6, 1.2 Hz, H-6'''), 7.61 (1H,

ddd, J 8.4, 6.6, 1.2 Hz, H-3'''), 7.28−7.34 (3H, m, H-8',2''',8'''),

7.23 (1H, ddd, J 7.8, 7.2, 1.2 Hz, H-3'), 7.18 (1H, ddd, J 8.4,

6.6, 1.5 Hz, H-7'''), 7.12 (1H, ddd, J 7.8, 7.2, 1.2 Hz, H-2'),

6.56−6.61 (2H, m, H-4',6'), 6.43 (1H, ddd, J 7.8, 7.2, 1.2 Hz,

H-7'), 6.02 (1H, dd, J 7.2, 1.2 Hz, H-5'), 5.82 (1H, s, H-4),

3.46−3.49 (1H, m, H-1''a), 2.22−2.27 (1H, m, H-1''b),

1.12−1.16 (2H, m, H-2''), 0.64 (3H, t, J 7.8 Hz, H-3'').

3.6.2. 1-Phenyl-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (29b)

Yield 40 mg, 42%. Light brown solid. Mp 182.0−184.0 °C.

[Found: C 78.13; H 6.45; N 11.20; C₂₄H₂₃N₃O (369.46)

1

requires C 78.02; H 6.27; N 11.37%]; H NMR (600 MHz) δ_H

3.7. General procedure for the synthesis of 1-alkyl/aryl-3-

benzyl-spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-

= 9.35 (1H, s, NH-10'), 7.25 (2H, dd, J 8.4, 1.2 Hz, H-1',8'),

7.16 (2H, ddd, J 8.4, 7.2, 1.2 Hz, H-3',6'), 6.99−7.03 (4H, m,

ones

30a–e

and

4-(acridin-9'''-yl)-3-benzyl-

H-2''',6''',3''',5'''), 6.87 (2H, dd,

J 8.4, 0.9 Hz, H-4',5'),

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-one (30f)

6.80−6.85 (1H, m, H-4'''), 6.82 (2H, ddd, J 8.4, 7.2, 0.9 Hz, H-

2',7'), 3.62 (2H, s, H-4), 3.26 (2H, t, J 7.2 Hz, H-1''), 1.48−1.52

(2H, m, H-2''), 0.87 (3H, t, J 7.2 Hz, H-3'').

To

a

solution

of

1-alkyl/aryl-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-2-thiones

28a−f (0.26 mmol) in dry acetonitrile (5 mL), mesitylnitrile

oxide (42 mg, 0.26 mmol) was added at once and the reaction

mixture was stirred at room temperature for 6 h. The reaction

was followed by TLC (petrolether/ethyl acetate, 2:1). After its

completion, the product was filtered off, washed with

3.6.3. 1-(4'''-Methoxyphenyl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (29c)

Yield 72 mg, 69%. Light brown solid. Mp 220.0−221.0 °C.

[Found: C 75.08; H 6.20; N 10.32; C₂₅H₂₅N₃O₂(399.48)

requires C 75.16; H 6.31; N 10.52%]; ν_max3301, 1674, 1615,

1585, 1510, 1480, 1426, 1342, 1244, 1198, 1034, 825, 749,

628, 588, 528 cm^-1; ¹H NMR (600 MHz) δ_H= 9.27 (1H, s, NH-

10'), 7.35 (2H, dd, J 7.8, 1.2 Hz, H-1',8'), 7.14−7.17 (2H, m, H-

3',6'), 6.84−6.87 (2H, m, H-2',7'), 6.82 (2H, dd, J 8.4, 1.2 Hz,

H-4',5'), 6.74−6.76 (2H, m, H-2''',6'''), 6.57−6.60 (2H, m, H-

3''',5'''), 3.69 (2H, s, H-4), 3.57 (3H, s, MeO), 3.26 (2H, t, J 7.2

Hz, H-1''), 1.50−1.55 (2H, m, H-2''), 0.89 (3H, t, J 7.2 Hz, H-

3'').

petrolether, dried, and crystallized from

a mixture of

chloroform/diethyl ether or chloroform/n-heptane (f).

3.7.1. 3-Benzyl-1-methyl-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-one (30a)

Yield 73 mg, 79%. Brown solid. Mp 185.0−189.0 °C. [Found:

C 77.83; H 5.95; N 11.57; C₂₃H₂₁N₃O (355.43) requires C

77.72; H 5.96; N 11.82%]; ν_max3291, 1673, 1613, 1584, 1478,

1444, 1401, 1326, 1243, 1038, 876, 849, 748, 699, 612, 566,

480 cm^-1; ¹H NMR (600 MHz) δ_H= 9.30 (1H, s, NH-10'),

7.29−7.33 (2H, m, H-3'',5''), 7.24−7.25 (2H, m, H-2'',6''),

7.21−7.24 (1H, m, H-4''), 7.18 (2H, ddd, J 8.4, 7.5, 1.5 Hz, H-

3',6'), 7.11 (2H, dd, J 7.8, 1.5 Hz, H-1',8'), 6.88 (2H, dd, J 8.4,

1.2 Hz, H-4',5'), 6.87 (2H, ddd, J 7.8, 7.5, 1.2 Hz, H-2',7'), 4.38

(2H, s, NCH₂), 3.27 (2H, s, H-4), 2.43 (3H, s, Me).

3.6.4. 1-(4'''-Fluorophenyl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (29d)

Yield 85 mg, 84 %. White solid. Mp 231.0−232.0 °C. [Found:

C 74.20; H 5.99; N 10.74; C₂₄H₂₂FN₃O (387.45) requires C

74.40; H 5.72; N 10.85%]; ν_max3263, 1667, 1619, 1531, 1485,

1444, 1345, 1256, 1216, 1150, 1088, 831, 742, 696, 521, 499

cm^-1; ¹H NMR (600 MHz) δ_H= 9.35 (1H, s, NH-10'), 7.29 (2H,

dd, J 8.4, 1.5 Hz, H-1',8'), 7.15−7.19 (2H, m, H-3',6'),

6.93−6.96 (2H, m, H-2''',6'''), 6.83−6.90 (6H, m, H-2',7',

4',5',3''',5'''), 3.67 (2H, s, H-4), 3.27 (2H, t, J 7.2 Hz, H-1''),

1.49−1.54 (2H, m, H-2''), 0.89 (3H, t, J 7.8 Hz, H-3'').

3.7.2. 3-Benzyl-1-phenyl-spiro[dihydroacridine-

9'(10'H),5-imidazolidine]-2-one (30b)

Yield 67 mg, 62%. Yellow solid. Mp 196.0−197.0 °C. [Found:

80.37; H 5.67; N 10.07; C₂₈H₂₃N₃O (417.50) requires C 80.55;

H 5.55; N 10.06%]; ν_max3340, 1678, 1608, 1582, 1477, 1411,

1325, 1265, 1029, 884, 749, 692, 582, 517 cm^-1; ¹H NMR (600

MHz) δ_H= 9.30 (1H, s, NH-10'), 7.30−7.35 (4H, m, H-

2'',6'',3'',5''), 7.24−7.28 (1H, m, H-4''), 7.19 (2H, dd, J 7.5, 1.5

Hz, H-1',8'), 7.12 (2H, ddd, J 8.1, 7.2, 1.5 Hz, H-3',6'),

6.99−7.03 (4H, m, H-2''', 6''',3''',5'''), 6.83−6.86 (1H, m, H-4'''),

6.81 (2H, dd, J 8.1, 1.2 Hz, H-4',5'), 6.77 (2H, ddd, J 7.5, 7.2,

1.2 Hz, H-2',7'), 4.49 (2H, s, NCH₂), 3.50 (2H, s, H-4).

3.6.5. 1-(4'''-Nitrophenyl)-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (29e)

Yield 55 mg, 51%. Yellow solid. Mp 192.0−193.0 °C. [Found:

C 69.39; H 5.20; N 13.37; C₂₄H₂₂N₄O₃(414.46) requires C

69.55; H 5.35; N 13.52%]; ¹H NMR (600 MHz) δ_H= 9.55 (1H,

s, NH-10'), 7.93−7.95 (2H, m, H-3''',5'''), 7.46−7.49 (2H, m, H-

2''',6'''), 7.20 (2H, ddd, J 8.1, 7.2, 1.5 Hz, H-3',6'), 7.12 (2H, dd,

J 8.1, 1.5 Hz, H-1',8'), 6.99 (2H, dd, J 8.1, 1.2 Hz, H-4',5'), 6.81

(2H, ddd, J 8.1, 7.2, 1.2 Hz, H-2',7'), 3.60 (2H, s, H-4), 3.27

(2H, t, J 7.2 Hz, H-1''), 1.47−1.52 (2H, m, H-2''), 0.84 (3H, t, J

7.8 Hz, H-3'').

3.7.3. 3-Benzyl-1-(4'''-methoxyphenyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (30c)

Yield 85 mg, 73%. Light brown solid. Mp 264.0−265.0 °C.

[Found: C 77.77; H 5.48; N 9.22; C₂₉H₂₅N₃O₂(447.53)

requires C 77.83; H 5.63; N 9.39%]; ν_max3285, 1671, 1614,

ACCEPTED MANUSCRIPT

18

Tetrahedron

1585, 1510, 1486, 1436, 1341, 1244, 1026, 828, 748, 695,

and the insoluble residue was extracted three times with

boiling n-heptane (3×100 mL) for 30 min. The combined

heptane layers were dried over magnesium sulfate, the

dessicant filtered off, and the crude product, which precipitated

on cooling, was purified by crystallization from cyclohexane to

give the pure 9-ethylacridine in the yield 93%, whose mp

corresponded with the literature.²⁵

656, 543, 509 cm^-1; ¹H NMR (600 MHz) δ_H= 9.25 (1H, s, NH-

10'), 7.34−7.39 (4H, m, H-2'',6'',3'',5''), 7.28−7.30 (3H, m, H-

1',8',4''), 7.14 (2H, ddd, J 8.4, 7.2, 1.2 Hz, H-3',6'), 6.82 (2H,

ddd, J 8.4, 7.2, 1.2 Hz, H-2',7'), 6.79 (2H, dd, J 8.4, 1.2 Hz, H-

4',5'), 6.74−6.77 (2H, m, H-2''',6'''), 6.60−6.62 (2H, m, H-

3''',5'''), 4.52 (2H, s, NCH₂), 3.58 (2H, s, H-4), 3.58 (3H, s,

MeO).

To a solution of 31 (1.0 g, 4.8 mmol) in tetrachloromethane

(20 mL), N-bromosuccinimide (2.56 g, 14.40 mmol) and

azobisisobutyronitrile (0.12 g, 0.74 mmol) were added. The

reaction mixture was heated at 80 °C under irradiation by a 100

W halogen lamp (Philips) for 6 h. The reaction mixture was

3.7.4. 3-Benzyl-1-(4'''-fluorophenyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (30d)

Yield 90 mg, 79%. Brown solid. Mp 199.0−200.0 °C. [Found:

C 77.07; H 5.34; N 9.41; C₂₈H₂₂FN₃O (435.49) requires C

77.22; H 5.09; N 9.65%]; ¹H NMR (600 MHz) δ_H= 9.32 (1H,

s, NH-10'), 7.32−7.38 (4H, m, H-2'',6'',3'',5''), 7.27−7.30 (1H,

m, H-4''), 7.24 (2H, dd, J 7.8, 1.2 Hz, H-1',8'), 7.15 (2H, ddd, J

7.8, 7.5, 1.2 Hz, H-3',6'), 6.93−6.97 (2H, m, H-2''',6'''),

6.88−6.92 (2H, m, H-3''',5'''), 6.83 (2H, dd, J 7.8, 0.6 Hz, H-

4',5'), 6.80 (2H, ddd, J 7.8, 7.5, 0.6 Hz, H-2',7'), 4.52 (2H, s,

NCH₂), 3.57 (2H, s, H-4).

extracted with

a saturated aqueous solution of sodium

bicarbonate (3×20 mL) to remove succinimide, the organic

layer was dried over magnesium sulfate, filtered, evaporated,

and the residual oil was extracted with petrolether (3×15 mL),

combined organic layers were concentrated in vacuo to give

the pure 9-(1-bromoethyl)acridine (32). Yield 1.05 g, 73 %.

1

Yellow oil. H NMR (600 MHz) δ_H= 8.90 (1H, broad s) and

8.66 (1H, broad s - H-1',8'), 8.23 (2H, d, J 8.5 Hz, H-4',5'),

7.90 (2H, ddd, J 8.5, 6.6, 0.9 Hz, H-3',6'), 7.74−7.77 (2H, m,

H-2',7'), 7.02 (1H, q, J 7.2 Hz, CH), 2.34 (3H, d, J 7.2 Hz,

CH₃).

3.7.5. 3-Benzyl-1-(4'''-nitrophenyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (30e)

3.9. Synthesis of N-[1-(acridin-9-yl)ethyl]propan-1-amine

(33)

Yield 64 mg, 53%. Yellow solid. Mp 196.0−197.0 °C. [Found:

C 72.56; H 4.62; N 12.03; C₂₈H₂₂N₄O₃(462.50) requires C

72.71; H 4.79; N 12.11%]; ν_max3314, 1685, 1614, 1585, 1481,

To a solution of n-propylamine (310 mg, 0.43 mL, 5.25

mmol)

1429, 1320, 1268, 1112, 844, 745, 701, 468 cm^-1; H NMR

1

in

dry

tetrahydrofuran

(10

mL),

9-(1-

(600 MHz) δ_H= 9.51 (1H, s, NH-10'), 7.93−7.95 (2H, m, H-

3''',5'''), 7.47−7.49 (2H, m, H-2''',6'''), 7.28−7.31 (4H, m, H-

2'',6'',3'',5''), 7.24−7.26 (1H, m, H-4''), 7.15 (2H, ddd, J 7.5, 7.2,

0.6 Hz, H-3',6'), 7.07 (2H, d, J 7.8 Hz, H-1',8'), 6.90 (2H, dd, J

7.5, 0.6 Hz, H-4',5'), 6.75 (2H, dd, J 7.8, 7.2 Hz, H-2',7'), 4.52

(2H, s, NCH₂), 3.48 (2H, s, H-4).

bromoethyl)acridine (32, 500 mg, 1.75 mmol) and potassium

carbonate (0.266 g, 1.93 mmol) were added. The reaction

mixture was refluxed for 56 h, the solvent was evaporated in

vacuo and the pure product was obtained by column

chromatography (petrolether/ethyl acetate, 4:1). Yield 330 mg,

1

71%. Brown oil. H NMR (600 MHz) δ_H= 8.21 (1H, d, J 8.4

Hz, H-5'), 8.11 (1H, d, J 9.0 Hz, H-4'), 7.89−7.92 (1H, m, H-

8'), 7.88−7.91 (1H, m, H-6'), 7.76−7.79 (2H, m, H-1',3'), 7.68

(1H, ddd, J 7.2, 6.6, 1.8 Hz, H-7'), 7.54 (1H, broad, H-2'), 5.39

(1H, q, J 6.6 Hz, 4-CH), 2.47−2.51 (1H, m, CH_a), 2.06−2.11

(1H, m, CH_b), 1.65 (3H, d, J 6.6 Hz, 4-CH₃), 1.31−1.37 (2H,

m, CH₂), 0.74 (3H, t, J 7.2 Hz, CH₃); ¹³C NMR (150 MHz) δ_C

= 148.6 (C-10'a), 148.5 (C-4'a), 146.1 (C-9'), 131.2 (C-6'),

130.4 (C-4'), 130.1 (C-1',3'), 130.0 (C-5'), 127.7 (C-7'), 125.7

(C-2', broad), 125.2 (C-8'), 124.8 (C-9'a), 120.6 (C-8'a), 53.5

(4-CH), 50.6 (NCH₂), 23.3 (CH₂), 23.0 (Pr-CH₃), 12.3 (4-CH₃).

3.7.6. 4-(Acridin-9'''-yl)-3-benzyl-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-one (30f)

Yield 92 mg, 68%. Yellow solid. Mp 276.0−277.0 °C. [Found:

C 80.91; H 4.95; N 10.60; C₃₅H₂₆N₄O (518.61) requires C

81.06; H 5.05; N 10.80%]; ν_max3273, 1677, 1616, 1586, 1526,

1479, 1453, 1338, 880, 743, 703, 694 cm^-1; ¹H NMR (600

MHz) δ_H= 8.48 (1H, dd, J 8.4, 1.2 Hz, H-1'''), 8.40 (1H, s, NH-

1), 8.35 (1H, s, NH-10'), 7.95 (1H, dd, J 8.4, 1.2 Hz, H-5'''),

7.92 (1H, dd, J 8.4, 1.2 Hz, H-4'''), 7.65−7.63 (1H, m, H-3'''),

7.64−7.62 (1H, m, H-1'), 7.59 (1H, ddd, J 8.4, 6.6, 1.2 Hz, H-

6'''), 7.42 (1H, dd, J 7.8, 1.2 Hz, H-8'), 7.34 (1H, ddd, J 8.4,

6.6, 1.2 Hz, H-2'''), 7.12−7.16 (2H, m, H-3',4''), 7.06−7.09 (2H,

m, H-3'',5''), 7.03 (1H, ddd, J 7.8, 7.2, 1.2 Hz, H-2'), 6.94 (1H,

ddd, J 8.7, 6.6, 1.2 Hz, H-7'''), 6.76−6.78 (2H, m, H-2'',6''),

6.69−6.71 (1H, m, H-8'''), 6.62 (1H, ddd, J 8.1, 7.2, 1.2 Hz, H-

6'), 6.52 (1H, ddd, J 7.8, 7.2, 1.2 Hz, H-7'), 6.45 (1H, dd, J 7.8,

1.2 Hz, H-4'), 6.00 (1H, dd, J 8.1, 1.2 Hz, H-5'), 5.47 (1H, s,

H-4), 5.02 (1H, d, J 15.0 Hz, NCH_a), 3.22 (1H, d, J 15.0 Hz,

NCH_b).

3.10. General procedure for the synthesis of 1-aryl-3-(n-

propyl)-4-methyl-spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-thiones (35b–e)

To

a chloroform solution (3 mL) of N-[1-(acridin-9-

yl)ethyl]propan-1-amine (33, 100 mg, 0.38 mmol),

a

chloroform solution (3 mL) of apropriate isothiocyanate (1.20

equiv, 0.46 mmol) was added. The reaction mixture was stirred

at room temperature for 6 h. A small amount of the pure

product 35b–e was obtained by precipitation with diethyl ether

and used for NMR characterization. The filtrate was

evaporated to give the oil which, however, could not be

purified by chromatography as it decomposed on silica gel.

3.8. Synthesis of 9-(1-bromoethyl)acridine (32)

To prepare starting 9-ethylacridine (31),²⁵we have improved

the described procedure for 9-methylacridine.²³A mixture of

diphenylamine (10 g, 59.1 mmol) and propionic acid (13.13 g,

13.2 mL, 177.3 mmol) was heated in the presence of

anhydrous zinc chloride (40 g, 293.5 mmol) to 220 °C for 6 h

to give a black tarry product. Next day, the reaction mixture

was made strongly alkaline with aqueous ammonia (25 mL)

3.10.1. 4-Methyl-1-phenyl-3-(n-propyl)-

spiro[dihydroacridine-9'(10'H),5-imidazolidine]-

2-thione (35b)

Yield 101 mg, 67%. Yellow oil. ¹H NMR (600 MHz) δ_H= 9.31

(1H, s, NH-10'), 7.33 (1H, dd, J 7.8, 1.2 Hz, H-8'), 7.23 (1H,

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ddd, J 8.4, 6.6, 1.8 Hz, H-3'), 7.15 (1H, dd, J 7.8, 1.8 Hz, H-1'),

Supplementary data

7.10 (1H, ddd, J 8.4, 6.6, 1.2 Hz, H-6'), 7.02−7.05 (4H, m, H-

2''',6''',3''',5'''), 6.95−6.99 (1H, m, H-4'''), 6.92 (1H, dd, J 8.4,

1.2 Hz, H-4'), 6.88 (1H, ddd, J 7.8, 6.6, 1.2 Hz, H-2'),

6.79−6.82 (1H, m, H-7'), 6.77−6.81 (1H, m, H-5'), 3.98 (1H, q,

J 6.6 Hz, 4-CH), 3.86−3.91 (1H, m, H-1''a), 3.38−3.42 (1H, m,

H-1''b), 1.60−1.66 (1H, m, H-2''a), 1.52−1.60 (1H, m, H-2''b),

0.90 (3H, t, J 7.8 Hz, H-3''), 0.79 (3H, d, J 6.6 Hz, 4-CH₃).

Crystallographic data of 28e (CCDC 948527) have been

deposited at the Cambridge Crystallographic Database Centre.

These data can be obtained free of charge via

www.ccdc.cam.ac.uk/conts/retrieving.html (or from the

CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44

1223 336 033; e–mail: deposit@ccdc.cam.ac.uk).

3.10.2. 4-Methyl-1-(4'''-methoxyphenyl)-3-(n-

propyl)-spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-thione (35c)

References

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Yield 109 mg, 67%. Brown oil. ¹H NMR (600 MHz) δ_H= 9.25

(1H, s, NH-10'), 7.40 (1H, dd, J 7.8, 1.2 Hz, H-8'), 7.22 (1H,

ddd, J 8.4, 7.2, 1.2 Hz, H-3'), 7.19 (1H, dd, J 8.4, 1.2 Hz, H-1'),

7.10 (1H, ddd, J 7.8, 7.2, 1.2 Hz, H-6'), 6.87−6.91 (4H, m, H-

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3.10.3. 4-Methyl-1-(4'''-fluorophenyl)-3-(n-

propyl)-spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-thione (35d)

Yield 101 mg, 64%. Light brown oil. ν_max3247, 1608, 1581,

1473, 1318, 1245, 1157, 908, 810, 744, 603, 517, 499 cm^-1; ¹H

NMR (600 MHz) δ_H= 9.32 (1H, s, NH-10'), 7.38 (1H, dd, J

7.8, 1.2 Hz, H-8'), 7.27 (1H, ddd, J 8.4, 6.6, 1.2 Hz, H-3'), 7.16

(1H, dd, J 7.8, 1.2 Hz, H-1'), 7.13 (1H, ddd, J 7.8, 7.8, 1.2 Hz,

H-6'), 7.00−7.05 (2H, m, H-2''',6'''), 6.91−6.96 (4H, m, H-

2',4',3''',5'''), 6.84 (1H, ddd, J 7.8, 1.2 Hz, H-7'), 6.81 (1H, dd, J

7.8, 1.2 Hz, H-5'), 4.01 (1H, q, J 6.6 Hz, 4-CH), 3.85−3.90

(1H, m, H-1''a), 3.38−3.43 (1H, m, H-1''b), 1.61−1.68 (1H, m,

H-2''a), 1.53−1.61 (1H, m, H-2''b), 0.90 (3H, t, J 7.8 Hz, H-3''),

0.80 (3H, d, J 6.6 Hz, 4-CH₃).

3.10.4. 4-Methyl-1-(4'''-nitrophenyl)-3-(n-

propyl)-spiro[dihydroacridine-9'(10'H),5-

imidazolidine]-2-thione (35e)

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419–426.

Yield 110 mg, 66%. Brown oil. ν_max3366, 1613, 1581, 1480,

1

1453, 1417, 1312, 1234, 1110, 844, 743, 531 cm^-1; H NMR

(600 MHz) δ_H= 9.47 (1H, s, NH-10'), 7.97−8.00 (2H, m, H-

3''',5'''), 7.44−7.47 (2H, m, H-2''',6'''), 7.29 (1H, ddd, J 7.8, 7.2,

1.2 Hz, H-3'), 7.20 (1H, dd, J 7.8, 1.5 Hz, H-8'), 7.15 (1H, ddd,

J 7.8, 7.2, 1.5 Hz, H-6'), 7.02−7.04 (1H, m, H-1'), 7.01−7.02

(1H, m, H-4'), 6.90−6.91 (1H, m, H-5'), 6.90 (1H, ddd, J 7.8,

7.2, 1.2 Hz, H-2'), 6.77−6.80 (1H, m, H-7'), 3.97 (1H, q, J 6.6

Hz, 4-CH), 3.88−3.93 (1H, m, H-1''a), 3.37−3.42 (1H, m, H-

1''b), 1.60−1.66 (1H, m, H-2''a), 1.50−1.56 (1H, m, H-2''b),

0.88 (3H, t, J 7.8 Hz, H-3''), 0.78 (3H, d, J 6.6 Hz, 4-CH₃).

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Acknowledgements

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This work was supported by the Grant Agency for Science of

the Slovak Ministry of Education (VEGA), grant no.

1/0672/11, the Slovak State NMR Programme No.

2003SP200280203, and the ITMS project 26110230056,

supported by the Operational Program Education funded by the

European Social Fund. Assoc. Prof. I. Potočnák is gratefully

acknowledged for crystallographic analysis of the compound

28e, Dr. Slávka Bekešová for the mass spectra measurements,

Dr. I. Danihel and Assoc. Prof. S. Böhm for quantum chemical

calculations, and Prof. P. Kristian, Assoc. Prof. J. Bernát and

Dr. K. D. Klika for valuable suggestions.

ACCEPTED MANUSCRIPT

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Tetrahedron

Article Doi

Spontaneous cyclization of (acridin-9-ylmethyl)thioureas to spiro [dihydroacridine-9′(10′H),5-imidazolidine]-2-thiones, a novel type of acridine spirocycles

DOI: 10.1016/j.tet.2013.12.001

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