New approaches to the synthesis of 4-(2-aminophenyl)-1,3-dihydro-2H- imidazol-2-ones and 3-ureidoindoles and a study of their interconversion

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Helvetica Chimica Acta – Vol. 91 (2008)

New Approaches to the Synthesis of 4-(2-Aminophenyl)-1,3-dihydro-2H-

imidazol-2-ones and 3-Ureidoindoles and a Study of Their Interconversion

by Antonín Kla´sek*^a), Antonín Lycˇka^b), Michal Holcˇapek^c), and Igna´c Hoza^d)

^a) Department of Chemistry, Faculty of Technology, Tomas Bata University, CZ-76272 Zlín

(e-mail: klasek@ft.utb.cz)

^b) Research Institute for Organic Syntheses, Rybitví 296, CZ-53354 Pardubice 20

^c) Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice,

CZ-53210 Pardubice

^d) Department of Food Engineering, Faculty of Technology, Tomas Bata University, CZ-76272 Zlín

ˇ

Dedicated to Professor Vojeslav Sterba on the occasion of his 85th birthday

3-Alkyl/aryl-3-ureido-1H,3H-quinoline-2,4-diones (2) and 3a-alkyl/aryl-9b-hydroxy-3,3a,5,9b-tetra-

hydro-1H-imidazo[4,5-c]quinoline-2,4-diones (3) react in boiling concentrated HCl to give 5-alkyl/aryl-

4-(2-aminophenyl)-1,3-dihydro-2H-imidazol-2-ones (6). The same compounds were prepared by the

same procedure from 2-alkyl/aryl-3-ureido-1H-indoles (4), which were obtained from the reaction of 3-

alkyl/aryl-3-aminoquinoline-2,4(1H,3H)-diones (1) with 1,3-diphenylurea or by the transformation of

3a-alkyl/aryl-9b-hydroxy-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones (3) and 5-alkyl/

aryl-4-(2-aminophenyl)-1,3-dihydro-2H-imidazol-2-ones (6) in boiling AcOH. The latter were converted

into 1,3-bis[2-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)phenyl]ureas (5) by treatment with triphosgene. All

compounds were characterized by ¹H- and ¹³C-NMR and IR spectroscopy, as well as atmospheric

pressure chemical-ionisation mass spectra.

1. Introduction. – In our laboratory, much attention has been paid to study the

reactivity of 3-alkyl/aryl-3-hydroxy-quinoline-2,4(1H,3H)-diones and their 3-amino

analogues 1 [1 – 9]. Both types of compounds readily rearrange into other heterocyclic

systems. In the case of the 3-hydroxy derivatives, thermally induced rearrangement

produces dioxindoles or 3,1-benzoxazin-2-ones [1][2], rearrangement in an alkaline

environment produces dioxindoles and 2-hydroxyindoxyls [3]. 3-Amino derivatives

rearrange, when treated with urea in boiling AcOH, to yield imidazo[1,5-c]quinazoline-

3,5-diones [4] or 3-ureidoindolin-2-ones [5]. The reaction of 3-aminoquinoline-2,4-

diones 1 with nitrourea in dioxane was successful in preparing anticipated reaction

intermediates of this rearrangement [6][7], whereas the reaction with isocyanates

yielded 3’-substituted 3-ureidoquinoline-2,4-diones 2 or their cyclic isomers 3 [8].

These compounds rearrange in boiling AcOH to give either mixtures of 3-

ureidoindoles 4 and 1,3-disubstituted ureas 5, or merely 1,3-disubstituted ureas 5

(Scheme 1) [9]. Refluxing compounds 4 in conc. HCl changes the indole system into

imidazolinone, and compounds 6 prepared in this manner provide compounds 5 by a

reaction with triphosgene [9].

The discovery that the addition products of 3-aminoquinoline-2,4-diones and

isocyanates (2 and 3) rearrange to indole and imidazolinone derivatives, opens up a

ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 91 (2008)

355

Scheme 1

path for the preparation of new compounds of type 4, 5, and 6, which may be interesting

structures for studying biological activity. For example, 2-phenyl-3-semicarbazidoin-

doles, which have a structure similar to 4, display antimicrobial and antihistaminic

activity [10][11]; interesting biological activity is described for many imidazolin-2-ones

[12], and a number of 1,3-diarylureas act as anti-cytokinine agents [13].

Transformation of compounds 2 and/or 3 to compounds 4 occurs only in rather low

yield, and the main or even sole product in most cases are 1,3-disubstituted ureas 5 [9].

Another difficulty is, that mixtures of 4 and 5 can be separated only with great

difficulty. For that reason, we tried to find reaction conditions where 3-ureidoindoles 4

or imidazolinones 6 arise, while the formation of compounds 5 is limited. This paper

describes the results achieved in this matter so far.

2. Results and Discussion. – Our first aim was to find reaction conditions that would

enable us to prepare 3-ureidoindoles 4 directly from a-amino ketones 1. In one of our

earlier papers [6], we described that 3-aminoquinoline-2,4-diones 1 in boiling AcOH

yield products of molecular rearrangement not only in the reaction with urea but also in

reactions with monosubstituted or 1,1-disubstituted ureas (butylurea, phenylurea, 1,1-

dibenzylurea). Under the given reaction conditions, monosubstituted or 1,1-disubsti-

tuted ureas split into the respective amine and isocyanic acid, which reacts with

3-aminoquinoline-2,4-diones 1 giving rise to intermediates analogous to 2 and 3

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Helvetica Chimica Acta – Vol. 91 (2008)

(R³¼ H), subject of molecular rearrangement. This fact led to the idea that, under

similar reaction conditions, 1,3-disubstituted ureas could produce the corresponding

amine and isocyanate that would react with 1 to yield intermediates 2 and/or 3, which

subsequently rearrange to the products 4. This assumption was confirmed, and from the

reaction of 3-aminoquinolones 1f, 1h, and 1l with 1,3-diphenylurea in boiling AcOH

(Scheme 2) the rearranged compounds 4f, 4h, and 4l were isolated as the main products

(Table 1, Method A).

Scheme 2

As a side product, acetanilide was isolated. Additionally, in one single case, the

diarylurea 5l was obtained in negligible quantities. Other side products, which exhibited

a molecular peak of even m/z values in the mass spectra were obtained in two cases

(starting from 1f and 1l). Their molecular peaks split into two primary fragments, which

differ by a value of m/z 26. Such splitting of the molecular ion is typical for 1,3-

disubstituted ureas [9] and, therefore, we propose structure 7 for the side products of

the reaction of compounds 1f and 1l with 1,3-diphenylurea (Scheme 2). This proposal

was confirmed by synthesizing 7 from 6 and phenyl isocyanate. The formation of

compounds 7f and 7l may be explained by a reaction mechanism analogous to that of

the transformation of compounds 2 and 3 into 4 and 5 via an intermediate A [9]

(Scheme 2). The reaction of amines 1 with diphenylurea (Table 1, Method A) gives

generally lower yields of 4 than the reaction of 2 or 3, which are transformed to 4 in

boiling AcOH [9]; but the formation of 1,3-diarylureas is limited in every case.

However, the disadvantage of the direct transformation of 1 into 4 (Method A) is its

limitation to 3-ureidoindoles 4 that bear a Ph group in position 1’ (R³¼ Ph). When

compounds 1 were reacted with 1,3-dibutylurea, we merely obtained inseparable

mixtures of products. A further disadvantage of the direct transformation of 1 to 4 is the

difficult chromatographic separation of 4 from the reaction mixture containing

considerable quantities of unreacted 1,3-diphenylurea and acetanilide. A considerable

proportion of compounds displaying a polar character also arose, and these could not

Helvetica Chimica Acta – Vol. 91 (2008)

357

Table 1. Preparation of 3-Ureidoindoles 4 from Compounds 1 (Method A), 2 (Methods B and E), 3

(Methods B and E), and 6 (Method D)

Entry

Starting compound

Method

Reaction time [h]

Products (Yield [%])

R¹

R²

R³

1

2

3

4

5

6

7

8

2a

3a

6a

6b

3c

6c

2d

6d

3e

6e

1f

Bu

Ph

Bu

Ph

H

Me

Bu

PhCH₂

Bu

Ph

Bu

Ph

Bu

Ph

Bu

Ph

Bu

Ph

Bu

Ph

Bu

Ph

E

B

D

E

D

E

D

E

D

A

D

A

B

D

E

D

A

D

E

B

D

B

E

D

1 þ 1.5

4a (68)

1.5

4a (18), 5a (67)

4a (31), 5a (53)

4a (45)

4a (30)

4b (31)

4c (82)

4c (67)

4d (65)

4e (42), 6e (31)

4e (28)

4f (21), 7f (8)

4f (29), 7f (6)

4f (76)

4g (86)

4h (33)

4h (36), 5h (28)

4h (56)

4i (53)

1.5

3

1.5

1

1 þ 1.5

1

9

1 þ 1.5

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

1

1 þ 1.5

2

1.5

2

1

3

4.5

0.5

4

3.5

2.5

1 þ 1.5

1

1f

6f

6g

1h

3h

6h

6i

6j

4j (36)

4k (67)

3k

6k

1l

4k (43), 8k (16), 6k (7)

4l (47), 5l (3), 7l (8)

4l (58)

4m (53), 6m (12), 8m (9)

4m (4), 5m (51), 6m (12)

4m (14), 6m (25), 8m (21)

4n (4), 5n (34), 6n (32)

4n (77)

6

3

6l

Bu

3m

6m

3n

6n

PhCH₂

1 þ 1.5

0.5

5

0.5

1 þ 1.5

1.5

3

4n (21), 8n (16), 6n (32)

4n (16), 8n (25), 6n (32)

be separated by chromatography. For this reason, we abandoned this path for preparing

3-ureidoindoles 4 and sought for other possibilities.

We propose a reaction mechanism with a rearrangement of compounds 2 and 3 in

boiling AcOH to 4 and 5 (or 5 only) via the formation of an intermediate A’ (Scheme 3)

[9]. This intermediate partly hydrolyses to give 6, which is transformed to 4 as indicated

in Scheme 4. However, at the same time, A’ reacts with 6 to yield the disubstituted urea

5. It can be assumed that, in the presence of excess H₂O, compounds 4 should arise as

the sole products. Therefore, we carried out the rearrangement of compounds 2a and

3a, 3h, 3m, and 3n in aqueous AcOH (Method B). However, the results of these

experiments (Table 1, Entries 2, 3, 18, 27, and 29) show that even under these reaction

conditions, intermediate A’ reacts with the amino group of 6, and mixtures of 4 and 5

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Helvetica Chimica Acta – Vol. 91 (2008)

Scheme 3

Scheme 4

arise. In cases where R¹¼ Ph, compounds 6 are obtained as well (Table 1, Entries 27 and

29). This finding is in accordance with the fact that, in these cases, the tendency for

intramolecular addition of the amino group in 6 is lowered [9]. Because the use of

Method B does not lead to satisfactory results, these experiments were discontinued.

Compounds 6 are also possible sources for the preparation of 3-ureidoindoles 4. As

already described [9], compounds 6 are unstable in polar solvents, and some of them

were converted back to compounds 4 during NMR spectra collection in (D₆)DMSO.

This conversion is particularly easy when R²¼ H. However, there is a question how 6

Helvetica Chimica Acta – Vol. 91 (2008)

359

can be easily prepared. We have described the transformation of 3-ureidoindoles 4a,

4b, 4f, 4h, 4i, 4j, and 4l to imidazolones 6a, 6b, 6f, 6h, 6i, 6j, and 6l (Scheme 1) by boiling

compounds 4 in HCl [9]. Compounds 4c, 4d, 4e, 4g, 4k, 4m, and 4n have not been

available earlier, because only 1,3-disubstituted ureas 5 were isolated from the

corresponding reaction mixtures after reacting the corresponding compounds 2 or 3

with urea in AcOH. However, the easy transformation of 3-ureidoindoles 4 into

imidazolinones 6 led us to reason that compounds 6 could also be formed by direct

transformation of ureidoquinolinediones 2 or their cyclic isomers 3 in strongly acidic

aqueous environments. This assumption was fully confirmed, and the corresponding

dihydroimidazolones 6 were isolated in high yields from the reactions of 2a – 2d or 3c,

3e – 3n with conc. HCl (Table 2, Method C). Acid-catalyzed rearrangement of 2 or 3

(Scheme 3) gives rise to carbocation B, followed by the opening of the indolone ring

under formation of intermediate A’. The latter immediately hydrolyses in a strongly

acidic aqueous environment to give dihydroimidazolone 6 and, therefore, formation of

disubstituted ureas 5 cannot take place.

Table 2. Preparation of Dihydroimidazolones 6, from Compounds 2, 3, 4, and 8 under Reflux in conc.

HCl (Method C)^a)^b)

Entry Starting

Reaction Product

(Yield [%])

Entry Starting

Reaction Product

compound time [h]

compound time [h] (Yield [%])

1

2

3

4

5

6

7

8

2a

2

1

4

1

0.5

2.5

2

0.5

1.5

2

6a (80)

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

4g

3h

3i

1

0.5

2

1

6g (83)

6a (54)

6a (76)

6b (74)

6c (79)

6c (78)

6c (68)

6d (83)

6d (79)

6e (75)

6e (80)

6f (83)

6f (73)

6f (63)

6g (92)

6h (66)

6h (52)

6i (72)

6j (50)

6k (85)

6k (75)

6k (65)

6l (78)

6m (72)

6m (79)

6m (49)

6n (73)

6n (54)

6n (53)

3a

2b

2c

3c

4c

2d

4d

3e

4e

3f

3g

3j

3k

4k

8k

3l

3m

4m

8m

3n

4n

8n

9

1.5

1

10

11

12

13

14

15

1

0.5

2.5

1

3

1

^a) For substituents, see Table 1. ^b) Conversion of compounds 4a, 4b, 4f, 4h, 4i, 4j, and 4l to the

corresponding compounds 6 has been described in [9].

Now we found that reconversion of 6 into ureidoindoles 4 may be successfully

executed in boiling AcOH (Table 1, Method D). In a weakly acidic environment,

compounds 6 undergo an intramolecular nucleophilic addition of the amino group to

form intermediate C. The intermediateꢁs imidazolidinone ring is opened, and

ureidoindoles 4 are formed (Scheme 4).

The anticipated intermediates C are aza-analogues of hexahydropyrrolo[2,3-

b]indole alkaloids, which are cyclic analogues of N-acylated derivatives of tryptophane.

It is well-known, that these alkaloids and their synthetic analogues arise from N-

acylated tryptophane derivatives in a strongly acidic environment but, under weakly

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Helvetica Chimica Acta – Vol. 91 (2008)

acidic conditions, they reconvert into acyclic tautomers [14 – 18]. The transformation of

6 to 4 via the intermediate C bears a certain distant analogy to the conversions of

hexahydropyrrolo[2,3-b]indoles. Despite all efforts, we did not succeed in our earlier

work [9] and have not yet succeeded in isolating or trapping anticipated intermediates

C. In a majority of cases, heating 6 in AcOH to reflux merely provided the

corresponding compounds 4 (Table 1, Method D). However, the reaction of 6k, 6m,

and 6n in AcOH gave, apart from the corresponding products 4k, 4m, and 4n and

unreacted 6k, 6m, and 6n, other side products (8k, 8m, and 8n). These compounds

revert to 6 in boiling conc. HCl (Table 2, Method C). Hence, 6k, 6m, and 6n, which

differ from other compounds 6 by the presence of a Ph group at C(5) of the

imidazolone nucleus, obviously convert only slowly into indole derivatives 4 by heating

in AcOH, and a competitive transformation into acetylated compounds 8 occurs

(Scheme 4). The structure of 8 was confirmed by its synthesis from 6 and Ac₂O. The

reason why this transformation from 6 to 8 does not take place in the case of 6l, which

bears a Ph group at C(5) like 6k, 6m, and 6n, is an issue we failed to resolve.

Rearrangement of compounds 2 or 3 in conc. HCl (Table 2, Method C) offers high

yields of imidazolinones 6 (mostly in a 74 – 92% range). In a number of cases, however,

the following transformation of 6 into ureidoindoles 4 (Table 1, Method D) shows

substantially lower yields (28 – 86%). If the target products are compounds 4, it is much

more favorable to prepare them from compounds 2 or 3 by performing a two-stage

reaction without isolating an intermediate (Scheme 3, Table 1, Method E). Compounds

4a, 4c, 4d, 4k, and 4n were prepared from 2a, 3c, 2d, 3k, and 3n in this manner with

yields of 65 – 82% (Table 1). In the cases of 3e and 3m, compounds 6 were obtained

additionally to 4 (Table 1).

In our previous work [9], we described the preparation of 5a, 5f, 5h, 5i, 5j, and 5l by

a reaction of the corresponding dihydroimidazolones 6 with triphosgene (bis(trichlor-

omethyl) carbonate). The other compounds of type 5 could not be prepared because

ureidoindoles 4 were not available from the reactions of 2 and/or 3 in AcOH, thus

dihydroimidazolones 6 could not be prepared either. But now, having in hand the

relevant compounds 6 from the reaction of 2 and/or 3 in conc. HCl, we attempted to

prepare the remaining 5c, 5d, 5e, 5g, 5k, 5m, and 5n. As in our previous work [9], we

found that compounds 6 react with triphosgene at room temperature in CH₂Cl₂very

slowly, even though this procedure has been currently employed by other groups

[19][20]. The disubstituted ureas 5e, 5g, 5k, 5m, and 5n were obtained by performing

the reaction in boiling benzene and in the presence of a catalytic quantity of 4-

(dimethylamino)pyridine (Scheme 5). Preparation failed only in cases where 6 is not

substituted at C(1) (R²¼ H). Similar to our previous work [9], where compound 5a was

prepared in only 6% yield and preparation of 5b was not possible, we obtained 5c in

only 12% yield and failed to prepare 5d.

In conclusion, we would like to emphasise that the elaborated methods enable us to

prepare 3-ureidoindoles 4 and/or dihydroimidazolones 6 from 3-aminoquinolinediones

1 via the intermediates 2 or 3 in high yields. The unprecedented mutual transformation

of 4 and 6 is not merely of theoretical importance but enables, through a simple

procedure, a targeted preparation of new types of compounds suitable for biological

testing as well as for studying further transformations, particularly in the case of

dihydroimidazolones 6 bearing a reactive aniline fragment.

Helvetica Chimica Acta – Vol. 91 (2008)

361

Scheme 5

This study was supported by the Ministry of Education, Youth and Sports of the Czech Republic

(Grant No. MSM 7088352101) and Czech Science Foundation (grant No. 203/07/0320). M. H.

acknowledges the support of grant projects MSM 0021627502 (the Ministry of Education, Youth and

Sports of the Czech Republic) and 203/05/2106 (Czech Science Foundation). The authors thank Mrs. H.

ˇ

´

Gerzova (Faculty of Technology, Tomas Bata University in Zlín), and Mr. R. Jirasko (University of

Pardubice) for technical help.

Experimental Part

1. General. Reactions, as well as the course of separation and also the purity of substances, were

monitored by TLC (elution systems benzene/AcOEt, 4 :1 (solvent system S3), CHCl₃/EtOH, 9 :1 (S4)

and/or 19 :1 (S5), and CHCl₃/AcOEt, 7:3 ( S6)) on Alugram^ꢀSIL G/UV₂₅₄foils (Macherey-Nagel).

Column chromatography (CC) was carried out on silica gel (Merck, grade 60, 70 – 230 mesh), using

CHCl₃, and then successive mixtures of CHCl₃/EtOH (99 :1 to 8 :2, solvent system S1) or benzene, and

then successive mixtures of benzene/AcOEt (99 :1 to 8 :2, solvent system S2). M.p.: Kofler block or

Gallencamp apparatus. IR (KBr) Spectra: Mattson 3000 spectrophotometer. NMR Spectra were

recorded on a Bruker Avance spectrometer (500.13 MHz for ¹H and 125.76 MHz for ¹³C) in (D₆)DMSO.

¹H and ¹³C chemical shifts are given on the d scale (in ppm) and are referenced to internal TMS. All 2D

experiments (gradient-selected (gs)-COSY, NOESY, gs-TOCSY, gs-HMQC, gs-HMBC) were per-

formed using the manufacturerꢁs software. ¹H-NMR Spectra were assigned using gs-COSY. Protonated

C-atoms were assigned by gs-HMQC. Quaternary C-atoms were assigned by gs-HMBC. The positive-ion

atmospheric pressure chemical ionization (APCI) mass spectra were measured on an ion trap analyzer

Esquire 3000 (Bruker Daltonics) within the mass range m/z 50 – 500. Samples were dissolved in MeCN

and analyzed by direct infusion at the flow rate of 50 ml/min. The ion-source temp. was 3508, the APCI

probe temp. was 3008, the flow rate and the pressure of N₂were 4 l/min and 45 psi, resp. For MS/MS

measurements, the isolation width of precursor ions was 4 m/z and the collision amplitude was 1 V.

Elemental analyses (C, H, N): EA 1108 Elemental Analyzer (Fisons Instrument).

Starting compounds 2 and 3 were prepared from the corresponding compounds 1 according to the

protocol described in [8]. Yields of products 4, 6, and 8 are given in Tables 1 and 2.

2. General Procedures for the Preparation of (1H-Indol-3-yl)ureas 4 and 4-(2-Acetamidophenyl)-1,3-

dihydroimidazol-2-ones 8. Method A. A soln. of 1 (0.5 mmol) and 1,3-diphenylurea (117mg, 0.55 mmol)

in AcOH (2 ml) was heated to reflux for the time given in Table 1. After cooling, the precipitated crystals

were filtered off with suction and recrystallized from an appropriate solvent. In cases when crystallization

failed, the mixtures were evaporated in vacuo to dryness, and the residue was crystallized from an

appropriate solvent. In some cases, mother liquors were chromatographed on silica gel using solvent

systems S1 or S2.

Method B. A soln. of 2 or 3 (0.5 mmol) in aq. AcOH (70% v/v, 6 ml) was heated to reflux for the time

given in Table 1. After cooling, the solvent was evaporated in vacuo to dryness, and the residue was

crystallized from an appropriate solvent. In some cases, mother liquors were worked up by CC on silica

gel.

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Helvetica Chimica Acta – Vol. 91 (2008)

Method D. A soln. of 6 (0.5 mmol) in AcOH (6 ml) was heated to reflux for the time given in Table 1.

Following treatment of the reaction mixture, workup was carried out as described in Method B.

Method E. A soln. of compound 2 or 3 (0.5 mmol) in conc. HCl (5 ml) was heated to reflux for 1 h.

After cooling, the soln. was evaporated in vacuo to dryness, the residue was dissolved in pyridine (5 ml),

anh. K₂CO₃(350 mg) was added, and the mixture was stirred for 1 h. Insoluble material was filtered off,

the filtrate was evaporated do dryness, dissolved in AcOH (5 ml), and the mixture was heated to reflux

for 1.5 h. After cooling, the solvent was evaporated in vacuo to dryness, and the residue was crystallized

from an appropriate solvent. In some cases, mother liquors were separated by CC on silica gel.

2.1. 1-Butyl-1-(2-butyl-1H-indol-3-yl)urea (4a). Prepared from 2a (Methods B (besides 5a) and E),

3a (Method B), and 6a (Method D). Colorless crystals. M.p. 136 – 1418 (benzene/hexane), identical in all

respects to authentic 4a of m.p. 135 – 1428, prepared from 2a and 3a [9].

2.2. 1-(2-Butyl-1H-indol-3-yl)-1-phenylurea (4b). Prepared from 6b (Method D). Colorless crystals.

M.p. 205 – 2088 (AcOEt), identical in all respects to authentic 4b of m.p. 204 – 2088, prepared from 2b [9].

2.3. 1-Butyl-1-(2-phenyl-1H-indol-3-yl)urea (4c). Prepared from 3c (Method E) and 6c (Method D).

Colorless crystals. M.p. 212 – 2158 (benzene). IR: 3445, 3306, 3218, 3195, 3064, 2952, 2932, 2869, 1641,

1581, 1491, 1464, 1453, 1427, 1379, 1356, 1339, 1309, 1279, 1231, 1179, 1036, 1115, 1074, 1028, 1008, 965,

921, 764, 739, 697, 630, 614, 564. ¹H- and ¹³C-NMR: see Table 3. APCI-MS (pos.): 308 (28, [M þ H]^þ), 291

(100, [M þ HꢀNH₃]^þ), 263 (36, [M þ HꢀNH₃ꢀCO]^þ). APCI-MS/MS (pos.) of m/z 308: 291 (100,

[M þ HꢀNH₃]^þ). APCI-MS (neg.): 306 (100, [M ꢀ H]^ꢀ), 261 (18, [M ꢀ HꢀCOOH]^ꢀ), 233 (4, [M ꢀ

HꢀBuNH₂]^ꢀ). APCI-MS/MS (neg.) of m/z 306: 263 (43, [M ꢀ HꢀNHCO]^ꢀ), 249 (75, [M ꢀ

HꢀBu]^ꢀ), 206 (100, [M ꢀ HꢀBuꢀNHCO]^ꢀ). Anal. calc. for C₁₉H₂₁N₃O (307.39): C 74.24, H 6.89, N

13.67; found: C 74.32, H 6.92, N 13.51.

2.4. 1-Phenyl-1-(2-phenyl-1H-indol-3-yl)urea (4d). Prepared from 2d (Method E) and 6d (Method

D). Colorless crystals. M.p. 250 – 2568 (benzene). IR: 3458, 3394, 3318, 3190, 3061, 1659, 1579, 1492, 1453,

1404, 1340, 1264, 1239, 1198, 1148, 1073, 1030, 829, 763, 741, 693, 637, 616, 564, 519. ¹H- and ¹³C-NMR: see

Table 3. APCI-MS (pos.): 328 (67 , M[ þ H]^þ), 311 (55, [M þ HꢀNH₃]^þ), 283 (100, [M þ

HꢀCOOH]^þ), 206 (3, [M þ HꢀCOOHꢀPh]^þ). APCI-MS/MS (pos.) of m/z 328: 311 (100, [M þ

HꢀNH₃]^þ), 284 (5, [M þ HꢀNH₂CO]^þ), 209 (6, [M þ HꢀPhNCO]^þ). APCI-MS (neg.): 326 (100,

[M ꢀ H]^ꢀ), 282 (94, [M ꢀ HꢀNH₂CO]^ꢀ). APCI-MS/MS (neg.) of m/z 326: 283 (100, [M ꢀ

HꢀNH₂CO]^ꢀ). Anal. calc. for C₂₁H₁₇N₃O (327.38): C 77.04, H 5.23, N 12.84; found: C 77.14; H 5.36,

N 12.69.

2.5. 1-Butyl-1-(2-butyl-1H-indol-3-yl)-3-methylurea (4e). Prepared from 3e (Method E, besides 6e)

and from 6e (Method D). Colorless crystals. M.p. 127– 130 8 (hexane). IR: 3348, 3249, 2959, 2930, 2872,

2745, 1613, 1523, 1458, 1409, 1383, 1292, 1227, 1185, 1144, 1124, 1011, 924, 768, 743, 715, 646, 568, 521. ¹H-

and ¹³C-NMR: see Table 3. APCI-MS (pos.): 302 (100, [M þ H]^þ), 271 (45, [M þ HꢀMeNH₂]^þ), 243

(50, [M þ HꢀMeNH₂ꢀCO]^þ), 215 (22, [M þ HꢀMeNH₂ꢀbutene]^þ), 172 (79, [M þ

HꢀMeNH₂ꢀbuteneꢀNHCO]^þ). APCI-MS/MS (pos.) of m/z 302: 271 (100, [M þ HꢀMeNH₂]^þ),

243 (72, [M þ HꢀMeNH₂ꢀCO]^þ), 215 (37, [M þ HꢀMeNH₂ꢀbutene]^þ), 172 (79, [M þ

HꢀMeNH₂ꢀbuteneꢀNHCO]^þ). APCI-MS (neg.): 300 (100, [M ꢀ H]^ꢀ), 269 (3, [M ꢀ HꢀMeNH₂]^ꢀ).

APCI-MS/MS (neg.) of m/z 300: 243 (100, [M ꢀ HꢀBu]^ꢀ), 186 (45, [M ꢀ Hꢀ2 Bu]^ꢀ), 170 (5, [M ꢀ

HꢀBuꢀBuNH₂]^ꢀ). Anal. calc. for C₁₈H₂₇N₃O (301.43): C 71.72, H 9.03, N 13.94; found: C 71.62, H

9.14, N 13.79.

2.6. 1-(2-Butyl-1H-indol-3-yl)-3-methyl-1-phenylurea (4f). Prepared from 1f (Method A) and from

6f (Method D). Colorless crystals. M.p. 208 – 2148 (AcOEt), identical in all respects to authentic 4f of

m.p. 204 – 2088, prepared from 3f [9]. In a small quantity (8 and 6%, resp.), a side-product with

m.p. 229 – 2348 (benzene/hexane), identical in all respects to synthetic 7f (Section 6.1), was isolated from

the reactions of 1f with diphenylurea (Method A).

2.7.1,3-Dibutyl-1-(2-butyl-1H-indol-3-yl)urea (4g). Prepared from 6g (Method D). Yellowish oil. IR:

2958, 2929, 2870, 1708, 1639, 1586, 1517, 1458, 1379, 1330, 1287, 1225, 1178, 1148, 1128, 1014, 924, 845, 767,

1

743, 624, 522. H- and ¹³C-NMR: see Table 3. APCI-MS (pos.): 344 (100, [M þ H]^þ), 271 (13, [M þ

HꢀBuNH₂]^þ), 243 (12, [M þ HꢀBuNHCOH]^þ), 215 (5, [M þ HꢀBuNH₂ꢀbutene]^þ). APCI-MS/

MS (pos.) of m/z 344: 271 (85, [M þ HꢀBuNH₂]^þ), 243 (100, [M þ HꢀBuNHCOH]^þ), 215 (32, [M þ

HꢀBuNH₂ꢀbutene]^þ), 172 (54, [M þ HꢀBuNH₂ꢀbuteneꢀNHCO]^þ). APCI-MS (neg.): 342 (100,

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363

364

Helvetica Chimica Acta – Vol. 91 (2008)

[M ꢀ H]^ꢀ), 241 (3, [M ꢀ HꢀPhNHCOH]^ꢀ). APCI-MS/MS (neg.) of m/z 342: 285 (19, [M ꢀ HꢀBu]^ꢀ),

243 (100, [M ꢀ HꢀPhNCO]^ꢀ), 186 (94, [M ꢀ HꢀPhNCOꢀBu]^ꢀ), 143 (7, [M ꢀ HꢀPhNCOꢀ

BuꢀNHCO]^ꢀ). Anal. calc. for C₂₁H₃₃N₃O (343.51): C 73.43, H 9.68, N 12.23; found: C 73.31, H 9.75,

N 12.13.

2.8. 3-Butyl-1-(2-butyl-1H-indol-3-yl)-1-phenylurea (4h). Prepared from 1h (Method A), 3h

(Method B, besides 5h), and 6h (Method D). Colorless crystals. M.p. 166 – 1698 (benzene/hexane),

identical in all respects to authentic 4h of m.p. 168 – 1718, prepared from 3h [9].

2.9. 3-Benzyl-1-butyl-1-(2-butyl-1H-indol-3-yl)urea (4i). Prepared from 6i (Method D). Colorless

crystals. M.p. 135 – 1408 (benzene/hexane), identical in all respects to authentic 4i of m.p. 137– 142 8,

prepared from 3i [9].

2.10. 3-Benzyl-1-(2-butyl-1H-indol-3-yl)-1-phenylurea (4j). Prepared from 6j (Method D). Colorless

crystals. M.p. 152 – 1568 (cyclohexane), identical in all respects to authentic 4j of m.p. 153 – 1578,

prepared from 3j [9].

2.11. 1,3-Dibutyl-1-(2-phenyl-1H-indol-3-yl)urea (4k). Prepared from 3k (Method E) and from 6k

(Method D, besides 8k and unreacted 6k). Colorless crystals. M.p. 150 – 1538 (benzene/hexane). IR:

3426, 3185, 2956, 2929, 2870, 1632, 1585, 1518, 1455, 1383, 1335, 1285, 1227, 1147, 1113, 1032, 1007, 916,

764, 744, 695, 633, 613, 563. ¹H- and ¹³C-NMR: see Table 3. APCI-MS (pos.): 364 (100, [M þ H]^þ), 291

(10, [M þ HꢀBuNH₂]^þ). APCI-MS/MS (pos.) of m/z 364: 291 (100, [M þ HꢀBuNH₂]^þ), 265 (51,

[M þ HꢀBuNCO]^þ), 235 (9, [M þ HꢀBuNH₂ꢀbutene]^þ). APCI-MS (neg.): 362 (100, [M ꢀ H]^ꢀ), 261

(4, [M ꢀ HꢀBuNHCOH]^ꢀ). APCI-MS/MS (neg.) of m/z 362: 305 (12, [M ꢀ HꢀBu]^ꢀ), 263 (52, [M ꢀ

HꢀBuNCO]^ꢀ), 206 (100, [M ꢀ HꢀBuNCOꢀBu]^ꢀ). Anal. calc. for C₂₃H₂₉N₃O (363.50): C 76.00, H

8.04, N 11.56; found: C 75.88, H 8.15, N 11.39.

2.12. 4-(2-Acetamidophenyl)-1,3-dibutyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one (¼ N-[2-(1,3-Di-

butyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]acetamide; 8k). Prepared from 6k (Method

D, besides 4k and unreacted 6k). Colorless crystals. M.p. 135 – 1378 (hexane). IR: 3290, 3074, 2956, 2936,

2871, 1679, 1604, 1580, 1526, 1454, 1443, 1406, 1372, 1296, 1257, 1209, 1115, 1074, 1009, 944, 869, 769, 760,

703, 677, 649, 597, 550, 535. ¹H- and ¹³C-NMR: see Table 4. APCI-MS (pos.): 406 (100, [M þ H]^þ), 364 (3,

[M þ HꢀNCO]^þ). APCI-MS/MS (pos.) of m/z 406: 364 (100, [M þ HꢀNCO]^þ), 332 (7, [M þ

Hꢀbutene]^þ), 307(15, [ M þ HꢀNCOꢀBu]^þ), 291 (11, [M þ HꢀNCOꢀBuNH₂]^þ), 265 (42, [M þ

HꢀNCOꢀBuNCO]^þ). APCI-MS (neg.): 404 (100, [M ꢀ H]^ꢀ). APCI-MS/MS (neg.) of m/z 404: 362

(5, [M ꢀ HꢀNCO]^ꢀ), 348 (32, [M ꢀ Hꢀbutene]^ꢀ), 306 (100, [M ꢀ HꢀbuteneꢀNCO]^ꢀ), 263 (16, [M ꢀ

HꢀNCOꢀBuNCO]^ꢀ), 206 (8, [M ꢀ HꢀNCOꢀBuNCOꢀBu]^ꢀ). Anal. calc. for C₂₅H₃₁N₃O₂(405.53): C

74.04, H 7.70, N 10.36; found: C 74.18, H 7.56, 10.29.

2.13. 3-Butyl-1-phenyl-1-(2-phenyl-1H-indol-3-yl)urea (4l). Prepared from 1l (Method A) and from

6l (Method D). Colorless crystals. M.p. 230 – 2328 (AcOH), identical in all respects to authentic 4l of

m.p. 226 – 2308, prepared from 3l [9]. Two side products were isolated besides 4l from the reaction of 1l

with diphenylurea: compound of m.p. 224 – 2298 (benzene/hexane), identical in all respects to synthetic

7l (Section 6.2) and compound of m.p. 260 – 2658, identical in all respects to authentic 5l, prepared from 3l

[9].

2.14. 3-Benzyl-1-butyl-1-(2-phenyl-1H-indol-3-yl)urea (4m). Prepared from 3m (Method E, besides

6m and 8m and Method B, besides 5m and 6m) and from 6m (Method D, besides 6m and 8m). Colorless

crystals. M.p. 164 – 1668 (benzene/hexane). IR: 3419, 3061, 2955, 2928, 2969, 1638, 1603, 1584, 1512, 1452,

1

1418, 1383, 1333, 1296, 1227, 1167, 1113, 1027, 965, 827, 763, 738, 719, 693, 612, 563H. - and ¹³C-NMR: see

Table 3. APCI-MS (pos.): 398 (100, [M þ H]^þ), 381 (3, [M þ HꢀNH₃]^þ), 291 (25, [M þ

HꢀNH₃ꢀMeC₆H₃]^þ). APCI-MS/MS (pos.) of m/z 398: 381 (33, [M þ HꢀNH₃]^þ), 291 (100, [M þ

HꢀNH₃ꢀMeC₆H₃]^þ), 235 (17, [M þ HꢀNH₃ꢀMeC₆H₃ꢀbutene]^þ), 193 (4, [M þ HꢀNH₃ꢀ

MeC₆H₃ꢀbuteneꢀNCO]^þ). APCI-MS (neg.): 396 (100, [M ꢀ H]^ꢀ), 261 (9, [M ꢀ HꢀC₆H₆ꢀBu]^ꢀ),

233 (7, [M ꢀ HꢀC₆H₆ꢀBuꢀCO]^ꢀ). APCI-MS/MS (neg.) of m/z 396: 339 (17, [M ꢀ HꢀBu]^ꢀ), 295 (18,

[M ꢀ HꢀBuNHCOH]^ꢀ), 263 (77, [M ꢀ HꢀBuꢀC₆H₆]^ꢀ), 206 (100, [M ꢀ Hꢀ2 BuꢀC₆H₆]^ꢀ). Anal. calc.

for C₂₆H₂₇N₃O (397.51): C 78.56, H 6.85, N 10.57; found: C 78.41, H 6.94, N 10.41.

2.15. 4-(2-Acetamidophenyl)-1-benzyl-3-butyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one (¼ N-[2-(1-

Benzyl-3-butyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]acetamide; 8m). Prepared from 6m

(Method D, besides 4m and 6m). Colorless crystals. M.p. 120 – 1218 (hexane). IR: 3410, 3315, 3063, 3032,

Helvetica Chimica Acta – Vol. 91 (2008)

365

Table 4. ¹H- and ¹³C-Chemical Shifts (d [ppm]) of Compounds 7 and 8 in (D₆)DMSO

Position

7f

7l

8k

8m

8n

d_Hd_C

d_H

d_C

d_H

d_C

d_H

d_C

d_H

d_C

2

4

5

1’

2’

3’

4’

5’

–

152.5

–

152.2

115.8

123.0

117.8

138.8

119.6 7.79

129.1 7.35

121.6 7.12

132.5 7.24

–

152.9

116.5

121.1

137.8

123.7 7.76

129.4 7.35

124.0 7.14

132.4 7.26

–

153.1

117.3

121.2

121.4

137.9

124.0 7.66

129.1 7.17

124.2 6.91

132.4 7.03

129.1

126.5

128.4

127.0

–

152.5

117.0

122.4

113.9

122.7–

118.2

138.9

–

120.4

137.9

122.9

129.3

123.5

132.1

128.9

8.06 119.6 7.90

7.27 129.1 7.21

6.95 121.8 6.85

7.11 132.0 7.13

2.42 22.8

1.50 30.1

1.23 21.6

0.74 13.4

6’

1’ (R¹)

2’ (R¹)

3’ (R¹)

4’ (R¹)

1’ (R²)

2’ (R²)

3’ (R²)

4’ (R²)

5’ (R²)

1’ (R³)

2’ (R³)

3’ (R³)

4’ (R³)

C(2’)ꢀNHCO

NHPh

–

128.8

–

129.0

–

a

b

)

129.4 7.29

128.5 7.34

127.2 7.12

128.4 7.32

127.9 7.24

)

a

b

3.34 27.7 3.86, 3.60 40.1 3.73, 3.60 40.7^c) 4.97, 4.78 44.5 5.02, 4.84 44.7

–

1.52

1.23

0.81

–

30.9 1.38

19.4 1.15

13.5

–

30.8^c) –

138.2

128.2

128.4

127.9

–

137.9

19.2^c) 7.23

13.4^c) 7.18

)

b

d

b

)

b

–

7.23

135.4

–

135.2 3.56, 3.31 40.7^c) 3.62, 3.32 41.0

–

135.5

a

b

7.12 126.4

7.23 128.4

7.16 126.5

9.14 152.1 9.03

7.85

)

126.8 1.38

128.5 1.15

126.9

151.9 8.96

30.8^c) 1.41

19.2^c) 1.14

13.4^c) 0.75

168.3 9.10

30.8

19.2

13.4

)

a

b

d

b

)

168.3 9.09

167.6

7.84

–

NHPh or NHMe –

139.6

139.6 1.96

118.5

128.9

23.6 1.98

23.6 1.86

23.7

7.44 118.3 7.42

7.29 128.9 7.33

7.02 122.0 7.03

122.0

b

^a) Strong overlap of ¹H resonances (d(¹H) ¼ 7.16 – 7.35). ) Strong overlap of ¹H and ¹³C resonances of

c

three Ph groups, d(¹H) ¼ 7.16 – 7.36 (m, 15 H), d(¹³C) ¼ 129.9, 128.5, 128.4, 127.0, 126.9, 126.7.

)

¹³C

Resonances of appropriate pairs in two Bu group signals differ maximally in 0.04 ppm. ^d) d(¹H) ¼ 0.77 or

0.72.

2957, 2930, 2871, 1678, 1606, 1580, 1530, 1497, 1451, 1402, 1368, 1299, 1252, 1209, 1030, 975, 941, 764, 752,

724, 701, 659, 598, 550. ¹H- and ¹³C-NMR: see Table 4. APCI-MS (pos.): 440 (100, [M þ H]^þ). APCI-MS/

MS (pos.) of m/z 440: 422 (10, [M þ H ꢀ H₂O]^þ), 398 (9, [M þ HꢀNCO]^þ), 349 (100, [M þ

HꢀMeC₆H₄]^þ), 332 (6, [M þ HꢀMeC₆H₄ꢀNH₃]^þ), 307(21, [ M þ HꢀMeC₆H₄ꢀNCO]^þ). APCI-MS

(neg.): 438 (100, [M ꢀ H]^ꢀ). APCI-MS/MS (neg.) of m/z 438: 382 (5, [M ꢀ HꢀBu]^ꢀ), 347(43, [ M ꢀ

HꢀMeC₆H₅]^þ), 304 (100, [M ꢀ HꢀMeC₆H₅ꢀNHCO]^þ), 291 (4, [M ꢀ HꢀMeC₆H₅ꢀbutene]^þ), 262

(5, [M ꢀ HꢀMeC₆H₅ꢀNCO]^þ). Anal. calc. for C₂₈H₂₉N₃O₂(439.55): C 76.51, H 6.65, N 9.56; found: C

76.35, H 6.69, N 9.39.

2.16. 3-Benzyl-1-phenyl-1-(2-phenyl-1H-indol-3-yl)urea (4n). Prepared from 3n (Method B, besides

5n and 6n or Method E), and from 6n (Method D, besides 8n and 6n). Colorless crystals. M.p. 222 – 2248

(benzene/hexane). IR: 3427, 3342, 3061, 3027, 2949, 1669, 1620, 1584, 1512, 1491, 1454, 1374, 1321, 1284,

1244, 1151, 1113, 1075, 1028, 918, 741, 696, 632, 562, 517. ¹H- and ¹³C-NMR: see Table 3. APCI-MS

366

Helvetica Chimica Acta – Vol. 91 (2008)

(pos.): 418 (100, [M þ H]^þ), 401 (3, [M þ HꢀNH₃]^þ), 311 (11, [M þ HꢀNH₃ꢀMeC₆H₃]^þ), 283 (51,

[M þ HꢀNH₃ꢀMeC₆H₃ꢀCO]^þ). APCI-MS/MS (pos.) of m/z 418: 401 (52, [M þ HꢀNH₃]^þ), 375 (8,

[M þ HꢀNHCO]^þ), 311 (100, [M þ HꢀNH₃ꢀMeC₆H₃]^þ), 285 (54, [M þ HꢀC₆H₅CH₂NCO]^þ).

APCI-MS (neg.): 416 (100, [M ꢀ H]^ꢀ), 282 (41, [M ꢀ HꢀPhꢀBu]^ꢀ), 255 (3, [M ꢀ HꢀPhꢀBu ꢀ

HCN]^ꢀ). APCI-MS/MS (neg.) of m/z 416: 283 (100, [M ꢀ HꢀPhꢀbutene]^ꢀ). Anal. calc. for

C₂₈H₂₃N₃O (417.50): C 80.55, H 5.55, N 10.06; found: C 80.42, H 5.67, N 10.11.

2.17. 4-(2-Acetamidophenyl)-1-benzyl-3,5-diphenyl-1,3-dihydro-2H-imidazol-2-one (¼ N-[2-(1-Ben-

zyl-2-oxo-3,5-diphenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]acetamide; 8n). Prepared from 6n (Method

D, besides 4n and 6n). Colorless crystals. M.p. 237– 241 8 (benzene/hexane). IR: 3341, 3335, 3061, 2953,

1677, 1595, 1579, 1520, 1493, 1453, 1383, 1296, 1253, 1231, 1158, 1125, 1042, 1015, 957, 887, 820, 781, 763,

1

747, 736, 710, 700, 651, 592, 519, 502. H- and ¹³C-NMR: see Table 4. APCI-MS (pos.): 460 (100, [M þ

H]^þ), 416 (15, [M þ HꢀNCO]^þ). APCI-MS/MS (pos.) of m/z 460: 442 (50, [M þ H ꢀ H₂O]^þ), 418

(32, [M þ HꢀNCO]^þ), 401 (9, [M þ HꢀNCOꢀNH₃]^þ), 369 (100, [M þ HꢀMeC₆H₄]^þ), 352 (12,

[M þ HꢀMeC₆H₄ꢀNH₃]^þ), 327(48, [ M þ HꢀMeC₆H₄ꢀNCO]^þ), 309 (11, [M þ HꢀMeC₆H₄ꢀ

NCO ꢀ H₂O]^þ). APCI-MS (neg.): 458 (100, [M ꢀ H]^ꢀ), 416 (5, [M ꢀ HꢀNCO]^ꢀ). APCI-MS/MS

(neg.) of m/z 458: 416 (12, [M ꢀ HꢀNCO]^ꢀ), 325 (55, [M ꢀ HꢀC₆H₅CH₂NCO]^ꢀ), 282 (100, [M ꢀ

HꢀC₆H₅CH₂NCOꢀNCO]^ꢀ). Anal. calc. for C₃₀H₂₅N₃O₂(459.54): C 78.41, H 5.48, N 9.14; found: C

78.29, H 5.62, N 9.09.

3. General Procedure for the Preparation of 4-(2-Aminophenyl)-1,3-dihydro-2H-imidazol-2-ones (6)

from Compounds 2, 3, 4, and 8 (Method C). A soln. of respective starting compound 2, 3, 4, and 8

(2.5 mmol) in conc. HCl (25 ml) was heated to reflux for the time given in Table 2. If necessary, AcOH

was added to dissolve poorly soluble starting compound. After cooling, the soln. was evaporated in vacuo

to dryness. The residue was dissolved in pyridine (5 ml), anh. K₂CO₃(350 mg) was added and the mixture

was stirred for 1 h. The insoluble material was filtered off, the filtrate was evaporated to dryness, and the

residue was crystallized from an appropriate solvent or separated by CC on silica gel.

3.1. 5-(2-Aminophenyl)-1,4-dibutyl-1,3-dihydro-2H-imidazol-2-one (6a). Prepared from 2a and 3a.

Colorless crystals. M.p. 134 – 1398 (benzene/cyclohexane), identical in all respects to authentic 6a of

m.p. 135 – 1408, prepared from 4a [9].

3.2. 5-(2-Aminophenyl)-4-butyl-1-phenyl-1,3-dihydro-2H-imidazol-2-one (6b). Prepared from 2b.

Colorless crystals. M.p. 134 – 1408 (without recrystallization), identical in all respects to authentic 6b of

m.p. 138 – 1418, prepared from 4b [9].

3.3. 5-(2-Aminophenyl)-1-butyl-4-phenyl-1,3-dihydro-2H-imidazol-2-one (6c). Prepared from 2c, 3c,

and 4c. Colorless crystals. M.p. 167– 169 8 (benzene/hexane). IR: 3457, 3345, 3142, 3057, 2959, 2933, 2871,

1675, 1615, 1604, 1574, 1506, 1490, 1453, 1403, 1376, 1361, 1310, 1264, 1158, 1115, 1077, 1031, 969, 935, 908,

751, 693, 665, 520, 498. ¹H- and ¹³C-NMR: see Table 5. APCI-MS (pos.): 308 (100, [M þ H]^þ), 291 (59,

[M þ HꢀNH₃]^þ), 263 (28, [M þ HꢀCOOH]^þ). APCI-MS/MS (pos.) of m/z 308: 291 (100, [M þ

HꢀNH₃]^þ), 265 (15, [M þ HꢀNHCO]^þ), 252 (21, [M þ Hꢀbutene]^þ), 235 (22, [M þ HꢀNH₃ꢀ

butene]^þ), 209 (29, [M þ HꢀBuNCO]^þ). APCI-MS (neg.): 306 (100, [M ꢀ H]^ꢀ), 261 (11, [M ꢀ

HꢀCOOH]^ꢀ), 233 (4, [M ꢀ HꢀBuNH₂]^ꢀ). APCI-MS/MS (neg.) of m/z 306: 263 (82, [M ꢀ

HꢀNHCO]^ꢀ), 249 (92, [M ꢀ HꢀBu]^ꢀ), 206 (100, [M ꢀ HꢀBuꢀNHCO]^ꢀ). Anal. calc. for C₁₉H₂₁N₃O

(307.39): C 74.24, H 6.89, N 13.67; found: C 74.29, H 6.98, N 13.53.

3.4. 5-(2-Aminophenyl)-1,4-diphenyl-1,3-dihydro-2H-imidazol-2-one (6d). Prepared from 2d and 4d.

Colorless crystals. M.p. 297– 309 8 (benzene/dioxane). IR: 3432, 3333, 3134, 3061, 3030, 2978, 2878, 2762,

1674, 1622, 1596, 1492, 1454, 1392, 1309, 1256, 1151, 1072, 1030, 915, 853, 776, 764, 747, 709, 693, 664, 649,

549, 504. ¹H- and ¹³C-NMR: see Table 5. APCI-MS (pos.): 328 (100, [M þ H]^þ), 311 (4, [M þ

HꢀNH₃]^þ), 283 (99, [M þ HꢀCOOH]^þ), 208 (3, [M þ HꢀCOOHꢀC₆H₃]^þ). APCI-MS/MS (pos.)

of m/z 328: 311 (82, [M þ HꢀNH₃]^þ), 285 (78, [M þ HꢀNHCO]^þ), 235 (48, [M þ HꢀNH₃ꢀC₆H₄]^þ),

209 (100, [M þ HꢀNHCOꢀC₆H₄]^þ), 182 (51, [M þ HꢀNHCOꢀC₆H₄-HCN]^þ). APCI-MS (neg.): 326

(66, [M ꢀ H]^ꢀ), 282 (100, [M ꢀ HꢀNH₂CO]^ꢀ), 255 (31, [M ꢀ HꢀNH₂CO ꢀ HCN]^ꢀ). APCI-MS/MS

(neg.) of m/z 326: 283 (100, [M ꢀ HꢀNHCO]^ꢀ). Anal. calc. for C₂₁H₁₇N₃O (327.38): C 77.04, H 5.23, N

12.84; found: C 76.85, H 5.35, N 12.71.

3.5. 4-(2-Aminophenyl)-3,5-dibutyl-1-methyl-1,3-dihydro-2H-imidazol-2-one (6e). Prepared from 3e

and 4e. Colorless crystals. M.p. 74 – 788 (hexane). IR: 3401, 3337, 3226, 3028, 2957, 2931, 2866, 1668, 1632,

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1567, 1493, 1457, 1401, 1370, 1317, 1265, 1152, 1081, 1023, 950, 940, 825, 749, 656, 599, 552.H- and

¹³C-NMR: see Table 5. APCI-MS (pos.): 302 (100, [M þ H]^þ), 256 (7, [M þ H ꢀ HCOOH]^þ). APCI-

MS/MS (pos.) of m/z 302: 284 (10, [M þ H ꢀ H₂O]^þ), 258 (100, [M þ HꢀNH₂CO]^þ), 246 (98, [M þ

Hꢀbutene]^þ), 201 (85, [M þ HꢀNH₂COꢀBu]^þ), 189 (78, [M þ HꢀbuteneꢀBu]^þ), 172 (97, [M þ

HꢀbuteneꢀBuꢀNH₃]^þ). APCI-MS (neg.): 300 (100, [M ꢀ H]^ꢀ). APCI-MS/MS (neg.) of m/z 300:

257(3, [ M ꢀ HꢀNHCO]^ꢀ), 243 (100, [M ꢀ HꢀBu]^ꢀ), 199 (13, [M ꢀ HꢀBuꢀNH₂CO]^ꢀ), 186 (15, [M ꢀ

Hꢀ2 Bu]^ꢀ). Anal. calc. for C₁₈H₂₇N₃O (301.43): C 71.72, H 9.03, N 13.94; found: C 71.52, H 9.14, N 13.87.

3.6. 4-(2-Aminophenyl)-5-butyl-1-methyl-3-phenyl-1,3-dihydro-2H-imidazol-2-one (6f). Prepared

from 3f. Colorless crystals. M.p. 155 – 1608 (benzene/hexane), identical in all respects to authentic 6f

of m.p. 154 – 1628, prepared from 4f [9].

3.7.4-(2-Aminophenyl)-1,3,5-tributyl-1,3-dihydro-2H-imidazol-2-one (6g). Prepared from 3g and 4g.

Yellowish oil. IR: 3464, 3331, 2957, 2932, 2871, 1676, 1640, 1573, 1494, 1457, 1412, 1368, 1310, 1260, 1157,

1112, 939, 749, 653, 555. ¹H- and ¹³C-NMR: see Table 5. APCI-MS (pos.): 344 (100, [M þ H]^þ), 298 (41,

[M þ H ꢀ HCOOH]^þ), 271 (6, [M þ HꢀBuNH₂]^þ), 243 (9, [M þ HꢀBuNHCOH]^þ). APCI-MS/MS

(pos.) of m/z 344: 300 (4, [M þ HꢀNH₂CO]^þ), 288 (4, [M þ Hꢀbutene]^þ), 271 (20, [M þ

HꢀBuNH₂]^þ), 243 (100, [M þ HꢀBuNHCOH]^þ). APCI-MS (neg.): 342 (100, [M ꢀ H]^ꢀ), 312 (18,

[M ꢀ HꢀCH₂O]^ꢀ), 241 (11, [M ꢀ HꢀBuNHCOH]^ꢀ). APCI-MS/MS (neg.) of m/z 342: 285 (12, [M ꢀ

HꢀBu]^ꢀ), 243 (100, [M ꢀ HꢀBuNCO]^ꢀ), 186 (92, [M ꢀ HꢀBuNCOꢀBu]^ꢀ). Anal. calc. for

C₂₁H₃₃N₃O (343.51): C 73.43, H 9.68, N 12.23; found: C 73.52, H 9.59, N 12.37.

3.8. 4-(2-Aminophenyl)-1,5-dibutyl-3-phenyl-1,3-dihydro-2H-imidazol-2-one (6h). Prepared from

3h. Colorless crystals. M.p. 115 – 1218 (benzene/hexane), identical in all respects to authentic 3h of

m.p. 115 – 1228, prepared from 4h [9].

3.9. 4-(2-Aminophenyl)-1-benzyl-3,5-dibutyl-1,3-dihydro-2H-imidazol-2-one (6i). Prepared from 3i.

Colorless crystals. M.p. 98 – 1048 (hexane), identical in all respects to authentic 6i of m.p. 98 – 1058,

prepared from 4i [9].

3.10. 4-(2-Aminophenyl)-1-benzyl-5-butyl-3-phenyl-1,3-dihydro-2H-imidazol-2-one (6j). Prepared

from 3j. Colorless crystals. M.p. 87– 93 8 (hexane), identical in all respects to authentic 6j of m.p. 88 – 948,

prepared from 4j [9].

3.11. 4-(2-Aminophenyl)-1,3-dibutyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one (6k). Prepared from

3k, 4k, and 8k. Colorless crystals. M.p. 77 – 818 (hexane). IR: 3466, 3424, 3336, 3229, 3059, 2953, 2930,

2867, 1663, 1625, 1602, 1573, 1491, 1457, 1406, 1366, 1312, 1262, 1209, 1159, 1114, 1077, 1027, 938, 805, 749,

701, 664, 651, 624, 550, 513. ¹H- and ¹³C-NMR: see Table 5. APCI-MS (pos.): 364 (100, [M þ H]^þ), 318

(15, [M þ H ꢀ HCOOH]^þ), 263 (10, [M þ HꢀBuNHCOH]^þ). APCI-MS/MS (pos.) of m/z 364: 346 (8,

[M þ H ꢀ H₂O]^þ), 308 (38, [M þ Hꢀbutene]^þ), 291 (9, [M þ HꢀBuNH₂]^þ), 263 (100, [M þ

HꢀBuNHCOH]^þ). APCI-MS (neg.): 362 (100, [M ꢀ H]^ꢀ), 206 (26, [M ꢀ HꢀBuNCOꢀBu]^ꢀ). APCI-

MS/MS (neg.) of m/z 362: 306 (45, [M ꢀ Hꢀbutene]^ꢀ), 263 (100, [M ꢀ HꢀBuNCO]^ꢀ), 206 (71, [M ꢀ

HꢀBuNCOꢀBu]^ꢀ). Anal. calc. for C₂₃H₂₉N₃O (363.50): C 76.00, H 8.04, N 11.56; found: C 75.87, H

7.87, N 11.42.

3.12. 4-(2-Aminophenyl)-1-butyl-3,5-diphenyl-1,3-dihydro-2H-imidazol-2-one (6l). Compound was

prepared from 3l. Colorless crystals. M.p. 65 – 738 (without recrystallization), identical in all respects to

authentic compound of m.p. 54 – 578, prepared from 4l [9].

3.13. 4-(2-Aminophenyl)-1-benzyl-3-butyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one (6m). Prepared

from 3m, 4m, and 8m. Colorless crystals. M.p. 114 – 1158 (benzene/hexane). IR: 3451, 3325, 3203, 3063,

3029, 2954, 2932, 2872, 1672, 1622, 1600, 1572, 1489, 1448, 1398, 1356, 1308, 1265, 1155, 1075, 1028, 951,

921, 775, 749, 702, 831, 577, 501. ¹H- and ¹³C-NMR: see Table 5. APCI-MS (pos.): 398 (100, [M þ H]^þ),

352 (10, [M þ H ꢀ HCOOH]^þ). APCI-MS/MS (pos.) of m/z 398: 381 (25, [M þ HꢀNH₃]^þ), 355 (25,

[M þ HꢀNHCO]^þ), 307(100, [ M þ HꢀMeC₆H₄]^þ), 263 (29, [M þ HꢀMeC₆H₄ꢀNH₂CO]^þ), 208 (33,

[M þ HꢀMeC₆H₄ꢀBuNCO]^þ). APCI-MS (neg.): 396 (100, [M ꢀ H]^ꢀ). APCI-MS/MS (neg.) of m/z

396: 340 (31, [M ꢀ Hꢀbutene]^ꢀ), 263 (100, [M ꢀ HꢀbuteneꢀC₆H₅]^ꢀ), 219 (15, [M ꢀ

HꢀbuteneꢀC₆H₅ꢀNH₂CO]^ꢀ), 206 (42, [M ꢀ HꢀbuteneꢀC₆H₅Bu]^ꢀ). Anal. calc. for C₂₆H₂₇N₃O

(397.51): C 78.56, H 6.85, N 10.57; found: C 78.41, H 6.94, N 10.39.

3.14. 4-(2-Aminophenyl)-1-benzyl-3,5-diphenyl-1,3-dihydro-2H-imidazol-2-one (6n). Prepared from

3n, 4n, and 8n. Colorless crystals. M.p. 209 – 2128 (benzene/hexane). IR: 3465, 3366, 3061, 3028, 2926,

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1687, 1615, 1600, 1572, 1498, 1453, 1427, 1386, 1370, 1310, 1241, 1157, 1130, 1072, 1026, 953, 917, 824, 784,

763, 745, 701, 660, 587, 544, 520. ¹H- and ¹³C-NMR: see Table 5. APCI-MS (pos.): 418 (100, [M þ H]^þ),

373 (16, [M þ HꢀCOOH]^þ). APCI-MS/MS (pos.) of m/z 418: 401 (11, [M þ H ꢀ H₂O]^þ), 375 (12,

[M þ HꢀNHCO]^þ), 327(100, [ M þ HꢀMeC₆H₄]^þ), 283 (52, [M þ HꢀMeC₆H₄ꢀNH₂CO]^þ). APCI-

MS (neg.): 416 (100, [M ꢀ H]^ꢀ). APCI-MS/MS (neg.) of m/z 416: 325 (100, [M ꢀ HꢀMeC₆H₄]^ꢀ), 283

(48, [M ꢀ HꢀMeC₆H₄ꢀNH₂CO]^ꢀ). Anal. calc. for C₂₈H₂₃N₃O (417.50): C 80.55, H 5.55, N 10.06; found:

C 80.41, H 5.67, 10.12.

4. General Procedure for the Preparation of 4-(2-Acetamidophenyl)-5-phenyl-1,3-dihydro-2H-

imidazol-2-ones (8). A mixture of 6 (0.1 mmol), Ac₂O (1 ml), and pyridine (1 ml) was left at r.t. for 4 h,

evaporated to dryness in vacuo, and the residue was crystallized from an appropriate solvent. The

following compounds 8, identical in all respects to those described in Sect. 3.2, were prepared: 8k (86%

yield), 8m (92 % yield), and 8n (96% yield).

5. General Procedure for the Preparation of 1,3-Bis[2-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)-

phenyl]ureas (5). Compounds 5c, 5e, 5g, 5k, 5m, and 5n were prepared from the corresponding

compounds 6 and triphosgene according to the same procedure as was reported for preparation of

compounds 5a, 5f, 5h, 5i, 5j, and 5l [9].

5.1. 1,3-Bis[2-(3-butyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]urea (5c). Prepared

from 6c in 12% yield. Colorless crystals. M.p. 176 – 1868 (AcOEt/hexane), identical in all respects to

authentic 6c of m.p. 173 – 1798, prepared from 3c [9].

5.2. 1,3-Bis[2-(3,5-dibutyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)phenyl]urea (5e). Prepared

from 6e in 18% yield. Yellowish oil, identical in all respects to authentic 5e prepared from 3e [9].

5.3. 1,3-Bis[2-(1,3,5-tributyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)phenyl]urea (5g). Prepared from

6g in 55% yield. Yellowish oil, identical in all respects to authentic 5g prepared from 3g [9].

5.4. 1,3-Bis[2-(1,3-dibutyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]urea (5k). Prepared

from 6k in 65% yield. Colorless crystals. M.p. 173 – 1768 (hexane), identical in all respects to authentic 5k

of m.p. 154 – 1648, prepared from 3k [9].

5.5. 1,3-Bis[2-(1-benzyl-3-butyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]urea (5m).

Prepared from 6m in 68% yield. Colorless crystals. M.p. 94 – 988 (hexane), identical in all respects to

authentic 5m of m.p. 95 – 1008, prepared from 3m [9].

5.6. 1,3-Bis[2-(1-benzyl-2-oxo-3,5-diphenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]urea (5n). Pre-

pared from 6n in 78% yield. Colorless crystals. M.p. 242 – 2488, identical in all respects to authentic 5n

of m.p. 227– 232 8, prepared from 3n [9].

6. General Procedure for the Preparation of Ureas 7 from Dihydroimidazolones 6. Phenylisocyanate

(0.03 ml, 0.28 mmol) was added under stirring at r.t. to the soln. of 6 (0.25 mmol) in CHCl₃(2 ml). The

mixture was stirred for 2.5 h at r.t., evaporated in vacuo to dryness, and the residue was crystallized from

benzene/hexane (1:1, v/v).

6.1. 1-[2-(5-Butyl-1-methyl-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]-3-phenylurea

(7f). Prepared from 6f in 91% yield. Colorless crystals. M.p. 235 – 2378 (benzene/hexane). IR: 3335,

3298, 2957, 2932, 2868, 1709, 1670, 1645, 1600, 1584, 1554, 1530, 1500, 1443, 1396, 1294, 1259, 1229, 1198,

889, 753, 684, 633, 535, 506. ¹H- and ¹³C-NMR: see Table 4. APCI-MS (pos.): 441 (100, [M þ H]^þ), 348

(38, [M þ HꢀPhNH₂]^þ), 322 (37, [M þ HꢀPhNCO]^þ). APCI-MS/MS (pos.) of m/z 441: 397(13, [ M þ

HꢀNH₂CO]^þ), 348 (37, [M þ HꢀPhNH₂]^þ), 322 (98, [M þ HꢀPhNCO]^þ), 265 (21, [M þ

HꢀPhNCOꢀBu]^þ), 203 (7, [M þ Hꢀ2 PhNCO]^þ), 172 (100, [M þ HꢀPhNCOꢀPhNH₂ꢀBu]^þ).

APCI-MS (neg.): 439 (42, [M ꢀ H]^ꢀ), 346 (9, [M ꢀ HꢀPhNH₂]^ꢀ), 320 (100, [M ꢀ HꢀPhNCO]^ꢀ).

APCI-MS/MS (neg.) of m/z 439: 320 (100, [M ꢀ HꢀPhNCO]^ꢀ). Anal. calc. for C₂₇H₂₈N₄O₂(440.54): C

73.61, H 6.41, N 12.72; found: C 73.52, H 6.24, N 12.67.

6.2. 1-[2-(1-Butyl-2-oxo-3,5-diphenyl-2,3-dihydro-1H-imidazol-4-yl)phenyl]-3-phenylurea (7l). Pre-

pared from 6l in 79% yield. Colorless crystals. M.p. 221 – 2288 (benzene/hexane). IR: 3342, 3302, 3057,

2957, 2932, 2861, 1713, 1672, 1599, 1582, 1527, 1497, 1446, 1395, 1292, 1258, 1229, 1192, 1094, 755, 695, 656,

505. ¹H- and ¹³C-NMR: see Table 4. APCI-MS (pos.): 503 (100, [M þ H]^þ), 410 (28, [M þ

HꢀPhNH₂]^þ), 384 (31, [M þ HꢀPhNCO]^þ). APCI-MS/MS (pos.) of m/z 503: 410 (100, [M þ

HꢀPhNH₂]^þ), 384 (52, [M þ HꢀPhNCO]^þ), 354 (9, [M þ HꢀPhNH₂ꢀbutene]^þ), 285 (25, [M þ

HꢀPhNCOꢀBuNCO]^þ). APCI-MS (neg.): 501 ([M ꢀ H]^ꢀ), 382 ([M ꢀ HꢀPhNCO]^ꢀ). APCI-MS/

370

Helvetica Chimica Acta – Vol. 91 (2008)

MS (neg.) of m/z 501: 382 (100, [M ꢀ HꢀPhNCO]^ꢀ). Anal. calc. for C₃₂H₃₀N₄O₂(502.61): C 76.47, H

6.02, N 11.15; found: C 76.57, H 6.19, N 11.02.

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Received August 31, 2007

Article Doi

New approaches to the synthesis of 4-(2-aminophenyl)-1,3-dihydro-2H- imidazol-2-ones and 3-ureidoindoles and a study of their interconversion

DOI: 10.1002/hlca.200890040

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