Preparation of fused tetracyclic quinazolinones by combinations of aza-wittig methodologies and CuI-catalysed heteroarylation processes

FULL PAPER

DOI: 10.1002/ejoc.200900082

Preparation of Fused Tetracyclic Quinazolinones by Combinations of

Aza-Wittig Methodologies and Cu^I-Catalysed Heteroarylation Processes

Juan Antonio Bleda,^[a]Pilar M. Fresneda,*^[a]Raul Orenes,^[b]and Pedro Molina*^[a]

Keywords: Iminophosphoranes / Wittig reactions / Heteroarylation / Fused quinazolines / Nitrogen heterocycles / Sulfur

heterocycles

A number of linear quinazolinones fused to five-membered

rings – benzimidazo[2,1-b]quinazolinones 8 and benzothi-

azolo[2,3-b]quinazolinones 10 – have been prepared from imi-

benzimidazo[1,2-c]quinazoline 16 from the initially formed

3H-quinazolin-4-one. When an acetyl group is present in the

N-aryl substituent of 4, aza-Wittig reactions with isocyanates

nophosphoranes 4, derived from N-substituted o-azidobenz- lead directly to 4-methylene-4H-3,1-benzoxazines 18; this

amides by a combination of the aza-Wittig methodology and

Cu^I-catalysed heteroarylation. The presence of a nitrogen

functionality in the N-aryl substituent of 4 promotes hetero-

cyclization after an aza-Wittig reaction/reductive process,

either across the 2-position, to afford quinazolino[2,1-b]quin-

azolinones 11–14, or across the 4-position, to afford the

transformation involves the initial formation of a carbodi-

imide, which undergoes ring-closure through the enol form

of the carboxamide group and eventually an unprecedented

iminobenzoxazine/methylenebenzoxazine rearrangement.

Germany, 2009)

Over the past twenty years, the aza-Wittig reactions of

iminophosphoranes have been receiving increasing atten-

Introduction

The synthesis of derivatives of quinazolinone has been tion in view of their utility in the synthesis of nitrogen het-

the focus of great interest recently. This is in part due to the erocyclic compounds.^[5]Among the aza-Wittig methodolo-

broad spectrum of biological properties of these com- gies that have been developed, the tandem aza-Wittig/hetero-

pounds. Some of these activities include antimicrobial,^[1]cumulene-mediated annulation process allows the prepara-

anti-inflammatory,^[2]antifungal,^[3]anticancer and AMPA tion of 2-substituted quinazolinone derivatives.^[6]This type

receptor antagonistic properties.^[4]The range of biological of heterocyclization reaction is achieved by the use of a

activities and characteristic chemical structures have made functional iminophosphorane bearing an amido group

synthetic studies of quinazolinones very attractive.

placed at an appropriate position. In particular, iminophos-

Scheme 1. Fused quinazoline derivatives from o-functionalized (arylimino)phosphoranes.

phoranes derived from N-aryl-substituted o-azidobenz-

[a] Departamento de Quimica Orgánica, Facultad de Química,

Universidad de Murcia,

amides react with alkyl or aryl isocyanates to give 2-[alkyl-

(aryl)amino]quinazolin-4(3H)-ones.^[7]

Campus de Espinardo, 30100 Murcia, Spain

Fax: +34-968364149

We now wish to report an extension of this methodology

that paves the way for the preparation of the not readily

available linear or angular tetracyclic ring systems incorpo-

rating quinazoline moieties. Our approach is based on the

E-mail: fresneda@um.es, pmolina@um.es

[b] Servicio de Apoyo a las Ciencias Experimentales,

Campus de Espinardo, 30100 Murcia, Spain

Fax: +34-96837302

E-mail: raorenes@um.es

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Fused Tetracyclic Quinazolinones

use of (arylimino)phosphoranes bearing N-(o-substituted- Table 1. Compounds 3 and 4 prepared.

aryl)amide substituents at their ortho-positions (Scheme 1).

Aryl azide 3

Yield [%]

Iminophosphorane 4

Yield [%]

These building blocks first undergo an aza-Wittig/heterocu-

mulene-mediated cyclization process on treatment with iso-

cyanates and carbon disulfide to give the expected 2-amino-

or 2-mercapto-substituted quinazolinones. These intermedi-

ate products are able to undergo a plethora of heterocycli-

zation reactions depending on the nature of the functional

groups present at the N-aryl substituents, as well as on the

functionality generated at the quinazolinone ring 2-posi-

tions. Several combinations could give rise to the target

tetracyclic ring systems through second cyclization pro-

cesses across either the 2-positions or the 4-positions of the

preformed quinazoline rings (Scheme 1).

3a

3b

3c

3d

3e

3f

90

75

86

85

78

85

77

4a

4b

4c

4d

4e

4f

98

97

96

95

97

96

3g

4g

Aza-Wittig reactions between the iminophosphoranes

4a–d and benzyl isocyanate in dry toluene at reflux tem-

perature then provided the 2-benzylamino-substituted quin-

azolinones 5 in low yields ranging from 5 to 80%

(Scheme 3, Table 2). Better yields were obtained when the

heating was carried out in o-xylene at reflux temperature or

under microwave irradiation conditions. Under these condi-

Results and Discussion

The starting iminophosphoranes 4 (Scheme 2) have been tions, compounds 5 were obtained in high yields from 75 to

prepared by the following two-step process: (a) acylation of 87%.

the appropriate arylamines 2 with o-azidobenzoyl chloride

It is important to note that variable amounts of the cor-

(1)^[8]in dichloromethane in the presence of pyridine to give responding 4H-3,1-benzoxazine-4-imines 6 were isolated,

the N-aryl-substituted o-azidobenzamides 3 in 77–90% depending on the reaction conditions, from the aza-Wittig

yields, and (b) Staudinger reactions between the azides 3 reactions between iminophosphoranes 4 and benzyl isocy-

and triphenylphosphane in dichloromethane at room tem- anate (Table 2). High yields of quinazolinones 5 are ob-

perature to give the iminophosphoranes 4 in almost quanti- tained either by heating in o-xylene for 5 h or by microwave

tative yields (95–98%, Table 1).

heating for 15 min, whereas when the reaction is carried out

Scheme 2. Preparation of o-functionalized aryl azides 3 and (arylimino)phosphoranes 4. Reagents and conditions: (a) CH₂Cl₂, anhydrous

pyridine, 0 °C Ǟ room temp. (77–90%); (b) Ph₃P, CH₂Cl₂, 0 °C Ǟ room temp. (95–98%).

Scheme 3. Preparation of benzimidazo[2,1-b]quinazoline-12(5H)-ones 8. Reagents and conditions: (a) BnNCO, toluene, reflux, 5 (5–80%),

6 (10–90%), or microwaves, o-xylene, sealed tube, 15 min, 5 (75–87%), 6 (8–20%); (b) BnNCO, o-xylene, reflux or microwaves, o-xylene,

sealed tube; (c) CuI, NaH, diglyme, 100 °C, 7 (70–80%); (d) CF₃COOH, 100 °C, 8 (65–70%).

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J. A. Bleda, P. M. Fresneda, R. Orenes, P. Molina

Table 3. Hydrogen bonds [Å and °] in 6d.^[a]

FULL PAPER

Table 2. Compounds 5 and 6 prepared.

Compound

Yield [%]

Compound

Yield [%]

D–H···A

d(D–H) d(H···A) d(D···A) Ͻ(DHA)

[a] [b]

5

(

)

6

( )

N(4)–H(04)···N(1)

N(4)–H(04)···O(2)#1

C(30)H(30A)···N(1)#2

0.79(2)

0.99

2.02(2)

2.59(2)

2.58

2.646(2)

3.138(2)

3.418(2)

136(2)

127(2)

141.9

5a

5b

5c

5d

5e

5f

10 (80)

21 (85)

5 (85)

58 (75)

80 (87)

20 (85)

6a

6b

6c

6d

6e

6f

79 (15)

70 (10)

90 (10)

15 (20)

10 (8)

[a] Symmetry transformations used to generate equivalent atoms:

#1: –x + 1, y + 1/2, –z + 1/2; #2: –x + 1, y – 1/2, –z + 1/2.

57 (10)

Copper-catalysed C–N bond formation through coupling

between amines or amides and aryl halides has received sig-

nificant attention and has provided a versatile method for

the synthesis of a wide range of arylamines.^[9]A number of

useful synthetic protocols utilizing various combinations of

a copper source, a ligand, a base, and a solvent have been

developed to achieve high efficiency in Ullmann-type amin-

ation reactions of various substrates under mild condi-

tions.^[10]Intramolecular Ullmann coupling reactions, on the

other hand, have remained less explored. To the best of our

knowledge, only a few examples of intramolecular copper-

catalysed amination of aryl (or vinyl) halides leading to the

formation of indole rings have been reported.^[11]With this

in mind, quinazolinones 5 may be considered suitable can-

didates for the generation of fused imidazole rings. In this

context, the intramolecular arylamination process was

studied. The copper-mediated imidazolization of precursors

5 was carried out with copper(I) iodide in the presence of

NaH in bis(2-methoxyethyl) ether at 100 °C to give the cor-

responding benzimidazo[2,1-b]quinazolin-12(5H)-ones 7 in

70–80% yields (Scheme 3, Table 4). Removal of the benzyl

groups by treatment with neat trifluoroacetic acid^[12]pro-

vided compounds 8 in 65–70% yields (Table 4). This tetra-

cyclic ring system has been prepared previously,^[13]and has

been found to present promising antitumour activity, with

the benzimidazole and quinazoline moieties serving to in-

tercalate DNA, thereby effectively truncating proliferation

of human tumour cell lines.^[14]

[a] Yields obtained by heating in toluene. [b] Yields obtained under

microwave irradiation conditions.

in toluene at reflux temperature compounds 6 are found to

be the major products. We believe that the formation of

compounds 6 involves initial aza-Wittig reactions between

the iminophosphoranes 4 and benzyl isocyanate to give car-

bodiimides as highly reactive intermediates that easily un-

dergo ring-closure by nucleophilic attack of the hard end

of the carboxamide group (the oxygen atom) on the hard

electrophilic sp-hybridized carbon atom of the carbodi-

imide moiety to give the 3,1-benzoxazine ring with concom-

itant addition of the second molecule of isocyanate on the

formed amino group. When compounds 6 are heated either

in o-xylene at reflux temperature or in a microwave oven,

the quinazolinones 5 are obtained in almost quantitative

yields. An unambiguous structural characterization of com-

pound 6d was achieved by X-ray crystallographic analysis

(Figure 1).

Table 4. Compounds 7 and 8 prepared.

Compound

Yield [%]

Compound

Yield [%]

7a

7b

7c

7d

80

75

70

73

8a

8b

8c

8d

70

68

65

66

Figure 1. ORTEP view of the molecular structure of 6d showing

the atom labelling.

Iminophosphoranes 4a–d also reacted in aza-Wittig-type

fashion with carbon disulfide to provide functionalized aryl

The 4H-benzo[d][1,3]oxazin-2-yl derivative 6d is almost isothiocyanates (Scheme 4), which under thermal condi-

planar (the mean deviation from planarity is 0.047Å and is tions underwent cyclization to give the 2-thio-substituted

rotated by just 21.4° with respect to the mean plane of the quinazolinones 9 in 70–80% yields. Similar CuI-catalysed

urea atoms). The two benzyl substituents are rotated by S-arylation yielded the benzothiazolo[2,3-b]quinazolinones

88.7° and 90.7° with respect to the mean plane of the urea 10 in 72–80% yields (Table 5). A number of synthetic meth-

atoms, so the 4H-benzo[d][1,3]oxazin-2-yl moiety is almost ods for the preparation of this ring system have been devel-

perpendicular to the benzyl substituents on the urea (72.8° oped. These include reactions between heteroaromatic 2-

and 110.7°). The 4H-benzo[d][1,3]oxazin-2-yl and the (2- amino esters and 2-(methylthio)-2-thiazoline,^[15]solid-phase

bromo-5-nitrophenyl)imine components are also nearly per- methods,^[16]condensations of substituted anthranilic acids

pendicular (109.6°). A C30–H30A···N1 intermolecular hy- or esters with methyl 2-chlorothiazole-5-carboxylate,^[17]and

drogen bond is observed in the compound, linking the the electrochemical oxidation of catechols in the presence

molecules in a chain parallel to the b axis (Table 3).

of 2-mercapto-3H-quinazolin-4-one.^[18]

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Fused Tetracyclic Quinazolinones

Scheme 4. Preparation of benzothiazolo[2,3-b]quinazoline-12(5H)-ones 10. Reagents and conditions: (a) CS₂, sealed tube, toluene, 100 °C

(60–74%); (b) CuI, NaH, diglyme, 150 °C (72–80%).

Table 5. Compounds 9 and 10 prepared.

ried out with lithium tetrahydridoaluminate, compound 14,

resulting from the reduction of the carbonyl group, was ob-

tained in 72% yield. A similar result was obtained when the

quinazolinone 5e was used under similar reducing condi-

tions. Unambiguous structural characterization of com-

pound 14 was achieved by X-ray crystallographic analysis

(Figure 2).

Compound

Yield [%]

Compound

Yield [%]

9a

9b

9c

9d

70

74

63

60

10a

10b

10c

75

72

80

The 6,12-dehydro-5H-quinazolino[3,2-a]quinazoline 14 is

nearly planar (the mean deviation from planarity of all its

atoms is 0.057 Å). The phenyl ring is rotated by 109.7° with

respect to the quinazoline ring. These molecules are inter-

linked by C13–H13···O1, C16–H16A···O1 and O1–

H01···N1 hydrogen bonds, forming ribbons parallel to the

c axis (Table 6).

Likewise, compound 5f provided an interesting example

of annulation at the 4-position in the quinazolinone ring.

Catalytic hydrogenation of compound 5f with Pd/C

(Scheme 6) afforded an 80% yield of the diamino-substi-

tuted quinazolinone 15, which on treatment with phospho-

rus pentachloride underwent cyclization to give the benz-

imidazo[1,2-c]quinazoline derivative 16 in 78% yield.

Although the 4H-3,1-benzoxazine ring system displays

The capability of functionalized quinazolinones 5 to af-

ford the quinazolino-quinazoline ring system is clearly illus-

trated by the behaviour of quinazolinone 5e towards dif-

ferent reducing agents. At first, the hydrogenation of the

cyano functionality was accomplished with Pd/C in the

presence of formic acid. The dihydroquinazolinone-annu-

lated product 11 (Scheme 5) was isolated in 80% yield. In

view of the number of steps involved in the formation of

11 – (a) reduction of the nitrile group to a primary amine,

(b) removal of the benzyl group and concomitant hydrolysis

of the resulting imine to a carbonyl group, and finally, (c)

intramolecular condensation of the amino group with the

carbonyl group at the 2-position in the quinazolinone ring –

the yield of the final product can be regarded as excellent.

Cyclization at the 2-position could also be achieved by important biological activity, and a wide variety of deriva-

varying the reducing agent. Thus, when quinazolinone 5e tives of this ring system have been used as fungicidal and

was treated with sodium borohydride at room temperature, anti-inflammatory agents, as ostheoclasis inhibitors, as anti-

only the tetracyclic product 12 (Scheme 5), resulting from rheumatics and as DNA-binding antitumour agents,^[19]only

the addition of the secondary amino function onto the cy- a limited number of methods for the preparation of 4-alk-

ano group, was isolated in 90% yield. Further N-deben- ylidene-4H-3,1-benzoxazines have been reported. A very re-

zylation under standard conditions provided the quinazol- cent approach involves the palladium-catalysed cyclization/

ino[2,1-b]quinazoline derivative 13 in 67% yield. Unexpec- alkoxycarbonylation of various substituted 2-[(trimethyl-

tedly, though, when the reduction of compound 12 was car- silyl)ethynyl]aniline amide or urea derivatives.^[20]

Scheme 5. Preparation of quinazolino[2,1-b]quinazolines 11–14. Reagents and conditions: (a) HCOOH, MeOH, Pd/C (80%); (b) NaBH₄,

THF, room temp. (90%); (c) H₂/Pd/C (67%); (d) LiAlH₄, THF, 0 °C Ǟ room temp. (75%).

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J. A. Bleda, P. M. Fresneda, R. Orenes, P. Molina

FULL PAPER

Here we wish to report a one-pot procedure for the prep-

aration of the otherwise not readily available 4-methylene-

4H-3,1-benzoxazines 19 (Scheme 7) from the readily pre-

pared iminophosphorane 4g. Compound 4g was prepared

by the following two-step procedure: (a) acylation of 2-ami-

noacetophenone with o-azidobenzoyl chloride to give N-(2-

acetylphenyl)-2-azidobenzamide in 77% yield, and (b)

Staudinger reaction between this azide and triphenylphos-

phane to give the iminophosphorane 4g in 99% yield.

Scheme 7. Preparation of 2-aryl-4-methylene-4H-3,1-benzoxazines

19. Reagents and conditions: (a) RNCO, toluene, 1h, room temp.

Ǟ reflux, 6–14 h.

When iminophosphorane 4g was treated with alkyl or

aryl isocyanates in dry toluene, first at room temperature

and then with heating at reflux temperature, the previously

unreported 2-aryl-4-methylene-4H-3,1-benzoxazines 19

were obtained as the only reaction products in yields rang-

ing from 75 to 88%^[21](Table 7).

Figure 2. (a) ORTEP view of the molecular structure of 14 showing

the atom labelling. (b) View of some of the hydrogen bonds in

compound 14.

Table 7. Compounds 19 prepared.

Compound

R

Yield (%)

19a

19b

19c

19d

19e

19f

Et

Pr

Ph

85

78

80

75

85

88

Table 6. Hydrogen bonds [Å, °] in 14.^[a]

4-CH₃OC₆H₄

Bn

4-CH₃OC₆H₄CH₂

D–H···A

d(D–H) d(H···A) d(D···A) Ͻ(DHA)

C(13)–H(13)···O(1)#1

C(16)–H(16A)···O(1)#2

O(1)–H(01)···N(1)#2

C(24)–H(24)···N(4)#3

0.95

0.99

2.57

2.49

3.291(2)

3.451(2)

133.1

163.3

174(3)

142.1

0.89(3) 1.89(3) 2.777(2)

0.95 2.61 3.414(3)

The conversion of 4 into 19 can be explained in terms of

an initial aza-Wittig reaction between the iminophos-

phorane 4g and the isocyanate to give the carbodiimide 17

as a highly reactive intermediate that easily undergoes ring

closure through nucleophilic attack of the hard end of the

carboxamide group (the oxygen atom) on the hard electro-

philic sp-hybridized carbon atom of the carbodiimide

moiety to give the 4-imino-4H-3,1-benzoxazine ring 18. Al-

though it is well known that the isomerization of the imino-

benzoxazine ring to a quinazolinone ring takes place under

relatively mild conditions,^[22]in this sequence the intermedi-

ate iminobenzoxazine 18 undergoes an unprecedented ring

interconversion through nucleophilic attack of the enol

form of the acetyl group at the 4-position in 18 to afford

the new 2-aryl-4-methylene-4H-3,1-benzoxazine ureas 19,

[a] Symmetry transformations used to generate equivalent atoms:

#1: –x, –y + 1, –z + 1; #2: –x, –y + 1, –z + 2; #3: x + 1, –y +

3/2, z + 1/2.

Scheme 6. Preparation of the benzimidazo[1,2-c]quinazoline 16.

Reagents and conditions: (a) H₂/Pd/C, THF, room temp., 80%; (b)

PCl₅, toluene reflux, 78%.

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Fused Tetracyclic Quinazolinones

instead of the expected quinazolinone derivative. This con- bond between the NH group and the oxygen atom of the

version represents the first example of a rearrangement urea is observed in the compound, linking the molecules in

from an iminobenzoxazine to a methylenebenzoxazine a chain parallel to the a axis (Table 8).

(Scheme 7).

As a representative case, the structure of the 2-aryl-4-

Conclusions

methylene-4H-3,1-benzoxazine 19e was confirmed by X-ray

analysis (Figure 3).

We have developed an efficient route to fused quinaz-

olines by using (arylimino)phosphoranes bearing N-(o-sub-

stituted-aryl)carboxamide substituents at their ortho posi-

tions. Aza-Wittig reactions between iminophosphoranes

4a–d, each bearing a bromine group in the N-aryl substitu-

ent, and benzyl isocyanate or carbon disulfide provided the

expected 2-(benzylamino)quinazolinones 5 and 2-mercapto-

quinazolinones 9, respectively. Similarly, and under appro-

priate reaction conditions, 4H-3,1-benzoxazine-4-imines 6

were isolated and characterized. The formation of quinazol-

inones 5 and 9 involves initial formation of a carbodiimide

or an isothiocyanate as a highly reactive intermediate that

undergoes cyclization through nucleophilic attack of the N–

H group of the carboxamide on the central carbon atom of

the heterocumulene moiety, whereas the formation of 6

could be explained by heterocyclization through the hard

end of the carboxamide unit (oxygen atom).

Cu^I-catalysed N- and S-arylation of quinazolinones 5

and 9 afforded the expected fused ring systems: the benzim-

idazo[2,1-b]quinazolinones 8 and the benzothiazolo[2,3-b]-

quinazolinones 10. Reduction of the cyano functionality of

quinazolinone 5e, available through the aza-Wittig reaction

between iminophosphorane 4e (R¹= CN, R²= R³= H)

and benzyl isocyanate, with different reducing agents (Pd/

C/formic acid, NaBH₄, LiAlH₄) yielded derivatives of the

quinazolino[2,1-b]quinazoline ring system.

Treatment of iminophosphorane 4g, derived from N-(2-

acetylphenyl)-2-azidobenzamide, with aliphatic and aro-

matic isocyanates gave 4-methylene-4H-3,1-benzoxazines

18. This transformation involves a novel aza-Wittig/car-

bodiimide ring closure/enol-induced rearrangement of a 4-

imino-3,1-benzoxazine to afford a 4-methylene-3,1-benz-

oxazine.

Experimental Section

Figure 3. (a) ORTEP view of the molecular structure of 19e show-

ing the atom labelling. (b) View of some of the hydrogen bonds in

compound 19e.

General Methods: All reactions were carried out under N₂, and the

solvents were dried by standard procedures. Column chromatog-

raphy was performed on silica gel (60 Å, 70–200 µm, SDS) as sta-

tionary phase. All melting points were determined with a hot-plate

melting point apparatus and are uncorrected. IR spectra were re-

corded with a Nicolet 380 FT-IR instrument. NMR spectra

(Bruker Avance 300 MHz, 400 MHz and 600 MHz) were deter-

mined with tetramethylsilane as an internal standard. The proton

(¹H NMR) and carbon (¹³C NMR) signals were assigned by DEPT

or two-dimensional NMR experiments. Mass spectra were re-

corded with Agilent 5973 (EI), Agilent VL (ESI) and HPLC/MS

TOF 6220 mass spectrometers. Elemental analyses were performed

with a Carlo Erba EA-1108 elemental analyser.

The 2-aryl-4-methylene-4H-3,1-benzoxazine 19e is al-

most planar (the mean deviation from planarity is 0.044Å,

but is rotated by 41.7° with respect to the mean plane of

the urea atoms). An intermolecular N–H···O hydrogen

Table 8. Hydrogen bonds [Å, °] in 19e.^[a]

D–H···A

d(D–H)

d(H···A)

d(D···A)

Ͻ(DHA)

N(2)–H(02)···O(1)#1 0.884(16) 1.985(16) 2.8354(14) 160.8(13)

2-Azido-N-arylbenzamides (3): A solution of an o-azidoaroyl chlo-

ride 1 (20 mmol) in anhydrous CH₂Cl₂(2 mL) was added dropwise

at 0 °C under nitrogen to a solution of an amino compound 2

[a] Symmetry transformations used to generate equivalent atoms:

#1: x – 1, y, z.

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J. A. Bleda, P. M. Fresneda, R. Orenes, P. Molina

FULL PAPER

(20 mmol) in dry pyridine (15 mL). The resultant mixture was

stirred at room temperature for 1 h. Afterwards, the mixture was

poured into ice/H₂O (200 mL) to give a solid that was purified by

column chromatography on silica gel with EtOAc/n-hexane (6:4) as

eluent to provide a 2-azido-N-arylbenzamide 3.

(100), 90 (55). C₁₃H₈BrN₅O₃(362.14): calcd. C 43.12, H 2.23, N

19.34; found C 43.05, H 2.27, N 19.28.

2-Azido-N-(2-cyanophenyl)benzamide (3e): This compound (4.1 g,

78%) was obtained as white prisms, m.p. 137–138 °C (CH₂Cl₂/n-

1

hexane, 4:1). H NMR (400 MHz, CDCl₃, 25 °C): δ = 10.55 (br. s,

1 H), 8.67 (dd, J = 9.1, 1.1 Hz, 1 H), 8.31 (ddd, J = 8.0, 1.7, 0.4 Hz,

1 H), 7.63 (dd, J = 7.9, 1.6 Hz, 1 H), 7.62 (ddd, J = 9.1, 7.4, 1.6 Hz,

1 H), 7.59 (ddd, J = 8, 7.4, 1.7 Hz,1 H), 7.32 (ddd, J = 8.0, 7.4,

1.1 Hz, 1 H), 7.19 (ddd, J = 7.9, 7.4, 1.1 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃, 25 °C): δ = 162.7, 141.6, 137.5, 134.2, 133.6,

132.8, 132.3, 125.3, 124.0, 127.3, 121.2, 118.7, 117.1 102.3 ppm. IR

2-Azido-N-(2-bromophenyl)benzamide (3a): This compound (5.71 g,

90%) was obtained as white prisms, m.p. 120.5–121.5 °C (CH₂Cl₂/

n-hexane, 4:1). H NMR (400 MHz, CDCl₃, 25 °C): δ = 9.98 (br.

s, 1 H), 8.57 (dd, J = 8.3, 1.5 Hz, 1 H), 8.27 (dd, J = 7.9, 1.6 Hz,

1 H), 7.59 (dd, J = 8.0, 1.5 Hz, 1 H), 7.56 (ddd, J = 8.0, 7.4, 1.6 Hz,

1 H), 7.35 (ddd, J = 8.3, 7.4, 1.5 Hz, 1 H), 7.30 (ddd, J = 7.91, 7.4,

1.0 Hz, 1 H), 7.26 (dd, J = 8.0, 1.0 Hz, 1 H), 7.0 (ddd, J = 8.0, 7.4,

1.5 Hz, 1 H, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ =

162.5, 137.0, 136.5, 133.0, 132.7, 132.4, 128.3, 125.3, 125.2, 124.8,

1

(Nujol): ν = 2216, 2156, 1694, 1586, 1538, 1376, 1316, 746 cm^–1.

˜

MS (FAB positive): m/z (%) = 286 (100) [M + Na]⁺, 258 (94), 236

(54), 170, 1 (50), 152, 1 (19), 150.1 (57). C₁₄H₉N₅O (263.25): calcd.

C 63.87, H 3.45, N 26.60; found C 63.81, H 3.40, N 26.52.

122.5, 118.6, 113.7 ppm. IR (CH Cl ): ν = 3281, 2140, 1675, 1585,

˜

2

1540, 751 cm^–1. MS (EI): m/z (%) = 318 (7) [M + 2]⁺, 316 (7), 290

(19) [M + 2 – N₂]⁺, 288 (17) [M – N₂]⁺, 237 (40), 209 (99), 181

(71), 152 (44), 90 (100). C₁₃H₉BrN₄O (317.14): calcd. C 49.23, H

2.86, N 17.67; found C 49.15, H 2.82, N 17.61.

2-Azido-N-(2-nitrophenyl)benzamide (3f): This compound (4.81 g,

85%) was obtained as white prisms, m.p. 154–155 °C (CH₂Cl₂/n-

1

hexane, 4:1). H NMR (400 MHz, CDCl₃, 25 °C): δ = 11.69 (br. s,

1 H), 9.39 (dd, J = 8.6, 1.3 Hz, 1 H), 8.23 (dd, J = 8.4, 1.6 Hz, 1

H), 8.15 (dd, J = 8.2, 1.6 Hz, 1 H), 7.70–7.66 (m, 1 H), 7.58 (ddd,

J = 8.0, 7.4, 1.60 Hz, 1 H), 7.31–7.27 (m, 2 H), 7.23 (ddd, J = 8.4,

7.3, 1.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ =

163.7, 137.7, 137.6, 135.4, 134.4, 133.3, 132.4, 125.8, 125.2, 125.0,

2-Azido-N-(2,4-dibromophenyl)benzamide (3b): This compound

(5.94 g, 75%) was obtained as white prisms, m.p. 115.5–116.2 °C

(CH₂Cl₂/n-hexane, 4:1). ¹H NMR (400 MHz, CDCl₃, 25 °C): δ =

10.04 (br. s, 1 H), 8.50 (d, J = 8.9 Hz, 1 H), 8.27 (dd, J = 7.9,

1.46 Hz, 1 H), 7.73 (d, J = 2.3 Hz, 1 H), 7.57 (ddd, J = 8.0, 7.3,

1.7 Hz, 1 H), 7.46 (ddd, J = 8.9, 2.3, 0.4 Hz, 1 H), 7.30 (ddd, J =

7.9, 7.4, 1.1 Hz, 1 H), 7.26 (ddd, J = 8.0, 1.1, 0.4 Hz, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 162.5, 137.0, 135.8, 134.6,

133.2, 132.8, 131.2, 125.4, 124.4, 123.4, 118.6, 116.7, 114.0 ppm.

123.6, 123.3, 118.8 ppm. IR (CH Cl ): ν = 3254, 2141, 1667, 1589,

˜

2

1507, 1343, 1305, 1276, 738 cm^–1. MS (EI): m/z (%) = 283 (5) [M]

⁺, 255 (23) [M – N₂]⁺, 179 (18), 140 (23), 121 (46), 90 (100).

C₁₃H₉N₅O₃(283.24): calcd. C 55.13, H 3.20, N 24.73; found C

55.08, H 3.27, N 24.65.

IR (CH Cl ): ν = 3300, 2136, 1676, 1585, 1523, 1304, 746 cm^–1.

˜

2

N-(2-Acetylphenyl)-2-azidobenzamide (3g): This compound (4.31 g,

77%) was obtained as white prisms, m.p. 156–157 °C (CH₂Cl₂/n-

MS (EI): m/z (%) = 396 (5) [M + 2]⁺, 394 (3) [M]⁺, 368 (9) [M –

N₂]⁺, 289 (30), 287 (32), 120 (79), 92 (30), 90 (100). C₁₃H₈Br₂N₄O

(396.04): calcd. C 39.43, H 2.04, N 14.15; found C 39.38, H 2.01,

N 14.09.

1

hexane, 4:1). H NMR (400 MHz, CDCl₃, 25 °C): δ = 12.25 (s, 1

H), 8.82 (dd, J = 8.5, 1.0 Hz, 1 H), 7.84 (dd, J = 8.0, 1.5 Hz, 1 H),

7.80 (dd, J = 8.0, 1.6 Hz, 1 H), 7.52 (ddd, J = 8.5, 7.5, 1.5 Hz, 1

H), 7.44 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H), 7.20–7.14 (m, 2 H), 7.09

(ddd, J = 8.0, 7.5, 1.0 Hz, 1 H), 2.60 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃, 25 °C): δ = 202.2, 164.9, 140.3, 137.6, 134.9,

132.2, 131.5, 130.9, 127.6, 125.0, 123.0, 122.8, 121.5, 119.1,

2-Azido-N-(2-bromo-4-fluorophenyl)benzamide (3c): This com-

pound (5.76 g, 86%) was obtained as white prisms, m.p. 139–

140 °C (CH₂Cl₂/n-hexane, 4:1). ¹H NMR (400 MHz, CDCl₃,

25 °C): δ = 9.85 (br. s, 1 H), 8.44 (dd, J = 9.2, 5.6 Hz, 1 H), 8.20

(dd, J = 7.4,1.6 Hz, 1 H), 7.50 (ddd, J = 8.0, 7.5, 1.6 Hz, 1 H), 7.27

(dd, J = 7.8, 2.9 Hz, 1 H), 7.23 (ddd, J = 7.9, 7.5, 1.0 Hz, 1 H),

7.20 (dd, J = 8.0, 1.0 Hz, 1 H), 7.01 (ddd, J = 9.2, 7.9, 2.9 Hz, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 162.5, 158.5 (d,

28.6 ppm. IR (Nujol): ν = 3164, 2137, 1660, 1583, 1537, 1322, 1260,

˜

749 cm^–1. MS (ESI): m/z (%) = 282 (23) [M + 2]⁺, 281 (100) [M +

1]⁺, 280 (14) [M]⁺, 254 (17), 253 (42), 252 (24), 211 (42), 136 (45),

120 (43). C₁₅H₁₂N₄O₂(280.28): calcd. C 64.28, H, 4.32; N, 19.99;

found C 64.22, H 4.37, N 19.92.

4

¹J_C,F= 248.4 Hz), 137.0, 133.1,133.0 (d, J_C,F= 3.0 Hz), 132.7,

3

2

125.4, 124.5, 123.6 (d, J_C,F= 8.1 Hz), 119.5 (d, J_C,F= 25.7 Hz),

N-Aryl-2-[(triphenylphosphoranylidene)amino]benzamides (4): Tri-

phenylphosphane (13.6 mmol) in CH₂Cl₂(70 mL) was added drop-

wise at 0 °C under nitrogen to a solution of the appropriate 2-

azido-N-arylbenzamide 3 (12 mmol) in anhydrous CH₂Cl₂(70 mL).

The resultant mixture was stirred at 0 °C for 1 h and then at room

temperature for 12 h. Afterwards, the solvent was removed under

reduced pressure, and the residue was crystallized from CH₂Cl₂/

hexane (1:1) to give the iminophosphorane 4 in quantitative yield.

2

3

118.6 (C-6), 115.1 (d, J_C,F

= 21.8 Hz), 113.9 (d, J_C,F=

9.4 Hz) ppm. IR (CH Cl ): ν = 3294, 2132, 1670, 1596, 1539, 1482,

˜

2

892, 854, 746 cm^–1. MS (EI): m/z (%) = 336 (5) [M + 2]⁺, 334 (5)

[M]⁺, 308 (9) [M + 2 – N₂]⁺, 306 (8) [M – N₂]⁺, 289 (30), 287

(32), 227 (69), 199 (35), 146 (28), 120 (35), 90 (100). C₁₃H₈BrFN₄O

(335.13): calcd. C 46.59, H 2.41, N 16.72; found C 46.52, H 2.48,

N 16.67.

2-Azido-N-(2-bromo-5-nitrophenyl)benzamide (3d): This compound

(6.15 g, 85%) was obtained as white prisms, m.p. 173–174 °C

N-(2-Bromophenyl)-2-[(triphenylphosphoranylidene)amino]benz-

amide (4a): This compound (6.47 g, 98%) was obtained as yellow

(CH₂Cl₂/n-hexane, 4:1). ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = prisms, m.p. 212–214 °C (CH₂Cl₂/n-hexane, 1:1). ¹H NMR

10.26 (br. s, 1 H), 9.44 (d, J = 2.6 Hz, 1 H), 8.25 (dd, J = 8.0,

1.5 Hz, 1 H, 1 H), 7.79 (dd, J = 8.8, 2.6 Hz, 1 H), 7.69 (d, J =

(400 MHz, CDCl₃, 25 °C): δ = 13.07 (s, 1 H), 8.28 (dt, J = 7.9,

2.2 Hz, 1 H), 8.26 (dd, J = 7.8, 1.5 Hz, 1 H), 7.77–7.71 (m, 6 H),

8.8 Hz, 1 H), 7.55 (ddd, J = 8.0, 7.4, 1.5 Hz, 1 H), 7.27 (ddd, J = 7.57–7.52 (m, 3 H), 7.44–7.40 (m, 7 H), 7.35–7.31 (m,1 H), 6.97–

8.0, 7.4, 1.1 Hz, 1 H), 7.22 (dd, J = 8.0, 1.1 Hz, 1 H) ppm. ¹³C 6.92 (m, 2 H), 6.77 (ddd, J = 7.9, 7.3, 1.1 Hz, 1 H), 6.49 (d, J =

NMR (75 MHz, CDCl₃, 25 °C): δ = 162.7, 147.7, 137.7, 137.1,

133.7, 133.0, 132.9, 125.6, 123.7, 119.9, 119.2, 118.7, 116.9 ppm.

8.11 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 166.5

(d, ⁴J = 1.5 Hz), 150.2 (d, ²J = 2.6 Hz), 137.4, 132.6 (d, ²J =

9.8 Hz), 132.3 (d, ⁴J = 2.8 Hz), 132.2, 131.6 (d, ³J = 3.3 Hz), 131.4,

129.2 (d, ¹J = 102.2 Hz), 128.9 (d, ³J = 12.2 Hz), 127.5, 125.7, 125.3

IR (CH Cl ): ν = 3261, 2127, 1669, 1532, 1516, 1474, 1310,

˜

2

757 cm^–1. MS (EI): m/z (%) = 363 (5) [M + 2]⁺, 361 (5) [M]⁺, 335

(17) [M + 2 – N₂]⁺, 333 (15) [M – N₂]⁺, 254 (81), 208 (67), 120

(d, ³J = 20.2 Hz), 124.9, 122.4 (d, J = 12.2 Hz), 117.6, 116.2 ppm.

4

2496

www.eurjoc.org

Eur. J. Org. Chem. 2009, 2490–2504

Fused Tetracyclic Quinazolinones

³¹P NMR (125 MHz, CDCl₃, 25 °C): δ = 10.45 ppm. MS (EI): m/z (400 MHz, [D₆]DMSO, 25 °C): δ = 13.90 (s, 1 H), 8.06–8.02 (m, 2

(%) = 552 (31) (31) [M + 2]⁺, 551.0 (23) [M + 1]⁺, 550.0 (44)

[M]⁺, 471.0 (54), 380.0 (100), 352 (28), 262 (30), 201 (61), 183 (90),

152 (50), 108 (77), 91 (71). C₃₁H₂₄BrN₂OP (551.41): calcd. C 67.52,

H 4.39, N 5.08; found C 67.45, H 4.43, N 5.02.

H), 7.78 (dd, J = 12.2, 7.3 Hz, 6 H), 7.71–7.61 (m, 5 H), 7.50 (dt,

J = 7.6, 3.0 Hz, 6 H, 6 H), 7.27 (t, J = 7.6 Hz, 1 H), 7.0 (dt, J =

7.6, 1.7 Hz, 1 H), 6.72 (t, J = 7.4 Hz, 1 H), 6.47 (d, J = 8.1 Hz, 1

H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO, 25 °C): δ = 165.4, 150.3

2

4

(d, J = 2.6 Hz), 141.0, 133.6, 132.8 (d, J = 2.7 Hz), 132.7, 132.3

(d, ²J = 10.0 Hz), 132.1, 131.0 (d, ⁴J = 2.4 Hz), 129.3 (d, ³J =

12.2 Hz), 127.9 (d, ¹J = 100.1 Hz), 124.7, 124.6, 123.5 (d, ³J =

20.4 Hz), 122.2 (d, ³J = 12.5 Hz), 117.5, 116.7, 105.3 ppm. ³¹P

NMR (125 MHz, CDCl₃, 25 °C): δ = 12.38 ppm. MS (ESI): m/z

(%) =500 (30) [M + 3]⁺, 499 (61) [M + 2]⁺, 498 (11) [M + 1]⁺, 381

(18), 380 (90), 279 (100), 221 (17), 218 (20). C₃₂H₂₄N₃OP (497.53):

calcd. C 77.25, H 4.86, N 8.45; found C 77.20, H 4.92, N 8.37.

N-(2,4-Dibromophenyl)-2-[(triphenylphosphoranylidene)amino]benz-

amide (4b): This compound (7.33 g, 97%) was obtained as yellow

prisms, m.p. 239–240 °C (CH₂Cl₂/n-hexane 4:1). ¹H NMR

(400 MHz, CDCl₃, 25 °C): δ = 13.11 (s, 1 H), 8.20 (dt, J = 7.9,

2.2 Hz, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.69–7.64 (m, 6 H), 7.53–

7.48 (m, 3 H), 7.46 (d, J = 2.3 Hz, 1 H), 7.40–7.35 (m, 7 H), 6.89

(ddd, J = 8.1, 7.2, 2.2 Hz, 1 H), 6.71 (ddd, J = 7.9, 7.2, 1.1 Hz, 1

H), 6.43 (dt, J = 8.1, 1.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz,

4

2

CDCl₃, 25 °C): δ = 166.5 (d, J = 1.7 Hz), 150.3 (d, J = 2.8 Hz),

N-(2-Nitrophenyl)-2-[(triphenylphosphoranylidene)amino]benzamide

(4f): This compound (6.02 g, 97%) was obtained as yellow prisms,

m.p. 173–175 °C (CH₂Cl₂/n-hexane, 4:1). ¹H NMR (400 MHz,

CDCl₃, 25 °C): δ = 13.81 (s, 1 H), 8.51 (dd, J = 8.4, 1.2 Hz, 1 H),

8.19 (dt, J = 7.9, 1.3 Hz, 1 H), 7.99 (dd, J = 8.4, 1.5 Hz, 1 H),

7.80–7.74 (m, 6 H), 7.60 (ddd, J = 8.4, 7.3, 1.5 Hz, 1 H), 7.55–7.51

(m, 3 H), 7.43–7.39 (m, 6 H), 7.14 (ddd, J = 8.4, 7.3, 1.2 Hz, 1 H),

6.98 (ddd, J = 8.0, 7.5, 1.3 Hz, 1 H), 6.76 (ddd, J = 7.9, 7.5, 0.9 Hz,

1 H), 6.50 (d, J = 8.0 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃,

2

4

136.7, 134.2, 133.6 (d, J = 12.1 Hz), 132.4 (d, J = 2.8 Hz), 131.6

3

1

(d, J = 3.0 Hz), 131.6, 130.5, 129.0 (d, J = 100.5 Hz), 128.9 (d,

³J = 12.2 Hz), 126.6, 124.8 (d, ³J = 20.8 Hz), 122.4 (d, ⁴J =

12.5 Hz), 117.7, 116.5, 116.3 ppm. ³¹P NMR (125 MHz, CDCl₃,

25 °C): δ = 11.05 ppm. MS (EI): m/z (%) = 630 (3) [M + 2]⁺, 628

(2) [M]⁺, 381 (27), 380 (100), 201 (44), 183 (67), 108. (21), 77 (15).

C₃₁H₂₃Br₂N₂OP (630.31): calcd. C 59.07, H 3.68, N 4.44; found C

59.01, H 3.72, N 4.38.

4

25 °C): δ = 167.1 (d, J = 1.8 Hz), 150.5, 139.3, 134.5, 134.1, 132.5

N-(2-Bromo-4-fluorophenyl)-2-[(triphenylphosphoranylidene)amino]-

benzamide (4c): This compound (6.56 g, 96%) was obtained as yel-

low prisms, m.p. 134–136 °C (CH₂Cl₂/n-hexane, 4:1). ¹H NMR

(400 MHz, CDCl₃, 25 °C): δ = 13.17 (s, 1 H), 8.28 (dt, J = 7.9,

2.0 Hz, 1 H), 8.16 (dd, J = 9.0, 5.8 Hz, 1 H), 7.77–7.70 (m, 6 H),

7.58–7.54 (m, 3 H), 7.45–7.41 (m, 6 H), 7.15 (dd, J = 8.1, 2.9 Hz,

1 H), 7.06 (ddd, J = 9.0, 8.0, 2.9 Hz, 1 H), 6.96 (ddd, J = 8.1, 7.1,

2.0 Hz, 1 H), 6.78 (ddd, J = 8.1, 7.9, 1.0 Hz, 1 H), 6.49 (dt, J =

7.1, 1.0 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ =

(d, ²J = 9.9 Hz), 132.2 (d, ⁴J = 3.0 Hz), 131.9, 131.7 (d, ³J =

2.5 Hz), 129.0 (d, ¹J = 100.9 Hz), 128.9 (d, ³J = 12.3 Hz), 128.5,

125.2, 125.0 (d, ³J = 21.2 Hz), 123.0, 122.5 (d, ⁴J = 12.3 Hz),

117.6 ppm. ³¹P NMR (125 MHz, CDCl₃, 25 °C): δ = 10.31 ppm.

MS (EI): m/z (%) = 518 (8) [M + 1]⁺, 517 (25) [M]⁺, 380 (99), 380

(90), 277 (29), 201 (77), 183 (27) (100) 108, 77 (37). C₃₁H₂₄N₃O₃P

(517.51): calcd. C 71.95, H 4.67, N 8.12; found C 71.91, H 4.72, N

8.08.

4

1

2

166.5 (d, J = 1.9 Hz), 158.6 (d, J_C,F= 246.7 Hz), 150.2 (d, J =

N-(2-Acetylphenyl)-2-[(triphenylphosphoranylidene)amino]benz-

amide (4g): This compound (5.92 g, 96%) was obtained as yellow

prisms, m.p. 195–196 °C (CH₂Cl₂/n-hexane, 4:1). ¹H NMR

(400 MHz, CDCl₃, 25 °C): δ = 13.40 (s, 1 H), 8.27 (dd, J = 8.3,

1.1 Hz, 1 H), 8.07 (dt, J = 7.8, 2.2 Hz, 1 H), 7.79–7.73 (m, 6 H),

7.62 (dd, J = 7.9, 1.5 Hz, 1 H), 7.51–7.43 (m, 4 H), 7.39–7.34 (m,

6 H), 7.08 (ddd, J = 7.9, 7.3,1.1 Hz, 1 H), 6.92 (ddd, J = 7.2, 8.1,

2.2 Hz, 1 H), 6.71 (ddd, J = 7.2, 7.8, 1.0 Hz, 1 H), 6.46 (dt, J =

8.1, 1.0 Hz, 1 H), 2.22 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃,

25 °C): δ = 199.4, 167.5 (d, ⁴J = 1.1 Hz), 150.0 (d, ²J = 1.9 Hz),

138.6 132.8, 132.6 (d, ²J = 9.7 Hz), 132.0 (d, ⁴J = 2.9 Hz), 131.5

4

2

2.8 Hz), 133.1 (d, J_C,F= 2.8 Hz), 132.6 (d, J = 9.8 Hz), 132.3 (d,

⁴J = 2.9 Hz), 131.6 (d, ³J = 2.4 Hz), 131.5, 129.0 (d, ¹J = 100.3 Hz),

128.9 (d, ³J = 12.1 Hz), 126.3 (d, J_C,F= 8.4 Hz), 124.9 (d, ³J =

3

20.5 Hz), 122.5 (d, ⁴J = 12.1 Hz), 119.0 (d, ²J_C,F= 25.0 Hz), 117.7,

3

2

116.2 (d, J_C,F= 10.8 Hz), 114.4 (d, J_C,F= 21.5 Hz) ppm. ³¹P

NMR (125 MHz, CDCl₃, 25 °C): δ = 10.52 ppm. MS (EI): m/z (%)

= 570 (30) [M + 2]⁺, 569 (21) [M + 1]⁺, 568 (40) [M]⁺, 489 (54),

261 (26), 201 (64), 198 (98), 152 (49), 108 (100), 78 (47).

C₃₁H₂₃BrFN₂OP (569.40): calcd. C 65.39, H 4.07, N, 4.92; found

C 65.32, H 4.24, N 4.85.

4

1

(d, J = 2.8 Hz), 131.4, 129.8, 129.7 (d, J = 100.7 Hz), 128.7 (d,

N-(2-Bromo-5-nitrophenyl)-2-[(triphenylphosphoranylidene)amino]-

benzamide (4d): This compound (6.87 g, 96%) was obtained as yel-

low prisms, m.p. 272–273 °C (CH₂Cl₂/n-hexane, 4:1). ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 13.53 (s, 1 H), 9.21 (d, J = 3.3 Hz,

1 H), 8.28 (dt, J = 7.9, 2.0 Hz, 1 H), 7.78–7.69 (m, 7 H), 7.60–7.54

(m, 3 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.48–7.42 (m, 6 H), 6.98 (ddd,

J = 8.1, 7.2, 2.0 Hz, 1 H), 6.79 (ddd, J = 7.9, 7.2, 1.1 Hz, 1 H),

6.50 (d, J = 8.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C):

δ = 166.8 (d, ⁴J = 1.5 Hz), 150.5 (d, ²J = 3.0 Hz), 147.4, 138.8,

³J = 12.4 Hz), 128.2, 126.7 (d, ³J = 21.9 Hz), 123.9, 122.7, 122.4

2

(d, J = 12.0 Hz), 117.3, 28.5 ppm. ³¹P NMR (161.9 MHz, CDCl₃,

25 °C): δ = 7.73 ppm. MS (ESI): m/z (%) =516 (23) [M + 2]⁺, 515

(100) [M + 1]⁺. C₃₃H₂₇N₂O₂P (514.55): calcd. C 77.03, H 5.20, N

5.44; found C 77.01, H 5.25, N 5.47.

3-Aryl-2-benzylamino-3H-quinazolin-4-ones (5). Method A: A mix-

ture of the appropriate N-aryl-2-[(triphenylphosphoranylidene)

amino]benzamide 4 (1.6 mmol) and benzyl isocyanate (0.43 g,

3.2 mmol) in anhydrous toluene (60 mL), was stirred at room tem-

perature under nitrogen for 1 h and then was heated at reflux tem-

perature for 6 h. Afterwards, the solvent was removed under re-

duced pressure, and the mixture was separated by column

chromatography on silica gel with EtOAc/n-hexane (2:3) as eluent

to provide 3-aryl-2-(benzylamino)-3H-quinazolin-4-ones 5 in 5–

80% yields and 1-[4-(arylimino)-4H-benzo[d][1,3]oxazin-2-yl]-1,3-

dibenzylureas 6 in 10–90% yields. Method B: A mixture of an N-

2

4

132.6 (d, J = 9.9 Hz), 132.6, 132.5 (d, J = 2.9 Hz), 132.0, 131.7

3

1

(d, J = 2.3 Hz), 129.0 (d, J = 12.2 Hz), 128.9 (d, J = 100.5 Hz),

124.4 (d, ³J = 20.6 Hz), 122.7, 122.5 (d, ⁴J = 12.3 Hz), 120.0, 118.9,

117.9 ppm. ³¹P NMR (125 MHz, CDCl₃, 25 °C): δ = 11.71 ppm.

MS (EI): m/z (%) =597 (7) [M + 2]⁺, 595 (7) [M]⁺, 381 (29), 380

(100), 201 (62), 183 (95), 108 (15), 90 (17). C₃₁H₂₃BrN₃O₃P

(596.41): calcd. C 62.43, H 3.89, N 7.05; found C 62.35, H 3.93, N

7.01.

N-(2-Cyanophenyl)-2-[(triphenylphosphoranylidene)amino]benz- aryl-2-[(triphenylphosphoranylidene)amino]benzamide 4

amide (4e): This compound (5.67 g, 95%) was obtained as yellow

(0.45 mmol), benzyl isocyanate (0.54 mmol), and anhydrous o-xy-

lene (5 mL) was introduced under nitrogen into a pressure vial

prisms, m.p. 206–208 °C (CH₂Cl₂/n-hexane, 4:1). ¹H NMR

Eur. J. Org. Chem. 2009, 2490–2504

www.eurjoc.org

2497

J. A. Bleda, P. M. Fresneda, R. Orenes, P. Molina

FULL PAPER

(10 mL) containing a magnetic stirrer bar. The vessel reaction was

irradiated in a single-mode microwave (CEM Discover Focused

Synthesizer) at 160 °C (by modulation of the power) for 15 min.

The mixture was cooled rapidly to room temperature. Afterwards,

the solvent was removed at reduced pressure, and the mixture was

separated by column chromatography on silica gel with EtOAc/n-

hexane (2:3) as eluent to provide 3-aryl-2-benzylamino-3H-quin-

azolin-4-ones 5 in 75–87 % yields and 1-[4-(arylimino)-4H-

benzo[d][1,3]oxazin-2-yl]-1,3-dibenzylureas 6 in 8–20% yields.

1.1 Hz, 1 H), 4.82 (dd, J = 14.8, 6.0 Hz, 1 H), 4.59 (dd, J = 14.8,

5.0 Hz, 1 H), 4.13 (t, J = 5.5 Hz, 1 H) ppm. ¹³C NMR (75 MHz,

CDCl₃, 25 °C): δ = 161.7, 149.3, 148.2, 147.5, 137.8, 135.5, 135.4,

135.3, 131.9, 128.7, 127.7, 127.6, 127.3, 126.4, 126.0, 125.4, 123.3,

117.2, 45.8 ppm. MS (EI): m/z (%) = 452 (11) [M + 2]⁺, 450 (10)

[M]⁺, 372 (47), 371 (100), 325 (40), 293 (17), 247 (14), 162 (19), 145

(15), 119 (29), 106 (47), 92 (22), 91 (87). C₂₁H₁₅BrN₄O₃(451.27):

calcd. C 55.89, H 3.35, N 12.42; found C 55.84, H 3.39, N 12.35.

2-(Benzylamino)-3-(2-cyanophenyl)-3H-quinazolin-4-one (5e): This

2-(Benzylamino)-3-(2-bromophenyl)-3H-quinazolin-4-one (5a): This compound (0.138 g, 87%) was obtained as white prisms, m.p. 207–

compound (0.15 g, 80%) was obtained as white prisms, m.p. 147–

209 °C (EtOAc/n-hexane, 3:2). ¹H NMR (400 MHz, [D₆]DMSO,

25 °C): δ = 8.15 (dd, J = 8.0, 1.4 Hz, 1 H), 7.98–7.91 (m, 2 H),

150 °C (EtOAc/n-hexane, 2:3). ¹H NMR (400 MHz, CDCl₃, 25 °C):

δ = 8.08 (dd, J = 8.0, 1.3 Hz, 1 H), 7.72 (dd, J = 8.4, 1.4 Hz, 1 H), 7.79–7.75 (m, 2 H), 7.66–7.61 (m, 1 H), 7.32–7.26 (m, 5 H), 7.21–

7.57 (ddd, J = 8.3, 7.1, 1.3 Hz, 1 H), 7.44 (ddd, J = 8.0, 7.3, 1.4 Hz,

1 H), 7.39 (dd, J = 8.3, 0.5 Hz, 1 H), 7.34–7.30 (m, 2 H), 7.26–7.16

7.14 (m, 2 H), 6.86 (t, J = 6.0 Hz, 1 H), 4.60–4.49 (m, 2 H) ppm.

¹³C NMR (100 MHz, [D₆]DMSO, 25 °C): δ = 162.0, 150.1, 149.7,

(m, 5 H), 7.13 (ddd, J = 8.0, 7.1, 0.5 Hz, 1 H), 4.70 (dd, J = 15.0, 140.1, 138.0, 135.8, 135.4, 134.8, 131.4, 130.9 (2 C), 128.5, 127.2,

5.8 Hz, 1 H), 4.55 (dd, J = 15.0, 5.3 Hz, 1 H), 4.16 (t, J = 5.4 Hz, 127.0, 126.9, 125.2, 122.6, 116.9, 116.3, 113.3, 44.5 ppm. IR (Nu-

1 H) ppm. ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 161.9, 149.4, jol): ν = 3390, 2234, 1678, 1582, 770, 718, 694 cm^–1. MS (ESI): m/z

˜

148.5, 138.2, 134.8, 134.5, 134.1, 131.5, 130.8 (2 C), 129.5, 129.5 (2

C), 127.4 (3 C), 127.4, 125.2, 123.7, 122.8, 117.6, 45.6 ppm. MS

(EI): m/z (%) = 407 (16) [M + 2]⁺, 405 (17) [M]⁺, 327 (58), 326

(100), 248 (74), 221 (51), 119 (74), 106 (45), 91 (75). C₂₁H₁₆BrN₃O

(406.28): calcd. C 62.08, H 3.97, N 10.34; found C 62.02, H 4.03,

N 10.28.

(%) = 354 (22) [M + 2]⁺, 353 (100) [M + 1]⁺, 278 (23), 152 (23),

150 (78). C₂₂H₁₆N₄O (352.39): calcd. C 74.98, H 4.58, N 15.90;

found C 74.93, H 4.64, N 15.85.

2-(Benzylamino)-3-(2-nitrophenyl)-3H-quinazolin-4-one (5f): This

compound (0.14 g, 85%) was obtained as white prisms, m.p. 145–

149 °C (EtOAc/n-hexane, 2:3). ¹H NMR (300 MHz, CDCl₃, 25 °C):

δ = 8.15 (dd, J = 8.1, 1.4 Hz, 1 H), 8.01 (dd, J = 7.9, 1.2 Hz, 1 H),

7.74 (ddd, J = 7.8, 1.4 Hz, 1 H), 7.65–7.55 (m, 2 H), 7.40 (dd, J =

7.8, 1.1 Hz, 2 H), 7.26–7.11 (m, 6 H), 4.70 (dd, J = 5.7, 4.8 Hz, 1

H), 4.57 (dd, J = 5.2, 4.8 Hz, 1 H), 4.14 (t, J = 5.5 Hz, 1 H) ppm.

¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 162.2, 149.3, 148.3, 146.9

(2 C), 138.1, 135.1 (2 C), 131.6, 131.2, 128.7, 127.6, 127.5, 127.2,

126.5, 125.3, 123.1, 117.3, 45.8 ppm. MS (EI): m/z (%) = 372 (4)

[M]⁺, 355.1 (47), 326.0 (47), 324 (26), 251 (19), 249 (32), 248 (68),

2-(Benzylamino)-3-(2,4-dibromophenyl)-3H-quinazolin-4-one (5b):

This compound (0.185 g, 85%) was obtained as white prisms, m.p.

134–136 °C (EtOAc/n-hexane, 2:3). ¹H NMR (400 MHz, CDCl₃,

25 °C): δ = 8.14 (ddd, J = 8.0, 1.5, 0.5 Hz, 1 H), 7.95 (d, J =

2.1 Hz,1 H), 7.65 (ddd, J = 8.2, 7.1, 1.5 Hz, 1 H), 7.64 (dd, J =

8.4, 2.1 Hz, 1 H), 7.46 (dd, J = 8.2, 0.5 Hz, 1 H), 7.35–7.25 (m, 5

H), 7.25 (d, J = 8.4 Hz, 1 H), 7.21 (ddd, J = 8.0, 7.1, 1.1 Hz, 1 H),

4.77 (dd, J = 14.9, 5.9 Hz, 1 H), 4.62 (dd, J = 14.9, 5.3 Hz, 1 H),

4.20 (t, J = 5.4 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): 237 (35), 236 (30), 235 (60), 146 (30), 91 (100). C₂₁H₁₆N₄O₃

δ = 161.7, 149.4, 148.1, 138.1, 137.1, 135.0, 133.3, 132.9, 131.9,

128.7 (2 C), 127.6 (3 C), 127.3, 125.2, 124.8, 124.7 (2 C), 123.0,

117.4, 45.7 ppm. MS (EI): m/z (%) = 487 (5) [M + 4]⁺, 485 (10) [M

+ 2]⁺, 483 (5) [M]⁺, 406 (30), 404 (39), 326 (10), 119 (11), 106 (18),

91 (100). C₂₁H₁₅Br₂N₃O (485.17): calcd. C 51.99, H 3.12, N 8.66;

found C 51.93, H 3.18, N 8.61.

(372.38): calcd. C 67.73, H 4.33, N 15.05; found C 67.68, H 4.39,

N 15.01.

1,3-Dibenzyl-1-{4-[(2-bromophenyl)imino]-4H-benzo[d][1,3]oxazin-2-

yl}urea (6a): This compound (0.19 g, 79%) was obtained as white

prisms, m.p. 115–119 °C (EtOAc/n-hexane, 2:3). ¹H NMR

(600 MHz, CDCl₃, 25 °C): δ = 10.53 (t, J = 5.3 Hz, 1 H), 8.10 (dd,

J = 7.8, 1.5 Hz, 1 H), 7.56 (dd, J = 8.0, 1.2 Hz, 1 H), 7.46 (ddd, J

= 7.8, 7.6, 1.5 Hz, 1 H), 7.34–7.30 (m, 4 H), 7.25–7.17 (m, 3 H),

7.08–7.01 (m, 4 H), 6.95 (ddd, J = 8.0, 7.8, 1.5 Hz, 1 H), 6.81 (dd,

J = 7.9, 1.5 Hz, 1 H), 6.58 (d, J = 7.0 Hz, 2 H), 4.80 (br. s, 2 H),

4.56 (d, J = 5.3 Hz, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃,

2-(Benzylamino)-3-(2-bromo-4-fluorophenyl)-3H-quinazolin-4-one

(5c): This compound (0.16 g, 85%) was obtained as white prisms,

m.p. 145–146 °C (EtOAc/n-hexane, 2:3). ¹H NMR (400 MHz,

CDCl₃, 25 °C): δ = 8.14 (dd, J = 7.9, 0.9 Hz, 1 H), 7.65 (ddd, J =

8.2, 7.0, 1.4 Hz,1 H), 7.54 (dd, J = 7.7, 2.7 Hz, 1 H), 7.46 (d, J =

8.2 Hz, 1 H), 7.37 (dd, J = 8.7, 5.4 Hz, 1 H), 7.31–7.13 (m, 7 H), 25 °C): δ = 154.0, 150.2, 145.7, 144.7, 142.8, 138.3, 137.2, 134.5,

4.77 (dd, J = 14.9, 5.8 Hz, 1 H), 4.62 (dd, J = 14.9, 5.2 Hz, 1 H),

133.0, 128.7, 128.3, 128.0, 127.4, 127.4, 127.0, 127.0, 126.9, 126.3,

4.21 (t, J = 5.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): 125.3, 124.1, 122.4, 115.7, 115.6, 46.1, 45.1 ppm. MS (ESI): m/z

1

δ = 162.8 (d, J_C,F= 225.6 Hz), 161.9, 149.4, 148.4, 138.1, 135.0,

(%) = 542 (34) [M + 4]⁺, 541 (47) [M + 3]⁺, 540 (48) [M + 2]⁺, 539

(100) [M + 1]⁺, 538 (16) [M]⁺, 408 (43), 407 (28), 406 (46), 301

(79), 299 (78), 235 (75). C₂₉H₂₃BrN₄O₂(539.42): calcd. C 64.57, H

4.30, N 10.39; found C 64.52, H 4.37, N 10.33.

3

4

131.9 (d, J_C,F= 9.2 Hz), 130.3 (d, J_C,F= 3.9 Hz), 128.7, 127.6,

3

2

127.5, 127.4, 125.2, 124.6 (d, J_C,F= 10 Hz), 123, 122 (d, J_C,F

=

25.5 Hz), 117.5, 116.9 (d, ²J_C,F= 22.6 Hz), 45.7 ppm. MS (EI): m/z

(%) = 425 (10) [M + 2]⁺, 423 (10) [M]⁺, 344 (56), 319 (16), 266

(19), 239 (27), 235 (22), 133 (67), 132 (60), 106 (24), 105 (59), 104

(72), 91 (100). C₂₁H₁₅BrFN₃O (423.04): calcd. C 59.45, H 3.56, N

9.90; found C 59.41, H 3.60, N 9.85.

1,3-Dibenzyl-1-{4-[(2,4-dibromophenyl)imino]-4H-benzo[d][1,3]ox-

azin-2-yl}urea (6b): This compound (0.196 g, 70%) was obtained

as white prisms, m.p. 140–142 (EtOAc/n-hexane, 2:3). ¹H NMR

(400 MHz, CDCl₃, 25 °C): δ = 10.48 (t, J = 5.2 Hz, 1 H), 8.08 (dd,

J = 7.8, 1.2 Hz, 1 H), 7.63 (d, J = 2.1 Hz, 1 H), 7.49 (ddd, J = 7.9,

7.4, 1.2 Hz, 1 H), 7.33–7.31 (m, 4 H), 7.24–7.22 (m, 2 H), 7.21 (dd,

J = 8.4, 2.1 Hz, 1 H), 7.11–7.10 (m, 3 H), 7.05 (d, J = 7.9 Hz, 1

H), 6.65–6.62 (m, 2 H), 6.58 (d, J = 8.4 Hz, 1 H), 4.82 (br. s, 2 H),

4.56 (d, J = 5.2 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃,

25 °C): δ = 153.8, 150.0, 146.2, 143.8, 142.8, 138.3, 137.0, 135.0,

2-(Benzylamino)-3-(2-bromo-5-nitrophenyl)-3H-quinazolin-4-one

(5d): This compound (0.20 g, 75%) was obtained as white prisms,

m.p. 191–193 °C (EtOAc/n-hexane, 2:3). ¹H NMR (300 MHz,

CDCl₃, 25 °C): δ = 8.26 (dd, J = 2.6, 0.4 Hz, 1 H), 8.23 (dd, J =

8.6, 2.6 Hz, 1 H), 8.13 (ddd, J = 7.9, 1.6, 0.4 Hz, 1 H), 7.99 (dd, J

= 8.6, 0.4 Hz, 1 H), 7.68 (ddd, J = 8.3, 7.1,1.6 Hz, 1 H), 7.49 (dd,

J = 8.3, 1.1 Hz, 1 H), 7.31–7.25 (m, 5 H), 7.24 (ddd, J = 7.9, 7.1, 134.7, 131.0, 128.7, 128.4, 127.4, 127.4, 127.0, 126.9, 126.5, 125.9,

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Eur. J. Org. Chem. 2009, 2490–2504

Fused Tetracyclic Quinazolinones

124.2, 123.3, 116.9, 116.7 (2 C), 115.3, 46.3, 45.1 ppm. MS (ESI):

115.3, 46.2, 45.1 ppm. MS (ESI): m/z (%) = 529 (30) [M + 1 + Na]

m/z (%) = 641 (36) [M + 2 + Na]⁺, 639 (23) [M + Na]⁺, 620 (43) ⁺, 528 (100) [M + Na]⁺, 507 (16) [M + 2]⁺, 506 (47) [M + 1]⁺, 396

[M + 4]⁺, 619 (100) [M + 3]⁺, 617 (37) [M + 1]⁺, 488 (45), 486 (70), (38), 374 (24), 373 (41), 330 (21), 301 (25), 279 (61). C₂₉H₂₃N₅O₄

484 (46), 330 (19), 279 (64). C₂₉H₂₂Br₂N₄O₂(618.32): calcd. C

56.33, H 3.59, N 9.06; found C 56.28, H 3.64, N 8.97.

(505.52): calcd. C 68.90, H 4.59, N 13.85; found C 68.85, H 4.63,

N 13.81.

5-Benzylbenzimidazo[2,1-b]quinazolin-12(5H)-ones 7: CuI (0.33 g,

1.71 mmol) was added under nitrogen to a solution of a 3-aryl-

2-(benzylamino)-3H-quinazolin-4-one 5 (0.34 mmol) in anhydrous

diglyme (20 mL). The mixture was stirred at room temperature for

30 min. NaH (0.075 g, 1.88 mmol) was then added, and the re-

sulting mixture was stirred at 100 °C for 24 h. The solution was

poured into aq. NH₄OH (5%, 200 mL) and stirred for 1 h, followed

by extraction with CH₂Cl₂(3ϫ150 mL). The combined organic

layers were washed with H₂O and dried (MgSO₄). After filtration,

the solvent was removed under reduced pressure, and the residual

material was chromatographed on a silica gel column with EtOAc/

n-hexane (2:3) to give 7 in good yields.

1,3-Dibenzyl-1-{4-[(2-bromo-4-fluorophenyl)imino]-4H-benzo[d][1,3]-

oxazin-2-yl}urea (6c): This compound (0.225 g, 90%) was obtained

as white prisms, m.p. 142–145 °C (EtOAc/n-hexane, 2:3). ¹H NMR

(400 MHz, CDCl₃, 25 °C): δ = 10.55 (t, J = 5.3 Hz, 1 H), 8.17 (dd,

J = 7.9, 0.9 Hz, 1 H), 7.56 (ddd, J = 8.0, 7.4, 1.5 Hz, 1 H), 7.42–

7.39 (m, 4 H), 7.38–7.28 (m, 3 H), 7.18–7.15 (m, 3 H), 7.11 (dd, J

= 8.1, 0.5 Hz, 1 H), 6.94–6.92 (m, 1 H), 6.79–6.73 (m, 3 H), 4.90

(br. s, 2 H), 4.63 (d, J = 5.3 Hz, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 159.0 (d, ¹J_C,F= 247.8 Hz), 153.9, 150.1, 146.2,

4

142.8, 140.8 (d, J_C,F= 3.2 Hz), 138.3, 137.1, 134.6, 128.7, 128.3,

3

127.4, 127.4, 127.0, 126.4, 126.2, 124.2, 122.7 (d, J_C,F= 8.3 Hz),

2

3

119.9 (d, J_C,F= 25.1 Hz), 115.7 (d, J_C,F= 9.6 Hz), 115.5, 46.2,

45.1 ppm. MS (ESI): m/z (%) = 579 (100) [M + Na]⁺, 559 (3) [M

+ 3]⁺, 557 (5) [M + 1]⁺, 448 (10). C₂₉H₂₂BrFN₄O₂(557.1): calcd.

C 62.49, H 3.98, N 10.05; found C 62.43, H 4.04, N 9.98.

5-Benzylbenzimidazo[2,1-b]quinazolin-12(5H)-one (7a): This com-

pound (88 mg, 80%) was obtained as white prisms, m.p. 218–220

(CH₂Cl₂/n-hexane, 2:3). ¹H NMR (400 MHz, CDCl₃, 25 °C): δ =

8.57 (dd, J = 7.6, 1.0 Hz, 1 H), 8.35 (dd, J = 8.0, 1.4 Hz, 1 H), 7.66

(ddd, J = 8.3, 6.9, 1.4 Hz, 1 H), 7.60 (dd, J = 8.3, 0.5 Hz, 1 H),

7.33–7.21 (m, 8 H), 7.09 (dd, J = 7.7, 0.6 Hz, 1 H), 5.42 (s, 2 H)

ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 160.0, 149.3, 146.7,

135.3, 134.4, 131.5, 128.9, 128.1, 127.5, 127.0, 126.0, 126.0, 125.8,

123.0, 122.2, 116.3, 116.3, 108.7, 45.6 ppm. MS (EI): m/z (%) = 326

(13) [M + 1]⁺, 325 (57) [M]⁺, 324 (16), 102 (12), 92 (21), 91 (100).

C₂₁H₁₅N₃O (325.36): calcd. C 77.52, H 4.65, N 12.91; found C

77.48, H 4.69, N 12.87.

1,3-Dibenzyl-1-{4-[(2-bromo-5-nitro-phenyl)imino]-4H-benzo[d][1,3]-

oxazin-2-yl}urea (6d): This compound (39 mg, 15%) was obtained

as white prisms, m.p. 155–159 °C (EtOAc/n-hexane, 2:3). ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 10.48 (t, J = 5.3 Hz, 1 H), 8.17 (dd,

J = 7.9, 1.2 Hz, 1 H), 7.81 (dd, J = 8.8, 2.6 Hz, 1 H), 7.72 (d, J =

8.8 Hz, 1 H), 7.65–7.59 (m, 2 H), 7.41–7.31 (m, 6 H), 7.16 (dd, J

= 8.1, 0.5 Hz, 1 H), 7.08–7.05 (m, 3 H), 6.61 (dd, J = 7.2, 1.60 Hz,

2 H), 4.85 (br. s, 2 H), 4.62 (d, J = 5.3 Hz, 2 H) ppm. ¹³C NMR

(75 MHz, CDCl₃, 25 °C): δ = 153.6 149.8, 147.6, 147.4, 146.1,

143.0, 138.1, 136.7, 135.2, 133.4, 128.7, 128.6, 128.3, 127.4, 127.4,

127.2, 127.0, 125.4, 124.4, 122.9, 119.5, 117.1, 114.8, 46.4,

45.2 ppm. MS (ESI): m/z (%) = 606 (21) [M + Na]⁺, 586 (37) [M

+ 3]⁺, 584 (17) [M + 1]⁺, 541 (33), 503 (72), 500 (84), 463 (46), 356

(37), 264 (30), 263 (100), 241 (56). C₂₉H₂₂BrN₅O₄Br (584.42):

calcd. C 59.60, H 3.79, N 11.98; found C 59.52, H 3.83, N 11.92.

5-Benzyl-8-bromobenzimidazo[2,1-b]quinazolin-12(5H)-one (7b):

This compound (0.135 g, 75%) was obtained as white prisms, m.p.

261–263 (CH₂Cl₂/n-hexane, 2:3). ¹H NMR (400 MHz, CDCl₃,

25 °C): δ = 8.41 (d, J = 8.5 Hz, 1 H), 8.33 (dd, J = 8.0, 1.6 Hz, 1

H), 7.67 (dd, J = 8.3, 1.6 Hz, 1 H), 7.59 (dd, J = 8.3, 0.7 Hz, 1 H),

7.34 (dd, J = 8.5, 1.8 Hz, 1 H), 7.31–7.24 (m, 6 H), 7.21 (d, J =

1.8 Hz, 1 H), 5.37 (s, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃,

25 °C): δ = 159.8, 149.1, 146.5, 134.8, 134.6, 132.8, 129.1, 128.3,

127.5, 127.0, 125.9, 125.2, 125.0, 123.4, 119.3, 117.3, 117.0, 111.8,

45.7 ppm. MS (EI): m/z (%) = 406 (7) [M + 3]⁺, 405 (29) [M +

2]⁺, 404 (11) [M + 1]⁺, 403 (30) [M]⁺, 205 (9), 204 (8), 102 (16), 91

(100). C₂₁H₁₄BrN₃OBr (404.26): calcd. C 62.39, H 3.49, N 10.39;

found C 62.33, H 3.53, N 10.33.

1,3-Dibenzyl-1-{4-[(2-cyanophenyl)imino]-4H-benzo[d][1,3]oxazin-2-

yl}urea (6e): This compound (22 mg, 10%) was obtained as white

prisms, m.p. 145–146 °C (EtOAc/n-hexane, 2:3). ¹H NMR

(600 MHz, CDCl₃, 25 °C): δ = 10.53 (t, J = 5.3 Hz, 1 H), 8.19 (d,

J = 7.7 Hz, 1 H), 7.62 (dd, J = 7.8, 0.9 Hz, 1 H), 7.59–7.56 (m, 1

H), 7.47–7.45 (m, 1 H), 7.42–7.39 (m, 4 H), 7.33–7.30 (m, 2 H),

7.21–7.18 (m, 1 H), 7.17–7.12 (m, 4 H), 6.92 (d, J = 8.1 Hz), 6.70

(d, J = 6.9 Hz, 2 H), 4.91 (br. s, 2 H), 4.64 (d, J = 5.3 Hz, 2 H)

ppm. ¹³C NMR (150 MHz, CDCl₃, 25 °C): δ = 153.8, 149.8, 148.9,

146.8, 142.9, 138.2, 137.0, 135.0, 133.4, 133.0, 128.7, 128.4, 127.5,

127.4, 127.1, 126.6, 126.1, 124.3, 122.1, 117.0, 115.3, 105.7, 46.2,

45.2 ppm. MS (ESI): m/z (%) = 487 (17) [M + 2]⁺, 486 (44) [M +

1]⁺, 374 (18), 352 (26), 247 (26), 246 (85), 235 (51), 149 (83), 137

(37), 123 (56), 111 (62), 110 (100). C₃₀H₂₃N₅O₂(485.54): calcd. C

74.21, H 4.77, N 14.42; found C 74.17, H 4.82, N 14.35.

5-Benzyl-8-fluorobenzimidazo[2,1-b]quinazolin-12(5H)-one (7c):

This compound (82 mg, 70%) was obtained as white prisms, m.p.

243–244 °C (CH₂Cl₂/n-hexane, 2:3). ¹H NMR (300 MHz, CDCl₃,

25 °C): δ = 8.58 (dd, J = 8.8, 4.9 Hz, 1 H), 8.41 (ddd, J = 8.1, 1.5,

0.4 Hz, 1 H), 7.75 (ddd, J = 8.3, 6.9, 1.5 Hz, 1 H), 7.67 (dd, J = 8.3,

0.8 Hz, 1 H), 7.41–7.30 (m, 6 H), 6.99 (ddd, J = 9.4, 8.8, 2.4 Hz, 1

H), 6.86 (dd, J = 8.4, 2.4 Hz, 1 H), 5.46 (s, 2 H) ppm. ¹³C NMR

1

(75 MHz, CDCl₃, 25 °C): δ = 161.0 (d, J_C,F= 244.5 Hz), 159.7,

3

149.0, 147.0, 134.8, 134.5, 132.7 (d, J_C,F= 12.5 Hz), 129.0, 128.3,

1,3-Dibenzyl-1-{4-[(2-nitrophenyl)imino]-4H-benzo[d][1,3]oxazin-2-

yl}urea (6f): This compound (0.128 g, 57%) was obtained as white

prisms, m.p. 141–143 °C (EtOAc/n-hexane, 2:3). ¹H NMR

(400 MHz, CDCl₃, 25 °C): δ = 10.54 (t, J = 5.29 Hz, 1 H), 8.10

(dd, J = 7.9, 1.5 Hz, 1 H), 8.0 (dd, J = 8.3, 1.4 Hz, 1 H), 7.57 (ddd,

J = 8.2, 7.6, 1.5 Hz, 1 H), 7.47 (ddd, J = 8.0, 7.5, 1.4 Hz, 1 H),

7.41–7.37 (m, 4 H), 7.34–7.28 (m, 2 H), 7.22 (ddd, J = 8.3, 7.5,

3

127.5, 126.9, 125.9, 123.3, 122.2 (d, ⁴J_C,F= 2.1 Hz), 117.2 (d, J_C,F

2

= 9.7 Hz), 116.9, 109.0 (d, J_C,F= 24.1 Hz), 96.9 (d, J_C,F

=

29.1 Hz), 45.8 ppm. MS (EI): m/z (%) = 345 (4) [M + 2]⁺, 344 (31)

[M + 1]⁺, 343 (65) [M]⁺, 342 (21), 252 (21), 224 (17), 102 (19), 91

(100). C₂₁H₁₄FN₃O (343.35): calcd. C 73.46, H 4.11, N 12.24;

found C 73.41, H 4.15, N 12.18.

1.3 Hz, 1 H), 7.14–7.07 (m, 4 H), 6.88 (dd, J = 8.0, 1.3 Hz, 1 H), 5-Benzyl-9-nitrobenzimidazo[2,1-b]quinazolin-12(5H)-one (7d): This

6.65 (dd, J = 7.3, 1.2 Hz, 2 H), 4.82 (br. s, 2 H), 4.63 (d, J = 5.3 Hz, compound (92 mg, 73%) was obtained as white prisms, m.p. 280–

2 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 153.8, 149.9, 282 °C (CH₂Cl₂/n-hexane, 2:3). ¹H NMR (300 MHz, CDCl₃,

146.7, 142.8, 141.0, 140.9, 138.2, 137.0, 134.9, 133.9, 128.7, 128.3,

127.4, 127.4, 127.2, 126.9, 126.5, 125.8, 125.3, 124.3, 124.0, 123.6,

25 °C): δ = 9.16 (d, J = 2.4 Hz, 1 H), 8.40 (dd, J = 8.9, 2.4 Hz, 1

H), 8.30 (dd, J = 8.0, 1.5 Hz, 1 H), 7.84 (ddd, J = 8.3, 7.1, 1.5 Hz,

Eur. J. Org. Chem. 2009, 2490–2504

www.eurjoc.org

2499

J. A. Bleda, P. M. Fresneda, R. Orenes, P. Molina

FULL PAPER

1 H), 7.67 (d, J = 8.9 Hz, 2 H), 7.47–7.42 (m, 3 H), 7.36–7.28 (m, 2.4 Hz, 1 H), 8.25 (dd, J = 8.0, 1.2 Hz, 1 H), 7.83 (ddd, J = 8.3,

3 H), 5.60 (s, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 7.3, 1.2 Hz, 1 H), 7.62 (d, J = 8.9 Hz, 1 H), 7.55 (d, J = 8.3 Hz, 1

159.1, 148.5, 147.3, 141.6, 136.8, 135.8, 135.0, 128.8, 127.9, 127.4,

126.6, 125.9, 125.5, 123.9, 122.6, 116.8, 110.3, 109.3, 45.0 ppm. MS

(EI): m/z (%) = 371 (6) [M + 1]⁺, 370 (24) [M]⁺, 91 (100).

C₂₁H₁₄N₄O₃(370.36): calcd. C 68.10, H 3.81, N 15.13; found C

68.05, H 3.84, N 15.07.

H), 7.39 (ddd, J = 8.0, 7.3, 0.9 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

[D₆]DMSO, 70 °C): δ = 158.2, 149.6, 145.4, 141.8, 140.5, 135.0,

127.4, 126.8, 122.7, 121.3, 118.7, 114.5, 113.7, 109.9 ppm. MS (EI):

m/z (%) = 281 (17) [M + 1]⁺, 280 (100) [M]⁺, 250 (30), 248 (31),

235 (55), 234 (74), 207 (39), 130 (37), 103 (21), 90 (23). C₁₄H₈N₄O₃

(280.24): calcd. C 60.00, H 2.88, N 19.99; found C 59.94, H 2.95,

N 19.93.

Benzimidazo[2,1-b]quinazolin-12(5H)-ones 8: A solution of the ap-

propriate 5-benzylbenzimidazo[2,1-b]quinazolin-12(5H)-one 7

(0.31 mmol) in triflic acid (5 mL) was stirred under nitrogen at

70 °C for 36 h. After the mixture had been cooled to 0 °C, MeOH

(8 mL) was added, and the resulting mixture was stirred for 5 min.

Afterwards, a solution of NH₄OH (30%) was added until pH = 7

was reached, and the solution was extracted with EtOAc

(3ϫ50 mL). The combined organic extracts were dried (MgSO₄),

the solvent was removed under reduced pressure, and the residue

was chromatographed on a silica gel column with CH₂Cl₂/MeOH

(9:1) as eluent to give the compounds 8.

3-Aryl-2-mercapto-3H-quinazolin-4-ones 9: A solution of the appro-

priate iminophosphorane 4 (2.72 mmol) and carbon disulfide

(6.6 mL) in anhydrous toluene (20 mL) was heated at 100 °C in a

sealed tube for 12 h. The solvent was then removed under reduced

pressure, and the residue was chromatographed on a silica gel col-

umn with EtOAc/n-hexane (3:2) as eluent to give the compounds

9 as a white solid.

3-(2-Bromophenyl)-2-mercapto-3H-quinazolin-4-one (9a): This com-

pound (0.64 g, 70 %) was obtained as white prisms, m.p. 262–

264 °C (CH₂Cl₂/n-hexane, 2:3). ¹H NMR (400 MHz, [D₆]DMSO,

25 °C): δ = 13.17 (s, 1 H), 7.97 (dd, J = 8.0, 1.2 Hz, 1 H), 7.81

(ddd, J = 8.0, 7.3, 1.5 Hz, 1 H), 7.75 (dd, J = 7.8, 1.1 Hz, 1 H),

7.53–7.45 (m, 3 H), 7.39–7.34 (m, 2 H) ppm. ¹³C NMR (75 MHz,

[D₆]DMSO, 25 °C): δ = 175.0, 159.0, 139.7, 138.1, 136.1, 132.8,

131.3, 130.3, 128.7, 127.5, 124.7, 122.4, 115.9, 115.7 ppm. MS (EI):

m/z (%) = 353 (100) [M – Br]⁺, 252 (27), 224 (17), 127 (16), 90 (14).

C₁₄H₉BrN₂OS (333.20): calcd. C 50.46, H 2.72, N 8.41; found C

50.41, H 2.77, N 8.36.

Benzimidazo[2,1-b]quinazolin-12(5H)-one (8a): This compound

(50 mg, 70 %) was obtained as white prisms, m.p. Ͼ300 °C

1

(CH₂Cl₂/n-hexane, 2:3). H NMR (300 MHz, [D₆]DMSO, 70 °C):

δ = 12.32 (br. s, 1 H), 8.42 (d, J = 7.8 Hz, 1 H), 8.24 (dd, J = 8.0,

1.2 Hz, 1 H), 7.76 (ddd, J = 8.3, 7.1, 1.2 Hz, 1 H), 7.52 (dd, J =

8.3, 1.1 Hz, 1 H), 7.47 (dd, J = 8.0, 1.5 Hz, 1 H), 7.42 (ddd, J =

8.0, 7.3, 1.2 Hz, 1 H), 7.32 (ddd, J = 8.0, 7.1, 1.1 Hz, 1 H), 7.28

(ddd, J = 7.8, 7.3, 1.5 Hz, 1 H) ppm. ¹³C NMR (75 MHz, [D₆]

DMSO, 70 °C): δ = 158.6, 146.7, 145.2, 135.6, 134.1, 126.8, 126.3,

125.3, 121.7, 121.1, 120.6, 114.5, 114.4, 112.6 ppm. MS (EI): m/z

(%) = 235 (100) [M]⁺, 207 (32), 205 (40), 179 (15), 104 (12), 103

(31), 90 (100). C₁₄H₉N₃O (235.24): calcd. C 71.48, H 3.86, N 17.86;

found C 71.43, H 3.93, N 17.81.

3-(2,4-Dibromophenyl)-2-mercapto-3H-quinazolin-4-one (9b): This

compound (0.83 g, 74%) was obtained as white prisms, m.p. 261–

262 °C (CH₂Cl₂/n-hexane, 2:3). ¹H NMR (400 MHz, [D₆]DMSO,

25 °C): δ = 13.22 (s, 1 H), 8.03 (d, J = 2.1 Hz, 1 H), 7.98 (dd, J =

8.2, 1.2 Hz, 1 H), 7.81 (ddd, J = 8.2, 7.3, 1.5 Hz, 1 H), 7.73 (dd, J

= 8.4, 2.1 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.46 (dd, J = 7.9,

1.5 Hz, 1 H), 7.37 (ddd, J = 7.9, 7.3, 1.2 Hz, 1 H) ppm. ¹³C NMR

(75 MHz, [D₆]DMSO, 25 °C): δ = 174.7, 158.9, 139.6, 137.7, 136.0,

134.8, 132.9, 131.7, 127.4, 124.6, 123.7, 122.1 (2 C), 115.9,

115.6 ppm. MS (EI): m/z (%) = 334 (33) [M + 2 – Br]⁺, 332 (100)

[M + 1 – Br]⁺, 331 (39) [M – Br]⁺, 330 (96), 223 (30), 133 (29), 102

8-Bromobenzimidazo[2,1-b]quinazolin-12(5H)-one (8b): This com-

pound (66 mg, 68%) was obtained as white prisms, m.p. Ͼ300 °C

1

(CH₂Cl₂/n-hexane, 2:3). H NMR (400 MHz, [D₆]DMSO, 70 °C):

δ = 12.70 (br. s, 1 H), 8.28 (d, J = 8.4 Hz, 1 H), 8.21 (dd, J = 8.0,

1.3 Hz, 1 H), 7.78 (ddd, J = 8.3, 7.1, 1.3 Hz, 1 H), 7.65 (d, J =

1.8 Hz, 1 H), 7.50 (d, J = 8.3 Hz, 1 H), 7.40 (dd, J = 8.4, 1.8 Hz,

1 H), 7.33 (ddd, J = 8.0, 7.1, 0.9 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, [D₆]DMSO, 70 °C): δ = 158.4, 147.4, 143.0, 140.3, (18), 90 (18). C₁₄H₈Br₂N₂OS (412.10): calcd. C 40.80, H 1.96, N

134.6, 126.9, 126.7, 123.2, 122.0, 119.2, 117.4, 116.8, 115.8, 6.80; found C 40.73, H 2.05, N 6.72.

113.8 ppm. MS (EI): m/z (%) = 315 (95) [M + 1]⁺, 313 (100) [M]⁺,

3-(2-Bromo-4-fluorophenyl)-2-mercapto-3H-quinazolin-4-one (9c):

234 (24), 206 (25), 179 (11), 103 (18), 102 (19), 90 (12).

This compound (0.60 g, 63%) was obtained as white prisms, m.p.

C₁₄H₈BrN₃O (314.14): calcd. C 53.53, H 2.57, N 13.38; found C

274–276 °C (CH₂Cl₂/n-hexane, 2:3). ¹H NMR (400 MHz, [D₆]-

DMSO, 25 °C): δ = 13.20 (s, 1 H), 7.97 (d, J = 7.7 Hz, 1 H), 7.81

53.48, H 2.61, N 13.32.

8-Fluorobenzimidazo[2,1-b]quinazolin-12(5H)-one (8c): This com-

pound (53 mg, 65%) was obtained as white prisms, m.p. Ͼ300 °C

(CH₂Cl₂/n-hexane, 2:3). H NMR (400 MHz, [D₆]DMSO, 70 °C):

(dd, J = 7.7, 7.5 Hz, 1 H), 7.75 (dd, J = 8.4, 2.6 Hz, 1 H), 7.57 (dd,

J = 8.8, 5.7 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.40 (ddd, J = 8.8,

1

8.5, 2.6 Hz, 1 H), 7.37 (dd, J = 8.2, 7.5 Hz, 1 H) ppm. ¹³C NMR

1

δ = 12.57 (br. s, 1 H), 8.35 (dd, J = 8.7, 5.1 Hz, 1 H), 8.22 (dd, J

(75 MHz, [D₆]DMSO, 25 °C): δ = 175.1, 161.4 (d, J_C,F

=

4

= 8.0, 1.2 Hz, 1 H), 7.78 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H), 7.51 (d, 249.2 Hz), 159.1, 139.7, 136.1, 134.8 (d, J_C,F= 3.5 Hz), 132.6 (d,

J = 8.2 Hz, 1 H), 7.33 (dd, J = 8.0, 7.2 Hz, 1 H), 7.29 (dd, J = 9.4, ³J_C,F= 9.2 Hz), 127.5, 124.7, 123.2 (d, J_C,F= 10.6 Hz), 120.0 (d,

3

2.4 Hz, 1 H), 7.07 (ddd, J = 9.8, 8.7, 2.4 Hz, 1 H) ppm. ¹³C NMR

²J_C,F= 25.9 Hz), 115.9, 115.8 (d, J_C,F= 21.4 Hz), 115.7 ppm. MS

2

1

(75 MHz, [D₆]DMSO, 70 °C): δ = 160.2 (d, J_C,F= 239.1 Hz), (EI): m/z (%) = 273 (23) [M + 2 – Br]⁺, 272 (57) [M + 1 – Br]⁺,

158.4, 147.8, 143.0, 139.6, 134.6, 126.7, 124.3, 122.1, 119.4, 115.3

271 (100) [M – Br]⁺, 270 (65), 243 (32), 242 (43), 136 (20), 108 (61),

(d, J_C,F= 10.2 Hz), 113.8, 107.6 (d, J_C,F= 24.8 Hz), 101.2 (d, 92 (33), 90 (40). C₁₄H₈BrFN₂OS (351.19): calcd. C 47.88, H 2.30,

3

2

²J_C,F= 27.2 Hz) ppm. MS (EI): m/z (%) = 254 (42) [M + 1]⁺, 253

(100) [M]⁺, 225 (52), 224 (46), 197 (12), 103 (18), 90 (7).

C₁₄H₈FN₃O (253.23): calcd. C 66.40, H 3.18, N 16.59; found C

66.35, H 3.23, N 16.52.

N 7.98; found C 47.84, H 2.37, N 7.92.

3-(2-Bromo-4-nitrophenyl)-2-mercapto-3H-quinazolin-4-one (9d):

This compound (0.62 g, 60%) was obtained as white prisms, m.p.

Ͼ300 °C (CH₂Cl₂/n-hexane, 2:3). ¹H NMR (300 MHz, [D₆]DMSO,

25 °C): δ = 13.34 (s, 1 H), 8.56 (d, J = 2.7 Hz, 1 H), 8.22 (dd, J =

8.8, 2.7 Hz, 1 H), 8.09 (d, J = 8.8 Hz, 1 H), 7.99 (dd, J = 8.0,

1.1 Hz, 1 H), 7.86–7.81 (m, 1 H), 7.48 (d, J = 8.1 Hz, 1 H), 7.42

(m, 1 H) ppm. ¹³C NMR (75 MHz, [D₆]DMSO, 25 °C): δ = 174.7,

9-Nitrobenzimidazo[2,1-b]quinazolin-12(5H)-one (8d): This com-

pound (57 mg, 66%) was obtained as white prisms, m.p. Ͼ300 °C

1

(CH₂Cl₂/n-hexane, 2:3). H NMR (400 MHz, [D₆]DMSO, 70 °C):

δ = 12.49 (br. s, 1 H), 9.10 (d, J = 2.4 Hz, 1 H), 8.30 (dd, J = 8.9,

2500

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Eur. J. Org. Chem. 2009, 2490–2504

Fused Tetracyclic Quinazolinones

159.1, 147.5, 139.7, 139.6, 136.2, 134.2, 130.9, 127.5, 126.6, 124.9,

[D₆]DMSO, 25 °C): δ = 8.15 (d, J = 8.2 Hz, 1 H), 8.27 (d, J =

8.0 Hz, 1 H), 7.93 (br. s, 1 H), 7.61 (ddd, J = 8.1, 7.1, 1.6 Hz, 1

124.8, 116.0, 115.8 ppm. MS (EI): m/z (%) = 379 (5) [M + 2]⁺, 377

(10) [M]⁺, 335 (12), 333 (10), 254 (33), 208 (22), 146 (30), 90 (100). H), 7.36–7.33 (m, 2 H), 7.29–7.26 (m, 1 H), 7.21 (d, J = 8.1 Hz, 1

C₁₄H₈BrN₃O₃S (378.20): calcd. C 44.46, H 2.13, N 11.11; found C

44.41, H 2.19, N 11.03.

H), 7.16 (ddd, J = 8.0, 7.1, 1.0 Hz, 1 H), 4.29 (s, 1 H) ppm. ¹³C

NMR (75 MHz, [D₆]DMSO, 25 °C): δ = 161.4, 151.7, 149.0, 135.1,

133.2, 128.4, 127.5, 127.4, 126.5, 126.9, 124.2, 122.5, 122.0, 118.3,

41.6 ppm. MS (EI): m/z (%) = 249 (30) [M]⁺, 248 (43), 167 (34),

149 (100), 113 (13), 83 (13), 71 (30). C₁₅H₁₁N₃O (249.27): calcd. C

72.28, H 4.45, N 16.86; found C 72.22, H 4.51, N 16.82.

Benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones 10: CuI (0.42 g,

2.2 mmol) was added under nitrogen to a solution of a 3-aryl-2-

mercapto-3H-quinazolin-4-one 9 (0.44 mmol) in anhydrous di-

glyme (20 mL). The mixture was stirred at room temperature for

30 min. NaH (0.097 g, 2.42 mmol) was then added, and the re-

sulting mixture was stirred at 150 °C for 12 h. The solution was

poured into aq. NH₄OH (5%, 200 mL) and stirred for 1 h, followed

by extraction with CH₂Cl₂(3ϫ100 mL). The combined organic

layers were washed with H₂O and dried (MgSO₄). After filtration,

the solvent was removed under reduced pressure, and the residual

material was chromatographed on a silica gel column with EtOAc/

n-hexane (2:3) to give the compounds 10 in good yield.

6-Benzyl-5-imino-5,6-dihydroquinazolino[3,2-a]quinazolin-12-one

(12): NaBH₄(0.026 g, 0.682 mmol) in anhydrous THF (5 mL) was

added at room temperature under nitrogen to a solution of 2-[2-

(benzylamino)-4-oxo-4H-quinazolin-3-yl]benzonitrile (5e, 0.2 g,

0.568 mmol) in anhydrous THF (15 mL). The mixture was stirred

at room temperature for 24 h. Afterwards, it was poured into cool

H₂O (100 mL) and extracted with EtOAc (3ϫ30 mL). The com-

bined organic layers were dried (MgSO₄) and filtered, and the sol-

vent was removed under reduced pressure. The resulting solid was

recrystallized from EtOAc/n-hexane (1:1) to give compound 12 as

white prisms (0.18 g, 90 % yield), m.p. 167–169 °C. ¹H NMR

(600 MHz, [D₆]DMSO, 25 °C): δ = 9.58 (s, 1 H), 8.70 (d, J =

8.5 Hz, 1 H), 8.27 (dd, J = 8.0, 1.0 Hz, 1 H), 8.09 (dd, J = 7.8,

0.9 Hz, 1 H), 7.71 (ddd, J = 8.1, 7.3, 0.9 Hz, 1 H), 7.67 (ddd, J =

8.5, 7.4, 1.0 Hz, 1 H), 7.51 (dd, J = 7.9, 7.4 Hz, 1 H), 7.43 (d, J =

7.5 Hz, 5 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.33 (dd, J = 7.8, 7.3 Hz,

1 H), 7.25 (dd, J = 7.7, 7.5 Hz, 1 H), 7.17 (dd, J = 7.7, 7.3 Hz, 1

H), 5.70 (s, 1 H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO, 25 °C): δ

= 161.5, 153.0, 146.3, 144.1, 138.0, 135.1, 132.2, 131.5, 128.0, 127.5,

127.1, 126.7, 126.6, 126.2, 125.2, 124.2, 121.5, 118.9, 118.2,

46.1 ppm. MS (ESI): m/z (%) = 375 (21) [M + Na]⁺, 355 (20), [M

+ 2]⁺, 354 (100) [M +1]⁺. C₂₂H₁₆N₄O (352.39): calcd. C 74.98, H

4.58, N 15.90; found C 74.93, H 4.63, N 15.82.

Benzo[4,5]thiazolo[2,3-b]quinazolin-12-one (10a): This compound

(91 mg, 75 %) was obtained as white prisms, m.p. 193–195 °C

(EtOAc/n-hexane, 2:3). ¹H NMR (400 MHz, CDCl₃, 25 °C): δ =

8.19 (dd, J = 8.0, 1.2 Hz, 1 H, 1 H), 7.80 (ddd, J = 8.0, 2.6, 1.2 Hz,

1 H), 7.68–7.64 (m, 1 H), 7.59–7.56 (m, 1 H), 7.53–7.49 (m, 2 H),

7.45–7.43 (m, 1 H), 7.39–7.35 (m, 1 H) ppm. ¹³C NMR (75 MHz,

CDCl₃, 25 °C): δ = 160.9, 152.1, 147.6, 134.9, 134.6, 134.3, 132.2,

131.4, 129.0, 127.5, 127.1, 126.7, 124.4, 120.0 ppm. MS (EI): m/z

(%) = 253 (17) [M + 1]⁺, 252 (100) [M]⁺, 224 (26), 112 (11), 90

(15). C₁₄H₈N₂OS (252.29): calcd. C 66.65, H 3.20, N 11.10; found

C 66.61, H 3.27, N 11.07.

8-Bromobenzo[4,5]thiazolo[2,3-b]quinazolin-12-one (10b): This com-

pound (0.10 g, 72 %) was obtained as white prisms, m.p. 272–

273 °C (EtOAc/n-hexane, 2:3). ¹H NMR (300 MHz, CDCl₃, 25 °C):

δ = 8.85 (d, J = 8.9 Hz, 1 H), 8.37 (dd, J = 8.0, 0.9 Hz, 1 H), 7.79–

7.73 (m, 1 H), 7.70 (d, J = 1.8 Hz, 1 H), 7.62 (d, J = 8.3 Hz, 1 H),

7.55 (dd, J = 8.9, 1.8 Hz, 1 H), 7.47–7.42 (m, 1 H) ppm. ¹³C NMR

(75 MHz, CDCl₃, 25 °C): δ = 160.7, 156.2, 147.2, 135.1, 133.7,

130.0, 127.2, 126.2, 126.1, 125.8, 124.5, 120.4, 119.9, 118.6 ppm.

MS (EI): m/z (%) = 332 (83) [M + 2]⁺, 331 (39) [M + 1]⁺, 330 (100)

[M]⁺, 304 (22), 223 (80), 133 (38), 90 (16). C₁₄H₇BrN₂OS (331.19):

calcd. C 50.77, H 2.13, N 8.46; found C 50.72, H 2.18, N 8.40.

5-Aminoquinazolino[3,2-a]quinazolin-12-one (13): A solution of 6-

benzyl-5-imino-5,6-dihydroquinazolino[3,2-a]quinazolin-12-one

(12, 0.1 g, 0.29 mmol) in dry EtOH (20 mL) in the presence of pal-

ladium on charcoal (10%, 0.062 g, 0.058 mmol) was stirred under

hydrogen at room temperature for 48 h. The mixture was filtered

through Celite, the solvent was removed at reduced pressure, and

the resulting solid was recrystallized from EtOAc/n-hexane (1:1) to

give compound 13 as white prisms (0.05 g, 67 % yield), m.p.

8-Fluorobenzo[4,5]thiazolo[2,3-b]quinazolin-12-one (10c): This com-

pound (96 mg, 80 %) was obtained as white prisms, m.p. 217–

219 °C (EtOAc/n-hexane, 2:3). ¹H NMR (400 MHz, CDCl₃, 25 °C):

δ = 8.98 (dd, J = 9.2, 4.8 Hz, 1 H), 8.30 (ddd, J = 8.1, 1.5, 0.5 Hz,

1 H), 7.76 (ddd, J = 8.3, 7.1, 1.5 Hz, 1 H), 7.64–7.61 (m, 1 H), 7.46

(ddd, J = 8.1, 7.1, 1.2 Hz, 1 H), 7.30 (dd, J = 7.6, 2.7 Hz, 1 H), 7.2

(ddd, J = 9.2, 8.6, 2.7 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃,

1

Ͼ300 °C. H NMR (300 MHz, [D₆]DMSO, 25 °C): δ = 9.26 (d, J

= 8.8 Hz, 1 H), 8.49 (br. s, 1 H), 8.36 (br. s, 1 H), 8.28 (dd, J =

8.0, 1.3 Hz, 1 H), 8.13 (dd, J = 8.8, 1.4 Hz, 1 H), 7.81 (ddd, J =

8.8, 7.3, 1.3 Hz, 1 H), 7.73 (ddd, J = 8.2, 7.6, 1.4 Hz, 1 H), 7.58

(dd, J = 8.0, 7.3 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.31 (dd, J =

8.0, 7.6 Hz, 1 H) ppm. ¹³C NMR (75 MHz, [D₆]DMSO, 25 °C): δ

= 162.8, 159.2, 148.1, 147.9, 137.3, 134.8, 132.9, 127.0, 126.4, 124.9,

124.4, 123.4, 120.9, 117.7, 114.0 ppm. MS (EI): m/z (%) = 262 (100)

[M]⁺, 236 (29), 233 (26), 220 (17), 145 (24), 144 (22), 120 (34), 119

(30), 117 (36), 102 (39), 90 (41). C₁₅H₁₀N₄O (262.27): calcd. C

68.69, H 3.84, N 21.36; found C 68.62, H 3.89, N 21.30.

1

25 °C): δ = 160.7 (d, J_C,F= 248.7 Hz), 160.6, 156.5, 147.1, 135.0,

3

4

132.4 (d, J_C,F= 1.5 Hz), 127.1, 126.1, 126.0, 125.5 (d, J_C,F

=

3

2

10.0 Hz), 120.6 (d, J_C,F= 8.5 Hz), 118.6, 114.1 (d, J_C,F

2

23.1 Hz), 109.1 (d, J_C,F= 27.4 Hz) ppm. MS (EI): m/z (%) = 272

(18) [M + 2]⁺, 271 (43) [M + 1]⁺, 270 (100) [M]⁺, 242 (53), 241

(38), 121 (22), 108 (59), 90 (17). C₁₄H₇FN₂OS (270.28): calcd. C

62.21, H 2.61, N 10.36; found C 62.17, H 2.66, N 10.29.

6-Benzyl-5-imino-6,12-dihydro-5H-quinazolino[3,2-a]quinazolin-12-

ol (14): A solution of 2-[2-(benzylamino)-4-oxo-4H-quinazolin-3-

5,7-Dihydroquinazolino[3,2-a]quinazolin-12-one (11): A mixture of yl]benzonitrile (5e, 0.27 g, 0.77 mmol) in anhydrous THF (30 mL)

2-[2-(benzylamino)-4-oxo-4H-quinazolin-3-yl]benzonitrile (5e,

0.2 g, 0.568 mmol), palladium on charcoal (10 %, 0.2 g,

0.187 mmol) and formic acid (85%, 4 mL) in MeOH (20 mL) was

warmed at 50 °C under nitrogen for 15 h. After cooling, the mix-

ture was filtered through Celite, the solvent was removed under

reduced pressure, and the resulting solid was recrystallized from

EtOAc/n-hexane (1:1) to give compound 11 as white prisms

was cooled to 0 °C, and LiAlH₄(1  solution in THF, 0.8 mL,

0.8 mmol) was added slowly under nitrogen. The reaction mixture

was warmed at room temperature and stirred for 2 h. Afterwards,

it was poured into H₂O (100 mL) and extracted with EtOAc

(3ϫ40 mL). The combined organic layers were dried (MgSO₄) and

filtered, and the solvent was removed under reduced pressure. The

residual solid was recrystallized from EtOAc/n-hexane (1:1) to give

compound 14 as white prisms (0.19 g, 70% yield), m.p. 178–180 °C.

1

(0.115 g, 80% yield), m.p. 189.9–192.1 °C. H NMR (600 MHz,

Eur. J. Org. Chem. 2009, 2490–2504

www.eurjoc.org

2501

J. A. Bleda, P. M. Fresneda, R. Orenes, P. Molina

FULL PAPER

¹H NMR (600 MHz, [D₆]DMSO, 25 °C): δ = 8.98 (s, 1 H), 8.19 (d,

m.p. 191–193 °C (EtOAc/n-hexane, 1:1). ¹H NMR (400 MHz, [D₆]-

J = 7.8 Hz, 1 H), 7.77 (d, J = 8.6 Hz, 1 H), 7.65–7.62 (m, 1 H), DMSO, 25 °C): δ = 11.06 (s, 1 H), 8.39 (d, J = 8.8 Hz, 1 H), 8.0

7.42 (d, J = 7.6 Hz, 2 H), 7.37 (d, J = 7.3 Hz, 1 H), 7.28–7.24 (m, (d, J = 8.2 Hz, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.63 (d, J = 8.0 Hz,

4 H), 7.16 (t, J = 7.2 Hz, 1 H), 7.06 (t, J = 7.3 Hz, 1 H), 7.03 (dd, 1 H), 7.49–7.43 (m, 2 H), 7.32 (dd, J = 7.9, 7.4 Hz, 1 H), 7.17 (br.

J = 7.9, 0.9 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 1 H), 6.85 (d, J = 8.9 Hz,

1 H), 5.74 (d, J = 14.4 Hz, 1 H), 5.64 (d, J = 14.4 Hz, 1 H) ppm.

¹³C NMR (75 MHz, [D₆]DMSO, 25 °C): δ = 153.5, 142.4, 140.9,

138.8, 136.3, 132.7, 129.2, 127.9, 127.6, 127.2, 126.3, 123.1, 123.0,

122.7, 122.6, 115.6, 115.2, 74.7, 45.1 ppm. MS (ESI): m/z (%) =

s, 1 H), 7.02 (dd, J = 8.2, 7.4 Hz, 1 H), 5.14 (d, J = 2.9 Hz, 1 H),

4.82 (d, J = 2.9 Hz, 1 H), 3.18 (q, J = 7.2 Hz, 2 H), 1.11 (t, J =

7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO, 25 °C): δ =

154.8, 154.5, 150.3, 141.9, 136.8, 132.4, 130.9, 128.4, 128.1, 126.2,

123.0, 120.0, 119.7, 119.4, 113.9, 87.2, 34.2, 15.1 ppm. MS (EI):

356 (17) [M + 2]⁺, 355 (100) [M + 1]⁺, 338 (14), 337 (56), 327 (20), m/z (%) = 307 (25) [M]⁺, 263 (99), 235 (100), 219 (43), 146 (26).

247 (21). C₂₂H₁₈N₄O (354.40): calcd. C 74.56, H 5.12, N 15.81;

found C 74.51, H 5.20, N 15.73.

C₁₈H₁₇N₃O₂(307.35): calcd. C 70.34, H 5.58, N 13.67; found C

70.27, H 5.63, N 13.62.

3-(2-Aminophenyl)-2-(benzylamino)-3H-quinazolin-4-one (15): A

solution of 2-(benzylamino)-3-(2-nitrophenyl)-3H-quinazolin-4-

one (5f, 0.1 g, 0.27 mmol) in anhydrous THF (30 mL) in the pres-

ence of palladium on charcoal (10 %, 0.086 g, 0.08 mmol) was

stirred under hydrogen at room temperature for 2 h. The mixture

was filtered through Celite, the solvent was removed under reduced

pressure, and the resulting solid was recrystallized from CH₂Cl₂/n-

hexane (1:1) to give the diamino compound 15 as white prisms

(0.073 g, 80 % yield), m.p. 166–168 °C. ¹H NMR (400 MHz,

CDCl₃, 25 °C): δ = 8.15 (ddd, J = 7.9, 1.6, 0.4 Hz, 1 H), 7.63 (ddd,

J = 8.3, 7.1, 1.6 Hz, 1 H), 7.44 (dd, J = 8.3, 1.1 Hz, 1 H), 7.32–

7.22 (m, 6 H), 7.19 (ddd, J = 7.9, 7.1, 1.1 Hz, 1 H), 7.10 (dd, J =

8.2, 1.5 Hz, 1 H), 6.92–6.88 (m, 2 H), 4.73–4.71 (m, 1 H), 4.68 (dd,

J = 6.1, 2.2 Hz, 2 H), 3.74 (br. s, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 162.1, 149.6, 149.3, 143.6, 138.4, 134.8, 131.1,

129.3, 128.6, 127.7, 127.2, 125.0, 127.7, 120.0, 119.6, 117.6, 117.5,

45.3 ppm. MS (EI): m/z (%) = 343 (7) [M + 1]⁺, 342 (24) [M]⁺, 324

(22), 322 (23), 236 (25), 234 (73), 219 (70), 182 (100), 180 (75), 106

(35), 90 (35). C₂₁H₁₈N₄O (342.39): calcd. C 73.67, H 5.30, N 16.36;

found C 73.61, H 5.38, N 16.29.

1-[2-(4-Methylene-4H-benzo[d][1,3]oxazin-2-yl)phenyl]-3-propylurea

(19b): This compound (0.195 g, 78%) was obtained as white prisms,

m.p. 194–195 °C (EtOAc/n-hexane, 1:1). ¹H NMR (400 MHz, [D₆]-

DMSO, 25 °C): δ = 11.04 (s, 1 H), 8.37 (dd, J = 8.5, 0.9 Hz, 1 H),

8.0 (dd, J = 8.1, 1.6 Hz, 1 H), 7.70 (dd, J = 8.0, 1.2 Hz, 1 H), 7.62

(dd, J = 7.7, 0.7 Hz, 1 H), 7.48–7.42 (m, 2 H), 7.31 (ddd, J = 8.0,

7.4, 0.7 Hz, 1 H), 7.15 (t, J = 5.2 Hz, 1 H), 7.01 (ddd, J = 8.1, 7.2,

0.9 Hz, 1 H), 5.12 (d, J = 2.8 Hz, 1 H), 4.81 (d, J = 2.8 Hz, 1 H),

3.10 (q, J = 6.5 Hz, 2 H), 1.51 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H)

ppm. ¹³C NMR (100 MHz, [D₆]DMSO, 25 °C): δ = 154.7, 154.6,

150.3, 141.9, 136.8, 132.3, 130.8, 128.3, 128.0, 126.2, 122.9, 119.9,

119.7, 119.5, 114.0, 87.1, 41.2, 22.6, 11.1 ppm. MS (EI): m/z (%) =

321 (19) [M]⁺, 264 (60), 263 (78), 236 (31), 235 (100), 219 (39), 146

(26), 118 (28). C₁₉H₁₉N₃O₂(321.37): calcd. C 71.01, H 5.96, N

13.08; found C 70.96, H 6.02, N 13.02.

1-[2-(4-Methylene-4H-benzo[d][1,3]oxazin-2-yl)phenyl]-3-phenylurea

(19c): This compound (0.224 g, 80%) was obtained as white prisms,

m.p. 240–242 °C (EtOAc/n-hexane, 1:1). ¹H NMR (300 MHz, [D₆]-

DMSO, 25 °C): δ = 11.36 (s, 1 H), 9.69 (s, 1 H), 8.27 (dd, J = 8.5,

0.9 Hz, 1 H), 8.05 (dd, J = 8.1, 1.6 Hz, 1 H), 7.73 (dd, J = 7.8,

1.2 Hz, 1 H), 7.59–7.49 (m, 4 H), 7.46 (dt, J = 7.6, 1.2 Hz, 1 H),

7.34–7.26 (m, 3 H), 7.11 (ddd, J = 8.1, 7.6, 0.9 Hz, 1 H), 7.00 (dt,

J = 7.4, 1.0 Hz, 1 H), 5.16 (d, J = 2.8 Hz, 1 H), 4.83 (d, J = 2.8 Hz,

1 H) ppm. ¹³C NMR (75 MHz, [D₆]DMSO, 25 °C): δ = 154.7,

152.4, 150.4, 141.0, 139.6, 136.8, 132.5, 131.0, 128.7, 128.6, 128.3,

126.5, 123.1, 122.3, 121.1, 120.5, 119.8, 119.2, 115.1, 87.5 ppm. MS

(EI): m/z (%) = 356 (26) [M + 1]⁺, 355 (76) [M]⁺, 262 (98), 235

(99), 219 (61), 217 (46), 206 (37), 205 (35), 146 (55), 119 (34), 116

(35), 90 (100). C₂₂H₁₇N₃O₂(355.39): calcd. C 74.35, H 4.82, N

11.82; found C 74.30, H 4.87, N 11.76.

6-Aminobenzo[4,5]imidazo[1,2-c]quinazoline (16): Phosphorus

pentachloride (0.06 g, 0.29 mmol) was added under nitrogen at

0 °C to a solution of 3-(2-aminophenyl)-2-(benzylamino)-3H-quin-

azolin-4-one (15, 0.1 g, 0.29 mmol) in dry toluene (20 mL). The

reaction mixture was stirred at room temperature for 1 h. Triethyl-

amine (0.029 g, 0.29 mmol) was added, and the resulting mixture

was heated at reflux temperature and stirred for 1 h. The mixture

was poured into ice/H₂O (200 mL) and extracted with EtOAc

(3ϫ100 mL). The combined organic layers were dried (MgSO₄),

filtered and concentrated to dryness. The resulting solid was recrys-

tallized from EtOAc/n-hexane (1:1) to give compound 16 (0.053 g,

78% yield) as white prisms, m.p. Ͼ300 °C (EtOAc/n-hexane, 1:1).

¹H NMR (400 MHz, [D₇]DMF, 80 °C): δ = 8.49 (d, J = 7.9 Hz, 1

H), 8.30 (dd, J = 8.0, 1.6 Hz, 1 H), 7.77 (ddd, J = 8.3, 7.1, 1.6 Hz,

1 H), 7.58 (d, J = 8.3 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.46–

7.42 (m, 1 H), 7.36–7.28 (m, 2 H), 3.08 (br. s, 2 H) ppm. ¹³C NMR

(100 MHz, [D₇]DMF, 80 °C): δ = 159.3, 147.5, 146.3, 136.1, 134.4,

127.7, 126.8, 125.7, 122.1, 121.9, 121.1, 115.3, 115.1, 112.8 ppm.

MS (EI): m/z (%) = 235 (100) [M + 1]⁺, 207 (33), 206 (37), 179

(15), 117 (18), 103 (52), 91 (31). C₁₄H₁₀N₄(234.26): calcd. C 71.78,

H 4.30, N 23.92; found C 71.73, H 4.39, N 23.87.

1-(4-Methoxyphenyl)-3-[2-(4-methylene-4H-benzo[d][1,3]oxazin-2-

yl)phenyl]urea (19d): This compound (0.224 g, 75%) was obtained

as white prisms, m.p. 223–226 °C (EtOAc/n-hexane, 1:1). ¹H NMR

(400 MHz, [D₆]DMSO, 25 °C): δ = 11.32 (s, 1 H), 9.46 (s, 1 H),

8.28 (d, J = 7.8 Hz, 1 H), 8.05 (dd, J = 8.1, 1.5 Hz, 1 H), 7.73 (d,

J = 7.7 Hz, 1 H), 7.53–7.48 (m, 1 H), 7.44 (d, J = 8.03 Hz, 1 H),

7.40 (d, J = 8.4 Hz, 2 H), 7.33–7.29 (m, 1 H), 7.11–7.07 (m, 1 H),

6.89 (d, J = 8.4 Hz, 2 H), 6.87–6.83 (m, 1 H), 5.16 (d, J = 2.8 Hz,

1 H), 4.83 (d, J = 2.8 Hz, 1 H), 3.71 (s, 3 H) ppm. ¹³C NMR

(100 MHz, [D₆]DMSO, 25 °C): δ = 155.0, 154.7, 152.5, 150.3,

141.2, 136.8, 132.4, 130.9, 130.3, 128.4, 128.1, 126.3, 123.0, 121.3,

120.7, 120.2, 119.8, 114.9, 113.7, 87.5, 55.1 ppm. MS (EI): m/z (%)

= 385 (9) [M]⁺, 384 (13), 263 (64), 235 (100), 219 (36), 149 (30),

146 (44), 123 (71),108 (32). C₂₃H₁₉N₃O₃(385.14): calcd. C 71.67,

H 4.97, N 10.90; found C 71.61, H 5.05, N 10.83.

1-Substituted 3-[2-(4-Methylene-4H-benzo[d][1,3]oxazin-2-yl)phen-

yl]ureas 19: The appropriate isocyanate (1.56 mmol) was added at

room temperature under nitrogen to a solution of N-(2-ace-

tylphenyl)-2-(triphenylphosphoranylideneamino)benzamide (4g,

0.4 g, 0.78 mmol) in dry toluene (40 mL). The resulting mixture

was warmed at reflux temperature for 6–12 h. After removal of the

solvent under reduced pressure, the residue was recrystallized from

EtOAc/n-hexane (1:1).

1-Benzyl-3-[2-(4-methylene-4H-benzo[d][1,3]oxazin-2-yl)phenyl]urea

(19e): This compound (0.244 g, 85%) was obtained as white prisms,

m.p. 169–172 °C (EtOAc/n-hexane, 1:1). ¹H NMR (600 MHz, [D₆]-

DMSO, 25 °C): δ = 11.21 (s, 1 H), 8.41 (dd, J = 8.5, 1.2 Hz, 1 H),

8.03 (dd, J = 8.1, 1.7 Hz, 1 H), 7.77 (t, J = 6.0 Hz, 1 H), 7.72 (dd,

1-Ethyl-3-[2-(4-methylene-4H-benzo[d][1,3]oxazin-2-yl)phenyl]urea

(19a): This compound (0.20 g, 85%) was obtained as white prisms,

2502

www.eurjoc.org

Eur. J. Org. Chem. 2009, 2490–2504

Fused Tetracyclic Quinazolinones

Table 9. Crystal data for 6d, 14 and 19e.

6d

14

19e

Empirical formula

Crystal size [mm]

Crystal system

Space group

a [Å]

b [Å]

c [Å]

C₂₉H₂₂BrN₅O₄

0.25ϫ0.09ϫ0.06

orthorhombic

Pbca

16.5034(6)

8.8217(3)

35.1457(12)

90

C₂₂H₁₈N₄O

0.26ϫ0.05ϫ0.04

monoclinic

P2(1)/c

10.2462(7)

22.6820(14)

10.9986(7)

90

C₂₃H₁₉N₃O₂

0.40ϫ0.15ϫ0.09

monoclinic

P2(1)/c

4.7354(2)

38.794(2)

9.9132(5)

90

α [°]

β [°]

90

5116.8(3)

8

101.928(2)

90

1721.57(18)

4

98.697(2)

90

1592.92(12)

4

γ [°]

V [Å³]

Z

λ [Å]

0.71073

1.517

2384

0.71073

1.367

744

0.71073

1.363

776

ρ_calcd.[Mgm^–3]

F(000)

T [K]

100(2)

1.653

1.69–28.26

–21ՅhՅ21

–11ՅkՅ 11

–46ՅlՅ44

55934

100(2)

0.087

2.09–28.20

–9ՅhՅ9

–29ՅhՅ30

–14ՅhՅ14

19698

100(2)

0.089

2.10–26.37

–5ՅhՅ14

–48ՅkՅ48

–12ՅlՅ12

19681

µ [mm^–1]

θ range [°]

Index ranges

Reflections collected

Independent reflections

R_int

6114

0.0567

4012

0.044

3669

0.049

Refinement method

Data/restraints/parameters

GOOF on F²

full-matrix least squares on F²

6114/0/356

1.033

full-matrix least squares on F²

4012/9/252

1.149

full-matrix least squares on F²

3669/0/298

1.038

[a]

R₁

0.035

0.084

0.413/–0.351

0.068

0.146

0.435/–0.279

0.039

0.097

0.215/–0.181

[b]

wR₂

Largest difference peak [eÅ^–3]

[a] R₁= Σ||F_o| – |F_c||/Σ|F_o| for reflections with IϾ2σ(I). [b] wR₂= {Σ[w(F_o– F_c) ]/Σ[w(F_o²)²]}^0.5for all reflections; w^–1= σ²(F_o²) +

2

2 2

(aP)²+ bP, where P = (2F_c+ F_o²)/3 and a and b are constants set by the program.

2

J = 8.0, 1.3 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.49–7.44 (m, 2

H), 7.37–7.30 (m, 5 H), 7.25–7.23 (m, 1 H), 7.06 (ddd, J = 8.1, 7.2,

Mo-K_αradiation in ω-scan mode (Table 9). The structures were

solved by direct methods. All were refined anisotropically on F².

1.3 Hz, 1 H), 5.14 (d, J = 2.9 Hz, 1 H), 4.83 (d, J = 2.9 Hz, 1 H), The methyl groups were refined by use of rigid groups, and the

4.38 (d, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO,

25 °C): δ = 154.7, 154.7, 150.3, 141.7, 140.2, 136.8, 132.3, 130.8,

128.3, 128.0, 128.0, 126.9, 126.4, 126.3, 122.9, 120.2, 119.7, 119.5,

114.1, 87.2, 42.8 ppm. MS (ESI): m/z (%) = 393 (16) [M + Na +

other hydrogen atoms were refined with use of a riding model. Spe-

cial features: For compound 6d: the NH hydrogen atoms were re-

fined freely; for compound 14: the NH and OH hydrogen atoms

were refined freely; for compound 19e: the phenyl group C21–C26

1]⁺, 369 (100) [M]⁺, 354 (45), 353 (96), 339 (21), 279 (59), 278 (41), is disordered over two positions. CCDC-716954 (6d), -716955 (14)

277 (86), 150 (51). C₂₃H₁₉N₃O₂(369.42): calcd. C 74.78, H 5.18, N

11.37; found C 74.72, H 5.23, N 11.30.

and -716956 (19e) contain the supplementary crystallographic data

for this paper. This data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

1-(4-Methoxybenzyl)-3-[2-(4-methylene-4H-benzo[d][1,3]oxazin-2-

yl)phenyl]urea (19f): This compound (0.273 g, 88%) was obtained

as white prisms, m.p. 173–176 °C (EtOAc/n-hexane, 1:1). ¹H NMR

(400 MHz, [D₆]DMSO, 25 °C): δ = 11.23 (s, 1 H), 8.39 (dd, J =

8.5, 0.9 Hz, 1 H), 8.01 (dd, J = 8.1, 1.5 Hz, 1 H), 7.82 (t, J =

5.9 Hz, 1 H), 7.73 (dd, J = 7.9, 1.1 Hz, 1 H), 7.67 (d, J = 7.9 Hz,

1 H), 7.49–7.43 (m, 2 H), 7.31 (dt, J = 7.9, 1.2 Hz, 1 H), 7.25 (d,

J = 8.7 Hz, 2 H), 7.03 (ddd, J = 8.1, 7.3, 0.9 Hz, 1 H), 6.88 (d, J

= 8.7 Hz, 2 H) 5.16 (d, J = 2.8 Hz, 1 H), 4.82 (d, J = 2.8 Hz, 1 H),

4.27 (d, J = 5.9 Hz, 2 H), 3.71 (s, 3 H) ppm. ¹³C NMR (100 MHz,

[D₆]DMSO, 25 °C): δ = 158.1, 154.8, 154.7, 150.4, 141.9, 136.9,

132.6, 132.3, 131.0, 128.5, 128.4, 128.2, 126.5, 123.1, 120.3, 119.8,

119.6, 114.1, 113.7, 87.4, 55.0, 42.3 ppm. MS (EI): m/z (%) = 399

(75) [M]⁺, 264 (39), 235 (23), 136 (49), 121 (100), 91 (17).

C₂₄H₂₁N₃O₃(399.00): calcd. C 72.16, H 5.30, N 10.52; found C

71.97, H 5.01, N 10.58.

Acknowledgments

We thank the Foundation Seneca (Comunidad Autónoma de la

Región de Murcia) for financial support (project number 00582/PI/

04).

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Published Online: April 8, 2009

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Preparation of fused tetracyclic quinazolinones by combinations of aza-wittig methodologies and CuI-catalysed heteroarylation processes

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