Remarkable regioselectivities in the course of the synthesis of two new Luotonin A derivatives

Tetrahedron 73 (2017) 3231e3239

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Tetrahedron journal homepage: www.elsevier.com/locate/tet

Remarkable regioselectivities in the course of the synthesis of two new Luotonin A derivatives
ra Bogda
n b, Maryam Brügger a, Norbert Haider a, *, Pe
ter Ma
tyus b Mohamed Atia a, Do a b

Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, A-1090, Vienna, Austria }gyes Endre u. 7, H-1092, Budapest, Hungary Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Ho

a r t i c l e i n f o

a b s t r a c t

Article history: Received 6 March 2017 Received in revised form 20 April 2017 Accepted 21 April 2017 Available online 26 April 2017

Ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate reacts selectively with trimethylaluminium-activated 2-amino- or 4-aminobenzoic acid ethyl esters to give the corresponding anilides without selfcondensation of the aminobenzoate building blocks. After propargylation, the quinazolinones were treated with Hendrickson's reagent, but only the para-substituted ester was found to undergo the expected [4 þ 2] cycloaddition reaction, affording a new Luotonin A derivative. A different regioselectivity was observed with the ortho-substituted ester which affords a benzoxazinone under identical conditions. When the ester group in the ortho-substituted intermediate is replaced with a nitrile function, the outcome of the reaction with Hendrickson's reagent depends on the absence or presence of a base (DBU), yielding either a triphenylphosphonium-substituted iminobenzoxazine or a 4-cyano-substituted Luotonin A derivative. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Luotonin A Weinreb amidation Hendrickson's reagent Cycloaddition

1. Introduction Since its discovery in 1997,1 the alkaloid Luotonin A has attracted considerable interest due to its structural resemblance to the potent topoisomerase I poison, Camptothecin (CPT).2 The latter natural product had served as a lead structure for the development of improved analogs (such as 14-aza-CPT),3,4 including clinically used anticancer agents such as Topotecan and Irinotecan (Fig. 1).5 Although the topoisomerase I inhibitory activity of Luotonin A is significantly lower than that of CPT,6 its core structure appears quite attractive for the development of new and improved chemotherapeutic agents that do not possess the typical bladder toxicity of CPT-derived drugs. This severe side effect results from ring-opening and re-closure processes of the labile lactone ring structure (ring E) at different pH values during absorption, distribution and excretion.5 Since this lactone structure is absent in Luotonin A, the aforementioned adverse effect is avoided. Thus, improving the topoisomerase-I-inhibitory activity remains as the main challenge in the development of anticancer drugs based on the Luotonin A lead structure. In recent years, a number of synthetic approaches to this pentacyclic compound have been elaborated by several groups, and

they are nicely summarized in a comprehensive review article.7 Some of these synthetic pathways were used for the preparation of derivatives bearing various substituents mainly at rings A, B and E of the quinolino[20 ,3':3,4]pyrrolo[2,1-b]quinazoline system. In our group, two complementary synthetic strategies had been employed that permit the selective placement of different functionalities at positions 1, 2, 3, and 4 of the pentacyclic skeleton: the “southern route” to 2- or 4-substituted derivatives8 makes use of a modified cycloaddition strategy that was first described by Zhou et al.9,10 for the total synthesis of Camptothecin and Luotonin A; the “northern route” to 1- or 3-substituted congeners11 also utilizes an intramolecular [4 þ 2] cycloaddition reaction as the key step, but features a different arrangement of the diene and dienophile components (Scheme 1). Via the latter pathway, we had prepared (among other Luotonin A derivatives) the ethyl esters of the 1-carboxylic acid and the 3carboxylic acid.11 The corresponding 2- and 4-substituted isomers have remained unknown so far, but now became an object of interest to us in order to enlarge our library of potential anticancer agents. Herein, we report on our investigations aimed at the synthesis of these target compounds. 2. Results and discussion

* Corresponding author. Tel.: þ431427755624. E-mail address: [email protected] (N. Haider). http://dx.doi.org/10.1016/j.tet.2017.04.052 0040-4020/© 2017 Elsevier Ltd. All rights reserved.

As depicted in Scheme 1, the selective introduction of a

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M. Atia et al. / Tetrahedron 73 (2017) 3231e3239

O

O A

B

A

C N

B

D

N

C N N

E O

Camptothecin

H3C

OH O

14-aza-CPT

14

A

B

4

N

3

D

N

1

13

O

2

C N

12 11

D

5

E O

10

N

E

6

7

H3C

OH O

9

8

Luotonin A

CH3 N

CH3

N

CH3

HO

N

O

O

N

O

N

O N N

O

Topotecan

H3C

O

OH O

H3C

Irinotecan

OH O

Fig. 1. Camptothecin (CPT), 14-aza-CPT, Luotonin A (IUPAC numbering scheme) and CPT-derived drugs.

O 2

2

R

O

R

O

N

N

N

N "southern route"

N

4

R

4

R

+

Ph

1

O

N

P Ph Ph

1

O O N

3

N

R N

"northern route"

N O

R

N 3

R

R

R O

R

4

2

1

R

N

H N

3

R

N H2N

N

N

N O

Scheme 1. Two orthogonal cycloaddition routes to A-ring-substituted Luotonin A derivatives8,11 (some bond angles are deliberately drawn incorrectly in order to better visualize the diene/dienophile arrangement).

substituent at position 2 or at position 4 of the alkaloid can be accomplished by an intramolecular aza-Diels-Alder reaction of a 3propargyl-4-oxo-3,4-dihydroquinazoline-2-carboxanilide with an appropriate substituent in ortho or para position at the phenyl moiety. On treatment with bis(triphenyl)oxodiphosphonium triflate12e15 (also known as Hendrickson's reagent), prepared in situ from triphenylphosphine oxide and trifluoromethanesulfonic anhydride, the secondary amide function of the educt is transformed into an imidoester-like species that contains the required C]N unit as part of the azadiene component.10 In the course of the cycloaddition reaction, the phosphorus-containing auxiliary group is split off and triphenylphosphine oxide is liberated. For the preparation of such anilide-type intermediates, we had developed an efficient route, starting from the known ethyl 4-oxo3,4-dihydroquinazoline-2-carboxylate (1).16 This ester can be directly converted into various anilides in high yields,8 applying Weinreb's method17,18 for amine activation with trimethylaluminium. For the present project (i.e., the synthesis of ethoxycarbonylsubstituted Luotonin A derivatives), however, this proven amidation method appeared somewhat challenging: here, two competing ester groups would be present (one in the quinazolinone synthon and another one in the aniline building block). As a possible workaround to avoid self-condensation of the aminobenzoate, we considered to use e instead of the aminobenzoic acid ethyl esters e

some bulky esters that could be later transesterified with ethanol. Another option would be to use the free aminobenzoic acid as the aniline component. However to our delight, we found that the Weinreb amidation reaction of the ester 1 with 4-aminobenzoic acid ethyl ester in the presence of trimethylaluminium in 1,2dichloroethane solution cleanly affords the desired anilide 2a without any noticeable polymerisation of the reagent (Scheme 2). As the only precaution, we conducted the initial aniline/trimethylaluminium complexation step at lower temperature than usual (0  C instead of room temperature), as well as the subsequent reaction with the substrate 1 (50  C instead of 84  C). After acidic quenching and extractive work-up, the amide 2a was obtained in 74% yield. We assume that this unexpected selectivity of the activated aniline towards the desired ester function results from deactivation of the undesired (i.e., benzoic) ester group by a conjugative effect of the electron-rich amino group in its complexed state. In a completely analogous fashion, the ester 1 could be also transformed into the ortho-substituted anilide 2b, using ethyl anthranilate as the aniline building block (Scheme 2). The slightly lower yield (63%) in this case probably results from some steric hindrance of the amino function in the latter synthon. For the introduction of the requisite propargyl group at N-3 of the quinazoline system, compound 2a was treated with propargyl bromide under our standard conditions (dimethylformamide as

M. Atia et al. / Tetrahedron 73 (2017) 3231e3239

H2N

propargyl bromide DMF/ K2CO3

O CO2Et

AlMe3 Cl

NH N

Cl

H N

74%

O N

O

CO2Et

2a

H N

N

73%

O

O

3233

CO2Et

3a

NH OEt

N

CO2Et H2N

O

1

AlMe3 Cl

Cl

O

63%

NH N

H N

CO2Et

propargyl bromide DMSO/ KOH / TBAB )))

O

62%

N

N

CO2Et

H N O

O

2b

3b

Scheme 2. Preparation of the intermediates 3a,b.

solvent, potassium carbonate as base, room temperature) to afford the key intermediate 3a in good yield (73%). In the case of the isomeric anilide 2b, however, these conditions failed because of the very low solubility of this substrate. Finally, we could successfully introduce the required three-carbon side chain by a modified protocol with dimethylsulfoxide as solvent, potassium hydroxide as base and tetrabutylammonium bromide (TBAB) as phase-transfer catalyst. After sonication of this initial mixture, propargyl bromide has to be added very slowly in order to avoid a local excess of the alkylating agent (which could result in undesired bis-alkylation at N-3 and at the amide nitrogen as a side reaction19). In this manner, compound 3b was obtained in satisfactory yield (62%). When the amide 3a was treated with Hendrickson's reagent in dry dichloromethane, the expected cycloaddition reaction (Scheme 3) was found to afford a quantitative yield of the target compound 4 after a reaction time of 24 h at room temperature. The new Luotonin A derivative 4 precipitates from the reaction mixture and can be isolated simply by filtration. Its structure is in full agreement with its MS, 1H NMR and 13C NMR data as well as elemental analysis (see Experimental). In the 400 MHz 1H NMR spectrum, all protons at the aromatic rings appear as distinct signals (except for the partially overlapping resonances of 3-H and 10-H) and the separate spin systems at ring E and ring A are clearly visible in the COSY experiment. The isolated proton at ring B (14-H) gives a singlet at 8.56 ppm and shows the expected crosspeaks with 1-H and the adjacent methylene group of ring C in the NOESY spectrum. Among the 13C NMR signals (which were assigned on the basis of HSQC and HMBC experiments), the resonance of the C-ring methylene group at 47.5 ppm is of particular diagnostic value and clearly confirms the formation of 4. In solution, the compound shows the typical blue fluorescence of most Luotonin A derivatives.

3a

Ph3PO (CF3SO2)2O

O

EtO2C

However, with the isomeric amide 3b as the substrate, the reaction with Hendrickson's reagent took a different course (Scheme 4). On TLC, we noticed the formation of a non-polar product lacking any fluorescence. This compound (5), obtained in 53% yield, is very sparingly soluble in any organic solvent. From its EI-HRMS (Mþ peak at m/z ¼ 329.0793) and 1H NMR spectrum (13C NMR failed because of insufficient solubility), we conclude that it is the benzoxazinone derivative shown in Scheme 4. On attempted purification by recrystallisation from various solvents, compound 5 undergoes a rapid transformation into a more polar compound that was unambiguously identified as the carboxylic acid 6, based on its MS, HRMS, 1H NMR and 13C NMR data (dC of the carboxyl group at 169.2 ppm). As an explanation for this unexpected behavior of the orthosubstituted anilide 3b, it can be assumed that in this case the oxophilic phosphorus atom in Hendrickson's reagent preferentially attacks the ester oxygen rather than the amide oxygen, because the latter is sterically more shielded than its counterpart in the parasubstituted anilide 3a. In the positively charged intermediate, a subsequent intramolecular attack of the adjacent amide oxygen would lead to the formation of a six-membered ring and, after elimination of triphenylphosphine oxide and ethanol, to the benzoxazinone 5, as displayed in Scheme 5. As an alternative to the failed introduction of an ester group into position 4 of the Luotonin A skeleton, we considered the corresponding carbonitrile as an interesting target structure. Recently, we had successfully prepared a 2-cyano derivative of the alkaloid,8 employing the pathway depicted in Scheme 1 as “southern route”. Thus, it appeared worthwile to attempt the synthesis of the 4isomer using the same strategy. The requisite cycloaddition precursor 8 was obtained in two

EtO2C

O N

N N

N O Ph

P

+

Ph

- Ph3PO - CF3SO3H

Ph TfO

Scheme 3. Cycloaddition of 3a into the Luotonin A derivative 4.

N N

4

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M. Atia et al. / Tetrahedron 73 (2017) 3231e3239

O N N

3b

N

CO2Et

Ph3PO (CF3SO2)2O

O

O attempted purification

N

N

N

N O

5

H N

N

O HO2C

6 O

Scheme 4. Formation of the benzoxazinone 5 from 3b.

O

O R

N

N

H N

N

- Ph3PO

H N

N

O O

Ph + P Ph Ph

OEt

Ph + Ph P O + Ph P Ph Ph Ph 2 CF SO 3

R

O O

- CF3SO3H +

OEt

2 CF3SO3-

3

O

O N

R

N

H2O N

N O Ph + P Ph O Ph

- Ph3PO - EtOH - CF3SO3H

R N

N O

OEt

O

5

CF3SO3Scheme 5. Proposed mechanism for the formation of 5.

steps from the ester 1, again following the proven synthetic protocols: Weinreb amidation of 1 with anthranilonitrile gave the anilide 7 in 80% yield, followed by propargylation using the DMSO/ KOH/TBAB/ultrasound system which afforded 8 in 77% yield (Scheme 6). For the crucial cycloaddition step, we again had to expect an undesired attack of the positively charged phosphorus atom in Hendrickson's reagent at the “wrong” functional group, and indeed this was found to be the case when we subjected compound 8 to the standard conditions (generation of the reagent in situ from

triphenylphosphine oxide and triflic anhydride in dry dichloromethane, addition of the substrate after 30 min at 0  C). TLC monitoring indicated the formation of a complex mixture with one non-polar product clearly dominating after a reaction time of 24 h at room temperature. This compound (9) could be isolated in 56% yield by extractive work-up and it was purified by recrystallisation from chloroform. Interestingly, this product was found to be a triflate salt of a triphenylphosphonium-substituted iminobenzoxazine derivative (Scheme 7), as evidenced by MS (including negative-ion ESI MS showing the triflate anion), HRMS, 1H NMR

CN H2N

1

O

AlMe3 Cl

Cl

NH N

80%

H N

CN

propargyl bromide DMSO / KOH / TBAB )))

O

77%

N

N

O

O

7

8 Scheme 6. Preparation of the intermediate 8.

H N

CN

M. Atia et al. / Tetrahedron 73 (2017) 3231e3239

and 13C NMR data. Such an ionic structure, however, is in clear contradiction with the observed migration behavior on TLC. Therefore, we suspected that the salt (9) undergoes some transformation into an uncharged, non-polar species under the conditions of silica gel adsorption chromatography. Indeed, this assumption could be veryfied by passing a sample of 9 through a silica gel column, eluting with dichloromethane/ethyl acetate (4 þ 1). Evaporation of the eluate gave another pure compound (10) with an identical RF value on TLC as before, but with significantly different MS and NMR properties than those of 9. Whereas a triphenylphosphoranylidene residue is still present in the molecule, the benzoxazine ring obviously has undergone ring opening, leading to the N-aroylphosphazene 10 (Scheme 7). The proposed structure is well supported by the characteristic chemical shift of the C]O resonance in the 13C NMR spectrum at 175.3 ppm with a 2 JC-P coupling constant of 8.0 Hz which is in very good agreement with the data reported for the C]O signal in N-benzoyl-P,P,P-triphenylphosphazene (176.3 ppm, 2JC-P ¼ 7.9 Hz).20 The formation of the salt 9 (Scheme 7) can be rationalized in an analogous fashion as that of the benzoxazinone 5 (compare Scheme 5). Here again, attack of the phosphorus atom in Hendrickson's reagent does not take place at the (sterically hindered) amide oxygen, but at a more accessible atom which in this case is the nitrile nitrogen. Subsequently, the activated nitrile carbon suffers attack by the adjacent amide oxygen, thus generating the iminobenzoxazine structure of the product (9). Under the mild hydrolytic conditions of silica gel chromatography, the oxazine ring is then opened, affording the uncharged N-aroylphosphazene (10). The observed reaction behavior of the ortho-substituted anilide 8 (in contrast to its para-substituted isomer8) is not unexpected in view of the formation of the benzoxazinone 5 from compound 3b (deviating from the transformation 3a / 4), as discussed above. In both cases, the relative position of a functional group at the Nphenyl moiety (either para or ortho) determines the outcome of the reaction with Hendrickson's reagent. However, in the case of the nitrile 8 we finally succeeded in guiding the reaction towards the desired direction (i.e., a [4 þ 2] cycloaddition) by slightly modifying the conditions. When the substrate 8 is pre-treated with 1.5 equivalents of the base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), deprotonation of its secondary amide function increases the nucleophilicity of the amide oxygen sufficiently to ensure bond formation with the phosphorus atom. The resultant imidoester-like species then serves as part of the requisite azadiene structure in the desired manner and the reaction (Scheme 8) affords the target 4Ph3PO (CF3SO2)2O

3235

cyano-substituted Luotonin A.21 This product can be isolated very easily in acceptable yield (45%) by filtration of the reaction mixture. Increasing the amount of Hendrickson's reagent and DBU does not improve the yield. Again, structure proof rests on MS, HRMS, 1H NMR and 13C NMR data (dC of the CH2 group at 47.6 ppm) with full signal assignments based on COSY, NOESY, HSQC and HMBC experiments. 3. Conclusion In conclusion, we found that both 4-amino- as well as 2aminobenzoic acid ethyl ester can be successfully employed as aniline-type building blocks in the Weinreb amidation of the ethyl ester 1, obviously due to a sufficient difference in the reactivities of the two competing ester functionalities. For the synthesis of an ethoxycarbonyl-substituted Luotonin A derivative via an intramolecular [4 þ 2] cycloaddition process, however, only the parasubstituted precursor 3a can be utilized. Under identical reaction conditions (treatment with Hendrickson's reagent in dry dichloromethane), the ortho-substituted intermediate 3b does not afford a pentacyclic system, but a benzoxazinone derivative (5) as a result of a different regioselectivity in the attack of the electrophilic phosphorus atom of the reagent. An analoguous observation was made with the ortho-substituted nitrile 8 which yields an iminobenzoxazine derivative under “standard” conditions. In this case, however, carrying out the reaction in the presence of a base (DBU) directs the attack of the phosphorus atom towards the amide oxygen of the substrate and thus affords the desired 4-cyanosubstituted Luotonin A derivative (11) via an intramolecular [4 þ 2] cycloaddition. 4. Experimental 4.1. General Melting points (uncorrected) were determined on a Kofler hotstage microscope (Leica GmbH, Wetzlar, Germany). 1H NMR and 13C NMR spectra were recorded on a Bruker Avance III 400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) at 400 MHz and 100 MHz, respectively; chemical shifts were referenced to residual amounts of undeuterated solvents. Mass spectra (EI) were obtained on a Shimadzu QP5050A DI 50 instrument (Shimadzu Corp., Kyoto, Japan); high-resolution mass spectra (ESI) were recorded on a Bruker maXis HD spectrometer (Bruker Daltonics

O N N

Ph Ph + + Ph P O P Ph Ph Ph

8

2

N N

CF3SO3O

O silica gel chromatography

N

56%

N

N

N

O O

O CF3SO3-

9

Ph Ph

+

P

Ph

H N

N

N

Ph

10

Scheme 7. Reaction of 8 with Hendrickson's reagent in the absence of a base.

Ph

P Ph

N

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M. Atia et al. / Tetrahedron 73 (2017) 3231e3239

O

Ph3PO (CF3SO2)2O DBU

[4+2] cycloaddition

N

8

N

N O

N

O N N

45%

N

+

Ph P Ph CF3SO3- Ph

N

11

Scheme 8. Transformation of 8 into the Luotonin A derivative 11.

GmbH, Bremen, Germany). Column chromatography was carried out on Merck Kieselgel 60, 0.063e0.200 mm; thin layer chromatography was done on Merck aluminium sheets pre-coated with Kieselgel 60 F254 (Merck, Darmstadt, Germany) Microanalyses were performed at the Microanalytical Laboratory, Faculty of Chemistry, University of Vienna. Ethyl 4-oxo-3,4-dihydroquinazoline-2carboxylate16 (1) was prepared according to a literature procedure.10 4.2. Procedures 4.2.1. Ethyl 4-{[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl] amino}benzoate (2a) A solution of 4-aminobenzoic acid ethyl ester (0.991 g, 6 mmol) in dry 1,2-dichloroethane (20 mL) was cooled to 0  C under an argon atmosphere. At the same temperature, a 2.0 M solution of trimethylaluminium in heptane (3.0 mL, 6 mmol) was added dropwise with stirring. The mixture was stirred for 30 min at 0  C, then the ester 1 (1.091 g, 5 mmol) was added in one portion. Stirring was continued for 10 min at 0  C, then for 2 h at room temperature and finally for 1 h at 50  C. The mixture was cooled to 0  C again and 5% hydrochloric acid (20 mL) was added slowly with stirring, followed by the addition of water (80 mL). The suspension was extracted with CH2Cl2 (5  100 mL) and the combined extracts were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was recrystallized from EtOH to afford 2a (1.249 g, 74%) as colorless crystals, mp 232e234  C. MS (EI, 70 eV) m/z: 337 (Mþ, 27%), 264 (16), 147 (19), 146 (100), 119 (55), 118 (11), 91 (8), 90 (18); 1H NMR (400 MHz, DMSO-d6) d 12.58 (br s, 1H, 3-H), 11.07 (s, 1H, amide-NH), 8.21 (d, J ¼ 7.6 Hz, 1H, 5-H), 8.06e8.04 (BB0 part of an AA'BB0 system, 2H, phenyl 30 -H, 50 -H), 8.00e7.98 (AA0 part of an AA'BB0 system, 2H, phenyl 20 -H, 60 -H), 7.97e7.88 (m, 2H, 7-H, 8-H), 7.65 (ddd, J ¼ 8.1, 6.6, 1.7 Hz, 1H, 6-H), 4.31 (q, J ¼ 7.1 Hz, 2H, OCH2), 1.33 (t, J ¼ 7.1 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) d 165.2 (ester C]O), 161.1 (4-C), 158.6 (amide C]O), 146.8 (8a-C), 145.8 (2-C), 142.0 (phenyl 40 -C), 134.8 (7-C), 130.1 (phenyl 20 -C, 60 -C), 128.4 (6-C), 127.9 (8-C), 126.2 (5-C), 125.5 (phenyl 10 -C), 122.8 (4a-C), 120.0 (phenyl 30 -C, 50 C), 60.6 (OCH2), 14.2 (CH3). Anal. Calcd. for C18H15N3O4  0.25 H2O: C, 63.25; H, 4.57; N, 12.29. Found: C, 63.34; H, 4.28; N, 12.07. HRMS (ESI-TOF) Calcd. for C18H15N3NaO4 ([MþNa]þ): 360.0955. Found: 360.0953. 4.2.2. Ethyl 2-{[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl] amino}benzoate (2b) This compound was prepared as described for 2a, starting from 2-aminobenzoic acid ethyl ester (0.991 g, 6 mmol). Recrystallisation of the crude product from EtOH gave 2b (1.062 g, 63%) as almost colorless crystals, mp 253e255  C. MS (EI, 70 eV) m/z: 337 (Mþ, 23%), 265 (19), 264 (100), 147 (15), 146 (57), 145 (16), 119 (36), 90 (37); 1H NMR (400 MHz, DMSO-d6) d 12.74 (s, 1H, NH), 12.62 (br s,

1H, NH), 8.72 (d, J ¼ 7.6 Hz, 1H, phenyl 30 -H), 8.21 (dd, J ¼ 7.9, 1.1 Hz, 1H, 5-H), 8.09 (dd, J ¼ 8.0, 1.5 Hz, 1H, phenyl 60 -H), 7.98e7.90 (m, 1H, 7-H), 7.82 (d, J ¼ 7.8 Hz, 1H, 8-H), 7.77e7.70 (m, 1H, phenyl 40 H), 7.66 (t, J ¼ 7.5 Hz, 1H, 6-H), 7.34e7.26 (m, 1H, phenyl 50 -H), 4.45 (q, J ¼ 7.1 Hz, 2H, OCH2), 1.39 (t, J ¼ 7.1 Hz, 3H, CH3); 13C NMR22 (100 MHz, DMSO-d6) d 166.7 (C]O), 157.9, 139.0, 134.9 (7-C), 134.6 (phenyl 40 -C), 131.1 (phenyl 60 -C), 128.4 (6-C), 126.3 (5-C), 124.0 (phenyl 50 -C), 120.1 (phenyl 30 -C), 116.9, 61.5 (OCH2), 14.1 (CH3). Anal. Calcd. for C18H15N3O4: C, 64.09; H, 4.48; N, 12.46. Found: C, 63.97; H, 4.49; N, 12.21. 4.2.3. Ethyl 4-({[4-oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazolin2-yl]carbonyl}amino)benzoate (3a) To a solution of compound 2a (1.011 g, 3 mmol) in DMF (23 mL) were added K2CO3 (0.456 g, 3.3 mmol) and an 80% solution of propargyl bromide in toluene (0.490 g, 3.3 mmol). The mixture was stirred for 24 h at room temperature and the reaction progress was monitored by TLC (CH2Cl2/ethyl acetate, 9 þ 1). The mixture was poured into water (100 mL) and it was extracted with CH2Cl2 (3  100 mL). The combined extracts were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. Recrystallisation of the residue from EtOH afforded 3a (0.825 g, 73%) as colorless needles, mp 226e227  C. MS (EI, 70 eV) m/z: 375 (Mþ, 22%), 374 (55), 346 (39), 303 (22), 302 (100), 184 (16), 155 (21), 146 (39), 129 (26), 119 (29), 90 (25); 1H NMR (400 MHz, CDCl3) d 9.89 (br s, 1H, NH), 8.37 (ddd, J ¼ 8.0, 1.5, 0.5 Hz, 1H, 5-H), 8.13e8.07 (BB0 part of an AA'BB0 system, 2H, phenyl 20 -H, 60 -H), 7.89e7.82 (m, 3H, 7-H, phenyl 30 -H, 50 -H), 7.80 (dd, J ¼ 7.5, 0.7 Hz, 1H, 8-H), 7.63 (ddd, J ¼ 8.3, 7.0, 1.4 Hz, 1H, 6-H), 5.59 (d, J ¼ 2.5 Hz, 2H, NCH2), 4.39 (q, J ¼ 7.1 Hz, 2H, OCH2), 2.27 (t, J ¼ 2.5 Hz, 1H, acetylenic H), 1.41 (t, J ¼ 7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) d 166.1 (ester C]O), 161.3 (4-C), 158.4 (amide C]O), 145.0 (2-C or 8a-C), 144.8 (8a-C or 2-C), 140.9 (phenyl 40 -C), 135.2 (7-C), 131.0 (phenyl 20 -C, 60 -C), 129.4 (6-C), 127.9 (8-C), 127.7 (5-C), 127.1 (phenyl 10 -C), 121.9 (4a-C), 119.4 (phenyl 30 -C, 50 -C), 78.9 (propargyl 2-C), 72.2 (propargyl 3-C), 61.2 (OCH2), 33.9 (NCH2), 14.5 (CH3). Anal. Calcd. for C21H17N3O4: C, 67.19; H, 4.56; N, 11.19. Found: C, 67.03; H, 4.41; N, 11.09. 4.2.4. Ethyl 2-({[4-oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazolin2-yl]carbonyl}amino)benzoate (3b) To a suspension of finely powdered 2b (1.011 g, 3 mmol) in DMSO (120 mL) were added finely ground KOH (0.204 g, 3.6 mmol) and tetrabutylammonium bromide (60 mg, 0.19 mmol). The mixture was sonicated for 10 min in an ultrasound cleaning bath, then a solution of propargyl bromide (0.490 g of an 80% solution in toluene, 3.3 mmol) in DMSO (60 mL) was added dropwise with vigorous stirring over a period of 2 h. The mixture was stirred at room temperature for 24 h, then additional portions of propargyl bromide (0.245 g of an 80% solution in toluene, 1.65 mmol), finely ground KOH (0.102 g, 1.8 mmol) and tetrabutylammonium bromide

M. Atia et al. / Tetrahedron 73 (2017) 3231e3239

(30 mg, 0.09 mmol) were added and the mixture was stirred until TLC (CH2Cl2/ethyl acetate, 9 þ 1) indicated complete consumption of 2b. Insoluble material was removed by filtration and the filter was washed with little DMSO. The filtrate and washings were poured into water (800 mL) and extracted with ethyl acetate (3  300 mL). The combined extracts were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. Recrystallisation of the residue from EtOH gave 3b (0.699 g, 62%) as almost colorless crystals, mp 216e218  C. MS (EI, 70 eV) m/z: 375 (Mþ, 13%), 346 (11), 329 (17), 302 (100), 184 (34), 156 (51), 146 (67), 129 (63), 119 (74), 90 (81); 1H NMR (400 MHz, CDCl3) d 12.90 (br s, 1H, NH), 8.85 (dd, J ¼ 8.5, 1.0 Hz, 1H, phenyl 30 -H), 8.36 (dd, J ¼ 8.0, 1.0 Hz, 1H, 5-H), 8.14 (dd, J ¼ 8.0, 1.6 Hz, 1H, phenyl 60 -H), 7.90 (dd, J ¼ 8.1, 0.8 Hz, 1H, 8-H), 7.84 (ddd, J ¼ 8.2, 7.1, 1.5 Hz, 1H, 7-H), 7.63e7.56 (m, 2H, 6-H, phenyl 40 -H), 7.24e7.17 (m, 1H, phenyl 50 -H), 5.53 (d, J ¼ 2.5 Hz, 2H, NCH2), 4.46 (q, J ¼ 7.1 Hz, 2H, OCH2), 2.24 (t, J ¼ 2.5 Hz, 1H, acetylenic H), 1.44 (t, J ¼ 7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) d 167.8 (ester C]O), 161.5 (4-C), 159.6 (amide C] O), 146.1 (2-C), 145.5 (8a-C), 140.2 (phenyl 20 -C), 135.0 (7-C), 134.6 (phenyl 40 -C), 131.3 (phenyl 60 -C), 129.0 (6-C), 128.4 (8-C), 127.5 (5C), 123.8 (phenyl 50 -C), 121.9 (4a-C), 120.8 (phenyl 30 -C), 117.0 (phenyl 10 -C), 78.9 (propargyl 2-C), 72.2 (propargyl 3-C), 61.7 (OCH2), 33.6 (NCH2), 14.4 (CH3). Anal. Calcd. for C21H17N3O4: C, 67.19; H, 4.56; N, 11.19. Found: C, 67.47; H, 4.71; N, 10.68. HRMS (ESITOF) Calcd. for C21H17N3NaO4 ([MþNa]þ): 398.1111. Found: 398.1112. 4.2.5. Ethyl 11-oxo-11,13-dihydroquinolino[20 ,3':3,4]pyrrolo[2,1-b] quinazoline-2-carboxylate (4) To a solution of triphenylphosphine oxide (835 mg, 3 mmol) in dry CH2Cl2 (22 mL) was added dropwise trifluoromethanesulfonic anhydride (0.25 mL, 1.5 mmol) at 0  C under argon, and the mixture was stirred at the same temperature for 15 min. Then, compound 3a (375 mg, 1 mmol) was added in one portion at 0  C, and the mixture was stirred for 24 h at room temperature (TLC monitoring: CH2Cl2/ethyl acetate, 9 þ 1). The precipitate was collected by filtration and washed with CH2Cl2 to afford 4 (355 mg, 99%) as pale yellow crystals, mp 336e338  C (EtOH). MS (EI, 70 eV) m/z: 358 (25%), 357 (Mþ, 100), 329 (28), 312 (15), 284 (28), 142 (13); 1H NMR (400 MHz, CDCl3) d 8.69 (d, J ¼ 1.7 Hz, 1H, 1-H), 8.56 (s, 1H, 14-H), 8.50 (d, J ¼ 8.9 Hz, 1H, 4-H), 8.43e8.40 (m, 2H, 3-H. 10-H), 8.12 (d, J ¼ 8.0 Hz, 1H, 7-H), 7.87 (ddd, J ¼ 8.4, 7.2, 1.6 Hz, 1H, 8-H), 7.64e7.55 (m, 1H, 9-H), 5.38 (s, 2H, 13-CH2), 4.49 (q, J ¼ 7.1 Hz, 2H, OCH2), 1.48 (t, J ¼ 7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) d 165.8 (ester C] O), 160.6 (11-C), 153.3 (5a-C), 152.3 (5b-C), 151.2 (4a-C), 149.3 (6a-C), 134.9 (8-C), 133.1 (14-C), 131.02 (1-C or 4-C), 130.97 (4-C or 1-C), 130.32 (13a-C), 130.30 (3-C), 130.28 (14a-C), 129.0 (7-C), 128.0 (2-C), 127.9 (9-C), 126.7 (10-C), 121.5 (10a-C), 61.9 (OCH2), 47.5 (13-C), 14.5 (CH3). Anal. Calcd. for C21H15N3O3: C, 70.58; H, 4.23; N, 11.76. Found: C, 70.29; H, 4.17; N, 11.61. 4.2.6. Reaction of compound 3b with Hendrickson's reagent To a solution of triphenylphosphine oxide (835 mg, 3 mmol) in dry CH2Cl2 (22 mL) was added dropwise trifluoromethanesulfonic anhydride (0.25 mL, 1.5 mmol) at 0  C under argon, and the mixture was stirred at the same temperature for 15 min. Then, compound 3b (375 mg, 1 mmol) was added in one portion at 0  C, and the mixture was stirred for 72 h at room temperature (TLC monitoring: CH2Cl2/ethyl acetate, 9 þ 1). The fine precipitate was collected by filtration and washed with CH2Cl2 to afford 2-[4-oxo-3-(prop-2-yn1-yl)-3,4-dihydroquinazolin-2-yl]-4H-3,1-benzoxazin-4-one (5) (175 mg, 53%) as almost colorless crystals, mp 186e188  C. MS (EI, 70 eV) m/z: 329 (Mþ, 18%), 301 (62), 272 (19), 244 (20), 146 (62), 129 (25), 90 (100), 69 (51); 1H NMR (400 MHz, CDCl3) d 8.44 (d, J ¼ 8.2 Hz, 1H), 8.35 (d, J ¼ 7.5 Hz, 1H), 8.19 (d, J ¼ 8.2 Hz, 1H),

3237

8.07e8.00 (m, 1H), 7.98 (d, J ¼ 8.0 Hz, 1H), 7.90 (d, J ¼ 7.9 Hz, 1H), 7.85e7.79 (m, 1H), 7.76 (t, J ¼ 8.1 Hz, 1H), 5.48 (d, J ¼ 2.4 Hz, 2H), 2.31 (t, J ¼ 2.4 Hz, 1H). HRMS (EI, 70 eV) Calcd. for C19H11N3O3 (Mþ): 329.0795. Found: 329.0793. On attempted recrystallisation (toluene, ethanol), compound 5 was quantitatively transformed into 2-({[4-oxo-3-(prop-2-yn-1-yl)3,4-dihydroquinazolin-2-yl]carbonyl}amino)benzoic acid (6) which was obtained as colorless crystals, mp 216e220  C (toluene). MS (EI, 70 eV) m/z: 347 (Mþ, 1%), 329 (3), 301 (10), 272 (3), 244 (4), 156 (5), 146 (14), 129 (9), 119 (9), 90 (24), 81 (12), 69 (100), 65 (34); 1H NMR (400 MHz, DMSO-d6) d 12.97 (s, 1H, NH), 8.69 (d, J ¼ 7.6 Hz, 1H, phenyl 30 -H), 8.25 (dd, J ¼ 8.0, 1.1 Hz, 1H, 5-H), 8.09 (dd, J ¼ 7.9, 1.5 Hz, 1H, phenyl 60 -H), 7.98 (ddd, J ¼ 8.6, 7.2, 1.5 Hz, 1H, 7-H), 7.80 (d, J ¼ 7.6 Hz, 1H, 8-H), 7.75e7.67 (m, 2H, 6-H, phenyl 40 -H), 7.33e7.25 (m, 1H, phenyl 50 -H), 5.24 (d, J ¼ 2.4 Hz, 2H, NCH2), 3.26 (t, J ¼ 2.4 Hz, 1H, acetylenic H); 13C NMR (100 MHz, DMSO-d6) d 169.2 (carboxyl C]O), 160.5 (4-C), 158.9 (amide C]O), 146.3 (2C), 144.8 (8a-C), 139.5 (phenyl 20 -C), 135.4 (7-C), 134.4 (phenyl 40 C), 131.5 (phenyl 60 -C), 129.2 (6-C), 127.7 (8-C), 126.7 (5-C), 123.9 (phenyl 50 -C), 121.1 (4a-C), 119.8 (phenyl 30 -C), 117.3 (phenyl 10 -C), 79.3 (propargyl 2-C), 74.4 (propargyl 3-C), 33.8 (NCH2). HRMS (ESITOF) Calcd. for C19H13N3NaO4 ([MþNa]þ): 370.0798. Found: 370.0799. 4.2.7. N-(2-cyanophenyl)-4-oxo-3,4-dihydroquinazoline-2carboxamide (7) To a solution of 2-aminobenzonitrile (0.945 g, 8 mmol) in dry 1,2-dichloroethane (20 mL) was slowly added under an argon atmosphere a 2.0 M solution of trimethylaluminium in heptane (4.0 mL, 8 mmol) with stirring. The mixture was stirred for 30 min at room temperature, then the ester 1 (1.091 g, 5 mmol) was added in one portion. Stirring was continued for 10 min at room temperature, then for 2 h at 80  C. The mixture was cooled to 0  C and 5% hydrochloric acid (20 mL) was added slowly with stirring, followed by the addition of water (80 mL). The precipitate was collected by filtration and it was washed thouroughly with 70% EtOH (500 mL), then dried in vacuo. The amide 7 (1.170 g, 80%) was obtained as almost colorless crystals, mp 284e285  C (DMF). MS (EI, 70 eV) m/z: 290 (Mþ, 37%), 146 (100), 119 (99), 118 (23), 91 (25), 90 (60), 64 (19), 63 (21); 1H NMR (400 MHz, DMSO-d6) d 12.68 (br s, 1H, NH), 11.04 (br s, 1H, NH), 8.22 (d, J ¼ 7.7 Hz, 1H, 5-H), 7.96e7.90 (m, 3H, 7-H, phenyl 30 -H, 60 -H), 7.85 (d, J ¼ 8.1 Hz, 1H, 8-H), 7.82e7.75 (m, 1H, phenyl 50 -H), 7.67 (t, J ¼ 7.5 Hz, 1H, 6-H), 7.46 (t, J ¼ 7.6 Hz, 1H, phenyl 40 -H); 13C NMR (100 MHz, DMSO-d6) d 161.5 (4-C), 158.9 (amide C]O), 147.1 (8a-C), 145.7 (2-C), 139.6 (phenyl 10 C), 135.4 (7-C), 134.6 (phenyl 50 -C), 133.6 (phenyl 30 -C), 129.0 (6-C), 128.3 (8-C), 126.9 (phenyl 40 -C), 126.8 (5-C), 125.3 (phenyl 60 -C), 123.4 (4a-C), 117.0 (nitrile-C), 107.7 (phenyl 20 -C). HRMS (ESI-TOF) Calcd. for C16H11N4O2 ([MþH]þ): 291.0877. Found: 291.0879. 4.2.8. N-(2-cyanophenyl)-4-oxo-3-(prop-2-yn-1-yl)-3,4dihydroquinazoline-2-carboxamide (8) To a suspension of finely powdered 7 (290 mg, 1 mmol) in DMSO (20 mL) were added finely ground KOH (73 mg, 1.3 mmol) and tetrabutylammonium bromide (20 mg, 0.06 mmol). The mixture was sonicated for 10 min in an ultrasound cleaning bath, then a solution of propargyl bromide (178 mg of an 80% solution in toluene, 1.2 mmol) in DMSO (10 mL) was added dropwise with vigorous stirring over a period of 2 h. The mixture was stirred at room temperature for 24 h (TLC monitoring: CH2Cl2/ethyl acetate, 19 þ 1), then it was diluted with water (100 mL) and stirred for another 10 min. The precipitate was collected by filtration, washed with water and dried in vacuo to afford compound 8 (255 mg, 77%) as almost colorless crystals, mp 209e211  C (EtOH). MS (EI, 70 eV) m/z: 328 (Mþ, 47%), 327 (84), 302 (32), 299 (100), 184 (26),

3238

M. Atia et al. / Tetrahedron 73 (2017) 3231e3239

155 (50), 129 (67), 119 (60), 102 (57), 90 (88), 63 (33); 1H NMR (400 MHz, CDCl3) d 10.73 (br s, 1H, NH), 8.59 (d, J ¼ 8.8 Hz, 1H, phenyl 60 -H), 8.37 (d, J ¼ 7.4 Hz, 1H, 5-H), 7.89e7.83 (m, 2H, 7-H, 8H), 7.72e7.61 (m, 3H, 6-H, phenyl 30 -H, 50 -H), 7.30e7.26 (m, 1H, phenyl 40 -H), 5.61 (d, J ¼ 2.4 Hz, 2H, CH2), 2.28 (t, J ¼ 2.4 Hz, 1H, acetylenic H); 13C NMR (100 MHz, CDCl3) d 161.4 (4-C), 158.4 (amide C]O), 144.6 (8a-C), 143.9 (2-C), 139.8 (phenyl 10 -C), 135.3 (7-C), 134.4 (phenyl 30 -C or 50 -C), 132.7 (phenyl 50 -C or 30 -C), 129.6 (6-C), 128.5 (8-C), 127.6 (5-C), 125.1 (phenyl 40 -C), 121.9 (4a-C), 120.8 (phenyl 60 -C), 116.2 (nitrile-C), 103.1 (phenyl 20 -C), 78.9 (propargyl 2-C), 72.2 (propargyl 3-C), 33.8 (CH2). HRMS (ESI-TOF) Calcd. for C19H13N4O2 ([MþH]þ): 329.1033. Found: 329.1032. 4.2.9. ({2-[4-Oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazolin-2-yl]4H-3,1-benzoxazin-4-ylidene}amino)(triphenyl)phosphonium trifluoromethanesulfonate (9) To a solution of triphenylphosphine oxide (1.42 g, 5.1 mmol) in dry CH2Cl2 (22 mL) was added dropwise trifluoromethanesulfonic anhydride (0.42 mL, 2.55 mmol) at 0  C under argon, and the mixture was stirred at the same temperature for 30 min. Then, the anilide 8 (328 mg, 1 mmol) was added in one portion at 0  C, and the mixture was stirred for 24 h at room temperature (TLC monitoring: CH2Cl2/MeOH, 9 þ 1). After addition of 10% aq. NaHCO3 solution (10 mL), the mixture was stirred for 30 min, then it was extracted with CH2Cl2 (3  100 mL). The combined extracts were washed with water, dried over Na2SO4 and evaporated under reduced pressure. The residue was triturated with CHCl3 to afford crude 9 (414 mg, 56%) which was recrystallized from CHCl3 to give colorless crystals, mp 215e220  C. 1H NMR (400 MHz, CDCl3) d 8.80 (dd, J ¼ 8.0, 1.2 Hz, 1H, benzoxazine 5-H), 8.36 (dd, J ¼ 8.0, 1.1 Hz, 1H, quinazoline 5-H), 8.07 (td, J ¼ 7.8, 1.5 Hz, 1H, benzoxazine 7-H), 8.03e7.95 (m, 6H, phenyl 20 -H, 60 -H), 7.95e7.89 (m, 1H, benzoxazine 6-H), 7.88e7.81 (m, 2H, benzoxazine 8-H, quinazoline 7-H), 7.77e7.69 (m, 3H, phenyl 40 -H), 7.66e7.60 (m, 7H, quinazoline 6-H, phenyl 30 -H, 50 -H), 7.47 (d, J ¼ 7.6 Hz, 1H, quinazoline 8-H), 5.31 (d, J ¼ 2.5 Hz, 2H, CH2), 2.17 (t, J ¼ 2.5 Hz, 1H, acetylenic H); 13C NMR (100 MHz, CDCl3) d 161.9 (d, J ¼ 11.2 Hz, benzoxazine 4-C), 160.6 (quinazoline 4-C), 146.8 (benzoxazine 2-C), 145.6 (quinazoline 8aC), 143.2 (d, J ¼ 2.7 Hz, benzoxazine 8a-C), 143.0 (quinazoline 2-C), 139.2 (benzoxazine 7-C), 135.3 (quinazoline 7-C), 135.2 (d, J ¼ 1.8 Hz, phenyl 40 -C), 133.7 (d, J ¼ 11.4 Hz, phenyl 20 -C, 60 -C), 132.3 (benzoxazine 6-C), 130.2 (d, J ¼ 13.5 Hz, phenyl 30 -C, 50 -C), 129.9 (benzoxazine 5-C), 129.6 (quinazoline 6-C), 128.5 (benzoxazine 8C), 127.9 (quinazoline 8-C), 127.8 (quinazoline 5-C), 121.8 (quinazoline 4a-C), 121.7 (d, J ¼ 102.2 Hz, phenyl 10 -C), 118.5 (d, J ¼ 14.6 Hz, benzoxazine 4a-C), 78.7 (propargyl 2-C), 73.2 (propargyl 3-C), 34.8 (CH2). MS (negative-ion ESI-TOF) Calcd. for CF3O3S (triflate [MH]e): 148.95. Found: 148.8. HRMS (ESI-TOF) Calcd. for C37H26N4O2P: 589.1788. Found: 589.1784. 4.2.10. 4-Oxo-3-(prop-2-yn-1-yl)-N-{2[(triphenylphosphoranylidene)carbamoyl]phenyl}-3,4dihydroquinazoline-2-carboxamide (10) A solution of compound 9 (148 mg, 0.2 mmol) in CH2Cl2 (20 mL) was placed on top of a silica gel column (2  20 cm), followed by elution with CH2Cl2/ethyl acetate (4 þ 1). The eluate was evaporated and dried in vacuo to afford compound 10 (120 mg, 99%) as almost colorless crystals, mp 202e205  C (CHCl3). MS (EI, 70 eV) m/ z: 277 (17%), 111 (16), 97 (21), 86 (68), 84 (100), 71 (38), 69 (26), 57 (59), 55 (31); 1H NMR (400 MHz, CDCl3) d 14.21 (br s, 1H, NH), 8.86e8.79 (m, 1H, phenylene 600 -H), 8.33 (dd, J ¼ 7.9, 1.5 Hz, 1H, phenylene 300 -H), 8.22e8.13 (m, 1H, 5-H), 7.77e7.64 (m, 6H, phenyl 20 -H, 60 -H), 7.55e7.46 (m, 1H, phenylene 500 -H), 7.45e7.39 (m, 5H, 6H, 7-H, phenyl 40 -H), 7.37e7.32 (m, 6H, phenyl 30 -H, 50 -H), 7.22e7.13 (m, 1H, phenylene 400 -H), 7.06e6.97 (m, 1H, 8-H), 5.46 (d, J ¼ 2.5 Hz,

2H, CH2), 2.31 (t, J ¼ 2.5 Hz, 1H, acetylenic H); 13C NMR (100 MHz, CDCl3) d 175.3 (d, J ¼ 8.0 Hz, P]NeC]O), 161.0 (4-C), 159.6 (amide C]O), 147.8 (2-C), 145.5 (8a-C), 139.3 (phenylene 100 -C), 134.1 (7-C), 133.3 (d, J ¼ 10.4 Hz, phenyl 20 -C, 60 -C), 132.9 (d, J ¼ 2.2 Hz, phenyl 40 -C), 132.5 (phenylene 500 -C), 131.8 (d, J ¼ 2.1 Hz, phenylene 300 -C), 128.8 (d, J ¼ 12.7 Hz, phenyl 30 -C, 50 -C), 128.0 (6-C), 127.8 (8-C), 127.0 (5-C), 126.1 (d, J ¼ 101.4 Hz, phenyl 10 -C), 124.8 (d, J ¼ 17.3 Hz, phenylene 200 -C), 123.7 (phenylene 400 -C), 121.7 (4a-C), 120.2 (phenylene 600 -C), 78.6 (propargyl 2-C), 72.5 (propargyl 3-C), 32.8 (CH2). HRMS (ESI-TOF) Calcd. for C37H28N4O3P ([MþH]þ): 607.1894. Found: 607.1893. 4.2.11. 11-Oxo-11,13-dihydroquinolino[20 ,3':3,4]pyrrolo[2,1-b] quinazoline-4-carbonitrile (11) To a solution of triphenylphosphine oxide (835 mg, 3 mmol) in dry CH2Cl2 (22 mL) was added dropwise trifluoromethanesulfonic anhydride (0.25 mL, 1.5 mmol) at 0  C under argon, and the mixture was stirred at the same temperature for 30 min. Then, a solution/ suspension of the anilide 8 (328 mg, 1 mmol) in dry CH2Cl2 (7 mL), containing DBU (228 mg, 1.5 mmol), was added in one portion at 0  C, and the mixture was stirred for 24 h at room temperature (TLC monitoring: CH2Cl2/ethyl acetate, 9 þ 1). The precipitate was collected by filtration on a G4 gouch and it was washed with CH2Cl2. The material was re-suspended in water (10 mL) and aq. 10% NaHCO3 solution (1 mL), stirred for 10 min and filtered off again, washed with water and dried in vacuo to afford compound 11 (140 mg, 45%) as colorless crystals, mp > 350  C (decomp.). MS (EI, 70 eV) m/z: 310 (Mþ, 27%), 282 (9), 254 (11), 178 (10), 165 (33), 153 (51), 139 (27), 138 (27), 130 (44), 102 (69), 90 (49), 77 (56), 76 (100), 75 (60), 64 (59), 63 (92), 50 (69); 1H NMR (400 MHz, DMSO-d6) d 8.96 (s, 1H, 14-H), 8.56e8.52 (m, 2H, 1-H, 3-H), 8.32 (dd, J ¼ 8.0, 1.1 Hz, 1H, 10-H), 8.06 (d, J ¼ 7.6 Hz, 1H, 7-H), 7.97 (ddd, J ¼ 8.3, 7.1, 1.5 Hz, 1H, 8-H), 7.91 (dd, J ¼ 8.2, 7.3 Hz, 1H, 2-H), 7.67 (ddd, J ¼ 8.1, 7.2, 1.2 Hz, 1H, 9-H), 5.37 (s, 2H, 13-CH2); 13C NMR (100 MHz, DMSO-d6) d 159.6 (11-C), 153.6 (5a-C), 152.5 (5b-C), 148.9 (6a-C), 147.2 (4a-C), 137.5 (3-C), 134.7 (8-C), 134.1 (1-C), 133.1 (14-C), 133.0 (13a-C), 128.5 (14a-C), 128.3 (7-C), 127.8 (2-C), 127.6 (9-C), 125.9 (10-C), 121.2 (10a-C), 117.3 (nitrile-C), 112.1 (4-C), 47.6 (13-C). HRMS (ESI-TOF) Calcd. for C19H11N4O ([MþH]þ): 311.0927. Found: 311.0927. Acknowledgement D.B. gratefully acknowledges support by an Ernst Mach fellow€ ship (AOU) of the Austrian Federal Ministry of Science, Research and Economy. Supplementary data Copies of 1H and 13C NMR spectra for all products. Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2017.04.052. These data include MOL files and InChiKeys of the most important compounds described in this article. References 1. Ma Z-Z, Hano Y, Nomura T, Chen Y-J. Heterocycles. 1997;46:541e546. 2. Du W. Tetrahedron. 2003;59:8649e8687. 3. Cheng K, Rahier NJ, Eisenhauer BM, Gao R, Thomas SJ, Hecht SM. J Am Chem Soc. 2005;127:838e839. 4. Elban MA, Sun W, Eisenhauer BM, Gao R, Hecht SM. Org Lett. 2006;8: 3513e3516. 5. Pizzolato JF, Saltz LB. Lancet. 2003;361:2235e2242. 6. Cagir A, Jones SH, Gao R, Eisenhauer BM, Hecht SM. J Am Chem Soc. 2003;125: 13628e13629. 7. Liang JL, Cha HC, Jahng Y. Molecules. 2011;16:4861e4883.

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18. 19. 20. 21.

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Lipton MF, Basha A, Weinreb SM. Org Synth. 1979;59:49e53. Louko I. MSc Thesis, University of Vienna, 2013. Chou W-N, Pomerantz M, Witzcak MK. J Org Chem. 1990;55:716e721. When triethylamine instead of DBU was used as a base, only small amounts of 11 were formed, as indicated by TLC. An attempt to change also the behavior of compound 3b towards Hendrickson’s reagent by addition of DBU did not afford any cycloaddition product. 22. Compound 2b is very sparingly soluble in common NMR solvents. Therefore, most of the 13C NMR signals of quaternary carbon atoms could not be detected. Chemical shifts and assignments for most of the other C resonances are based on the HSQC spectrum.